NIH grants awarded to Rutgers Faculty

STRUCTURAL INSIGHT INTO NOVEL MECHANISMS OF TYPE III SECRETION

2011-12-01T09:09:00.001-08:00

Start Date: 12/1/2011

Award Number: 1R01AI094623-01A1

NIH Funding Organization: NIAID

Principal Investigator: KALODIMOS, CHARALAMPOS

Co-PI: Not Applicable

FY Total Cost by IC: $141290

Program(s): Adopted;Animals;Anti-Infective Agents;ATP phosphohydrolase;Bacteria;base;Binding (Molecular Function);Biochemical;Biological Assay;biological systems;Bordetella;Cell physiology;Cell surface;Cells;Child Mortality;Complex;Cytoplasm;Cytosol;Data;Defect;design;Disease;Dysentery;enteropathogenic Escherichia coli;Eukaryotic Cell;Event;Food Poisoning;Human;In Vitro;in vivo;Infantile Diarrhea;Infection;Insecta;insight;Kinetics;kinetosome;Membrane;mimicry;Molecular Chaperones;Molecular Conformation;nanomachine;Needles;Nematoda;novel;Nucleotides;operation;pathogen;Pathogenesis;pathogenic bacteria;pathogenic Escherichia coli;Plague;Plants;Preparation;prevent;Process;Property;Protein Export Pathway;Proteins;Proton-Motive Force;prototype;Pseudomonas;Resolution;Role;Salmonella;secretion process;Shigella;Signal Transduction;Spottings;Structure;success;System;therapeutic protein;Thermodynamics;Type III Secretion System Pathway;Typhoid Fever;Vaccines;Virulence;Virulence Factors;

Abstract: DESCRIPTION (provided by applicant): A large number of bacterial pathogens, including Shigella, Salmonella, Bordetella, Pseudomonas, and pathogenic E. coli that are pathogenic for humans, other animals including insects or nematodes, and plants are equipped with a special protein- export apparatus called a type III secretion system (TTSS) or an injectisome. The injectisome is a highly sophisticated nanomachine that has specifically evolved to allow bacteria to deliver proteins into eukaryotic cells. The TTSS enables these pathogens to inject virulence proteins (known as effectors) directly into the cytoplasm of the eukaryotic host cells they infect. Many of these type III translocated effectors mimic eukaryotic factors and are capable of subverting key host cellular processes to the benefit of the pathogen during infection. Over the past decade, significant progress has been made in understanding the structure, assembly and the mode of operation of TTSS. The cytosolic components, the principal structural building proteins of the injectisome, from the basal body embedded in the inner and outer bacterial membrane to the tip of the needle protruding from the cell surface, have been extensively characterized. Virulence factors (effectors, needle proteins and translocators) form tight complexes with cognate chaperones in the cytosol and are subsequently targeted specifically to an ATPase protein located at the base of the injectisome. Powered by ATP, the effector is then translocated through the needle and is secreted in the eukaryotic cell. Fundamental questions about the functional mechanisms underpinning these processes remain unaddressed. We propose to use an integrated approach combining structural, dynamic, thermodynamic, kinetic, biochemical and in vitro and in vivo functional assays to provide insight into the early events of the secretion process that involve the recognition and binding of virulence factors (effectors and translocators) by cognate chaperones and the targeting of these substrates to the ATPase. We have extensively characterized over the last 3 years TTS protein components from the enteropathogenic Escherichia coli (EPEC), a prototype for TTSS and the major cause of infantile diarrhea and child mortality worldwide. The specific aims are designed to provide atomic-resolution insight into (i) the mechanisms of specific interaction between TTS chaperones and virulence factors, (ii) the structural and dynamic properties of the ATPase, (iii) the 'recognition' or 'secretion' signal, and (iv) the specific targeting of chaperone-substrate complexes to the ATPase. PUBLIC HEALTH RELEVANCE: Type III secretion system (TTSS) is encoded by many bacterial pathogens, including Shigella, Salmonella, Bordetella, Pseudomonas, and pathogenic E. coli that are pathogenic for humans and cause diseases such as plague, typhoid fever, bacterial dysentery and common food poisoning.

NATIONAL EPIDEMIOLOGIC SURVEY ON ALCOHOL AND RELATED CONDITIONS: DNA REPOSITORY

2011-12-01T09:09:00.000-08:00

Start Date: 12/1/2011

Award Number: 1U24AA021085-01

NIH Funding Organization: NIAAA

Principal Investigator: TISCHFIELD, JAY ARNOLD

Co-PI: Not Applicable

FY Total Cost by IC: $3008117

Program(s): Accidents;alcohol use disorder;Alcoholism;Alcohols;Aliquot;Automation;Bacterial DNA;base;Biocompatible Materials;Biological Assay;Biological Preservation;Caring;Cells;Chemistry;Collection;cost;cost effective;design;Disease;DNA;DNA Sequence;Dyes;Engineering;Ensure;Environment;Epidemiology;Equipment and supply inventories;Ethnicity aspects;Event;Fingerprint;Future;Gender;gene environment interaction;genetic epidemiology;genetic risk factor;Genome;Genomics;Human;instrument;Laboratories;Libraries;Liquid substance;Management Information Systems;Measurement;Medical;Molecular Genetics;Molecular Weight;Monitor;National Institute on Alcohol Abuse and Alcoholism;next generation;novel;Nucleic Acids;Population;Prevention strategy;Process;Productivity;programs;Qualifying;Quality Control;repository;response;RNA;Robot;Saliva;Sampling;Secure;Sequence Analysis;Services;social;success;Surveys;System;Technology;treatment strategy;Tube;Universities;Violence;

Abstract: DESCRIPTION (provided by applicant): The National Epidemiological Surveys on Alcohol and Related Conditions (NESARC I and II) are the largest and most ambitious epidemiological surveys on alcoholism and related disorders in the civilian, non-institutionalized US population. NESARC-III is even more ambitious as it aims to collect saliva samples from as many as 46,500 subjects and extract DNA from each in an effort to identify genetic risk factors for alcohol use disorders (AUDs) and co-morbid disorders through large-scale DNA re-sequencing and to examine gene-environment interactions. We propose to establish the Saliva DNA Repository for the NIAAA NESARC-III study. Our Aims are: 1. Genomic DNA Extraction from Human Saliva Samples: We will employ state-of-the-art automation and bead-based chemistry to enrich for high molecular weight human genomic DNA relatively free of contaminants and of RNA and undesirable DNA species (i.e., bacterial DNA contamination). 2. Comprehensive Nucleic Acid Quality Control: We have engineered and validated a novel, comprehensive analytical and functional quality control (QC) program that ensures the highest quality of DNA and its utility for future sequencing analyses. Analytical QC consists of absorbance and dye-based concentration and purity measurements, precision non-contact volume measurements, and specific quantification of the amount of human genomic DNA in each sample. Functional QC employs a high-throughput, molecular genetic fingerprinting SNP assay (the RUID). We will also use several different Next Generation sequencing platforms to demonstrate the utility of this saliva DNA for future sequencing. 3. Integrated Nucleic Acid Storage and Distribution: All NESARC-III samples will be stored at -80 degrees C in dedicated freezers that are monitored 24/7/365 in a secure facility that contains state-of-the-art redundant power and HVAC systems. All sample extraction, QC, storage, biomaterial requests and distribution workflows are documented and managed by the RUCDR STARLIMS, an enterprise-level laboratory information management system. PUBLIC HEALTH RELEVANCE: Alcohol use disorders (AUDs) cost our nation billions of dollars due to lost productivity, provision of medical care, accidents, violence and the breakup of social order. In addition, they are responsible for much human misery and suffering. We must understand the causes, onset and lifetime progression of AUDs through epidemiology and genetics studies if we are to develop better treatment and prevention strategies.

EFFECT OF TISSUE TROPISM ON RNA VIRAL EVOLUTIONARY RATES: THREE FAMILY-LEVEL ANAL

2011-09-30T09:08:00.001-07:00

Start Date: 9/30/2011

Award Number: 1R03AI096265-01

NIH Funding Organization: NIAID

Principal Investigator: DUFFY, SIOBAIN MARIE DEIRDRE

Co-PI: Not Applicable

FY Total Cost by IC: $77083

Program(s): Affect;Antiviral Agents;Antiviral Therapy;Anus;Apple;Bioinformatics;Caliciviridae;Calicivirus;Capsid Proteins;Caring;Computer software;Computing Methodologies;Country;Data;Data Set;Development;Drug resistance;Ensure;Enteral;Evolution;Family;Family Picornaviridae;foodborne illness;Gastrointestinal tract structure;Genbank;Genes;Health;Human;Human poliovirus;Immune response;Individual;Infantile Diarrhea;Intestines;member;Meta-Analysis;Methodology;Methods;Mutate;Norovirus;Nucleotides;Paper;pathogen;Pattern;Phylogenetic Analysis;Polioviruses;programs;Publishing;Relative (related person);Reoviridae;Reovirus sp.;Research;RNA Viruses;Rotavirus;Sampling Biases;Serotyping;Testing;Time;tissue tropism;Tissues;trait;treatment planning;Tropism;Vaccines;Variant;Viral;viral RNA;virology;Virus;Work;

Abstract: DESCRIPTION (provided by applicant): RNA viruses mutate and evolve more quickly than all other human pathogens. However, RNA viruses do not all evolve at the same fast rate. It is important to distinguish the faster evolving RNA viruses because they are more likely to create drug-resistant variants or evade vaccine-induced immune responses. Whole families of RNA viruses are known to be more evolvable than others, but we know very little about what causes individual viruses to evolve more rapidly than closely related viruses in the same family. We will test whether tissue tropism could be one of the factors affecting evolutionary rates. Specifically, we are testing if genes within enteric viruses, those that infect the gastro-intestinal tract, evolve more quickly than related viruses that infect other tissues in the same hosts. Long-term nucleotide substitution rates will be calculated from members of three important RNA virus families that have large numbers of sequences in GenBank: Caliciviridae, which include the leading cause of foodborne illness in this country, Picornaviridae, which include poliovirus, and Reoviridae, which include rotavirus, the most common cause of infant diarrhea worldwide. We will contrast the rates of evolution of the same gene in primarily enteric and primarily non-enteric viruses, which will allow us an apples-to-apples comparison between viruses. The BEAST software we use takes a Bayesian phylogenetic coalescent approach to calculating evolutionary rates. The accuracy of such estimates changes over different timescales, and the time to the coalescent of some of our analyses varies over an order of magnitude (i.e., some data coalesce in 70 years, others in 700 years). Since many of the enteric virus data sets coalesce more quickly than the non-enteric virus data sets, additional controls will be conducted to ensure our results are not biased by coalescent time. Our work has the potential to open up avenues of research into whether enteric tissue tropism mechanistically leads to faster rates of RNA viral evolution, and to highlight weaknesses in a widely used software program. PUBLIC HEALTH RELEVANCE: Faster evolving RNA viruses are more difficult to control and treat than slower evolving RNA viruses, but we have not identified many traits that cause viruses to evolve more quickly. This research tests whether enteric viruses, those that infect the mammalian gastrointestinal tract such as poliovirus, norovirus and rotavirus, evolve more quickly than their relatives that infect other mammalian tissues. If infecting enteric tissue leads to faster rates of viral evolution, virologists will know to take more care can when developing vaccines and durable antivirals for enteric viruses.

CENTER FOR EDUCATION AND RESEARCH ON MENTAL HEALTH THERAPEUTICS

2011-09-30T09:08:00.000-07:00

Start Date: 9/30/2011

Award Number: 1U19HS021112-01

NIH Funding Organization: AHRQ

Principal Investigator: CRYSTAL, STEPHEN

Co-PI: Not Applicable

FY Total Cost by IC: $

Program(s):

Abstract: DESCRIPTION (provided by applicant): The Rutgers-Columbia Center for Education and Research on Mental Health Therapeutics will focus on safe and effective use of therapeutics for persons with behavioral health disorders. Center projects and activities will address critical gapsin the evidence base on the comparative effectiveness of mental health treatments and services system innovations. We will build on the solid foundation of infrastructure, partnerships, dataset development, and lines of research from our first five years of work as a CERTs Research Center to address all five programmatic interest areas. The proposed work will be guided by systematic stakeholder input through an advisory committee representing organizations that are well positioned to translate Center findings into improved care processes and outcomes. Research and educational activities will be supported by a Data, Methods and Biostatistics Core and an Education, Translation and Stakeholder Core and organized within population-based cores for 1) youth, 2) adults, and 3) the frail elderly. Specific projects include: 1) a comparativ effectiveness analysis of alternative pharmacological strategies to manage treatment-resistant schizophrenia, 2) an analysis of the impact of an innovative statewide community mental health center-based medical home model for the safe and effective use of mental health therapeutics, 3) a comparative safety analysis of anti-dementia medications in the nursing home elderly, 4) an examination of the potential impact of structured diagnostic interviewing on the management and outcome of youth with severe psychiatric disorders, and 5) an assessment of premature mortality in schizophrenia patients and their underlying quality of general medical care. Through these projects and related educational activities, the Center aims to serve as a trusted national resource to inform decision's making of mental health stakeholders, with an emphasis on broad populations -under treatment, especially in Medicaid and Medicare. Our experience working with states and federal policy makers also qualifies us to provide leadership of new cross-CERTs initiatives involving Medicaid agencies and complex, high-cost patients PUBLIC HEALTH RELEVANCE: Mental health conditions account for a substantial share of overall illness burden and health care expenditure, and substantially complicate the course and treatment of other medical disorders. The Center's work will address these critical issues, serving as a national observatory on the use and outcomes of mental health treatments in large, usual-care settings, incorporating strong partnerships with key stakeholders.

NEURON-SPECIFIC EFFECTS OF IL-1B

2011-09-15T09:09:00.002-07:00

Start Date: 9/15/2011

Award Number: 1R21NS076867-01

NIH Funding Organization: NINDS

Principal Investigator: FRIEDMAN, WILMA J

Co-PI: Not Applicable

FY Total Cost by IC: $231250

Program(s): Astrocytes;Attenuated;Binding (Molecular Function);Brain;Brain Injuries;cell type;Cells;Complex;cytokine;Disease;Event;Goals;hippocampal pyramidal neuron;Hippocampus (Brain);Inflammation;Inflammatory;inhibitor/antagonist;Injury;Interleukin-1;interleukin-1 receptor accessory protein;Interleukin-1 Receptors;Interleukins;Long-Term Potentiation;Mediating;Microglia;Mus;Neuroglia;neuron loss;Neurons;novel;Outcome;Physiological;Play;Population;Production;Protein Isoforms;Proteins;receptor;response;RNA Splicing;Role;Signal Pathway;Signal Transduction;Signaling Protein;Stress;synaptic function;Therapeutic;therapeutic development;therapy development;tool;Variant;Wild Type Mouse;

Abstract: DESCRIPTION (provided by applicant): Inflammation occurs as a consequence of brain injury, and results in the production of inflammatory cytokines, which contribute to the progression of the insult. One of the most potent inflammatory cytokines is interleukin-1 (IL-1), which is induced by many types of brain injury and can potentiate neuronal loss. IL-1 inhibitors have been suggested as therapeutic tools following brain injury to attenuate neuronal loss. However, IL-1¿ is also expressed in the brain under physiological conditions, and may play a role in mediating normal hippocampal function. We have previously demonstrated that IL-1¿ activates distinct signaling pathways in neurons versus glial cells in the brain. Therefore, to assess the consequences of inflammation that occur following injury, and the potential therapeutic value of inhibiting inflammation, it is critical to understand the cell-specific consequences and to distinguish physiological versus pathophysiologial roles for this key cytokine. IL-1 signals via a receptor complex composed of the type 1 IL-1 receptor (IL-1R1) and the IL-1 Receptor Accessory Protein (IL-1RAcP). A novel isoform of the IL-1RAcP, termed AcPb, has been identified that is expressed exclusively in CNS neurons, providing a new opportunity to investigate the mechanisms governing neuron-specific IL- 1 actions. To identify the function of the neuron-specific IL-1RAcPb we will establish neuronal cultures from AcPb-/- mice compared to wild type neurons and to neurons lacking both isoforms of the protein (AcP-/-). The effects of IL-1¿ on these neurons will be analyzed to determine the role of AcPb in mediating neuron-specific signaling pathways, and the consequences for neuronal function. PUBLIC HEALTH RELEVANCE: Interleukin-1 is a potent and pleiotropic cytokine that is induced in the brain by injury, disease, and stress. The recent identification of a neuron-specific isoform of a key IL-1 signaling protein provides a novel opportunity to investigate mechanisms governing the specific effects of IL-1 on neuronal function. These studies may also facilitate the development of therapeutic approaches to distinguish physiological versus pathophysiologial roles for this key cytokine in the brain.

1/8-COLLABORATIVE GENOMIC STUDIES OF TOURETTE DISORDER

2011-09-15T09:09:00.001-07:00

Start Date: 9/15/2011

Award Number: 1R01MH092293-01A1

NIH Funding Organization: NIMH

Principal Investigator: HEIMAN, GARY A.

Co-PI: TISCHFIELD, JAY ARNOLD

FY Total Cost by IC: $190874

Program(s): Affect;Alleles;Attention deficit hyperactivity disorder;base;Biocompatible Materials;Caucasians;Caucasoid Race;Cell Line;Child;Clinical;Collaborations;Collection;Communities;Comorbidity;Complementary DNA;Complex;Copy Number Polymorphism;cost;Data;data management;Development;Diagnostic;Disease;DNA;DNA Sequence;European;exome;experience;Family;Family member;follow-up;Future;gene discovery;Gene Expression;Gene Expression Profile;Genes;Genetic;genetic pedigree;Genetic Predisposition to Disease;genome wide association study;genome-wide;Genomics;Genotype;Gilles de la Tourette syndrome;Health Benefit;Heterogeneity;Human;Individual;International;Joints;Koreans;Measures;member;Mental disorders;Molecular;Motor Tics;Mutation;neuropsychiatry;next generation;novel;Obsessive-Compulsive Disorder;Parents;Pilot Projects;Population;Prevalence;proband;public health medicine (field);Recruitment Activity;Research Project Grants;Resources;Risk;RNA;Sample Size;Sampling;Site;Symptoms;Syndrome;Techniques;Time;Translating;Tube;Variant;Vocal Tics;

Abstract: DESCRIPTION (provided by applicant): SUMMARY/ABSTRACT: Tourette Disorder (TD) is a developmental neuropsychiatric syndrome characterized by the combination of persistent vocal and motor tics. While initially considered rare, the world-wide prevalence is now estimated to be 0.3-1%. Both as a consequence of potentially disabling symptoms as well as very high rates of psychiatric co-morbidity, particularly with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), TD represents a significant public health concern. Despite decades of evidence supporting a significant genetic contribution, progress in identifying risk alleles has been slow. This difficulty is thought to be, in part, a consequence of complex inheritance and substantial genetic and phenotypic heterogeneity. This collaborative study unites an international group of highly expert clinicians specializing in TD with statistical and molecular geneticists and is motivated by three central hypotheses: 1) that a key rate- limiting factor for TD gene discovery has been the paucity of publically available, large-scale biomaterial resources of the kind that are now commonplace for many neuropsychiatric disorders; 2) based on recent data from a host of other genetically complex disorders, a comprehensive genomics study of TD will require large samples sizes and should focus on the potential contribution of rare as well as common alleles and both sequence and structural variants; and 3) an increased understanding of the genetic etiology of TD will translate into novel and more effective approaches to treating this often-debilitating disorder, and consequently will have marked public health benefits. The application elaborates three specific aims: Specific Aim 1: To recruit 5050 individuals with TD (and their family members), and make DNA, cell-lines, cDNA/RNA and phenotypic data publicly available within one year of collection. The sample will include a subset of 3195 European Caucasian (EC) probands; 1250 Korean probands, and 3295 parent-child trios allowing for the study of de novo variation. We will also recruit each year at least 10 TD pedigrees with 4 or more affected members as a resource for family-based gene discovery. Specific Aim 2: To employ state-of-the-art techniques to identify and confirm rare and common variants contributing to TD. We will genotype the sample on Illumina HumanOmni2.5 -Quad BeadChips to support copy number variation (CNV) analysis (Aim 2A) and genome wide association studies (GWAS) (Aim 2B); whole exome sequencing will be employed in select, multiply-affected TD pedigrees (Aim 2C); and we will follow up on the most promising loci identified in the aforementioned studies using a pooled next generation re-sequencing strategy (Aim 2D) at two time points, evaluating a minimum of 50 genes in a total of 3195 EC and 3195 matched controls; Specific Aim 3: To perform preliminary analyses of 300 transcriptomes of TD subjects to investigate the implications of selected structural and sequence variations for cis, trans and genome-wide expression. With no cost to this project, PAXgene tubes will be collected from all subjects and made available to the scientific community to enable future studies by our group and others. PUBLIC HEALTH RELEVANCE: Project Narrative: Tourette Disorder (TD) is a poorly understood, often debilitating neuropsychiatric disorder characterized by a combination of persistent vocal and motor tics, affecting between 3 in 1000 and 1 in 100 people worldwide, predominantly children. Our international team of experts in TD and other mental disorders proposes to recruit 5050 affected individuals, undertake a comprehensive gene discovery effort, and make the collected biomaterials and clinical data rapidly available to the broad scientific community, thereby enabling both current and future TD research. Understanding the causes of TD may facilitate the development of novel and improved treatments.

PHENOTYPIC ANALYSIS OF HUMAN IPSC CARRYING ADDICTION-ASSOCIATED GENE VARIANTS

2011-09-15T09:09:00.000-07:00

Start Date: 9/15/2011

Award Number: 1R21DA032984-01

NIH Funding Organization: NIDA

Principal Investigator: TISCHFIELD, JAY ARNOLD

Co-PI: HART, RONALD P

FY Total Cost by IC: $231000

Program(s): addiction;Addictive Behavior;Adoption;Adult;Affect;Alleles;Amino Acids;Archives;Authorization documentation;base;Behavior;Biochemical;Biological Assay;Blood;Blood specimen;Brain Diseases;Calcium;cell bank;Cell Culture Techniques;Cell Line;Cell model;Cell physiology;Cell Surface Receptors;cell type;Cells;Child Abuse;Cholinergic Receptors;Chronic;Collection;cost;Crime;Cultured Cells;Data;DNA;Drug abuse;Drug Addiction;Electrophysiology (science);embryonic stem cell;Employment;Episome;expectation;Family;Gene Expression;gene function;Genes;genetic variant;Genomics;Genotype;Goals;Health;Housing;Human;Image;immunocytochemistry;Individual;induced pluripotent stem cell;Inherited;Intervention;Laboratories;Lymphocyte;Maps;Methods;Modeling;Molecular;molecular marker;molecular modeling;Molecular Models;Morphine;Mutate;Mutation;National Institute of Drug Abuse;National Institute of Mental Health (U.S.);National Institute on Alcohol Abuse and Alcoholism;nerve stem cell;Neuronal Differentiation;Neurons;Nicotine;Nicotinic Receptors;novel;novel strategies;Opioid;Opioid Receptor;Patients;Pharmaceutical Preparations;Pharmacology;Phenotype;Physiological;Physiology;pluripotency;Property;Protocols documentation;Publishing;release of sequestered calcium ion into cytoplasm;Reporting;repository;Research;Research Personnel;Resources;response;Risk Factors;Sampling;Screening procedure;second messenger;Second Messenger Systems;Signal Transduction;Societies;Source;Staging;Stem Cell Research;Stem cells;Study models;Substance abuse problem;Substance of Abuse;System;Techniques;Technology;Testing;Time;Universities;Variant;Variation (Genetics);vector;Viral;

Abstract: DESCRIPTION (provided by applicant): Identification of genetic variations associated with addictive behaviors provides a novel opportunity for using cell cultures to model molecular and cellular mechanisms that underlie addiction. The observed genetic variations have been mapped to amino acid changes in cell surface receptors, presumably affecting neuronal circuits involved in addiction behaviors. However, cellular context is likely to be important in determining the function of these genes. Construction of induced pluripotent stem cells (iPSC) from adult cells derived from drug abusing individuals carrying known genetic variants provides a means for developing physiologically relevant culture systems for understanding addiction. For the culture cell model to be useful it must not only express the affected gene but it must also provide an appropriate cellular context for studying pharmacology or cell signaling. There is no clear expectation about what type of iPSC-derived cultures would be useful in studying the cellular physiology altered by gene variants. Our hypothesis is that the altered physiology of genetic variants associated with addiction liability can be modeled in cultured neurons derived from iPSCs constructed from donor lymphocyte samples. We propose to construct several iPSC lines from donor lymphocyte samples, differentiate these iPSC into functional neurons, and then to develop methods to assay possible phenotypic differences between variant-derived cells and wild-type. These cells will be valuable for identifying cell and molecular responses to substances of abuse, to examine the effects of a known genotype on the cellular phenotype, as well as to develop novel approaches for pharmacologic intervention. PUBLIC HEALTH RELEVANCE: Drug abuse and addiction are a major burden to society, with the total cost of substance abuse in the U.S. exceeding $500 billion annually. Addiction is a chronic brain disease that leads to a compulsive desire for drugs despite significantly harmful consequences, including direct effects on health as well as detriments to society, including disintegration of families, child abuse, loss of employment, and a broad array of crimes. While addiction may be treatable, the discovery that some forms of addiction have an inherited component demonstrates that physiology contributes to addictive behaviors. To exploit new techniques of cellular reprogramming to prepare human neuronal cultures, we will establish induced pluripotent cell (iPSC) lines derived from donor blood samples carrying mutations in two genes known to be risk factors for addiction-an acetylcholine receptor and an opioid receptor. The blood lymphocyte samples already exist in the NIDA Center for Genomic Studies collection and will be used with permission from the collecting investigator. These iPSC will then be induced to differentiate into specific types of neurons for use in investigating the molecular bases of addiction and for screening new treatment therapies.

MODELING AGE-ASSOCIATED NEURONAL SPROUTING AND FUNCTIONAL DECLINE IN A GENETIC SY

2011-09-15T09:08:00.000-07:00

Start Date: 9/15/2011

Award Number: 1R21AG041498-01

NIH Funding Organization: NIA

Principal Investigator: DRISCOLL, MONICA A.

Co-PI: Not Applicable

FY Total Cost by IC: $169494

Program(s): Address;Adult;Age;Aging;aging brain;Aging-Related Process;Alzheimer's Disease;Animals;Appearance;Axon;base;Biology;biomarker;Brain;Caenorhabditis elegans;cell body (neuron);Cell Death;cell type;Cells;Cessation of life;combat;Development;dietary restriction;Disease;Documentation;drug discovery;drug efficacy;drug use screening;Environmental Risk Factor;Exhibits;Experimental Models;Foundations;Frequencies (time pattern);functional decline;Future;Genes;Genetic;genetic analysis;genetic technology;Germ Cells;Health;healthy aging;Human;Imaging technology;Impaired cognition;improved;Individual;insight;insulin signaling;interest;Intervention;Investigation;Label;Lead;Life;Longevity;Maintenance;Metformin;Microscope;mimetics;Mitochondria;mitochondrial dysfunction;Modeling;Molecular;Monitor;Nematoda;Nerve Degeneration;Nervous system structure;Neurobiology;neuron loss;Neuronal Dysfunction;Neurons;neuroprotection;new growth;novel;Pathway interactions;Pharmaceutical Preparations;Phenotype;Physiological;Predisposition;Process;protein aggregation;receptor;Reporter;research study;Resveratrol;Risk Factors;Structure;Surveys;Synapses;synaptic function;system architecture;Testing;Therapeutic Intervention;Tissues;Touch sensation;Work;

Abstract: DESCRIPTION (provided by applicant): Subtle changes in the aging human brain, such as neuronal sprouting and restructuring, are thought to underlie cognitive decline and may promote neuronal dysfunction in Alzheimer's disease. We study fundamental processes relevant to neuronal function and neurodegeneration in the 959-celled nematode C. elegans. In this transparent roundworm, we can directly observe individual fluorescently labeled neurons, as well as synapses and mitochondria, in the living animal. Recently we carefully documented how some C. elegans neurons change as animals grow old. We find that like human brain aging, there is little neuron loss as C. elegans ages. However, some types of neurons exhibit dramatic novel branching and outgrowth with age. We can score new growth using a high magnification dissecting microscope, which facilitates relatively rapid analysis within live, aging animals. We propose to characterize morphological neuronal aging in C. elegans to establish a facile model for analysis of genetic and environmental factors that influence neuronal aging. Aim 1 is to extend our initial cell-specific analysis to diverse neuronal classes to better define what neuronal types are susceptible to age-associated morphological changes. This tractable work will document the basic neurobiology of C. elegans aging, definitively establishing an overview of differential susceptibility of specific neurons to age-associated morphological change. Aim 2 is to survey four mechanisms hypothesized to contribute to age-associated neuronal regrowth (neuronal function, synaptic function, disrupted proteostasis, and mitochondrial changes) to identify which contributes to morphological aging. In this aim we might also identify fluorescent synaptic and mitochondrial indicators of neuronal aging. These experiments may suggest the most potent factors in age-associated neuronal restructuring. Aim 3 is to test whether dietary restriction, a conserved mechanism for lifespan extension that has been found to improve human neuronal aging, can protect against neuronal morphological aging phenotypes. We will also test DR-mimetic drugs for efficacy in the nematode model. This work may identify a conserved mechanism for neuroprotection and establish proof-of-principle for the suitability of this new model to be used in for anti-neuronal aging drug discovery. Our work will define the first model for high throughput genetic and drug studies of age-associated neuronal morphological abnormalities that may inform on mechanisms and interventions that can better maintain the aging human nervous system. PUBLIC HEALTH RELEVANCE: Neuronal aging in the human brain, a major risk factor for Alzheimer's disease also proposed to influence cognitive decline in healthy aging, is associated with synaptic changes and aberrant sprouting. Recently, we discovered that some neurons in aging C. elegans exhibit aberrant branching and outgrowth and we have documented a global decline of synaptic structure with age, suggesting that fundamental neuronal aging mechanisms may be conserved from simple animals to humans. We plan to develop the C. elegans model of neuronal aging to describe susceptible neurons and identify process that can promote or protect against neuronal decline. Documentation of this model should lead to advanced mechanistic understanding that might ultimately suggest novel and efficacious therapies to combat human brain aging.

PTSD AND ADDICTION DISORDER SCREENING AND TREATMENT FOR INCARCERATED MEN

2011-09-02T09:09:00.000-07:00

Start Date: 9/2/2011

Award Number: 1R01MH095206-01

NIH Funding Organization: NIMH

Principal Investigator: WOLFF, NANCY

Co-PI: Not Applicable

FY Total Cost by IC: $731468

Program(s): addiction;Address;Administrator;Adult;aged;Alcohol consumption;Alcohol or Other Drugs use;arm;Attention;base;Behavioral;behavioral health;care systems;Cognitive;compare effectiveness;Computer software;computerized;Computers;cost effective;Development;Diffuse;Disease;Drops;Drug usage;effective intervention;Effectiveness;emotional abuse;empowerment;evidence base;Evidence based intervention;experience;Focus Groups;Freedom;Goals;group intervention;Health;Health Personnel;Housing;Imprisonment;improved;Individual;informant;Institute of Medicine (U.S.);Intervention;Interview;Lead;Left;Life;male;medical schools;men;Mental disorders;Mental Health;Methods;mindfulness;mindfulness meditation;Modality;Modeling;National Institute of Mental Health (U.S.);New Jersey;Outcome;Phase;phase 1 study;physical abuse;Population;population based;Post-Traumatic Stress Disorders;preference;Prisons;provider intervention;public health medicine (field);Randomized;Randomized Controlled Trials;Recovery;Reporting;Research Support;Risk Factors;Safety;Screening procedure;Security;Services;Sexual abuse;skills;Staging;Strategic Planning;Substance Use Disorder;Surgeon;Testing;Time;Trauma;Trauma recovery;treatment as usual;Veterans;Work;

Abstract: DESCRIPTION (provided by applicant): At least one-fifth of men inside state prisons have mental health problems, over half have experienced physical, sexual, or emotional abuse (referred to as 'interpersonal trauma') during their formative years and often in adulthood, and the majority has alcohol or drug use problems. Interpersonal trauma is highly correlated with health and behavioral health problems and criminality. Few male inmates receive treatment for behavioral health disorders related to interpersonal trauma while incarcerated even though these problems are risk factors for returning to prison after release. While the Surgeon General's Report and the President's New Freedom Commission Report highlighted the importance of trauma-informed services and systems of care, trauma- related behavioral health problems among incarcerated men have received little attention. This application addresses both screening for and treatment of Post-Traumatic Stress Disorder (PTSD) and substance use disorders (SUD) within an adult male correctional setting. The proposed study will be conducted at an adult medium security prison in New Jersey that houses ~1900 male inmates primarily aged 18 to 25. We propose a two-phase study that: (1) tests the reliability (test-retest) of computer-administered screening for PTSD and SUD compared to clinician-administered screening (goal: to develop a cost-effective population- based screening procedure for PTSD and SUD within incarcerated settings) and (2) conduct a randomized controlled trial (RCT) in which 240 male inmates are assigned to two evidence-based, manualized first stage trauma interventions (Seeking Safety (SS) and Trauma Recovery and Empowerment Model version for men with substance use problems (M-TREM) (goal: to identify effective interventions for PTSD and SUD among incarcerated men). The RCT will be enhanced in two ways: (1) those who decline treatment participation will be shown a 10-minute educational video on PTSD and SUD and after viewing the video invited a second time to participate in the RCT and (2) determined by random assignment, two-thirds of participating subjects (n=160) will be randomly assigned to treatment and the other one-third (n=80) will choose treatment based on their preference for one intervention over the other. We will be testing overall effectiveness of screening and treatment interventions and the marginal impact of educational-enhancement and preferences on outcomes. PUBLIC HEALTH RELEVANCE: This study has the potential to identify cost-effective methods for screening PTSD and SUD among incarcerated men and effective interventions for treating these conjoint behavioral health problems. The importance of focusing on PTSD screening and trauma-informed treatment was highlighted in the Surgeon General's Report, the President's New Freedom Commission on Mental Health and a variety of reports by The Institute of Medicine. This application is responsive to the current NIMH Strategic Plan, specifically Objectives #3 (Develop New and Better Interventions that Incorporate the Diverse Needs and Circumstances of People with Mental Illnesses) and #4 (Strengthen the Public Health Impact of NIMH-Supported Research).

AN INTEGRATED PROBABILISTIC FRAMEWORK FOR SHAPE AND SURFACE INTERPRETATION

2011-09-01T09:09:00.003-07:00

Start Date: 9/1/2011

Award Number: 1R01EY021494-01A1

NIH Funding Organization: NEI

Principal Investigator: FELDMAN, JACOB

Co-PI: SINGH, MANISH

FY Total Cost by IC: $294099

Program(s): Accounting;Architecture;base;Brain;Classification;Code;Cognitive deficits;Collection;Comprehension;Computer Simulation;Conceptions;Data;Disease;Figs - dietary;Functional disorder;Goals;Growth;Human;human subject;Image;Literature;Medial;Methods;Modeling;Nervous system structure;neural model;novel;novel strategies;object recognition;Ownership;Perception;Plague;programs;Psychological Models;reconstruction;Research;research study;Shapes;skeletal;Skeleton;Source;Stochastic Processes;Structure;Surface;Techniques;Testing;Texture;theories;Universities;Visual;Visual Cortex;Visual system structure;Work;

Abstract: DESCRIPTION (provided by applicant): An integrated probabilistic framework for shape and surface interpretation Jacob Feldman and Manish Singh, Rutgers University The representation of visual shape is one of the central problems of perception, influencing many aspects of object recognition and scene understanding. But a comprehensive and principled account of how the human brain computes shape representationsdoes not yet exists. A key difficulty is in understanding how the brain divides the image into distinct surfaces at distinct depths, interprets the 3D shape of each surface, and divides each shape into distinct parts. In previous work the PIs have developed novel, principled mathematical methods for understanding human shape representation, based around the idea of Bayesian estimation of the shape skeleton. The shape skeleton is a representation of the axial structure of the shape, related to though different from classical medial axis representations. Medial axis representations break shapes down into their component axes, about which the shape is approximately locally symmetric. The PI's approach recasts this as a probabilistic inference problem, consistent with most contemporary neurocompuational modeling, but unlike most other computational models of shape. This allows the approach to be expanded in scope, encompassing the broader problem of the decomposition of the image into distinct surfaces and the interpretation of 3D shape. The approach is theoretically unified, and is mathematically suitable to be implemented in a parallel computational architecture, making it plausible as a model of neural shape coding. The aim of this research program is to fully develop shape representation as a probabilistic es- timation problem, and test the many empirical predictions that emanate from this framework. Specific aims include expanding and testing the probabilistic approach to shape representation, and generalizing it to critical related problems, including figure/ground interpretation and 3D shape. This expansion will make it possible to fully integrate shape representation with the comprehension of surfaces in the visual image, in a coherent mathematical framework consistent with what is known about computation in visual cortex. PUBLIC HEALTH RELEVANCE: This project involves empirical studies of critical functions of the human visual system, including the interpretation of visual shapes and surfaces. The research contributes to a foundational understanding of the human nervous system, thus helping us achieve better functional understanding of the mechanisms of disease in perceptual dysfunctions and cognitive deficits.

ESTROGEN REGULATION OF CHANNELS INVOLVED IN THE CONTROL OF ENERGY HOMEOSTASIS

2011-09-01T09:09:00.002-07:00

Start Date: 9/1/2011

Award Number: 4R00DK083457-03

NIH Funding Organization: NIDDK

Principal Investigator: ROEPKE, TROY ADAM

Co-PI: Not Applicable

FY Total Cost by IC: $248287

Program(s): Acute;Address;Adult;Affect;Agonist;Animals;Attenuated;bisphenol A;Cations;Cell physiology;cell type;Cells;Coupled;Development;Disease;Electrophysiology (science);Endocrinology;Environmental Estrogen;Epidemic;Estradiol;Estrogen Receptor alpha;Estrogen Receptors;Estrogens;Etiology;Event;Exposure to;Female;G Protein-Coupled Receptor Genes;G-Protein-Coupled Receptors;Gene Expression;Gene Expression Regulation;Goals;Health;Homeostasis;Hormone replacement therapy;Human;Hypothalamic structure;Instruction;Knowledge;Lead;Learning;Ligands;Link;Measures;Mediating;Membrane;Membrane Potentials;Mentors;mouse model;Mouse Strains;Neurologic;neuronal excitability;Neurons;Neurosciences;novel;novel strategies;Obesity;Oils;Ovariectomy;Patch-Clamp Techniques;Pathway interactions;Phase;Physiological;Play;Polychlorinated Biphenyls;Postmenopause;Property;Regulation;reproductive;Research;Role;Signal Transduction;Steroids;Techniques;Time;Transgenic Mice;Transgenic Organisms;Weight Gain;Wild Type Mouse;Woman;Women's Health;

Abstract: No abstract available.

BIOMEDICAL (APPLIED/EXPLORATORY)

2011-09-01T09:09:00.001-07:00

Start Date: 9/1/2011

Award Number: 276201100016C-0-0-1

NIH Funding Organization: NLM

Principal Investigator: TISCHFIELD, JAY

Co-PI: Not Applicable

FY Total Cost by IC: $1435419

Program(s): Blood specimen;Cell Line;Clinical;Collection;Communities;computerized data processing;Contracts;cost effective;Data;Disease;DNA;Ensure;Ethics;Funding;Genes;Genetic;Genetic Determinism;Genetic Materials;genetic pedigree;genetic variant;Grant;immortalized cell;Individual;Institutes;Lymphocyte;Maintenance;Mission;National Institute of Diabetes and Digestive and Kidney Diseases;Participant;Population;Population Control;Qualifying;Quality Control;repository;Research;Research Personnel;Resource Sharing;Resources;RNA;Sample Size;Sampling;United States National Institutes of Health;Work;

Abstract: Discovery of disease related genes requires a population of individuals with the genetic variant, as well as a population of control (unaffected) individuals. Thus, a repository of genetic materials, including DNA samples, cryopreserved lymphocytes, immortalized cell lines, and accompanying clinical and pedigree data is clearly an invaluable resource for the research community studying diseases related to the mission of the NIDDK. This project, which will be referred to herein as ¿The Genetics Repository¿, continues an important collection begun in 2003 and is conceptually related to repositories in existence at other institutes at the NIH. The repository will allow the continued storage, maintenance, and quality control, and equitable, ethical distribution of DNA and other resources important to the study of diseases under the mandate of the NIDDK. It facilitates sharing of resources, thus encouraging work by a broad group of investigators and, perhaps, increasing the sample size and the resulting power of a study to identify genetic determinants of a disease. It helps to ensure that research participants will be making a maximal contribution, and decreases duplicative sampling efforts.

NECTIN-LIKE CELL ADHESION MOLECULES AND THE MECHANISMS OF MYELINATION

2011-09-01T09:09:00.000-07:00

Start Date: 9/1/2011

Award Number: 1R01NS065218-01A2

NIH Funding Organization: NINDS

Principal Investigator: MAUREL, PATRICE

Co-PI: Not Applicable

FY Total Cost by IC: $337,240

Program(s): Address;Adhesions;Axon;Binding (Molecular Function);Cell Adhesion;Cell Adhesion Molecules;Cell Differentiation process;Characteristics;Complex;Data;Development;Electron Microscopy;Exhibits;Extracellular Domain;Fiber;Goals;Image;In Vitro;in vivo;insight;knock-down;loss of function;Mediating;Mediator of activation protein;Membrane;Molecular;mutant;Myelin;myelination;nectin;Neuregulin 1;Neuroglia;Neurons;Neuropathy;NGFR Protein;novel;novel therapeutics;PAWR gene;Peripheral;Peripheral Nervous System;Phenotype;Proteins;receptor;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Recruitment Activity;Reporting;research study;Resolution;Role;scaffold;Schwann Cells;Signal Transduction;small hairpin RNA;Staging;Testing;transcription factor;

Abstract: DESCRIPTION (provided by applicant): Axon-glial interactions are critical for the induction of myelination and the domain organization of myelinated fibers. We recently reported that in the peripheral nervous system (PNS) neurons and myelinating Schwann cells express a new set of cell adhesion molecules called the Nectin-like (Necl) proteins. In particular, Necl-1 on axons mediates adhesion by specifically binding to Necl-4 on Schwann cells. We showed that Necl-4 is required to initiate PNS myelination. These results implicate the Necl proteins as new, crucial mediators of axon-glia interactions. A key question is how the Necl proteins, and in particular Necl-4, mediates Schwann cell myelination. The Necls mediate cell adhesion though their Ig-like extracellular domain, and interact with scaffolding intracellular proteins through a FERM- and PDZ-binding domains. Through these latter interactions the Necl proteins can assemble polarity and signaling complexes. In preliminary studies we have obtained evidence that Necl-4 interacts with the polarity protein Par-3. These studies have also pointed out a possible interaction (direct or indirect) between Necl-4 and the Schwann cell ErbB receptors that transduce the instructive, axon-derived myelinating signal. Using mutant versions of Necl-4 in combination with lentiviral knockdown/rescue strategies, in vivo an in vitro, we will characterize the requirement of the PDZ-binding domain of Necl-4 in the initial stages of Schwann cell myelination, address the functional significance of the Necl-4/Par-3 interaction, and investigate how Necl-4 influence ErbB receptor signaling. The overall goal of this project is to provide novel insights into the mechanisms that regulate myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to provide novel insights into the mechanisms that regulate axon- glia interactions and myelin formation in the PNS. A detailed understanding of the molecular mechanism by which components, required for myelination, cooperates is highly significant, and should provide valuable insights for the development of new therapeutic strategies to promote remyelination in peripheral demyelinating neuropathies.

DISPOSITION OF ENVIRONMENTAL CHEMICALS DURING PREGNANCY

2011-09-01T09:08:00.002-07:00

Start Date: 9/1/2011

Award Number: 1R01ES020522-01

NIH Funding Organization: NIEHS

Principal Investigator: ALEKSUNES, LAUREN M

Co-PI: Not Applicable

FY Total Cost by IC: $493634

Program(s): Adverse effects;ATP phosphohydrolase;Back;Biological Assay;Blood Circulation;Cells;Chemical Exposure;Chemicals;Communities;Data;design;Development;Diabetes Mellitus;Endocrine Disruptors;Endocrine system;Environment;environmental chemical;Epigenetic Process;epigenetic variation;Exposure to;fetal;Fetal Tissues;Fetus;Genetic;Genetic Polymorphism;genetic variant;Genistein;Goals;Human;human ABCG2 protein;in utero;In Vitro;in vivo;Knowledge;Laboratories;loss of function;Malignant Neoplasms;mammary gland development;Membrane;MicroRNAs;Modeling;Mus;Mycotoxins;Obesity;offspring;overexpression;Patients;Perinatal Exposure;Pesticides;Phytoestrogens;Placenta;placental transfer;Plasticizers;Poisons;Precocious Puberty;Predisposition;Pregnancy;Pregnant Women;prenatal;prenatal exposure;prevent;protein expression;protein function;protein transport;Regulation;reproductive;reproductive development;Reproductive system;Research;response;Risk;Rodent;Role;Source;Staging;Testing;Tissues;Toxic Environmental Substances;toxicant;translational study;Untranslated RNA;Variant;Variation (Genetics);Vesicle;Voice;Xenobiotics;

Abstract: DESCRIPTION (provided by applicant): Over the last decade, there has been increasing concern regarding disruption of endocrine and reproductive systems as a consequence of in utero exposure to xenobiotics. Key to preventing these responses is identification of cellular mechanisms that regulate prenatal disposition of endocrine disrupting chemicals (EDCs). One potential way to reduce levels of EDCs in the fetus is to transport them across the placenta back to the maternal circulation. One prominent transporter, breast cancer resistance protein (BCRP), has been shown to participate in the placental transfer of chemicals. Recent data from this laboratory demonstrate that the model EDC, the phytoestrogen genistein, is a BCRP substrate, and that various EDCs inhibit BCRP transport. We hypothesize that BCRP maintains low concentrations of EDCs in the fetal compartment by actively transporting them back to the maternal circulation. This is important because impaired BCRP function would increase fetal levels of EDCs and enhance disruption of reproductive development. This hypothesis will be tested using a combination of in vitro and in vivo approaches that evaluate BCRP transport of EDCs and identify the regulatory mechanisms that influence BCRP expression and activity in human placenta. We anticipate that EDCs will be BCRP substrates and that reduced Bcrp transporter function will increase EDC levels in mouse fetuses. Further, it is expected that Bcrp-null offspring will have more profound abnormalities in reproductive and mammary gland development following prenatal genistein exposure, compared to wild-types. These studies will fill significant knowledge gaps in the fields of placental transport and fetal susceptibility to environmental toxicants. The proposed research is critically needed because multiple sources of EDCs exist in our environment and exposure to EDCs has been documented in pregnant women. A detailed understanding of the regulation of placental BCRP will allow us to predict which patients are at greater risk for adverse effects of EDCs. PUBLIC HEALTH RELEVANCE: The mechanism by which the placenta removes toxic chemicals away from the fetus is poorly understood. These studies will determine whether the placental transporter BCRP reduces in utero exposure to endocrine disrupting chemicals and protects the fetus from developmental abnormalities.

POLYCYSTINS AND CILIA IN C. ELEGANS

2011-09-01T09:08:00.001-07:00

Start Date: 9/1/2011

Award Number: 2R01DK059418-12

NIH Funding Organization: NIDDK

Principal Investigator: BARR, MAUREEN M

Co-PI: Not Applicable

FY Total Cost by IC: $372639

Program(s): 1-Phosphatidylinositol 4-Kinase;Address;Affect;Afferent Neurons;Animals;Autosomal Dominant Polycystic Kidney;Behavior;Biochemical;Biological;Biological Models;Biology;Caenorhabditis elegans;Candidate Disease Gene;Cells;Cellular biology;Chromosome Mapping;Cilia;ciliopathy;cilium biogenesis;Complex;Cystic kidney;Defect;Development;Diffusion;Disease;Double-Stranded RNA;Down-Regulation;Electrophysiology (science);End stage renal failure;Enzymes;Essential Genes;Esthesia;Excision;feeding;Genes;Genetic;Goals;Health;Hereditary Disease;Homologous Gene;Human;Human Development;human disease;Human Genetics;human TNF protein;Image;in vivo;Individual;insight;interdisciplinary approach;Ion Channel;Joubert syndrome;Kidney Diseases;Laboratories;Length;male;Mammalian Cell;Mechanics;Medical;Modeling;Molecular;Molecular Genetics;molecular imaging;Molecular Motors;Morphogenesis;Motor;Mus;Mutate;Mutation;Nematoda;Neurons;novel;novel strategies;Organ;Organelles;Partner in relationship;Phosphatidylinositols;Phosphoric Monoester Hydrolases;PKD2 protein;Play;polycystic kidney disease 1 protein;Post-Translational Protein Processing;Process;Promotor (Genetics);protein function;Proteins;Purkinje Cells;Reagent;receptor;Renal function;Reproducibility;Research;RNA Interference;Role;sensor;Sensory;Shapes;Signal Pathway;Signal Transduction;Stimulus;System;Techniques;Testing;tool;trafficking;Transgenic Animals;Tubulin;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;ubiquitin-protein ligase;Ubiquitination;Work;

Abstract: DESCRIPTION (provided by applicant): Cilia are cellular organelles that are important for human development, organ function, and sensation. Defects in cilia formation or function results in devastating human diseases or ciliopathies, including autosomal dominant polycystic kidney disease (ADPKD). ADPKD affects 1/400-1000 individuals, often resulting in end- stage renal disease. In humans, mutations in the polycystin-1 or polycystin-2 receptor-channel complex cause ADPKD. Despite the profound medical importance of cilia in human health, how cilia are specialized in form and function remains poorly understood. This proposed research is focused on uncovering fundamental principals of cilia biology not possible in human studies or easily studied in vertebrate model systems. C. elegans is a transparent, multicellular animal with specialized sensory cilia, features that enable in vivo imaging that is unprecedented in its simplicity and reproducibility. We have developed the tools and reagents to study polycystin localization and function in C. elegans. We will employ genetic, molecular, imaging, biochemical, and electrophysiological approaches to address three specific aims. First, we will dissect polycystin signaling pathways. Next, we will determine the molecular details of mechanisms regulating polycystin localization, focusing on the roles of phosphoinositides and tubulin post-translational modifications. Finally, we will identify new genes regulating PKD-2 localization using transgenic animals that are hypersensitive to neuronal RNAi. This multidisciplinary approach will provide a comprehensive picture of the molecules that influence polycystin channel assembly and trafficking, and will provide critical insight to ciliary receptor trafficking in general. Thus these studies will have important implications in human diseases such as ADPKD in which cilia play an important and central role. PUBLIC HEALTH RELEVANCE: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting 1/400-1000 individuals, and having no treatment or cure. Several human genetic disorders, including ADPKD, share two common features: ciliary localized gene products and kidney cysts. Given that it is prohibitively difficult in humans to study the connection between ciliary protein function, localization, and disease, alternative experimental systems are necessary. In C. elegans it is feasible to study the roles of human disease gene homologs in cilia formation, morphogenesis, and signaling. This proposal is aimed at understanding the molecular mechanisms controlling the subcellular trafficking of the C. elegans ADPKD gene products.

GUSTATORY LOSS AND RECOVERY OF PATIENTS WITH MIDDLE EAR SURGERY

2011-09-01T09:08:00.000-07:00

Start Date: 9/1/2011

Award Number: 1R21DC011393-01A1

NIH Funding Organization: NIDCD

Principal Investigator: BRESLIN, PAUL A.S.

Co-PI: ARTZ, GREGORY

FY Total Cost by IC: $229951

Program(s): Anterior;Apoptotic;Axon;axon regeneration;Basic Science;Biopsy;Body Weight;Body Weight decreased;cell type;Cells;Chemicals;chorda tympani;Clinical;Cranial Nerves;Data;Dendritic Cells;Detection;Dissection;Eating;Esthesia;Etiology;Excision;experience;Facial nerve structure;Foliate Papilla;Food;Functional disorder;Fungiform Papilla;Human;human tissue;Immune;Incus structure;Inflammatory;Injury;interest;Ipsilateral;Lateral;Leucocytic infiltrate;Lymphocyte;macrophage;Malleus;Mammals;Measures;Medial;Methods;Microscopic;middle ear;middle ear disorder;Morphology;Natural regeneration;Nature;Nerve;Nerve Crush;nerve supply;Operative Surgical Procedures;Oral cavity;Organ;Otologic Surgical Procedures;Patients;Peripheral;Phenotype;Physicians;Procedures;Process;Psychophysiology;receptor;Receptor Cell;Recovery;regenerative;Reporting;Resected;Risk;Rodent;Severities;Side;Stimulus;Stomach;Stretching;Taste Bud Cell;Taste Buds;Taste Perception;Testing;Time;Tissues;Tongue;tongue apex;Trauma;Tympanic membrane structure;Work;

Abstract: DESCRIPTION (provided by applicant): Taste is the paramount sense governing which foods are accepted or rejected. It is the final arbiter of what goes into the stomach and what is rejected. We believe this is because the taste of food is, in general, the most important marker of its identity and acceptability. To this point, chemosensory clinical patients who present with taste complaints are twice as likely to report weight loss as those who present with olfactory dysfunction (40% vs. 20%) and enjoy food less. We, therefore, wish to understand the loss and recovery of chemosensory taste function in patients who have iatrogenic taste nerve damage during middle ear surgery. The chorda tympani (CT) nerve, which innervates the taste buds of the anterior two-thirds of the tongue, may be damaged during this surgery. As a clinical problem, the physician is unable to predict for their patient the degree or chemospecificity of their potential taste loss or precisely when normal function will return. From a basic research perspective, the proposed work will investigate the potential for a human cranial nerve and receptor end organs to re-grow and regenerate. A better understanding of a fully regenerating organ and tissue has great potential to help us understand how other human tissues, which do not spontaneously regenerate, may be induced to do so. The Aims of this proposal are to explore the loss and recovery of taste perception as a function of the type of CT nerve damage that occurs during surgery and the concomitant changes to human taste buds. PUBLIC HEALTH RELEVANCE: Taste is the final arbiter of what is eaten and what is rejected. Patients who present with taste complaints may lose interest in food and body weight. We wish to understand the loss and recovery of taste function in patients who have taste nerve damage during surgery of the middle ear. We will explore the loss and recovery of taste that occurs during surgery and the concomitant changes to human taste buds.

TRANSIENT BEHAVIORS OF ADAPTING BIOLOGICAL SYSTEMS

2011-08-19T09:09:00.000-07:00

Start Date: 8/19/2011

Award Number: 1R01GM100473-01

NIH Funding Organization: NIGMS

Principal Investigator: SONTAG, EDUARDO

Co-PI: Not Applicable

FY Total Cost by IC: $327212

Program(s): Apoptosis;Area;base;Behavior;Biologic Characteristic;biological systems;Biology;Biomedical Engineering;Cell Proliferation;Cellular biology;Chemicals;Chemotactic Factors;Chemotaxis;Colorectal Cancer;Cues;Detection;Development;Embryo;Environment;Epidermal Growth Factor;Fluorescence Resonance Energy Transfer;Fostering;Goals;Homeostasis;Immune system;Individual;insight;Ligands;Link;Mathematics;Measurement;Microfluidics;Molecular;Morphogenesis;Motion;Nonlinear Dynamics;Organism;pathogen;Pathway interactions;Pattern;Play;Primary carcinoma of the liver cells;Property;Proteins;response;Role;Sensory;Signal Pathway;Signal Transduction;spatiotemporal;Stem cells;Stimulus;Stress;System;Systems Biology;Technology;Testing;theories;Time;Tissues;tool;Tumor Angiogenesis;Uncertainty;Variant;Work;Wound Healing;

Abstract: DESCRIPTION (provided by applicant): The behavior, adaptability, and survival of organisms, including pathogens or immune system components, depend critically upon the capability to formulate appropriate responses, at different time scales, to fluctuating temporal patterns of environmental cues such as ligand concentrations or stresses. Traditionally, mathematical studies have focused on constant environments and steady-state behaviors, not on naturally occurring signals and transient behavior. The ultimate goal of this work is to investigate, both theoretically and experimentally, the characteristics of biological responses to time-varying signaling and what information is encoded in them. The primary focus will be on the study of invariance with respect to sensory symmetries, with an initial emphasis on fold-change-detection (FCD), a property that confers signaling systems robustness to scale uncertainty. Recent molecular cell biology studies have experimentally discovered FCD behavior in prokaryotic chemotaxis pathways, allowing responses to broad ranges of chemoattractant concentrations, and in the eukaryotic epidermal growth factor ERK and the Wnt signaling pathways, allowing robustness of behavior in the face of large variations in protein abundances. One aim of this work is to develop new, and to significantly expand existing, theory of FCD and other symmetries. This aim will involve foundational work in areas of mathematics ranging from control theory to group representations. Broader significance will include new insights in nonlinear dynamics and systems biology, as the properties studied are emergent synthetic behaviors, not explainable easily from the properties of individual chemicals in isolation. A complementary aim is to develop an experimental platform to study transient behaviors, particularly in chemotaxis. New experimental tools will be established, based on microfluidic technology and on molecular level analysis of intracellular signaling (FRET), to afford unprecedented spatiotemporal control of stimuli during measurements and to allow the effective testing of mathematical predictions. Broader significance will be in fostering the development of new microfluidic technology of wide applicability in biology and biomedical engineering. PUBLIC HEALTH RELEVANCE: Chemotaxis plays a key role in bacterial motion, as well as in embryonic morphogenesis, tissue organization, tumor angiogenesis, and wound healing. Activity of the ERK pathway controls cell proliferation, differentiation, and apoptosis. The Wnt signaling pathway plays a role in embryonic patterning and stem cell homeostasis, and its disregulation has been linked to colorectal cancer and hepatocellular carcinoma.

EPIGENETIC TRANSGENERATIONAL EFFECTS OF ENDOCRINE DISRUPTORS VIA FEMALE GERM LINE

2011-08-12T09:09:00.000-07:00

Start Date: 8/12/2011

Award Number: 1R21ES017847-01A1

NIH Funding Organization: NIEHS

Principal Investigator: UZUMCU, MEHMET

Co-PI: Not Applicable

FY Total Cost by IC: $231125

Program(s): Aberrant DNA Methylation; Address; Adult; Affect; Aging; Anxiety; Apoptosis; base;Behavior;beryllium trifluoride;bisulfite;Breeding;Chemical Exposure;Child;demethylation;density;Development;Disease susceptibility;DNA Methylation;DNA Methyltransferase;DNA Modification Methylases;DNA Sequence;Dose;Embryo;Endocrine Disruptors;Endogenous Retroviruses; Environment;environmental stressor;Epigenetic Process;Event;Exhibits;Exposure to;Female;Fertility;fetal;folliculogenesis;follow-up;Future;Future Generations;Gene Expression;Generations;Genes;Germ Cells;Germ Lines;Global Change;Goals;Gonadal structure;grandchild;H19 gene;Health;Health Care Costs;imprint;in utero;Inbreeding;Incidence;Individual;innovation;Knowledge;Lead;Life;Link;male;Mediating;Mediator of activation protein;Methods;Methoxychlor;Methylation;Modeling;Morphology;Neonatal;novel;Onset of illness;Oocytes;Ovarian;Ovary;Ovulation;Parents;Partner in relationship;Pathology;Pattern;Perinatal Exposure;Periodicity;Pesticides;Phenotype;Play;postnatal;prevent;programs;Puberty;public health medicine (field);Rattus;reproductive;reproductive function;Research;Retrotransposon;Reverse Transcriptase Polymerase Chain Reaction;Risk;Role;sex;Sex Ratio;sperm cell;Testing;Time;TimeLine;Tissues;Toxic Environmental Substances;vinclozolin;Woman;Women's Role;

Abstract: DESCRIPTION (provided by applicant): It is well established that exposure to environmental stressors or toxicants such as endocrine-disrupting chemicals (EDCs) during in utero and/or neonatal development can result in adult-onset diseases. Such detrimental changes have been linked to aberrant DNA methylation patterns as well as other epigenetic mechanisms. It is of great concern that recent studies have suggested that such disease susceptibilities can be transmitted via epigenetic mechanisms to subsequent generations that were never directly exposed to the EDCs. For example, testicular abnormalities were transmitted to F2-F4 generation males via the male germ line after in utero exposure to an EDC. However, these effects were found to be sex-specific since F2-F3 females exhibited milder phenotypes that required exposure of both parents to the EDC. In this proposal, our objective is to address the critical issue of whether the female germ line is involved in such transgenerational (TG) effects of EDC exposure. Methoxychlor (MXC) is an EDC that has actions mimicking those of many other EDCs in the environment and was shown to cause epigenetic changes in the gonad; it will therefore be used as a model EDC in this proposal. Our hypothesis is that exposure to MXC during the critical window of development, defined here as the period of gonad differentiation through oocyte epigenetic reprogramming, leads to TG effects in the ovary that are mediated by epigenetic changes in the oocyte. To test our hypothesis, the proposal has two interrelated but distinct specific aims: (1) Determine somatic TG epigenetic effects of MXC in the ovary of F3 generation following exposure of F1. F1-generation inbred female rats will be treated with 0, 20 5g/kg/day MXC, or 50-100 mg/kg/day MXC between E11 and PND7. These females will be bred with untreated males, and F2-F4 females will be generated. Initially, ovarian morphology and gene expression and fertility will be assessed only in the F3 females since observation of TG effects in F3 generation is the minimum requirement for establishing TG effects. Gene expression changes and global and gene-specific DNA methylation changes will be investigated using conventional methods as well as array-based approaches. (2) Investigate the epigenetic changes induced by MXC in F1/F2 oocytes that may lead to TG effects in F3. DNA methylation patterns in imprinted genes and parasitic DNA sequences such as retrotransposons in oocytes will be analyzed, as aberrant methylation patterns in these sequences can be pathogenic. Oocytic gene expression patterns will also be examined; any correlation between the changes in gene expression and DNA methylation will be elucidated. The proposed study will be the first to investigate the epigenetic TG effects of EDCs transmitted via the female germ line beyond the F2 generation. We recognize the considerable risk associated with this study, but implications to the health of present and future generations are significant given the widespread presence of EDCs in the environment. A mechanistic understanding of the TG epigenetic actions of MXC will broaden our knowledge of how EDCs, in general, disrupt normal epigenetic programming in females, and facilitate the development of strategies to prevent and treat EDC-induced TG abnormalities. PUBLIC HEALTH RELEVANCE: Exposure to environmental endocrine-disrupting chemicals during development can harm the exposed individuals, and this effect can be passed on to their children and grandchildren through epigenetic alterations within the germ cells. The objectives of this research are to investigate the transgenerational epigenetic effects of endocrine disruptors in females and to understand the mechanisms by which these compounds affect the germ cells and transmit these effects to subsequent generations. A better understanding of transgenerational epigenetic effects of endocrine disruptors has direct implications for public health because such an understanding can help us prevent and ameliorate these effects, thereby reducing future health costs.

SUMMER RESEARCH TRAINING IN ENVIRONMENTAL HEALTH SCIENCES

2011-08-09T09:09:00.000-07:00

Start Date: 8/9/2011

Award Number: 1R25ES020721-01

NIH Funding Organization: NIEHS

Principal Investigator: LASKIN, DEBRA LYNN

Co-PI: Not Applicable

FY Total Cost by IC: $57510

Program(s): Achievement;Advertising;Applications Grants;Area;Awareness;base;Basic Science;Biochemical;Biomedical Research;carcinogenesis;career;career development;Case Study;Chemoprevention;Commit;Community Health Education;Community Outreach;Core Facility;Dentistry;design;Development;Disadvantaged;Disease;Ecology;Educational aspects;Educational workshop;Endocrine disruption;Engineering;Ensure;Environmental and Occupational Exposure;Environmental Exposure;Environmental Health;Environmental Protection;Evaluation;experience;Exposure to;Faculty;Fellowship;Fellowship Program;Funding;Goals;Government;Graduate Education;Grant;Health Educators;Health Sciences;Immunotoxicology;improved;Individual;Industry;Institutes;Instruction;Joints;Laboratories;Letters;literacy;medical schools;Medicine;meetings;member;Mentors;Mentorship;Methodology;National Institute of Environmental Health Sciences;neurotoxicity;New Jersey;news;novel;Occupational Health;Pharmacy Schools;Positioning Attribute;Preparation;Professional Education;programs;public health relevance;Recommendation;Research;research and development;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Resources;responsible research conduct;Science;Series;Signal Transduction;skills;Structure;Students;Technology;Time;Toxicology;Training;Training Support;Translational Research;United States National Institutes of Health;Universities;Wood material;

Abstract: DESCRIPTION (provided by applicant): The summer program proposed in this grant application will introduce undergraduate students to the field of environmental health sciences as part of the existing Summer Undergraduate Research Fellowship (SURF) at Rutgers University. The purpose of SURF is to provide undergraduates with 10-week basic science and translational research experiences in preparation for careers in biomedical research. Since its inception, SURF has provided 30 undergraduates with summer research experiences and this proposal will establish an additional 10 fellowships for students to conduct research in toxicology and environmental sciences. Strong applications from talented students will be identified by scholastic achievement, letters of recommendation, and compelling personal statements. Recruitment strategies have been designed to attract students from disadvantaged and under-represented backgrounds into the fellowship program. Under the guidance and instruction of NIH-funded investigators, SURF students will conduct hands-on research projects in laboratories focused on environmental health sciences. Students will meet with mentors weekly to receive one-on-one training, ensure continued development of research skills, and evaluate progress of scientific projects. This program draws upon the resources, infrastructure, and expertise of faculty at Rutgers University and UMDNJ- Robert Wood Johnson Medical School who are members of the Environmental and Occupational Health Sciences Institute, and part of our joint NIEHS T32 training grant and NIEHS Center for Environmental Exposures and Disease. Students will also participate in weekly seminars and workshops on the topics of career development, responsible conduct of research, and environmental research. In addition, students will discuss topics 'in the news' that are related to environmental exposures, which will promote overall science literacy. They will also tour core facilities established as part of the NIEHS Center and be instructed in state-of- the-art technology for biomedical research. Students will make a 20-minute PowerPoint presentation of their research at the end of the summer. The SURF Directors and Project Managers have developed an evaluation plan to ensure the continued development and improvement of the fellowship program over subsequent years. Public Health Relevance: The structured hands-on research, didactic, and career activities in this proposal are designed to encourage and prepare undergraduate students for graduate and professional education in environmental health sciences.

NATURAL PRODUCTS IN THE PREVENTION OF CANCER

2011-08-01T09:09:00.000-07:00

Start Date: 8/1/2011

Award Number: 1R13CA159733-01A1

NIH Funding Organization: NCI

Principal Investigator: SUH, NANJOO

Co-PI: PEZZUTO, JOHN M

FY Total Cost by IC: $5000

Program(s): Achievement;Agreement;Anniversary;anticancer research;Area;Biological;Biological Assay;Biological Factors;cancer chemoprevention;cancer prevention;cancer therapy;carcinogenesis;Chemistry;Chemoprevention;Chemopreventive Agent;Clinical;Collaborations;Collection;Communication;Complex;Data;design;Development;Discipline;Disease;disorder prevention;drug candidate;Environment;Epidemiology;Fostering;Future;General Population;Goals;graduate student;Hawaii;Health;Human;improved;Incidence;interest;International;Island;Lead;lectures;Malignant Neoplasms;Medicinal Plants;meetings;Modification;Mortality Vital Statistics;North America;novel;Parents;Participant;Pharmaceutical Preparations;Phytochemical;Plants;Play;pre-clinical;prevent;Prevention;Prevention approach;Prevention Research;Prevention strategy;Preventive;public health medicine (field);Publications;Publishing;Research;Research Personnel;Resources;Role;Scientist;Secure;Series;Societies;Staging;success;symposium;Thinking, function;United States National Institutes of Health;Vaccines;Work;

Abstract: DESCRIPTION (provided by applicant): Natural products provide diverse resources in the development of new drugs for cancer treatment and prevention. Cancer chemoprevention is defined as an approach for the prevention, delay, or reversal of carcinogenesis. To discover and develop new cancer chemo preventive agents, many natural product researchers and medicinal chemists have focused on the exploration of plants with biological activity in bioassays designed to detect potential cancer preventive agents and the isolation of natural products as lead molecules, as well as modification of the active components for further synthesis. Recent advances in the chemistry of novel bioactive natural products provide improvement and development of new drugs. For the purpose of prevention of complex diseases such as cancer, there have been tremendous efforts of diverse groups of scientists working together to develop new and safe drugs from naturally-occurring resources. In order to review recent progress in this area and help to define a path to the future, we have assembled a group of internationally renowned experts in cancer prevention to participate in a symposium and present their recent work. Principal topics of the session will be potential chemopreventive agents developed from natural products and medicinal plants. The meeting will cover preclinical, clinical and epidemiological data in the area of cancer prevention research with compounds, either naturally occurring or derived from natural products components. There will be ten invited speakers for the session. Further discussion on the future direction of natural product research in the area of cancer prevention will be of great interest. At the start of the symposium, a lecture will be presented to overview the lectures to come, highlight the challenges of the field, and set the stage for the proceedings to come. The objective of the session is to critically evaluate progress and begin to chart of course for future work. Each lecture will include questions and answers and discussion. At the end of the session, a round table discussion will be moderated that will include each of the speakers and the audience. The symposium will be conducted as part of the 50th Annual Meeting of the Phytochemical Society of North America that will be held during the period of December 10-14, 2011, on the Kohala Coast of the Big Island of Hawaii. We will employ all of the resources assembled by the meeting organizers to assure the success of this symposium. The audience will be diverse and international. The venue is centrally located to facilitate East/West interaction. Very favorable hotel rates have been secured to promote broad attendance including graduate students and other trainees. It is expected the attendees will reflect broad diversity. The proceedings of the symposium will be published by Springer in their renowned series entitled Topics in Current Chemistry (impact factor 5.270; 2009). Each chapter as well as the preface will acknowledge presentation at the meeting and support provided by the NIH. This will be a landmark achievement in the field of cancer chemoprevention. PUBLIC HEALTH RELEVANCE: Prevention of cancer is a safe and effective way to reduce human suffering. In principle, cancer chemoprevention could play a role as dominant as vaccines in the prevention of disease. Nonetheless, despite the great promise of this approach, progress has been hampered. We propose to organize a meeting that will bring outstanding researchers from both cancer prevention and natural products research field together. The objective is to increase communication, disseminate new findings, prepare a platform for increased collaborations in the use and development of novel components and their derivatives from natural products as potential cancer preventive agents, and to explore and define barriers and ways to overcome these barriers. A prevention approach with natural products is an important part of cancer prevention strategies for improving general public health. We believe that the conference may contribute to achieving the goal of the NIH, and will provide a better understanding and approaches to reduce cancer incidence and mortality in the coming decades.

R25 IMSD MINORITY BIOMEDICAL RESEARCH SUPPORT PROGRAM (MBRS)

2011-07-01T09:09:00.001-07:00

Start Date: 7/1/2011

Award Number: 1R25GM096161-01

NIH Funding Organization: NIGMS

Principal Investigator: KOMISARUK, BARRY RICHARD

Co-PI: Not Applicable

FY Total Cost by IC: $624224

Program(s): Achievement;Behavioral;Behavioral Research;Biomedical Research;career;Communities;Consult;Counseling;Data;design;Development;Doctor of Medicine;Doctor of Philosophy;Drug Formulations;Educational workshop;Ensure;Evaluation;experience;Feedback;Fostering;Goals;improved;Institution;Interview;Knowledge;Lead;Mainstreaming (Education);meetings;Mentors;metropolitan;Minority;Monitor;Motivation;New Jersey;New York City;Outcome;Participant;Performance;Personal Satisfaction;Phase;Play;Population;Positioning Attribute;Process;Process Assessment (Health Care);programs;psychologic;Publications;Questionnaires;Recommendation;Recruitment Activity;Research;Research Support;Research Training;Role;Schools;Self Efficacy;Services;skills;Students;symposium;Testing;Time;Time Management;Training;Underrepresented Minority;Universities;

Abstract: DESCRIPTION (provided by applicant): The goal of this new proposed IMSD Program is to increase the number of minority students who enter careers in biomedical and behavioral research in which they are under-represented. Our proposed comprehensive program will play a significant role in overcoming the still-existing disparities, between minority and non-minority undergraduate and doctoral students at Rutgers, in their progressing into careers in biomedical/behavioral research. Through accomplishing this goal, our proposed IMSD Program will improve our overall Institutional outcomes. To accomplish this goal, our objectives are to provide the undergraduate and doctoral students in our Program with the academic and research skills, self-efficacy, motivation, and credentials that are essential to developing their competitiveness toward entering the next phases of their career - i.e., doctoral programs or postdoctorates, respectively. Thus, our proposed IMSD Program will: ' Provide the undergraduate and doctoral students with a carefully-mentored, rigorous research experience that includes supervised conceptualization, formulation, performance, analysis, presentation at professional scientific conferences, and publication of their own research or doctoral dissertation project; ' Provide a sequentially-coordinated, closely and continuously monitored spectrum of academic and personal support components to promote the students' highest academic performance levels, including, e.g., academic enrichment classes in gate-keeper courses, test-taking skills workshops, psychological counseling services, career guidance workshops, mentored graduate school and postdoctoral application processes, all designed to develop the students' professional self-efficacy, ensure their personal well- being and retention through to completion of their undergraduate or doctoral training on campus, and facilitate their entry into doctoral or postdoctoral programs; ' 'Mainstream' the students into the academic campus community by articulating our IMSD Program with other relevant University programs, prominent among which is the new 'Garden State LS-AMP Program.' The lead institution for this major new Program is Rutgers-Newark, so our campus will play a major role in its development, and it would be a major new interaction opportunity for our IMSD Program. ' Cast a wide net to recruit potential IMSD students -- especially doctoral students, who are particularly underrepresented in the biomedical and behavioral-related departments on our campus -- from multiple venues both on and off-campus, including the new Garden State LS-AMP Program and its participating New Jersey institutions, and the greater metropolitan New York City institutions with significant under- represented minority student populations totaling several hundred IMSD-eligible students in relevant major fields. ' Monitor continuously the performance of our IMSD Program via data gathering, analysis, and review of our quantitative goals by the IMSD PD and staff, and regular meetings with our IMSD participants, toward eliminating any gaps in performance between our IMSD students and the students in the university community at large. Assisting in this assessment process will be annual formal evaluations by SageFox Consulting, which will perform interviews, provide and analyze questionnaires, and provide feedback and recommendations to the students, mentors, advisory board, and PD of our Program. ' Among the quantitative expected outcomes for our IMSD undergraduate students: at least 90% of the undergraduates accepted into our IMSD Program will earn the baccalaureate, of whom at least 70% will proceed to enter a Ph.D. or Ph.D./M.D. program. And at least 90% of the doctoral students accepted into our IMSD Program will earn the Ph.D., of whom at least 80% will proceed to a postdoctoral position. PUBLIC HEALTH RELEVANCE: The goal of this new proposed IMSD Program is to increase the number of minority students who enter careers in biomedical and behavioral research in which they are under-represented. Our proposed comprehensive Program will play a significant role in overcoming the still-existing disparities, between Minority and non-Minority undergraduate and doctoral students in our Institution, in their progressing into careers in biomedical/behavioral research. Through accomplishing this goal, our proposed IMSD Program will improve our overall Institutional outcomes. To accomplish this goal, our objectives are to provide the undergraduate and doctoral students in our Program with the academic and research skills, self-efficacy, motivation, and credentials that are essential to developing their competitiveness toward entering the next phases of their career - i.e., doctoral programs or postdoctorates, respectively.

ENDOSOME TO GOLGI RETROGRADE RECYCLING IN C.ELEGANS

2011-07-01T09:09:00.000-07:00

Start Date: 7/1/2011

Award Number: 1F32GM096599-01

NIH Funding Organization: NIGMS

Principal Investigator: NORRIS, ANNE

Co-PI: Not Applicable

FY Total Cost by IC: $51326

Program(s): Alleles;Amino Acids;Apoptotic;Architecture;ATP phosphohydrolase;base;Binding (Molecular Function);Biological Assay;Caenorhabditis elegans;Cell Adhesion Molecules;Cell physiology;Cell Polarity;Cell Surface Proteins;Cells;Clathrin;Complex;Data;Defect;Degradation Pathway;Development;Disease;DNA;E-Cadherin;Early Endosome;Endocytosis;Endosomes;Energy Transfer;Epithelial Cells;Equilibrium;Event;Generations;Genes;Genetic;genetic analysis;Genetic Epistasis;Genetic Screening;Goals;Golgi Apparatus;Homeostasis;Immunoprecipitation;in vivo;insight;Intercellular Junctions;Intestines;Knowledge;Laboratories;Late Onset Alzheimer Disease;Left;Link;Lipids;Location;Lysosomes;Maintenance;Malignant Neoplasms;Mammalian Cell;Mammals;Mediating;Membrane;Membrane Protein Traffic;Modeling;Molecular;Molecular Chaperones;Multivesicular Body;mutant;novel;Nutrient;Organism;Pathway interactions;Process;Protein Binding;Protein Region;protein transport;Proteins;Recycling;Regulation;Research Design;research study;retrograde transport;RNA Interference;Role;Route;Saccharomyces cerevisiae;Screening procedure;Shiga Toxin;Signal Transduction;Signaling Molecule;Sorting - Cell Movement;Technology;Tertiary Protein Structure;Testing;Tissues;trafficking;Transmembrane Transport;uptake;Work;Yeasts;

Abstract: DESCRIPTION (provided by applicant): Title of Project: Endosome to Golgi Retrograde Recycling in C. elegans Background: Cells and tissues establish and maintain their unique architectures in large part through the tight regulation of protein and membrane transport. Key aspects of this process include the decision to recycle or degrade a given molecule, particularly signaling and adhesion molecules, a process that goes awry in many cancers. After endocytosis lipids and trans membrane cargo enter the early endosome for sorting. Cargo may be directed to degrade via targeting to the lysosome, recycled to the PM directly or through the recycling endosome, or sorted for delivery to the Golgi via the retrograde route. A number of observations hint that these routes compete with each other for various cargo, and that the decision to recycle or degrade is a key point of regulation. Our focus is on the much underappreciated branch point between the retrograde route and the degradative route to the lysosome. It has been suggested that competition between these two routes is mediated by microdomains that form on the early endosome and multivesicular body. The clathrin/HGRS-1(Hrs)/ESCRT complexes form one microdomain that promotes degradation via the lysosome, and the retromer/RME-8 complex forms a competing microdomain and promotes the retrograde pathway, recycling cargo from the endosome to the Golgi. The goal of our proposal is to better understand the molecular mechanisms controlling the decision of cargo to traffic via the retrograde or degradative pathways, as well as to find new retrograde components. Objective/Hypothesis: Our lab has recently made advances in our understanding of the molecular mechanism of this competition between the clathrin/HGRS-1(Hrs)/ESCRT and RME- 8/retromer microdomains. Our data suggest that SNX-1, a retromer component, potentiates the binding of RME-8 to the chaperone HSP-1(Hsc70), an interaction that antagonizes the buildup of endosomal clathrin and the associated degradative subdomain via clathrin uncoating activity. Furthermore preliminary evidence suggests that HGRS-1(Hrs) directly competes with this clathrin uncoating process potentially by titrating SNX-1 away from RME-8, leaving clathrin free to build up and promote lysosomal degradation. We aim to test this microdomain maintenance hypothesis, as well as dramatically extend our knowledge of the retrograde pathway in a multicellular organism by large-scale RNAi-based screening. Specific Aims: (1) To determine the functional consequence of SNX-1/RME-8 interaction (2) Distinguish between two models to explain the HGRS-1(Hrs)/SNX-1 interaction, especially as it relates to RME-8/HSP-1(Hsc70) mediated endosomal sorting and (3) To identify novel components of the retrograde sorting pathway. Study design: We propose to analyze our competition model using a combination of in vivo rescue experiments with interaction impaired mutants of RME-8, epistasis analysis, and Fvrster resonance energy transfer (FRET) analysis. Additionally we propose a simple yet powerful large scale RNAi screen to identify novel retrograde pathway components. Significance: All of the components of retrograde and lysosomal sorting we are studying are conserved in mammals. Defects in retrograde transport are linked to late-onset Alzheimer's disease, E-cadherin mis-localization, defects in the generation of Wnt signaling gradients, and defects in the clearance of dead apoptotic cells. Additionally the retrograde sorting route is the mode of entry for Shiga Toxin. We believe that a better understanding the molecular mechanism that target MIG-14 to its proper location within the cell, as well as identifying new genes that have a role in this process, will help us to understand the underlying molecular events leading a vast array of disease states. PUBLIC HEALTH RELEVANCE: Endocytosis and endosomal sorting involves the uptake of lipids and proteins from the cell surface followed by their proper distribution in the cell. This 'trafficking' is critical for diverse cellular functions such as signaling, cell-cell junction maintenance, nutrient uptake, and development. Defects in transport are linked to late- onset Alzheimer's disease, defects in cellular polarity (knowing its top from its bottom) and defects in the clearance of dead cells.

MARIJUANA CUES, AROUSAL AND THE CENTRAL AUTONOMIC NETWORK

2011-07-01T09:08:00.000-07:00

Start Date: 7/1/2011

Award Number: 1R03DA031060-01

NIH Funding Organization: NIDA

Principal Investigator: BATES, MARSHA E

Co-PI: Not Applicable

FY Total Cost by IC: $227652

Program(s): Abstinence;Activation Analysis;addiction;Addictive Behavior;Affect;Alcohol or Other Drugs use;Alcohols;Amygdaloid structure;Area;Arousal;Autonomic nervous system;Back;Baroreflex;Behavior;Biofeedback;Biological Neural Networks;Brain;Brain imaging;Brain region;Brain Stem;Cardiovascular Physiology;Cardiovascular system;Chronic;Cognitive;cue reactivity;Cues;Data;design;drug craving;drug of abuse;Drug usage;Drug Use Disorder;Electrocardiogram;emerging adult;Emotional;emotional experience;emotional reaction;Emotions;Environment;experience;feeding;Fingers;Foundations;Functional Magnetic Resonance Imaging;Goals;Graph;Human;improved;Individual;interest;Intervention;Knowledge;Learning;Link;Marihuana;Marijuana Smoking;marijuana user;Medial;memory process;Methodology;Modeling;Nervous System Physiology;Neuraxis;neuroimaging;neuromechanism;neurophysiology;novel strategies;operation;Participant;Peripheral Nervous System;Persons;Pharmaceutical Preparations;Physiologic pulse;Prefrontal Cortex;Prevention;Process;Psychophysiology;public health medicine (field);Regulation;Relapse;relating to nervous system;Relative (related person);Research;Research Personnel;research study;Respiration;response;Role;skills;Smoker;Smoking;Stimulus;Structure;Support System;System;Time;Training;Translational Research;Visceral;Vision;Visual;Work;

Abstract: DESCRIPTION (provided by applicant): This application is in response to PAR-09-073 to facilitate the entry of two addiction researchers into the area of functional magnetic resonance imaging (fMRI). We are currently characterizing moment-to-moment changes in cardiovascular arousal in response to emotionally-valenced and appetitive visual cues. This research focus is of substantial public health significance due to the fundamental role of cue reactivity and drug craving in motivating alcohol and drug seeking, use, and relapse following treatment. Visceral changes in autonomic nervous system (ANS) functions contribute significantly to the phenomenal experience of emotional arousal through extensive ANS and central nervous system (CNS) interconnections and the baroreflex. Yet, understanding of dynamic mechanisms that control cue reactivity has been hampered by conceptualizing ANS functions in isolation from the neural system(s) within which they operate. We seek to apply a neurophysiological systems approach to characterize how intra-individual changes in functional, regulatory aspects of emotional arousal in response to environmental cues are integrated across the ANS and CNS. The specific aims are to gain expertise in fMRI methodology and analysis, and to apply this expertise to study a dynamic neural system that modulates cardiovascular response to drug cues. As proof-of-concept, an experiment merging psychophysiological and neuroimaging methodologies is proposed as a fMRI and connectivity analysis learning vehicle (Aim 1) and to examine substantive differences in integrated brain and cardiovascular system response to marijuana-related picture cues in regular marijuana users compared to matched controls who do not use marijuana (Aim 2). fMRI data during cue exposure will be gathered using a 3-Tesla magnet, and the spread of activation between brain regions involved in arousal modulation will be examined using brain connectivity analysis. Activation and connectivity of three brain regions (medial prefrontal cortex, amygdala, brain stem) will be quantitatively linked to cardiovascular modulation within a graph theoretical connectivity model. If successful, this application will yield (1) preliminary support for a new approach wherein ANS reactivity can be linked dynamically (in a time-varying manner, not as a correlation) to neural systems that modulate cue reactivity, (2) new knowledge about how activation in three brain regions interrelates with baroreflex modulation of cardiovascular response to cues, and (3) the groundwork for translational research aimed at evaluating whether biofeedback interventions that improve specific cardiovascular functions can be used to affect inhibition in brain systems that control arousal in response to drug cues. PUBLIC HEALTH RELEVANCE: Cues in the environment, such as the sight of someone smoking, can produce a powerful emotional reaction that increases the likelihood that susceptible individuals will seek or use a drug of choice, even following periods of abstinence. The visceral experience of emotional arousal is an important component of reactivity to drug cues. This application seeks to characterize how the autonomic nervous system works together with the brain to control visceral response to marijuana cues.

MOLECULAR MECHANISMS OF RAPID AND SLOW ENDOCYTOSIS

2011-06-01T09:09:00.000-07:00

Start Date: 6/1/2011

Award Number: 4R00NS051401-02

NIH Funding Organization: NINDS

Principal Investigator: PARADISO, KENNETH

Co-PI: Not Applicable

FY Total Cost by IC: $249000

Program(s): Action Potentials;Affect;Agrin;Alzheimer's Disease;Area;ATP phosphohydrolase;Auditory;Axon;Binding (Molecular Function);Brain;Brain Stem;Calcium;Calcium Oscillations;Communication;Data;Development;Electric Capacitance;electrical measurement;Endocytosis;Exocytosis;Generations;Goals;Grant;Huntington Disease;information processing;Instruction;Kinetics;Knockout Mice;Measurement;Measures;Membrane;Membrane Potentials;Mission;Molecular;Na(+)-K(+)-Exchanging ATPase;National Institute of Neurological Disorders and Stroke;Nerve;nervous system disorder;Neurons;neurotransmitter release;Ouabain;Parkinson Disease;patch clamp;Pathology;Pharmacology;Phase;Physiological;postsynaptic;Potassium Channel;presynaptic;Presynaptic Terminals;Pump;Recovery;Research;research study;response;Rest;Role;Schizophrenia;Sodium;Staging;Synapses;Synaptic Cleft;Synaptic Transmission;Techniques;Testing;Time;Training;Travel;uptake;Work;

Abstract: No abstract available.

IN VIVO STUDIES OF ABORTIVE INITIATION

2011-04-15T12:05:00.000-07:00

Start Date: 4/15/2011

Award Number: 1R01GM088343-01A2

NIH Funding Organization: NIGMS

Principal Investigator: NICKELS, BRYCE EDWARD

Co-PI: Not Applicable

Award Amount:

Program(s): Address;Affect;Bacteria;base;Cells;chromatin immunoprecipitation;Collection;Coupled;density;detector;Development;Disease Pathway;DNA biosynthesis;DNA Microarray Chip;DNA-Directed DNA Polymerase;DNA-Directed RNA Polymerase;Exonuclease;Gene Expression;Gene Expression Regulation;Genes;Genetic;Genetic Transcription;Goals;Gram-Negative Bacteria;Growth;Health;Homeostasis;Human;In Vitro;in vivo;Lead;Life;Mediating;Microarray Analysis;Modeling;novel;oligoribonuclease;Phase;Physiological;Process;Pseudomonas aeruginosa;Research;RNA;RNA chemical synthesis;Small RNA;Structure;Transcript;Transcription Initiation;Work;

Abstract: In this work, we will investigate the possible existence of a novel class of regulatory small RNAs that function via a novel mode of action. Small RNAs have emerged as key regulators of cellular homeostasis as well as numerous developmental pathways and disease processes. Thus, the proposed research will lead to discoveries with important implications for pubic health.

PROSTATE CANCER PREVENTION BY TOCOPHEROLS

2011-04-01T12:05:00.003-07:00

Start Date: 4/1/2011

Award Number: 1R01CA152826-01A1

NIH Funding Organization: NCI

Principal Investigator: KONG, AH-NG TONY

Co-PI: Not Applicable

Award Amount:

Program(s): Age;Animal Model;Anti-inflammatory;Anti-Inflammatory Agents;Antioxidants;Apoptosis;base;biological adaptation to stress;biomarker;Blood;cancer cell;Cancer Etiology;Cancer Model;Carcinogenesis Inhibition;Carcinoma;Cell Culture System;Cell Cycle Arrest;Cell Death Induction;Cell Line;Cells;Cessation of life;Chemicals;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;cost effective;design;Development;Dietary Supplements;Disease;Dose;Effectiveness;Elderly man;Epigenetic Process;Failure (biologic function);Future;Gene Expression;Genes;Goals;Growth;Human;Immunohistochemistry;In Vitro;in vivo;Incidence;Individual;Inflammatory;Intervention;Intraepithelial Neoplasia;Lesion;LNCaP;macrophage;Malignant neoplasm of prostate;Malignant Neoplasms;Mediating;men;Metastatic Prostate Cancer;Metastatic to;Modification;Molecular;mouse model;Mus;Neoplasm Metastasis;neoplastic;novel;Outcome;Oxidative Stress;Palpable;Pre-Clinical Model;prevent;Preventive;Prostate;prostate cancer prevention;prostate carcinogenesis;Prostatic Neoplasms;Publishing;Regimen;Research;Research Project Grants;response;Response Elements;Role;Sampling;SCID Mice;Selenium;Selenium and Vitamin E Efficacy Trial;Signal Transduction;Staging;success;Therapeutic;Tissues;Tocopherols;Translating;tumor;tumor xenograft;United States;Vitamin E;Xenograft procedure;

Abstract: Prostate cancer (PCa) remains the second leading cause of cancer death in men in the US. The long term goal of this application is to develop an effective and safe strategy for prevention of PCa in men using a novel high content of ? mixed tocopherols (?-TmT), particularly in view of the recent failure of the SELECT trial.

SYNTHETIC COUNTER-LIGANDS FOR INHIBITION OF ATHEROSCLEROSIS

2011-04-01T12:05:00.002-07:00

Start Date: 4/1/2011

Award Number: 1R01HL107913-01

NIH Funding Organization: NHLBI

Principal Investigator: MOGHE, PRABHAS V

Co-PI: UHRICH, KATHRYN ELIZABETH

Award Amount:

Program(s): Address;Adult;Affinity;American;Animal Model;Anti-inflammatory;Anti-Inflammatory Agents;arm;Arterial Fatty Streak;Arteries;atherogenesis;Atherosclerosis;Attenuated;base;Behavior;Behavior Therapy;Binding (Molecular Function);Biocompatible Materials;Biological;Biomedical Engineering;Blood Vessels;Cardiovascular Diseases;CD36 gene;Cessation of life;Charge;Cholesterol;Chronic;Clinical;Coronary Arteriosclerosis;cost;Country;design;Development;Diabetes Mellitus;diabetic;Disease;Docking;Endothelial Cells;Endothelium;Evaluation;Event;Exhibits;Fatty acid glycerol esters;Goals;hydrophilicity;improved;In Vitro;in vivo;in vivo Model;Individual;Inflammation;Inflammatory;inflammatory marker;inhibitor/antagonist;innovation;insight;Laboratories;Life;Ligands;Lipids;LOX gene;macrophage;Mediating;Molecular;molecular modeling;Molecular Models;monocyte;Mortality Vital Statistics;Myocardial Infarction;novel;novel strategies;Outcome;oxidized low density lipoprotein;Pathology;Patients;Peripheral Vascular Diseases;Pharmacotherapy;Physiological;Polymers;receptor;receptor binding;Research;Research Personnel;Research Proposals;response;scavenger receptor;Serum;Staging;stroke;Structure;sugar;Tail;Testing;Therapeutic;therapy design;Thrombosis;trigger point;uptake;Vascular Diseases;Vertebral column;

Abstract: This project is concerned with the design of polymeric biomaterials with biological activity and efficacy against atherosclerosis, the progressive blockage of lipid (fat) filled blood vessels leading to heart attacks and strokes, a leading cause of adult mortality in the U.S. Outcomes will be insights into the structure-function relations between polymers and their blockage of cholesterol uptake; effects on inhibition of inflammation; and the identification of improved biodegradable polymeric materials as therapeutics for treatment of vascular and inflammatory diseases.

CANCER SURVIVORS IN ASSISTED LIVING: HEALTH BELIEFS AND BEHAVIORS

2011-04-01T12:05:00.001-07:00

Start Date: 4/1/2011

Award Number: 1R03CA136012-01A2

NIH Funding Organization: NCI

Principal Investigator: ROSENTHAL, MARSHA

Co-PI: Not Applicable

Award Amount:

Program(s): abstracting;Address;Adherence (attribute);Affect;Age;Aging;Assisted Living Facilities;Attention;Awareness;base;Behavior;Behavioral;Behavioral Model;Belief;cancer recurrence;Cancer Survivor;Cancer Survivorship;Chronic;Communication;coping;Coping Behavior;Data;Data Analyses;Decision Making;diet and exercise;Discipline of Nursing;Elderly;Emotional;Environment;evidence base;experience;Eye;Face;Feedback;follow-up;Foundations;Future;Goals;Guidelines;Habits;Health;Health behavior;health belief;Hypertension;illness perceptions;improved;insight;Interview;Judgment;Knowledge;Lead;Learning;Literature;malignant breast neoplasm;Malignant Neoplasms;Measures;medical attention;Mentally Ill Persons;Methods;Modeling;normal aging;Nurses;older patient;older women;Participant;Patients;Perception;Pharmaceutical Preparations;Population;Provider;Recommendation;Recording of previous events;Research;response;Risk;Screening procedure;Self Care;Self Management;self-neglect;Shapes;Signs and Symptoms;Site;Specific qualifier value;Survivors;Symptoms;Training;Training Programs;Woman;

Abstract: By targeting nurses and breast cancer survivors with hypertension, which is a highly prevalent condition, this research will help provide an evidence-based foundation for a future training program that will enhance providers' awareness of survivors' needs, and help them optimize survivors' overall health behaviors.

COCAINE, APPETITIVE MEMORY AND NEURAL CONNECTIVITY

2011-04-01T12:05:00.000-07:00

Start Date: 4/1/2011

Award Number: 1K01DA029047-01A1

NIH Funding Organization: NIDA

Principal Investigator: RAY, SUCHISMITA

Co-PI: Not Applicable

Award Amount:

Program(s): addiction;Affect;Amygdaloid structure;Anterior;Area;Attention;Behavior;Bioinformatics;Brain;Brain region;career development;Chronic;Cocaine;cocaine exposure;cocaine use;Cocaine Users;Cognitive;cognitive neuroscience;Conscious;Consult;craving;Cues;Data Analyses;Disease;Dorsal;Drug usage;Educational workshop;Environment;experience;extrastriate visual cortex;Functional Imaging;Functional Magnetic Resonance Imaging;Goals;high risk;Hippocampus (Brain);Human;Imaging Techniques;implicit memory;Individual;Insula of Reil;interest;Intervention;Knowledge;Left;Light;Link;Memory;memory process;Mentors;Modeling;Neurobiology;Neurocognitive;neuroimaging;neuromechanism;operation;Participant;Performance;Persons;Pharmaceutical Preparations;Pharmacotherapy;Phase;Play;Population;Prefrontal Cortex;Prevention program;Recognition (Psychology);relating to nervous system;Relative (related person);Research;Research Personnel;research study;Research Training;Risk;Role;Sampling;Semantic memory;Semantics;Smoker;Smoking;Stimulus;Substance Addiction;Substance of Abuse;symposium;System;Temporal Lobe;Testing;theories;tool;Training;Treatment outcome;treatment program;Unconscious State;

Abstract: Relevance. This application applies cutting-edge fMRI techniques and is the first study to examine neural mechanisms that underlie implicit and explicit memory processes for cocaine-related stimuli in individuals who vary in cocaine exposure. Brain areas related to memory and craving and connectivity between memory and craving related brain areas will be explored while individuals perform implicit and explicit memory tasks involving cocaine and neutral picture cues. This approach to understanding neural and cognitive influences that underlie risk for addiction and characterize chronic cocaine users will contribute to the candidate's ability to conduct research on the integrated operation of the autonomic nervous and neural systems, which constitute a multi-system vulnerability to substance addiction, and will be useful for clinicians seeking to make prevention and treatment programs more effective.

ASSEMBLY DYNAMICS AND ROLE OF PI4P ENRICHED REPLICATION ORGANELLES FOR ENTEROVIRA

2011-03-15T12:04:00.000-07:00

Start Date: 3/15/2011

Award Number: 1R01AI091985-01A1

NIH Funding Organization: NIAID

Principal Investigator: ALTAN-BONNET, NIHAL

Co-PI: Not Applicable

Award Amount:

Program(s): 1-Phosphatidylinositol 4-Kinase;Address;base;Binding (Molecular Function);Binding Sites;Biochemical;Biochemical Genetics;Capsid Proteins;Cells;Clathrin;combat;Complex;Computing Methodologies;Coupling;density;design;Diffusion;DNA-Directed RNA Polymerase;Drug Delivery Systems;Elements;Enzymes;Event;Genetic;Goals;human disease;Image;imaging modality;in vivo;insight;Integration Host Factors;Intracellular Membranes;Light;light microscopy;Link;Lipid Binding;Lipids;Location;Membrane;Membrane Lipids;Methodology;nanoscale;novel;novel therapeutics;Nuclear Magnetic Resonance;Organelles;Pathway interactions;phosphatidylinositol 4-phosphate;Phosphatidylinositols;Phosphotransferases;Plant Roots;Polymerase;prevent;Process;Property;Proteins;Reaction;Regulation;Resolution;RNA;RNA chemical synthesis;RNA replication;RNA Viruses;RNA-Directed RNA Polymerase;Role;single molecule;Site;spatiotemporal;spectroscopic imaging;Surface;Tail;Testing;Time;Translations;Viral;Viral Proteins;viral RNA;virology;Virus;Virus Diseases;Work;

Abstract: Plus-strand RNA viruses are at the root of many human diseases. Upon infecting cells, they hijack specific cellular proteins to build novel membrane-bound organelles; the virus uses the surface of the membranes of the organelles for RNA replication. The hijacked proteins impart on these organelle membranes unique properties, which we found were necessary for replicating viral RNA. Our goals are to determine how these membrane properties regulate viral RNA replication and how specific cellular proteins are hijacked to impart these properties.

EFFECTS OF STATINS ON THE NEUROBIOLOGY OF LEARNING AND MEMORY ACROSS THE LIFESPAN

2011-03-04T12:05:00.000-08:00

Start Date: 3/4/2011

Award Number: 1R03HD068960-01

NIH Funding Organization: NICHD

Principal Investigator: PHAN, MIMI LE

Co-PI: PYTTE, CAROLYN L

Award Amount:

Program(s): 8 year old;Academy;Address;Adolescent;Adult;adult neurogenesis;Age;age group;aged;American;Animal Model;Area;Auditory;Basic Science;Behavior;Behavioral;Biological Assay;Biological Models;Birds;Blood - brain barrier anatomy;Brain;Child;Childhood;Cholesterol;clinical effect;Clinical Sciences;clinically relevant;Cognitive;cognitive function;Conflict (Psychology);critical period;Data;Development;Dose;Exposure to;Family history of;Growth;Human;Hydroxymethylglutaryl-CoA Reductase Inhibitors;hypercholesterolemia;indexing;juvenile animal;Knowledge;Lead;Learning;Longevity;mature animal;Measures;meetings;Memory;memory acquisition;Methodology;Methods;motor learning;Neuraxis;Neurobiology;neurodevelopment;neurogenesis;neuromechanism;Neuronal Plasticity;Neurons;NHANES;obesity in children;Oral;Pathway interactions;Pediatrics;Play;Population;Process;Production;Property;Prosencephalon;Recommendation;relating to nervous system;Research;Research Personnel;Risk;Rodent Model;Role;Safety;Sensory;Short-Term Memory;Songbirds;sound;Specificity;Speech;Stimulus;System;Technology;Testing;United States;vocal learning;vocalization;

Abstract: We will assess the longitudinal effects of oral statins on learning and memory across the lifespan. Negative effects on cognitive processes might be relevant to assessing the safety of long-term statin exposure, especially in children. Additionally, we will explore how rates of neuron production and survival across the lifespan contribute to learning and memory in normal brains. Data on neurogenesis and survival, in conjunction with functional consequences, will lead to new hypotheses about the role of the cholesterol synthesis pathway in critical aspects of neural development and plasticity.

OPTOGENETIC ANALYSIS OF NEOSTRIATAL CIRCUITS ENGAGED BY CHOLINERGIC INTERNEURONS

2011-03-01T12:05:00.001-08:00

Start Date: 3/1/2011

Award Number: 1R01NS072950-01

NIH Funding Organization: NINDS

Principal Investigator: KOOS, TIBOR

Co-PI: TEPPER, JAMES M

Award Amount:

Program(s): Action Potentials;Animals;Basal Ganglia;base;Behavior;Behavioral;Brain;Breeding;cell type;Characteristics;Chimeric Proteins;Chloride Ion;Chlorides;cholinergic;Corpus striatum structure;Disease;Ensure;Event;Exhibits;gamma-Aminobutyric Acid;Generations;Genetic;Gilles de la Tourette syndrome;Gramicidin;Halorhodopsins;Huntington Disease;In Vitro;in vivo;Individual;Injection of therapeutic agent;Internal Ribosome Entry Site;Interneurons;Light;Link;Mediating;Mental disorders;Methods;Mus;Neostriatum;nervous system disorder;Neurons;neuropeptide Y;Nicotinic Antagonists;Nicotinic Receptors;novel;Obsessive-Compulsive Disorder;Optics;Parkinson Disease;Parvalbumins;Pathway interactions;Pattern;Play;Population;presynaptic;Presynaptic Terminals;Property;Psychological reinforcement;Pump;receptor;recombinase;Recurrence;research study;response;Role;Schizophrenia;Signal Transduction;Slice;Source;Stimulus;Structure;Synapses;System;Testing;Transgenic Animals;Transgenic Mice;Transgenic Organisms;Tyrosine 3-Monooxygenase;Viral;Whole-Cell Recordings;

Abstract: Numerous important neurological and psychiatric disorders including Parkinson's and Huntington's diseases, schizophrenia, Tourette's syndrome, obsessive compulsive disorder arise from pathological conditions of the neostriatum. Several of these are directly or indirectly linked to a major neuromodultory system the cholinergic interneurons of this structure, yet critically important issues about the functional role of these interneurons remains unanswered. The proposal will elucidate the organization and functional role of a newly discovered circuit mechanism that is responsible for mediating the reinforcement related population responses of these neurons which under pathological conditions may directly contribute to specific behavioral abnormalities associated with these disorders.

MODULATING PRONGF-INDUCED CELL DEATH IN EPILEPSY: STRATEGIES FOR NEUROPROTECTION

2011-03-01T12:05:00.000-08:00

Start Date: 3/1/2011

Award Number: 1R01NS070173-01A1

NIH Funding Organization: NINDS

Principal Investigator: FRIEDMAN, WILMA J

Co-PI: HEMPSTEAD, BARBARA L;SCHARFMAN, HELEN E

Award Amount:

Program(s): Acute;Address;Adult;Alleles;Animals;Antibodies;Apoptosis;Astrocytes;Attenuated;Binding (Molecular Function);Brain;C-terminal;Cell Death;cell type;Cells;Cessation of life;Chronic;Cleaved cell;clinical application;Code;Complex;Detection;Development;disability;Effectiveness;Electroencephalography;Elements;Epilepsy;Epileptogenesis;Epitopes;Equilibrium;Exons;FDA approved;Genetic;Hippocampus (Brain);Impaired cognition;In Vitro;in vivo;Infusion procedures;Injury;Knock-in Mouse;Lead;Ligand Binding;Ligands;Mediating;Modeling;mouse model;Mus;Nervous system structure;Neuraxis;Neuroglia;neuron apoptosis;neuron loss;Neuronal Differentiation;Neuronal Injury;neuronal survival;Neurons;neuroprotection;neurotrophic factor;neutralizing antibody;NGFR Protein;novel;Outcome;patient population;Pattern;Pharmaceutical Preparations;Pilocarpine;Preclinical Drug Evaluation;prevent;Process;Promotor (Genetics);Proteins;Reagent;receptor;Recurrence;Relative (related person);Resistance;Risk;Rodent Model;Role;Seizures;Signal Transduction;sortilin;Status Epilepticus;stroke;Synapses;Testing;tool;Toxic effect;transcriptional coactivator p75;Traumatic Brain Injury;Up-Regulation (Physiology);uptake;Wild Type Mouse;

Abstract: Insults or injury that cause severe seizures can lead to neuronal loss and the development of epilepsy, but the underlying mechanisms that lead to these outcomes are not clear, and there are few strategies to prevent them. ProNGF is produced in the brain after experimental status epilepticus (SE), and leads to neuronal death. We will use a proNGF knock-in mouse model to investigate which cells secrete proNGF under basal conditions and after SE and whether neuronal loss and the development of recurrent seizures (epilepsy) are exacerbated by excess proNGF. We will also determine whether antagonists of proNGF binding to p75 neurotrophin receptor protect neurons from apoptosis after SE and prevent epileptogenesis. The possibility of identifying approved drugs that have the capacity to prevent neuronal death after insults or injury associated with severe seizures has significant potential for clinical application.

IMAGING THE EFFECTS OF EXPECTATIONS ON FEEDBACK-BASED LEARNING

2011-03-01T06:29:00.000-08:00

Start Date: 3/1/2011

Award Number: 1R03DA029170-01A1

NIH Funding Organization: NIDA

Principal Investigator: TRICOMI, ELIZABETH

Co-PI: Not Applicable

Award Amount:

Program(s): abstracting;Achievement;Affect;Animals;Anterior;Attenuated;base;Behavior;Behavioral;Biological Models;Brain;Brain imaging;Brain region;Brain scan;cognitive control;contextual factors;Corpus striatum structure;Data;Development;Drug Addiction;drug efficacy;drug of abuse;Drug usage;Expectancy;expectation;Feedback;Fibrinogen;Food;Fostering;Functional Magnetic Resonance Imaging;Future;Goals;Human;Illicit Drugs;Image;Incentives;Individual;Individual Differences;insight;Label;Lead;Learning;Maintenance;motivated behavior;Motivation;neuromechanism;Outcome;Participant;peer;Performance;performance tests;Pharmaceutical Preparations;Placebo Effect;Prefrontal Cortex;Prevention strategy;Probability Learning;Process;programs;Psychological reinforcement;reinforcer;relating to nervous system;Relative (related person);Research;research study;response;reward processing;Rewards;Signal Transduction;skills;social;success;System;Task Performances;Testing;treatment strategy;Work;

Abstract: The proposed experiments examine contextual influences on the brain mechanisms involved in learning from behavioral reinforcers. These same mechanisms are involved in the development of drug addiction, so the research findings may suggest principles by which the ability of drugs to act as behavioral incentives could be altered through changes in motivational context.

WHAT MAKES ACCULTURATION SUCCESSFUL? A STUDY OF IMMIGRANT STUDENTS AT RUTGERS

2011-02-01T12:05:00.000-08:00

Start Date: 2/1/2011

Award Number: 1R21HD065053-01A1

NIH Funding Organization: NICHD

Principal Investigator: GUARNACCIA, PETER J

Co-PI: Not Applicable

Award Amount:

Program(s): Academic achievement;Acculturation;Admission activity;Adult;American;Anthropology;Asia;base;Child;Child Development;college;Communities;comparative;Complement;Country;Development;Discrimination (Psychology);Educational aspects;Elements;Ethnic group;experience;Family;Focus Groups;Future;Generations;Goals;Health;high school;Immigrant;In-Migration;innovation;Interview;Knowledge;Latin America;Life;Literature;Measures;Mediation;National Institute of Child Health and Human Development;New Jersey;Parents;Population;Process;Psychometrics;Questionnaires;Reporting;Research;resilience;Secondary Schools;skills;Social Adjustment;social integration;Social status;Societies;Students;success;Support System;theories;trait;United States;Universities;university student;Work;young adult;Youth;

Abstract: In the late 20th and early 21st Centuries, the United States has been experiencing large scale and continuing immigration of people from around the world, but particularly Latin America and Asia. Estimates are that by 2020, 15% of the U.S. population will be foreign born, surpassing the impacts of immigration on the U.S. at the turn of the 20th Century. This makes understanding processes of acculturation and their relation to successful social adjustment, especially educational attainment, critical issues. The future health of American society and of young adults who are immigrants or children of immigrants is dependent on their successful educational attainment and adaptation and adjustment.

WHAT MAKES ACCULTURATION SUCCESSFUL? A STUDY OF IMMIGRANT STUDENTS AT RUTGERS

2011-02-01T10:33:00.000-08:00

Start Date: 2/1/2011

Award Number: 1R21HD065053-01A1

NIH Funding Organization: NICHD

Principal Investigator: GUARNACCIA, PETER J

Co-PI: Not Applicable

Award Amount: $231,000

Program(s): 0-11 years old;21+ years old;Academic achievement;Acculturation;Acculturations;Admission;Admission activity;Adult;adult human (21+);adult youth;American;Anthropology;Asia;base;Child;Child Development;Child Youth;children;Children (0-21);Cognitive Discrimination;college;college student;Communities;comparative;Complement;Complement Proteins;Country;Cultural Assimilation;Development;Discrimination;Discrimination (Psychology);Education;Educational aspects;Elements;Ethnic group;experience;Family;Focus Groups;Future;Generations;Goals;Health;high school;Human, Adult;Human, Child;Immigrant;Immigrations;In-Migration;Infant and Child Development;innovate;innovation;innovative;Interview;Knowledge;Latin America;Life;Literature;Measures;Mediation;National Institute of Child Health and Human Development;National Institutes of Health;National Institutes of Health (U.S.);Negotiating;Negotiation;New Jersey;news;News;News (PT);News [Publication Type];NICHD;NIH;Parents;Population;Process;Psychometric;Psychometrics;public health relevance;Questionnaires;Reporting;Research;resilience;Secondary Schools;skills;social adaptation;Social Adjustment;social integration;Social status;Social Support System;Societies;Students;success;Support System;theories;trait;United States;United States National Institutes of Health;Universities;university student;Work;young adult;youngster;Youth;Youth 10-21;

Abstract: DESCRIPTION (provided by applicant): In the late 20th and early 21st Centuries, the United States has been experiencing large scale and continuing immigration of people from around the world, but particularly Latin America and Asia. Estimates are that by 2020, 15% of the U.S. population will be foreign born, surpassing the impacts of immigration on the U.S. at the turn of the 20th Century. This makes understanding processes of acculturation and their relation to successful social adjustment, especially educational attainment, critical issues. This proposal responds to the call in the report Questions that Matter (SSRC, 2005) for research that examines the impacts of ethnic identity, family, and community factors on the successful transition from high school to college. It complements the literature on the adaptation and adjustment of immigrant and second generation youth to secondary schools. It amplifies recent work supported by NICHD that focuses on educational success among immigrant children and the development of skills to have a successful, productive, and healthy adult life (Glick & White, 2003; Fuligni & Witkow, 2004; NIH News, 2004). More broadly, the proposed study focuses on resilience factors among immigrant children and their families that promote the ability of immigrant youth to take succeed in this important developmental transition. The goal of this application is to carry out a study of immigrant students who have entered Rutgers, the State University of New Jersey, to delineate the key processes of adaptation and adjustment that immigrant youth and their families go through to successfully negotiate life in the United States. The proposed study will employ focus groups with 200 immigrant students to understand in-depth their experiences of adaptation and adjustment to U.S. society and the factors that helped them successfully attain college admission. A final product of the proposed study will be the identification of key items for a new acculturation measure. PUBLIC HEALTH RELEVANCE: In the late 20th and early 21st Centuries, the United States has been experiencing large scale and continuing immigration of people from around the world, but particularly Latin America and Asia. Estimates are that by 2020, 15% of the U.S. population will be foreign born, surpassing the impacts of immigration on the U.S. at the turn of the 20th Century. This makes understanding processes of acculturation and their relation to successful social adjustment, especially educational attainment, critical issues. The future health of American society and of young adults who are immigrants or children of immigrants is dependent on their successful educational attainment and adaptation and adjustment.

INTERACTION OF RICIN A CHAIN WITH THE RIBOSOMAL STALK

2011-01-01T13:01:00.000-08:00

Start Date: 1/1/2011

Award Number: 1R03TW008418-01A1

NIH Funding Organization: FIC

Principal Investigator: TUMER, NILGUN E

Co-PI: Not Applicable

Award Amount: $63,280

Program(s): anti-viral protein, Phytolacca americana;anti-viral protein, pokeweed;Apoptosis;Apoptosis Pathway;Archaea;Archaebacteria;Archaeobacteria;Archaeon;Architecture;Bacteria;base;Binding;Binding (Molecular Function);Biochemical;Biological Models;biological signal transduction;Cell Communication and Signaling;Cell Death;Cell Death, Programmed;Cell Signaling;Cells;Collaborations;Complex;Country of Poland;CSBP1;CSBP2;CSPB1;cytotoxicity;Data;Defect;Depurination;Development;Docking;Engineering / Architecture;Environment;EXIP;gene product;Genetic analyses;genetic analysis;Genetics-Mutagenesis;Glycine cleavage system P-protein;glycine decarboxylase;Glycine dehydrogenase (decarboxylating);Grant;Human;Human, General;in vivo;Induction of Apoptosis;insight;Intracellular Communication and Signaling;JNK;JNK1;JNK1A2;JNK21B1/2;Lectin, Castor Bean;Lectin, Ricinus;Link;Lytotoxicity;Mammalian Cell;Man (Taxonomy);Man, Modern;MAP Kinase 8 Gene;MAPK14;MAPK14 gene;MAPK8;MAPK8 gene;Messenger RNA;Methods;Model System;Modeling;Models, Biologic;Molecular;Molecular Biology, Mutagenesis;Molecular Interaction;Molecular Probes;mRNA;Mutagenesis;mutant;Mxi2;Myelin Basic Protein P2;Myelin P2 Protein;National Institutes of Health;National Institutes of Health (U.S.);Nature;necrocytosis;New Brunswick;New Jersey;NIH;novel;P-protein;P-protein, glycine decarboxylase;P2 Protein;p38;p38 MAPK Gene;p38Alpha;PAP protein, Phytolacca;parent grant;Parents;Peptide Biosynthesis, Ribosomal;pokeweed antiviral protein;Poland;Preparation;prevent;preventing;PRKM14;PRKM15;PRKM8;Procedures;Protein Biosynthesis;Protein Biosynthesis, Ribosomal;protein synthesis;Protein Synthesis, Ribosomal;Proteins;public health relevance;RCA 60;RCA60;Research;Research Resources;Resistance;resistant;Resources;Ribosomal Proteins;Ribosomal RNA;ribosome inactivating protein, Phytolacca;Ribosomes;Ricin;Ricin A Chain;Ricinus Communis Agglutinin II;Ricinus Toxin;RNA Splicing;RNA, Messenger;RNA, Small Interfering;Role;rRNA;Saccharomyces;SAPK1;SAPK2A;Shiga-Like Toxins;Signal Pathway;Signal Transduction;Signal Transduction Systems;Signaling;siRNA;Site;Small Interfering RNA;social role;Spain;Specificity;Splicing;Structure;System;System, LOINC Axis 4;Time;tool;United States National Institutes of Health;Universities;Vero Cell Cytotoxins;Vero Cytotoxin;Vero Cytoxins;Vero Toxins;Verotoxins;Yeasts;

Abstract: DESCRIPTION (provided by applicant): This is a FIRCA application for the collaboration between Dr. Nilgun Tumer at Rutgers University, New Brunswick, New Jersey and Dr. Marek Tchsrzewski at the Maria Curie Sklodowska University in Poland. This research will be done at the Maria Curie Sklodowska University in Poland as an extension of NIH Grant No. R01-AI072425, 3-15-2007 to 2-29-2012. This collaboration makes use of the unique resources and research environment in Dr. Tchsrzewski's lab to use ricin A chain (RTA) as a molecular tool to probe the function of the eukaryotic ribosomal stalk and to identify the functional part of the stalk structure. In spite of its fundamental importance in protein synthesis, the molecular architecture of the eukaryotic stalk and details of its function are not known due to the lack of appropriate molecular tools. Dr. Tchsrzewski has developed the yeast strains and the methods to isolate the in vivo assembled eukaryotic ribosomal stalk for the first time. Isolation of the whole native stalk from yeast has revolutionized the method of stalk preparation and facilitated research on the function of the eukaryotic ribosomal stalk. Dr. Tumer has developed the model systems to study the activity of ricin A chain (RTA) and discovered that RTA binds to the ribosomal stalk to inhibit protein synthesis. In collaboration with Dr. Tchsrzewski, Dr. Tumer showed direct interaction between RTA and the isolated native yeast ribosomal stalk, and obtained preliminary data demonstrating that RTA can be used as a very specific molecular tool to probe the structure and the function of the eukaryotic stalk. We propose to identify the stalk components critical for binding RTA, study the interaction of RTA with stalk complexes from different species, including bacteria, archaea, yeast and human and to identify the functional part of the stalk structure. This collaboration will connect the ongoing structure function analysis of RTA in the parent grant with biochemical, structural and genetic analysis of the stalk in Dr. Tchsrzewski's lab in Poland and will provide new insights into the role of the ribosomal stalk in protein synthesis. PUBLIC HEALTH RELEVANCE: This project seeks to probe the function of the eukaryotic ribosomal stalk and to identify the functional part of the stalk structure using ricin A chain as a molecular probe. It will provide a better understading of the stalk structure and its role in protein synthesis.

MULTIFUNCTIONAL PEG HYDROGEL NANO/MICROPARTICLES FOR TARGETED TREATMENT OF NSCLC

2011-01-01T12:32:00.000-08:00

Start Date: 1/1/2011

Award Number: 1R01CA155061-01

NIH Funding Organization: NCI

Principal Investigator: SINKO, PATRICK J.

Co-PI: Not Applicable

Award Amount: $387,246

Program(s): (S)-4-ethyl-4-hydroxy-1H-pyrano-[3',4'[{..}]6,7]indolozino[1,2-b]quinoline-3,14(4H,12H)-dione;1,2-Dithiolane-3-pentanoic acid;1H-Pyrano(3',4'[{..}]6,7)indolizino(1,2-b)quinoline-3,14(4H,12H)-dione, 4-ethyl-4-hydroxy-, (S)-;1H-Pyrano[3',3'.6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, 4-ethyl-4hydroxy-(S)-(9CI);2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, (4S-(4alpha,4aalpha,5alpha,5aalpha,6alpha,12aalpha))-;20-(S)-camptothecine;21, 22-secocamptothecin-21-oic acid lactone;92-kDa Gelatinase;92-kDa Type IV Collagenase;absorption;Absorption;Accounting;Adherence;Adherence (attribute);Adverse effects;Affinity;alpha-6-Deoxyoxytetracycline;alpha-Lipoic Acid;Anti-Cancer Agents;Anti-Tumor Agents;Anti-Tumor Drugs;anticancer agent;anticancer drug;Antineoplastic Agents;Antineoplastic Drugs;Antineoplastics;Antiproliferative Agents;Antiproliferative Drugs;Anzatax;Apoptosis;Apoptosis Pathway;Apoptotic;Asotax;Aspiration, Respiratory;Binding;Binding (Molecular Function);biological signal transduction;Body Tissues;Breathing;Bristaxol;Camptothecin;Cancer Cause;cancer cell;Cancer Drug;Cancer Etiology;cancer metastasis;Cancer of Lung;Cancer Patient;Carcinoma, Non-Small-Cell Lung;Caring;caspase;Cell Communication and Signaling;Cell Death, Programmed;Cell Signaling;Cell surface;Cell Surface Receptors;Cell-Death Protease;Cessation of life;chemoattractant cytokine;chemokine;chemotherapeutic agent;Chemotherapeutic Agents, Neoplastic Disease;chemotherapy;CXC-R4;CXCL12;CXCL12 gene;CXCR-4;CXCR4;CXCR4 gene;cystein protease;cystein proteinase;cysteine endopeptidase;Cytokines, Chemotactic;cytotoxic;D2S201E;Data;Death;design;designing;Development;Diagnosis;Diffuse;Disease;disease/disorder;Disorder;Dose;Doxycycline;Drug Delivery;Drug Delivery Systems;Drug Targeting;Drug Targetings;drug/agent;Drugs;Engineering;Engineerings;Evaluation;FB22;Filtration;Forecast of outcome;Fractionation, Filtration;Gel;Gelatinase B;Goals;HM89;Homologous Chemotactic Cytokines;HSY3RR;Hydrogels;ICE-like protease;Immunoglobulin Enhancer-Binding Protein;improved;Inflammation;Inflammatory;INFLM;Inhalation;Inhaling;Injectable;inspiration;Inspiration, Respiratory;Intercrines;Intracellular Communication and Signaling;kappa B Enhancer Binding Protein;LAP3;LCR1;LESTR;Life;Ligands;Lipoic Acid;Lung;lung cancer;lung function;Lung Neoplasms;macrophage;Macrophage Gelatinase;Malignant Cell;Malignant neoplasm of lung;Malignant Tumor of the Lung;Mammals, Mice;Matrix Metalloproteinase-9;Medication;men;men's;Metastasis;Metastasize;Metastatic Lesion;Metastatic Neoplasm;Metastatic Tumor;Mice;migration;MMP-9;MMP-9 Protein;MMP9;Molecular Interaction;mouse model;Murine;Mus;nano;nano particle;nanoparticle;natural flow;Neoplasm Metastasis;neoplastic cell;NF-kappa B;NF-kappaB;NF-kB;NFKB;Non-Small Cell Lung Cancer;Non-Small-Cell Lung Carcinoma;nonsmall cell lung cancer;novel;NPY3R;NPYR;NPYRL;NPYY3R;NSCLC;NSCLC - Non-Small Cell Lung Cancer;Nuclear Factor kappa B;nuclear factor kappa beta;Nuclear Transcription Factor NF-kB;outcome forecast;Paclitaxel;Paclitaxel (Taxol);pathway;Pathway interactions;Patients;Pattern;PBSF;Peptide Fragments;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacodynamics;Platinum;Platinum Black;Praxel;Prevention;Process;Process of absorption;Prognosis;programs;Programs (PT);Programs [Publication Type];Pt element;public health relevance;pulmonary;Pulmonary Cancer;Pulmonary malignant Neoplasm;Pulmonary Neoplasms;receptor binding;Research;residence;Resistance;resistant;respiratory function;Respiratory physiology;Respiratory System, Lung;SCYB12;SDF-1A;SDF-1B;SDF1;SDF1A;SDF1B;Secondary Neoplasm;Secondary Tumor;Series;side effect;Signal Transduction;Signal Transduction Systems;Signaling;SIS cytokines;site targeted delivery;Solubility;Specificity;Staging;Structure;Surface;System;System, LOINC Axis 4;targeted delivery;Taxol;Taxol (Old NSC);Taxol A;Taxol Konzentrat;therapy adverse effect;Thioctic Acid;Time;Tissues;TLSF-A;TLSF-B;Toxic effect;Toxicities;TPAR1;Transcription Factor NF-kB;treatment adverse effect;Treatment Side Effects;Tumor Cell;Tumor Cell Migration;Tumor of the Lung;Tumor-Specific Treatment Agents;Type V Collagenase;United States;Vibramycin;Viral;vMIP-II;Woman;

Abstract: DESCRIPTION (provided by applicant): The long-term goal of the proposed research program is to develop an intravenously (IV) administered lung- targeted nanoparticle (NP)/gel microparticle (GMP) delivery system for the treatment of non-small cell lung cancer (NSCLC). After the initial diagnosis, greater than half of the patients with localized lung cancer survive at least 5 years suggesting a benefit to an approach that limits metastatic spread from the primary lung cancer. While targeting is an effective approach for improving drug concentrations and minimizing side effects, the options for lung targeting are narrow. Thus, targeted lung delivery approaches for treating NSCLC are urgently needed. Two levels of targeting are proposed. The first is passive targeting. GMPs selectively accumulate in the lung after IV administration. Our compelling preliminary data demonstrates that passive targeting achieves a 10-fold increase in anti-cancer drug potency and 10-fold lower peak systemic drug concentrations. The second is active targeting. Two types of NPs are proposed to achieve active targeting. Using a novel fabrication process, high drug loading into NPs is achieved that overcomes the solubility limitations of hydrophobic cancer drugs. The NP surfaces are functionalized with ligands that selectively target cancer cells. The second NP group is also functionalized with cell surface ligands, however, instead of delivering drug cargo selectively inside the cancer cell, these NPs are engineered to tightly bind to cancer cell surface receptors and remain there in order to inhibit the metastatic signaling cascade. Once the GMPs passively accumulate in the lung, the NPs imbedded in the GMP diffuse out and seek cancer cells resulting in an extraordinary degree of targeting specificity. Three specific aims are proposed: AIM 1: Engineer and evaluate a series of GMPs to achieve (a) optimal passive lung targeting efficiency, retention and elimination and (b) minimal pulmonary toxicity (structural and functional alterations and inflammation) in normal mice and in an orthotropic mouse model of lung cancer. AIM 2: Design, fabricate, and assess NPs and GMPs that enhance the pro-apoptotic effect of camptothecin (CPT). Actively targeted NPs will be developed that specifically deliver CPT and alpha lipoic acid (ALA) to lung cancer cells to exploit synergy in tumor cell apoptosis induced by these two chemotherapeutic agents. AIM 3: Design, fabricate, and assess CXCR4/7-targeted NPs and GMPs that reduce the occurrence of metastasis. Two active targeting approaches will be investigated: (1) direct CXCR4/7 receptor binding and (2) inhibition of downstream pro-metastatic signaling factors NF-kB, ERK and/or MMP-9. If successful, an injectable lung targeted drug delivery system will be produced that: (1) utilizes passive targeting to exploit the natural flow-filtration pattern of the lung to achieve high local and minimal systemic drug concentrations; (2) exploits synergy in chemotherapy-induced tumor cell apoptosis and active targeting to reduce the required effective drug and MP doses; and (3) utilizes active targeting to reduce the occurrence of metastatic lesions by interfering with the CXCR4/7 - CXCL12 chemokine pathway. PUBLIC HEALTH RELEVANCE: Lung cancer is currently the leading cause of cancer deaths in both men and women in the United States and Non-Small Cell Lung Cancer (NSCLC) accounts for the vast majority of lung cancer cases. There is a pressing need to develop new treatment approaches for this highly fatal disease. This project involves the development and evaluation of a novel targeted delivery system (injected intravenously) that uses nanoparticles imbedded into microparticles to deliver chemotherapeutic drugs and other agents specifically to the lungs of patients in order to treat NSCLC and reduce therapy-limiting side effects.

INTERACTION OF RICIN A CHAIN WITH THE RIBOSOMAL STALK

2011-01-01T06:42:00.000-08:00

Start Date: 1/1/2011

Award Number: 1R03TW008418-01A1

NIH Funding Organization: FIC

Principal Investigator: TUMER, NILGUN E

Co-PI: Not Applicable

Award Amount: $63,280

HTS FLUORESCENCE POLARIZATION ASSAY FOR INHIBITORS OF KEAP1-NRF2 INTERACTION

2010-12-03T10:33:00.000-08:00

Start Date: 12/3/2010

Award Number: 1R03MH093197-01

NIH Funding Organization: NIMH

Principal Investigator: HU, LONGQIN

Co-PI: Not Applicable

Award Amount: $46,431

Program(s): 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (E,E)-;Active Oxygen;Address;Adverse effects;anti-oxidant;anticarcinogenic;Antioxidants;Assay;base;Binding;Binding (Molecular Function);Bioassay;Biologic Assays;biological adaptation to stress;Biological Assay;Biological Factors;Cancer Causing Agents;Cancers;Carcinogens;Cell Culture Techniques;Cell Nucleus;Cells;Chemicals;Chemoprevention;Chemopreventive;Chemopreventive Agent;Complex;Curcumin;Cysteine;Defense Mechanisms;Development;Diferuloylmethane;Disease;disease/disorder;Disorder;Dissociation;Dose;drug/agent;Drugs;EGCG;EGCG cpd;Enzymes;epigallo-catechin gallate;Epigallocatechin Gallate;Epigallocatechingallate;Exhibits;experiment;experimental research;experimental study;Factor, Biologic;Fluorescence Polarization;Fluorescent Probes;fruits and vegetables;Funding;Future;gene product;Genes;Goals;Green Tea Extract;Green Tea Polyphenols;Half-Cystine;high risk;High Throughput Assay;high throughput screening;Immunologic, Luciferase;Inflammation;Inflammatory;INFLM;inhibitor;inhibitor/antagonist;Isothiocyanates;Knockout Mice;L-Cysteine;Label;language translation;Libraries;Luciferases;malignancy;Malignant Neoplasms;Malignant Tumor;Mammals, Mice;Medication;Mercaptans;Mercapto Compounds;methylsulfoxybutylisothiocyanate;Mice;Mice, Knock-out;Mice, Knockout;Modification;Molecular Bank;Molecular Interaction;mouse model;Murine;Mus;Natural Products;neoplasm/cancer;NF-E2-related factor 2;novel;Nrf2 protein;Nucleus;Null Mouse;Oncogens;oxidation reduction reaction;Oxidation-Reduction;Oxidative Stress;Oxygen Radicals;pathway;Pathway interactions;Peptide Domain;Peptides;Pharmaceutic Preparations;Pharmaceutical Preparations;Population;Pro-Oxidants;Production;Protein Domains;protein protein interaction;Proteins;psychological defense mechanism;public health relevance;R01 Mechanism;R01 Program;reaction; crisis;Reactive Oxygen Species;Redox;Reporter;Research;Research Grants;Research Project Grants;Research Projects;Research Projects, R-Series;research study;Resistance;resistant;response;Response Elements;RPG;Safety;screening;Screening procedure;screenings;sensor;side effect;Signal Pathway;small molecule;small molecule libraries;Solutions;Source;Stress;stress response;stress; reaction;Sulfaforaphane;Sulfhydryl Compounds;sulfhydryl group;sulforafan;Sulforaphane;sulforophane;System;System, LOINC Axis 4;Tea;Tea catechin;Tertiary Protein Structure;Testing;therapy adverse effect;Thiols;Transcription Activation;Transcriptional Activation;Translating;Translatings;treatment adverse effect;Treatment Side Effects;Turmeric Yellow;Up-Regulation;Up-Regulation (Physiology);Upregulation;Work;

Abstract: DESCRIPTION (provided by applicant): HTS fluorescence polarization assay for inhibitors of Keap1-Nrf2 interaction Keap1-Nrf2-antioxidant response element (ARE) system regulates cellular defense mechanisms that protect cells from oxidative stress. Indirect inhibitors of Keap1-Nrf2 interaction such as sulforaphane, curcumin, and epigallocatechin gallate are being tested as chemopreventive agents. However, there are general concerns over their use as chemopreventive agents because of their chemical reactivity and their putative irreversible mechanism of action. High throughput screening of chemical libraries is an effective approach to discover small molecule leads as direct reversible inhibitors of protein-protein interactions like Keap1-Nrf2; such direct inhibitors of Keap1-Nrf2 interaction would address concerns over the general use of purified natural thiol- reactive inhibitors as chemopreventive agents. The goal of this current application is to translate our fluorescence polarization (FP) assay to a MLPCN screening center for the screening of MLPCN library. The FP assay detects competitive inhibitors of a fluorescently labeled-Nrf2 peptide from binding to Keap1 kelch domain. Funding for the development of the fluorescent probe and the FP assay has been provided in part by R01 CA133791, Hu L (PI). Secondary and tertiary assays have been established in our labs including an SPR binding assay and a cell-based ARE-luciferase reporter assay. Limited chemical modification will also be performed in the second year to derive initial SAR to enable the selection of hits as leads for future optimization into potent direct inhibitors of Keap1-Nrf2 interaction. Such inhibitors will be useful as important pharmacological probes for the elucidation of cytoprotective pathways and as potential chemopreventive agents of cancer and other diseases in high risk populations. PUBLIC HEALTH RELEVANCE: Screening of the MLPCN library with our high throughput fluorescence polarization assay will enable the discovery of novel small molecules as direct inhibitors of Keap1-Nrf2 interaction. Specific and potent Keap1- Nrf2 inhibitors will be useful as important pharmacological probes for the elucidation of cytoprotective pathways and as potential cancer chemopreventive agents in high risk populations.

NANORNA-MEDIATED CONTROL OF GENE EXPRESSION

2010-09-30T12:32:00.000-07:00

Start Date: 9/30/2010

Award Number: 1R01GM096454-01

NIH Funding Organization: NIGMS

Principal Investigator: NICKELS, BRYCE EDWARD

Co-PI: DOVE, SIMON L

Award Amount: $668,814

Program(s): abstracting;Autoregulation;Bacteria;balance;balance function;Biochemical;Cell model;Cells;Cellular model;Coupled;Deoxynucleoside-triphosphate[{..}]DNA deoxynucleotidyltransferase (DNA-directed);Development;Disease Pathway;DNA biosynthesis;DNA Polymerases;DNA Replication;DNA Synthesis;DNA-Dependent DNA Polymerases;DNA-Dependent RNA Polymerases;DNA-Directed DNA Polymerase;DNA-Directed RNA Polymerase;EC 2.7.7.6;EC 2.7.7.7;Equilibrium;Gene Action Regulation;Gene Expression;Gene Expression Regulation;Gene Products, RNA;Gene Regulation;Gene Regulation Process;Gene Transcription;Genetic;Genetic Transcription;Health;heavy metal lead;heavy metal Pb;Homeostasis;Human;Human, General;Lead;Life;Man (Taxonomy);Man, Modern;Mediating;Modeling;novel;Nucleoside-triphosphate[{..}]RNA nucleotidyltransferase (DNA-directed);Pb element;Physiological Homeostasis;Process;Research;Ribonucleic Acid;RNA;RNA chemical synthesis;RNA Expression;RNA Polymerases;RNA synthesis;RNA, Non-Polyadenylated;Small RNA;Structure;Transcript;Transcription;Transcription, Genetic;Work;

Abstract: DESCRIPTION (provided by applicant): Transcription is the first step in gene expression and the step at which most gene regulation occurs. Transcription in all cells is carried out by multi-subunit RNA polymerases (RNAPs) that are conserved in sequence, structure and function from bacteria to humans. Whereas initiation of DNA synthesis by DNA polymerase requires use of a primer, it is widely accepted that the initiation of RNA synthesis by RNAP occurs 'de novo' (i.e. RNAP initiates RNA synthesis using free NTPs alone). The proposed research will challenge this conventional paradigm. Specifically, we will investigate the hypothesis that a significant fraction of transcription does not occur 'de novo', but rather relies upon use of small ~2-5 nt RNA transcripts that serve as primers to initiate transcription. We refer to these ~2-5 nt RNA transcripts as 'nanoRNAs'. According to our model, the cell balances nanoRNA-primed transcription and de novo transcription to maintain cellular homeostasis. Furthermore, celular perturbations that alter the balance betwen nanoRNA-primed transcription and de novo transcription lead to global alterations in gene expression. Consistent with this model, we have found that increasing the intracellular concentration of nanoRNAs leads to global alterations in gene expression coupled with an apparent increase in the occurrence of nanoRNA-primed transcription. Building on these findings, we propose to use genetic and biochemical approaches in conjunction with high- throughput sequencing to determine how nanoRNA priming can alter gene expression, identify factors that control the nanoRNA content of the cell, and systematically identify nanoRNAs. The proposed research has the potential to redefine our view of a fundamental process that occurs in all living cells (i.e. transcription) and, in parallel, uncover a novel class of regulatory small RNAs, 'nanoRNAs', that function in all living cells via a novel mode of action. PUBLIC HEALTH RELEVANCE: The proposed work will investigate the existence of a novel class of regulatory small RNAs, 'nanoRNAs', that function via a novel mode of action. Small RNAs have emerged as key regulators of cellular homeostasis as well as numerous developmental pathways and disease processes. Thus, the proposed research will lead to discoveries with important implications for public health.

INFRASTUCTURE FOR CER ON INNOVATIVE DELIVERY SYSTEMS FOR COMPLEX PATIENTS

2010-09-30T10:33:00.002-07:00

Start Date: 9/30/2010

Award Number: 1R24HS019678-01

NIH Funding Organization: AHRQ

Principal Investigator: CANTOR, JOEL C

Co-PI: Not Applicable

Award Amount:

Program(s):

Abstract: DESCRIPTION (provided by applicant): This project will establish a statewide data infrastructure for Comparative Effectiveness Research (CER) on healthcare delivery innovations for complex patients in low-income communities. It addresses two CER priorities established by the Institute of Medicine in 2009 to evaluate outcomes of: (1) '...comprehensive care coordination programs, such as the medical home, in managing children and adults with severe chronic disease, especially in populations with known health disparities'; and (2) 'accountable care systems ...for geographically defined populations of patients with one or more chronic diseases.' Responding to the Agency for Healthcare Research and Quality request for applications (RFA-HS-10-001) to expand research capability to study comparative effectiveness in complex patients, this project has three specific aims: 1. Build a sustainable longitudinal database of linked hospital, Medicaid, and charity care claims and encounter records in New Jersey for CER on strategies to improve the delivery of care to complex patients in low-income communities. 2. Build and evaluate measures of resource use and quality of care for CER on innovative delivery systems for complex patients in low-income communities using the database developed under Aim 1. 3. Demonstrate the potential of this new research infrastructure by conducting a pilot evaluation of health services resource use and quality for complex patients served by an innovative care coordination program in Camden, NJ. Designed to become an ongoing enterprise, the data infrastructure will initially consist of six years of state program administrative records. Products of this work will be disseminated widely and the database will be released for public use. The project builds on a long-standing collaboration between university researchers and agencies of New Jersey government, and will take place in the context of state policies encouraging innovation in health care delivery for low-income urban populations. New Jersey is especially well suited to CER on health system delivery innovations because it has exceptionally high rates of preventable utilization of expensive hospital care. PUBLIC HEALTH RELEVANCE: Patients with complex health conditions in low-income communities frequently experience inadequate and fragmented health services, leading to avoidable use of expensive hospital care and poor outcomes. This project will build research capacity to compare the cost and quality of health care delivery system innovations to care typically received by medically complex patients in low-income communities in New Jersey.

COMPARATIVE EFFECTIVENESS OF PREHOSPITAL AND HOSPITAL EMERGENCY CARE

2010-09-30T10:33:00.001-07:00

Start Date: 9/30/2010

Award Number: 1R01HS020097-01

NIH Funding Organization: AHRQ

Principal Investigator: DELIA, DEREK

Co-PI: Not Applicable

Award Amount:

Program(s):

Abstract: DESCRIPTION (provided by applicant): Patients with critical conditions such as cardiac arrest or major trauma often depend on prehospital emergency medical services (EMS) for life-saving care. Nevertheless, the evidence base for that care, particularly as it relates to transitions between prehospital and hospital settings, is extremely limited. These transitions are poorly understood because data linking prehospital and hospital services are lacking. Without linked data, many important questions about the effectiveness of emergency care systems and protocols cannot be answered. This project will create a data infrastructure for comparative effectiveness research (CER) that bridges prehospital and hospital care using newly available electronic patient care records for prehospital EMS transports in New Jersey (Specific Aim 1). These data will be linked to all-payer hospital discharge abstract data and death certificates to support a wide range of comparative effectiveness studies on patient- and system-level interventions where prehospital and hospital services are tightly connected. The linkage draws on an innovative partnership between academic researchers and the New Jersey Department of Health and Senior Services (DHSS) which has access to confidential patient identifiers. The data infrastructure will be applied to a comparative effectiveness study of clinical outcomes after provision of therapeutic hypothermia (TH) for initial survivors of out-of-hospital cardiac arrest (Specific Aim 2). Out-of-hospital cardiac arrest (OHCA) is a major public health challenge, afflicting over 295,000 US residents annually. Two small randomized clinical trials demonstrated that therapeutic hypothermia can improve neurologically intact survival among patients with restored spontaneous circulation following OHCA. Nevertheless, despite the promulgation of national guidelines for use of hypothermia treatment, there have been no large-scale studies comparing this treatment to usual normothermic post-arrest care. The study will compare rates of neurologically intact survival at discharge and at 30 days between OHCA patients receiving and not receiving TH. Multivariate models will be used to adjust for confounders such as patient risk factors, EMS response times, and prehospital procedures performed. Differences in in-hospital complications (e.g., seizures, arrhythmias, shock) and resource use (overall length of stay and days in the ICU) will also be compared. Finally, access to this technology will be assessed among AHRQ priority populations. This project is innovative in creating one of the largest linked prehospital/hospital data sets in the U.S. and in conducting one of the first large-scale CER studies of TH. The linked database will enable a much wider scope of research and surveillance than is currently possible with narrowly defined trauma and cardiac event registries. The project draws on the expertise of a diverse team of senior experts in health services research, health policy, emergency medicine, and EMS operations. PUBLIC HEALTH RELEVANCE: Patients with critical conditions such as cardiac arrest or major trauma often depend on prehospital emergency medical services for life-saving care, but the evidence base for that care is extremely limited. This project will create a statewide data infrastructure in NJ for comparative effectiveness research linking prehospital to hospital data. A study of therapeutic hypothermia care for initial survivors of out-of-hospital cardiac arrest will demonstrate the value of this data infrastructure.

ACCELERATING UTILIZATION OF CE FINDINGS IN MEDICAID MENTAL HEALTH

2010-09-30T10:33:00.000-07:00

Start Date: 9/30/2010

Award Number: 1R18HS019937-01

NIH Funding Organization: AHRQ

Principal Investigator: CRYSTAL, STEPHEN

Co-PI: Not Applicable

Award Amount:

Program(s):

Abstract: DESCRIPTION (provided by applicant): State Medicaid programs play a central role in the provision of mental health services in the U.S., particularly for lower-income youth and adults with severe mental illness, whose mental health treatment is often sub- optimal and varies widely, often without apparent clinical rationale. Building on an existing network partnership, the Network for Evidence Based Treatment (NET) will bring together seven state Medicaid programs accounting for 33% of Medicaid enrollment nationally, together with experts from the Rutgers-Columbia mental health CERTs and other partners, into a consortium that will implement an innovative, multi-component initiative to increase the utilization of evidence-based clinical and delivery system practices in the provision of mental health treatment for beneficiaries of state Medicaid programs. Ten specific clinical target areas have been identified for measurement and intervention based on CE evidence: mental health drug polypharmacy; management of metabolic risks of antipsychotics; antipsychotic utilization for children under age six; higher than recommended doses of antipsychotics; utilization of appropriate mental health services as a complement or alternative to psychotropic treatments; consistency between diagnoses and treatments; geographical, provider, racial/ethnic, and other treatment lacking clinical rationale; improvement of treatment adherence for adults with severe mental illness; identification and prediction of high risk/high utilization beneficiaries and targeting of services to these subpopulations; safe and effective psychotropic and mental health services use by foster care youth. The NET will improve treatment practices in these clinical target areas by implementing highly effective organizational practices including the systematic utilization of administrative and clinical data to monitor and guide policy, systematic provision of provider feedback, multi-state networking to support transfer of successful innovations across states, and creation of multi-agency, multi-stakeholder quality collaboratives within states in order to implement an innovative multi-state, multi-faceted, data-driven CQI program in each state. We will put into place in collaborating states an integrated system of quality improvement tools including baseline and follow-up state profiles of use to identify and track variation in treatment patterns; implementation and systematic use of a set of quality metrics and a system of provider feedback utilizing the metrics; and development of a multi-stakeholder quality collaborative, a state quality improvement plan, and a continuous quality improvement process in each state. Results will be evaluated and disseminated nationally. The potential impact of the NET is enormous given Medicaid's central role in financing mental health care, and the large number of beneficiaries affected. PUBLIC HEALTH RELEVANCE: State Medicaid programs play a central role in the provision of mental health services in the U.S., particularly for lower-income youth and adults with severe mental illness, whose mental health treatment is often sub- optimal and varies widely, often without apparent clinical rationale. Building on an existing network partnership, the Network for Evidence Based Treatment (NET) will bring together seven state Medicaid programs accounting for 33% of Medicaid enrollment nationally, together with experts from the Rutgers-Columbia mental health CERTs and other partners, into a consortium that will implement an innovative, multi-component initiative to increase the utilization of evidence-based clinical and delivery system practices in the provision of mental health treatment for beneficiaries of state Medicaid programs. We will put into place in collaborating states an integrated system of quality improvement tools including baseline and follow-up state profiles of use to identify and track variation in treatment patterns; implementation and systematic use of a set of quality metrics and a system of provider feedback utilizing the metrics; and development of a multi-stakeholder quality collaborative, a state quality improvement plan, and a continuous quality improvement process in each state. Results will be evaluated and disseminated nationally; the potential impact is extremely large given the large number of beneficiaries affected.

COMPUTATIONAL THINKING-VISUAL CLINICAL PROBLEM THREADING FOR CASE SUMMARIZATION

2010-09-27T10:33:00.000-07:00

Start Date: 9/27/2010

Award Number: Contract

NIH Funding Organization: NLM

Principal Investigator: CORAL, MICHELE

Co-PI: Not Applicable

Award Amount: $300,216

Program(s): Age;biomedical scientist;Caring;Chronic Disease;chronic disease/disorder;chronic disorder;Chronic Illness;Clinical;clinical data repository;clinical data warehouse;Cognition;Cognitive;Collaborations;Competence;Complement;Complement Proteins;Complex;Computers;Contracting Opportunities;Contracts;Data Banks;Data Bases;data repository;Databank, Electronic;Databanks;Database, Electronic;Databases;Decision Making;design;designing;Disease Management;Disorder Management;Face;facial;Family;flexibility;Funding;History;Human;Human, General;Imagery;Individual;Information Management;innovate;innovation;innovative;Intelligence;Investigators;kernel methods;Knowledge;Learning, Machine;Machine Learning;Man (Taxonomy);Man, Modern;Medical;Memory;Methods;new approaches;novel approaches;novel strategies;novel strategy;Patients;Population;R01 Mechanism;R01 Program;rapid growth;Recording of previous events;relational database;Research;Research Grants;Research Personnel;Research Project Grants;Research Projects;Research Projects, R-Series;Researchers;RPG;Solutions;Speed;Speed (motion);statistical learning;support vector machine;System;System, LOINC Axis 4;Thinking;Thinking, function;Visual;Visualization;

Abstract: In biomedicine, clinicians and researchers now face formidable challenges in information management, innovation, and decision-making in an era which is seeing extraordinarily rapid growth of knowledge, distributed among a host of databases, and on a scale far larger than can be mastered by an individual. The remarkable speed, memory capacity, and symbol-manipulating power of computers, if properly harnessed, can complement human cognitive strengths so as to enable efficient use of all of the knowledge relevant to solution of clinical and scientific problems. To invigorate research in the arena of computation and cognition, a number of fresh concepts have arisen in recent years: computational intelligence, machine learning, intelligence amplifying systems, flexible competence, human-computer collaboration, and computational thinking. As part of its ¿Medical Advanced Research Projects Initiative,¿ the NLM is funding novel approaches to computational thinking, in order to evaluate the feasibility of using innovative computational approaches to enhance the ability of clinicians and biomedical scientists to solve one or more significant cognitive tasks and bring improvements in medical care to patient, families and the public.

HUMAN TRANSCRIPTION FACTOR IMMUNOGENS: GENERATION OF A COMPLETE SET

2010-09-23T10:33:00.000-07:00

Start Date: 9/23/2010

Award Number: 1U01DC011485-01

NIH Funding Organization: NIDCD

Principal Investigator: ANDERSON, STEPHEN

Co-PI: ARROWSMITH, CHERYL H;MARCOTRIGIANO, JOSEPH ;MONTELIONE, GAETANO T

Award Amount: $979,896

Program(s): 3-D structure;3-dimensional structure;3D structure;Address;Affinity;Affinity Chromatography;affinity purification;Agreement;Antibodies;Antigenic Determinants;Antigens;Archives;Arizona;ATGN;Atlases;Attention;Baculoviruses;base;Binding;Binding (Molecular Function);Binding Determinants;Binding Proteins;Biological;Biosynthetic Proteins;Cancers;Cells;Characteristics;ChIP (chromatin immunoprecipitation);CHIP assay;Chromatin;chromatin immunoprecipitation;Chromatography, Affinity;clinical data repository;clinical data warehouse;Collection;Complex;Computer Software Tools;cost;Cytolysis;Data Banks;Data Bases;data repository;Databank, Electronic;Databanks;Database, Electronic;Databases;Deoxyribonucleic Acid;Deposit;Deposition;design;design and construction;designing;Disease;disease/disorder;Disorder;DNA;Documentation;E coli;Electronics;Embryo;Embryonic;Ensure;Epitopes;Escherichia coli;Exhibits;experience;expression vector;Future;Gametes;gene product;Generations;Genes;Genetic;Germ Cells;Germ-Line Cells;Goals;Human;Human Biology;Human Genome Project;Human, General;immunogen;Informatics;initial cell;Insecta;Insects;Instruction;Invertebrates, Insects;Jobs;kidney cell;Laboratories;Ligand Binding Protein;Lysis;malignancy;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Man, Modern;meetings;Membrane;membrane structure;Metals;milligram;Mining;Minings;Moab, Clinical Treatment;Molecular Interaction;Monoclonal Antibodies;neoplasm/cancer;Occupations;Plasmids;polypeptide;Principal Investigator;Procedures;Process;Production;Professional Postions;protein expression;Proteins;Proteome;Protocol;Protocols documentation;Reagent;Recombinant Proteins;Recombinants;Records;relational database;Renal Cell;repository;Reproductive Cells;Research Resources;Residual;Residual state;Resources;Running;Sampling;scale up;SCHED;Schedule;Scientist;screening;Screening procedure;screenings;SEQ-AN;Sequence Analyses;Sequence Analysis;Sex Cell;sexual cell;Shipping;Ships;Software Tools;Structure;success;System;System, LOINC Axis 4;Technology;Testing;three dimensional structure;Tools, Software;transcription factor;Universities;vector;wasting;Wheat;Work;Yeasts;

Abstract: DESCRIPTION (provided by applicant): The goal of the proposed project is to assemble a collection of optimized immunogens based on the complete set of human transcription factors. These immunogens will be used by others to create renewable affinity reagents such as monoclonal antibodies. An initial, high priority application envisioned for such reagents is chromatin immunoprecipitation studies, and our aim is to design our immunogens so as to optimize them for this purpose. We will do this primarily using two strategies: (a) we will express transcription factor domains that flank the DNA recognition domain but do not overlap it in order to minimize inducing antibodies that might interfere with chromatin binding; and (b) wherever possible we will focus on transcription factor flanking domains that fold into complex three dimensional structures (native folds) and thus present highly specific 3D epitopes. We already have a protein production pipeline up and running that is producing > 1000 purified protein samples (including hundreds of human proteins) per year at the multi- milligram scale, so we are highly experienced in the relevant technologies, and meeting the goals of this FOA will require adding only a modest amount of extra capacity. We also have specialized software tools for the sophisticated analysis of human transcription factor sequences and the design of appropriate expression constructs. Our experience has shown that paying attention to the proper curation of genes and construct design at the beginning pays dividends downstream in terms of timely and cost-effective protein production because it minimizes wasting expensive wet lab resources on sub-par targets. Finally, we have a range of adaptable expression technologies that can be tailored to other classes of human protein targets (including secreted and membrane-bound proteins) in the future, so our approach is highly amenable to expressing additional sectors of the human proteome beyond transcription factors. RELEVANCE: The human genome project gave us a complete blueprint for the genetic instructions that control human biology. This proposal concerns a special set of human proteins known as 'transcription factors', which are the master effector proteins in the cell that have the job of interpreting these instructions and telling the cell what to do under all sets of conditions. In diseases such as cancer these instructions can become garbled, which is why it is important to understand how transcription factors work. This proposal concerns the creation of a specific collection of human transcription factor-derived proteins that will allow scientists to precisely interrogate which transcription factors address which sets of instructions under a variety of conditions, thus establishing the outlines of the master control circuits in human cells.

MECHANISTIC STUDIES OF HCV E2

2010-09-15T12:31:00.000-07:00

Start Date: 9/15/2010

Award Number: 1R01AI080659-01A2

NIH Funding Organization: NIAID

Principal Investigator: MARCOTRIGIANO, JOSEPH

Co-PI: Not Applicable

Award Amount: $374,200

Program(s): 1-Beta-D-ribofuranosyl-1,2,4-triazolo-3-carboxamide;1-Beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide;Acquired Immune Deficiency Syndrome Virus;Acquired Immunodeficiency Syndrome Virus;Affective;AIDS Virus;Alpha Virus;Alphavirus;analytical ultracentrifugation;anti-retroviral;Anti-Retroviral Agents;Antibodies;Antigenic Determinants;antiretroviral;Antiretroviral Agents;Antiviral Agents;Antiviral Drugs;Antivirals;Arbovirus, Group B;Arboviruses, Group A;Assay;base;Binding;Binding (Molecular Function);Binding Determinants;Bioassay;Biochemical;Biologic Assays;Biological Assay;Carcinoma of the Liver Cells;CD36 protein;CD81;CD81 gene;Cell Culture Techniques;Cell membrane;Cells;Cellular Membrane;Chromatography, Molecular Sieve;Chronic;Cirrhosis;Complex;conformation;conformational state;Crystallography, X-Ray;Crystallography, X-Ray Diffraction;Crystallography, X-Ray/Neutron;Crystallography, Xray;Cytoplasmic Membrane;Cytosol;Data;design;designing;Development;dimer;DISSEC;Dissection;disulfide bond;DNA Sequence Rearrangement;drug/agent;Drugs;Endosomes;env Antigens;env Gene Products;env Polyproteins;env Protein;Envelope Protein;Epitopes;Event;experiment;experimental research;experimental study;Exposure to;Flavivirus;Foundations;gene product;Gene Products, env;Genetic;Genome;Genotype;Glycoproteins;glycosylation;Goals;Grant;HCC;HCV;HCV infection;heavy metal lead;heavy metal Pb;Hepatic Cirrhosis;Hepatic Disorder;Hepatitis C;Hepatitis C virus;Hepatitis C virus infection;hepatitis non A non B;hepatitis nonA nonB;Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted;Hepatitus C;Hepatocellular cancer;Hepatocellular Carcinoma;Hepatoma;hepatopathy;High Prevalence;Histidine;Histidine, L-isomer;HIV;HTLV-III;Human;Human Immunodeficiency Viruses;Human T-Cell Leukemia Virus Type III;Human T-Cell Lymphotropic Virus Type III;Human T-Lymphotropic Virus Type III;Human, General;Hydrogen Oxide;IFN;immune receptor;Immunologic Receptors;Immunological Receptors;Individual;Infection;inhibitor;inhibitor/antagonist;interest;Interferons;L-Histidine;Laboratories;large scale production;LAV-HTLV-III;Lead;Liver Cirrhosis;Liver diseases;liver disorder;Lymphadenopathy-Associated Virus;Mammalian Cell;Man (Taxonomy);Man, Modern;Maps;Mediating;Medication;Membrane;Membrane Fusion;membrane structure;Metabolic Glycosylation;Methods and Techniques;Methods, Other;Molecular;Molecular Configuration;Molecular Conformation;Molecular Interaction;Molecular Sieve Chromatography;Molecular Stereochemistry;Molecular Virology;monomer;multidisciplinary;NANBH;neutralizing antibody;non A non B hepatitis;non A, non B hepatitis;non-A non-B hepatitis;non-A, non-B hepatitis;novel;Nucleocapsid;Parenterally-Transmitted Non-A, Non-B Hepatitis;Patients;Pb element;Pestivirus;Pharmaceutic Preparations;Pharmaceutical Preparations;Physiologic;Physiological;Plasma Membrane;plasmalemma;Polyproteins;Population;Primary carcinoma of the liver cells;Production;prophylactic;Protein Cleavage;protein folding;Proteins;Proteolysis;protonation;PT-NANBH;Public Health;public health medicine (field);public health relevance;Publications;Publishing;Radiation, X-Rays;Radiation, X-Rays, Gamma-Rays;Rearrangement;receptor;receptor binding;Receptor Protein;Receptors, Immunologic;Receptosomes;Recombinants;research study;Resolution;response;Ribavirin;Ribovirin;Roentgen Rays;Role;RTCA;scavenger receptor B type I;scavenger receptor B1;scavenger receptor BI;scavenger receptor class B type I;scavenger receptors, class B, type I;Scientific Publication;sensor;Series;Side;Single Crystal Diffraction;Size Exclusion Chromatography;social role;SR-BI receptor;Staging;Structure;Surface;System;System, LOINC Axis 4;TAPA-1;TAPA1;Techniques;Therapeutic;Therapy, Vaccine;Time;tool;Transmission;transmission process;Tribavirin;TSPAN28;VAC-TX;Vaccine Therapy;Vaccines;Viral;Viral Diseases;Viral Gene Products;Viral Gene Proteins;Viral Genome;viral infection;Viral Proteins;Virion;Virus;Virus Diseases;virus infection;Virus Particle;virus protein;Virus-HIV;Viruses, General;Water;X Ray Crystallographies;X-Radiation;X-Ray Crystallography;X-Rays;Xrays;

Abstract: DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is a causal agent of chronic liver disease in humans, afflicting more than 123 million people worldwide (approximately 2% of the human population). In many cases HCV infection becomes chronic, which can progress to liver cirrhosis and hepatocellular carcinoma. There is no vaccine available for HCV and the only treatment is pegylated interferon-? in combination with ribavirin, which leads to a sustained response in only 50% of patients. The high prevalence of infection, lack of HCV specific inhibitors, and poor response rate to the current treatment underscore the importance of new therapies. The HCV virion consists of a membrane enveloped nucleocapsid and two glycoproteins (E1 and E2), which are important for recognizing and entering a target host cell. As in the case of other enveloped viruses such as pestiviruses, alphaviruses, and other flaviviruses, HCV infection requires fusion between viral and host cell membrane before the viral genome can be released into the host cell cytosol. This critical step is thought to occur in the endosomal compartment, is triggered by low pH, and likely requires structural rearrangement of the glycoproteins. In addition to its role in membrane fusion, E2 is thought to be responsible for targeting since it has been shown to bind host cellular receptors CD81 and scavenger receptor class B type I (SR-BI). Despite the progress that has been made in understanding E2 function using virus-neutralizing antibodies and genetic approaches, more in-depth mechanistic dissection of E2 requires complementary biochemical, biophysical and molecular virology techniques. Progress has been hindered by the inability to make sufficient quantities of properly folded protein as E2 protein production is challenging due to its heavy glycosylation and presence of intramolecular disulfide bonds. Recently, our laboratory has devised and published a novel expression system in mammalian cells to produce eE2 (E2 ectodomain) protein that retains the functionality of E2 present on virions. Together with our comprehensive biochemical and biophysical characterization of eE2, we have established a foundation to better define the functional role of E2 in HCV infection. In this proposal, we will focus on assessing the role of E2 in triggering low-pH dependent membrane fusion and explore possible oligomeric and structural rearrangements necessary for this critical step in HCV infection. A multidisciplinary experimental plan that integrates biochemical, biophysical, genetic and molecular virology techniques will be used to: (1) define the physiological oligomeric form of E2 relevant to HCV infection; (2) characterize the role of E2 in sensing a decrease in pH, as encountered by the virus during endosomal acidification; and (3) determine the domain organization of E2 and possible rearrangements upon pH change. Results from the proposed studies will contribute substantially to our understanding of the mechanisms responsible for viral entry and have important implications for the development of novel therapies and vaccines to control HCV infection. Similar studies on the HIV glycoproteins have lead to the development of a new class of antiretroviral that block HIV entry. PUBLIC HEALTH RELEVANCE: Currently, 2% of the human population - approximately 123 million people worldwide - is chronically infected with hepatitis C virus (HCV), making virus transmission a major public health concern. There is no vaccine against HCV and the current drugs are not affective for many people. The goal of the proposed grant will provide a better understanding of how HCV recognizes and enter cells. This information will be valuable for designing new therapies or a vaccine against HCV.

EPIGENETIC EFFECTS OF DEVELOPMENTAL ENDOCRINE DISRUPTOR EXPOSURE IN THE OVARY

2010-09-10T13:01:00.000-07:00

Start Date: 9/10/2010

Award Number: 1R56ES017059-01A1

NIH Funding Organization: NIEHS

Principal Investigator: UZUMCU, MEHMET

Co-PI: Not Applicable

Award Amount: $154,000

Program(s): 21+ years old;4',5,7-Trihydroxyisoflavone;4,4' isopropylidinediphenol;5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one;adiposity;Adult;adult human (21+);Affect;Age;age dependent;age related;Aging;Aging, Premature;Animals;Antral;Applications Grants;Assay;base;Benzene, 1,1'-(2,2,2-trichloroethylidene)bis(4-methoxy)-;Binding;Binding (Molecular Function);Bioassay;Biologic Assays;Biological Assay;bisphenol A;bisulfite;Body Weight;Cancers;Cannot achieve a pregnancy;Cardiovascular;Cardiovascular Body System;Cardiovascular system;Cardiovascular system (all sites);Causality;Chemical Exposure;Chemotherapy-Hormones/Steroids;ChIP (chromatin immunoprecipitation);CHIP assay;chromatin immunoprecipitation;circulatory system;corpulence;corpulency;corpulentia;Culturing, in vitro Organ;Culturing, in vitro Vertebrate, Organ;Data;Defect;Deoxyribonucleic Acid;Development;Developmental Process;Diagnosis;Dianisyl Trichloroethane;dietary deficiency;Difficulty conceiving;diphenylolpropane;Disease;disease causation;disease etiology;disease/disorder;disease/disorder etiology;Disorder;disorder etiology;DMDT;DNA;DNA Methylation;DNA Methylation Inhibition;Dysfunction;Embryo;Embryonic;Endocrine;Endocrine Disrupter;endocrine disrupter exposure;Endocrine disrupting agent;Endocrine Disrupting Chemicals;endocrine disrupting compound;endocrine disruptor exposure;Endocrine Disruptors;Endocrine Gland Secretion;Environment;environmental chemical;Environmental Factor;environmental risk;Environmental Risk Factor;Epidemiology;Epigenetic;Epigenetic Change;Epigenetic Mechanism;Epigenetic Process;Estrogen Receptor 2;Estrogen Receptors;Etiology;exposed human population;Exposure to;Fecundability;Fecundity;Female;Female infertility;Fertility;fetal;folliculogenesis;Functional disorder;Future;Gene Expression;Gene Expression Alteration;gene product;Generations;Genes;Genestein;Genistein;Genisteol;Genital System, Female, Ovary;Genital System, Female, Uterus;Genital System, Male, Prostate;Genital System, Male, Testis;genome-wide;Gonadal structure;Gonadotropins;Gonads;Grant Proposals;Grants, Applications;Growing Follicle;Health;Health Care Costs;Health Costs;Healthcare Costs;heavy metal lead;heavy metal Pb;Hormonal;Hormone Responsive;Hormones;Human;human disease;human exposure;Human Prostate;Human Prostate Gland;human puberty;Human, Adult;Human, General;hydrogen sulfite;hydrosulfite;Hypermethylation;improved;in utero;In Vitro;in vivo;Individual;infertile;Infertility;interest;Intermediary Metabolism;Lead;Link;Litter Size;living system;malignancy;Malignant Neoplasms;Malignant Tumor;Malnutrition;mammary;Mammary gland;Mammary Glands, Human;Man (Taxonomy);Man, Modern;Mediating;Menstrual cycle;Metabolic Processes;Metabolic syndrome;Metabolism;METBL;methoxy DDT;Methoxychlor;Methylation;Modeling;Molecular;Molecular Interaction;Nature;neonatal exposure;neoplasm/cancer;Neuroendocrine;Neuroendocrine System;Neurosecretory Systems;novel;Nutritional Deficiency;obese;obese people;obese person;obese population;Obesity;Organ;Organ Culture;Organ Culture Techniques;Organ System, Cardiovascular;Organism;Ovarian;Ovary;Ovulation;Pathology;pathophysiology;Pb element;Pesticides;Physiopathology;Play;Population;postnatal;Precocious Puberty;Premature aging syndrome;Prevention;Preventive;Prostate;Prostate Gland;Prostatic Gland;Protein Methylation;Proteins;Protocol;Protocols documentation;Prunetol;Psychological Stress;Puberty;Public Health;public health medicine (field);public health relevance;Regulation;Reproduction;reproductive;reproductive axis;Reproductive system;Research;Role;screening;Screening procedure;screenings;Senescence;senescent;social role;Staging;Stress;Superovulation;Surface;System;System, LOINC Axis 4;Testicles;Testing;Testis;Therapeutic;Therapeutic Hormone;Time;transcription factor;treatment days;treatment duration;Treatment Period;unable to bear children;Undernutrition;Uterus;Vascular, Heart;womb;

Abstract: No abstract available.

EPIGENETIC EFFECTS OF DEVELOPMENTAL ENDOCRINE DISRUPTOR EXPOSURE IN THE OVARY

2010-09-10T06:42:00.000-07:00

Start Date: 9/10/2010

Award Number: 1R56ES017059-01A1

NIH Funding Organization: NIEHS

Principal Investigator: UZUMCU, MEHMET

Co-PI: Not Applicable

Award Amount: $154,000

Abstract: No abstract available.

TECH PROJECT

2010-09-01T12:32:00.012-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $195,447

Program(s):

Abstract: No abstract available.

STRUCTURE BIOINFO PROJECT

2010-09-01T12:32:00.011-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $116,239

Program(s): Family;structural genomics;Structure;

Abstract: No abstract available.

NMR STRUCTURE PRODUCTION PROJECT

2010-09-01T12:32:00.010-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $340,661

Program(s): Family;Production;structural genomics;Structure;

Abstract: No abstract available.

STRUCTURAL GENOMICS OF EUKARYOTIC DOMAIN FAMILIES

2010-09-01T12:32:00.009-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $6,954,401

Program(s):

Abstract: DESCRIPTION (provided by applicant): The Northeast Structural Genomics Consortium (NESG) is one of four Large-Scale Centers (LSCs) for structure production funded by the NIH NIGMS Protein Structure Initiative (PSI). The goals of the PSI LSCs are to (i) generate three-dimensional (3D) structures for large numbers of proteins selected using broad biological, genomic, and bioinformatics criteria, together with targets selected from specific biological theme projects, so as to provide significant structural coverage of a large number of protein sequences In nature, (ii) develop and disseminate novel and/or improved technologies for structural biology and bioinformatics, and (iii) make these structures, structure production data, and the associated reagents and technologies publicly available to the worldwide scientific community. In PSI:Biology, the next phase of the PSI program, the NESG will expand Its mission by carrying our collaborative structural genomics projects together with several PSI Consortia for High-Through-Put (HTP) Enabled Structural Biology Partnerships (Biology Partnerships) and associated Program Announcements (PARs). The primary goal of the NESG In PSI:Biology is to provide > 1,100 new 3D protein structures to the Protein Data Bank (PDB) over 5 years, together with extensive raw and processed data, protocols for sample production, structure/function annotations, and thousands of homology models derived from these structures. This will complement the ~ 900 structures deposited by NESG in PSI Phases 1 and 2. In particular, NESG will provide novel 3D structural information useful in modeling large numbers of eukaryotic and human proteins. Our efforts will span five classes of target types: (i) proteins nominated In collaborations to be established with PSI Biology Partnerships, (ii) domain families (referred to as BIG, MEGA, and META families) defined by the central PSI:Biology Target Selection Subcommittee to provide course-grained coverage of large protein domain families; (iii) proteins defined by the NESG Biomedical Theme of 'Networks of Proteins Associated with Human Cancer and Developmental Biology'; (iv) proteins nominated by the general biomedical research community, and (v) proteins selected for specific technology-development goals. Protein targets in the first two of these classes, representing ~ 80% of the overall NESG effort, will be selected in a coordinated process together with the other LSCs and Biology Partnerships so as to maximize biological impact and minimize redundant efforts. The many methods and technologies for structural genomics research developed in this project will provide the next- generation tools for traditional hypothesis-driven biological research, and will thus have powerful and broad impact on the infrastructure for biological science and engineering.

UNIVERSITY OF GEORGIA PROJECT

2010-09-01T12:32:00.008-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: PRESTEGARD, JAMES H

Co-PI: Not Applicable

Award Amount: $165,088

Program(s): Universities;

Abstract: No abstract available.

COLUMBIA PROJECT

2010-09-01T12:32:00.007-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MURRAY, DIANA

Co-PI: Not Applicable

Award Amount: $193,136

Program(s): Family;structural genomics;

Abstract: No abstract available.

NEW TECH DEVELOPMENT PROJECT

2010-09-01T12:32:00.006-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $139,342

Program(s): Development;

Abstract: No abstract available.

UB SUNY PROJECT

2010-09-01T12:32:00.005-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: SZYPERSKI, THOMAS A.

Co-PI: Not Applicable

Award Amount: $437,854

Program(s): Family;structural genomics;

Abstract: No abstract available.

TU MUENCHEN GERMANY PROJECT

2010-09-01T12:32:00.004-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: ROST, BURKHARD

Co-PI: Not Applicable

Award Amount: $165,088

Program(s): Family;Germany;structural genomics;

Abstract: No abstract available.

SPINE/PLIMS PROJECT

2010-09-01T12:32:00.003-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $228,451

Program(s): backbone;Spinal Column;Spine;Vertebral column;

Abstract: No abstract available.

PROTEIN PRODUCTION PROJECT

2010-09-01T12:32:00.002-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $1,326,797

Program(s): gene product;Production;Proteins;

Abstract: No abstract available.

ADMIN CORE PROJECT

2010-09-01T12:32:00.001-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount: $235,051

Program(s): Family;structural genomics;

Abstract: No abstract available.

UNIVERSITY OF GEORGIA PROJECT

2010-09-01T12:32:00.000-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: PRESTEGARD, JAMES H

Co-PI: Not Applicable

Award Amount: $139,675

Program(s): Family;structural genomics;Universities;

Abstract: No abstract available.

MIAMI PROJECT

2010-09-01T12:31:00.002-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: KENNEDY, MICHAEL A.

Co-PI: Not Applicable

Award Amount: $368,387

Program(s):

Abstract: No abstract available.

NEURAL BASIS OF PERCEIVING CONTROL: IMPLICATIONS FOR EMOTION REGULATION

2010-09-01T12:31:00.001-07:00

Start Date: 9/1/2010

Award Number: 1F32DA027308-01A1

NIH Funding Organization: NIDA

Principal Investigator: LEOTTI, LAUREN AIMEE

Co-PI: Not Applicable

Award Amount: $47,606

Program(s): abuse of substances;Affective;Attention;Aversive Stimulus;base;Behavior;Behavioral;Belief;Brain;Brain region;Choice Behavior;Choices and Control;Cognitive;Confounding Factor, Epidemiologic;Confounding Factors (Epidemiology);Confounding Variables;Decision Making;design;designing;doubt;emotion regulation;Emotional;Encephalon;Encephalons;Environment;Exercise;Exercise, Physical;experience;fMRI;Foundations;Functional Magnetic Resonance Imaging;Future;hedonic;Individual;Knowledge;living system;Magnetic Resonance Imaging, Functional;Maintenance;Maintenances;Mediating;Mental disorders;Mental health disorders;mental illness;Motor;MRI, Functional;Nervous;Nervous System, Brain;neural;neural mechanism;neuromechanism;Organism;Outcome;Perception;Physiology;Preparation;Process;Psychiatric Disease;Psychiatric Disorder;psychologic;psychological;psychological disorder;public health relevance;Punishment;recruit;Recruitment Activity;Regulation;relating to nervous system;Research;response;Rewards;Risk;substance abuse;Substance abuse problem;Testing;Uncertainty;Unspecified Mental Disorder;Visual Fields;

Abstract: DESCRIPTION (provided by applicant): Converging evidence suggests the perception of control - or the collective beliefs in one's ability to exert control over the environment and to produce desired results - is integral for an individual's general wellbeing. Research has demonstrated that the presence or absence of perceived control can have a significant impact on the regulation of emotion, behavior, and physiology. In fact, the absence of perceived control is believed to be at the core of many psychiatric disorders, such as substance abuse. However, the psychological and neural mechanisms underlying the experience of control and its impact on emotion regulation are not well understood. The proposed research attempts to fill this gap in our knowledge by examining the cognitive and affective processes mediating the experience of control in three fMRI studies. In the proposed studies, perceived control is operationalized as the opportunity to exercise choice, since choice behavior is the means by which organisms exert control over their environments (e.g. selecting where to focus attention in the visual field). By exploiting this simple, yet fundamental basis of perceiving control, we can determine how the perception of control influences our ability to regulate emotional responses to appetitive and aversive stimuli. In Expt 1, we characterize the hedonic experience of choice (Aim 1) by examining brain activity during the anticipation of choice (vs. non-choice), controlling for potential confounding variables related to decision-making, such as differences in response selection, motor preparation, and uncertainty of outcomes. Expt 2 builds on this choice paradigm to assess how the affective experience of choice is modulated by the valence and risk of the potential outcomes. Expt 3 was designed to determine whether prior experience with control and choice moderates emotional responses to future potential rewards and punishments (Aim 2). To test this hypothesis, we will experimentally manipulate prior choice experience between two subject groups and then examine the behavioral and brain responses to potential monetary rewards and punishments under choice and no-choice conditions. We expect the perception of control, as it is exercised through choice behavior, to recruit corticostriatal brain regions involved in the experience of reward and regulation of negative effect. PUBLIC HEALTH RELEVANCE: The proposed research will provide the foundation for understanding how the presence or absence of the perception of control can influence our ability to regulate emotional responses. Thus, the proposed research has significant implications for understanding the psychological and neural mechanisms related to the origin, maintenance, and potential treatment of many psychiatric disorders and substance abuse.

TECH PROJECT

2010-09-01T12:31:00.000-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: MARCOTRIGIANO, JOSEPH

Co-PI: Not Applicable

Award Amount: $129,440

Program(s):

Abstract: No abstract available.

STRUCTURAL GENOMICS OF EUKARYOTIC DOMAIN FAMILIES

2010-09-01T12:05:00.000-07:00

Start Date: 9/1/2010

Award Number: 3U54GM094597-01S1

NIH Funding Organization: NIGMS

Principal Investigator: MONTELIONE, GAETANO T

Co-PI: Not Applicable

Award Amount:

Program(s): Amino Acid Sequence;Area;base;Base Sequence;Binding (Molecular Function);Bioinformatics;Biological;biological research;Biological Sciences;Biology;Biomedical Research;Cancer Biology;Cells;Cereals;Chemicals;Collaborations;Communities;Complement;Complex;Computer software;computerized data processing;Computing Methodologies;Consensus;Coupling;Crystallization;Data;Databases;Deposition;design and construction;Developmental Biology;Disease;Disulfides;Educational aspects;Educational workshop;Engineering;Escherichia coli;expression vector;Family;Funding;Genomics;Germ Cells;Goals;Grant;Health;Homology Modeling;Human;Hybrids;improved;Information Dissemination;Insect Proteins;Institutes;instrument;knowledge base;Ligands;Light;Literature;Malignant Neoplasms;meetings;method development;Methods;Mission;Modeling;Molecular Chaperones;monomer;National Institute of General Medical Sciences;Nature;new technology;next generation;NIH Program Announcements;novel;Nuclear;Ontario;Peptide Sequence Determination;Phase;Principal Investigator;Process;Production;programs;protein complex;protein expression;protein structure;Protein Structure Initiative;Proteins;Proteome;Protocols documentation;Publications;Reagent;Relaxation;repository;Research;Research Infrastructure;Research Project Grants;Residual state;Resources;Roentgen Rays;Sampling;Scientist;Sequence Analysis;Solubility;Source;structural biology;structural genomics;Structure;success;Synchrotrons;System;Technology;technology development;Tertiary Protein Structure;three dimensional structure;tool;Training;United States National Institutes of Health;Universities;web site;Wheat;X-Ray Crystallography;

Abstract: PUBLIC HEALTH RELEVANCE: The NESG consortium will make 3D structural information a routinely and broadly used component of biological research. The proposed program includes plans for training young scientists. We will provide structural coverage of hundreds of human proteins associated with cancer and developmental biology, as well as coverage of many eukaryotic protein domain families. This discovery research program will generate new technologies and novel specific biomedical hypotheses, along with the information and reagents needed for follow on functional studies, providing the basis for new R01-type research programs.

OCI/UHN PROJECT

2010-09-01T10:33:00.007-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: ARROWSMITH, CHERYL H

Co-PI: Not Applicable

Award Amount: $231,159

Program(s): Family;structural genomics;

Abstract: No abstract available.

OCI/UHN PROJECT

2010-09-01T10:33:00.006-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: ARROWSMITH, CHERYL H

Co-PI: Not Applicable

Award Amount: $246,407

Program(s): Family;structural genomics;

Abstract: No abstract available.

COLUMBIA

2010-09-01T10:33:00.005-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: HENDRICKSON, WAYNE A.

Co-PI: Not Applicable

Award Amount: $1,384,887

Program(s): Family;structural genomics;

Abstract: No abstract available.

COLUMBIA

2010-09-01T10:33:00.004-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: HONIG, BARRY H

Co-PI: Not Applicable

Award Amount: $194,852

Program(s): Family;structural genomics;

Abstract: No abstract available.

PROBING RNA METAL BINDING WITH SPECIFICALLY LABELED RNA

2010-09-01T10:33:00.003-07:00

Start Date: 9/1/2010

Award Number: 3R01GM079760-08S1

NIH Funding Organization: NIGMS

Principal Investigator: JONES, ROGER A

Co-PI: Not Applicable

Award Amount: $99,989

Program(s): 2-Amino-6-Hydroxypurine;3-D structure;3-dimensional structure;3D structure;5' Capped RNA;5' mRNA Cap Structure;6H-Purin-6-one, 2-amino-1,7-dihydro-;adenosine 5'-(pentahydrogen tetraphosphate), 5'-5'-ester with adenosine;adenosine(5')tetraphospho(5')adenosine;analog;Ap4A;AppppA;balance;balance function;Binding;Binding (Molecular Function);Binding Sites;biofilm;Biological;bis(3',5')-cyclic diguanylic acid;bis(5'-adenosyl)tetraphosphate;c-(GpGp);c-di-GMP;Catalytic RNA;cGpGp;Collaborations;Combining Site;Complex;cross-link;crosslink;cyclic diguanylic acid;Detection;diadenosine 5',5'''-P(1),P(4)--tetraphosphate;diadenosine tetraphosphate;Dinucleoside Polyphosphates;Equilibrium;experiment;experimental research;experimental study;Gene Probes, RNA;Gene Products, RNA;Genetic Polymorphism;Goals;Guanine;Health;Human;human disease;Human, General;Hydrogen Bonding;inorganic phosphate;Intervening Sequences;Introns;Investigators;Label;Life;Ligands;Man (Taxonomy);Man, Modern;Messenger RNA;Metal Binding Site;Metals;Methods;Microbial Biofilms;Molecular Interaction;Monitor;mRNA;new approaches;novel approaches;novel strategies;novel strategy;O element;O2 element;Oligo;Oligonucleotides;Oxygen;P(1), P(4)-diadenosine-5'tetraphosphate;pathway;Pathway interactions;Phosphates;Play;Polyamine Compound;Polyamines;polymorphism;Polymorphism (Genetics);Polymorphism, Genetic;Polyphosphates;Preparation;Process;Progress Reports;Public Health;public health medicine (field);purine;Purines;Reactive Site;Research Personnel;research study;Researchers;Ribonucleic Acid;Ribozymes;RNA;RNA Caps;RNA Probes;RNA Splicing;RNA, Messenger;RNA, Non-Polyadenylated;Role;Route;Series;Shapes;Signaling Molecule;Site;Small RNA;social role;Solid;Solutions;Spliceosomes;Splicing;Structure;thiophosphate;three dimensional structure;Titrations;

Abstract: Metals play a crucial role in helping to shape the intricate three-dimensional structure of RNA and tocontrol its many functions that are key to all forms of life. We have found that 15N NMR is an excellent non-perturbing method that is particularly sensitive to the effects of metals that are site-specifically bound tocertain RNA motifs. Titration of 15N specifically labeled oligonucleotides with metals monitored by 15N NMRcan provide unique information about RNA'metal interactions. We have demonstrated specific interactionswith Mg2+ at a tandem GA pair and K+ at a tandem GU pair. Our long term goal is to develop a detailedunderstanding of RNAHigandinteractions. This proposal is focused on RNA*metal interactions. Theexperiments described below will allow us to gather precise information about metal binding to several smallRNA motifs, as well as to somewhat larger ribozyme fragments. The specific aims described here will focuson the synthesis of a variety of 15N specifically labeled RNAs, their 15N NMR in the presence of metals, aswell as other structural and functional studies. Many human diseases involve RNA malfunction, from splicingof mRNA, to its decay pathways, to the pathogenic effects of bacterial biofilms. A deeper understanding oftheir modes of action is critically important for public health. 1. Synthesize and study by 15N NMR three series of small specifically labeled duplexes containing metalbinding sites to identify their essential features. 2. Synthesize and study by 15N NMR several specifically labeled spliceosome and group II intronfragments to explore metal interactions that are critical for the mRNA splicing process. 3. Synthesize specifically labeled capped RNA by a novel approach using two solid supports. 4. Study by 15N NMRmultilabeled capped RNAs and multilabeledAp4A to probe purine metal binding andto identify the specificphosphate oxygen atoms that also interact with metals. 5. We will synthesize specifically labeled versions ofc-di-GMP to determine by NMR (1H, 13C, 31P, and15N) full structures of the metal dependent complexes present in solution; will use15Nchemical shift changesto monitor metal interactions at the core; and will study the equilibrium among the structures as a function ofmetal and concentration, including titrations ofMg2*/K* mixtures and addition of polyamines.

COLUMBIA PROJECT

2010-09-01T10:33:00.002-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: HUNT, JOHN FRANCIS

Co-PI: Not Applicable

Award Amount: $246,404

Program(s): Family;structural genomics;

Abstract: No abstract available.

HAUPTMAN WOODWARD PROJECT

2010-09-01T10:33:00.001-07:00

Start Date: 9/1/2010

Award Number: 1U54GM094597-01

NIH Funding Organization: NIGMS

Principal Investigator: DETITTA, GEORGE T

Co-PI: Not Applicable

Award Amount: $470,036

Program(s):

Abstract: No abstract available.

REGULATORY AND RECOGNITION MECHANISMS OF TRANSLOCASE ATPASE SECA

2010-09-01T10:33:00.000-07:00

Start Date: 9/1/2010

Award Number: 3R01GM073854-05S1

NIH Funding Organization: NIGMS

Principal Investigator: KALODIMOS, CHARALAMPOS

Co-PI: Not Applicable

Award Amount: $115,500

Program(s): Adenosine Triphosphatase;Adenosinetriphosphatase;adhesin;Adhesins, Bacterial;Affect;anti-bacterial;Anti-Bacterial Agents;antibacterial;Antibacterial Agents;ATP phosphohydrolase;ATPase;Bacterial Adhesins;bacterial disease;Bacterial Gene Proteins;Bacterial Infections;Bacterial Proteins;base;Binding;Binding (Molecular Function);Binding Sites;Biochemical;body system, allergic/immunologic;Calorimetry;Chaperone;Characteristics;Combining Site;Complex;conformation;conformational state;Coupled;Couples;Data;design;designing;Development;Disease;disease/disorder;Disorder;DNA Helicases;DNA unwinding enzyme;DNA Unwinding Proteins;Expenditure;Family;flexibility;gene product;Gene Products, Bacterial;Goals;helicase;Human;Human, General;Hydrolysis;Immune system;inhibitor;inhibitor/antagonist;insight;Investigators;Label;Length;Ligands;Link;Man (Taxonomy);Man, Modern;Maps;Metabolic;Methods;Modeling;Molecular;Molecular Chaperones;Molecular Configuration;Molecular Conformation;Molecular Interaction;Molecular Stereochemistry;Motor;mutant;N-terminal;NH2-terminal;NMR Spectroscopy;nuclear magnetic resonance spectroscopy;Nucleotides;organ system, allergic/immunologic;Peptide Signal Sequences;polypeptide;Process;programs;Programs (PT);Programs [Publication Type];Property;Property, LOINC Axis 2;protein signal sequence;Proteins;Reactive Site;Research;Research Personnel;Researchers;Resolution;secretion process;secretory protein;Signal Peptide;Signal Sequences;Signal Sequences, Peptide;Site;Solutions;Spectroscopy, NMR;Spin Labels;Structure;success;Surface;System;System, LOINC Axis 4;Thermodynamic;Thermodynamics;Titrations;Toxin;translocase;Variant;Variation;

Abstract: DESCRIPTION (provided by applicant): SecA is a highly conserved and essential helicase-like motor protein of the bacterial Sec translocase machinery. SecA recognizes secretory proteins and couples their transport through the transmembrane SecYEG channel with the expenditure of metabolic energy provided by ATP binding and hydrolysis. Our long term goals are to (i) elucidate the regulatory properties of the helicase motor of SecA and understand how they are controlled during the ATP catalytic cycle, (ii) delineate the recognition mechanisms that enable SecA to differentiate between secretory and non-secretory proteins, and (iii) provide the structural basis of the interaction of SecA with all of its translocation ligands. The hypothesis behind the proposed research is that SecA (i) switches to a highly flexible state during its activation, wherein disorder-order transitions regulate the properties of the motor, and (ii) accomplishes the promiscuous signal sequence recognition by using alternate binding sites. Based on preliminary observations, the specific aims are designed to provide atomic-resolution insight into (i) how SecA switches among functional conformational states during the catalytic cycle, (ii) the recognition mechanisms of the promiscuous binding of signal sequences, and (iii) the interaction of SecA with preprotein substrates, the SecB chaperone and SecYEG. We aim to: 1. Delineate the conformational and dynamic properties of SecA's motor during the ATPase cycle, to understand the underlying mechanisms of the motor functionality. 2. Elucidate the molecular determinants of the promiscuous signal peptide recognition by SecA, to understand how a single translocase system is able to recognize and secrete a wide variety of protein substrates. 3. Characterize by NMR the interaction of SecA with its translocation partners (preprotein, SecB, SecYEG), to understand how the cascade of the binding phenomena results in the assembly of the complete translocase machinery. Upon bacterial infection, SecA becomes responsible for the secretion of hundreds of protein substrates, among them several toxins and adhesins that affect the human immune system. A long-term goal of the proposal is to provide the appropriate physicochemical basis towards development of antibacterial inhibitors targeting SecA.