# projects

application_id: 9193426
project_number: 1R21AR070620-01
project_title: Effects of Sodium-dependent Glucose Co-transporter 2 Inhibition on Bone.
administering_ic: NIAMS
award_notice_date: 2016-06-25
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AR
serial_number: 070620
program_official: ALEKEL, D LEE
project_start_date: 2016-07-01
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 MOSS-V (02)]
contact_pi_person_id: 1919059
contact_pi: THRAILKILL, KATHRYN M
other_pis: NYMAN, JEFFRY STEPHEN
congressional_district: 06
department: PEDIATRICS
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:
Project SummaryPersons with type 1 and type 2 diabetes (T1D T2D) both have increased fracture risk attributedto specific deficits in the microarchitecture material properties and strength of diabetic bone.Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are a new class of FDA-approved glucose-regulating agents for use in persons with T2D. These drugs (canagliflozindapagliflozin and empagliflozin are FDA-approved in the USA and Europe) increase urinaryglucose excretion by inhibiting glucose reabsorption in the renal proximal tubule and therebyimprove glycemic control in persons with type 2 diabetes. They are likely to play a prominentrole in the future treatment of T2D because of this unique mechanism of action and becausethey provide concurrent beneficial reductions in body weight and blood pressure. Howeverearly clinical studies have demonstrated a possible ~30% increase in bone fractures in patientsreceiving these medications with fractures occurring as early as 12 weeks of therapy. Atpresent very little is known about the effects of SGLT2 inhibition on bone mineral homeostasisbone turnover or bone microarchitecture or how these drugs specifically impact diabetic bonedisease. Therefore the objective of this proposal is to utilize several relevant rodent models(slc5a2-functional mutants STZ-induced diabetes TallyHo) to investigate potential mechanismscontributing to the adverse effects of SGLT2-inhibitor therapy on the skeleton. Furthermore wewill investigate the efficacy of co-therapy with anti-calciuric thiazide diuretic drugs to potentiallymitigate the negative effects of SGLT2-inhibitor therapy on the skeleton. Recognizing that alifelong increased risk for fragility fracture is now an established comorbidity of diabetes a betterunderstanding of the effects of SGLT2 inhibitors on bone health is both timely and highlyrelevant to the future of diabetes treatment.

project_terms:
Adverse effects;Affect;Age;Attenuated;Blood Glucose;Blood Pressure;Body Weight;Bone Density;Bone Diseases;Bone Resorption;Caring;Clinical;Clinical Research;Clinical Trials;Communication;Comorbidity;Diabetes Mellitus;Diabetic mouse;Disease;Europe;Excretory function;Exhibits;FDA approved;Fracture;Functional disorder;Future;Genes;Glucose;Homeostasis;Human;Hydrochlorothiazide;Incidence;Insulin-Dependent Diabetes Mellitus;Kidney;Laboratories;Link;Measures;Mediating;Minerals;Modeling;Mus;Mutate;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nonsense Mutation;Obesity;Patients;Persons;Pharmaceutical Preparations;Phenotype;Physiology;Play;Population;Positioning Attribute;Pre-Clinical Model;Prevention;Property;Proximal Kidney Tubules;Reporting;Resistance;Risk;Rodent;Rodent Model;Role;Safety;Skeleton;Sodium;Streptozocin;Structure;Testing;Thiazide Diuretics;Time;Urine;blood glucose regulation;bone;bone health;bone turnover;clinically relevant;diabetic;diabetic patient;early onset;experience;glycemic control;hypercalciuria;improved;inhibitor/antagonist;innovation;mouse model;mutant;non-diabetic;preclinical study;prevent;skeletal;substantia spongiosa;symporter;type I and type II diabetes;urinary

public_health_relevance:
Project NarrativePersons with either Type 1 or Type 2 diabetes (T1D T2D) have an increased risk for bonefracture which is not predicted by bone mineral density testing alone; rather diabetic boneappears to be more brittle owing to diabetes-related changes in the microarchitecture andstrength of the skeleton. The SGLT2 inhibitor class of drugs is a new class of glucose-regulatingagents which improves glucose control in persons with diabetes by allowing the excess glucoseto be excreted in the urine. However these drugs appear to also further increase the risk offractures in diabetic patients; therefore the objectives of this proposal are to study themechanisms contributing to the increased fracture risk in persons receiving these medications.


application_id: 9193418
project_number: 1R01HG008988-01A1
project_title: Addressing Ethical Challenges in Networked Biorepositories
administering_ic: NHGRI
award_notice_date: 2016-09-28
opportunity_number: PA-14-276
application_type: 1
activity_code: R01
ic: HG
serial_number: 008988
suffix: A1
program_official: LOCKHART, NICOLE C
project_start_date: 2016-09-28
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZRG1 SEIR-R (01)]
contact_pi_person_id: 10692185
contact_pi: BROTHERS, KYLE BERTRAM
other_pis: GOLDENBERG, AARON J
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Accounting;Address;American;Area;Biological;Collection;Communities;Complex;Consent;Country;Data;Data Security;Data Set;Development;Disease;Elements;Ethics;Focus Groups;Future;Genomics;Health;Human Resources;Individual;Institution;Interview;Knowledge;Link;Literature;Medical;Methods;National Human Genome Research Institute;Participant;Patients;Persons;Policies;Precision Medicine Initiative;Privacy;Problem Solving;Process;Rare Diseases;Recommendation;Research;Research Personnel;Research Support;Resources;Sampling;Specimen;Structure;Time;Variation (Genetics);Work;biobank;cohort;data access;design;ethical legal social implication;experience;health data;informant;interest;meetings;network models;novel;patient subsets;personalized health care;precision medicine;prospective;repository;sharing data;symposium;targeted treatment;tool


application_id: 9193364
project_number: 1R01CA205941-01A1
project_title: Non-invasive detection of tumor extracellular pH using multispectral optoacoustic tomography
administering_ic: NCI
award_notice_date: 2016-05-19
opportunity_number: PAR-13-137
application_type: 1
activity_code: R01
ic: CA
serial_number: 205941
suffix: A1
program_official: ZHANG, YANTIAN
project_start_date: 2016-09-01
project_end_date: 2017-01-27
study_section: Clinical Molecular Imaging and Probe Development[CMIP]
contact_pi_person_id: 8230129
contact_pi: MCNALLY, LACEY 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:
Malignant melanoma is one of the fastest rising cancers in the US. While treatment for clinical stage I and IImelanoma involves wide local excision of the primary tumor with staging of the regional lymph nodes bysentinel lymph node (SLN) biopsy SLN biopsy is fraught with false-negative results. Technology that wouldreliably detect nodal metastases not just the first draining node could improve the sensitivity of melanomanodal staging. Therefore our objective is to (1) develop characterize validate and compare (A) optoacousticultra-acidic pH-responsive acidic pH targeted dye pHO dye and (B) external cell membrane anchored V7-pHO for tumor detection by multispectral optoacoustic tomography (MSOT) and (2) provide real-time colormaps of tissue pH to allow for identification of regions of tumor in lymph nodes. Based on our preliminary datawe reason that it is possible to use our targeting methodology to identify very small metastases which wouldallow complete lymph node dissection to be performed only for the 15% to 20% of patients who actually havecancer in the non-sentinel nodes. We hypothesize that pHO and V7-pHO dyes will facilitate detection ofmelanoma within lymph nodes and differentiate it from non-malignant fibrous or inflammatory tissue with highsensitivity and specificity using multispectral optoacoustic tomography. To test our hypothesis we propose thefollowing aims: 1) characterize and validate pHO and V7-pHO dyes to target acidic pHe for detection of tumorcells in vitro and in tissue phantoms; 2) assess pHO and V7-pHO dyes to facilitate detection of melanoma fromnon-malignant tissue in vivo using multispectral optoacoustic tomography; and 3) develop ratiometricalgorithms based upon the spectral modulation of the pHO and V7-pHO dyes to produce real-time pHemeasurement color maps and bi-color maps of tumors. Successful identification of melanoma containing lymphnodes using pHO or V7-pHO dyes detected using MSOT has potential to stratify patients for treatment in theclinic. Identification of metastases in lymph nodes or elsewhere in melanoma patients has potential for game-changing clinical management of patients with melanoma.

project_terms:
Algorithms;B-Cell Neoplasm;Benchmarking;Biodistribution;Cell membrane;Cicatrix;Clinic;Clinical;Clinical Management;Clinical Treatment;Color;Contrast Media;Data;Detection;Disease;Dyes;Environment;Evaluation;Excision;Image;In Vitro;Inflammatory;Light;Lymph Node Dissections;Lymph node excision;Lymphedema;Malignant - descriptor;Malignant Neoplasms;Maps;Measurement;Metastatic Neoplasm to Lymph Nodes;Methodology;Methods;Microelectrodes;Molecular;Mus;Neoplasm Metastasis;Nerve;Nodal;Noise;Non-Invasive Cancer Detection;Non-Malignant;Patients;Primary Neoplasm;Property;Reporter;Research;Resolution;Risk;Sensitivity and Specificity;Sentinel Lymph Node;Sentinel Lymph Node Biopsy;Signal Transduction;Staging;Stimulus;Structure of thyroid parafollicular cell;Technology;Testing;Time;Tissues;Tumor Tissue;Work;base;extracellular;imaging modality;improved;in vivo;lymph nodes;malignant breast neoplasm;melanoma;nano;neoplastic cell;novel;patient stratification;ratiometric;response;sound;spectroscopic imaging;tissue phantom;tomography;tumor;wound

public_health_relevance:
Identification of cancer within sentinel lymph nodes and non-sentinel lymph nodes is a criterion for staging ofmelanoma. Current methods of sentinel lymph node evaluation are prone to inaccurate results. This projectwill develop characterize and validate two novel contrast agents pHO and V7-pHO dyes to identifymelanoma within lymph nodes using multispectral optoacoustic tomography. Identification of metastases inlymph nodes or elsewhere in melanoma patients has potential to impact clinical management of patients withmelanoma.


application_id: 9192620
project_number: 1F30NS090714-01A1
project_title: Elucidating A Novel Mechanism for Dementia
administering_ic: NINDS
award_notice_date: 2016-06-20
opportunity_number: PA-14-150
application_type: 1
activity_code: F30
ic: NS
serial_number: 090714
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2016-12-15
project_end_date: 2018-12-14
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 11942576
contact_pi: IGHODARO, ESEOSA T.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Dementia is a devastating clinical syndrome that affects millions of elderly individuals worldwide. Treating patients with dementia is challenging because of the myriad number of pathologies underlying its clinical manifestation and progression. Therefore it is imperative to better understand the various mechanisms of dementia-inducing diseases in order to correctly diagnose and treat dementia patients. The focus of my proposed project is to study a common but relatively underappreciated and under-studied mechanism of dementia characterized by vascular abnormalities hippocampal shrinkage and abnormal protein accumulation (TDP-43) in the brain. Our lab has published several studies on two dementia-associated pathologies: hippocampal sclerosis of aging (HS-Aging) and brain arteriolosclerosis (B-ASC). HS-Aging is a common neurodegenerative pathology seen in up to 25% of individuals < 85 years at autopsy. B- ASC is a cerebrovascular pathology that increases in frequency and severity with advanced age. We have identified a common genetic risk variant in the ABCC9 gene with a polymorphism that changes risk for both B-ASC and HS-Aging pathologies. This phenomenon is exciting because it may point the way to a novel future therapeutic intervention related to ABCC9-modulating drugs. As a key step to better understanding the pathogenetic mechanism new experiments are required. My overall hypothesis is that genetic and pharmacological perturbations in ABCC9 or its gene product lead to B-ASC pathology which in turn lead to HS-Aging/TDP-43 resulting in the clinical presentation of dementia. We will address this hypothesis through the following specific aims: 1) Test the hypothesis that a SNP ABCC9.rs704180 is associated with altered vascular structure in aged individuals and 2) Test the hypothesis that chronic pharmacologic inhibition of ABCC9 gene product will cause B-ASC thus in turn exacerbating HS-Aging/TDP-43 pathology. In Aim 1 we will use human tissue samples from the University of Kentucky Alzheimer's Disease Center brain bio-bank to quantify vascular structures in individuals with varying ABCC9 SNP status. In Aim 2 we will treat mice with clinical and pathological HS-Aging characteristics (age-related TDP-43 pathology) to determine the effects of ABCC9 modifying drug treatment in these animals. Successful completion of this project will provide insight into a novel mechanism of dementia. In addition it will provide opportunities for me to diversify my skillset as I prepare for a future career as a physician-scientist in the field of translational neuroscience research.

project_terms:
Address;Affect;Aging;Alzheimer's Disease;Animal Model;Animals;Autopsy;Binding;Bioethics;Blood Vessels;Brain;Breeding;Characteristics;Chronic;Clinical;Computer software;Data;Dementia;Development;Diagnosis;Disease;Dissection;Early Diagnosis;Elderly;Family;Frequencies;Future;Genes;Genetic;Genetic Polymorphism;Genetic Risk;Hippocampus (Brain);Human;IACUC;Image Analysis;Immunohistochemistry;Individual;Journals;Kentucky;Knowledge;Lead;Learning;Life;Maintenance;Measures;Mediating;Morphology;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurology;Neurosciences Research;Paper;Pathology;Patients;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Proteins;Publishing;Research;Risk;Scientist;Severities;Single Nucleotide Polymorphism;Source;Structure;Sulfonylurea Compounds;Syndrome;Testing;Therapeutic Intervention;Thick;Tissue Sample;Training;Transcript;Universities;Vascular Smooth Muscle;age related;aged;aging brain;brain arteriolosclerosis;career;cerebrovascular;digital;effective therapy;gene product;hippocampal sclerosis;human tissue;inhibitor/antagonist;insight;member;mouse model;neuron loss;neuropathology;novel;pre-clinical;protein TDP-43;research study;risk variant;sulfonylurea receptor;therapeutic target;tissue processing;translational neuroscience;vascular abnormality

public_health_relevance:
Dementia is a devastating syndrome caused by a plethora of diseases in the brain. Understanding the underlying mechanisms and clinical presentations of these varying diseases will aid in early detection precise diagnosis and effective treatment of patients with this debilitating syndrome.


application_id: 9192090
project_number: 1F31NS093892-01A1
project_title: Defining the Role of Laforin in Glycogen Metabolism and Lafora Disease
administering_ic: NINDS
award_notice_date: 2016-06-10
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: NS
serial_number: 093892
suffix: A1
program_official: STEWART, RANDALL R
project_start_date: 2016-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1 F04B-D (20)]
contact_pi_person_id: 12497153
contact_pi: BREWER, MARY KATHRYN
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:
Project Summary/Abstract The goal of this proposal is to use the unique window offered by Lafora disease (LD) to understandhow laforin regulates glycogen metabolism and define the molecular perturbation of LD patientmutations. Lafora disease (LD) one of the five major progressive myoclonus epilepsies is a fatal geneticneurological disorder that manifests during adolescence and invariably leads to neurodegeneration and death.Patients with LD display accumulations of hyperphosphorylated aberrantly branched glycogen-like particlescalled Lafora bodies (LBs). LBs are found in most tissues but neurological symptoms predominate in LDpatients. Mutations in the gene encoding the glycogen phosphatase laforin cause approximately 70% of LDcases. LD largely centers on glycogen metabolism. Glycogen is the most important carbohydrate storagemolecule in mammals and misregulation of glycogen is implicated in many diseases. Recent studies show thatglycogen plays a dynamic role in brain function and that neurons are highly sensitive to glycogen perturbations.Although glycogen has been studied for many years gaps in our understanding of its regulation remain. TheGentry lab established laforin as the founding member of the glucan phosphatase family (i.e. enzymes thatrelease phosphate from carbohydrates) and studies on LD show that the absence of laforin triggers thetransformation of glycogen into the neurotoxic carbohydrate that makes up LBs. As the only glucanphosphatase in humans laforin is the lynchpin of glycogen regulation by phosphorylation. We recently determined the crystal structure of laforin. This proposal will couple insights from the structurewith biochemical and biophysical tools to define how laforin functions as a glucan phosphatase and regulatesglycogen metabolism. Further the 33 LD-associated missense mutations are scattered throughout thestructure and have different effects on laforin activity. A goal in our lab is to define the effect of all of thesemutations. Aim 1A will address the nature of the dimer interface which has been controversial in the field andthe molecular effect of LD mutations in this region. Aim 1B will define how laforin cooperatively binds theglucan chains in glycogen and the effects of length and branching. Aim 2 will establish the role of theinterdomain region of laforin (i.e. between the phosphatase and carbohydrate-binding domains) in maintainingC3- and C6-specific dephosphorylation of glycogen. A number of LD mutations fall in this region and this aimwill demonstrate their functional effects. In summary this proposal utilizes cross-disciplinary techniques tostudy glycogen homeostasis and the mechanisms of LD studies that will provide insights into brain metabolismand pave the way for patient-specific diagnoses and treatments.

project_terms:
Address;Adolescence;Affect;Affinity;Architecture;Binding;Biological Assay;Brain;Carbohydrates;Cessation of life;Clinical Research;Cystic Fibrosis;Data;Diabetes Mellitus;Diagnosis;Dimerization;Disease;Disease Progression;Enzymes;Epilepsy;Event;Family;Genes;Genetic;Glucans;Glucose;Glycogen;Goals;Heterogeneity;Homeostasis;Human;Hybrids;Impaired cognition;Investigation;Knockout Mice;Lafora Disease;Lead;Length;Light;Linear Models;Malignant Neoplasms;Mammals;Maps;Metabolic Diseases;Missense Mutation;Molecular;Mutation;Nature;Nerve Degeneration;Neurologic;Neurons;Oligosaccharides;Onset of illness;Outcome;Patients;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Point Mutation;Positioning Attribute;Potassium Glutamate;Progressive Myoclonic Epilepsies;Protein Dephosphorylation;Proteins;Publishing;Regulation;Reporting;Role;Seizures;Solubility;Source;Specificity;Structure;Symptoms;Techniques;Textbooks;Time;Tissues;abstracting;base;biochemical tools;biophysical tools;brain metabolism;carbohydrate metabolism;design;dimer;extracellular;falls;gain of function mutation;glycogen metabolism;inorganic phosphate;insertion/deletion mutation;insight;member;mouse model;mutant;nervous system disorder;neurotoxic;particle

public_health_relevance:
Project NarrativeLafora disease is a genetic neurological disorder with no cure that presents during adolescence and rapidlyprogresses into severe epilepsy cognitive decline and death. Mutations in the gene encoding the proteinlaforin lead to carbohydrate accumulations in many tissues which cause neurodegeneration. This proposal isdesigned to define how laforin regulates carbohydrate metabolism and shed light on the patient-specificmechanisms of Lafora disease.


application_id: 9191467
project_number: 1F30NS096876-01A1
project_title: Multi-mechanistic protection of mitochondria following traumatic brain injury
administering_ic: NINDS
award_notice_date: 2016-06-15
opportunity_number: PA-14-150
application_type: 1
activity_code: F30
ic: NS
serial_number: 096876
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-07-01
project_end_date: 2020-05-31
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 12672057
contact_pi: KULBE, JACQUELINE RENEE
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acrolein;Affect;Aldehydes;Antidepressive Agents;Attenuated;Back;Binding;Buffers;Calcium;Calpain;Clinical Treatment;Cyclosporine;Cytosol;Dose;Economic Burden;FDA approved;Functional disorder;Generations;Health;Homeostasis;Hour;Human;Immunosuppressive Agents;Impairment;Injury;Learning;Life;Lipid Peroxidation;Lipids;Memory;Mitochondria;Mitochondrial Proteins;Motor;Nerve Degeneration;Neurologic;Neurons;Nitrogen;Outcome Measure;Oxygen;Pathology;Peptide Hydrolases;Peroxonitrite;Pharmaceutical Preparations;Pharmacotherapy;Phenelzine;Process;Rattus;Respiratory physiology;Role;Silver Staining;Spectrin;Staining method;Stains;Stress;Synapses;Testing;Therapeutic;Translating;Traumatic Brain Injury;Western Blotting;behavioral impairment;cognitive function;controlled cortical impact;disability;improved;improved outcome;inhibitor/antagonist;mitochondrial dysfunction;mitochondrial permeability transition pore;morris water maze;neuroprotection;neurotoxic;novel;object recognition;oxidative damage;perhydroxyl radical;prevent;respiratory;response;uptake


application_id: 9191333
project_number: 5R01AI119022-03
project_title: Structure and mechanism of the ESX secretion system from pathogenic mycobacteria
administering_ic: NIAID
award_notice_date: 2016-12-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 119022
program_official: KRAIGSLEY, ALISON
project_start_date: 2015-07-25
project_end_date: 2019-12-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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): Tuberculosis (TB) is a devastating infectious disease caused by Mycobacterium tuberculosis that results in more than 8 million new cases and 1.4 million deaths every year. The efficacy of currently available anti-TB drugs has been compromised by the emergence of multidrug-resistant and extensively drug-resistant strains therefore there is an urgent need to develop novel therapeutic strategies against TB. In M. tuberculosis three paralogous protein secretion systems - ESX-1 ESX-3 and ESX-5 - secrete PE-PPE dimers during defined stages of the infection process. PE and PPE proteins represent two large families of highly polymorphic proteins that are especially abundant in pathogenic mycobacteria. PE/PPE proteins are either cell wall associated or secreted into the extracellular milieu. These protein families are targets for vaccine development and diagnostic reagents. Multiple PE/PPE proteins play a role in in virulence immune evasion and persistence in host. An outstanding question in the field is what the mechanisms of PE/PPE secretion and assembly in the cell wall of mycobacteria. This proposal is designed to help answer this important biological question by using a range of genetic biochemical and structural approaches including X-ray crystallography and mass-spectrometry. This study is significant because the protein secretion systems of M. tuberculosis the ESX system in particular are attractive targets for drug development. The results of our study will significantly advance our understanding of mycobacterial pathogenesis and will provide structural knowledge that will guide the development of novel therapeutic targets and the design of a better vaccine against TB.

project_terms:
Affect;Amino Acids;Antigens;Architecture;Binding;Biochemical;Biological;Biological Process;C-terminal;Carrier Proteins;Cell Wall;Cell surface;Cessation of life;Communicable Diseases;Complex;Data;Development;Diagnostic;Diagnostic Reagent;Dimerization;Drug Targeting;ELF3 gene;Environment;Enzymes;Essential Amino Acids;Family;Future;Genetic;Genus Mycobacterium;Goals;Growth;Homologous Gene;Human;Immune Evasion;Individual;Infection;Investigation;Knowledge;Macromolecular Complexes;Mass Spectrum Analysis;Membrane;Methods;Modeling;Molecular;Molecular Chaperones;Multi-Drug Resistance;Mutation;Mycobacterium tuberculosis;Pathogenesis;Pathogenicity;Pathway interactions;Peptide Hydrolases;Pilum;Play;Process;Protein Family;Protein Secretion;Proteins;Role;Specificity;Structure;Surface;System;Testing;Therapeutic;Tuberculosis;Vaccines;Virulence;Work;X-Ray Crystallography;design;dimer;drug development;drug discovery;experimental study;extensive drug resistance;extracellular;improved;inhibitor/antagonist;insight;mycobacterial;new therapeutic target;novel therapeutics;pathogen;protein aggregation;protein protein interaction;protein transport;public health relevance;resistant strain;tool;tuberculosis drugs;vaccine candidate;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed studies are expected to uncover the architecture and mechanism of the ESX secretion system a pathway essential for virulence and involved in the transport of multiple proteins to the cell surface or extracellular milieu in humanpathogen M. tuberculosis. The generated data will provide a framework for developing novel therapeutics and improved vaccines against tuberculosis.


application_id: 9190933
project_number: 1R01HL131647-01A1
project_title: Regulation of Metabolic Genes in the Heart
administering_ic: NHLBI
award_notice_date: 2016-05-27
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 131647
suffix: A1
program_official: WONG, RENEE P
project_start_date: 2016-06-01
project_end_date: 2020-05-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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_terms:
Ablation;Accounting;Acute;Address;Aging;Alzheimer's Disease;Area;Attenuated;Binding;Bioenergetics;Biological;Biological Assay;Biological Preservation;Biology;Cardiac;Cardiac Myocytes;Cell Line;Cell physiology;Cells;Collaborations;Coupled;Cues;Diabetes Mellitus;Disease;Elements;Enzymes;Event;Excision;Functional disorder;Gene Expression Regulation;Genes;Glucose;Goals;Heart;Heart failure;Hexosamines;Hypertrophy;Infarction;Knowledge;Laboratories;Life;Link;Mediating;Metabolic;Metabolism;MicroRNAs;Mitochondria;Molecular;Molecular Biology Techniques;Monosaccharides;Mus;Mutation;Myocardial Ischemia;Myocardium;Neurodegenerative Disorders;O-GlcNAc transferase;Outcome;Pathway interactions;Physiological;Positioning Attribute;Post-Translational Protein Processing;Production;Protein Chemistry;Proteins;Recording of previous events;Regulation;Research Personnel;Respiratory physiology;Role;Severities;Signal Transduction;Stress;System;Testing;Therapeutic;Time;Tissues;Vascular Diseases;Ventricular Function;Work;abstracting;authority;experience;human disease;improved;in vivo;innovation;insight;interest;loss of function;novel;peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase;phenomenological models;promoter;research study;respiratory;response;tool;transcription factor;vector


application_id: 9189289
project_number: 2R01AA015407-12A1
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2016-08-08
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AA
serial_number: 015407
suffix: A1
program_official: AKBAR, MOHAMMED
project_start_date: 2005-08-01
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZRG1 IFCN-C (02)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Apoptotic;Astrocytes;Behavior;Behavioral;Biological Models;Brain;Calpain;Complex;Development;Equilibrium;Ethanol;Fetal Alcohol Spectrum Disorder;Funding;Hour;Hyperactive behavior;In Vitro;Learning;Mediating;Mediator of activation protein;Memory;Mental Retardation;Mitochondria;Modeling;Molecular;Monocyte Chemoattractant Protein-1;Mus;Neonatal Alcohol Exposure;Nerve Degeneration;Neuraxis;Neurons;North America;Oxidative Stress;Pathway interactions;Phase;Play;Proteins;Research;Role;Signal Pathway;Signal Transduction;Testing;Therapeutic;Third Pregnancy Trimester;Time;alcohol behavior;alcohol consumption during pregnancy;alcohol effect;alcohol exposure;endoplasmic reticulum stress;improved;in vitro Model;in vivo Model;insight;monocyte chemoattractant protein 1 receptor;neuron loss;neurotoxicity;neurotrophic factor;novel;novel therapeutic intervention;postnatal;prenatal;programs


application_id: 9188629
project_number: 3R01CA193220-02S1
project_title: Ubiquilin1 regulates EMT and metastasis of human lung adenocarcinoma
administering_ic: NCI
award_notice_date: 2016-09-02
opportunity_number: PA-15-322
application_type: 3
activity_code: R01
ic: CA
serial_number: 193220
suffix: S1
program_official: AULT, GRACE S
project_start_date: 2015-08-07
project_end_date: 2020-07-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9743542
contact_pi: BEVERLY, LEVI J
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_terms:
Accounting;Adenocarcinoma;Adenocarcinoma Cell;Affect;Alleles;Amino Acids;Back;Biochemical;Biological;Biological Assay;Biological Process;CRISPR/Cas technology;Cancer Etiology;Cancer Patient;Cancer cell line;Cell Line;Cell physiology;Cells;Cessation of life;Client;Data;Diagnosis;Disease;Disseminated Malignant Neoplasm;Engineering;Epithelial Cells;FRAP1 gene;Family;Family member;Future;Genes;Genetic Engineering;Goals;Growth;Health;Human;Human body;IGF1R gene;In Vitro;Individual;Kinetics;Laboratories;Lead;Link;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metastatic Neoplasm to the Lung;Metastatic to;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Pathway interactions;Patients;Phenotype;Play;Primary Neoplasm;Process;Property;Protein Family;Proteins;Recurrence;Role;Sampling;Signal Pathway;Signal Transduction;Site;Staging;Therapeutic;Transgenic Mice;Tumor Burden;UBA Domain;UBQLN1 gene;Ubiquitin;Xenograft Model;Xenograft procedure;base;cancer cell;cell motility;epithelial to mesenchymal transition;in vivo;in vivo Model;insight;member;metastatic process;migration;mortality;mouse model;mutant;novel;predictive marker;protein function;research study;small hairpin RNA;success;therapeutic target;tumor;tumor progression;tumorigenesis;ubiquilin


application_id: 9187014
project_number: 5R01GM113832-03
project_title: Synthetic HDL_a potential sepsis therapy
administering_ic: NIGMS
award_notice_date: 2016-11-16
opportunity_number: RFA-HL-14-028
application_type: 5
activity_code: R01
ic: GM
serial_number: 113832
program_official: DUNSMORE, SARAH
project_start_date: 2015-01-01
project_end_date: 2019-11-30
study_section: ZHL1-CSR-O(S1)
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: SCHWENDEMAN, ANNA
congressional_district: 06
department: PEDIATRICS
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): Summary High-density lipoprotein (HDL) is key a component of circulating blood and plays essential roles in vascular endothelial cells and immunity. However the levels of HDL decrease by 40-70% in septic patients which is associated with a poor prognosis. Using ApoAI null mice as an HDL deficient model we recently reported that mice lacking HDL are susceptible to cecal ligation and puncture (CLP)-induced septic death and increase HDL levels by over expression of ApoAI protects CLP-induced septic death. These clinical and animal studies indicate that a decrease in HDL levels is a risk factor for sepsis and raising circulating HDL levels may provide an efficient therapy for sepsis. In the preliminary study we demonstrated that synthetic HDL (sHDL) treatment significantly protects mice from CLP-induced septic death indicating that sHDL is a potential effective therapy for sepsis. We hypothesize that sHDL therapy protects sepsis by restoring both HDL level and its immune- and vascular-protective functions. The objectives of this grant are to understand the mechanism(s) underlying sHDL vascular protection to use this information to tailor the sHDL composition and to optimize treatment strategy specifically for sepsis. To achieve the grant objectives we plan to: 1) determine the mechanisms of sHDL's protection against sepsis-induced vascular pathogenesis; 2) Tailor sHDL composition for increased efficacy in sepsis; and 3) Optimize the sHDL treatment regimen for sepsis and test in immunocompromised septic mice. Completion of this preclinical study will provide a body of mechanistic data for a novel sHDL-based therapeutic approach for treatment of sepsis and position it for rapid clinical translation.

project_terms:
Animals;Bacteria;Biodistribution;Biological;Biology;Biotechnology;Blood;Blood Vessels;Cessation of life;Chemicals;Clinical;Clinical Data;Data;Dose;Drops;Drug Kinetics;Effector Cell;Endothelial Cells;Endotoxins;Event;Extravasation;Frequencies;Generations;Goals;Grant;High Density Lipoprotein therapy;High Density Lipoproteins;Immune;Immunity;Immunocompromised Host;In Vitro;Industrialization;Inflammatory;Inflammatory Response;Knockout Mice;Knowledge;Lead;Ligation;Lipids;Lipoprotein (a);Mediating;Modeling;Mus;Pathogenesis;Pathway interactions;Patients;Peptides;Play;Positioning Attribute;Proteins;Puncture procedure;Regimen;Reporting;Research Personnel;Risk Factors;Role;Safety;Sepsis;Shapes;Signal Transduction;Testing;Therapeutic;Treatment Protocols;Vascular Endothelial Cell;aged;base;cardiovascular disorder therapy;clinical translation;cytokine;design;effective therapy;endothelial dysfunction;experience;in vitro Assay;in vivo;innovation;macrophage;mortality;multidisciplinary;novel;outcome forecast;overexpression;pre-clinical;preclinical study;reconstitution;septic;success;tool;treatment strategy;vascular endothelial dysfunction

public_health_relevance:
The goal of this application is to develop synthetic HDL for sepsis therapy. Weexpect that completion of this preclinical study will provide a body of mechanistic datafor a novel synthetic HDL-based therapeutic approach for treatment of sepsis andposition it for rapid clinical translation.


application_id: 9185943
project_number: 5R01AT008617-02
project_title: Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms
administering_ic: NCCIH
award_notice_date: 2016-11-22
opportunity_number: PAR-13-375
application_type: 5
activity_code: R01
ic: AT
serial_number: 008617
program_official: HOPP, CRAIG
project_start_date: 2015-12-01
project_end_date: 2020-11-30
study_section: Special Emphasis Panel[ZRG1-EMNR-V(55)R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Anti-Inflammatory Agents;Anti-inflammatory;Antigens;Bacteria;Binding;Biological;Cells;Chronic;Colitis;Communication;Complementary Medicine;Complex;Crohn's disease;Custom;Data;Dendritic Cells;Diet;Disease;Edible Plants;Encapsulated;Escherichia;Escherichia coli;Exposure to;Food;Foundations;Genes;Ginger;Goals;Grapefruit;Health;Homeostasis;Immune;Immune Tolerance;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Interleukin-1;Interleukin-1 beta;Interleukin-10;Interleukin-6;Intestines;Investigation;Killings;Lamina Propria;Lipids;Literature;Macrophage Activation;Mediating;MicroRNAs;Modeling;Molecular;Mononuclear;Mucous Membrane;Mus;Myeloid Cell Activation;Natural Products;Oral Administration;Pathway interactions;Patients;Phagocytes;Plant Extracts;Plants;Play;Prevention;Production;Property;Proteins;Publishing;RNA Binding;Role;Sampling;Signal Transduction;Small RNA;Sodium Dextran Sulfate;Sorting - Cell Movement;Study models;TNF gene;Testing;Untranslated RNA;Untranslated Regions;base;bioactive natural products;cytokine;exosome;experimental study;fruits and vegetables;in vitro testing;in vivo;lymph nodes;macrophage;mouse model;nanoparticle;prevent;public health relevance;transcription factor;uptake


application_id: 9185322
project_number: 5R01EY024051-03
project_title: The danger signals in autoimmune uveitis
administering_ic: NEI
award_notice_date: 2016-11-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 024051
program_official: MCKIE, GEORGE ANN
project_start_date: 2014-12-01
project_end_date: 2018-11-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Autoimmune uveitis mediated by T cells is a major cause of blindness in the USA and worldwide particularly among relative young and working populations. Proposed studies will focus on the danger signals in pathogenesis of chronic autoimmune uveitis using a murine model induced by the adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells. Aims described in this proposal will examine the release of danger signals initiated by uveitogenic IRBP-specific T cells and the role of them in ocular inflammation. Aim 1 will determine the Fas/FasL signaling in rapid release of HMGB1 from viable retinal cells after interaction with IRBP-specific T cells. Aim 2 will examine the roleof HMGB1 in sustaining and promoting IRBP-specific T cell function during chronic intraocular inflammation. Results of these studies will further our understanding of the molecular pathogenesis of autoimmune uveitis and identify novel targets for anti-inflammatory intervention to limit visual loss.

project_terms:
Adoptive Transfer;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antigen-Presenting Cells;Antigens;Apoptotic;Astrocytes;Blindness;CD95 Antigens;Caspase;Cell Death;Cell physiology;Cells;Chronic;Disease;Eye;Frequencies;Functional disorder;Generations;Goals;HMGB1 gene;Human;Immunity;Inflammation;Inflammatory;Intervention;Local Therapy;MAPK14 gene;MAPK8 gene;Maintenance;Mediating;Memory;Molecular;Pathogenesis;Pathogenicity;Phenotype;Population;Proteins;Regulatory T-Lymphocyte;Resistance;Retinal;Role;Signal Transduction;Systemic Therapy;T memory cell;T-Lymphocyte;Testing;Th1 Cells;Therapeutic Intervention;Uveitis;Western World;autoimmune uveitis;autoreactive T cell;cell mediated immune response;chemokine;cytokine;experimental study;inhibitor/antagonist;interstitial retinol-binding protein;mouse model;novel;novel therapeutic intervention;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Autoimmune uveitis is a common ocular inflammation mediated by auto-reactive T cells. Despite a wide range of local and systemic therapies to treat this disease uveitis is still one of the leading causes of blindness in the Western world. Experiments described in this proposal will examine danger signals in the progress of T cell immunity in the eye. The long-term goal of proposed studies is to identify targets for interventional therapy for the disease.


application_id: 9181440
project_number: 5R01HL111932-05
project_title: Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates
administering_ic: NHLBI
award_notice_date: 2016-11-25
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 111932
program_official: LIU, LIJUAN
project_start_date: 2013-02-01
project_end_date: 2018-11-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 2186060
contact_pi: TEMEL, RYAN EUGENE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe risk of coronary heart disease (CHD) the largest major killer of Americans is inversely associated withhigh-density lipoprotein cholesterol (HDL-C). The protective effects of HDL-C are believed to be due to therole of HDL in reverse cholesterol transport (RCT) a process whereby cholesterol from macrophage foam cellsin atherosclerotic plaques is effluxed to HDL transported to the liver and excreted in the feces. Despiteintense efforts to identify new therapeutic strategies to raise HDL this has proven to be a challenging endeavor.A new and promising target for increasing HDL-C and RCT is microRNA-33 (miR-33). In humans twoisoforms of this microRNA miR-33a and miR-33b are encoded in introns of the sterol response elementbinding factor (SREBF) 2 and SREBF1 genes and co-regulate cellular lipid homeostasis with their host genes.Notably miR-33a/b induce mRNA degradation and/or translational repression of genes involved in cholesterolefflux and fatty acid oxidation. A major target of miR-33a/b is the ATP binding cassette transporter A1(ABCA1) a protein essential for cholesterol efflux from foam cells and the formation of HDL. In mice whichencode only miR-33a an antisense oligonucleotide targeting miR-33 (anti-miR-33) increased hepatic andmacrophage ABCA1 HDL-C RCT and atherosclerosis regression. However the translational value of thestudies in mice was limited by the lack of miR-33b which is expressed in humans and non-humans primates.To test the effects of inhibiting both miR-33a and b we recently treated African green monkeys with anti-miR-33 and found that hepatic ABCA1 and HDL-C was elevated and very low-density lipoprotein (VLDL) triglyceridewas decreased. While the preclinical findings to date highlight the cardioprotective potential of anti-miR-33 theability of anti-miR-33 to induce the regression of atherosclerosis in a "human-like" species expressing bothmiR-33a and miR-33b is still unknown. In this application we propose to determine the effects of anti-miR-33on atherosclerosis regression and RCT in non-human primates. These studies will greatly aid in assessinganti-miR-33 as a potential clinical treatment for CHD.

project_terms:
ATP-Binding Cassette Transporters;Affect;American;Antisense Oligonucleotides;Aorta;Apolipoprotein A-I;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherosclerosis;Binding;Cercopithecus pygerythrus;Characteristics;Cholesterol;Clinical Treatment;Clinical Trials;Collagen;Complex;Coronary artery;Coronary heart disease;Feces;Fiber;Foam Cells;Future;Gene Targeting;Genes;Hepatic;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Homeostasis;Human;Implant;In Vitro;Inflammation;Introns;Lipids;Liver;Macaca fascicularis;Magnetic Resonance Imaging;Measures;Mediating;MicroRNAs;Molecular Sieve Chromatography;Monkeys;Mus;Patients;Process;Protein Isoforms;Proteins;Response Elements;Risk;Risk Factors;Role;Spectrometry Mass Electrospray Ionization;Sterols;Testing;Time;Translational Repression;fatty acid oxidation;gene repression;inflammatory marker;laser capture microdissection;mRNA Transcript Degradation;macrophage;nonhuman primate;novel therapeutic intervention;oxidation;pre-clinical;protective effect;reverse cholesterol transport;subcutaneous;very low density lipoprotein triglyceride

public_health_relevance:
Project NarrativeHigh density lipoprotein (HDL) cholesterol concentration is a strong inversely related risk factor for coronaryheart disease (CHD) the largest major killer of Americans. Therapies that raise HDL cholesterol have thepotential to reduce the risk of CHD. We propose to determine how treatment of non-human primates with anti-miR-33 affects not only HDL function and composition but also the regression of atherosclerosis.


application_id: 9181250
project_number: 1R21HL132263-01A1
project_title: 4D MR Imaging of Flow and Hemodynamics in Aortic Stenosis
administering_ic: NHLBI
award_notice_date: 2016-07-29
opportunity_number: PA-12-284
application_type: 1
activity_code: R21
ic: HL
serial_number: 132263
suffix: A1
program_official: EVANS, FRANK
project_start_date: 2016-08-01
project_end_date: 2018-06-30
study_section: Medical Imaging Study Section[MEDI]
contact_pi_person_id: 1880208
contact_pi: AMINI, AMIR A
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:
Aortic Stenosis (AS) is a progressive valvular disease which has a 2 year survival rate of 50% in symptomaticpatients left untreated. Accurate characterization of stenosis severity is crucial in evaluating patients for valvereplacement. To determine severity of AS several clinical indices are typically determined from Doppler flow:these are effective orifice area (EOA) transvalvular pressure gradient (TVPG) ejection time peak out-flowtract velocity and peak aortic jet velocity. However Doppler flow can only derive components of velocities inthe direction of insonification and existence of air bone or surgical scar present impediments to accurateevaluation. A dilemma that occurs is that in as many as 30% of patients with severe AS who undergoechocardiographic assessment the indices measured from Doppler are discordant requiring additionalinvasive hemodynamic catheterization studies. This may have a physiologic basis but it may also have a rootcause in image noise and geometric assumptions. MRI is noninvasive and as with ultrasound has thecapability to image the anatomy as well as velocity and flow. Compared to ultrasound however the velocitiescan be measured in all 3D directions and due to its tomorgraphic nature do not require any geometricassumptions. Furthermore with the advent of 4D flow imaging MRI permits 3D visualization of flow as part ofa single scan. Despite these advances in MRI current 4D flow imaging techniques suffer from longscan times and when imaging flow distal to severe stenotic valves are hampered by artifacts. We haveaddressed these shortcomings through two 4D flow imaging techniques both adopting non-Cartesian k-spacetrajectories which significantly reduce echo times (TE): on the one hand using an Ultra-Short Echo Time (UTE)sequence with radial k-space trajectory (4D UTE Flow) and on the other hand with Spiral k-space trajectory(4D Spiral Flow). The specific aims of the study are as follows: 1) We will construct rigid and distensible flowphantoms of the aortic arch with a stenotic valve. This will permit study of stenotic valvular flows andhemodynamic indices calculated from velocity images at high resolution in idealized and realistic curvedgeometries. 2) 33 subjects with severe AS as determined by Doppler echocardiography will undergo a 4DFlow MRI a Doppler Ultrasound examination and a hemodynamic study in the cath lab in close succession.From Doppler and MRI all currently adopted clinical indices will be measured and correlated with cath-basedmeasures as the gold standard. We hypothesize that measures derived from the proposed MRI approachescorrelate more closely with cath alleviating the need for invasive catheterization to resolve discrepant echofindings in many patients. 3) In addition to standard indices the nature of MRI permits 3D measurement ofpressure based on a novel noniterative calculation involving harmonic analysis of pressure gradients resultingin improved accuracy and speed. This and a new index of flow recirculation vorticity will be tested on phantomand patient data.

project_terms:
4D MRI;Address;Adopted;Adult;Air;Anatomy;Aortic Valve Stenosis;Area;Atherosclerosis;Beds;Catheterization;Catheters;Chronic;Cicatrix;Clinical;Color;Data;Data Quality;Diagnostic;Disease;Distal;Doppler Echocardiography;Doppler Ultrasound;Evaluation;Geometry;Gold;Heart;Human;Image;Imagery;Imaging Techniques;In Vitro;Inflammation;Lead;Left;Lipids;Magnetic Resonance Imaging;Maps;Measurement;Measures;Mitral Valve;Morphologic artifacts;Motion;Nature;NavierStokes equations;Noise;Operative Surgical Procedures;Patients;Physiological;Plant Roots;Process;Radial;Resolution;Scanning;Severities;Severity of illness;Slice;Speed;Stenosis;Survival Rate;Techniques;Testing;Time;Ultrasonography;aortic arch;aortic valve;aortic valve disorder;base;bone;calcification;clinical practice;hemodynamics;improved;indexing;novel;particle;pressure;prospective;valve replacement

public_health_relevance:
Aortic Stenosis (AS) is a significant disease of the aortic valve of the heart which is chronicprogressive and has a 2 year survival rate of 50% in symptomatic patients who are untreated.The most common cause of AS in adults is calcification of a normal trileaflet or congenitalbicuspid valve. The proposal aims to develop a new and improved test based on MRI fordetermination of diagnostic indices of this disease in subjects with severe AS.


application_id: 9181239
project_number: 1R03HD086512-01A1
project_title: Spinal loads during activities of daily living: Influences of unilateral lower-limb amputation
administering_ic: NICHD
award_notice_date: 2016-09-09
opportunity_number: PA-13-304
application_type: 1
activity_code: R03
ic: HD
serial_number: 086512
suffix: A1
program_official: MARDEN, SUSAN F
project_start_date: 2016-09-10
project_end_date: 2018-08-31
study_section: Function, Integration, and Rehabilitation Sciences Study Section[CHHD-K]
contact_pi_person_id: 10388308
contact_pi: BAZRGARI, BABAK
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryDespite the higher prevalence of low back pain (LBP) among persons with unilateral lower limb amputation(ULLA) compared to able-bodied individuals relatively little is known about the fundamental mechanismsunderlying this condition. Our research represents a first step toward investigating lower back biomechanicsusing advanced computational modeling techniques to inform the future design of effective interventions forLBP. Specifically the impact of trunk neuromuscular patterns adopted by persons with ULLA while performingactivities of daily living on spinal loads and the risk of spinal tissue damage will be investigated. This will beachieved via secondary biomechanical analyses of a large set of high-quality kinematics data obtained fromindividuals with and without ULLA performing the following tasks: 1) walking at self-selected and controlledspeeds 2) sit-to-stand and stand-to-sit and 3) stairs-up and stairs-down. Our central hypothesis is thatcompared to able-bodied individuals trunk movement strategies adopted by persons with ULLA to cope withphysical demands of common daily activities are associated with a complex pattern of internal muscle forcesthat result in larger loads on the spine and a higher probability for spinal tissue damage. Our dataset drawsfrom the Biomechanics Laboratory at Walter Reed National Military Medical Center (WRNMMC) which hasunprecedented access to a large population of service members with ULLA. Using this unique database wewill implement our novel finite element modeling approach to estimate the internal muscle forces (i.e. adoptedneuromuscular patterns) needed to perform daily physical activities on the basis of satisfying equilibrium andstability across the entire lumbar spine. Completion of this project will enable us to determine differences inmuscle recruitment as well as the resultant effects on spinal loads and the risk of spinal tissue damagebetween persons with and without ULLA. Hence this pilot project is expected to establish the initialgroundwork for future research involving the design of highly specific interventions aimed at trunkneuromuscular behaviors during post-amputation rehabilitation to lessen adverse effects on lower backbiomechanics and the potential for LBP.

project_terms:
Accounting;Activities of Daily Living;Adopted;Adverse effects;Amputation;Assessment tool;Back;Balance training;Behavior;Biomechanics;Clinical;Complex;Computer Simulation;Data;Data Analyses;Data Collection;Data Set;Databases;Development;Electromyography;Elements;Equilibrium;Ethics;Failure;Fatigue;Foundations;Frequencies;Future;General Population;High Prevalence;Individual;Intervention;Kinetics;Laboratories;Letters;Living Wills;Locomotion;Low Back Pain;Lower Extremity;Measurement;Measures;Medical center;Military Personnel;Modeling;Monitor;Motion;Motor;Movement;Muscle;Pathway interactions;Pattern;Persons;Physical activity;Pilot Projects;Play;Population;Prevalence;Probability;Protocols documentation;Quality of life;Recruitment Activity;Rehabilitation therapy;Research;Risk;Role;Services;Speed;Spinal;Techniques;Time;Tissues;Training;Translating;Translations;Variant;Vertebral column;Walking;Weight;Work;base;chronic pain;computerized tools;coping;design;effective intervention;experience;in vivo;kinematics;limb amputation;member;neuromuscular;novel;vector

public_health_relevance:
Project NarrativeThe prevalence of low back pain among persons with unilateral lower limb amputation is significantly higherthan the rate experienced by the general public. Chronic pain including low back pain limits functionalindependence and negatively impacts quality of life. As such this project will investigate the role of abiomechanical casual pathway in the development of low back pain; to do this we will explore the relationshipbetween the adopted neuromuscular patterns post-amputation to perform activities of daily living and the risk ofdeveloping spinal tissue damage.


application_id: 9181119
project_number: 3K23AR062069-03S1
project_title: Prolonged alterations to muscle following knee surgery and physical therapy
administering_ic: NIAMS
award_notice_date: 2015-12-23
opportunity_number: PA-11-194
application_type: 3
activity_code: K23
ic: AR
serial_number: 062069
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2013-02-01
project_end_date: 2016-01-31
study_section: ZAR1-CHW(M1)
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
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
project_abstract:
DESCRIPTION (provided by applicant): This is a K23 award application for Dr. Brian Noehren an Assistant Professor of Physical Therapy at the University of Kentucky. Dr. Noehren is establishing himself as a young investigator focused on patient orientated clinical research dedicated to the study of how rehabilitation strategies restore muscle function in patients to ultimately improve their long term functional outcomes. The K-23 award would provide Dr. Noehren the needed support to become a productive independent scientist who is able to measure the cellular and morphological properties of muscle in response to injury and subsequent physical therapy. Development of these skills will allow him in future studies to assess the effectiveness of new and novel rehabilitation treatments to improve muscle function and joint loading. To achieve these goals Dr. Noehren has assembled a mentorship team of acknowledged leaders in their respective fields. This team is led by the senior mentor Dr. Charlotte Peterson Associate Dean of Research College of Health Sciences and three co-mentors: Dr. Karyn Esser an expert in muscle health and disease Dr. Bruce Damon who is an expert in muscle structure and biophysics and Dr. Leslie Crofford an expert clinical trialist.  Quadriceps strength reductions after an anterior cruciate ligament reconstruction of greater than 20- 40% occur at a critical time when physical therapy is ending and the individual begins to return to activities that require higher muscular demands. The reduction in quadriceps strength during this period of time has been associated with poorer outcomes. The measurement of muscular strength after rehabilitation to date has been limited to gross measurements with little known of how the individual heads of the quadriceps such as the Vastus Lateralis respond to surgery. Therefore we propose two specific aims: (Aim 1) Assess the quadriceps muscle (vastus lateralis) fascicle length pennation angle and physiological cross sectional area before and after rehabilitation for ACL reconstruction. (Aim 2) Characterize muscle morphology through quantification of quadriceps muscle fiber type fiber cross sectional area and fibrosis after completing rehabilitation for an ACL reconstruction. In Aim 1 Dr. Noehren will use DTI-MRI established by one his mentors Dr. Damon to measure muscle properties strongly linked to maximum force production. In Aim 2 he will perform histo and immuno-histiochemical analysis in Dr. Peterson's laboratory of muscle biopsies taken from the Vastus Lateralis of the same group from Aim 1 to categorize the adaptations to muscle fiber cross sectional area fiber type as well as fatty in-growth and fibrosis. Dr. Esser will assist with training for this aim and the interpretation of the results. The aims will couple data from non invasive imaging with detailed cellular analysis of muscle which will inform rehabilitative practice. In addition Dr. Crofford wil provide the training of translating the results into clinical research clinical trials and data analysis.

project_terms:
Address;Anterior;Architecture;Area;Award;Biology;Biomechanics;Biophysics;Biopsy;Clinical;Clinical Research;Clinical Trials;Coupled;Data;Data Analyses;Degenerative polyarthritis;Diffusion;Disease;Effectiveness;Fascicle;Fiber;Fibrosis;Future;Goals;Growth;Head;Health;Health Sciences;Individual;Intervention;Joints;Kentucky;Knee;Laboratories;Left;Leg;Length;Ligaments;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Methods;Microscopic;Molecular;Morphology;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Physical therapy;Physiological;Physiology;Positioning Attribute;Process;Production;Property;Protocols documentation;Recovery;Rehabilitation therapy;Research;Research Design;Research Personnel;Scientist;Senior Scientist;Skills Development;Structure;Testing;Time;Tissues;Training;Translating;United States National Institutes of Health;Universities;anterior cruciate ligament reconstruction;base;clinically significant;cohort;college;evidence base;experience;follow-up;functional outcomes;improved;innovation;interest;joint loading;muscular structure;non-invasive imaging;novel;professor;quadriceps muscle;reconstruction;rehabilitation strategy;response to injury;skill acquisition;strength training;vastus lateralis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Identification of the underlying cellular and myofiber adaptations that contribute to the loss of quadriceps strength after an ACL reconstruction is essential to develop improved physical therapy interventions and functional outcomes.


application_id: 9180576
project_number: 1R03DK107851-01A1
project_title: Estrogen Regulation of Daily Metabolic Rhythms
administering_ic: NIDDK
award_notice_date: 2016-06-14
opportunity_number: PAR-15-343
application_type: 1
activity_code: R03
ic: DK
serial_number: 107851
suffix: A1
program_official: SPAIN, LISA M
project_start_date: 2016-07-01
project_end_date: 2018-06-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryObesity-related disorders account for 2.8 million deaths per year. The loss of circulating estrogen aftermenopause increases the prevalence of obesity and the risk of life-threatening obesity-related disorders suchas cardiovascular disease and stroke in women. Shift work and night-eating also increase the risk of obesityand metabolic syndrome suggesting that disruption of circadian rhythms causes metabolic dysfunction. Thisproject will determine how estrogen interacts with the circadian system to protect females from obesity andrelated disorders. In our previous studies we demonstrated a link between disruption of circadian rhythmsconsumption of high-fat diet and obesity in male mice. Male mice develop profound diet-induced obesity. Wefound that after only one week of high-fat diet consumption the daily rhythm of eating behavior wasimmediately altered and the timing of the circadian clock in the liver was robustly advanced in male mice. Incontrast female mice are resistant to diet-induced obesity. In our preliminary studies we found high-fat dietdoes not alter the daily rhythm of eating behavior or the liver clock in females. Thus we hypothesize thatretention of normal daily metabolic rhythms during high-fat diet consumption confers protection from diet-induced obesity in females. The goal of this proposal is to elucidate the molecular and behavioral mechanismsthat protect daily rhythms from high-fat diet in females. Our specific aims are (1) to determine if estrogenregulates the effects of high-fat diet on daily rhythms in female mice; and (2) to determine if estrogen regulationof the daily rhythm of eating behavior protects females from diet-induced obesity. The completion of this projectwill reveal mechanisms whereby females are protected from diet-induced obesity and inform the developmentof novel therapeutics for obesity in women.

project_terms:
Accounting;Adult;Behavior;Behavioral Mechanisms;Brain;Cardiovascular Diseases;Cessation of life;Circadian Rhythms;Consumption;Development;Diet;Disease;Eating;Eating Behavior;Epidemic;Epidemiologic Studies;Estrogen Receptor alpha;Estrogens;Excision;Fatty acid glycerol esters;Female;Functional disorder;Goals;High Fat Diet;Knock-out;Knockout Mice;Lead;Life;Link;Liver;Measures;Menopause;Metabolic;Metabolic syndrome;Metabolism;Modeling;Molecular;Mus;Neurons;Obesity;Ovariectomy;Peripheral;Phase;Physiology;Postmenopause;Prevalence;Regulation;Reporter;Resistance;Risk;Signal Transduction;Synapsins;System;Time;Tissues;Weight;Weight Gain;Woman;Work;circadian pacemaker;experience;feeding;glucose metabolism;male;novel therapeutics;obesity risk;phase change;prevent;shift work;stroke

public_health_relevance:
Obesity prevalence increases sharply in women after menopause demonstrating that estrogen has potent anti-obesity effects. Circadian disruption caused by shift-work and night-eating also increases the risk of obesity.This project will determine how estrogen interacts with the circadian system to inhibit obesity in females.


application_id: 9180219
project_number: 1K22CA197193-01A1
administering_ic: NCI
award_notice_date: 2016-07-19
opportunity_number: PAR-15-056
application_type: 1
activity_code: K22
ic: CA
serial_number: 197193
suffix: A1
program_official: JAKOWLEW, SONIA B
project_start_date: 2016-08-01
project_end_date: 2017-02-28
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
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_title:
The Role of Fatty Acid Synthase in Regulation of Cancer Cells Survival and Metastasis in Colorectal Cancer

project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). My long-termgoal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis byunderstanding how changes in de novo fatty acid synthesis contribute to metastatic disease. Fatty acidsynthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated and activated in CRCand its activity is associated with poor prognosis higher risk of disease recurrence and death. I have identifiedFASN as a potential target for advanced stages of disease and showed that upregulation of this enzyme is akey mechanism supporting metastasis in CRC. However the underlying mechanisms of regulation ofmetastasis by FASN are still poorly understood. This NCI Transition Career Development Award (K22)application proposes a comprehensive research and training plan to study the role of FASN in regulation ofcancer cells survival and metastasis in CRC. Two novel mechanisms of regulation of survival and metastasisby FASN in CRC will be elucidated in this proposal. First preliminary studies show that overexpression ofFASN is associated with an increase in cellular respiration including -oxidation inhibition of autophagy andaccumulation of lipid droplets. Therefore Aim 1 will elucidate the role of FASN in reprogramming of metabolicpathways and lipid storage in order to maintain energy homeostasis and promote survival of cancer cells.Furthermore our preliminary studies suggest that the primary product of de novo fatty acid synthesispalmitate is selectively used for sphingolipid synthesis and overexpression of FASN increases the level ofsphingosine-1-phosphate (S1P) a bioactive sphingolipid known to stimulate migration and invasion of cancercells. Therefore in Aim 2 I will test the hypothesis that FASN promotes metastasis via activation ofsphingosine kinases and an increase in S1P signaling. I will utilize biological samples from patients human primary cells and PDX models which are the mostadvanced models for pre-clinical target and drug evaluations. These models will be used in conjunction withstate-of-the-art approaches including Stable Isotope-Resolved Metabolomics (SIRM) to evaluate the effect ofFASN overexpression on cancer metabolism. The differential expression of FASN in normal versus cancer cells makes de novo lipogenesis a desirabletarget for therapeutic intervention. I anticipate that the proposed work will significantly advance ourunderstanding of the role of FASN in advanced CRC and potentially lead to the development of noveltherapeutic strategies to treat this disease.

project_terms:
Autophagocytosis;Biological;Cancer Control;Cancer Etiology;Cause of Death;Cell Respiration;Cell Survival;Cells;Cessation of life;Characteristics;Colorectal Cancer;Data;Development;Disease;Disease-Free Survival;Disseminated Malignant Neoplasm;Drug Evaluation;Enzymes;Fatty Acids;Fatty-acid synthase;Goals;Grant;Homeostasis;Human;Incidence;Lead;Link;Lipids;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic to;Modeling;Molecular;Neoplasm Metastasis;Newly Diagnosed;Oncogenic;Organ;Palmitates;Patients;Play;Pre-Clinical Model;Process;Production;Proteins;Publications;Publishing;Recurrence;Regulation;Research Training;Role;Sampling;Signal Transduction;Solid;Solid Neoplasm;Sphingolipids;Sphingosine;Staging;Stress;Testing;Therapeutic;Therapeutic Intervention;Transition Career Development Award (K22);Tumor Angiogenesis;United States;Up-Regulation;Woman;Work;Xenograft Model;advanced disease;anticancer research;base;cancer cell;colon cancer cell line;differential expression;fatty acid oxidation;high risk;in vivo;inhibition of autophagy;knock-down;lipid biosynthesis;men;metabolomics;migration;mortality;novel;novel strategies;novel therapeutics;outcome forecast;overexpression;oxidation;prevent;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;treatment strategy;tumor;tumor growth;tumor metabolism

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the 3rd most common newly diagnosed cancer and the 2nd most common cause of cancerdeath among men and women in the Unites States with a majority of the mortality associated with metastaticcancer that has spread to other organs. We have proposed to investigate the role of Fatty Acid Synthase akey enzyme of lipid synthesis in advanced disease. The completion of this study will help develop bettertherapeutic strategies for the treatment of colorectal cancer and other solid cancers.


application_id: 9178592
project_number: 5R01CA133429-10
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2016-11-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2019-11-30
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 142000 new cases and 51000 deaths are predicted for the year 2013. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of CRC patients. Our lab has been intensively focused on elucidating the role of a novel family of protein phosphatases PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase) in inhibiting CRC initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. In this proposed study we will determine the effect of PHLPP-loss on modulating lipid metabolism in CRC. Although recent advances in cancer metabolism research have begun to elucidate how metabolic changes support cancer cell growth and survival the regulation and functional importance of altered lipid metabolism in CRC remain elusive. This proposal centers on a novel hypothesis that PHLPP-loss plays a pivotal role in driving CRC progression by promoting lipogenesis. In exciting recent findings we demonstrate that downregulation of PHLPP expression results in an increase in the expression of activated SREBP1 a key activator of lipid biosynthesis. Consistently MEF cells isolated from PHLPP knockout mice have enhanced lipogenesis during differentiation into adipocytes. In addition we have found that silencing PHLPP expression leads to increased glucose uptake lactate production Krebs cycle activity and triacylglycerides accumulation in CRC cells suggesting a role of PHLPP in regulating cellular metabolism. The central hypothesis driving this proposed study is that PHLPP plays an essential role in inhibiting lipogenesis by negatively regulating the PI3K/Akt/mTOR pathway and loss of PHLPP expression promotes CRC progression as the result of metabolic reprogramming. The following specific aims are proposed: 1) to delineate the molecular mechanism by which PHLPP regulates lipogenesis in CRC cells. We will perform the Stable Isotope-Resolved Metabolomics (SIRM) analysis to determine how PHLPP-loss affects lipid metabolism in CRC cells; 2) to determine the functional importance of PHLPP-mediated regulation of lipogenesis. We will test if PHLPP-loss renders CRC cells more resistant to metabolic stress and chemotherapy drugs as the result of alterations in lipogenesis; and 3) to define the role of PHLPP in suppressing lipogenesis in vivo. The effect of PHLPP-loss on modulating lipid metabolism will be determined using both genetically modified mouse models and patient-derived xenograft models. Results from our studies will fill an important knowledge gap on how altered lipogenesis affects the prognosis and treatment efficacy in CRC patients. Ultimately by providing insight into the mechanisms by which PHLPP-mediated lipogenesis our findings will help to develop new treatment strategies in CRC patients.

project_terms:
Adenocarcinoma;Adipocytes;Affect;Automobile Driving;Cancer Cell Growth;Cancer Center;Cancer Etiology;Cell Proliferation;Cell Survival;Cells;Cessation of life;Citric Acid Cycle;Collection;Colon Carcinoma;Colorectal Cancer;Development;Down-Regulation;Ensure;Event;FRAP1 gene;Genetic;Human;Hypoxia;In Vitro;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolic stress;Metabolism;Molecular;NOD/SCID mouse;Oncogenes;PH Domain;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Production;Protein Family;Protein phosphatase;Proteins;Ras/Raf;Regulation;Research;Resistance;Role;Signal Transduction;Testing;Tissues;Translations;Treatment Efficacy;Tumor Suppressor Proteins;United States;Xenograft Model;cancer cell;cancer initiation;cancer therapy;chemotherapy;colon cancer patients;colon tumorigenesis;design;experimental study;glucose uptake;improved;in vivo;insight;leucine-rich repeat protein;lipid biosynthesis;lipid metabolism;mTOR Inhibitor;macromolecule;metabolomics;mouse model;novel;outcome forecast;public health relevance;stable isotope;success;therapy resistant;treatment strategy;tumor metabolism;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Approximately 140000 new cases and 51000 deaths are predicted for the year 2013. Although there has been some modest improvement in survival a better understanding of the molecular events leading to cancer progression and treatment resistance is needed in order to improve the prognosis of CRC patients.


application_id: 9177851
project_number: 1R21CA209045-01
project_title: Systemic delivery of miR-29 for basal-like breast cancer treatment
administering_ic: NCI
award_notice_date: 2016-06-16
opportunity_number: PAR-15-340
application_type: 1
activity_code: R21
ic: CA
serial_number: 209045
program_official: ARYA, SURESH
project_start_date: 2016-09-01
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZCA1 TCRB-Q (M3)]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: SHU, DAN
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:
ABSTACT Basal-like breast cancer is estrogen receptor (ER) progesterone receptor (PR) and Her2 negative; it isnot responsive to hormone therapy and drugs that target the HER2 protein. Therefore it is urgent to developnovel therapeutic strategies for basal-like breast cancer. Basal-like breast cancer is rich in tumor-initiating cells.Tumor initiating cells are drivers of cancer metastasis and relapses; thus targeting tumor-initiating cells iscritical for basal-like breast cancer treatment. Our recent study shows that 3WJ RNA nanoparticlesincorporated with EGFR aptamer successfully bind and enter into the basal-like breast cancer cell line MDA-MB 231 in culture and in the orthotopic mouse mammary tumor model. RNA aptamers targeting the tumorinitiating cell marker CD44 have been identified and characterized which offers a potential strategy fordelivering the 3-way junction (3WJ) RNA nanoparticles into tumor initiating cells. We and others recentlydemonstrate that miR-29b is a potent tumor suppressor for basal-like breast cancer. Expression of exogenousmiR-29b in basal-like breast cancer cell lines significantly inhibits cancer metastasis in orthotopic mammarytumor models and repressed malignant phenotypes in 3D culture. MiR-29 also demonstrate potent inhibitoryactivity on tumor-initiating cells. Therefore we predict that therapeutic delivery of miR-29b will inhibit basal-likebreast cancer progression and metastasis. The overall objective of this proposal is to develop a novelapproach to therapeutically deliver tumor suppressor miRNA into basal-like breast cancer. In combining withRNA aptamers to target cell surface markers of basal-like breast cancer and 2F modification to enhancemiRNA stability the RNA nanoparticle provides a powerful tool to therapeutically deliver miR-29 to basal-likebreast cancer. The central hypothesis of this proposal is that tumor suppressor miR-29b can betherapeutically delivered to basal-like breast cancer tissue using 3WJ RNA nanoparticles and subsequentlyrepresses cancer progression and metastasis. To test our central hypothesis and achieve the objective of thisproposal we have designed experiments with the following specific aims. Aim 1. Construct RNAnanoparticles harboring therapeutic miR-29b that will target basal-like breast cancer cells. Aim 2.Examine the biologic activity of multifunctional therapeutic RNA nanoparticles in the orthotopic mousemammary tumor model. Development of RNA nanoparticles that deliver miR-29b to basal-like breast cancertissue and tumor-initiating cells will overcome the current hurdle in utilizing miRNA for cancer therapy.Examining the potential of exogenous miR-29b in inhibiting progression and metastasis of basal-like breastcancer may identify a potential therapeutic strategy for this deadly disease.

project_terms:
Binding;Biodistribution;Biological;Biology;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Treatment;Breast Cancer cell line;Breast Cancer therapy;CD44 gene;Cancer Biology;Cancer Relapse;Cell surface;Cells;Clinical;Data;Development;Disease;Drug Kinetics;Drug Targeting;ERBB2 gene;Epidermal Growth Factor Receptor;Estrogen Receptors;In Vitro;Incidence;Injection of therapeutic agent;MDA MB 231;Malignant Neoplasms;Mammary gland;MicroRNAs;Modeling;Modification;Mus;Nanotechnology;Neoplasm Metastasis;Organ;Population;Positioning Attribute;Progesterone Receptors;Proteins;Publications;RNA;RNA Stability;Recurrent disease;Research;System;Testing;Therapeutic;Tissues;Treatment Efficacy;Tumor Suppressor Proteins;Tumor Tissue;anticancer research;aptamer;cancer therapy;design;functional restoration;hormone therapy;in vivo;malignant breast neoplasm;malignant phenotype;mouse model;multidisciplinary;nanoparticle;novel;novel strategies;novel therapeutics;research study;targeted treatment;therapeutic RNA;therapeutic miRNA;therapeutic target;three dimensional cell culture;tool;tumor;tumor progression

public_health_relevance:
Development RNA nanoparticles to specifically deliver miR-29b to basal-like breast cancer tissue and tumor-initiating cells will help to overcome the current hurdle for utilizing microRNA as a therapeutic target. Examiningthe potential of exogenous miR-29b in inhibiting progression and metastasis of basal-like breast cancer mayidentify a novel therapeutic strategy for this deadly disease.


application_id: 9176774
project_number: 2R01AI087849-05
project_title: Biosynthesis of nucleoside antibiotics targeting bacterial translocase I
administering_ic: NIAID
award_notice_date: 2016-04-25
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AI
serial_number: 087849
program_official: XU, ZUOYU
project_start_date: 2011-06-15
project_end_date: 2021-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
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_terms:
AIDS/HIV problem;Actinomyces Infections;Aldehydes;Amides;Anabolism;Anti-Bacterial Agents;Antibiotics;Bacteria;Cell Wall;Cessation of life;Chemicals;Clinic;Clinical;Data;Decarboxylation;Development;Dioxygenases;Disease;Drug resistance;Drug resistance in tuberculosis;Enzymes;Fatty Acids;Genetic Engineering;Genome;Genomics;Goals;Health;Hospitals;Human;In Vitro;Infection;Killings;Lead;Logic;Methionine;Methodology;Mining;Modality;Molecular;Multi-Drug Resistance;Mus;Natural Product Drug;Nucleosides;Oxidoreductase;Peptides;Peptidoglycan;Pharmaceutical Preparations;Phosphotransferases;Process;Proteins;Public Health;Pyridoxal Phosphate;Research;Scanning;Side;Staging;Streptomyces;Structure;System;TNFSF15 gene;Time;Toxic effect;Transaldolase;Transketolase;Tuberculosis;United States;Uridine;Uridine Monophosphate;Work;World Health Organization;analog;clinical application;community setting;drug discovery;enzyme pathway;expectation;improved;in vivo;in vivo Model;inhibitor/antagonist;member;methicillin resistant Staphylococcus aureus;multi-drug resistant pathogen;nanomolar;novel;nucleophilic substitution;pathogen;piperidine;prevent;scaffold;synthetic biology;tool;translocase


application_id: 9175415
project_number: 1R01HL130174-01A1
project_title: Metabolic optimization of cell therapy
administering_ic: NHLBI
award_notice_date: 2016-05-23
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 130174
suffix: A1
program_official: SCHWARTZ, LISA
project_start_date: 2016-06-01
project_end_date: 2021-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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_terms:
6-Phosphofructo-2-kinase;Affect;Attenuated;Biochemical;Carbon;Cardiac;Cause of Death;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplants;Cell physiology;Cells;Cicatrix;Clinical Treatment;Competence;Defect;Development;Diabetes Mellitus;Diabetic mouse;Enzymes;Equilibrium;Exhibits;Fatty acid glycerol esters;Fibrosis;Fructose-26-bisphosphatase;Functional disorder;Future;Glucose;Glycolysis;Heart;Heart failure;Hexosamines;In Vitro;Inflammation;Injury;Insulin;Intervention;Measurement;Mediating;Metabolic;Metabolic Pathway;Modeling;Mus;Myocardial;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Oxidation-Reduction;Pathway interactions;Patients;Pentosephosphate Pathway;Pentosephosphates;Phosphoric Monoester Hydrolases;Phosphotransferases;Property;Protein Isoforms;Protocols documentation;Radiolabeled;Reaction;Recovery;Resistance;Risk Factors;Role;Stem cells;Stress;Testing;Therapy trial;Tissues;Tracer;Transplantation;aerobic glycolysis;cell growth;db/db mouse;diabetic;diabetic patient;extracellular;feeding;glucose metabolism;impaired capacity;improved;inhibitor/antagonist;metabolomics;mortality;non-diabetic;novel therapeutic intervention;radiotracer;repaired;stable isotope;stem


application_id: 9173466
project_number: 5R01HL125228-03
project_title: Mineralocorticoid receptor and abdominal aortic aneurysm
administering_ic: NHLBI
award_notice_date: 2016-11-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 125228
program_official: TOLUNAY, ESER
project_start_date: 2014-11-15
project_end_date: 2018-10-31
study_section: Special Emphasis Panel[ZRG1-VH-A(03)]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
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): Abdominal aortic aneurysm (AAA) is a vascular disease with rising prevalence and a high mortality rate. Current treatment is limited to open or endovascular surgery a procedure for which only 10% of AAA patients are eligible highlighting an urgent need for new mechanistic understandings of AAA. With a long term goal to identify new therapeutic targets for AAA the current proposal will investigate the pathological roles of aldosterone (Aldo) mineralocorticoid receptor (MR) and high salt intake in AAA. Elevated plasma Aldo and high salt intake have been linked to a spectrum of cardiovascular diseases. MR antagonists have been shown to be effective in reducing cardiovascular mortality and hospitalizations for heart failure. However little is known of the roles of Aldo MR and high sal intake in AAA. Recently the applicants discovered that administration of MR agonists deoxycorticosterone acetate (DOCA) or Aldo to C57BL/6 male mice induced AAA in the presence of high salt. Importantly DOCA- or Aldo-salt-induced AAA mimicked human AAA with respect to oxidative stress vascular inflammation smooth muscle cell (SMC) degeneration metalloproteinase (MMP) activation and elastin degradation. Treatment of mice with spironolactone or eplerenone two clinically used MR antagonists effectively attenuated DOC- or Aldo-salt-induced aortic aneurysm formation and rupture. Building on these exciting and novel findings the applicants further demonstrated that in isolated mouse aorta administration of pathological plasma concentrations of Aldo and sodium activated MMP2 and induced oxidative stress suggesting a direct pathological effect of Aldo and salt on aorta. Interestinglydenuding endothelial cells from isolated aorta had no effect on Aldo-salt-induced MMP2 activation and oxidative stress indicating that MR in SMC (SMC-MR) is involved. Consistent with this concept the applicants found that p47phox a component of NADPH oxidase that has been implicated in human AAA was markedly upregulated by Aldo-salt in the medial layer of abdominal aortic wall and co-localized with SMC a-Actin which was completely abolished by treatment of mice with eplerenone. Moreover treatment of mice with temporal a free radical scavenger diminished DOCA-salt-induced AAA. Therefore the applicants hypothesize that increased plasma Aldo and salt activate SMC-MR and p47phox and thus result in oxidative stress MMP activation vascular inflammation SMC degeneration and elastin degradation thereby contributing to AAA. Three specific aims are: 1) test the hypothesis that SMC-MR is required for Aldo-salt-induced AAA; 2) define the mechanism by which SMC-MR targets p47phox to induce AAA; 3) determine whether targeting the Aldo/MR/salt axis is effective for treatment of AAA. To achieve these aims genetic animal models (SMC- specific MR knockout mice and global p47phox knockout mice) and various molecular biochemical and physiopathological approaches will be used. If proposed studies are successful they will have a profound impact on current basic researches and clinical practices on the etiology diagnosis and treatment of AAA.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Acetates;Affect;Age;Agonist;Aldosterone;Animal Genetics;Animal Model;Aorta;Aortic Aneurysm;Attenuated;Basic Science;Biochemical;Cardiovascular Diseases;Cardiovascular system;Cell Membrane Permeability;Cessation of life;Clinic;Clinical;Country;Deoxycorticosterone;Diagnosis;Disease;Elastin;Eligibility Determination;Endothelial Cells;Etiology;Free Radical Scavengers;Genetic Transcription;Goals;Heart failure;Hospitalization;Human;Hypertension;Intake;Kidney;Knockout Mice;Left Ventricular Hypertrophy;Link;MMP2 gene;MMP9 gene;Medial;Messenger RNA;Metalloproteases;Mineralocorticoid Receptor;Molecular;Mus;Myocardial Infarction;NADPH Oxidase;Operative Surgical Procedures;Oxidative Stress;Pathologic;Patients;Pharmaceutical Preparations;Plasma;Prevalence;Procedures;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Scheme;Smooth Muscle Myocytes;Sodium;Sodium Chloride;Spironolactone;Stress;Tamoxifen;Testing;Time;Vascular Diseases;Withdrawal;Woman;abdominal aorta;age related;alpha Actin;clinical practice;diagnosis evaluation;effective therapy;eplerenone;insight;loss of function;male;men;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;prevent;promoter;public health relevance;salt intake;stroke;tempol;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is defined as a permanent localized dilations of aorta affect 4 to 8% of men and 0.5 to 1.5% of women over the age of 60 and account for about 2% of all deaths in Western countries. AAA is a vascular disease with rising prevalence and a high mortality rate (65% to 85%) related to AAA rupture. Currently surgery is the only option for treatment of AAA and no drug has been approved for the treatment of this devastating disease. The goals of this application are to elucidate the mechanisms responsible for AAA and thereby identify new therapeutic targets to develop new drugs to treat AAA.


application_id: 9172742
project_number: 2R01HL107326-05
project_title: Sex Differences in Angiotensin-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2016-08-25
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: HL
serial_number: 107326
program_official: VARAGIC, JASMINA
project_start_date: 2012-03-21
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1 VH-N (02)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Abdomen;Abdominal Aortic Aneurysm;Adult;Angiotensin II;Angiotensins;Aorta;Awareness;Breeding;Cardiovascular Diseases;Cardiovascular system;Characteristics;Chromosomes;Chronic;Congenital chromosomal disease;DNA;Data;Development;Dose;Employee Strikes;Event;Exhibits;Female;Gender;Gender Identity;Gene Expression;Gene Targeting;Genes;Genotype;Gonadal Steroid Hormones;Human;Incidence;Incubated;Individual;Knowledge;Life;Link;Mus;Neonatal;Neprilysin;Pathway interactions;Pattern;Pharmacotherapy;Ploidies;Population;Predisposition;Regulation;Risk;Role;Ruptured Aneurysm;Severities;Sex Characteristics;Sex Chromosomes;Smooth Muscle Myocytes;Testing;Testosterone;Therapeutic;Turner's Syndrome;Vascular Diseases;X Chromosome;X Inactivation;Y Chromosome;abdominal aorta;chromosome X loss;effective therapy;follow-up;heme oxygenase-1;high risk;male;mortality;mouse model;novel;precision medicine;sex;sexual dimorphism;therapeutic target


application_id: 9171972
project_number: 4R13AI108234-02
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2015-11-05
opportunity_number: PA-12-212
application_type: 4
activity_code: R13
ic: AI
serial_number: 108234
program_official: MILLER, LARA R
project_start_date: 2013-07-01
project_end_date: 2016-10-31
study_section: ZAI1-ESB-M(M1)
contact_pi_person_id: 1863468
contact_pi: WOODWARD, JEROLD G
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): This proposal requests funds to support the annual Autumn Immunology Conference (AIC). The AIC was established in 1972 to promote Immunology research in the upper Midwest region of the United States. The conference provides a forum for the exchange of scientific data and ideas fosters collaboration between scientists at different institutions and provides career development and education opportunities to a diverse group of individuals with an interest in Immunology. The scientific focus of the meeting is intentionally broad; it includes basic Immunology and related biomedical fields such as cancer biology pathogenesis vaccine development inflammation and autoimmunity. Special emphasis is given to providing pre- and postdoctoral trainees with an opportunity to share their data participate in scientific and career discussions and to meet and exchange ideas with established investigators. The organizers also seek to attract involve and promote the careers of women and racial/ethnic minorities that are underrepresented in science. These objectives are met by inviting a group of outstanding Immunology researchers (12-13 each year) from around the world to speak at the meeting. All presenters present both an oral and poster presentation in sessions that are designed to provide the greatest opportunity for feedback to the trainees. Finally scholarship programs career development workshops and mentoring luncheons promote the inclusion of minority scientists and seek to recruit undergraduates into the discipline of Immunology.

project_terms:
Address;Allergic Disease;Applied Research;Autoimmunity;Award;Basic Science;Cancer Biology;Collaborations;Communicable Diseases;Data;Discipline;Education;Educational workshop;Equilibrium;Feedback;Fostering;Funding;Gender;Goals;Grant;Health;Immune System Diseases;Immunology;Individual;Inflammation;Institution;Mentors;Midwestern United States;Mission;National Institute of Allergy and Infectious Disease;Oral;Participant;Pathogenesis;Public Health;Recruitment Activity;Request for Applications;Request for Proposals;Research;Research Personnel;Scholarship;Science;Scientist;Staging;Travel;Underrepresented Minority;United States;United States National Institutes of Health;Vendor;Woman;career;career development;career preparation;design;ethnic minority population;interest;meetings;minority scientist;posters;pre-doctoral;prevent;programs;racial and ethnic;symposium;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: High quality scientific conferences are vital to the public health mission of the NIH. This application requests funding for an annual scientific conference called the Autumn Immunology Conference. The purpose of this meeting is to exchange and disseminate information and to explore contemporary problems in the field of Immunology. Thus it is consistent with the fiscal and programmatic priorities of the National Institutes of Allergy and Infectious Diseases (NIAID) which is to conduct and support basic and applied research to better understand treat and ultimately prevent infectious immunologic and allergic diseases.


application_id: 9171585
project_number: 7R01ES016893-08
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2015-11-07
opportunity_number: PA-11-260
application_type: 7
activity_code: R01
ic: ES
serial_number: 016893
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2018-12-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hexavalent chromium (Cr(VI)) also known as chromate is a major public health concern. Chromates particularly the insoluble compounds are well-established human lung carcinogens. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which are currently unknown. Recent studies indicate that particulate Cr(VI) induces chromosome instability which is a hallmark of human lung tumors. However how Cr(VI) induces chromosome instability is poorly understood. Our preliminary data show that chronic exposure to particulate Cr(VI) induces a DNA repair deficient phenotype that underlies the chromosome instability and thus the goal of this research is to characterize this repair deficiency and its impact and understand the mechanisms that cause it to occur. We will test the hypothesis that particulate Cr(VI) induces epigenetic changes inactivating homologous recombination repair of Cr(VI)-induced DNA double strand breaks resulting in increased chromosome instability and carcinogenesis. We will test this hypothesis through four interrelated specific aims. Aim 1 will characterize the homologous recombination repair defect and show that particulate Cr(VI) causes cells to inactivate Rad51-mediated response and switch to lower fidelity non-homologous end joining (NHEJ) repair using immunoblotting immunofluorescence and repair assays. Aim 2 will show that the cells with particulate Cr(VI)-inactivated Rad51 response acquire chromosome instability and undergo neoplastic transformation using cytogenetic techniques and assays for contact- uninhibited and anchorage independent growth. Aim 3 will identify an epigenetic change (increased acetylation) that causes the loss of Rad51 response by affecting E2F1 ATM Rad51C and Rad51 with assays for acetylation status gene expression and protein interactions and localization. FinallyAim 4 will characterize the mechanism for particulate Cr(VI)-induced acetylation changes studying Cr(VI) binding to acetyl groups using assays for acetylation and histone deacetylase activity. Each aim will focus on human lung cells and confirm key findings in human Cr(VI) tumors. Results will lead to the first reports of detailed information of the interactions of Cr(VI with DNA double strand break machinery acetylation status and the first characterizations of these aspects in tumors from Cr(VI)-exposed workers. This research is significant because it will provide: 1) An understanding of particulate Cr(VI)'s carcinogenic mechanism; 2) Essential information to better assess the risk of exposure to particulates; and 3) A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Acetylation;Affect;Anchorage-Independent Growth;Binding (Molecular Function);Biological Assay;Cancer Etiology;Carcinogen exposure;Carcinogens;Cells;Chromates;Chromium Compounds;Chromosomal Instability;Chronic;Cytogenetic Analysis;Cytoplasm;DNA Double Strand Break;DNA Repair;Data;Deacetylation;Defect;Double Strand Break Repair;E2F1 gene;Environmental and Occupational Exposure;Epigenetic Process;Epithelial Cells;Event;Exposure to;Fibroblasts;Frequencies (time pattern);Gene Expression;Genomic Instability;Goals;Health;Histone Deacetylase;Human;Immunoblotting;Immunofluorescence Immunologic;In Vitro;Ions;Lead;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mass Spectrum Analysis;Mediating;Metals;Modeling;Molecular;Mutation;Neoplastic Cell Transformation;Nonhomologous DNA End Joining;Nuclear;Particulate;Peptide Mapping;Phenotype;Proteins;Publishing;Reporting;Research;Risk;Salts;Solubility;Spectral Karyotyping;System;Techniques;Testing;Toxicology;Zinc;carcinogenesis;chromium hexavalent ion;homologous recombination;interest;prevent;public health medicine (field);recombinational repair;repaired;response;tandem mass spectrometry;tumor;zinc chromate

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hexavalent chromium (Cr(VI)) is a human lung carcinogen with widespread occupational and environmental exposure. How Cr(VI) causes human cancer is unknown. Our study advances our basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes cancer and informs us about how cells protect against Cr(VI)-induced genomic instability. Our findings will help us identify new potential treatment targets and approaches to reduce or prevent Cr(VI)-induced lung cancer and to better assess the risk of exposure to this major public health concern. Finally we will have established a mechanistic model in a human lung cell system that will allow us to conduct studies for other factors important for preventing human lung cancer both generally and by Cr(VI) and other agents.


application_id: 9170824
project_number: 2R15HL120068-02
project_title: Fibrin Clot Architecture Regulated by Factor XIII
administering_ic: NHLBI
award_notice_date: 2016-07-24
opportunity_number: PA-13-313
application_type: 2
activity_code: R15
ic: HL
serial_number: 120068
program_official: WARREN, RONALD Q
project_start_date: 2013-08-05
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1 VH-C (80)]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryIn blood coagulation thrombin cleaves fibrinogen (AB)2 sites for fibrin polymerization are revealed andfibrin clot formation begins. Thrombin-activated Factor XIII (FXIII) is responsible for catalyzing the formation of-glutamyl--lysyl crosslinks between fibrin molecules and in fibrin-enzyme complexes. Abnormal fibrinogenlevels altered fibrin clot structure and hindered FXIII-catalyzed crosslinking have each been associated withcardiovascular disease arteriosclerosis and bleeding disorders. The main objective of the research project isto examine how fibrin clot architecture can be regulated by fibrinogen (Fbg) and FXIII. Intermolecular cross-links involving the Fbg C region help secure lateral fibrin aggregation and lead to production of a more robustfibrin clot. Clot character can also be altered by the biochemical properties of FXIII and its mutants. A greaterunderstanding of the molecular details associated with Fbg C and FXIII can be translated into new strategiesto positively impact medical conditions. For the development of novel therapeutics to regulate blood clotstructure critical gaps in our knowledge must be resolved. More information is needed on 1) the kinetic andstructural features of Fbg C a key substrate for FXIII and 2) the role of individual FXIII A2 amino acids incontrolling activation conformation and transglutaminase function. The proposed research for this applicationwill thus address two hypotheses: 1) To be an effective substrate for FXIIIa the Fbg C region (233-425) ishypothesized to contain distinct reactive glutamine environments and to employ a transglutaminase interactionsite. Research will focus on the kinetics of the reactive glutamines and the structural features of C (233-425).Results will be correlated with pathophysiologic mutants within Fbg C. 2) FXIII A2 mutants within theactivation peptide segment and the catalytic core are hypothesized to regulate transglutaminase activationstability and function. The FXIII A2 mutants will include the common polymorphism L34 a series of V34Xmutants and FXIII-A deficiency causative mutants associated with Y283 and R260. The biochemical methodsrequired to address these aims include mass spectrometry solution NMR analytical ultracentrifugation andmeasurements of fibrin clot formation and architecture. The knowledge gained from these studies will be usedto improve the administration and utilization of these two key components involved in blood clot formation.

project_terms:
Address;Amino Acids;Anticoagulants;Architecture;Arteriosclerosis;Binding;Biochemical;Biological Assay;Blood Coagulation Disorders;Blood coagulation;Cardiovascular Diseases;Catalytic Domain;Cleaved cell;Coagulation Process;Coupling;Development;Dimerization;Disease;Environment;Escherichia coli;Factor XIII;Factor XIII Deficiency;Factor XIIIa;Fibrin;Fibrinogen;Fibrinopeptide A;Fibrinopeptide B;Genetic Polymorphism;Glutamine;Health;High Pressure Liquid Chromatography;Individual;Kinetics;Knowledge;Lateral;Lead;MALDI-TOF Mass Spectrometry;Maintenance;Mass Spectrum Analysis;Measurement;Medical;Methods;Modeling;Molecular;Molecular Conformation;Multienzyme Complexes;Mutate;Peptides;Plasma;Play;Production;Property;Proteins;Reporting;Research;Research Project Grants;Residual state;Risk;Role;Secure;Series;Site;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Structure;Thrombin;Transglutaminases;Translating;analytical ultracentrifugation;base;crosslink;design;gel electrophoresis;improved;mutant;novel;novel therapeutics;polymerization;programs

public_health_relevance:
NARRATIVE:Abnormal fibrinogen levels altered fibrin clot structure and hindered FXIII catalyzed crosslinking have eachbeen associated with cardiovascular disease and bleeding disorders. Using novel experimental approachesthe proposed research will provide critical information on how to control the activation and function of FactorXIII and how Fibrinogen regions are chosen for crosslinking sites. Stronger or weaker clots may be designed tohandle particular medical conditions.


application_id: 9170768
project_number: 2P30AG028383-11
project_title: Research Education Component (RL5)
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
subproject_number: 6813
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Address;Administrator;Advanced Practice Nurse;Aging;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Basic Science;Behavioral;Behavioral Symptoms;Caring;Chronic Disease;Clinical;Clinical Research;Communities;Coupling;Dementia;Detection;Development;Discipline of Nursing;Disease;Early Diagnosis;Education;Educational Activities;Extramural Activities;Faculty;Family;Funding;Future;Geriatrics;Goals;Growth;Health;Health Professional;Home Health Aides;Human;Impaired cognition;Individual;Intervention;Kentucky;Knowledge;Learning;Medical Students;Medicare;Neurobehavioral Manifestations;Neurodegenerative Disorders;Neurology;Occupational Therapist;Physician Assistants;Physicians;Postdoctoral Fellow;Primary Care Physician;Primary Health Care;Process;Provider;Psychologist;Quality of Care;Registered nurse;Research;Research Personnel;Research Support;Resources;Scientist;Series;Social Workers;Specialist;Students;Symptoms;Techniques;Telemedicine;Testing;Thinking;Training;Training Programs;Translating;Translational Research;Translations;Universities;Visit;Work;abstracting;advanced dementia;aging population;bench to bedside;career;caregiver education;caregiving;clinical care;collaborative environment;design;education research;interest;meetings;next generation;novel;physical symptom;prevent;profession allied to medicine;programs;screening;senior faculty;skills;student mentoring;success;symposium;training opportunity


application_id: 9170767
project_number: 2P30AG028383-11
project_title: Core E: Outreach and Recruitment Core
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
subproject_number: 6812
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Address;African American;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Biological Markers;Brain;Catchment Area;Clergy;Clinical;Clinical Research;Clinical Research Protocols;Clinical Trials;Clinical trial protocol document;Cognitive;Collaborations;Communication;Communities;Community Actions;Consent;DNA;Data Collection;Databases;Dementia;Development;Disease;Education;Education and Outreach;Educational Activities;Effectiveness;Elderly;Enrollment;Event;Extramural Activities;Failure;Fostering;Future;Goals;Healthcare;Individual;Intervention Trial;Kentucky;Lead;Link;Minority;Minority Groups;Minority Participation;Mission;Outcome Measure;Outreach Research;Participant;Plasma;Play;Poa plant;Program Development;Recording of previous events;Recruitment Activity;Reporting;Research;Research Activity;Research Support;Resources;Risk Factors;Role;Staging;System;Therapeutic Trials;Time;Translational Research;Translations;Universities;Update;Work;abstracting;cohort;dementia care;demographics;design;education research;health literacy;healthcare community;innovation;meetings;member;neuroimaging;neuropathology;outreach;parity;programs;research study;response;success;volunteer;willingness


application_id: 9170766
project_number: 2P30AG028383-11
project_title: Core D: Neuropathology Core
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
subproject_number: 6811
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Biological;Biological Markers;Biostatistics Core;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Cataloging;Catalogs;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Trials;Cognition Disorders;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Diagnosis;Diagnostic;Disease;Down Syndrome;Ensure;Freezing;Frontotemporal Lobar Degenerations;Genetic study;Genomics;Goals;Impaired cognition;Individual;Institutes;Investigation;Kentucky;Laboratory Research;Lesion;Lewy Body Dementia;Life;Medical Genetics;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preparation;Preventive measure;Protocols documentation;Publishing;Religion and Spirituality;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Services;Specimen;Staging;Synaptosomes;Syndrome;Tauopathies;Therapeutic;Tissue Banking;Tissue Banks;Tissue Sample;Tissues;Universities;Work;abeta deposition;abstracting;age related;aging brain;amyloid precursor protein processing;blood product;brain tissue;cerebrovascular;cohort;data management;digital;experience;genome wide association study;hippocampal sclerosis;innovation;meetings;mild cognitive impairment;mixed dementia;neuroinflammation;neuropathology;normal aging;novel;pre-clinical;protein TDP-43;repository;symposium;synucleinopathy;tau Proteins;tool


application_id: 9170765
project_number: 2P30AG028383-11
project_title: Core C: Data Management and Statistical Core
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
subproject_number: 6810
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Adopted;Advisory Committees;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Area;Attention;Biological Markers;Biometry;Cerebrospinal Fluid;Clinical;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Consult;Correlation Studies;Data;Data Analyses;Data Collection;Data Quality;Databases;Dementia;Elderly;Elements;Enrollment;Epidemiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Future;Generations;Genetic;Gerontology;Growth;Health Services Research;Kentucky;Leadership;Literature;Manuscripts;Mentors;Methodology;Methods;Mission;Modeling;Online Systems;Paper;Participant;Pathology;Phase;Pilot Projects;Process;Psychology;Public Health;Publications;Records;Recruitment Activity;Reporting;Research;Research Design;Research Personnel;Research Support;Risk Factors;Role;Scanning;Seasons;Secure;Services;Statistical Data Interpretation;Study Section;System;Tablets;Training;Translational trial;Translations;Universities;Ursidae Family;Vision;Work;abstracting;cohort;data management;direct application;doctoral student;imaging genetics;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;statistics;student training;success


application_id: 9170764
project_number: 2P30AG028383-11
project_title: Core B: Clinical Core
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
subproject_number: 6809
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Basic Science;Biological Markers;Blood;Brain;Cessation of life;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Collection;Communities;Correlative Study;Data;Data Collection;Data Set;Dementia;Development;Disease;Education and Outreach;Environment;Extramural Activities;Funding;Genetic Markers;Grant;Heart;Image;Individual;Industry;Intervention Trial;Kentucky;Leadership;Life;MRI Scans;Magnetic Resonance Imaging;Medical Genetics;Minority;Minority Participation;Mission;Pathogenesis;Pathology;Pharmaceutical Preparations;Phase;Play;Population;Positron-Emission Tomography;Publications;Reporting;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Subjects;Research Support;Role;Schedule;Specimen;Therapeutic Human Experimentation;Tissues;Translational Research;Translations;United States National Institutes of Health;Universities;Work;abstracting;base;cohort;data management;innovation;meetings;minority subjects;multidisciplinary;normal aging;novel therapeutics;operation;outreach;pre-clinical;prevent;programs;research and development;success;therapeutic development


application_id: 9170763
project_number: 2P30AG028383-11
project_title: Core A: Administrative Core
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
subproject_number: 6808
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Advisory Committees;African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Behavioral;Biological Markers;Caregivers;Clinical;Clinical Trials;Cognitive aging;Collaborations;Communication;Communities;Dementia;Development;Education and Outreach;Ensure;Ethics;Evaluation;Faculty Recruitment;Fostering;Foundations;Funding;Future;Goals;Grant;Growth;Health Professional;Human Volunteers;Impaired cognition;Industry;Institution;Intervention;Kentucky;Knowledge;Leadership;Medical;Minority Participation;Mission;Patients;Pilot Projects;Policies;Productivity;Quality of Care;Research;Research Activity;Research Infrastructure;Research Personnel;Resources;Staging;Strategic Planning;Tissues;Training;Training Programs;Translational Research;Translations;Trust;Universities;University resources;abstracting;beneficiary;career;caregiver education;clinical practice;collaborative environment;education research;innovation;meetings;multidisciplinary;novel therapeutics;outreach;outreach program;prevent;programs;research study;training opportunity


application_id: 9170762
project_number: 2P30AG028383-11
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2016-08-05
opportunity_number: RFA-AG-16-018
application_type: 2
activity_code: P30
ic: AG
serial_number: 028383
program_official: SILVERBERG, NINA B
project_start_date: 2006-07-15
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-G (M1)]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
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
arra_indicator: N
project_terms:
African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Health Education;Community Outreach;Comorbidity;Databases;Dementia;Development;Disease;Education and Outreach;Environment;Funding;Goals;Health Professional;Housing;Image;Impaired cognition;Impairment;Individual;Industry;Intervention;Kentucky;Lead;Mission;Nature;Neurodegenerative Disorders;Outcome;Outreach Research;Pathology;Pilot Projects;Relationship-Building;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Risk;Training;Translating;Translational Research;Translations;United States;Universities;Work;abstracting;aging brain;biomarker development;clinical practice;cohort;collaborative environment;community partnership;data management;education research;experience;healthcare community;innovation;knowledge translation;neuropathology;new therapeutic target;next generation;normal aging;novel therapeutics;outreach;pre-clinical;prevent;programs;research study;statistics;success


application_id: 9170369
project_number: 5R03DC014319-04
project_title: Integration of taste and olfactory signals in gustatory cortex
administering_ic: NIDCD
award_notice_date: 2016-11-03
opportunity_number: PAR-13-057
application_type: 5
activity_code: R03
ic: DC
serial_number: 014319
program_official: SULLIVAN, SUSAN L
project_start_date: 2014-12-01
project_end_date: 2018-11-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 8305266
contact_pi: SAMUELSEN, CHAD L
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Integration of sensory information from multiple modalities is believed to enhance the detection of convergent stimuli. This multimodal integration was originally theorized to occur only in higher order cortical areas such as prefrontal cortex. However recent research has shown multimodal sensory responses in every primary sensory cortex including gustatory cortex (GC). GC is the primary cortex responsible for processing information related to taste and is known to code multisensory information related to taste such as temperature touch and anticipatory cues. However the most conspicuous sensory interaction that of taste and olfaction has not been explored at the GC circuit-level. Taste and olfaction are intimately linked. Anatomical and neuroimaging studies have begun to describe the synergistic integration of these two modalities and suggest GC as a primary integrative chemosensory node. Despite this great progress very little information is available on whether and how single neurons in GC integrate multimodal chemosensory integration. The proposed research is a three step approach all of which rely upon multielectrode techniques to record ensembles of single neurons in GC while rats intraorally sample tastes and odors. The first experiment is designed to determine how taste and odor are represented by single neurons in GC. After a better understanding of GC chemosensory response the second experiment will test the hypothesis that odor-taste experience modulates chemosensory activity in GC. The third experiment continues along this trajectory to explore how incongruent odor-taste mixtures suppress chemosensory activity in GC. Altogether the experiments outlined in this R03 proposal will lay a foundation for an in depth understanding of the circuit-level integration of multimodal chemosensory information in GC of alert rodents. If successful this research will elucidate how single neurons in GC process ecologically synergistic chemosensory information and will establish GC as a primary area of multisensory integration of stimuli related to food.

project_terms:
Acetates;Address;Anatomy;Animal Model;Animals;Area;Association Learning;Behavioral;Benzaldehyde;Beverages;Bilateral;Cannulas;Citric Acid;Code;Consummatory Behavior;Cues;Data;Detection;Diet;Eating Disorders;Electrodes;Electrophysiology (science);Epithelial;Food;Foundations;Goals;Home environment;Implant;Individual;Knowledge;Lead;Learning;Link;Modality;Nasal Epithelium;Nasal cavity;Neurons;Nose;Odors;Olfactory Pathways;Oral;Prefrontal Cortex;Process;Property;Quinine;Rattus;Research;Rodent;Role;Sampling;Sensory;Signal Transduction;Site;Smell Perception;Stimulus;Sucrose;Taste Perception;Techniques;Temperature;Testing;Tongue;Touch sensation;Training;Water;design;drinking;experience;experimental study;food consumption;information processing;multimodality;multisensory;neuroimaging;olfactory receptor;preference;public health relevance;receptor;response;sensory cortex;sensory integration;taste system;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal aims to understand how neurons in the gustatory cortex (GC) integrate the chemosensory modalities of taste and smell. In rodents GC has been traditionally studied for its involvement in taste. Recent data suggests that neurons in GC are multimodal processing taste-related information such as temperature touch and anticipatory cues. While the role of GC in processing taste information is well established very little is known about its involvement in integrating olfactory information. With this proposal we intend to study how neurons in GC integrate and encode naturally related chemosensory information taste and odor. Multielectrode recordings in behaving rats will unveil how GC neurons represent tastes and retronasal odors how experience of an odor- taste association alters that representation and finally how odor-taste association learning modulates chemosensory activity. The results of these efforts will lay the foundation for an in depth understanding of ecologically related multimodal chemosensory processing at the circuit level in GC. If successful this research will expand our knowledge of chemosensory processing point to GC as a primary integrative area of information related to consummatory behaviors and reveal an area to study the interactions between chemosensory processing and behavioral food choice in animal models of eating disorders.


application_id: 9169999
project_number: 3U01DA033276-03S1
project_title: NDA-Enabling Lofexidine Program - Final Regulatory Clinical Requirements for NDA Submission
administering_ic: NIDA
award_notice_date: 2016-03-16
opportunity_number: PA-14-077
application_type: 3
activity_code: U01
ic: DA
serial_number: 033276
suffix: S1
program_official: ANDERSON, ANN
project_start_date: 2016-03-01
project_end_date: 2016-07-31
contact_pi_person_id: 2408657
contact_pi: GORODETZKY, CHARLES W.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the safety and efficacy profiles to address FDA-defined gaps in the clinical development program for lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The program includes two linked studies to be conducted consecutively at the same sites: Study 1 will generate pivotal efficacy/safety data for two doses of lofexidine hydrochloride in 600 subjects about to undergo total and abrupt withdrawal from short- acting opioids who will be randomized under double-blind conditions to either placebo (N=150) or lofexidine (2.4 mg or 3.2 mg total daily dose; N=225/group) for 7 days of inpatient treatment. Subsequently all subjects will be permitted to continue under open-label conditions for up to an additional 7 days of inpatient/outpatient variable-dose treatment depending on the wishes of the Site Investigator and subject. Safety will be assessed by evaluation of adverse event (AE) clinical laboratory electrocardiogram (with special attention toQTc) vital signs and physical exam data. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G) (the primary outcome measure is SOWS-G score area under the curve for Days 1-7) the Objective Opiate Withdrawal Scale (OOWS-Handelsman) the Visual Analog Scale for Efficacy (VAS-E) and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention completion rates concomitant medication use incidence of withdrawal-related AEs and subject treatment status 30 days post discharge. Study 2 will follow a similar 14-day dosing format but will be entirely open-label; and 200 to 400 subjects (different from those in Study 1) will receive lofexidine at a variable dose not to exceeda total of 3.2 mg per day or a single dose of 0.8 mg in an inpatient outpatient or a combination of settings as per the normal standard of care at the enrolling site. Study 2 is a translational research design aimed at gathering "real-world" effectiveness and safety data to supplement the existing lofexidine safety database and enable appropriate product labeling for end-users. Safety will be evaluated for all treated subjects and for two cohorts: those with urines negative and those with urines positive for drugs of abuse so that all possible causes of reported AEs may be considered for analysis. Effectiveness will be evaluated by the Clinical Opiate Withdrawal Scale (COWS) rate of detoxification completion and subject treatment status 30 days post discharge. An open-label variable-dose real-world design as planned in Study 2 is common in Phase 3 drug development and together with Study 1 which will provide pivotal efficacy data needed to support the proposed product indication the program has been designed to address FDA registration requirements for lofexidine. On approval of an NDA lofexidine will be the first approved non-narcotic non-addictive drug indicated for treatment of opioid withdrawal in the US providing an important alternative therapy for this indication.

project_terms:
Abstinence;Acute;Address;Adrenergic Agonists;Adverse effects;Adverse event;Alternative Therapies;American;Applications Grants;Area Under Curve;Attention;Buprenorphine;Clinical;Data;Databases;Development;Dose;Double-Blind Method;Drug Metabolic Detoxication;Effectiveness;Electrocardiogram;Enrollment;Evaluation;FDA approved;Financial Support;Health;Incidence;Inpatients;Laboratories;Life;Link;Literature;Marketing;Medical;Methadone;Narcotics;Opiates;Opioid;Outcome Measure;Outpatients;Pharmaceutical Preparations;Phase;Placebo Control;Placebos;Product Labeling;Program Development;Publishing;Randomized;Reporting;Research;Research Design;Research Personnel;Safety;Severe Adverse Event;Signs and Symptoms;Site;Symptoms;Translational Research;United Kingdom;United States Food and Drug Administration;Urine;Visual;Withdrawal;Work;analog;base;cohort;design;drug development;drug of abuse;experience;impression;lofexidine;meetings;open label;opioid withdrawal;phase 3 study;primary outcome;programs;standard of care;therapy development;treatment duration;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With a growing trend of millions of Americans becoming dependent on prescription and other short-acting opioid narcotics there is an unmet medical need for new detoxification treatments. The only drugs approved by the FDA for this indication (methadone and buprenorphine) are opioid replacement or substitution therapies which themselves have abuse potential. The proposed research program on lofexidine hydrochloride will: i) establish the dose range by examining the safety and efficacy of two different doses of lofexidine; ii) confirm that lofexidine may be used until the acute phase of opioid withdrawal is complete (i.e. up to 14 days); and iii) increase the safety database by employing a "real-world" strategy to study additional subjects and increase the likelihood of identifying potential safety issues that may be present in only a small percentage of users. NIDA's support of this development work on lofexidine is necessary to enable FDA approval of the first non-narcotic non-addictive treatment for opioid withdrawal.


application_id: 9169783
project_number: 7K01DK098321-04
project_title: Daily Rhythms and Health: Obesity and Related Disorders
administering_ic: NIDDK
award_notice_date: 2015-10-30
opportunity_number: PAR-12-020
application_type: 7
activity_code: K01
ic: DK
serial_number: 098321
program_official: SPAIN, LISA M
project_start_date: 2013-09-06
project_end_date: 2016-06-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this proposal is to foster my development into an independent investigator and educator focused on elucidating the mechanisms by which disruption of daily rhythms contributes to obesity. Studies in rodents and humans have demonstrated that the timing of food intake is altered in obese individuals but little is known about how this phenotype contributes to the pathophysiology of obesity. To investigate the tuning of rhythmic metabolic processes and how they are altered in diet-induced obesity I developed an acute model to monitor eating behavior and tissue rhythms in mice fed high-fat diet for one week. My preliminary studies demonstrate that the daily rhythm of eating behavior is immediately altered and the timing of the circadian clock in the liver is robustly advanced during consumption of high-fat diet rich in saturated fat. The proposed studies aim to elucidate the mechanism whereby consumption of high-fat diet alters eating behavior and liver physiology. In this proposal real-time imaging of eating behavior and monitoring of liver bioluminescence rhythms will be utilized to test the hypothesis that consumption of a diet rich in saturated fat (bt not monounsaturated fat) alters daily rhythms of feeding behavior and liver physiology through a toll-like receptor 4-mediated mechanism. To achieve the goals of this proposal I will combine my experience in circadian biology with new techniques assaying metabolic physiology. I will draw from the strengths of my co-mentors and mentoring committee and from my prior training to cultivate an independent and novel line of research. Key elements of my career development plan include didactic coursework in metabolic physiology immersion in an intellectual environment rich in the study of metabolism and circadian biology and acquisition of career development skills through formal seminars workshops and interactions with junior and senior scientists. By bringing together a talented mentoring team a synergistic research environment with state-of-the-art equipment and facilities and training in career success this career development award will allow me to achieve my long-term career goal of becoming a successful independent scientist whose research broadly impacts human health.

project_terms:
Acute;Adult;Animal Model;Animals;Behavior monitoring;Biological Assay;Biology;Bioluminescence;Brain;Cardiovascular Diseases;Child;Circadian Rhythms;Consumption;Data;Development;Development Plans;Diet;Disease;Eating;Eating Behavior;Educational workshop;Elements;Environment;Equipment;Family member;Fatty acid glycerol esters;Feeding behaviors;Food;Fostering;Functional disorder;Genetic;Goals;Health;Human;Image;Immersion Investigative Technique;Individual;Inflammation;K-Series Research Career Programs;Lipids;Liver;Mediating;Mentors;Metabolic;Metabolic syndrome;Metabolism;Modeling;Molecular;Monitor;Mus;Obesity;Overweight;Pancreas;Pattern;Phenotype;Physiology;Prevalence;Research;Research Personnel;Rodent;Saturated Fatty Acids;Scientist;Senior Scientist;System;Techniques;Testing;Time;Tissues;Training;Unsaturated Fatty Acids;Weight;aged;career;career development;circadian pacemaker;experience;feeding;metabolic abnormality assessment;monounsaturated fat;novel;obesity risk;pathogen;receptor;saturated fat;shift work;skills;success;toll-like receptor 4

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Roughly two-thirds of U.S. adults aged 20 and over are overweight or obese and the prevalence has increased sharply for both adults and children since the mid-1970's. It has recently been recognized that consumption of high-fat diet not only causes obesity but also alters the timing of food intake. The proposed studies aim to elucidate the mechanism whereby consumption of high-fat diet alters daily rhythms of eating behavior and physiology.


application_id: 9167790
project_number: 1R03AI126252-01
project_title: Functions of T. pallidum and L. interrogans PUR proteins
administering_ic: NIAID
award_notice_date: 2016-06-14
opportunity_number: PA-13-304
application_type: 1
activity_code: R03
ic: AI
serial_number: 126252
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2016-06-15
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (81)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
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:
ABSTRACTThe pathogenic spirochetes Treponema pallidum (syphilis) and Leptospira interrogans (leptospirosis) changetheir protein compositions during infection processes evidently as means to adapt to different niches. Despitethe significance of these two diseases essentially nothing is known about how either bacterium regulates geneexpression. Complicating matters there are no methods to genetically manipulate T. pallidum and the genetictoolbox for L. interrogans is largely limited to random mutagenesis. In our studies of a related spirocheteBorrelia burgdorferi (Lyme disease) we discovered a differentially expressed DNA- and RNA-binding proteinnamed BpuR which in turn controls expression of numerous genes and proteins. Mutant B. burgdorferi thatare unable to control BpuR levels are severely attenuated for mammalian infection. The protein's name derivesfrom its PUR-domain a motif also found in crucial regulatory proteins of humans and all other highereukaryotes as well as many pathogenic bacterial species. T. pallidum and L. interrogans each encode a singlePUR-domain protein which we named TpuR and LpuR respectively. We hypothesize that TpuR and LpuRwill bind specific sequences in their respective DNA and RNA as does every other known PUR-domainprotein. In silico analyses will then be applied to identify potential PUR protein-binding sites within eachspecies' genome and a subset of putative binding sites will be experimentally validated. We furtherhypothesize that T. pallidum and L. interrogans control production of their PUR proteins and that PURprotein levels correlate with differential expression of genes that contain PUR protein-binding sitesadjacent to their promoters. We predict that this combination of computational biochemical and in vivoanalyses will provide insight into regulatory mechanisms employed by these two pathogens important stepstoward understanding the bacteria's infectious properties and development of therapies that specifically blockadaptation to their human hosts.

project_terms:
Affect;Affinity;Attenuated;Bacteria;Bacterial Genes;Binding;Binding Proteins;Binding Sites;Biochemical;Biological;Birth;Borrelia;Borrelia burgdorferi;Cessation of life;Computer Simulation;Consensus;DNA;Data;Defect;Development;Disease;Engineering;Enzymes;Eukaryota;Gene Expression;Gene Expression Profile;Gene Expression Regulation;Gene Proteins;Genes;Genetic;Genetic Transcription;Genome;Homologous Protein;Human;In Vitro;Infection;Infectious Agent;Insecta;Leptospira interrogans;Leptospirosis;Lyme Disease;Metabolic;Methods;Molecular;Mus;Mutagenesis;Names;Nucleic Acid Binding;Order Spirochaetales;Organism;Plants;Process;Production;Property;Proteins;RNA;RNA-Binding Proteins;Recombinants;Regulatory Pathway;Rest;Reverse Transcriptase Polymerase Chain Reaction;Sexually Transmitted Diseases;Syphilis;Techniques;Tertiary Protein Structure;Therapeutic;Ticks;Tissue-Specific Gene Expression;Transcript;Treponema pallidum;Virulence Factors;differential expression;genetic regulatory protein;human disease;improved;in vivo;insight;mutant;nervous system development;novel strategies;nucleic acid binding protein;pathogen;promoter;therapy development;transcriptome sequencing;transcriptomics;vector

public_health_relevance:
PROJECT NARRATIVEThe spirochetes that cause syphilis and leptospirosis regulate expression of different genes during mammalianinfection but very little is known about the regulatory mechanisms of either pathogen. We found that eachproduces a protein with a PUR-domain a structural motif that binds to DNA and which is found in importantregulatory proteins of the Lyme disease spirochete and in human insects plants and many other organisms.We propose that the treponemal and leptospiral PUR-domain proteins serve similar functions which we willexplore through a combination of biochemical computational and molecular biological techniques.


application_id: 9166467
project_number: 1R21DE026280-01
project_title: Protease - protease inhibitor system of Tannerella forsythia
administering_ic: NIDCR
award_notice_date: 2016-09-20
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: DE
serial_number: 026280
program_official: LUNSFORD, DWAYNE
project_start_date: 2016-09-20
project_end_date: 2018-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
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:
Tannerella forsythia belongs to the red complex of oral bacteria strongly associated with progression ofchronic periodontitis. However in contrast to Porphyromonas gingivalis and Treponema denticola (othermembers of the red complex) relatively little is known about virulence factors produced by T. forsythia. Afeature in common between these and other periodontal pathogens is the production of high levels ofproteolytic enzymes. In T. forsythia the majority of proteolytic activity is due to six secreted proteases ofunique subdomain structure (KLIKK proteases) belonging to five different families of serine and metallo-proteases. On the genomic level every gene of the KLIKK protease is directly preceded by a gene encoding aputative lipoprotein in a seemingly co-transcriptional unit. Based on preliminary data it is clear that at least twoof these proteins are inhibitors of the adjacent protease. Therefore we collectively designated these genes asFLIPPINs (Forsythia Lipoprotein Protease INhibitors). Flippins are small proteins (118-152 residues) whichexhibit no sequence similarity with each other or with any other protein (the only exception is Flippins B1 andB2 which are 82% identical). Therefore we hypothesize that Flippins are outer-membrane anchored proteaseinhibitors with novel structure and function protecting T. forsythia from its own enzymes and thus essential forT. forsythia biological fitness. Furthermore we theorize that they will also inhibit host proteases as well asproteases secreted by other bacteria in the pathogenic subgingival biofilm to protect the native organism.Hence this research proposal will investigate the important and innovative concept that Flippins through theirability to control proteolysis in the biofilm may represent a new and previously unrecognized class of virulencedeterminants or modifiers. Therefore the main objective of this proposal is to characterize functionexpression specificity and role in T. forsythia biology of selected Flippins as outlined in two Specific Aims:(i) characterization of the specificity spectrum and mechanism of protease inhibition by Flippins; and(ii) determination the regulation of selective Flippins expression subcellular localization and their role in T.forsythia biology. The significance and impact of this project is that the functional characterization of Flippinsmay highlight novel regulatory mechanisms to control proteolytic activity and provide new insights on T.forsythia physiology its role in the subgingival biofilm and mechanism of virulence. This knowledge will createnovel perspectives in the treatment of periodontitis.

project_terms:
Address;Bacteria;Biological;Biology;Cells;Chronic;Complex;Data;DegP protease;Development;Environment;Enzyme Precursors;Enzymes;Exhibits;Family;Forsythia;Genes;Genomics;Gram-Negative Anaerobic Bacteria;Growth;Homeostasis;Hydrolysis;Immune response;Inflammation;Inflammatory;Kinetics;Knowledge;Light;Lipoproteins;Membrane;Messenger RNA;Microbial Biofilms;Natural Immunity;Operon;Oral;Organism;Peptide Hydrolases;Peptides;Periodontal Diseases;Periodontitis;Physiology;Porphyromonas gingivalis;Process;Production;Prokaryotic Cells;Protease Inhibitor;Proteins;Proteolysis;Regulation;Research;Research Proposals;Resistance;Role;Serine;Specificity;Structure;Subtilopeptidase A;Surface;System;Therapeutic Intervention;Tissues;Transcript;Treponema denticola;Virulence;Virulence Factors;antimicrobial;base;biological systems;drug development;fitness;in vivo;inhibitor/antagonist;innovation;insight;member;novel;novel therapeutics;oral bacteria;pathogen;periplasm;protease C;repaired;screening;subgingival biofilm;targeted treatment

public_health_relevance:
Tannerella forsythia is a Gram-negative anaerobic bacterium a member of dysbiotic subgingival bacterial floraconsidered the causative agent of a chronic inflammatory disease of the periodontium (chronic periodontitis). Inaddition to proteolytic enzymes known to interfere with the host immune response this bacterium produces sixunique protease inhibitors with the potential to control both bacterial and host proteases. As such theseinhibitors may represent a new and previously unrecognized class of virulence factors that are capable ofmodifying the dysbiotic character of the subgingival bacterial biofilm. In this study our results will cast light onthe structure and function of these unique proteins and may provide targets for therapeutic intervention againstperiodontitis.


application_id: 9165407
project_number: 1R21EY027033-01
project_title: Yap1 is essential to maintain adult RPE differentiation
administering_ic: NEI
award_notice_date: 2016-08-17
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: EY
serial_number: 027033
program_official: NEUHOLD, LISA
project_start_date: 2016-09-01
project_end_date: 2018-08-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 8891723
contact_pi: LI, QIUTANG
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYDuring development the transcription factor YAP1 is crucial in maintaining proliferation and dedifferentiation ofprogenitors as organ and tissue fields are formed. As cells expand to fill developing fields their cell-cellcontacts trigger activation of the Hippo kinase cascade which causes YAP1 to bind forming tight junctions atthe cell surface thereby preventing its entry into the nucleus. This cytoplasmic sequestration is then necessaryfor post-mitotic differentiation. Downregulation of tight junction genes in cancer leads to constitutive nucleartranslocation of YAP1 where it acts as an oncogene to drive proliferation and the dedifferentiating EMTresponsible for carcinoma invasion and metastasis. In an analogous fashion disruption of RPE cell-cellcontacts also allows nuclear translocation of YAP1 leading to EMT and a proliferative myofibroblasticphenotype responsible for PVR. These findings imply that YAP1 drives a dedifferentiating EMT in the nucleusand its Hippo-dependent interaction with tight junctions at the cell surface then represents a mean to block itsactivity. But there is emerging evidence that when sequestered in tight junctions at the cell surface YAP1binds to the Wnt pathway transcription factor -catenin. This interaction appears to prevent -catenin nuclearlocalization and to cause its ubiquitin-mediated turnover. These findings raise the possibility that cytoplasmicYAP1 might have a hitherto unanticipated function to negatively regulate Wnt/-catenin signaling. This is aninteresting possibility because Wnt/-catenin signaling is linked to maintenance of stem and progenitor cells inan undifferentiated state and it must be inhibited for differentiation of epithelial cells. Further reactivation ofWnt/-catenin signaling (such as when lacking YAP1-mediated inhibition on this pathway) in differentiatedepithelial cells drives dedifferentiating EMT and is a hallmark of a highly invasive phenotype for example incolorectal cancer. Based on these emerging findings we hypothesized that YAP1 has two key functions. The first is toserve as a nuclear transcription factor that drives proliferation whereas the second function is to actively blockWnt/-catenin signaling when sequestered at tight junctions and thereby maintain the differentiated phenotypein epithelial cells. By knocking YAP1 out after RPE differentiation we provide the first evidence thatdedifferentiating can be induced by loss of YAP1-mediated restriction of -catenin in the cytoplasm formaintaining RPE differentiation. We propose studies to validate this model of YAP1-dependent oscillationbetween differentiation and dedifferentiation.

project_terms:
Adult;Affect;Atrophic;Automobile Driving;Binding;Biological Assay;Carcinoma;Cell Death;Cell Differentiation process;Cell Nucleus;Cell Polarity;Cell Proliferation;Cell surface;Cells;Cessation of life;Coloboma;Colorectal Cancer;Cytoplasm;Cytoskeletal Modeling;Development;Disease;Down-Regulation;Embryo;Epithelial;Epithelial Cells;Equilibrium;Eye diseases;Functional disorder;Genes;Human;Immunohistochemistry;In Vitro;Knock-out;Knockout Mice;Link;LoxP-flanked allele;Maintenance;Malignant Neoplasms;Mediating;Mesenchymal;Mitotic;Modeling;Morphogenesis;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Oncogenes;Organ;Organ Size;Orthologous Gene;Pathologic;Pathway interactions;Phenotype;Phosphotransferases;Photoreceptors;Play;Polycystic Kidney Diseases;Pregnancy;Proliferative Vitreoretinopathy;Proteins;RPE65 protein;Regulation;Retinal Detachment;Retinal Diseases;Role;Signal Pathway;Signal Transduction;Stem cells;Structure of retinal pigment epithelium;Testing;Tight Junctions;Time;Tissue Differentiation;Tissues;Ubiquitin;Undifferentiated;Vision;Work;base;beta catenin;cell dedifferentiation;cell type;cellular microvillus;epithelial to mesenchymal transition;in vivo;innovation;interest;novel;novel therapeutics;overexpression;prevent;progenitor;promoter;recombinase;stem;transcription factor

public_health_relevance:
NARRATIVEThe retinal pigment epithelium plays a critical role for physically and physiologically supporting photoreceptorsand visual function; and dysfunction of RPE cells has been linked to many retinal diseases. We havegenerated an RPE-specific Yap1 knockout mouse line and identified the novel functions of YAP1 inmaintenance of a healthy RPE differentiation state and in regulation of Wnt/-catenin signaling pathways. Thisinnovating work allows us a better understanding of how the RPE cells maintain their cell-type-specificdifferentiated phenotypes and to uncover pathologic mechanisms causing many vision-threatening RPE-related ocular diseases such as Sveinsson's chorioretinal atrophy which will be ultimately beneficial todevelopment of novel therapeutics for treating RPE involved eye diseases.


application_id: 9165379
project_number: 1R21EY027032-01
project_title: Identifying novel c-Cbl antagonists to promote corneal epithelial regeneration
administering_ic: NEI
award_notice_date: 2016-07-20
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: EY
serial_number: 027032
program_official: MCKIE, GEORGE ANN
project_start_date: 2016-08-01
project_end_date: 2018-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT An intact and fully differentiated corneal epithelium is critical for proper vision and to keep foreign objects(bacteria viruses small particles) out of the eye. However damage to the corneal epithelium is one of themost common ocular problems presented in primary care facilities and arises from a variety of factorsincluding trauma disease and a side-effect of drugs. Despite the prevalence discomfort and potential forblindness associated with perturbation of the corneal epithelium there are no FDA-approved agents thatpromote the restoration and homeostasis of this tissue. The long-term goal of our research is to identify noveltools to modulate the molecular mechanisms that regulate and promote corneal epithelial wound healing andhomeostasis. The overall objective of this application is to identify novel compounds that prolong EGFRsignaling. To accomplish this we will test the central hypothesis that compounds that block c-Cbls ability toubiquitylate the EGFR will divert the activated EGFR from the lysosome for degradation. We believe inhibitionof this interaction will lead to greater EGFR activity and increase corneal epithelial cell migration proliferationand differentiation three cell biological responses that are central to the restoration and maintenance ofcorneal epithelial homeostasis. The rationale for these studies is based on our previous findings thatknockdown of c-Cbl and inhibition of ubiquitylation enhances EGFR-dependent corneal epithelial woundhealing. This research has the following specific aims: 1) Identify candidate compounds that bind with thehighest affinity for c-Cbl and 2) Determine whether the highest affinity compounds are the mostefficacious antagonists of EGFR ubiquitylation and best prolong EGFR signaling. We have completedan in silico screen of 28000000 compounds for their ability to disrupt EGFR:c-Cbl interactions. In Aim 1 wewill test the top 50 candidates for their ability to bind recombinant purified c-Cbl using a Thermofluor assayand Isothermal Titration Calorimetry. In Aim 2 we will use immortalized corneal epithelial cells to test whetherour highest affinity compounds are most effective in preventing ligand-dependent EGFR ubiquitylation slowingthe rate of receptor degradation and enhancing the rate of corneal epithelial wound healing. Our proposedstudies are innovative in our opinion because we will modulate novel ligand-independent molecularmechanisms to increase the magnitude and duration of EGFR activity as a means of accelerating restoration ofdamaged corneal epithelium. These studies are significant because accelerating re-epithelialization andhomeostasis of compromised corneas will decrease the duration of patient distress minimize the likelihood ofinfection and reduce the incidence of blindness. Corneal epithelial homeostasis is a significant public healthissue with limited treatment options. This research has the potential to identify new ways of treating damagedcorneas following trauma disease or as a side-effect of drug treatment as well as provide a betterunderstanding of the molecular mechanisms that regulate corneal epithelial homeostasis.

project_terms:
Advanced Development;Adverse drug effect;Adverse effects;Affinity;Antineoplastic Agents;Bacteria;Binding;Biological;Biological Assay;Biology;Biomedical Engineering;Blindness;Calorimetry;Cell Proliferation;Cells;Cetuximab;Chemical Injury;Chemicals;Complement;Complex;Computer Simulation;Cornea;Corneal Injury;Data;Development;Diabetes Mellitus;Disease;Distress;Drug Kinetics;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Epithelial Cells;Eye;Eye Infections;FDA approved;Foundations;Future;Goals;Growth Factor Receptors;Health;Homeostasis;Human;In Vitro;Incidence;Infection;Investigation;Kinetics;Laboratory Study;Lead;Ligands;Light;Lysosomes;Maintenance;Measures;Mediating;Mission;Modeling;Molecular;Natural regeneration;Operative Surgical Procedures;Oryctolagus cuniculus;Pain;Patients;Pharmacodynamics;Pharmacotherapy;Prevalence;Primary Health Care;Property;Public Health;Reagent;Receptor Signaling;Recombinants;Recurrence;Replacement Therapy;Research;Retina;Rodent;Signal Transduction;Stem cells;Structure;Testing;Therapeutic;Tissues;Titrations;Trauma;Virus;Vision;Wound Healing;base;biophysical analysis;cancer therapy;cell growth;cell motility;corneal epithelium;cytokine;experience;heat injury;improved;in vivo;innovation;interest;knock-down;limbal;novel;particle;prevent;receptor;response;restoration;small molecule;tool;ubiquitin-protein ligase

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because the integrity of the corneal epithelium is frequentlycompromised as the result of trauma surgery side effects of anti-cancer drugs and secondary effects ofdiabetes. This innovative line of investigation seeks to identify new compounds that will extend the duration ofepidermal growth factor receptor signaling to maintain and promote a healthy corneal epithelium. This projectis relevant to the NEIs mission because these findings will advance the development of new strategies topromote corneal epithelial wound healing and minimize the chances of eye infection and subsequentblindness.


application_id: 9162030
project_number: 261201300013I-0-26100007-1
project_title: IGF::OT::IGF R&D - SEER LINKED VIRTUAL TISSUE REPOSITORY (VTR)
administering_ic: NCI
project_start_date: 2015-09-11
project_end_date: 2017-09-10
contact_pi_person_id: 14259412
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The National Cancer Institute Surveillance Epidemiology and End Results (SEER) Program is interested in developing a SEER-linked Virtual Tissue Repository (VTR). A SEER VTR with its population representativeness and large sampling frame would be a unique resource for assembling robust collections of biospecimens even for rare tumors and outcomes. SEER demographic and clinical data can be augmented with custom annotation of data including detailed chemotherapy time to recurrence and body mass index.The objectives of the VTR Pilot Study are to assess the ability of SEER RegistriesTo serve as a resource for biospecimen researchTo locate cases with biospecimens in pathology laboratories and determine the requirements to retrieve those biospecimensTo provide custom annotation of specified data itemsThe VTR Pilot will also capture costs to identify and annotate these biospecimens.

project_terms:
Body mass index;Clinical Data;Collection;Custom;Data;Laboratories;Link;Medical Surveillance;National Cancer Institute;Outcome;Pathology;Pilot Projects;Population;Recurrence;Registries;Research;Resources;SEER Program;Sampling;Specific qualifier value;Time;Tissues;chemotherapy;cost;interest;repository;research and development;tumor;virtual


application_id: 9161902
project_number: 261201300013I-0-26100008-1
administering_ic: NCI
project_start_date: 2015-09-18
project_end_date: 2016-09-17
contact_pi_person_id: 14264372
contact_pi: HUANG, BIN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF EVALUATING FEASIBILITY OF AND POTENTIAL BIASES IN SUPPLEMENTING CANCER REGISTRY DATA USING EXTERNAL SOURCES

project_abstract:
The proposed study is to examine how data linkage with claims based data primarily Medicaid and private insurance data will improve the comorbidity and treatment variables in the Kentucky Cancer Registry (KCR) data and evaluate the accuracy and biases of data linkage through probabilistic linkage and compare differences between statistical estimate in statistical analyses based on the original KCR data and the enhanced KCR data.Objectives:1)Examine the probabilistic data linkage process and how cutoff values will introduce biases in identifying true matches.2)Examine how linking with Medicaid data improves the registry data for variables such as comorbidity and treatment information.3)Examine how linking with private insurance claims data such as Humana Anthem and state employee insurance data improves the registry data for variables such as comorbidity and treatment information.4)Examine how combinations of Medicare Medicaid and private insurance claims data improves the registry data for comorbidity treatment information and certain quality of care measures.5)Compare statistics estimates in modeling statistical analyses between the original registry data and augmented registry data such as logistic regression models and Cox regression survival models.

project_terms:
Comorbidity;Cox Models;Data;Data Linkages;Databases;Employee;Insurance;Kentucky;Link;Logistic Regressions;Measures;Medicaid;Medicare/Medicaid;Modeling;Process;Quality of Care;Source;Statistical Models;base;data registry;improved;neoplasm registry;statistics


application_id: 9161894
project_number: 261201300013I-0-26100010-1
administering_ic: NCI
project_start_date: 2015-09-18
project_end_date: 2016-09-17
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF IMPROVE COMPLETENESS OF TREATMENT AND OTHER KEY DATA ELEMENTS BY LINKAGES WITH 15-MONTH RESUBMITTED DATA FROM COMMISSION ON CANCER HOSPITALS PERIOD OF PERFORMANCE: 09/18/2015 - 09/17/2016

project_abstract:
This study will assess treatment reporting changes over time from data already collected by the SEER KCRs innovative CPDMS system.  The impact of data resubmission and linkages on SEER KCR treatment data will be evaluated from first submission through 15 months post diagnosis.  Results from this evaluation will measure the potential value of additional treatment data that would be available to other SEER registries.Objectives:1)Assess the changes in treatment data from the time cases are first reported to the SEER KCR through 15 months post diagnosis.  Results of the assessments will be presented for both CoC and non-CoC facilities and by the major SEER sites groups.2)Inform SEER*DMS with regard to modifications that may be required to accommodate continuous treatment update in an efficient manner for all SEER*DMS registries.

project_terms:
Cancer Hospital;Data;Data Element;Diagnosis;Evaluation;Measures;Modification;Performance;Registries;Reporting;Site;System;Time;Update;improved;innovation


application_id: 9161889
project_number: 261201300013I-0-26100009-1
project_title: IGF::OT::IGF EXPANDING SEER TO INCLUDE MOLECULAR PROFILING IN NON-SMALL CELL LUNG CANCER (NSCLC)
administering_ic: NCI
project_start_date: 2015-09-18
project_end_date: 2016-09-17
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
This study seeks to leverage electronic pathology (ePath) reports through NLP and machine learning methods to automate the annotation of NSCLC lung cases with results from EGFR and ALK gene mutation testing. Objectives:1)Develop and implement machine-learned predictive NLP models to automatically process ePath reports to ascertain the use of and reported results of EGFR and ALK testing in stage IV non-squamous NSCLC cases.  2)Conduct a multiphase validation study of the NLP algorithms initially involving cases included in the Kentucky SEER registry and posteriorly validating the algorithms for cases in the Seattle_Puget Sound SEER registry.3)Develop and evaluate an open source distributable software implementation of the NLP algorithms an accompanying application programming interface (API) and documentation that can be integrated into SEER*DMS and other registry software applications.

project_terms:
ALK gene;Algorithms;Annotation Automated;Computer software;Documentation;EGFR gene;Electronics;Epidermal Growth Factor Receptor;Gene Mutation;Kentucky;Lung;Machine Learning;Methods;Modeling;Molecular Profiling;Non-Small-Cell Lung Carcinoma;Pathology Report;Process;Registries;Reporting;Staging;Testing;c-erbB-1 Proto-Oncogenes;open source;programs;sound;validation studies


application_id: 9160051
project_number: 1R01HL133723-01
project_title: Adventitial-medial interactions in thoracic aortic diseases
administering_ic: NHLBI
award_notice_date: 2016-06-04
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 133723
program_official: MCDONALD, CHERYL
project_start_date: 2016-06-01
project_end_date: 2020-05-31
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: 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_terms:
Aneurysm;Angiotensin II;Angiotensin II Type 1 Receptor Blockers;Aorta;Aortic Aneurysm;Aortic Diseases;Area;Attenuated;Bicuspid;Blood Vessels;Cardiac;Chest;Communication;Complex;Data;Development;Disease;Dissection;Drug Targeting;Embryo;Employee Strikes;Expert Opinion;FBN1;Fibroblasts;Genetic;Guidelines;Heart;Hematoma;Human;Individual;Infusion procedures;Knowledge;Lead;Literature;Losartan;LoxP-flanked allele;Medial;Mediating;Medical;Modeling;Mus;Neural Crest;Pathologic Processes;Pathology;Patients;Pericytes;Phenotype;Plant Roots;Play;Process;Proteins;Recommendation;Reporting;Role;Severities;Site;Smooth Muscle Myocytes;Testing;Thoracic Aortic Aneurysm;Thoracic aorta;Transforming Growth Factor beta;Tunica Adventitia;abstracting;ascending aorta;base;cell dedifferentiation;clinical investigation;fibulin;fibulin-4;in vivo;insight;interest;migration;mouse model;mutant;receptor;research study;response;therapy development;transdifferentiation


application_id: 9152507
project_number: 261201500035C-0-0-1
project_title: IGF::OT::IGF R&D- MEDICAL: BIOMEDICAL (BASIC RESEARCH)
administering_ic: NCI
project_start_date: 2015-09-22
project_end_date: 2016-06-21
contact_pi_person_id: 14274979
contact_pi: LINDER, MARK
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 012986391
primary_uei: ZFN5J433DCT1
duns_number: 012986391
uei: ZFN5J433DCT1
fips: US
organization_id: 10019586
organization_name: PGXL TECHNOLOGIES, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40206
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The objective of this project is to deliver a fully integrated CLIA-certified assay that provides diagnostic and disease monitoring capabiliteis in gliablastoma using cell-free nucleic acids (cfNA). We will use a novel patented enrichment technique (NeXosome) coupled with nucleic acid isolation methods to isolate cfNA from blood as means to evaluate the glioblastoma marker IDH1 mutation status. The NeXosome platform couples size exclusion chromatography with proprietary buffers to preferential enrich cfNA from diseased tissue allowing for greater abundance and heterogeneity of cfNA compared to current techniques. The specific tasks for this Phase I contract are to: 1) Establish a robust method for comprehensive enrichment of cfNA.  2) Demonstrate that mutant IDH1 can be distinguished from wild type IDH1 in plasma.  3) Analytically validate mutIDH1 cfNA assay.  4) Develop a regulatory plan for the submission of mutIDH1 assay to the FDA. This SBIR contract will enable development of a fully integrated and robust cfNA enrichment and analysis system to support the use of cfNA molecular techniques in the diagnosis and management of glioblastoma.

project_terms:
Basic Science;Biological Assay;Blood;Buffers;Cells;Contracts;Coupled;Couples;Development;Diagnosis;Diagnostic;Disease;Glioblastoma;Heterogeneity;Legal patent;Medical;Methods;Molecular;Molecular Sieve Chromatography;Monitor;Mutation;Nucleic Acids;Phase;Plasma;Small Business Innovation Research Grant;Systems Analysis;Techniques;Tissues;mutant;novel;research and development


application_id: 9152201
project_number: 5F31NS092202-02
project_title: MMPs in microhemorrhage occurrence in cerebrovascular disease
administering_ic: NINDS
award_notice_date: 2016-08-31
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: NS
serial_number: 092202
program_official: CORRIVEAU, RODERICK A
project_start_date: 2015-09-28
project_end_date: 2017-08-18
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 12104649
contact_pi: WEEKMAN, ERICA MARIE
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): Dementia is defined as cognitive loss severe enough to affect daily living and unlike other leading causes of death the number of persons afflicted with dementia is increasing. The two most common forms of dementia are Alzheimer's disease (AD) and vascular contributions to cognitive impairment and dementia (VCID). Although they have different etiologies these two forms of dementia share some similar pathologies such as vasogenic edema and microhemorrhages. These pathologies were also exacerbated when anti- amyloid beta (A) immunotherapy was used for treatment of AD causing termination of the clinical trials. Matrix metalloproteinases (MMPs) are proteases that can break down the blood brain barrier leading to vasogenic edema and microhemorrhage. The specific goals of this proposal are to determine the contribution of two specific MMPs MMP2 and MMP9 to the occurrence of vasogenic edema and microhemorrhage and to evaluate whether the presence of VCID will reduce the efficacy of anti-A treatment. The overall goal of this proposal is to provide possible targets for adjunct therapies with anti-A immunotherapy and improve AD clinical trials by screening for VCID co-morbidities.  To achieve these goals this proposal will utilize in vivo (Aim 1) and in vitro (Aim 2) methods. In Aim 1 the effect of VCID on the efficacy f anti-A immunotherapy vasogenic edema and microhemorrhages will be determined. Transgenic mice with amyloid deposition will be placed on the hyperhomocysteinemia diet to induce VCID and then treated with an anti-A immunotherapy. When VCID is pre-existing in a model of amyloid deposition treatment with anti-A immunotherapy will increase activation of the MMP2 and MMP9 systems exacerbate microhemorrhages and vasogenic edema and have reduced efficacy on cognition. Vasogenic edema microhemorrhages cognitive changes and MMP2 and MMP9 activity will be determined for Aim 1. Aim 2 will evaluate the role of MMP9 in the degradation of tight junctions in endothelial and astrocyte co-culture. The effect of inhibitio of MMP9 on tight junction degradation will also be assessed. Inflammatory- mediated activation of MMP9 will degrade tight junctions between cerebrovascular endothelial cells leading to vasogenic edema and microhemorrhages and inhibition of MMP9 will reduce tight junction degradation. Tight junction permeability and MMP9 activity will be assessed for Aim 2. Together these aims will offer valuable information on the contribution of MMP2 and MMP9 to vasogenic edema and microhemorrhage occurrence and the effect VCID has on anti-A immunotherapy.  These studies will provide training in new techniques. Specifically the applicant will learn how t execute cell biology based assays such as the sodium fluorescein assay and the isolation of primary astrocytes along with data analysis and interpretation skills. These aims and the training potential provided by them will aid the applicant in achieving their long term career goals.

project_terms:
Affect;Alzheimer disease screening;Alzheimer's Disease;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Amyloid deposition;Animal Husbandry;Antibodies;Astrocytes;Biological Assay;Blood - brain barrier anatomy;Cause of Death;Cell Culture Techniques;Cells;Cellular biology;Cerebrovascular Disorders;Cerebrovascular system;Clinical Trials;Coculture Techniques;Cognition;Comorbidity;Data Analyses;Dementia;Diet;Endothelial Cells;Etiology;Gelatinase A;Gelatinase B;Goals;Hyperhomocysteinemia;Immunotherapy;Impaired cognition;In Vitro;Inflammatory;Inhibition of Matrix Metalloproteinases Pathway;Injection of therapeutic agent;Interleukin-1 beta;Knockout Mice;Learning;Life;Manuscripts;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Mediating;Methionine;Methods;Modeling;Mus;Pathology;Patients;Peptide Hydrolases;Permeability;Persons;Population;Proteins;Role;SB 3CT compound;Sodium Fluorescein;System;TIMP1 gene;TNF gene;Techniques;Testing;Tight Junctions;Training;Transgenic Mice;Vitamin B6;Writing;aged;base;behavioral outcome;career;cerebrovascular;cognitive change;design;extracellular;improved;in vivo;inhibitor/antagonist;mouse model;presenilin-1;public health relevance;screening;skills;therapeutic target;vascular contributions;vasogenic edema

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID) are the two most common forms of dementia affecting 55% and 20% of dementia patients respectively. This proposal is designed to offer valuable information on the contribution of specific proteins to pathologies common to Alzheimer's disease and VCID (vasogenic edema and microhemorrhage) and the effect VCID has on therapies for Alzheimer's disease (anti-A immunotherapy). With this information we will provide possible targets for adjunct therapies with anti-A immunotherapy and improved clinical trials of Alzheimer's disease by screening more closely for patients with VCID co-morbidities.


application_id: 9150756
project_number: 4R00CA181500-03
project_title: The Role of Protein Tyrosine Phosphate PRL3 in Leukemia Development
administering_ic: NCI
award_notice_date: 2015-12-10
opportunity_number: PA-11-197
application_type: 4
activity_code: R00
ic: CA
serial_number: 181500
program_official: JHAPPAN, CHAMELLI
project_start_date: 2015-12-15
project_end_date: 2018-11-30
study_section: NSS
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Acute T Cell Leukemia;Adult;Adverse effects;Animals;Award;Behavior;Cancer Model;Cell Line;Cells;Chemotherapy-Oncologic Procedure;Child;Childhood;Chronic Myeloid Leukemia;Clinical;Clinical Treatment;Communities;Coupled;Data;Development;Drug Targeting;Environment;Foundations;General Hospitals;Genes;Genetic Epistasis;Goals;Hand;Health;Human;Image;In Vitro;Induction of Apoptosis;Knowledge;Learning;Life;Malignant Neoplasms;Massachusetts;Mentors;Mentorship;Modeling;Molecular;Molecular Target;Multiple Myeloma;Mus;Nature;Oncogenes;Outcome;Pathway interactions;Patients;Phase;Phosphorylation;Play;Protein Tyrosine Phosphatase;Proteins;Relapse;Research;Research Personnel;Role;Sampling;Solid Neoplasm;Staging;Survival Rate;Techniques;Testing;Therapeutic;Therapeutic Uses;Thymus Gland;Time;Transgenic Animals;Tyrosine;Work;Xenograft Model;Xenograft procedure;Zebrafish;base;cancer type;chemotherapy;defined contribution;gain of function;improved;in vivo;inhibitor/antagonist;innovation;inorganic phosphate;knock-down;leukemia;loss of function;medical schools;molecular targeted therapies;mortality;mouse model;new therapeutic target;novel;outcome forecast;overexpression;phosphoproteomics;pre-clinical trial;research study;small molecule;small molecule inhibitor;success;tumor progression


application_id: 9150610
project_number: 5R01CA195573-02
project_title: Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
administering_ic: NCI
award_notice_date: 2016-08-08
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 195573
program_official: FU, YALI
project_start_date: 2015-09-25
project_end_date: 2020-08-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GUO, PEIXUAN ;THORSON, JON SCOTT
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
arra_indicator: N
project_terms:
Address;Antineoplastic Agents;Binding;Biodistribution;Biological Models;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cells;Cessation of life;Clinical;Colorectal Cancer;Coupled;Disease;Distant;Drug Delivery Systems;Drug Kinetics;Early treatment;Epithelial Cells;Excision;FOLR1 gene;Goals;Growth;Health;Human;In Vitro;Injection of therapeutic agent;Intestines;Kentucky;Killings;Laboratories;Liver;Malignant Neoplasms;Metastatic Neoplasm to the Liver;Modality;Molecular;Motor;Mucous Membrane;Mus;Nanotechnology;Neoplasm Metastasis;Organ;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Process;RNA;Research;Resistance;Safety;Signal Pathway;Staging;Submucosa;System;Technology;Tissues;Tumor Tissue;Universities;Xenograft procedure;antitumor effect;aptamer;base;cancer cell;cancer therapy;chemotherapeutic agent;design;immunogenic;improved;in vivo;innovation;metastatic colorectal;mortality;multidisciplinary;nanoparticle;novel;overexpression;receptor;research study;scaffold;small molecule inhibitor;systemic toxicity;targeted delivery;targeted treatment;tumor;uptake


application_id: 9150489
project_number: 5R44AA021331-03
project_title: Novel Drug Carrier System for the Treatment of Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2016-08-04
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: AA
serial_number: 021331
program_official: RADAEVA, SVETLANA
project_start_date: 2012-09-25
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-N(10)B]
contact_pi_person_id: 10119089
contact_pi: BAUER, PHILIP
other_pis: GOBEJISHVILI, LEILA ;MALDONADO, CLAUDIO
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and no FDA-approved therapy exists. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF-) and TNF--inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levelscorrelate with markers of the acute phase response reduced liver function and poor clinical outcome. The focus of this application is the delivery of a drug that uses a unique carrier system to target the liver and correct the dysregulated cytokine production. Preliminary studies in isolated cells indicated that cyclic AMP (cAMP) decreases when cells are exposed to alcohol and is associated with an increase in pro-inflammatory cytokine levels. Experiments in which cellular cAMP concentrations were increased attenuated this increase in pro-inflammatory cytokines. Also we have preliminary data implicating an increase in phosphodiesterase 4B (PDE 4B) in the decreased cAMP concentrations observed in alcohol-exposed cells. Our working hypothesis is that altered PDE 4B and cAMP metabolism cause abnormal cytokine production/activity which plays a critical role in the development and perpetuation of ALD. Our long-term goal is to develop therapeutic interventions based on this research thereby providing a much needed drug therapy for ALD. We have identified a highly effective PDE 4 inhibitor to treat ALD but in humans systemic administration of the inhibitor induces severe nausea when threshold levels cross the blood-brain-barrier and reach the central nervous system (CNS). In Phase I of this proposal we demonstrated that our carrier system targeted the drug to the liver and reduced PDE4 activity in liver but not in the brain. We concluded that administration of a PDE4 inhibitor in our carrier system limited access of the drug to the CNS reducing the potential for side effects. In Phase II we will optimize the carrier system and compare pharmacokinetic characteristics of free drug vs. drug in the carrier system. Also we will perform efficacy pharmacological safety and product stability studies of drug in the optimized carrier system. The data obtained will be used for an IND application to the FDA to initiate clinical trial and eventually for commercialization.

project_terms:
Abstinence;Acute-Phase Reaction;Adverse effects;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Antibodies;Attenuated;Blood;Blood - brain barrier anatomy;Brain;Cause of Death;Cells;Chemicals;Chronic;Cirrhosis;Clinical;Clinical Trials;Crohn's disease;Cyclic AMP;Data;Development;Disease;Dose;Drug Carriers;Drug Delivery Systems;Drug Kinetics;Drug Targeting;Drug usage;Endotoxins;Enteral;Excipients;FDA approved;Goals;Health;Hepatic;Hepatocyte;Human;IL8 gene;In Vitro;Inflammation;Inflammatory;Injury;Interleukin-10;Interleukin-18;Intestines;Kupffer Cells;Life;Lipids;Liver;Liver Regeneration;Liver diseases;Mediating;Metabolism;Modeling;Monitor;Multicenter Trials;Mus;Nausea;Nausea and Vomiting;Neuraxis;Oral;Outcome;PDE4B;Patients;Peripheral;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Phase;Physicians;Plasma;Play;Prednisone;Process;Production;Reporting;Research;Research Personnel;Rheumatoid Arthritis;Role;Rolipram;Safety;Serum;Severity of illness;Solubility;Staging;Stream;Surrogate Markers;Survival Rate;System;TLR4 gene;TNF gene;Testing;Therapeutic Effect;Therapeutic Intervention;Therapeutic Uses;Treatment Efficacy;Vesicle;Water;Work;alcohol exposure;aqueous;base;chemokine;clinical application;clinically relevant;commercialization;cost;cytokine;feeding;in vivo;inhibitor/antagonist;liver function;liver injury;macrophage;monocyte;mortality;mouse model;novel;novel therapeutics;pharmacokinetic characteristic;phosphodiesterase IV;receptor;research study;response;safety study;sucrose octaacetate;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD but oral systemic administration of the inhibitor induces severe nausea in humans when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating in the blood stream and concentrates drug in the liver thereby maximizing the therapeutic effect while minimizing severe side effects.


application_id: 9149769
project_number: 272201000033I-0-27200004-1
project_title: Task A86: Mouse Models for Evaluation of Therapeutics against
administering_ic: NIAID
project_start_date: 2010-03-22
project_end_date: 2017-03-21
contact_pi_person_id: 14259779
contact_pi: SEVERSON, WILLIAM
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
funding_mechanism: R and D Contracts
project_abstract:
This contract provides for the development and standardization of small animal models for infectious diseases and may include efficacy testing of candidate products.

project_terms:
Animal Model;Avian Influenza;Communicable Diseases;Contracts;Development;Influenza Therapeutic;Standardization;efficacy testing;mouse model;therapeutic evaluation


application_id: 9149749
project_number: 2R24OD010435-16
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2016-06-03
opportunity_number: PAR-13-253
application_type: 2
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZRG1 BBBP-Y (45)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Area;Bioinformatics;Biomedical Research;Body part;Brain;ChIP-seq;Chromatin;Chromosomes;Complex;DNA;DNA Library;DNA Methylation;DNA Sequence;Data;Data Set;Distal;Enhancers;Epigenetic Process;Erythroblasts;Funding;Future;Gene Expression;Gene Structure;Genetic;Genetic Transcription;Genome;Genomics;Human;Human Genome;Libraries;Limb structure;Location;Maps;Meiosis;Methods;Modeling;Molecular;Natural regeneration;Newts;Nucleic Acid Regulatory Sequences;Partner in relationship;Phase;Phylogenetic Analysis;Red-Spotted Newts;Regenerative Medicine;Regulatory Element;Research;Research Personnel;Resources;Salamander;Sampling;Site;Spinal Cord;Testing;Tissues;Transcript;Untranslated RNA;Vision;Work;chromatin modification;clinical application;design;epigenetic variation;histone modification;improved;innovation;interest;limb amputation;limb regeneration;methylation pattern;promoter;scaffold;stem cell biology;temporal measurement;tissue regeneration;transcriptome;transcriptome sequencing;web site;whole genome


application_id: 9147868
project_number: 1P01NS097197-01
project_title: Defining the therapeutic window for the treatment of Lafora Epilepsy
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8558
contact_pi_person_id: 12485842
contact_pi: GUINOVART, JOAN J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Adolescence;Alleles;Applications Grants;Behavioral;Biochemical;Birth;Brain;Child;Clinical;Complementary DNA;Deposition;Development;Disease;Disease Progression;Electrophysiology (science);Enzyme Inhibition;Enzymes;Epilepsy;Excision;Future;GYS1 gene;Gene Expression;Generations;Genes;Genetic;Glycogen;Glycogen (Starch) Synthase;Histologic;Human;Killings;Knock-out;Knockout Mice;Knowledge;Lafora Disease;Lead;Mus;Muscle;Myocardium;Nerve Degeneration;Neurons;Newly Diagnosed;Onset of illness;Pathogenesis;Pathology;Patients;Phase;Phenotype;Phosphoric Monoester Hydrolases;Physiological;Process;Protein Isoforms;Seizures;Specific qualifier value;Structure;Therapeutic;Therapeutic Intervention;Time;Tissues;Torture;disease phenotype;genome editing;mouse model;neuronal cell body;polyglucosan;prevent;research study;small molecule;symptomatic improvement;ubiquitin-protein ligase


application_id: 9147867
project_number: 1P01NS097197-01
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8557
contact_pi_person_id: 1888145
contact_pi: ROACH, PETER J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
funding_mechanism: Non-SBIR/STTR
project_terms:
Active Sites;Age-Months;Allosteric Site;Animals;Biochemical;Biological;Biological Assay;Blood - brain barrier anatomy;Brain;Cell Line;Cells;Chemicals;Childhood;Core Facility;Data;Deposition;Development;Disease;Dose;Drug Kinetics;Enzyme Kinetics;Epilepsy;Evaluation;Genes;Genetic;Genomics;Glucose-6-Phosphate;Glycogen;Glycogen (Starch) Synthase;Histologic;Human Cell Line;In Vitro;Investigation;Laboratories;Lafora Disease;Lead;Learning;Libraries;Long-Term Effects;Measurement;Monitor;Mus;Mutation;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Nervous System Physiology;Neurologic;Neurons;Pathology;Pattern;Penetration;Pharmaceutical Chemistry;Prevention;Property;Protocols documentation;Radioactive;Reading;Series;Staging;Structure;Structure-Activity Relationship;Symptoms;Testing;Therapeutic;Thinking;Tissues;Toxic effect;Toxicology;Validation;Weaning;analog;base;behavioral impairment;cohort;drug development;effective therapy;high throughput screening;human disease;in vitro activity;inhibitor/antagonist;mouse model;novel;novel strategies;phosphatase inhibitor;polyglucosan;pre-clinical;programs;response;small molecule;small molecule inhibitor


application_id: 9147866
project_number: 1P01NS097197-01
project_title: Genome editing mRNA suppression and chain termintion as therapy for Lafora Epilepsy
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8556
contact_pi_person_id: 11654552
contact_pi: MINASSIAN, BERGE A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Adolescence;Adolescent;Antiepileptic Agents;Antisense Oligonucleotide Therapy;Antisense Oligonucleotides;Base Pairing;Blood - brain barrier anatomy;Brain;CRISPR/Cas technology;Cessation of life;Chemistry;Child;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Cytoplasm;DNA;Dendrites;Dependovirus;Disease;Disease Progression;Enzymes;Epilepsy;Gene Targeting;Genes;Genetic;Genome;Glucose;Glycogen;Glycogen (Starch) Synthase;Homologous Gene;Hospitals;Human;Institutes;Intervention;Intractable Epilepsy;Ketones;Knock-out;Lafora Disease;Lead;Mediating;Messenger RNA;Mus;Mutation;Names;Nerve Degeneration;Neuraxis;Neurons;Oligonucleotides;Pathogenesis;Pathway interactions;Patients;Phosphoric Monoester Hydrolases;Plasmids;Positioning Attribute;Production;Property;Protein Isoforms;Proteins;RNA;Refractory;Regulation;Research;Solubility;Staging;Staphylococcus aureus;Starch;Structure;Symptoms;System;Therapeutic Intervention;Time;Translating;Universities;Virus;effective therapy;gene therapy;genome editing;hydroxyl group;innovation;ketogenic diet;knockout gene;member;mouse model;nervous system disorder;nuclease;polyglucosan;prevent;programs;receptor;research study;small molecule;ubiquitin-protein ligase;vector


application_id: 9147865
project_number: 1P01NS097197-01
project_title: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8555
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Accounting;Acute;Acute Disease;Address;Affect;Antiepileptic Agents;Apoptosis;Area;Astrocytes;Autophagocytosis;Biochemical;Biochemistry;Biochemistry and Cellular Biology;Biological Assay;Brain;Cell Culture Techniques;Cell physiology;Cells;Cessation of life;Clinical;Collaborations;Cystic Fibrosis;Data;Defect;Development;Diagnosis;Disease;Disease Progression;Energy Metabolism;Epilepsy;Event;Family;Functional disorder;Genes;Glucans;Glycogen;Goals;Homeostasis;International;Intervention;Ion Channel;Knowledge;Lafora Disease;Life;Metabolic;Modeling;Molecular;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotransmitters;Outcome;Oxidative Stress;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Production;Program Research Project Grants;Progressive Myoclonic Epilepsies;Proteins;Reading;Recovery;Research;Role;Sampling;Stress;Structural Biochemistry;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Toxic effect;Translating;Translations;Water;base;clinical application;design;disease-causing mutation;drug efficacy;endoplasmic reticulum stress;glycogen metabolism;in vitro Model;induced pluripotent stem cell;insight;member;molecular subtypes;mouse model;neuron apoptosis;neurotoxicity;new therapeutic target;novel;novel therapeutic intervention;overexpression;particle;personalized approach;personalized diagnostics;personalized therapeutic;potency testing;premature;protein degradation;protein expression;protein misfolding;receptor;restoration;small molecule;symptom treatment;tool;trafficking;ubiquitin-protein ligase


application_id: 9147864
project_number: 1P01NS097197-01
project_title: Biological Core
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8554
contact_pi_person_id: 9487963
contact_pi: WORBY, CAROLYN ANN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Aftercare;Antisense Oligonucleotides;Ataxia;Basic Science;Behavior;Biochemical;Biological;Cell Culture Techniques;Cell Line;Cell model;Cells;Cessation of life;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Consensus;Cytoplasm;Deterioration;Development;Diagnosis;Disease;Disease Progression;Disease model;Educational workshop;Electroencephalography;Encephalopathies;Ensure;Epilepsy;Funding;Genes;Glycogen;Goals;Grant;Hormonal;Human;Impaired cognition;Incidence;Intractable Epilepsy;Knock-in Mouse;Lafora Disease;Lead;Missense Mutation;Modeling;Molecular;Mutation;Myoclonic Epilepsies;Neurologic;Neurons;Nonsense Codon;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Plants;Preclinical Drug Evaluation;Program Research Project Grants;Progressive Myoclonic Epilepsies;Reagent;Research;Research Personnel;Side;Starch;Stimulus;Structure;Techniques;Teenagers;Therapeutic;TimeLine;Transgenic Mice;Transgenic Organisms;United States National Institutes of Health;Work;abstracting;base;behavioral study;drug testing;genome editing;high throughput screening;induced pluripotent stem cell;innovation;meetings;member;mouse model;multidisciplinary;nervous system disorder;patient advocacy group;personalized diagnostics;personalized medicine;polyglucosan;prevent;small molecule;success;ubiquitin-protein ligase


application_id: 9147863
project_number: 1P01NS097197-01
project_title: Medicinal Chemistry Core
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8553
contact_pi_person_id: 1964895
contact_pi: WATT, DAVID STEWART
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Affect;Affinity;Agreement;Aminoglycosides;Binding;Biological;Biological Assay;Biological Testing;Blood - brain barrier anatomy;Brain;Chemicals;Collaborations;Consultations;Cytoplasm;Dendrites;Deoxyglucose;Development;Diagnosis;Disease;Educational workshop;Enzymes;Epilepsy;Feedback;Funding;Generations;Glucose;Glycogen;Glycogen (Starch) Synthase;Grant;Human;Human Resources;Lafora Disease;Lead;Libraries;Molecular Probes;Mutation;Neurodegenerative Disorders;Neurologic;P-Glycoprotein;Pharmaceutical Chemistry;Phase;Phosphoric Monoester Hydrolases;Process;Program Research Project Grants;Research;Research Personnel;Services;Sorting - Cell Movement;Starch;Structure;Structure-Activity Relationship;Symptoms;Testing;Therapeutic;Time;United States National Institutes of Health;analog;base;cheminformatics;design;glycogen metabolism;high throughput screening;inhibitor/antagonist;innovation;mouse model;pharmacophore;pre-clinical;remediation;scaffold;screening;sex;small molecular inhibitor;small molecule;small molecule therapeutics;success;ubiquitin-protein ligase


application_id: 9147862
project_number: 1P01NS097197-01
project_title: Administrative Core
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8552
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_terms:
Administrative Personnel;Advertising;Advisory Committees;Biological;Biological Markers;Clinical;Clinical Trials;Collaborations;Committee Members;Communication;Communities;Diagnosis;Disease;Dreams;Educational workshop;Electronic Mail;Ensure;Epilepsy;Event;Family Physicians;Flowcharts;Goals;Grant;Housing;Innovative Therapy;Institution;Intellectual Property;Kentucky;Knowledge;Lafora Disease;Lead;Leadership;Medicine;Methods;Mission;Molecular Medicine;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurons;Neurosciences;Newborn Infant;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phase;Policies;Property Rights;Protocols documentation;Publications;Reagent;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Severities;Teleconferences;Therapeutic;United States National Institutes of Health;Universities;Work;career development;college;community planning;fundamental research;glycogen metabolism;innovation;meetings;member;operation;patient population;programs;sharing data;skills;tool;web site


application_id: 9147861
project_number: 1P01NS097197-01
project_title: Lafora Epilepsy - Basic mechanisms to therapy
administering_ic: NINDS
award_notice_date: 2016-07-01
opportunity_number: PAR-14-183
application_type: 1
activity_code: P01
ic: NS
serial_number: 097197
program_official: STEWART, RANDALL R
project_start_date: 2016-07-01
project_end_date: 2021-06-30
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adolescence;Antiepileptic Agents;Antisense Oligonucleotides;Bioenergetics;Biological;Biological Assay;Biological Models;Biological Products;Biology;Brain;Carbohydrates;Cessation of life;Chemistry;Child;Clinic;Clinical Research;Clinical Trials;Collaborations;Communities;Convulsions;Core Facility;Coupled;Cytoplasm;Data;Defect;Dementia;Dendrites;Development;Diagnosis;Diagnostic;Disease;Dreams;Employee Strikes;Enzymes;Epilepsy;Frequencies;Gene Expression;Generations;Genes;Genetic;Glycogen;Grant;Headache;Hormones;International;Intractable Epilepsy;Knowledge;Lafora Disease;Life;Medicine;Messenger RNA;Methods;Modality;Modeling;Molecular;Molecular Target;Mutation;Myoclonic Epilepsies;Myoclonus;National Institute of Neurological Disorders and Stroke;Neurodegenerative Disorders;Neurons;Neurosciences;Outcome;Pathology;Pathway interactions;Patients;Persons;Pharmaceutical Chemistry;Phase;Phosphoric Monoester Hydrolases;Physicians;Plants;Positioning Attribute;Process;Production;Program Research Project Grants;Pulmonary Inflammation;RNA;Reagent;Refractory;Research;Research Personnel;Scientist;Seizures;Shapes;Starch;Status Epilepticus;Structural Biochemistry;Techniques;Technology;Teenagers;Testing;Therapeutic;Time;Training;Translating;United States National Institutes of Health;Vision;Work;base;brain cell;career;clinical application;cognitive function;genome editing;glycogen metabolism;induced pluripotent stem cell;innovation;insight;member;mouse model;new technology;novel;personalized diagnostics;response;sex;small molecule;small molecule inhibitor;spelling;success;sugar;ubiquitin-protein ligase


application_id: 9146888
project_number: 5R01DK107646-02
project_title: Cold Induced Changed in Human Subcutaneous White Adipose
administering_ic: NIDDK
award_notice_date: 2016-07-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 107646
program_official: HAFT, CAROL R
project_start_date: 2015-09-21
project_end_date: 2018-07-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The recent rediscovery of human brown adipose tissue through PET-CT has initiated more research on thermogenesis and defense defense against obesity. Many studies have demonstrated that white adipose tissue (WAT) in mice has the ability to upregulate its thermogenic capacity and become "beige". No studies have demonstrated browning of typical human WAT depots except for our recent studies. We have recently examined the subcutaneous (SC) WAT of humans and found a considerable ability to upregulate UCP1 and other mitochondrial genes in response to cold and to seasons and we have demonstrated this phenomenon with human adipocytes in culture. The seasonal changes in WAT are of particular interest since this indicates a physiologic response to colder weather without provocative and unphysiologic experimental conditions. In addition we found that obese humans with a high SC WAT macrophage burden do not upregulate SC WAT UCP1 as well suggesting that adipose inflammation inhibits the increased thermogenic capacity of WAT. A number of immune-mediate functions are involved in this process. Based on these data we propose the following hypotheses. Hypothesis 1. Repeated exposure to cold temperatures will amplify changes in human subcutaneous WAT beiging. These beiging effects are seen acutely in response to seasons and involve an activation of immune mediators. Hypothesis 2. The beiging of SC WAT involves an acute increase in adipose tissue immune mediators which may be a source of catecholamines that activate protein kinase A (PKA). This process is inhibited by -blockers in vivo. Hypothesis 3. Obese insulin resistant subjects are resistant to cold induced changes in WAT due to the proinflammatory milieu which inhibits local mediators of beiging. Hypothesis 4. Cold- and season-induced changes in SC WAT will lead to functional changes in the tissue characterized by increased mitochondrial uncoupling increased TG turnover (lipolysis) and increased resting metabolic rate.

project_terms:
Acute;Adipocytes;Adipose tissue;Area;Basal metabolic rate;Biological Response Modifiers;Brown Fat;Catecholamines;Cyclic AMP-Dependent Protein Kinases;Data;Diabetes Mellitus;Energy Metabolism;Exposure to;Genes;Heart Diseases;Human;Immune;Inflammation;Inflammatory;Insulin Resistance;Lead;Link;Lipolysis;Mammals;Mediating;Mediator of activation protein;Metabolic syndrome;Mitochondria;Mus;Neck;Obesity;Phenotype;Physiological;Positron-Emission Tomography;Process;Property;Regulation;Research;Resistance;Rodent;Seasons;Societies;Source;Temperature;Thermogenesis;Tissues;Triglycerides;Vertebral column;Weather;base;cold temperature;glucose uptake;improved;in vivo;interest;macrophage;prevent;response;subcutaneous

public_health_relevance:
Obesity is closely linked with insulin resistance diabetes and heart disease. Recent studieshave focused on brown adipose tissue in humans which may increase energy expenditure andhelp prevent obesity. This proposal examines the extent to which subcutaneous white adiposecan become brown-like or beige. We will determine whether this process is inhibited by theinflammatory state of obesity/metabolic syndrome and we will characterize the effects of coldon adipose triglyceride turnover.


application_id: 9146714
project_number: 5R01NS091329-02
project_title: PERK as a central mediator of neurotoxicity in tauopathies
administering_ic: NINDS
award_notice_date: 2016-07-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091329
program_official: CORRIVEAU, RODERICK A
project_start_date: 2015-09-30
project_end_date: 2020-06-30
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 10569691
contact_pi: ABISAMBRA, JOSE FRANCISCO
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
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): Tauopathies are a group of nineteen known debilitating neurodegenerative disorders that affect nearly eight million people in the United States. Currently there is no cure for tauopathies and there are temporary and limited benefits to current therapeutic strategies. The endoplasmic reticulum (ER) stress sensor PERK (protein kinase R-like ER kinase) has been identified as a participant in the pathogenesis and progression of tauopathies. However the mechanism by which the PERK pathway causes neuronal dysfunction is still unknown. The long-term goal is to better understand the mechanism(s) that induce(s) neuronal dysfunction in tauopathies and the overall objective is to determine the mechanism by which tau and PERK synergize to induce neuronal dysfunction. The central hypothesis is that tau and PERK engage in a pathological cycle whereby aberrant accumulation of tau chronically activates PERK and active PERK activates enzymes that contribute to the production of pathogenic tau. The overall consequence of this cycle is potentiation of tau pathogenic pathways as well as chronic inhibition of protein synthesis. Characterizing the role of the PERK pathway in neuronal dysfunction will identify novel urgently needed therapeutic targets for tauopathies. The hypothesis will be tested in three specific aims. Aim 1 is designed to determine the extent to which the PERK pathway causes neuronal dysfunction in tauopathies. Aim 2 is designed to determine the mechanism by which PERK activity modulates tau pathology. Finally Aim 3 will determine the extent of PERK pathway activation in a newly described tauopathy called Primary Age-Related Tauopathy (PART). In Aim 1 we will use pharmacologic and genetic approaches to inhibit PERK in in vivo in situ and in vitro models of tauopathy; neuronal function will be measured by cognitive tests a novel and non-invasive imaging approach called manganese-enhanced MRI and electrophysiological measurements. Secondly we will use biochemical immunohistochemical and gene expression assays to determine the extent of PERK activity. In Aim 2 we will use pharmacologic and genetic approaches to activate and inhibit PERK in in vivo and in vitro models of tauopathy; we will measure changes to pathological tau and the PERK pathway. Finally in Aim 3 we will measure changes in the levels of PERK pathway markers and pathological tau in PART CSF and brain parenchyma. This will be the first extensive biochemical approach to PART which could unveil novel biomarkers of the disease. The identification of a pathogenic PERK-tau cycle is innovative because it departs from the status quo by identifying an effector of disease (PERK) that can cause neuronal dysfunction (downstream) while also potentiating tau aberrancies (upstream). Therefore the PERK pathway offers a unique repertoire of novel therapeutic targets that can modulate disease in multiple aspects. This approach is significant because of the central role the pathway plays in disease and therefore the potential to offer therapeutic solutions to tauopathies.

project_terms:
Acute;Affect;Alzheimer's Disease;Attenuated;Biochemical;Brain;CASP3 gene;Caspase;Cerebrospinal Fluid;Chemosensitization;Chronic;Cleaved cell;Code;Cognition;Data;Defect;Dementia;Development;Disease;Disease Progression;Electrophysiology (science);Endoplasmic Reticulum;Enzymes;Gene Expression Profiling;Genes;Goals;Health;Homeostasis;Human;Impaired cognition;In Situ;Individual;Lead;Link;Magnetic Resonance Imaging;Manganese;Measurement;Measures;Mediating;Mediator of activation protein;Modeling;Morphology;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurologic;Neuronal Dysfunction;Neurons;Outcome;Participant;Pathogenesis;Pathology;Pathway interactions;Patients;Phosphotransferases;Play;Prion Diseases;Production;Progressive Supranuclear Palsy;Protein Synthesis Inhibition;Proteins;Public Health;RNA;Reporting;Research;Risk;Role;Slice;Synapses;Tauopathies;Testing;Therapeutic;Time;Transgenic Mice;Translations;United States;Work;age related;aging population;attenuation;base;brain parenchyma;cerebral atrophy;cognitive testing;design;effective therapy;endoplasmic reticulum stress;genetic approach;immortalized cell;improved;in vitro Model;in vivo;innovation;mouse model;neurotoxicity;new therapeutic target;non-invasive imaging;novel;novel marker;novel therapeutics;protein kinase R;sensor;tau Proteins;tau aggregation;tau mutation;tau-protein kinase;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it aims to identify a pathway known as PERK as a contributor of damage to neurons in nineteen related neurodegenerative disorders called tauopathies the most common of which is Alzheimer's disease. These diseases present irreversible and severe brain atrophy and cognitive impairment and impact millions of people. Discovery of the mechanisms by which PERK damages neurons in the brain will establish a specific target that may lead to development of novel therapeutics.


application_id: 9145826
project_number: 3R01EY012354-15S1
project_title: Isolation of Congenital Stationary Night Blindness Genes
administering_ic: NEI
award_notice_date: 2015-09-21
opportunity_number: PA-11-260
application_type: 3
activity_code: R01
ic: EY
serial_number: 012354
suffix: S1
program_official: GREENWELL, THOMAS
project_start_date: 1999-02-01
project_end_date: 2015-12-31
study_section: Neurotransporters, Receptors, and Calcium Signaling Study Section[NTRC]
contact_pi_person_id: 1885008
contact_pi: GREGG, RONALD G
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): Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter glutamate from cone and rod photoreceptor terminals and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition.  There are two classes of bipolar cells hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor mGluR6 that signals to TRPM1 depolarizing in response to a light flash. Defects in transmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6 NYX TRPM1 and GPR179 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largely unknown. The long term goal of this project is study the molecular interactions between two recently discovered retinal components GPR179 and Cav1.1 and the other DBC signal transduction components. The specific aims are: 1) Determine the role of GPR179 in DBC signalplex assembly/function 2) determine the role of Cav1.1 in DBC signalplex assembly and function and 3) Determine functional and trafficking interdependence of DBC signalplex components.  At the completion of this project we will have characterized the function of newly discovered proteins (GPR179 and Cav1.1) critical to signal transmission in DBCs. Further we will have identified new candidate genes for congenital stationary night blindness.

project_terms:
Address;Alleles;Binding (Molecular Function);Brain;Candidate Disease Gene;Cations;Cells;Coin;Complex;Data;Defect;Disease;Dissection;Elements;Feedback;Functional disorder;Future;G-Protein-Coupled Receptors;GRM6 gene;Genes;Glutamate Receptor;Glutamates;Goals;Grant;Health;Human;Knock-out;Knockout Mice;Knowledge;L-Type Calcium Channels;Lateral;Lead;Left;Light;Literature;Mediating;Metabotropic Glutamate Receptors;Mus;Mutant Strains Mice;Mutate;Mutation;Nature;Neurons;Neurotransmitters;Night Blindness;Pathway interactions;Photoreceptors;Point Mutation;Positioning Attribute;Property;Protein Isoforms;Proteins;Publishing;Retinal;Retinal Cone;Retinal Ganglion Cells;Rods (Retina);Role;Signal Transduction;Skeletal muscle structure;Staging;Synapses;Synaptic Transmission;Therapeutic;Transmembrane Domain;Vision;Visual system structure;ganglion cell;horizontal cell;human disease;luminance;member;mutant;neurotransmitter release;novel;research study;response;trafficking;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Vision requires a light signal to be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as complete congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second order neurons in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function. Such knowledge is essential to future efforts to restore normal vision.   PUBLIC HEALTH RELEVANCE: Vision requires a light signal be converted to an electrical signal which is then transmitted to the brain via a neuronal network. The diseases being studied are referred to as congenital stationary night blindness. The studies in this proposal will characterize the nature of the defects and determine the function of newly identified proteins critical for normal vision which will set the stage of therapeutic approaches in the future.


application_id: 9145801
project_number: 5R01NS091582-02
project_title: The role of macrophage phenotype and age in spinal cord injury
administering_ic: NINDS
award_notice_date: 2016-07-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091582
program_official: JAKEMAN, LYN B
project_start_date: 2015-09-30
project_end_date: 2020-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
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
arra_indicator: N
project_terms:
Acute;Affect;Age;Age Factors;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Automobile Driving;Azithromycin;Biology;Cell Proliferation;Cells;Chronic;Clinical;Clinical Data;Contusions;Data;Development;Dose;Effectiveness;Equilibrium;Estradiol;Female;Flow Cytometry;Genes;Genetically Engineered Mouse;Goals;Gonadal Steroid Hormones;Healed;Health;Health Care Costs;Human;In Vitro;Incidence;Individual;Inflammatory;Inflammatory Response;Intervention;Investigation;Knockout Mice;Knowledge;Macrolide Antibiotics;Macrophage Activation;Mediating;Modeling;Mus;Outcome Measure;Paralysed;Pathology;Patients;Phenotype;Physiological;Process;Production;Progesterone;Publishing;Recovery;Recovery of Function;Research;Rodent;Role;Spinal cord injury;Techniques;Testing;Time;Tissues;United States;Work;Wound Healing;age effect;aged;arginase;axon growth;axon regeneration;base;clinical practice;clinically relevant;functional disability;gain of function;healing;improved;in vivo;injury and repair;innovation;loss of function;macrophage;male;middle age;mouse model;neuroinflammation;neuropathology;neuroprotection;neurotoxic;neurotoxicity;novel;pre-clinical;remyelination;repaired;response;sex;treatment strategy


application_id: 9145334
project_number: 2R01DA033862-04A1
project_title: Effect of structural interventions on substance use and HIV/HCV risk among rural PWUD
administering_ic: NIDA
award_notice_date: 2016-04-22
opportunity_number: PA-15-003
application_type: 2
activity_code: R01
ic: DA
serial_number: 033862
suffix: A1
program_official: DUFFY, SARAH Q
project_start_date: 2012-09-01
project_end_date: 2021-02-28
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this renewal application (R01DA033862) is to determine the influence of structural interventions on engagement in risk reduction and health promotion activities among rural Appalachian drug users. Results from the three-year R01 that the investigators seek to continue reveal an ever-changing landscape of prescription drug abuse; an epidemic that is still in its infancy. Unlike many rural and suburban areas there is little evidence for the transition to heroin abuse. In this cohort there has been  marked shift from abuse of OxyContin(r) (extended-release oxycodone) to immediate release oxycodone to more recently buprenorphine and gabapentin-containing products. In addition rates of HCV prevalence and incidence are high especially given the population density of rural Appalachia. Given the syndemic of opioid abuse and infectious disease transmission two structural interventions are particularly relevant to this population of rural people who use drugs
(PWUD). Medicaid (MC) expansion (under the Affordable Care Act [ACA]) and syringe access programs (SAP) are two structural interventions that may allow for increased engagement in health promotion among PWUD but are likely heavily influenced by individual network and community-level factors. Utilizing Latkin's Dynamic Social Systems model and leveraging the extant highly successful cohort of rural PWUD the aims include: 1) examining how dynamic factors of these structural interventions influence longitudinal trends in illicit and prescription
drug abuse; 2) determining the influence of these structural interventions on HIV/HCV incidence and engagement in risk reduction; and 3) assessing the influence of these structural interventions on uptake of substance abuse treatment. This study is highly significant given that understanding the mechanisms by which these specific structural interventions influence health promotion is key to improving public health in rural Appalachia. Substance abuse and HCV are two of the most important if not the most important health issues facing this region already plagued with marked health disparities. Using innovative measures of network and geospatial risk as well as conjoint analysis and multilevel longitudinal statistical models results will not
only inform development of interventions that optimize uptake and utilization of risk reduction services such as SAP and substance abuse treatment but may inform policies surrounding further implementation of health promotion programs in the rural U.S.

project_terms:
Accounting;Address;Affordable Care Act;Alcohol or Other Drugs use;Appalachian Region;Area;Biological Models;Buprenorphine;Communicable Diseases;Communities;Community Networks;Complement;County;Data;Data Collection;Development;Disease Outbreaks;Disease Outcome;Drug abuse;Drug usage;Drug user;Effectiveness;Enrollment;Epidemic;Epidemiology;Frequencies;Goals;HIV;HIV/HCV;Health;Health Promotion;Health behavior outcomes;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C Transmission;Hepatitis C virus;Heroin Abuse;Indiana;Individual;Injecting drug user;Injection of therapeutic agent;Insurance Coverage;Intervention;Kentucky;Laws;Literature;Measures;Medicaid;Modeling;Natural experiment;Nature;Needle Sharing;Outcome;Oxycodone;Participant;Personal Communication;Plague;Policies;Population;Population Density;Prevalence;Public Health;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Population;Services;Statistical Models;Sterility;Substance Use Disorder;Substance abuse problem;Syringes;System;Time;Treatment outcome;Uninsured;cohort;disease transmission;drug of abuse;follow-up;gabapentin;health disparity;improved;infancy;innovation;multilevel analysis;opioid abuse;prescription drug abuse;prescription opioid;programs;public health relevance;response;rural area;social;substance abuse treatment;suburb;therapy design;therapy development;trend;uptake


application_id: 9144758
project_number: 5R01DA040694-02
administering_ic: NIDA
award_notice_date: 2016-06-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 040694
program_official: WALTON, KEVIN
project_start_date: 2015-09-15
project_end_date: 2019-07-31
study_section: Pregnancy and Neonatology Study Section[PN]
contact_pi_person_id: 9641889
contact_pi: ASHFORD, KRISTIN H.
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
project_title:
The impact of electronic cigarettes (e-cigs) on perinatal immune responsiveness and birth outcomes in Appalachia

project_terms:
1-Butanol;Adult;Adverse effects;Air;Analysis of Covariance;Appalachian Region;Behavior;Biological;Biological Markers;Birth;Birth Weight;Bone Density;Butanones;Carbon Monoxide;Cigarette;Cotinine;Data;Data Analyses;Electronic cigarette;Exhibits;Female of child bearing age;Fetal Development;Fetus;Gestational Age;Goals;Harm Reduction;Health;Heart Diseases;Immune;Immune Sera;Immune response;Immunologic Markers;Infant;Interleukin-1 beta;Interleukin-10;Interleukin-6;Interleukin-8;Interleukins;Kentucky;Liquid substance;Literature;Malignant neoplasm of lung;Marketing;Measures;Methods;National Institute of Drug Abuse;Nature;Neutrophil Collagenase;Nicotine;Nitrosamines;Outcome;Participant;Perception;Perinatal;Pharmaceutical Preparations;Postpartum Period;Postpartum Women;Pregnancy;Pregnant Women;Premature Birth;Recruitment Activity;Relapse;Research;Risk;Safety;Series;Serum;Smoke;Smoking;Smoking Behavior;Smoking Status;Spontaneous abortion;Surveys;TNF gene;Time;Tobacco;Tobacco use;United States;United States Food and Drug Administration;Urine;Vulnerable Populations;Woman;Work;adverse pregnancy outcome;authority;burden of illness;cigarette smoking;cytokine;design;experience;fetal tobacco exposure;maternal tobacco use;meetings;modifiable risk;novel;premature;prenatal;prenatal smoking;prospective;smoking cessation;urinary


application_id: 9144606
project_number: 272201000033I-0-27200003-1
administering_ic: NIAID
project_start_date: 2015-06-20
project_end_date: 2016-06-19
contact_pi_person_id: 14145560
contact_pi: HIGDON, JOSEPH
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
funding_mechanism: R and D Contracts
project_title:
TASK A72: THERAPEUTICS TESTING IN A MURINE MODEL OF MULTIPLE DRUG RESISTANT (MDR) PSEUDOMONAS AERUGINOSA LUNG INFECTION

project_terms:
Animal Model;Communicable Diseases;Contracts;Development;Infection;Lung;Modeling;Multi-Drug Resistance;Mus;Pseudomonas aeruginosa;Standardization;Testing;Therapeutic;efficacy testing;therapeutic development


application_id: 9144376
project_number: 4U24DK097215-04
project_title: OUTREACH CORE
administering_ic: NIDDK
award_notice_date: 2016-09-01
opportunity_number: RFA-RM-11-016
application_type: 4
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6292
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
budget_end_date: 2017-08-31
project_abstract:
PROJECT SUMMARY (See instructions): Despite rapid advances in metabolomics technologies and the need for understanding the human metabolome metabolomics applications in biomedical research remain limited. This is partly due to the combination of lack of awareness in the value of large-scale metabolic understanding inadequate access to high end instrumentation lack of experience in experimental design sample handling/processing complex data analysis and biochemical interpretation. Since the inception of our Center for Regulatory and Environmental Analytical Metabolomics (CREAM) in 2007 we have learned that proper outreach training and educational efforts can overcome most barriers to integrating metabolomics approaches into mainstream basic and translational research. Thus with the proposed addition of resources for the new RCMRC-CREAM we will greatly expand our outreach and educational efforts in the Outreach & Education Core led by PI Fan. These goals will be achieved with the following Specific Aims: SA1. Provide education on metabolomics research via distance learning workshops symposia and a wiki. In addition to metabolomics education means for integration with other 'omics information will be illustrated. SA2. Provide hands-on training on how to acquire metabolomics information for integration into systems biological understanding. Hands-on training will complement the education component in SA1 and provides the most effective way for transferring metabolomics expertise and for its adoption by the research community. SA3. Collaborate with investigators of Pilot & Feasibility projects and others who wish to engage metabolomics research. There will be $1.5M available (with $0.5M match from UofL) over 5 years for funding at least 30 P&F projects. SA4. Disseminate metabolomics research achievements via scientific meetings and publications. We will hold two special symposia in addition to attending appropriate scientific meetings and writing manuscripts as warranted. We believe by applying metabolomics technologies in collaborative projects to address pressing health issues with high quality and breakthrough research results will facilitate the wide acceptance of this approach by the biomedical research community.

project_terms:
Achievement;Address;Adoption;Animal Model;Award;Awareness;Basic Science;Biochemical;Biochemical Pathway;Biochemistry;Biological;Biomedical Research;Cell model;Collaborations;Communities;Complement;Complex;Data;Data Analyses;Diagnosis;Disease;Distance Learning;Education;Education and Outreach;Educational process of instructing;Educational workshop;Experimental Designs;Funding;Generations;Goals;Grant;Health;Human;Informatics;Instruction;Joints;Knowledge;Learning;Letters;Mainstreaming;Manuscripts;Metabolic;Online Systems;Pathway interactions;Patients;Process;Publications;Research;Research Infrastructure;Research Personnel;Resources;Sampling;Science;Scientist;Specific qualifier value;Students;System;Technology;Textbooks;Time;Tracer;Training;Training and Education;Translational Research;Travel;Universities;Visit;Work;Writing;advanced system;biological systems;experience;handbook;human disease;instrumentation;interest;learning materials;meetings;metabolome;metabolomics;next generation;novel;outreach;programs;research and development;research study;stable isotope;symposium;wiki

public_health_relevance:
RELEVANCE (See instructions): It is now recognized that understanding human metabolome and disease-elicited perturbations is crucial to our ability to effectively diagnose and treat human diseases. The Outreach core will overcome current barriers to integrating metabolomics approaches into mainstream basic and translational research by proper outreach training and educational efforts along with demonstration of high quality and breakthrough research.


application_id: 9144375
project_number: 4U24DK097215-04
project_title: INFOMRATICS CORE
administering_ic: NIDDK
award_notice_date: 2016-09-01
opportunity_number: RFA-RM-11-016
application_type: 4
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6291
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
budget_end_date: 2017-08-31
project_abstract:
PROJECT SUMMARY (See instructions): Recent advances in metabolomics technologies especially those that combine the complementarity of mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) enables rapid analysis of tens of thousands of peaks representing thousands of metabolites. Yet the need for metabolite detection identification quantitative analysis and interpretation for reconstructing metabolic networks still represents key barriers to the optimal use of this flood of high quality interrelated data. The interpretability is substantially enhanced when atom-resolved pathway tracing with the use of stable isotope tracers (e.g. stable isotope resolved metabolomics or SIRM) is part of the experimental design but this imposes additional demands on the informatics and statistical analyses. The major goals of the Informatics Core are to provide the necessary bioinformatics biostatistical and systems biochemical analyses of metabolomics data from the Analytical Core as a set of automated and interactive services for the Clients of the RCMRCCREAM. These informatics capabilities will have broad applications from straightforward profiling for e.g. biomarker discovery to elucidation of metabolic reprogramming in response to disease pathogenesis or therapeutic interventions. We will achieve these goals by coordinating our efforts with the Administrative Sample Analytical Cores and the Clients via the following Specific Aims: Specific Aim 1. Support all RCMRC-CREAM's data handling needs via a web-based informatics platform. Specific Aim 2. Provide tools for raw data analysis and quality control of MS and NMR analytical data. Specific Aim 3. Provide basic biostatistical analysis of refined data. Specific Aim 4. Expand metabolic pathway reconstruction flux modeling tools and data integration for mechanism-based analysis.

project_terms:
Basic Science;Biochemical;Biochemical Pathway;Bioinformatics;Biological Markers;Client;Collaborations;Communities;Computer Analysis;Data;Data Analyses;Data Quality;Data Set;Databases;Deposition;Detection;Development;Disease;Doctor of Philosophy;Documentation;Elements;Experimental Designs;Floods;Funding;Goals;Imagery;Informatics;Instruction;Linux;Machine Learning;Maintenance;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metadata;Methods;Modeling;NMR Spectroscopy;Online Systems;Pathogenesis;Pathway interactions;Procedures;Process;Production;Proteomics;Quality Control;Resources;Sampling;Series;Services;Statistical Data Interpretation;System;Technology;Testing;Therapeutic Intervention;Time;Tracer;Translational Research;base;biomarker discovery;case control;computerized tools;data integration;experience;functional group;human disease;innovation;interest;learning strategy;metabolomics;new therapeutic target;novel marker;outreach;reconstruction;research study;response;sound;specific biomarkers;stable isotope;success;tool;transcriptomics;ultra high resolution;virtual;web-accessible;web-based informatics;wiki

public_health_relevance:
RELEVANCE (See instructions): The unprecedented richness of metabolomics data and particularly SIRM data requires sophisticated informatics and statistical analysis to optimize the range and accuracy of metabolite determination for systems biochemical interpretation. The Informatics Core will provide such crucial developments and services for RCMRC-CREAM thereby facilitating large-scale understanding of disease pathogenesis for the discovery of novel biomarkers and therapeutic targets


application_id: 9144374
project_number: 4U24DK097215-04
project_title: ANALYTICAL CORE
administering_ic: NIDDK
award_notice_date: 2016-09-01
opportunity_number: RFA-RM-11-016
application_type: 4
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6290
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
budget_end_date: 2017-08-31
project_abstract:
PROJECT SUMMARY (See instructions): Metabolomics requires identification and quantification of a large number of metabolites of many different biochemical classes from diverse biological samples including cells culture media tissue and biofluids. Where biochemical mechanism is desired it is imperative that metabolomic approach be coupled with stable isotope (e.g. 0-13 or N-15) tracer labeling for robust metabolic network reconstruction which increase the number of analytes to be determined by orders of magnitude. The goals of the Analytical Core of the RCMRC-CREAM are to provide analytical services for a wide coverage of metabolites including isotopomer and isotopologue analysis as efficiently as possible. To achieve this we use of a number of analytical platforms including high-resolution mass spectrometry with or without liquid chromatography gas. chromatography MS high resolution and in vivo NMR. The Core will continue to develop and implement improved methods of data collection and reduction to increase the overall metabolite coverage and analytical throughput. These include 1) upgrade existing and install new high throughput instrumentation dedicated to metabolomics; 2) incorporate chemoselective tagging approach for improved metabolite coverage and assignment. The Core will continue to update its databases and refines its standard operating procedures. The Core will consult with users on experimental design analytical methods and additional technologies that may be needed to identify and quantify "unknowns" that appear to be biologically important. The Analytical Core thus works closely with the Sample and the Informatics Cores to achieve these goals by the following Specific Aims. SA1. To provide access and expertise across a wide range of NMR and MS technologies to the Clients. SA2. To provide data processing support to the Clients in coordination with the Informatics Core for statistical analysis metabolic pathway and biochemical mechanism analyses. SA3. To implement additional hardware capabilities for enhanced sample throughput. SA4. To develop and implement new methods to enhance metabolomic capabilities.

project_terms:
Age;Biochemical;Biochemical Pathway;Biological;Biomass;Cell Culture Techniques;Cells;Chromatography;Client;Collaborations;Communities;Complement;Consult;Consultations;Coupled;Culture Media;Data;Data Analyses;Data Collection;Databases;Detection;Development;Diagnosis;Experimental Designs;Fourier transform ion cyclotron resonance;Gas-Liquid Chromatography;Goals;Human Resources;Informatics;Infusion procedures;Instruction;Isotopes;Journals;Label;Letters;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Methods;Mole the mammal;NMR Spectroscopy;Pathway interactions;Procedures;Process;Protocols documentation;Research;Resolution;Resources;Running;Sampling;Services;Statistical Data Interpretation;Study Section;System;Techniques;Technology;Therapeutic Intervention;Tissues;Tracer;United States National Institutes of Health;Update;Work;analytical method;base;computerized data processing;coping;data acquisition;data reduction;human disease;imaging system;improved;in vivo;instrument;instrumentation;meetings;metabolomics;operation;outcome forecast;outreach;pre-clinical;reconstruction;research study;stable isotope;treatment response;wiki

public_health_relevance:
RELEVANCE (See instructions): The Analytical Core serves the vital function of large-scale metabolite analyses to promote metabolomic research in biomedical community. In particular stable isotope-resolved metabolomic data procured by the Core will facilitate systems biochemical understanding of human diseases for the purpose of diagnosis prognosis therapeutics and response to therapeutic interventions.


application_id: 9144373
project_number: 4U24DK097215-04
project_title: SAMPLE CORE
administering_ic: NIDDK
award_notice_date: 2016-09-01
opportunity_number: RFA-RM-11-016
application_type: 4
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6289
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
budget_end_date: 2017-08-31
project_abstract:
PROJECT SUMMARY (See instructions): Recent advances in metabolomics technologies have made possible simultaneous analysis of hundreds of metabolites by mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR). As the "gateway" to meaningful metabolomics analysis sample processing has critical issues not widely addressed in metabolomics studies such as 1) sample integrity; 2) reproducibility and range of metabolite recovery; 3) tools for extending metabolite coverage enabling high throughput & robust metabolite analysis and facilitating de novo structure elucidation of unknowns. Our Center (CREAM) has developed test-proven protocols for processing a wide selection of biospecimens with the aim of maintaining biochemical integrity and reproducible recovery of metabolites in large-scale. These protocols have been applied to many stable isotope-resolved metabolomics (SIRM) studies to reveal key reprogrammed metabolic events in human diseases. We have also shown the utility of chemoselective (CS) tagging in enriching low-level labile and volatile carbonyl metabolites for high throughput analysis by direct infusion Fourier transform-ion cyclotron resonance-mass spectrometry (FTICR-MS). Our protocols can be further enhanced in terms of throughput and coverage of previously inaccessible metabolites. We will support sample processing activities for the U24 RCMRC with three Specific Aims: SA1. To process a wide range of biospecimens researched by Clients. These range from cells tissues media biofluids to animals. We have provided this service since 2007 and will greatly expand the operation with added resources including sample preparation for in vivo NMR. SA2. To implement microfluidics-based subcellular/cell separation and metabolite extraction. We will test and refine microfiuidic platforms for separation of subcellular particles cell sorting and metabolite extraction to offer more efficient speedy and high throughput sample processing than existing methods. SA3. To implement profiling and multiplexed quantification of metabolites and their labeling patterns by FTICR- MS in a wide range of biological systems using chemoselective (CS) tagging of functional groups (FG). We will implement the CS capture approach (funded by a separate Common Funds R01) for enriching previously inaccessible metabolites with carbonyl amino thiol and diol FG for robust identification and multiplexed analysis by FTICR-MS and NMR.

project_terms:
A549;Address;Aldehydes;Ammonium;Animals;Aspirate substance;Base Pairing;Biochemical;CD3 Antigens;Cell Extracts;Cell Separation;Cells;Chromatography;Client;Computer software;Consult;Coupled;Crude Extracts;Cultured Cells;Detection;Development;Diagnosis;Disease;Event;Factor V;Fourier Transform;Fourier transform ion cyclotron resonance;Fractionation;Funding;Glycols;Goals;Human Resources;Informatics;Infusion procedures;Instruction;Internet;Ions;Isomerism;Isotopes;Ketones;Label;Leukocytes;Link;Lipids;Lymphocyte;Magnetic Resonance Imaging;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Methods;Microfluidics;Molecular;Mus;NMR Spectroscopy;Nipples;Nucleotides;Parents;Pattern;Phase;Plasma;Population;Preparation;Process;Proteins;Protocols documentation;Reaction;Recovery;Reproducibility;Research;Resources;Rodent;Sample Size;Sampling;Scheme;Secure;Services;Solvents;Specimen;Speed;Structure;Subcellular Fractions;Sulfhydryl Compounds;Surface;Technology;Testing;Tissues;Urine;Weight;Work;adduct;base;biological systems;design;exosome;functional group;granulocyte;high throughput analysis;human disease;human tissue;improved;in vivo;instrument;macrophage;meetings;metabolomics;microvesicles;nano-electrospray;operation;particle;prevent;sound;stable isotope;tandem mass spectrometry;tool;ultra high resolution

public_health_relevance:
RELEVANCE (See instructions): Sound sample processing is a prerequisite to metabolomic studies which have tremendous potential for promoting large-scale functional understanding of human diseases. Such understanding will ultimately enhance our ability to prevent diagnose and treat intractable diseases such as cancer. The proposed sample processing plan should help expand and facilitate meaningful metabolomic analysis and interpretation.


application_id: 9144371
project_number: 4U24DK097215-04
project_title: ADMINISTRATIVE
administering_ic: NIDDK
award_notice_date: 2016-09-01
opportunity_number: RFA-RM-11-016
application_type: 4
activity_code: U24
ic: DK
serial_number: 097215
study_section: Special Emphasis Panel[ZRG1-BST-F]
subproject_number: 6288
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
budget_end_date: 2017-08-31
project_abstract:
PROJECT SUMMARY (See instructions): In this NIH Metabolomics Common Fund center proposal for a Regional Comprehensive Metabolomics Resource Core (RCMRC) "Resource Center for Stable Isotope-Resolved Metabolomics" we aim to continue and expand on our current successful Center for Regulatory and Environmental Analytical Metabolomics (CREAM). The role of the Administrative Core is to provide overall administration budgetary management oversee analytical services (e.g. sample tracking analysis status and billing) and oversight for the other 4 Cores' operations. The Core PI list comprises the current directorship of CREAM ensuring smooth personnel and management transition to the NIH RCMRC version of CREAM. This section describes both current and expanded operations with regards to administration of the proposed center and to ensure complete operational and policy harmony with the Common Funds goals. The Administrative Core will be responsible for all aspects of service scheduling and recharges financial management of the annually awarded Pilot and Feasibility projects maintaining all budgets and cost reporting of Cores organizing outreach workshops and symposia as well as coordinating annual reports regular meetings among the project personnel and all interactions with other RCMRC's program wide Executive Committee the Data Repository and Coordinating Center (DRCC) NIH Project Scientist & staff and any other appropriate entities. The specific aims of the Administrative Core are as follows: SA1. Establish the RCMRC-CREAM and evolve a tiered set of services for users. SA2. Coordinate with Clients and manage sample analytical and data workflow across all Cores. SA3. Provide administrative and budgetary oversight for the RCMRC-CREAM and across all Cores. SA4. Coordinate external efforts with other RCMRC facilities the Executive Committee NIH Project Scientists and staff NIH Common Fund programs and any other appropriate entities. SA5. Plan and implement transition to self-sustaining operations.

project_terms:
Annual Reports;Award;Biochemical;Budgets;Charge;Client;Clinical;Complex;Consultations;Contracts;Core Facility;Core Grant;Cost Effectiveness Analysis;Data;Data Analyses;Data Repository and Coordinating Center;Development;Diagnostic;Distance Learning;Doctor of Philosophy;Educational workshop;Ensure;Fees;Funding;Goals;Grant;Health;Health Services Research;Human Resources;Income;Informatics;Instruction;Legal patent;Letters;Occupational activity of managing finances;Personnel Management;Pharmaceutical Preparations;Phase;Policies;Reporting;Resources;Role;Sampling;Schedule;Scientist;Services;Source;Stream;Structure;System;Technology;Training;Translating;Travel;United States National Institutes of Health;base;commercialization;cost;human disease;meetings;metabolomics;metabolomics resource;new therapeutic target;novel marker;operation;outreach;programs;research study;stable isotope;symposium;web interface;web site

public_health_relevance:
RELEVANCE (See instructions): The Administrative Core is necessary to operate this complex metabolomics center for accelerating systems biochemical understanding of human diseases from which novel biomarkers and therapeutic targets for many critical health issues can be uncovered and translated into clinical development.


application_id: 9144370
project_number: 4U24DK097215-04
project_title: Resource Center for Stable Isotope-Resolved Metabolomics
administering_ic: NIDDK
award_notice_date: 2016-09-01
opportunity_number: RFA-RM-11-016
application_type: 4
activity_code: U24
ic: DK
serial_number: 097215
program_official: MARUVADA, PADMA
project_start_date: 2013-09-11
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-BST-F(50)R]
contact_pi_person_id: 8656419
contact_pi: HIGASHI, RICHARD M
other_pis: FAN, TERESA WHEI-MEI;LANE, ANDREW N.;MOSELEY, HUNTER NATHANIEL
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: The human metabolome represents the functional display of the human genome and proteome. The regulation of its homeostasis is highly sensitive to both intrinsic and external factors the perturbation of which can lead to disease development. Advances in mass spectrometry (MS) NMR informatics and sample processing have made possible large-scale interrogation of the human metabolome ("metabolomics") and is being increasingly applied to a variety of diseases such as cancer diabetes neurodegenerative and cardiovascular disorders for diagnosis and therapeutic purposes. The existing Center for Regulatory and Environmental Analytical Metabolomics (CREAM) conducts training and provides advice and full analytical resources from sample processing MS and NMR instrumentation to informatics which match with the major goals of the Common Fund. Moreover CREAM is now in its 6th year of self- sufficiency through client fees and conducts translational clinical research both of which are critical fifth-year exit goals of the Common Fund. Building on this solid foundation with added resources the proposed Common Fund Regional Comprehensive Metabolomics Resource Core (RCMRC) at the University of Louisville will greatly expand CREAM's capabilities in sample processing analytical/informatics developments and services and outreach efforts under the leadership of the PD and Pis who collectively have more than 95 years of experience in metabolomics. The Overall Goals of the RCMRC-CREAM are to facilitate and promote metabolomics research with an emphasis on stable isotope tracing for pathway elucidation in studies ranging from laboratory bench cell cultures model animals to human subjects and to provide the state-of-art analytical and informatics resources education and training for the biomedical research community. These goals will be achieved via the following specific aims: SA1: To administer comprehensive Metabolomics resources for bench to bedside research; SA2: To develop and implement integrated Metabolomics platforms to enhance performance sample & information throughput and scientific relevance; SA3: To provide outreach and education of the wider community in Metabolomics approaches.

project_terms:
Address;Adoption;Algorithms;Animal Model;Animals;Arts;Award;Biochemical Pathway;Biomedical Research;Cardiovascular Diagnostic Techniques;Cell Culture Techniques;Cells;Client;Clinical Research;Communities;Consultations;Data;Data Analyses;Detection;Development;Devices;Diabetes Mellitus;Disease;Distance Learning;Education and Outreach;Educational workshop;Ensure;Experimental Designs;Fees;Foundations;Fractionation;Freezing;Fresh Tissue;Funding;Goals;Grant;Homeostasis;Human;Human Genome;Informatics;Infusion procedures;Instruction;International;Internet;Joints;Laboratories;Laboratory Research;Lead;Leadership;Learning;Malignant Neoplasms;Mass Spectrum Analysis;Metabolism;Methodology;Microfluidics;Modeling;Neurodegenerative Disorders;Paper;Pathway interactions;Performance;Preparation;Procedures;Process;Proteome;Publications;Publishing;Qualifying;Regulation;Research;Research Personnel;Resected;Resource Informatics;Resources;Sampling;Services;Slice;Solid;Structure;System;Techniques;Technology;Therapeutic;Tissues;Tracer;Training;Training and Education;Transplantation;United States National Institutes of Health;Universities;Work;Xenograft procedure;base;bench to bedside;computerized data processing;cost;data acquisition;design;disease diagnosis;experience;handbook;human subject;instrumentation;meetings;metabolome;metabolomics;metabolomics resource;network models;new therapeutic target;operation;outreach;prevent;programs;software development;stable isotope;symposium;tandem mass spectrometry;therapy outcome;ultra high resolution

public_health_relevance:
RELEVANCE (See instructions): It is increasingly recognized that perturbations to the human metabolome is crucial to the development and therapeutic outcome of many major intractable diseases. The integrated metabolomic technologies and outreach efforts offered by the proposed RCMRC-CREAM will help promote adoption of metabolomic approaches in basic and translational biomedical research thereby accelerating our ability to prevent and diagnose diseases as well as to uncover novel therapeutic targets.


application_id: 9144362
project_number: 5R01DA040637-02
project_title: NK-1 Receptor Antagonism: A Role in Opioid Use Disorders
administering_ic: NIDA
award_notice_date: 2016-07-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 040637
program_official: ANDERSON, ANN
project_start_date: 2015-09-15
project_end_date: 2019-07-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe United States has experienced a dramatic rise in non-medical use of prescription opioids leading toincreased demand for effective treatments for opioid use disorders. Recent evidence suggests thatinactivation of Substance P receptors either through genetic deletion or pharmacological blockadesignificantly attenuates the rewarding effects of opioids in an array of laboratory models and suppressesexpression of opioid withdrawal signs. Neurokinin 1 (NK1) receptors for Substance P may offer an attractivenovel target for a non-addictive treatment approach. This project proposes two inpatient laboratory studies thatwill enroll individuals with opioid use disorders. These studies will provide the proof-of-concept evidence ofNK1 receptor system involvement in mediating the response to opioids as related to abuse potentialreinforcing efficacy and opioid withdrawal in humans. These randomized placebo-controlled double-blindinpatient studies will both employ a within-subject design and enroll otherwise healthy volunteers with currentnon-medical opioid use with (Exp. 1) and without (Exp. 2) physical dependence on opioids. Both studies willcapitalize on the availability of a novel brain-penetrant NK-1 antagonist VLY-686 for which requisite clinicalsafety data are available and the sponsor (Vanda) has agreed to provide support and clinical drug supply.Experiment 1 will examine the effects of maintenance on VLY-686 (100 mg/day) versus placebo on opioidresponses with oxycodone on an array of physiological subjective and behavioral outcomes (self-administration and experimental pain). Experiment 2 will enroll opioid dependent volunteers who will bemaintained on oxycodone throughout the study using an established procedure. This study will examine theeffects of maintenance on VLY-686 (0 and 100 mg/day) for its ability to attenuate expression of opioidwithdrawal signs and symptoms and to attenuate the response to opioid agonist challenge. These studies willprovide preliminary safety and key pharmacodynamic data in individuals with opioid use disorders both withand without physical dependence and provide proof-of- concept data for the NK-1 receptor system role inmediating critical factors in opioid use disorders.

project_terms:
Accounting;Acute;Admission activity;Agonist;Anxiety;Attenuated;Behavior;Brain;Buprenorphine;CD94 Antigen;Clinical;Clinical Trials;Cocaine;Crossover Design;Data;Dependence;Dose;Double-Blind Method;Enrollment;Equilibrium;Formulation;Genetic;Heroin;Heroin Abuse;Human;Individual;Inpatients;Intravenous;Laboratories;Laboratory Study;Maintenance;Measures;Mediating;Mediation;Methadone;Modeling;Morbidity - disease rate;Naltrexone;Narcotic Antagonists;Nociception;Opiate Addiction;Opioid;Opioid Receptor;Oral;Outcome;Oxycodone;Pain;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacotherapy;Phase;Physical Dependence;Physiological;Placebo Control;Placebos;Procedures;Randomized;Receptors Opioid mu;Research;Rewards;Role;Safety;Self Administration;Signs and Symptoms;Specific qualifier value;Stress;Substance P;Substance P Receptor;System;Testing;United States;base;behavioral outcome;design;effective therapy;experience;healthy volunteer;improved;laboratory experiment;meetings;mortality;novel;opioid use;opioid use disorder;opioid withdrawal;overdose death;prescription opioid;research study;response;volunteer

public_health_relevance:
PROJECT NARRATIVEThis research will provide important information regarding the potential utility of drugs which act through the NKreceptor system for a role in the treatment of opioid use disorders.


application_id: 9144295
project_number: 5R01AA023190-02
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2016-08-03
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 023190
program_official: WANG, JOE
project_start_date: 2015-09-15
project_end_date: 2020-08-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
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_terms:
Acute;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Bacterial Translocation;Butyric Acids;Carbohydrates;Cell Line;Chronic;Cirrhosis;Data;Development;Disease Progression;Effectiveness;Endotoxins;Enzymes;Epithelial;Epithelial Cells;Experimental Models;Fatty Liver;Fibrosis;Functional disorder;Goals;Goblet Cells;Health;Heating;Hepatic;Histology;Histones;Human;Hypoxia Inducible Factor;Immune response;In Vitro;Inflammation;Injury;Intervention;Intestinal Diseases;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Life;Liver;Mediating;Metagenomics;Morbidity - disease rate;Mucous body substance;Mus;Oral Administration;Outcome;Patients;Permeability;Pilot Projects;Plasma;Play;Preparation;Prevention;Prevention therapy;Probiotics;Process;Production;Proteins;Recombinants;Regulation;Reporting;Role;Sampling;Signal Transduction;Steatohepatitis;Supplementation;Testing;Tight Junctions;Volatile Fatty Acids;Work;alcohol exposure;antimicrobial peptide;bacterial metabolism;base;cathelicidin;cathelicidin antimicrobial peptide;comparative efficacy;compare effectiveness;feeding;gastrointestinal epithelium;gut microbiota;improved;in vivo;intestinal homeostasis;lipid metabolism;liver inflammation;liver injury;metabolomics;mortality;mouse model;novel therapeutic intervention;occludin;prevent;protective effect;repaired;transcription factor;trefoil factor


application_id: 9144184
project_number: 5R01AR068313-02
project_title: MYD88 Signaling in Mammalian Myoblast Fusion
administering_ic: NIAMS
award_notice_date: 2016-08-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 068313
program_official: BOYCE, AMANDA T
project_start_date: 2015-09-14
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-V(03)S]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by PI):  Myoblast fusion is a critical event that is required not only for the development of skeletal muscle during embryogenesis but also for the regeneration of adult myofibers upon injury and for load-induced skeletal muscle hypertrophy. Augmenting the natural process of muscle cell fusion in existing or introduced myogenic cells has enormous therapeutic potential to treat degenerative muscle diseases. However the mechanisms of myoblast fusion in vertebrates remain less understood. Accumulating evidence suggests that myoblast fusion in mammalian system involves the activation of specific cell signaling pathways such as MAPK non-canonical NF-B canonical Wnt signaling. However the upstream signaling mechanisms leading to their activation and how the activation of these pathways promotes myoblast fusion during myogenesis remain poorly understood. Our preliminary studies have identified that myeloid differentiation primary response gene 88 (Myd88) is a critical regulator of myoblast fusion both in vitro and in vivo. Our results show that the levels of Myd88 are increased during myogenesis. Genetic ablation of Myd88 impairs myoblast fusion whereas overexpression of Myd88 enhances the formation of myotubes in cultured myoblasts. Furthermore we have obtained initial evidence that Myd88 regulates the activation of specific profusion signaling pathways during myogenesis. Based on our preliminary studies we have proposed to establish the role and delineate the signaling and molecular mechanisms by which Myd88 mediates skeletal muscle formation in vitro and in vivo. Our working hypotheses are: (I) Myd88 promotes myoblast fusion in multiple conditions through augmenting the gene expression of specific profusion molecules; (II) Myd88 coordinates the activation of canonical Wnt and non-canonical NF-B signaling to promote myoblast fusion during myogenesis; (III) Both transcriptional and post-transcriptional mechanisms regulate the levels of Myd88 in differentiating myoblasts. We will test these hypotheses by addressing the following three specific aims. Aim I: Establish the role and investigate molecular mechanisms by which Myd88 mediates myoblast fusion; Aim II: Investigate the signaling networks through which Myd88 promotes myoblast fusion; and Aim III: Investigate the mechanisms by which levels of Myd88 are increased during myogenesis. Successful completion of this project will provide critical insights into the mechanisms of myoblast fusion and will lead to the identification of novel drug targets for treatment of muscle disorders.

project_terms:
3' Untranslated Regions;Ablation;Adaptor Signaling Protein;Address;Adult;Age;Attenuated;Binding;Bioinformatics;Caliber;Cell fusion;Cells;Consensus;DNA Sequence;Defect;Development;Drosophila genus;Drosophila melanogaster;Embryonic Development;Event;Family;Gene Expression;Genes;Genetic;Goals;Growth;Health;Hypertrophy;Immune response;Impairment;In Vitro;Injury;Interleukin-1;Knock-out;Knockout Mice;Knowledge;Lead;MAP Kinase Gene;Mediating;MicroRNAs;Molecular;Molecular and Cellular Biology;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscular Atrophy;MyD88 protein;Myelogenous;Myoblasts;Myogenic Regulatory Factors;Myogenin;Myopathy;Natural regeneration;Neonatal;Pathway interactions;Pattern;Play;Process;Promoter Regions;Research;Role;Seminal;Signal Pathway;Signal Transduction;Skeletal Muscle;Small Interfering RNA;System;TLR3 gene;Testing;Therapeutic;Toll-like receptors;Transcript;Vertebrates;Wild Type Mouse;Work;base;improved;in vivo;insight;interleukin-18 receptor;knock-down;mouse model;muscle form;muscle hypertrophy;myogenesis;new therapeutic target;novel therapeutics;overexpression;promoter;receptor;repaired;research study;response;response to injury;skeletal muscle growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Myoblast fusion is a fundamental process that is crucial for the repair and growth of skeletal muscle upon injury. Understanding of the mechanisms of myoblast fusion has enormous potential for the development of novel therapeutics aimed at treating various genetic and acquired degenerative muscle disorders. The primary goal of the proposed research is to understand the signaling mechanisms of myoblast fusion and thereby providing fundamental knowledge required to enhance the therapeutic potential of myogenic cells to treat muscle wasting in various muscle disorders.


application_id: 9143379
project_number: 3R01HL122581-02S1
project_title: Cardiac pathophysiology of histidyl dipeptides
administering_ic: NHLBI
award_notice_date: 2015-09-15
opportunity_number: PA-11-260
application_type: 3
activity_code: R01
ic: HL
serial_number: 122581
suffix: S1
program_official: ADHIKARI, BISHOW B
project_start_date: 2014-06-01
project_end_date: 2016-10-31
study_section: Special Emphasis Panel[ZRG1-CVRS-Q(02)]
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
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): Myocardial ischemia and reperfusion (I/R) results in increased glycolysis changes in internal pH inflammation and elevated levels of reactive oxygen species (ROS) that contribute to I/R injury and its clinical outcomes. However a common biochemical feature of myocardial I/R is increased formation of reactive carbonyls which are generated in high abundance in the ischemic heart and their concentration is further increased upon reperfusion. Previous work has shown that increased enzymatic detoxification of these carbonyls decreases myocardial I/R injury. Nevertheless it remains unclear which carbonyls are generated during I/R and how they contribute to tissue injury. As a result the general contribution of carbonyls to myocardial I/R injury remains unclear and no specific carbonyl quenching interventions have been developed to limit I/R injury. The current project is designed to understand the role of endogenous histidyl dipeptides synthesized by the heart in preventing carbonyl toxicity during I/R. Histidyl dipeptides such as carnosine and anserine react avidly with structurally-diverse carbonyls we propose that these peptides represent a general carbonyl detoxification pathway. To test this hypothesis we will elucidate the role of histidyl dipeptides in myocardial I/R injury. Using both in situ and ex vivo models of myocardial I/R injury we will examine whether increasing myocardial levels of histidyl dipeptides either by overexpression of histidyl dipeptide synthase (HDS) in the heart or exogenous delivery will diminish tissue injury. To assess whether the cardioprotective effects of these peptides are due to increased carbonyl detoxification we will determine whether increased myocardial levels of these peptides are associated with increased carbonyl removal and excretion Our studies will also delineate the mechanism by which histidyl dipeptides affect myocardial I/R injury. Specifically we will examine whether histidyl dipeptides generated during I/R inhibit the proteasome and induce ER stress and that histidyl dipeptides decrease myocardial damage by preventing protein carbonylation and thereby attenuating proteasomal dysfunction and ER stress. Finally we will examine the relative efficacy of endogenous and synthetic histidyl dipeptides against myocardial I/R injury. For this we will compare the relative efficacy of differet endogenous histidyl dipeptides and their synthetic analogs against carbonyl toxicity and investigate whether enhanced carbonyl quenching properties of these peptides result in greater protection against myocardial I/R injury. Completion of this project will lead to the identificatio and assessment of a novel antioxidant system present in the heart and how components of this system (histidyl peptides HDS) prevent critical features of ischemia injury (carbonyl toxicity). We expect that these studies will lead to the identification of specific carbonyls that mediate I/Rinjury and how they contribute to myocardial damage. These findings might lead to the development of robust and effective interventions that could be used clinically to limit ischemic and oxidative injury in the heart as well as in other tissues.

project_terms:
Acrolein;Advanced Glycosylation End Products;Aerobic Exercise;Affect;Aldehyde Reductase;Amino Acids;Anserine;Antioxidants;Attenuated;Biochemical;Brain;Buffers;Cardiac;Cardiac Myocytes;Carnosine;Cause of Death;Clinical;Development;Dipeptides;Drug Metabolic Detoxication;Enzymes;Excision;Excretory function;Fructose;Functional disorder;Glutathione S-Transferase;Glyceraldehyde;Glycolysis;Health;Heart;Heart Injuries;In Situ;Inflammation;Inflammatory;Injury;Intervention;Ischemia;Lead;Link;Lipids;Mediating;Mediator of activation protein;Membrane Lipids;Metabolic;Metals;Modeling;Mus;Myocardial;Myocardial Ischemia;Myocardial Reperfusion;Outcome;Pathway interactions;Peptides;Perfusion;Physiological;Process;Property;Proteins;Pyruvaldehyde;Reactive Oxygen Species;Recovery;Relative (related person);Reperfusion Injury;Reperfusion Therapy;Research;Role;Skeletal muscle structure;Stress;System;Testing;Therapeutic;Tissues;Toxic effect;Work;adduct;aldehyde dehydrogenases;analog;base;chelation;crosslink;design;effective intervention;effective therapy;link protein;multicatalytic endopeptidase complex;myocardial damage;myocardial infarct sizing;novel;overexpression;oxidation;prevent;protein aggregation;sugar

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Myocardial ischemic heart disease remains leading causes of death worldwide; no effective therapy is available to attenuate ischemic injury. Histidyl dipeptides are endogenously present defense molecules that can modulate different mediators of ischemic injury and thus can act as therapeutics to prevent or treat ischemic heart injury.


application_id: 9141450
project_number: 2R44HL129490-02A1
project_title: Development of Percutaneous DLC for Total Cavo-pulmonary Assistance
administering_ic: NHLBI
award_notice_date: 2016-08-11
opportunity_number: PA-15-269
application_type: 2
activity_code: R44
ic: HL
serial_number: 129490
suffix: A1
program_official: LEE, ALBERT
project_start_date: 2016-08-15
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1 CVRS-C (10)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Fontan procedure or total cavopulmonary connection (TCPC) is a standard palliative surgery for patients with complex single ventricle congenital heart anomalies. TCPC connects the inferior and superior vena cava (IVC and SVC) directly to the right pulmonary artery bypassing the heart. The single ventricle is then reserved for pumping oxygenated blood to the systemic circulation. The Fontan procedure has benefited thousands of patients but the Fontan circulation fails years later with relatively high mortality.
The failing Fontan circulation causes end organ dysfunction due to venous blood congestion from elevated central venous pressure and low arterial blood perfusion from low cardiac output. The only effective option for the failing Fontan patient is heart transplant but most of these patients are too sick to be transplant candidates. Cavopulmonary assist (CPA) is needed to pump venous blood from SVC/IVC through the Fontan connection to reverse failing Fontan pathophysiology. Our ultimate goal is to create a convenient and secure connection between the TCPC and the blood pump establishing an ambulatory percutaneous CPA system. Our enabling technology is one of the world's most complex double lumen cannula (DLC). Through only one percutaneous venous cannulation this DLC can easily connect the TCPC to a commercial blood pump without major surgery. This CPA system will bridge the failing Fontan patient to: 1) heart transplant 2) recovery and/or 3) further reconstructive heart surgery. In ou phase I study the working prototype demonstrated up to 4.5 l/min blood flow in our sheep model and completely reversed failing Fontan circulation (n=5) achieving total CPA. In this Phase II SBIR we will optimize the design based on our Phase I results and fabricate a final commercial quality CPA DLC prototype for bench test and 5 day survival in vivo studies. Specific Aim 1: To design and fabricate a percutaneous DLC for ambulatory CPA application. Two thin membrane umbrellas are designed on the DLC to prevent infusion flow recirculation ensuring efficient and reliable performance. These umbrellas do not block the blood flow from SVC and IVC to pulmonary artery guaranteeing safety if the CPA system malfunctions. Two infusion openings guide separate blood flow to each umbrella eliminating blood stagnancy and associated thrombosis formation. Particle image velocimetry (PIV) validated CFD will be used to optimize the design for maximum performance and minimal thrombotic potential. Specific Aim 2: To test the CPA DLC prototype in a simulated mock loop bench test. Bench testing will include performance/reliability evaluation one month durability test and PIV flow study. Specific Aim 3: To test the CPA DLC prototype in our TCPC sheep model. Short term in vivo studies (N=5) will test CPA DLC feasibility performance and reliability. Long term 5 day in vivo studies (N=8) will test performance reliability durability and biocompatibility. Although the CPA DLC market is small the impact on the patients that need CPA is significant.

project_terms:
Anastomosis - action;Animals;Biotechnology;Blood;Blood Circulation;Blood flow;Cannulas;Cannulations;Carbon Dioxide;Cardiac;Cardiac Surgery procedures;Cardiopulmonary Bypass;Cattle;Central venous pressure;Childhood;Clinical;Common Ventricle;Complex;Deterioration;Development;Devices;Drainage procedure;Engineering;Ensure;Evaluation;Excision;Fontan Procedure;Functional disorder;Future;Glycerol;Goals;Heart;Heart Transplantation;Hemolysis;Hypoxia;Image;In Vitro;Inferior;Infusion procedures;Kentucky;Laboratory Animal Production and Facilities;Life;Liquid substance;Low Cardiac Output;Lung;Marketing;Membrane;Modeling;Operative Surgical Procedures;Organ;Palliative Surgery;Patients;Performance;Phase;Polyurethanes;Procedures;Publications;Pulmonary Circulation;Pulmonary Vascular Resistance;Pulmonary artery structure;Pump;Reconstructive Surgical Procedures;Recovery;Research Support;Safety;Scientist;Secure;Sheep;Small Business Innovation Research Grant;Superior vena cava structure;Surgeon;System;Technology;Testing;Thrombosis;Transplantation;Universities;Validation;Velocimetries;Venous;Venous system;Ventricular;Work;artificial lung;base;biomaterial compatibility;blood perfusion;blood pump;commercialization;congenital heart disorder;design;experience;in vivo;mortality;particle;performance tests;phase 1 study;prevent;prototype;public health relevance;research and development;respiratory;simulation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: We are proposing to develop a percutaneous cavo-pulmonary assist system to bridge the patients with failing Fontan circulation for recovery reconstructive surgery and heart transplantation.


application_id: 9139953
project_number: 5UH2DA041115-02
project_title: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2016-06-09
opportunity_number: RFA-DA-15-017
application_type: 5
activity_code: UH2
ic: DA
serial_number: 041115
program_official: KLINE, RICHARD
project_start_date: 2015-09-15
project_end_date: 2017-07-31
study_section: ZDA1-JXR-D(12)R
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
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_terms:
Affect;Albumins;Animal Model;Animals;Antibodies;Binding;Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cell Line;Clinical;Clinical Data;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Communities;Computer Simulation;Data;Development;Dose;Drug Kinetics;Enzymes;Evaluation;FDA approved;Family;Formulation;Half-Life;Health;Housing;Human;Hydrolase;Hydrolysis;Immunoglobulins;In Vitro;Injection of therapeutic agent;Investigation;Investigational Drugs;Legal patent;Medical;Metabolic;Metabolism;Monkeys;Monoclonal Antibodies;Neuraxis;Neurons;Pathway interactions;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology and Toxicology;Plasma;Preclinical Testing;Process;Production;Proteins;Public Health;Rattus;Route;Self Administration;Self-Administered;Serum Albumin;Technology;Testing;Therapeutic;Toxic effect;Treatment Protocols;Vaccines;Work;base;cell bank;cocaine overdose;design;drug of abuse;enzyme therapy;expression cloning;immunogenicity;improved;in vivo;innovation;manufacturing process;manufacturing process development;mutant;novel;novel therapeutics;small molecule;social;success;treatment strategy


application_id: 9138899
project_number: 1R41CA199956-01A1
project_title: Developing a novel adjuvant system for therapeutic vaccines against lung cancer
administering_ic: NCI
award_notice_date: 2016-05-26
opportunity_number: PA-15-270
application_type: 1
activity_code: R41
ic: CA
serial_number: 199956
suffix: A1
program_official: KURTZ, ANDREW J
project_start_date: 2016-06-01
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1 OTC-H (13)]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 079603469
primary_uei: LNESEBSKBHK8
duns_number: 079603469
uei: LNESEBSKBHK8
fips: US
organization_id: 10037836
organization_name: FASCURE THERAPEUTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Therapeutics is focused on the development of adjuvant systems with desired immune activities for targeted indications. The Company's immune stimulatory adjuvant platform builds on combinatorial use of immune agonists with distinct immune targets and mechanisms of action for the generation of therapeutic immune responses. Critical to this platform technology is the use of novel forms of tumor necrosis factor ligand (TNFL) costimulatory family agents that directly modulate innate adaptive and regulatory immunity and cross- talk with pattern recognition receptors for sustained immune effector responses. The Company's lead adjuvant system ISAS-01 constitutes a novel form of 4-1BBL/streptavidin chimeric molecule formulated with monophosphoryl lipid A (MPL) as an agonist of toll-like receptor 4 (TLR4). The choice of 4-1BBL is based on the pleiotropic effects of
4-1BB costimulatory signaling in cells of innate (NK cells NKT cells macrophages neutrophils and DCs) adaptive (CD4+ and CD8+ T cells) and regulatory (CD4+CD25+FoxP3+ T regulatory (Treg) cells) immunity and the critical role of coordinated responses of these cell populations in
the eradication of cancer and control of recurrences. MPL complements the immune activities of 4-1BBL by upregulating the 4-1BB receptor and ligand on antigen presenting cells and 4-1BBL physically interacts with TLRs for sustained innate immune responses. Therefore the combined use of these two agents has the potential to generate robust immune effector responses and overcome immune evasion mechanisms culminating in the eradication of cancer and control of recurrences. In support of this we have recently shown that ISAS-01 as the adjuvant component of TAA-based protein vaccines was effective in eradicating tumors in various preclinical models. A mucin 1 (MUC1) TAA-based vaccine tecemotide against non-small cell lung cancer being developed by Merck KGaA has failed to meet its primary endpoint of improving overall patient survival in a phase III clinical study. Factors contributing to the vaccie inefficacy are unknown. We hypothesize that the lack of a potent adjuvant system able to generate a robust immune effector response as part of vaccine formulation as well as the need to overcome tumor immune evasion mechanisms may have contributed to the vaccine failure. Therefore the main objective of this Phase I STTR application is to test if the ISAS-01 adjuvant system generates robust cellular immune responses against MUC1 TAA and improves therapeutic efficacy of the tecemotide-based vaccine formulation using MUC1 transgenic (TG) mice as a stringent preclinical tumor model. Three specific Aims are designed to i) establish a reformulated vaccine that generate robust Th1 responses to MUC1 TAA ii) assess the therapeutic efficacy of the vaccine in eradicating lung carcinoma in MUC1 TG mice and iii) investigate immune responses associated with vaccine efficacy/failure. A better efficacy for the reformulated vaccine over the tecemotide-based vaccine formulation will indicate the need for further development of this vaccine and potential for entry into phase I clinical trials for lung cancer.

project_terms:
Adjuvant;Agonist;Antigen-Presenting Cells;Antigens;Benchmarking;CD28 gene;CD8B1 gene;Cancer Control;Cancer Vaccines;Cells;Cessation of life;Clinical Research;Clinical Trials;Communication;Complement;Dendritic Cells;Development;Effector Cell;Extracellular Domain;FDA approved;Face;Failure;Family;Family member;Formulation;Generations;Goals;Human;IL2RA gene;Immune;Immune Targeting;Immune response;Immunity;Immunologic Adjuvants;Inflammatory Response;Investigational New Drug Application;Lead;Ligands;Lipid A;Malignant Neoplasms;Malignant neoplasm of lung;Memory;Modeling;Mucin 1 protein;Natural Immunity;Natural Killer Cells;Nature;Non-Small-Cell Lung Carcinoma;Pathway interactions;Patients;Pattern recognition receptor;Peptides;Phase;Phase I Clinical Trials;Phase III Clinical Trials;Population;Pre-Clinical Model;Preparation;Proteins;Public Health;Publishing;Recurrence;Regulatory T-Lymphocyte;Research;Role;Signal Transduction;Small Business Technology Transfer Research;Specificity;Streptavidin;System;T cell anergy;T cell response;T-Cell Activation;T-Lymphocyte;TLR4 gene;TNF gene;Technology;Testing;Therapeutic;Toxic effect;Toxicology;Transgenic Mice;Treatment Efficacy;Tumor Necrosis Factor Receptor;United States;Vaccine Antigen;Vaccines;base;combinatorial;conventional therapy;cross immunity;design;improved;lung Carcinoma;macrophage;meetings;mouse model;neutrophil;novel;pleiotropism;pre-clinical;public health relevance;receptor;response;standard care;therapeutic development;therapeutic vaccine;tumor;tumor eradication;vaccine development;vaccine efficacy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cancer is a major public health problem in the United States and many other parts of the world. One in 4 deaths in the United States is due to cancer. Standard treatments are not effective and often relatively toxic. Research suggests that vaccines have the potential to treat cancer without the toxicity associated with standard treatments. FasCure Therapeutics LLC is developing a novel immune adjuvant system ISAS-01 that has shown therapeutic efficacy as a component of vaccines in several preclinical mouse models. The overall goal of this project is to test if ISAS-01 improves the therapeutic efficacy of
a lead vaccine formulation against lung cancer that has failed in a phase III clinical trial.


application_id: 9138191
project_number: 3R01AG047297-01A1S1
project_title: Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
administering_ic: NIA
award_notice_date: 2015-09-25
opportunity_number: PA-15-293
application_type: 3
activity_code: R01
ic: AG
serial_number: 047297
suffix: A1S1
program_official: ZIEMAN, SUSAN
project_start_date: 2015-02-01
project_end_date: 2020-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: FOLZ, RODNEY J
congressional_district: 03
department: NONE
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 NURSING
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Asthma is a common chronic inflammatory disorder of the distal airways characterized by recurring symptoms airway inflammation and reversible airflow constriction. It is considered a collection of various phenotypes (characteristics) instead
of a single disease. Currently there is no comprehensive phenotyping specific to older adults with asthma that considers multiple factors relevant to this population. Divergent asthma phenotypes and exposure to unique environmental triggers may affect asthma control in the elderly. In addition factors contributing to asthma quality of life in the elderly have not been wll explored. The aims of our study are to: (1) develop and systematically implement a phenotyping algorithm in older adults with asthma; (2) longitudinally investigate the effects of asthma phenotypes and volatile organic compounds (VOCs) exposures on asthma control in older adults with asthma; and (3) develop a predictive model for asthma quality of life for older adults with asthma. Sub-aims are to explore the impact on moving from community-based to congregate living settings (e. g assisted living) on the course of asthma in older adults and to identify barriers to successful asthma medication management. One hundred ninety participants 60 years of age or older will be enrolled. Inclusion criteria are: meet standard diagnostic criteri for asthma non-smokers have no other chronic respiratory diseases do not reside in a skilled nursing facility and have not recently had a major a medical illness. At baseline participants wil complete spirometry bronchodilator responsiveness fractional exhaled nitric oxide methacholine challenge (if not completed within past 5 years) allergic sensitization Immunoglobulin E (IgE) and sputum analysis as well as standardized questionnaires to assess asthma control quality of life knowledge and self-efficacy. Within 30 days an in-home environmental assessment will be conducted to obtain data on VOCs air particulates moisture temperature humidity pests and an asthma home environment checklist. At 9 and 18 months in-home data will be collected on participants' pulmonary status asthma control and asthma quality of life. At 9-months participants will also complete the measures of medication management. At 18-months we will conduct follow-up in-home environmental assessments collecting the same data we collected at baseline. Participants who have moved to congregate living facilities will be asked open-ended questions about their perception of the effects of the move on the course of their asthma. Using factor analysis we will perform a comprehensive phenotypic characterization that will include a wide range of demographics asthma-specific knowledge and self-efficacy and biomarkers. Predictive models for asthma control and asthma quality of life will be identified using generalized linear mixed-effects modeling. The findings of
this study will be used in future research to develop and test the efficacy of patient-centered interventions for older adults with asthma to improve asthma control and enhance quality of life.

project_terms:
4 year old;Acute;Address;Affect;Age;Age-Years;Air;Algorithms;Allergic;Area;Assisted Living Facilities;Asthma;Biological;Biological Markers;Bronchodilator Agents;Characteristics;Child;Chronic;Collection;Communities;Data;Diagnostic;Disease;Distal;Drug Interactions;Elderly;Emergency department visit;Enrollment;Environment;Environmental Exposure;Exhalation;Exposure to;Factor Analysis;Home environment;Hospitalization;Household Products;Humidity;IgE;Individual;Inflammatory;Intervention;Knowledge;Life;Life Style;Living Arrangement;Longitudinal Studies;Lung;Lung diseases;Measures;Medical;Medication Management;Methods;Modeling;Mortality Vital Statistics;NIH Program Announcements;Nitric Oxide;Non-smoker;Outcome;Paint;Participant;Particulate;Perception;Pesticides;Pharmaceutical Preparations;Phenotype;Physicians;Population;Prevalence;Quality of life;Questionnaires;Research;Research Personnel;Residential Facilities;Self Efficacy;Skilled Nursing Facilities;Spirometry;Sputum;Stress;Symptoms;Temperature;Testing;Therapeutic Intervention;Visit;airway inflammation;asthmatic;base;constriction;demographics;efficacy testing;experience;follow-up;improved;inclusion criteria;interest;meetings;methacholine;patient oriented;predictive modeling;public health relevance;residence;response;volatile organic compound


application_id: 9137115
project_number: 1R43HL132649-01
project_title: A Novel Lipotherapy to Reduce Infarct Size Following Myocardial Infarction
administering_ic: NHLBI
award_notice_date: 2016-04-07
opportunity_number: PA-15-269
application_type: 1
activity_code: R43
ic: HL
serial_number: 132649
program_official: DESVIGNE-NICKENS, PATRICE
project_start_date: 2016-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 CVRS-C (10)]
contact_pi_person_id: 10119089
contact_pi: BAUER, PHILIP
other_pis: MALDONADO, CLAUDIO ;TANG, XIAN-LIANG
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): According to the CDC in 2013 ischemic heart disease is the leading cause of death worldwide and in the US approximately 450000 patients died of ischemic heart disease. It is well established in clinical practice that recanalization of he infarct related artery (IRA) using percutaneous coronary intervention (PCI) enhances myocardial salvage and outcomes in patients with ST-segment elevation myocardial infarction (STEMI). When the duration of ischemia exceeds 1 h from onset of symptoms reperfusion injury following PCI often leads to infarct expansion due to the "no-reflow" phenomenon in the microvasculature of the "area at risk". Multiple mechanisms are thought to contribute to "no-reflow" and no effective treatment to ameliorate "no-reflow" and infarct expansion during reperfusion has been identified in large randomized clinical trials following STEMI and PCI. EndoProtech Inc. has developed a novel therapeutic approach that alters the lipid content of endothelial cells (ECs) during PCI which has a stabilizing effect on the microvascular endothelium and ameliorates "no-reflow" in the "area at risk" during reperfusion. The overall goal of this project is to demonstrate the safety and efficacy of our lipotherapy in enhancing myocardial salvage following STEMI and PCI. The aims of this Phase I proposal are: 1) Evaluate lipotherapy safety with preliminary screening tests for toxicity and 2) Evaluate lipotherapy efficacy in a swine infarct model. Successful completion of these aims will demonstrate that administration of our lipotherapy to the IRA during PCI just prior to reperfusion is safe reduces "no-reflow" in the are at risk and enhances myocardial salvage. During Phase II aims will be consistent with studies required by the FDA to ultimately provide the necessary data that will support a new drug application.

project_terms:
Anterior;Anti-Inflammatory Agents;Anti-inflammatory;Area;Arteries;Attenuated;Autopsy;Blood Vessels;Blood flow;Body Weight decreased;Cardiac;Cardiopulmonary;Catheters;Cause of Death;Cell Adhesion Molecules;Cell Culture Techniques;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical Chemistry;Complement;Coronary;Coronary artery;Cytoplasm;Data;Deposition;Drug Kinetics;Drug Stability;Edema;Endothelial Cells;Endothelium;Family suidae;Fibrinolysis;Glycocalyx;Goals;Heart;Imaging Techniques;Induced Heart Arrest;Infarction;Inflammation;Injury;Ischemia;Lead;Left;Leukocytes;Lipids;Microscopic;Modeling;Monitor;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial dysfunction;Myocardium;Organ;Outcome;Patients;Perfusion;Phase;Piloerection;Plasma;Plug-in;Randomized Clinical Trials;Reperfusion Injury;Reperfusion Therapy;Risk;Safety;Severities;Signal Transduction;Swelling;Symptoms;Therapeutic Embolization;Toxic effect;Toxicity Tests;Troponin I;Vesicle;Warm Ischemia;base;clinical practice;effective therapy;endothelial dysfunction;fluorescence imaging;in vivo;instrument;novel;novel therapeutic intervention;novel therapeutics;percutaneous coronary intervention;public health relevance;screening;systemic toxicity

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Percutaneous coronary intervention (PCI) to reopen blocked coronary arteries enhances myocardial salvage and outcomes but when blood flow is re-established (reperfusion) it can lead to infarct expansion. This infarct expansion is caused in part by the "no-reflow" phenomenon that occurs in the microvasculature of the "area at risk" during reperfusion. To reduce infarct expansion during reperfusion Endoprotech Inc. has developed a lipid-based treatment that protects the endothelium in the microvasculature from the "no- reflow" phenomenon and enhances myocardial salvage following PCI.


application_id: 9135960
project_number: 4U01ES022564-05
project_title: Countermeasures for chlorine-induced airway fibrosis
administering_ic: NIEHS
award_notice_date: 2016-07-07
opportunity_number: PAR-11-155
application_type: 4
activity_code: U01
ic: ES
serial_number: 022564
program_official: NADADUR, SRIKANTH
project_start_date: 2012-09-25
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent because of the possibility that it could be released in industrial accidents or terrorist attacks. Acute effects of chlorine inhalation include dyspnea hypoxemia pneumonitis and pulmonary edema. Longer term consequences of chlorine inhalation include pulmonary function impairment and airway structural changes that have been observed in some exposed individuals. We have developed a mouse chlorine inhalation model in which animals develop pulmonary edema inflammation airway obstruction and airway hyperreactivity within one day after exposure. In new studies related to the current application we have characterized injury and repair of the lung at longer times after chlorine inhalation. We have observed that airways with a partial loss of epithelium are repaired quickly by the proliferation and differentiation of epithelial cells that survive chlorine exposure. In contrast portions of airways with few surviving epithelial cells are repaired inefficiently and fibroproliferative lesions develop at such sites within a week after chlorine exposure. This development of airway fibrosis is associated with impaired lung function including increased respiratory system resistance and airway hyperreactivity to inhaled methacholine. In the current application we propose to develop countermeasures that can be administered following a chemical attack or accidental release to prevent chlorine-induced airway disease. The hypothesis to be tested in the proposed studies is that inefficient repair of airway epithelium following chlorine lung injury leads to airway fibrosis and impaired lung function; agents that mimic anti-fibrotic effects of airway epithelium or stimulate airway repair will ameliorate chlorin- induced airway disease. Specific Aim 1 will characterize airway epithelial repair airway fibrosisand lung function impairment following chlorine exposure in mice. Specific Aims 2-5 will evaluate the efficacy of the following potential countermeasures for the treatment of chlorine-induced airway disease: the prostanoid receptor agonists butaprost and iloprost; the long-lasting -agonist formoterol and the type 4 phosphodiesterase inhibitor rolipram; stimulation of plasminogen activation with urokinase-type plasminogen activator or the plasminogen activator inhibitor-1 inhibitor tiplaxtinin; and manipulation of Wnt/-catenin signaling with lithium chlorie or pyrvinium. Specific Aim 6 will involve development of a ferret model of chlorine-induced airway disease and testing of countermeasures in this non-rodent species. The proposed studies are expected to identify a countermeasure for prevention of chronic airway disease that develops as a result of an acute high level exposure to chlorine.

project_terms:
Acute;Adrenergic Agonists;Affect;Agonist;Airway Obstruction;Animals;Breathing;Cell Proliferation;Chemical Warfare;Chemicals;Chlorine;Chronic;Cyclic AMP;Development;Disease;Dyspnea;Epithelial;Epithelial Cells;Epithelium;Exposure to;Ferrets;Fibrosis;Goals;Health;Human;Hypoxemia;Iloprost;Impairment;Individual;Industrial Accidents;Inflammation;Irritants;Kinetics;Lesion;Lithium;Lithium Chloride;Lung;Measurement;Modeling;Mus;Non-Rodent Model;Phosphodiesterase Inhibitors;Plasminogen;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Poisons;Prevention;Production;Prostaglandins;Pulmonary Edema;Pulmonary Fibrosis;Pulmonary Inflammation;Recording of previous events;Research;Resistance;Resolution;Respiratory System;Respiratory physiology;Rodent;Rolipram;Signal Pathway;Signal Transduction;Site;Structure;Structure of respiratory epithelium;Testing;Time;Toxic effect;Unconscious State;United States;Urokinase;acute symptom;airway epithelium;airway hyperresponsiveness;animal rule;butaprost;chemical threat;chlorin;chlorine gas;efficacy testing;formoterol;inhibitor/antagonist;injury and repair;lung injury;methacholine;mouse model;novel;phosphoric diester hydrolase;prevent;pulmonary function;receptor;repaired;research study;respiratory;restoration

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal of the proposed experiments is to develop novel ways to treat chronic airway disease caused by acute high level exposure to chlorine gas. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals such as chlorine.


application_id: 9135494
project_number: 4P20GM103527-09
project_title: Role of Adipose Tissue TGF-b signaling on Adipose Dysfunction in Obesity
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5043
contact_pi_person_id: 9276432
contact_pi: FINLIN, BRIAN S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
Obesity is associated with adipose dysfunction which contributes to insulin resistance diabetes and heart disease. It has been proposed that adipose dysfunction is caused by an inappropriate response to hypoxia that results in increased ECM expression and reduced angiogenesis. Our data indicate that adipocytemacrophage crosstalk results in increased expression of thrombospondin-1 (TSP-1) a multifunctional protein that promotes fibrosis by activating TGF-beta signaling. TGF-beta has multiple effects on adipose in addition to inducing fibrosis including inhibiting adipogenesis and complicated effects on angiogenesis. Recently a whole-body knockout of SMAD3 to block TGF-beta signaling resulted in mice with improved metabolic function and browning of their white adipose; this was due in part to reversing the inhibition of TGF-beta on the expression of PGC-1 alpha. Our overall hypothesis is that increased TSP-1 expression and TGF-beta signaling in white adipose with obesity cause increased fibrosis reduced capillary density reduced PGC-1 alpha and reduced UCP-1 expression hence less "browning" and impaired WAT function. Thus inhibiting the TGF-beta pathway in humans may improve adipose function and reverse the effects of obesity on insulin resistance. The first aim will characterize the white adipose ECM and capillary density of TSP-1 knockout mice and their littermate controls challenged with a high fat diet. The second aim will knockout TGF-beta in adipose using cre/lox technology to elucidate the role of TGF-beta signaling on adipose function is response to high fat feeding. The third aim will determine whether the dramatic reduction in adipocyte PGC-1 alpha by macrophage coculture is TGF-beta dependent. The fourth aim will determine whether toll-like receptor (TLR) signaling is involved in the adipocyte-macrophage crosstalk that induces TSP-1 and TGF-beta signaling in macrophages. Thus the two mouse models will indicate the contribution of TSP-1 and TGF- beta to adipose dysfunction with obesity. The coculture studies will begin to define the mechanisms by which adipocytes and macrophages communicate with each other to induce TSP-1 expression by both cells types and to decrease PGC-1 alpha expression in adipocytes.

project_terms:
Adipocytes;Adipose tissue;Blood capillaries;Brown Fat;Cardiovascular Diseases;Coculture Techniques;Complex;Data;Diabetes Mellitus;Docosahexaenoic Acids;Euglycemic Clamping;Extracellular Matrix;Fatty acid glycerol esters;Fibrosis;Fish Oils;Functional disorder;Gene Expression;Glucose Clamp;Heart Diseases;High Fat Diet;Human;Hypoxia;Immune;Insulin Resistance;Interleukin-10;Knock-out;Knockout Mice;MADH3 gene;Measures;Mediating;Metabolic;Methods;Mus;Obesity;Pathway interactions;Process;Proteins;Receptor Signaling;Research;Role;Signal Transduction;Small Interfering RNA;TLR2 gene;TLR4 gene;Testing;Thrombospondin 1;Toll-like receptors;Transforming Growth Factor beta;angiogenesis;capillary;cell type;combat;density;feeding;glucose tolerance;improved;inhibitor/antagonist;insulin tolerance;lipid biosynthesis;macrophage;mouse model;receptor;recombinase-mediated cassette exchange;response

public_health_relevance:
Adipose tissue becomes dysfunctional with obesity by a complex process. We hypothesize that TGF-beta signaling contributes to this by promoting adiopose fibrosis and by inhibiting the ability of adipose to metabolize fat; inhibiting TGF-beta signaling may be an effective method to combat obesity.


application_id: 9135493
project_number: 4P20GM103527-09
project_title: Role of bioactive lipids in the protective pathways of obesity in ischemic cardi
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5042
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
Obesity is approaching epidemic state in the western worid and is a known risk factor for acute myocardial infarction (AMI). AMI and the subsequent ischemic heart disease (IHD) are often complicated with high mortality and poor overall prognosis despite significant advances in medical therapy and revascularization strategies. Currently short of heart transplantation with all of its inherit limitations there are no available treatment strategies that replace the infracted myocardium and therapies are largely palliative. Paradoxically obesity may also confer a protective effect against AMI-associated remodeling which leads to IHD. The molecular kiasis for this protection is poorly understood. AMI initiates poorly understood innate reparatory mechanisms through which BMSPCs are mobilized and home towards the ischemic myocardium contributing to myocardial regeneration and correlating with cardiac recovery. Our preliminary data indicates that bioactive lipids such as sphingosine-1 phosphate (SIP) but not traditional chemokines play a quintessential role in this mobilization and homing. Interestingly obesity and the associated metabolic syndrome are associated with alterations in bioactive lipids' metabolism. Our objective in this application therefore is to develop better understanding ofthe obesity-associated alterations in AMI-induced stem cell mobilization pathways specially those involving bioactive lipids and devise therapies that hamess this process for therapeutic myocardial regeneration strategies. Our central hypothesis has been formulated based upon the existing literature and our strong preliminary data demonstrating that BMSPCs express SIP receptors and will migrate towards plasma from AMI patients in an SI P dependent fashion. Our rationale for these studies is that understanding the protective role of bioactive lipids and stem cell mobilization during AMI in obesity would help establish a strong scientific framework for eventual generalizable human myocardial regenerative clinical trials utilizing the available and new pharmacological modulators of bioactive lipids and their receptors. In addition to clinical studies our approach will exploit small molecule-strategies in mouse models through examining the obesity associated molecular and cellular pathways specially those involving bioactive lipids that are activated by myocardial infarction (Aim 1); and examine the modulation of bioactive lipids' metabolism and receptor expression to enhance cardiac recovery following AMI (Aim 2).

project_terms:
Acute myocardial infarction;Adipose tissue;Bone Marrow;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Clinical Research;Clinical Trials;Data;Development;Diet;Epidemic;Exhibits;Goals;Heart;Heart Transplantation;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;Home environment;Homing;Human;Individual;Inherited;Injury;Laboratories;Lipids;Literature;Longevity;Medical;Metabolic syndrome;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Obesity;Overweight;Pathway interactions;Patients;Pharmacologic Substance;Plasma;Play;Population;Positioning Attribute;Process;Recovery;Research;Review Literature;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Staging;Stem cells;System;Therapeutic;Western World;Work;base;chemokine;expectation;improved;lipid mediator;lipid metabolism;mortality;mouse model;outcome forecast;palliative;peripheral blood;protective effect;receptor;receptor expression;regenerative;regenerative therapy;response;small molecule;sphingosine 1-phosphate;stem;treatment strategy

public_health_relevance:
Obesity increases the risk for acute myocardial infarction but may paradoxically exert protective effect from the subsequent cardiac remodeling. Our objective is to develop better understanding of obesity-associated alterations in myocardial infarction-induced stem cell mobilization pathways specially those involving bioactive lipids and devise therapies that'harness this process for myocardial regeneration strategies.


application_id: 9135492
project_number: 4P20GM103527-09
project_title: Role of lipinl in skeletal muscle mitochondrial homeostasis and oxidative energy
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5041
contact_pi_person_id: 10435377
contact_pi: REN, HONGMEI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
Body weight is determined by the balance between energy input and expenditure. Skeletal muscle is major site of mitochondrial oxidative metabolism of fatty acids and glucose and thereby plays a central role in whole body energy expenditure. Accordingly preservation or promotion of skeletal muscle metabolism could play a critical role in protection from diet induced obesity. Understanding the mechanisms that regulate skeletal muscle metabolism and their relationship to those controlling fatty storage and mobilization is therefore a critical goal in metabolic disease research. Lipinl is a phosphatidic acid (PA) phosphatase enzyme that catalyzes the penultimate step in triglyceride synthesis at the cytoplasmic surface of the endoplasmic reticulum and also serves as a nuclear transcriptional co-activator of PPAR-a responsive genes. Lipinl deficient mice (fatty liver dystrophy mice fid mice) exhibit impaired adipocyte differentiation circulating hyperlipidemia and neonatal hepatic steatosis associated with diminished rates of hepatic fatty acid oxidation. Lipinl is also expressed in skeletal muscle and transgenic overexpression of lipinl in this tissue reverses many ofthe phenotypes of lipinl deficient fid mice. Interestingly humans with heritable lipinl null mutations present with severe rhabdomyolysis (skeletal muscle degeneration) characterized by impaired carnitine palmitoyi acyltransferase (CPT) activity decreased mitochondrial fatty oxidation and respiratory chain function and the consequent destruction of skeletal muscle fibers. We made the seminal observation that lipinl is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids suggesting that lipinl deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipinl is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly we hypothesize that recruitment of lipinl to mitochondria directly promotes mitochondrial respiratory function and beta-oxidation through effects on mitochondrial homeostasis and lipid composition and that this is particularly important for skeletal muscle function in energy metabolism. In direct support of our hypothesis we found mitochondrial respiratory function is impaired in lipinl deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipinl deficient rnice. The broad goal of this research is to define the role of Lipinl in mitochondrial function and skeletal muscle physiology. Aim 1 defines the role of muscle cell lipinl PA phosphatase activity in regulating mitochondrial lipid composition and function while Aim 2 examines deletion of skeletal muscle lipinl in lean and obese mice.

project_terms:
Acyltransferase;Adipose tissue;Alleles;Animals;Biological Preservation;Blood Pressure;Body Weight;Cardiovascular Diseases;Carnitine;Cell Culture System;Cell Respiration;Cells;Consumption;Defect;Diabetes Mellitus;Diet;Down-Regulation;Embryo;Endoplasmic Reticulum;Energy Metabolism;Enzymes;Equilibrium;Exhibits;Expenditure;Fatty Acids;Fatty Liver;Fatty acid glycerol esters;Fibroblasts;Gene Expression;Genes;Genetic Polymorphism;Glucose;Goals;Hepatic;Homeostasis;Human;Hyperlipidemia;In Vitro;Link;Lipids;LoxP-flanked allele;Messenger RNA;Metabolic;Metabolic Diseases;Metabolism;Mitochondria;Morphology;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Weakness;Muscle function;Mutation;Myoblasts;Neonatal;Neuropathy;Nuclear;Obese Mice;Obesity;Oxidative Phosphorylation;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Phenotype;Phosphatidate Phosphatase;Phosphoric Monoester Hydrolases;Physiology;Play;Predisposition;Process;Recruitment Activity;Regulation;Research;Respiratory Chain;Respiratory physiology;Rhabdomyolysis;Role;Seminal;Site;Skeletal Muscle;Small Interfering RNA;Surface;System;Tissues;Transcription Coactivator;Transgenic Organisms;Transportation;Triglycerides;Variant;adipocyte differentiation;base;carbohydrate metabolism;fatty acid oxidation;in vivo;insight;insulin sensitivity;inter-individual variation;lipine;mitochondrial dysfunction;muscle degeneration;muscle metabolism;null mutation;overexpression;oxidation;research study;skeletal muscle metabolism

public_health_relevance:
Lipin l is emerging as a master regulator of metabolism. Inter-individual variation in lipinl expression and alterations in lipinl mRNA processing have been associated with human susceptibility to diet induced obesity. Our proposed studies promise to reveal a new facet of lipinl function in skeletal muscle and to define the role of lipinl as a link between fat storage in adipose tissue and consumption of mobilized fatty acids by skeletal muscle mitochondrial oxidative metabolism.


application_id: 9135491
project_number: 4P20GM103527-09
project_title: Quantifying the effect of obesity and comorbid hypertension on cardiac function
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5039
contact_pi_person_id: 9404495
contact_pi: FORNWALT, BRANDON K
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
Obesity is a major public health problem affecting over one third of adults in the United States and one in five children. Obesity is related to an increased risk of cardiovascular mortality which may in part be mediated through a direct effect on the heart leading to dysfunction. However the time course over which obesity leads to cardiac dysfuncfion the underlying mechanisms of myocardial dysfunction in obesity and potential treatments have not been fully elucidated. Our preliminary data ufilizing cardiac magnefic resonance imaging (MRI) show abnormalifies in the magnitude of contracfion synchrony of contraction and myocardial mass in the hearts of mice fed a high-fat Western diet. The objective of this project is to define the time course over which this dysfunction occurs in mice evaluate the role of hypertension in the development of this dysfunction and to translate this work into humans by determining whether children in our pediatric obesity clinic have evidence of cardiac dysfunction. This project has 3 specific aims as follows: 1) Determine the time course over which myocardial dysfunction develops in mice fed a high-fat Western diet. We will quantify advanced measures of cardiac function assessing mass contraction and relaxation and synchrony overtime in a longitudinal study using magnetic resonance imaging. 2) Determine the effect of anti-hypertensive therapy on the development of hypertrophy and cardiac dysfunction in mice fed a high-fat Western diet. Mice on a high-fat Western diet develop obesity-related hypertension that is reversible with anti-hypertensive therapy. However the effect of anti-hypertensive therapy on cardiac function in obese mice has not been studied and may elucidate underiying mechanisms. We will compare cardiac function measured in the'mice on a high-fat Western diet in specific aim 1 to a group of mice on a high-fat Western diet and hydralazine. 3) Quantify cardiac function in children with obesity using advanced MRI. State-of-the-art technology at the University of Kentucky enables us to directly translate our findings in mice into our pediatric obesity clinic with over 800 patients. The effect of obesity on myocardial function in children is largely unknown.

project_terms:
Adult;Affect;Animals;Antihypertensive Agents;Blood Pressure;Cardiac;Cardiac Function Study;Cardiovascular Diseases;Child;Clinic;Computer software;Data;Development;Diet;Fat-Restricted Diet;Fatty acid glycerol esters;Functional disorder;Heart;Heart Hypertrophy;High Fat Diet;Human;Hydralazine;Hypertension;Hypertrophy;Image;Kentucky;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Mus;Myocardial;Myocardial Contraction;Myocardial dysfunction;Obese Mice;Obesity;Obesity Related Hypertension;Patients;Pharmaceutical Preparations;Protocols documentation;Public Health;Relaxation;Research;Role;Technology;Time;Translating;Translations;United States;Universities;Weight;Work;cardiovascular risk factor;feeding;heart function;mortality;mouse model;normotensive;obesity in children;western diet

public_health_relevance:
Obesity affects over one third of adults in the United States and one in five children. The objective of this project is to understand the effects of obesity on the function of the heart using advanced magnetic resonance imaging (MRI) of the hearts of both mice and humans. Part of this project will also investigate the specific role of blood pressure medications on helping to protect the heart from the effects of obesity.


application_id: 9135489
project_number: 4P20GM103527-09
project_title: The role of IKKB in linking obesity to adipose tissue inflammation and adipogene
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5038
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The goal of this project is to investigate the role of IKB kinase beta (IKKB) a central coordinator of innate immunity and inflammation through activation of NF-KB in linking obesity to adipose tissue inflammation and adipogenesis. Obesity is associated with a state of chronic low-grade inflammation that has been considered to be a major contributor to diabetes and atherosclerosis. The transcriptional factor NF-KB is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKKB is the predominant catalytic subunit ofthe IKK complex that is required for canonical activation of NF-KB by inflammatory mediators. Given the defined role of IKKB in regulating NF-KB-mediated inflammation in several cell types it is unclear whether IKKB contributes to obesity-induced inflammation in adipocytes. In the proposed studies we will define the role of adipocyte-derived IKKB in high fat (HF) diet-induced obesity adipose inflammation and insulin resistance. In preliminary studies during Phase I support of this project we also defined the role of smooth muscle cell (SMC) IKKB in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKKB in SMCs we used SM22-Cre transgenic male mice carrying floxed IKKB alleles that were mated to female LDLR-/- mice carrying floxed IKKB alleles. During the course of these studies we made the novel finding that deficiency of IKKB in SMCs rendered mice resistant to the development of diet-induced obesity. Preliminary results demonstrate that SM22 is expressed in primary adipose stromal/vascular (SV) cells consistent with recent reports that SM22-Cre is active in mesenchymal stem cells (MSCs) that give rise to adipose tissue. Notably SV cells from SMC IKKB-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKKB in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKKB promotes adipocyte differentiation adipocyte inflammation and insulin resistance. In the proposed studies we will define mechanisms for IKKB-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKKB deficiency on the development of obesity adipose inflammation and insulin resistance in response to a HF diet. The proposed studies will elucidate new aspects of adipocyte biology and metabolic control and may lead to novel therapeutic targets for obesity and diabetes.

project_terms:
Ablation;Adipocytes;Adipose tissue;Affect;Alleles;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Catalytic Domain;Cells;Chronic;Complex;Country;Data;Development;Diabetes Mellitus;Diet;Disease;Epidemic;Exhibits;Fatty acid glycerol esters;Female;Goals;Hematopoietic;High Fat Diet;Human;Hypertrophy;I-kappa B Proteins;Immune response;Inflammation;Inflammation Mediators;Insulin Resistance;Intervention;Lead;Link;Low Density Lipoprotein Receptor;LoxP-flanked allele;Mediating;Mesenchymal Stem Cells;Metabolic Control;Metabolic Diseases;Modeling;Mus;Natural Immunity;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Partner in relationship;Pathway interactions;Phase;Phosphotransferases;Play;Regulation;Reporting;Research;Resistance;Risk;Role;Signal Transduction;Smooth Muscle Myocytes;Stem cells;Testing;Transgenic Organisms;adipocyte biology;adipocyte differentiation;cell type;feeding;gain of function;lipid biosynthesis;loss of function;male;new therapeutic target;novel;nutrition;obesity treatment;overexpression;population health;progenitor;promoter;response;stem cell differentiation;therapeutic target

public_health_relevance:
Obesity is a rapidly growing epidemic representing a serious threat to the health of the population in almost every country around the world. There is an urgent need to understand the mechanisms underlying the diet induced obesity and associated metabolic disorders. The proposed study will investigate a novel mechanism that links over nutrition and obesity.


application_id: 9135488
project_number: 4P20GM103527-09
project_title: Pathology Core D
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5037
contact_pi_person_id: 1879534
contact_pi: KATZ, WENDY S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The Pathology Core (D) will be located in the Charles T. Wethington Building at the University of Kentucky. This core will provide equipment services and training for processing and sectioning tissues embedded in paraffin. Dr. Katz will oversee this core which includes sectioning and basic stains as well as immunostains for common epitopes linked to obesity and adipose inflammation. Equipment includes a tissue processor two paraffln microtomes microscope and stage for stitching paraffin sections together through imaging software.

project_terms:
Adipose tissue;Cardiovascular Diseases;Common Epitope;Equipment;Frozen Sections;Image Analysis;Inflammation;Kentucky;Link;Mentors;Microscope;Microtome - medical device;Obesity;Paraffin;Paraffin Embedding;Paraffin Tissue;Pathology;Pilot Projects;Process;Research;Research Personnel;Sampling;Services;Staging;Staining method;Stains;Technical Expertise;Tissue Embedding;Tissue Sample;Tissue Stains;Tissues;Training;Universities;imaging software;interest;tissue processing

public_health_relevance:
The Pathology Core provides services and training for processing embedding sectioning and staining tissue samples related to studies on obesity and cardiovascular diseases.


application_id: 9135487
project_number: 4P20GM103527-09
project_title: Physiologic Core C
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5036
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The Physiologic Core (C) will be located in the Division of Animal Laboratory Resources within dedicated space at the University of Kentucky. This core will provide equipment services and training for quantifying cardiovascular diabetes and obesity phenotypes. This includes measurement of atherosclerosis quantifying sera lipoprotein cholesterol ultrasound for assessing vascular and cardiac function MRI for analyzing cardiac function and fat deposifion and tail cuff and radiotelemetry platforms to quantify blood pressure. For diabetes this includes training and service in performing glucose and insulin tolerance tests in mice and for small scale studies using euglycemic hyperinsulinemic clamps in mice. For obesity this includes echoMRI to quantify fat/lean mass TSE LabMaster chambers to quantify food/water intake physical activity and indirect calorimetry and PhenoMaster chambers for urine/feces collection.

project_terms:
Adipose tissue;Animals;Atherosclerosis;Blood Pressure;Blood Vessels;Cardiac;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Collection;Coronary Arteriosclerosis;Deposition;Development;Diabetes Mellitus;Energy Intake;Equipment;Expenditure;Fatty acid glycerol esters;Feces;Food;Goals;Human;Hypertension;Image;Indirect Calorimetry;Kentucky;Laboratory Animals;Magnetic Resonance;Measurement;Measures;Metabolism;Mus;Obese Mice;Obesity;Phase;Phenotype;Physical activity;Physiological;Research;Research Personnel;Research Support;Resources;Rodent;Rodent Model;Serum;Services;Tail;Technical Expertise;Testing;Training;Ultrasonography;Universities;Urine;Water consumption;blood glucose regulation;glucose tolerance;insulin tolerance;lipoprotein cholesterol

public_health_relevance:
The Physiologic Core provides services and training for quantifying major phenotypes associated with obesity diabetes and cardiovascular diseases in mice.


application_id: 9135486
project_number: 4P20GM103527-09
project_title: Analytical Core B
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5035
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The Analytical Core (B) will be located in the Biomedical Biological Sciences Building University of Kentucky. The Analytical Core will consist of the Director and research personnel for performing services of resolution and profiling of analytes using mass spectroscopy and for quantifying analytes using luminex platforms. An important part of Core activities will include methods development to analyze speciflc molecules of interest and for profiling lipids within animal and human tissue.

project_terms:
Area;Award;Biological;Biological Sciences;Cardiovascular Diseases;Centers of Research Excellence;Computers and Advanced Instrumentation;Consultations;Detection;Diagnosis;Electrospray Ionization;Fatty Acids;Fee-for-Service Plans;Fees;Flame Ionization;Funding;Gases;Goals;Grant;High Pressure Liquid Chromatography;Human;Human Resources;Individual;Institution;International;Investigation;Investments;Kentucky;Life;Lipids;Lipolysis;Mass Fragmentography;Mass Spectrum Analysis;Measurement;Measures;Mediator of activation protein;Mentors;Metabolic;Methods;Monitor;Mus;National Center for Research Resources;Obesity;Participant;Peptides;Phase;Positioning Attribute;Proteins;Publications;Reader;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Resolution;Series;Services;Suspension substance;Suspensions;Training;United States National Institutes of Health;Universities;Work;animal tissue;base;biomedical facility;carbohydrate metabolism;cost;detector;human tissue;instrument;instrumentation;interest;lipid biosynthesis;lipid metabolism;mass spectrometer;metabolomics;method development;operation;small molecule;stable isotope;success;synthetic polymer Bioplex;tandem mass spectrometry

public_health_relevance:
The Analytical Core provides services and methods development to investigators of the Center to quantify profile and resolve various analytes with a focus on lipids.


application_id: 9135485
project_number: 4P20GM103527-09
project_title: Administrative Core A
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
study_section: ZGM1-TWD-Y
subproject_number: 5033
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The Administrative Core (A) will be located to the adminstrative suite of the 5th floor Wethington Building University of Kentucky. The Administrative Core will consist ofthe Program Director Administrative Assistant Financial Assistant Executive Committee Internal Advisory Committee COCVD Committee and Biostatistician. The Core will oversee all aspects ofthe COCVD including fiscal affairs scheduling meetings retreats annual research day pilot project program website collecting quantitative measures of the COCVD and in preparing all reports on COCVD activities and progress.

project_terms:
Advisory Committees;Cardiovascular Diseases;Centers of Research Excellence;Floor;Institution;Kentucky;Measures;Obesity;Pilot Projects;Reporting;Research;Schedule;United States National Institutes of Health;Universities;meetings;programs;web site

public_health_relevance:
The Administrative Core oversees all aspects of the Center of Biomedical Research Excellence on Obesity and Cardiovascular Diseases and represents the program to the institution and the NIH.


application_id: 9135482
project_number: 4P20GM103527-09
project_title: Center of Research on Obesity and Cardiovascular Diseases
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103527
program_official: LIU, YANPING
project_start_date: 2008-09-08
project_end_date: 2018-07-31
study_section: ZGM1-TWD-Y(C2)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal builds upon the accomplishments made during the previous funding period and requests continuing support of the Center of Biomedical Research Excellence (COBRE) on Obesity and Cardiovascular Diseases (COCVD). Kentucky ranks within the top 10 states for the prevalence of obesity and cardiovascular diseases and the epidemic is not abating. Thus it is imperative that mechanisms linking obesity to cardiovascular diseases are identified. During the 4 years of support the COCVD has made significant strides advancing knowledge on obesity-associated cardiovascular diseases through support of junior investigators and the development of research cores. As a result we have experienced outstanding success with graduation of 75% of 12 supported junior investigators to independent R01 support including 15 new NIH R01s. The program has graduated 2 junior faculty/year to NIH R01 level support with 125 publications from junior investigators and an additional 318 publications from mentors. In addition we have supported 7 pilot projects that have contributed to 58 publications. New research cores to quantify obesity phenotypes and to provide analytical services in lipidomics have markedly increased the research infrastructure. As a direct result of COCVD activities the institution competed successfully for a CTSA to establish the Center for Clinical and Translational Sciences. In the second phase of the COCVD we propose to create a nationally recognized Center of Research Excellence to define mechanisms linking the epidemic of obesity to cardiovascular diseases the primary cause of death in the obese population. To accomplish this goal we will (1) develop a critical mass of funded investigators including basic and physician scientists with research programs directly related to the Center's unifying theme (2) provide strong mentoring programs (2) recruit new investigators to the Center through pilot project grant support which will be leveraged by the institution and the CTSA (4) expand and further develop an Analytical Core (with a focus on lipidomics) a Physiologic Core to quantify obesity and cardiovascular phenotypes and a Pathology Core to assess tissue histology.

project_terms:
Abate;Adipose tissue;Area;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Centers of Research Excellence;Clinical Sciences;Core Facility;Development;Epidemic;Exhibits;Faculty;Funding;Goals;Grant;Histology;Inflammation;Institution;Kentucky;Knowledge;Link;Mentors;Obesity;Obesity associated cardiovascular disease;Pathology;Phase;Phenotype;Physicians;Physiological;Pilot Projects;Positioning Attribute;Prevalence;Publications;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Support;Scientist;Services;Testing;Tissues;Translational Research;United States National Institutes of Health;bench to bedside;clinically significant;experience;multidisciplinary;programs;public health relevance;research and development;success

public_health_relevance:
The Center of Biomedical Research Excellence on Obesity and Cardiovascular Diseases seeks to define mechanisms for the rampant prevalence of cardiovascular diseases in the obese population. We will enhance the competitiveness of junior faculty with research programs in this highly significant area through research support mentoring and through development and access to cutting-edge research cores.


application_id: 9135184
project_number: 5R21AI124235-02
project_title: Role of STAT3 Signaling in GC B Cell Regulation
administering_ic: NIAID
award_notice_date: 2016-07-18
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 124235
program_official: JOHNSON, DAVID R
project_start_date: 2015-09-01
project_end_date: 2018-08-31
study_section: Cellular and Molecular Immunology - A Study Section[CMIA]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
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): Germinal centers (GCs) are unique microenvironment that has proliferative B cells undergoing class switching somatic hypermutation and affinity maturation. Although alternative pathways exist GCs are the major source of long-lived antibody (Ab)-secreting plasma cells and memory B cells. Previous studies have demonstrated that SLE may develop as a result of enhanced GC activity. Spontaneous GC formation has been found in the lupus-prone mice. In addition active lupus patients have abnormal GC reactions and increased plasma cells. Therefore understanding signaling pathways that regulate the GC formation and GC B cell differentiation may identify novel targets for the successful intervention of SLE.  The signal transducer and activator of transcription factor 3 (STAT3) signaling pathway is critical for human B cells to differentiate into Ab-secreting plasma cells. Dysregulation of STAT3 pathway has also been implicated in the development of SLE. However the role of STAT3 in the GC B cell response has been controversial. A previous study has demonstrated that B cell-specific STAT3 deficient mice have lower T- dependent IgG response but display normal GC formation. Paradoxically GC is the major source of both memory B cells and long-lived plasma cells. One caveat of this study is that they only examined GC response at day 12. Our preliminary studies demonstrated that B cell-specific STAT-3 KO mice had significantly decreased GC formation GC B cells and Tfh cells in the later phase (day 21) but not in the early time point (day 14). Furthermore STAT3-deficient autoreactive B cells had defective autoAb responses and GC B cell differentiation upon immunization. We hypothesize that STAT3 signaling is essential for the maintenance of the GC formation and GC B cell differentiation. Two Aims are proposed to address this hypothesis. Aim 1 determines the mechanisms by which STAT3 signaling regulates the maintenance of the GC formation and GC B cell response using C1-cre mice which specifically delete STAT3 in the GC B cells. We will also determine extracellular signals that stimulate STAT3 activation in GC B cells. Aim 2 examines whether B cell intrinsic STAT3 signaling is required for autoAb production and disease progression in lupus-prone MRL/lpr mouse model. In addition we will use anti-CD19 single chain variable fragment (scFv) miniAb to specifically deliver STAT3 siRNA into B cells in MRL/lpr mice. The therapeutic efficacy of this intervention will be determined. The overall goal of this proposal is to determine how STAT3 signaling regulates the GC formation and GC B cell response and whether ablation of STAT3 signaling specifically in autoreactive B cells provides benefit for lupus treatment.

project_terms:
Ablation;Address;Affinity;Antibodies;Antigens;Apoptotic;Autoantibodies;Autoantigens;Autoimmune Diseases;B cell differentiation;B-Cell Activation;B-Cell Development;B-Lymphocytes;CD19 gene;CD4 Positive T Lymphocytes;Cell Culture System;Cells;Development;Disease Progression;Etiology;Goals;Health;Helper-Inducer T-Lymphocyte;Human;Immunization;Immunoglobulin A;Immunoglobulin Class Switching;Immunoglobulin G;Immunoglobulin M;Immunoglobulin Somatic Hypermutation;In Vitro;Inbred MRL lpr Mice;Inflammatory;Interleukin-6;Intervention;Kidney;Kinetics;Knock-out;Knockout Mice;Life;Lupus;Maintenance;Measures;Memory B-Lymphocyte;Messenger RNA;Molecular;Mus;Organ;Pathogenesis;Pathology;Pathway interactions;Patients;Phase;Phosphorylation;Plasma Cells;Play;Process;Production;Reaction;Regulation;Role;STAT protein;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;Source;Staging;Structure;Structure of germinal center of lymph node;Systemic Lupus Erythematosus;T-Cell Activation;Testing;Time;Transcript;Transcription Factor 3;Transducers;Treatment Efficacy;autoreactive B cell;cytokine;extracellular;innovation;lupus prone mice;mouse model;novel;novel strategies;plasma cell differentiation;response;successful intervention;systemic autoimmune disease;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This study will determine the cellular and molecular mechanisms by which STAT3 signaling pathway regulates the germinal center formation and germinal center B cell response. The successful completion of this study may provide an innovative approach for autoimmune disease therapy such as systemic lupus erythematosus (SLE).


application_id: 9135070
project_number: 1R03DA039740-01A1
project_title: Role of Social Media and Mobile Apps in Sexual and Drug Co-Usage Networks of MSM
administering_ic: NIDA
award_notice_date: 2016-08-31
opportunity_number: PA-12-282
application_type: 1
activity_code: R03
ic: DA
serial_number: 039740
suffix: A1
program_official: SCHULDEN, JEFFREY D
project_start_date: 2016-09-01
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1 AARR-G (93)]
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
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
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this proposal is to examine the overlap in the sexual and drug co-usage networks of men who have sex with men (MSM) and to overlay information about sexual partnerships facilitated by the use of social networking applications (e.g. Grindr Scruff etc.) to determine the relationship between app use and network-level patterns of HIV risk behavior. Many MSM are using social media and/or smartphone applications ("apps") to meet sex partners and evidence suggests that use of these apps is associated with increased sexual risk behavior and possibly drug use although research on the latter is scarce. Unfortunately network- based research in this area has focused almost exclusively on sexual networks; thus little is known about the interaction of MSM sexual- and drug-related risk networks and how network structure is influenced by the use of mobile apps. Moreover previous studies generally have lacked necessary detail about partnerships to be able to determine the interconnectivity of relationships. Finally the overwhelming majority of studies on MSM app use have been conducted in large urban areas despite research indicating that similar patterns of online- and app-based sex-seeking occur among MSM in rural and mid-sized cities. The gap in knowledge is notable considering evidence suggesting that rural MSM experiencing stigma and isolation often use the Internet to find sex partners and travel to/from nearby urban areas to meet them. The proposed study will be conducted in a mid-sized city in the South in close proximity to rural Central Appalachia. The study was developed in response to the need for more integrative network-level research on app use and the drug co-usage and sexual relationships of MSM residing outside of large urban areas. Through the use of a name generator and collection of detailed demographic information about partners the proposed study will allow inferences to be drawn about overlap in sexual and drug co-usage partnerships in a network structure representing the direct and indirect connections among all participants and their partners (i.e. a sociometric network). The network will reveal the relationship between app use and co-occurrence of drug and sexual partnerships and through the integration of spatial data on locations of sexual encounters will permit examination of the relationships among risk behavior network structure and spatial context. Identifying "high-risk" spatial locations and network structures will be critical in determining ho best to reach MSM using combined geo-targeted and network- driven approaches as well as app- or web-based technologies.

project_terms:
Accounting;Alcohol or Other Drugs use;Alcohols;Appalachian Region;Area;Behavior;Cellular Phone;Cities;Collection;Communities;Cybersex;Data;Drug usage;Goals;HIV;HIV Infections;HIV risk;HIV/HCV;HIV/STD;Health;Hornets;Individual;Infection;Internet;Intervention;Joints;Knowledge;Location;Measures;Names;Nature;Network-based;Online Systems;Participant;Pattern;Pharmaceutical Preparations;Play;Prevalence;Prevention;Recruitment Activity;Reporting;Research;Risk;Risk Behaviors;Risk Reduction;Role;Rural;Sampling;Sex Behavior;Sexual Partners;Social Environment;Social Network;Structure;Technology;Travel;United States;Unsafe Sex;base;behavior measurement;experience;high risk;illicit drug use;innovation;meetings;men who have sex with men;mobile application;public health relevance;response;seroconversion;sex;sex risk;sexual encounter;sexual relationship;social media;social stigma;spatial integration;tool;transmission process;urban area;virtual;web app

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The overarching aim of proposed project is to examine overlap in the sexual and drug co-usage networks of men who have sex with men (MSM) and to overlay information about sexual partnerships facilitated by the use of social networking applications (e.g. Grindr Scruff etc.) to determine the association between app use and spatial and network-level patterns of HIV risk behavior using data collected in a mid-size city in the South. Identifying "high-risk" spatial locations and network structures will be critical to identifing how best to reach MSM using combined geo-targeted network-driven and web/app-based approaches for intervention.


application_id: 9134926
project_number: 1R56HL122580-01A1
project_title: Metabolic regulation of cardiac stem cells
administering_ic: NHLBI
award_notice_date: 2015-09-11
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: HL
serial_number: 122580
suffix: A1
program_official: SCHWARTZ, LISA
project_start_date: 2015-09-11
project_end_date: 2016-08-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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): Ischemic heart disease is a leading cause of mortality in the United States and accounts for 1 in 8 deaths. While several experimental and clinical studies have shown improvements in heart function after CSC transplantation the therapeutic efficacy of these cells may be limited by co-morbid conditions such as obesity and diabetes. In the US a large percentage of patients with heart failure have Type 2 diabetes (T2D); however we do not understand how metabolic dysregulation associated with the conditions of obesity and diabetes affect CSC therapy. Our preliminary data show that CSCs maintain relatively high rates of glycolysis and although they express functional insulin receptors their glucose transport is not regulated by insulin. As a result their glycolytic activity increases during hyperglycemia and the efficacy of CSC therapy is attenuated in obese-hyperglycemic mice. We have also found that prolonged exposure to hyperglycemia in diabetic mice upregulates CSC glycolysis and prevents CSC proliferation and differentiation. Moreover diabetic CSCs transplanted into non-diabetic mice appear to worsen infarct-induced heart failure. Based on these observations we propose that excessive glycolysis promotes stem cell dormancy prevents differentiation and diminishes the reparative capacity of CSCs. To test this hypothesis we will: (1) determine how experimental modulation of glycolytic activity affects CSC function; (2) elucidate the mechanism by which diabetes affects CSCs; and (3) delineate the contribution of glycolysis to CSC therapy in diabetic mice. Results of this project will identify key metabolic pathways that regulate CSC function and competence and elucidate how they are affected by disease conditions such as diabetes and insulin resistance. We expect to identify specific metabolic factors that regulate the efficacy of CSC therapy and to delineate metabolic strategies to enhance CSC-mediated myocardial repair. This understanding will help facilitate the optimization of cell therapy protocols for both diabetic and non-diabetic patients and provide new direction to ongoing and future clinical trials.

project_terms:
Accounting;Affect;Animals;Attenuated;Cardiac;Cause of Death;Cell Proliferation;Cell Therapy;Cell physiology;Cells;Cessation of life;Clinical;Clinical Research;Clinical Trials;Competence;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Engraftment;Exposure to;Fatty acid glycerol esters;Fructose;Functional disorder;Future;Glucose;Glycolysis;Health;Heart failure;Hyperglycemia;Hyperglycemic Mice;In Vitro;Infarction;Insulin;Insulin Receptor;Insulin Resistance;Isogenic transplantation;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mortality Vital Statistics;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Patients;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Production;Property;Proto-Oncogene Protein c-kit;Protocols documentation;Recovery;Regulation;Respiration;Role;Stem cell transplant;Stem cells;Structure;Testing;Transplantation;Treatment Efficacy;United States;Work;base;cardiac repair;cell injury;db/db mouse;design;diabetic;diabetic patient;feeding;fructose 26-diphosphate;glucose transport;heart function;hemodynamics;improved;in vivo;inhibitor/antagonist;myocardial damage;non-diabetic;novel therapeutic intervention;overexpression;preclinical study;prevent;repaired;research study;self-renewal;stem cell division;stem cell therapy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Heart failure is a leading cause of death and is prominent in patients with diabetes. In this project we will examine the mechanisms by which cardiac stem cells are damaged by diabetes and how stem cell therapy can be improved to ameliorate heart failure. These studies could lay the groundwork for the development of novel therapeutic interventions to reverse myocardial damage and prevent heart failure in both non-diabetic and diabetic patients.


application_id: 9134677
project_number: 5U01AG050636-02
project_title: Preclinical Development of a Selective Suppressor of Neuroinflammation for MCI/AD
administering_ic: NIA
award_notice_date: 2016-05-11
opportunity_number: PAR-12-015
application_type: 5
activity_code: U01
ic: AG
serial_number: 050636
program_official: PETANCESKA, SUZANA
project_start_date: 2015-09-01
project_end_date: 2018-04-30
study_section: ZAG1-ZIJ-6(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: WATTERSON, DANIEL MARTIN
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
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): Alzheimer's disease (AD) is one of the largest global public health crises facing us today and is predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent cure or slow the progression of disease and new therapeutic strategies are urgently needed. Our strategy is to target the abnormal glial activation and neuroinflammation that arises early in AD progression and that is becoming of increased interest as a therapeutic target. Dysregulated neuroinflammation responses such as proinflammatory cytokine overproduction from abnormally activated glia are seen early in AD and are thought to be a key contributor to downstream synaptic dysfunction and cognitive deficits. This raises the possibility that selective targeting of the dysregulated cytokine response may be a useful therapeutic approach. This application seeks three years of support to bring to IND status a novel experimental therapeutic (termed MW151) whose pharmacological mechanism of action is to attenuate disease- and injury-induced proinflammatory cytokine overproduction thereby reducing downstream synaptic and cognitive dysfunction in multiple animal models of CNS disorders. MW151 is a water-soluble orally bioavailable CNS-penetrant small molecule with outstanding chemical and metabolic stability. MW151 has been extensively de-risked through several non-GLP pharmacological and toxicology screens and a GMP compatible production scheme has been developed. However MW151 has not progressed into final GLP preclinical development. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with mild cognitive impairment due to AD. With U01 funding we will pursue three aims that are milestone-driven with clear Go/No Go decision criteria. Aim 1: Perform preclinical pharmacokinetics and safety assessment of MW151. Aim 2: Produce GMP drug substance (API) and oral drug product. Aim 3: Obtain an IND for future first-in-human clinical investigations. This project will advance development of a promising drug candidate with the potential to prevent the transition to or slow the progression of AD. In addition successful development of MW151 could have broad clinical applications not only to AD but to a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.

project_terms:
Acute Brain Injuries;Address;Advanced Development;Adverse event;Age;Alzheimer's Disease;Animal Model;Attenuated;Bioavailable;Biological Availability;Brain;Canis familiaris;Central Nervous System Diseases;Cessation of life;Chemicals;Clinical;Clinical Research;Cognitive deficits;Communication;Critical Care;Data;Dementia;Development;Disease;Disease Progression;Dose;Drug Kinetics;Formulation;Functional disorder;Funding;Future;Guidelines;Head;Health;Homeostasis;Human;Impaired cognition;Individual;Injury;Intellectual Property;Intervention;Intravenous;Investigation;Investigational Drugs;Investigational Therapies;Knock-in;Medicine;Metabolic;Modeling;Neurodegenerative Disorders;Neuroglia;Neurological outcome;Neurons;Oral;Oral Administration;Outcome;Parents;Pathology;Pathway interactions;Patients;Penetration;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Phase I Clinical Trials;Physiological;Population;Production;Public Health;Publishing;Rattus;Reporting;Risk;Role;Route;Safety;Scheme;Staging;Stress;Synapses;Testing;Therapeutic;Time;TimeLine;Toxicogenetics;Toxicology;Traumatic Brain Injury;Water;Work;analog;attenuation;base;clinical application;clinical investigation;cytokine;drug candidate;effective therapy;experience;glial activation;healthy volunteer;humanized mouse;interest;mild cognitive impairment;neuroinflammation;novel;novel therapeutic intervention;phase 2 study;pre-clinical;prevent;progressive neurodegeneration;response;safety study;small molecule;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed preclinical campaign addresses the urgent and critical need to develop effective disease-modifying therapeutics to prevent delay and treat AD. We are proposing to develop a promising drug candidate that in animal models attenuates the overactive proinflammatory cytokine aspect of neuroinflammation and prevents the downstream neuron dysfunction and cognitive impairment that characterizes neurodegenerative disease progression. The aims are focused on FDA guidelines for investigational new drug status.


application_id: 9133750
project_number: 261201300013I-0-26100006-1
project_title: IGF::OT::IGF PATTERNS OF CARE/QUALITY OF CARE: DIAGNOSIS YEAR 2014 (SEER)
administering_ic: NCI
project_start_date: 2015-08-15
project_end_date: 2016-08-14
contact_pi_person_id: 14214062
contact_pi: KIMBLER, KIMBERLY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
SEER Patterns of Care Studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States.   SEER Patterns of Care/Quality of Care Studies (POC/QOC) are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a) (2) (C) adopted November 4 1988) to the National Cancer Institute (NCI) to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports.  To select the cancers to satisfy this directive the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment.  This years Patterns of Care (POC) Study shall investigate state-of-the-art therapies for patients with cancers of sites: Stage IV colon cancer Chronic lymphocytic leukemia (CLL) and multiple myeloma.

project_terms:
Adjuvant Therapy;Adopted;Age;Beds;Biological Markers;Cancer Patient;Characteristics;Chronic Lymphocytic Leukemia;Clinical Trials;Colon Carcinoma;Communities;Community Practice;Comorbidity;Data;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Educational process of instructing;Ethnicity aspects;Geographic Locations;Hospitals;Immunotherapy;Insurance Coverage;Laws;Link;Malignant Neoplasms;Medicare;Multiple Myeloma;National Cancer Institute;Operative Surgical Procedures;Outcome;Patients;Pattern;Patterns of Care;Physicians;Quality of Care;Race;Radiation therapy;Reporting;Staging;Time;United States;Work;cancer site;cancer therapy;chemotherapy;clinical practice;hormone therapy;sex


application_id: 9133405
project_number: 4R01GM104123-04
project_title: Functional analysis of programmed genome rearrangement
administering_ic: NIGMS
award_notice_date: 2016-08-22
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: GM
serial_number: 104123
program_official: CARTER, ANTHONY D
project_start_date: 2013-09-01
project_end_date: 2018-08-31
study_section: Genetic Variation and Evolution Study Section[GVE]
contact_pi_person_id: 9381521
contact_pi: SMITH, JERAMIAH JAMES
other_pis: Not Applicable
congressional_district: 06
department: 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    This proposal stems from our recent discovery that the sea lamprey (unlike other vertebrates) undergoes large- scale genome rearrangements during the normal course of its embryonic development. Programmed genome rearrangement (PGR) results in the highly reproducible elimination of ~20% of the lamprey's genome during the establishment of somatic cell lineages in the early embryo. Recent work has revealed that: 1) hundreds of gene-coding fragments are eliminated 2) human homologs of lost genes generally possess "pluripotency" functions 3) computational analysis of "next-gen" sequence datasets identify predicted recombination sites that mediate deletion events which have been validated experimentally indicating that PGR is mediated in part by recombination and 4) proteins expressed in the early embryo show sequence-specific binding to validated recombination sites. With the advent of extensive sequence resources for lamprey and methods for gene knockdown and transcript replacement lamprey will continue to provide unique insights into the rearrangement biology of vertebrate genomes and the genetics of somatic vs. germline cell fate. As such this research is broadly relevant to NIGMS research programs in genetics and developmental biology particularly towards understanding the biology of genomes chromosomes and epigenetics vertebrate developmental genetics stem cell biology genetic mechanisms of DNA recombination/repair and oncogenesis. The specific aims of this proposal will seek to further characterize lamprey PGR at the genetic level in order to deduce its molecular mechanisms and use this information to guide functional studies of the biological causes and consequences of genome rearrangement. Specific Aim 1 will allow us to further refine our functional models of PGR by developing a meiotic map for the lamprey genome and integrating this with existing somatic and germline genome assemblies. Analyses of this map will shed critical light on the scale distribution biological function and likely mechanisms of deletion. Specific Aim 2 dissects the biological function of genes that are deleted through PGR. Experiments performed under this aim will use morpholino mediated gene knockdowns and transcript replacement to elucidate the function of somatically deleted genes and their human homologs. Specific Aim 3 identifies genes that mediate PGR and characterizes their molecular function. Experiments performed under this aim will use morpholino-mediated knockdown to elucidate the function of genes that bind recombination sites during PGR then use transcript replacement to test whether human homologs can partly or completely replace these functions. This will provide a direct assay for the capacity of identified human homologs to participate in somatic recombination. Critically these approaches do not rely on pre-existing knowledge regarding the function of human genes and therefore hold great potential for the discovery of new gene functions. These studies are expected to provide unique insight into vertebrate genome biology and yield information that might not be achievable outside of the context of PGR.

project_terms:
Binding;Binding Proteins;Biological;Biological Assay;Biological Process;Biology;Candidate Disease Gene;Cell Death;Cell Lineage;Cell Proliferation;Cells;Chromosomes;Code;Computer Analysis;Control Animal;DNA;Data Set;Development;Developmental Biology;Disease;Embryo;Embryonic Development;Epigenetic Process;Event;Fertility;Fertilization in Vitro;Gene Deletion;Genes;Genetic;Genetic Polymorphism;Genetic Recombination;Genome;Genome Stability;Genomics;Health;Homologous Gene;Human;Human Genome;Individual;Knowledge;Lampreys;Light;Maintenance;Maps;Mass Spectrum Analysis;Measures;Mediating;Meiosis;Methods;Modeling;Molecular;National Institute of General Medical Sciences;Outcome;Pattern;Petromyzon marinus;Play;Population;Property;Proteins;Regulation;Research;Resistance;Resolution;Resources;Role;Site;Somatic Cell;Specificity;Staging;Study models;Testing;Transcript;Vertebrates;Work;analog;base;comparative;design;developmental genetics;gene function;genome sequencing;genome-wide;genomic data;germline stem cells;insight;knock-down;next generation sequencing;novel;pleiotropism;pluripotency;programs;promoter;recombinational repair;research study;scaffold;stem;stem cell biology;tumorigenesis;vertebrate genome

public_health_relevance:
PUBLIC HEALTH RELEVANCE:     Programmed rearrangement of the lamprey genome provides a highly reproducible model for studying the causes and consequences of genome rearrangement especially as it relates to the biology of germline stem cells. Proposed research will use the lamprey as a model for studying 1) the genetic consequences of programmed gene deletions 2) the molecular basis of rearrangement and 3) the capacity of specific human genes to mediate rearrangement. This work will shed new light on the molecular basis of genome stability/instability and fundamental molecular properties of germline stem cells focusing on genes with human homologs.


application_id: 9132723
project_number: 5R01CA194409-03
project_title: sEcad as a novel target and therapy for IGF-1R expressing tumors
administering_ic: NCI
award_notice_date: 2016-08-15
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 194409
program_official: MUSZYNSKI, KAREN
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Cancer Immunopathology and Immunotherapy Study Section[CII]
contact_pi_person_id: 7799129
contact_pi: BROUXHON, SABINE M
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Over the last decade the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone-receptor-positive disease. In combination with adjuvant chemotherapy drugs such as trastuzumab (anti-HER2 antibody) or tamoxifen (hormone therapy) have significantly reduced relapses and increased disease-free survival in patients with metastatic disease. However despite an initial positive response the majority of patient's exhibit resistance - rendering the therapy ineffective within one year of treatment. Increased expression and hyperactivation of the insulin-like growth factor 1 receptor (IGF-1R) and its associated downstream signaling components (MAPK-PI3K/Akt/mTOR- IAP) have been implicated in this de novo and acquired resistance. Therefore identification of novel targets and antineoplastic agents that modulate IGF-1R signaling is paramount.  We have recently identified soluble E-cadherin termed sEcad as a novel oncogenic target that is selectively increased in human breast cancers. Additionally we have discovered that sEcad imparts its tumorigenic effects (enhances proliferation migration and invasion) by activating many of these resistance pathways including IGF-1R and downstream MAPK-PI3K/Akt/mTOR-IAP signaling. More importantly using a purified IGF-1R holoreceptor we are the first to discover that sEcad acts as a true ligand for IGF-1R and in the presence of its natural ligand IGF-1 synergistically increases IGF-1R phosphorylation. Furthermore we have evidence that sEcad synergizes with the high-affinity HER and IGF-1R ligands IGF1 and EGF to promote cancer cell proliferation migration and invasion in vitro and act as an oncogenic driver in xenograft tumors in vivo. Therefore we propose that sEcad is a valid and innovative therapeutic target for breast cancer.  Additionally we have recently tested region-specific antibodies against sEcad that successfully suppressed HER2+ and hormone-receptor positive breast cancers by directly inducing tumor cell death (apoptosis and necrosis) via down-regulating the IGF-1R HER and MAPK-PI3K/Akt/mTOR-IAP axis. In trastuzumab-resistant breast cancer xenografts (which endogenously overexpress IGF-1R) and MMTV-PyMT mice our studies demonstrate that targeted inhibition of sEcad successfully reduced tumor burden by inhibiting proliferation and inducing cell death. Consistent with the in vivo findings this targeted therapy inhibited proliferation and directly induced apoptosis and necrosis in hormone-receptor-positive and trastuzumab-resistant breast cancer cells without showing any off-target cytotoxic effects in normal cells.  In this translational study we have assembled an outstanding research team to: 1) biochemically and biophysically characterize the sEcad-IGF-1R interactions; 2) determine whether targeted inhibition of sEcad suppresses IGF-1R expressing breast cancers in vitro and in vivo; 3) gain mechanistic insights into how the antibody functions to down-regulate the IGF-1R axis; and 4) perform rodent efficacy PK/PD studies and evaluation of off-target effects.  Of note although monoclonal antibodies against IGF-1R have given mixed results in clinical trials these anti-sEcad antibodies potentially represent a completely different class of IGF1R inhibitors with a very unique and innovative targeting mechanism.

project_terms:
Address;Adjuvant Chemotherapy;Affinity;Antibodies;Antigens;Antineoplastic Agents;Apoptosis;Binding;Biochemical;Breast;Breast Cancer Cell;Breast Carcinogenesis;Breast Oncology;Breast cancer metastasis;Cell Death;Cell Proliferation;Cells;Cetuximab;Clinical Trials;Development;Disease;Disease-Free Survival;Drug Kinetics;E-Cadherin;EGF gene;ERBB2 gene;Effectiveness;Endocytosis;Epidermal Growth Factor Receptor;Evaluation Studies;Exhibits;FRAP1 gene;Grant;Growth;Health;Hormone Receptor;Human;IGF1 gene;IGF1R gene;In Vitro;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;Lead;Ligands;MAP Kinase Gene;Malignant Neoplasms;Mediating;Modeling;Monoclonal Antibodies;Mouse Mammary Tumor Virus;Mus;Necrosis;Neoplasm Metastasis;Normal Cell;Oncogenic;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phosphorylation;Proteins;Receptor Inhibition;Receptor Signaling;Relapse;Research;Resistance;Rodent;Signal Transduction;Tamoxifen;Testing;Trastuzumab;Tumor Burden;Woman;Xenograft procedure;biophysical properties;cancer cell;crosslink;cytotoxic;hormone therapy;in vivo;ineffective therapies;inhibitor/antagonist;innovation;insight;malignant breast neoplasm;migration;mouse model;neoplastic cell;new therapeutic target;novel;novel anticancer drug;novel therapeutics;overexpression;receptor;response;safety testing;targeted treatment;therapeutic target;translational study;tumor;tumor growth;tumor xenograft;tumorigenic

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Breast cancer is the most common cancer in women with 1.7 million new cases in 2012 worldwide. Soluble E-cadherin a small protein produced by cancer cells in large quantities appears to enhance cancer growth and expansion. In this R01 grant we will study the function of soluble E-cadherin in breast cancer development and how it binds to a cancer growth promoting receptor IGF-1R. Additionally we will test the effectiveness of a new therapy we developed against this soluble fragment in human cells and mouse models of breast cancer so as to understand whether IGF-1R is involved. We believe that our discovery will lead to a new therapy for human breast cancer.


application_id: 9132456
project_number: 3R01EY024173-02S1
project_title: Parallel Tectothalamic Pathways
administering_ic: NEI
award_notice_date: 2015-08-27
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: EY
serial_number: 024173
suffix: S1
program_official: FLANDERS, MARTHA C
project_start_date: 2014-09-02
project_end_date: 2019-08-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Affect;Animals;Back;Butyric Acids;Cell Nucleus;Cells;Code;Detection;Disease;Dorsal;Dyslexia;Electron Microscopy;Electrons;Health;Homologous Gene;In Vitro;Investigation;Lateral;Lateral Geniculate Body;Lateral posterior nucleus of thalamus;Literature;Microscopic;Motion;Motion Perception;Movement;Mus;Neurons;Output;Pathway interactions;Perception;Population;Process;Property;Pulvinar structure;Reaction;Relative (related person);Research;Rodent;Schizophrenia;Signal Transduction;Site;Stimulus;Stream;Structure;Synapses;Techniques;Tectum Mesencephali;Thalamic structure;Vision;Visual;Visual Motion;Visual system structure;Whole-Cell Recordings;area striata;base;brain circuitry;cell type;detector;extrastriate;extrastriate visual cortex;insight;magnocellular;motion sensitivity;novel;optogenetics;parvocellular;receptive field;research study;response;segregation;superior colliculus Corpora quadrigemina;visual neuroscience;visual stimulus


application_id: 9131675
project_number: 5R00DA033373-05
project_title: Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen
administering_ic: NIDA
award_notice_date: 2016-08-10
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: DA
serial_number: 033373
program_official: SORENSEN, ROGER
project_start_date: 2014-09-15
project_end_date: 2017-08-31
study_section: NSS
contact_pi_person_id: 9713925
contact_pi: BECKMANN, JOSHUA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The proposed career development plan is designed to provide the PI with a unique skill set and experience tomeet the short-term goal of becoming a productive independent researcher and long-term goal of becoming asignificant contributor to the understanding and treatment of substance abuse disorders. The plan will becarried out at the University of Kentucky an institution with a rich history of interdisciplinary substance abuseresearch. The PI will be mentored by Dr.Michael Bardo and co-mentored by Dr. Greg Gerhardt establishedexperts in neuropsychopharmacology and neurochemistry respectively. The plan proposes to use enzyme-based microelectrode arrays to uncover the role of sub-second tonic/phasic mesocorticolimbic glutamaterelease in individual differences in incentive salience/value attribution to reward-related cues and cocainereinforcement in a preclinical rat model. When a stimulus reliably predicts reward some animals attributeincentive value to the stimulus and thus will approach and contact it (sign-trackers); other animals use thestimulus as a simple signal of forthcoming reward and thus will approach the receptacle into which reward willbe delivered (goal-trackers). Recently it has been demonstrated that differences in sign and goal tracking arerelated to novelty seeking impulsivity initial vulnerability to cocaine reinforcement and relapse vulnerability.In addition to mesocorticolimbic dopamine stimulus-reward learning and drugs of abuse are known to altermesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive valueattribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; thisdifferential release is then exacerbated by repeated cocaine self-administration giving rise to differentialsubstance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/phasicglutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals.Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal-tracking and underlying tonic/phasic glutamate signaling. Specific Aim 3 will determine if second-by-secondtonic and phasic glutamatergic signaling in sign- and goal-tracking animals changes differentially withrepeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptorfunction on cocaine self-administration and tonic/phasic glutamate signaling in sign- and goal-trackers.Collectively these results will provide insight into the role of tonic/phasic glutamate signaling in stimulus-reward learning incentive value attribution to reward-associated stimuli and cocaine reinforcement whileproviding the PI with unique training in neuropsychopharmacology and neurochemistry by experts in bothfields.

project_terms:
Abstinence;Addictive Behavior;Affect;Animals;Behavior;Cell Nucleus;Chronic;Cocaine;Control Animal;Cues;Development;Development Plans;Disease;Dopamine;Dopamine Antagonists;Dopamine Receptor;Enzymes;Exhibits;Food;Glutamates;Goals;Impulsivity;Incentives;Individual;Individual Differences;Institution;Kentucky;Learning;Maintenance;Mediating;Mentors;Microdialysis;Microelectrodes;Modeling;Neurons;Pharmaceutical Preparations;Pharmacotherapy;Phase;Play;Psychological reinforcement;Rattus;Receptor Inhibition;Recording of previous events;Relapse;Research;Research Personnel;Rewards;Role;Schedule;Self Administration;Self-Administered;Signal Transduction;Stimulus;Substance Use Disorder;Substance abuse problem;Technology;Time;Training;Universities;awake;base;career development;classical conditioning;cocaine exposure;design;drug of abuse;experience;glutamatergic signaling;incentive salience;insight;meetings;neurochemistry;neuropsychopharmacology;novel;pre-clinical;prevent;receptor function;research study;response;skills;substance abuse treatment;temporal measurement

public_health_relevance:
Although many people may experiment with drugs of abuse few come to develop a substance use disorders.These individual differences suggest that some people may be more or less prone to develop such disorders.These individual differences may be related to differential attribution of incentive value to reward-relatedstimuli; the broad goal of this research is to identify the underlying neurochemical basis for individualdifferences in substance abuse vulnerability and will be beneficial in identifying novel pharmacological targetsfor the development of substance abuse pharmacotherapies.


