# projects

application_id: 7769896
project_number: 5R01DC007176-06
project_title: Neurotrophin regulation of taste system development
administering_ic: NIDCD
award_notice_date: 2010-02-03
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2011-04-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-01
project_abstract:
DESCRIPTION (provided by applicant): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. The present research is designed to investigate gustatory innervation in support of two long terms goals: 1) to determine the cellular and molecular mechanisms that allow gustatory neurons to innervate the correct target (taste buds) with a specific mount of innervation and 2) to determine if and/or how these connections are important for central gustatory development or taste function. The proposed project focuses on the role of neurotrophins in regulating gustatory neuron number and peripheral and central targeting during embryonic development. It is known that the number of gustatory ganglion neurons that will exist at birth to innervate taste buds on the tongue and palate is somehow determined by brain-derived neurotrophic factor (BDNI0 and neurotrophin-4 (NT4). However the mechanism(s) by which BDNF and NT4 regulate innervation are unknown and could involve any number of different developmental processes during numerous different embryonic stages. The proposed studies combine in situ hybridization cell counting tract tracing immunohistochemistry and SEM in gene knockout mice to: 1) determine when and where the embryonic taste system is exposed to BDNF and NT4 2) determine when BDNF and NT4 regulate gustatory neuron number and whether this regulation is accomplished by reducing proliferation or by increasing cell death 3) determine whether BDNF and/or NT4 is required for initial target invasion and 4) determine if BDNF and/or NT4 regulate the central distribution of tongue and palatal sensory afferents. Together these studies test the hypotheses that: 1) NT4 is expressed along gustatory fiber projection pathways and regulates gustatory neuron survival before initial innervation of peripheral and central targets and 2) BDNF is expressed in gustatory epithelia and regulates neuron survival after initial peripheral and central target innervation. Because these experiments examine how neurotrophins regulate the amount and location of sensory innervation this project has important implications for the potential therapeutic use of these powerful signaling molecules in controlling neural regeneration following injury.

project_terms:
Adult;Afferent Neurons;Axon;Biological Assay;Birth;Brain-Derived Neurotrophic Factor;Bromodeoxyuridine;Cell Count;Cell Cycle;Cell Death;Cell Nucleus;Cessation of life;Computer Systems Development;Development;Developmental Process;Embryo;Embryonic Development;Epithelium;Fiber;Fungiform Papilla;Future;Ganglia;Genes;Genotype;Goals;Growth;Hybrids;Immunohistochemistry;In Situ Hybridization;Injury;Knockout Mice;Knowledge;Label;Location;Maintenance;Mediating;Microscopy Electron Scanning;Molecular;Mus;Myxoid cyst;Nerve Fibers;Nerve Regeneration;Neurites;Neuronal Differentiation;Neurons;Oral cavity;Palate;Pathway interactions;Pattern;Peripheral;Principal Investigator;Process;Regulation;Research;Robin bird;Role;Sensory;Sensory Ganglia;Signal Pathway;Signaling Molecule;Staging;Structure of geniculate ganglion;System;Taste Buds;Taste Perception;TdT-Mediated dUTP Nick End Labeling Assay;Testing;The Sun;Therapeutic Uses;Time;Tongue;Withdrawal;axon regeneration;design;ganglion cell;nerve supply;neural circuit;neuron development;neuron loss;neurotrophic factor;neurotrophin 4;postnatal;programs;receptor;research study;response;synaptogenesis;tongue papilla


application_id: 7769893
project_number: 5R21AI082143-02
project_title: Functional role of a host metabolic enzyme in viral replication
administering_ic: NIAID
award_notice_date: 2010-01-22
opportunity_number: PA-06-181
application_type: 5
activity_code: R21
ic: AI
serial_number: 082143
program_official: PARK, EUN-CHUNG
project_start_date: 2009-02-13
project_end_date: 2012-01-31
study_section: Special Emphasis Panel[ZRG1-IDM-P(91)S]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Plus-stranded (+)RNA viruses infect all kind of species and cause many serious diseases in humans animals and plants leading to major losses in food production and representing significant risk to human health and welfare. The least understood aspect of virus - host interaction is the contribution of the host cells. Due to their small genome sizes RNA viruses greatly depend on the co-opted host proteins during replication. In spite of the significance of host proteins in viral pathogenesis our current knowledge on host factors co- opted for virus replication is surprisingly incomplete. The relatively slow progress in this area is mainly due to the lack of tractable virus - host systems. Therefore development of highly tractable model systems such as Tomato bushy stunt tombusvirus (TBSV) and the yeast model host has promoted rapid and significant progress in our understanding of the roles of host factors in viral replication. The PI will use TBSV which is currently one of the most advanced among viral systems to progress rapidly in understanding the mechanism of RNA replication and the role of the host proteins. Indeed the PI's research using a systems biology approach including genome-wide screens and proteomics approaches has led to a remarkably extensive data set containing close to 200 host proteins affecting tombusvirus replication evolution and pathogenesis. Moreover using novel cell-free system with a yeast extract capable of supporting authentic tombusvirus replication in combination with cell biology approach allows the PI to dissect the actual functions of the identified host proteins in tombusvirus replication. The PI has shown that the discoveries made in yeast are also relevant in the native host plant thus validating the approach. These advances have put tombusviruses into the forefront of RNA viruses as a system of choice to further our understanding how RNA viruses "re-program" the infected cells. The PI's work will likely lead to major new insights into RNA virus replication and viral pathogenesis. Additional advantage of the similarity of TBSV replicase proteins to proteins of important pathogens such as Hepatitis C virus (HCV) dengue virus West Nile virus and other Flaviviruses and Pestiviruses. Collectively the major advances with TBSV allow the PI to conduct experiments on the roles of host factors that are feasible with TBSV and will stimulate development of new approaches for studying RNA replication and host - pathogen interactions for important human pathogens. This proposal focuses on a key host factor present in the viral replicase complex namely GAPDH (glyceraldehyde-3-phosphate dehydrogenase) metabolic protein that binds to the viral RNA and essential for tombusvirus replication in yeast and in the native host plant. The proposed work will unravel the multiple functions of GAPDH in the viral replicase. These studies by the PI will certainly lead to further significant advances on the essential role of the host in RNA virus replication evolution and virus-host interaction. Accordingly GAPDH has been shown to bind to AU-rich sequences present in various RNA viruses including hepatitis A virus (HAV) hepatitis C virus and human parainfluenza virus type 3. The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect all types of living organisms. (ii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication. (iii) This research is expected to lead to groundbreaking new discoveries in viral RNA replication. The highly tractable in vitro and in vivo TBSV system developed by the PI could prove highly beneficial to studies of other less amenable RNA viruses. The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication host-virus interactions and the adaptation of viruses to their hosts. PUBLIC HEALTH RELEVANCE: RNA viruses which pose significant risks to human health and cause major losses for agriculture depend heavily on host factors to replicate in infected cells. The roles of the subverted host factors in virus replication are currently poorly understood due to the lack of tractable virus-host systems. The PI will use the powerful Tomato bushy stunt virus (TBSV)-yeast model system to dissect the role of a key co-opted host factor namely GAPDH (glyceraldehyde-3-phosphate dehydrogenase) metabolic protein that binds to the viral RNA and essential for tombusvirus replication in yeast and in the native host plant. The proposed work will lead to deeper understanding of the role of the host in RNA virus infections and likely open new antiviral strategies.

project_terms:
Affect;Agriculture;Animals;Antiviral Agents;Area;Binding (Molecular Function);Biochemical;Biological Assay;Biological Models;Cataloging;Catalogs;Cell-Free System;Cells;Cellular biology;Complex;Data;Data Set;Dengue Virus;Development;Disease;Enzymes;Evolution;Flavivirus;Food;Genes;Genome;Glyceraldehyde-3-Phosphate Dehydrogenases;Health;Hepatitis A Virus;Hepatitis C virus;Human;In Vitro;Integration Host Factors;Knowledge;Lead;Life;Metabolic;Organism;Para-Influenza Virus Type 3;Pathogenesis;Pestivirus;Plants;Play;Production;Protein Binding;Proteins;Proteomics;RNA Virus Infections;RNA Viruses;RNA replication;RNA-Directed RNA Polymerase;Recruitment Activity;Research;Risk;Role;Social Welfare;Societies;System;Systems Biology;Tomatoes;Tombusvirus;Viral;Viral Pathogenesis;Viral Physiology;Virus;Virus Replication;West Nile virus;Work;Yeast Model System;Yeasts;base;genome wide association study;in vivo;insight;novel;novel strategies;pathogen;programs;public health relevance;replicase;research study;tomato bushy stunt virus;transcription factor;viral RNA;virus host interaction;yeast genetics

public_health_relevance:
RNA viruses which pose significant risks to human health and cause major losses for agriculturedepend heavily on host factors to replicate in infected cells. The roles of the subverted host factors invirus replication are currently poorly understood due to the lack of tractable virus-host systems. The PIwill use the powerful Tomato bushy stunt virus (TBSV)-yeast model system to dissect the role of a keyco-opted host factor namely GAPDH (glyceraldehyde-3-phosphate dehydrogenase) metabolic proteinthat binds to the viral RNA and essential for tombusvirus replication in yeast and in the native host plant.The proposed work will lead to deeper understanding of the role of the host in RNA virus infections andlikely open new antiviral strategies.


application_id: 7769840
project_number: 5R01AR055246-03
project_title: Circadian rhythms and skeletal muscle
administering_ic: NIAMS
award_notice_date: 2010-02-26
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 055246
program_official: BOYCE, AMANDA T
project_start_date: 2008-03-01
project_end_date: 2013-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 8263548
contact_pi: ESSER, KARYN A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Circadian rhythms have long been known to influence behavioral and biological processes such as physical activity and feeding behavior. The fundamental importance of this system which works to link physiology with the day/night cycle is underscored by its presence in every known species and the growing evidence linking alterations in core clock function and diseases such as cancer diabetes and mental health.   
  
Recent studies from our laboratory have shown that mutations of the canonical circadian genes Clock and Bmal1 dramatically disrupt muscle function. This is the first genetic evidence linking skeletal muscle function to circadian rhythms. Expression profiling studies of skeletal muscle over 48 hours identified that MyoD is a circadian gene. Molecular experiments went on to demonstrate that the MyoD promoter is directly bound and regulated by the core clock factors CLOCK and BMAL1.   
  
The studies outlined in this proposal combine molecular cell biological and biophysical approaches to understand the mechanisms by which the core clock mechanism is regulated in skeletal muscle and how loss of this rhythm leads to altered MyoD expression and loss of muscle function. The hypotheses for this proposal are 1) Synchronization of core clock gene expression in skeletal muscle requires intact innervation 2) Muscle specific mutations of Bmal1 or Clock will be sufficient to cause arrhythmic MyoD expression and muscle dysfunction 3) Loss of maximal force capacity/specific tension in muscle of circadian clock- compromised mice is due to decreased actin:myosin interaction resulting from disruption of sarcomeric structure and/or altered stoichiometry of myofilament proteins.   
  
The results of the experiments outlined in this proposal have significant implications for maintenance of muscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia and problems associated with metabolic diseases such as insulin resistance. In addition our understanding of circadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cord injury patients and people that are exposed to prolonged periods of bed rest. PUBLIC HEALTH RELEVANCE. The results of the proposed work will determine the role of the biological clock in maintaining normal skeletal muscle structure and function. The findings have significant implications for maintenance of muscle with an impact on our understanding and treatment of sarcopenia muscle wasting/cachexia and problems associated with metabolic diseases such as insulin resistance. In addition our understanding of circadian regulation of skeletal muscle will have likely applications for rehabilitation therapies for spinal cord injury patients and people that are exposed to prolonged periods of bed rest.

project_terms:
Actinin;Actins;Aging;Bed rest;Behavior;Binding (Molecular Function);Biological;Biological Clocks;Biological Process;Brain;Cachexia;Cell physiology;Cells;Chronic Disease;Circadian Rhythms;Clinical;Complement;Development;Diabetes Mellitus;Disease;Down-Regulation;Electron Microscopy;Enhancers;Feedback;Feeding behaviors;Fiber;Fluorescence Microscopy;Functional disorder;Gel;Gene Expression;Gene Proteins;Gene Targeting;Genes;Genetic;Genetic Transcription;Hour;Hypothalamic structure;In Situ Hybridization;Insulin Resistance;Intrinsic drive;Knock-out;Laboratories;Lesion;Link;Liver;Maintenance;Malignant Neoplasms;Mammals;Measures;Mechanics;Mental Health;Metabolic Diseases;Microfilaments;Molecular;Molecular Profiling;Mus;Muscle;Muscle Fibers;Muscle function;Mutant Strains Mice;Mutation;Myosin ATPase;Myosin Heavy Chains;Normal Cell;Operative Surgical Procedures;Pattern;Peripheral;Physical activity;Physiology;Promotor (Genetics);Protein Isoforms;Proteins;Regulation;Rehabilitation therapy;Role;Skeletal muscle structure;Spinal cord injury patients;Structure;System;Time;Tissues;Translations;Work;behavior influence;circadian pacemaker;connectin;cryptochrome;design;extensor digitorum;mutant;nebulin;nerve supply;novel;public health relevance;rehabilitation strategy;research study;sarcopenia;skeletal;stoichiometry;suprachiasmatic nucleus;transcription factor;wasting


application_id: 7769571
project_number: 5R01AI065974-05
project_title: Molecular pathogenesis of Francisella tularnesis
administering_ic: NIAID
award_notice_date: 2010-01-21
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 065974
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2006-03-01
project_end_date: 2013-02-28
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The causative agent of the fatal disease Tularemia Francisella tularensis (Ft) is a gram negative highlyinfectious intracellular bacterium that is classified as a Category A Select Bioterrorism Agent. Intracellularreplication of Ft within macrophages is essential for disease manifestation. It is rather astonishing therelative paucity of knowledge about the molecular and cellular aspects of pathogenesis of this versatile andextremely virulent pathogen. Our preliminary data indicate that upon entry into macrophages Ft-containingphagosome (FCP) evades lysosomal fusion. The organism escapes from the phagosome into the cytoplasmby 2-12h post-infection. Our hypothesis is that specific modes of entry of Ft into macrophages allow theorganism to modulate biogenesis of its phagosome by specific exported bacterial effectors into a niche thatdoes not fuse to the lysosomes and allow subsequent escape of the organism into the cytoplasm where itreplicates. To test this hypothesis our specific aims are: I. To dissect the cell biology of intracellular F.tularensis and the unique mechanisms that halt phagosome biogenesis at a non-acidified late endosome-likestage. II. To identify mutants defective in arresting phagosome biogenesis and escape into the cytoplasm. . To characterize the bacterial factors involved in arresting phagosome biogensis and escape into thecytoplasm. Significance: Pathogenesis of the Category A Select Bioterrorism Agent Ft is one of the leaststudied and understood among intracellular bacterial pathogens. Understanding how this organism exploitsmacrophages for proliferation and disease manifestation is fundamental to our knowledge of tularemia. Thebacterial effectors involved in exploiting the macrophage are potential targets for treatment as well aspotential vaccine candidates.

project_terms:
Abbreviations;Adenylate Cyclase;Attenuated Vaccines;Bacteria;Biogenesis;Biological;Bioterrorism;Categories;Cellular biology;Cytoplasm;Data;Degradation Pathway;Disease;Francisella;Francisella tularensis;Human;Infection;Knowledge;Lactate Dehydrogenase;Lysosomes;Molecular;Nuclear;Organism;Ovalbumin;Pathogenesis;Pathogenicity Island;Phagosomes;Relative (related person);Route;Staging;Testing;Texas red;Therapeutic Intervention;Transmission Electron Microscopy;Tularemia;Vacuole;Virulent;design;late endosome;lysosomal proteins;macrophage;monocyte;mutant;novel;pathogen;pathogenic bacteria;vaccination strategy;vaccine candidate;weapons


application_id: 7768413
project_number: 5R03DA025948-02
project_title: Development of Antagonists for M5 Muscarinic Acetylcholine Receptor
administering_ic: NIDA
award_notice_date: 2010-01-15
opportunity_number: PAS-07-327
application_type: 5
activity_code: R03
ic: DA
serial_number: 025948
program_official: HILLERY, PAUL
project_start_date: 2009-02-15
project_end_date: 2013-01-31
study_section: Special Emphasis Panel[ZRG1-MNPS-C(09)S]
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Drug abuse continues to cause great societal burden. Despite intensive efforts effective pharmacotherapeutic treatments for drug dependence are still lacking indicating new strategies and targets are needed. A growing body of evidence supports our hypothesis that selective antagonism at the M5 muscarinic acetylcholine receptor (mAChR) represents a novel target for the treatment of drug dependence. The rewarding effects of most drugs of abuse are believed to be mediated by the mesolimbic dopaminergic pathway projecting from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to the nucleus accumbens (NAc) and striatum respectively. The M5 receptor is the only subtype localized on dopaminergic neurons of the VTA and SNc. Microinfusion of the non-selective mAChR antagonist scopolamine into the VTA or SNc substantially reduces DA release in NAc or striatum respectively. Although there are no selective M5 receptor antagonists currently available behavioral studies using mice lacking functional M5 receptors have shown a reduction in reward and withdrawal responses following morphine and cocaine administration and also a reduction in the rate of cocaine self-administration. These results show a role of the M5 receptor in modulating cocaine and opiate addiction. Furthermore co-administration of scopolamine with cocaine reduces self-administration of cocaine by rhesus monkeys and scopolamine has been shown to be effective for detoxification of heroin addicts in clinical studies. We reasoned that the effectiveness of scopolamine is due to antagonism of the M5 receptor; however the involvement of other subtypes can not be ruled out. To date the physiological and pharmacological roles of the M5 mAChR are still obscure and research has been hampered by the lack of subtype-selective M5 ligands. The objective of this application is to discover potent and selective M5 receptor antagonists which in our long-term goal can be developed into medical treatments for drug dependence. We expect that compounds developed in this research project will also serve as pharmacological tools useful for studying physiological functions of the M5 receptor. New compounds will be designed and synthesized based on the structural scaffold of literature reports on low selectivity and low potency M5 antagonists. Compounds synthesized will be characterized for receptor binding affinities in recombinant Chinese hamster ovarian (CHO- K1) cells expressing the individual human muscarinic receptor subtypes ability to inhibit carbachol-induced phosphatidylinositol (PI) hydrolysis in CHO cells expressing hM5 receptors and by inhibition of oxotremorine- evoked dopamine release from superfused rat striatal slices (functional assay). PUBLIC HEALTH RELEVANCE: These studies will pioneer the development of selective M5 receptor antagonists which have potential as efficacious treatments for drugs of abuse.

project_terms:
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole;Affinity;Behavioral;Binding (Molecular Function);Biological Assay;Carbachol;Carboxylic Acids;Cells;Chinese Hamster;Chinese Hamster Ovary Cell;Clinical Research;Cocaine;Corpus striatum structure;Development;Dopamine;Drug Addiction;Drug Metabolic Detoxication;Drug abuse;Effectiveness;Esters;Evaluation;Exhibits;Goals;Heroin;Human;Hydrolysis;Individual;Ligands;Literature;Macaca mulatta;Measures;Mediating;Medical;Membrane;Modification;Morphine;Mus;Muscarinic Acetylcholine Receptor;Muscarinic M1 Receptor;Muscle Rigidity;Nucleus Accumbens;Opiate Addiction;Ovarian;Oxotremorine;Pathway interactions;Phosphatidylinositols;Physiological;Rattus;Receptor Inhibition;Recombinants;Reporting;Research;Research Project Grants;Rewards;Role;Scopolamine;Self Administration;Slice;Substantia nigra structure;Testing;Ventral Tegmental Area;Withdrawal;analog;base;design;dopaminergic neuron;drug of abuse;novel;pars compacta;pharmacophore;public health relevance;receptor;receptor binding;receptor function;response;scaffold;tool

public_health_relevance:
These studies will pioneer the development of selective M5 receptor antagonists which have potential asefficacious treatments for drugs of abuse.


application_id: 7766973
project_number: 5R01DK080901-02
project_title: Glucocorticoids and endocannabinoids in vagal complex
administering_ic: NIDDK
award_notice_date: 2009-12-07
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 080901
program_official: MALOZOWSKI, SAUL N
project_start_date: 2009-02-15
project_end_date: 2013-11-30
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The experiments in this research grant proposal will identify the cellular and synaptic effects of endogenous cannabinoid (eCB) ligands and of glucocorticoid-induced release of eCBs in the dorsal motor nucleus of the vagus (DMV). Neurons in the DMV regulate parasympathetic output to most of the subdiaphragmatic viscera and therefore critically control feeding digestion glucose and insulin secretion and other metabolic functions. Their activity is largely controlled by synaptic input to the DMV which is modulated by locally released chemicals and circulating hormones. Regulation of DMV neurons by cannabinoids vanilloids and glucocorticoids has been suggested; when applied centrally these compounds profoundly alter parasympathetic function. Several eCB ligands which are thought to be released from cell membranes in a retrograde fashion activate both cannabinoid type 1 receptors (CB1R) and transient receptor potential vanilloid type 1 (TRPV1). In the DMV activation of TRPV1 enhances neurotransmitter release whereas CB1R tends to inhibit synapses. Both effects occur by activation of receptors on presynaptic terminals. Preliminary evidence suggests that eCB ligands are released from DMV neurons and that glucocorticoids or depolarization can induce this release. Thus eCB activity in the DMV may modulate both TRPV1 and CB1R activity. Neither the type(s) of eCB ligands released the effects of most eCB ligands on synaptic activity nor the trigger or mechanism of eCB release in the DMV are known. We will use whole-cell patch-clamp recordings from DMV neurons in brainstem slices to identify effects of eCB ligands on cellular activity in the DMV and will also identify the compounds released by cells in the area using pharmacological and biochemical methods. The experiments will be guided by three specific aims: 1) Differentiate effects of eCB ligands on CB1R and TRPV1 in the DMV; 2) Determine the eCB involvement in mediating rapid effects of glucocorticoids on local circuitry in the DMV; and 3) Identify the cellular pathway of the glucocorticoid effect. We will test the hypotheses that eCBs alter TRPV1 and CBR1 activity in the DMV in specific and predictable spatial temporal functionally relevant and activity-dependent patterns and that glucocorticoids induce eCB release from DMV cells by acting at membrane-bound G protein-coupled receptors on DMV neurons. Drugs based on the eCB system are being investigated for therapeutic use in a variety of nervous system pathologies including disorders related to feeding digestion and obesity. Glucocorticoids which release eCBs in some systems are widely prescribed and are also released by stressful stimuli. Results of these studies will be critical to predicting and understanding how these compounds interact with each other and affect parasympathetic function. Possible translational benefits also exist because of the benefit in controlling eCB levels in the vagal system of patients with elevated glucocorticoids. PUBLIC HEALTH RELEVANCE Endogenous cannabinoid compounds have particularly complex actions in the area of the brainstem most responsible for maintaining functions of organ systems and a number of drugs therapies based on altering these compounds in the brain are being developed without knowledge about their effects in this critical brain area. The experiments in this research grant proposal will identify the characteristics of these drugs how they are released by glucocorticoid hormones and what actions they have on the neurons. Results of these studies will be critical for predicting and understanding how these compounds interact to affect digestive functions and they will also be applicable to multiple other neuronal systems.

project_terms:
Accounting;Affect;Agonist;Anxiety;Applications Grants;Area;Binding (Molecular Function);Biochemical;Blood;Brain;Brain Stem;Calcium;Cannabinoids;Cell membrane;Cells;Characteristics;Complex;Data;Dependence;Digestion;Disease;Endocannabinoids;Enzymes;Ethanolamines;G-Protein-Coupled Receptors;Glucocorticoids;Glucose;Glutamates;Hormones;Hypertension;Hypothalamic structure;Knowledge;Ligand Binding;Ligands;Lipase;Mediating;Membrane;Metabolic;Methods;Moods;Movement;Multiple Sclerosis;Nervous system structure;Neurons;Obesity;Output;Pathology;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Phosphotransferases;Presynaptic Terminals;Rattus;Receptor Activation;Reflex action;Regulation;Research Project Grants;Slice;Stimulus;Synapses;System;Testing;Therapeutic Uses;Time;Transgenic Mice;Vanilloid;Viscera;Visceral;anandamide;base;body system;cannabinoid receptor;chemical release;dorsal motor nucleus;endogenous cannabinoid system;feeding;gamma-Aminobutyric Acid;insulin secretion;neurotransmission;neurotransmitter release;painful neuropathy;patch clamp;postsynaptic;public health relevance;receptor;research study;response


application_id: 7766941
project_number: 5R01AI049367-09
project_title: Blockade of host apoptosis by Toxoplasma gondii
administering_ic: NIAID
award_notice_date: 2010-01-14
opportunity_number: PA-04-119
application_type: 5
activity_code: R01
ic: AI
serial_number: 049367
program_official: WALI, TONU M
project_start_date: 2001-03-01
project_end_date: 2012-02-28
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Toxoplasma gondii infected cells exhibit a profound blockade of apoptosis that manifests at multiple points inthe apoptotic cascade. Our studies have shown an essential role for the hose transcription factor NFKB in theestablishment of the parasite-directed anti-apoptotic state. Activation of NFxB by diverse cellular pathwaysoccurs via the phosphorylation of specific Ser residues on its inhibitor kB. This phosphorylation event iscatalyzed by a unique cellular kinase complex defining the kB kinase signalosome (IKK). In T.gondiiinfected cells Phospho-kB localizes at the parasitophorous vacuole membrane (PVM) the oraganelledefining the intracellular replication-permissive niche. The detection of P-kBat the PVM in cells devoid of allIKK activity suggested the presence of a parasite-encoded kinase (TglKK) is responsible. We find just suchan activity in parasite extracts and PVM-enriched fractions. We focus here on identifying the gene(s)encoding the TglKK activity and examining its role both in NFxB activation and the blockade of apoptosis.Our data indicate that TglKK activity alone is not sufficient to drive NFKB gene expression in cells withdefects in IKK. Initial studies examining the temporal nature of NFxB activation reveal a biphasic pattern ofNFKB expression suggesting independent but temporally linked contributions of the host and parasite IKKactivities. We propose to use host cell lines with specific lesions in patheways upstream of IKK as well ascell lines "locked" into a defined expression profile to better characterize the pertinent cellular pathwayssubverted by T.gondii infection. Finally we have developed a genetic screen to identify parasite genesinvolved in NFKB activation. Initial results bear out the evidence that the mechanism to subvert NFKB ismultifactorial. Identification of these parasite genes and the elucidation of their roles in NFKB activation in thecontext of the studies on the cellular components will help define the signaling networks subverted by theparasite. Dissection of these pathways is particularly important given the targets of NFKB many of thecytokines implicated both in the pathogenesis of acute toxoplasmosis and the development of immunity tothe parasite.

project_terms:
Acute;Apoptosis;Apoptotic;Arts;Biochemical Genetics;Biological;Biphasic Pattern;Cell Line;Cells;Complex;Cytoplasm;Data;Defect;Detection;Development;Dissection;Event;Exhibits;Gene Expression;Generations;Genes;Genetic Screening;I Kappa B-Alpha;IkappaB kinase;Immunity;Infection;Knock-out;Lesion;Link;Maps;Membrane;Molecular;Molecular Profiling;NF-kappa B;Nature;Organelles;Parasites;Pathogenesis;Pathway interactions;Phosphorylation;Phosphotransferases;Protein Isoforms;Regulation;Role;Signal Transduction;Technology;Toxoplasma gondii;Toxoplasmosis;Ursidae Family;Vacuole;base;cytokine;inhibitor/antagonist;mutant;pathogen;research study;success;transcription factor


application_id: 7766939
project_number: 5F32HL095281-02
project_title: ACE2 in Hypercholesterolemia and Angiotensin II-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2010-02-26
application_type: 5
activity_code: F32
ic: HL
serial_number: 095281
program_official: MEADOWS, TAWANNA
project_start_date: 2009-02-01
project_end_date: 2012-01-31
study_section: Special Emphasis Panel[ZRG1-F10-H(21)L]
contact_pi_person_id: 9412060
contact_pi: THATCHER, SEAN ERIC
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-02-01
project_abstract:
DESCRIPTION (provided by applicant): Angiotensin converting enzyme-2 (ACE-2) catabolizes angiotensin II (Angll) to form the vasodilator Angiotensin1-7 (Ang1-7). The sponsor's laboratory has demonstrated that Angll increases atherosclerotic lesions and induces formation of abdominal aortic aneurysms (AAAs) in hyperlipidemic mice. Preliminary data generated by the applicant demonstrates ACE2 expression in macrophages and localization to atherosclerotic and AAA lesions. ACE2 has been implicated in blood pressure regulation however it is unclear whether dysregulated ACE2 contributes to Angll-induced vascular diseases. The long term objective of this study is to understand the role of ACE-2 in the development of atherosclerotic lesions and in Angll-induced AAA formation. Since macrophages are key mediators in developing atherosclerotic lesions and AAAs we will focus on macrophage ACE2 as a regulator of Angll-induced vascular diseases. The following specific aims will address our goal: 1) determine the effect of whole-body and/or bone marrow-derived ACE2 deficiency on hypercholesterolemia-induced atherosclerosis in low density lipoprotein receptor (LDLr) -/- mice; 2) determine the effect of whole body and/or bone marrow-derivedACE2 deficiency on Angll-induced AAAs in LDLr-/- mice. In aim 1 we will first examine the effect of ACE2 deficiency in LDLr-/- mice on high fat diet-induced atherosclerosis. Additional studies will use chimeric LDLr-/- mice repopulated with bone marrow from ACE2-/y mice to define the role of leukocytes in hypercholesterolemia-induced atherosclerosis. Mechanisms for ACE2 regulation by hypercholesterolemia will be examined using mouse peritoneal macrophages. In aim 2 we will define effects of ACE2 deficiency in LDLr-/- mice on Angll-induced AAAs and in follow up studies determine effects of ACE2 deficiency in bone marrow-derived cells on AAA formation. The relevance of the proposed research is to define mechanisms contributing to the development of two different types of common vascular diseases that negatively impact the health of millions of Americans. Identification of a regulatory role of the enzymeACE2 in Angll-induced atherosclerosis and AAAs may lead to novel medical therapies for these cardiovascular diseases.

project_terms:
Abdominal Aortic Aneurysm;Address;American;Angiotensin II;Angiotensin Type 1a Receptor;Angiotensinogen;Arterial Fatty Streak;Atherosclerosis;Blood Pressure;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;C57BL/6 Mouse;Cardiovascular Diseases;Cells;Data;Development;Diet;Fatty acid glycerol esters;Follow-Up Studies;Goals;Health;Homologous Gene;Infusion procedures;Laboratories;Lead;Lesion;Leukocytes;Low Density Lipoprotein Receptor;Mediator of activation protein;Medical;Mus;Pathology;Peptides;Peptidyl-Dipeptidase A;Peritoneal Macrophages;Play;Regulation;Renin;Research;Role;Signal Transduction;Source;Vascular Diseases;Vasodilator Agents;Work;blood pressure regulation;cardiovascular disorder therapy;cell type;hypercholesterolemia;macrophage;novel;response


application_id: 7765565
project_number: 5R01DA024598-03
project_title: Social networks and HIV risk among rural drug users
administering_ic: NIDA
award_notice_date: 2010-01-14
opportunity_number: PA-07-103
application_type: 5
activity_code: R01
ic: DA
serial_number: 024598
program_official: HARTSOCK, PETER
project_start_date: 2008-04-05
project_end_date: 2013-01-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  This application is in response to PA-06-478 "Research on Rural Mental Health and Drug Abuse Disorders". One of the research areas highlighted by this PA is the examination of rural HIV transmission using social network analysis. The overall goal of the study is to examine the prevalence incidence and risk factors for HIV and other blood borne infections (BBIs) such as hepatitis B (HBV) and C (HCV) among rural Appalachian drug users using social network analysis and multilevel modeling. HIV continues to be a major public health problem in the United States especially among drug users. However little is known about HIV in rural areas in which there are marked health disparities. Therefore given that studies among urban drug users have found that social network indicators are robust predictors of HIV risk both social network and individual characteristics will be measured for their association with HIV risk among rural drug users. The specific aims are: 1) To determine the prevalence and incidence of HIV HCV and HBV among rural injection and non- injection drug users; 2) To examine HIV and other BBI risk among rural injection and non-injection drug users; and 3) To examine longitudinal changes in rural HIV HCV and HBV risk at 6-months 12-months and 18- months post-baseline. To meet these aims a sample 500 rural injection and non-injection drug users will be recruited using respondent driven sampling (RDS). In addition to biologic testing for HIV HCV and HBV rural participants will be given an interviewer-administered questionnaire pertaining to their social networks (drug sexual and support networks) sociodemographics drug use HIV risk behaviors psychiatric diagnoses intravention and norms. Since individuals will be nested within networks data will be analyzed using multilevel random effects regression that allows for the simultaneous examination of social network and individual-level risk. Consistent with the priorities of the NIDA AIDS Research Program this proposal will explore the social network structure in a rural drug using population in order to better understand how network factors may affect HIV risk in rural areas using an innovative multilevel approach. Results from the proposed study will inform the design and implementation of HIV interventions in rural areas and help to determine the appropriate population for which to target such activities in order to reduce the morbidity and mortality associated with HIV and other BBIs.   
  
Although HIV remains a significant public health problem in the United States especially among drug users little is known about HIV risk in rural areas such as Appalachia. It has been shown in urban populations that relationships among drug users also known as social networks are important predictors of HIV risk. Therefore this study seeks to characterize rural HIV risk by measuring both social network and individual behaviors in order to inform prevention activities in health resource-deprived rural areas.

project_terms:
Acquired Immunodeficiency Syndrome;Affect;Appalachian Region;Area;Automobile Driving;Behavior;Blood;Centers for Disease Control and Prevention (U.S.);Characteristics;Communities;Data;Disease;Drug Prescriptions;Drug abuse;Drug usage;Drug user;Epidemic;Face;Goals;Growth;HIV;HIV Infections;Health Resources;Hepatitis B;Hepatitis B Virus;Hepatitis C;Hepatitis C virus;Human immunodeficiency virus test;Incidence;Individual;Individual Adjustment;Infection;Injecting drug user;Injection of therapeutic agent;Intervention;Interview;Interviewer;Kentucky;Measures;Mental Health;Modeling;Morbidity - disease rate;Mortality Vital Statistics;National Institute of Drug Abuse;Participant;Pathway Analysis;Pharmaceutical Preparations;Population;Prevalence;Prevention;Principal Investigator;Psychiatric Diagnosis;Questionnaires;Recruitment Activity;Reporting;Research;Research Priority;Respondent;Risk;Risk Behaviors;Risk Factors;Rural;Rural Population;Sampling;Serologic tests;Seroprevalences;Social Network;Structure;Testing;Time;United States;Urban Population;Ursidae Family;design;health disparity;high risk;innovation;meetings;multilevel analysis;programs;public health medicine (field);response;rural area;transmission process;urban area


application_id: 7764669
project_number: 5R01CA100323-07
project_title: Autoantibodies in NSCLC as Markers for Disease
administering_ic: NCI
award_notice_date: 2010-02-25
application_type: 5
activity_code: R01
ic: CA
serial_number: 100323
program_official: KIM, KELLY Y
project_start_date: 2003-09-05
project_end_date: 2012-02-28
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 7875285
contact_pi: HIRSCHOWITZ, EDWARD A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-01
project_abstract:
DESCRIPTION (provided by applicant): The use of only age and smoking history as selection criteria in population-based CT screening trials has afforded a low yield of cancer detection at significant cost. Moreover the routine identification of indeterminate pulmonary nodules during CT screening often requires additional workup magnifying the cost and adding potential morbidity from related interventional diagnostic procedures. We have developed a blood test for NSCLC that may address these limitations when integrated into the early detection paradigm. Specifically we exploited the expansive autoantibody repertoire of lung cancer patients to develop a multi-marker assay that compensates for NSCLC heterogeneity. Capture proteins were selected from cDNA tumor libraries using antibodies in patient plasma and in turn used to measure tumor-associated antibodies as markers of disease. Fluorescent microarray was adapted as a platform to accommodate a multiple marker approach. Individual markers were ranked by statistical differences between case and control samples and Receiver Operating Characteristic (ROC) was used to statistically define an optimal combination of those markers with high discriminatory value. Classifiers for a combined marker set were then built on known case and control samples and used to predict disease in available samples. Performance results indicate excellent potential for clinical utility. Having successfully completed the biomarker discovery phase of this project the current proposal has three primary objectives: 1) To evaluate assay performance for established lung cancer diagnosed in an expanded clinical population 2) to define a role for this assay in management of radiographically identified indeterminate pulmonary nodules independent of a screening study and 3) to confirm results that indicate this marker set may detect cancer and predict the onset of NSCLC prior to radiographic detection in a screened population. Relevance to Public Health. A blood test for lung cancer could improve the capability and cost- effectiveness of early detection as a viable strategy for reducing mortality from this disease.

project_terms:
Address;Age;Antibodies;Appearance;Autoantibodies;Bacteriophages;Benign;Biological Assay;Blinded;Blood Tests;Cancer Detection;Cancer Patient;Chest;Clinical;Clinical Research;Complement;Complementary DNA;Detection;Diagnosis;Diagnostic Procedure;Disease;Disease Marker;Disease Outcome;Dose;Early Detection Research Network;Early Diagnosis;Environment;Equipment and supply inventories;Glass;Heterogeneity;High-Risk Cancer;Imaging Techniques;Incidence;Individual;Kentucky;Lesion;Libraries;Lung;Lung diseases;Lung nodule;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measurement;Measures;Morbidity - disease rate;Mortality Vital Statistics;Non-Malignant;Non-Small-Cell Lung Carcinoma;Patients;Performance;Phase;Plasma;Population;Positron-Emission Tomography;Protein Array;Proteins;Pulmonary Coin Lesion;Receiver Operating Characteristics;Reporting;Research Personnel;Role;Sampling;Scanning;Screening procedure;Selection Criteria;Sensitivity and Specificity;Serological;Slide;Smoking History;Staging;Testing;Tumor Antibodies;Tumor Markers;Validation;X-Ray Computed Tomography;biomarker;cancer diagnosis;case control;clinical application;cost;cost effectiveness;design;follow-up;high risk;improved;performance tests;population based;programs;public health medicine (field);tool;tumor


application_id: 7763896
project_number: 5R01HD052694-05
project_title: Endothelin-2 in Ovarian Follicle Rupture
administering_ic: NICHD
award_notice_date: 2010-03-05
application_type: 5
activity_code: R01
ic: HD
serial_number: 052694
program_official: TAYMANS, SUSAN
project_start_date: 2006-05-15
project_end_date: 2012-02-28
study_section: Cellular, Molecular and Integrative Reproduction Study Section[CMIR]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-03-01
project_abstract:
The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in folliclerupture. The program of ovulation is activated by a surge of luteinizing hormone which initiates dramaticchanges in molecular biochemical and physical aspects of the ovary eventually leading to rupture offollicles. However the factors involved in and the mechanism governing the process of follicle rupture are yetto be unveiled. Using a gene expression profiling approach we have identified EDN-2 a potent smoothmuscle constrictor which is exclusively and transiently expressed in the granulosa cells of periovulatoryfollicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in theovarian tissue while tezosentan an endothelin receptor antagonist released the contraction. These novelfindings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture ofthe follicle. Supporting the hypothesis immunohistochemical analysis identified a well-organized smoothmuscle layer in the theca externa of each follicle which forms a sponge-like smooth muscle network at thewhole ovarian level. Furthermore we found that intraovarian injection of tezosentan prior to ovulationcompletely blocked follicle rupture. In this study we will elucidate the mechanism of EDN-2 action in folliclerupture. We will determine the target tissues of EDN-2 action the endothelin receptor subtype(s) thatmediates EDN-2 action and the ovarian concentration of EDN-2. We will also determine the mechanism ofendothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrice molecules(VIPs PACAPs and prostaglandins). In addition the functional link of progesterone estrogen andprostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposalis in the identification of EDN-2 and the ovarian smooth muscle network as the key components of folliclerupture. The novelty of the proposed experiments is the interdisplinary approachs (genome-wide geneexpression profiling intraovarian injection and isometric tension measurement). The proposed studies areexceptionally important in order to further our understanding of the mechanism of follicle rupture. Theproposed experiments will provide clinical direction in identifying the therapeutic target for the cure ofannovulatory symptoms one of the leading causes of female infertility.

project_terms:
Animal Model;Binding Sites;Biochemical;Biochemical Process;Clinical;Cyst;Databases;Development;Disease;Endothelin;Endothelin Receptor;Endothelin Receptor Antagonist;Endothelin-2;Estrogen Receptor alpha;Estrogens;Experimental Models;Failure (biologic function);Female infertility;Gene Expression;Gene Expression Profiling;Genes;Goals;Growth;Hormonal;Immunohistochemistry;In Situ Hybridization;Individual;Indomethacin;Infertility;Injection of therapeutic agent;Isometric Exercise;Knockout Mice;Knowledge;Label;Lead;Link;Luteinizing Hormone;Mammalian Oviducts;Measurement;Measures;Mediating;Molecular;Molecular Profiling;Mus;Oocytes;Ovarian;Ovarian Diseases;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;PTGS2 gene;Pattern;Pituitary Gonadotropins;Porifera;Process;Progesterone;Progesterone Receptors;Prostaglandins;RU-486;Radioimmunoassay;Rattus;Research Personnel;Residual state;Reverse Transcriptase Polymerase Chain Reaction;Role;Rupture;Smooth muscle (tissue);Symptoms;Syndrome;System;Techniques;Theca Externa;Tissues;Vasoactive Intestinal Peptide;constriction;corpus luteum;genome-wide;granulosa cell;in vivo;inhibitor/antagonist;intraovarian;muscular structure;muscular system;novel;programs;receptor;research study;tezosentan;therapeutic development;therapeutic target


application_id: 7762825
project_number: 5F31HL095302-02
project_title: L-type Channel Calcium Entry Triggered Diastolic Calcium Sparks
administering_ic: NHLBI
award_notice_date: 2010-04-28
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: HL
serial_number: 095302
program_official: MEADOWS, TAWANNA
project_start_date: 2009-02-01
project_end_date: 2011-01-31
study_section: Special Emphasis Panel[ZRG1-DIG-E(29)L]
contact_pi_person_id: 9438690
contact_pi: LESTER, WILLIAM CECIL
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dysregulation of calcium in the cardiac ventricular myocyte is prevalent in many pathological models of heart disease such as heart failure and sudden cardiac death. Over the steady state plasma membrane (PM) calcium entry must equal plasma membrane calcium extrusion to maintain calcium homeostasis. The major PM entry pathway is the L-type Ca channel and the major PM extrusion pathway is the Na-Ca exchanger (NCX). Calcium may enter the cytosol during diastole via PM leak and via unitary releases of calcium from intracellular stores - labeled as calcium sparks. Sodium-Calcium exchanger extrusion of calcium during diastole contributes a depolarization of membrane potential. Thus diastolic calcium fluxes via forward mode NCX can trigger ventricular cardiac arrhythmias and can contribute to sudden cardiac death. Diastolic sparks are well-characterized in terms of dimension and location yet the mechanism of how they are triggered remains a mystery. However my pilot data suggests that calcium entry through the L-type calcium channel is a required input for a diastolic spark to occur in developing mouse ventricular myocyte. Therefore the overall purpose of this proposal is to determine the trigger and the source of diastolic calcium sparks. My preliminary data leads me to the overall driving hypothesis: the L-type calcium channel entry triggers diastolic calcium sparks. This proposal will provide major inisght to calcium handling in adult and pathological conditions (i.e. heart failure). This overall goal will be accomplished by separating L-type channel dependent and independent diastolic sparks. Understanding spark inititiation could lead to discovering a therapuetic target for cardiac arrhythmias. I will use fast-scanning 2D confocal imaging to study the amplitude rate of rise and kinetics of diastolic calcium sparks in embryonic adult and thoracic aortic banded mice (i.e. heart failure model). If time allows or if needed simultaneous whole patch electrophysiology and calcium imaging can be used to dissect the two populations of diastolic sparks in the adult and their voltage dependence.

project_terms:
Acute;Address;Adult;Animals;Arrhythmia;Automobile Driving;Biological Models;Buffers;Calcium;Calcium Channel;Cardiac;Cell membrane;Chest;Coupling;Cytosol;Data;Death Sudden Cardiac;Dependence;Diastole;Dimensions;Disease;Electrophysiology (science);Embryo;Excision;Exhibits;Frequencies (time pattern);Goals;Heart Diseases;Heart failure;Homeostasis;Image;Kinetics;L-Type Calcium Channels;Label;Lead;Location;Membrane Potentials;Modeling;Mus;Muscle Cells;Pathology;Pathway interactions;Phenotype;Physiological;Population;Proteins;Route;RyR2;Ryanodine Receptor Calcium Release Channel;Ryanodine Receptors;Sarcoplasmic Reticulum;Scanning;Series;Sodium-Calcium Exchanger;Source;Time;Ventricular;Ventricular Arrhythmia;Work;base;design;extracellular;mature animal;release of sequestered calcium ion into cytoplasm;voltage


application_id: 7761245
project_number: 5R01AI071047-03
project_title: Adjuvant Functions of Detoxified LPS
administering_ic: NIAID
award_notice_date: 2010-01-15
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 071047
program_official: LEITNER, WOLFGANG W
project_start_date: 2008-02-01
project_end_date: 2013-01-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Monophosphoryl lipid A (MLA) is a detoxified form of TLR4 agonist LPS that is approved for use as a vaccine adjuvant in Europe and is nearing approval for use in the US. Extensive testing shows that MLA in its clinical grade from MLA adjuvant is as safe as the current adjuvant standard alum but is far more effective at generating protective antibody responses. In spite of this extensive testing for safety and efficacy very little is known about the mechanism by which MLA efficiently triggers TLR4 signaling while showing so little of the endotoxic properties of its parent compound LPS. TLR4 is unique among TLRs in that it signals by activating both MyD88 and TRIF signaling pathways. This proposal will test the central hypothesis that MLA's adjuvant effects are associated with preferential stimulation of the TLR4/Trif pathway. Because MLA is manufactured from endotoxin synthetic forms are preferred by vaccine manufactures. However the synthetic forms that are feasible to manufacture on a mass scale have variations of structure relative to MLA that cause them to have a wide range of distinct adjuvant functions. These functional variations are interesting but also make it more difficult to predict which will ultimately be best suited for widespread use in prophylactic vaccination. This proposal is designed to elucidate the molecular basis for MLA's TRIF- biased adjuvant effects on T and B cell so that its success can be replicated and improved in next generation synthetic forms. The specific aims of this proposal are: I. To identify the molecular mechanism(s) of MLA's Trif-biased signaling in monocytes. II. To identify TLR4 signaling pathways required for low toxicity adjuvant effects on T cells. III. To identify pro-inflammatory requirements for TLR4-mediated adjuvant effects on B cells. PUBLIC HEALTH RELEVENCE: Non-infectious vaccines are typically the safest way to protect against infectious disease and bioterrorism but vaccines are relatively inefficient unless "adjuvants" that boost the human immune response are added. This proposal will decipher the means by which new adjuvants that are just beginning to be used in human vaccines influence the responses of T cells an important component of the immune system. Our work will allow next- generation adjuvants to be improved for use in new vaccines against a broad array of infectious threats.

project_terms:
Acids;Adjuvant;Agonist;Antibody Formation;B-Lymphocytes;Bioterrorism;CD4 Positive T Lymphocytes;Clinical;Clonal Expansion;Communicable Diseases;Data;Drug Formulations;Endotoxins;Europe;Figs - dietary;Future;Gout;Human;Immune response;Immune system;In Vitro;Inflammatory;Mediating;Molecular;Nature;Nucleic Acids;Parents;Pathway interactions;Principal Investigator;Production;Property;Proteins;Publishing;Reagent;Relative (related person);Science;Signal Pathway;Signal Transduction;Structure;System;T cell response;T-Lymphocyte;TLR4 gene;Testing;Time;Toxic effect;Uric Acid;Vaccination;Vaccine Adjuvant;Vaccines;Variant;Work;aluminum sulfate;base;design;improved;in vivo;interest;monocyte;monophosphoryl lipid A;next generation;novel vaccines;programs;prophylactic;public health medicine (field);safety testing;success;ward


application_id: 7759642
project_number: 5R01AA017226-03
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2009-03-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AA
serial_number: 017226
program_official: JUNG, KATHY
project_start_date: 2008-03-05
project_end_date: 2013-02-28
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adaptor Signaling Protein;Adult;Alcohol abuse;Alcohol consumption;Alcoholism;Alcohols;American;Animal Model;Breast Cancer Cell;Cell Communication;Cell-Cell Adhesion;Cells;Cellular Structures;Complex;Development;Disease;Dissociation;E-Cadherin;ERBB2 gene;Epidemiologic Studies;Epidermal Growth Factor Receptor;Epithelial Cells;Esophagus;Ethanol;Etiology;Family;Future;Genus Cola;Goals;Health;Heavy Drinking;Human;In Vitro;Larynx;Liver;Malignant - descriptor;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Medical;Membrane;Molecular;Mucin-1 Staining Method;Mucins;Neoplasm Metastasis;Nude Mice;Oral cavity;Organ;Outcome;Ovary;Oxidative Stress;Pathogenesis;Patients;Pharyngeal structure;Phosphorylation;Play;Protein Tyrosine Kinase;Proto-Oncogenes;Reactive Oxygen Species;Rectum;Research Personnel;Risk;Role;Stomach;Testing;Therapeutic;Transgenic Mice;Transgenic Organisms;Tumor Promoters;Tumor Promotion;United States;Up-Regulation (Physiology);alcohol effect;alcohol related problem;cancer cell;cancer risk;carcinogenesis;cell motility;cell transformation;cellular targeting;chronic alcohol ingestion;cost;human disease;in vivo;in vivo Model;insight;malignant breast neoplasm;medical complication;member;migration;novel;problem drinker;tumor;tumor progression;tumorigenesis


application_id: 7759159
project_number: 5R01NS050242-04
project_title: Relationship between BOLD effects on DA degeneration
administering_ic: NINDS
award_notice_date: 2010-02-19
application_type: 5
activity_code: R01
ic: NS
serial_number: 050242
program_official: SIEBER, BETH-ANNE
project_start_date: 2007-02-16
project_end_date: 2012-01-31
study_section: Clinical Neuroscience and Disease Study Section[CND]
contact_pi_person_id: 2154561
contact_pi: ZHANG, ZHIMING
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-02-01
project_abstract:
DESCRIPTION (provided by applicant):  The hallmark of Parkinson's disease (PD) is the loss of dopamine neurons in the substantia nigra. However clinical symptoms of PD do not manifest until the loss of dopamine neurons exceeds a critical threshold. Thus for the early detection of PD there is particular interest in using an objective noninvasive sensitive and cost-effective imaging method to supplement existing clincal measures and response to treatments. The primary goal of this project is to determine whether BOLD-phMRI can meet these aforementioned criteria as an imaging biomarker of PD. Recently we.have demonstrated that the blood oxygenation level dependent (BOLD) response to dopaminergic stimulation as measured by pharmacological MRI (phMRI) correlated with specific histological and behavioral features of the parkinsonian state. For example d-amphetamine-evoked activations correlated with the number of surviving dopamine neurons and stronger apomorphine-induced activations were seen in more severely motor impaired parkinsonian rhesus macaques (see preliminary studies). In addtion apomorphine-induced activations in the dopamine denervated putamen were attenuated by a neurorestorative therapy (chronic intraputamenal infusion of GDNF). Therefore by using the imaging proctocol developed by our group over several years we are now proposing a large scale study in groups of rhesus monkeys that are: 1) normal animals 2) MPTP-lesioned but asymptomatic 3) MPTP-lesioned but mild unilateral symptoms and 4) MPTP-lesioned with severe unilateral symptoms in order to address the following specific aims: 1) whether BOLD-phMRI can be used to monitor the progression of the disease namely to determine if the BOLD effects will correlate with severity of PD features assessed behaivorally and also with pathological stages of the disease; and 2) whether BOLD-phMRI can be used to assess responses to therapy such as L-dopa treatment. If proven predictive of changes in dopamine functions BOLD-phMRI could be used in the future as an imaging biomarker to supplement existing clinical measures and to provide valuable information about the disease process or intervention. In addition because of the noninvasive highly sensitive highly reproducible and cost-effective features of BOLD-phMRI this technique may be used to screen the general population to investigate pathogenesis of the disease.

project_terms:
Address;Amphetamines;Animal Model;Animals;Apomorphine;Appearance;Attenuated;Basal Ganglia;Behavioral;Biological Process;Chronic;Clinical;Corpus striatum structure;Deterioration;Development;Dextroamphetamine;Disease;Disease Progression;Dopamine;Dopamine Agonists;Dopamine Receptor;Dopaminergic Cell;Early Diagnosis;Fiber;Future;General Population;Geographic Locations;Goals;Image;Imaging Techniques;Infusion procedures;Intervention;Kentucky;Lesion;Levodopa;MPTP Poisoning;MRI Scans;Macaca mulatta;Magnetic Resonance Imaging;Measures;Modeling;Monitor;Motor;Outcome;Parkinson Disease;Parkinsonian Disorders;Pathogenesis;Pathological Staging;Patients;Positron-Emission Tomography;Process;Protocols documentation;Published Comment;Recovery of Function;Research;Research Personnel;Research Proposals;Rest;Severities;Signal Transduction;Signs and Symptoms;Specificity;Staging;Substantia nigra structure;Suggestion;Symptoms;System;Techniques;Testing;Therapeutic Agents;Universities;base;biomarker;blood oxygen level dependent;blood oxygenation level dependent response;cost;cost effective;dopamine system;dopaminergic neuron;functional restoration;glial cell-line derived neurotrophic factor;imaging modality;interest;meetings;motor impairment;neurorestoration;nigrostriatal system;novel therapeutics;programs;putamen;response;treatment center


application_id: 7758851
project_number: 5R24MD002757-03
project_title: Faith Moves Mountains: A CBPR Appalachian Wellness & Cancer Prevention Program
administering_ic: NIMHD
award_notice_date: 2010-01-27
opportunity_number: RFA-MD-07-003
application_type: 5
activity_code: R24
ic: MD
serial_number: 002757
program_official: GOODWIN, PAULA
project_start_date: 2008-05-22
project_end_date: 2013-01-31
study_section: ZMD1-RN(01)R
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Appalachian communities are disproportionately affected by many of the leading risk factors associated with cancer incidence and mortality factors amenable to primary and secondary prevention. Extensive involvement with our community partners has demonstrated strong community preference for a holistic approach toward cancer prevention; The proposed intervention extends our successful faith-based trained lay health advisor tailored intervention "Faith Moves Mountains" (R01CA108696) initiated three years ago to administer a culturally appropriate CBPR intervention. Working in partnership with 70 faith based institutions in rural Southeastern Kentucky we propose to administer evaluate and disseminate a tailored wellness and cancer prevention program focused on four of the most common prevention activities that have the potential of greatly preventing and reducing cancer morbidity and mortality. These prevention activities include smoking cessation (targeting all chronic diseases cervical and lung cancer); energy balance including dietary modification and physical activity promotion (targeting all chronic diseases and colorectal cancer (CRC)) and cancer screenings (targeting CRC cervical and breast cancer).  
  
Consistent with our Faith Moves Mountains and cancer control approach faith-based organizations will sponsor a "kick off event" or health fair in which participants will undergo a health risk appraisal (baseline). Participants will then select one or more wellness activities (smoking cessation energy balance cancer screening); then trained lay health advisors will offer modules on each of these wellness activities. Smoking cessation will include the culturally relevant Cooper-Clayton method (outcome: smoking abstinence). For those targeting dietary modification and physical activity a rural Appalachian modified Healthy Body/Healthy Spirit program will be administered (outcome: dietary change and physical activity participation). Tailored cancer screening promotion will be based on our current Faith Moves Mountains design (outcome: receipt of any recommended CRC screening test Pap test for cervical cancer and/or mammogram). To assess the intervention but remain consistent with community norms we will employ a staggered intervention design. Throughout the project the RE-AIM model will inform our evaluation. During phase three this CBPR wellness approach to cancer prevention will undertake qualitative process evaluation interviews and disseminate the intervention to medically underserved Appalachian Ohio in collaboration with partners at Ohio State University. This collaboration will facilitate dissemination of successful intervention to additional rural Appalachian populations with high rates of cancer health disparities.

project_terms:
Abstinence;Address;Affect;Cancer Control;Cervical;Chronic Disease;Collaborations;Colorectal Cancer;Communities;Diet;Diet Modification;Effectiveness of Interventions;Ensure;Evaluation;Event;Fostering;Goals;Health;Health Fairs;Health Risk Appraisals;Incidence;Institution;Intervention;Intervention Studies;Interview;Kentucky;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Methods;Modeling;Monoclonal Antibody R24;Morbidity - disease rate;Mortality Vital Statistics;National Center on Minority Health and Health Disparities;Ohio;Outcome;Pap smear;Participant;Phase;Physical activity;Population;Prevention;Prevention program;Process;Randomized;Regimen;Research;Research Design;Risk Factors;Rural;Rural Health;Screening for cancer;Secondary Cancer Prevention;Secondary Prevention;Smoking;Testing;Training;Trust;Universities;Work;base;cancer health disparity;cancer prevention;cancer risk;colorectal cancer screening;community based participatory research;design;diet and exercise;energy balance;health disparity;holistic approach;malignant breast neoplasm;medically underserved;member;preference;prevent;programs;response;smoking cessation;successful intervention;therapy design


application_id: 7758785
project_number: 5R01HL074091-06
project_title: Mechanisms of Long-term Cardiac Ion Channel Regulation
administering_ic: NHLBI
award_notice_date: 2010-05-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074091
program_official: PRZYWARA, DENNIS
project_start_date: 2009-06-01
project_end_date: 2014-05-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Ca dysregulation in cardiac myocytes contributes to heart development defects and diseases of the aging heart. The long-term objective of this proposal is to provide a molecular mechanism that explains how cardiac L-type Ca channels (LTCC) sense and transduce signals that homeostatically regulate cardiac myocytes. Cardiac myocytes present a conundrum with respect to Ca signaling to the nucleus. Cytosolic Ca amplitude varies >10-fold during each cardiac cycle yet alterations of Ca somehow are differentially decoded for longer-term transcriptional signaling. In this funding period we will test whether Ca channel activity and the cardiac L-type Ca channel itself encodes Ca signaling for long-term regulation. In the past funding period we discovered that RGK chronically inhibited ICaL (LTCC current) and this RGK inhibition of ICaL resulted in a compensatory up-regulation of CaV1.2 mRNA. This suggests that ICaL block may signal transcriptional events in the nucleus. In new studies we confirmed and extended this notion by showing that LTCC-pharmacological- block but not internal Ca in general is responsible for perturbing heart development. Along the same lines in mature heart long-term blockade of LTCC also causes a compensatory up-regulation of LTCC and ICaL. Our driving hypothesis is that signaling is not simply determined by Ca but by active Ca channels. The discovery that mobile segment of LTCC is localized to the nucleus or t-tubules coupled with the recent report that this peptide is a transcription factor drives the exciting new hypothesis that this segment of the LTCC regulates LTCC expression. We will study this aspect of long-term channel regulation in three aims: 1. We will assess nuclear translocation of a domain of the LTCC and determine the interaction between LTCC activity and sub- cellular localization; 2. We will determine the ability of LTCC to auto-regulate itself transcriptionally; and 3. We will determine the compensatory changes of SL Ca handling proteins in response to LTCC blockade. This work may provide a missing molecular link between LTCC function and downstream signaling events. PUBLIC HEALTH RELEVANCE: These studies show that widely used clinically-relevant drugs that are used to block LTCC may inadvertently exacerbate heart dysfunction by paradoxically increasing LTCC function. This proposal will lead to understanding of a new mechanism whereby ion channels that control cardiac electrical activity also may control long-term signaling pathways that are critical for maintenance of cardiac structure and function.

project_terms:
Abbreviations;Acute;Adrenergic Agents;Adult;Aging;Automobile Driving;C-terminal;Cardiac;Cardiac Myocytes;Cell Nucleus;Chronic;Coupled;Data;Defect;Disease;Down-Regulation;Drug usage;Elements;Event;Functional disorder;Funding;Growth and Development function;Heart;Homeostasis;Ion Channel;L-Type Calcium Channels;Lead;Link;Maintenance;Messenger RNA;Molecular;Monomeric GTP-Binding Proteins;Muscle Cells;Nuclear;Nuclear Translocation;Pathway interactions;Peptides;Pharmaceutical Preparations;Protein Phosphatase 2A Regulatory Subunit PR53;Protein phosphatase;Proteins;Regulation;Reporting;Signal Pathway;Signal Transduction;Structure;Testing;Transducers;Up-Regulation (Physiology);Ventricular;Work;adrenergic;cardiogenesis;chromatin immunoprecipitation;clinically relevant;heart electrical activity;in vitro Model;in vivo;novel;protein expression;public health relevance;response;sensor;trafficking;transcription factor


application_id: 7758262
project_number: 5R01AG024377-05
project_title: Characterization of the Sch9 -Longevity Pathway in Yeast
administering_ic: NIA
award_notice_date: 2010-03-11
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 024377
program_official: CHATTERJI, MINKI
project_start_date: 2004-09-01
project_end_date: 2013-12-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1879389
contact_pi: DICKSON, ROBERT CARL
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Model organisms such as Saccharomyces cerevisiae have proven effective in elucidating genes and metabolites that modulate life span and this knowledge forms a basis for understanding human aging and longevity. These studies have identified the Akt/PKB protein kinases as conserved regulators of aging. However it is not entirely clear how they work. One focus of our research is the S. cerevisiae Sch9 protein kinase an AKT homolog that regulates chronological life span (CLS). From in vitro studies we identified sphingolipid long chain bases (LCBs) and Pkh1 a homolog of human phosphoinositide-dependent protein kinase 1 (PDK1) as the first upstream regulator of Sch9. In addition we identified the first Sch9 substrates Rli1 involved in translation initiation and ribosome biogenesis and Ahp1 an alkyl hydroperoxide reductase that protects against oxidative stress. We will build upon these novel results and determine if phosphorylation of Rli1 and Ahp1 by Sch9 plays a role in CLS. We will also determine in vivo if LCBs and Pkh1 act upstream to regulate Sch9 during chronological aging. Although we have successfully identified Sch9 substrates there are likely to be others and we propose to search for new substrates by classical biochemical strategies newer automated but complementary strategies and a genetic screening strategy. In summary the results of these studies will provide the much needed mechanistic understanding of how Akt (Sch9) activity is regulated in yeast and how it regulates CLS through downstream substrates. This knowledge will help to provide a molecular basis for understanding human aging and longevity. PUBLIC HEALTH RELEVANCE:  The proposed research will determine how the Sch9 protein kinase a functional homolog of mammalian Akts/PKBs regulates chronological life span in the Baker's yeast Saccharomyces cerevisiae. Signal transduction pathways that contain Akt/PKB type protein kinases play important roles in regulating aging and life span and these pathways have been conserved from yeast to mammals. Thus information gained from these studies should provide a more mechanistic basis for understanding how aging and life span are regulated in humans.

project_terms:
Affect;Age;Aging;Alanine;Alleles;Animal Model;Binding (Molecular Function);Biochemical;Biogenesis;Biological Assay;Caloric Restriction;Cell Fraction;Cell Fractionation;Cells;Cellular Membrane;Chimeric Proteins;Chromatin;Density Gradient Centrifugation;Down-Regulation;Enzymes;Genes;Genetic;Genetic Screening;Glass;Homologous Gene;Human;In Vitro;Ion-Exchange Chromatography Procedure;Knowledge;Label;Libraries;Longevity;Longevity Pathway;Mammals;Mass Spectrum Analysis;Measures;Mediator of activation protein;Membrane;Molecular;Mutate;Organelles;Oxidative Stress;Pathway interactions;Phase;Phosphatidylinositols;Phosphorylation;Physiological;Play;Protein Binding;Protein Biosynthesis;Protein Kinase;Proteins;Proto-Oncogene Proteins c-akt;Research;Ribosomes;Role;Saccharomyces cerevisiae;Serine;Signal Transduction Pathway;Slide;Sphingolipids;Temperature;Testing;Translation Initiation;Work;Yeasts;alkyl hydroperoxide reductase;analog;base;cell type;dihydroceramide desaturase;dosage;in vivo;mutant;novel;prevent;public health relevance;uptake;yeast protein


application_id: 7756667
project_number: 5R01GM047915-15
project_title: Modified Photoproteins as Labels and Molecular Switches in Bioanalysis
administering_ic: NIGMS
award_notice_date: 2009-11-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 047915
program_official: EDMONDS, CHARLES G
project_start_date: 1995-01-01
project_end_date: 2010-08-31
study_section: Instrumentation and Systems Development Study Section[ISD]
contact_pi_person_id: 1964876
contact_pi: DAUNERT, SYLVIA
other_pis: CAMMERS, ARTHUR
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Continuous discoveries in bioengineering and more efficient molecular biology methods have allowed scientists to create new designer biomolecules with unique and distinct properties. In that regard bio- nanotechnology and nanoscale analysis are becoming increasingly prevalent raising the demand for techniques with high sensitivity that can detect biomolecules in biological samples. Bioluminescent photoproteins such as aequorin possess great potential to provide with a solution to this new challenge because they can be detected at low concentrations and have different emission wavelengths depending on the protein variant used a property that can be exploited in multiplex analysis. We now propose to prepare new aequorin variants to broaden the scope of their use in bioanalysis thus allowing for detection of biomolecules that are not detectable by other technologies. Protein molecular switches with optical properties are another type of designer biomolecules that in the presence of a target ligand demonstrate an altered response manifested by an "on/off" signal. These molecules can be useful in a variety of applications such as in the development of nanosensors for in vitro and in vivo detection. To that end we plan to design and develop bioluminescent molecular switches that incorporate the recognition properties of binding proteins with the bioluminescence afforded by the aequorin variants. The hypotheses formulated for the proposed work are based on knowledge gained during our current funding period and investigate the use of a series of computational and synthetic approaches along with genetic engineering strategies targeting the alteration of the electronic environment of the chromophore that should lead to new bioluminescent proteins and molecular switches with a wide range of spectral properties. These photoproteins will be employed in the development of assays for important biomolecules. Finally we will investigate the use of the newly prepared bioluminescent molecular switches in the multiplex analysis of biomolecules and in the simultaneous analysis of molecules in single cells. We anticipate that the new photoproteins will provide with new enabling technologies for in vitro and in vivo biosensing imaging and multiplex analysis that have a number of advantages over existing methods.  
  
PUBLIC HEALTH RELEVANCE: NARRATIVE The increasing importance of nanoscale analysis has raised the demand for highly sensitive systems that can detect biomolecules in biological samples. Bioluminescent photoproteins such as aequorin possess great potential to provide a solution to this new challenge because they can be detected at very low concentrations in physiological fluids. In that regard we plan to design and prepare genetically modified photoproteins that form the basis of enabling technologies for the detection of relevant biomolecules and panels of biomarkers for in vitro and in vivo applications.

project_terms:
Aequorin;Affect;Amber;Amino Acid Sequence;Amino Acids;Apoproteins;Binding (Molecular Function);Binding Proteins;Biological;Biological Assay;Bioluminescence;Biomedical Engineering;Biosensing Techniques;Biotechnology;Categories;Cells;Characteristics;Codon Nucleotides;Computer Analysis;Detection;Development;DsRed;Electronics;Engineering;Environment;Family;Funding;Genetic Code;Genetic Engineering;Goals;Half-Life;Hydrogen Bonding;Image;In Vitro;Knowledge;Label;Lead;Libraries;Life;Ligands;Liquid substance;Luciferases;Luminescent Proteins;Methods;Microfluidics;Molecular;Molecular Biology;Nanotechnology;Optics;Peptide Sequence Determination;Performance;Physiological;Play;Post-Translational Protein Processing;Preparation;Property;Protein Binding Domain;Proteins;Protocols documentation;Research;Resolution;Role;Sampling;Scaffolding Protein;Scheme;Scientist;Series;Signal Transduction;Site;Solutions;Source;Structure;System;Techniques;Technology;Time;Variant;Work;analog;assay development;base;biomarker;chromophore;coelenterazine;computer studies;design;directed evolution;hybrid protein;in vivo;luminescence;molecular recognition;mutant;nanoscale;nanosensors;obelin;protein structure;public health relevance;response;scaffold;tool

public_health_relevance:
NARRATIVEThe increasing importance of nanoscale analysis has raised the demand for highlysensitive systems that can detect biomolecules in biological samples. Bioluminescentphotoproteins such as aequorin possess great potential to provide a solution to thisnew challenge because they can be detected at very low concentrations in physiologicalfluids. In that regard we plan to design and prepare genetically modified photoproteinsthat form the basis of enabling technologies for the detection of relevant biomoleculesand panels of biomarkers for in vitro and in vivo applications.


application_id: 7755515
project_number: 2R01HL062053-10A1
project_title: Host Response to P. carinii in Neonatal Mice
administering_ic: NHLBI
award_notice_date: 2009-07-17
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: HL
serial_number: 062053
suffix: A1
program_official: PEAVY, HANNAH H
project_start_date: 1998-09-30
project_end_date: 2014-06-30
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adoptive Cell Transfers;Adult;Age;Agonist;Alveolar Macrophages;Anti-Inflammatory Agents;Anti-inflammatory;Antibodies;Autopsy;Binding (Molecular Function);CD 200;CD4 Positive T Lymphocytes;Cell physiology;Child;Cyst;Cytokine Activation;Data;Defect;Environment;Environmental Risk Factor;Epithelial Cells;Funding;Glucans;Goals;Health Services Accessibility;Immune response;Immune system;In Vitro;In-Migration;Incidence;Individual;Infant;Infection;Intrinsic factor;Life;Ligation;Lung;Macrophage-1 Antigen;Mannans;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neonatal;Newly Diagnosed;Pattern recognition receptor;Phagocytosis Induction;Phenotype;Pneumocystis;Pneumocystis carinii;Pneumocystis carinii Pneumonia;Production;Signal Pathway;Signal Transduction;Site;Specificity;Specimen;Stimulus;Sudden infant death syndrome;T-Lymphocyte;TLR2 gene;TNFSF5 gene;Testing;Transgenic Mice;Up-Regulation (Physiology);antiretroviral therapy;cytokine;dectin 1;in vivo;macrophage;mannose receptor;neonate;non-compliance;public health relevance;pup;receptor;response


application_id: 7755324
project_number: 3R44RR021289-03S1
project_title: L1 retrotransposon-based mutagenesis for rat models of human diseases
administering_ic: NCRR
award_notice_date: 2009-01-10
opportunity_number: PA-06-120
application_type: 3
activity_code: R44
ic: RR
serial_number: 021289
suffix: S1
program_official: WATSON, WILLIAM T
project_start_date: 2005-02-14
project_end_date: 2010-05-31
study_section: Special Emphasis Panel[ZRG1-GGG-J(10)B]
contact_pi_person_id: 3075176
contact_pi: OSTERTAG, ERIC M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 145182338
duns_number: 145182338
fips: US
organization_id: 10004431
organization_name: TRANSPOSAGEN BIOPHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-06-01
project_abstract:
DESCRIPTION (provided by applicant): In many aspects the rat is a better animal model than the mouse for functional genomic studies. The physiology and drug metabolism of rats and humans are more similar than that of mice and humans. The rat is larger than the mouse making many studies easier to perform and sampling more accurate. The recent completion of the Brown Norway rat genome improves further the potential of the rat as an excellent organism for studying human diseases. Unfortunately many genetic manipulation techniques available in the mouse such as random mutagenesis with a gene trap (both retroviral-based and non-retroviral-based) gene knock- outs gene knock-ins and conditional mutations have not been possible in the rat because there is no way to effectively harvest and culture rat embryonic stem cells. Existing methods for producing gene deletions in rats including cloning and chemical mutation are inefficient and not practical. This deficiency leads to a severe bottleneck in our ability to create rat models of human disease. The product that will arise from this proposal will be rats with single gene knockouts for use as models of human disease in research and drug discovery (MutaRat Animal Models). Transposagen has developed a novel technology based on human L1 retrotransposons to generate animals with a high rate of random gene mutations in germ cells.In MutaRats mutagenesis will occur in sperm and oocytes and some offspring will contain single gene disruptions. These offspring can be used to establish authentic gene knockout rat lines. In Phase I we successfully developed and characterized MutaMice generating 22 potential founders.We have subsequently developed similar "mutator" founder rats (MutaRats) and in Phase II we intend to characterize these rats and use them to generate rats with stable singe gene deletions (gene knockout MutaRat Animal Models). Specific aim 1 isto screen existing MutaRatfounder lines to determine the line with the highest frequency of mutation. This line will then be bred to establish a breeding colony that can be used to obtain single gene knockout rats in Specific Aim 2. We do not intend to characterize the phenotypes of these lines nor to establish breeding colonies of individual knockout rat linesas part of this proposal but instead to establish a sperm bank comprising sequenced insertional gene disruptions the MutaRat Germ Line Resource. In Specific Aim 3 we will develop the MutaRat Germ Line Resourceof cryopreserved sperm from rats with single gene knockouts. We estimate that we will have a sperm bank with at least 100 different gene knockouts by the endof this project in December 2008. This MutaRat Germ Line Resource will be the only technology capable of creating and rapidly mapping random gene knockouts in rats. Knockout ratswill be provided to the academic community in accordance with the NIH policy on sharing of model organisms for biomedical research and will be distributed by the National Rat Resource and Research Center. In Phase III we will establish a distribution partnership with an existing laboratory animal company to market establish and validate (as necessary) and distribute these lines and others as they are developed. The innovation of this proposal is the use of a novel retrotransposon technology to create the only system able to rapidly create and map insertional deletions in the rat and other mammals. This technology is expected to offer significant advantages in cost and speed when compared with existing mutagenesis systems available in mice and to generate novel gene knockout models that have not previously been available in any vertebrate. Transposagen's MutaRat Animal Models will contribute to human health by providing new vertebrate models of disease for studying pathogenesis and for discovery and development of pharmaceutical compounds.

project_terms:
Animal Model;Animals;Biological Assay;Biomedical Research;Breeding;Cells;Chemicals;Cloning;Communities;DNA;Data;Development;Disease model;Exhibits;Exons;Freezing;Frequencies (time pattern);Gene Deletion;Gene Mutation;Generations;Genes;Genetic;Germ;Germ Cells;Germ Lines;Harvest;Health;Human;Individual;Inherited;Insertional Mutagenesis;Introns;Knock-out;Laboratory Animals;Location;Mammals;Maps;Marketing;Methods;Modeling;Mus;Mutagenesis;Mutation;Oocytes;Organism;Pathogenesis;Pathology;Pattern;Pharmacologic Substance;Phase;Phenotype;Physiology;Policies;Population;Process;Production;Rat Strains;Rat Transgene;Rattus;Rattus norvegicus;Research;Resources;Retrotransposition;Retrotransposon;Sampling;Speed (motion);Sperm Banks;System;Tail;Techniques;Technology;Testing;Transgenes;United States National Institutes of Health;base;cost;drug discovery;drug metabolism;embryonic stem cell;functional genomics;genetic manipulation;human disease;improved;innovation;knockout gene;male;new technology;novel;offspring;rat genome;sperm cell;success


application_id: 7755037
project_number: 5R01DE017138-05
project_title: Oral Immunity and Adjuvant Receptors
administering_ic: NIDCR
award_notice_date: 2010-01-26
application_type: 5
activity_code: R01
ic: DE
serial_number: 017138
program_official: BURGOON, PENNY W
project_start_date: 2006-02-01
project_end_date: 2010-09-14
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6712964
contact_pi: HAJISHENGALLIS, GEORGIOS
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-02-01
project_abstract:
The need to develop new vaccines against mucosal pathogens has compelled a search for adjuvants thatcan effectively stimulate mucosal immunity to vaccine proteins most of which are poor immunogens. Toll-like receptors (TLRs) and gangliosides are considered "adjuvant receptors" because their interaction withcertain classes of noxious microbial molecules generates potent immunomodulatory signals in antigen-presenting cells (APCs) that mobilize adaptive immunity. An ideal adjuvant should thus stimulate adjuvantreceptors without however inducing toxic effects. This proposal will investigate the adjuvant activities of anovel ganglioside-binding TLR2 agonist recently identified by our group. The molecule under investigationis the pentameric B subunit of a unique E. coli enterotoxin designated Type Mb(LT-llb) and quite differentfrom Type I enterotoxins such as cholera toxin. In contrast to the intact toxin the B subunit (designated LT-llb-B) induces TLR2-dependent activation of transcription factor NF-KB which plays a central role in theinduction of immunoregulatory cytokines and costimulatory molecules on APCs such as dendritic cells. Theoverall hypothesis is that LT-llb-B exhibits immunomodulatory activity which requires the cooperation ofGD1a ganglioside and TLR2 promotes antigen-presenting cell function and induces mucosal immunity. Wethus aim to elucidate the immunomodulatory mechanisms of LT-llb-B and demonstrate its mucosaladjuvanticity. Specifically using immunological biophysical and cell imaging techniques we will determinecooperative interactions between gangliosides and TLR2 in response to LT-llb-B and the importance ofthese interactions in upregulating dendritic cell-mediated functional costimulation to CD4+T cells. Moreoverit will be determined if these adjuvant mechanisms of LT-llb-B correlate with induction of mucosal adjuvantactivity in vivo. The proposed studies are supported by a plethora of preliminary findings and are facilitatedby the availability of (a) engineered wild-type and single point substitution mutants of LT-II molecules (b)model cell systems where expression of receptors of interest is manipulated and (c) a well-establishedmouse mucosal immunization model. Using these models and state-of-the-art interdisciplinary techniquesthe generated data will form the basis for our ultimate objective which is to establish LT-llb-B as a safe andeffective adjuvant in vaccine formulations against oral or other mucosal pathogens.

project_terms:
Address;Adjuvant;Adjuvanticity;Agonist;Antibodies;Antigen-Presenting Cells;Antigens;Arts;Bacterial Adhesins;Binding (Molecular Function);Biological Assay;CD4 Positive T Lymphocytes;Catalytic Domain;Cell Line;Cell Proliferation;Cell model;Cell physiology;Cholera Toxin;Co-Immunoprecipitations;Complex;Data;Dendritic Cells;Drug Formulations;Engineering;Enterotoxins;Escherichia coli;Exhibits;Fluorescence Microscopy;Fluorescence Resonance Energy Transfer;GD1a ganglioside;Gangliosides;Genitourinary system;Human;Imaging Techniques;Immune response;Immunity;Immunization;Infection;Invaded;Investigation;Ligands;Lymphoid Cell;Mediating;Membrane Microdomains;Modeling;Molecular;Molecular Structure;Monitor;Mucosal Immune Responses;Mucosal Immunity;Mucous Membrane;Mus;Oral;Play;Point Mutation;Production;Proteins;Reagent;Research Personnel;Role;Route;Scanning;Signal Transduction;Specificity;Stimulus;Stomach;Streptococcus mutans;Structure;Structure-Activity Relationship;Surface;System;TLR2 gene;Techniques;Time;Toll-Like Receptor 2;Toll-like receptors;Toxic effect;Toxin;Up-Regulation (Physiology);Vaccines;adaptive immunity;base;cellular imaging;cytokine;improved;in vivo;interdisciplinary collaboration;interest;microbial;monocyte;mouse model;mutant;novel;novel vaccines;oral immunity;oral pathogen;pathogen;programs;receptor;receptor expression;respiratory;response;trafficking;transcription factor


application_id: 7754388
project_number: 5R01CA124630-04
project_title: PTTG Role in Ovarian Tumorigenesis and Matastasis
administering_ic: NCI
award_notice_date: 2009-12-04
application_type: 5
activity_code: R01
ic: CA
serial_number: 124630
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2007-03-26
project_end_date: 2011-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-01-01
project_abstract:
Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause ofdeath from gynecologic malignancies in the United States. Molecular mechanisms that initiate and supportovarian tumorigenesis are not well defined. We cloned a novel oncogene "PTTG" also known as securin fromhuman testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional proteinand is highly expressed in many tumors including tumors of ovary. Introduction of PTTG into NIH3T3 andHEK293 cells induces cellular transformation and promotes tumor formation in nude mice suggesting itsstrong oncogenic function. Notably PTTG has been shown to inhibit separation of sister chromatids and toincrease the synthesis and secretion of bFGF VEGF and IL-8 as well as activate the expression of theoncogene c-myc and PI3K/AKT signaling pathway suggesting that the oncogenic activity of PTTG mayinvolve induction of aneuploidy and chromosomal instability increased angiogenesis and production ofgrowth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitroand its deletion in animals (Knockout) results in reduction of tumor development suggesting its importantrole in maintenance of cancer phenotype. The long-term objectives of this application are to understand therole of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti-neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG inovarian epithelial cells on cellular transformation and tumor development in nude mice; ii) to determine theeffect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation progressionand metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis;and iii)to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumorsuppression and metastasis and determine mechanisms that lead to suppression of tumor growth andmetastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovariantumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTGfunction as anti-neoplastic agents. In addition transgenic animal model developed from our studies couldenhance efforts aimed at developing new methods for detection prevention and treatment of ovarian cancer.

project_terms:
5q35.1;AKT Signaling Pathway;Address;Adenoviruses;Aneuploidy;Animal Model;Antineoplastic Agents;Base Sequence;Boxing;Cancer Model;Cause of Death;Cell Proliferation;Cells;Cessation of life;Chromosomal Instability;Chromosome abnormality;Chromosomes;Complementary DNA;Crossbreeding;Cytoplasm;Data;Detection;Developed Countries;Development;Down-Regulation;Enzyme-Linked Immunosorbent Assay;Epithelial Cells;Epithelium;Fetal Kidney;Fetal Liver;Fibroblast Growth Factor 2;Gene Expression;Genes;Genetic;Genetically Engineered Mouse;Genomic Instability;Growth;Gynecologic;Health;Human;IL8 gene;In Vitro;Laboratories;Lead;Maintenance;Malignant Neoplasms;Malignant neoplasm of ovary;Mediating;Messenger RNA;Methods;Modeling;Molecular;Molecular Cloning;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Protein;Nuclear Proteins;Nude Mice;Oncogene Proteins;Oncogenes;Oncogenic;Ovarian;Ovarian Surface Epithelial-Stromal Tumor;Ovary;PI3K/AKT;PTTG1 gene;Phenotype;Preclinical Testing;Prevention;Process;Production;Proline-Rich Domain;Promotor (Genetics);Protein Sequence Analysis;Proteins;Reporting;Research Personnel;Role;Sister Chromatid;Sister Chromatid Exchange;Small Interfering RNA;Staging;Structure;Surface;System;Testis;Time;Transgenic Animals;Transgenic Mice;Tumor Suppression;United States;Vascular Endothelial Growth Factors;Woman;angiogenesis;base;c-myc Genes;cancer diagnosis;cell type;expression vector;gene function;human PTTG1 protein;human tissue;in vivo;indexing;knockout animal;loss of function;malignant breast neoplasm;metaplastic cell transformation;neoplastic;neoplastic cell;novel;ovarian neoplasm;overexpression;pituitary tumor-transforming proteins;programs;small molecule;therapy development;tumor;tumor growth;tumor initiation;tumorigenesis;tumorigenic


application_id: 7754132
project_number: 5R01DA025032-02
project_title: Agonist Replacement Therapy for Methamphetamine Dependence: Human Lab Studies
administering_ic: NIDA
award_notice_date: 2010-01-12
opportunity_number: PA-07-333
application_type: 5
activity_code: R01
ic: DA
serial_number: 025032
program_official: OVERSBY, STEVEN
project_start_date: 2009-01-01
project_end_date: 2013-12-31
study_section: ZDA1-MXH-H(20)
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Methamphetamine dependence is a significant public-health concern. The results of clinical trials suggest that agonist replacement therapies (e.g. d-amphetamine) may be effective for methamphetamine dependence. The present project has three specific aims. The first specific aim is to demonstrate the safety tolerability and behavioral effects of intranasal methamphetamine in humans maintained on d-amphetamine. To accomplish this aim we will conduct one experiment in which non-treatment seeking volunteers with recent histories of illicit stimulant use will receive ascending doses of intranasal methamphetamine while maintained on increasing doses of d-amphetamine (Exp. 1). Cardiovascular indices will be used to determine the safety and tolerability of the d-amphetamine-methamphetamine combinations while subjective-effect questionnaires will be used to characterize the behavioral effects. The results of this experiment will guide the selection of doses to be tested in subsequent studies. The second specific aim is to demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of methamphetamine. To accomplish this aim we will determine the reinforcing effects of intranasal methamphetamine during d-amphetamine maintenance using a progressive-ratio procedure (Exp. 2). Pharmacotherapies that attenuate the reinforcing effects of methamphetamine may be effective for initiating abstinence. The third specific aim is to demonstrate that d-amphetamine maintenance attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim volunteers will learn to discriminate intranasal methamphetamine (Exp. 3). The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e. a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide important additional clinical information regarding the efficacy of agonist replacement therapies for methamphetamine dependence. By using two sophisticated human laboratory procedures one to model abstinence initiation (i.e. drug self-administration) and the other to model relapse prevention (i.e. drug discrimination) the proposed research will determine the mechanisms that mediate the clinical efficacy of d-amphetamine for methamphetamine dependence. By inference then the proposed research will identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e. initiate abstinence or prevent relapse). Finally because d-amphetamine reduces methamphetamine use these clinical findings can be used as a reference to determine the predictive validity of human laboratory procedures. Identifying procedures for assessing the efficacy of putative pharmacotherapies via a "beside-to-bench" or "reverse engineering" strategy is important because human laboratory studies can be conducted more rapidly and efficiently than clinical trials. PUBLIC HEALTH RELEVANCE: Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the efficacy of agonist replacement therapy for methamphetamine dependence. The proposed research will also identify the optimal conditions under which d-amphetamine would be effective as a pharmacotherapy for methamphetamine dependence (i.e. initiate abstinence or prevent relapse). Finally the proposed research will determine appropriate human laboratory procedures for testing pharmacotherapies for methamphetamine dependence. Identifying appropriate human laboratory procedures for assessing the efficacy of pharmacotherapies for methamphetamine dependence is important because laboratory studies can be conducted more rapidly and efficiently than clinical trials.

project_terms:
Abstinence;Admission activity;Agonist;American;Attenuated;Behavior;Behavioral;Behavioral Mechanisms;Cardiovascular system;Clinical;Clinical Trials;Cocaine;Cocaine Dependences;Cocaine Users;Dependence;Dextroamphetamine;Dose;Educational process of instructing;Engineering;Epidemiology;Goals;Great Lakes Region;Human;Institution;Intelligence;Kentucky;Laboratories;Laboratory Animals;Laboratory Procedures;Laboratory Study;Learning;Location;Maintenance;Mediating;Methadone;Methamphetamine;Methamphetamine dependence;Methods;Modeling;Nicotine;Opiate Addiction;Pharmaceutical Preparations;Pharmacotherapy;Placebos;Procedures;Psychostimulant dependence;Questionnaires;Recording of previous events;Relapse;Replacement Therapy;Reporting;Research;Safety;Self Administration;Signal Transduction;Stimulus;Testing;Uncertainty;bench to bedside;clinical effect;clinical efficacy;design;disorder later incidence prevention;drug abstinence;drug discrimination;effective therapy;indexing;methamphetamine abuse;nicotine replacement;novel;preclinical study;prevent;public health medicine (field);public health relevance;research study;volunteer


application_id: 7753574
project_number: 5R01HL055477-14
project_title: Toxicity and Detoxification of 4Hydroxyalkenals in Heart
administering_ic: NHLBI
award_notice_date: 2009-12-24
application_type: 5
activity_code: R01
ic: HL
serial_number: 055477
program_official: LIANG, ISABELLA Y
project_start_date: 1998-12-01
project_end_date: 2012-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-01-01
project_abstract:
Although several studies suggest that myocardial injury during ischemia/reperfusion is in part due to reactiveoxygen species the mechanisms by which these oxidants injure the heart and those by which the heartprotects itself from their effects are not known. We propose that the myocardial effects of oxidative stressare mediated in part by 4-hydroxyalkenals such as 4-hydroxy-trans-2-nonenal (HNE) which are derived fromoxidation of lipoproteins and membrane lipids. Our previous work has led to the identification of the majorbiochemical pathways of HNE detoxification in cardiovascular tissues. These results suggest that aldosereductase (AR)-catalyzed reduction of HNE and its glutathione conjugate is a particularly critical step in thismetabolism because inhibition of AR increases HNE accumulation in the ischemic heart and abolishes thecardioprotective effects associated with the late phase of ischemic preconditioning (PC). Based on theseobservations and our preliminary data we now plan to test how the ischemic heart metabolizes HNE andwhether this is facilitated by the activation of AR due to nitric oxide (NO) generated during ischemia. Usingboth ex vivo and in situ murine models of myocardial ischemia-reperfusion injury we will identify ischemicchanges in AR and HNE metabolism and identify the chemical nature of AR modification and the oxidantsand triggers that induce it (Aim 1). In addition we will determine the role of endothelial and inducible NOsynthases (NOS) in activating AR and increasing HNE detoxification in the ischemic heart using micedeficient in individual NOS isoforms or overexpressing inducible NO synthase in the heart (Aim 2). Tounderstand the mechanisms of AR-mediated cardioprotection we will examine changes in the mitochondriaand myocardial survival signaling (Aim 3) and elucidate how pharmacologic inhibition of AR or cardiospecificoverexpression of AR (or its murine homolog FR-1) affects ischemia-reperfusion-induced mitochondrialpermeability transition and NF-kappaB activation (Aim 3). Successful completion of this project will lead to a better understanding of mechanisms of cardioprotection due to ischemic PC and NO and could form the basis of new clinical approaches to limit myocardial infarction. Delineation of the contribution of specific enzymes to HNE metabolism in the ischemic heart will be useful in identifying population subgroups that may be highly susceptible to oxidative stress caused by cardiovascular disease.

project_terms:
Affect;Aldehyde Reductase;Aldehydes;Atherosclerosis;Attenuated;Biochemical Pathway;Biochemical Process;Cardiac;Cardiovascular Diseases;Cardiovascular system;Cell Survival;Chemicals;Chronic;Clinical;Data;Development;Drug Metabolic Detoxication;Enzymes;Excision;Glutathione;Glutathione S-Transferase;Heart;Heart Mitochondria;Heart failure;Homologous Gene;In Situ;Individual;Injury;Ischemia;Ischemic Preconditioning;Kinetics;Knockout Mice;Lead;Lipid Peroxidation;Lipoproteins;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Membrane Lipids;Metabolism;Mitochondria;Modeling;Modification;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;NF-kappa B;Nature;Nitric Oxide;Nitric Oxide Synthase;Oxidants;Oxidation-Reduction;Oxidative Stress;Permeability;Phase;Population;Process;Protein Isoforms;Proteins;Reactive Oxygen Species;Regulation;Reperfusion Injury;Reperfusion Therapy;Role;Signal Transduction;Subgroup;Testing;Tissues;Toxic effect;Work;aldehyde dehydrogenases;base;gain of function;human NOS2A protein;injured;insight;loss of function;novel;overexpression;oxidation;preconditioning;prevent;research study;response


application_id: 7753223
project_number: 5R01CA133429-03
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2010-04-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2014-02-28
study_section: Molecular Oncogenesis Study Section[MONC]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Agreement;Apoptosis;Automobile Driving;Binding (Molecular Function);Biological Models;Cancer Center;Cancer Etiology;Cell Polarity;Cell Proliferation;Cells;Cellular biology;Cessation of life;Colon Carcinoma;Colorectal Cancer;Colorectal Neoplasms;Development;Diagnosis;Down-Regulation;Epithelial;Epithelial Cells;Failure (biologic function);Family;Frequencies (time pattern);Goals;Growth;Homeostasis;Howard Temin Award;Human;Human Development;Incidence;Intercellular Junctions;Intestines;Isoenzymes;Knock-out;Knockout Mice;Light;Malignant Neoplasms;Mediating;Mentored Research Scientist Development Award;Molecular;Names;Non-Small-Cell Lung Carcinoma;Oncogenic;PH Domain;Pathway interactions;Pharmacology and Toxicology;Phosphatidylinositols;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Physiological;Play;Process;Protein Dephosphorylation;Protein Kinase;Protein Kinase C;Protein phosphatase;Proteins;Proto-Oncogene Proteins c-akt;Publishing;Regulation;Research Personnel;Role;Scheme;Signal Pathway;Signal Transduction;Specimen;Targeted Research;Testing;Tumor Suppressor Proteins;Ubiquitin;United States;Up-Regulation (Physiology);base;cancer cell;cancer therapy;cell growth;citrate carrier;design;falls;gastrointestinal epithelium;in vivo;insight;leucine-rich repeat protein;multicatalytic endopeptidase complex;novel;overexpression;prevent;professor;public health relevance;research study;tumor;tumor growth;tumor initiation;tumorigenesis


application_id: 7752504
project_number: 5R01EY012974-08
project_title: The role of costimulatory molecules in uveitis
administering_ic: NEI
award_notice_date: 2009-11-25
application_type: 5
activity_code: R01
ic: EY
serial_number: 012974
program_official: SHEN, GRACE L
project_start_date: 2001-08-01
project_end_date: 2011-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-12-01
project_abstract:
The identification of costimulatory molecules has provided important insights into molecular mechanisms forthe regulation of the immune response andmore importantly into several novel approaches for autoimmuneor tumor immunotherapy. The growing number of known T cell costimulatory pathways together with thedynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatorymolecules regulating responses of naive effector and memory T cells. With the support of the current grantmy laboratory has made significant progress in understanding the role of costimulatory molecules inautoimmune uveitis. However our studies have also raised two important questions: (1) why are effectoruveitogenic T cells more resistant than naive T cells to treatment by costimulatory molecule blockers? (2) Dopathogenic and regulatory T cells rely on different costimulation so that a specific treatment regimen can beidentified to maximally suppress the pathogenic response with a minimal inhibitory effect on regulatory T cellactivation?For human disease immunotherapies that can interfere with an ongoing autoimmune disease are moreimportant than those preventing the development of disease since disease has already started by the time thepatient visits the doctor. Thus the long-term goal of this proposal is to explore therapeutic approachesinhibiting already activated autoreactive effector T cells. We will therefore determine whether CD28/B7costimulatory molecules are crucial for the pathogenic effect of uveitogenic T cells specifically: (1) whethereffector and regulatory T cells use CD28/B7 differently in terms of time and quantity and whether blockade of acombination of costimulatory molecules favors the treatment of ongoing autoimmune disease; (2) whether wecan identify therapeutic regimens that have a limited impact on regulatory T cell activity while inhibitingpathogenic activity; and (3) whether a combined treatment acting on costimulation of autoreactive T cell andocular inflammation can provide better control of ongoing disease. To provide a working model that will allowbetter understanding of the pathogenesis of recurrent uveitis we have established chronic recurrent models inthe rat and mouse. These studies should provide insights into the pathogenic mechanism leading to diseaseprogression and help in the development of supplementary therapies for this devastating disease.

project_terms:
Acute;Animals;Anti-Inflammatory Agents;Antibodies;Autoimmune Diseases;Autoimmune Process;CTLA4-Ig;Cells;Chronic;Clinical Treatment;Combined Modality Therapy;Complex;Data;Development;Disease;Disease Progression;Disease model;Disease remission;Dose;Environmental Risk Factor;Eye;Generations;Genetic;Goals;Grant;Guanine Nucleotide Dissociation Inhibitors;Human;Immune response;Immunotherapy;Inflammation;Inflammatory;LTB4R gene;Laboratories;Leukotriene B4;Ligation;Lymphoid;MHC antigen;Mediating;Modeling;Molecular;Mus;Nature;Onset of illness;Pathogenesis;Pathway interactions;Patients;Pattern;Phase;Rattus;Reaction;Recruitment Activity;Recurrence;Regimen;Regulation;Regulatory T-Lymphocyte;Relapse;Research Personnel;Resistance;Rodent;Role;Signal Transduction;Study models;T memory cell;T-Cell Activation;T-Lymphocyte;Therapeutic;Therapeutic Effect;Time;Treatment Protocols;Uveitis;Visit;Work;autoimmune uveitis;autoreactive T cell;cell motility;chemokine;cytokine;disorder control;human disease;insight;novel strategies;prevent;programs;protective effect;receptor;response;treatment effect;tumor


application_id: 7751850
project_number: 5K23DE015298-05
project_title: Central Pain Processing in Chronic Face Pain:fMRI Study
administering_ic: NIDCR
award_notice_date: 2010-01-19
opportunity_number: PA-00-004
application_type: 5
activity_code: K23
ic: DE
serial_number: 015298
program_official: HARDWICK, KEVIN S
project_start_date: 2006-02-01
project_end_date: 2012-01-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7351795
contact_pi: DE LEEUW, RINSKJE
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This proposal for a K23 "Mentored Patient-Oriented Research Career Development Award" will provide thecandidate with five years of continuous funding to gain a broad knowledge in the design and conduct ofcomplex clinical oral health trials. This training will enhance the research environment of the Orofacial PainCenter and mentoring capacity of the University of Kentucky College of Dentistry. The candidate earned aPhD in General Medicine from the University of Groningen and received three years of postgraduategraduate training in Orofacial Pain at the University of Kentucky. This award would allow the candidate toevolve to an independent investigator and would prepare the candidate to successfully mentor MS and PhDcandidates in orofacial pain research. The training program consists of two phases: a didactic componentemphasizing courses in research design biostatistics data analysis and epidemiology and a researchphase involving a neuroimaging investigation of central pain processing in patients with chronic face pain.Three specific aims are proposed in this training application: Specific Aim 1. To assess the presence of painaugmentation in patients with chronic masticatory myofascial pain; Specific Aim 2. To investigate differencesin location and extent of activation of brain regions involved in trigeminal pain processing between patientswith chronic masticatory muscle pain and pain-free volunteers; and Specific Aim 3. To investigate theinfluence of estrogen level on cerebral activation in response to an acute experimental pain stimulus inpatients with chronic masticatory muscle pain and pain-free volunteers. Dr. Charles Carlson PhD ProfessorDepartments of Psychology and Oral Health Science and research director of the Orofacial Pain Center andDr. Don Gash PhD Alumni Professor and Chair Department of Anatomy and Neurobiology and director ofthe Magnetic Resonance Imaging and Spectroscopy Center will mentor the candidate. There is limitedinformation on cerebral activation in response to stimulation of trigeminal structures in healthy pain-freevolunteers as well as in chronic face pain patients. The available data support that there are importantdifferences in the cerebral processing of pain in chronic pain patients compared to pain-free subjects.Moreover the existing data suggest that in chronic pain conditions the medial pain system the structuresassociated with the processing of the emotional-affective component of pain exhibits altered activity.Additionally there is a lack of information about the influence of estrogen on the central processing of pain.The available data suggest that estrogen may have an inhibitory / anxiolytic effect on the perception of painpossibly by modulating the endogenous opioid system. Because neuroimaging data on this topic are scarceand chronic pain conditions are predominant in women of reproductive age the role of estrogen on painshould be further explored.

project_terms:
Acute;Acute Pain;Address;Affect;Affective;Age;Age of Onset;Anatomy;Animals;Anterior;Anti-Anxiety Agents;Anxiety;Area;Award;Awareness;Behavioral;Biometry;Brain;Brain imaging;Brain region;Burn injury;Burning Mouth Syndrome;Cerebrum;Chronic;Clinical;Cognitive;Complex;Data;Data Analyses;Dentistry;Diagnosis;Distant;Doctor of Philosophy;Emotional;Endogenous Opiates;Environment;Epidemiology;Estrogens;Etiology;Exhibits;Facial Pain;Female;Female of child bearing age;Fibromyalgia;Functional Magnetic Resonance Imaging;Funding;Gonadal Steroid Hormones;Head and neck structure;Human;Hyperalgesia;Hypersensitivity;Incidence;Intervention;Investigation;Irritable Bowel Syndrome;Kentucky;Knowledge;Life;Limbic System;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Mandible;Masticatory muscles;Measures;Medial;Medicine;Menstruation;Mentored Patient-Oriented Research Career Development Award;Mentors;Migraine;Modality;Monitor;Mouth Diseases;Musculoskeletal Diseases;Musculoskeletal Pain;Myalgia;Neuraxis;Neurobiology;Neurons;Opioid;Oral health;Orofacial Pain;Outcome;Pain;Pain Clinics;Pain Disorder;Pain Research;Pain Threshold;Pain management;Pain-Free;Participant;Pathology;Patients;Pattern;Perception;Peripheral;Personal Satisfaction;Persons;Phase;Physiological Processes;Play;Prefrontal Cortex;Prevalence;Principal Investigator;Process;Protocols documentation;Psychology;Puberty;Recurrent pain;Reporting;Research;Research Design;Research Personnel;Resistance;Role;Sample Size;Scanning;Sensory;Serum;Signal Transduction;Site;Somatosensory Cortex;Spectrum Analysis;Stimulus;Stress;Structure;System;Temperature;Temporomandibular Joint Disorders;Testing;Thalamic structure;Training;Training Programs;Trigeminal Neuralgia;Trigeminal System;Trigeminal nerve structure;Universities;Woman;base;central pain;chronic neuropathic pain;chronic pain;cingulate cortex;cold temperature;college;design;experience;health science research;interdisciplinary approach;interest;male;masticatory myalgia;mechanical pressure;neuroimaging;pressure;professor;programs;reproductive;response;volunteer


application_id: 7751340
project_number: 5R01AI064421-05
project_title: Analyzing and modulating immunoregulatory defects in autoimmune disease.
administering_ic: NIAID
award_notice_date: 2009-12-28
application_type: 5
activity_code: R01
ic: AI
serial_number: 064421
program_official: BOURCIER, KATARZYNA
project_start_date: 2006-01-01
project_end_date: 2011-12-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-01-01
project_abstract:
Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimrnunity.Although the thymus appears to be a major site of CD4+CD25+ T cell development it is stillunclear whether there are also peripheral sites of development. We have found recently thatCD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in theperiphery. Conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells may be a veryimportant mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenanceand a defect in this process could contribute to autoimmune disease development. We havefound that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in thethymus but a significantly lower percentage in the periphery. Furthermore NOD CD4+CD25"Tcells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function stronglysuggesting that NOD mice may have a defect in this conversion process and may therefore beunable to maintain this regulatory population. The central hypothesis of this proposal is thatenhanced conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD micecan prevent diabetes. We will test this hypothesis by studying the mechanisms and defects inconversion in NOD mice determinewhether this process can be restored and whether restorationis associated with amelioration of disease. By understanding the defects in conversion ofCD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice it may be possible todevise strategies to overcome these defects andthereby develop therapies to prevent or treatautoimmune disease.

project_terms:
Address;Antigens;Autoimmune Diseases;Autoimmunity;Cells;Defect;Development;Diabetes Mellitus;Disease;Exposure to;Goals;Homeostasis;Inbred NOD Mice;Insulin-Dependent Diabetes Mellitus;Maintenance;Mouse Strains;Mus;Organ;Peripheral;Phenotype;Population;Process;Regulatory T-Lymphocyte;Site;T-Cell Development;T-Lymphocyte;Testing;Thymus Gland;in vivo;prevent;reconstitution;response;restoration;therapy development


application_id: 7751300
project_number: 5R01NS062306-03
project_title: PPAR Inhibition of Spinal Pain Transmission
administering_ic: NINDS
award_notice_date: 2009-11-20
opportunity_number: PA-07-282
application_type: 5
activity_code: R01
ic: NS
serial_number: 062306
program_official: PORTER, LINDA L
project_start_date: 2008-12-18
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1-IFCN-E(02)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Peroxisome proliferator-activated receptor gamma (PPAR 3) is well-characterized as a key target of the thiazolinedione (TZD) class of anti-diabetic drugs. Our preliminary results describe the existence of PPAR 3 mRNA and protein in the dorsal horn. Furthermore we demonstrate that the mechanical and thermal hypersensitivity associated with inflammation or nerve injury was rapidly reduced by intrathecal administration of rosiglitazone (a TZD) and 15d-PGJ2 (an endogenous PPAR 3 ligand) in a dose- and PPAR 3-dependent manner and by systemic administration of pioglitazone a BBB-permeant FDA-approved ligand. The central hypothesis of this proposal is that ligand-dependent activation of PPAR3 in the dorsal horn decreases injury- induced activation of spinal neurons and glia that then dampens behavioral signs of inflammatory and neuropathic pain. The objective of the present application is to identify the mechanisms underlying PPAR- mediated inhibition of inflammatory or neuropathic pain with a focus on pioglitazone. The long-term goal of our research program is to harness the therapeutic potential of PPAR signaling to alleviate chronic pain in humans. AIM 1 will test the hypothesis that PPAR 3 agonists reduce allodynia and hyperalgesia. We will use pharmacological agents and nervous system-specific PPAR 3 deletion mutants to determine the contribution of PPAR 3 signaling in the spinal cord to the induction and maintenance of chronic pain. First we will determine whether single intrathecal or systemic administration of pioglitazone and 15d-PGJ2 reduces behavioral signs of inflammatory and neuropathic pain. We predict that their analgesic actions will be blocked with PPAR 3 antagonists. Second we will determine whether chronic intrathecal or oral administration of PPAR 3 agonists begun before or after tissue or nerve injury reduces behavioral signs of inflammatory and neuropathic pain. Third we predict that anti-allodynic actions will not occur in mice with neuron-specific PPAR 3 knockdown. AIM 2 will test the hypothesis that PPAR 3 ligands reduce injury-induced activation of neurons and microglia in the dorsal horn. Somatosensory stimulation of injured rats induces the expression of the immediate early gene c-fos in the superficial laminae of the dorsal horn. We predict that intrathecal pioglitazone will reduce inflammation- and nerve injury-induced expression of Fos immunoreactive neurons as well as the expression of OX-42 a marker of microglia activation. AIM 3 will test the hypothesis that endogenous PPAR 3 systems tonically inhibit allodynia. First we will determine if PPAR3 expression occurs in neurons and/or glia that are activated during pain. Second in an extension of Aims 1-2 we will determine whether receptor antagonists and genetic deletion increase allodynia and neuronal/glial activation. If affirmative then we will determine whether the PPAR3 signaling elements co- vary with allodynia. At various times after nerve injury or persistent inflammation we will evaluate: behavior and A) PPAR 3 mRNA and protein; B) phosphorylated PPAR 3; and C) 15d-PGJ2 levels with LC/MS/MS. PUBLIC HEALTH RELEVANCE Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. We propose that ligands for peroxisome proliferator-activated receptor gamma (PPAR 3) such as rosiglitazone and pioglitazone represent a novel class of analgesic / anti-allodynic compounds. These conceptually innovative experiments are important and timely because TZDs are commercially available for diabetes and are in clinical trials for CNS neurodegenerative diseases. Thus confirmation of our hypothesis could lead to rapid translation to the clinical treatment of chronic pain.

project_terms:
Adverse effects;Agonist;Analgesics;Antidiabetic Drugs;Astrocytes;Basic Science;Behavior;Behavioral;Chronic;Clinical Treatment;Clinical Trials;Cobalt;Diabetes Mellitus;Dose;FDA approved;Genetic;Goals;Healthcare;Human;Hyperalgesia;Hypersensitivity;Immediate-Early Genes;Immunohistochemistry;Inflammation;Inflammatory;Injury;Lead;Ligands;Maintenance;Mass Spectrum Analysis;Mechanics;Mediating;Messenger RNA;Microglia;Mus;Nervous system structure;Neurodegenerative Disorders;Neuroglia;Neurons;Oral Administration;PPAR gamma;Pain;Pain management;Peripheral;Peripheral nerve injury;Peroxisome Proliferator-Activated Receptors;Pioglitazone;Protein Isoforms;Proteins;Rattus;Receptor Inhibition;Receptor Signaling;Regulation;Research;Signal Transduction;Spinal;Spinal Cord;Stimulus;System;Testing;Therapeutic;Thiazolidinediones;Time;Tissues;Transgenic Mice;Translations;Western Blotting;allodynia;chronic pain;dorsal horn;inflammatory neuropathic pain;injured;innovation;mutant;nerve injury;novel;painful neuropathy;programs;public health relevance;receptor;research study;rosiglitazone;somatosensory;transmission process


application_id: 7751214
project_number: 5F31NS057928-04
project_title: Contribution of endogenous NPY signaling to chronic pain
administering_ic: NINDS
award_notice_date: 2009-12-25
opportunity_number: PA-07-106
application_type: 5
activity_code: F31
ic: NS
serial_number: 057928
program_official: PORTER, LINDA L
project_start_date: 2008-01-01
project_end_date: 2010-12-31
study_section: Special Emphasis Panel[ZRG1-F02B-G(20)L]
contact_pi_person_id: 8717038
contact_pi: SOLWAY, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammation or peripheral nerve injury increases neuropeptide Y (NPY) expression in pain-relevant areas of the nervous system such as large primary afferents and lamina l/ll of the dorsal horn of the spinal cord. However the contribution of endogenous NPY to chronic pain is unclear. This NRSA proposes to test the overall hypothesis that NPY tonically inhibits nociceptive signaling in the spinal cord and brain following inflammation or nerve injury. Specific Aim #1 will test the hypothesis that genetic knockdown of NPY increases allodynia and/or hyperalgesia associated with nerve injury and inflammation. Aim #1 experiments utilize a conditional knockout mouse (Npytet) that contains a doxycycline (Dox)-regulated cassette (tTA) upstream of Npy exons to evaluate the contribution of NPY to the development (Aim 1 A) and maintenance (Aim 1B) of chronic pain and correlate these changes with NPY expression using immunohistochemistry and western blot (Aim 1C). While Aim #1 establishes a contribution of NPY inhibition to behavioral manifestations of chronic pain Specific Aim #2 uses direct microinjection techniques to investigate the site of action of NPY. NPY Y1 and NPY Y2 receptors decorate lamina l/ll of the dorsal horn. I propose to target these receptors with intrathecal injection of selective Y1 or Y2 receptor antagonists (Aim 2A). Previous studies indicate that inflammation up-regulates the expression of NPY and Y1 in the arcuate nucleus of the hypothalamus (ARC) and that microinjection of NPY into the ARC attenuated behavioral signs of heat hypersensitivity. In Aim 2B I propose to microinject Y1 or Y2 antagonists into the ARC and predict that this will exacerbate allodynia and hyperalgesia.

project_terms:
Address;Animals;Area;Attenuated;Behavior;Behavioral;Brain;Data;Development;Doxycycline;Exhibits;Exons;Freund's Adjuvant;Genes;Genetic;Hand;Heating;Hyperalgesia;Hypersensitivity;Hypothalamic structure;Immunohistochemistry;Inflammation;Inflammatory;Injection of therapeutic agent;Intrathecal Injections;Knock-out;Knockout Mice;Maintenance;Masks;Microinjections;Modeling;Mus;National Research Service Awards;Nervous system structure;Neuropeptide Y Receptor;Nociception;Pain;Peripheral nerve injury;Prevention;Ramp;Signal Transduction;Site;Spinal;Spinal Cord;Spinal Ganglia;Spinal cord posterior horn;Structure of nucleus infundibularis hypothalami;Techniques;Testing;Transgenic Mice;Western Blotting;allodynia;chronic pain;dorsal horn;inflammatory neuropathic pain;inflammatory pain;nerve injury;neuropeptide Y;painful neuropathy;receptor;research study;response


application_id: 7750753
project_number: 7R01AA015407-05
project_title: GSK-3 beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2009-01-12
application_type: 7
activity_code: R01
ic: AA
serial_number: 015407
program_official: NORONHA, ANTONIO
project_start_date: 2005-08-01
project_end_date: 2010-07-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2008-02-06
project_abstract:
DESCRIPTION (provided by applicant): Two of the most striking effects of ethanol exposure during development are the disruption of neuronal migration and the deletion of neurons in certain areas of the central nervous system (CMS). The cellular/ molecular mechanisms underlying these damages remain unclear. Glycogen synthase kinase-3/beta (GSK3beta) is predominantly expressed in neurons in the developing CMS and emerges as a critical signaling component regulating diverse events of neuronal development such as neuronal migration and proliferation/survival. It has also been implicated in abnormalities in the adult brain such as neurodegenerative diseases. The activity of GSK3beta is regulated by phoshorylation and subcellular localization. GSK3beta is activated by various cellular stresses including endoplasmic reticulum (ER) stress. We have demonstrated that ethanol exposure induces ER stress and significantly alters the phosphorylation state of a GSK3beta in vitro and in vivo event at modest concentrations (50-100 mg/dl); blocking GSK3beta activation mitigates ethanol-induced neuronal death. Although ethanol alone at relatively low concentrations does not cause neuronal death it greatly potentiates apoptosis caused by various exogenous insults which also activate GSK3beta. In contrast ethanol does not affect cell death induced by pro-apoptotic signals which are independent of GSK3beta. We hypothesize that GSK3beta is a critical mediator of ethanol neurotoxicity. In this proposal we will characterize the effect of ethanol on phosphorylation/activity subcellular localization and expression of GSK3beta in the developing neurons using various model systems (cultured neurons organotypic slice culture of rat cerebellum and the developing cerebellum). Subsequently we will determine the role of GSK3beta in ethanol-induced cell cycle arrest apoptosis inhibition of neurite outgrowth and aberrant migration patterns; we will determine whether blocking GSK3beta activation by selective inhibitors or over- expression of dominant negative GSK3beta (DN-GSK3beta) or GSK3beta binding protein (GBP) provides neuroprotection against ethanol-induced damage. In addition we will investigate the role of Chop (GADD153) another ER stress responsive factor in ethanol-induced neuronal damages. Futhermore we will elucidate the mechanisms underlying GSK3beta activation; we will systematically investigate up-stream signaling of GSK3beta and the contribution of ER stress-responsive components such as protein phosphatase 2A to ethanol-induced GSK3beta activation. Finally we will investigate whether ethanol-induced sensitization or potentiation to apoptosis caused by other insults is dependent on GSK3beta we will determine whether over- expression of DN- GSK3beta and GBP abolishes ethanol-induced potentiation to neuronal death triggered by other pro-apoptotic stimuli. As a unit these experiments will explore a novel mechanism underlying ethanol- induced damage to the CMS using in vitro and in vivo model systems. The systematical study may establish GSK3beta as a potential therapeutic target for the treatment of alcohol neurotoxicity

project_terms:
Adult;Affect;Alcoholism;Apoptosis;Apoptotic;Area;Binding Proteins;Biological Models;Brain;Cause of Death;Cell Cycle Arrest;Cell Cycle Progression;Cell Death;Cell Death Induction;Cell Death Inhibition;Cell Survival;Cell-Free System;Cells;Cellular Stress;Central Nervous System Diseases;Cerebellum;Cessation of life;Chemosensitization;Development;Disruption;Dominant-Negative Mutation;Endoplasmic Reticulum;Ethanol;Event;Exposure to;Fetal development of the mammalian embryo or fetus;Functional disorder;Glycogen Synthase Kinase 3;In Vitro;In-Migration;Induction of Apoptosis;Inhibition of Apoptosis;Mediating;Mediator of activation protein;Molecular;Nerve Degeneration;Neuraxis;Neurites;Neurodegenerative Disorders;Neurons;Neuropathogenesis;Pattern;Phosphorylation;Predisposition;Protein phosphatase;Range;Rattus;Role;Series;Signal Transduction;Slice;Stimulus;Stream;Stress;Strikes Employee;alcohol abuse therapy;alcohol effect;alcohol exposure;biological adaptation to stress;glycogen synthase kinase 3 beta;in vivo;in vivo Model;inhibitor/antagonist;insight;migration;nervous system disorder;neuropathology;neuroprotection;neurotoxicity;novel;prenatal exposure;pup;research study;synaptogenesis;therapeutic target


application_id: 7750750
project_number: 7R01AA017226-02
project_title: Alcohol and Breast Cancer
project_terms: Alcohols;Malignant neoplasm of breast
administering_ic: NIAAA
award_notice_date: 2009-01-14
opportunity_number: PA-07-070
application_type: 7
activity_code: R01
ic: AA
serial_number: 017226
program_official: JUNG, KATHY
project_start_date: 2008-03-05
project_end_date: 2013-02-28
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcoholism alcohol abuse and the medical complications of excessive drinking are major world-wide health problems. Alcohol is a tumor promoter. Epidemiological studies indicate that heavy alcohol consumption increases risk of breast cancer and is associated with advanced and invasive breast tumors. However the etiology of alcohol-induced tumor promotion is elusive. Cellular/molecular mechanisms underlying alcohol-promoted tumor development and progression remain unknown. ErbB2 a member of the epidermal growth factor receptor tyrosine kinase family is frequently over-expressed in human breast cancers. We have demonstrated that alcohol dramatically promotes migration/invasion of mammary epithelial cells and breast cancer cells over-expressing ErbB2. We also reveal that the human transmembrane mucin (MUC1) is highly sensitive to alcohol. -catenin is a proto-oncogene and plays an important role in tumorigenesis and cancer progression. The E-cadherin/-catenin complex a critical component of cell-cell adherens maintains the integrity of epithelial cell interactions and regulates cell migration/invasion. We propose a novel role of MUC1 as an adaptor protein that bridges ErbB2 and -catenin and facilitate ErbB2/-catenin interaction and the dissociation of E- cadherin/ -catenin complex. Our central hypothesis is that ethanol-induced oxidative stress up- regulates MUC1 as an adaptor protein to promote ErbB2/ -catenin interaction which induces dissociation of the -catenin/E-cadherin complex leading to cell transformation and cell migration/invasion. Both in vitro and in vivo models will be utilized to test this novel hypothesis. Specific Aim 1 will establish the pivotal role of MUC1 in ethanol-promoted ErbB2/ -catenin interaction. Specific Aim 2 will determine whether ethanol-promoted cell transformation and cancer cell migration/invasion is mediated by MUC1-dependent dissociation of the E-cadherin/2-catenin complex. Specific Aim 3 will investigate in vivo effects of ethanol. We will investigate the effect of ethanol on mammary tumorigenesis/metastasis in MMTV-Neu transgenic mice. We will further investigate the effect of ethanol on the interactions among MUC1 ErbB2 -catenin and E-cadherin as well as the role of ROS and MUC1 in ethanol- mediated tumorigenesis/metastasis in the transgenic and nude mice. As a cohesive unit the multi-disciplinary approaches using in vitro and in vivo models will systematically explore the mechanisms underlying alcohol-promoted tumorigenesis and malignant progression of breast cancer. The study will elucidate a novel function of ErbB2 and MUC1 in alcohol-induced tumor promotion. The expression/activity of ErbB2 and MUC1 is frequently aberrant in many other human cancers and in a variety of human diseases; their levels are also developmentally regulated. Understanding the interactions among alcohol ErbB2 and MUC1 will also provide an important insight into the pathogenesis of some human diseases related to alcohol abuse as well as alcohol's teratogenic effect during development.


application_id: 7750514
project_number: 5R01CA129015-02
project_title: The role of Pdcd4 in colorectal tumor progression
administering_ic: NCI
award_notice_date: 2009-12-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129015
program_official: JHAPPAN, CHAMELLI
project_start_date: 2009-01-01
project_end_date: 2013-11-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 8737920
contact_pi: YANG, HSIN-SHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer-related deaths in the United States largely due to invasion and metastasis to the liver and lymph nodes. Thus a thorough understanding of invasion/metastasis is necessary for prevention and treatment of colon cancer. Over- expression of programmed cell death 4 (Pdcd4) a novel tumor suppressor inhibits invasion and AP-1 dependent transcription in colon tumor cells. Pdcd4 expression is frequently down-regulated in colon tumor tissues as compared to adjacent normal tissues. The objective of the proposed study is to define the function of Pdcd4 in tumor invasion/metastasis and elucidate the molecular mechanisms involved in these processes. We knocked down Pdcd4 expression in colon tumor GEO and HT29 cells and found that Pdcd4 knock-down triggers morphological changes induces invasion and activates 2-catenin/Tcf and AP-1 dependent transcription. Our preliminary results further demonstrated that a decrease in E-cadherin expression correlates with an increase in the protein level of Slug a transcription repressor for E-cadherin expression. We therefore hypothesize that Pdcd4 knock-down promotes colon tumor cell invasion/metastasis through down-regulation of E-cadherin and activation of 2-catenin/Tcf and AP-1 dependent transcription. To test our hypothesis four Specific Aims are proposed. Aim 1: determine whether Pdcd4 functions as a metastasis inhibitor in colon tumor cells. Epithelial-to-mesenchymal transition and metastasis in mice will be assayed using Pdcd4 knock- down and over-expressed cells. Aim 2: examine whether activation of 2-catenin/Tcf dependent transcription led by E-cadherin down-regulation in Pdcd4 knock-down cells promotes invasion/metastasis. We will test activation of 2-catenin/Tcf dependent transcription by knocking down E-cadherin reversion of the invasive/metastatic ability by inhibiting 2-catenin/Tcf dependent transcription verification of uPAR and c-Myc as the target genes of 2-catenin/Tcf dependent transcription and inhibition of 2-catenin/Tcf4 dependent transcription and its target gene expression by over-expressing Pdcd4. Aim 3: determine whether activation of 2-catenin/Tcf4 dependent transcription in Pdcd4 knock-down cells up-regulates MAP4K1 expression and AP-1 activity through c-Myc. We will establish the c-Myc as a regulator of MAP4K1 expression and activation of 2- catenin/Tcf dependent transcription causing up-regulation of MAP4K1 expression JNK activation and AP-1 dependent transcription. Aim 4: determine whether Pdcd4 translationally inhibits transcription repressor Slug expression resulting in up-regulation of E-cadherin and suppression of invasion/metastasis. Translation inhibition and the inhibitory mechanism will be analyzed using in vitro and in vivo translation assays followed by an examination of E-cadherin expression level and the ability of invasion/metastasis in Slug knock-down and Pdcd4 expressing cells. This work will provide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds great promise for novel interventions for preventing and treating colon cancer. PUBLIC HEALTH RELEVANCE Colorectal cancer is the second most fatal cancer in the United States largely due to invasion and metastasis to the liver and lymph nodes. In this proposal we intend to understand the effects of a novel tumor suppressor Pdcd4 on colon tumor metastasis and the molecular mechanism involved in this process. This work will provide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds great promise for novel interventions for preventing and treating colon cancer.

project_terms:
5' Untranslated Regions;Address;Apoptosis;Binding (Molecular Function);Binding Sites;Biological Assay;Cancer Etiology;Cancerous;Cells;Cessation of life;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Colorectal Neoplasms;Complex;Cultured Cells;Dominant-Negative Mutation;Down-Regulation;E-Cadherin;Epithelial;Fibroblasts;Fractionation;Free Energy;Gene Expression;Gene Targeting;Genetic Transcription;HT29 Cells;In Vitro;Injection of therapeutic agent;Intervention;Knowledge;Liver;MAPK8 gene;Malignant Neoplasms;Measures;Mesenchymal;Messenger RNA;Methods;Molecular;Mus;Mutate;Mutation;Neoplasm Metastasis;Normal tissue morphology;Nude Mice;Oncogene Activation;Polyribosomes;Prevention;Process;Promotor (Genetics);Proteins;Publications;Reagent;Reverse Transcription;Role;Site-Directed Mutagenesis;Slug protein;Staining method;Stains;Structure;Testing;Tissues;Transcription Factor AP-1;Transcription Repressor/Corepressor;Translational Repression;Translations;Tumor Cell Invasion;Tumor Suppressor Proteins;Tumor Tissue;Tumor-Suppressor Gene Inactivation;United States;Up-Regulation (Physiology);Work;base;c-myc Genes;cancer cell;chromatin immunoprecipitation;design;epithelial to mesenchymal transition;implantation;in vivo;inhibitor/antagonist;insight;knock-down;lymph nodes;mutant;neoplastic cell;novel;novel therapeutics;prevent;public health relevance;slug;translation assay;tumor progression


application_id: 7749649
project_number: 1F31AA018588-01
project_title: Adenosine Receptors and Ethanol Withdrawal
administering_ic: NIAAA
award_notice_date: 2009-08-04
application_type: 1
activity_code: F31
ic: AA
serial_number: 018588
program_official: CUI, CHANGHAI
project_start_date: 2009-09-01
project_end_date: 2011-05-08
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 9706316
contact_pi: BUTLER, TRACY RENEE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-09-01
project_abstract:
DESCRIPTION (provided by applicant): Previous studies suggest an innate sex difference in adenosine receptor density and/or function which is mediated at least in part by NMDA receptors (Butler et al. 2008). The currently proposed studies will investigate effects of chronic ethanol (EtOH) exposure on adaptive changes in adenosine and NMDA receptor proteins which may confer sensitivity to neurotoxicity during ethanol withdrawal (EWD) in a concentration- and/or sex-dependent manner. Male and female organotypic hippocampal slice cultures will be continuously exposed to EtOH (0 25 or 50 mM) for ten days. Upon removal of EtOH immunohistochemistry will be employed for the adenosine A1 and A2A receptor subtypes and the NMDA NR1 and NR2B subunits to quantify receptor density in the primary cell layers of the dentate gyrus and the CA3 and CAI regions of the hippocampus. Western blotting will be conducted for an additional quantitative measure of changes in receptor proteins throughout the whole hippocampal formation in male and female EtOH-exposed cultures (0 25 50 mM). Additional studies will examine functional consequences of pharmacological antagonism of adenosine Al receptor antagonism during EWD. Cultures will be exposed to EtOH for ten days before twenty-four hour EWD. For the duration of EWD cultures will be exposed to an Air antagonist; an Air antagonist + Air agonist; or an Air antagonist + NMDAr antagonist; and all cultures will be exposed to propidium iodide (PI) for labeling of dead/dying cells. Cultures will then be formalin-fixed for immunohistochemical labeling of mature neurons with neuronal nuclear protein (NeuN). Additional cultures will be exposed to the same drug treatments described but will be exposed to Calcium (Ca2+) Orange at the end of twenty-four hour EWD to measure whether toxicity caused by A1r antagonism during EWD is correlated with potentiated Ca2+ influx. Slices will be visualized using fluorescent microscopy and data will be quantified using densitometry and confocal imaging. Correlational analyses will determine if the measures of cell viability (PI NeuN Ca2-*- orange) are related. These techniques allow for a comprehensive characterization of changes in the adenosinergic and NMDA receptor systems induced by EtOH exposure and the functional consequences of those hypothesized adaptations during EWD. A significant amount of evidence suggests that the female brain of both humans and rodents is more sensitive to neurotoxicity in response to EtOH exposure and/or EWD. The current studies will contribute to our knowledge of EtOH- induced neuronal adaptations and potential sex differences in brain structure and/or function and may contribute to the advent of novel pharmacotherapies to ameliorate EtOH and/or EWD-related toxicity.

project_terms:
Adenosine;Agonist;Air;Alcohol withdrawal syndrome;Brain;Calcium;Calculi;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Chronic;Confocal Microscopy;Data;Densitometry;Ethanol;Excision;Excitatory Amino Acids;Female;Fluorescence;Formalin;Glutamates;Hippocampal Formation;Hippocampus (Brain);Hour;Human;Image;Imagery;Immunofluorescence Immunologic;Immunohistochemistry;In Vitro;Knowledge;Label;Laboratories;Measures;Mediating;Microscopy;Modeling;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NMDA receptor antagonist;NR1 gene;Neurons;Nuclear Protein;Nuclear Proteins;Oranges;Pharmaceutical Preparations;Pharmacotherapy;Polyamines;Propidium Diiodide;Purinergic P1 Receptors;Rattus;Reporting;Rodent;Sex Characteristics;Slice;Structure;System;Techniques;Toxic effect;Treatment Protocols;Western Blotting;Withdrawal;Work;alcohol effect;alcohol exposure;density;dentate gyrus;design;follow-up;in vivo;male;neurotoxicity;neurotransmission;novel;polypeptide;prevent;receptor;receptor density;research study;response;sex


application_id: 7748956
project_number: 5R01CA119028-06
project_title: Mechanisms of As-Induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2009-12-30
application_type: 5
activity_code: R01
ic: CA
serial_number: 119028
program_official: BLAIR, DONALD G
project_start_date: 2006-02-01
project_end_date: 2010-12-31
study_section: Special Emphasis Panel[ZRG1-ONC-E(02)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-01-01
project_abstract:
DESCRIPTION (provided by applicant): Arsenic (As) is a well-documented human carcinogen. Environmental and occupational exposures to As-containing compounds are major public health issues. Understanding the mechanism of As-induced carcinogenesis is very important for early detection for risk assessment for establishment of an exposure standard and for development of intervention and prevention strategies. While increasing evidence has linked arsenic exposure and generation of reactive oxygen species (ROS) we do not clearly understand the exact nature of the specific reactive species the source and mechanism of ROS generation the sequence of formation of different reactive species and the specific species that are responsible for the arsenic-induced carcinogenesis. The goal of this proposal is to test the hypothesis that As-induced carcinogenesis is mediated by oxidative stress. To test this hypothesis we will: (a) identify the molecular mechanism of As-induced ROS generation in cells with emphasis on 02.- radical generation since this radical is a precursor of other reactive oxygen species; (b) develop and apply an in vivo electron spin resonance (ESR) method for detection and identification of As-induced free radical generation in living animals; (c) determine oxidative stress lipid peroxidation protein oxidation and oxidative DNA damage following As exposure in vivo; and (d) elucidate the role of oxidative stress in Cr(VI)-induced cell transformation and tumorigenesis. We will use As-treated HaCat cells to examine As-induced tumorigenesis in athymic nude mice and investigate the involvement of specific ROS species. We anticipate that As generates ROS which cause activation of NF-KB and activator protein (AP-1) leading to tumorigenesis in nude mice. The methods used in the proposal are multi-disciplinary representing a combination of physical chemical and molecular approaches. The results obtained from this proposal will provide a fundamental understanding concerning the role of ROS in As-induced carcinogenesis.

project_terms:
3-nitrotyrosine;Animal Model;Animals;Antioxidants;Arsenic;Biology;Carcinogens;Cells;Chemicals;Chronic;Confocal Microscopy;DNA Damage;Detection;Development;Early Diagnosis;Electron Spin Resonance Spectroscopy;Environmental and Occupational Exposure;Exposure to;Free Radicals;Generations;Glutathione Disulfide;Goals;Human;Hydroxyl Radical;Intervention;Kidney;Life;Link;Lipid Peroxidation;Liver;Lung;Malignant neoplasm of urinary bladder;Measures;Mediating;Medicine;Methods;Molecular;Nature;Nude Mice;Oxidative Stress;Play;Post-Translational Protein Processing;Prevention strategy;Protein Overexpression;Proteins;Reaction;Reactive Oxygen Species;Research Personnel;Risk Assessment;Role;Signaling Protein;Skin;Skin Carcinogenesis;Source;Spin Trapping;Superoxide Dismutase;Superoxides;Techniques;Testing;Tumorigenicity;cancer risk;carcinogenesis;catalase;cell injury;cell transformation;chromium hexavalent ion;design;free radical oxygen;global health;glutathione peroxidase;in vivo;inhibitor/antagonist;keratinocyte;oxidation;oxidative DNA damage;programs;public health medicine (field);response;therapy development;tumor;tumorigenesis


application_id: 7748922
project_number: 5R01HD060915-02
project_title: Latexin's role in parsing stem cells
administering_ic: NICHD
award_notice_date: 2009-12-03
opportunity_number: RFA-AG-08-003
application_type: 5
activity_code: R01
ic: HD
serial_number: 060915
program_official: WINER, KAREN
project_start_date: 2008-12-15
project_end_date: 2012-11-30
study_section: ZAG1-ZIJ-2(M2)
contact_pi_person_id: 7673209
contact_pi: VAN ZANT, GARY
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Juvenile factors that have potential effects on aging are myriad but fall into two broad categories: conscious and unconscious. An example of the former is taking up smoking as a pre-teen or adopting other dangerous lifestyles when young that are known at least on a statistical basis to shorten lifespan. Of course not all conscious decisions have detrimental effects. Many decisions about diet for example could promote healthy aging and a longer lifespan. This application is concerned with the "unconscious" category of factors detectable at early developmental stages that influence either positively or negatively not only overall lifespan but the quality of life with accumulating years. We focus on the number and functional capabilities of adult stem cells and the factors that parse their limited numbers and functional properties over a lifetime. Our underlying hypothesis is that quantitative and qualitative alterations in stem cells influence lifespan and successful aging. We study hematopoietic stem cells as a paradigm adult stem cell population and have shown age-related changes in stem cell number and function in mice. Moreover we have sought genetic determinants of stem cell properties that have an effect during aging. This proposal narrowly focuses on a quantitative trait the number of stem cells at a young age also correlated with lifespan. By utilizing the tools afforded by modern mouse genetics we have identified a quantitative trait gene and its protein product latexin that is important in mammals in parsing stem cells. In this application we propose to investigate the pattern of latexin expression in hematopoietic stem cells during embryonic development and at multiple points during adulthood and correlate these data with quantitative and qualitative parameters of stem cells and organismal longevity. An important tool we will make use of in these studies is latexin knockout mice which we are currently generating. In constitutive knockout animals we will study the effects on stem cells and aging when latexin is absent throughout development and adulthood. In conditional knockout mice we will determine when during development and young adulthood the presence of latexin is critical. Moreover the conditional knockouts will enable us to study the tissues in which latexin's expression is important and when. Lastly we investigate the genetic and epigenetic regulation of latexin expression segmentally at different stages of organismal development and adulthood. Preliminary data demonstrate in specific mouse strains that latexin expression is differentially regulated by both polymorphisms in the promoter and differential methylation of CG dinucleotides comprising a CpG island in the latexin promoter. In aggregate these descriptive and mechanistic studies will provide definitive information on the basic premise that adult stem cells influence aging and in particular the role that latexin plays as a mechanistic factor in this pathway. The median age of the U.S population continues to increase and will accelerate in the upcoming few decades. Healthy aging is thus a national priority especially given the rapidly rising costs of health care. Yet many of the physiological events occurring during development and early in childhood that have serious repercussions on the quality of life later are poorly understood. We believe that the regulation of stem cells and particularly the parsing of these populations chronologically is an important and neglected aspect of this quest. The proposed studies based on firm preliminary results specifically focus on the role of a novel stem cell regulator latexin on the hematopoietic stem cell population in a mammalian species the mouse.

project_terms:
Accounting;Adolescent;Adopted;Adult;Age;Aging;Apoptosis;Bone Marrow;C57BL/6 Mouse;Categories;Cell Aging;Cell Count;Cells;Childhood;Chronology;Conscious;CpG Islands;CpG dinucleotide;DNA Damage;Data;Development;Diet;Elderly;Embryo;Embryonic Development;Ensure;Epigenetic Process;Event;Genes;Genetic;Genetic Determinism;Genetic Polymorphism;Health Care Costs;Hematopoiesis;Hematopoietic;Hematopoietic System;Hematopoietic stem cells;Knock-out;Knockout Mice;Life;Life Style;Longevity;Mammals;Methylation;Modeling;Mouse Strains;Mus;Organ;PC3.1 antigen;Pathway interactions;Pattern;Physiological;Play;Population;Population Sizes;Promotor (Genetics);Property;Proteins;Quality of life;Reactive Oxygen Species;Regulation;Relative (related person);Role;Smoking;Specificity;Staging;Stem Cell Factor;Stem cells;Teenagers;Tissues;Transgenic Mice;Uncertainty;Unconscious State;adult stem cell;age effect;age related;base;cell age;emerging adult;falls;fetal;functional decline;healthy aging;knockout animal;neglect;novel;progenitor;stem cell population;tool;trait;young adult


application_id: 7747055
project_number: 1R41DK081296-01A2
project_title: ApoFasL as a novel treatment for Type 1 Diabetes in Nonhuman Primates
administering_ic: NIDDK
award_notice_date: 2010-09-03
opportunity_number: PA-08-051
application_type: 1
activity_code: R41
ic: DK
serial_number: 081296
suffix: A2
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2010-09-05
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZRG1 IMM-G (10)]
contact_pi_person_id: 8392573
contact_pi: MACLEOD, KATHRYN J
other_pis: ECKHOFF, DEVIN E;SHIRWAN, HAVAL
congressional_district: 03
department: Unavailable
primary_duns: 140646345
duns_number: 140646345
fips: US
organization_id: 4350801
organization_name: APOVAX, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021246
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-09-05
project_abstract:
DESCRIPTION (provided by applicant):  Pancreatic islet transplantation is a viable approach for the treatment of type 1 diabetes (T1D). However this therapeutic approach suffers from graft rejection. Dr. Shirwan founder of ApoImmune has developed a novel immunotherapeutic approach aimed at tolerance induction to alloantigens without chronic use of general immunosuppression. This approach termed ApoFasL involves engineering pancreatic islets ex vivo using the Company's platform ProtEx(tm) technology in a rapid practical and nontoxic manner to efficiently display a novel form of Fas ligand (FasL) on the islet surface. Engineered islets transplanted into diabetic allogeneic mice recipients treated with a short course (15 days) of rapamycin resulted in 100% survival over an observation period of >200 days without any sign of rejection. Moreover since the last submission of this grant we have now followed these animals long-term. Recipients of FasL-engineered islet grafts enjoyed rejection-free survival unless their Treg cells were depleted. Some of these animals are over 500 (n=8) and 400 (n=12) days with functioning islets in the absence of any immunosuppression. These data demonstrate that tolerance induction is sufficient for long-term drug free survival.  
Building on this and other strong data obtained in rodent models the primary objective of this proposal is to test the efficacy of this novel therapeutic approach ApoFasL for tolerance induction to allogeneic pancreatic islets in rhesus macaques. FasL will be displayed on rhesus macaque donor islets using ProtEx(tm) technology prior to transplantation into chemically-induced diabetic macaques. Transplants will be done under transient cover of rapamycin a pharmaceutical agent used in the clinic for the prevention of graft rejection. The rationale for using rapamycin in these experiments is two-fold. First it will face fewer regulatory hurdles and ease translation of the ApoFasL protocol into the clinic. And second it works in synergy with FasL to eliminate pathogenic T effector cells and generate/expand protective T regulatory cells thereby enhancing ApoFasL's efficacy. We hypothesize that islets engineered to display FasL on their surface will induce tolerance by physically eliminating alloreactive pathogenic lymphocytes responding to the transplanted islets through Fas/FasL interaction. Rapamycin is expected to further augment this response by eliminating T effector cells and/or expanding T regulatory cells thereby creating donor- specific immune tolerance leading to the survival of transplanted islets. Proof-of-principle in a nonhuman primate model will be followed by a Phase II SBIR application to further develop ApoFasL into a lead product. Tolerance to allogeneic islets in a nonhuman primate model will serve as the first step towards translation of this novel immunotherapy to the clinic for the treatment of T1D. If proven effective ApoFasL may improve the quality of life for millions of individuals worldwide with an economic impact in the billions of dollars.  
PUBLIC HEALTH RELEVANCE: ApoFasL is a novel immunotherapy being developed for the treatment of Type 1 Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabetic nonhuman primate model will be a significant step toward developing ApoFasL for clinical trials. This novel therapy has the potential to break new grounds for the clinical treatment of T1D.

project_terms:
Acute;Alloantigen;Allogenic;Animals;Apoptosis;Apoptotic;Architecture;Autoantigens;Biotin;CD95 Antigens;Cell Maintenance;Cell surface;Cells;Chimeric Proteins;Chronic;Clinic;Clinical;Clinical Treatment;Clinical Trials;Critiques;Data;Diabetes Mellitus;Disease;Effector Cell;Engineering;Event;Extracellular Domain;Face;Figs - dietary;Freedom;Generations;Gold;Graft Rejection;Graft Survival;Grant;Harvest;Homeostasis;Human;Immune;Immune Tolerance;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;Implant;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Islet Cell;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Licensing;Lymphocyte;Macaca;Macaca mulatta;Metabolic;Modeling;Modification;Mus;Natural immunosuppression;Outcome;Peripheral;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physiology;Play;Pre-Clinical Model;Prevention;Primates;Procedures;Proteins;Protocols documentation;Publishing;Quality of life;Recovery;Regulatory T-Lymphocyte;Replacement Therapy;Rodent;Rodent Model;Role;Series;Sirolimus;Small Business Innovation Research Grant;Streptavidin;Streptozocin;Surface;T-Lymphocyte;Technology;Testing;Therapeutic;Therapy Clinical Trials;Translating;Translations;Transplantation;Treatment Efficacy;Tumor Necrosis Factor Ligand Superfamily Member 6;Work;base;commercialization;diabetic;economic impact;efficacy testing;immunogenicity;immunoregulation;improved;insulin secretion;islet;nonhuman primate;novel;novel therapeutic intervention;public health relevance;research study;response

public_health_relevance:
PROJECT NARRATIVE ApoFasL is a novel immunotherapy being developed for the treatment of Type 1Diabetes (T1D). Successful completion of this proposal testing ApoFasL in a diabeticnonhuman primate model will be a significant step toward developing ApoFasL forclinical trials. This novel therapy has the potential to break new grounds for the clinicaltreatment of T1D.


application_id: 7746604
project_number: 1R43RR025737-01A1
project_title: A non-surgical embryo transfer (NSET) device for producing gene-modified mice
administering_ic: NCRR
award_notice_date: 2009-09-03
opportunity_number: PA-08-050
application_type: 1
activity_code: R43
ic: RR
serial_number: 025737
suffix: A1
program_official: O'NEILL, RAYMOND R
project_start_date: 2009-09-03
project_end_date: 2010-09-02
study_section: Special Emphasis Panel[ZRG1 GGG-J (10)]
contact_pi_person_id: 9438013
contact_pi: BASS, SHANNON
other_pis: SPEAR, BRETT
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  The ability to genetically modify mice through methods of gene transfer in fertilized mouse embryos (transgenic mice) or gene modification in embryonic stem (ES) cells (gene targeting) has dramatically increased the value and use of mice in biomedical research. . The production of gene-modified mice requires the surgical transfer of embryos into female mice. This surgery requires anesthesia (with potential complications) post-operative care of female mice (which may include the use of analgesics) as well as technical expertise on the part of the person carrying out the surgery as. At the same time there is a strong desire in the animal research community to reduce the morbidity stress and pain of animals used for research purposes. To overcome these problems we have developed a Non-Surgical Embryo Transfer (NSET) device that can be used for the non-surgical transfer of embryos into female mice. This procedure is rapid (transfer requires about 10 seconds) does not require surgery (including the associated anesthesia and post-operative care) and requires little expertise. Our preliminary data indicate that our NSET device is equally successful as standard surgical embryo transfer in mice in the production of transgenic mice. Preliminary studies were performed with hand-made NSET devices. We have now manufactured a NSET device enabling us to produce large numbers of NSET devices with a high degree of uniformity. The aims of this proposal are to demonstrate the efficacy of this manufactured NSET device for the non-surgical transfer of embryos that (1) have may be transgenic by DNA microinjection (2) have been cryopreserved and (3) were generated by in vitro fertilization of embryos with cryopreserved sperm. Success in these aims will provide the foundation for the commercialization of the NSET device for academic and bio/pharma mouse facilities.  
  
PUBLIC HEALTH RELEVANCE:  We have developed a device for the non-surgical transfer of embryos into recipient female mice that represents a substantial advance over existing methods of generating gene-modified mice in that it eliminates surgery including anesthesia and post-operative care. The goal of this proposal is to determine the efficacy of a manufactured non-surgical embryo transfer device for the transfer of embryos that are transgenic cryopreserved or generated by in vitro fertilization.

project_terms:
Analgesics;Anesthesia procedures;Animal Experimentation;Biomedical Research;Caring;Communities;Contracts;DNA;Data;Development;Devices;Embryo;Embryo Transfer;Female;Fertilization in Vitro;Foundations;Gene Targeting;Gene Transfer;Gene-Modified;Genes;Goals;Grant;Hand;Hand functions;Lead;Legal patent;Licensing;Mediating;Medical;Methods;Microinjections;Modification;Molds;Morbidity - disease rate;Mouse Strains;Mus;Operative Surgical Procedures;Pain;Performance;Persons;Phase;Postoperative Period;Procedures;Production;Research;Savings;Scientist;Speed (motion);Stress;Technical Expertise;Technology;Time;Transgenic Mice;Transgenic Organisms;Work;animal pain;base;commercialization;cost;embryonic stem cell;improved;large scale production;novel;public health relevance;sperm cell;success

public_health_relevance:
NarrativeWe have developed a device for the non-surgical transfer of embryos intorecipient female mice that represents a substantial advance over existingmethods of generating gene-modified mice in that it eliminates surgery includinganesthesia and post-operative care. The goal of this proposal is to determine theefficacy of a manufactured non-surgical embryo transfer device for the transfer ofembryos that are transgenic cryopreserved or generated by in vitro fertilization.


application_id: 7746425
project_number: 5R01CA116697-04
project_title: Oxidative Stress in Cr(VI)-induced Carcinogenesis
administering_ic: NCI
award_notice_date: 2009-12-16
application_type: 5
activity_code: R01
ic: CA
serial_number: 116697
program_official: BLAIR, DONALD G
project_start_date: 2007-02-07
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1-ONC-T(04)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-01-01
project_abstract:
DESCRIPTION (provided by applicant): Hexavalent chromium [Cr(VI)] is a known environmental carcinogen. Environmental exposure to Cr(VI)-containing compounds causes cancers of various organs. Its mechanism of carcinogenic actions remains to be investigated. Recent studies have demonstrated that reduction of Cr(VI) to its lower oxidation states is important for Cr(VI)-induced carcinogenesis. It has been shown that cellular reduction of Cr(VI) generates reactive oxygen species (ROS) which cause various cellular injuries. We hypothesize that Cr(VI) induces generation of ROS which activate nuclear transcription factors leading to cell transformation and tumorigenesis. In Specific Aim 1 we will identify ROS generated in Cr(VI) treated human lung bronchial epithelial (BEAS-2B) cells and the mechanism involved. We will emphysize the role of CDC42 signaling and the involvement of p47phox and NADPH oxidases in the molecular mechanism of Cr(VI)-induced ROS production. In Specific Aim 2 we will detect reactive Cr(V) intermediates produced in Cr(VI) reduction by living animals and identify the chemical structures of these intermediates. We will also detect and identify superoxide (O2'-) and hydroxyl ('OH) radicals produced by intact animals exposed to Cr(VI). Major methods to be used in this aim are low frequency electron spin resonance (ESR) spectroscopy and ESR spin trapping. In Specific Aim 3 we will investigate Cr(VI)-induced activation of NF-kappaB and AP-1 in BEAS-2B cells and in transgenic mice. We will use a dominant negative mutant MEK1/2 a dominant negative mutant ERK2 or a dominant negative mutant c-jun (TAM67) respectively to investigate the role of the MEK1/2-ERKs-AP-1 pathway in Cr(VI)-induced cell transformation. We will also use a dominant negative mutant IkappaBa or a dominant negative mutant IKK? respectively to determine the role of the IKK?-lkappaBa-NF-kappaB pathway in Cr(VI)-induced cell transformation. The involvement of ROS in these pathways will be investigated using expressions of specific antioxidant enzymes. Tumorigenesis will be investigated by injecting the transformed cells into athymic nude mice. We anticipate that Cr(VI) causes activation of transcription factors through ROS reactions leading to cell transformation and tumorigenesis. We attempt to link the cell transformation and tumorigenesis with specific transcription factors and specific reactive oxygen species.

project_terms:
Animals;Antioxidants;Biology;CDC42 gene;California;Cancer Etiology;Carcinogens;Cells;Chemical Structure;Chemicals;Consumption;DNA Damage;Detection;Development;Dominant-Negative Mutation;Early Diagnosis;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Environmental Exposure;Enzymes;Epithelial;Exposure to;Free Radicals;Frequencies (time pattern);Generations;Goals;Human;Hydroxyl Radical;Incidence;Inhalation Exposure;International Agency for Research on Cancer;Intervention;JUN gene;Life;Link;Lipid Peroxidation;Lung;MAPK1 gene;Malignant neoplasm of lung;Medicine;Methods;Molecular;NADPH Oxidase;NF-kappa B;Nose;Nuclear;Nude Mice;Occupational;Occupational Groups;Oral;Organ;Oxidative Stress;Pathway interactions;Play;Post-Translational Protein Processing;Prevention strategy;Production;Reaction;Reactive Oxygen Species;Risk Assessment;Role;Signal Transduction;Spin Trapping;Stress;Superoxides;Techniques;Testing;Transcription Factor AP-1;Transgenic Mice;Water;cancer risk;carcinogenesis;carcinogenicity;cell injury;cell transformation;chromium hexavalent ion;free radical oxygen;in vivo;oxidation;response;transcription factor;tumorigenesis


application_id: 7745675
project_number: 1R43HD062065-01
project_title: Active Distributed Electrode Array Network for Electrical Stimulation Therapy
administering_ic: NICHD
award_notice_date: 2009-08-01
opportunity_number: PA-08-050
application_type: 1
activity_code: R43
ic: HD
serial_number: 062065
program_official: SHINOWARA, NANCY
project_start_date: 2009-08-01
project_end_date: 2012-01-31
study_section: Special Emphasis Panel[ZRG1 MOSS-F (15)]
contact_pi_person_id: 7771781
contact_pi: HARTMAN, ERIC C
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 129360637
duns_number: 129360637
fips: US
organization_id: 4168101
organization_name: CUSTOMKYNETICS, INC.
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403401290
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-08-01
budget_end_date: 2012-01-31
project_abstract:
DESCRIPTION (provided by applicant):  Transcutaneous electrical stimulation applications involving high numbers of stimulated muscles have been an area of growing interest in recent years. customKYnetics has been approached in recent months by research groups and stimulation application developers requesting high channel count stimulation devices for use in their spinal cord injury rehabilitation research studies and products. Existing devices do not offer the features and/or number of stimulation channels required for these applications. Such high channel count devices are often cost prohibitive due to the size and complexity of the stimulator and the limited market for any particular configuration. Devices that are available lack the technological capability to coordinate the activity of the electrode pairs in an application-specific manner. Such applications have also lacked clinical acceptance because managing the large number of wires has been burdensome and impractical. We propose the novel Active Distributed Electrode Array (ADEA) technology that solves these problems by allowing the outputs of the applicants 2-channel stimulation unit to be shared thereby forming a stimulator with an essentially unlimited number of virtual stimulation channels. Virtual channels can be added or removed simply by connecting additional low cost modular 'stimulation nodes'. Nodes will be connected to one another in a daisy-chain fashion to minimize burdensome wiring. The CK200 will provide the stimulation control capability to deploy the electrical stimulation modality in any application no matter the complexity. This technology will enable improve efficacy of reduce cost and improve availability of high channel count stimulation applications for exercise and rehabilitation. The goals of this Phase I SBIR project will be to demonstrate feasibility of ADEA technology through development and bench testing of concept validation versions of ADEA circuits. In Phase II we will develop clinically viable stimulation nodes application firmware for the stimulation unit and user interface designs. We will demonstrate efficacy of the technology in one or more high channel count electrical stimulation based exercise and/or rehabilitation applications for individuals with spinal cord injury. We will additionally consider development of an application specific integrated circuit (ASIC) to implement the stimulation node in a small and lightweight package that can be easily donned at the electrode site using either a elastic band or adhesively to the stimulating electrode itself. The target markets for this device would be clinics who serve patients undergoing rehabilitation following spinal cord injury or stroke and electrical stimulation application developers who serve these populations. The target price for the system will be $3000 for an 8-channel configuration. PUBLIC HEALTH RELEVANCE: The proposed work may benefit public health through development of a clinically viable electrical stimulation technology for use in myriad rehabilitation applications. Compared to existing devices and techniques the technology may improve efficacy availability ease of use and reduce cost of the therapeutic interventions requiring high numbers of muscles to be activated using electrical stimulation in a well controlled / coordinated fashion.

project_terms:
Area;Cations;Client;Clinic;Clinical;Complex;Custom;Data;Detection;Development;Development Plans;Devices;Electric Stimulation;Electrodes;Engineering;Exercise;Goals;Government;Individual;Institution;Lead;Marketing;Memory;Methods;Modality;Monitor;Muscle;Noise;Output;Pain management;Patients;Phase;Physiologic pulse;Population;Predisposition;Price;Problem Solving;Protocols documentation;Rehabilitation Research;Rehabilitation therapy;Relative (related person);Research;Site;Skeletal muscle structure;Small Business Innovation Research Grant;Spinal cord injury;Stream;Subgroup;System;Technology;Testing;Therapeutic Intervention;Time;Training;Transcutaneous Electric Nerve Stimulation;Validation;Width;Work;base;cost;design;improved;interest;light (weight);neuromuscular;novel;public health medicine (field);public health relevance;research and development;research study;stroke;technology/technique;virtual

public_health_relevance:
Project Narrative / RelevanceActive Distributed Electrode Array Network for Electrical Stimulation Therapy Applicant Institution: customKYnetics Inc. (PI: Hartman Eric C.)The proposed work may benefit public health through development of a clinically viable electrical stimulationtechnology for use in myriad rehabilitation applications. Compared to existing devices and techniques thetechnology may improve efficacy availability ease of use and reduce cost of the therapeutic interventionsrequiring high numbers of muscles to be activated using electrical stimulation in a well controlled / coordinatedfashion.


application_id: 7745514
project_number: 5R01AI033481-16
project_title: Yersiniabactin and plague pathogenesis
administering_ic: NIAID
award_notice_date: 2009-11-12
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 033481
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-07-01
project_end_date: 2013-11-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis causes a zoonotic disease plague with well established reservoirs on every inhabited continent except Australia. Although humans are an accidental dead-end host bubonic and pneumonic plague has caused widespread loss of human life during recurrent pandemics. Nearly 2000 human plague cases occur yearly and outbreaks in Africa South America and Southeast Asia are common. In addition Y. pestis is a category A select agent with potential use for bioterrorism. The ability of pathogens to acquire iron from their hosts is a critical requirement for the development of nearly all infectious disease processes. Y. pestis encodes a large number of proven or putative iron transport systems but the siderophore- dependent yersiniabactin (Ybt) and Yfe systems are the most important for causing bubonic plague. In a mouse model of bubonic plague the Ybt system is essential in the early phases of disease while the Yfe system plays an important role in the later stages of plague. Mutations in ybt but not yfe affect the pathogenesis of pneumonic plague. Our studies indicate that Yfe and Feo (a ferrous iron transporter) play somewhat redundant roles in iron uptake - mutants lacking both systems show more severe phenotypes for in vitro growth intracellular growth and pathogenesis in bubonic and pneumonic plague. All these genes are regulated by Fur and iron availability. In addition the Ybt system is activated by the AraC-type regulator YbtA and the Ybt siderophore. The ultimate goals of my laboratory are to 1) genetically and biochemically characterize the iron transport systems of Y. pestis; 2) determine the mechanisms regulating expression of these systems; 3) assess the relative importance of these systems in bubonic and pneumonic plague; and 4) explore the potential for new antimicrobial therapies and vaccine components based on these transport systems. In this proposal we will focus on the Ybt system. The specific aims of this proposal are to 1) characterize Ybt regulation 2) investigate Ybt transport and iron utilization and 3) examine Ybt roles in bubonic and pneumonic plague pathogenesis. PUBLIC HEALTH RELEVANCE: Most bacterial pathogens require iron in order to grow and cause disease. Yersinia pestis the causative agent of plague produces a small molecule called a siderophore that can remove the iron that it needs from host iron-binding compounds and plays a very important role in both bubonic and pneumonic plague. Understanding how the bacterium makes this siderophore and how its production is regulated may eventually lead to the development of either a vaccine or new drugs against plague and other bacterial diseases.

project_terms:
Affect;Africa;Australia;Bacteria;Bacterial Infections;Binding (Molecular Function);Bioterrorism;Categories;Cells;Communicable Diseases;Development;Disease;Disease Outbreaks;Genes;Genetic Transcription;Goals;Growth;Human;In Vitro;Investigation;Iron;Laboratories;Lead;Life;Manganese;Microarray Analysis;Mutation;Pathogenesis;Periplasmic Binding Proteins;Pharmaceutical Preparations;Phase;Phenotype;Plague;Play;Pneumonic Plague;Principal Investigator;Process;Production;Proteins;Recurrence;Regulation;Regulon;Relative (related person);Role;Siderophores;Signal Transduction;Site;South America;Southeastern Asia;Staging;Subcutaneous Injections;System;Techniques;Tissues;Transcriptional Activation;Vaccine Therapy;Vaccines;Yersinia pestis;antimicrobial;base;member;mouse model;mutant;pandemic disease;pathogen;permease;programs;public health relevance;receptor;small molecule;uptake;yersiniabactin


application_id: 7743737
project_number: 5R01HL086644-04
project_title: Computer Modeling of Perlecan as a Vascular Regulator
administering_ic: NHLBI
award_notice_date: 2009-12-07
application_type: 5
activity_code: R01
ic: HL
serial_number: 086644
program_official: OH, YOUNGSUK
project_start_date: 2007-01-19
project_end_date: 2011-12-31
study_section: Modeling and Analysis of Biological Systems Study Section[MABS]
contact_pi_person_id: 1879706
contact_pi: FANNON, MICHAEL W
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2010-01-01
project_abstract:
Blood circulation is a complex system. At every moment a multitude of molecules are transportedsimultaneously and continuously to specific targets in the vasculature. The ability to regulate whole panelsof molecules by controlling the circulating concentration of a single moiety if discrete could provide apowerful tool to understand the causes prevention and treatment of cardiovascular disease and otherdisorders relating to blood vessels. Perlecan an important molecule in blood vessel and tumor growth couldbe such a molecule. Our hypothesis is that based on its high affinity for a number of growth factors that arecrucial to normal and pathological vascular growth and development circulating perlecan has the potential tosequester these growth factors in blood preventing their interactions with vascular surfaces. Because of thecomplexity of this system however it is difficult to characterize at a macro level using in vitro or in vivoapproaches alone. Computer modeling provides us with a powerful tool to test parameters and conditionssuch as multiple ligand interactions in solution and on vascular surfaces under flow which are crucialcomponents in developing an accurate understanding. A simulated vessel model under flow will be used totest the predictive value of the model using a variety of testable conditions. Our specific aims are to:1. Develop a model of endothelial cell binding based on the binding characteristics of three growth factorsand the proteoglycan perlecan2. Test the model using competitive binding assays with growth factors alone or in combination with otherfactors as a function of perlecan concentration3. Refine the model to mimic the interactions of the growth factors and perlecan under flow and adjust themodel to accommodate changes between what is observed in experimental assays and what is predictedbased on flow conditionsOur model will be the first step in attaining our long range goal of designing and testing Pharmaceuticals thatexploit similar regulatory characteristics. By using a systems biology approach the interrelatedness of theblood vessels and the components being transported through them will be characterized at the level of theorganism as a whole.

project_terms:
Address;Affinity;Binding (Molecular Function);Binding Sites;Biological Assay;Biological Availability;Bioreactors;Blood;Blood Circulation;Blood Vessels;Blood capillaries;Blood flow;Cardiovascular Diseases;Cell surface;Cells;Characteristics;Competitive Binding;Complex;Computer Simulation;Development;Disease;Elements;Endothelial Cells;Extracellular Matrix;Fibroblast Growth Factor;Goals;Growth Factor;Growth Factor Interaction;Growth and Development function;In Vitro;Kinetics;Lead;Ligands;Measures;Modeling;Neoplasms in Vascular Tissue;Organ;Organism;Pharmacologic Substance;Predictive Value of Tests;Prevention;Proteoglycan;Pulsatile Flow;Pump;Regulation;Research;Research Personnel;Role;Signal Pathway;Signal Transduction;Simulate;Site;Solutions;Surface;System;Systems Biology;Testing;Therapeutic;Tissues;Tube;base;capillary;design;in vitro Assay;in vivo;in vivo Model;novel;perlecan;prevent;programs;reaction rate;response;tool;tumor growth


application_id: 7743683
project_number: 1R41GM088859-01
project_title: Ultra-soft atomic force microscope (USAFM) technology using nano-cantilevers for
administering_ic: NIGMS
award_notice_date: 2009-09-14
opportunity_number: PA-08-051
application_type: 1
activity_code: R41
ic: GM
serial_number: 088859
program_official: LEWIS, CATHERINE D
project_start_date: 2009-09-30
project_end_date: 2011-09-29
study_section: Special Emphasis Panel[ZRG1 BST-G (10)]
contact_pi_person_id: 9165003
contact_pi: YAZDANPANAH, MEHDI M
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 799015305
primary_uei: EHZNC3QFL2A8
duns_number: 799015305
uei: EHZNC3QFL2A8
fips: US
organization_id: 10015006
organization_name: NAUGANEEDLES
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402201756
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): NaugaNeedles LLC in collaboration with researchers from Purdue University are proposing to develop an advanced new Ultra-Soft Atomic Force Microscope (USAFM). This USAFM can gently create images of soft biological samples in buffer solutions with sub-picoNewton (pN) forces and sub-nm lateral resolution. This new AFM technology will have a high-bandwidth to ensure compatibility with high speed scanners. The USAFM requires development of (1) a new small mass ultra-soft yet high frequency cantilevers with sharp tips and (2) an advanced motion detector instrumentation to detect ultra-soft cantilever motions. The key is to significantly decrease the cantilever's mass which will consequently increase its resonance frequency and decrease its thermal vibration at low frequencies. Metallic silver-gallium (Ag2Ga) nano- cantilevers produced by NaugaNeedles are Ideal candidates for ultra-sensitive cantilevers since (a) they are orders of magnitude smaller than conventional cantilevers (b) have approximately two orders of magnitude softer (k~10-4 N/m) bending stiffness and (c) have a resonance frequencies of approximately 1-2 orders of magnitude higher than the softest commercially available cantilevers. Since this new AFM technology will have a high-bandwidth it will be compatible with high speed scanners. To demonstrate the feasibility of the USAFM Phase I has three specific aims: 1. Fabrication of ultra-soft probes (USPs): Silver-gallium (Ag2Ga) crystalline nano- cantilevers will be fabricated in various lengths (5 to 50 <m) and widths (100 to 500 nm). A sharp molecular tip (e.g. Fibrinogen fiber) will be grown on each nano-cantilever to provide a small tip radius (5-10 nm) converting the bare nano-cantilever into high-resolution ultra-soft- probes (USPs) for USAFM. 2. Optical detection of nano-cantilever deflection: Nano-cantilevers with different length-to- diameter ratios fabricated under aim 1 will be tested to optimize the optical detection of their motion using an existing scanning micro-Laser Doppler Vibrometer (LDV). Thermal vibration spectra of the nano-cantilevers in air and under water will be measured using the micro-LDV to estimate the force measurement limits of the proposed USAFM. 3. Experimental calibration and imaging under liquids: USPs fabricated on commercially- available AFM cantilevers will be tested in a conventional AFM to establish force calibration protocols and compatibility for scanning under liquids. In Phase II a prototype of USAFM head will be built and tested for high resolution imaging and studying the electromechanical properties of biological systems under liquids. Also a batch fabrication process will be developed to mass produce USPs at a low cost. In Phase III NaugaNeedles will partner with Nanotec Electronica and Agilent (the manufacturer of the AFM controller) and Polytec (the LDV manufacturer) to commercialize the USAFM. The annual market size for the USAFM and USPs (that are consumable products) is expected to exceed $50 million by 2012 with no competition in sight. PUBLIC HEALTH RELEVANCE: The focus of this proposal is to develop an ultra-soft atomic force microscope (USAFM). The USAFM can gently create images of soft biological samples with molecular resolution in liquid environments. This is done by applying sub-picoNewton (pN) forces to the molecules. To successfully develop a USAFM NaugaNeedles should first develop (1) a new small mass ultra-soft yet high frequency cantilevers with sharp tips and (2) an advanced motion detector instrumentation to detect ultra-soft cantilever motions. This new and enhanced AFM technology will have a high-bandwidth ensuring its compatibility with high speed scanners.

project_terms:
Air;Antibodies;Area;Atomic Force Microscopy;Biological;Biophysics;Buffers;Caliber;Calibration;Cells;Collaborations;Computers and Advanced Instrumentation;Detection;Development;Ensure;Environment;Fiber;Fibrinogen;Frequencies (time pattern);Gallium;Head;Image;Immunoglobulin G;Immunoglobulin M;Individual;Lasers;Lateral;Legal patent;Length;Letters;Liquid substance;Location;Manufacturer Name;Marketing;Measurement;Measures;Mechanics;Medicine;Microscopy;Molecular;Motion;Optics;Phase;Physiological;Process;Property;Proteins;Protocols documentation;Radial;Research Personnel;Resolution;Sampling;Scanning;Scanning Probe Microscopes;Signal Transduction;Silver;Solutions;Speed (motion);Stimulus;Structure;Technology;Testing;Universities;Vision;Water;Width;analytical tool;biological systems;cantilever;cost;detector;drug discovery;instrumentation;nanocantilever;prototype;public health relevance;research study;ultra high resolution;vibration

public_health_relevance:
PROJECT NARRATIVEThe focus of this proposal is to develop an ultra-soft atomic force microscope (USAFM). TheUSAFM can gently create images of soft biological samples with molecular resolution inliquid environments. This is done by applying sub-picoNewton (pN) forces to the molecules.To successfully develop a USAFM NaugaNeedles should first develop (1) a new smallmass ultra-soft yet high frequency cantilevers with sharp tips and (2) an advanced motiondetector instrumentation to detect ultra-soft cantilever motions. This new and enhanced AFMtechnology will have a high-bandwidth ensuring its compatibility with high speed scanners.


application_id: 7743586
project_number: 5F31AA017346-03
project_title: The role of PKC epsilon in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2009-11-23
application_type: 5
activity_code: F31
ic: AA
serial_number: 017346
program_official: RADAEVA, SVETLANA
project_start_date: 2007-12-01
project_end_date: 2010-04-30
study_section: ZAA1-JJ(14)
contact_pi_person_id: 9020505
contact_pi: KAISER, JONATHAN PHILLIP
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-12-01
project_abstract:
DESCRIPTION (provided by applicant): Hepatic Steatosis is a critical stage in the pathology of alcoholic liver disease. It has been suggested that not only does the severity of steatosis predict the severity of later stages of ALD but that preventing steatosis caused by ethanol could also prevent the later stages of ALD (i.e. fibrosis and cirrhosis). In a previous study done by our laboratory it was shown that metformin an insulin sensitizing drug blocks steatosis caused by ethanol suggesting that insulin resistance could play a causal role in ethanol-induced steatosis. Protein kinase c-epsilon (PKCe) has been shown to cause hepatic insulin resistance as well non-alcoholic fatty liver disease therefore we hypothesize that PKCe has a causal role in ALD by causing hepatic insulin resistance. This hypothesis will be tested via the following Specific Aims. 1). To test the hypothesis that PKCe has a causal role in ethanol-induced steatosis. In the Preliminary Studies it was shown that acute ethanol exposure leads to an increase in PKCe activity before the onset of ethanol-induced steatosis. Next we determined that PKCe-/- mice are partially protected against steatosis due to ethanol. The goal of this aim is to build on these Preliminary Studies. 2). To determine the mechanism by which ethanol is increasing diacylglycerol (DAG) synthesis. One of the prominent activators of PKCe is DAG. De novo DAG formation can be increased by alcohol via an increase in flux of long chain fatty-acyl CoAs and/or glyceraldehyde-3-phosphate into the triacylglycerol pathway. However the relative contributions of these potential pathways are unclear. Therefore the goal of this aim is to determine the relative contribution of these 2 potential pathways of DAG formation under these conditions. 3). To test the hypothesis that PKCe and Gdc1 inhibition will prevent liver damage owing to chronic exposure. We expect the results of Specific Aims 1 and 2 to determine that PKCe plays a causal role in ethanol-induced steatosis. However the role of this enzyme in chronic ethanol exposure is not yet known. Therefore the goal of this aim is to determine the effect of genetic inhibition of PKCe and Gdc1 on liver damage caused by chronic ethanol exposure. ALD is one of the leading causes of death in the world affecting millions of people per year. From the years 1985 to 1992 it is estimated that over $148 billion was spent to treat people with this disease. However due to poor understanding of the biochemical mechanisms responsible for ALD there is no FDA approved therapy to treat the disease. Therefore the goal of this work is to provide better understanding of the mechanisms responsible for ALD in hopes of identifying a therapeutic target to not only prevent but also reverse the progression of the disease.

project_terms:
12-diacylglycerol;Acute;Affect;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Animal Model;Biochemical;Cause of Death;Chronic;Cirrhosis;Clinic;Data;Development;Diglycerides;Disease;Disease Progression;Enteral;Enzymes;Epidemiologic Studies;Ethanol;FDA approved;Fatty Liver;Fibrosis;Genetic;Glyceraldehyde 3-Phosphate;Glycerol;Goals;Health;Hepatic;Inflammation;Insulin;Insulin Resistance;Laboratories;Liver;Liver diseases;Measures;Mediating;Metformin;Modeling;Mus;Necrosis;Nonesterified Fatty Acids;Oxidative Stress;Oxidoreductase;Pathology;Pathway interactions;Phosphotransferases;Play;Population;Protein Kinase;Relative (related person);Risk;Role;Serum;Severities;Staging;Testing;Therapeutic;Triglycerides;Work;alcohol exposure;indexing;inorganic phosphate;insulin sensitizing drugs;insulin signaling;non-alcoholic fatty liver;prevent;protein kinase C epsilon;therapeutic target


application_id: 7743463
project_number: 5R01HL074351-06
project_title: Hypercholesterolemia in Cardiac Function Survival and Repair
administering_ic: NHLBI
award_notice_date: 2009-11-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074351
program_official: SCHWARTZ, LISA
project_start_date: 2003-07-01
project_end_date: 2012-11-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 7372371
contact_pi: TANG, XIAN-LIANG
other_pis: ROKOSH, GREGG
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Mounting mechanistic and translational studies support the use of cell-based therapies to repair myocardial tissue destroyed by infarction and to restore cardiac function. Several phenotypically distinct subsets of adult primitive cell populations have been shown to improve cardiac structure and function in animal models of myocardial infarction (MI) and heart failure. Small clinical trials of stem cell therapy have recapitulated these beneficial effects in patients with ischemic cardiomyopathy. Recent discovery of cardiac stem cells (CSCs) has sparked intense hope for the development of promising stem cell therapies for cardiac repair/regeneration because CSCs are inherently programmed to reconstitute cardiac tissue. In recent studies we found that intracoronary delivery of CSCs to rats with either acute or chronic MI and to pigs with chronic MI ameliorated cardiac function and regenerated new cardiac cells. However human patients needing cardiac reparative therapies generally possess an array of cardiovascular risk factors such as hypercholesterolemia (HC) diabetes hypertension etc. With the recent surge of interest in cell therapies for patients it is important to understand the impact of these risk factors on cell-mediated cardiac repair. In particular HC is a highly prevalent risk factor and contributes to a range of pathophysiological consequences. Hence the overall goal of this proposal is to investigate the impact of HC on CSC-mediated cardiac repair. Our fundamental hypothesis is that depending on the specific conditions cholesterol can be beneficial or detrimental in CSC-mediated cardiac repair. We propose that mild elevations of plasma cholesterol or the presence of the minimally oxidatively modified form of LDL-cholesterol precondition both the myocardium and the CSCs; the resulting combination of a primed myocardial microenvironment for cell engraftment and enhanced paracrine signaling mechanisms of preconditioned CSCs work in concert to enhance CSC-mediated cardiac repair. We further propose that marked elevations of plasma cholesterol or the presence of the completely oxidized form of LDL- cholesterol provoke oxidative injury to both the CSCs and the myocardium leading to loss of efficacy of cell therapies for cardiac repair. We will test these hypotheses under 3 specific aims using both in vitro cultured CSCs and cardiomyocytes in the presence of differently modified LDLs and in vivo rat models of MI with different levels of plasma cholesterol. Aim 1 will determine the effects of HC on CSC-mediated cardiac repair in vivo; Aim 2 will determine the effects of LDLs on CSC function and reparative capability in vitro; and Aim 3 will determine whether pretreatment of CSCs with differently modified LDLs in vitro alters the efficacy of cardiac reparative therapy in vivo. Given that plasma cholesterol is a modifiable risk factor but is also essential for cellular function understanding the effects of this prevalent risk factor on stem cell-based therapies will have translational and mechanistic importance. This project will provide novel insights into a much-needed preclinical framework to develop cell-based therapies for cardiac repair in patients with cardiovascular risk factors. PUBLIC HEALTH RELEVANCE: Increasing evidence has demonstrated that adult stem/progenitor cells can repair myocardium with functional benefits in animal models of myocardial infarction and heart failure. Small clinical trials of stem cell therapy in human patients with myocardial infarction and ischemic cardiomyopathy have recapitulated these beneficial effects. Recent discovery that heart itself contains cardiac stem cells (CSCs) has sparked intense hope for the development of most promising stem cell therapies for cardiac repair because CSCs are inherently programmed to reconstitute cardiac tissue. However in the clinical arena patients who need cardiac reparative therapies are mostly associated with cardiovascular risk factors such hypercholesterolemia diabetes hypertension etc. With the recent surge of interest in cell therapies for patients it is important to understand the impacts of these risk factors on stem cell-mediated cardiac repair. Hypercholesterolemia is a most prevalent risk factor and imposes various pathophysiological impacts in the biological system. In this application we will conduct experiements to investigate the impacts of hypercholesterolemia on CSC-mediated cardiac repaie. We will use both normocholesterolemic and hypercholesterolemic rat models of myocardial infarction. Rats with myocardial infarction will receive CSC therapy. The efficacy of CSC therapy for cardiac repair will be assessed using comprehensive evaluation of myocardial performance including echocardiography and hemodynamic pressure-volume catheterization and tissue structure repair including morphology immunohistochemistry light and confocal microscopy. Regardless our results are "positive" or "negative" this project will provide novel insights into preclinical framework to develop effective cell-based therapies for cardiac repair in patients with cardiovascular risk factors. Given that plasma cholesterol is a modifiable risk factor and essential for cellular function understanding the effects of this prevalent risk factor on stem cell- based cardiac repair will have translational and mechanistic importance.

project_terms:
Acute;Address;Adult;Affect;Animal Model;Animals;Arterial Fatty Streak;Atherosclerosis;Biochemical;Blood Vessels;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cardiovascular Diseases;Cardiovascular Physiology;Catheterization;Caveolae;Cell Communication;Cell Therapy;Cell physiology;Cells;Cholesterol;Chronic;Clinic;Clinical;Clinical Trials;Complex;Confocal Microscopy;Coronary Occlusions;Data;Development;Diabetes Mellitus;Diet;Dose;EFRAC;Echocardiography;Endoplasmic Reticulum;Engraftment;Evaluation;Experimental Models;Family suidae;Funding;Goals;Heart;Heart failure;Homing;Human;Hypertension;Immunohistochemistry;In Vitro;Infarction;Injury;Integrins;Ischemic Preconditioning;LDL Cholesterol Lipoproteins;Light;Low Density Lipoprotein oxidation;Low-Density Lipoproteins;Matrix Metalloproteinases;Measures;Mediating;Membrane Microdomains;Modeling;Molecular Biology;Morphology;Motion;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial perfusion;Myocardial tissue;Myocardium;Natural regeneration;Outcome;Paracrine Communication;Pathology;Patients;Performance;Physiology;Plasma;Population;Preparation;Process;Proteins;Rattus;Reperfusion Therapy;Research;Risk;Risk Factors;Role;Signal Transduction;Specimen;Stem cells;Stromal Cell-Derived Factor 1;Structure;Testing;Tissue Extracts;Tissues;Transplanted tissue;Work;base;biological adaptation to stress;biological systems;cardiovascular risk factor;cell type;endoplasmic reticulum stress;extracellular;feeding;hemodynamics;hypercholesterolemia;improved;in vitro testing;in vivo;insight;interdisciplinary approach;interest;low density lipoprotein inhibitor;migration;modifiable risk;novel;oxidation;pre-clinical;preconditioning;pressure;primitive cell;programs;public health relevance;reconstitution;repaired;research study;response;stem;stem cell therapy;translational study

public_health_relevance:
Project NarrativeIncreasing evidence has demonstrated that adult stem/progenitor cells can repairmyocardium with functional benefits in animal models of myocardial infarction and heartfailure. Small clinical trials of stem cell therapy in human patients with myocardialinfarction and ischemic cardiomyopathy have recapitulated these beneficial effects.Recent discovery that heart itself contains cardiac stem cells (CSCs) has sparkedintense hope for the development of most promising stem cell therapies for cardiacrepair because CSCs are inherently programmed to reconstitute cardiac tissue.However in the clinical arena patients who need cardiac reparative therapies are mostlyassociated with cardiovascular risk factors such hypercholesterolemia diabeteshypertension etc. With the recent surge of interest in cell therapies for patients it isimportant to understand the impacts of these risk factors on stem cell-mediated cardiacrepair. Hypercholesterolemia is a most prevalent risk factor and imposes variouspathophysiological impacts in the biological system. In this application we will conductexperiements to investigate the impacts of hypercholesterolemia on CSC-mediatedcardiac repaie. We will use both normocholesterolemic and hypercholesterolemic ratmodels of myocardial infarction. Rats with myocardial infarction will receive CSC therapy.The efficay of CSC therapy for cardiac repair will be assessed using comprehensiveevaluation of myocardial performance including echocardiography and hemodynamicpressure-volume catheterization and tissue structure repair including morphologyimmunohistochemistry light and confocal microscopy. Regardless our results are"positive" or "negative" this project will provide novel insights into preclinical frameworkto develop effective cell-based therapies for cardiac repair in patients with cardiovascularrisk factors. Given that plasma cholesterol is a modifiable risk factor and essential forcellular function understanding the effects of this prevalent risk factor on stem cell-based cardiac repair will have translational and mechanistic importance.


application_id: 7743449
project_number: 5R01HD058299-28
project_title: Hepatic Drug Elimination in Pregnancy
administering_ic: NICHD
award_notice_date: 2009-11-19
application_type: 5
activity_code: R01
ic: HD
serial_number: 058299
program_official: ZAJICEK, ANNE
project_start_date: 1979-09-30
project_end_date: 2012-11-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2009-12-01
project_abstract:
This proposal focuses on the function and expression of MRP2 (ABCC2) the ABC transporter that mediatesthe biliary excretion of glucuronide and glutathione conjugates from the hepatocyte into bile. The proposalbuilds on our findings that 1) MRP2 transports tauroursodeoxycholate (TUDC) a bile acid used for thetreatment of cholestatic liver disease including intrahepatic cholestasis of pregnancy (ICP) 2) estradiol-17[3-D-glucuronide (E217G) causes increased permeability of the hepatocellular tight junction that coincides withendocytic retrieval of MRP2 and the bile salt export pump (BSEP) from the canalicular membrane anddecreased bile flow and 3) identification of upstream open reading frames (uORF) in the 5' leadersequences of rathuman and mouse MRP2. Aim 1 will characterize MRP2-mediated transport of hydrophilicbile acids including TUDC (3-muricholicacid and tetrahydroxy bile acids and the importance of heterotropicand homotropic activation in their transport. We will also examine the ability of MRP2 variants to transportthese bile acids. We will use an MRP2 baculovirus expression system in Sf9 cells to characterize transport.Aim 2 will determine the role of protein kinase C (PKC) and tight junction permeability in E217G-inducedcholestasis. We will test the hypothesis that E217G disrupts hepatocyte tight junctions in a PKC-dependentmanner that coincides with endocytic retrieval of key transporters MRP2 and BSEP from the canalicularmembrane leading to cholestasis. We will use 4 model systems to test this hypothesis: in vivo studies in therat the isolated perfused rat liver isolated rat hepatocyte couplets and HepG2 cells coupled with confocalfluorescence and electron microscopy to monitor the localization of transporters and tight junction proteinsafter treatment with E217G and in the presence and absence of PKC inhibitors. Aim 3 will characterize theimportance of the uORF in rathuman and mouse MRP2 mRNA on the translational regulation of MRP2protein. We will characterize the differential tissue expression of MRP2 mRNA transcripts expressing theuORF and use site-directed mutagenesis to disrupt the uORF coupled with in vitro translation assays toinvestigate the importance of leaky scanning and the sequence of the peptide encoded by the uORF inregulating translation of Mrp2/MRP2. We will also determine whether the peptide encoded by the rat uORFis expressed in vivo. Significance: MRP2 is critical for elimination of polar metabolites from liver and kidneyas well decreasing the intestinal absorption of dietary carcinogensand its expression in liver is decreasedinpregnancy. Characterization of mechanisms of regulation of the activity localization and expression ofMRP2 can lead to improved drug therapy for women in pregnancy and development of therapeutic measuresto increase MRP2 function in cholestatic liver disease particularly in ICP.

project_terms:
5' Untranslated Regions;ATP-Binding Cassette Transporters;Aftercare;Amniotic Fluid;Baculovirus Expression System;Bile Acids;Bile fluid;Biliary;Biological Models;Cells;Cholestasis;Coupled;Data;Electron Microscopy;Estradiol;Estrogens;Excretory function;Fluorescence;Generations;Glucuronides;Glutathione;Glycine;Hepatic;Hepatocyte;Human;In Vitro;Initiator Codon;Inorganic Sulfates;Intestinal Absorption;Kidney;Kinetics;Laboratories;Laboratory Animals;Lead;Liver;Liver diseases;Measures;Mediating;Membrane;Messenger RNA;Microtubules;Monitor;Multidrug Resistance-Associated Proteins;Mus;Nucleotides;Open Reading Frames;Patients;Peptides;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Plasma;Pregnancy;Protein Isoforms;Protein Kinase C;Protein Kinase C Inhibitor;Proteins;Pump;Rattus;Recovery;Regulation;Retrieval;Role;Scanning;Single Nucleotide Polymorphism;Site-Directed Mutagenesis;Taurine;Testing;Tight Junctions;Tissues;Transcript;Translational Regulation;Translations;Treatment Efficacy;Unspecified or Sulfate Ion Sulfates;Urine;Variant;Woman;base;bile salts;citrate carrier;estradiol-3-glucuronide;hydroxyl group;improved;in vivo;intrahepatic cholestasis of pregnancy;muricholic acid;prevent;protein aminoacid sequence;protein expression;therapeutic development;translation assay;ursodeoxycholate


application_id: 7743034
project_number: 5R01HL088989-03
project_title: Role of B cells in host defense against Pneumocystis
administering_ic: NHLBI
award_notice_date: 2009-11-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 088989
program_official: PEAVY, HANNAH H
project_start_date: 2007-12-06
project_end_date: 2012-11-30
study_section: Special Emphasis Panel[ZRG1-AARR-C(04)M]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pneumocystis pneumonia is an AIDS-defining illness that has continued to cause significant morbidity and mortality among HIV-infected patients with compromised CD4 T cells. Susceptibility to Pneumocystis (PC) infection is largely due to reduced CD4 T cell number or function however B cells are also critical for host defense against PC. Using murine models we have found that B-T cell interactions through costimulatory molecules such as MHC class II and CD40 on B cells have profound effects on T cell function. In the absence of B cells CD4 T cells are not primed appropriately and fail to expand when transferred into PC-infected mice lacking T or B cells (severe combined immunodeficient SCID mice). We hypothesize that cognate interactions in draining lymph nodes between T and B cells within the first week after PC infection provides signals for T cell expansion and CD4 T cell memory generation. Our specific aims for addressing this hypothesis are as follows: 1. To determine whether cognate or costimulatory interactions between B and T cells are required for proliferation and survival of CD4 T cells. 2. To determine whether cytokine production by B cells drives T cell survival expansion or memory cell generation. We will utilize established murine models of PC infection to address these three aims. These models include generation of mixed chimeric mice whose B cells are deficient in costimulatory molecules or cytokines adoptive transfer models in which T cells are primed in the presence or absence of B cells and then transferred to SCID hosts inducible depletion of dendritic cells using transgenic mice and depletion of B cells using a drug combination relevant to HIV disease. In addition to determining what molecules are critically involved in T-B cell interactions we will also perform kinetics experiments to determine when during the immune response these critical interactions take place. In addition to reduced CD4 T cell numbers HIV-infected patients have abnormal B cell function that is related to viral load. Understanding how T and B cells must interact for efficient control of opportunistic infections is critically important for devising strategies to prevent these often times fatal opportunistic infections.

project_terms:
Address;Adoptive Transfer;Apoptosis;Apoptotic;B-Lymphocytes;CD4 Positive T Lymphocytes;Cell Communication;Cell Count;Cell Survival;Cell physiology;Cells;Critiques;Dendritic Cells;Disease;Drug Combinations;Generations;HIV;Host Defense;Immune response;Immunohistochemistry;Kinetics;Lung;MHC Class II Genes;Memory;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Opportunistic Infections;Pathway interactions;Patients;Phase;Pneumocystis;Pneumocystis Infections;Pneumocystis carinii Pneumonia;Population;Predisposition;Production;Published Comment;Role;SCID Mice;Signal Transduction;Staining method;Stains;System;T-Lymphocyte;TNFRSF5 gene;Techniques;Time;Transgenic Mice;Viral Load result;annexin A5;caspase-3;cytokine;improved;in vivo;interest;lymph nodes;memory CD4 T lymphocyte;prevent;research study


application_id: 7742396
project_number: 3R01HL074185-05S1
project_title: Inhibitor ameliorates oxidative and proteolytic stress
administering_ic: NHLBI
award_notice_date: 2008-12-09
application_type: 3
activity_code: R01
ic: HL
serial_number: 074185
suffix: S1
program_official: SCHWARTZ, LISA
project_start_date: 2003-09-05
project_end_date: 2009-08-31
study_section: Experimental Cardiovascular Sciences Study Section[ECS]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Endocardial endothelial (EE) dysfunction and accumulation of oxidized-matrix between endothelial and muscle are the hallmarks of congestive heart failure (CHF). The overall objective of this project is to understand the mechanism of oxidized-matrix accumulation and EE dysfunction in CHF. Previous studies have suggested an association between induction of oxidative stress decrease in endothelial cell density activation of matrix metalloproteinase (MMP) collagenolysis and repression of cardiac tissue inhibitor of metalloproteinase (CIMP) in CHF. The novelty of this proposal is that among all known tissue inhibitors of metalloproteinase (TIMP) the TIMP-4 (i.e. CIMP) is highly expressed in the heart. The purpose of this proposal is to test a central hypothesis that oxidized-matrix accumulation and EE dysfunction are due to increased levels of MMP activity and collagenolysis. These levels are associated with decreased levels of EE nitric oxide and CIMP in response to increased levels of reactive oxygen species (ROS) during protracted cycles of ischemia/reperfusion in volume overload. The increased levels of CIMP protects EE against oxidative and proteolytic stresses. We will test the central hypothesis by the following three specific aims: 1. To determine whether CIMP decreases oxidative stress by increasing EE nitric oxide concentration. Plasma and left ventricle levels of nitric oxide ROS and nitrotyrosine will be measured in chronic volume overload arteriovenous fistula mice treated with and without CIMP. 2. To determine whether CIMP protein transfer inhibits collagenolysis. MMP activity will be measured by in situ zymography. The levels of CIMP activity will be measured by reverse zymography. Total collagen and its degradation fragments will be measured by Western-blot analysis using anti-collagen antibody. 3. To determine whether CIMP ameliorates endocardial endothelial dysfunction. Contractile responses to acetylcholine bradykinin and nitroprusside in cardiac rings will be measured in a tissue myobath. These studies will enable us to determine whether CIMP improves the hearts response to nitric oxide donors. Identification of major players involved in the control of oxidative and proteolytic stresses will help to develop strategies to prevent CHF.

project_terms:
3-nitrotyrosine;Abbreviations;Acetylcholine;Acids;Antibodies;Antigens;Arginine;Arteriovenous fistula;Biochemical;Bradykinin;CD31 Antigens;Cardiac;Cell Density;Cells;Chronic;Collagen;Complex;Congestive Heart Failure;Diastolic blood pressure;Disulfides;Endothelial Cells;Endothelium;Extracellular Matrix;Feedback;Functional disorder;Goals;Heart;Heart failure;Hydroxyeicosatetraenoic Acids;Hypertrophy;In Situ;Ischemia;Left;Left ventricular structure;Matrix Metalloproteinases;Measures;Metalloproteases;Methods;Molecular;Mus;Muscle;Myocardial;NADH;Nicotinamide adenine dinucleotide;Nitric Oxide;Nitric Oxide Donors;Nitroprusside;Nuclear;Oxidases;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Oxides;Peroxisome Proliferator-Activated Receptors;Peroxonitrite;Physiological;Plasma;Poly(ADP-ribose) Polymerases;Principal Investigator;Prostaglandins;Protein Kinase C;Proteins;Reactive Oxygen Species;Reperfusion Therapy;Reporting;Repression;Role;Stress;Sulfhydryl Compounds;Techniques;Testing;Tissue Inhibitor of Metalloproteinases;Tissues;Tyrosine;Ventricular;Western Blotting;arginine methyl ester;catalase;human NOS3 protein;improved;inhibitor/antagonist;prevent;progesterone 11-hemisuccinate-(2-iodohistamine);programs;research study;response;tetrahydrobiopterin;tissue inhibitor of metalloproteinase 4


application_id: 7741837
project_number: 1R01AG033649-01A1
project_title: Metabolic syndrome and hippocampal Ca2+ dysregulation in aging-related memory dec
administering_ic: NIA
award_notice_date: 2009-07-31
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: AG
serial_number: 033649
suffix: A1
program_official: PETANCESKA, SUZANA
project_start_date: 2009-08-01
project_end_date: 2014-07-31
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
24-thiazolidinedione;Address;Adipose tissue;Affect;Age;Age-Months;Age-associated memory impairment;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Animals;Attenuated;Behavioral;Brain;Cells;Cholesterol;Classification;Clinical;Cognition;Cognitive;Complement;Development;Diabetes Mellitus;Diet;Down-Regulation;Drug usage;Dyslipidemias;Ensure;Epidemic;Epidemiology;Exhibits;Fatty acid glycerol esters;Functional disorder;Gene Expression;Genes;Glucose;Goals;Grant;Hippocampus (Brain);Homeostasis;Hyperglycemia;Hyperinsulinism;Hypertension;Image;Impaired cognition;Inbred F344 Rats;Incidence;Individual;Inflammation;Insulin;Insulin Resistance;Insulin Signaling Pathway;Intervention;Learning;Link;Longitudinal Studies;Measures;Mediating;Memory;Memory impairment;Metabolic;Metabolic Brain Diseases;Metabolic Marker;Metabolic Pathway;Metabolic syndrome;Monitor;Mouse Strains;N-Methyl-D-Aspartate Receptors;Neurobiology;Neurons;Obesity;Obesity associated disease;Outcome Measure;PPAR gamma;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Pioglitazone;Process;Rattus;Regulation;Reporting;Research;Resistance;Rodent;Rodent Model;Series;Short-Term Memory;Signal Pathway;Signal Transduction;Slice;Societies;Synaptic plasticity;Techniques;Testing;Thiazolidinediones;Time;Tissue Sample;Tissues;Vascular Diseases;Work;age effect;age related;aged;aging brain;aging gene;biomarker;brain cell;cognitive function;cytokine;diabetic;direct application;feeding;glycemic control;improved;indexing;insulin sensitivity;insulin signaling;male;multidisciplinary;new therapeutic target;normal aging;prevent;public health medicine (field);public health relevance;research study;response;voltage


application_id: 7741662
project_number: 5R25ES016248-03
project_title: Summer Education Experience for Research
administering_ic: NIEHS
award_notice_date: 2009-11-18
opportunity_number: RFA-ES-06-009
application_type: 5
activity_code: R25
ic: ES
serial_number: 016248
program_official: HUMBLE, MICHAEL C
project_start_date: 2008-01-01
project_end_date: 2012-11-30
study_section: ZES1-LKB-A(R5)
contact_pi_person_id: 1862358
contact_pi: VORE, MARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)  
  
The primary objective of the Summer Education Experience in Research (SEER) in Toxicology is to provide 6 students with an opportunity to participate actively in ongoing research together with an educational seminar series that provides a background in research in environmental health sciences. The immediate goals are to provide a research experience for students at a critical time of career decision-making and to develop the research skills and expose the students to the potential and excitement of research careers. The long-term goal is to recruit these students into the Toxicology doctoral program. Students will have hands-on responsibilities in research projects in which reasonable conclusions can be obtained in a 9-week period and will spend 85% of their time in the laboratory. Research opportunities in specialty areas of Oxidative Stress DNA Repair and Mutagenesis Biochemical Toxicology and Chlorinated Organics and Cardiovascular Toxicity are provided by a group of 17 faculty members with experience in mentoring graduate and undergraduate students. Students will work with faculty who are primarily Core and Joint Faculty in the Graduate Center for Toxicology and who are Training Grant Faculty on the Molecular Mechanisms of Toxicity NIEHS T32 Training Grant or the Superfund Training Core. Students will be recruited from the University of Puerto Rico (UPR) as the continuation of a program for students from UPR that has been cosponsored by the University of Kentucky (UK) and UPR for about 9 years and was supported by an NIEHS T35 program from 2001 - 2006. The investigators will work with experienced faculty from the UPR to identify and recruit students for the SEER Toxicology program. Applicants must provide their student transcripts and will be interviewed by the UPR faculty to identify those with the maturity and academic excellence to succeed in a summer research experience. The UPR faculty will send the applications of the best students to Dr. Vore who will review them along with 2 other UK faculty mentors and select the top 6 applicants. This group will also match the interests of the applicants with those of the faculty who are able to work with the students in any given summer. A seminar series that exposes students to the broader issues in the environmental health sciences is also provided along with seminars on the responsible conduct of research and a presentation of how to prepare and apply for Graduate School. Students will make a 15-minute presentation of their research findings in a symposium-type format at the end of the summer. A plan for evaluating student satisfaction the effectiveness of mentors and the program has been developed and will be used to enhance the program in ensuing years.

project_terms:
Area;Biochemical;Cardiovascular system;DNA Repair;Decision Making;Educational aspects;Effectiveness;Environmental Health;Faculty;Goals;Grant;Hand;Interview;Joints;Kentucky;Laboratories;Mentors;Molecular;Mutagenesis;National Institute of Environmental Health Sciences;Oxidative Stress;Puerto Rico;Recruitment Activity;Research;Research Personnel;Research Project Grants;Schools;Series;Students;Superfund;Time;Toxic effect;Toxicology;Training;Transcript;Universities;Work;career;experience;interest;medical specialties;member;programs;responsible research conduct;satisfaction;skills;symposium;university student


application_id: 7741650
project_number: 5R01EY017131-03
project_title: Proteomic Analysis of Retinal Ganglion Cell Death in Glaucoma
administering_ic: NEI
award_notice_date: 2009-11-25
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 017131
program_official: AGARWAL, NEERAJ
project_start_date: 2007-12-01
project_end_date: 2012-11-30
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 6803489
contact_pi: TEZEL, GULGUN
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Only through a better understanding of the pathogenic mechanisms of glaucoma will improved and innovative treatments evolve. Preliminary studies using different series of in vitro and in vivo experiments as well as histopathological studies using human donor eyes have provided evidence that alterations in protein expression protein protein interactions post translational protein modifications and proteolytic cleavage change the protein complement of retinal ganglion cells (RGCs) during glaucomatous neurodegeneration with important implications in pathogenic mechanisms. The proposed experiments in this application are based on the hypothesis that an innovative analytical approach using the proteomics technology can identify time dependent alterations in the RGC protein complement on a large scale which characterize precise mechanisms of the RGC response to injury from initial insult to execution of cell death in glaucoma. The specific aims that will address this hypothesis include the identification of alterations in the RGC protein expression and post translational protein modifications during the course of glaucomatous neurodegeneration in an experimental rat model of chronic pressure induced glaucoma. Time dependent alterations of the RGC proteome such as up regulation or down regulation of protein expression will be quantitatively evaluated by comparing the proteomic datasets between ocular hypertensive and control eyes using RGC protein samples obtained at different time points by pooling from rat eyes matched for intraocular pressure (IOP) exposure and axon loss. Relationship between the differential protein expression and the level of IOP exposure and axon loss will be statistically determined. To improve the sensitivity of the detection identification and relative quantification of protein expression complementary proteomic approaches will be utilized which will include 2D PAGE based and gel free techniques using mass spectrometry. Oxidatively modified RGC proteins will be identified through 2D oxylot analysis and phosphorylated RGC proteins and their interacting proteins in enriched phosphoprotein complexes will be identified through complementary approaches of the targeted proteomics. Parallel experiments will also determine cellular localization of the identified proteins using immunohistochemistry. In addition to histological sections obtained from ocular hypertensive and control rat eyes glaucomatous and normal retinas obtained from human donor eyes will also be utilized to better validate the relevance of new findings to human disease. These studies should provide comprehensive information about the cellular mechanisms associated with RGC death at the protein level thereby offering biomarkers and novel treatment targets for neuroprotective interventions in glaucoma a leading cause of blindness. The information obtained from these studies is also expected to be useful in multiple disciplines to characterize pathogenic processes of various other neurodegenerative diseases leading to RGC death.   
In glaucoma a specific type of nerve cells the retinal ganglion cells progressively die leading to gradual loss of visual function. Since the current treatment of this blinding disease is not sufficient to prevent disease progression additional treatment strategies need to be developed to protect these cells in glaucomatous eyes. As a requirement to accomplish this goal this project aims to identify the precise mechanisms associated with the nerve cell death in glaucoma using a powerful technology in animal experiments as well as performing experiments utilizing human donor eyes. These studies are expected to provide comprehensive information about the nerve cell death process thereby allowing new treatment possibilities for 3 million Americans suffering from glaucoma.

project_terms:
Address;Affect;American;Animal Experiments;Axon;Axoplasmic Streaming;Blindness;Cell Death;Cell Death Process;Cell physiology;Cells;Chronic;Complement;Complex;Data;Data Set;Databases;Detection;Development;Discipline;Disease;Disease Progression;Distal;Down-Regulation;Ensure;Event;Experimental Designs;Experimental Models;Eye;Foundations;Funding;Future;Gel;Glaucoma;Goals;Health;Human;Immunohistochemistry;In Vitro;Injury;Interruption;Intervention;Investigation;Mass Spectrum Analysis;Modeling;Modification;Nerve Degeneration;Nerve Tissue Proteins;Neurodegenerative Disorders;Neuroglia;Neurons;Ocular Hypertension;Optic Disk;Optic Nerve;Phosphoproteins;Phosphorylation;Physiologic Intraocular Pressure;Population;Post-Translational Protein Processing;Procedures;Process;Proteins;Proteome;Proteomics;Published Comment;Rattus;Reactive Oxygen Species;Relative (related person);Research;Research Personnel;Retina;Retinal Ganglion Cells;Sampling;Series;Signal Transduction;Suggestion;Techniques;Technology;Time;Tissues;Trust;Two-Dimensional Polyacrylamide Gel Electrophoresis;Up-Regulation (Physiology);Vision;Work;base;biomarker;cell body (neuron);experience;human disease;improved;in vivo;injured;innovation;innovative technologies;novel;oxidative damage;pressure;prevent;protein expression;protein protein interaction;research study;response;response to injury;success;treatment strategy


application_id: 7741398
project_number: 2R01NS045734-06
project_title: Vascular responses as therapeutic targets after SCI
administering_ic: NINDS
award_notice_date: 2009-07-28
opportunity_number: PA-08-015
application_type: 2
activity_code: R01
ic: NS
serial_number: 045734
program_official: KLEITMAN, NAOMI
project_start_date: 2004-05-03
project_end_date: 2011-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6902570
contact_pi: HAGG, THEO
other_pis: WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: Y
project_abstract:
Endothelial cells (ECs) are among the first cells to die acutely after contusive spinal cord injury (SCI) triggeringsecondary degeneration including axon and myelin loss. Remaining and newly angiogenic blood vessels areleaky and dysfunctional enabling detrimental leukocyte infiltration. We made substantial progress inunderstanding these vascular responses and targeting them with pharmacological treatments forneuroprotection. For example i.v. treatments with the Tie2 ligand angiopoietin-1 (Ang1) plus the v3/51integrin agonist C16 provide high levels of functional recovery vascular and tissue protection and reducedinflammation. Key to the success is the i.v. route which is rapid and clinically highly relevant. However it isessential that we find additional therapeutic methods or targets as we rescue less than half of the bloodvessels and white matter and no long-projecting descending pathways. This is critically important whenconsidering translation of these EC-targeted treatments to humans which do not recover neurological functioneven remotely as well as mice do. We suggest that this is possible by adding the neuroprotective effects ofprotein tyrosine phosphatase (PTP) inhibition which rescues axons projecting through the injury site. Toidentify additional opportunities for neuroprotective treatments Aim 1 will determine whether PTP inhibition canfurther enhance the effect of C16+Ang1 on EC survival and tissue sparing and whether EC sparing mediatesrescue of long-projecting axons and whether this involves VE-PTP which normally inactivates Tie2. We havealso found new avenues to study and modulate angiogenesis which we now recognize as one of the criticaland beneficial EC response to SCI. We developed a novel microvascular purification method and using EC-specific microarrays identified thrombospondin-1 (TSP-1) a potent anti-angiogenic factor which also inducesEC apoptosis as the most highly upregulated gene (60-fold) in these vessels 24 hours post-SCI. Aim 2 willdelineate the role of CD36 and CD47 two domain-specific TSP-1 EC receptors in mediating vascularresponses after SCI. We will take both gain and loss of function pharmacological approaches in vivo.Subsequent in vitro experiments will address mechanism(s) of successful treatments. These 2 revised aimswill identify additional molecular targets and much better EC-targeted intravenous treatments for improvedtissue locomotor function following traumatic SCI.

project_terms:
Acute;Address;Agonist;Angiogenic Factor;Angiopoietin-1;Apoptosis;Axon;Binding (Molecular Function);Binding Sites;Blood Vessels;CD36 gene;CD47 gene;Cell Death;Cell Survival;Cell physiology;Cells;Chronic;Data;Endothelial Cells;Functional disorder;Funding;Genes;Genetic;Homeostasis;Hour;Human;In Vitro;Infiltration;Inflammation;Injury;Integrins;Intravenous;Knockout Mice;Lead;Leukocytes;Ligands;Mediating;Mediator of activation protein;Methods;Modeling;Molecular;Molecular Target;Mus;Myelin;Nervous System Physiology;Pathogenesis;Pathway interactions;Pharmaceutical Preparations;Pharmacological Treatment;Play;Protein Tyrosine Phosphatase;Recovery of Function;Role;Route;Site;Spinal cord injury;Therapeutic;Therapeutic Intervention;Thrombospondin 1;Tissues;Translating;Translations;Traumatic CNS injury;Wallerian Degeneration;angiogenesis;bisperoxo(110-phenanthroline)oxovanadate(1-);improved;in vivo;loss of function;minimally invasive;mutant;nervous system disorder;neuroprotection;neurovascular unit;novel;receptor;research study;response;stroke;success;therapeutic target;white matter

public_health_relevance:
We use complementary classes of neuroprotective pharmacological agents that target endothelial cell deathand dysfunction using intravenous delivery which is rapid and clinically highly relevant to acute neurotrauma inhumans. If successful our studies would pave the way for translating a minimally-invasive pharmacologicalstrategy relevant to acute human neurological disorders including traumatic CNS injury and stroke. Ourtreatments also lead to much reduced inflammation which is relevant to a large number of more chronicconditions.


application_id: 7740926
project_number: 1R21AA017956-01A1
project_title: In vitro and In vivo models for ethanol withdrawal and antepartum hypoxia
administering_ic: NIAAA
award_notice_date: 2009-09-04
opportunity_number: PA-06-181
application_type: 1
activity_code: R21
ic: AA
serial_number: 017956
suffix: A1
program_official: BAIZER, LAWRENCE
project_start_date: 2009-09-05
project_end_date: 2011-08-31
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 1865376
contact_pi: BARRON, SUSAN
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Fetal Alcohol Spectrum Disorder describes a wide range of behaviors and deficits that can occur as a consequence of prenatal alcohol exposure. These effects can range from relatively subtle learning deficits to significant mental retardation. Various explanations for differences in sensitivity to alcohol's effects have been proposed. One theory suggests that "provocative factors" can play a role in increasing the severity and/or providing a context in which the damaging effects of ethanol are increased. We propose that prenatal alcohol exposure may increase the adverse consequences of brief periods of hypoxia during the antepartum period when brief periods of hypoxia routinely occur. Normally the fetus/newborn is fairly resilient against mild hypoxia during labor and delivery however additional challenges (such as a history of in utero alcohol exposure or alcohol withdrawal) may put these infants at increased risk for adverse outcome. In this application we propose to develop two models. The first is an in vitro organotypic hippocampal slice culture model taken from 1-day-old rats. These cultures will be exposed to chronic alcohol followed by withdrawal and challenged with oxygen glucose deprivation (as a model of hypoxia). The hypothesis is that alcohol and hypoxia will produce greater damage than exposure to either challenge alone. Sub-threshold doses will also be included in this Specific Aim to assess the sensitivity of the hippocampus to these challenges. The 2nd model we will develop involves three trimester in vivo administration of alcohol first to pregnant dams and then to Sprague Dawley rat pups on postnatal day 1-7. Following alcohol withdrawal the pups will also be exposed to a mild hypoxic challenge and subsequently tested for a variety of behavioral endpoints including activity and measures of learning and memory. Our working hypothesis is that alcohol exposure and/or withdrawal and hypoxic challenges share similar mechanisms (including overactivity of NMDAR increased GLU activity and polyamine release) that could result in increased excitotoxic damage. The studies proposed will allow us to determine the potential validity of these models. In addition once we have established these models we can begin to study the underlying mechanisms and potential pharmacotherapeutic interventions to try and reduce the damage/deficits associated with alcohol withdrawal and hypoxia. These data could have significant clinical potential since our premise (and model) focuses on a relatively narrow developmental window which conceptually overlaps a time when women would typically be seeking medical assistance (i.e. labor and delivery) and intervention would be more likely.  
  
PUBLIC HEALTH RELEVANCE:  Mild bouts of hypoxia (or reduced oxygen availability) commonly occur during normal labor and delivery and the newborn is usually not affected by these if the bouts are not severe. We propose that one of the effects of prenatal alcohol exposure is to increase the risk of these minor bouts resulting in behavioral and CNS damage. The studies in this application will develop cell culture and rodent models to begin to address this clinically-relevant question.

project_terms:
Abbreviations;Address;Affect;Alcohol withdrawal syndrome;Alcohols;Animal Model;Behavior;Behavioral;Birth;Brain;Cell Culture Techniques;Cessation of life;Chronic;Clinical;Data;Development;Dose;Environmental Risk Factor;Ethanol;Excitatory Amino Acid Antagonists;Exposure to;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Fetal alcohol effects;Fetus;Future;Genetic;Glucose;Glutamates;Hippocampus (Brain);Human;Hypoxia;In Vitro;Infant;Intervention;Learning;Life;Measures;Medical Assistance;Memory;Mental Retardation;Minor;Modeling;Neonatal;Newborn Infant;Outcome;Oxygen;Perinatal;Play;Polyamines;Pregnancy;Preparation;Published Comment;Rattus;Recording of previous events;Relative (related person);Research;Risk;Rodent Model;Role;Severities;Slice;Sprague-Dawley Rats;System;Teratogens;Testing;Time;Variant;Withdrawal;Woman;Work;alcohol effect;alcohol exposure;alcohol sensitivity;aspartate receptor;cell injury;clinically relevant;deprivation;excitotoxicity;expectation;in utero;in vitro Model;in vivo;in vivo Model;neurotoxicity;novel;offspring;postnatal;pregnant;prenatal;prenatal exposure;public health relevance;pup;response;theories

public_health_relevance:
Narrative: Mild bouts of hypoxia (or reduced oxygen availability) commonly occursduring normal labor and delivery and the newborn is usually not affected by these if thebouts are not severe. We propose that one of the effects of prenatal alcohol exposureis to increase the risk of these minor bouts resulting in behavioral and CNS damage.The studies in this application will develop cell culture and rodent models to begin toaddress this clinically-relevant question.


application_id: 7739108
project_number: 1R03AI079442-01A1
project_title: MHC-Ib restricted T cell responses against Listeria monocytogenes
administering_ic: NIAID
award_notice_date: 2009-06-18
opportunity_number: PA-06-180
application_type: 1
activity_code: R03
ic: AI
serial_number: 079442
suffix: A1
program_official: MILLS, MELODY
project_start_date: 2009-06-18
project_end_date: 2011-05-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): 1 Listeria monocytogenes (Lm) is a category B priority pathogen that causes outbreaks of 2 foodborne illness with a high incidence of morbidity and mortality. To achieve sterilizing 3 immunity against Lm CD8+ T cells must recognize antigens bound to MHC-I proteins on the 4 surface of infected cells an event that results in activation of the T cells and acquisition of 5 protective effector functions. Classical MHC-I proteins (MHC-Ia) have been studied for 6 decades however comparatively little is known about most of the non-classical MHC-I proteins 7 (MHC-Ib). We developed a MHC-Ia deficient mouse model of Lm infection to study the role of 8 MHC-Ib restricted T cells in the clearance of intracellular bacterial pathogens. Our central 9 hypothesis is that Lm-immune mice contain memory CD8+ T cells that recognize novel MHC-Ib 10 proteins and that these T cells play a significant role in the clearance of secondary Lm infection. 11 In preliminary studies we showed that CD8+ T cells that recognize antigen in the context of a 12 novel (not M3) MHC-Ib protein are activated during Lm infection. We have identified nine 13 murine MHC-Ib genes as likely candidates to express proteins that could serve as antigen 14 presenting molecules during infection. In this application we propose to: 1) develop a panel of 15 human macrophage-like cells transfected with each of the nine candidate MHC-Ib genes and 2) 16 use the MHC-Ib transfectants to determine how many different MHC-Ib proteins are capable of 17 presenting antigen to T cells during Lm infection. These studies will help to define the role of 18 MHC-Ib restricted T cells in protective immune responses against Lm and may facilitate the 19 identification of new classes of antigens for all intracellular bacterial pathogens. Since most 20 MHC-Ib proteins are non-polymorphic antigens that bind to MHC-Ib proteins are likely to be 21 recognized by most if not all of the individuals in a given population. This makes MHC-Ib 22 antigens particularly attractive candidates for inclusion in vaccines designed to protect against 23 infection with intracellular bacterial pathogens. PUBLIC HEALTH RELEVANCE: One of the significant hurdles faced in trying to design vaccines to protect against infection with bacteria that can survive inside host cells is the identification of antigens that will be recognized by all individuals regardless of their blood type (MHC haplotype). In this study we will characterize a subset of T cells that recognize antigens derived from Listeria monocytogenes bound to MHC-Ib proteins a class of proteins that is non- polymorphic (displays little variation among individuals) in both mice and humans. These studies have the potential to lead to new therapeutic strategies to protect against infections with a variety of intracellular bacteria including prevalent human pathogens such as Mycobacteria tuberculosis and Chlamydia trachomatis.

project_terms:
Antigenic Specificity;Antigens;Attention;Bacteria;Bacterial Infections;Binding (Molecular Function);Blood typing procedure;CD8B1 gene;Categories;Cell Line;Cell surface;Cells;Chlamydia;Chlamydia trachomatis;Disease Outbreaks;Event;Genes;Genetic Polymorphism;Genus Mycobacterium;Haplotypes;Harvest;Human;Immune;Immune response;Immunity;Incidence;Individual;Infection;Lead;Lipids;Listeria monocytogenes;Mediating;Mediator of activation protein;Memory;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Mycobacterium tuberculosis;Organism;Peptides;Play;Population;Proliferating;Proteins;Qa-1 Antigen;Reporting;Role;Salmonella;Splenocyte;Surface;T memory cell;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;Time;Vaccine Design;Variant;antigen binding;design;foodborne;foodborne illness;macrophage;mouse model;novel;novel therapeutics;pathogen;public health relevance;research study;response

public_health_relevance:
Project Narrative:One of the significant hurdles faced in trying to design vaccines to protect against infection with bacteria thatcan survive inside host cells is the identification of antigens that will be recognized by all individuals regardlessof their blood type (MHC haplotype). In this study we will characterize a subset of T cells that recognizeantigens derived from Listeria monocytogenes bound to MHC-Ib proteins a class of proteins that is non-polymorphic (displays little variation among individuals) in both mice and humans. These studies have thepotential to lead to new therapeutic strategies to protect against infections with a variety of intracellularbacteria including prevalent human pathogens such as Mycobacteria tuberculosis and Chlamydia trachomatis.


application_id: 7738831
project_number: 1R03DE019490-01A1
project_title: Is Mitf the Missing Puzzle Linking NFATc1 to Osteoclastogenesis
administering_ic: NIDCR
award_notice_date: 2009-06-19
opportunity_number: PAR-07-418
application_type: 1
activity_code: R03
ic: DE
serial_number: 019490
suffix: A1
program_official: SHUM, LILLIAN
project_start_date: 2009-07-01
project_end_date: 2010-01-04
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 7875075
contact_pi: LIN, YI-LING
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Osteoclasts are bone-resorbing cells essential for maintaining bone mass through modeling and remodeling. In pathological osteolytic conditions osteoclasts are activated by environmental factors which disrupt the balance between bone formation and bone resorption and tip the equilibrium to bone loss. Despite recent advances in restorative dentistry treating and controlling chronic bone loss in oral cavity is still one of the most challenging tasks for dentists. The condition affects millions of people around the world and is often associated with permanent tooth loss. Although pharmacological agents such as bisphosphonate have much success in preventing metabolic bone loss associated with menopause it is not effective in preventing bone loss in periodontitis [8]. In periodontitis chemotactic factors released from oral bacterial infection recruit B and T cells from peripheral blood circulation and these immune cells are the important local sources of RANKL which promotes osteoclastogenesis leading to chronic alveolar bone loss. To develop effective treatment against unregulated osteoclast activation we need to know how differentiation signals are transmitted from osteoclast surface receptors to the downstream targets and how individual molecules are linked together as a network. Studies of naturally mutated and transgenic osteopetrotic mice have revealed many important genes involving in osteoclastogenesis. Among these Mitf is unique in its tissue-specific effects restricted to melanocytes mast cells and osteoclasts. Although osteoclast-specific Mitf has never been identified melanocyte-specific Mitf and mast cell-specific Mitf are present believing to be responsible for lineage-specific gene activation. Among all the essential transcription factors in osteoclastogenesis NFATc1 is considered the master transcription factor which activation turns on osteoclastogenesis even in the absence of RANKL. Nonetheless it is not clear how a ubiquitous factor like NFATc1 is able to direct an osteoclast-specific differentiation program. We propose that Mitf through its tissue-specific effects is the prime candidate to provide osteoclast-specific transcriptional regulation for NFATc1. In this proposal we will examine whether the two major Mitf isoforms present in osteoclasts are able to provide osteoclast-specific transcriptional regulation to assist NFATc1 in orchestrating osteoclastogenesis. We will determine if there are differences between the two isoforms in their abilities to promote osteoclastogenesis and transactivate downstream targets. We will also determine their relationships with NFATc1. Experiments are proposed to examine whether and how Mitf interacts with the NFATc1 pathway. Mitf is known to synergize with NFATc1 on some transcriptional targets shared by Mitf and NFATc1. We will also examine the ability of the two Mitf isoforms in synergizing with NFATc1 on these compound transcriptional targets. The proposed project will allow us to unravel the osteoclast-specific role of Mitf in osteoclastogenesis and to determine which isoform is responsible in assisting NFATc1 to master osteoclast differentiation.   
  
PUBLIC HEALTH RELEVANCE: NFATc1 is the master transcription factor of osteoclastogenesis. However it is not clear how a ubiquitous factor like NFATc1 is able to direct an osteoclast-specific differentiation program. We propose that Mitf through its tissue-specific effects is the prime candidate that provides osteoclast-specific transcriptional regulation to link NFATc1 to osteoclast differentiation.

project_terms:
Affect;Alveolar Bone Loss;Bacterial Infections;Biological;Biological Assay;Blood Circulation;Bone Resorption;Cell Differentiation process;Cell Line;Cell Lineage;Cells;Chemotactic Factors;Chronic;Dentists;Development;Development Plans;Environmental Risk Factor;Equilibrium;Exhibits;Gene Activation;Gene Targeting;Genes;Human;Immune;Individual;Link;Menopause;Metabolic;Modeling;Mus;Mutate;Mutation;Oral;Oral cavity;Osteoclasts;Osteogenesis;Osteolytic;Outcome;Pathway interactions;Pattern;Periodontitis;Protein Isoforms;RNA Interference;Recruitment Activity;Relative (related person);Reporter;Role;Signal Transduction;Source;Specificity;Surface;T-Lymphocyte;TNFSF11 gene;Testing;Tissue-Specific Gene Expression;Tissues;Tooth Loss;Trans-Activation (Genetics);Transcriptional Regulation;Transgenic Organisms;base;bisphosphonate;bone;bone loss;bone mass;effective therapy;macrophage;mast cell;melanocyte;microphthalmia-associated transcription factor;nuclear factors of activated T-cells;osteoclastogenesis;peripheral blood;permanent tooth;precursor cell;prevent;programs;public health relevance;receptor;recombinant virus;research study;restorative dentistry;success;transcription factor

public_health_relevance:
NARRATIVES:NFATc1 is the master transcription factor of osteoclastogenesis. However it is not clear how a ubiquitousfactor like NFATc1 is able to direct an osteoclast-specific differentiation program. We propose that Mitf throughits tissue-specific effects is the prime candidate that provides osteoclast-specific transcriptional regulation tolink NFATc1 to osteoclast differentiation.


application_id: 7738232
project_number: 1R21AA017937-01A1
project_title: Re-entry Alcohol Services for Rural Offenders
administering_ic: NIAAA
award_notice_date: 2009-07-31
opportunity_number: PA-08-008
application_type: 1
activity_code: R21
ic: AA
serial_number: 017937
suffix: A1
program_official: MATTSON, MARGARET
project_start_date: 2009-08-01
project_end_date: 2011-07-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall aim of the proposed project is to examine the feasibility of using innovative telemedicine technology to deliver an evidence-based alcohol intervention (MET) to rural offenders re-entering the community from prison. Hazardous use of alcohol is a considerable problem in rural areas. A primary correlate of the problem of hazardous alcohol use in rural areas is the limited access to and availability of health and behavioral services. In the absence of available and accessible re-entry alcohol interventions rural offenders with a history of hazardous drinking are at heightened risk for alcohol relapse and recidivism when they return to the community. The study will include screening and recruiting rural offenders with a pre- incarceration history of hazardous drinking using the AUDIT. Participants (N=142) who meet criteria for hazardous drinking (AUDIT score of 8+) will be interviewed within one week of their release from prison and randomized to one of two study conditions: 1) Motivational Enhancement Telemedicine (METelemedicine) combined with usual re-entry services (n=71) and 2) Re-entry services as usual (n=71). In both study conditions participants will have a referral to a community case manager (Social Service Clinician - SSC) by their parole officer indicating that they are in need of alcohol services and will meet criteria for outpatient level of care. In the METelemedicine condition participants will also be provided with four sessions of MET with a therapist in an urban-based university treatment clinic using telemedicine videoconferencing. Outcome data will be collected at 3-months post release to examine number of days of alcohol abstinence at re-entry. The specific aims of the study include: (1) Implement innovative telemedicine technology to deliver Motivational Enhancement Therapy (METelemedicine) to re-entering rural offenders with a pre-incarceration history of hazardous drinking and (2) Examine the feasibility of using METelemedicine by re-entering rural offenders with a pre-incarceration history of hazardous drinking. If findings from this study establish feasibility of telemedicine as an approach for delivering an evidence-based practice an R01 application will be developed to test the approach in a larger scale trial. The long-term objective of this research agenda is to increase access to effective treatment approaches for rural re-entering offenders in order to promote alcohol abstinence and reduce recidivism.  
  
PUBLIC HEALTH RELEVANCE: The overall aim of the proposed project is to examine the feasibility of using innovative telemedicine technology to deliver an evidence-based alcohol intervention (MET) to rural offenders re-entering the community from prison. The significance of this study for public health includes the opportunity to build on advances made by other uses of telemedicine that have included providing health and mental health services to individuals in rural areas and to incarcerated individuals. This study is innovative with the focus on offenders at community re-entry as well as the use of telemedicine as a new technology to increase access to evidence- based alcohol services in real-world settings.

project_terms:
Address;Adherence (attribute);Affect;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcohols;Caring;Case Manager;Clinic;Communities;Consumption;Data;Emerging Technologies;Equipment;Evaluation;Evidence based intervention;Evidence based practice;Health;Health Services Accessibility;Imprisonment;Individual;Interview;Mental Health Services;National Institute on Alcohol Abuse and Alcoholism;Outcome;Outpatients;Participant;Perception;Prevalence;Prisoner;Prisons;Procedures;Process;Randomized;Recording of previous events;Recruitment Activity;Reporting;Research;Research Personnel;Research Priority;Risk;Rural;Rural Population;Screening procedure;Services;Social work (field);System;Technology;Telemedicine;Testing;Training;Transportation;Travel;United States National Institutes of Health;Universities;Videoconferences;Videoconferencing;alcohol abstinence;alcohol abuse therapy;alcohol intervention;alcohol relapse;alcohol services;alcohol use disorder;base;behavioral health;community reentry;cost;cost effectiveness;drinking;effective therapy;eligible participant;evidence base;follow-up;hazardous drinking;innovation;innovative technologies;medical specialties;meetings;motivational enhancement therapy;new technology;offender;parole;public health medicine (field);public health relevance;recidivism;response;rural area;service utilization;treatment program

public_health_relevance:
The overall aim of the proposed project is to examine the feasibility of using innovative telemedicinetechnology to deliver an evidence-based alcohol intervention (MET) to rural offenders re-entering thecommunity from prison. The significance of this study for public health includes the opportunity to build onadvances made by other uses of telemedicine that have included providing health and mental health servicesto individuals in rural areas and to incarcerated individuals. This study is innovative with the focus on offendersat community re-entry as well as the use of telemedicine as a new technology to increase access to evidence-based alcohol services in real-world settings.


application_id: 7738197
project_number: 2R01DA012964-09A1
project_title: Novelty Dopamine and Response to Amphetamine
administering_ic: NIDA
award_notice_date: 2009-06-09
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: DA
serial_number: 012964
suffix: A1
program_official: LYNCH, MINDA
project_start_date: 2000-03-01
project_end_date: 2014-06-30
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 1884463
contact_pi: BARDO, MICHAEL T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adolescent;Amphetamines;Basic Science;Behavior;Behavioral;Behavioral inhibition;Brain region;Corpus striatum structure;Development;Dopamine;Dose;Drug Addiction;Drug abuse;Environment;Environmental Risk Factor;Exposure to;Genetic;Genetic Predisposition to Disease;Health;Impulsivity;Incentives;Individual;Intake;Intervention;Life;Medial;Metabolism;Modeling;Molecular;Motivation;Neurobiology;Nucleus Accumbens;Play;Positive Reinforcer;Prefrontal Cortex;Presynaptic Terminals;Procedures;Process;Rattus;Research;Rewards;Risk;Role;Self Administration;Serotonin;Stimulus;Sucrose;System;Technology;Testing;Visual;Work;base;design;drug of abuse;drug reward;environmental enrichment for laboratory animals;insight;monoamine;neurobehavioral;neuronal patterning;novel;protective effect;response;stimulant abuse;uptake;young adult


application_id: 7738165
project_number: 7F31NS057928-02
project_title: Contribution of endogenous NPY signaling to chronic pain
administering_ic: NINDS
award_notice_date: 2008-11-20
opportunity_number: PA-07-106
application_type: 7
activity_code: F31
ic: NS
serial_number: 057928
program_official: PORTER, LINDA L
project_start_date: 2008-01-01
project_end_date: 2010-12-31
study_section: Special Emphasis Panel[ZRG1-F02B-G(20)L]
contact_pi_person_id: 8717038
contact_pi: SOLWAY, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Inflammation or peripheral nerve injury increases neuropeptide Y (NPY) expression in pain-relevant areas of the nervous system such as large primary afferents and lamina l/ll of the dorsal horn of the spinal cord. However the contribution of endogenous NPY to chronic pain is unclear. This NRSA proposes to test the overall hypothesis that NPY tonically inhibits nociceptive signaling in the spinal cord and brain following inflammation or nerve injury. Specific Aim #1 will test the hypothesis that genetic knockdown of NPY increases allodynia and/or hyperalgesia associated with nerve injury and inflammation. Aim #1 experiments utilize a conditional knockout mouse (Npytet) that contains a doxycycline (Dox)-regulated cassette (tTA) upstream of Npy exons to evaluate the contribution of NPY to the development (Aim 1 A) and maintenance (Aim 1B) of chronic pain and correlate these changes with NPY expression using immunohistochemistry and western blot (Aim 1C). While Aim #1 establishes a contribution of NPY inhibition to behavioral manifestations of chronic pain Specific Aim #2 uses direct microinjection techniques to investigate the site of action of NPY. NPY Y1 and NPY Y2 receptors decorate lamina l/ll of the dorsal horn. I propose to target these receptors with intrathecal injection of selective Y1 or Y2 receptor antagonists (Aim 2A). Previous studies indicate that inflammation up-regulates the expression of NPY and Y1 in the arcuate nucleus of the hypothalamus (ARC) and that microinjection of NPY into the ARC attenuated behavioral signs of heat hypersensitivity. In Aim 2B I propose to microinject Y1 or Y2 antagonists into the ARC and predict that this will exacerbate allodynia and hyperalgesia.

project_terms:
Absence of pain sensation;Address;Analgesics;Area;Arthritis;Attenuated;BIBO 3304;BIIE 0246;Behavior;Behavioral;Blotting Western;Brain;Breeding;Caliber;Chronic;Data;Development;Down-Regulation;Doxycycline;Exons;Fiber;Filament;Ganglia Spinal;Genetic;Germ Lines;Grant;Heating;Hyperalgesia;Hypersensitivity;Hypothalamic structure;Immunohistochemistry;Inflammation;Inflammatory;Intrathecal Injections;Knock-out;Laboratories;Lead;Learning;Maintenance;Mice Knockout;Microinjections;Modeling;Mus;National Research Service Awards;Nervous system structure;Neurons;Neurons Afferent;Neuropeptide Y Receptor;Nociception;Pain;Peptides;Peripheral;Peripheral nerve injury;Plastics;Promotor (Genetics);Proteins;Receptor Signaling;Rodent Model;Sensory;Signal Transduction;Site;Spinal;Spinal Cord;Spinal cord posterior horn;Structure of nucleus infundibularis hypothalami;Techniques;Technology;Testing;Training;Up-Regulation (Physiology);Wild Type Mouse;allodynia;chronic pain;dorsal horn;inflammatory neuropathic pain;inflammatory pain;nerve injury;neuropeptide Y;novel strategies;pain inhibition;painful neuropathy;peripherin;receptor;research study;selective expression;somatosensory;transmission process


application_id: 7737625
project_number: 2R01GM070559-06
project_title: Molecular analysis of juvenile hormone action
administering_ic: NIGMS
award_notice_date: 2010-01-22
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: GM
serial_number: 070559
program_official: CHIN, JEAN
project_start_date: 2005-02-01
project_end_date: 2014-01-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There has been a continuous demand for the development of insect control methods that are target-specific. Juvenile hormone (JH) and ecdysteroids (20-hydroxyecdysone 20E is the most active form) are the major hormones that regulate development and reproduction in insects. Since these hormones are not present in vertebrates they represent attractive targets for the development of insect control methods. Hindering this effort is the lack of understanding of the molecular basis of JH action. During the current grant period seven proteins that are components of multi-protein complexes involved in JH signal transduction and its cross-talk with 20E were identified. Ligand binding studies performed using labeled JH showed that none of these proteins bind to JH with high affinity. While these proteins are likely involved in JH action and its cross-talk with 20E none of them are JH receptors. Search for a better system to study JH action without interference from ecdysteroids discovered JH regulation of reproduction in Tribolium castaneum an ideal system to study JH action without interference from ecdysteroids. In this insect JH without the interference from ecdysteroids regulates vitellogenin gene expression in the fat body and vitellogenin uptake by the oocytes. These two systems provide a unique opportunity to study both genomic (fat body) and non-genomic (ovary) actions of JH in the same insect at the same time. Therefore the renewal application proposes to study mechanism of JH action in regulation of vitellogenin gene expression in the fat body and vitellogenin uptake into the oocytes with a major goal of identifying receptors transcription factors and protein modifiers critical for JH signal transduction. Completion of whole genome sequencing availability of microarrays functioning of systemic RNA interference (RNAi) and excellent response to JH and its analogs make T. castaneum an excellent model system for studies on JH action. In the first specific aim microarray RNAi qRT-PCR electrophoretic mobility shift assays and ligand-binding assays will be employed to identify and characterize receptors transcription factors and protein modifiers involved in JH regulation of vitellogenin gene expression. In the second specific aim a panel of in vivo cell culture and in vitro assays will be used to determine whether any of the 51 G- protein-coupled receptors indentified in T. castaneum as those required for egg production and embryogenesis are activated by JH to regulate vitellogenin uptake into the oocytes. JH analogs are being used for mosquito control but some mosquitoes are already developing resistance to these analogs. The results from these studies will aid in understanding the mode of action of JH analogs thus facilitating their judicious use. The genes identified will be useful to develop screening assays to identify new insect disease vector control agents. The receptors identified can also be used in medicine by developing gene switches for various applications such as gene therapy tissue engineering and therapeutic protein production. PUBLIC HEALTH RELEVANCE Insect juvenile hormone analogs are being used for mosquito control but some mosquitoes are already developing resistance to these analogs. The results from these studies will aid in understanding the mode of action of JH analogs thus facilitating their judicious use. The genes identified will be useful to develop screening assays to identify new insect disease vector control agents and for developing gene switches useful for various applications such as gene therapy tissue engineering and therapeutic protein production.

project_terms:
Adult;Affinity;Agonist;Anabolism;Biological;Biological Assay;Biological Metamorphosis;Biological Models;Cell Culture Techniques;Code;Culicidae;Data;Development;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ecdysterone;Electrophoretic Mobility Shift Assay;Embryonic Development;Event;Extracellular Space;Fat Body;Female;Flour;Food;G-Protein-Coupled Receptors;Gene Expression;Genes;Genome;Genomics;Goals;Grant;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insecta;Juvenile Hormones;Label;Life Cycle Stages;Ligand Binding;Livestock;Medicine;Membrane;Messenger RNA;Methods;Methoprene;Molecular;Molecular Analysis;Molting;Mosquito Control;Oocytes;Oogenesis;Ovary;Play;Production;Promoter Regions (Genetics);Protein Binding;Protein Precursors;Proteins;RNA Interference;Regulation;Reproduction;Resistance development;Role;Screening procedure;Sensory;Set protein;Signal Transduction;Switch Genes;System;Time;Tissue Engineering;Tribolium (beetle);Vertebrates;Vitellogenesis;Vitellogenins;analog;base;egg;follicular epithelial cell;gene therapy;genome sequencing;hormone analog;hormone biosynthesis;hormone regulation;in vitro Assay;in vivo;insect disease;knock-down;meetings;non-genomic;prevent;protein complex;public health relevance;receptor;reproductive;research study;response;therapeutic protein;transcription factor;uptake;vector control


application_id: 7729934
project_number: 2R01AI050656-06A2
project_title: Molecular Mechanisms Controlling NK Receptors
administering_ic: NIAID
award_notice_date: 2009-09-16
opportunity_number: PA-07-070
application_type: 2
activity_code: R01
ic: AI
serial_number: 050656
suffix: A2
program_official: MILLER, LARA R
project_start_date: 2003-09-01
project_end_date: 2011-08-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882143
contact_pi: LUTZ, CHARLES T.
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Affect;Attention;Binding (Molecular Function);CREB1 gene;Cancer Patient;Cataloging;Catalogs;Cells;Chromatin;Communicable Diseases;Complement component C1s;DNA;DNA Methylation;DNA-Directed RNA Polymerase;Development;Disease;Dysmyelopoietic Syndromes;Elements;Epigenetic Process;Future;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Goals;Health;Histone Deacetylase Inhibitor;Human;Immunity;Immunoglobulins;In Vitro;Individual;Interleukin-15;Interleukin-2;Killer Cells;Licensing;Lymphocyte;Lymphoma;Maintenance;Malignant Neoplasms;Messenger RNA;Methylation;Molecular;Mus;NK Cell Activation;Natural Immunity;Natural Killer Cells;Non-Malignant;Patients;Pattern;Pharmaceutical Preparations;Physiology;Polymerase;Production;Promotor (Genetics);Reagent;Receptor Cell;Receptor Gene;Regulation;Research;Research Personnel;Testing;Text;Time;Work;base;cancer cell;cancer immunotherapy;cancer therapy;cell killing;chemokine;cooperative study;cytokine;cytotoxic;cytotoxicity;effective therapy;health application;human disease;in vivo;public health medicine (field);public health relevance;receptor;receptor expression;transcription factor

public_health_relevance:
Modified PublicHealthRelevance Using for information your application. Using Enter the text herethat is the new publichealthrelevance Enterthe text here that is the new public health relevance information for your application. health' to of the describe relevance of thisresearch public no more than two or three sentences describe the relevance this research to public health. two or threesentences no morethan adaptive Natural killer (NK) cells infectedand rnalignantcells and direct subsequent Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive of canccrand treatmenls cancer and immunity. The long-range goal is to useNK cells as effective immunrtv-The long-range goal is to use NK cells as effective treatments infectious diseases. As the next logical step toward that goal the current objectives are to diseases.As fhc next logical steptoward rhat goalthe currentobjectivesare to infectious further characterize NK gene expression control in normal physiology and in cancersand NK geneexpreisioncontrol normal physiologyand cancers and further charaoterize syndrorne. pre-cancers such as Lymphoma and myelodysplastic syndrome. such as lymphomaand rnyelodysplastic pre-cancerscad6-26-9 L4:37 09 RECEI\JED 66-26-' 14:37 BECEIVED4+..'"FHOMFEOll-luTO-P7/11 PAAT /AU.


application_id: 7729814
project_number: 1R01AG034605-01
project_title: Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
administering_ic: NIA
award_notice_date: 2009-08-31
opportunity_number: RFA-AG-09-010
application_type: 1
activity_code: R01
ic: AG
serial_number: 034605
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-01
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZAG1 ZIJ-5 (M2)]
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application proposes to address a fundamental unresolved question in the field of cognitive aging the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices concomitant Ca2+ imaging in recorded neurons extensive immunohistochemistry with a battery of stains diffusion tensor imaging (MRI/DTI) separate microarray analysis of each individual rat and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral electrophysiological microarray and immunohistochemical analyses to test the proposition that conversion to UCA has been slowed and if it has to determine through which hippocampal pathways this occurred. Overall these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA and should importantly determine the role of myelinogenic programs in cognitive aging. Further the proposed longitudinal studies should have direct translational relevance.  
  
PUBLIC HEALTH RELEVANCE: This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

project_terms:
Address;Age;Age-Months;Aging;Anemia;Animal Feed;Animal Model;Animals;Arts;Astrocytes;Behavioral;Binding (Molecular Function);Bioenergetics;Bioinformatics;Brain;Cholesterol;Classification;Cognition;Cognitive;Cognitive aging;Corpus Callosum;Cuprizone;Data;Diet;Dietary Iron;Diffusion Magnetic Resonance Imaging;Elderly;Electrophysiology (science);Event;Exhibits;Figs - dietary;Fostering;Gene Expression;Genes;Genomics;Guanosine Triphosphate Phosphohydrolases;Hemochromatosis;Hippocampus (Brain);Human;Image;Immune;Immunohistochemistry;Impaired cognition;Individual;Inflammation;Inflammatory;Intake;Intervention;Investigation;Iron;Left;Link;Lipids;Liver;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Memory;Methods;Microarray Analysis;Modeling;Monkeys;Myelin;Nature;Neurites;Neurobiology;Neurons;Oligodendroglia;Oxidative Stress;Pathway interactions;Performance;Phase;Play;Process;Protocols documentation;Rattus;Regulation;Research;Resources;Role;Sampling;Serum;Signal Transduction;Slice;Staining method;Stains;Stimulus;Structure;Techniques;Testing;Therapeutic;Translating;Up-Regulation (Physiology);Validation;Work;age related;aged;aging brain;base;behavior test;biological adaptation to stress;biomarker;cognitive function;density;indexing;insight;interest;middle age;morris water maze;multidisciplinary;myelination;programs;protein degradation;public health relevance;response;trafficking;young adult

public_health_relevance:
This proposed research will be conducted in an established rat model of aging which shows demonstratedrelevance to human aging. These studies will elucidate neurobiological markers of and processes influencingthe divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have bothpredictive and therapeutic value in determining the course of human cognitive aging.


application_id: 7729609
project_number: 1R01DA025649-01A1
project_title: Neuropharmacology of Tramadol: Clinical Efficacy and Abuse Potential
administering_ic: NIDA
award_notice_date: 2009-07-16
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DA
serial_number: 025649
suffix: A1
program_official: BOUGH, KRISTOPHER J
project_start_date: 2009-08-01
project_end_date: 2011-07-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Prescription opioid misuse and abuse are increasing problems in the United States. In the 2006 National Survey on Drug Use and Health 5.2 million Americans had illicitly used a prescription opioid in the past month. National rates of illicit prescription opioid use are higher than those for heroin cocaine or methamphetamine and are exceeded only by marijuana. Moreover the number of individuals initiating illicit use of prescription opioids was greater than that for marijuana in 2004 and 2005. These findings indicate that illicit prescription opioid use represents a significant public health concern greater than that of cocaine heroin or methamphetamine and perhaps approaching that of marijuana. The increase in illicit prescription opioid use may be due to increased availability of opioid analgesics medications with significant abuse potential. Discovery and development of opioid analgesics with reduced abuse potential may serve to decrease prescription opioid misuse and the subsequent development of opioid use disorders. Tramadol is an unscheduled atypical analgesic with opioid activity. While rare cases of tramadol abuse and physical dependence have been reported it has reduced abuse potential relative to typical prescription opioids. The reduced abuse potential of tramadol has been attributed to its novel pharmacology. Tramadol is a mu opioid agonist but also blocks reuptake of serotonin and norepinephrine. The specific aim of the present application is to elucidate the relative contributions of mu opioid serotonin and norepinephrine receptor systems to the effects of tramadol using an array of pharmacologic measures relevant to its abuse potential and analgesic efficacy in human volunteers. The knowledge gained about tramadol from the proposed experiments in terms of its neuropharmacology will aid in the discovery and development of other opioid medications with reduced abuse potential. Specifically if the non-mu mediated effects of tramadol contribute to its analgesic efficacy and reduced abuse potential these findings would support the development of other analgesics with similar neuropharmacological mechanisms. This project will employ placebo-controlled randomized and double blind testing procedures to evaluate the behavioral effects of tramadol across three experiments. Overall this project will contribute important clinical information regarding the pharmacology of tramadol in relation to its analgesic efficacy and reduced abuse potential and provide basic science information about the behavioral effects of prescription opioids in humans. PUBLIC HEALTH RELEVANCE: The research proposed in this application seeks to understand better the human neuropharmacology of tramadol an atypical analgesic with opioid action that has reduced abuse potential relative to other opioid analgesics. We are seeking to understand how the neuropharmacology of tramadol influences both its analgesic efficacy and reduced abuse potential in an effort to aid development of other analgesic medications with reduced abuse potential. Developing analgesics with reduced abuse potential may reduce the prevalence of prescription opioid misuse and subsequent opioid use disorders.

project_terms:
Agonist;American;Analgesics;Animals;Basic Science;Behavioral;Clinical;Cocaine;Data;Development;Disease;Dose;Double-Blind Method;Drug usage;Enrollment;Future;Health;Heroin;Human;Human Volunteers;Hydrocodone;Hydromorphone;Individual;Knowledge;Marihuana;Measures;Mediating;Methamphetamine;Naltrexone;Neuropharmacology;Neurotransmitters;Norepinephrine;Norepinephrine Receptors;Opioid;Opioid Analgesics;Oxycodone;Performance;Pharmaceutical Preparations;Pharmacology;Physical Dependence;Physicians;Physiological;Placebo Control;Placebos;Prevalence;Procedures;Randomized;Receptors Opioid mu;Relative (related person);Reporting;Research;Rewards;Role;Serotonin;Stimulus;Surveys;System;Testing;Time;Tramadol;United States;aged;clinical efficacy;noradrenergic;norepinephrine system;novel;opioid abuse;opioid misuse;opioid withdrawal;public health medicine (field);public health relevance;research study;reuptake;tramadol abuse;volunteer

public_health_relevance:
Project NarrativeThe research proposed in this application seeks to understand better the humanneuropharmacology of tramadol an atypical analgesic with opioid action that hasreduced abuse potential relative to other opioid analgesics. We are seeking tounderstand how the neuropharmacology of tramadol influences both its analgesicefficacy and reduced abuse potential in an effort to aid development of other analgesicmedications with reduced abuse potential. Developing analgesics with reduced abusepotential may reduce the prevalence of prescription opioid misuse and subsequentopioid use disorders.


application_id: 7729355
project_number: 1R01DA022451-01A2
project_title: Enhancement of Sexual Motivation
administering_ic: NIDA
award_notice_date: 2010-01-26
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: DA
serial_number: 022451
suffix: A2
program_official: WETHERINGTON, CORA LEE
project_start_date: 2010-02-01
project_end_date: 2015-01-31
study_section: Special Emphasis Panel[ZRG1 BBBP-T (03)]
contact_pi_person_id: 7876913
contact_pi: AKINS, CHANA K.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): There is considerable evidence for a co-morbid relationship between cocaine abuse and risky sexual behavior. Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. Controlled preclinical studies that utilize animal models have demonstrated that prior repeated exposure to cocaine enhances sexual motivation and behavior. However no parametric or systematic studies further investigating the basic mechanisms underlying this relationship have been conducted. The goal of the proposed experiments is to utilize an animal model whose sexual behavior system has been well-studied Japanese quail. In addition to the benefits of using quail to study sexual behavior the use of a visually-oriented species in studying drug effects may be of additional relevance to studying human drug addiction. We currently have preliminary evidence in male Japanese quail that preexposure to cocaine enhances sexual motivation. This finding ties in well with clinical observations that indicate that cocaine use in humans may increase sexual motivation thereby increasing the likelihood of the occurrence of high-risk sexual behavior. The overall working hypothesis of this proposal is that the magnitude of the sexual response depends on several cocaine preexposure parameters including dose amount of exposure time between exposures and the withdrawal period before sexual behavior testing. Additionally we hypothesize that cocaine preexposure increases the resistance to extinction (harder to eliminate) and facilitates the reacquisition of a sexual response that has been extinguished. The proposed research has the potential to contribute to our understanding of cocaine preexposure effects on sexual motivation using a visually-oriented animal model. For example in males sexual motivation may be enhanced by prior cocaine exposure. Such an enhancement might translate in humans as high risk or compulsive sexual behaviors such as increased frequency of sexual activity sex with multiple partners and unprotected sex. These risky sexual behaviors have been linked with considerable health consequences such as the transmission of HIV and hepatitis C. The goal of the proposed project is to contribute to understanding underlying mechanisms of cocaine's effects on sexual motivation.  PUBLIC HEALTH RELEVANCE: Clinical studies have shown a correlation between cocaine use and risky sexual practices such as increased frequency an increased number of partners and unprotected sex. These sexual practices have been linked to adverse health consequences including high prevalence rates for sexually-transmitted diseases. The current application is a preclinical model used to investigate how drugs of abuse alter sexual motivation.

project_terms:
Acute;Animal Model;Animals;Association Learning;Behavior;Brain region;Breeding;Chronic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Conditioned Stimulus;Coturnix japonica;Cues;Dependence;Dose;Drug Addiction;Drug abuse;Drug usage;Empirical Research;Ethics;Event;Extinction (Psychology);Female;Food;Frequencies (time pattern);Goals;HIV;Health;Hepatitis C;High Prevalence;Human;Investigation;Learning;Length;Light;Link;Long-Term Effects;Measures;Memory;Mentored Research Scientist Development Award;Methods;Modeling;Motivation;Multiple Partners;Partner in relationship;Performance;Pharmaceutical Preparations;Phase;Physiological Effects of Drugs;Pre-Clinical Model;Procedures;Property;Publishing;Quail;Recovery;Research;Research Training;Resistance;Rewards;Rodent;Saline;Seasons;Sensory;Sex Behavior;Sexually Transmitted Diseases;Signal Transduction;Simulate;Stimulus;System;Testing;Time;Translating;United States;Unsafe Sex;Visual;Withdrawal;Work;addiction;approach behavior;behavior test;clinically relevant;cocaine exposure;cocaine use;conditioning;drug of abuse;drug testing;experience;high risk;high risk sexual behavior;indexing;male;neural circuit;preclinical study;public health medicine (field);public health relevance;research study;response;sex;transmission process


application_id: 7728496
project_number: 1R01HL091924-01A1
project_title: Telomerase in Inflammation and Atherosclerosis
administering_ic: NHLBI
award_notice_date: 2009-08-31
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: HL
serial_number: 091924
suffix: A1
program_official: SRINIVAS, POTHUR R
project_start_date: 2009-09-01
project_end_date: 2011-08-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8010784
contact_pi: BRUEMMER, DENNIS CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Telomeres the DNA TTAGGG repeat sequences at the ends of eukaryotic chromosomes are stabilized by telomerase to serve as protective capping and to prevent degradation. Stem cells constitutively overexpress the catalytic core telomerase reverse transcriptase (TERT) manifesting high levels of telomerase activity which confers an apparently indefinite lifespan and is rate limiting for tissue renewal. In contrast the majority of human adult somatic cells are thought to transcriptionally repress TERT resulting in telomere shortening and cellular senescence. Although most adult cells display low basal telomerase activity mounting evidence indicates that TERT transcription is tightly regulated and inducible in various cell types in response to changes in environmental cues. In human atherosclerosis telomerase is activated and TERT expression correlates with the extent of the disease; however the mechanisms underlying telomerase activation and the physiological role of inducible TERT expression in atherosclerosis remain to be discovered. Our preliminary studies confirm increased TERT expression in macrophages of human atherosclerotic lesions and telomerase activation during atherosclerosis development. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that telomerase is induced in macrophages and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize cellular and molecular approaches to determine the transcriptional regulation of TERT activation in macrophages and test the hypothesis that TERT constitutes a NFk _B-regulated target gene in macrophages. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis. Ultimately the results of these studies will not only characterize the mechanisms underlying telomerase activation in atherosclerosis but also advance our understanding of the role of telomerase in atherosclerosis.

project_terms:
Adult;Architecture;Arterial Fatty Streak;Atherosclerosis;Biology;Blood Vessels;Breeding;Catalytic Domain;Cause of Death;Cell Aging;Cells;Chromatin;Chromosomes;Cues;DNA;Development;Developmental Process;Disease;Engineering;Enzymes;Epigenetic Process;Exhibits;Foundations;Gene Cluster;Gene Expression;Gene Silencing;Gene Targeting;Generations;Genes;Genetic Transcription;Heterochromatin;Histones;Homeostasis;Human;Inflammation;Inflammatory;Inflammatory Response;Longevity;Low Density Lipoprotein Receptor;Lymphoid Cell;Macrophage Activation;Molecular;Molecular Profiling;Mus;Myelogenous;Pathway interactions;Physiological;Process;Promotor (Genetics);Property;Relative (related person);Role;Signal Pathway;Somatic Cell;Staging;Stem cells;Stimulus;Telomerase;Telomere Maintenance;Telomere Shortening;Testing;Tissues;Transcriptional Regulation;United States;atherogenesis;base;cell type;improved;insight;macrophage;novel;overexpression;prevent;programs;protein complex;research study;response;telomerase reverse transcriptase;telomere

public_health_relevance:
Atherosclerotic cardiovascular disease is the leading cause of death in the United States and inflammatory pathways contribute to all stages of the disease. This application will investigate the mechanisms by which telomerase an enzyme that generates protective caps at the ends of chromosomes and controls gene expression programs influences the development of atherosclerosis. The results of these studies may ultimately characterize telomerase-dependent activation of inflammation as a novel pathway contributing to atherosclerosis and improve our understanding of the inflammatory components of atherosclerosis.


application_id: 7727740
project_number: 1R01CA137052-01A1
project_title: Identifying candidate modifier elements of a breast cancer risk associated allele
administering_ic: NCI
award_notice_date: 2009-05-08
opportunity_number: PA-07-070
application_type: 1
activity_code: R01
ic: CA
serial_number: 137052
suffix: A1
program_official: SHARMAN, ANU
project_start_date: 2009-05-08
project_end_date: 2014-04-30
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 6825342
contact_pi: SAMUELSON, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Alleles;Animal Model;Anthracenes;Area;Automobile Driving;BRCA1 gene;BRCA2 gene;Basic Research Breast Cancer;Biological Assay;Biological Models;Breast Cancer Genetics;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinoma;Candidate Disease Gene;Cause of Death;Chromosomes Human Pair 2;Chromosomes Human Pair 5;Complex;DNA Resequencing;Development;Disease;Elements;Environmental Risk Factor;Epigenetic Process;Frequencies (time pattern);Functional RNA;Genes;Genetic;Genetic Markers;Genetic Models;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Goals;Human;Human Chromosomes;In Vitro;Inbred Strains Rats;Incidence;Individual;Inherited;Intercistronic Region;Knowledge;Lead;Location;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Maps;Modeling;Molecular Genetics;Molecular Target;Mortality Vital Statistics;Nature;PTPRJ gene;Phenotype;Population;Predisposition;Principal Investigator;Quantitative Trait Loci;Rat-1;Rattus;Recombinants;Research;Research Project Grants;Risk;STAT5a Transcription Factor;Single Nucleotide Polymorphism;Staging;Susceptibility Gene;System;Testing;Transgenic Model;Translating;Transplantation;Variant;Variation (Genetics);Woman;Work;abstracting;aged;anticancer research;cancer prevention;cancer risk;candidate validation;comparative;congenic;disorder risk;genetic analysis;genetic element;genome wide association study;in vivo;knockout gene;malignant breast neoplasm;novel;novel strategies;public health relevance;rat genome;research study


application_id: 7724789
project_number: 1R15GM085722-01A1
project_title: Mechanisms of Action of UmuD in Regulating DNA Damage-Induced Genes in a umuC- De
administering_ic: NIGMS
award_notice_date: 2009-07-17
opportunity_number: PA-06-042
application_type: 1
activity_code: R15
ic: GM
serial_number: 085722
suffix: A1
program_official: PORTNOY, MATTHEW
project_start_date: 2009-08-01
project_end_date: 2013-01-20
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduates to research; and 3) strengthening the research environment in non-research intensive universities. The long term goal of this research is to understand the mechanisms by which cells respond to DNA damage. The link between DNA damage and human health is well-established: the inability to correctly repair damaged DNA can result in various forms of colon breast and ovarian cancers in humans. This project focuses on the translesion synthesis SOS response to DNA damage which is accomplished by Y-family polymerases (Cordonnier & Fuchs 1999). The existence of similar extensive DNA damage sensing and repair mechanisms in organisms ranging from humans to bacteria demonstrates this central role of DNA integrity. Homologs to bacterial Y-family polymerases exist in humans (e.g. pol 7) and other eukaryotes (polymerase Rev1p and Rad30p) (McDonald et al. 1999; Goodman 2002; Nohmi 2006) where mutations in pol 7 predispose humans to skin cancer (Cleaver 2000). In a typical bacterial SOS response pathway after DNA damage the UmuD protein is induced self-cleaves and then acts with its partner UmuC to function as a translesion synthesis DNA polymerase. To accomplish our overall goals we will establish how an unusual homolog of UmuD present in the ubiquitous soil bacterium Acinetobacter baylyi strain ADP1 functions after DNA damage. Both the genetics and functioning of the response to DNA damage in ADP1 is unlike other bacteria: the umuC gene is interrupted and incomplete. Furthermore the UmuD of ADP1 (UmuDAb) is unique: it contains an extra N-terminal region and it regulates the expression of a DNA damage-inducible gene ddrR. We propose two hypotheses for UmuDAb involvement in the DNA damage response of ADP1: (A) UmuDAb can behave like other UmuD proteins cleaving itself after DNA damage and acting with UmuC and (B) The "extra" N-terminal region of UmuDAb is required for its action as a regulator. To test these hypotheses our aims will be to determine: (i) if UmuDAb is activated for self- cleavage by DNA damage using Western blotting analyses of UmuDAb (or UmuDAb fragments) after exposure of ADP1 cells to DNA damaging chemicals (ii) if UmuDAb can interact with an exogenous UmuC to conduct translesion DNA synthesis or checkpoint functions by complementing either an Escherichia coli umuD- mutant with the ADP1 umuDAb allele or the ADP1 strain with the E. coli umuC and (iii) if the "extra" N-terminal region of UmuDAb is required for its regulation of ddrR by measuring the inducible expression of a ddrR::lacZ gene fusion in an ADP1 strain with a mutant umuDAb allele lacking the extra N- terminal domain This research is significant because it will enhance our understanding of the ways in which cells can achieve DNA repair specifically with the SOS response. This project will provide research training opportunities for Morehead State University undergraduates 66% of whom grew up in Appalachia and have largely not been exposed to nor ever engaged in scientific research. The increased research infrastructure expectation of and opportunities for student engagement in authentic research will benefit the entire biology department and Morehead State University. PUBLIC HEALTH RELEVANCE: To enhance our understanding of the mechanisms that human as well as bacterial cells use to repair their DNA this research will characterize mechanisms of action of an atypical bacterial DNA damage response protein that is a component of an error-prone polymerase. Similar polymerases exist in bacteria yeast and humans with defects in these polymerases causing human cancer after exposure to ultraviolet light. This project has additional biomedical implications for bacterial disease as the SOS response in bacteria can be induced by antibiotic treatment and lead to the spread of antibiotic resistance and other virulence genes among bacteria.

project_terms:
Acinetobacter;Alleles;Amino Acids;Antibiotic Resistance;Antibiotic Therapy;Appalachian Region;Bacteria;Bacterial DNA;Bacterial Infections;Biology;Breast;Cell Death;Cells;Chemicals;Cleaved cell;Colon;Complement;DNA;DNA Damage;DNA Repair;DNA biosynthesis;DNA-Directed DNA Polymerase;Defect;Environment;Escherichia coli;Eukaryota;Exposure to;Failure (biologic function);Family;Galium;Gene Fusion;Gene Mutation;Genes;Genetic;Genome;Goals;Hares;Health;Homologous Gene;Human;Investigation;LacZ Genes;Lead;Life;Link;Malignant Neoplasms;Malignant neoplasm of ovary;Measures;Mutagenesis;Mutation;N-terminal;Operon;Organism;Pathway interactions;Play;Polymerase;Proteins;Regulation;Research;Research Infrastructure;Research Training;Role;SOS Response (Genetics);Single-Stranded DNA;Skin Cancer;Soil;Son of Sevenless Proteins;Students;Testing;Ultraviolet Rays;Universities;Virulence;Walkers;Western Blotting;Yeasts;cancer type;expectation;gene induction;genetic regulatory protein;human DNA damage;mutant;novel;programs;public health relevance;repaired;response

public_health_relevance:
Project Narrative To enhance our understanding of the mechanisms that human as well as bacterial cells use  to  repair  their  DNA  this  research  will  characterize  mechanisms  of  action  of  an  atypical bacterial  DNA  damage  response  protein  that  is  a  component  of  an  error-prone  polymerase.  Similar  polymerases  exist  in  bacteria  yeast  and  humans  with  defects  in  these  polymerases causing human cancer after exposure to ultraviolet light. This project has additional biomedical implications for bacterial disease as the SOS response in bacteria can be induced by antibiotic treatment  and  lead  to  the  spread  of  antibiotic  resistance  and  other  virulence  genes  among bacteria.


application_id: 7721045
project_number: 1P20RR021954-01A2
project_title: CENTER OF RESEARCH IN OBESITY AND CARDIOVASCULAR DISEASE (1P20 RR021954-01A1)
administering_ic: NCRR
award_notice_date: 2008-09-07
opportunity_number: PAR-07-229
application_type: 1
activity_code: P20
ic: RR
serial_number: 021954
suffix: A2
project_start_date: 2008-09-08
project_end_date: 2009-06-30
subproject_number: 7170
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.  
Description (provided by applicant): The objective of this revised application is to create a Center of Biomedical Research Excellence in Obesity and Cardiovascular Disease (COCVD) to identify mechanisms linking the epidemic of obesity to the high incidence of cardiovascular diseases in the obese population and to use this focus as a platform to develop promising junior project investigators and enhance their success at competing for NIH grant support. We will achieve this objective by (1) assembling a group of established extramurally-supported scientists who will mentor faculty serving as principal project investigators on research projects that address timely and significant questions related to obesity and cardiovascular disease (2) providing a variety of mentoring approaches that will facilitate the development of research projects by project investigators leading to independent NIH-supported research (3) developing and supporting shared use core facilities that support and extend research methods critical to the study of obesity and cardiovascular disease (4) providing pilot grants for new projects focused on obesity and cardiovascular diseases (5) facilitating symposia seminars and meetings of participants researching obesity and cardiovascular diseases (6) focusing on the research of the center at retreats dedicated to evaluating progress by project investigators studying obesity and cardiovascular diseases (7) strategically hiring promising new faculty to develop a critical mass of productive physician and basic scientists studying obesity and cardiovascular diseases. Five project investigators representing both physician and basic scientists will serve as principal project investigators on research projects that address a central hypothesis and that utilize a common model of diet-induced obesity to study obesity-induced hypertension atherosclerosis and platelet dysfunction/vascular inflammation. The central hypothesis of this revised proposal is that obesity induces changes in the production and release of adipokinins and other inflammatory mediators to promote cardiovascular diseases. Each project addresses aspects of this hypothesis using a common model of diet-induced obesity and the projects synergize through their focus on adipokinesis inflammation and through coordinate development of multiple cardiovascular diseases. The proposed structure and mentoring mechanisms will meet the need of increasing NIH supported research and will develop a multi-disciplinary Center around the clinically significant area of obesity and cardiovascular disease.

project_terms:
Address;Area;Atherosclerosis;Blood Platelets;Cardiovascular Diseases;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Development;Diet;Epidemic;Faculty;Functional disorder;Funding;Grant;Hypertension;Incidence;Inflammation;Inflammatory;Institution;Link;Mediator of activation protein;Mentors;Methodology Research;Modeling;Obesity;Participant;Physicians;Production;Research;Research Personnel;Research Project Grants;Research Support N.I.H.;Resources;Scientist;Source;Structure;United States National Institutes of Health;clinically significant;success;symposium;vascular inflammation


application_id: 7721044
project_number: 1P20RR024489-01A1
project_title: CENTER OF EXCELLENCE IN DIABETES AND OBESITY RESEARCH
administering_ic: NCRR
award_notice_date: 2008-09-24
opportunity_number: PAR-07-229
application_type: 1
activity_code: P20
ic: RR
serial_number: 024489
suffix: A1
project_start_date: 2008-09-26
project_end_date: 2009-06-30
subproject_number: 7169
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.  
Description (provided by applicant): This proposal is to promote the initiation and the development of a multi-disciplinary thematic Center of Excellence in Diabetes and Obesity Research at the University of Louisville. The primary objective and the central focus of the Center are to enable promote and support scientific research related to the cardiovascular causes and consequences of diabetes and obesity. The second major aim of program is to provide mentoring and guidance to junior investigators in the Center with the overall goal of discovering new tierapies for the treatment and prevention of diabetes and obesity. Specific objectives of the program are to: [1) Build and develop a thematic multi-disciplinary research center focused on diabetes and obesity research; (2) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease (3) Expand and bridge on-going research programs to integrate current expertise into a thematically coherent program (4) Promote collaborative interactions to build complementary individual and multi-investigator research projects; (6) Foster research careers of junior investigators leading to their development as independent principal investigators; (7) Build upon our existing research capabilities and core facilities to provide the state-of-the-art infrastructure support; (8) Develop a nationally-competitive program that will attract the best clinical cardiology fellows graduate students postdoctoral fellows and new faculty; and most importantly to discover new and effective means for preventing and treating diabetes and obesity. The five related projects of junior investigators for the first phase of the Center are to: (1) delineate the contribution of oxidative stress to hyperglycemic injury and test whether antioxidant interventions prevent vascular injury in diabetes; (2) to investigate whether hyperglycemia impairs the cardiac reparative potential of mesenchymal stem cells and whether transplantation of stem cells with greater potential for cardiac repair will result in greater improvement of function in diabetic hearts following infarction; (3) delineate the mechanisms contributing to premature senescence and death of cardiac progenitor cells leading to non-ischemic diabetic cardiomyopathy; (4) examine whether hyperglycemic stimulation of foam cell formation is mediated by ER stress and the unfolded protein response and if drug that act as chemical chaperone ameliorate accelerated atherogenesis in diabetic animals; and (5) identify the regulation of high glucose-triggered inflammatory signaling (NF-KB activation) by specific micro RNAs. These investigations will be supported by establishing state-of-the-art core facilities in confocal microscopy flow cytometry cardiovascular pathology animal models and imaging and function. We believe that a Center focused on diabetes and obesity will add to the academic success of the University and will have a positive impact on the field of diabetes and obesity research in the nation.

project_terms:
Animal Model;Animals;Antioxidants;Arts;Blood Vessels;Cardiac;Cardiology;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Chemicals;Clinical;Computer Retrieval of Information on Scientific Projects Database;Core Facility;Death Cardiac;Development;Diabetes Mellitus;Diabetes prevention;Faculty;Flow Cytometry;Foam Cells;Fostering;Funding;Glucose;Goals;Grant;Heart;Hyperglycemia;Image;Individual;Infarction;Inflammatory;Injury;Institution;Intervention;Investigation;Mediating;Mentors;Mesenchymal Stem Cells;MicroRNAs;Microscopy Confocal;Molecular;Molecular Chaperones;Obesity;Oxidative Stress;Pharmaceutical Preparations;Phase;Postdoctoral Fellow;Principal Investigator;Proteins;Regulation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Signal Transduction;Source;Stem cell transplant;Stem cells;Stress;Students;Testing;United States National Institutes of Health;Universities;atherogenesis;career;diabetic;diabetic cardiomyopathy;functional improvement;prevent;programs;repaired;response;senescence;success


application_id: 7720981
project_number: 5P20RR020145-05
project_title: CHRONIC INFLAMMATION AT MUCOSAL SURFACS: INTERVENTION WITH NOVEL ANTIOXIDANTS
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7108
contact_pi_person_id: 7130705
contact_pi: OZ, HELIEH S
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The chronic lesions of inflammatory bowel disease (IBD) and Crohn's disease (CD) have many similarities to the chronic immunoinflammatory response in the oral cavity that destroys the soft and hard tissues of the periodontium (ie. periodontitis) potentially resulting in exfoliation of the teeth.  While evaluation of the literature supports the common molecular components of the destructive inflammatory responses at the mucosal sites of these diseases minimal data is available comparing/contrasting their characteristics in a common model system.  Moreover there is a burgeoning literature regarding dietary strategies for manipulation of IBD/CD and other inflammatory diseases (eg. rheumatoid arthritis psoriasis) these approaches are minimally developed with regard to adjunctive therapeutics for periodontal disease.  Thus we have developed 2 specific aims for this proposal that utilize a well defined animal model of mucosal inflammation and evaluate the impact of controlling reactive oxygen species (ROS) generated by the inflammation for ameliorating the disease symptoms.
Specific Aim 1: To test the hypothesis that challenge of the periodontium with DSS or TNBS (agents that are known to elicit IBD in murine models) will stimulate periodontitis in these animals.
Specific Aim 2:  To test the hypothesis that treatment of mice with either Green tea polyphenols or 2-(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA) which target antioxidant pathways will ameliorate periodontitis induced by DSS and TNBS.

project_terms:
Angioplasty Transluminal Percutaneous Coronary;Animal Model;Animals;Antioxidants;Biological Models;Carboxylic Acids;Characteristics;Chronic;Computer Retrieval of Information on Scientific Projects Database;Crohn's disease;Data;Disease;Epigallocatechin Gallate;Evaluation;Funding;Grant;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Institution;Intervention;Lesion;Literature;Modeling;Molecular;Mucositis;Mus;Oral cavity;Pathway interactions;Periodontal Diseases;Periodontitis;Periodontium;Psoriasis;Reactive Oxygen Species;Research;Research Personnel;Resources;Rheumatoid Arthritis;Source;Symptoms;Testing;Therapeutic;Tissues;Tooth Exfoliation;United States National Institutes of Health;mucosal site;novel;response


application_id: 7720980
project_number: 5P20RR020145-05
project_title: RENOVATION AND ALTERATIONS
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7107
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Unexpended funds from previous years were redirected to fund a renovation and expansion of the DDKCRC Clinical Research Center for Oral Health Studies at the University of Kentucky College of Dentistry under the approval of NIH.  The UK Vice President for Research and the College of Dentistry also provided ~$300000 in matching funds for this renovation & expansion.  The DDKCRC clinic is a state-of-the-art clinical research center comprised of 3 dental operatories with full digital radiography capability office space for clinical coordinators secure records storage area and reception area for recruiting patients.  This facility has served as the NCRR/NIH dental core for the GCRC during the COBRE project.  The demands on this facility have grown beyond the capability of the facility "spilling out" to contiguous teaching clinics.  This R&A subproject will double the operatories and records storage and create a private waiting area and reception for our clinic patients.  Patient access will be improved and research activities will be easier to isolate from non-research activities.

project_terms:
Area;Arts;Centers of Research Excellence;Clinic;Clinical;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Dental;Dentistry;Educational process of instructing;Funding;Grant;Institution;Kentucky;Oral health;Patients;Radiography Digital;Records;Recruitment Activity;Research;Research Activity;Research Personnel;Resources;Secure;Source;United States National Institutes of Health;Universities;college;improved


application_id: 7720979
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: INFLAMMATORY MEDIATORS LEVELS FULL MOUTH EXTRACTIONS
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7106
contact_pi_person_id: 2045756
contact_pi: CUNNINGHAM, LARRY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Hypothesis:  Full mouth tooth extraction in patients with advanced periodontal disease will lead to significantly decreased systemic inflammation determined by levels of C-reactive protein IL-6 and serum amyloid A.
The aims have been studied using a prospective longitudinal design to model the loss of systemic inflammatory risk factors related to dental therapy resulting in an edentate patient.  Patients (ages 18-80) who selected treatment plans that include extraction of all remaining teeth will be eligible for the study.  In this pilot study to provide preliminary data for proof of concept we will enroll approximately 40 patients with 20 in each group (eg. generalized periodontitis dental caries).  Patients who have elected to have all their teeth removed and to have dentures made will be recruited.  On the day of their surgery blood will be drawn for baseline levels of CRP IL-6 and SAA.  Extractions will then be completed as normal with separate standard surgical informed consent.  Post-surgery visits at 1 3 6 and 12 months will be scheduled coordinated with routine denture follow-up appointments for collection of blood and analysis of changes in CRP IL-6 and SAA.  The analysis of the mediators will be accomplished through the Core Translational Diagnostic Laboratory of the CBBOSD.

project_terms:
Age;Appointment;Blood;C-reactive protein;Collection;Computer Retrieval of Information on Scientific Projects Database;Data;Dental;Dental caries;Dentures;Diagnostic;Enrollment;Funding;Grant;Inflammation;Inflammatory;Informed Consent;Institution;Interleukin-6;Laboratories;Lead;Mediator of activation protein;Modeling;Operative Surgical Procedures;Oral cavity;Patients;Periodontal Diseases;Periodontitis;Pilot Projects;Recruitment Activity;Research;Research Personnel;Resources;Risk Factors;Schedule;Serum amyloid A protein;Source;Standards of Weights and Measures;Tooth Extraction;Tooth structure;United States National Institutes of Health;Visit;concept;cysteine rich protein;day;design;follow-up;prospective;treatment planning


application_id: 7720978
project_number: 5P20RR020145-05
project_title: SMOKING: EFFECTS OF GENOTYPE ON PERIODONTITIS
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7105
contact_pi_person_id: 8534338
contact_pi: AL-SABBAGH, MOHANAD
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Specific Aim 1: To determine the distribution of select pro- and anti-inflammatory gene polymorphisms in smokers with and without periodontitis.
Specific Aim 2:  To determine the distribution of gene polymorphisms for select tissue remodeling genes in smokers with and without periodontitis.
Specific Aim 3:  To determine the distribution of gene polymorphisms for select factors controlling reactive oxygen species in smokers with and without periodontitis.
The objective of this proposal is that for more effective management of periodontitis it would be desirable to identify subsets of individuals at greatest risk for developing smoking-related periodontitis. Identification of genetic markers that confer increased risk to periodontitis in smokers would permit more effective allocation of healthcare resources and permit targeted interventions. It would also contribute to our general understanding of the mechanisms by which smoking confers risk.  We proposed to conduct a case-control study of 500 smokers with or without periodontitis. We will compare these groups with regard to certain genetic polymorphisms that may be associated with increased risk for periodontitis.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Case-Control Studies;Computer Retrieval of Information on Scientific Projects Database;Funding;Genes;Genetic Markers;Genotype;Grant;Healthcare;Individual;Institution;Intervention;Periodontitis;Polymorphism Genetic;Reactive Oxygen Species;Research;Research Personnel;Resources;Risk;Smoke;Smoker;Smoking;Source;Tissues;United States National Institutes of Health


application_id: 7720977
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: VIRAL INFECTIONS IN CHRONIC ORAL DISEASES
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7104
contact_pi_person_id: 9185054
contact_pi: LI, MENGTAO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Although bacteria are the primary pathogens in periodontitis human herpesviruses have a purported relationship with inflamed periodontal tissues. This could be important because herpesviruses modulate host immune responses through a variety of mechanisms.  The goal of this research was to test the hypothesis that herpesviruses enhance the pathogenesis of periodontal diseases.  Our hypothesis is being examined using three approaches:  1) determine the role of herpesviruses in periodontitis by  analyzing clinical samples from patients with and without periodontal disease 2) investigating the ability of herpesvirus to enhance the progression of periodontitis in the rat model;  and 3) define mechanisms of immunomodulation by cytomegalovirus (CMV).  To address component 1 we are analyzing dental plaque from healthy and diseased sites and parallel saliva samples from 100 patients with periodontal disease.  Real-time PCR is being used to detect DNA of human herpesvirus in the samples obtained longitudinally over 6 months.  In the second project the rat CMV (RCMV) Maastricht strain has been obtained propagated and titered.  Animals have been inoculated with P. gingivalis and/or RCMV to establish infections and evaluate the periodontal response. In the study of molecular mechanisms of immunomodulation by CMV we have cloned and characterized novel isoforms of CMV vIL-10 gene and recently cloned EBV vIL-10. Because these viruses can modulate the immune response we have initiated studies that determine their role in modulating the host response of oral epithelia and gingival fibroblasts against invasion by periodontal bacterial pathogens.  Using human primary macrophages and THP-1 derived macrophage as models we have studied the effects of CMV and EBV infection on the function of macrophage in response to four oral microorganisms: P. gingivalis (Pg) and A. actinomycetemcomitans (Aa); opportunistic pathogen F. nucleatum (Fn); and non-pathogen S. gordonii (Sg) and have demonstrated that CMV and EBV alters the TNFa response of macrophages to these oral microorganisms. We are in the process of determining if lytic genes of CMV and/or EBV are required for the altered response and whether these viruses also inhibit the phagocytosis activity of macrophages to these bacteria.

project_terms:
Actinobacillus actinomycetemcomitans;Address;Animals;Bacteria;Chronic;Clinical;Computer Retrieval of Information on Scientific Projects Database;Cytomegalovirus;DNA;Dental;Dental Plaque;Epstein-Barr Virus Infections;Fibroblasts;Funding;Fusobacterium nucleatum;Genes;Gingiva;Goals;Grant;Herpesviridae;Herpesvirus 4 Human;Human;Immune response;Infection;Institution;Lytic;Modeling;Molecular;Mouth Diseases;Oral;Pathogenesis;Patients;Periodontal Diseases;Periodontitis;Phagocytosis;Polymerase Chain Reaction;Porphyromonas gingivalis;Process;Protein Isoforms;Rat Cytomegalovirus;Rattus;Research;Research Personnel;Resources;Role;Saliva;Sampling;Simplexvirus;Site;Source;Streptococcus gordonii;Testing;Time;Tissues;United States National Institutes of Health;Virus;Virus Diseases;immunoregulation;macrophage;microorganism;novel;oral cavity epithelium;oral infection;pathogen;response


application_id: 7720976
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: DIETARY REGULATION OF INFLAMMATORY RESPONSES
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7103
contact_pi_person_id: 8263389
contact_pi: DAWSON, DOLPHUS R.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Periodontal disease is a chronic inflammatory condition that may have a significant negative impact on systemic conditions such as diabetes and cardiovascular disease.  Previous studies have suggested that controlling oral infection and inflammation may have beneficial systemic effects.  Studies have also shown that many well-recognized disorders are associated with excessive intake of dietary fat including obesity insulin resistance coronary heart disease and some forms of cancer.  While intake of saturated trans and arachidonic fatty acids has been linked to the development of chronic disease research shows n-3 polyunsaturated fatty acids (n-3 PUFA) specifically fish oils (e.g. Cold-water fish such as mackerel) can contribute to the prevention and treatment of disease.  Dietary n-3 PUFA provides a benefit by reducing inflammation and improving antibacterial and autoimmune responses in many chronic inflammatory medical conditions.  It is hypothesized that the use of n-3 PUFA as a dietary supplement could have an important impact on systemic health by reducing chronic periodontal disease and systemic inflammation either alone or when combined with periodontal therapy.  This project will study the effects of dietary n-3 PUFA capsules (1000 mg t.i.d.) compared to placebo (corn/soybean oil) capsules in 200 subjects with generalized periodontitis a condition known to have negative systemic outcomes and be associated with a hyper-inflammatory phenotype as demonstrated by elevated inflammatory cell function and elevated systemic levels of C-reactive protein (CRP).  Using a randomized double-blind placebo controlled intervention study of 4 groups (50 subjects per group) we will study the effects of combining n-3 PUFA or placebo with oral hygiene or scaling and root planing on systemic inflammation (measured by CRP); periodontal inflammation and clinical outcomes (clinical measures and inflammatory mediators in gingival crevicular fluid); and bacterial colonization of plaque (changes in levels of P. gingivalis T. denticola and T. forsythensis).  A three month period of study organization followed the notification of funding in September 2004. Therefore initial study recruitment did not begin until early 2005.  Currently there have been four subjects enrolled into the study; 104 subjects pre-screened and 30 qualified and ready for enrollment.  No data analysis has been done.

project_terms:
Anti-Bacterial Agents;Autoimmune Responses;C-reactive protein;Cardiovascular Diseases;Cell physiology;Chronic;Chronic Disease;Clinical;Computer Retrieval of Information on Scientific Projects Database;Condition;Corn of toe;Coronary heart disease;Data Analyses;Dental;Dental Hygiene;Development;Diabetes Mellitus;Dietary Fats;Dietary Supplements;Disease;Double-Blind Method;Enrollment;Fatty Acids;Fatty Acids Polyunsaturated;Fish Oils;Fishes;Funding;Gingival Crevicular Fluid;Grant;Health;Inflammation;Inflammatory;Inflammatory Response;Institution;Insulin Resistance;Intake;Intervention Studies;Link;Maize;Malignant Neoplasms;Measures;Mediator of activation protein;Medical;N-3 polyunsaturated fatty acid;Notification;Obesity;Outcome;Periodontal Diseases;Periodontitis;Phenotype;Placebo Control;Placebos;Porphyromonas gingivalis;Prevention;Qualifying;Randomized;Regulation;Research;Research Personnel;Resources;Source;Soybean Oil;Treponema denticola;United States National Institutes of Health;Water;Zea mays;capsule (pharmacologic);improved;oral infection;scaling and root planing


application_id: 7720975
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: IMPACT ON GESTATIONAL DIABETES
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7102
contact_pi_person_id: 1880406
contact_pi: NOVAK, KAREN F.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Our GENERAL HYPOTHESIS is that women with GDM are at higher risk for developing more severe periodontal disease than women without GDM and that the combination of GDM and periodontal disease will be associated with an increased negative impact on maternal and fetal health.  These prospective clinical data will be correlated with basic science laboratory evaluations of the microflora and host response to provide insight into the pathogenic mechanisms contributing to negative maternal and fetal outcomes associated with inflammatory periodontal disease and GDM.  
This project consists of three specific aims that are designed to study the effects of Gestational Diabetes Mellitus (GDM) on the clinical microbiologic and immunologic characteristics of periodontal disease and the associations between these potential risk factors and maternal and fetal health.  At enrollment the investigator performs a clinical periodontal examination to document the presence and severity of periodontitis (Specific Aim 1).   Patients who are enrolled early in their pregnancy (31 weeks) may only be seen for one visit.  Comparable examinations are performed on the controls without GDM who have been matched with the test subjects for age race/ethnicity and gestational week.  The subjects are stratified into four groups based on diabetic status and the presence or absence of periodontitis  Group 1:  GDM with periodontitis (GDM + PD); Group 2:  GDM without periodontitis (GDM  PD); Group 3: normal controls with periodontitis (NC + PD); and Group 4: normal controls without periodontitis (NC  PD).   In addition to performing the clinical examinations dental plaque and serum samples are collected as part of the baseline and 34 week examinations allowing us to characterize the subgingival biofilm microbiota (Specific Aim 2) and quantify levels of systemic inflammatory biomarkers (Specific Aim 3) in each group and at each time point. The study population consists of a group of ambulatory women aged 16-45 whose pregnancies are being managed through the University of Kentucky Clinics the Gordon and Salter Inc. practice in Richmond KY and the Georgetown Obstetrics and Gynecology practice in Georgetown KY.  We have currently enrolled 271 subjects into the following categories:  GDM + PD 56; GDM  PD 83; NC + PD 42; NC  PD 90.  The ethnic/racial profiles are 100 White 120 Hispanic/Latino 29 Black/African American and 22 Asian.  All of the data including maternal and fetal outcomes have been collected on 230 of these subjects.

project_terms:
African American;Age;Asians;Basic Science;Biological Markers;Categories;Characteristics;Clinic;Clinical;Clinical Data;Computer Retrieval of Information on Scientific Projects Database;Data;Dental;Dental Plaque;Diabetes Gestational;Discipline of obstetrics;Disease Association;Enrollment;Ethnicity aspects;Evaluation;Funding;Grant;Gynecology;Health;Hispanics;Immune response;Immunologics;Inflammatory;Institution;Kentucky;Laboratories;Latino;Outcome;Patients;Periodontal Diseases;Periodontitis;Population Study;Pregnancy;Race;Research;Research Personnel;Resources;Risk;Risk Factors;Sampling;Serum;Severities;Source;Testing;Time;United States National Institutes of Health;Universities;Visit;Week;Woman;aged;base;design;diabetic;fetal;insight;oral infection;prospective;racial and ethnic;subgingival biofilm


application_id: 7720974
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: ORAL INFECTIONS: COX-2
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7101
contact_pi_person_id: 8351945
contact_pi: LOFTIN, CHARLES DAVID
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Specific Aim 1:. Determine the effect of non-selective COX and selective COX-2 inhibition on P. gingivalis-induced vascular disease in mice. 

Specific Aim 2:  Define the role of 12/15-lipoxygenases in P. gingivalis-induced periodontal disease and  atherosclerosis.

project_terms:
Arachidonate 15-Lipoxygenase;Atherosclerosis;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Dental;Funding;Grant;Institution;Mus;PTGS2 gene;Periodontal Diseases;Porphyromonas gingivalis;Prostaglandin-Endoperoxide Synthase;Research;Research Personnel;Resources;Role;Source;United States National Institutes of Health;Vascular Diseases;cyclooxygenase 1;oral infection


application_id: 7720973
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: DENTAL CLINICAL RESEARCH CENTER
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7100
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.A primary focus of the DDKCRC is to create a research infrastructure to: 1) develop and train clinical research professionals research coordinators and research staff and 2) define and impact oral health disparities in rural communities of Kentucky.  An initial emphasis will be on investigations to determine oral-systemic disease linkages in these rural populations and to define biological genetic and socio-behavioral factors contributing to these disparities.  The DDKCRC personnel have focused on the preparation and submission of forms for IRB approval for all projects.  These have all been obtained and the projects initiated.  The personnel contribute to the recruitment of patients for these same projects as well as collecting biological specimens for the projects.  Finally the laboratory personnel in the DDKCRC provide support for evaluation of host analytes in various biological fluids for all projects.  In addition the laboratory has developed a real-time quantitative PCR methodology for assessment of target microorganisms in the subgingival plaque.

project_terms:
Behavioral;Biological;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Dental;Ethics Committees Research;Evaluation;Funding;Genetic;Grant;Human Resources;Institution;Investigation;Kentucky;Laboratories;Laboratory Personnel;Liquid substance;Methodology;Oral;Oral health;Polymerase Chain Reaction;Preparation;Recruitments Patient;Research;Research Infrastructure;Research Personnel;Resources;Rural Community;Rural Population;Source;Specimen;Systemic disease;Time;Training;United States National Institutes of Health;health disparity;microorganism


application_id: 7720972
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: BIOINFORMATICS & BIOSTATISTICS CORE
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7099
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This core provides expert advice on experimental design data management subject recruitment and data analysis to the clinical projects in this COBRE and it provides expertise on the analysis of the bioinformatics data generated in the basic science projects.  This advice promotes efficiency in terms of the minimal number of patients to be recruited to a clinical study or the minimum number of chips to be processed in a microarray experiment so that information is maximized. Advice rendered at an early stage in the design of the project makes a difference. It also significantly improves the chances that the project will be successful as evidenced by the role this core played in one success in each area. Inherent in this core is a training component since its personnel supervise graduate students trainees in their own discipline and work on a one to one basis with young investigators in the dental sciences.  The younger faculty in this core are also mentored by the senior faculty.  A journal paper summarizing a pilot project supporting a current clinical project and several abstracts based on related dental graduate student research have been submitted. An R01 application in the basic science area in which this core provided key technical support has been awarded and another application is in progress.  As the projects in this COBRE mature personnel in this core will analyze the data generated and when needed will create new methodology to help interpret the results.

project_terms:
Area;Award;Basic Science;Bioinformatics;Biostatistics Core;Centers of Research Excellence;Clinical;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Data;Data Analyses;Dental;Discipline;Experimental Designs;Faculty;Funding;Grant;Human Resources;Institution;Journals;Mentors;Methodology;Numbers;Paper;Patients;Pilot Projects;Play;Process;Recruitment Activity;Research;Research Personnel;Resources;Role;Science;Source;Staging;Students;Training;United States National Institutes of Health;Work;abstracting;base;data management;design;improved;research study;success


application_id: 7720971
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: ADMINISTRATIVE AND EDUCATIONAL CORE
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7098
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The Administrative/Educational Core of the CBBO/SD has facilitated the research and training goals of the COBRE by: (1) To schedule and organize meetings for the CBBO/SD participants; (2) To organize meetings of the Scientific Advisory Committee (SAC); (3) To provide fiscal administration and accounting; (4) To interface with institutional administration in new faculty recruitment; (5) To oversee the funding of new pilot projects; (6) To interface and provide appropriate reporting to the NIH and other regulatory agencies; (7) To sponsor and organize research career development and training opportunities; and (8) To provide outcomes assessment of the CBBO/SD.

project_terms:
Accounting;Advisory Committees;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Dental;Development;Faculty;Funding;Goals;Grant;Institution;Outcome Assessment (Health Care);Participant;Pilot Projects;Reporting;Research;Research Personnel;Research Training;Resources;Schedule;Source;Training;United States National Institutes of Health;career


application_id: 7720970
project_number: 5P20RR020145-05
project_title: UKY DENTAL COBRE: ORAL INFECTIONS AND HIV RECRUDESCENCE
administering_ic: NCRR
award_notice_date: 2008-08-25
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(02)
subproject_number: 7097
contact_pi_person_id: 8367053
contact_pi: HUANG, CHIFU BRAD
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Specific Aim 1: To determine the capacity of selected oral microorganisms to activate HIV-1 in latently infected T lymphocytes and macrophages.
Specific Aim 2:  To determine the ability of selected oral microorganisms to elicit mediators from resident cell populations that can activate HIV-1 in latently infected T lymphocytes and macrophages.
Specific Aim 3:  To determine the target receptors for bacterial and host stimulation of the HIV promoter and HIV reactivation in latently infected T cells and macrophages.

project_terms:
Cells;Computer Retrieval of Information on Scientific Projects Database;Dental;Funding;Grant;HIV;HIV-1;Institution;Mediator of activation protein;Oral;Population;Promotor (Genetics);Recrudescences;Research;Research Personnel;Resources;Source;T-Lymphocyte;United States National Institutes of Health;macrophage;microorganism;oral infection;receptor


application_id: 7720906
project_number: 5P20RR020171-05
project_title: ANTIBODY PRODUCTION AND MOUSE GENOTYPING CORE
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7033
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The genotyping core will be based on the second floor of the BBSRB.  At present the core is still being set up.  We have developed the PCR-based methodology for genotype analysis and have optimized the DNA preparation protocols.  All of the technologies have been tested on a small scale (~50 animals).  The equipment heat blocks Robocycler PCR machine repeating pipette sets and large format agarose electrophoresis apparati are in place.  A detailed set of user instructions are being written to describe what services are to be provided and what the user needs to supply the core in terms of sample PCR primer sets and reaction conditions.  An advertisement for a technician to run the facility has been circulated and applicants are being interviewed.  The technician will handle the mouse genotyping and antibody production.

project_terms:
Advertisements;Animals;Antibody Formation;Computer Retrieval of Information on Scientific Projects Database;Condition;DNA;Electrophoresis;Equipment;Floor;Funding;Genotype;Grant;Heating;Institution;Instruction;Interview;Methodology;Mus;Polymerase Chain Reaction;Preparation;Protocols documentation;Reaction;Research;Research Personnel;Resources;Running;Sampling;Sepharose;Services;Source;Technology;Testing;United States National Institutes of Health;Writing;base


application_id: 7720905
project_number: 5P20RR020171-05
project_title: THE INHIBITORY ROLE OF INTEGRIN ?5 IN ADIPOCYTE DIFFERENTIATION
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7032
contact_pi_person_id: 6876032
contact_pi: LIU, JUN S
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.This study is directed toward understanding adipocyte differentiation a critical process that contributes to the development of excess adipose mass and obesity. While changes in the ECM and integrin receptor expression have been observed during adipocyte differentiation the ability of these processes to regulate adipogenesis is largely unexplored. The overall GOAL of this proposed study is to elucidate the anti-adipogenic function of integrin 5. This goal will be accomplished by determining (1) whether the loss of integrin 5 expression promotes adipocyte differentiation and obesity; and (2) the mechanism whereby the 5 integrins regulates the Rac activity in preadipocytes.

project_terms:
Adipose tissue;Computer Retrieval of Information on Scientific Projects Database;Development;Extracellular Matrix;Funding;Goals;Grant;Institution;Integrins;Obesity;Process;Research;Research Personnel;Resources;Role;Source;United States National Institutes of Health;adipocyte differentiation;lipid biosynthesis;receptor expression


application_id: 7720904
project_number: 5P20RR020171-05
project_title: REGULATION OF ALTERNATIVE PRE-MRNA PROCESSING BY SMALL NUCLEOLAR RNAS
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7031
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The objective of the project is to determine how the loss of small nucleolar RNA (snoRNA) expression contributes to the Prader-Willi syndrome the most frequent genetic cause for life-threatening obesity. We will determine which alternative splicing patterns are influenced by the snoRNAs missing in individuals with Prader-Willi syndrome and elucidate the molecular basis by which one of these snoRNAs HBII-52 influences alternative splicing patterns. The central hypothesis is that snoRNAs missing in individuals with Prader- Willi syndrome regulate alternative splicing by masking splicing regulatory elements on pre-mRNAs. Thus these snoRNAs regulate expression of numerous genes by changing their alternative splicing patterns. The rationale for the proposed research is that the genes regulated by these snoRNAs represent drug targets for treatment of the Prader-Willi syndrome. We use overexpression of snoRNA-expressing constructs to validate bioinformatically predicted target genes. The proposed work is innovative because it shows a complete new role for snoRNAs in the regulation of alternative pre-mRNA splicing. It may well change the current 'textbook knowledge' that snoRNAs only regulate non-mRNAs. The proposed research is significant because it would show a novel role of snoRNAs identify the molecular defects in Prader-Willi syndrome and help to predict the influence of small RNAs on splice site selection.

project_terms:
Alternative Splicing;Computer Retrieval of Information on Scientific Projects Database;Defect;Drug Delivery Systems;Funding;Gene Targeting;Genes;Genetic;Grant;Heterogeneous Nuclear RNA;Individual;Institution;Knowledge;Life;Masks;Molecular;Obesity;Pattern;Prader-Willi Syndrome;Process;Protein Overexpression;RNA Splicing;Regulation;Regulatory Element;Research;Research Personnel;Resources;Role;Site;Small Nucleolar RNA;Small RNA;Source;Textbooks;United States National Institutes of Health;Work;base;innovation;mRNA Precursor;novel


application_id: 7720903
project_number: 5P20RR020171-05
project_title: ORGANIC SYNTHESIS CORE
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7030
contact_pi_person_id: 9175312
contact_pi: WATT, DAVID
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The organic synthesis core is designed to provide access to novel compounds not available through commercial sources.  The well-trained technical staff as well as the core director will consult with investigators to understand the particular need and will design and synthesize the appropriate molecules.  The facility staff will undertake for example the synthesis and characterization of a novel probe a photoactive analog a better soluble version of a compound than one now in use a fluorescent analog that would replace a radiolabeled compound that is now in use a modified natural product that might covalently bind a receptor an unnatural peptide that would have better stability than its wild-type counterpart a polymer-bound compound needed for a particular purification etc.  The core is equipped with appropriate equipment to prepare and characterize organic compounds with molecular weights of 2 kDa or less and has access to appropriate chromatographic and analytical techniques including NMR and mass spectrometry that will be used to confirm structural assignments.

project_terms:
Binding (Molecular Function);Biological Factors;Commercial Sources;Computer Retrieval of Information on Scientific Projects Database;Consult;Equipment;Funding;Grant;Institution;Molecular Weight;Organic Synthesis;Peptides;Polymers;Radiolabeled;Research;Research Personnel;Resources;Source;Spectrum Analysis Mass;Techniques;Training;United States National Institutes of Health;analog;design;novel;radiotracer;receptor


application_id: 7720902
project_number: 5P20RR020171-05
project_title: A COMBINATORIAL APPROACH FOR THE INVESTIGATION AND DEVELOPMENT OF NEW CALMODULIN
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7029
contact_pi_person_id: 9077753
contact_pi: BRADLEY, LUKE H
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.A range of biochemical and structural studies suggest that a unique structural element the central linker plays a major role in conferring the calmodulin (CaM) low binding specificity. The central linker region serves as a molecular hinge allowing CaM to assume large conformational changes throughout the protein in order to present a structurally dynamic surface of hydrophobic and acidic residues to recognize bind and ultimately transmit the calcium signal to its numerous target proteins. Attempts to decipher what interactions are responsible for the CaM low binding specificity have recently focused on trying to improve CaM binding affinity towards a single target molecule. 
In contrast to these previous studies which attempted to increase binding specificity by redesigning particular binding interactions a priori a different approach is to explore binding affinity/specificity through the generation of combinatorial protein libraries. The proposed research would involve using the binary patterning approach towards the creation of high-quality productive combinatorial libraries of the CaM central linker to test the hypothesis that CaM binding affinity and specificity are a result of a combination of amino acid contacts and structural plasticity provided by this unique region. Biochemical characterization of selected proteins would not only contribute to the understanding of the native CaM's function but will also validate the application of this de novo protein design approach towards a new protein scaffold. In addition these libraries would serve as a starting point for obtaining proteins with altered ligand specificities using high throughput screens and selections.

project_terms:
Affinity;Amino Acids;Binding (Molecular Function);Biochemical;Calcium Signaling;Calmodulin;Computer Retrieval of Information on Scientific Projects Database;Development;Elements;Funding;Generations;Grant;Hydrophobic Surfaces;Institution;Investigation;Libraries;Ligands;Molecular;Pattern;Play;Proteins;Range;Research;Research Personnel;Resources;Role;Scaffolding Protein;Source;Specificity;Testing;United States National Institutes of Health;combinatorial;design;high throughput screening;improved


application_id: 7720901
project_number: 5P20RR020171-05
project_title: STUDIES OF RILP AND RILP-BINDING PROTEIN DYNACTIN P150GLUED AND HUNTINGTIN
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7028
contact_pi_person_id: 7875223
contact_pi: SHIMOJO, MASAHITO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion in the huntingtin protein.  It was suggested that the longer polyglutamine domain induce conformational changes causing it to form intracellular aggregates as nuclear inclusions in most cases.  HD is characterized by disturbances in motor cognitive and psychiatric function.  It has been postulated that the expanded polyglutamine repeat causes huntingtin to interact abnormally with other cellular proteins.  Wild-type huntingtin was found to interact with the transcriptional regulator REST which represses most neuronal gene expression in non-neuronal cells.  The interaction between huntingtin and REST kept REST in the cytosol thereby preventing REST target genes repression.  It was shown that wild-type and mutant huntingtin mediate REST dependent neuronal gene expression of BDNF through its regulatory DNA element RE1.  We have cloned another REST interacting protein we called RILP for REST/NRSF-Interacting LIM domain Protein.  RILP is a novel protein which is required for the nuclear targeting and function of REST.  We have preliminarily identified another RILP-interacting protein which is dynactin p150Glued and have shown that huntingtin and dynactin p150Glued copurify with RILP.  Dynactin p150Glued is an accessory protein for the microtubule motor protein dynein which is thought to be involved in trafficking steroid receptors and some other transcription factors between the cytoplasm and nucleus in a dynactin dependent process.  We thus postulate that RILP dynactin p150Glued and huntingtin are involved in targeting cytoplasmically synthesized REST through the dynein-microtubule pathway to the nucleus.  Disruption of this function could contribute to the neuronal dysfunction and death seen in diseases such as Huntington's disease (HD).

project_terms:
Binding Proteins;Brain-Derived Neurotrophic Factor;Cell Nucleus;Cessation of life;Cognitive;Computer Retrieval of Information on Scientific Projects Database;Cytoplasm;Cytosol;DNA;Disease;Disruption;Dynein ATPase;Elements;Funding;Gene Expression;Grant;Huntingtin protein human;Huntington Disease;Inherited;Institution;LIM Domain Protein;Mediating;Microtubule Proteins;Microtubules;Motor;Neurodegenerative Disorders;Neuroglia;Neuronal Dysfunction;Neurons;Nuclear;Nuclear Inclusion;Pathway interactions;Process;Proteins;Receptors Steroid;Research;Research Personnel;Resources;Source;Thinking function;United States National Institutes of Health;dynactin;gene repression;mutant;novel;polyglutamine;prevent;trafficking;transcription factor


application_id: 7720900
project_number: 5P20RR020171-05
project_title: KY COBRE:THERAPEUTICS IN A MOUSE MODEL OF INCLUSION BODY MYOSITIS
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7027
contact_pi_person_id: 1937719
contact_pi: MURPHY, MICHAEL P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.Inclusion body myositis (IBM) is a common degenerative muscular disease afflicting a significant proportion of the elderly. It has no effective treatment. A hallmark of IBM pathology is an accumulation of amyloid precursor protein (APP) derived peptides such as the 40 or 42 amino acid A? peptide or 83 or 99 residue C-terminal fragments (CTFs). IBM parallels AD with regards to the presence of A? although in AD the peptide is deposited extracellularly instead of intracellularly which is the case in IBM. In collaboration with Dr. Frank LaFerla at UC Irvine we recently reported the development of a transgenic mouse model of IBM made by overexpressing APP in skeletal muscle via a creatine kinase promoter. To our knowledge this is the only mouse model of IBM to utilize full length APP and therefore offers a unique opportunity to study both the development of IBM pathology and to evaluate possible treatment strategies. One
of the strengths of our group has been the development of potential AD therapeutics. We now propose to apply our
resources and knowledge to test three distinct approaches in the IBM mouse model each targeting a specific aspect of APP processing: treatment with (i) typical and atypical NSAIDs (which reduce production of A?42) (ii) a potent global inhibitor of the ?-secretase enzyme (which reduces the production of all forms of A? and causes C-terminal fragments of APP to accumulate) or (iii) passive immunization with anti-A? antibodies (which target extracellular A?). These approaches are either currently available for patient use or are currently in clinical trial and may thus be available within a few years as potential IBM therapies. In addition to answering important questions about potentially effective therapeutics this study will also directly address several theoretical issues about the development of IBM pathology. Is
A? production in general required for the development of the pathology or is the longer more amyloidogenic A?42 the critical factor (as it is in AD)? Alternatively are the presence of intracellular APP CTFs responsible? Is the presence of secreted or extracellular A? important? A careful comparison of the outcomes of each aim will help to elucidate these issues hopefully helping to resolve these long standing debates regarding IBM pathogenesis.

project_terms:
Address;Amino Acids;Amyloid beta-Protein Precursor;Anti-Inflammatory Agents Non-Steroidal;Antibodies;C-terminal;Clinical Trials;Collaborations;Computer Retrieval of Information on Scientific Projects Database;Creatine Kinase;Deposition;Development;Elderly;Enzymes;Funding;Grant;Immunization Passive;Information Resources;Institution;Knowledge;Length;Myopathy;Myositis Inclusion Body;Outcome;Pathogenesis;Pathology;Patients;Peptides;Production;Promotor (Genetics);Protein C;Protein Overexpression;Reporting;Research;Research Personnel;Resources;Skeletal muscle structure;Source;Testing;Therapeutic;Therapeutic Studies;Transgenic Organisms;United States National Institutes of Health;amyloid precursor protein processing;extracellular;inhibitor/antagonist;mouse model;peptide A;secretase


application_id: 7720899
project_number: 5P20RR020171-05
project_title: KY COBRE: PROTEOMICS CORE
administering_ic: NCRR
award_notice_date: 2008-07-21
opportunity_number: RFA-RR-03-014
application_type: 5
activity_code: P20
ic: RR
serial_number: 020171
project_start_date: 2008-08-01
project_end_date: 2009-07-31
study_section: ZRR1-RI-5(01)
subproject_number: 7026
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH sourceand thus could be represented in other CRISP entries. The institution listed isfor the Center which is not necessarily the institution for the investigator.The proteomics core is designed to provide quantitative and qualitative protein profiling and identification analysis as well as post-translational modification and sequence analysis through a combination of 2D gel mass spectrometry and Edman sequencing analysis services. The core is equipped with Bio-Rad IPG and SDS-PAGE apparatus for 2D gel analysis a Typhoon phosphorimager/scanner system for detection and quantitation of fluorescent protein dyes (Cy-dyes) and stains (SYPRO-Ruby Pro-Q Diamond) used to analyze 1D and 2D gels a Ciphergen SELDI-TOF protein profiling system an ABI QSTAR II Q-TOF Mass Spectrometer with both MALDI and LC/ESI source capabilities Waters HPLC systems and multiple PCs for data acquisition and analysis including a site license for PDQuest software and a 5 station site license for Ciphergen software. Fully trained technical staff will assist investigators with the full range of proteomics analytical services. The staff will instruct investigators and their laboratory staff (students post-doctoral fellows and technicians) in sample preparation 2D gel analysis and quantitation by fluorescent staining methods. Protein fragmentation mass peptide mapping and protein sequencing by both MS/MS mass spectrometry and chemical sequencing will be performed by Dr. Beach on samples provided by individual investigators. Preparation and analysis of samples with the Ciphergen system will be facilitated by automated robotic work stations. Data analysis will be performed by investigators and their colleagues through multiple distant work stations connected to the Ciphergen system via the web.

project_terms:
Amino Acid Sequence;Chemicals;Chromatography High Pressure Liquid;Computer Retrieval of Information on Scientific Projects Database;Computer software;Data Analyses;Detection;Diamond;Distant;Dyes;Funding;Gel;Grant;Individual;Institution;Internet;Laboratories;Licensing;Peptide Mapping;Peptide Sequence Determination;Postdoctoral Fellow;Preparation;Pro-Q aerosol foam;Protein Processing Post-Translational;Proteins;Proteomics;Range;Research;Research Personnel;Resources;Robotics;Sampling;Sequence Analysis;Services;Site;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Spectrum Analysis Mass;Staining method;Stains;Students;System;Training;United States National Institutes of Health;Water;Work;aerobic respiration control protein;data acquisition;design;mass spectrometer


