# projects

application_id: 8208065
project_number: 5R01DK055664-10
project_title: Hepatocyte Nitric Oxide Synthase Regulation by Glucagon and Insulin
administering_ic: NIDDK
award_notice_date: 2011-11-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 055664
program_official: SERRANO, JOSE
project_start_date: 2001-02-15
project_end_date: 2013-02-28
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 2093531
contact_pi: HARBRECHT, BRIAN G.
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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:
ABSTRACT/SUMMARYThe immune response to sepsis involves a series of complex highly integrated homeostatic responses that ifprolonged and excessive can lead to organ dysfunction and death. Nitric oxide (NO) synthesis is upregulatedby sepsis in many tissues and is an essential component of the host immune response. Nitric oxide synthesiscan be beneficial and improve immune and organ function but if synthesis is excessive and prolonged NOcan promote organ injury tissue inflammation and death. NO is produced in hepatocytes by the induciblenitric oxide synthase (iNOS) that is stimulated by cytokines and proinflammatory stimuli. Excessive NO fromiNOS produces cellular dysfunction and hepatic injury. Glucagon and cyclic adenosine monophosphate(cAMP) regulate hepatic iNOS expression in vitro and in vivo and by doing so decrease NO-mediated hepaticinjury. Our preliminary data demonstrate that insulin also down-regulates cytokine-induced iNOS expression.Both glucagon and insulin alter specific intracellular signaling pathways in hepatocytes but the mechanismsinvolved in the regulation of hepatocyte function in sepsis by glucagon and insulin and specifically theregulation of hepatocyte iNOS expression have not been identified. In this proposal we will determine themechanisms responsible for the regulation of hepatocyte iNOS expression by glucagon and insulin. In Aim Iwe will continue our work in determining the mechanism for the glucagon and cAMP-induced inhibition ofhepatocyte iNOS expression. We will focus on protein kinase A (PKA)-independent pathways induced bycAMP and evaluate the role of the guanine nucleotide exchange factor Epac and the role of calcium. In Aim IIwe will determine the mechanisms responsible for the inhibition of iNOS by insulin. By defining how thesehormones regulate hepatocyte iNOS expression we will provide a framework for understanding the basicpathophysiologic cellular events in shock and sepsis that may lead to novel cellular-based therapies forcritically ill patients. Project NarrativeNitric oxide is synthesized in critically ill patients during septic shock and when overproduced canincrease cellular dysfunction tissue injury and death. Glucagon and insulin primarily regulate bloodglucose which has become an important facet of the care of critically ill patients but we have foundthat they also regulate hepatic nitric oxide production. We will determine the mechanismsresponsible for the regulation of hepatocyte inducible nitric oxide synthase (iNOS) expression byglucagon and insulin. By defining these mechanisms we will provide a framework for understandingthe basic cellular events in shock and sepsis which may lead to novel cellular-based therapies forcritically ill patients.

project_terms:
Adult;Area;Biology;Blood Glucose;Calcium;Caring;Cell physiology;Cessation of life;Complex;Critical Care;Critical Illness;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Development;Endocrinology;Event;Functional disorder;Glucagon;Guanine Nucleotide Exchange Factors;Hepatic;Hepatocyte;Hormones;Immune;Immune response;In Vitro;Infection;Inflammation;Injury;Insulin;Intracellular Second Messenger;Lead;Mediating;Mediator of activation protein;Metabolism;Molecular;Mortality Vital Statistics;Multiple Organ Failure;Nitric Oxide;Nuclear;Operative Surgical Procedures;Organ;Pathway interactions;Patients;Physiological;Production;Regulation;Research;Role;Second Messenger Systems;Sepsis;Septic Shock;Series;Shock;Signal Pathway;Signal Transduction;Stimulus;Study Section;Tissues;Transplantation;Work;base;cytokine;human NOS2A protein;improved;in vivo;novel;nutrition;prevent;programs;response;septic


application_id: 8207322
project_number: 5F32DC011427-02
project_title: The role of cAMP signaling in OSN axon convergence in the olfactory bulb
administering_ic: NIDCD
award_notice_date: 2011-07-14
opportunity_number: PA-10-110
application_type: 5
activity_code: F32
ic: DC
serial_number: 011427
program_official: CYR, JANET
project_start_date: 2010-09-01
project_end_date: 2013-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 10351735
contact_pi: HERON, PAULA MICHELLE
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): This postdoctoral F32 Kirschstein NRSA proposes a comprehensive research and training plan in the study of neurogenesis and axon guidance in the olfactory system with relevance to neural regeneration therapies. Failure of the damaged nervous system to repair itself has debilitating consequences for millions of people worldwide. Regeneration therapies are focused on restoring damaged circuitry by regrowth and guidance of the axons of spared neurons or replacement of dead neurons. The olfactory system provides a useful model to study cell replacement and axon targeting in a mature nervous system. Although the mechanisms by which olfactory sensory neuron (OSN) axons are targeted to the olfactory bulb remain largely unknown the anterior-posterior patterning of glomerular convergence in the bulb correlates with neuronal levels of cAMP and altered expression of activity-dependent guidance cues. However direct evidence of the involvement of cAMP in axon targeting and the genetic mechanisms involved are lacking. The specific aims of this proposal will test the hypothesis that cAMP plays a definitive role in glomerular convergence of axons in the bulb. If this idea is correct then transgenic mice exhibiting sustained increases in cAMP in immature OSNs should show altered glomerular convergence and position. Aim 1 will use transgenic mice that express a constitutively active G-protein-coupled receptor GPR12 in immature OSNs. GPR12 couples to Gas adenylyl cyclase and cAMP production. To follow specific populations of OSN axons GPR12 transgenic mice will be crossed with OR-tauLacZ mice such as the M71-tauLacZ strain. This will allow visualization of the coalescence of OSN axons. Aim 2 will investigate changes in cAMP-mediated downstream signaling events that lead to alterations in gene expression. Identification of cAMP driven signal transduction in immature OSNs will help to elucidate mechanisms that control the position of OSN axon convergence in the olfactory bulb. Aim 3 will test whether cAMP over expression will rescue the lack of target innervation in mice lacking the emx2 gene. The results from these studies will provide novel insight into the role of cAMP signaling in OSN axon growth and convergence in the olfactory bulb.  
  
PUBLIC HEALTH RELEVANCE: Cell replacement as a regenerative approach to repair the injured nervous system remains promising. My research aims will contribute to understanding the processes that allow normal cellular replacement and appropriate target innervation in the olfactory system. This understanding of endogenous neural replacement can only help advance the design of effective regenerative therapies for brain and spinal cord injuries.

project_terms:
Adenylate Cyclase;Affect;Afferent Neurons;Anterior;Axon;Behavior;CREB1 gene;Cells;Coupled;Couples;Cues;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Event;Exhibits;Failure (biologic function);G-Protein-Coupled Receptors;Gases;Gene Expression;Genes;Genetic;Genetic Transcription;Growth;Imagery;Internal Ribosome Entry Site;Lead;Link;Location;MAP Kinase Gene;Measures;Mediating;Modeling;Mus;National Research Service Awards;Natural regeneration;Nerve Regeneration;Nervous System Trauma;Nervous system structure;Neurons;Neurophysiology - biologic function;Neuropilin-1;Olfactory Epithelium;Olfactory Nerve;Pattern;Penetration;Physiological Processes;Play;Population;Positioning Attribute;Process;Production;Proto-Oncogene Proteins c-akt;Research;Research Training;Role;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Transduction Gene;Transgenic Mice;axon growth;axon guidance;design;emx2 protein;injured;insight;knockout animal;nerve supply;neural circuit;neurogenesis;novel;offspring;olfactory bulb;overexpression;public health relevance;reconstruction;regenerative;regenerative therapy;relating to nervous system;repaired;spinal cord and brain injury;success

public_health_relevance:
PROJECT NARRATIVECell replacement as a regenerative approach to repair the injured nervous systemremains promising. My research aims will contribute to understanding the processes thatallow normal cellular replacement and appropriate target innervation in the olfactorysystem. This understanding of endogenous neural replacement can only help advancethe design of effective regenerative therapies for brain and spinal cord injuries.


application_id: 8207280
project_number: 5R01CA138410-03
project_title: Regulation of miRNA in breast cancer
administering_ic: NCI
award_notice_date: 2011-12-30
opportunity_number: PA-07-021
application_type: 5
activity_code: R01
ic: CA
serial_number: 138410
program_official: FORRY, SUZANNE L
project_start_date: 2010-01-01
project_end_date: 2013-12-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM resistance is unknown and biomarkers of TAM-response may be useful to monitor clinical response. MicroRNAs (miRNAs) are a class of naturally-occurring small non-coding RNA molecules that are involved in regulating the translation and processing of mRNAs usually by binding to the 3' untranslated region of target mRNAs and targeting the mRNA transcript to be degraded or by blocking translation. The human genome contains > 700 miRNAs. Aberrant patterns of miRNA expression have been recently implicated in human disease with miRNAs differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ER1 and progesterone receptor tumor stage number of positive lymph nodes and vascular invasion. Using the NIH-R21 mechanism we obtained preliminary data identifying miRNAs regulated by estradiol (E2) in an ER1-dependent manner in MCF-7 human breast cancer cells and identified downstream target genes that were upregulated via E2 downregulation of miR-21. However to date no one has examined TAM affects the pattern of miRNA expression in human breast cancer and only 2 reports have identified miRNA expression patterns in TAM-resistant derivatives of MCF-7 breast cancer cells. Specific Aim 1 is to identify miRNAs that are differentially regulated by E2 and 4-hydroxyTAM (4-OHT) in antiestrogen- sensitive MCF-7 and T47D breast cancer cells. Specific Aim 2 is to identify miRNAs and their target genes in antiestrogen/ TAM- sensitive versus -resistant breast cancer cell lines and tumor xenografts. This Aim tests the hypothesis that miRNA expression is dysregulated in endocrine/TAM- resistant versus -sensitive breast cancer cells. Specific Aim 3 is to determine if the E2- regulated and 4-OHT- regulated miRNAs identified in breast cancer cell lines show aberrant expression in human breast tumors and correlate with clinical diagnostic measures and patient response to tamoxifen therapy. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.    PUBLIC HEALTH RELEVANCE: Aromatase inhibitor therapy is not useful for all ER1 positive breast cancer patients and the selective estrogen receptor modulator tamoxifen (TAM) remains the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM/endocrine resistance is unknown. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.

project_terms:
3' Flanking Region;3' Untranslated Regions;4-Hydroxy-Tamoxifen;Affect;Aromatase Inhibitors;BCL2 gene;Binding (Molecular Function);Bioinformatics;Biological Assay;Blood Vessels;Breast;Breast Cancer Cell;Cancer Patient;Cancer cell line;Cells;Clinical;Clinical Markers;Cloning;Computer Simulation;Data;Development;Diagnostic;Diagnostic Neoplasm Staging;Down-Regulation;Endocrine;Estradiol;Estrogen Antagonists;Estrogen Receptor Modulators;Estrogen Receptor alpha;Estrogen Receptors;Estrogen receptor negative;Estrogen receptor positive;Estrogens;Exploratory/Developmental Grant;Functional RNA;Gene Expression;Gene Targeting;Genes;Goals;Human;Human Genome;ICI 182780;In Vitro;Individual;Lead;Luciferases;MAPK3 gene;MCF7 cell;Malignant Neoplasms;Mammary Neoplasms;Measures;Messenger RNA;MicroRNAs;Monitor;PTEN gene;Patients;Pattern;Positive Lymph Node;Prevention;Progesterone Receptors;Promotor (Genetics);Proteins;RNA;Regulation;Renilla Luciferases;Reporter;Reporting;Repression;Research;Resistance;Response Elements;Reverse Transcriptase Polymerase Chain Reaction;Role;Sampling;Seeds;Selective Estrogen Receptor Modulators;Site;Small Interfering RNA;T47D;Tamoxifen;Testing;Therapeutic;Time;Transcript;Transcription Factor AP-1;Transfection;Translation Process;Translations;Tumor stage;United States National Institutes of Health;Western Blotting;biomarker;cancer therapy;expression vector;follow-up;hormone therapy;human disease;in vivo;inhibitor/antagonist;insight;mRNA Stability;malignant breast neoplasm;migration;non-genomic;novel;outcome forecast;overexpression;public health relevance;research study;response;treatment planning;tumor;tumor xenograft

public_health_relevance:
Aromatase inhibitor therapy is not useful for all ER positive breast cancer patients and the selective estrogenreceptor modulator tamoxifen (TAM) remains the most widely used endocrine therapy for the treatment andprevention of estrogen receptor alpha (ER) positive breast cancer. However ~ 40% of initially TAM-sensitivetumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM/endocrine resistance isunknown. The overall goal of the proposed research is to determine the identity and gene targets of miRNAsthat may provide novel biomarkers and new insights into the mechanisms by which breast tumors gainendocrine/TAM-resistance and become invasive and metastatic.


application_id: 8207278
project_number: 5R01CA129975-04
project_title: Adenovirus E1B55K Functions Related to Oncolytic Replication
administering_ic: NCI
award_notice_date: 2011-12-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129975
program_official: WELCH, ANTHONY R
project_start_date: 2009-03-01
project_end_date: 2014-12-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7746559
contact_pi: ZHOU, HESHAN SAM
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
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): Two major "hallmarks" of all cancer cells include dysregulated cell cycle and inhibited apoptosis both of which are also involved in adenovirus (Ad) infection. These two processes are primarily conducted by viral oncoproteins E1A and E1B. Since the function of viral E1 protein is similar to that of cancer cellular factors that promote proliferation and inhibit apoptosis viruses with mutations in oncoprotein E1A and E1B can selectively replicate in cancer cells. One such mutant with deletion of E1B55K known as dl1520 has been used in clinical trials documenting oncolytic effects. However the mechanism of viral oncolytic replication has not been well characterized and the therapeutic efficacy needs improvement. It is generally believed that the major role of E1B55K is to bind to and inhibit p53 activation but many studies have documented that E1B55K-mediated p53 inactivation is not required for virus replication. Our laboratory has shown: (1) that the limited spread of mutant viruses in large tumors is a key factor in decreased therapeutic efficacy; (2) increased Ad E1A expression enhances virus-oncolytic replication; and (3) apoptosis caused by E1B deletion can partially decrease virus replication but does not change the final outcome of virus-mediated cancer killing. Our recent studies have revealed that E1B55K has a novel function in the induction of cyclin E and other cell cycle-related genes. Most importantly we also observed that increased cyclin E expression is correlated with virus replication efficiency. E1B55K-induced cyclin E expression is required for virus replication in normal cells but is not necessary in cancer cells. We hypothesize that E1B55K may target cellular factor(s) to increase cyclin E expression and this factor(s) may already be activated in cancer cells. Thus cyclin E dysregulation in cancer cells may be the molecular basis for oncolytic replication of E1B55K-deleted viruses. Our research team will (1) identify cellular factors targeted by E1B55K for cyclin E induction (2) define the mechanism by which E1B55K activates cyclin E expression and (3) determine the relationship between cyclin E overexpression and oncolytic replication of E1B-deleted viriuses. If we confirm that oncolytic replication relies on cyclin E expression and cell proliferation patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy. PUBLIC HEALTH RELEVANCE: Adenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells. Therefore the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55K function and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studies have revealed that E1B55K has a novel function in the induction of cyclin E expression which is crucial for DNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. We reason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNA replication. Cancer cells may already have the factors activated; therefore cancer cells do not require the E1B55K function. The study of this possibility is very important. If we confirm that mutated virus replication relies on cyclin E expression patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy.

project_terms:
Adenovirus Infections;Adenovirus Protein;Adenoviruses;Affect;Apoptosis;Binding (Molecular Function);Cancer Etiology;Cell Cycle;Cell Proliferation;Clinical Trials;Cyclin E;DNA biosynthesis;E2F Transcription Factor 1;E2F transcription factors;Genes;Goals;Health;Human papillomavirus 16 E1 protein;In Vitro;Killings;Laboratories;Malignant Neoplasms;Mediating;Molecular;Mus;Mutate;Mutation;Normal Cell;Oncogene Proteins;Oncogenes;Oncolytic;Oncolytic viruses;Outcome;Pathway interactions;Patients;Process;Promotor (Genetics);Proteins;Publishing;Regulation;Research;Retinoblastoma Protein;Role;Site;Testing;Treatment Efficacy;Viral;Viral Physiology;Virus;Virus Replication;Work;Xenograft Model;base;cancer cell;cellular targeting;clinical application;gene therapy;genetic analysis;in vivo;mutant;novel;oncolysis;overexpression;response;tumor;viral DNA

public_health_relevance:
Project NarrativeAdenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells.Therefore the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55Kfunction and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studieshave revealed that E1B55K has a novel function in the induction of cyclin E expression which is crucial forDNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. Wereason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNAreplication. Cancer cells may already have the factors activated therefore cancer cells do not require theE1B55K function. The study of this possibility is very important. If we confirm that mutated virus replicationrelies on cyclin E expression patients with aggressively growing tumors and dysregulated cyclin E shouldgreatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy ofoncolytic cancer gene therapy.


application_id: 8207270
project_number: 5R01CA035635-25
project_title: Specificity of Intercalation Reactions
administering_ic: NCI
award_notice_date: 2011-12-30
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 035635
program_official: MISRA, RAJ N
project_start_date: 1984-03-01
project_end_date: 2014-12-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
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:
DESCRIPTION (provided by applicant): DNA is an underrepresented target for small molecule therapeutic agents. One reason for the dearth of DNA targeted drugs is that the fundamental molecular mechanisms that govern sequence- and structural-selective ligands to DNA remain poorly understood. In order to develop design principles for targeting specific DNA sites a thorough understanding of the binding mechanisms of existing compounds that bind to DNA with unique types of selectivity is needed. The long-range goal of this project is to understand the mechanism of DNA intercalation reactions with particular emphasis on the energetic basis of sequence- and structural-selective binding. Renewal is sought for a successful and highly productive basic science program that has produced several promising avenues for DNA-targeted drug development. Four-stranded G-quadruplex DNA structures have emerged as important functional elements within the genome and represent important new targets for therapeutic drugs. G-quadruplexes are functional elements that are important in telomere biology and are emerging as important control elements in the expression of many genes particularly oncogenes. Research in the next funding period will focus on biophysical studies of G-quadruplex structure folding and stability and on their selective interactions specific quadruplex structures with drug-like molecules. Specific aims include: 1. Determination of the structure of the 200 nt single-stranded DNA overhang that is a conserved feature of human telomeres. 2. Determination of the thermodynamic stability of higher-order quadruplex structures and the kinetics of the folding. 3. Determination of the thermodynamics and kinetics of drug binding to specific quadruplex structures including the higher-order structures in telomeric DNA and the G-quadruplex "silencer" element found in the c-myc promoter. The results of these proposed studies will deepen our understanding of the structure and stability of functionally important G-quadruplexes and will provide fundamental mechanistic information of use in the rational design of new small molecules to selectively target functionally important quadruplex structures.    PUBLIC HEALTH RELEVANCE: G-quadruplexes are four-stranded DNA structures that are thought to be functionally import elements in the human genome. Quadruplexes have emerged as potential drug targets. The proposed project will use computational and biophysical methods to study the structure stability and drug binding of functionally significant quadruplex structures. The results will be of fundamental use for guiding the design of new drugs targeted toward quadruplexes.

project_terms:
Base Sequence;Basic Science;Beryllium;Binding (Molecular Function);Binding Proteins;Biology;Calorimetry;Cell Cycle;Coupled;Crystallography;DNA;DNA Intercalation;DNA Structure;Diffusion;Drug Delivery Systems;Drug Kinetics;Drug Stability;Elements;Fluorescence;Foundations;Funding;G-Quartets;Gene Expression;Genes;Genome;Goals;Higher Order Chromatin Structure;Human;Human Genome;In Vitro;Indium;Kinetics;Ligand Binding;Ligands;Methods;Molecular;New Agents;Oncogenes;Pharmaceutical Preparations;Process;Promotor (Genetics);Property;Proteins;Radial;Reaction;Refractory;Regulatory Element;Research;Research Design;Resolution;Sedimentation process;Single-Stranded DNA;Site;Specificity;Structural Models;Structure;Telomerase;Testing;Therapeutic Agents;Thermodynamics;Time;Transcriptional Silencer Elements;base;c-myc Genes;design;dimer;driving force;drug development;innovation;intercalation;light scattering;molecular dynamics;new therapeutic target;programs;public health relevance;sedimentation velocity;small molecule;telomere

public_health_relevance:
G-quadruplexes are four-stranded DNA structures that are thought to be functionallyimport elements in the human genome. Quadruplexes have emerged as potential drugtargets. The proposed project will use computational and biophysical methods to studythe structure stability and drug binding of functionally significant quadruplex structures.The results will be of fundamental use for guiding the design of new drugs targetedtoward quadruplexes.


application_id: 8207127
project_number: 1R03DA033175-01
project_title: Identification of substances that change alternative pre-mRNA splicing of the ser
administering_ic: NIDA
award_notice_date: 2011-07-01
opportunity_number: PAR-09-129
application_type: 1
activity_code: R03
ic: DA
serial_number: 033175
program_official: SINGH, HARI
project_start_date: 2011-07-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1 BST-F (50)]
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:
DESCRIPTION (provided by applicant): Identification of substances that change alternative pre-mRNA splicing of the serotonin 2C receptor the serotonin receptor 2C (5-HT2CR) protein is a validated anti-obesity drug target that binds to the anorectic substances fen-phen (fenfluramine and phentermin). Due to their cross-reactivity with other receptors these drugs are no longer in use.  The activity of the 5-HT2CR protein is regulated by alternative processing pathways of its pre- mRNA. Only when the alternative exon Vb is included in the mRNA a functional receptor can be formed. This inclusion can be achieved by two mechanisms: (i) RNA editing which generates less active receptors and (ii) promotion by specific small nuclear RNAs which generates the most active receptors. Patients with Prader-Willi syndrome do not express the small nuclear RNAs which most likely contributes to their obesity.  We propose to identify compounds that promote inclusion of the alternative exon Vb without a change on RNA editing. This change in pre-mRNA processing will generate the most active 5-HT2CR protein that is likely to exert an anti-appetite effect.  We generated cell lines containing a fluorescent-based splicing reporter construct. These cell lines were successfully validated in a pilot screen using a library of 1692 compounds. The screen was robust (Z factor 6.1) and resulted in one compound pyrvinium pamoate that showed an IC50 of 65M in established secondary and tertiary PCR-based screens.  Our preliminary analysis of pyrvinium pamoate and small nuclear RNAs acting on serotonin pre-mRNA processing suggests that exon Vb functions similar to a bacterial riboswitch. A conformational change triggered by low molecular weight compounds causes a change in its structure that allows its splice site to be recognized leading to its inclusion.  To gain insight into structure activity relationships we therefore further propose to test the influence of pyrvinium pamoate and other validated hits on serotonin receptor 2C pre-mRNA structure. In addition to conventional structure probing experiments we will use RNA oligonucleotides with modified bases that reflect an alteration in structure by a change in fluorescence the selective modification of the processing pathways of a structured pre-mRNA has not been attempted yet and is the major innovation of the proposal. The identification of compounds that promote the activity of the serotonin receptor 2C by changing its pre-mRNA processing would be highly significant as they are expected to have anti-appetite properties. Identifying a compound that combats obesity would have a major therapeutic impact and the possible identification of the first mammalian riboswitch will have a strong scientific impact.  
  
PUBLIC HEALTH RELEVANCE: Obesity is a major health problem affecting more than 26% of adult Americans. This project will identify compounds that change the way the body makes the serotonin receptor protein. Since this protein is a major control point of hunger the compounds are expected to decrease appetite which could help fighting the obesity epidemic.

project_terms:
Adult;Adverse effects;Affect;Agonist;Alternative Splicing;American;Amino Acids;Anti-Obesity Agents;Appetite Depressants;Binding (Molecular Function);Biological Assay;Cell Line;Chemicals;Data;Desire for food;Drug Binding Site;Drug Delivery Systems;Drug Receptors;Eating;Epidemic;Exons;Fenfluramine;Fluorescence;Gene Expression Profile;Health;Hormonal;Human;Hunger;Inhibitory Concentration 50;Intervention;Libraries;Marketing;Messenger RNA;Modeling;Modification;Molecular Bank;Molecular Weight;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oligonucleotides;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Population;Prader-Willi Syndrome;Prevalence;Process;Production;Property;Protein Isoforms;Proteins;Public Sector;Pyrvinium pamoate;RNA;RNA Editing;RNA Splicing;Receptor Serotonin 5-HT2C;Regulation;Reporter;Research Personnel;Role;Screening procedure;Serotonin;Site;Small Nuclear RNA;Small Nucleolar RNA;Structure;Structure of nucleus infundibularis hypothalami;Structure-Activity Relationship;Testing;Therapeutic;United States National Institutes of Health;Work;base;combat;cost;cross reactivity;fighting;gene function;high throughput screening;innovation;insight;mRNA Precursor;mouse model;receptor;research study;response;serotonin 5 receptor;serotonin receptor;small molecule

public_health_relevance:
Obesity is a major health problem affecting more than 26% of adult Americans. This project will identify compounds that change the way the body makes the serotonin receptor protein. Since this protein is a major control point of hunger the compounds are expected to decrease appetite which could help fighting the obesity epidemic.


application_id: 8207098
project_number: 2T03OH008846-06
project_title: Agricultural Safety and Health Training for Public Health Graduate Students
administering_ic: NIOSH
award_notice_date: 2011-08-01
opportunity_number: PAR-10-288
application_type: 2
activity_code: T03
ic: OH
serial_number: 008846
program_official: NEWHALL, JIM
project_start_date: 2006-07-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZOH1 BBK (51)]
contact_pi_person_id: 1939811
contact_pi: BROWNING, STEVEN R
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  We propose a five year renewal for a Training Program Grant (TPG) focused on agricultural occupational safety and health for students seeking a Master of Public Health (MPH) Doctor of Public Health (DrPH) and PhD degree in Epidemiology and Biostatistics. The program will be administered by the University of Kentucky College of Public Health and the Southeast Center for Agricultural Health and Injury Prevention. The Health of Agricultural Populations (HAP) TPG will apply agricultural occupational safety and health training across traditional public health course work research training and field experiences. The HAP-TPG contains cross-cutting competencies for occupational safety and health in agriculture and is available for students across six departments of the University of Kentucky College of Public Health: Health Services Management Health Behavior Epidemiology Environmental Health Gerontology and Biostatistics. The current TPG was first funded in July 2006 with a modest budget of about $60000 annually. To date we have graduated four students from the program with partial NIOSH support and an additional four students are currently enrolled two of whom are scheduled to graduate in 2011. The renewal is requesting $125000 total costs per year to fund at least five trainees a year via two student stipends and three student tuition packages each year. MPH students in the HAP TPG will require 42 to 44 semester hours to graduate of which 15 semester hours are directly related to agricultural health and safety. DrPH students must complete 74 to 78 semester hours to graduate of which 25 hours will be HAP-TPG intensive. PhD students in Epidemiology and Biostatistics require at least 58 hours to graduate plus dissertation research and the corresponding residency credits. At least 16 of these hours must be directly related to agricultural occupational health and safety. Between 2011 and 2016 we anticipate at least 10 MPH students four DrPH students and four PhD (Epidemiology/Biostatistics) students will graduate. A strong evaluation and diversity of recruitment strategies are planned. The University of Kentucky has proposed a commitment of $94400 for student tuition and other support across the next five years. The continuation of this TPG is highly relevant to public health because it will increase the number of systematically trained well-equipped practitioners who can more fully address agricultural occupational safety and health problems through prevention intervention practice and service.  
  
PUBLIC HEALTH RELEVANCE:  We propose a five-year renewal of a Training Program Grant (TPG) focused on agricultural occupational safety and health for students seeking a Master of Public Health (MPH) Doctor of Public Health (DrPH) and PhD degree in Epidemiology and Biostatistics at the University of Kentucky. The program will be administered by the University of Kentucky College of Public Health and the Southeast Center for Agricultural Health and Injury Prevention. The Health of Agricultural Populations (HAP) TPG will apply agricultural occupational safety and health training across traditional public health course work research training and field experiences in order to foster cross-cutting competencies in program graduates who are expected to attain long-term leadership positions in public health practice.

public_health_relevance:
We propose a five-year renewal of a Training Program Grant (TPG) focused on agricultural occupational safety and health for students seeking a Master of Public Health (MPH) Doctor of Public Health (DrPH) and PhD degree in Epidemiology and Biostatistics at the University of Kentucky. The program will be administered by the University of Kentucky College of Public Health and the Southeast Center for Agricultural Health and Injury Prevention. The Health of Agricultural Populations (HAP) TPG will apply agricultural occupational safety and health training across traditional public health course work research training and field experiences in order to foster cross-cutting competencies in program graduates who are expected to attain long-term leadership positions in public health practice.


application_id: 8206511
project_number: 5R01CA143428-02
project_title: Rel B mediated-redox regulation of radiation therapy
administering_ic: NCI
award_notice_date: 2011-12-30
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 143428
program_official: BERNHARD, ERIC J
project_start_date: 2011-01-01
project_end_date: 2015-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
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): Accumulating data suggest that prostate cancers exist in an elevated state of oxidative stress and that reactive oxygen species (ROS) contribute importantly to the cytotoxic effect of ionizing radiation (IR). However ROS also participate in cellular signaling processes leading to adaptive responses that reduce the effectiveness of radiation therapy. Thus despite rapid advances in treatment techniques the outcome of radiation therapy especially for patients with tumors with unfavorable prognoses remains to be improved. The goal of this project is to identify novel mechanisms that could lead to the development of specific measures for effective treatment of aggressive prostate cancers. We have identified the alternative pathway of the redox sensitive nuclear factor kappa beta (NF-?B) as a major contributor to prostate cancer growth and progression. Preliminary data indicate that: 1) aggressive prostate cancers have high nuclear RelB a member of the alternative pathway of NF-:B and manganese superoxide dismutase (MnSOD) a critical antioxidant enzyme levels; 2) suppression of RelB in androgen independent-aggressive prostate cancer cells results in reduction of interleukin 8 (IL8) levels in tumor cells and reduced tumor growth in vivo; 3) overexpression of RelB in androgen responsive prostate cancer cells results in enhanced tumor growth and production of IL8 but reduced prostate specific androgen (PSA) production; and 4) suppression of RelB nuclear translocation enhances radiation sensitivity of prostate cancer. Based on these novel and important preliminary findings we hypothesize that RelB regulates prostate cancer response to radiation via a MnSOD dependent NF-?B switch to activate expression of IL8 and suppress expression of PSA in prostate cancer cells. We propose that clinical testing for recurrent tumor growth should involve measuring levels of IL8 in addition to employing the standard PSA test. Combining these tests will enhance accurate cancer detection and prognosis. To test this hypothesis and validate the proof-of-concept for the combined use of IL8 and PSA as prognostic factors three interrelated specific aims will be addressed. Aim 1 will elucidate the mechanism by which MnSOD modulates the effect of RelB on the transcription of IL8 and PSA in prostate cancer cells using biochemical and molecular biology approaches. Aim 2 will examine the role of IL8 in the protection against the effects of radiation therapy of prostate cancer. Aim 3 will determine whether serum IL8 level is a predictive marker of prostate cancer response to radiation therapy using samples from cancer patients.  These mechanistic based bench to bedside approaches should provide novel insights into the mechanisms of prostate cancer resistant to radiation therapy and may provide practical predictive measures for prostate cancer diagnostic treatment planning and surveillance.    PUBLIC HEALTH RELEVANCE: Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die from prostate cancer is unacceptably high. The results obtained from this study will provide insights into the novel mechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated and will test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treating prostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment of prostate cancer.

project_terms:
Address;Affinity Chromatography;Androgens;Animal Model;Antioxidants;Basic Science;Binding (Molecular Function);Biochemical;Biological Assay;Cancer Center;Cancer Detection;Cancer Diagnostics;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Clinical;Clinical Research;Cultured Cells;Data;Development;Diagnosis;Diagnostic Neoplasm Staging;Effectiveness;Enzymes;Family;Gene Expression;Genes;Genetic Transcription;Goals;Growth;Human;Immunoprecipitation;Interleukin-8;Ionizing radiation;Kentucky;Lead;Link;Malignant Neoplasms;Malignant neoplasm of prostate;Manganese Superoxide Dismutase;Measures;Mediating;Modeling;Molecular Biology;NF-kappa B;Nuclear;Nuclear Translocation;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Patients;Physicians;Play;Predictive Factor;Production;Prognostic Factor;Prostate;Prostate-Specific Antigen;Proteomics;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrent tumor;Regulation;Resistance;Risk;Role;Sampling;Serum;Site-Directed Mutagenesis;Small Interfering RNA;Techniques;Testing;Time;Transcriptional Regulation;Translating;Tumorigenicity;Universities;Visit;base;bench to bedside;cancer cell;cancer diagnosis;cancer type;computerized data processing;cytotoxic;cytotoxicity;effective therapy;follow-up;improved;in vivo;inflammatory marker;insight;member;men;neoplastic cell;novel;outcome forecast;overexpression;public health relevance;research clinical testing;research study;response;treatment planning;treatment strategy;tumor;tumor growth

public_health_relevance:
Project Narrative Prostate cancer is the most frequently diagnosed cancer in men and the number of men who die fromprostate cancer is unacceptably high. The results obtained from this study will provide insights into the novelmechanisms by which interleukin 8 (IL8) and prostate specific antigen (PSA) are differentially regulated andwill test a proof-of-concept for using their relationship to predict the efficacy of radiation therapy for treatingprostate cancer. Thus this study will enable physicians to tailor risk-adjusted strategies for treatment ofprostate cancer.


application_id: 8205808
project_number: 2U01DA013519-10
project_title: Development of Novel Therapies or Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2012-07-12
opportunity_number: PA-10-067
application_type: 2
activity_code: U01
ic: DA
serial_number: 013519
program_official: APPEL, NATHAN M
project_start_date: 2000-08-15
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 MDCN-C (56)]
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): Methamphetamine (METH) abuse continues to escalate and effective treatments are not currently available. METH interacts with the vesicular monoamine transporter-2 (VMAT2) promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA concentrations which is thought to be associated with its abuse liability. The overall objective of this project is to provide a clinical candidate for the treatment of METH abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively inhibits DA uptake by VMAT2 inhibits METH-evoked DA release from synaptic striatal vesicles and slices and exhibits selectivity does not interact with nicotinic receptors or DA transporters. Off-target evaluation at a cadre of neurotransmitter-related steroid and ion channel sites second messenger prostaglandin growth factor and hormones brain/gut peptides and enzymes revealed outstanding selectivity. Translation to whole animals models revealed that GZ-793A specifically decreases METH self-administration without altering responding for sucrose does not produce tolerance to the decrease in METH self- administration upon repeated administration and decreases METH seeking in the cue-induced reinstatement. Acute GZ793A pretreatment also protects against the neurotoxic effects of METH as measured by striatal DA depletion. Although the physicochemical properties of GZ-793A are favorable in terms of druggability GZ-793A has only 2-3% oral bioavailability likely due to the presence of the hydroxyl functionalities in the molecule which are likely sites for high first-pass metabolism. Thus new optimized analogs of GZ-793A are the focus of the current application with the goal of identifying analogs with the required pharmacological properties druggability increased oral bioavailability and acceptable pharmacokinetic profile. Compounds with these characteristics would be high value preclinical candidates for advancement toward clinical trials as treatments for METH abuse. Thus we propose to expand our existing molecular library of analogs by performing the final steps of optimization of GZ-793A to identify a high value preclinical candidate as a potential therapeutics for METH abuse. In future work the best candidate will undergo comprehensive toxicological evaluation for subsequent preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.  
  
PUBLIC HEALTH RELEVANCE: Currently there is no pharmacotherapeutic available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and which exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model of self-administration. We propose to expand our existing molecular library by performing the final steps of optimization of the chemical structure of GZ-793A with the aim of providing additional leads that are druggable orally-bioavailable high value preclinical candidates. The outcome of the proposed project is to bring the best candidate to comprehensive toxicological evaluation for preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.

project_terms:
Acute;Affinity;Animal Model;Behavioral;Binding Sites;Bioavailable;Biological Availability;Brain;CYP2C19 gene;CYP2D6 gene;Characteristics;Chemical Structure;Clinical;Clinical Trials;Collaborations;Corpus striatum structure;Cues;Cytosol;Data;Development;Dopamine;Dose;Drug Kinetics;Enzymes;Evaluation;Event;Exhibits;Food;Future;Generations;Goals;Growth Factor;Half-Life;Hepatic;Hydroxyl Radical;Ilex vomitoria;In Vitro;Intravenous;Investigational New Drug Application;Ion Channel;Lead;Libraries;Lobeline;Measures;Metabolism;Methamphetamine;Modification;Molecular Bank;National Institute of Drug Abuse;Neurotransmitters;Nicotinic Receptors;Oral;Oral Administration;Outcome;Peptides;Pharmaceutical Preparations;Phase;Plasma;Preparation;Prodrugs;Property;Prostaglandins;Rattus;Rewards;Route;Safety;Salts;Second Messenger Systems;Self Administration;Site;Slice;Somatotropin;Specificity;Steroids;Structure-Activity Relationship;Sucrose;Synapses;Synaptic Vesicles;Therapeutic;Therapeutic Agents;Translations;Variant;Vesicle;Work;analog;base;dihydrotetrabenazine;dopamine system;dopamine transporter;effective therapy;extracellular;improved;inhibitor/antagonist;methamphetamine abuse;neurotoxic;neurotoxicity;new therapeutic target;novel;piperidine;pre-clinical;preference;second messenger;small molecule;sulfation;uptake;vesicular monoamine transporter 2;water solubility

public_health_relevance:
Currently there is no pharmacotherapeutic available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently we identified a novel small molecule (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and which exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model of self-administration. We propose to expand our existing molecular library by performing the final steps of optimization of the chemical structure of GZ-793A with the aim of providing additional leads that are druggable orally-bioavailable high value preclinical candidates. The outcome of the proposed project is to bring the best candidate to comprehensive toxicological evaluation for preparation of an Investigational New Drug application to the FDA as a proposed treatment for methamphetamine abuse.


application_id: 8204615
project_number: 5R01NS054708-05
project_title: Genetic approaches to functional remyelination after SCI
administering_ic: NINDS
award_notice_date: 2011-12-02
opportunity_number: PAS-05-092
application_type: 5
activity_code: R01
ic: NS
serial_number: 054708
program_official: JAKEMAN, LYN B
project_start_date: 2008-01-01
project_end_date: 2013-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(05)M]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: Not Applicable
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: N
project_abstract:
Our recently work show that glial restricted precursor cells (GRPs) grafted into a demyelinating orcontusive spinal cord injury (SCI) partially restore electrophysiological conduction and hindlimb locomotorrecovery. We will build on those data and determine the potential of human embryonic stem cells (hESC) torestore function after engraftment into the damaged spinal cord. Aim 1. Using the focal VLF+DLFdemyelinating lesion and grafting D15A-GRPs (A2B5+/NG2+/O4-) we will determine whether inhibition ofBMP and Notch signaling pathways demonstrated in vitro to inhibit oligodendrocyte differentiation canenhance the remyelination capacity of the engrafted cells. We will examine a number of genetic andmolecular biological approaches to inhibiting BMP and Notch signaling. Aim 2. Determine whether deliveryof CNTF or NRG1 types I or III neurotrophic factors known to potentiate oligodendrocyte proliferation andmaturation in vitro and in vivo will enhance remyelination by engrafted GRPs. Aim 3. Using optimalparameters established in Aims 1 and 2 and the more clinically relevant contusion SCI we will ask whetherremyelination can result in enhanced recovery of function. We hypothesize that both remyelination andenhanced white matter sparing are needed for optimal recovery and will distinguish between those effects inthese animals.

project_terms:
Address;Adult;Animals;Axon;Behavioral;Biological;Brain-Derived Neurotrophic Factor;CSPG4 gene;Cells;Chest;Ciliary Neurotrophic Factor;Contusions;Data;Demyelinations;Dominant-Negative Mutation;Engraftment;Environment;Failure (biologic function);Functional disorder;GRP gene;Gene Deletion;Genetic;Heterozygote;Hindlimb;Impairment;In Vitro;Injury;Intervention;Lentivirus Vector;Lesion;Locomotor Recovery;Magnetism;Measures;Methods;Modeling;Modification;Molecular Genetics;Monitor;Motor Evoked Potentials;Mus;NRG1 gene;Natural regeneration;Neuregulins;Notch Signaling Pathway;Oligodendroglia;Play;Publications;Publishing;Rattus;Recovery;Recovery of Function;Research Personnel;Retroviridae;Role;Signal Pathway;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal cord damage;Spinal cord injury;Stem cells;Work;cell type;clinically relevant;combinatorial;functional restoration;human embryonic stem cell;in vivo;injury prevention;insight;mouse model;myelination;neurotrophic factor;nicastrin protein;notch protein;partial recovery;precursor cell;remyelination;response;success;treatment strategy;vector;white matter


application_id: 8204540
project_number: 5R21EY020647-02
project_title: P23H Rhodopsin Mutant Swine Model of Reninitis Pigmentosa
administering_ic: NEI
award_notice_date: 2011-11-30
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: EY
serial_number: 020647
program_official: SHEN, GRACE L
project_start_date: 2010-12-01
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1-CB-G(90)S]
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: ROSS, JASON W
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): Retinal degeneration is a leading cause of blindness in the Western world and retinitis pigmentosa (RP) is the most common cause of hereditary visual loss in adult life. Although the genetic basis of RP has been well explored the translation of this insight into successful genetic therapy has been hindered because of the mutational heterogeneity that underlies this group of diseases. In addition to gene therapy we and others are exploring alternative therapeutic approaches employing recent advances in stem cell therapy as well as the retinal prosthesis bioengineering and pharmacology. Together these hold the promise for successful neural reconstitution in RP.  Using the method of single cell nuclear transfer we produced six male miniature swine (mini-swine) on a NIH cc haplotype carrying a mutant Pro23His (P23H) human rhodopsin transgene at the National Swine Resource Research Center at the University of Missouri-Columbia. Our preliminary data show that these founders exhibited an electrophysiologic phenotype characteristic of RP. Since P23H is the most common autosomal dominant mutation responsible for RP in man we propose to establish a colony and characterize three independent transgenic lines of this new mini-swine model of photoreceptor degeneration. While outside the time frame of this application in the near future it can be used by us and the vision community for novel therapeutic interventions.   
  
PUBLIC HEALTH RELEVANCE:  Using the method of single cell nuclear transfer we produced six male miniature swine (mini-swine) on a NIH cc haplotype carrying a mutant Pro23His (P23H) human rhodopsin transgene at the National Swine Resource Research Center at the University of Missouri-Columbia. Our preliminary data show that these founders exhibited an electrophysiologic phenotype characteristic of retinitis pigmentosa (RP). Since P23H is the most common autosomal dominant mutation responsible for RP in humans we propose to establish a colony and characterize three independent transgenic lines of this new mini-swine model of photoreceptor degeneration for future therapeutic interventions.

project_terms:
Adult;Age;Animal Model;Area;Artificial Insemination;Biomedical Engineering;Blindness;Cells;Characteristics;Clinical;Communities;Congenital Abnormality;Data;Disadvantaged;Disease;Disease Progression;Exhibits;Extinction (Psychology);Eye;Family suidae;Future;Genetic;Haplotypes;Heterogeneity;Histologic;Histology;Human;Image;Inbreeding;Inheritance Patterns;Inherited;Life;Methods;Miniature Swine;Missouri;Modeling;Molecular Abnormality;Morphology;Mutation;Nuclear;Peripheral;Pharmacology;Phenotype;Photography;Population;Positioning Attribute;Principal Investigator;Research Project Grants;Resources;Retinal;Retinal Cone;Retinal Degeneration;Retinitis Pigmentosa;Rhodopsin;Rods (Retina);Severities;Site;Therapeutic;Therapeutic Intervention;Time;Transgenes;Transgenic Organisms;Translational Research;Translations;United States National Institutes of Health;Universities;Vision;Visual;Western World;Work;base;clinical phenotype;gene therapy;innovation;insight;light microscopy;male;man;mutant;neurotrophic factor;novel therapeutic intervention;nuclear transfer;offspring;photoreceptor degeneration;prevent;programs;reconstitution;relating to nervous system;research study;retinal prosthesis;retinal regeneration;somatic cell nuclear transfer;stem cell therapy;transmission process;treatment effect

public_health_relevance:
Using the method of single cell nuclear transfer we produced six male miniature swine (mini-swine) on a NIH cc haplotype carrying a mutant Pro23His (P23H) human rhodopsin transgene at the National Swine Resource Research Center at the University of Missouri-Columbia. Our preliminary data show that these founders exhibited an electrophysiologic phenotype characteristic of retinitis pigmentosa (RP). Since P23H is the most common autosomal dominant mutation responsible for RP in humans we propose to establish a colony and characterize three independent transgenic lines of this new mini-swine model of photoreceptor degeneration for future therapeutic interventions.


application_id: 8204439
project_number: 5R21AI092074-02
project_title: Transgenic mouse models of HCV infection and replication
administering_ic: NIAID
award_notice_date: 2011-11-16
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AI
serial_number: 092074
program_official: KOSHY, RAJEN
project_start_date: 2010-12-03
project_end_date: 2012-11-30
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 10304717
contact_pi: JIANG, JIEYUN
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): Hepatitis C virus (HCV) is the leading cause of chronic hepatitis cirrhosis and hepatocellular carcinoma (HCC). HCV chronically infects approximately 4 million people in the U.S. and 170 million people worldwide. HCV co-infection with HIV is very common with overall 25-30% of HIV-positive persons particularly among drug abusers with up to 70% co-infection (2). HCV infection is a major risk factor for HCC development. HCV- associated end-stage of liver diseases is the leading indication for liver transplantation. Advances on HCV research have been significantly hampered by the lack of a robust cell culture HCV propagation system and reliable small animal models of HCV infection and replication. Recent breakthroughs have been the development of robust cell culture systems for replication of HCV replicon RNAs and production of infectious HCV which allows genetic studies of the entire HCV life cycle. However development of small animal models of HCV infection and replication is challenging and that the lack of a reliable small animal model represents a major barrier to HCV research. Recently we have demonstrated that genotype 2a HCV RNA replicated efficiently in mouse embryonic fibroblasts (MEF) albeit inefficiently in mouse hepatocytes. More importantly we have demonstrated that the cDNA-derived HCV RNA inside the cell resulted in robust production of infectious HCV. A recent study by Charlie Rice's group has demonstrated that the expression of human CD81 and occludin in mouse hepatocytes is essential and sufficient for infection of HCV pseudotyped particles. These remarkable advances provide a firm foundation to develop novel transgenic mouse models of HCV infection and replication. We hypothesize that cell type-specific cellular proteins are important for efficient HCV RNA replication and that transgenic mice expressing human CD81 and occludin in hepatocytes are susceptible to HCV infection. The overall goal of this exploratory research proposal is to develop novel transgenic HCV mouse models. Specifically we will 1) identify cellular proteins important for efficient HCV RNA replication in mouse cells using proteomics biochemical and genetic complementation approaches (Specific Aim 1); 2) develop novel transgenic mice that either contain full-length cDNAs of luciferase-expressing JFH1 HCV RNAs or express both human CD81 and occludin under the control of a liver-specific promoter (Specific Aim 2); and 3) determine HCV infection and replication in transgenic mice using luciferase-expressing HCV in conjunction with the administration of mouse interferon and HCV NS3 protease- and NS5B polymerase-specific inhibitors (Specific Aim 3). The successful development of transgenic HCV mouse models will represent a paradigm shift in the field of HCV research and will allow us to determine the roles and mechanisms of action of viral and cellular proteins in HCV infection replication pathogenesis and carcinogenesis as well as the effects of illicit drugs and alcohol on HCV replication and pathogenesis. Additionally transgenic HCV mouse models will facilitate the anti-HCV drug discovery and HCV vaccine development to eventually control HCV infection.    PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) infection remains a major global health problem affecting approximately 170 million people worldwide and 4 million Americans. Our overall goal of this research proposal is to develop novel transgenic HCV mouse models for the determination of the molecular mechanisms of HCV replication pathogenesis carcinogenesis and the effects of illicit drugs and alcohol on HCV replication and pathogenesis. Additionally transgenic HCV mouse models will facilitate the antiviral drug discovery and vaccine development to eventually control HCV infection.

project_terms:
Affect;Albumins;Alcohols;American;Animal Model;Antiviral Agents;Biochemical Genetics;CD81 gene;Catalytic RNA;Cell Culture System;Cell Culture Techniques;Cell Line;Cells;Chronic Hepatitis;Cirrhosis;Complementary DNA;DNA Polymerase II;Development;Drug abuser;Embryo;Fibroblasts;Foundations;Genetic;Genetic Transcription;Genome;Genomics;Genotype;Goals;HCV Vaccine;HIV;HIV Seropositivity;Hepatitis C;Hepatitis C virus;Hepatitis Delta Virus;Hepatocyte;Human;Illicit Drugs;Infection;Infectious hepatitides;Interferons;Knowledge;Laboratories;Length;Life Cycle Stages;Liver;Liver diseases;Luciferases;Measures;Molecular;Mouse Cell Line;Mus;Pathogenesis;Peptide Hydrolases;Persons;Polymerase;Primary carcinoma of the liver cells;Production;Promotor (Genetics);Proteins;Proteomics;RNA;RNA Sequences;RNA replication;Replicon;Research;Research Proposals;Rice;Risk Factors;Role;Staging;Structure;System;Transgenic Mice;Transgenic Organisms;Variant;Viral;Viral Proteins;Virion;Virus;Virus Receptors;Virus Replication;Work;anti-hepatitis C;base;carcinogenesis;cell type;drug development;drug discovery;global health;hepatitis C virus NS3 protein;hepatoma cell;in vivo;inhibitor/antagonist;innovation;interdisciplinary approach;liver transplantation;mouse model;novel;occludin;particle;public health relevance;receptor;vaccine development;viral RNA

public_health_relevance:
Hepatitis C virus (HCV) infection remains a major global health problem affecting approximately 170million people worldwide and 4 million Americans. Our overall goal of this research proposal is to developnovel transgenic HCV mouse models for the determination of the molecular mechanisms of HCVreplication pathogenesis carcinogenesis and the effects of illicit drugs and alcohol on HCV replicationand pathogenesis. Additionally transgenic HCV mouse models will facilitate the antiviral drug discoveryand vaccine development to eventually control HCV infection.


application_id: 8203793
project_number: 1R03CA162520-01
project_title: Bionanoconjugates for Detection of Circulating Tumor Cells in Lung Cancer
administering_ic: NCI
award_notice_date: 2011-07-18
opportunity_number: PAR-08-055
application_type: 1
activity_code: R03
ic: CA
serial_number: 162520
program_official: YOUNG, MATTHEW R
project_start_date: 2011-07-18
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZCA1 SRLB-H (M1)]
contact_pi_person_id: 7875285
contact_pi: HIRSCHOWITZ, EDWARD A.
other_pis: KNECHT, MARC
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Measurement of circulating tumor cells (CTC) has potential to fill major gaps in the clinical care and management of lung cancer patients. Validation of CTC as a prognostic marker in breast cancer patients set an important precedent for CTC measurement; however histochemical CTC enumeration now used as a clinical correlate in breast and prostate cancer has proven to be neither robust nor reliable enough for application to lung cancer. This is due in large part to the phenotypic heterogeneity and high antigen variability associated with lung tumors as compared to other solid tumors. PCR amplification of cancer protein transcripts is a conceptually appealing alternative approach to CTC measurement that offers sensitivity and unlimited capabilities for multiple antigen measurements. Although literature indicates that PCR detection of CTC correlates with lung cancer stage disease recurrence and survival this approach remains investigational. Since mRNA transcript is used as a surrogate for tumor protein expression PCR is criticized for lack of specificity. We have devised an approach that combines the specificity of immuno-histochemistry with the sensitivity of PCR. This application details testing and optimization of a novel nanoparticle-based system to overcome technical and biological hurdles encountered in lung cancer CTC measurement. Specifically bio-nanoconjugates are constructed to carry one antigen specific monoclonal antibody and a conjugate-specific double stranded DNA tag sequence for nano-specific identification. When conjugates bind antigen on a cell surface a single strand of the DNA tag can be released into suspension by briefly heating the complex mixture; liberated DNA strands amplified by PCR provide a highly sensitive and quantifiable measure of cellular binding and corresponding antigen expression. Signal amplification of the antigen-bound bio-nanoconjugate allows detection of low frequency proteins on low concentration CTC in peripheral blood and multiplexing capabilities inherent to the technology offer increasing sensitivity without reduced specificity making this particularly well suited for the measurement of lung cancer CTC. Sensitivity of the approach will be determined with peripheral blood spiked at various concentrations with cultured tumor cells with known antigen expression. CTC enrichment using antibody-mediated separation of CTC from peripheral blood mononuclear cells is expected to further increase the limits of detection while also reducing the potential for false positive results. We anticipate being able to achieve unrivaled detection limits with high degrees of specificity for lung cancer CTC. This application details the comparative and systematic phases of initial development and testing of this promising initiative.  
  
PUBLIC HEALTH RELEVANCE:  Measurement of circulating tumor cells (CTC) has potential to fill major gaps in the clinical care and management of lung cancer patients. There is not a currently reliable method for clinical application in lung cancer. This application details testing and optimization of a novel nanoparticle-based system to overcome technical and biological hurdles encountered in lung cancer CTC measurement.

project_terms:
Antibodies;Antigens;Binding (Molecular Function);Biological;CTAG1 gene;Cancer Patient;Cell Adhesion Molecules;Cell surface;Cells;Clinical;Clinical Management;Complex;Complex Mixtures;Coupling;Cultured Tumor Cells;DNA;DNA Sequence;Detection;Development;Diagnostic Neoplasm Staging;Disease;Epithelial Cells;Fluorescence;Foundations;Frequencies (time pattern);Future;Gold;Heating;Heterogeneity;Histocytochemistry;Imagery;Literature;Logic;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measurement;Measures;Mediating;Messenger RNA;Methodology;Methods;Microscopy;Monoclonal Antibodies;Nanoconjugate;Non-Small-Cell Lung Carcinoma;Peripheral Blood Mononuclear Cell;Phase;Population;Prognostic Marker;Proteins;Recurrence;Reverse Transcriptase Polymerase Chain Reaction;Sampling;Signal Transduction;Single-Stranded DNA;Solid Neoplasm;Solutions;Specificity;Staining method;Stains;Surface;Suspension substance;Suspensions;System;TACSTD2 gene;Techniques;Technology;Testing;Transcript;Tumor Antigens;Validation;Visual;Whole Blood;antigen antibody binding;antigen binding;base;clinical application;clinical care;comparative;cost;cost effective;design;ds-DNA;improved;malignant breast neoplasm;nano;nanoparticle;neoplastic cell;novel;particle;peripheral blood;protein expression;research study;surface coating;survivin;tumor

public_health_relevance:
Measurement of circulating tumor cells (CTC) has potential to fill major gaps in the clinical care and management of lung cancer patients. There is not a currently reliable method for clinical application in lung cancer. This application details testing and optimization of a novel nanoparticle-based system to overcome technical and biological hurdles encountered in lung cancer CTC measurement.


application_id: 8203674
project_number: 1R13CA162812-01
project_title: Side effects of Cancer Therapy: Chemobrain: Mechanisms & Assessments
administering_ic: NCI
award_notice_date: 2011-08-23
opportunity_number: PA-10-071
application_type: 1
activity_code: R13
ic: CA
serial_number: 162812
program_official: O'MARA, ANN M
project_start_date: 2011-09-01
project_end_date: 2012-08-31
study_section: Special Emphasis Panel[ZCA1 PCRB-G (P3)]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
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): Cancer therapy-induced injury to normal tissue is a major side effect experienced by cancer patients and is unfortunately an understudied area. The number of cancer survivors now exceeds 11 million in the US alone and the total number of survivors worldwide is constantly increasing. The University of Kentucky Markey Cancer Center Conference on the Side Effects of Cancer Therapy:Chemobrain: Mechanisms & Assessments will be held in Lexington Kentucky during October 12-14 2011 and will include an opening session with cancer survivors. Two prominent scientists in the area of cognition and memory Larry Squire from UCSD and James McGaugh from UC Irvine have agreed to be keynote speakers. The conference is sponsored by the Markey Cancer Center and is an international symposium bringing together a community of scientists physicians nurses health care professionals physicians and scientists-in-training in the area of clinical oncology. The objectives of the meeting are to coordinate exchange and disseminate information and to explore potential intervention. The focus will be the mechanisms of neuronal injury resulting from anticancer chemotherapeutic agents not directly targeting the brain strategies for assessments intervention strategies and possible translation from basic studies into clinical practice.  
  
PUBLIC HEALTH RELEVANCE: Cancer therapy-induced normal tissue injury is a major side effect experienced by cancer patients and is an understudied area. The number of cancer survivors now exceeds 11 million in the US alone. As such the need to provide health care that supports a high quality of life after cancer treatment has become a new health care challenge and injury to noncancerous tissue is in need of special attention. The University of Kentucky Markey Cancer Center Conference on Side Effects of Cancer Therapy: Chemobrain: Mechanisms & Assessments is a very timely and important topic for the benefit of patients. The conference will be held in Lexington Kentucky during October 12-14 2011 and will include an opening session with cancer survivors. The conference is an international symposium bringing together a community of clinicians and scientists in the area of cancer research and chemotherapy. The goals of the conference are to coordinate exchange and disseminate information and to explore novel strategies to diagnose and to prevent or minimize the neurological problems associated with chemotherapeutic drugs not directly targeting the brain.

project_terms:
Adverse effects;Area;Attention;Brain;Cancer Center;Cancer Patient;Cancer Survivor;Chemotherapy-Oncologic Procedure;Clinical;Clinical Oncology;Cognition;Collaborations;Communities;Data;Development;Diagnosis;Disease;Funding;Goals;Health Professional;Healthcare;Injury;International;Intervention;Kentucky;Knowledge;Life;Memory;Methodology;Minority;National Cancer Institute;Neurologic;Neuronal Injury;Normal tissue morphology;Nurses;Patients;Pharmaceutical Preparations;Physicians;Preventive;Publishing;Quality of life;Research;SEER Program;Scientist;Societies;Survivors;Therapeutic;Tissues;Training;Translations;Universities;Woman;anticancer research;base;cancer therapy;chemobrain;chemotherapeutic agent;clinical practice;experience;improved;meetings;member;novel strategies;prevent;success;symposium

public_health_relevance:
Cancer therapy-induced normal tissue injury is a major side effect experienced by cancer patients and is an understudied area. The number of cancer survivors now exceeds 11 million in the US alone. As such the need to provide health care that supports a high quality of life after cancer treatment has become a new health care challenge and injury to noncancerous tissue is in need of special attention. The University of Kentucky Markey Cancer Center Conference on Side Effects of Cancer Therapy: Chemobrain: Mechanisms & Assessments is a very timely and important topic for the benefit of patients. The conference will be held in Lexington Kentucky during October 12-14 2011 and will include an opening session with cancer survivors. The conference is an international symposium bringing together a community of clinicians and scientists in the area of cancer research and chemotherapy. The goals of the conference are to coordinate exchange and disseminate information and to explore novel strategies to diagnose and to prevent or minimize the neurological problems associated with chemotherapeutic drugs not directly targeting the brain.


application_id: 8202543
project_number: 1F31AG039208-01A1
project_title: Emotion regulation and self-regulation in older adults
administering_ic: NIA
award_notice_date: 2011-09-16
opportunity_number: PA-10-108
application_type: 1
activity_code: F31
ic: AG
serial_number: 039208
suffix: A1
program_official: NIELSEN, LISBETH
project_start_date: 2011-09-26
project_end_date: 2013-09-25
study_section: Special Emphasis Panel[ZRG1 F12A-R (20)]
contact_pi_person_id: 10423010
contact_pi: EVANS, DANIEL REID
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): Emotion regulation among older adults appears to be a relatively preserved capacity that is vital for wellbeing and successful aging. However the limits of this ability and the circumstances under which older adults might be less capable of regulating their emotions are unclear. Furthermore current theories that seek to explain how older adults regulate their emotions such as increased allocation of resources for emotion regulation or improved efficiency of emotion regulation have not been compared to each other. Therefore the aims of the proposed project are to 1) test the limits of older adults' emotion regulation capacity and 2) gain a better understanding of how older adults use their more limited resources to regulate their emotions. These aims are part of a long-term goal of producing a scientific knowledge base for improving the emotional health and wellbeing of older adults. The proposed project will use a paradigm from the strength model of self-regulation that posits a limited fatigable and common pool of self-regulatory resources that are drawn on by any act of self- regulation-controlling one's thoughts emotions and behaviors-such that performance on a subsequent but unrelated act of self-regulation tends to be impaired. An equal number of older and younger participants will be randomly assigned to one of four experimental groups involving an initial activity that is high or low in self- regulatory demand followed by a dependent task of emotion regulation or attention regulation. Comparing the performance of older and younger adults on the dependent emotion regulation task will provide results relevant to Aim 1. The proposed project will also include resting heart rate variability (HRV) a physiological measure that may provide an index of self-regulatory capacity. Examining the relationships between performance on the dependent self-regulation tasks and HRV will provide a measure of the extent to which participants are allocating self-regulatory resources for the different tasks results relevant to Aim 2. It is hypothesized that 1) older adults will perform better than younger adults on the emotion regulation task but worse on the attention regulation task and 2) older adults will allocate more resources than younger adults for the emotion regulation task. The proposed project would yield valuable information about the limits of emotion regulation in older adults provide more information about how older adults regulate their emotions and generate hypotheses for future research about the potential costs and benefits of different self-regulation strategies and priorities in older adults.  
  
PUBLIC HEALTH RELEVANCE: The ability to control one's emotions is important for wellbeing especially for older adults who experience declines in many other areas of physical and mental functioning. Older adults seem to maintain their ability to control their emotions well yet the limits of this ability and the way they are able to do this is unclear. Therefore this project seeks to test those limits and shed light on the strategies older adults use to control their emotions so that better interventions can be developed to improve the wellbeing and emotional health of older adults.

project_terms:
Affect;Aging;Area;Attention;Awareness;Behavior;Costs and Benefits;Elderly;Emotional;Emotions;Failure (biologic function);Fatigue;Goals;Health;Informal Social Control;Intervention;Life;Light;Literature;Maintenance;Measures;Modeling;Participant;Pattern;Performance;Physical Function;Physiological;Psyche structure;Randomized;Regulation;Resource Allocation;Resources;Rest;Role;Testing;Thinking function;Time;age group;base;emotion regulation;experience;heart rate variability;improved;indexing;knowledge base;theories;young adult

public_health_relevance:
The ability to control one's emotions is important for wellbeing especially for older adults who experience declines in many other areas of physical and mental functioning. Older adults seem to maintain their ability to control their emotions well yet the limits of this ability and the way they are able to do this is unclear. Therefore this project seeks to test those limits and shed light on the strategies older adults use to control their emotions so that better interventions can be developed to improve the wellbeing and emotional health of older adults.


application_id: 8201328
project_number: 1R43GM099206-01
project_title: Novel method to create knockout rats using endonucleases and spermatagonialstem
administering_ic: NIGMS
award_notice_date: 2011-09-05
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: GM
serial_number: 099206
program_official: MAAS, STEFAN
project_start_date: 2011-09-05
project_end_date: 2013-09-04
study_section: Special Emphasis Panel[ZRG1 IMST-J (15)]
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: 2011-09-05
budget_end_date: 2013-09-04
project_abstract:
DESCRIPTION (provided by applicant): The laboratory rat is the preferred rodent model in pre-clinical drug studies and encompasses the bulk of accumulated knowledge in drug development. Their larger size facilitates procedures otherwise difficult in mice including studies using instrumentation blood sampling and surgeries. Although rats are more suitable than mice for pharmacological toxicological physiological and many biological assays the absence of genetic engineering technologies suitable for use in the rat has made the mouse the preeminent rodent model. However the recent emergence of new and more precise gene targeting techniques for the rat has resulted in significant growth in the production of genetically modified rats which will undoubtedly expand at an exponential rate. A limiting factor in the adoption of genetically modified rats as the rodent model of choice has been the expensive inefficient and labor intensive manipulations required for their production resulting in costs as high as $50000 to $100000 per genetically modified rat line. Consequently it is essential to develop more viable technologies for rat genome engineering that result in more accurate efficient and cost-effective production of genetically modified rats. Transposagen Biopharmaceuticals Inc. is the worldwide leader in the generation of genetically modified rat models and is uniquely positioned to facilitate advancements in this field. Precision BioSciences develops custom genome engineering enzymes based on engineered homing endonucleases. This research proposal is a collaborative effort to merge the two technologies and test the feasibility of using engineered homing endonucleases as an extremely specific and efficient method to produce genetically modified rats. In Phase I we will attempt to knockout the rat Rag1 gene in spermatagonial stem cells (SSCs) using a Rag1-specific endonuclease. These modified cells will then be used to generate knockout Rag1 mutant rats. For comparison we will attempt to achieve the same result using conventional gene targeting methods in SSCs. The incorporation of an engineered endonuclease in SSCs should greatly streamlines the knockout rat production process Transposagen Biopharmaceuticals and Precision BioSciences will collaborate in a large-scale Phase II project to generate precisely engineered high-value rat models. Success in this project will significantly reduce the cost of transgenic rat production and give academic and industry investigators greater access to improved rodent models.  
  
PUBLIC HEALTH RELEVANCE: The laboratory rat has been a valuable animal model for biomedical research due to its similarity to human physiology. However the ease and lower costs associated with generating mutations in mice has lead to a greater reliance on genetically engineered mouse models despite the inability of many of these models to mimic human diseases. We outline a novel strategy that integrates our expertise in spermatogonial stem cells (SSCs) with a site-specific enzyme technology to increase efficiency of mutagenesis. We aim to establish an innovative transgenic rat service that will provide clients with a lower cost and more efficient alternative to the current genetically modified rat technology. Thus if feasibility is demonstrated this project would benefit many goals of public health by making the production of mutations in the rat that model human diseases readily accessible to the research community.

project_terms:
Adoption;Agreement;Animal Model;Biological Assay;Biological Products;Biomedical Research;Blood specimen;Cell Line;Cell Separation;Cells;Client;Clone Cells;Communities;Custom;DNA;DNA Double Strand Break;Deletion Mutation;Diphtheria Toxin;Embryo;Engineering;Enzymes;Event;Feasibility Studies;Female;Frameshift Mutation;Frequencies (time pattern);Gene Targeting;Generations;Genes;Genetic;Genetic Engineering;Genetic Recombination;Genetically Engineered Mouse;Genome engineering;Genomics;Goals;Growth;Homing;Hour;Human;In Vitro;Industry;Knock-out;Knowledge;Laboratory Animals;Laboratory Rat;Lead;Libraries;Licensing;Measures;Mediating;Methods;Microinjections;Modeling;Mus;Mutagenesis;Mutation;Neomycin;Operative Surgical Procedures;Pharmaceutical Preparations;Phase;Physiological;Physiology;Plasmids;Polymerase;Positioning Attribute;Procedures;Process;Production;RAG1 gene;Rag1 Mouse;Rat Cell Line;Rattus;Reliance;Research;Research Personnel;Research Proposals;Resistance;Rodent Model;Services;Site;Stem cells;Sterility;Study models;Techniques;Technology;Testing;Testis;Transfection;Transgenic Organisms;Transplantation;Validation;antibiotic G 418;arm;base;cost;cost effective;drug development;endonuclease;hepatoma cell;homologous recombination;human disease;improved;innovation;instrumentation;male;mouse model;mutant;new technology;novel;novel strategies;pre-clinical;public health medicine (field);pup;rat genome;success;transmission process;vector

public_health_relevance:
The laboratory rat has been a valuable animal model for biomedical research due to its similarity to human physiology. However the ease and lower costs associated with generating mutations in mice has lead to a greater reliance on genetically engineered mouse models despite the inability of many of these models to mimic human diseases. We outline a novel strategy that integrates our expertise in spermatogonial stem cells (SSCs) with a site-specific enzyme technology to increase efficiency of mutagenesis. We aim to establish an innovative transgenic rat service that will provide clients with a lower cost and more efficient alternative to the current genetically modified rat technology. Thus if feasibility is demonstrated this project would benefit many goals of public health by making the production of mutations in the rat that model human diseases readily accessible to the research community.


application_id: 8200711
project_number: 1R43HL110438-01
project_title: Sleep Apnea Diagnostic
administering_ic: NHLBI
award_notice_date: 2011-08-08
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: HL
serial_number: 110438
program_official: LEWIN, DANIEL S
project_start_date: 2011-08-09
project_end_date: 2012-07-31
study_section: Special Emphasis Panel[ZRG1 HDM-K (10)]
contact_pi_person_id: 7795913
contact_pi: HAHN, JEROME
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 829912182
duns_number: 829912182
fips: US
organization_id: 10024016
organization_name: TELEHEALTH HOLDINGS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071936
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-09
budget_end_date: 2012-07-31
project_abstract:
DESCRIPTION (provided by applicant): Sleep apnea is a common respiratory disorder during sleep which has significant individual healthcare system and societal impact. The current gold standard method for sleep apnea assessment is full night polysomnography (PSG). However its high cost inconvenience long waiting lines and immobility have persuaded researchers to seek simple and portable devices to detect sleep apnea. Our team has developed and reported on a new technology for sleep apnea- hypopnea detection and monitoring which only requires two data channels: tracheal breathing sounds and the SaO2 signal which have been found to be good representatives of the PSG-based apnea-hypopnea index (AHI) values. Concurrently our team has initiated evaluation of the association between apnea events and the body's sleeping position. Translating the method into a home-based diagnostic system represents a promising alternative to PSG. The end-point of this development and feasibility testing track will be an effective home-based technology-- non-intrusive and affordably priced for consumers - for individuals with mild to moderate apnea levels to be used through the night to identify when they are experiencing sleep-disturbing breathing problems.  
  
PUBLIC HEALTH RELEVANCE: Sleep apnea and sleep-related breathing problems represent a large and expanding public health problem as our population ages and obesity drives up prevalence. Current diagnostic and treatment gold standards are inadequate to address looming demands. We propose development and feasibility testing of a novel home-based technology-- non- intrusive and affordably priced for consumers - for individuals with mild to moderate apnea levels to be used through the night to identify apnea/hypopnea events.

project_terms:
Address;Affect;Age;Algorithms;Apnea;Blood;Boxing;Breathing;Clinic;Clinical;Complement;Continuous Positive Airway Pressure;Data;Detection;Development;Devices;Diagnosis;Diagnostic;Drops;Equipment;Evaluation;Event;Fingers;Forehead;Frequencies (time pattern);Gold;Head and neck structure;Health Technology;Healthcare Systems;Home environment;Hour;Individual;Legal patent;Link;Lung;Marketing;Masks;Measures;Methods;Monitor;Obesity;Obstructive Sleep Apnea;Oxygen;Participant;Patients;Performance;Persons;Phase;Physiologic pulse;Polysomnography;Population;Positioning Attribute;Prevalence;Price;Records;Reporting;Research;Research Personnel;Respiration Disorders;Respiratory Sounds;Sampling;Severities;Signal Transduction;Silver;Sleep;Sleep Apnea Syndromes;Sleep Disorders;Snoring;Societies;System;Techniques;Technology;Technology Assessment;Testing;Translating;Travel;Validation;Wireless Technology;Work;Wrist;base;body position;commercialization;consumer product;cost;cost effective;experience;improved;indexing;laptop;meetings;new technology;novel;programs;public health medicine (field);satisfaction;sensor;sleep position;sound;standard care;usability;user-friendly

public_health_relevance:
Sleep apnea and sleep-related breathing problems represent a large and expanding public health problem as our population ages and obesity drives up prevalence. Current diagnostic and treatment gold standards are inadequate to address looming demands. We propose development and feasibility testing of a novel home-based technology-- non- intrusive and affordably priced for consumers - for individuals with mild to moderate apnea levels to be used through the night to identify apnea/hypopnea events.


application_id: 8199961
project_number: 1R43AI096605-01
project_title: A transfollicular nanovaccine against leishmaniasis
administering_ic: NIAID
award_notice_date: 2011-07-20
opportunity_number: PA-10-123
application_type: 1
activity_code: R43
ic: AI
serial_number: 096605
program_official: MO, ANNIE X Y
project_start_date: 2011-07-20
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1 IMM-N (12)]
contact_pi_person_id: 6721291
contact_pi: GHOROGHCHIAN, PAIMAN PETER
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 808379072
duns_number: 808379072
fips: US
organization_id: 10020780
organization_name: VINDICO NANOBIOTECHNOLOGY, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405072003
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-07-20
budget_end_date: 2012-06-30
project_abstract:
DESCRIPTION (provided by applicant): The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually 2 million people are infected with Leishmania species and 270000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today with over 2500 U.S. military personnel diagnosed with cutaneous leishmaniasis (CL). Current non-immunization based treatments are variably effective highly toxic expensive and there are no vaccines in clinical use. Significant evidence has supported the role of the immune system in controlling Leishmania infection. Thus a vaccination remains an attractive disease prevention strategy. Two significant scientific knowledge gaps must be addressed: 1) a vaccine that can access the skin resident dendritic cells (DCs) and 2) the identification of Leishmania antigens that are biologically relevant in humans. Needle based vaccines bypass these immunopotent skin cells.  The long-term objective of this proposal is to develop a nanoscale polymersome-based vaccine that delivers an antigen and adjuvant to skin dendritic cells through transfollicular immunization (TFI). We will characterize the feasibility of integrating the Toll-like receptor 7/8 agonist resiquimod (RSQ) into the polymersome membrane and encapsulating a model Leishmania antigen Leishmania homolog of receptors for activated C kinase (LACK) into the aqueous core. We will then evaluate its functional properties in generating a TH1-type cytokine profile and functional cytotoxic CD8+ T cells in vivo. We hypothesize that co-encapsulation of LACK and RSQ into the nanovaccine can be achieved in a stepwise manner and that the resulting nanovaccine will penetrate the follicle and activate skin DCs. We also hypothesize that the topical administration of this nanovaccine will induce a LACK-specific T cell response. Finally we hypothesize that this nanovaccine will protect against challenge with a visceral Leishmania strain in a hamster model. AIM 1 Construct a nanovaccine encapsulating the antigen LACK and TLR7/8 agonist RSQ (LACK/RSQ-NPS). AIM 2 Determine the optimal physicochemical properties of LACK/RSQ-nanovaccine to penetrate the follicular duct activate skin DCs and induce a LACK-specific adaptive immune response. AIM 3 Determine if the LACK/RSQ-nanovaccine induces protective immune responses in vivo.  We anticipate the data generated from this proposal will result in a commercially viable topical nanovaccine that can access skin DCs via the transfollicular route. The NIAID supports basic preclinical and clinical research on immune-mediated diseases such as leishmaniasis and the development of effective vaccines. The aims proposed in this SBIR Phase I program are consistent with the mission statement of the NIAID.  
  
PUBLIC HEALTH RELEVANCE: The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually 2 million people are infected with Leishmania species and 270000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today. We plan to develop a nanovaccine against Leishmania that delivers the vaccine payload through the hair follicle duct to stimulate skin immune cells all without a needle. This major advance in Leishmania vaccine design may provide the first effective vaccine against Leishmania and would create biotechnology jobs in the US via US military contracts and international government contracts in countries suffering from leishmaniasis.

project_terms:
Activities of Daily Living;Address;Adjuvant;Affect;Agonist;Antibodies;Antigens;Area;Basic Science;Biotechnology;Bypass;CD8B1 gene;Cells;Child;Clinical;Clinical Research;Communicable Diseases;Conflict (Psychology);Contracts;Country;Cream;Cutaneous Leishmaniasis;Data;Dendritic Cells;Dendritic cell activation;Department of Defense;Development;Diagnosis;Disease;Dose;Drug Formulations;Duct (organ) structure;Encapsulated;Generations;Goals;Government;Hair follicle structure;Hamsters;Heating;Homologous Gene;Human;Immune;Immune response;Immune system;Immunity;Immunization;Infection;Infectious Skin Diseases;International;Killings;Kinetics;Knowledge;Lead;Leishmania (genus);Leishmaniasis;Life;Mediating;Membrane;Methods;Military Personnel;Mission;Modeling;Monitor;Mus;National Institute of Allergy and Infectious Disease;Needles;Occupations;Parasites;Parasitic Diseases;Pathway interactions;Penetration;Phase;Prevalence;Prevention strategy;Property;Regimen;Resolution;Risk;Rodent Model;Role;Route;Skin;Small Business Innovation Research Grant;Solubility;System;T cell response;T-Lymphocyte;TLR7 gene;Technology;Testing;Topical application;Translating;Vaccination;Vaccine Adjuvant;Vaccine Design;Vaccines;Visceral;Visceral Leishmaniasis;World Health Organization;aqueous;base;cancer prevention;cytokine;cytotoxic;design;disorder prevention;human TLR7 protein;immunogenic;in vivo;nanomaterials;nanoparticle;nanoscale;novel;pre-clinical research;programs;prophylactic;receptors for activated C kinase;resiquimod;subcutaneous;vaccine delivery

public_health_relevance:
The World Health Organization estimates that over 350 million people are at risk of developing leishmaniasis and infection prevalence is 14 million people in the world. Annually 2 million people are infected with Leishmania species and 270000 will die. Leishmaniasis is one of the most important parasitic diseases affecting the U.S. military today. We plan to develop a nanovaccine against Leishmania that delivers the vaccine payload through the hair follicle duct to stimulate skin immune cells all without a needle. This major advance in Leishmania vaccine design may provide the first effective vaccine against Leishmania and would create biotechnology jobs in the US via US military contracts and international government contracts in countries suffering from leishmaniasis.


application_id: 8199742
project_number: 3R21AA017937-02S1
project_title: Re-entry Alcohol Services for Rural Offenders
administering_ic: NIAAA
award_notice_date: 2011-01-06
opportunity_number: PA-08-008
application_type: 3
activity_code: R21
ic: AA
serial_number: 017937
suffix: S1
program_official: ROACH, DEIDRA
project_start_date: 2009-08-01
project_end_date: 2012-07-31
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;adverse outcome;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: 8199371
project_number: 1R43CA159527-01A1
project_title: Modulation of In Vivo Tumor Oxygenation via Polymersome-encapsulated Myoglobin
administering_ic: NCI
award_notice_date: 2011-09-26
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: CA
serial_number: 159527
suffix: A1
program_official: WEBER, PATRICIA A
project_start_date: 2011-09-27
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-D (13)]
contact_pi_person_id: 6721291
contact_pi: GHOROGHCHIAN, PAIMAN PETER
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 808379072
duns_number: 808379072
fips: US
organization_id: 10020780
organization_name: VINDICO NANOBIOTECHNOLOGY, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405072003
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-09-27
project_abstract:
DESCRIPTION (provided by applicant): Over 250000 new cases of head and neck cancers (HNCs) and non-small cell lung cancers (NSCLCs) are diagnosed every year in the United States. At the time of diagnosis 60% of these cases are regionally advanced (stage III and IV). Wide surgical excision is not the immediate therapeutic option for most of these locally advanced solid tumor malignancies. A number of studies have shown that a course of combined chemotherapy and radiotherapy also known as chemoradiotherapy (CRT) promises superior results over chemotherapy or radiation therapy alone. The ability of radiation to eradicate cancer cells depends critically upon the presence of molecular oxygen a potent radiosensitizer involved in mediating DNA damage. While low oxygen levels (hypoxia) has been recognized as a cause of treatment failure in solid tumors for more than 50 years previous attempts to improve tumor oxygenation including whole-body hyperbaric oxygen and systemic erythropoietin treatments have had limited success. Vindico NanoBioTechnology Inc. (Vindico) proposes to develop a novel nanoparticle-based therapeutic adjuvant that improves radiation and chemotherapy of HNCs NSCLCs as well as other solid tumor malignancies. The goal of this Phase I SBIR project is to create nanoparticle composites that exhibit the requisite in situ properties for safe and effective in vivo oxygen delivery. In colaboration with researchers from Duke University these agents will be tested for their ability to modulate in vivo tumor oxygenation. Subsequent Phase II work will generate crucial pre-clinical animal data regarding toxicity and the ability of these novel nanoparticles to augment radiotherapy.  
  
PUBLIC HEALTH RELEVANCE: The proposed project aims to utilize nanotechnology to deliver a natural protein that increases tumor oxygen levels. This research will have a major impact on public health by resulting in a novel agent that improves cancer radiation and chemotherapy. The end result wil be increased patient survival and an enhanced standard of care. Significant additional advantages include tremendous cost savings to the health care system in reduced operating and therapeutic costs as well as local job creation and economic stimulus.

project_terms:
Acute;Adjuvant;Aerobic;Affect;Binding (Molecular Function);Biodegradation;Blood Circulation Time;Boron;Caliber;Cell Proliferation;Characteristics;Chemistry;Collaborations;Cost Savings;Creatinine clearance measurement;DNA Damage;Development;Diagnosis;Distant;Drug Formulations;Drug Kinetics;Economics;Encapsulated;Equilibrium;Erythropoietin;Excision;Exhibits;Generations;Goals;Growth;Head Cancer;Head and Neck Cancer;Healthcare Systems;Hemoglobin;Human;Hyperbaric Oxygen;Hypertension;Hypoxia;Image;In Situ;Infusion procedures;Injection of therapeutic agent;Kinetics;Laboratories;Lead;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Metmyoglobin;Microcirculation;Molecular;Monitor;Mus;Myoglobin;Myoglobinuria;Nanotechnology;Neck Cancer;Nitric Oxide;Non-Small-Cell Lung Carcinoma;Occupations;Operative Surgical Procedures;Oxygen;Oxygen measurement partial pressure arterial;Particle Size;Patients;Pharmacodynamics;Phase;Polymers;Production;Property;Proteins;Radiation;Radiation Oncology;Radiation therapy;Radiation-Sensitizing Agents;Reporter;Research;Research Personnel;Resistance;Rhabdomyolysis;Site;Small Business Innovation Research Grant;Solid Neoplasm;Solutions;Staging;Stimulus;Structure;Suspension substance;Suspensions;System;TNFRSF5 gene;Tail;Testing;Therapeutic;Time;Tissues;Toxic effect;Treatment Failure;Tumor Oxygenation;United States;Universities;Vascular constriction (function);Veins;Vesicle;Viscosity;Weight;Work;animal data;base;cancer cell;cancer diagnosis;chemical stability;chemotherapy;cost;hyperthermia treatment;hypoxia inducible factor 1;immunogenicity;improved;in vivo;meetings;nanobiotechnology;nanoparticle;nanoscale;nephrotoxicity;novel;particle;pre-clinical;prevent;professor;public health medicine (field);response;standard of care;success;tumor;uptake

public_health_relevance:
The proposed project aims to utilize nanotechnology to deliver a natural protein that increases tumor oxygen levels. This research will have a major impact on public health by resulting in a novel agent that improves cancer radiation and chemotherapy. The end result wil be increased patient survival and an enhanced standard of care. Significant additional advantages include tremendous cost savings to the health care system in reduced operating and therapeutic costs as well as local job creation and economic stimulus.


application_id: 8199338
project_number: 2R44HD062065-02
project_title: Active Distributed Electrode Array Network for Electrical Stimulation Therapy
administering_ic: NICHD
award_notice_date: 2011-08-30
opportunity_number: PA-10-050
application_type: 2
activity_code: R44
ic: HD
serial_number: 062065
program_official: SHINOWARA, NANCY
project_start_date: 2009-08-01
project_end_date: 2013-08-31
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: 2011-09-01
budget_end_date: 2012-08-31
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 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 Active Distributed Electrode Array (ADEA) technology which offers two novel features that address these problems: network architecture and end-user programmability. With these features the ADEA system will be fully configurable (both in hardware and software) by the application developer (i.e. researcher specialized clinician or OEM company) to create application-specific stimulation/sensing networks and stimulation regimens. No end-user programming experience will be required. We successfully completed Phase I work including feasibility demonstration of the node concept. The goals of this Phase II SBIR project will be to develop clinically viable stimulation and sensing nodes an ADEA stimulator/controller module and an end-user programming suite and to demonstrate efficacy of the technology. The target markets for this device will be specialized clinics research groups and OEM companies. The target price for the system will be $3000 in volume for an 8-channel configuration (OEM market).  
  
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:
Address;Area;Characteristics;Clinic;Clinical;Clinical Research;Computer Architectures;Computer software;Data;Delaware;Development;Devices;Doctor of Philosophy;Electric Stimulation;Electrodes;Electromagnetics;Environment;Evaluation;Generic Drugs;Goals;Government;Human;Industry;Knowledge;Lead;Maintenance;Marketing;Muscle;Orthotic Devices;Performance;Phase;Physiologic pulse;Price;Progress Reports;Regimen;Rehabilitation Research;Rehabilitation therapy;Research;Research Personnel;Risk Management;Small Business Innovation Research Grant;Spinal cord injury;System;Technology;Testing;Therapeutic Intervention;Transcutaneous Electric Nerve Stimulation;Universities;Work;clinical application;clinical efficacy;commercial application;commercialization;cost;design;empowered;experience;improved;interest;meetings;novel;programs;prototype;public health medicine (field);research and development;research study;technology/technique;tool

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.


application_id: 8199298
project_number: 1R43DA032161-01
project_title: Transdermal Cannabidiol Prodrug Delivery
administering_ic: NIDA
award_notice_date: 2011-07-14
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: DA
serial_number: 032161
program_official: PARK, MOO KWANG
project_start_date: 2011-07-15
project_end_date: 2011-12-31
study_section: Special Emphasis Panel[ZRG1 MOSS-D (12)]
contact_pi_person_id: 1866585
contact_pi: STINCHCOMB, AUDRA L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178031683
primary_uei: EKBZRSBPS8A3
duns_number: 178031683
uei: EKBZRSBPS8A3
fips: US
organization_id: 10006751
organization_name: ALLTRANZ, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs) alcohol abuse is among the top three preventable public health problems in the U.S. and the world. AUDs commonly referred to as alcoholism have a complex etiology where chronic alcohol associated neurodegeneration withdrawal-related anxiety and persistent alcohol craving are predictive of high relapse and poor clinical outcomes. The treatment of AUDs would benefit from a pharmacological approach that could address these overlooked endpoints to improve clinical outcomes. However of the three drugs currently FDA-approved for the treatment of excessive alcohol consumption none address neurodegeneration withdrawal or anxiety. Cannabidiol (CBD) is a drug that could improve these three syndromes.  Transdermal drug delivery of cannabinoids is a viable alternative to oral dosing. Most of the cannabinoids are highly metabolized in the liver. The oral bioavailability of CBD is only about 6% and very low plasma drug levels were detected in CBD oral dose clinical trials. It is highly possible that clinical trials of oral dose cannabinoids in patients have given inconsistent results because of a poor choice of drug dosage form. We hypothesize that a CBD transdermal dosage form can be developed and that this dosage form could provide therapeutic levels of drug in a future clinical study with alcoholic patients. The long-term hypothesis of the overall project is that CBD will decrease withdrawal related anxiety and control alcohol craving thereby decreasing high relapse susceptibility in alcoholics by modulating the endocannabinoid system. In the first step towards this goal a proof of concept evaluation of CBD prodrugs delivered via transdermal microneedles will be conducted. CBD itself does not permeate the skin at a therapeutic rate unless it is applied as a gel to a large skin surface area as the area of transdermal application is directly proportional to the delivery rate. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. AllTranz has preliminary data showing that CBD prodrugs alone do not improve skin permeation unless the prodrugs are specifically designed for use with microneedles. Additionally CBD delivery with microneedles alone is not significantly enhanced as compared to optimized CBD prodrugs for microneedle delivery. Specifically we aim to synthesize prodrugs of CBD that will be very skin permeable in combination with a microneedle device. We then aim to assess their in vitro human skin permeation for optimum flux. In future studies we will develop the prototype product and apply for an IND and begin Phase I clinical trials in healthy controls and alcoholics. The future CBD transdermal system could also be tested in Phase II clinical trials for opiate addiction analgesic effect inflammation relief (arthritis) and nausea and vomiting treatment as there is substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications.  
  
PUBLIC HEALTH RELEVANCE:   
With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs) alcohol abuse is among the top three preventable public health problems in the U.S. and the world. Currently approved pharmacological treatments in the treatment of alcoholism and other types of drug addiction are limited in that they do not address multiple aspects of addiction: craving neurodegeneration withdrawal and anxiety. The proposed preclinical research will accelerate testing of cannabidiol (CBD) in an appropriate delivery system to assess its potential benefits as a lead candidate in the search for novel alcoholism and other drug addiction pharmacotherapies. The future CBD transdermal system could also be tested in Phase II clinical trials for analgesic effect inflammation relief and nausea and vomiting treatment as there is also substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications.

project_terms:
Address;Adverse effects;Affect;Alcohol abuse;Alcoholism;Alcohols;Analgesics;Anti-Anxiety Agents;Anticonvulsants;Anxiety;Area;Arthritis;Back;Behavior;Biological Availability;Brain;Bypass;Cannabidiol;Cannabinoids;Chronic;Clinical;Clinical Data;Clinical Research;Clinical Trials;Cognitive deficits;Complex;Data;Dependence;Development;Devices;Diagnostic;Diffusion;Dosage Forms;Dose;Drug Addiction;Drug Delivery Systems;Drug Formulations;Endocannabinoids;Ethanol;Etiology;Evaluation;FDA approved;Feces;Future;Gastrointestinal tract structure;Gel;Genetic;Goals;Heavy Drinking;Human;In Vitro;Inflammation;Intake;Intoxication;Lead;Liver;Metabolism;Methods;Modeling;Naltrexone;Nausea and Vomiting;Nerve Degeneration;Neuroprotective Agents;Opiate Addiction;Oral;Outcome;Parents;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacological Treatment;Phase I Clinical Trials;Phase II Clinical Trials;Plasma;Play;Population;Predisposition;Process;Prodrugs;Property;Relapse;Rewards;Role;Route;Skin;Solubility;Stratum corneum;Surface;Syndrome;System;Testing;Therapeutic;Transdermal substance administration;Withdrawal;absorption;acamprosate;addiction;alcohol craving;alcohol reward;alcohol use disorder;alcoholism therapy;binge drinking;craving;design;drinking;drug addiction pharmacotherapy;drug withdrawal;executive function;experience;gastrointestinal;improved;meetings;neurotoxicity;novel;pre-clinical;pre-clinical research;problem drinker;progressive neurodegeneration;prototype;public health medicine (field);success;theories

public_health_relevance:
With over 8.5% of the U.S. population and 75 million people worldwide meeting the diagnostic criteria for alcohol use disorders (AUDs) alcohol abuse is among the top three preventable public health problems in the U.S. and the world. Currently approved pharmacological treatments in the treatment of alcoholism and other types of drug addiction are limited in that they do not address multiple aspects of addiction: craving neurodegeneration withdrawal and anxiety. The proposed preclinical research will accelerate testing of cannabidiol (CBD) in an appropriate delivery system to assess its potential benefits as a lead candidate in the search for novel alcoholism and other drug addiction pharmacotherapies. The future CBD transdermal system could also be tested in Phase II clinical trials for analgesic effect inflammation relief and nausea and vomiting treatment as there is also substantial preclinical/clinical data with CBD to justify therapeutic utility for these indications.


application_id: 8198255
project_number: 1R43EY021940-01
project_title: Implantable Optical Intraocular Pressure Sensor for Improved Glaucoma Treatment
administering_ic: NEI
award_notice_date: 2012-03-09
opportunity_number: PA-10-050
application_type: 1
activity_code: R43
ic: EY
serial_number: 021940
program_official: WUJEK, JEROME R
project_start_date: 2012-04-01
project_end_date: 2014-03-31
study_section: Special Emphasis Panel[ZRG1 ETTN-E (12)]
contact_pi_person_id: 8625040
contact_pi: HASTINGS, JEFFREY TODD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964829142
primary_uei: ZJUUV8RMN287
duns_number: 964829142
uei: ZJUUV8RMN287
fips: US
organization_id: 10027679
organization_name: BROCKMAN-HASTINGS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
Brockman-Hastings LLC seeks to reduce vision loss for glaucoma sufferers by creating a simple accurate and clinically acceptable sensor for monitoring intraocular pressure (IOP). Trends indicate that by 2020 approximately 80 million people worldwide will have glaucoma 11 million of whom will become completely blind. Elevated IOP remains the key risk factor and treated symptom for glaucoma and ophthalmologists routinely measure IOP during office visits. However infrequent single point measurements are insufficient to fully characterize and manage the disease and infrequent measurements make it difficult to assess the effectiveness of pharmaceutical or surgical treatments. To address this problem several research groups have developed implantable intraocular pressure sensors; yet these devices have proven too large complex inaccurate and/or high risk for rapid clinical adoption. In contrast to these devices the Brockman-Hastings  sensor concept does not include any implanted microelectronic circuitry or external or internal power sources. Instead the system relies on the reflection of light from the sensor s active region (smaller than one square millimeter). A hand held or eye-glass-mounted readout unit emits and captures an infrared signal that is reflected off the sensor to measure IOP. The simplicity of our sensor minimizes its physical size providing for an aesthetic implant and allowing for a simple and reversible implantation procedure. The long-term goal of the project is to reduce vision loss by providing physicians with highly accurate long-term IOP measurements on which to base treatment decisions and assess treatment effectiveness. Our Phase I hypothesis is that an optical IOP sensor implanted in the anterior chamber of the rabbit eye will provide IOP measurements with sufficient accuracy for glaucoma management and will be well tolerated during implantation for one month. Our specific aims are (1) to demonstrate <1 mmHg sensing accuracy in a simulated physiological environment and (2) to demonstrate <2 mmHg sensing precision and one month tolerability in a rabbit model of glaucoma. Successfully accomplishing these aims will lay the foundation for Phase II an evaluation of sensor accuracy and tolerability in a longer term (1-2 year) and larger scale animal study along with FDA pre-clinical testing. Successful commercialization of such a device could ultimately benefit millions of glaucoma patients especially those that could immediately combine the sensor implantation with another non-laser based eye surgery. Even this narrower market encompasses ~100000 glaucoma patients per year in the U.S. alone.  
  
PUBLIC HEALTH RELEVANCE:   
Trends indicate that by 2020 there will be &#8776; 80 million people worldwide with glaucoma 11 million of whom will become blind. Vision loss could be reduced if more frequent and longer term intraocular pressure monitoring were available to glaucoma patients and their physicians. In this SBIR Brockman- Hastings LLC will validate the accuracy and tolerability of a simple reversibly implantable sensor that allows such measurements and thus provide better data for managing glaucoma.

project_terms:
Address;Adoption;Agreement;Animal Model;Animals;Biocompatible Materials;Blindness;Cataract Extraction;Clinical;Clinical Trials;Complex;Compliance behavior;Cornea;Corneal Endothelium;Data;Development;Device Designs;Devices;Disease;Effectiveness;Electronics;Elements;Ensure;Environment;Esthetics;Evaluation;Eye;Foundations;Glass;Glaucoma;Goals;Gold;Hand;Histology;Hour;Implant;Implantation procedure;In Vitro;Joints;Knowledge;Laboratories;Lasers;Lead;Light;Longitudinal Studies;Manufacturer Name;Marketing;Measurement;Measures;Medical Device;Microscopy;Modeling;Monitor;Office Visits;Operative Surgical Procedures;Ophthalmic examination and evaluation;Ophthalmologic Surgical Procedures;Ophthalmologist;Optics;Oryctolagus cuniculus;Patients;Performance;Pharmacologic Substance;Phase;Physicians;Physicians' Offices;Physiologic Intraocular Pressure;Physiological;Plant Roots;Power Sources;Preclinical Testing;Reading;Recovery;Reproducibility;Research;Risk;Risk Factors;Signal Transduction;Simulate;Site Visit;Small Business Innovation Research Grant;Specialist;Surgical Management;Symptoms;System;Technology;Thick;Third-Party Payer;Transducers;Treatment Effectiveness;Vacuum;Visual;Visual impairment;anterior chamber;base;biomaterial compatibility;blind;commercial application;commercialization;cost;design;digital;experience;high intraocular pressure;high risk;image processing;implantation;implanted sensor;improved;millimeter;novel;novel strategies;optic imaging;pressure;prevent;prototype;research clinical testing;scale up;seal;sensor;tonometry;trend

public_health_relevance:
Trends indicate that by 2020 there will be &#8776; 80 million people worldwide with glaucoma 11 million of whom will become blind. Vision loss could be reduced if more frequent and longer term intraocular pressure monitoring were available to glaucoma patients and their physicians. In this SBIR Brockman- Hastings LLC will validate the accuracy and tolerability of a simple reversibly implantable sensor that allows such measurements and thus provide better data for managing glaucoma.


application_id: 8197930
project_number: 5R44AG035410-03
project_title: Generating Blood-based Diagnosis for Alzheimer Disease
administering_ic: NIA
award_notice_date: 2011-12-30
opportunity_number: PA-09-080
application_type: 5
activity_code: R44
ic: AG
serial_number: 035410
program_official: HSIAO, JOHN
project_start_date: 2010-04-15
project_end_date: 2013-11-30
study_section: Special Emphasis Panel[ZRG1-IMST-E(15)B]
contact_pi_person_id: 1860379
contact_pi: WANG, EUGENIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 805479370
primary_uei: KPMEKJJTDUS5
duns_number: 805479370
uei: KPMEKJJTDUS5
fips: US
organization_id: 10020610
organization_name: ADVANCED GENOMIC TECHNOLOGY, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416052
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The present lack of blood-based diagnosis requires AD patients to be subjected to either invasive spinal fluid (CSF) tapping expensive MRI or PET imaging or arduous psychological testing all unsuitable and costly for our elderly. Strategically we shall address this unmet need by generating systemic biomarkers detectable in peripheral mononuclear cells (PBMC) and serum/plasma focusing on two classes of molecules micro- RNAs and their target genes which generally exhibit an inverse relationship because the former noncoding RNA functions by partially repressing the latter"s expression as a "dimmer switch" via binding either at the co- ding region of the message thus degrading it or at the 3"-untranslated region to inhibit translation. Thus key microRNAs and their targets can serve as disease biomarkers in "see-saw" balance applicable for new diagnostics and/or therapy. Our pilot study with a small cohort of 16 AD and 16 age-matched normal elderly controls (NEC) revealed: 1. Predominant down-regulation of gene expression at the message level in AD PBMC; and 2. Correlated up-regulation of microRNA (miR) expression in PBMC of the same individuals. In this proposal we focus on a specific up-regulated microRNA miR-34a whose known targets are SIRT1 cdk4 cdk6 cyclin E2 bcl2 etc. SIRT1 is a member of the 7-member Silent Information Regulator protein family. Caloric restriction extends longevity through triggering expression of SIRT1 which can also be mimicked by resveratrol a red wine polyphenol. SIRT1 reduction is linked to accumulation of Tau and A242 production two hallmarks of AD etiopathogenesis. Thus we suggest that in AD there is a systemic effect detectable in PBMC and serum/plasma; up-regulated miR-34a may induce down-regulation of SIRT1 with attendant pathophysiologic results. In this proposal we plan to generate for this "see-saw" of changes miR-34a/SIRT1 Target Pair Ratio (TPR) indices to quantify both disease presence as well as progress; the indices should also provide an unprecedented evaluation of drug efficacy. This Fast-track proposal of two phases is planned with our existing small cohort study as the roadmap for the larger cohort investigation: Phase I of six months with our existing small 16 AD and 16 NEC sample cohorts to: Aim 1. study possible down-regulation of miR-34a"s known targets; and Aim 2. develop a feasibility study of pilot miR-34a/SIRT1 TPR-indices; and Phase II of two years with larger cohorts of 200 AD and 200 NEC participants: Aim 1.Establish a Bio-Repository of PBMC-DNA -RNA & -protein specimens and serum/plasma samples for assays in Aims 2 & 3; Aim 2. Generate PBMC-based miR34a/SIRT1 (& other targets) TPR indices; and Aim 3. Perform feasibility study to develop serum/plasma-based miR- 34a/SIRT1-TPR indices. Success of this project will allow us to generate PBMC- and serum-based miR-TPR indices as personalized diagnostics for AD victims meeting an urgent need in health care a huge gain for disease victims their caregivers and our society at large.    PUBLIC HEALTH RELEVANCE:  At present the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patients to enduring arduous neuropsychological testing invasive cerebrospinal fluid tapping and/or expensive MRI or PET imaging with definitive diagnosis deferred until brain autopsy. Our preliminary findings based on new science concerning a novel molecular species microRNAs (miR) and their "see-saw" partial repression of the expression of their target gene(s) suggest that potential disease biomarkers for AD are detectable systemical- ly in peripheral blood mononuclear cells and/or serum/plasma and may be quantified as miR-Target Pair Ra- tios (TPR). Our plan is to define AD-specific TPR indices initially focusing on miR-34a and its target SIRT1 whose reduction is known to be associated with increased Tau and A242 two hallmarks of AD etiopathogene- sis; our ultimate goal is a "Tool-Box" of TPR indices miR-34a/SIRT1-TPR being the first such AD diagnostic indicating not only disease presence but also its progress (and even drug efficacy monitoring) a huge strate- gic gain for the victims of this costly disease and our society at large!

project_terms:
3' Untranslated Regions;Address;Age;Aging;Alzheimer's Disease;Apoptosis;Autopsy;Back;Binding (Molecular Function);Biogenesis;Biological Assay;Blood;Boxing;Brain;Brain Pathology;CDK4 gene;Caloric Restriction;Caregivers;Cell Cycle;Cells;Cerebrospinal Fluid;Code;Cohort Studies;DNA;DNA Repair;Deacetylase;Diagnosis;Diagnostic;Disease;Down-Regulation;Elderly;Equilibrium;Evaluation;Exhibits;Family;Feasibility Studies;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Targeting;Genes;Genetic Transcription;Genotoxic Stress;Goals;Healthcare;Homeostasis;Individual;Investigation;Investments;Knowledge;Lead;Link;Longevity;Magnetic Resonance Imaging;MicroRNAs;Modeling;Molecular;Molecular Profiling;Monitor;Mononuclear;Neurofibrillary Tangles;Neuropsychological Tests;Oxidation-Reduction;Oxidative Stress;Participant;Patients;Peripheral;Peripheral Blood Mononuclear Cell;Phase;Physiological;Pilot Projects;Plasma;Positron-Emission Tomography;Printing;Production;Protein Family;Proteins;Psychological Tests;RNA;Repression;Research;Resveratrol;Risk;Sampling;Science;Screening procedure;Senile Plaques;Serum;Signal Transduction;Societies;Specimen;Stress;Synapses;Testing;Translations;Untranslated RNA;Up-Regulation (Physiology);Work;amyloid precursor protein processing;base;biomarker;cohort;cyclin E2;drug efficacy;feeding;foot;gene repression;indexing;interest;meetings;member;novel;novel diagnostics;polyphenol;protein expression;public health relevance;red wine;repository;response to injury;senescence;success;tau Proteins;tau aggregation;tool;trend

public_health_relevance:
Project Title: "Generating Blood-based Diagnosis for Alzheimer's Disease" At present the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patientsto enduring arduous neuropsychological testing invasive cerebrospinal fluid tapping and/or expensive MRI orPET imaging with definitive diagnosis deferred until brain autopsy. Our preliminary findings based on newscience concerning a novel molecular species microRNAs (miR) and their "see-saw" partial repression of theexpression of their target gene(s) suggest that potential disease biomarkers for AD are detectable systemical-ly in peripheral blood mononuclear cells and/or serum/plasma and may be quantified as miR-Target Pair Ra-tios (TPR). Our plan is to define AD-specific TPR indices initially focusing on miR-34a and its target SIRT1whose reduction is known to be associated with increased Tau and A42 two hallmarks of AD etiopathogene-sis; our ultimate goal is a "Tool-Box" of TPR indices miR-34a/SIRT1-TPR being the first such AD diagnosticindicating not only disease presence but also its progress (and even drug efficacy monitoring) a huge strate-gic gain for the victims of this costly disease and our society at large!


application_id: 8197875
project_number: 5R25ES016248-05
project_title: Summer Education Experience for Research
administering_ic: NIEHS
award_notice_date: 2011-12-01
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: 2014-11-30
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:
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 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. We will work with experienced faculty from the UPR to identify and recruit students for the SEER in 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-min 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;Hispanics;Interview;Joints;Kentucky;Laboratories;Mentors;Molecular;Mutagenesis;National Institute of Environmental Health Sciences;Oxidative Stress;Puerto Rico;Recruitment Activity;Research;Research Project Grants;Schools;Series;Students;Superfund;Time;Toxic effect;Toxicology;Training;Transcript;Universities;Work;career;design;education planning;experience;graduate student;interest;medical specialties;programs;responsible research conduct;satisfaction;skills;symposium;undergraduate student;university student

public_health_relevance:
This research education plan is designed to provide a research experience for undergraduate students from the University of Puerto Rico at a critical time of career decision-making and to develop their research skills and expose them to the potential and excitement of research careers. The long-term goal is attract Hispanic students into research careers in the environmental health sciences.


application_id: 8197775
project_number: 5R01NS055228-05
project_title: Multiple circadian oscillators: Regulation of a neuroendocrine rhythm
administering_ic: NINDS
award_notice_date: 2011-11-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: NS
serial_number: 055228
program_official: HE, JANET
project_start_date: 2007-12-15
project_end_date: 2014-05-31
study_section: Special Emphasis Panel[ZRG1-IFCN-D(02)M]
contact_pi_person_id: 1891761
contact_pi: DUNCAN, MARILYN J.
other_pis: LEGAN, SANDRA J.
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
project_abstract:
DESCRIPTION (provided by applicant): Exciting recent studies have demonstrated autonomous circadian oscillators in many regions outside of the suprachiasmatic nucleus (SCN) the site of the mammalian master circadian pacemaker. The existence of multiple oscillators had been postulated for decades as a basis for the desynchrony of overt circadian rhythms that occurs during shift work jet lag and depression. These extra-SCN oscillators have been studied mainly in vitro using tissues explanted from males; thus the physiological role of these oscillators is not yet known especially in females. We propose to investigate the regulation of circadian rhythms in clock gene expression in vivo in female neuroendocrine cells the gonadotropin releasing hormone (GnRH) neurons because they have an easily measured physiologically important output the preovulatory luteinizing hormone (LH) surge. Although the LH surge depends on the SCN the GnRH neurons themselves express the circadian clock gene Per1. Furthermore immortalized GnRH neurons GT1-7 cells exhibit circadian rhythms of clock gene expression in vitro. Disruption of these molecular circadian rhythms in GT1-7 cells alters their pattern of GnRH secretion suggesting that molecular circadian clocks are necessary for the  
secretory function of GnRH neurons. This proposal aims to study the regulation and function of a circadian molecular oscillation in native GnRH neurons in female hamsters. The specific aims are to investigate:  
  
Aim 1) the role of circadian phase advances in control of the LH surge Aim 2) the role of SCN GABA-A receptors in control of the LH surge Aim 3) the role of circadian clock genes in the SCN in control of the LH surge Aim 4) the role of vasopressin as an output signal from the SCN regulating GnRH neurons and Aim 5) the expression of PER1 in endogenous GnRH neurons and its role in the LH surge. These studies will exploit the GnRH neurons as a model system with an essential physiological role and easily measured output in order to elucidate the regulation and function of an extra-SCN brain oscillator in vivo.   
  
Understanding multiple oscillators is important for the amelioration of internal desynchrony of circadian rhythms that occurs during shift work and jet lag. Also by studying females the findings of this project may be relevant to the disruptions in circadian hormone rhythms seen in women with affective disorders.This project seeks to understand the regulation and interaction of multiple circadian oscillators that regulate circadian neuroendocrine rhythms. Understanding multiple circadian oscillators is important for amelioration of circadian rhythms desynchrony which occurs during shift work jet lag aging and depression and increases the risk of obesity cardiovascular disease cognitive deficits and depression.  
  
Because this project focuses on females the findings will also be relevant to disruptions in circadian hormone rhythms seen in women with affective disorders such as pre-menstrual dysphoric syndrome post-partum depression and postmenopausal depression.

project_terms:
Acute;Address;Affect;Aging;Animals;Area;Barbiturates;Biological Assay;Biological Models;Blood specimen;Brain;Budgets;Calendar;Cardiovascular Diseases;Categories;Cells;Circadian Rhythms;Cognitive deficits;Critiques;Data;Distal;Effectiveness;Estradiol;Exhibits;Female;GABA-A Receptor;Gene Expression;Genes;Gonadotropin Hormone Releasing Hormone;Hamsters;Hormones;Immunohistochemistry;In Vitro;Injection of therapeutic agent;Jet Lag Syndrome;Lead;Lesion;Luteinizing Hormone;Measurement;Measures;Medial;Mental Depression;Messenger RNA;Microdialysis;Molecular;Mood Disorders;Neuroendocrine Cell;Neurons;Neuropeptides;Neurosciences;Neurosecretory Systems;Norepinephrine;Outcome;Output;Pattern;Peptides;Phase;Phenobarbital;Physiological;Postmenopause;Postpartum Depression;Preoptic Areas;Principal Investigator;Proteins;Protocols documentation;Published Comment;Rattus;Recovery;Regulation;Role;Signal Transduction;Site;Synapses;Syndrome;Third ventricle structure;Time;Tissues;Translating;Vasopressins;Wages;Woman;barbituric acid salt;base;circadian pacemaker;cost;design;in vivo;mRNA Expression;male;neurotransmitter release;obesity risk;organum vasculosum of the lamina terminalis;prevent;professor;programs;research study;shift work;suprachiasmatic nucleus


application_id: 8197685
project_number: 5R03AI092170-02
project_title: Novel activities and the T. gondii vacuolar membrane
administering_ic: NIAID
award_notice_date: 2011-11-16
opportunity_number: PA-10-064
application_type: 5
activity_code: R03
ic: AI
serial_number: 092170
program_official: MCGUGAN, GLEN C
project_start_date: 2010-12-01
project_end_date: 2013-06-30
study_section: Special Emphasis Panel[ZRG1-IDM-B(02)M]
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:
DESCRIPTION (provided by applicant): The protozoan parasite Toxoplasma gondii is an important opportunistic parasite causing life threatening infections in the immune compromised and severe birth defects when acquired in utero. The parasite grows within a specialized compartment the parasitophorous vacuole (PV) within the infected host cell. The boundary defining this niche is the PV membrane (PVM) that serves as the interface between the parasite and host. Despite its importance investigation of the PVM has been limited. We have recently completed a proteomic analysis of the T. gondii PVM resulting in the identification of 123 proteins of which 70 appear to be novel. Of these novel proteins 26 are annotated as "hypothetical ORF's" precluding any assignment of function. As hypothetical ORF's these loci lack any identifiable motif indicating they are truly novel. While several appear unique to Toxoplasma others have similarly annotated homologs in other less tractable Apicomplexa including Plasmodium and Cryptosporidium spp. suggesting conserved function. As novel proteins that are potentially localized to the PVM an organelle found only in the context of parasite infection these hypothetical ORF's represent potentially unique activities that may serve as drug targets. In this study we exploit recently developed technologies to epitope tag and localize the hypothetical ORF's as a prelude to cloning the validated genes and attempting the gene knockouts. Together these studies represent a secondary analysis of an existing data set as a limited short term project with a high potential of revealing novel activities. As such it is ideally suited to the RO3 funding mechanism. With this proposal we aim to perform the initial characterization of these orphan genes toward establishing their functions in parasite biology.    PUBLIC HEALTH RELEVANCE: Toxoplasma gondii causes serious illness in immune compromised individuals and is a model organism for several less experimentally tractable parasites. This study aims to investigate truly novel proteins that were identified as being components of the parasitophorous vacuole membrane a unique and essential parasite organelle. We expect with the completion of this work to open new areas of investigation in parasite biology.

project_terms:
Acute;Address;Affinity;Animal Model;Antigens;Apicomplexa;Area;Biochemical;Bioinformatics;Biological;Biological Process;Biology;Cells;Cellular biology;Cloning;Complex;Congenital Abnormality;Coupled;Cryptosporidium;Cyst;Cytoskeleton;Data Set;Development;Drug Delivery Systems;Employment;Endoplasmic Reticulum;Epitopes;Expression Library;Fibroblasts;Funding Mechanisms;Gene Targeting;Genes;Genome;Grant;Heart;Homologous Gene;Immune;Immune Sera;In Situ;Individual;Infection;Investigation;Length;Life;Manuscripts;Membrane;Methods;Mitochondria;Molecular;Molecular Biology;Nutrient;Open Reading Frames;Organelles;Orphan;Oryctolagus cuniculus;Parasites;Plasmodium;Preparation;Proteins;Proteome;Proteomics;Reagent;Resources;Rewards;Risk;Role;Screening procedure;Signal Transduction;System;Technology;Toxoplasma;Toxoplasma gondii;Vacuole;Work;base;biological systems;cDNA Expression;gene function;genome-wide;in utero;insight;interest;knockout gene;novel;parasite genome;pathogen;public health relevance;stem

public_health_relevance:
Project NarrativeToxoplasma gondii causes serious illness in immune compromised individuals and is a model organism forseveral less experimentally tractable parasites. This study aims to investigate truly novel proteins that wereidentified as being components of the parasitophorous vacuole membrane a unique and essential parasiteorganelle. We expect with the completion of this work to open new areas of investigation in parasite biology.


application_id: 8197417
project_number: 5R01HL062846-08
project_title: Sources and effects of angiotensin peptides in atherosclerosis
administering_ic: NHLBI
award_notice_date: 2011-11-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 062846
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2000-09-20
project_end_date: 2013-11-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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): This is a revised application for which we have now developed the mice that were requested in the previous reviews: floxed angiotensinogen and AT1a receptors. Therefore all the critical reagents to the proposed studies are now available. Evidence has evolved primarily in the last decade demonstrating that the renin angiotensin system (RAS) has a profound effect on atherogenic mechanisms. However many questions remain regarding the origin of the bioactive peptides and the mechanisms of the effects. Based on the findings of the previously funded period and others the focus of the proposed research is to determine the relative importance of the systemic versus local RAS to the development of atherosclerosis. The central hypothesis of this proposal is that macrophage-derived RAS components are responsible for the local generation of angiotensin peptides that propagate atherosclerosis primarily via stimulation of AT1a receptors expressed on endothelial cells. To determine the validity of this hypothesis the following specific aims are proposed. Aim 1: Determine the contribution of angiotensinogen from the liver (systemic) versus macrophages (local) to lesion size and characteristics of hypercholesterolemia-induced atherosclerosis. Aim 2: Determine the contribution of ACE1 and ACE2 expression on bone marrow-derived cells to the development of atherosclerotic lesion size and characteristics. Aim 3: Determine the cellular location of AT1a receptor expression that influences the atherogenic process.    PUBLIC HEALTH RELEVANCE: Atherosclerotic diseases are the major cause of morbidity and mortality in the US population. Therefore investigations to prevent these diseases have vast public health implications.

project_terms:
Abdominal Aortic Aneurysm;Adhesions;Aneurysm;Angiotensin II;Angiotensinogen;Angiotensins;Area;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Bone Marrow;Breeding;Cells;Characteristics;Chemicals;Data;Development;Diet;Disease;Endothelial Cells;Enzymes;Funding;Generations;Genetic;Hepatocyte;In Vitro;Inflammatory;Investigation;Laboratories;Lesion;Liver;Location;Low Density Lipoprotein Receptor;Morbidity - disease rate;Mortality Vital Statistics;Mus;Pathology;Peptides;Population;Process;Production;Promotor (Genetics);Reagent;Relative (related person);Renin;Renin-Angiotensin System;Reporting;Research;Role;Series;Smooth Muscle Myocytes;Source;Tissues;Uncertainty;aortic arch;base;blood pressure regulation;cell type;enzyme deficiency;feeding;hypercholesterolemia;insight;macrophage;monocyte;prevent;public health medicine (field);public health relevance;receptor;receptor expression;saturated fat

public_health_relevance:
Atherosclerotic diseases are the major cause of morbidity and mortality in the USpopulation. Therefore investigations to prevent these disease have vast public healthimplications.


application_id: 8197357
project_number: 5R01HL088989-05
project_title: Role of B cells in host defense against Pneumocystis
administering_ic: NHLBI
award_notice_date: 2011-11-18
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: 2013-11-30
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:
Acquired Immunodeficiency Syndrome;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;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: 8197237
project_number: 5R01HL074351-08
project_title: Hypercholesterolemia in Cardiac Function Survival and Repair
administering_ic: NHLBI
award_notice_date: 2011-12-09
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: 2013-11-30
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:
Project Summary AbstractMounting mechanistic and translational studies support the use of cell-based therapies to repair myocardialtissue destroyed by infarction and to restore cardiac function. Several phenotypically distinct subsets of adultprimitive cell populations have been shown to improve cardiac structure and function in animal models ofmyocardial infarction (MI) and heart failure. Small clinical trials of stem cell therapy have recapitulated thesebeneficial effects in patients with ischemic cardiomyopathy. Recent discovery of cardiac stem cells (CSCs) hassparked intense hope for the development of promising stem cell therapies for cardiac repair/regenerationbecause CSCs are inherently programmed to reconstitute cardiac tissue. In recent studies we found thatintracoronary delivery of CSCs to rats with either acute or chronic MI and to pigs with chronic MI amelioratedcardiac function and regenerated new cardiac cells. However human patients needing cardiac reparativetherapies 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 tounderstand the impact of these risk factors on cell-mediated cardiac repair. In particular HC is a highlyprevalent risk factor and contributes to a range of pathophysiological consequences. Hence the overall goal ofthis proposal is to investigate the impact of HC on CSC-mediated cardiac repair. Our fundamental hypothesisis that depending on the specific conditions cholesterol can be beneficial or detrimental in CSC-mediatedcardiac repair. We propose that mild elevations of plasma cholesterol or the presence of the minimallyoxidatively modified form of LDL-cholesterol precondition both the myocardium and the CSCs; the resultingcombination of a primed myocardial microenvironment for cell engraftment and enhanced paracrine signalingmechanisms of preconditioned CSCs work in concert to enhance CSC-mediated cardiac repair. We furtherpropose 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 celltherapies for cardiac repair. We will test these hypotheses under 3 specific aims using both in vitro culturedCSCs and cardiomyocytes in the presence of differently modified LDLs and in vivo rat models of MI withdifferent levels of plasma cholesterol. Aim 1 will determine the effects of HC on CSC-mediated cardiac repair invivo; Aim 2 will determine the effects of LDLs on CSC function and reparative capability in vitro; and Aim 3 willdetermine whether pretreatment of CSCs with differently modified LDLs in vitro alters the efficacy of cardiacreparative therapy in vivo. Given that plasma cholesterol is a modifiable risk factor but is also essential forcellular function understanding the effects of this prevalent risk factor on stem cell-based therapies will havetranslational and mechanistic importance. This project will provide novel insights into a much-neededpreclinical framework to develop cell-based therapies for cardiac repair in patients with cardiovascular riskfactors.

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;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;abstracting;base;biological adaptation to stress;biological systems;cardiac repair;cardiovascular risk factor;cell type;endoplasmic reticulum stress;extracellular;feeding;hemodynamics;hypercholesterolemia;improved;in vitro testing;in vivo;insight;interdisciplinary approach;interest;light microscopy;low density lipoprotein inhibitor;migration;modifiable risk;novel;oxidation;pre-clinical;preconditioning;pressure;primitive cell;programs;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: 8197185
project_number: 5R01DC008861-04
project_title: Role of Staircase Hair Bundle Morphology in Auditory Mechanotransduction
administering_ic: NIDCD
award_notice_date: 2011-11-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DC
serial_number: 008861
program_official: FREEMAN, NANCY
project_start_date: 2008-12-01
project_end_date: 2013-11-30
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
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): While number of proteins responsible for structural integrity of the mechanosensory bundle of the inner ear hair cells has been identified how most of these proteins contribute to mechano-electrical transduction is still unknown. Also unknown is whether the lack or modification of MET contributes to the development of deafness and/or vestibular disorders that result from mutations of hair bundle proteins. The goal of the current project is to determine the role of the myosin XVa-based stereocilia elongation complex in mechanotransduction. In homozygous shaker 2 mice (Myo15sh2/sh2) a recessive point mutation in the motor domain of myosin XVa prevents normal localization of this protein to the tips of stereocilia resulting in abnormally short stereocilia. According to our preliminary data cochlear outer hair cells of young postnatal Myo15sh2/sh2 mice possess numerous obliquely oriented "tip links" and apparently normal mechanotransduction. In contrast Myo15sh2/sh2 inner hair cells have equally short stereocilia without any obliquely oriented tip links but with numerous "top-to-top" links perpendicular to the core of stereocilia. In spite of their abnormal morphology Myo15sh2/sh2 inner hair cells have a prominent transduction current with "wild type" nanoampere-scale amplitude but abnormal directional sensitivity and no rapid Ca2+dependent deactivation known as "fast adaptation". The central hypothesis of the proposal is that the myosin XVa- based stereocilia elongation complex is not required for mechanosensitivity of hair cells but may affect directional sensitivity and adaptation of mechanotransduction. This study will determine: 1) the role of myosin XVa in directional sensitivity of the hair bundle; 2) localization of known molecular components of stereocilia links in the myosin XVa-deficient hair bundles; 3) the role of myosin XVa and its molecular partner whirlin in the fast adaptation of the transduction current. This study represents a step toward my long-term goal to understand how the hair cells acquire and maintain mechanosensitivity in normal and pathological conditions. Apart from being important for understanding the basic mechanisms of hair cell mechanotransduction this study will establish how developmental abnormalities of stereocilia growth may affect the transduction machinery. This project will also be the first to study mechanotransduction during restoration of the hair bundle morphology and/or tip links in mammalian cochlear hair cells. Finally our study will provide a wealth of data on hair cell function in shaker 2 and whirler mice the animal models for DFNB3 and DFNB31 hereditary deafness in humans. This research is relevant to public health because it investigates exactly how sensory cells of the inner ear acquire and maintain mechanosensitivity in normal and pathological conditions. Our experimental results will help scientists to better understand prevent and develop treatments for developmental abnormalities in the sensory cells of the inner ear which lead to congenital deafness.

project_terms:
Affect;Animal Model;Auditory;Cell physiology;Cells;Complex;Data;Deafness;Development;Disease;Goals;Growth;Hair;Hair Cells;Human;Inherited;Inner Hair Cells;Kinetics;Labyrinth;Lateral;Lead;Link;Mediating;Microscopy Electron Scanning;Modification;Molecular;Morphology;Motor;Mus;Mutation;Myosin ATPase;Outer Hair Cells;Point Mutation;Protein Isoforms;Proteins;Recovery;Research;Role;Scaffolding Protein;Scientist;Sensory;Stereocilium;Structure;Technology;Testing;Utricle structure;base;congenital deafness;human CDH23 protein;human PTPRT protein;insight;postnatal;prevent;public health medicine (field);repaired;research study;response;restoration

public_health_relevance:
NARRATIVEThis research is relevant to public health because it investigates exactly how sensory cells of the inner earacquire and maintain mechanosensitivity in normal and pathological conditions. Our experimental resultswill help scientists to better understand prevent and develop treatments for developmental abnormalities inthe sensory cells of the inner ear which lead to congenital deafness.


application_id: 8197127
project_number: 5R01CA129015-04
project_title: The role of Pdcd4 in colorectal tumor progression
administering_ic: NCI
award_notice_date: 2011-12-01
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;Health;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;Primary Neoplasm;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;slug;translation assay;tumor progression

public_health_relevance:
Project NarrativeColorectal cancer is the second most fatal cancer in the United States largely due to invasion and metastasisto the liver and lymph nodes. In this proposal we intend to understand the effects of a novel tumor suppressorPdcd4 on colon tumor metastasis and the molecular mechanism involved in this process. This work willprovide a comprehensive understanding of how Pdcd4 modulates colon tumor progression and holds greatpromise for novel interventions for preventing and treating colon cancer.


application_id: 8196933
project_number: 5R01HD060915-04
project_title: Latexin's role in parsing stem cells
administering_ic: NICHD
award_notice_date: 2011-12-09
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:
Juvenile factors that have potential effects on aging are myriad but fall into two broad categories: consciousand unconscious. An example of the former is taking up smoking as a pre-teen or adopting other dangerouslifestyles when young that are known at least on a statistical basis to shorten lifespan. Of course not allconscious decisions have detrimental effects. Many decisions about diet for example could promote healthyaging and a longer lifespan. This application is concerned with the "unconscious" category of factors detectableat early developmental stages that influence either positively or negatively not only overall lifespan but thequality of life with accumulating years. We focus on the number and functional capabilities of adult stem cellsand the factors that parse their limited numbers and functional properties over a lifetime. Our underlyinghypothesis 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-relatedchanges in stem cell number and function in mice. Moreover we have sought genetic determinants of stemcell properties that have an effect during aging. This proposal narrowly focuses on a quantitative trait thenumber of stem cells at a young age also correlated with lifespan. By utilizing the tools afforded by modernmouse genetics we have identified a quantitative trait gene and its protein product latexin that is important inmammals in parsing stem cells. In this application we propose to investigate the pattern of latexin expression inhematopoietic stem cells during embryonic development and at multiple points during adulthood and correlatethese data with quantitative and qualitative parameters of stem cells and organismal longevity. An importanttool we will make use of in these studies is latexin knockout mice which we are currently generating. Inconstitutive knockout animals we will study the effects on stem cells and aging when latexin is absentthroughout development and adulthood. In conditional knockout mice we will determine when duringdevelopment and young adulthood the presence of latexin is critical. Moreover the conditional knockouts willenable us to study the tissues in which latexin's expression is important and when. Lastly we investigate thegenetic and epigenetic regulation of latexin expression segmentally at different stages of organismaldevelopment and adulthood. Preliminary data demonstrate in specific mouse strains that latexin expression isdifferentially regulated by both polymorphisms in the promoter and differential methylation of CG dinucleotidescomprising a CpG island in the latexin promoter. In aggregate these descriptive and mechanistic studies willprovide definitive information on the basic premise that adult stem cells influence aging and in particular therole that latexin plays as a mechanistic factor in this pathway. Narrative/RationaleThe median age of the U.S population continues to increase and will accelerate in theupcoming few decades. Healthy aging is thus a national priority especially given therapidly rising costs of health care. Yet many of the physiological events occurring duringdevelopment and early in childhood that have serious repercussions on the quality of lifelater are poorly understood. We believe that the regulation of stem cells and particularlythe parsing of these populations chronologically is an important and neglected aspect ofthis quest. The proposed studies based on firm preliminary results specifically focus onthe role of a novel stem cell regulator latexin on the hematopoietic stem cell populationin a mammalian species the mouse.

project_terms:
Accounting;Adolescent;Adopted;Adult;Age;Aging;Apoptosis;Bone Marrow;C57BL/6 Mouse;Categories;Cell Aging;Cell Count;Cell physiology;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: 8196742
project_number: 5F31DE020240-03
project_title: AI-2-dependent quorum sensing in Aggregatibacter actinomycetemcomitans
administering_ic: NIDCR
award_notice_date: 2011-11-11
opportunity_number: PA-07-002
application_type: 5
activity_code: F31
ic: DE
serial_number: 020240
program_official: FRIEDEN, LESLIE A
project_start_date: 2009-12-01
project_end_date: 2012-01-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9851704
contact_pi: NOVAK, ELIZABETH ANN
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
project_abstract:
DESCRIPTION (provided by applicant): Dental plaque is a complex oral biofilm comprised of a diverse microbial community which necessitates that bacteria coordinate their behavior and function based on the environment and other organisms in the biofilm. In the oral pathogen Aggregatibacter actinomycetemcomitans this intimate cell-to- cell communication potentially occurs via the quorum sensing circuit dependent upon the soluble signaling molecule autoinducer-2 (AI-2). Previous results suggest that the response circuits of A. actinomycetemcomitans differ from the established paradigms for AI-2 signaling. Thus we hypothesize that the AI-2-mediated quorum sensing response circuit in A. actinomycetemcomitans is tailored towards the specific survival strategies employed by this organism in the oral biofilm and contributes to its in vivo persistence and virulence through AI-2 regulation of iron acquisition. To address this hypothesis we will further characterize the molecular mechanisms of AI-2-dependent quorum sensing in A. actinomycetemcomitans. Our first specific aim is to determine the importance of AI-2-dependent quorum sensing in the persistance and virulence of A. actinomycetemcomitans. Since periodontal diseases are mixed bacterial infections of the oral cavity it is theorized that populational shifts in the biofilm that leads to overrepresentation of certain organisms rather than their absence or presence is a major contributing factor to the onset and progression of oral diseases. Using the Baker model of periodontitis we will determine if AI-2-mediated quorum sensing is important in vivo during single infections with either wild type or AI-2 receptor-deficient strains of A. actinomycetemcomitans. Our second specific aim is to identify the component that links AI-2 detection to downstream gene regulation. Initial studies suggest that the two- component system QseBC may link detection and gene regulation. To address our hypothesis we will determine if QseBC regulates biofilm formation in A. actinomycetemcomitans. This will be accomplished by constructing QseBC mutants and analyzing their ability to form biofilms in vitro. We will also determine if QseBC influences the expression of AI-2-regulated genes such as iron acquisition by utilizing quantitative PCR.     Public Health Relevance: Determining the extra- and intracellular physiologic roles of AI-2 will provide rationale for the development of novel quorum sensing inhibitors as a way to prevent the growth of A. actinomycetemcomitans biofilms associated with oral diseases as well as other diseases (e.g. cardiovascular disease). Furthermore innovative methods to control biofilm formation in the oral cavity would have a major impact on healthcare costs

project_terms:
Actinobacillus actinomycetemcomitans;Address;Bacteria;Bacterial Infections;Behavior;Cardiovascular Diseases;Cell Communication;Cell physiology;Cells;Communication;Communities;Complex;Dental Plaque;Detection;Development;Disease;Disease Progression;Environment;Escherichia coli;Event;Exhibits;Gene Expression Regulation;Genes;Goals;Growth;Health Care Costs;In Vitro;Infection;Iron;Link;Mediating;Methods;Microbial Biofilms;Modeling;Molecular;Mouth Diseases;Onset of illness;Operon;Oral cavity;Organism;Outcome;Periodontal Diseases;Periodontitis;Physiological;Porphyromonas gingivalis;Regulation;Research;Role;Salmonella;Signal Transduction;Signaling Molecule;System;Therapeutic Intervention;VAI-2;Vibrio;Virulence;base;extracellular;in vivo;inhibitor/antagonist;innovation;microbial;microbial community;mutant;novel;oral biofilm;oral pathogen;periplasm;prevent;public health relevance;quorum sensing;receptor;response;uptake


application_id: 8196733
project_number: 5R03DC011360-02
project_title: Clinical measurement of vocal fold impact stress in children
administering_ic: NIDCD
award_notice_date: 2011-11-15
opportunity_number: PAR-10-055
application_type: 5
activity_code: R03
ic: DC
serial_number: 011360
program_official: SHEKIM, LANA O
project_start_date: 2010-12-01
project_end_date: 2012-07-31
study_section: ZDC1-SRB-Y(55)
contact_pi_person_id: 9635662
contact_pi: PATEL, RITA R
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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
project_abstract:
DESCRIPTION (provided by applicant): Nationwide over one million or 6-9%1 of all children suffer from dysphonia. Dysphonia can be detrimental to children both psychologically and academically hence early identification and restoration of optimal vocal health is critical. Direct visualization of vocal fold vibratory patterns is fundamental to appropriate diagnosis and treatment of vocal fold pathology. Objective assessments of vocal fold physiology are non-existent in the field of pediatric voice care leading to delayed diagnosis and deferred development of effective treatments. The long term goal of the proposed research is to improve treatment outcomes and early identification in children with hoarseness by establishing age appropriate quantitative measurements of immature vocal fold function that contribute to voice disorders. To accomplish this goal it is necessary to quantify vocal fold vibrations resulting from differences in the multilayered vocal fold structure of children compared with adults. Most voice problems in children are thought to be caused by mechanical trauma to the vocal folds manifested as high impact stress leading to the development of vocal nodules. The specific goal of this project is to identify the impact of growth and development of the layered structure of the vocal folds on vocal physiology and the relationship of these factors to the development of vocal fold nodules in children. This research proposes 1 milestone-driven aim and 2 hypotheses-driven aims. Therefore the specific aims of this application are: 1) to optimize a 2-point laser projection system developed in our laboratory for precision and to compute expected measurement variability to fully translate use of this system to children 2) to quantify the relationship between short vocal fold length and increased vibratory amplitude during the developmental process in children with and without nodules and 3) to quantify spatiotemporal features of vocal fold impact stress in children as a function of age and pathology. A total of 80 children will be recruited to participate (ages: 5-12) 40 with and 40 without nodules. Forty adults (21-45 years) will be recruited to obtain the developmental end point for maturation of vibratory motion because adults have a well-defined layered structure of the vocal folds. The following spatiotemporal features of vocal fold vibrations will be measured using a novel 2-point pediatric laser high speed digital imaging system to identify impact stress: mid membranous amplitude-to-length ratio peak vocal fold acceleration(mm/sec2) peak closing velocity (mm/sec) open quotient and vibratory stiffness (ratio of maximum velocity by maximum displacement) and closed quotient. The proposed research is significant in filling a gap in knowledge concerning the most effective methods for assessing vibratory function and identifying predisposing factors in children with hoarseness. The fundamental knowledge of vibratory function obtained from this work will directly translate to the clinic by producing meaningful findings and measures that can be applied to pediatric vocal health outcomes and will thus reduce the burden of illness and disability caused by voice disorders in children.    PUBLIC HEALTH RELEVANCE: It has been estimated that over one million1 children suffer from voice disorders nationwide with potentially detrimental psychological effects. Knowledge of vocal fold vibratory motion is fundamental for measuring treatment outcomes in children but has been slow to emerge due to technical challenges. This work is the first to examine spatiotemporal measurements of vocal fold motion that lead to the development of impact stress and voice disorders in children and to use a novel custom-built pediatric imaging system to examine the relationship of the immature vocal system and the formation of vocal fold nodules.

project_terms:
12 year old;Acceleration;Adult;Aftercare;Age;Biomechanics;Caring;Child;Childhood;Chronic;Clinic;Clinical;Clinical assessments;Coupled;Custom;Development;Developmental Process;Diagnosis;Disease;Dysphonia;Early identification;Endoscopes;Ensure;Foundations;Goals;Growth;Growth and Development function;Health;Hoarseness;Image;Imagery;Individual;Investigation;Knowledge;Laboratories;Larynx;Lasers;Lead;Length;Lesion;Loudness;Measurement;Measures;Mechanics;Methodology;Methods;Modeling;Motion;Movement;Nodule;Outcome;Pathology;Pattern;Phonation;Physiology;Population;Predisposing Factor;Production;Recruitment Activity;Relative (related person);Research;Risk;Shapes;Speed (motion);Stress;Structure;System;Therapeutic;Translating;Trauma;Traumatic Stress Disorders;Treatment outcome;Voice;Voice Disorders;Work;base;burden of illness;clinical application;digital imaging;disability;effective therapy;glottis;high standard;imaging modality;improved;innovation;insight;kinematics;novel;programs;prototype;psychologic;public health relevance;restoration;spatiotemporal;theories;tool;trend;vibration;vocal cord

public_health_relevance:
It has been estimated that over one million1 children suffer from voice disorders nationwide with potentiallydetrimental psychological effects. Knowledge of vocal fold vibratory motion is fundamental for measuringtreatment outcomes in children but has been slow to emerge due to technical challenges. This work is the firstto examine spatiotemporal measurements of vocal fold motion that lead to the development of impact stressand voice disorders in children and to use a novel custom-built pediatric imaging system to examine therelationship of the immature vocal system and the formation of vocal fold nodules.


application_id: 8194406
project_number: 1R01AG038651-01A1
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2011-08-26
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AG
serial_number: 038651
suffix: A1
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2016-08-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
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): Population demographics suggest that with the expected dramatic increase in age-associated dementias a public health crisis is looming. Current emphasis is on disease prevention with a focus on elderly individuals who express some cognitive impairment. We propose to identify authoritatively the risk and protective factors for cognitive decline in older persons. We have shown how to define these impaired states retrospectively how to account for reverse transitions how to distinguish prevalence from incidence and how to account for competing risks by using a unique statistical (Markov) model. But sufficient longitudinal and neuropathological data is currently not available to distinguish among different types of dementia. No single Alzheimer's Disease Center (ADC) or cooperative study has an adequate sample size to reliably track transitions to dementia and differentiate Alzheimer's disease (AD) from other prevalent brain diseases that include vascular dementia (VaD) and Lewy body disease (LBD). This project will pool data from six well established longitudinal cohorts to identify risk factors for (1) preservation of intact cognition in those meeting neuropathological criteria for varying types of dementia and MCI and (2) specific forms of dementia (clinical and neuropathological). This will improve our understanding of intervening impaired states and factors that promote resistance to clinical symptoms despite the presence of neuropathology. These considerations lead to the specific aims below. Specific Aim 1: To merge databases from six large projects that follow cohorts of cognitively intact subjects to dementia for the purpose of rigorous statistical biologically-informed analyses that accentuate longitudinal follow-up: BRAiNS (University of Kentucky) Nun Study (University of Minnesota) Memory and Aging Project (Washington U) Kuakini Honolulu-Asia Aging Study Religious Orders Study (ROS Rush Medical University) and the OHSC ADC (Oregon Health & Science University). The database would be made publicly accessible. Specific Aim 2: To identify appropriate intervening states between intact cognition and dementia based on periodic assessments of cognition and functional skills from data collected at these centers. Specific Aim 3: To study transitions and associated risk factors (e.g. genetic medical time in an impaired state) using novel statistical methods. Specific Aim 4: To standardize the neuropathological findings across databases (including quantitative neuropathological assessments) to enable the analysis of novel pathogenetic determinants of outcomes. This aim allows us to evaluate how actual brain pathology (e.g. microinfarcts Lewy bodies hippocampal sclerosis and mixed pathologies) relates to antemortem states in the subset of participants coming to autopsy. This aim could support proposed revisions of current neuropathological and clinical research diagnostic criteria in dementia and preclinical dementia conditions.  
  
PUBLIC HEALTH RELEVANCE: With the graying of America the cost of caring for demented elderly will rise substantially in the next few decades. Current emphasis is on preventing this disease. This project will identify risk factors for various forms of dementia as well as impaired states that precede this disease.

project_terms:
Accounting;Age;Aging;Alzheimer's Disease;Americas;Asia;Autopsy;Biological Preservation;Brain Diseases;Brain Pathology;Caring;Clinical;Clinical Data;Clinical Research;Clinical assessments;Cognition;Cognitive;Cohort Studies;Communities;Complement;Complex;Consensus;Data;Databases;Dementia;Diagnostic;Disease;Elderly;Epidemiology;Evaluation;Funding;Gray unit of radiation dose;Health Care Costs;Health Sciences;Hippocampus (Brain);Impaired cognition;Incidence;Individual;Investigation;Kentucky;Lead;Lewy Bodies;Lewy Body Disease;Magnetic Resonance Imaging;Measures;Medical;Medical Genetics;Memory;Meta-Analysis;Minnesota;Modeling;National Institute on Aging;Oregon;Outcome;Participant;Pathology;Patients;Population;Prevalence;Prevention strategy;Registries;Religion and Spirituality;Research;Research Personnel;Resistance;Resources;Risk;Risk Factors;Role;Sample Size;Sampling;Sclerosis;Series;Statistical Methods;Statistical Models;Symptoms;Time;United States National Institutes of Health;Universities;Validation;Vascular Dementia;Washington;aging brain;base;biomarker;cohort;cooperative study;cost;demographics;design;disorder prevention;experience;follow-up;improved;innovation;insight;markov model;meetings;mild cognitive impairment;neuropathology;novel;pre-clinical;prevent;prevention clinical trial;public health medicine (field);skills;treatment strategy

other_pis:
KAYE, JEFFREY A;LIM, KELVIN O.;LIPTON, RICHARD B.;SCHMITT, FREDERICK ;TYAS, SUZANNE LEIGH;WHITE, LON RAY;XIONG, CHENGJIE ;YU, LEI


application_id: 8191585
project_number: 1R03DA030570-01A1
project_title: Transdermal delivery of 2-Arachidonoyl glycerol (2-AG) for the treatment of arthr
administering_ic: NIDA
award_notice_date: 2011-06-10
opportunity_number: PA-10-064
application_type: 1
activity_code: R03
ic: DA
serial_number: 030570
suffix: A1
program_official: RAPAKA, RAO
project_start_date: 2011-07-01
project_end_date: 2011-12-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
contact_pi_person_id: 9761868
contact_pi: PAUDEL, KALPANA
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
project_abstract:
DESCRIPTION (provided by applicant):  This research proposes to improve the transdermal delivery of 2-arachidonoylglycerol (2-AG) for the adjunct treatment of osteoarthritis rheumatoid arthritis (RA) and joint pain secondary to other autoimmune diseases such as inflammatory bowel disease multiple sclerosis and systemic lupus erythematosus. Current methods of treatment for these conditions do not always provide adequate pain relief in many patients or are associated with addiction various side effects and/or patient noncompliance. Systemic RA treatments have drastically improved over the last decade; however many patients still have substantial unrelieved joint pain and stiffness even though their joint deterioration may be arrested by new biological agents. Thus there is a strong need for the development of novel drug treatments for joint pain.  2-AG an endocannabinoid has been shown to play a strong role in alleviation of inflammatory pain via CB2 receptors. A recent study has shown that intra-articular injection of 2-AG in a preclinical model of arthritic pain decreased joint pain. Topical products are better than painful local injections in providing local therapeutic benefit while reducing the risk of systemic adverse effects. Additionally this product would not have the abuse liability problems of opioids that some patients use to treat joint pain. Thus we hypothesize that a transdermal gel or patch containing a prodrug of 2-AG will be an important adjunct treatment in arthritis and joint pain associated with autoimmune diseases and would be a significant improvement in patient care and quality of life.  In our preliminary diffusion studies with hairless guinea pig skin 2-AG flux was found to be 137.7127.1 ng/cm2/h and the drug content in the skin (upper layer) was 965.21516 5g of drug/g of skin. Published data shows that the dermis concentration of hydrophobic compounds may reach only about 25-50% compared to the upper skin layer because of the difficulty in partitioning out of the stratum corneum. In a recently published 2-AG study an initial concentration of about 1 mg/ml was needed in synovial fluid to treat joint pain with 50% efficacy. Hence an enhancement of 2-AG diffusion by at least 2-4 fold will be needed to reach this concentration in the deeper layers of tissue and into the synovium. We aim to synthesize hydrophilic prodrugs of 2-AG to improve permeation across the skin into synovial fluid. Prodrugs should improve the delivery rates of 2-AG across the skin because of optimized physiochemical properties for faster diffusion. If prodrugs fail to improve the flux of 2-AG microneedle assisted delivery of salts of 2-AG or its prodrugs will be carried out. The specific aims of this project include: (1) to synthesize a series of 2-AG prodrugs for transdermal flux optimization (2) to characterize the physicochemical parameters of the drugs including solubilities and stabilities in select solvents (3) to measure the penetration and concurrent bioconversion of the prodrugs in hairless guinea pig and human skin in vitro and (4) to compare the transdermal delivery of 2-AG prodrugs with methanandamide and O-1812 the stable analogs of anandamide.  
  
PUBLIC HEALTH RELEVANCE: Autoimmune diseases immune system defects that cause the body to attack its own organs tissues and cells consist of more than 80 chronic diseases and affect more than 20 million Americans. Rheumatoid arthritis (RA) is an autoimmune disease which affects approximately 1.3 million Arthritis and related conditions such as RA cost the U.S. economy nearly $128 billion per year in medical care and indirect expenses including lost wages and productivity. Current methods of treatment for these conditions do not always provide adequate pain relief in many patients or are associated with various side effects drug addiction potential and/or patient noncompliance. This research proposes to improve the transdermal delivery of 2-arachidonoylglycerol (2-AG) for the adjunct treatment of osteoarthritis rheumatoid arthritis (RA) and joint pain secondary to other autoimmune diseases such as inflammatory bowel disease multiple sclerosis and systemic lupus erythematosus. A transdermal system can provide more local drug effect at the site of application and also have fewer systemic drug side effects.

project_terms:
2-arachidonylglycerol;Absence of pain sensation;Adverse drug effect;Adverse effects;Affect;American;Animals;Arthralgia;Arthritis;Autoimmune Diseases;Binding (Molecular Function);Biological Products;Caring;Cavia;Cells;Chronic Disease;Combined Modality Therapy;Compliance behavior;Data;Defect;Degenerative polyarthritis;Dermis;Deterioration;Development;Diffusion;Dosage Forms;Drug Addiction;Endocannabinoids;Future;Gel;Human;Immune system;In Vitro;Inflammatory Bowel Diseases;Injection of therapeutic agent;Intra-Articular Injections;Joints;Measures;Medical;Methods;Multiple Sclerosis;Opioid;Oral;Organ;Pain;Pain-Free;Pathway interactions;Patient Care;Patient Noncompliance;Patients;Penetration;Permeability;Pharmaceutical Preparations;Pharmacodynamics;Pharmacotherapy;Play;Population;Pre-Clinical Model;Prodrugs;Productivity;Property;Publishing;Quality of life;Receptor Cannabinoid CB1;Receptor Cannabinoid CB2;Research;Rheumatoid Arthritis;Risk;Role;Route;Salts;Secondary to;Series;Site;Skin;Solubility;Solvents;Stratum corneum;Structure;Synovial Fluid;Synovial Membrane;System;Systemic Lupus Erythematosus;TRPV1 gene;Testing;Therapeutic;Tissues;United States;United States National Institutes of Health;Vanilloid;Wages;addiction;analog;anandamide;cost;effective therapy;improved;in vivo;inflammatory pain;joint stiffness;methanandamide;novel;receptor;tool

public_health_relevance:
Autoimmune diseases immune system defects that cause the body to attack its own organs tissues and cells consist of more than 80 chronic diseases and affect more than 20 million Americans. Rheumatoid arthritis (RA) is an autoimmune disease which affects approximately 1.3 million Arthritis and related conditions such as RA cost the U.S. economy nearly $128 billion per year in medical care and indirect expenses including lost wages and productivity. Current methods of treatment for these conditions do not always provide adequate pain relief in many patients or are associated with various side effects drug addiction potential and/or patient noncompliance. This research proposes to improve the transdermal delivery of 2-arachidonoylglycerol (2-AG) for the adjunct treatment of osteoarthritis rheumatoid arthritis (RA) and joint pain secondary to other autoimmune diseases such as inflammatory bowel disease multiple sclerosis and systemic lupus erythematosus. A transdermal system can provide more local drug effect at the site of application and also have fewer systemic drug side effects.


application_id: 8191422
project_number: 1R21CA139359-01A2
project_title: Mechanisms of Wnt/beta-catenin inhibition by resveratrol and its derivatives
administering_ic: NCI
award_notice_date: 2011-08-10
opportunity_number: PA-10-088
application_type: 1
activity_code: R21
ic: CA
serial_number: 139359
suffix: A2
program_official: KIM, YOUNG S
project_start_date: 2011-08-10
project_end_date: 2013-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
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
project_abstract:
DESCRIPTION (provided by applicant):  This is a revised application in response to PA-10-088 "Exploratory Cancer Prevention Studies Involving Molecular Targets for Bioactive Food Components (R21)". In this project we will characterize a novel molecular target of resveratrol for colorectal cancer prevention. Colorectal cancer is the second leading cause of cancer-related mortality in the United States and accounts for more than 56000 deaths per year. Colorectal cancer is initiated by mutations of adenomatous polyposis coli (APC) and 2-catenin genes which result in abnormal activation of Wnt signaling. Inhibition Wnt signaling is essential for colorectal cancer chemoprevention. Resveratrol is found in the skin of red grape and also present in the red wine. Resveratrol and many of its analogs have anti-cancer activity. We found several resveratrol analogs including pterostilbene found in blueberry can strongly inhibit Wnt signaling while cis-resveratrol cannot. We have designed and synthesized a panel of novel resveratrol analogs and have identified several novel inhibitors for Wnt/2-catenin signaling. Our central hypothesis is that resveratrol and its analogs inhibit Wnt signaling thus prevent of 2-catenin-induced cancers particularly colorectal cancers. To further understand the molecular mechanisms of resveratrol in Wnt/2-catenin inhibition and to develop better inhibitors for chemoprevention we will pursue the following two specific aims: 1) to delineate the mechanisms of how resveratrol inhibits Wnt signaling using cell models; and 2) to investigate how resveratrol and its analogs inhibits Wnt signaling using a novel inflammation-related mouse colon cancer model.  
  
PUBLIC HEALTH RELEVANCE:  Colorectal cancer is the second leading cause of cancer death in the United States. This project is to explore a novel mechanism of cancer prevention by resveratrol a product from red grapes. We found that resveratrol blocks Wnt signaling a key pathway in colon cancer formation. The studies in this project will provide a better understanding of resveratrol function in cancer prevention and will lead to better chemoprevention agents in the future.

project_terms:
APC gene;Accounting;Adenomatous Polyposis Coli;Biological Factors;Biometry;Blueberries;CTNNB1 gene;Cancer Center;Cancer Etiology;Cancer Model;Cell Proliferation;Cell model;Cessation of life;Chemicals;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Research;Colitis;Colon;Colon Carcinoma;Colorectal Cancer;Dimethylhydrazines;Exhibits;Future;Genes;Goals;Grapes;Growth;Hand;In Vitro;Inflammation;Interdisciplinary Study;Lead;Malignant Neoplasms;Modeling;Modification;Molecular;Molecular Target;Mortality Vital Statistics;Mus;Mutation;New Agents;Nude Mice;Pathology;Pathway interactions;Pharmaceutical Preparations;Physicians;Plants;Proteomics;Publications;Research;Resveratrol;Signal Transduction;Skin;Staging;Stilbenes;Testing;Toxic effect;United States;Universities;Work;Xenograft procedure;adenoma;analog;base;beta catenin;bioactive food component;cancer cell;cancer chemoprevention;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;in vivo;inhibitor/antagonist;insight;mouse model;novel;phytoalexin;phytoalexins;prevent;red wine;response;trans-resveratrol;tumor;tumor growth

public_health_relevance:
Colorectal cancer is the second leading cause of cancer death in the United States. This project is to explore a novel mechanism of cancer prevention by resveratrol a product from red grapes. We found that resveratrol blocks Wnt signaling a key pathway in colon cancer formation. The studies in this project will provide a better understanding of resveratrol function in cancer prevention and will lead to better chemoprevention agents in the future.


application_id: 8190176
project_number: 1R21NS072611-01A1
project_title: Post Traumatic Sleep: An Individualized Indicator of Severity and Recovery
administering_ic: NINDS
award_notice_date: 2011-05-06
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: NS
serial_number: 072611
suffix: A1
program_official: HICKS, RAMONA R
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2048186
contact_pi: LIFSHITZ, JONATHAN
other_pis: O'HARA, BRUCE FREDERICK
congressional_district: 06
department: NEUROLOGY
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): The purpose of sleep continues to be debated. Prevailing hypotheses suggest a role in restoring energy balance permitting synaptic reorganization or cellular repair. With a traumatic brain injury the mechanical forces and ensuing cellular signaling disrupt energy balance initiate synaptic deafferentation followed by plasticity and damage membranes proteins and structural elements. Thus acute post-traumatic sleep may mitigate injury-related damage. However for the more than 1.4 million concussed individuals per year in the United States prevailing folklore recommends that they should not be allowed to sleep or be awoken regularly which is unsupported by medical evidence. Moreover this sleep disturbance counteracts the natural repair processes of sleep that would be promoted by the ubiquitous inflammatory response after brain injury as occurs with cytokine signaling upon infection. Surprisingly the utility or detriment of acute post-traumatic sleep has yet to be explored. The current proposal tests the hypothesis that sleep is an immediate natural response to diffuse brain injury likely promoting recovery of the injured brain. Aim 1 will correlate quantitative sleep parameters acutely following mild and moderate diffuse brain injury in the mouse to chronic physiological behavioral and histopathological outcomes. Aim 2 will explore the consequences of sleep disturbance on cognitive function cytokine and glucocorticoid levels and histopathology across limbic and sleep structures. Post- traumatic sleep will be monitored by novel non-invasive technology validated for sleep- wake studies. This system employs custom-designed pressure sensors on the cage floor that continuously monitor for the motion associated with rhythmic breathing while animals are in a sleep posture. These experiments examine for the first time the effects of diffuse brain injury on sleep-wake patterns. Post-traumatic interventions to disrupt sleep may worsen or mitigate the behavioral and histopathological consequences of injury. Post-traumatic sleep may come to serve as an individualized biomarker to measure the severity of the initial injury and monitor the recovery process. For mild TBI sleep itself could become a plausible behavioral intervention to mitigate the enduring neurological consequences of TBI.  
  
PUBLIC HEALTH RELEVANCE: After a concussion prevailing folklore recommends that individuals should not be allowed to sleep or be awoken regularly. Since sleep may be responsible for cellular repair and reorganization post-injury sleep disturbance may delay or even prevent recovery. This proposal evaluates post-injury sleep in a mouse model of traumatic brain injury and the consequences good or bad of disturbing sleep shortly after injury.

project_terms:
Acute;Address;Animals;Astrocytes;Behavior;Behavior Therapy;Behavioral;Belief;Brain;Brain Concussion;Brain Injuries;Brain region;Breathing;Chronic;Cognition;Cognitive;Coma;Custom;Cytokine Signaling;Data;Deafferentation procedure;Diffuse;Diffuse Brain Injury;Elements;Floor;Folklore;Future;Glucocorticoids;Head;Histopathology;Home environment;Hospitals;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory Response;Injury;Intervention;Investigation;Measures;Mechanics;Medical;Membrane Proteins;Microglia;Military Personnel;Monitor;Motion;Mus;Nature;Neurologic;Neurons;Outcome;Patient Self-Report;Pattern;Physiological;Physiology;Posture;Prevalence;Process;Recovery;Role;Severities;Signal Transduction;Sleep;Sleep Stages;Sleep Wake Cycle;Sleep disturbances;Structure;Superstitions;Synapses;System;Technology;Testing;Therapeutic Intervention;Time;Traumatic Brain Injury;United States;awake;base;biomarker;cognitive function;cranium;cytokine;design;energy balance;experience;flu;injured;interest;mouse model;neglect;novel;pressure;prevent;receptor;repaired;research study;response;sensor

public_health_relevance:
After a concussion prevailing folklore recommends that individuals should not be allowed to sleep or be awoken regularly. Since sleep may be responsible for cellular repair and reorganization post-injury sleep disturbance may delay or even prevent recovery. This proposal evaluates post-injury sleep in a mouse model of traumatic brain injury and the consequences good or bad of disturbing sleep shortly after injury.


application_id: 8189673
project_number: 1R21AG038652-01A1
project_title: Aging susceptibility to lung injury ^ tissue remodeling and oxidative stress
administering_ic: NIA
award_notice_date: 2011-08-18
opportunity_number: PA-10-044
application_type: 1
activity_code: R21
ic: AG
serial_number: 038652
suffix: A1
program_official: MACCHIARINI, FRANCESCA
project_start_date: 2011-09-01
project_end_date: 2013-07-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
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
project_abstract:
DESCRIPTION (provided by applicant): Acute lung injury occurs in over 200000 subjects in the U.S. each year and over 40% of affected individuals succumb to this disease. Elderly patients represent a disproportionate number of afflicted individuals with acute lung injury but the factors responsible for this increased susceptibility remain unclear. We now have evidence suggesting that aging renders the lung susceptible to disrepair through the establishment of a 'pro-fibrotic' state that is unleashed only after exposure to an injurious agent. When comparing mice at 2 months and 24 months of age we found that at baseline the lungs of senescent mice show increased expression of the pro-fibrotic growth factor transforming growth factor beta its receptor TGF-RI and its main intracellular transducer Smad3; the fibronectin splicing variant EDA a matrix glycoprotein linked to lung fibrogenesis; and the proteases MMP2 and MMP9. We also found that fibroblasts harvested from the lungs of senescent mice show decreased expression of Thy-1; Thy-1 negative fibroblasts promote fibrogenic responses. Importantly when exposed to bleomycin elderly animals show greater fibrosis as demonstrated histologically and by quantification of hydroxyproline. In view of the importance of the above findings we turned our attention to the factors promoting these events. That search led us to investigate the role of oxidant stress. It has been shown that elderly animals (and humans) manifest oxidation of their plasma cysteine/cystine redox potential. We demonstrated that this type of oxidant stress promotes lung fibroblast proliferation myofibroblast transdifferentiation and expression of TGF- and fibronectin in vitro. Based on the above we hypothesize that aging through oxidation of the cysteine/cystine redox potential results in a 'pro- fibrotic' state that renders the host susceptible to disrepair and the development of acute lung injury after an insult. The hypothesis will be investigated by examining how oxidation of the extracellullar cysteine/cystine redox potential promotes a pro-fibrotic state in senescent murine lungs by determining the impact of nutritional interventions as preventive strategies and by testing for evidence of this pro-fibrotic state in the bronchoalveolar lavage fluid of young versus elderly humans who are otherwise healthy.  
  
PUBLIC HEALTH RELEVANCE: The incidence and mortality from acute lung injury are more common in elderly patients. Many reports suggest that senescent lungs are proned to disrepair after injury but the mechanisms responsible for this remain incompletely understood. We believe that a special kind of oxidant stress (oxidation of the cysteine/cystine redox potential) induce a 'pro-fibrotic' state in senescent lungs thereby increasing susceptibility to acute lung injury. This project seeks to explore this possibility with the hope of identifying dietary interventions that could serve as preventive therapy.

project_terms:
Acute respiratory failure;Adult Respiratory Distress Syndrome;Affect;Age;Age-Months;Aging;Alcohols;Animals;Antioxidants;Attention;Bleomycin;Bronchoalveolar Lavage Fluid;Collagen;Critical Care;Critical Illness;Cysteine;Cystine;Data;Development;Dietary Intervention;Dietary Supplements;Disease;Elderly;Endotoxemia;Endotoxins;Event;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Funding;Glycoproteins;Growth Factor;Harvest;Histologic;Histology;Human;Hydroxyproline;In Vitro;Incidence;Individual;Inflammatory;Inflammatory Response;Injury;Integration Host Factors;Investigation;Laboratories;Lead;Link;Lung;Lung Injury Acute;MMP2 gene;MMP9 gene;Mortality Vital Statistics;Mus;Myofibroblast;Nicotine;Nutritional;Organ;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Peptide Hydrolases;Plasma;Predisposition;Prevention strategy;Preventive;Preventive Intervention;Process;Production;RNA Splicing;Reporting;Research;Role;Signal Transduction;Sirolimus;Surface;Testing;Tissues;Transducers;Transforming Growth Factor beta;Transforming Growth Factors;Variant;Virus;Work;age related;base;collagenase;design;fibrogenesis;human FRAP1 protein;improved;injured;lung injury;novel;older patient;oxidant stress;oxidation;prevent;receptor;repaired;response;senescence;therapy design;transcription factor;transdifferentiation

public_health_relevance:
The incidence and mortality from acute lung injury are more common in elderly patients. Many reports suggest that senescent lungs are proned to disrepair after injury but the mechanisms responsible for this remain incompletely understood. We believe that a special kind of oxidant stress (oxidation of the cysteine/cystine redox potential) induce a 'pro-fibrotic' state in senescent lungs thereby increasing susceptibility to acute lung injury. This project seeks to explore this possibility with the hope of identifying dietary interventions that could serve as preventive therapy.


application_id: 8189662
project_number: 1K99CA158009-01A1
project_title: The role of the first mammalian N-term. methyltransferase NRMT in tumorigenesis
administering_ic: NCI
award_notice_date: 2011-09-05
opportunity_number: PA-10-063
application_type: 1
activity_code: K99
ic: CA
serial_number: 158009
suffix: A1
program_official: SCHMIDT, MICHAEL K
project_start_date: 2011-09-05
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZCA1 RTRB-K (M1)]
contact_pi_person_id: 8476980
contact_pi: SCHANER-TOOLEY, CHRISTINE E
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_abstract:
DESCRIPTION (provided by applicant): During my postdoctoral fellowship I successfully purified and identified the first mammalian N-terminal methyltransferase NRMT. Shown by microarray analysis to have reduced expression/copy number in human breast cancers I have also illustrated NRMT knockdown results in increased cell proliferation and a multi- spindle phenotype. Given that NRMT knockdown results in these two cancer prone phenotypes I intend to further study how it is regulated how N-terminal methylation affects substrate function and how NRMT misregulation leads to tumorigenesis. My goal after completion of my postdoctoral work is to obtain a tenure- track position at an academic research institution and establish an independent research program. Successful completion of my research goals includes training in a mouse mammary transplant model. As I have no previous mouse research experience the additional training time provided by a K99 will be imperative for learning these skills. Obtaining a K99 will also allow for further training in mass spectrometry fluorescent- activating cell sorting and FRET analysis. The long-term goal of my research is to use the NRMT mouse model to dissect the signaling pathways that lead to breast cancer. As personalized medicine treatments become increasingly necessary I want to create a model where combinations of genes can be easily manipulated simultaneously. These models can be used to test which current drug treatments are most effective for patients with specific combinations of mutations and to screen for new and more effective therapeutic agents. Research The list of genes involved in tumorigenesis is quite extensive however many of their biological functions remain unknown. One such gene Mettl11a (now renamed NRMT) has been shown to be under-expressed in breast cancers but has only recently been identified as the first mammalian N-terminal methyltransferase. Reduction of NRMT also results in a multi-spindle phenotype and the associated aneuploidy is often considered to contribute to cancer progression. As NRMT is a newly discovered protein the goals of this proposal are to understand the role of N-terminal methylation on protein and cellular function in order to study how its misregulation leads to tumorigenesis. The first two aims determining whether N-terminal methylation is constitutive and determining whether N-terminal methylation universally alters the DNA binding of its substrates are designed to better understand the basic biology of N-terminal methylation. These aims will involve mass spectrometry fluorescent-activating cell sorting FRET analysis and construction of a knockout mouse. The objective of the third aim is to determine the role of NRMT in development and tumorigenesis. A mouse mammary transplant model will be established for assaying if the multi-spindle NRMT knockdown phenotype leads to developmental defects and/or tumorigenesis. The key element of the career development aspect of this proposal will be learning the mouse system needed for successful completion of the third aim. The experiments of aims one and two have been designed for the downtime between surgeries and gland or tumor harvesting. Environment The University of Virginia is well equipped for completion of all three aims of this proposal. The on-campus mass spectrometry facility of advisory committee member Dr. Don Hunt has a Fourier transform mass spectrometer necessary for distinguishing N-terminal methylation from acetylation. The UVA Flow Cytometry Core will provide the training necessary for all fluorescent-activating cell sorting experiments. The UVA Gene Targeting and Transgenic Facility will create the NRMT knockout mouse. The Research Histology Core will paraffin embed and make slides of all normal mouse tissue and tumors. My advisory committee member Dr. Amy Bouton will aid in interpretation of the histology. The expertise and reagents of advisory committee member Dr. Todd Stukenberg will aid in characterization of the NRMT multi-spindle phenotype. The UVA W.M. Keck Center for Cellular Imaging supplies state-of-the art imaging facilities for immunofluorescent imaging of mouse tissue samples and training in FRET analysis. The Macara lab currently has three expert mouse biologists available for training in mouse handling and surgical techniques. In addition UVA offers numerous courses aimed at career development/training including the UVA transgenic methods and applications workshop the Flow Cytometry Training Workshop the Workshop on FRET Microscopy and a monthly career development seminar series offered by the Office of Postdoctoral Professional Development.  
  
PUBLIC HEALTH RELEVANCE: The biological roles of many genes involved in tumorigenesis remain unknown. We need to study their functions in order to achieve a complete understanding of cancer progression and obtain an inclusive list of potential druggable targets. One such protein NRMT the newly identified mammalian N-terminal methyltransferase is under-expressed in breast cancers and its knockdown results in mitotic defects often considered to contribute to cancer progression. The goal of this proposal is to understand how NRMT is regulated and how its misregulation contributes to tumorigenesis.  
  
  
The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" above summarizes the final opinions of the committee.

project_terms:
A Mouse;Acetylation;Advisory Committees;Affect;Aneuploidy;Antibodies;Apoptotic;Binding (Molecular Function);Biological;Biological Assay;Biological Process;Biology;Cell Cycle;Cell Line;Cell Proliferation;Cell Separation;Cell physiology;Chromatin;Committee Members;Consensus Sequence;Critiques;Cytoplasm;DNA;DNA Binding;DNA repair protein;DNA-Binding Proteins;Data;Defect;Development;Educational workshop;Elements;Embryo;Environment;Epithelial Cells;Exhibits;Fatty acid glycerol esters;Fellowship;Fibroblasts;Flow Cytometry;Fluorescence Resonance Energy Transfer;Fourier Transform;Future;Gene Combinations;Gene Targeting;Genes;Genetic;Gland;Glioblastoma;Goals;Growth;Harvest;Histology;Human;Image;Immunoprecipitation;In Vitro;Individual;Institution;Knockout Mice;Lead;Learning;Malignant Neoplasms;Mammary gland;Mass Spectrum Analysis;Measures;Medicine;Mentors;Methods;Methylation;Methyltransferase;Microarray Analysis;Microscopy;Mitotic;Modeling;Modification;Monitor;Mono-S;Mus;Mutation;N-terminal;Neoplasm Metastasis;Nuclear;Oncogene Proteins;Operative Surgical Procedures;Paraffin Embedding;Patients;Pattern;Pharmaceutical Preparations;Phase;Phenotype;Positioning Attribute;Post-Translational Protein Processing;Process;Proteins;Reagent;Research;Retinoblastoma Protein;Role;Running;Series;Signal Pathway;Site;Slide;System;Techniques;Testing;Therapeutic Agents;Time;Tissue Sample;Training;Transgenic Organisms;Transplantation;Tumor Suppressor Genes;Tumor Suppressor Proteins;Tumor Tissue;Universities;Virginia;Work;Writing;career development;cellular imaging;chromatin immunoprecipitation;design;experience;in vitro Assay;in vivo;interest;leukemia;malignant breast neoplasm;mass spectrometer;meetings;mouse model;mutant;myosin light chain 2;programs;protein function;research study;skills;stoichiometry;tool;tumor;tumor progression;tumorigenesis

public_health_relevance:
The biological roles of many genes involved in tumorigenesis remain unknown. We need to study their functions in order to achieve a complete understanding of cancer progression and obtain an inclusive list of potential druggable targets. One such protein NRMT the newly identified mammalian N-terminal methyltransferase is under-expressed in breast cancers and its knockdown results in mitotic defects often considered to contribute to cancer progression. The goal of this proposal is to understand how NRMT is regulated and how its misregulation contributes to tumorigenesis.  
  
  
The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" above summarizes the final opinions of the committee.


application_id: 8189506
project_number: 1K02AG033629-01A2
project_title: Self-Regulation and Aging: Substrates and Health Consequences
administering_ic: NIA
award_notice_date: 2012-03-12
opportunity_number: PA-10-057
application_type: 1
activity_code: K02
ic: AG
serial_number: 033629
suffix: A2
program_official: NIELSEN, LISBETH
project_start_date: 2012-03-15
project_end_date: 2017-02-28
study_section: Behavior and Social Science of Aging Study Section[NIA-S]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
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): Suzanne C. Segerstrom is an independent investigator (PhD 1997) who has established a productive research program in personality self-regulation and physiology. The application proposes to protect a high level of research effort (80%) by releasing her from teaching service and administrative responsibilities. This support will facilitate an expansion of her research program in the interactions among self-regulation physiology well-being and health in older adults. The application has three foci: (i) executive cognitive function and heart rate variability are predicted to covary with self-regulatory success (ii) self-regulatory success across domains (e.g. control of repetitive thought acquisition of social or status resources) is predicted to correlate with mental and physical health and (iii) social resources will have disproportionate effects on health with increasing age as predicted by socioemotional selectivity theory. Career development activities under the award will include didactic and experiential training in aging longitudinal design and analysis and the responsible conduct of research; collaborations with dedicated aging researchers in cognition neuropsychology immunology neurology and methodology; and spearheading special projects and meetings. Research activities will include analysis of the relationship between executive function and self- regulation in her existing R01-funded longitudinal research with community-dwelling older adults (N = 150) and studies of self-regulation and health in the R01 sample a cross-sectional study of younger and older women focusing on immunosenescence (N=76) a longitudinal follow-up in a study of middle-aged adults (N = 96) that began in 1994 and a longitudinal study of amyotrophic lateral sclerosis patients and caregivers (N = 266). Proposed studies illustrating future directions examine the role of goal selection and optimization in promoting psychological and physiological well-being in older women with pain and the role of self-regulation in socioemotional selectivity and the contributions of executive cognitive function and heart rate variability to this relationship in older adults. The University of Kentucky and the Department of Psychology provide a rich environment for the development of this work. It is expected that K02 support would allow Dr. Segerstrom to acquire additional expertise in cognition physiology and aging; produce and disseminate cutting-edge research in self-regulation aging and health; expand her grant portfolio to continue this line of research; and train PhD students in the conduct of this research.  
  
PUBLIC HEALTH RELEVANCE: NARRATIVE Older adults' ability to control thoughts emotions and behaviors - that is to self-regulate - is important for acquiring and maintaining resources such as social relationships as well as meeting other demands such as compliance with medical regimens. Understanding the underlying resources for self-regulation such as cognitive function as well as the psychological social and physical consequences of self-regulatory ability and success is important for optimizing older adults' health and well-being.

project_terms:
Adult;Age;Aging;Amyotrophic Lateral Sclerosis;Attention;Award;Behavior;Caregivers;Cognition;Collaborations;Communities;Cross-Sectional Studies;Data Collection;Databases;Development;Disease Progression;Doctor of Philosophy;Educational process of instructing;Elderly;Emotional;Emotions;Environment;Failure (biologic function);Funding;Future;Goals;Grant;Health;Health Resources;Hydrocortisone;Immune response;Immunology;Individual;Individual Differences;Inflammation;Informal Social Control;Interleukin-6;Kentucky;Lead;Longevity;Longitudinal Studies;Medical;Memory;Mental Depression;Mental Health;Methodology;Neurology;Neuropsychology;Pain;Patients;Peripheral;Personal Satisfaction;Personality;Physiological;Physiology;Process;Psychology;Regimen;Regulation;Research;Research Activity;Research Personnel;Resources;Rest;Risk;Role;Sampling;Science;Self-control as a personality trait;Series;Services;Social Interaction;Social status;Students;Testing;Thinking function;Time;Training;United States National Institutes of Health;Universities;Vaccination;Work;behavior change;beta-2 Microglobulin;career development;cognitive function;executive function;falls;follow-up;heart rate variability;immune activation;immunosenescence;longitudinal analysis;longitudinal design;meetings;middle age;older women;physical conditioning;programs;psychologic;psychosocial;public health medicine (field);research study;response;responsible research conduct;satisfaction;social;success;theories;thought control;young woman


application_id: 8189385
project_number: 7R03HL097012-03
project_title: Vitamin D Status in Pulmonary Fibrosis
administering_ic: NHLBI
award_notice_date: 2010-12-22
opportunity_number: RFA-HL-08-008
application_type: 7
activity_code: R03
ic: HL
serial_number: 097012
program_official: REYNOLDS, HERBERT Y
project_start_date: 2009-05-11
project_end_date: 2012-04-30
study_section: ZHL1-CSR-H(M1)
contact_pi_person_id: 7852167
contact_pi: RAMIREZ, ALLAN
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: Y
project_abstract:
DESCRIPTION (provided by applicant):     Idiopathic pulmonary fibrosis is a diffuse interstitial lung disease of unknown etiology characterized by chronic inflammation and progressive fibrosis and carries a 3-year 50% mortality. Currently there are no effective treatments for IPF as it responds poorly to currently available therapy which consists of corticosteroids and other immunosuppressive agents. Hence there is a critical need to develop pharmacologic agents that delay or reverse pulmonary fibrosis. Accumulating evidence indicates that transforming growth factor-beta plays an important role in the pathogenesis of pulmonary fibrosis and therefore TGF? antagonists may serve as important therapeutic target for pulmonary fibrosis. Our search for pathways that inhibit the actions of TGF? led us to the study of signal transduction by Vitamin D and its receptor (VDR). In this project we will test the hypothesis that the lung is a target organ for 125 dihydroxyvitamin D and that dysregulated Vitamin D metabolism and signaling in lung is associated with progressive IPF. The aims of this proposal are to: i) quantitate lung and systemic Vitamin D metabolites in IPF and control subjects ii) determine lung-specific expression and activation state of the Vitamin D receptor and iii) characterize the expression and distribution of the Vitamin D 25- 11- and 24- hydroxylases in the lung. Collectively these studies will provide important mechanistic insights into the regulation of lung homeostasis by Vitamin D signaling pathways.  PUBLIC HEALTH RELEVANCE: In trying to determine a mechanism of disease the goal of this project is to establish a link between vitamin D deficiency and pulmonary fibrosis. This research has broader implications for the treatment of scarring diseases of other organs.  (End of Abstract)

project_terms:
125 (OH) vitamin D;Adrenal Cortex Hormones;Area;Biocompatible Materials;Cells;Characteristics;Chronic;Cicatrix;Clinical;Connective Tissue;Deposition;Development;Diagnosis;Diffuse;Dihydroxycholecalciferols;Disease;Epithelial Cells;Etiology;Fibroblasts;Fibrosis;Goals;Hamman-Rich syndrome;Homeostasis;Hormones;Immunohistochemistry;Immunosuppressive Agents;Inflammation;Interstitial Lung Diseases;Investigation;Lesion;Link;Lung;Lung diseases;Mediating;Metabolism;Mixed Function Oxygenases;Modeling;Mortality Vital Statistics;Mus;Myofibroblast;Organ;Pathogenesis;Pathway interactions;Patients;Play;Prevalence;Process;Pulmonary Fibrosis;Receptor Activation;Regulation;Relative (related person);Reporting;Research;Reverse Transcriptase Polymerase Chain Reaction;Risk Factors;Role;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Structure of parenchyma of lung;Testing;Therapeutic;Time;Transforming Growth Factor beta;Transforming Growth Factors;Transplantation;United States;Vitamin D;Vitamin D Deficiency;Vitamin D3 Receptor;Waiting Lists;abstracting;analog;base;cytokine;effective therapy;insight;novel;outcome forecast;public health relevance;receptor;stem;therapeutic target

public_health_relevance:
Project Narrative:In trying to determine a mechanism of disease the goal of this project is to establish a link between vitamin Ddeficiency and pulmonary fibrosis. This research has broader implications for the treatment of scarringdiseases of other organs.


application_id: 8189176
project_number: 1K08CA155764-01A1
project_title: The Significance of Isocitrate Dehydrogenase Mutations in Gliomas
administering_ic: NCI
award_notice_date: 2011-08-12
opportunity_number: PA-10-059
application_type: 1
activity_code: K08
ic: CA
serial_number: 155764
suffix: A1
program_official: MYRICK, DORKINA C
project_start_date: 2011-08-12
project_end_date: 2016-07-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 9285753
contact_pi: HORBINSKI, CRAIG MICHAEL
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_abstract:
DESCRIPTION (provided by applicant): The goal of this research proposal is to determine the mechanism(s) by which mutant isocitrate dehydrogenase 1 (IDH1) causes brain tumors to be less aggressive. The most common type of brain tumor is the diffusely infiltrative glioma; these tumors cannot be completely excised surgically and are difficult to treat with radiation and chemotherapy. Thus infiltrative gliomas are incurable. A specific point mutation in IDH1 (and a less common analogous mutation in IDH2) has been found to be quite frequent in these gliomas. When present it is a powerful favorable prognostic factor being strongly associated with longer patient survival. Mutant IDH1 has recently been shown to produce a novel compound 2-hydroxyglutarate (2-HG). However the effects of mutant IDH1 and 2-HG on glioma cells are unknown. Other work showed that 2-HG causes oxidative stress in nonneoplastic tissue models and our preliminary data indicate that 2-HG is toxic to glioma cells and induces autophagy ERK activation and reactive oxygen species production. We therefore hypothesize that the improved survival imparted by mutant IDH1 in diffuse gliomas is due to 2-HG-induced production of reactive oxygen species leading to oxidative damage and cell death. We also hypothesize that the cell death is primarily by autophagy a form of programmed cell death involving lysosomes that has been shown to be prominent in many gliomas. To test these hypotheses glioma cells will be treated with 2-HG or transfected with mutant IDH1 and multiple well-described markers of autophagy and reactive oxygen species will be measured. Response of glioma cells to autophagy and reactive oxygen species modulation will be assessed. For patient-derived tumor biopsies and human-mouse xenografts immunohistochemical markers of autophagy and oxidative stress will be quantified and correlated with IDH mutation status. Success in this project would determine whether mutant IDH1 causes increased oxidative stress and autophagy in gliomas thereby producing a less aggressive glioma compared to tumors that are wild type for IDH1. This knowledge could then be exploited to develop novel ways of treating gliomas. I am fortunate to have been mentored by exceptional scientists and physicians thus instilling in me a desire to pursue a career that synthesizes what I have learned as a scientist and neuropathologist.My graduate and postdoctoral work in neuroscience and my work in neuro-oncology have given me a diverse array of techniques and approaches that will be used in this project. My current position as an Assistant Professor in the Department of Pathology in the University of Kentucky offers the ideal opportunity to pursue my goal of being an independent investigator. I have nine person-months (75%) of guaranteed protected time for research separate laboratory space that has been fully equipped a full-time technician to increase output and sufficient funds to conduct experiments for the next four years. All this has been put in place by my chairman Dr. Paul Bachner independent of my success in securing extramural funding. I also benefit from a collaborative environment superb mentorship by Drs. Natasha Kyprianou Arie Perry and Jeremy Rich and excellent technical resources. Now that I have completed my clinical training the funding provided by this K08 award would allow me to develop as an independent investigator. Furthermore the project described in this proposal provides a superb opportunity to discover why mutant IDH1 imparts a more favorable survival in patients afflicted with gliomas in turn helping to identify pathways and targets for effective therapeutic interventions.  
  
PUBLIC HEALTH RELEVANCE: This research explores why mutant isocitrate dehydrogenase 1 an abnormal enzyme found in many brain tumors is such a powerful marker of longer patient survival. Discovering why this is so will help find new ways to treat these incurable tumors.  
  
  
The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.

project_terms:
3-methyladenine;Abbreviations;Affect;Analysis of Variance;Antioxidants;Apoptosis;Arginine;Autophagocytosis;Award;Binding Sites;Biology;Biopsy;Brain Neoplasms;Bromodeoxyuridine;Cell Death;Cell Survival;Cells;Cessation of life;Chairperson;Clinical;Codon Nucleotides;Critiques;Data;Detection;Diffuse;Environment;Enzymes;Epidermal Growth Factor Receptor;Extramural Activities;Formalin;Funding;Future;Genetic;Glioma;Gliomagenesis;Glutathione Disulfide;Goals;Green Fluorescent Proteins;Human;In Vitro;Individual;Isocitrate Dehydrogenase (NAD+);Isocitrates;Kentucky;Knowledge;Laboratories;Lead;Learning;Lesion;Light;Lysosomes;MAP1 Microtubule-Associated Protein;MGMT gene;Manganese Superoxide Dismutase;Measurement;Measures;Mentors;Mentorship;Metabolic;Methods;Mus;Mutate;Mutation;NADP;Neurosciences;O(6)-Methylguanine-DNA Methyltransferase;Output;Oxidative Stress;Paraffin Embedding;Pathology;Pathway interactions;Patients;Persons;Phosphatidylethanolamines;Physicians;Point Mutation;Positioning Attribute;Primary Neoplasm;Production;Prognostic Factor;Radiation;Reactive Oxygen Species;Research;Research Personnel;Research Proposals;Resources;Scientist;Secure;Techniques;Testing;Tetrazolium Salts;Therapeutic Intervention;Time;Tissue Model;Tissues;Training;Tumor-Derived;Universities;Work;World Health Organization;Writing;Xenograft procedure;alpha ketoglutarate;career;chemotherapy;clinically relevant;clinically significant;dichlorofluorescin;expectation;glioma cell line;improved;inhibition of autophagy;isocitrate;meetings;monodansylcadaverine;mutant;neuro-oncology;novel;outcome forecast;oxidative damage;phosphatidylethanolamine;professor;prognostic;research study;response;success;tumor

public_health_relevance:
This research explores why mutant isocitrate dehydrogenase 1 an abnormal enzyme found in many brain tumors is such a powerful marker of longer patient survival. Discovering why this is so will help find new ways to treat these incurable tumors.  
  
  
The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.


application_id: 8188510
project_number: 2P01HL078825-06
project_title: Diabetic Dyfuntion of CPCs
administering_ic: NHLBI
opportunity_number: PAR-10-285
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7459
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-05
budget_end_date: 2012-05-31
project_terms:
Acids;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptosis;Attenuated;Cardiac;Cell Therapy;Cell physiology;Cells;Competence;Cytoprotection;Development;Diabetes Mellitus;Diabetic mouse;Differentiation and Growth;Doctor of Medicine;Electron Spin Resonance Spectroscopy;Electron Transport;Fatty Acids;Fatty acid glycerol esters;Functional disorder;Generations;Glucose;Glycolysis;Goals;Growth Factor;Heart;Heart failure;Heme Oxygenase (Decyclizing);Hyperactive behavior;Inflammation;Inflammatory Response;Instruction;Insulin Resistance;Intervention;Lead;Length;Measures;Mediating;Metabolism;Mitochondria;Mortality Vital Statistics;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Oxidative Stress;Oxygen Consumption;Palmitic Acids;Patients;Principal Investigator;Process;Production;Reactive Oxygen Species;Regimen;Resistance;Risk Factors;Role;Stem cells;Stimulus;Telomerase;Testing;Therapeutic Intervention;Transplantation;Tumor Necrosis Factor Receptor;UCP2 protein;adiponectin;cell growth;cytokine;design;diabetic;diabetic patient;fatty acid metabolism;feeding;glucose transport;glucose uptake;improved;in vivo;insulin sensitivity;insulin signaling;migration;mouse model;non-diabetic;nutrient metabolism;outcome forecast;overexpression;prevent;receptor;repaired;senescence;stem cell therapy;telomere


application_id: 8188507
project_number: 2P01HL078825-06
project_title: Tumor Necrosis Factor Modulation of CPCs
administering_ic: NHLBI
opportunity_number: PAR-10-285
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7457
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-05
budget_end_date: 2012-05-31
project_terms:
Adrenergic Agents;Arrhythmia;Biological;Cardiac;Cardiac Myocytes;Catecholamines;Cell Density;Cell Differentiation process;Cell Surface Receptors;Cell Therapy;Cell Transplantation;Cell membrane;Cell physiology;Cells;Clinical;Competence;Cytoprotection;Disease;Doctor of Medicine;Dominant-Negative Mutation;Etanercept;Healed;Heart;Heart failure;Human;In Vitro;Inflammation;Inflammatory;Injury;Instruction;Label;Left Ventricular Remodeling;Left ventricular structure;Light;MAP Kinase Gene;MAPK14 gene;Mediating;Mediator of activation protein;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Nuclear;Phenotype;Play;Principal Investigator;Process;Promotor (Genetics);Proteins;Proto-Oncogene Protein c-kit;Role;Secondary to;Signal Transduction;Staging;Stem cell transplant;Stem cells;TNFRSF1A gene;TNFRSF1B gene;Testing;Therapeutic;Tissues;Transgenic Organisms;Transplantation;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Tyrosine 3-Monooxygenase;Wound Healing;adrenergic;cell behavior;cell type;cytokine;healing;improved;in vivo;indexing;inhibitor/antagonist;injured;nerve stem cell;nestin protein;novel;receptor;repaired;research study;response;time use


application_id: 8188504
project_number: 2P01HL078825-06
project_title: Role of the NO-CO Module in Regulating CPC Function
administering_ic: NHLBI
opportunity_number: PAR-10-285
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
project_start_date: 2005-04-15
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7456
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
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: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2011-08-05
budget_end_date: 2012-05-31
project_abstract:
The discovery of cardiac progenitor cells (CPCs) provides a potential new approach to the treatment of heartfailure (HF) The initial results of our first-in-humans clinical study of CPCs in patients with HF (SCIPIO) areencouraging. However CPC-based therapies are severely limited by the fact that almost all (at least 97%)of the transplanted CPCs die shortly after transplantafion. This implies that increasing the survival oftransplanted cells by prevenfing apoptosis will enhance the efficacy of CPC therapy. In the current fundingperiod of this Program Project we have found that carbon monoxide (CO) and nitric oxide (NO) exertpowerful anti-apoptotic actions and form a closely inter-related functional module (CO-NO module) which isregulated by heme oxygenase-1 (HO-1) extracellular superoxide dismutase (ecSOD) and inducible NOsynthase (iNOS). We will exploit this discovery to enhance cell-based therapies. The overall goal of Proiect1 is to elucidate the role of the CO-NO module in regulating CPC function and to evaluate its therapeuticutility after myocardial infarction (Ml). We propose that augmenting this module will greatly potentiate theeffectiveness of transplanted CPCs and dramaticallv enhance CPC-mediated cardiac repair. This Projectrepresents the natural evolution of our previous work in this Program Project; having discovered that the CO-NO module affors powerful protection against mmyocardial ischemia we will now build on this work toenhance the reparative ability of CPCs. In Aim 1 we will determine the roles of HO-1 and CO in modulatingCPC function. In Aim 2 we will establish the role of ecSOD in regulating CPC function and mediating HO-1-induced protection of CPCs. In Aim 3 we will determine the role of NO in modulating CPC function and therole of HO-1 and ecSOD in mediating the effects of NO on CPCs. Using both gain- and loss-of-functionapproaches in all three Aims we will systematically evaluate fundamental parameters of CPC competence invitro and the ability of CPCs to repair cardiac damage in vivo in a murine model of post-MI LV remodelingand dysfunction. In Aim 4. we will elucidate the molecular mechanisms whereby CO and NO upregulateecSOD and NO upregulates HO-1 and ecSOD in CPCs focusing on the transcription factor Nrf2. These willbe the first studies to examine the role of CO and NO and their supporting proteins HO-1 ecSOD andINOS in modulating CPC function. The results will be entirely new and will add a new dimension to ourunderstanding of CPC biology. In addition these studies will provide proof-of-principle for the therapeuticutility of manipulations that potentiate the CO-NO module in CPCs which may lay the groundwork for futuretrials of genetically or pharmacologically enhanced CPCs in patients with HF.RELEVANCE (See instructions):In 2009 we started SCIPIO a study of c-kit+ cardiac progenitor cells (CPCs) in patients with heart failureand the initial results are encouraging. Project 1 builds on SCIPIO. We will test a new therapy - genetically-modified or preconditioned CPCs which promise to be superior to the cells currently being used in SCIPIO.If the results confirm our working hypothesis these studies will lay the groundwork for testing more effectiveCPCs for the treatment of heart failure and thus may facilitate translation of cell therapies to humans.

project_terms:
Apoptosis;Apoptotic;Carbon Monoxide;Cardiac;Cell Survival;Cell Therapy;Cell Transplants;Cell physiology;Cells;Cellular biology;Chemotaxis;Clinical Research;Competence;Deet;Dimensions;Doctor of Medicine;Effectiveness;Evolution;Functional disorder;Funding;Future;Gene Transfer;Generations;Genetic;Genetic Transcription;Goals;Heart failure;Heme;Heme Oxygenase (Decyclizing);Human;In Vitro;Instruction;Ischemia;Left Ventricular Remodeling;Length;Measures;Mediating;Mediator of activation protein;Minority;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Oxidative Stress;Patients;Phase I Clinical Trials;Principal Investigator;Proteins;Proto-Oncogene Protein c-kit;Reactive Oxygen Species;Resistance;Role;Stem cells;Structure;Superoxide Dismutase;Telomerase;Testing;Therapeutic;Translations;Transplantation;Up-Regulation (Physiology);Work;clinical application;cytokine;extracellular;gain of function;human NOS2A protein;in vivo;inhibitor/antagonist;loss of function;novel strategies;oxidative damage;phase 1 study;pre-clinical;preconditioning;prevent;programs;repaired;senescence;telomere;transcription factor


application_id: 8187763
project_number: 1R01AG039732-01A1
project_title: The Role of Adipose Tissue in Age-dependent Sensitivity to Critical Illness
administering_ic: NIA
award_notice_date: 2011-07-29
opportunity_number: PA-10-042
application_type: 1
activity_code: R01
ic: AG
serial_number: 039732
suffix: A1
program_official: FRANKOWSKI, DAVID WITT
project_start_date: 2011-08-01
project_end_date: 2016-07-31
study_section: Special Emphasis Panel[ZRG1 BDCN-M (02)]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
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): Aging is characterized by an altered stress response that underlies a compromised resistance to disease or injury. Activation of inflammatory and coagulant pathways is a frequent consequence of severe critical illnesses and results in the progression of systemic inflammatory response syndrome (SIRS). Recent evidence suggests that adipose tissue-derived signaling proteins including cytokines coagulation factors and hormones may play an important role in the inflammatory response. Our long-term goals are to identify the mechanisms by which adipose tissue contributes to age-dependent severity of SIRS and to develop therapeutic strategies for decreasing vulnerability to critical illnesses in the aged. For these studies we will use two widely accepted mouse models of SIRS - acute endotoxemia induced by injection with bacterial endotoxin lipopolysaccharide and an intra-abdominal sepsis model induced by cecal ligation and puncture. The objective of this project is to identify and evaluate the expression of adipose-derived inflammatory and coagulant factors that differ by aging upon inflammatory stress. Our central hypothesis is that expression patterns of inflammatory / coagulant factors in the adipose tissue during SIRS are significantly altered by aging and that this alteration contributes to age-dependent severity of critical illnesses. To achieve the above goals we will pursue the following three specific aims: (1) To define the role of adipose tissue in age-related alterations of coagulation during critical illness. (2) To understand the mechanisms of age-related inflammatory cytokine production in the adipose tissue during critical illness. (3) To evaluate methods of body fat loss as potential therapies and preventative measures for reducing severity of critical illness in the aged. These studies will provide significant insight into the association of the previously neglected adipose organ in aging and critical illness.  
  
PUBLIC HEALTH RELEVANCE:  This project is relevant to public health because it will enhance our understanding of the roles of adipose tissue in increased severity of critical illness in the elderly. This project will also provide information for the development of treatments and preventative therapies to decrease incidence rates and deaths related to critical illness in the aged. Preventative therapies will likely result in reduced patient visits and decreased health care costs. The development of effective treatments for systemic inflammation of which there are currently none available will be beneficial to elderly patients who suffer from critical illnesses.

project_terms:
Abbreviations;Acute;Adipose tissue;Age;Age Reporting;Aging;Animal Model;Blood Coagulation Factor;Body fat;Burn Trauma;Cessation of life;Coagulants;Coagulation Process;Complication;Critical Illness;Death Rate;Development;Disease Resistance;Disseminated Intravascular Coagulation;Elderly;Endotoxemia;Endotoxins;Excision;Foundations;Functional disorder;Gene Expression;Genes;Genetic;Goals;Growth Factor;Health Care Costs;Hormones;In Vitro;Incidence;Inflammation;Inflammatory;Inflammatory Response;Injection of therapeutic agent;Injury;Interleukin-1 Receptors;Interleukin-6;Intra-abdominal;Knockout Mice;Ligation;Link;Lipopolysaccharides;Lung;Measures;Mediating;Mediator of activation protein;Methods;Modeling;Mortality Vital Statistics;Mus;Operative Surgical Procedures;Organ;Organ Culture Techniques;Pathway interactions;Patients;Pattern;Plasminogen Activator Inhibitor 1;Plasminogen Activator Inhibitor 2;Plasminogen Inactivators;Play;Predisposition;Preventive;Process;Production;Puncture procedure;Role;Sepsis;Sepsis Syndrome;Severities;Signaling Protein;Source;Stress;System;TNF gene;Testing;Therapeutic;Thromboplastin;Thrombosis;Transgenic Organisms;Transplantation;Visceral;Visit;Wild Type Mouse;acute pancreatitis;age related;aged;biological adaptation to stress;cytokine;dietary restriction;effective therapy;improved;insight;middle age;mouse model;mutant;neglect;older patient;public health medicine (field);research study;therapy development


application_id: 8185539
project_number: 1R01CA158275-01A1
project_title: ???Novel melampomagnolide B-based prodrugs for the treatment of leukemia???
administering_ic: NCI
award_notice_date: 2011-07-01
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: CA
serial_number: 158275
suffix: A1
program_official: FU, YALI
project_start_date: 2011-07-01
project_end_date: 2011-07-02
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8236531
contact_pi: CROOKS, PETER ANTHONY
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
project_abstract:
DESCRIPTION (provided by applicant): The long-term objective of this proposal is to develop a novel class of anti-cancer agents based on the plant derived compound parthenolide (PTL). Previous studies have demonstrated that PTL has potent cytotoxic activity against a broad range of malignancies including cancers of the breast lung prostate colon liver kidney pancreas brain and bone. In addition to solid tumor studies several groups including our own have focused on human leukemia (or related hematologic malignancies). We have demonstrated that PTL is highly cytotoxic to primary human leukemia specimens but non-toxic to normal blood-forming tissues. Thus the collective evidence suggests that PTL has broad potential as an anti-cancer agent. However despite the remarkable properties of this compound clinical development has been very limited likely due to the poor pharmacological properties of PTL. Indeed to our knowledge the only PTL-based compound to reach clinical trial stage work is dimethylamino parthenolide (DMAPT) which we previously developed as an orally bioavailable PTL analog. Thus going forward we believe that applying novel strategies to create more pharmacologically useful forms of PTL-based agents is a high priority. In the course of performing various chemical modifications of PTL it was demonstrated that the C-10 methyl group can be hydroxylated by reaction with a suitable oxidizing agent. This reaction changes the geometry of the C-9-C-10 double bond from Z to E to afford a hydroxymethyl 1(10)-cis-parthenolide analogue a compound previously described as melampomagnolide B (MM-B). Intriguingly the biological activity of MM-B is identical to PTL retaining strong specificity for leukemia cells. The presence of the C-10 hydroxymethyl group now creates the opportunity for designing an entirely new class of PTL analog. Thus in the present application we propose to develop and test novel MM-B-based products. Specifically the aims of the study will be to 1) synthesize novel water-soluble MM-B prodrugs 2) perform pharmacological and biological efficacy studies and 3) perform molecular and cellular characterization of the mechanism of action of MM-B. Taken together these studies will create and validate an entirely new type of anti-cancer agent. In addition by characterizing the molecular mechanism of action of this novel PTL derivative it should be possible to further refine strategies for the selective eradication of cancer cells.  
  
PUBLIC HEALTH RELEVANCE: The goal of this project is to identify new and better ways to treat leukemia. We propose to develop new drugs derived from the naturally occurring compound parthenolide which has shown significant activity as an anti-leukemia agent. Our studies will synthesize and test novel orally-available parthenolide derivatives

project_terms:
Animal Model;Antineoplastic Agents;Bioavailable;Biochemical;Biological;Biological Models;Biological Process;Biotin;Blood;Brain;Buffers;Cells;Chemicals;Clinical;Clinical Trials;Colon;Data;Development;Disease;Drug Kinetics;Family;Goals;Half-Life;Hematologic Neoplasms;Hematopoietic Neoplasms;Human;Hydrolysis;In Vitro;Kidney;Killings;Kinetics;Lactones;Lead;Liquid substance;Liver;Lung;Malignant - descriptor;Malignant Neoplasms;Metabolic;Modification;Molecular;Molecular Mechanisms of Action;Nature;Normal Cell;Normal tissue morphology;Oral;Oral Administration;Oxidants;Pancreas;Parents;Pharmaceutical Preparations;Pharmacologic Substance;Phase I Clinical Trials;Plants;Plasma;Prodrugs;Property;Prostate;Reaction;Relative (related person);Reporting;Role;Series;Sesquiterpenes;Simulate;Solid Neoplasm;Specificity;Specimen;Staging;Structure;Testing;Therapeutic Agents;Time;Tissues;Toxic effect;Toxicology;Water;Work;analog;aqueous;base;bone;cancer cell;carbene;cell type;cytotoxic;design;drug development;efficacy testing;gastrointestinal;improved;in vivo;leukemia;malignant breast neoplasm;member;methyl group;novel;novel strategies;parthenolide;pi bond;pre-clinical

public_health_relevance:
The goal of this project is to identify new and better ways to treat leukemia. We propose to develop new drugs derived from the naturally occurring compound parthenolide which has shown significant activity as an anti-leukemia agent. Our studies will synthesize and test novel orally-available parthenolide derivatives


application_id: 8185414
project_number: 1R01NS072302-01A1
project_title: Preclinical evaluation of IGF1 therapy for traumatic brain injury
administering_ic: NINDS
award_notice_date: 2011-07-04
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: NS
serial_number: 072302
suffix: A1
program_official: HICKS, RAMONA R
project_start_date: 2011-07-15
project_end_date: 2016-06-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 6875991
contact_pi: SAATMAN, KATHRYN E
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
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): Traumatic brain injury (TBI) afflicts an estimated 1.5 million people each year in the US. Survivors often suffer persistent neurological dysfunction compromising their quality of life and productivity. Despite the expanding base of knowledge regarding the complex pathophysiology of TBI no clinically proven therapeutic interventions have been identified. TBI produces acute neurovascular damage and cell death resulting in early functional deficits. Recovery of function may be limited by the inability of the injured brain to adequately harness endogenous repair mechanisms. The central hypothesis of this proposal is that treatment with insulin-like growth factor-1 (IGF-1) will improve neurobehavioral function through the attenuation of neurovascular damage and the augmentation of posttraumatic neurogenesis and angiogenesis. We previously showed that administration of recombinant human IGF-1 (rhIGF-1) improves motor and cognitive function in brain-injured rats. However no studies have examined the neuroprotective or neurorestorative capabilities of IGF-1 in the traumatized brain. We propose to conduct the first comprehensive investigation of the multiple potentially synergistic mechanisms underlying the behavioral efficacy of IGF-1. Importantly we will evaluate the efficacy of rhIGF-1 treatment initiated within a clinically relevant therapeutic window of 8 hr and demonstrate sustained protection up to 5 weeks postinjury. In the setting of TBI IGF-1 is a promising therapeutic candidate as it has neuroprotective properties and helps to sustain or enhance myelination. Therefore after demonstrating in Aim 1 that a 7 day systemic infusion of rhIGF-1 initiated at 15 min 3 hr or 8 hr postinjury improves motor and cognitive function in mice subjected to cortical impact brain injury in Aim 2 we will test the hypothesis that IGF-1 protects against neuronal loss and axonal degeneration. IGF-1 is also known to stimulate proliferation of progenitor cells promote neuronal oligodendroglial and endothelial differentiation and increase angiogenesis in the brain. Therefore in Aim 3 we will test the hypothesis that infusion of rhIGF-1 enhances neurogenesis in the subgranular and subventricular zones. In Aim 4 we will employ novel vascular perfusion techniques to quantify densities of total and angiogenic vessels in brain- injured mice treated with rhIGF-1 or vehicle to test the hypothesis that IGF-1 effectively enhances posttraumatic angiogenesis. Finally in Aim 5 we will test the hypothesis that rhIGF-1 administration delayed 48 hr can selectively enhance neurogenesis and angiogenesis resulting in cognitive recovery in the absence of acute neuroprotection. These data will provide unique and valuable insights into the neurovascular targets for IGF-1 in the injured brain. By establishing long term (up to 5 wks postinjury) histological benefits and correlating these with behavioral responses the proposed studies have the potential for high clinical impact. Ultimately our goal is to provide a catalyst to accelerate the translation of IGF-1 therapy into clinical application in order to improve the health and well-being of individuals burdened with TBI.  
  
PUBLIC HEALTH RELEVANCE: Project Narrative In light of the high incidence and devastating socioeconomic costs of traumatic brain injury development of an effective treatment strategy is of utmost importance. Our proposed studies will provide multiple lines of evidence that treatment with insulin-like growth factor-1 initiated within a clinically feasible therapeutic window improves functional outcome and reduces brain damage following contusion brain injury. These studies will provide new insights into how this growth factor protects the traumatized brain yielding information critical to translating this treatment into clinical trials.

project_terms:
Acute;Age;Attenuated;Axon;Behavioral;Blood Vessels;Brain;Brain Injuries;Bromodeoxyuridine;Cause of Death;Cell Death;Cells;Cerebral Ischemia;Cessation of life;Clinical;Clinical Trials;Cognition;Cognitive;Complex;Contusions;Cortical Contusions;Data;Demyelinations;Enrollment;Evaluation;Functional disorder;Goals;Health;Hippocampus (Brain);Human;IGF1 gene;Individual;Infusion procedures;Injury;Insulin-Like Growth Factor I;Investigation;Isolectin;Label;Learning;Measurement;Memory;Motor;Mus;Myelin;Nerve Degeneration;Neurologic Dysfunctions;Neurons;Outcome;Patients;Perfusion;Personal Satisfaction;Productivity;Proliferating;Property;Quality of life;Rattus;Recombinants;Recovery of Function;Research;Silver Staining;Spinal cord injury;Staining method;Stains;Stem cells;Survivors;Techniques;Testing;Therapeutic;Therapeutic Intervention;Time;Translations;Traumatic Brain Injury;Wound Healing;angiogenesis;attenuation;axonal degeneration;brain repair;catalyst;cell injury;cell type;central nervous system injury;clinical application;clinically relevant;cognitive function;cognitive recovery;cognitive rehabilitation;controlled cortical impact;density;disability;functional outcomes;improved;injured;insight;knowledge base;myelination;neurobehavioral;neurogenesis;neuron loss;neuronal survival;neuroprotection;neurorestoration;novel;preclinical evaluation;rehabilitation strategy;repaired;response;stem;subventricular zone;tomato lectin


application_id: 8185278
project_number: 2R01NS039041-11A2
project_title: Neurogenic Amplification of Pancreatitis Pain
administering_ic: NINDS
award_notice_date: 2011-06-22
opportunity_number: PA-10-006
application_type: 2
activity_code: R01
ic: NS
serial_number: 039041
suffix: A2
program_official: PORTER, LINDA L
project_start_date: 2000-04-01
project_end_date: 2015-06-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN 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
project_abstract:
DESCRIPTION (provided by applicant): For patients with inflamed or cancerous pancreas the precipitating complaint is pain generated by local tissue inflammation fibrosis ductal stenosis edema and fluid pressure. The pain relayed by visceral afferent nerves from chronically inflamed pancreas can become severe and intractable with no effective long-term treatment options. The studies proposed in this competitive renewal extend the original aims of the parent grant with two serendipitously discovered novel and potentially related findings. Discovery #1: Our recent unpublished findings indicate that high fat diet and alcohol induce increased expression of transient receptor potential vanilloid 4 (TRPV4) channels on pancreas cells. TRPV4 channels are non-selective cation channels responsive to conditions present in the local cellular microenvironment after tissue injury including lipid mediators and tissue edema. Some alcohol metabolites are lipid mediators that can activate TRPV4. Excessive TRPV4 activation initiates cellular influx of calcium that initiates damaging intracellular cascades and pancreas afferent nerve activation. Discovery #2: We found that pancreatic tissue damage inflammation and pain-related behaviors are significantly reduced by gene therapy inducing overexpression of the endogenous opioid peptide met- enkephalin. We propose new studies using a chronic pancreatitis model in rats and clonal pancreatic cells to further investigate significant tissue injury-induced changes in the cell microenvironment that are relevant to inducible TRPV4 expression and activation responses during the development of chronic pain. Hypothesis: Alcohol-induced injury in pancreas cells increases TRPV4 expression and activation which are reduced by met-enkephalin protection Aim 1 Determine the effects of alcohol injury on TRPV4 expression and activation in the pancreas. Aim 2 Determine if alcohol-induced TRPV4 expression and activation is reduced by met-enkephalin. Our overall goal is to discover local cellular microenvironment interactions that impact chronic pain and that provide inroads for development of future clinical treatments for chronic inflammatory visceral pain. The impact of TRPV4 induced in local reactive cells after tissue damage and the role of TRPV4 in chronic pain have not been well studied. The findings will provide knowledge about analgesic protective and reparative effects of met-enkephalin related to TRPV4. Expected outcomes of challenging pancreatic cells in vitro with TRPV4 activators are that TRPV4 expression and activation responses will increase except in the presence of met- enkephalin. Further TRPV4 inhibitors and met-enkephalin will reduce pain-related behaviors in the rat model of chronic pancreatitis. The findings will extend understanding of TRPV4 mediated events in the local microenvironment that impact both peripheral and central sensitization during the transition from acute to chronic visceral pain. Study of the transition to chronic pain is a mission of the NIH Blueprint and NINDS.  
  
PUBLIC HEALTH RELEVANCE: We propose that alcohol and other related injurious agents present in the inflamed pancreas increase expression and activation of the cation channel protein transient receptor protein vanilloid 4 (TRPV4). We propose studies to confirm this preliminary finding and to determine if the endogenous opioid peptide met-enkephalin can interfere with the destructive actions induced by alcohol injury on TRPV4 expression and activation. Our novel findings have implications for improved pancreatic function and reduction of pain for patients with pancreatitis and pancreatic cancer.


application_id: 8185225
project_number: 1G20RR032478-01
project_title: Enhancement of the Biological-Pharmaceutical Animal Facility
administering_ic: NCRR
award_notice_date: 2011-06-22
opportunity_number: RFA-RR-10-011
application_type: 1
activity_code: G20
ic: RR
serial_number: 032478
program_official: MCCULLOUGH, WILLIE
project_start_date: 2011-07-01
project_end_date: 2012-06-30
study_section: Scientific and Technical Review Board on Biomedical and Behavioral Research Facilities[STRB]
contact_pi_person_id: 1903578
contact_pi: STILLS, HAROLD F
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
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: ORGANIZED RESEARCH UNITS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky (UK) Division of Laboratory Animal Resources (DLAR) requests $484475 to purchase individually ventilated caging (IVC) and animal transfer stations. This proposal will equip 3 rooms in a suite of 4 presently unoccupied rodent housing rooms with shared procedure rooms and provide desperately needed caging capacity in the newly constructed Biological-Pharmaceutical (Bio-Pharm) Building animal facility. The Bio-Pharm facility is a modern research facility and the largest academic and research building in the State of Kentucky. The facility was constructed and the lower four levels (basement- animal facility and NMR facility floors 1&2-academic instruction floor 3- research) outfitted with state funding. The fourth and fifth research laboratory floors are presently being completed with university funding with an anticipated March 2011 occupancy. These two floors will support an increased emphasis on research in the College of Pharmacy and expansion of cancer related research at the university. Additional successful investigators are presently being recruited for these areas of emphasis. The requested caging will maximize potential housing capabilities and provide optimal animal housing environments while reducing labor requirements for these additional investigators. The additional caging capability will also permit NIH-funded UK investigators to move their mouse housing from the nearby Lexington Veterans Administration (Lexington VA) facility to UK facilities that are much closer to their laboratories. This relocation will reduce the transport of animals from the Lexington VA to UK research laboratories a process that jeopardizes animal biosecurity and exposes patients at the Lexington VA Hospital the UK A. B. Chandler Medical Center and the UK Clinic (outpatient facility) to rodent allergens and potentially infectious agents. The acquisition of the requested caging will permit the university to maximize use of the newly constructed animal facility and improve the ability of the university to support NIH-funded investigators using mice in biomedical research.

project_terms:
Academic Medical Centers;Allergens;Ambulatory Care Facilities;Animal Housing;Animals;Area;Biological;Biomedical Research;Environment;Floor;Funding;House mice;Housing;Infectious Agent;Instruction;Kentucky;Laboratories;Laboratory Animals;Laboratory Research;Malignant Neoplasms;Mus;Patients;Pharmacologic Substance;Pharmacy facility;Procedures;Process;Recruitment Activity;Research;Research Personnel;Rodent;United States Department of Veterans Affairs;United States National Institutes of Health;Universities;University Hospitals;animal facility;animal resource;biosecurity;college;improved;research facility


application_id: 8184594
project_number: 1R01EY021231-01A1
project_title: The functional role of sarcomeric nonmuscle myosin IIB in extraocular muscles
administering_ic: NEI
award_notice_date: 2011-07-18
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: EY
serial_number: 021231
suffix: A1
program_official: ARAJ, HOUMAM H
project_start_date: 2011-08-01
project_end_date: 2014-07-31
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 7875119
contact_pi: MONCMAN, CAROLE L.
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
project_abstract:
DESCRIPTION (provided by applicant): The extraocular muscles (EOMs) are categorized as skeletal muscles; however emerging evidence indicates that they deviate significantly from the prototypical members of this muscle class. For example many myofilament cytoskeletal and extracellular matrix proteins have unique expression patterns in developing and adult EOMs including the sustained expression of embryonic and fetal myosin isoforms (MyHC) the presence of a unique EOM-specific MyHC and co-expression of cardiac and skeletal muscle isoforms of thick and thin filament accessory proteins. We demonstrated that a nonmuscle myosin (nmMyH IIB) is present in the sarcomeric A band of putative tonic EOM fibers. Although small amounts of nmMyH IIB are found in the Z-line of cardiac and skeletal muscles its unique distribution within the A band in EOM tonic fibers is further evidence of the complexity and unconventional developmental program of the eye muscles. We will use genetically engineered mice to delete nmMyH IIB in a tissue and time-specific manner in order to test the following central hypothesis: the sarcomeric distribution of nmMyH IIB in EOM fibers depends on normal visual experience postnatally and is necessary for normal EOM contractile function in the adult. Thus we have defined the following specific aims: 1) determine whether normal visual experience early in life is necessary for the expression and sarcomeric localization of nmMyH IIB in rodent EOMs 2) define the role of nmMyH IIB on sarcomeric structure in rodent EOMs and 3) determine the influence of nmMyH IIB on the contractile function of rodent EOMs. These results will establish the role of nmMyH IIB in EOM fibers during early postnatal development and in the adult and should provide valuable insights into our understanding of the normal EOM phenotype and how it might change with disease.)  
  
PUBLIC HEALTH RELEVANCE: In addition to the sensory pathways the ability to direct the eyes to items of interest is also key for normal vision. The extraocular muscles are the small muscles responsible for coordinated eye movements. This project will examine the function of a structural protein found in a unique position only in the extraocular muscles and that may be important for normal eye movements.)

project_terms:
Adult;Appearance;Biochemical;Biological Assay;Birth;Development;Disease;Embryo;Extracellular Matrix Proteins;Eye;Eye Movements;Eyelid structure;Fiber;Genetically Engineered Mouse;Imaging Techniques;In Vitro;Life;Longevity;Mesoderm;Microfilaments;Mus;Muscle;Muscle Development;Muscle Fibers;Myocardium;Myofibrillogenesis;Myosin ATPase;Myosin Heavy Chains;Neural Crest;Neuromuscular Junction;Nonmuscle Myosin Type IIB;Pathway interactions;Pattern;Perinatal;Peripheral;Phenotype;Positioning Attribute;Protein Isoforms;Proteins;Rattus;Research Personnel;Rodent;Role;Sarcomeres;Sensory;Skeletal muscle structure;Skin;Slide;Striated Muscles;Structural Protein;Structure;Testing;Thick Filament;Thin Filament;Time;Tissues;Vision;Visual;cell motility;early experience;experience;fetal;in vivo;insight;interest;member;muscular structure;non-muscle myosin;orbit muscle;postnatal;programs;research study;vision development

public_health_relevance:
In addition to the sensory pathways the ability to direct the eyes to items of interest is also key for normal vision. The extraocular muscles are the small muscles responsible for coordinated eye movements. This project will examine the function of a structural protein found in a unique position only in the extraocular muscles and that may be important for normal eye movements.)


application_id: 8184506
project_number: 1R01HL106173-01A1
project_title: Resolution of inflammation in obesity and diabetes: Role of lipid mediators
administering_ic: NHLBI
award_notice_date: 2011-07-28
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: HL
serial_number: 106173
suffix: A1
program_official: TOLUNAY, ESER
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8656605
contact_pi: SPITE, MATTHEW R
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
project_abstract:
DESCRIPTION (provided by applicant):  Type 2 diabetes (T2D) and obesity have emerged as major public health crises. These conditions increase the risk of cardiovascular diseases and cause microvascular dysfunction. Patients with T2D also show deficits in wound healing and tissue repair. Although the mechanisms leading to T2D are not well understood recent work has shown that the states of diabetes and obesity are associated with low-grade chronic inflammation which triggers and sustains insulin resistance in target tissues. This project is to test the hypothesis that chronic inflammation in obesity and diabetes is sustained in part due to the failure of pro-resolving pathways. This hypothesis predicts that innate immune responses activated in obesity and diabetes fail to resolve leading to chronic inflammation and insulin resistance. It also predicts that restoration of endogenous pro-resolving mediators should extinguish inflammation and restore insulin sensitivity. The specific aims of this project are to: (1) Define changes in resolution of inflammation during diabetes and obesity; (2) Determine whether restoring resolution will diminish inflammation and insulin resistance; and (3) Identify the mechanism by which promotion of resolution affects insulin resistance. To accomplish these aims we will examine the time course of the development and the resolution of acute inflammation. We will measure changes in pro-resolving lipid mediators by a mass-spectrometry-based lipidomic approach establish the temporal relationship between changes in lipid mediator synthesis and insulin resistance and identify the mechanisms by which diabetes and obesity affect the biosynthesis of pro-resolution mediators. To assess the functional significance of the changes in resolution in diabetes and obesity we will test whether treatment with resolvin D1 (RvD1) will correct the resolution defect and improve glucose tolerance systemic insulin resistance and wound healing in high-fat fed and db/db mice. We will determine how RvD1 affects vascular inflammation and adipose-tissue macrophage phenotype. To delineate the mechanism of action we will examine whether obesity and diabetes affects the expression and function of the RvD1-receptor Frp2 in macrophages and adipose tissue and whether Frp2 deletion will abolish the pro-resolving effects of RvD1 as well as its ability to diminish chronic inflammation insulin resistance and promote wound healing. To distinguish between the effect of RvD1 on macrophages and adipocytes and as a gain-of-function test of our hypothesis we will test whether myeloid- specific overexpression of human FPR2 will enhance resolution of inflammation in diabetes and promote the pro-resolving actions of RvD1. We will identify the mechanisms by which binding of RvD1 to Fpr2 promotes macrophage phagocytosis. Results of this project will provide new knowledge about the processes that sustain chronic adipose tissue inflammation and promote insulin resistance in diabetes and obesity and could lead to the development of an entirely new approach for the treatment of insulin resistance and wound healing in diabetes and obesity.  
  
PUBLIC HEALTH RELEVANCE:  This project will provide a new understanding of the mechanisms that contribute to chronic inflammation in diabetes and obesity and will provide new avenues for treating insulin resistance in diabetes and obesity. These results could also be developed as an adjunct treatment for promoting resolution of inflammation and wound healing in diabetics.

project_terms:
Acute;Adipocytes;Adipose tissue;Affect;Anabolism;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Apoptotic;Binding (Molecular Function);Cells;Chronic;Defect;Development;Diabetes Mellitus;Diet;Disease;Dopamine D1 Receptor;Excision;Failure (biologic function);Fatty acid glycerol esters;Functional disorder;Health;Homeostasis;Human;Immune;Immune response;Infection;Inflammation;Inflammatory;Injury;Insulin;Insulin Resistance;Interruption;Invaded;Kidney Diseases;Knowledge;Lead;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Metabolic;Mus;Myelogenous;Natural immunosuppression;Neuropathy;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Patients;Phagocytes;Phagocytosis;Phenotype;Process;Recurrence;Resolution;Retinal Diseases;Risk;Role;Signal Transduction;Stimulus;Testing;Therapeutic;Time;Tissue Expansion;Tissues;Work;Wound Healing;base;cardiovascular disorder risk;db/db mouse;diabetic;feeding;gain of function;glucose tolerance;improved;insulin sensitivity;lipid mediator;macrophage;mouse model;novel strategies;novel therapeutic intervention;overexpression;pathogen;prevent;programs;public health medicine (field);response;restoration;vascular inflammation

public_health_relevance:
This project will provide a new understanding of the mechanisms that contribute to chronic inflammation in diabetes and obesity and will provide new avenues for treating insulin resistance in diabetes and obesity. These results could also be developed as an adjunct treatment for promoting resolution of inflammation and wound healing in diabetics.


application_id: 8182581
project_number: 1R01DC011285-01A1
project_title: Response of aging intrinsic laryngeal muscles to chronic electrical stimulation
administering_ic: NIDCD
award_notice_date: 2011-06-22
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: DC
serial_number: 011285
suffix: A1
program_official: SHEKIM, LANA O
project_start_date: 2011-06-22
project_end_date: 2016-05-31
study_section: Motor Function, Speech and Rehabilitation Study Section[MFSR]
contact_pi_person_id: 8274830
contact_pi: MCMULLEN, COLLEEN 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
project_abstract:
DESCRIPTION (provided by applicant): This application is in response to the NIH Research Project Grant (Parent R01) (PA-10-067). As individuals age muscle weakness and the development of neuromuscular disorders have the potential to severely diminish the quality of one's life. The larynx is part of a complex sensorimotor system that serves as both a vibratory source for phonation and as a regulatory valving mechanism that protects the airway from the incursion of foreign bodies and food. In the elderly age-related changes in the laryngeal muscles may compromise voice quality impairing the ability of individuals to communicate and diminishing their ability to remain socially active and engaged. More significantly laryngeal muscle dysfunction may contribute to the emergence of dysphagia and subsequent increases in the risk of aspiration factors that contribute to higher rates of mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. More specifically therapies for certain voice disorders contend to use common principles of skeletal muscle rehabilitation in the hope of increasing muscle mass strength and endurance. However the rationale and applicability of limb muscle rehabilitation concepts to the laryngeal muscles has not been empirically tested. Therefore this proposal has three principle objectives:(1) to use chronic electrical stimulation as a fictive endurance "exercise" program in aging rat laryngeal muscle; (2) to characterize the morphological changes consequent to the fictive exercise model; and (3) to provide the background data to eventually extend these findings to clinical treatments with humans using vocal exercises. We will test the central hypothesis that the physiology of aged laryngeal muscle can be modified as a function of chronically-induced activity using the Fisher 344-Brown Norway F1 hybrid rat model of aging. We will examine to what extent chronic electrical stimulation remodels the aging posterior cricoarytenoid (PCA vocal fold abductor) and thyoarytenoid (TA vocal fold adductor) laryngeal muscles. Specific Aim I will examine the effects of chronic electrical stimulation on muscle morphology in aging PCA and TA. Specific Aim 2 will test whether chronic stimulation modifies the metabolic capacity in the aging PCA and TA muscles. Specific Aim 3 will determine to what extent chronic nerve stimulation will reverse functional denervation in aging laryngeal muscles. These studies will be a first test of the applicability of limb muscle rehabilitation interventions intended to effectively alleviate reverse and/or compensate for age-related dysfunction in the laryngeal muscles. This project will generate novel data to assist in the development of interventions aimed at preventing reversing and/or compensating for age-related dysfunction in the human larynx providing a first step toward testing the efficacy and legitimacy of current voice disorder interventions.  
  
PUBLIC HEALTH RELEVANCE: In older individuals changes in the laryngeal muscles may compromise voice quality impairing the ability to communicate and diminishing the ability to remain socially active and engaged. This project examines the muscle biophysiological changes that occur as a function of exercise and training using a well-accepted animal model for aging. Understanding the consequences of these changes is deemed important for eventually developing preventative and rehabilitative strategies for laryngeal muscle-related dysfunction in the older human population.


application_id: 8180393
project_number: 1R15CA156322-01A1
project_title: Nanotube Antibody Arrays for Profiling Circulating Diseased Cells
administering_ic: NCI
award_notice_date: 2011-08-09
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: CA
serial_number: 156322
suffix: A1
program_official: YOUNG, MATTHEW R
project_start_date: 2011-08-09
project_end_date: 2015-07-31
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 10177876
contact_pi: PANCHAPAKESAN, BALAJI
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Sensitive and quantitative technologies for molecular characterization of scant cells in easily accessible bodily sources such as fine needle aspirates biopsies whole blood saliva and urine can potentially have significant impacts in life sciences and clinical practice. Current laboratory procedures used for cancer biomarker testing require collection of the body fluids and aspirates transfer of those materials to the laboratory for testing with turn-around-times in the range of a day to several days. This sometimes could lead to phenotypic/apoptotic changes of sampled cells. This project will develop a nanotube-antibody biosensor arrays for rapid detection of circulating cancer cells in blood that can identify surface markers directly on cancer cells within 15 minutes. The project will seek to accomplish the following specific aims: 1. Detection of molecular surface receptors namely IGF1R Her2 and EpCAM in BT474 MCF7 SKBR3 and MCF10A cancer cells in blood. Creation of expression level and malignancy maps to rapidly profile the circulating tumor cells in blood within minutes. 2. Use nanoneedle probes to investigate the binding forces of receptors to antibodies for non-specific and specific interactions to create an expression level and malignancy maps based on interaction forces. 3. Demonstrate that our biosensors have the detection sensitivities and specificities that is comparable to standard immunoassays such as ELISA. Blood from breast cancer patients will be tested using both standard technique and our nanotube-biosensor technique and statistical correlation of these data will help standardize this technique for future testing. The successful accomplishment of these aims will lead to developing a quick and very inexpensive test that uses a very small quantity of blood (micro-liter or less) to detect tumor cells on a patient's blood circulation in a matter of a few minutes. This inexpensive test definitely has a strong commercial potential as we have plans for commercialization of the products after proofing the concept during the period of this proposal.  
  
PUBLIC HEALTH RELEVANCE: This project will develop nanotube-antibody biosensor arrays for rapid profiling of circulating cancer cells in blood within minutes. Based on the sensor arrays a device will be developed that will be used in detecting and profiling circulating breast cancer cells in blood. This new technology will be compared against standard immunoassays such as ELISA.

project_terms:
Antibodies;Apoptotic;Aspirate substance;Binding (Molecular Function);Biological Assay;Biological Sciences;Biopsy;Biopsy Specimen;Biosensor;Blood;Blood Circulation;Body Fluids;Breast;Breast Cancer Cell;Cancer Patient;Cell Count;Cell Line;Cells;Cellular Membrane;Clinical;Clinical Laboratory Techniques;Collection;Correlation Studies;Data;Detection;Devices;Diagnosis;Diagnostic;Drops;Electronics;Elements;Enrollment;Enzyme-Linked Immunosorbent Assay;Event;Fine needle aspiration biopsy;Future;Glutamate Carboxypeptidase II;IGF1R gene;Immunoassay;Immunoglobulin G;Individual;Laboratories;Laboratory Procedures;Lead;MCF7 cell;Magnetism;Malignant Neoplasms;Maps;Measurement;Measures;Molecular;Monitor;Nanoarray Analytical Device;Nanotubes;Needles;Optics;Patients;Preparation;Procedures;Proteins;Reporting;SKBR3;Saliva;Sampling;Scanning Probe Microscopes;Screening procedure;Sensitivity and Specificity;Shapes;Signal Transduction;Single Parent;Source;Staging;Surface;System;TACSTD2 gene;Techniques;Technology;Testing;Time;Urine;Whole Blood;base;biomarker;breast cancer diagnosis;cancer cell;circulating cancer cell;clinical practice;commercialization;malignant breast neoplasm;nano;neoplastic cell;new technology;rapid detection;receptor;research study;response;scale up;sensor;tumor

public_health_relevance:
This project will develop nanotube-antibody biosensor arrays for rapid profiling of circulating cancer cells in blood within minutes. Based on the sensor arrays a device will be developed that will be used in detecting and profiling circulating breast cancer cells in blood. This new technology will be compared against standard immunoassays such as ELISA.


application_id: 8179930
project_number: 1R15MH094955-01
project_title: Long-term effects of early-life antipsychotic drug treatment
administering_ic: NIMH
award_notice_date: 2011-06-01
opportunity_number: PA-10-070
application_type: 1
activity_code: R15
ic: MH
serial_number: 094955
program_official: HUPALO, SOFIYA
project_start_date: 2011-06-01
project_end_date: 2015-05-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application represents a submission for an AREA R15 award. These awards are intended to support research that involves undergraduates at institutions that have limited NIH funding. The purpose of this research is to begin defining the long-term behavioral effects of early-life exposure to antipsychotic drugs (APDs). Over the past 15 years the use of APDs in pediatric populations has doubled - a phenomenon that has garnered considerable attention in the scientific community and national media. This increase has occurred in the relative absence of basic research documenting the effects of early-life APD exposure on later brain and behavioral function. Studies of APD action in laboratory rats would serve as a significant first step in filling this void. It has been well established in adult rats that continuous receptor blockade caused by long-term APD treatment leads to compensatory yet transient changes in brain dopamine function. In contrast there is currently no body of research that has ascertained the long-term effects of APD treatment in developing rats. Our hypothesis is that due to the timing of such treatment early-life exposure to APDs may engender compensatory yet permanent changes in brain dopamine function that persist through adulthood. Our own preliminary research has shown that rats treated daily with the atypical APD risperidone from postnatal days 14 - 42 exhibit sensorimotor gating deficits and persistent locomotor hyperactivity as young adults - behaviors linked to forebrain dopamine function. Guided by these data and our hypothesis the current application will determine if there are critical periods for the effects of early-life risperidone exposure on locomotor activity and sensorimotor gating during adulthood and whether early-life risperidone heightens the sensitivity of these behaviors to dopamine agonists enhances impulsivity and disrupts forebrain dopamine release in adulthood. The proposed work would act as a foundation for the applicant to establish a program of research aimed at elucidating the effects of early-life APD treatment. In turn this would provide researchers policy-makers and practitioners with critical information regarding the long-term consequences of prolonged APD treatment during development. Finally the proposed research will be used as a vehicle to engage undergraduates in unique and integrative research experiences in psychopharmacology developmental neuroscience and neurochemistry.  
  
PUBLIC HEALTH RELEVANCE: The use of antipsychotic drugs in pediatric populations has doubled over the past 15 years despite the relative absence of basic research documenting the effects of such drug exposure on later brain and behavioral function. The purpose of this research is to ascertain the long-term behavioral effects of early-life exposure to antipsychotic drugs in laboratory rats. This research will provide researchers policy-makers and practitioners with critical information regarding the long-term consequences of prolonged antipsychotic drug treatment during development in addition to enhancing research experiences in neuroscience among college undergraduates at Northern Kentucky University.

project_terms:
Accounting;Address;Adult;Adverse effects;Affect;Age;Animal Experimentation;Antipsychotic Agents;Attention;Auditory;Autistic Disorder;Award;Basic Science;Behavior;Behavioral;Brain;Brain region;Child;Childhood;Collaborations;Communities;Corpus striatum structure;Data;Development;Disease;Dopamine;Dopamine Agonists;Dopamine Receptor;Dorsal;Drug Exposure;Drug Prescriptions;Drug effect disorder;Drug usage;Drug user;Elements;Exhibits;Exposure to;FDA approved;Female;Foundations;Funding;Gene Expression;Hyperactive behavior;Impulsivity;Institution;Interdisciplinary Study;Kentucky;Laboratory Rat;Life;Link;Long-Term Effects;Measurable;Measures;Mental disorders;Microelectrodes;Motor Activity;Neurosciences;Neurotransmitter Receptor;Neurotransmitters;Nucleus Accumbens;Policy Maker;Population;Prefrontal Cortex;Principal Investigator;Prosencephalon;Protocols documentation;Psychological reinforcement;Psychopharmacology;Psychotropic Drugs;Rattus;Relative (related person);Reporting;Research;Research Personnel;Research Support;Risperidone;Sensorimotor functions;Speed (motion);Staging;Symptoms;System;Technology;Testing;Time;United States National Institutes of Health;Universities;Work;atypical antipsychotic;autism spectrum disorder;base;clinical efficacy;cognitive function;college;critical period;discounting;early life exposure;experience;male;neurochemistry;neuron development;postnatal;prepulse inhibition;programs;receptor;receptor binding;research study;serotonin receptor;young adult

public_health_relevance:
The use of antipsychotic drugs in pediatric populations has doubled over the past 15 years despite the relative absence of basic research documenting the effects of such drug exposure on later brain and behavioral function. The purpose of this research is to ascertain the long-term behavioral effects of early-life exposure to antipsychotic drugs in laboratory rats. This research will provide researchers policy-makers and practitioners with critical information regarding the long-term consequences of prolonged antipsychotic drug treatment during development in addition to enhancing research experiences in neuroscience among college undergraduates at Northern Kentucky University.


application_id: 8179805
project_number: 2P01HL078825-06
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2011-08-04
opportunity_number: PAR-10-285
application_type: 2
activity_code: P01
ic: HL
serial_number: 078825
program_official: LIANG, ISABELLA Y
project_start_date: 2005-04-15
project_end_date: 2016-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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:
DESCRIPTION (provided by applicant):   
  
Lack of understanding of basic stem cell mechanisms limits current therapeutic approaches. In this renewal application we will focus on the use of c-kit* cardiac progenitor cells (CPCs) to protect the heart against post-myocardial infarction (Ml) remodeling and heart failure (HF). The overall goal is to elucidate the molecular mechanisms that regulate the properties of CPCs and to evaluate the therapeutic utility of enhancing CPC function in order to optimize cardiac repair. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Belli) will elucidate the role of CO and NO in regulating CPC function and therapeutic efficacy. The central hypothesis is that these gases are key determinants of CPC competence and that augmenting their levels will dramatically enhance CPC-mediated cardiac repair. Project 2 (Prabhu) will illuminate the deleterious effects of TNF on CPC competence and reparative ability. This project will test the hypothesis that differential TNF signaling via TNFR1 TNFR2 and NF-KB plays a critical role in determining adrenergic versus cardiomyogenic fate and consequently the reparative capacity of CPCs following Ml. Project 3 (Jones) will examine the role of protein 0-GlcNAcylation in modulating the fundamental properties of CPCs and will test the hypothesis that the 0-GlcNAc alarm signal plays a critical role in regulating CPC proliferation survival differentiation and paracrine function. Project 4 (Bhatnagar) will determine how diabetes affects CPC-mediated myocardial repair and how CPC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes undermines CPC competence by inducing insulin resistance. Thus all four Projects focus cohesively on CPCs. These Projects will be supported by four Cores that will provide expertise in mouse surgery cell transplantation CPC culture and phenotyping pathology flow cytometry and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. These will be the first studies to examine the role of CO and NO TNF 0-GlcNAcylation and type 2 diabetes on CPC function: consequently the results will be entirely new and will advance our understanding of CPC biology. In addition these studies may lay the groundwork for new translational investigations of CPC therapy in patients with HF. Since we have already initiated the first-in-humans clinical trial of unmodified CPCs in patients with HF we are well positioned to rapidly translate anv insights derived from this Program into new clinical investigations.

public_health_relevance:
RELEVANCE: In 2009 we started SCIPIO the first-in-humans study of c-kit+ cardiac progenitor cells (CPCs). The initial results are encouraging. This Program builds on SCIPIO and seeks to optimize the effectiveness of these promising CPCs therapies. If our hypotheses are confirmed the results will lead to the use of more efficacious cell therapies in patients with heart failure. Since we have developed the infrastructure to launch new clinical studies of CPCs any new insights gained in this Program will be rapidly translated.


application_id: 8179538
project_number: 1R01NS075871-01
project_title: DNA Nanoparticle Gene Therapy in Brain
administering_ic: NINDS
award_notice_date: 2011-06-29
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: NS
serial_number: 075871
program_official: TAGLE, DANILO A
project_start_date: 2011-07-01
project_end_date: 2016-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
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 proposed studies will determine the feasibility of compacting plasmid DNA into "nanoparticles" and using these nanoparticles to deliver their payload into cells of the central nervous system (CNS) as a non-viral gene therapy technique. DNA compacting techniques will be used to form nanoparticles containing condensed DNA plasmids with diameters in the range of 8-12 nanometers. In a series of recent publications coming out of our laboratories we have shown that synthetic nanoparticles containing DNA plasmids can be used to transfect brain cells and establish both short- and long-term transgene activities following a single injection of DNA nanoparticles (DNP) directly into brain tissue. These encouraging results have lead us to propose a series of studies to further characterize and test the potential of using synthetic vectors to deliver therapeutic genes to the brain as a possible treatment for neurodegenerative disorders. My laboratory has considerable experience testing neurotrophic factor therapy as well as cellular replacement therapies in animal models of Parkinson's disease (PD) and we propose to examine the feasibility of delivering a gene encoding for the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) to brain cells as a means to protect the brain against neuronal degeneration that occurs in an animal model of PD. The first set of experiments will expand upon our current knowledge of DNP technology. In Specific Aim 1 we will attempt to further optimize plasmids design and mode of intracerebral delivery of compacted DNA nanoparticles (DNPs) and then assess the immunogenicity of this treatment. In the second specific aim we will determine if DNP transfection of the lesion brain is greater than in the intact brain and whether or not the aged brain is more susceptible to DNP transfection than younger brain; this studies will determine if an up-regulation of astrocytes at the site of neurodegeneration actually benefits transfection efficiency of DNPs because our preliminary studies indicate DNPs have a tropism for astrocytes. Finally our third specific aim will determine whether or not intracerebral infusion of modified hGDNF DNPs prevent neurodegeneration of dopaminergic neurons following a neurotoxic lesion of the nigrostriatal pathway. Successful results in these studies could then be applied to animal models of neurodegenerative disorders and possibly lead to translational studies for the treatment of neurological disorders such as Parkinson's disease.  
  
PUBLIC HEALTH RELEVANCE: The proposed studies will use a novel nanoparticle technology that allows nucleic acids (DNA) to be compacted near their theoretical limit; this technology almost duplicates the compaction efficiency of viruses. We present preliminary data showing proof-of-concept that these nanoparticles can be used as a non-viral gene therapy for transfecting cells in the brain. Successful results from our animal studies could then be translated to human studies using these targeted nanoparticles as a form of non-viral gene therapy to treat various neurological disorders.


application_id: 8179331
project_number: 1R03AR061561-01
project_title: Sensory-Targeted Ankle Rehabilitation Strategies (STARS)
administering_ic: NIAMS
award_notice_date: 2011-06-29
opportunity_number: PAR-09-031
application_type: 1
activity_code: R03
ic: AR
serial_number: 061561
program_official: PANAGIS, JAMES S
project_start_date: 2011-07-01
project_end_date: 2013-04-30
study_section: Special Emphasis Panel[ZAR1 EHB (M1)]
contact_pi_person_id: 9341091
contact_pi: MCKEON, PATRICK OWEN
other_pis: WIKSTROM, ERIK A
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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
project_abstract:
DESCRIPTION (provided by applicant): Injury associated with sport and recreation is a leading reason for physical activity cessation which is linked with significant long-term negative sequelae. Ankle sprains are the most common injuries associated with physical activity and at least 1 out of every 3 individuals who sprain their ankle will go on to develop chronic ankle instability (CAI) defined by life-long residual symptoms including decreased physical activity. Traditional rehabilitation strategies for CAI have focus on motor impairments but the high incidence of disability post- traumatic ankle osteoarthritis and consequent healthcare burdens clearly indicate that this treatment model is ineffective. Thus a pressing need exists for a paradigm shift in the development of effective evidenced-based interventions to treat CAI. To date little attention has been paid to the potential to improve function by intervening through sensory pathways. Research has shown that the sensorimotor system shifts reliance on various sensory inputs depending on the demands placed on the system. Those with CAI place a greater emphasis on cutaneous and musculotendinous receptors due to damage of the lateral ankle joint receptors. However by using sensory-targeted ankle rehabilitation strategies such as ankle joint mobilizations plantar massage and triceps surae stretching we hypothesize that we can enhance the information available to the sensorimotor system in order to tune effective movement solutions. Indeed our evidence suggests that sensory-targeted strategies may be essential to most effectively treating those with CAI. Therefore the purpose of this proposal is to determine the effectiveness of sensory-targeted ankle rehabilitation strategies at causing immediate and prolonged improvements in subjective and objective outcome measures of clinical disablement and sensorimotor dysfunction in those with CAI. This preliminary investigation will be a randomized controlled trial in which 80 subjects with CAI will be randomly assigned to receive one of three experimental interventions (mobilization massage stretch) or a control treatment. To evaluate the effects of the experimental treatments the following baseline measures will be taken: 1) self-assessed disability 2) ankle dorsiflexion range of motion and 3) sensorimotor function via measures of postural control and gait initiation. Subjects will then be randomly assigned to receive ankle mobilization (n=20) plantar massage (n=20) triceps surae stretching (n=20) or a control treatment (n=20). Follow up measures will be taken immediately after the first and final treatment of a two-week intervention as well as 1-month after receiving the treatment intervention. For this investigation separate MANOVAs will assess the effects of treatment (mobilization massage stretch control) and time (baseline post 1st treatment post final treatment 1-month follow-up) on subjective and objective measures of clinical disablement and sensorimotor function in those with CAI. The results of this randomized controlled study will elucidate the effectiveness of sensory-targeted ankle rehabilitation strategies at improving sensorimotor function and disability in those with CAI.  
  
PUBLIC HEALTH RELEVANCE:: Ankle sprains are the most common injury experienced by those who are physically active and recurrent disability associated with these injuries is extremely common. In this study we aim to determine the benefits of sensory-targeted ankle rehabilitation strategies on subjective and objective outcomes of clinical disablement and sensorimotor function in those with chronic ankle instability. By developing new sensory-targeted strategies for this pervasive condition we hope to optimize treatment efficiency and quality for patients with chronic ankle instability and subsequently reduce their associated long-term negative sequelae and disability.

project_terms:
Activities of Daily Living;Aftercare;Ankle;Articular Range of Motion;Attention;Chronic;Clinical;Cutaneous;Data;Degenerative polyarthritis;Development;Effectiveness;Equilibrium;Evaluation;Evidence based intervention;Foundations;Functional disorder;Gait;Goals;Health;Healthcare;Impairment;Incidence;Individual;Injury;Intervention;Investigation;Lateral;Life;Link;Lower Extremity;Massage;Measures;Modeling;Motor Pathways;Motor output;Movement;Musculoskeletal Equilibrium;Outcome;Outcome Measure;Pathway interactions;Patient Self-Report;Patients;Physical activity;Quality of life;Randomized;Randomized Controlled Trials;Recreation;Recurrence;Regulation;Reliance;Research;Research Proposals;Residual state;Sensorimotor functions;Sensory;Solutions;Source;Sports;Sprain;Stretching;Symptoms;System;Testing;Time;Triceps brachii muscle structure;Weight-Bearing state;ankle joint;base;coping;cost;disability;effective therapy;experience;follow-up;foot;improved;improved functioning;innovation;joint mobilization;motor impairment;novel strategies;pressure;public health medicine (field);receptor;rehabilitation strategy;sensorimotor system;treatment effect

public_health_relevance:
: Ankle sprains are the most common injury experienced by those who are physically active and recurrent disability associated with these injuries is extremely common. In this study we aim to determine the benefits of sensory-targeted ankle rehabilitation strategies on subjective and objective outcomes of clinical disablement and sensorimotor function in those with chronic ankle instability. By developing new sensory-targeted strategies for this pervasive condition we hope to optimize treatment efficiency and quality for patients with chronic ankle instability and subsequently reduce their associated long-term negative sequelae and disability.


application_id: 8179013
project_number: 1R21AI096323-01
project_title: Mechanism of inhibition of +RNA virus replication by cyclophilins
administering_ic: NIAID
award_notice_date: 2011-06-10
opportunity_number: PA-10-069
application_type: 1
activity_code: R21
ic: AI
serial_number: 096323
program_official: PARK, EUN-CHUNG
project_start_date: 2011-06-15
project_end_date: 2013-05-31
study_section: Virology - B Study Section[VIRB]
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):  Host factors are key determinants of RNA virus pathology host - virus interactions and evolution of viruses. Recent genome-wide screens with several viruses have identified several host proteins which directly inhibit +RNA virus accumulation. These host proteins might be novel components of the host innate systems against viruses. Among the identified inhibitory host proteins are the family of cyclophilins which are effective against several viruses. Cyclophilins are a large family of ubiquitous highly conserved proteins that have peptidyl-prolyl isomerase and protein chaperone activities. Cyclophilins are involved in several diseases such as human cancers neurodegenerative diseases and viral infections. Determining the mechanism of inhibition by host factors like cyclophilins is a major frontier in current virology research. The identified inhibitory host factors could be used in antiviral approaches with several advantages over traditional antivirals including broader antiviral effects against many related viruses and more durable antiviral effects since viruses may have a more difficult challenge to evolve mutants that evade these host factors.  Progress in our understanding of the mechanisms of the inhibitory activity of host factors is slow due to functional redundancy in the host cells or lack of knowledge about their functions. However easily tractable virus - host systems such as Tomato bushy stunt virus (TBSV) and yeast as a model host can greatly contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role of cyclophilins in virus-host interactions. This advance could immensely help other scientists working with less tractable but devastating viral pathogens for which similar studies are currently not yet feasible.  The gained knowledge will not only be useful for TBSV but to other significant human pathogens such as West Nile virus Dengue virus and other flaviviruses and pestiviruses due to the similarity of their replicase proteins. Collectively the major advances with TBSV will stimulate development of new approaches for studying RNA replication and host - pathogen interactions for important human pathogens.  The following are the major strengths of the proposal: (i) Viral RNA replication is clearly of immense importance for viruses to infect living organisms. (ii) Cyclophilins are major proteins affecting viral and other human diseases yet their functional roles are currently poorly defined. (iii) The combination of yeast and authentic cell-free assay developed by the investigator is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) 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:  The host cells express antiviral proteins that restrict RNA viruses which are important pathogens of humans animals and plants. Cyclophilins which are involved in human cancers neurodegenerative diseases and viral infections are a large family of ubiquitous conserved proteins that have peptidyl-prolyl isomerase and protein chaperone activities. The investigator will use the powerful Tomato bushy stunt virus (TBSV)-yeast model system to determine the molecular mechanism of antiviral activity of several cyclophilins thus contributing to our understanding of host-virus interactions.

project_terms:
Affect;Animals;Antiviral Agents;Area;Biochemical;Biological Assay;Cataloging;Catalogs;Cells;Complex;Cyclophilins;Dengue Virus;Development;Disease;Evolution;Family;Flavivirus;Genes;Human;Integration Host Factors;Knowledge;Lead;Life;Malignant Neoplasms;Modeling;Molecular;Molecular Chaperones;Neurodegenerative Disorders;Organism;Pathology;Peptidylprolyl Isomerase;Pestivirus;Plants;Play;Protein Family;Proteins;Proteomics;RNA Viruses;RNA replication;Research;Research Personnel;Role;Scientist;Societies;System;Tombusvirus;Viral;Viral Pathogenesis;Virus;Virus Diseases;Virus Replication;West Nile virus;Work;Yeast Model System;Yeasts;base;frontier;genome wide association study;human disease;insight;mutant;novel;novel strategies;pathogen;replicase;tomato bushy stunt virus;viral RNA;virology;virus host interaction;yeast genetics

public_health_relevance:
The host cells express antiviral proteins that restrict RNA viruses which are important pathogens of humans animals and plants. Cyclophilins which are involved in human cancers neurodegenerative diseases and viral infections are a large family of ubiquitous conserved proteins that have peptidyl-prolyl isomerase and protein chaperone activities. The investigator will use the powerful Tomato bushy stunt virus (TBSV)-yeast model system to determine the molecular mechanism of antiviral activity of several cyclophilins thus contributing to our understanding of host-virus interactions.


application_id: 8176462
project_number: 1R01AA020005-01A1
project_title: Alcohol Myopia and Aggression
administering_ic: NIAAA
award_notice_date: 2011-08-09
opportunity_number: PA-10-067
application_type: 1
activity_code: R01
ic: AA
serial_number: 020005
suffix: A1
program_official: GRAKALIC, IVANA
project_start_date: 2011-08-10
project_end_date: 2016-07-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 7876958
contact_pi: GIANCOLA, PETER 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This application has 2 main goals: 1) to test a psychological model [the Alcohol Myopia Model (AMM); Steele & Josephs 1990] that can explain the relation between alcohol intoxication and aggression and 2) to understand how established risk factors for intoxicated aggression operate within the AMM. The AMM contends that alcohol intoxication disrupts cognitive functioning thus creating a "myopic" or a narrowing effect on attentional capacity. This myopic effect facilitates aggression by restricting one's attention onto more salient provocative cues inherent in a hostile situation rather than less salient non-provocative or inhibitory cues. STUDY 1 will examine how distraction from provocation influences aggression under the influence of alcohol. It will also determine whether key trait risk factors (i.e. hostile rumination beliefs about aggression anger self-awareness and empathy) moderate the alcohol-aggression relation within the context of the AMM. Subjects will be 420 adult male and female social drinkers randomly assigned to 1 of 3 alcohol dose groups (alcohol placebo sober) and 1 of 2 distraction groups (distraction no-distraction). Trait risk factors will be measured using validated self-report measures. Aggression will then be assessed using a version of the well- established Taylor Aggression Paradigm (TAP; Taylor 1967) in which subjects administer and receive electric shocks to/from a fictitious opponent under the guise of a competitive reaction-time task. Aggression will be operationalized as a composite index of the shock intensity and duration administered by the subject to the fictitious opponent. STUDY 2 builds on Study 1 by testing the external validity of the AMM (to the extent possible in a laboratory setting) in explaining alcohol's effects on aggression by assessing the effectiveness of a contextual cue manipulation designed to mimic a more real-world setting. Its results will lend further credence to the AMM as it will demonstrate that a more externally valid distraction (i.e. a contextual manipulation comparing aggression-inhibiting vs. aggression-promoting cues) will also be effective in suppressing aggression. Subjects will be 240 adult male and female social drinkers randomly assigned to 1 of 3 beverage groups (alcohol placebo sober) and 1 of 2 cue manipulation groups (aggression-inhibiting or aggression-promoting). Aggression will be measured using the TAP.  
  
PUBLIC HEALTH RELEVANCE: This project will provide a new understanding of the causes of alcohol-related violence. It will have significant implications for the development of public health interventions designed to reduce the negative consequences particularly violence associated with alcohol consumption. Support for these hypotheses will encourage public health researchers to develop new and innovative interventions marked by frequent and highly salient positive anti-violence and health-promoting cues in situations where violence is often the result of alcohol intoxication (e.g. bars sports venues college campuses etc).


application_id: 8174560
project_number: 5P20RR021954-03
project_title: INFLAMMATION DURING OBESITY: IMMUNE RESPONSES TO GUT ANTIGENS IN MESENTERIC FAT
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6038
contact_pi_person_id: 8628150
contact_pi: ECKHARDT, ERIK
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: 2010-07-01
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.Project 5: Inflammation During Obesity: Immune Responses to Gut Antigens in Mesenteric Fat

Erik Eckhardt

Obese individuals have greatly enlarged fat tissue and they are also more likely to suffer from cardiovascular disease diabetes and other diseases. Interestingly all these diseases carry an inflammatory component and it has therefore long be suspected that fat tissues may have an effect on whole body inflammation. Indeed recent work has clearly shown that fat tissues from obese individuals are often inflamed and release substances into the circulation that can cause inflammation elsewhere. What then causes fat tissues from obese individuals to be inflamed? The answer may lie in the intestine because it is mostly fat tissue near the intestine such as mesenteric fat which is inflamed in obesity whereas subcutaneous fat while equally enlarged often is not inflamed. We hypothesize that bacteria or bacterial products in the intestine enter mesenteric fat tissue when obese individuals ingest high fat meals because large amounts of dietary fat can induce leakiness in the intestine. Our data with mice so far suggest that this is indeed the case. If we confirm these data and our hypothesis in general we can then look at how to reduce the number of pro-inflammatory bacteria in the intestine that cause fat tissue inflammation.

project_terms:
Antigens;Bacteria;Blood Circulation;Cardiovascular Diseases;Computer Retrieval of Information on Scientific Projects Database;Data;Diabetes Mellitus;Dietary Fats;Disease;Fatty acid glycerol esters;Funding;Grant;Immune response;Individual;Inflammation;Inflammatory;Institution;Intestines;Mesentery;Mus;Obesity;Research;Research Personnel;Resources;Source;Tissues;United States National Institutes of Health;Work;subcutaneous


application_id: 8174559
project_number: 5P20RR021954-03
project_title: PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6037
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
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: 2010-07-01
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.Project 4: Platelet Activation with Obesity Promotes Atherothrombotic Vascular Events 

Zhenyu Li

Obesity is associated with an increased risk of cardiovascular death independent of its other recognized consequences such as hypertension and hyperlipidemia. One potential contributing factor to this excess in cardiovascular deaths may be related to the pro-thrombotic and pro-inflammatory states induced by increases in adipose mass both of which are critical components of the pathogenesis of the clinic manifestations of atherosclerosis. Platelets play a central role in arterial thrombosis are activated in inflammatory states and are directly influenced by specific adipokines and therefore have the potential to serve as an essential mediator of the cardiovascular consequences of obesity. Consistent with this obesity has been associated with increases in platelet aggregation elevations in surface expression of markers of platelet activation such as P-selectin and heightened platelet microparticle formation. More importantly reduction in adipose mass leads to normalization of markers of enhanced platelet activation. However how platelets are activated in obesity and a causal role for platelet hyperactivation in obesity-related cardiovascular disorders remains to be established. Several characteristics and proven biological activities of platelets make them an appealing candidate for triggering and maintaining the inflammatory response of obesity. This study will test the central hypothesis that platelet activation/secretion secondary to obesity plays a causal role in triggering and maintaining the pro-inflammatory and pro-thrombotic state of obesity creating a feedback loop involving adipose tissue activated platelets and vascular endothelium that culminates in an environment favorable for atherothrombotic vascular events.

project_terms:
Adipose tissue;Atherosclerosis;Biological;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Characteristics;Clinic;Computer Retrieval of Information on Scientific Projects Database;Environment;Event;Feedback;Funding;Grant;Hyperlipidemia;Hypertension;Inflammatory;Inflammatory Response;Institution;Mediator of activation protein;Obesity;P-Selectin;Pathogenesis;Platelet Activation;Platelet aggregation;Play;Research;Research Personnel;Resources;Role;Secondary to;Source;Surface;Testing;Thrombosis;United States National Institutes of Health;Vascular Endothelium;adipokines;cardiovascular risk factor


application_id: 8174558
project_number: 5P20RR021954-03
project_title: MATERNAL CONSUMPTION OF A WESTERN DIET PROMOTES OBESITY-INDUCED CV DISEASE AND D
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6036
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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: 2010-07-01
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.Project 3: MATERNAL CONSUMPTION OF A WESTERN DIET PROMOTES OBESITY AND HYPERTENSION IN OFFSPRING

PI Kevin Pearson

PROJECT DESCRIPTION:

The intrauterine environment affects the development of the growing embryo and an unsuitable environment can lead to termination of pregnancy. However emerging research has shown that more subtle factors can potentially influence long-term health in the offspring. For instance malnourished pregnant mothers produce smaller offspring that have a higher incidence of obesity diabetes and heart disease during adulthood. However in the Western world maternal obesity is an ever-increasing problem and epidemiology studies are now pointing to metabolic derangements in their offspring. Taking these findings into consideration the general hypothesis of this proposal is maternal consumption of a Western (high fat) diet during pregnancy and nursing will promote obesity and hypertension in offspring through activation of the renin-angiotensin system and maternal consumption of resveratrol will block the negative effects. The goal is to gain detailed insights into the effects of pre-weaning environmental changes caused by unhealthy diets or the presence of resveratrol on obesity and cardiovascular disease in mice. For this purpose we will manipulate the dietary composition of female mice six weeks prior to mating (or at mating) throughout pregnancy and until 14 days after giving birth. Offspring from mothers in all groups will then be fed a normal low-fat diet after weaning. Obesity glucose and insulin tolerance and hypertension will be monitored in the offspring. Obesity diabetes and cardiovascular disease are at epidemic levels and interventions targeting gestation might be an efficient way to stem the tide.

project_terms:
Adult;Affect;Birth;Cardiovascular Diseases;Computer Retrieval of Information on Scientific Projects Database;Consumption;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Embryo;Environment;Epidemic;Fat-Restricted Diet;Fatty acid glycerol esters;Female;Funding;Glucose;Goals;Grant;Health;Heart Diseases;Hypertension;Incidence;Institution;Intervention;Lead;Metabolic;Monitor;Mothers;Mus;Obesity;Partner in relationship;Pregnancy;Renin-Angiotensin System;Research;Research Personnel;Resources;Resveratrol;Source;Termination of pregnancy;United States National Institutes of Health;Weaning;Western World;environmental change;epidemiology study;feeding;insight;insulin tolerance;offspring;pregnant;stem


application_id: 8174557
project_number: 5P20RR021954-03
project_title: MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 DEFICIENCY ATTENUATES DIET-INDUCED OBESITY
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6035
contact_pi_person_id: 8341067
contact_pi: KING, VICTORIA L
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: 2010-07-01
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.Project 2. Microsomal prostaglandin E synthase-1 deficiency attenuates the development of development of diet-induced obesity in male mice

The focus of our project is to determine the effect of inflammatory molecules on the development and/or progression of diet-induced obesity.  Previous studies have suggested that prostaglandin E2 (PGE2) which is an inflammatory mediator that is produced at a very high concentration during inflammation can inhibit break down of fat cells to free fatty acids and glycerol which may result in a decrease in fat mass.  Preliminary data from our studies demonstrate that deficiency of the major enzyme microsomal prostaglandin E synthase-1 which produces PGE2 attenuates the development of obesity in mice fed a high fat diet.  Our preliminary studies also demonstrate that the reduction in body weight and adipose tissue mass in the mice is not due reductions in food consumption or physical activity.  Our data suggests that there is a reduction in energy expenditure in the mice which suggests that the reduction in body weight gain and adipose tissue mass may be due to an increase in fat cell break down.  The future direction on our project will determine if the mice have an increase in fat cell break down and determine if reductions in PGE2 is responsible for the reduction in fat cell break down and how this occurs.  During the development of obesity inflammatory cells move into the fat tissue.  Our studies will also determine if reductions in PGE2 from inflammatory cells or fat cells is responsible for the reduction in weight gain.

project_terms:
Adipocytes;Adipose tissue;Attenuated;Body Weight;Cells;Computer Retrieval of Information on Scientific Projects Database;Data;Development;Diet;Dinoprostone;Energy Metabolism;Enzymes;Fatty acid glycerol esters;Funding;Future;Glycerol;Grant;Inflammation;Inflammation Mediators;Inflammatory;Institution;Mus;Nonesterified Fatty Acids;Obesity;Physical activity;Prostaglandins;Research;Research Personnel;Resources;Source;Tissues;United States National Institutes of Health;Weight Gain;feeding;food consumption;male;prostaglandin E synthase-1


application_id: 8174556
project_number: 5P20RR021954-03
project_title: THROMBOSPONDIN1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOTE
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6034
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
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: 2010-07-01
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.Project 1: Thrombospondin1 mediates macrophage infiltration into adipose tissue and promotes atherosclerosis in obese mice 

PI Shuxia Wang
Description:

Obesity is becoming a global public health problem and is associated with an increased risk of atherosclerosis.  Accumulating evidence suggests that obesity-induced chronic low-grade inflammation is an important mechanism for the adverse effects of adiposity on atherosclerosis. Thrombospondin1 (TSP1) a multifunctional extracellular matrix protein with multi-domains exhibits several effects on the vasculature that would be anticipated to contribute to the development and progression of atherosclerosis. TSP1 has been shown to be up-regulated in adipose tissue of mice with diet or genetically induced obesity.  Moreover recent studies demonstrate that TSP1 expression is increased in adipocytes from obese humans and correlates positively to obesity and adipose tissue inflammation.  Preliminary data demonstrate that adipose tissue from high fat (HF)-fed TSP1 deficient mice exhibits reduced numbers of infiltrating macrophages compared to HF-fed wild type controls. Importantly reductions in macrophage infiltration into adipose tissue of TSP1-/- HF-fed mice were observed even though mice exhibited similar levels of obesity as wild type controls.  Based on these studies we hypothesize that specific domains of TSP1 mediate increased macrophage infiltration into adipose tissue with diet-induced obesity and promote atherosclerosis in apoE-/- mice.  To address this hypothesis we will determine the specific domains of TSP1 responsible for increased macrophage adhesion and/or migration in Aim 1 and determine if TSP1 deficiency decreases atherosclerosis in apoE-/- mice with diet-induced obesity in Aim 2.  These studies will provide novel information on the role of TSP1 in obesity associated atherosclerosis and may lead to development of therapeutic targets for treatment of this disease.

project_terms:
Address;Adhesions;Adipocytes;Adipose tissue;Adverse effects;Apolipoprotein E;Atherosclerosis;Chronic;Computer Retrieval of Information on Scientific Projects Database;Data;Development;Diet;Disease;Exhibits;Extracellular Matrix Proteins;Fatty acid glycerol esters;Funding;Grant;Human;In-Migration;Infiltration;Inflammation;Institution;Lead;Mediating;Mus;Obese Mice;Obesity;Research;Research Personnel;Resources;Risk;Role;Source;United States National Institutes of Health;base;feeding;macrophage;novel;public health medicine (field);therapeutic target


application_id: 8174555
project_number: 5P20RR021954-03
project_title: PATHOLOGY AND METABOLIC RESEARCH CORE
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6033
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
budget_start_date: 2010-07-01
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.Pathology and Metabolic Research Core Description

This core provides services to COBRE investigators for (1) measurement of whole body metabolism in mice (2) measurement of blood pressure by radiotelemetry in mice (3) quantification of atherosclerosis in mice (4) assessment of tissue pathology (5) diabetes measurements.  For measurement of whole body metabolism 16 TSE LabMaster Platforms are available to quantify food and water consumption physical activity and indirect calorimetry in mice.  The system is overseen by a research technician who places mice in the chambers runs all equipment and provides data in excel format to investigators.  Mice are housed in the system for 3.5 days for measurements.  A protocol has been designed requesting use of the system and for scheduling purposes.  For measurement of blood pressure 8 DSI platforms with software are available to COBRE investigators.  Training in surgical techniques for implantation of carotid artery catheters and implants is provided.  For quantification of atherosclerosis training is available for en face quantification of atherosclerotic lesions in aortic arch.  For tissue pathology investigators submit tissue samples for paraffin embedding and sectioning and basic stains.  A trained technician handles all tissue preparation and provides training to investigator personnel.  For diabetes we are establishing methods for euglycemic hyperinsulinemic clamp technology in mice.  The core also provides assistance for training in performance of glucose and insulin tolerance tests in mice.

project_terms:
Arterial Fatty Streak;Atherosclerosis;Blood Pressure;Carotid Arteries;Catheters;Centers of Research Excellence;Computer Retrieval of Information on Scientific Projects Database;Computer software;Data;Diabetes Mellitus;Equipment;Face;Food;Funding;Glucose;Grant;House mice;Human Resources;Implant;Indirect Calorimetry;Institution;Measurement;Metabolic;Metabolism;Methods;Mus;Operative Surgical Procedures;Paraffin Embedding;Pathology;Performance;Physical activity;Protocols documentation;Research;Research Personnel;Resources;Running;Schedule;Services;Source;Staining method;Stains;System;Techniques;Technology;Testing;Tissue Sample;Tissues;Training;United States National Institutes of Health;Water consumption;aortic arch;design;implantation;insulin tolerance;tissue preparation


application_id: 8174554
project_number: 5P20RR021954-03
project_title: ANALYTICAL CORE
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6032
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
budget_start_date: 2010-07-01
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.Analytical Core Description

The analytical core of the COCVD provides technical services and support to participating investigators in the broad area of detection and quantitation of biological molecules of relevance to the diagnosis treatment and experimental investigation of obesity and cardiovascular diseases. A major purpose of the core is to administer and operate sophisticated advanced instrumentation that would be beyond the capabilities of individual participating investigators.  This includes a BioPlex solution array microplate reader a gas chromatograph and instrumentation for tandem mass spectrometry.

project_terms:
Area;Biological;Cardiovascular Diseases;Computer Retrieval of Information on Scientific Projects Database;Computers and Advanced Instrumentation;Detection;Diagnosis;Funding;Gases;Grant;Individual;Institution;Investigation;Obesity;Reader;Research;Research Personnel;Resources;Services;Solutions;Source;United States National Institutes of Health;instrumentation;synthetic polymer Bioplex;tandem mass spectrometry


application_id: 8174553
project_number: 5P20RR021954-03
project_title: ADMINISTRATIVE CORE
administering_ic: NCRR
award_notice_date: 2010-06-23
opportunity_number: PAR-07-229
application_type: 5
activity_code: P20
ic: RR
serial_number: 021954
project_start_date: 2010-07-01
project_end_date: 2011-06-30
subproject_number: 6031
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
budget_start_date: 2010-07-01
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.Administrative Core Description

The administrative core coordinates research and training objectives of the Center. The aims of this core are to provide administrative leadership support for fiscal grant accounting and writing meeting organization oversight of the pilot project mechanism facilitation of hiring of new faculty construction and maintenance of a website coordination and organization of data for assessment statistical consultation and assistance with compliance issues.

project_terms:
Accounting;Computer Retrieval of Information on Scientific Projects Database;Consultations;Data;Faculty;Funding;Grant;Institution;Leadership;Maintenance;Pilot Projects;Research;Research Personnel;Research Training;Resources;Source;United States National Institutes of Health;Writing;meetings;web site


application_id: 8168487
project_number: 5P20RR020145-07
project_title: STRESS RESPONSE IN PATIENTS WITH TEMPOROMANDIBULAR DISORDERS & FIBROMYALGIA
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8313
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 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 overall goal of this proposal is to define the relationships between symptom severity stress exposure and stress physiology of women with temporomandibular disorder (TMD) with and without concomitant fibromyalgia (FM).  Our overall hypothesis is that individuals with TMD can have variable intensity of symptoms and that those with concomitant FM will fall on the severe end of the spectrum.  Further symptom severity will correlate with stress exposure (e.g. childhood vs adult life events vs daily hassles) and stress physiology (e.g. salivary cortisol heart-rate variability). We will recruit individuals from the University of Kentucky orofacial pain clinic and the Kentucky Women's Health Registry.  Subjects will be classified into TMD without FM TMD with FM and healthy age matched controls.  We will recruit 30 women with TMD anticipating that at least half will have comorbid FM and 15 healthy controls.  We are limiting this pilot study to women because the large majority of patients are women and because we will be evaluating stressors as they pertain to women.  Stress perception and exposure will be evaluated using well-validated survey instruments.  All subjects will undergo evaluation of stress-response physiology including diurnal cortisol and ambulatory heart-rate variability to monitor autonomic activity. The specific aims to be tested are as follows: 
Specific Aim 1:  To compare temporomandibular disorder (TMD; n=30) in the presence or absence of fibromyalgia (FM) with regard to severity of symptoms and stress physiology. 
Specific Aim 2:  To determine the association between psychosocial stress and distress and symptom profile diagnostic groups (TMD  FM n=30 and healthy matched controls n=15) and stress physiology.
Stress exposure measures and psychosocial phenotyping include the MINI Neuropsychiatric Interview SF-12v2 CES-D Scl-90R MASQ PSQI Gracely Pain Scale McGill Pain Questionnaire Hassles & Uplifts Sclare Perceived Stress Scale PCL-C Job Content Questionnaire National Violence Against Women Survey and the Psychological Maltreatment of Womens Inventory.
Stress physiology phenotyping includes diurnal salivary cortisol levels to assess baseline HPA axis function salivary cortisol measurement at 30 minutes post-waking to assess stimulated HPA axis function heart-rate variability and skin conductance.  We will also measure serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels to assess generalized immune system activation.

project_terms:
Adult;Age;C-reactive protein;Childhood;Computer Retrieval of Information on Scientific Projects Database;Diagnostic;Distress;Equipment and supply inventories;Evaluation;Event;Fibromyalgia;Funding;Galvanic Skin Response;Goals;Grant;Hydrocortisone;Immune system;Individual;Institution;Interleukin-6;Interview;Kentucky;Life;McGill Pain Scale;Measurement;Measures;Monitor;Occupations;Orofacial Pain;Pain;Pain Clinics;Patients;Perception;Phenotype;Physiology;Pilot Projects;Psychosocial Stress;Questionnaires;Recruitment Activity;Registries;Research;Research Personnel;Resources;Salivary;Serum;Severities;Source;Stress;Surveys;Symptoms;Temporomandibular Joint Disorders;Testing;United States National Institutes of Health;Universities;Woman;Women's Health;biological adaptation to stress;falls;heart rate variability;maltreatment;neuropsychiatry;psychologic;psychosocial;stressor;violence against women


application_id: 8168486
project_number: 5P20RR020145-07
project_title: GENE THERAPY FOR OROFACIAL PAIN
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8312
contact_pi_person_id: 8535290
contact_pi: DANAHER, ROBERT
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.Chronic orofacial (OFP) pain is common worldwide adversely influences quality of life and imposes substantial costs on the healthcare system.  It has been found that inflammatory and neuropathic components can contribute to the maintenance of these pain conditions mediated by sensory neurons housed within the trigeminal (V) brain stem sensory nuclear complex.  Direct gene transfer to sensory nerves at these sites offers the ability to selectively interrupt nociceptive neurotransmission or interfere with underlying processes contributing to the maintenance of persistent pain. In this proposal we describe studies that use innovative technology (i.e. viral vector-based gene transfer) for the treatment of chronic OFP pain.  Our goal is to alleviate inflammatory (Aim 1) and neuropathic (Aim 2) OFP pain in a safe (Aim 3) and effective manner using recombinant herpes simplex virus (HSV)-based vectors that are naturally suited to provide delivery of human genes to the trigeminal ganglia (TG). Our overall hypothesis is that HSV based gene therapy can be used effectively and safely to alleviate chronic orofacial pain. To address this hypothesis we will use recombinant replication-incompetent HSV vectors engineered to produce human opioid peptides or glutamic acid decarboxylase (GAD) in TG neurons for the relief of chronic pain in the orofacial region.  Our Specific Aims are: 
1. Test the hypothesis that expression of endomorphin in rat TGs results in more effective abrogation of inflammatory orofacial pain than expression of enkephalin and glutamic acid decarboxylase. 
2. Test the hypothesis that expression of glutamic acid decarboxylase in rat TGs results in more effective abrogation of neuropathic orofacial pain than expression of enkephalin and endomorphin. 
3. Test the hypothesis that replication defective HSV based gene delivery to the TG is safe.

project_terms:
Address;Afferent Neurons;Brain Stem;Chronic;Complex;Computer Retrieval of Information on Scientific Projects Database;Engineering;Enkephalins;Funding;Gene Delivery;Gene Transfer;Genes;Glutamate Decarboxylase;Goals;Grant;HSV vector;Healthcare Systems;Housing;Human;Inflammatory;Institution;Maintenance;Mediating;Neurons;Neuropathy;Nociception;Nuclear;Opioid Peptide;Orofacial Pain;Pain;Persistent pain;Process;Quality of life;Rattus;Recombinants;Research;Research Personnel;Resources;Sensory;Simplexvirus;Site;Source;Structure of trigeminal ganglion;Testing;Trigeminal System;United States National Institutes of Health;Viral Vector;afferent nerve;base;chronic pain;cost;gene therapy;innovative technologies;neurotransmission;orofacial;vector


application_id: 8168485
project_number: 5P20RR020145-07
project_title: ONTOGENY OF INNATE IMMUNE RESPONSES AT MUCOSAL SURFACES
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8311
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
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 hallmark of the vertebrate immune system is its ability to maintain an equilibrium between reactivity and quiescence of responses while geared to respond and adapt rapidly to noxious and potentially lethal challenge.  The system must recognize the challenge develop and express a response to control the challenge and terminate the reaction in regulating the response.  These reactions are the responsibility of components of innate immunity that include cellular receptors and biomolecules at mucosal surfaces and within the systemic circulation.  Due to the complexity of the microbial challenge in the oral cavity it is clear that the innate immune system must play a crucial role in regulating host responses to the commensal microbiota.  This proposal engages a collaborative relationship to enable determination of these responses in a human-like model of oral infection and inflammation:  (1) This proposal will focus on the use of a nonhuman primate (rhesus) model of periodontal infection and inflammation. It is built upon a unique resource the Caribbean Primate Research Center (CPRC); (2) This proposal is a collaborative relationship between investigators at the University of Kentucky the CPRC and the University of Puerto Rico Dental School; (3) This proposal will provide novel information on innate immunity in cross-sectional studies related to age using various cohorts from young to aged animals and related to the expression of periodontitis; and (4) Using the nonhuman primate model of periodontal infection and disease we will determine longitudinal changes in innate immune responses througout age of development of the individual specifically related to the initiation progression and resolution of the disease process.  This model provides for a controlled study of these processes that cannot be accomplished in humans but provides a human-like model of infection disease and host responses. The General Hypothesis for the project is that "Innate immune response components in gingival tissues vary with age and periodontal disease expression."  This will enable the identification of crucial innate immune molecular events that contribute to gingival homeostasis. The studies proposed in this application will use an innovative strategy in 2 Specific Aims to interface a nonhuman primate model of periodontitis with microarray gene expression technology to address these critical questions regarding the characteristics and ontogeny of innate responses in the oral cavity.

project_terms:
Address;Age;Animals;Blood Circulation;Caribbean region;Characteristics;Computer Retrieval of Information on Scientific Projects Database;Controlled Study;Cross-Sectional Studies;Dental Schools;Development;Disease;Equilibrium;Event;Funding;Gene Expression;Gingiva;Grant;Growth;Homeostasis;Human;Immune;Immune response;Immune system;Individual;Infection;Inflammation;Institution;Kentucky;Macaca mulatta;Modeling;Molecular;Natural Immunity;Oral cavity;Periodontal Diseases;Periodontal Infection;Periodontitis;Play;Primates;Process;Puerto Rico;Reaction;Research;Research Personnel;Resolution;Resources;Role;Source;Surface;System;Technology;Tissues;United States National Institutes of Health;Universities;cohort;innovation;microbial;nonhuman primate;novel;oral infection;receptor;response


application_id: 8168484
project_number: 5P20RR020145-07
project_title: CHRONIC ORAL INFLAMMATION AND INFLAMMATORY BOWEL DISEASE
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8310
contact_pi_person_id: 9645586
contact_pi: ARSENESCU, RAZVAN I.
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 oral cavity provides a biotope for many bacterial species which may be considered commensal opportunistic or pathogenic. The host defense systems are important for monitoring the composition of the bacterial microbiota and preventing disease initiation and progression. Innate and adaptive immune mechanisms serve to prevent inappropriate responses to commensal microbes regulate opportunistic species and sequester pathogens. Dysregulation of these responses can lead to chronic inflammatory conditions in the oral cavity i.e. gingivitis and periodontitis. Understanding the molecular signaling mechanisms that maintain homeostasis in the oral cavity is key to understanding the pathology of diseases in response to oral bacteria. Host cells respond to microorganisms through pattern recognition receptors (PRRs) such as Toll-like Receptors (TLRs) which recognize broad classes of pathogen associated molecular patterns (PAMPs) including lipopolysaccharide (LPS) lipopeptides and microbial nucleic acids. Inflammatory bowel diseases (Crohn's and Ulcerative colitis) are chronic conditions that reflect an altered communication between resident gut flora and both the innate and acquired immune arms. The initiating factor is unknown but lately a primary epithelial defect has been favored. A significant number of patients with inflammatory bowel diseases develop oral lesions but the incidence of periodontitis has not been adequately established. Patients with IBD (inflammatory bowel diseases) represent a heterogeneous group more so when expression of individual genes within the gut mucosa is analyzed.  We have recently identified unique subgroups of patients with Crohn's disease based on expression of biomarkers for innate immunity in the colonic mucosa. Additionally we have uncovered strong associations with a fat derived anti-inflammatory adipokine adiponectin. The current proposal investigates the association between periodontitis and Crohn's disease and the relevance of disease specific biomarkers for this oral chronic inflammatory condition using a GENERAL HYPOTHESIS that patients with IBD have a greater risk for periodontitis due to an underlying defect in innate immune responses at mucosal surfaces.

project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Cells;Chronic;Communication;Computer Retrieval of Information on Scientific Projects Database;Crohn's disease;Defect;Disease;Epithelial;Fatty acid glycerol esters;Funding;Genes;Gingivitis;Grant;Homeostasis;Host Defense;Immune;Immune response;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Institution;Lead;Lipopolysaccharides;Molecular;Monitor;Mucous Membrane;Natural Immunity;Nucleic Acids;Oral;Oral cavity;Pathology;Patients;Pattern;Pattern recognition receptor;Periodontitis;Research;Research Personnel;Resources;Risk;Signal Transduction;Source;Subgroup;Surface;System;Toll-like receptors;Ulcerative Colitis;United States National Institutes of Health;adiponectin;arm;base;biomarker;commensal microbes;microbial;microorganism;oral bacteria;oral lesion;pathogen;prevent;response


application_id: 8168483
project_number: 5P20RR020145-07
project_title: PHYSIOLOGY OF THE STRESS RESPONSE IN PATIENTS WITH TMD AND FIBROMYALGIA
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8309
contact_pi_person_id: 8772180
contact_pi: YEPES, JUAN FERNANDO
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.Temporomandibular disorders (TMD) are a complex heterogeneous group of clinical conditions involving pain and/or dysfunction in the muscles of mastication and related muscles of the head and neck and/or the temporomandibular joint. The localized symptoms of TMD often co-occur with the more generalized pain syndrome of fibromyalgia (FM) defined as a widespread pain stiffness and altered pain processing involving the locomotor system.  In addition to the chronic pain both TMD and FM usually present with other symptoms such as fatigue mood disturbance cognitive dysfunction and sleep difficulty.  We and others have made the case that this symptom complex is associated with significant perceived psychological or physical stress and with physiologic deficits in the stress response.  In FM and TMD altered function of stress-response systems includes the hypothalamic-pituitary-adrenal (HPA) axis autonomic nervous system and immune system.  All previous studies have been limited in scope however focusing on either specific diagnostic group or stress exposure. Indeed a specific patient may accumulate several diagnoses in addition to TMD and FM including chronic fatigue syndrome irritable bowel syndrome chronic daily headache and others.  The General Hypothesis is that "individuals with FM and TMD can overlap significantly with respect to symptoms and stress physiologic phenotypes (e.g. salivary cortisol heart-rate variability). The symptoms rather than diagnostic group are expected to correlate with specific neuroendocrine profile.  We will recruit individuals from the University of Kentucky outpatient rheumatology and orofacial pain clinics and the Kentucky Women's Health Registry.  Subjects will be classified into 4 groups (FM TMD FM and TMD and healthy matched controls).  The specific aims to be tested are:  Specific Aim 1:  Examine the relationship between FM and TMD and the presence and severity of symptom profiles to determine the relationship between diagnostic group and symptoms; Specific Aim 2:  Determine the association between psychosocial stress and distress on symptoms diagnostic groups (TMD FM TMD and FM and healthy matched controls) and stress physiology; and Specific Aim 3: Compare the stress physiology phenotypes of four subject groups: (1) TMD (2) FM (3) TMD and FM and (4) healthy age-matched controls.

project_terms:
Age;Autonomic nervous system;Chronic Daily Headaches;Chronic Fatigue Syndrome;Clinical;Complex;Computer Retrieval of Information on Scientific Projects Database;Diagnosis;Diagnostic;Distress;Fatigue;Fibromyalgia;Functional disorder;Funding;Grant;Head and Neck Muscle;Hydrocortisone;Immune system;Impaired cognition;Individual;Institution;Irritable Bowel Syndrome;Kentucky;Masticatory muscles;Neurosecretory Systems;Orofacial Pain;Outpatients;Pain;Pain Clinics;Patients;Phenotype;Physiological;Physiology;Process;Psychosocial Stress;Recruitment Activity;Registries;Research;Research Personnel;Resources;Rheumatology;Salivary;Severities;Sleep;Source;Stress;Symptoms;System;Temporomandibular Joint;Temporomandibular Joint Disorders;Testing;United States National Institutes of Health;Universities;Women's Health;biological adaptation to stress;chronic pain;disturbance in affect;heart rate variability;hypothalamic-pituitary-adrenal axis;psychologic


application_id: 8168482
project_number: 5P20RR020145-07
project_title: CHRONIC INFLAMMATION AT ORAL AND CERVICO-VAGINAL MUCOSA
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8308
contact_pi_person_id: 9342359
contact_pi: ASHFORD, KRISTIN
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.Preterm birth (PTB; 37 weeks gestation) and low birthweight (LBW; 2500 g) deliveries continue to increase in the U.S. resulting in substantial economic and societal costs.  Adverse pregnancy outcomes are disproportionately expressed in ethnic and racial minority populations and historically underserved populations particularly from rural regions of the nation.  However a substantial proportion of the general overall increase in incidence of PTB and LBW including severe PTB (32 weeks) and very low birthweight (1500 g) cannot be explained by classical risk factors for these negative birth outcomes.  Thus a broader view of the potential interrelationships leading to adverse pregnancy outcomes including biologic markers or processes could provide some predictive value allowing earlier intervention to reduce this burden in the population.  This investigation will test the General Hypothesis that "women who deliver preterm will have higher levels of prenatal inflammatory markers in whole saliva serum and cervico-vaginal fluid (CVF) which are displayed earlier in pregnancy compared to women who deliver term". Three specific aims will be used to guide the study in testing this hypothesis: Specific Aim 1:  To compare and contrast the expression of trimester-specific prenatal inflammatory markers in whole saliva serum and CVF. Rationale: This aim will determine our ability of detect trimester-specific inflammatory markers in saliva serum and CVF.  Specific Aim 2: To define the differences in the expression of trimester-specific prenatal inflammatory markers between women who do and do not experience preterm birth in a multi-racial/ethnic population. Rationale: This aim will establish PTB-specific risk factors based on prenatal inflammatory biomarker profiles in a racially/ethnically diverse population of Caucasian African American and Hispanic/Latino women) and preterm birth (37 completed weeks of gestation). Specific Aim 3:  To determine if trimester-specific prenatal inflammatory markers linked with psychosocial and biobehavioral variables pose a significant risk for preterm birth in a multi-racial/ethnic sample of pregnant women. Rationale: This aim will establish if trimester-specific systemic and local prenatal markers of inflammation coupled with psychosocial and biobehavioral variables impact preterm birth risk and self-reported levels of prenatal depressive symptoms; anxiety; stress urine cotinine and self-reported prenatal SHS exposure

project_terms:
African American;Anxiety;Biological Markers;Birth;Caucasians;Caucasoid Race;Chronic;Computer Retrieval of Information on Scientific Projects Database;Cotinine;Coupled;Early treatment;Economics;Funding;Grant;Hispanics;Incidence;Inflammation;Inflammatory;Institution;Investigation;Latino;Link;Low Birth Weight Infant;Minority Groups;Mucous Membrane;Oral;Outcome;Patient Self-Report;Population;Population Heterogeneity;Predictive Value;Pregnancy;Pregnancy Outcome;Pregnant Women;Premature Birth;Process;Research;Research Personnel;Resources;Risk;Risk Factors;Rural;Saliva;Sampling;Serum;Source;Stress;Testing;Underserved Population;United States National Institutes of Health;Urine;Vagina;Woman;base;biobehavior;biomarker;cost;depressive symptoms;experience;inflammatory marker;prenatal;psychosocial;racial and ethnic;vaginal fluid


application_id: 8168481
project_number: 5P20RR020145-07
project_title: UKY DENTAL COBRE: DENTAL CLINICAL RESEARCH CENTER
administering_ic: NCRR
award_notice_date: 2010-09-10
opportunity_number: RFA-RR-08-007
application_type: 5
activity_code: P20
ic: RR
serial_number: 020145
project_start_date: 2010-08-01
project_end_date: 2011-07-31
study_section: ZRR1-RI-B(01)
subproject_number: 8307
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.The clinical research environment at the University of Kentucky is excellent.  The DDKCRC occupies 4000 sq. ft. of space in the College of Dentistry.  The clinical research initiatives of the COBRE are coordinated in the DDKCRC with 4 hygienists/study coordinators and a Clinical Research Assistant Professor clinician who manages the operations of the clinic.  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; 2) define and impact oral health disparities in rural communities of Kentucky; and 3) support the clinical projects of the CBBO/SD grant.  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.

project_terms:
Behavioral;Biological;Centers of Research Excellence;Clinic;Clinical;Clinical Research;Computer Retrieval of Information on Scientific Projects Database;Dental;Dentistry;Environment;Funding;Genetic;Grant;Institution;Investigation;Kentucky;Oral;Oral health;Research;Research Infrastructure;Research Personnel;Resources;Rural Community;Rural Population;Source;Systemic disease;Training;United States National Institutes of Health;Universities;college;health disparity;operation;professor;square foot


