# projects

application_id: 9355051
project_number: 5R21NS099781-02
project_title: Validation of a Point of Care Diagnostic for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2017-08-18
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 099781
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-09-30
project_end_date: 2019-08-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Traumatic brain injury (TBI) is a substantial health care issue affecting both civilian and militarypopulations. Although extremes of head injury are recognizable mild to moderate TBI (MMTBI) is moredifficult to diagnose leading to a need for the identification of circulating biomarkers of brain injury that mayfacilitate early identification. Using a rat model of TBI we identified a novel marker of neuronal injury visininlike protein 1 (VILIP-1) that is released into blood rapidly after injury. To facilitate rapid measurement ofcirculating VILIP-1 we developed a combined lateral flow device (LFD) that provides detection of the biomarkerin less than 20 min. Although initial testing in human TBI patients are promising there is a need for furthertesting in blood samples drawn clinically well characterized TBI patients soon after injury. The aim of thecurrent proposal is to further validate the use of our LFD as a point of care diagnostic for TBI using acombination of archived serum samples from normal control subjects as well as patients with systemictraumatic injuries but no TBI and subjects with mild to moderate TBI and whole blood samples from patientsbeing evaluated in the emergency department of Orlando Regional Medical Center. If successful theproposed studies will validate the use of our VILIP-1 LFD for rapid in field detection of MMTBI and will providethe preliminary data to support a larger clinical trial of the device that could ultimately benefit both civilian andmilitary populations.

project_terms:
Accident and Emergency department;Acute;Adult;Affect;Afghanistan;Archives;Biological Markers;Blinded;Blood;Blood specimen;Brain;Brain Injuries;Cerebrospinal Fluid;Clinical;Clinical Trials;Code;Color;Coma;Computers;Craniocerebral Trauma;Data;Databases;Detection;Devices;Diagnosis;Diagnostic radiologic examination;Diffuse;Early identification;Enrollment;Enzyme-Linked Immunosorbent Assay;Enzymes;Filament;Fracture;Future;Healthcare;Hemorrhage;Hospitals;Hour;Human;Immunoassay;Injury;Iraq;Kentucky;Lateral;Link;Measurement;Measures;Medical center;Military Personnel;Modeling;Modernization;Myelin Basic Proteins;Nature;Neuron-Specific Enolase;Neuronal Injury;Neurons;Operative Surgical Procedures;Patients;Phase;Population;Prospective cohort study;Proteins;Rattus;Research;Sampling;Scanning;Serum;Specificity;Sports;TBI Patients;Temperature;Testing;Therapeutic;Time;Trauma patient;Traumatic Brain Injury;Traumatic injury;Universities;Use Effectiveness;Validation;Veterans;Visual;War;Whole Blood;X-Ray Computed Tomography;blood-based biomarker;circulating biomarkers;controlled cortical impact;falls;injured;interest;male;mild traumatic brain injury;neurotrophic protein S100beta;novel marker;point of care;point-of-care diagnostics;prospective;screening;sensor;tomography;vehicular accident;visinin

public_health_relevance:
NarrativeTraumatic brain injury (TBI) is a substantial health care issue affecting both civilian and militarypopulations. Despite considerable research there remains a critical need for a biomarker test that canrapidly measure a maker of mild to moderate TBI (MMTBI) in blood or cerebrospinal fluid and provideidentification of patient during a clinically useful time frame. Preliminary and future studies described inthis proposal aim to test the usefulness of a lateral flow device (LFD) that quantifies visinin like protein1 (VILIP-1) a neuron specific Ca2+-sensor protein released into blood following TBI.


application_id: 9353405
project_number: 5R01DK112282-02
project_title: The activation of brown and beige fat and role in insulin sensitivity
administering_ic: NIDDK
award_notice_date: 2017-08-14
opportunity_number: RFA-DK-15-031
application_type: 5
activity_code: R01
ic: DK
serial_number: 112282
program_official: LAUGHLIN, MAREN R
project_start_date: 2016-09-15
project_end_date: 2019-08-31
study_section: ZDK1-GRB-7(O2)S
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:
There has been much interest in exploiting brown adipose tissue (BAT) and beige adiposetissue for the treatment of obesity and related complications. Although brown and beigeadipocytes are derived from different precursors and display unique patterns of gene expressionmarkers both cells have increased mitochondrial content and express UCP1 which uncouplesoxidative respiration to generate heat. In addition both brown and beige adipocytes requirePPAR for their development and both cell types are induced through the -adrenergic receptor(AR)/PKA pathway. BAT and beige fat are activated through the sympathetic nervous systemor by the use of AR agonist drugs. Adipose tissue contains 3AR and there have beenattempts to treat obesity with 3 agonists. Currently mirabegron (Myrbetriq Astellas) is ahighly specific 3 agonist marketed for overactive bladder with minimal side effects at therecommended dose. In addition the diabetes drug pioglitazone is a PPAR agonist whichreduces inflammation and improves insulin sensitivity. We hypothesize that the combination ofpioglitazone and mirabegron will be more effective than either drug alone at activating both BATand beige adipose tissue and in improving insulin sensitivity. We hypothesize that themechanism of this improvement in insulin sensitivity will result from an increased partitioning oflipid into oxidative pathways improved metabolic flexibility and decreased adiposeinflammation.Hypothesis 1. Chronic treatment of insulin resistant subjects with a 3 agonist will result inincreased mass and activity of BAT and beige adipose tissue along with increased restingmetabolic rate.Hypothesis 2. The combined treatment with both a TZD (PPAR agonist) and a 3 agonist willresult in an additional stimulation of BAT and beige adipose mass and activity.Hypothesis 3. The activation of BAT and beige adipose tissue will be associated with reducedskeletal muscle lipotoxicity and improvements in adipose tissue inflammation.Hypothesis 4. The activation of BAT and beige adipose tissue by combined TZD and 3agonists will result in a greater improvement in insulin sensitivity than by monotherapy alone.These studies are important because the repurposing of these common drugs couldsynergistically improve many of the metabolic dysfunctions in obese individuals.

project_terms:
Adipocytes;Adipose tissue;Adverse effects;Agonist;Basal metabolic rate;Biogenesis;Brown Fat;CREB1 gene;Cells;Chronic;Combined Modality Therapy;Cyclic AMP-Dependent Protein Kinases;Development;Diabetes Mellitus;Dose;Energy Metabolism;Fatty acid glycerol esters;Functional disorder;Gene Expression Profile;Genetic Transcription;Heart Diseases;Human;Individual;Inflammation;Insulin Resistance;Lead;Link;Lipids;Lipolysis;Mammals;Metabolic;Metabolism;Mitochondria;Mus;Obesity;Overactive Bladder;Oxidative Phosphorylation;PET/CT scan;PPAR gamma;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Pioglitazone;Respiration;Role;Skeletal Muscle;Sympathetic Nervous System;Thermogenesis;Tissues;beta-adrenergic receptor;cell type;flexibility;improved;insulin sensitivity;interest;natural hypothermia;obesity treatment;prevent;therapeutic target;transcription factor;transdifferentiation;uncoupling protein 1

public_health_relevance:
Obesity is closely linked with insulin resistance diabetes and heart disease. Brown and beigeadipose tissue can increase energy expenditure and help prevent obesity complications. Thisproposal examines two common drugs which may synergistically increase brown/beige fatwhich could lead to improvement the metabolic dysfunction in adipose tissue and improveinsulin sensitivity.


application_id: 9352511
project_number: 3R01HL111932-04S1
project_title: Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates
administering_ic: NHLBI
award_notice_date: 2016-09-17
opportunity_number: PA-11-260
application_type: 3
activity_code: R01
ic: HL
serial_number: 111932
suffix: S1
program_official: LIU, LIJUAN
project_start_date: 2013-02-01
project_end_date: 2017-11-30
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
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;Apolipoproteins;Arterial Fatty Streak;Arteries;Atherosclerosis;Binding;Cells;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;inflammatory marker;laser capture microdissection;mRNA Transcript Degradation;macrophage;nonhuman primate;novel therapeutic intervention;oxidation;pre-clinical;protective effect;reverse cholesterol transport;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: 9350788
project_number: 1DP2CA228043-01
project_title: Harnessing Single Cell Technology to Define Self-Renewal in Normal and Malignant Stem Cells
administering_ic: NCI
award_notice_date: 2017-09-18
opportunity_number: RFA-RM-16-004
application_type: 1
activity_code: DP2
ic: CA
serial_number: 228043
program_official: KLAUZINSKA, MALGORZATA
project_start_date: 2017-09-22
project_end_date: 2022-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-R (56)]
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_abstract:
!Project Summary A major clinical issue in most cancers is relapse. Patients often respond very well tochemotherapy and can go years without any sign of disease but a subset of patients will invariably re-develop their cancer with a poor final prognosis. Relapse occurs because our current chemotherapiesare unable to reliably and completely eliminate tumor propagating cells also known as cancer stem cells.These cells are unique among the tumor cell population in that they can self-renew meaning that theycan replenish a tumor cell population indefinitely similar to the role of the normal tissue stem cells intissue and organ maintenance. Preventing self-renewal in tumor propagating cells would cause them toterminally differentiate thereby blocking their ability to form relapse. Unfortunately self-renewal of tumorpropagating cells is not well understood precluding rational drug design. A major issue in regards tostudying these cells is their rarity; they often comprise 1 in every 105-107 cells within the total tumor cellpopulation in human cancers and mouse models and culture ex vivo alters their self-renewal capability.Researchers necessarily rely on FACS enrichment based on certain cell surface markers but this biasestowards the cells expressing the markers and excludes some subsets of self-renewing cells. The goal of this project is to have a major impact in the biomedical field by defining self-renewalin tumor propagating cells in a completely unbiased manner. We will use leukemia propagating cells as amodel and determine how these cells differ from normal hematopoeitic stem cells which can also self-renew and how are they unique from other leukemic cells that cannot self-renew. Based on these datawe will find ways to detect leukemia propagating cells in patients and identify drugs that can inhibit theirself-renewal ability. Initially we will use a panel of high self-renewing acute lymphoblastic leukemias andnormal hematopoietic stem cells isolated from zebrafish models which will allow us to use single cellRNA sequencing to identify the unique gene expression profile of self-renewing leukemia propagatingcells without the need for FACS enrichment. We will translate our findings to human cells to build abiomarker panel that can detect the frequency of self-renewing cells in patient samples and tell uswhether chemotherapy has successfully eliminated them. We will also characterize the stem cell niche inleukemias with high and low self-renewal rates to identify how the niche is regulating self-renewal rate.Finally we will use transplantation approaches in zebrafish as well as new zebrafish models in which theleukemia propagating cells are fluorescently labeled for high-throughput in vivo drug screens to identifycompounds that impair self-renewal. In total this project will provide an unbiased genomic and functionalanalysis of tumor propagating cells allowing us to answer fundamental questions about the biology ofthis important tumor cell type.

project_terms:
Acute Lymphocytic Leukemia;Automobile Driving;Biology;Cancer Biology;Cancer Model;Cancer Relapse;Cell surface;Cells;Clinical;Data;Disease;Drug Design;Frequencies;Gene Expression Profile;Genomics;Goals;Hematopoietic stem cells;Human;Impairment;Label;Leukemic Cell;Maintenance;Malignant Neoplasms;Modeling;Normal tissue morphology;Organ;Patients;Pharmaceutical Preparations;Population;Preclinical Drug Evaluation;Relapse;Research Personnel;Role;Sampling;Stem cells;Technology;Tissues;Translating;Transplantation;Zebrafish;base;biomarker panel;cancer stem cell;cell type;chemotherapy;in vivo;leukemia;mouse model;neoplastic cell;outcome forecast;patient subsets;prevent;self renewing cell;self-renewal;single cell sequencing;single cell technology;stem cell niche;success;transcriptome sequencing;tumor;tumor progression

public_health_relevance:
!Project NarrativeCancer stem cells are the major drivers of cancer progression and relapse due to their capability ofindefinite self-renewal. This project will use single cell sequencing technology and unique zebrafishmodels to define the mechanisms driving self-renewal in these cell. Success in this project willcontribute to our fundamental understanding of cancer biology and allow for new rational drug design totarget these cells.


application_id: 9350381
project_number: 5R03HD086512-02
project_title: Spinal loads during activities of daily living: Influences of unilateral lower-limb amputation
administering_ic: NICHD
award_notice_date: 2017-08-23
opportunity_number: PA-13-304
application_type: 5
activity_code: R03
ic: HD
serial_number: 086512
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-1-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
arra_indicator: N
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;Low Prevalence;Lower Extremity;Measurement;Measures;Medical center;Military Personnel;Modeling;Monitor;Motion;Motor;Movement;Muscle;Pathway interactions;Pattern;Persons;Physical activity;Pilot Projects;Play;Population;Probability;Protocols documentation;Quality of life;Recruitment Activity;Rehabilitation therapy;Research;Risk;Role;Speed;Spinal;Standardization;Techniques;Time;Tissues;Training;Translating;Translations;Variant;Vertebral column;Walking;Weight;base;chronic pain;computerized tools;design;effective intervention;experience;in vivo;kinematics;limb amputation;neuromuscular;novel;secondary analysis;service member;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: 9347611
project_number: 1R41DK111314-01A1
project_title: SA-FasL-engineered human islets as a novel product for the treatment of type 1 diabetes
administering_ic: NIDDK
award_notice_date: 2017-06-23
opportunity_number: PA-16-303
application_type: 1
activity_code: R41
ic: DK
serial_number: 111314
suffix: A1
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2017-07-01
project_end_date: 2019-06-30
study_section: Special Emphasis Panel[ZRG1 EMNR-W (10)]
contact_pi_person_id: 8029708
contact_pi: YOLCU, ESMA S
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:
PROJECT SUMMARYType 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide. Exogenousinsulin treatment is the standard of care for T1D but often negatively affects the quality of life and is ineffectivein preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show that humanislet allografts can restore long-term normoglycemia and insulin independence protect from severehypoglycemia and slow progression of microvascular lesions in immunosuppressed T1D patients. Howeverimmune rejection and continuous use of immunosuppression to control rejection are two major limitationsof clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survivaland also has significant adverse effects on the graft and graft recipients. Therefore the development of novelapproaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. FasCure Therapeutics is focused on the development of biologics with desired immune modulatoryactivities for targeted indications. The Company has exclusive rights to a portfolio of proprietary novel immuneinhibitory ligands as components of an immunomodulatory platform for prevention and treatment ofautoimmune diseases and graft rejection. The Companys lead therapeutic platform includes islets engineeredwith a novel form of Fas ligand immunomodulatory protein SA-FasL. T cells are the main culprits of T1D aswell as allogeneic islet graft rejection. T cells upregulate Fas receptor on their surface following antigenactivation and become sensitive to Fas/FasL-mediated apoptosis. Importantly FasL-induced apoptosis playsan important role in T cell homeostasis and tolerance to self-antigens. As such SA-FasL has significantpotential for the induction of tolerance to auto and alloantigens. Consistent with this notion the transientdisplay of SA-FasL protein on pancreatic islets have shown robust efficacy in overcoming immune rejection invarious allogeneic and xenogeneic rodent transplantation models. The major goals of this phase I STTRapplication is to: i) assesses the feasibility of engineering human islets with SA-FasL protein withoutnegatively impacting their function and ii) test the efficacy of SA-FasL-engineered islets in overcomingrejection in a humanized mouse model in the absence of continuous immunosuppression. If feasibilityand efficacy are shown in the humanized mouse model the SA-FasL-engineered human islets will be furtherdeveloped as a novel product in a Phase II STRR application for translation into clinic.

project_terms:
Acute;Adverse effects;Affect;Alloantigen;Allogenic;Allografting;Antigens;Apoptosis;Apoptotic;Autoantigens;Autoimmune Diseases;Autoimmunity;Binding;Biologic Development;Biotin;CD95 Antigens;Cell surface;Cells;Chronic;Cleaved cell;Clinic;Clinical;Clinical Trials;Contracts;Data;Development;Diabetes Mellitus;Engineering;Ensure;Eragrostis;Extracellular Domain;FOXP3 gene;Failure;Generations;Goals;Graft Rejection;Graft Survival;Home environment;Homeostasis;Human;Human Engineering;Hyperglycemia;Hypoglycemia;IL2RA gene;Immune;Immune Targeting;Immunomodulators;Insulin;Insulin-Dependent Diabetes Mellitus;Investigational New Drug Application;Islets of Langerhans;Islets of Langerhans Transplantation;Lead;Lesion;Ligands;Manufacturer Name;Matrix Metalloproteinases;Mediating;Membrane;Membrane Proteins;Memory;Metabolic Control;Metalloproteases;Modeling;Mutation;Natural immunosuppression;Pathway interactions;Patients;Phase;Phase I Clinical Trials;Physiological;Play;Population;Prevention;Proteins;Quality of life;Recurrence;Regulatory T-Lymphocyte;Rights;Rodent;Role;Site;Small Business Technology Transfer Research;Solid;Streptavidin;Surface;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Translations;Transplantation;Tumor Necrosis Factor Ligand Superfamily Member 6;base;cGMP production;chimeric gene;chronic autoimmune disease;clinical application;clinical translation;design;efficacy testing;gene therapy;graft function;humanized mouse;immunoregulation;immunosuppressed;improved;insulin secretion;interest;islet;islet allograft;mouse model;negative affect;novel;novel strategies;prevent;product development;response;scale up;stability testing;standard care;standard of care;technological innovation

public_health_relevance:
PROJECT NARRATIVEType 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of the populationworldwide. Insulin as a standard treatment has major long-term complications; therefore the development ofnovel approaches to prevent and treat T1D is a significant therapeutic goal. The primary objective of thisproposal is to engineer human pancreatic islets with an immunomodulatory biologic and test the efficacy ofengineered islets in preventing rejection and treating diabetes in a humanized mouse model. If effective thisapproach will have immediate and important implications for the use of allogeneic islets for the treatment ofT1D in humans.


application_id: 9346060
project_number: 5R44DK105692-03
project_title: A New Technique for Diabetic Foot Ulcers
administering_ic: NIDDK
award_notice_date: 2017-08-09
opportunity_number: PA-15-269
application_type: 5
activity_code: R44
ic: DK
serial_number: 105692
program_official: JONES, TERESA L Z
project_start_date: 2015-04-01
project_end_date: 2021-08-31
study_section: Special Emphasis Panel[ZRG1-SBIB-G(11)B]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Diabetes is the leading cause of nontraumatic lower extremity amputations in theUnited States. Diabetic foot ulcers (DFUs) are responsible for more hospitalizationsthan any other diabetic complications. Currently even the best available treatmentsachieve only a 50% healing rate for these woundsand this healing is often onlytemporary with a 66% chance of recurring. Our company has developed an intracellular ATP delivery technique (ATP-vesicles orVitaSolTM) for tissue ischemia. When used in wound treatment it heals wounds fasterthan many control dressings. During the Phase I period VitaSolTM healed wounds fasterthan Regranex and showed no toxic effects in the local lymph nodes or reproductivesystems in both male and female rabbits. One special feature of VitaSolTM is its ability totrigger extremely rapid tissue regenerationgranulation growth appears within 24 hoursafter application. This growth continues and covers the wound cavity within a fewdaysa phenomenon never seen or reported before with any other treatment strategy. The Phase II study will bring this new technique closer from the bench to bedside.We will first undertake a larger scale manufacturing of VitaSolTM in a cGMP facility tomeet FDA requirements and to produce VitaSolTM in a practical package for easyapplication. We will then test the new VitaSolTM preparation in an animal model close toDFU (12-month diabetes plus ischemia) and to compare the healing effects withRegranex. Our approach is a potential game changer for DFU treatment: The wound healingprocess involves hemostasis inflammation proliferation and remodeling resulting in a36 day lag before granulation tissue starts to appear. This process seems to becarved in stone and no one has ever been able to change it. The elimination of the lagtime and the ability to support cell survival and proliferation in a wound cavity withoutblood supply are two features never been achieved with any other treatment. Thesecharacteristics could have tremendous potential in the treatment of DFUs. The potentialimpact is high.

project_terms:
Amputation;Animal Model;Becaplermin;Caring;Cell Proliferation;Cell Survival;Characteristics;Clinical;Complications of Diabetes Mellitus;Cyclic GMP;Cytoplasmic Granules;Diabetes Mellitus;Diabetic Foot Ulcer;Diabetic wound;Effectiveness;Female;Goals;Granulation Tissue;Growth;Hemostatic function;Hospitalization;Hour;Human;Inflammation;Ischemia;Life;Lower Extremity;Oryctolagus cuniculus;Outcome;Phase;Preparation;Process;Reporting;Reproductive system;Sterile coverings;Supporting Cell;Techniques;Testing;Time;Tissues;Toxic effect;United States;Vascular blood supply;Vesicle;Wound Healing;anxious;bench to bedside;chronic wound;clinical application;comparative;diabetic;healing;improved;innovation;inorganic phosphate;lymph nodes;male;novel strategies;phase 1 study;phase 2 study;programs;tissue regeneration;treatment strategy;wound

public_health_relevance:
NARRATIVE Our company has developed a new technique for intracellular ATP delivery to providethe diabetic wounds with much needed energy. The Phase I study has shown itssuperior healing capability than Regranex and no toxicity was found in local lymphnodes and the reproductive systems in both male and female rabbits. The Phase II willproduce the dressing in cGMP facility to make the package for easy application and totest its healing effects in 12-month diabetic plus ischemic wounds. This new approach isa potential game changer for diabetic foot ulcers.


application_id: 9346008
project_number: 5R01AG053999-02
project_title: Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2017-06-20
opportunity_number: PAR-15-358
application_type: 5
activity_code: R01
ic: AG
serial_number: 053999
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2016-09-15
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(56)R]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
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_terms:
4 hydroxynonenal;Abeta clearance;Aging;Alleles;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Animal Model;Apolipoprotein E;Biological Markers;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;Brain Diseases;Brain Injuries;CREB1 gene;Carnosine;Cell Culture Techniques;Cell model;Cerebrospinal Fluid;Cerebrovascular Circulation;Clinical;Clinical Data;Cognitive;Data;Dementia;Deposition;Diagnosis;Disease Progression;Early Onset Familial Alzheimer's Disease;Eicosanoids;Etiology;Genotype;Goals;Hormones;Human;Hypertrophy;Impaired cognition;Impairment;Injectable;Injection of therapeutic agent;Injury;Interleukin-1 beta;Intervention;Kentucky;Knock-out;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipid Peroxidation;Lipid Peroxides;London;Low-Density Lipoproteins;Malondialdehyde;Measures;Mediating;Medical Research;Membrane;Metabolic;Metabolic Diseases;Modeling;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Pancreas;Pancreatic Hormones;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Peroxides;Pharmacologic Substance;Physiological;Plasma;Prevention strategy;Property;Protein Isoforms;Rattus;Research Project Grants;Rest;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Specimen;Testing;Toxic effect;Transgenic Animals;Universities;Vascular Diseases;Work;apolipoprotein E-4;brain tissue;cerebrovascular;clinically relevant;college;cytotoxicity;data modeling;diabetic;diabetic rat;experimental study;human data;human disease;human tissue;inflammatory milieu;inhibitor/antagonist;insight;islet amyloid polypeptide;lipid peroxidation inhibitor;mutation carrier;nervous system disorder;neuroinflammation;neurotoxicity;neurovascular unit;novel;presenilin-1;prevent;repository;therapeutic evaluation;therapeutic target


application_id: 9345868
project_number: 1R41HD090792-01A1
project_title: TheraBracelet: The first and only wearable to instantly improve stroke hand function
administering_ic: NICHD
award_notice_date: 2017-07-23
opportunity_number: PA-16-303
application_type: 1
activity_code: R41
ic: HD
serial_number: 090792
suffix: A1
program_official: CRUZ, THERESA
project_start_date: 2017-08-01
project_end_date: 2018-10-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
contact_pi_person_id: 9744137
contact_pi: SEO, NA JIN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 045576080
duns_number: 045576080
fips: US
organization_id: 10041408
organization_name: THERABRACELET, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041715
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-08-01
project_abstract:
Project Summary: Post-stroke hand impairment is highly prevalent and severely restricts functional ability andindependence. In fact every 40 seconds a new stroke occurs and stroke is recognized as the leading cause oflong-term disability. Yet there is no assistive device to help hand function at home every day during activitiesof daily living. Existing devices such as hand-opening orthoses are expensive (e.g. Myomo and Bioness arepriced at $7500+) uncomfortable bulky and meant for use during short therapy sessions as opposed toduring daily living. Thus their impact is limited. Consequently the development of efficacious and affordableassistive device is of paramount importance. This proposal addresses this critical gap by providing aninnovative patent-pending technology. The TheraBracelet is a wristband applying imperceptible white-noisevibration to skin. TheraBracelet is efficacious as it has been shown to immediately improve chronic strokesurvivors touch sensation and hand dexterity in preliminary studies. TheraBracelet is affordable by using onlya low-cost vibrator. TheraBracelet is also translational because a vibrator strategically placed at the wrist doesnot interfere with dexterous finger motions and it is low-risk by involving only imperceptible vibration on skin.These practicalities assure easy adoption in home environment for large impact on sensorimotor impairment.The essential next step toward commercialization thus the objective of this Phase I proposal is to determinethe feasibility and safety of using this assistive device all day every day for a month during daily activity and todetermine if TheraBracelets instant effects are sustained during prolonged use. This objective will beaccomplished in a double-blinded randomized controlled crossover design study. Feasibility (compliance ofusing the device everyday) and safety (no worsening of sensation strength dexterity pain spasticity skinirritation) will be assessed for the treatment condition compared to the control condition (wearing the devicewithout vibration) through weekly evaluations. The feasibility and safety level comparable to those of wearing awatch and of a comparable FDA-approved device will support commercial viability of TheraBracelet withnecessary regulatory approvals. In addition TheraBracelets instant benefits in improving hand function will beassessed weekly. Persistence of TheraBracelets instant benefits across all weekly evaluations will supportdurability (i.e. desensitization to vibration does not occur during extended daily use over a one-month period).The knowledge of feasibility safety and durability will pave the way toward commercialization of this noveltechnology. This project is expected to lead to an assistive wristband that increases hand function duringactivities of daily living thus increasing independence and quality of life and reducing caregiver burden for alarge number of stroke survivors with hand impairment.

project_terms:
Activities of Daily Living;Address;Adoption;Adverse event;American;Budgets;Calibration;Caregiver Burden;Communities;Crossover Design;Data;Development;Device or Instrument Development;Devices;Double-Blind Method;Economics;Employment;Engineering;Esthesia;Evaluation;FDA approved;Facilities and Administrative Costs;Feedback;Fingers;Forearm;Frequencies;Future;Hand;Hand Strength;Hand functions;Home environment;Hour;Hygiene;Impairment;Intellectual Property;Investigation;Knowledge;Laboratories;Lead;Legal patent;Lower Extremity;Medical;Medical Device;Medicare;Minor;Monitor;Motion;Muscle;Noise;Orthotic Devices;Pain;Participant;Patient Self-Report;Phase;Price;Quality of life;Randomized;Research;Research Design;Risk;Safety;Self Care;Self-Help Devices;Severities;Skin;Spastic;Technology;Testing;Therapeutic;Time;Touch sensation;Upper Extremity;Visit;Vocation;Wrist;base;chronic stroke;commercialization;cost;desensitization;dexterity;disability;hand dysfunction;hand rehabilitation;improved;innovation;new technology;phase 1 study;post stroke;rehabilitation service;research clinical testing;safety and feasibility;skin irritation;spasticity;stroke;stroke survivor;vibration

public_health_relevance:
Project Narrative: There are approximately 6.6 million Americans who have had a stroke with a totalprojected cost of $2.2 trillion from 2005 to 2050 and $13 billion annually in indirect costs associated with lossof earnings. Following a stroke more than two-thirds end up with a disability in the upper limb that lowers theability to perform many daily activities including self-care and vocations thus diminishing the quality of life.This project aims to test a new technology that may improve hand function impaired from a stroke therebyimproving independence and quality of life.


application_id: 9345861
project_number: 1R43ES028171-01
administering_ic: NIEHS
award_notice_date: 2017-09-12
opportunity_number: PA-16-302
application_type: 1
activity_code: R43
ic: ES
serial_number: 028171
program_official: HENRY, HEATHER F
project_start_date: 2017-09-15
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1 IMST-B (12)]
contact_pi_person_id: 14657253
contact_pi: BOEHME, LINDSAY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079388085
primary_uei: JD9MTUKKNG13
duns_number: 079388085
uei: JD9MTUKKNG13
fips: US
organization_id: 10036767
organization_name: POWERTECH WATER, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40508
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-09-15
project_title:
Anode Modification to Target Pb Removal for Drinking Water Purification using Inverted Capacitive Deionization

project_abstract:
Project Summary/AbstractPowerTech Water (PTW) intends to demonstrate the use of inverted capacitive deionzation (i-CDI) technology totarget the removal of heavy metals lead (Pb) in particular from drinking water. Heavy metals such as lead andcopper can enter the water distribution system due to corrosion of pipes and fittings contaminating drinking water.The US Environmental Protection Agency (EPA) established The Lead and Copper Rule in 1991 to limit exposure ofthese elements and set action levels to 0.015 ppm (15 ppb) and 1.3 ppm for lead and copper respectively. The watercrisis that occurred in Flint Michigan last year is an unfortunate case that shows how important it is to ensure lead isbelow the action level in drinking water.Point-of-use (POU) solutions for lead removal include chemical precipitation coagulation ion-exchange and reverseosmosis (RO) all of which have arduous regeneration steps and/or require costly maintenance to replace materials.PTW's solution offers a low-cost low-maintenance reversible adsorption technology that can target metals removal.More specifically using unique surface chemistries to impart selectivity to the carbon anode metals can reversiblyadsorb and desorb from solution using PTW's patented i-CDI process that provides stability and pH control duringoperation.The specific aims of this Phase I grant application include: 1. Demonstrating functionalization of carbon-based anodes with soft base ligands to induce specificity for metals adsorption. 2. Determining the minimum metal concentration in tap water allowed to maintain an adsorption selectivity >50% over non-metal divalent ions.

project_terms:
Adopted;Adoption;Adsorption;Anodes;Applications Grants;Biological;Carbon;Cations;Cereals;Chemicals;Chemistry;Child;Coagulation Process;Complex;Copper;Corrosion;Development;Devices;Electrodes;Elements;Ensure;Excision;Goals;Hardness;Heavy Metals;Home environment;Ion Exchange;Ions;Iron;Kentucky;Lead;Lead Poisoning;Lead levels;Legal patent;Ligands;Maintenance;Measures;Medical;Metals;Methods;Michigan;Modification;Natural regeneration;Osmosis;Phase;Plumbing;Population;Precipitation;Process;Property;Research;Site;Sodium Chloride;Solid;Source;Specificity;Stream;Surface;System;Technology;Translating;United States Environmental Protection Agency;Universities;Water;Water Purification;Water Supply;base;blood lead;commercialization;contaminated drinking water;conventional therapy;cost;drinking water;effective therapy;feeding;hazard;improved;innovation;interest;novel;operation;research and development;toxic metal;voltage;water solution;water treatment

public_health_relevance:
Project NarrativeThe goal of this proposal is to develop an affordable and widely adoptable solution to remove toxic metalslead (Pb) in particular from drinking water. To achieve this a novel anode that is capable of preferentiallyremoving metal ions from water using PowerTech Water's patented inverted capacitive deionization (i-CDI)process will be demonstrated. If successful this technology will provide a practical and efficient method forremoving metals from drinking water.


application_id: 9345560
project_number: 271201100017C-8-0-1
project_title: OTHER FUNCTIONS: Development and Manufacture of Pharmaceutical Products for Addic
administering_ic: NIDA
project_start_date: 2011-09-18
project_end_date: 2016-09-17
contact_pi_person_id: 12576703
contact_pi: MURTY, RAM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 943117366
primary_uei: DNJBTJ3XBQM6
duns_number: 943117366
uei: DNJBTJ3XBQM6
fips: US
organization_id: 3514301
organization_name: MURTY PHARMACEUTICALS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405091016
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of this contract is to carry out the development and manufacture of pharmaceutical preparations to be used in the medications development program of the National Institute on Drug Abuse (NIDA) for addiction treatment.

project_terms:
Clinical Trials;Contractor;Contracts;Data Reporting;Development;Documentation;Dosage Forms;Evaluation;Formulation;Generations;Maintenance;National Institute of Drug Abuse;Pharmaceutical Preparations;Pharmacologic Substance;Placebos;Preparation;Program Development;Resources;Site;Validation;addiction;analytical method;method development;pre-clinical


application_id: 9344557
project_number: 5K22CA201036-02
project_title: Defining epigenetic vulnerabilities of subtype-specific lung cancers
administering_ic: NCI
award_notice_date: 2017-08-10
opportunity_number: PAR-15-056
application_type: 5
activity_code: K22
ic: CA
serial_number: 201036
program_official: JAKOWLEW, SONIA B
project_start_date: 2016-09-30
project_end_date: 2019-08-31
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
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): Future Research Questions: As an independent investigator I will focus on answering two important questions: 1) What are the cells-of-origin orepigenetic programs that produce the two major types of lung tumors? and 2) How can epigenetic therapies be incorporated into useful cancer therapeutics? Background Lung cancer remains the leading cause of cancer related deaths world-wide. Precision medicine options for lung cancer patients may help to decrease the mortality of the disease by targeting the most vulnerable pathways in each specific cancer. However these efforts are complicated by both the genetic and epigenetic complexity of lung tumors. How epigenetic programs influence critical aspects of lung tumorigenesis and normal lung biology remains an uncharted area. Furthermore the lineage relationship and epigenetic differences between the two major subtypes of non-small cell lung cancer namely lung adenocarcinoma and lung squamous cell carcinoma are unclear. My main goal is to find methods to incorporate epigenetic drugs into effective cancer therapies. I will initially focus on lung stem cell biology as my platform to elucidate the cellular origins and epigenetic therapeutic vulnerabilities in lung cancer. Methodology The research proposed herein will allow for direct comparison of the transformation capacity of several lung stem/progenitor cell pools through FACS isolation lentiviral genetic modulation and 3D organotypic culture. The transformation potential and subtype acquisition of the cell pools will be tested by injection into the lungs of immunocompromised mice. This novel system will allow for careful dissection of what lung cells can serve as tumor cells-of-origin and in what contexts (i.e. genetic mutations and epigenetic modulation). These results can be linked back to the most permissible epigenetic states for transformation and allow understanding of how epigenetic programs are co-opted by tumor cells during malignant transformation. In parallel I will study the effects of different epigeneti therapeutics namely inhibition of BRD4 EZH2 or G9A on genetically defined murine lung tumors. I will again use the 3D organotypic culture assay which I have optimized for primary tumor cell growth. This approach will allow cost-effective but biologically relevant assessment of the effects of epigenetic therapies on varied subtypes and genotypes of lung cancer. Both of these approaches will be translated to human biology by using human cells in the 3D cultures. Career Potential I have had a very successful post-doctoral career in the laboratory of Carla Kim at Boston Children's Hospital and I have established a strong relationship with my collaborators for this award Drs. Leonard Zon and Kwok- Kin Wong. I have an outstanding environment and a comprehensive plan that will allow me to transition to an independent research role. My ultimate goal is to lead a research group exploring the relationships between stem cells and cancer with a specific focus on novel cancer therapeutics. I know that the K22 award would greatly aid me in realizing these goals.

project_terms:
AGTR2 gene;ATAC-seq;Adenocarcinoma;Area;Award;Back;Basal Cell;Biological;Biological Assay;Biology;Boston;Cancer Etiology;Cancer Patient;Cells;Cessation of life;ChIP-seq;Complex;DNA Sequence Alteration;Disease;Dissection;Drug Combinations;EZH2 gene;Environment;Epidermal Growth Factor Receptor;Epigenetic Process;Genes;Genetic;Genomics;Genotype;Goals;Growth;Histology;Human;Human Biology;Immunocompromised Host;Infection;Injection of therapeutic agent;K22 Award;Knowledge;Laboratories;Lead;Link;Lung;Lung Adenocarcinoma;Lung Neoplasms;Magnetic Resonance Imaging;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Methods;Mus;Non-Small-Cell Lung Carcinoma;Organoids;Pathway interactions;Patients;Pediatric Hospitals;Pharmaceutical Preparations;Phenotype;Postdoctoral Fellow;Primary Neoplasm;Reader;Research;Research Methodology;Research Personnel;Role;Running;Sampling;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;Stem cells;Structure of parenchyma of lung;System;TP53 gene;Techniques;Testing;Therapeutic;Translating;Transplantation;Tumor Subtype;Vision;Xenograft procedure;cancer therapy;career;cell growth;cell transformation;clinical application;cost effective;disorder subtype;epigenetic drug;experimental study;fitness test;in vivo;inhibitor/antagonist;lung tumorigenesis;mortality;mouse model;neoplastic cell;novel;pre-clinical;precision medicine;programs;public health relevance;response;stem;stem cell biology;three dimensional cell culture;transcriptome sequencing;tumor;tumor initiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE   Lung cancer is the leading cause of cancer-related deaths worldwide and is a highly complex disease with many possible cells-of-origin and genetic drivers. These studies will allow for a better understanding of which cells can serve as cells-of-origin of lung tumors and how differences in epigenetic programs can influence tumor initiation and subtype acquisition. In addition these experiments will help to determine the contexts in which epigenetic therapies which are widely believed to be game-changing in the field of cancer therapeutics will be viable strategies to treat lineage-specific lung cancers.


application_id: 9343261
project_number: 2R44AT008312-02
project_title: Harvesting specific plant metabolites from hairy root cultures using magnetized nanoparticles
administering_ic: NCCIH
award_notice_date: 2017-03-28
opportunity_number: PA-16-302
application_type: 2
activity_code: R44
ic: AT
serial_number: 008312
program_official: HOPP, CRAIG
project_start_date: 2014-06-01
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZRG1 BST-F (10)]
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Plant cell cultures are becoming a commercially valuable source of pharmaceuticals particularlythose that are too complex for economical chemical synthesis. For example Phyton Biotech in Germany hasachieved great commercial success by generating taxoids for Paclitaxel production in sterile plant cellbioreactors. However the efficiency of these systems is limited by the loss in viability of the slow-growing plantcells associated with conventional extraction procedures. The objective here is to develop a system thatallows plant cells to be harvested repeatedly for high value pharmaceutical products without losing viability.Phase I demonstrated that nanoparticles can be functionalized to enter plant cells and bind specific bioactiveflavonoid metabolites before being extruded and these metabolites recovered all without loss of plant cellviability. Phase II now aims to demonstrate that a similar but more selective approach can be used to harvesthigher value pharmaceuticals from plant cells (i.e. proof of application). The most valuable types of metabolitecurrently produced from plants include isoflavones alkaloids and monoclonal antibodies (the latter fromtransgenic plants). Phase II aims to show that each of these types of product can be harvested from plant cellsby their selective binding to nanoparticles on which specific oligopeptides have been conjugated. Each productexample is relevant to anti-cancer therapeutics. The first is the phytoestrogen liquiritigenin which is a selectiveagonist of the estrogen receptor (ER)beta that should reduce risk of breast cancer post-menopause. Thisflavanone will be harvested from overproducing mutant cultures of licorice root by selective binding to theERbeta ligand-binding oligopeptide conjugated to nanoparticles. The second example is to nanoharvest thechemotherapeutic vinca alkaloids (currently extracted from intact plant material by Eli Lilly) from overproducingmutant cultures of Catharanthus roseus. These alkaloids will be harvested by affinity to nanoparticles bearingoligopeptides representing their binding sites on human tubulin. These two examples are natural metabolitesbut the most commercially important application of this technology may be to harvest foreign polypeptides i.e.biologics such as antibodies from transgenic plant cells. Here the example will be the harvesting fromtransgenic tobacco cell cultures of a monoclonal antibody (mAbH10) directed against tumor cells. Selectivebinding will be achieved using nanoparticles in which an oligopeptide mimicking the antibody-binding site onthe antigen has been conjugated to the surface. In all of these examples the objective is to show thatnanoparticles can repeatedly remove the desired commercial product without loss of plant cell viability. Thiswill reduce down time and could also reduce response time for example the urgent requirement forantibodies or vaccines in an outbreak of disease. In addition separation of product by affinity to anoligopeptide binding site means that the harvested products will be simultaneously semi-purified. Phase IIshould demonstrate proof of application for the nanoparticle harvesting technology as applied to high valueanti-cancer pharmaceuticals. The applicants will then move toward commercialization in partnership withidentified pharmaceutical and biotechnology companies in the US and Europe (see Commercialization Plan).

project_terms:
Affect;Affinity;Agonist;Agreement;Alkaloids;Antibodies;Antibody Binding Sites;Antigens;Artificial nanoparticles;Binding;Binding Sites;Bioreactors;Biotechnology;Catharanthus roseus;Cell Culture Techniques;Cell Survival;Cells;Characteristics;Chemicals;Complex;Development;Disadvantaged;Disease Outbreaks;Engineering;Equilibrium;Estrogen Receptor beta;Europe;Excision;Exposure to;Flavanones;Flavonoids;Fluorescence;Germany;Harvest;Human;Immobilization;In Vitro;Individual;International;Isoflavones;Legal patent;Licensing;Licorice;Ligand Binding;Malignant Neoplasms;Monoclonal Antibodies;Mutation;Nicotiana tabacum;Oligopeptides;Paclitaxel;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phase;Phytoestrogens;Plant Roots;Plants;Postmenopause;Procedures;Production;Proteins;Quartz;Reaction Time;Risk;Source;Sterility;Surface;System;Taxoids;Technology;Testing;Therapeutic Effect;Time;Tissues;Tobacco;Transgenic Organisms;Transgenic Plants;Tubulin;Vaccines;Vinca Alkaloids;anti-cancer therapeutic;antigen binding;base;cell injury;chemical synthesis;chemotherapy;commercialization;crystallinity;experimental study;indexing;kartocid;malignant breast neoplasm;mutant;nanoparticle;neoplastic cell;polypeptide;protein aminoacid sequence;radioligand;solvent extraction;success

public_health_relevance:
Project narrativeDrugs can be produced in plant cell cultures as an alternative to extracting them from intact plants. This hassome advantages but a major disadvantage is that harvesting the drugs requires the destruction of the slowgrowing and expensive plant cell cultures. This phase II proposal is to further develop a continuous harvestingsystem in which nanoparticles can be used to extract drugs from plant cells without damaging the cells.


application_id: 9343053
project_number: 5R01NS095229-02
project_title: CNS Functions of Calpain 5
administering_ic: NINDS
award_notice_date: 2017-06-06
opportunity_number: PAS-15-029
application_type: 5
activity_code: R01
ic: NS
serial_number: 095229
program_official: RIDDLE, ROBERT D
project_start_date: 2016-09-01
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-MDCN-C(02)S]
contact_pi_person_id: 1903444
contact_pi: GEDDES, JAMES W.
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:
Actins;Active Sites;Acute;Acute Promyelocytic Leukemia;Afferent Neurons;Affinity;Affinity Chromatography;Alzheimer's Disease;Basic Science;Binding;Binding Sites;Biotin;Brain;C2 Domain;CRISPR/Cas technology;Caenorhabditis elegans;Calcium;Calpain;Caspase;Cell Line;Cell Nucleus;Cell membrane;Cells;Cessation of life;Characteristics;Chronic;Cleaved cell;Computer Simulation;Cysteine;Cytokinesis;Data;Dynein ATPase;EF Hand Motifs;EF-Hand Domain;Family;Genes;Genetic;Genetic Transcription;Human;Impairment;In Vitro;Knock-out;Knockout Mice;Lipids;Long-Term Potentiation;Mass Spectrum Analysis;Membrane;Membrane Lipids;Messenger RNA;Methods;Microtubules;Mitochondria;Necrosis;Nerve Degeneration;Neurodegenerative Disorders;Neurosciences;Nomenclature;Nuclear;Pathologic;Pentas;Peptide Hydrolases;Phenotype;Phospholipids;Physiological;Property;Proprotein Convertase 1;Proprotein Convertase 2;Protease Domain;Protein Isoforms;Proteins;Research;Role;Signal Transduction;Site-Directed Mutagenesis;Spinal Cord;Structure;Techniques;Toxic effect;Traumatic Brain Injury;Triad Acrylic Resin;alpha Actinin;alpha Tubulin;base;beta Tubulin;in vivo;inhibitor/antagonist;insight;interest;knock-down;member;migration;novel;overexpression;protein TDP-43;response;sensor;sex determination;stroke


application_id: 9342859
project_number: 5U24DK097215-05
project_title: OUTREACH CORE
administering_ic: NIDDK
award_notice_date: 2017-09-12
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2021-02-28
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: 2017-09-01
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 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;Publishing;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;experimental study;handbook;human disease;instrumentation;interest;learning materials;meetings;metabolome;metabolomics;next generation;novel;outreach;programs;research and development;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: 9342858
project_number: 5U24DK097215-05
project_title: INFOMRATICS CORE
administering_ic: NIDDK
award_notice_date: 2017-09-12
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2021-02-28
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: 2017-09-01
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:
Archives;Basic Science;Biochemical;Biochemical Pathway;Bioinformatics;Biological Markers;Biometry;Client;Collaborations;Communities;Computer Analysis;Data;Data Analyses;Data Analytics;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;Standardization;Statistical Data Interpretation;Supervision;System;Technology;Testing;Therapeutic Intervention;Time;Tracer;Translational Research;base;biomarker discovery;case control;computerized tools;data integration;experience;experimental study;functional group;human disease;innovation;interest;learning strategy;metabolomics;new therapeutic target;novel marker;outreach;reconstruction;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: 9342856
project_number: 5U24DK097215-05
project_title: ANALYTICAL CORE
administering_ic: NIDDK
award_notice_date: 2017-09-12
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2021-02-28
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: 2017-09-01
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:
Aging;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;Gases;Goals;Human Resources;Informatics;Infusion procedures;Instruction;Isotopes;Journals;Label;Letters;Liquid Chromatography;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Metabolic Pathway;Methods;Mole the mammal;NMR Spectroscopy;Pathway Analysis;Procedures;Process;Protocols documentation;Research;Resolution;Resources;Running;Sampling;Services;Standardization;Statistical Data Interpretation;Statistical Study;Study Section;System;Techniques;Technology;Therapeutic Intervention;Tissues;Tracer;United States National Institutes of Health;Update;Work;analytical method;base;computerized data processing;data acquisition;data reduction;experimental study;human disease;imaging system;improved;in vivo;instrument;instrumentation;metabolomics;operation;outcome forecast;outreach;pre-clinical;reconstruction;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: 9342853
project_number: 5U24DK097215-05
project_title: ADMINISTRATIVE
administering_ic: NIDDK
award_notice_date: 2017-09-12
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
project_end_date: 2021-02-28
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: 2017-09-01
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;Complex;Consultations;Contracts;Core Facility;Core Grant;Cost Effectiveness Analysis;Data;Data Analyses;Data Repository and Coordinating Center;Distance Learning;Doctor of Philosophy;Educational workshop;Ensure;Fees;Funding;Goals;Grant;Health;Health Services Research;Human Resources;Income;Informatics;Legal patent;Letters;Occupational activity of managing finances;Operations Research;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;clinical development;clinical diagnostics;commercialization;cost;experimental study;human disease;meetings;metabolomics;metabolomics resource;new therapeutic target;novel marker;operation;outreach;programs;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: 9342848
project_number: 5U24DK097215-05
project_title: Resource Center for Stable Isotope-Resolved Metabolomics
administering_ic: NIDDK
award_notice_date: 2017-09-12
opportunity_number: RFA-RM-11-016
application_type: 5
activity_code: U24
ic: DK
serial_number: 097215
program_official: MARUVADA, PADMA
project_start_date: 2013-09-11
project_end_date: 2021-02-28
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;Award;Biochemical Pathway;Biomedical Research;Cardiovascular Diagnostic Techniques;Cell Culture Techniques;Cells;Client;Clinical Research;Communities;Computer software;Consultations;Data;Data Analyses;Detection;Development;Devices;Diabetes Mellitus;Disease;Distance Learning;Education and Outreach;Educational workshop;Ensure;Experimental Designs;Fees;Foundations;Fractionation;Freezing;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;Proteome;Publications;Publishing;Regulation;Research;Research Personnel;Resected;Resource Informatics;Resources;Sampling;Services;Slice;Solid;Structure;Study Subject;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;stable isotope;symposium;systems research;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: 9341223
project_number: 5R21DE025345-02
project_title: Nanoparticle delivery vehicles targeting P. gingivalis
administering_ic: NIDCR
award_notice_date: 2017-08-23
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: DE
serial_number: 025345
program_official: LUNSFORD, DWAYNE
project_start_date: 2016-09-01
project_end_date: 2019-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: STEINBACH-RANKINS, JILL
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Porphyromonas gingivalis is strongly associated with adult periodontitis a widespread and costly disease that is primarily manifest in the oral cavity but also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. The adherence of P. gingivalis to commensal organisms such as Streptococcus gordonii facilitates the initial colonization of the oral cavity by P. gingivalis and our prior work identifed a peptide that potently inhibits this interaction. The main goal of this application is to develop ne nanoparticle (NP) delivery vehicles that will deliver high localized concentrations of the peptide for prolonged periods of time to sites in the oral cavity that are colonized by P. gingivalis. Two approaches will be used. Aim 1 will generate NPs that are surfacemodified with the peptide in order increase effectiveness of the peptide by facilitating multivalent interactions with P. gingivalis. The potency of the modified NPs will be compared to soluble peptide using established in vitro biofilm models and an in vivo animal model of periodontitis. In Aim 2 we willinitially synthesize sustained release NPs that encapsulate the peptide. The load and release properties of the NPs will be optimized such that NPs will release an inhibitory concentration of the peptide for at least 24 hrs. Once NPs with the desired release properties are obtained they will be surface modified with the CafA protein which mediates coaggregation of Actinomyces with S. gordonii. The efficiency of NP adherence to streptococci will be determined and the function of sustained release NPs will be assessed using both in vitro biofilm models and a mouse model of periodontitis. It is anticipated that by targeting sustained release NPs to streptococci the peptide will be delivered and released into a niche in the oral biofilm that is normally occupied by P. gingivalis thus increasing the effectiveness of the peptide inhibitor.

project_terms:
Actinomyces;Adherence;Adult;Animal Model;Antigens;Atherosclerosis;Bolus Infusion;Cost of Illness;Development;Drug Delivery Systems;Effectiveness;Encapsulated;Environment;Event;Glycolates;Goals;Heart Diseases;Homeostasis;Human;I-antigen;In Vitro;Infection;Inflammation;Mediating;Methods;Microbe;Microbial Biofilms;Minor;Modeling;Mouth Diseases;Nanotechnology;Oral;Oral cavity;Organism;Peptides;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Property;Prophylactic treatment;Proteins;Reagent;Rheumatoid Arthritis;Site;Streptococcus;Streptococcus gordonii;Surface;Symbiosis;System;Systemic disease;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissues;Virulence;Work;compare effectiveness;density;improved;in vivo;in vivo Model;inhibitor/antagonist;mouse model;nanoparticle;novel;novel therapeutics;oral biofilm;oral microbiome;oral streptococci;pathogen;prevent;public health relevance;research clinical testing;subgingival biofilm;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Porphyromonas gingivalis is strongly associated with adult periodontitis a common oral disease that is present in up to 40% of the adult population and with systemic illnesses such as heart disease and rheumatoid arthritis. We have discovered a peptide that inhibits the colonization of the oral cavity by P. gingivalis. This study will use nanotechnology to develop new drug delivery vehicles that will deliver higher amounts of this peptide to sites in the oral cavity that are commonly occupied by P. gingivalis. It is anticipated that the effectiveness of the peptide to reduce periodontitis and limit P. gingivalis colonization will be improved if it can be delivered in greater amounts and for longer periods of time.


application_id: 9341202
project_number: 5R44DC012741-03
project_title: Microfabricated Cochlear Electrode Array
administering_ic: NIDCD
award_notice_date: 2017-08-24
opportunity_number: PA-15-269
application_type: 5
activity_code: R44
ic: DC
serial_number: 012741
program_official: MILLER, ROGER
project_start_date: 2014-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-ETTN-G(12)B]
contact_pi_person_id: 11208190
contact_pi: JOHNSON, ANGELIQUE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 969965800
primary_uei: NPHRMGVU99E8
duns_number: 969965800
uei: NPHRMGVU99E8
fips: US
organization_id: 10030414
organization_name: MEMSTIM, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022654
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractCurrent cochlear implants while beneficial in their use are limited in their capabilities by hand-assembly of the electrode arrays. This tedious manufacturing method is very costly extremely labor-intensive and inadequate in implementing new technologies for improving speech recognition andmusic appreciation. A superior alternative to hand assembly is microfabrication which is a fullyautomated low cost and high yield manufacturing process that is capable of implementing a varietyof innovations including smaller array size for residual hearing preservation drug delivery channelsfor inner ear health and cell regeneration and strain gauges for improved performance duringsurgical insertion. Microfabrication is a very promising alternative to hand-assembly but has yet tomeet the following requirements for commercialization: (1) substrates must be composed of provenlong-term implantable materials (USP class VI) (2) electrode arrays must be compatible withstandard surgical insertion techniques (3) substrate and electrode sites must be able to withstandlong-term electrical stimulation in the body (4) the array must be long enough to extend from the tipof the cochlea to the location behind the ear where the electronics are implanted under the skin and(5) the array must have electrical wiring that is compatible with the electrical feedthrough pins of theimplantable cochlear stimulator (ICS).During Phase I MEMStim showed that it is feasible to produce a microfabricated cochlear electrodearray out of medical grade materials that can meet the commercial requirements (1)  (3). The goal ofPhase II will be to produce just such an array as a minimum viable product (MVP) for cochlearimplant manufacturers. The MVP will address requirements (4)  (5) and further improve upon thePhase I results of requirement (2). In order to accomplish the Phase II goal the following SpecificAims will be accomplished: (Aim 1) produce a full length microfabricated cochlear array with anintegrated cable that can be bonded to an implantable cochlear stimulator and complies withelectrical mechanical durability biocompatibility and FDA safety requirements specified incommunications with cochlear implant manufacturers and (Aim 2) produce a connector scheme forintegrating a microfabricated cochlear electrode to the feedthroughs of an implantable cochlearstimulator. The expected outcome is an array that can be integrated by customers into their cochlearimplant systems and pass all handling/use/safety tests that cochlear implant manufacturers wouldneed to seek approval from the FDA.

project_terms:
Address;Adopted;Adult;Basilar Membrane;Biological Preservation;Cells;Clinical;Clinical Trials;Cochlea;Cochlear Implants;Communication;Corrosion;Deposition;Dimensions;Drops;Drug Delivery Systems;Ear;Electric Stimulation;Electric Wiring;Electrodes;Electronics;Environment;Fracture;Goals;Hand;Health;Hearing;Hearing Aids;Hearing Impaired Persons;Human;Implant;Labyrinth;Length;Ligaments;Location;Manufacturer Name;Mechanics;Medical;Methods;Microfabrication;Music;Natural regeneration;Operative Surgical Procedures;Otolaryngology;Outcome;Performance;Pharmaceutical Preparations;Phase;Physiologic pulse;Positioning Attribute;Prevention;Process;Research;Residual state;Safety;Saline;Scheme;Shapes;Site;Skin;Specific qualifier value;Speech;Spiral Lamina;System;Techniques;Technology;Temporal bone structure;Testing;Time;Toxicity Tests;Work;biomaterial compatibility;commercialization;cost;cytotoxicity;hearing impairment;improved;innovation;manufacturing process;millimeter;nanometer;new technology;novel;prototype;safety testing;speech recognition;success;systemic toxicity;technological innovation;visual feedback

public_health_relevance:
Project NarrativeCochlear implants allow the profoundly deaf to achieve reasonable word recognition inquiet environments but technological innovations to achieve fuller appreciation of musicand speech are severely limited by the shortcomings of current hand assemblymanufacturing methods for cochlear electrode arrays. MEMStim LLC will develop asuperior alternative to hand-assembly microfabrication. This novel method is a fullyautomated low cost and high yield manufacturing process capable of implementingtechnological innovations that will provide benefits such as small electrode array size forresidual hearing prevention drug delivery channels for inner ear health and cellregeneration and strain gauges for improved surgical safety outcomes.


application_id: 9341197
project_number: 5R03DA039740-02
project_title: Role of Social Media and Mobile Apps in Sexual and Drug Co-Usage Networks of MSM
administering_ic: NIDA
award_notice_date: 2017-08-04
opportunity_number: PA-12-282
application_type: 5
activity_code: R03
ic: DA
serial_number: 039740
program_official: SCHULDEN, JEFFREY D
project_start_date: 2016-09-01
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-AARR-G(93)S]
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
arra_indicator: N
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:
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;data integration;experience;high risk;illicit drug use;innovation;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;transmission process;urban area;urban setting;virtual;web app;web-based tool

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: 9340858
project_number: 3R44DK105692-02S1
project_title: A New Technique for Diabetic Foot Ulcers
administering_ic: NIDDK
award_notice_date: 2016-09-07
opportunity_number: PA-15-269
application_type: 3
activity_code: R44
ic: DK
serial_number: 105692
suffix: S1
program_official: JONES, TERESA L Z
project_start_date: 2015-04-01
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-SBIB-G(11)B]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
project_abstract:
ABSTRACT Diabetes is the leading cause of nontraumatic lower extremity amputations in theUnited States. Diabetic foot ulcers (DFUs) are responsible for more hospitalizationsthan any other diabetic complications. Currently even the best available treatmentsachieve only a 50% healing rate for these woundsand this healing is often onlytemporary with a 66% chance of recurring. Our company has developed an intracellular ATP delivery technique (ATP-vesicles orVitaSolTM) for tissue ischemia. When used in wound treatment it heals wounds fasterthan many control dressings. During the Phase I period VitaSolTM healed wounds fasterthan Regranex and showed no toxic effects in the local lymph nodes or reproductivesystems in both male and female rabbits. One special feature of VitaSolTM is its ability totrigger extremely rapid tissue regenerationgranulation growth appears within 24 hoursafter application. This growth continues and covers the wound cavity within a fewdaysa phenomenon never seen or reported before with any other treatment strategy. The Phase II study will bring this new technique closer from the bench to bedside.We will first undertake a larger scale manufacturing of VitaSolTM in a cGMP facility tomeet FDA requirements and to produce VitaSolTM in a practical package for easyapplication. We will then test the new VitaSolTM preparation in an animal model close toDFU (12-month diabetes plus ischemia) and to compare the healing effects withRegranex. Our approach is a potential game changer for DFU treatment: The wound healingprocess involves hemostasis inflammation proliferation and remodeling resulting in a36 day lag before granulation tissue starts to appear. This process seems to becarved in stone and no one has ever been able to change it. The elimination of the lagtime and the ability to support cell survival and proliferation in a wound cavity withoutblood supply are two features never been achieved with any other treatment. Thesecharacteristics could have tremendous potential in the treatment of DFUs. The potentialimpact is high.

project_terms:
Amputation;Animal Model;Becaplermin;Caring;Cell Proliferation;Cell Survival;Characteristics;Clinical;Complications of Diabetes Mellitus;Cyclic GMP;Diabetes Mellitus;Diabetic Foot Ulcer;Diabetic wound;Effectiveness;Female;Goals;Granulation Tissue;Growth;Healed;Hemostatic function;Hospitalization;Hour;Human;Inflammation;Ischemia;Life;Lower Extremity;Oryctolagus cuniculus;Outcome;Phase;Preparation;Process;Reporting;Reproductive system;Sterile coverings;Supporting Cell;Techniques;Testing;Time;Tissues;Toxic effect;United States;Vascular blood supply;Vesicle;Wound Healing;anxious;bench to bedside;chronic wound;clinical application;comparative;diabetic;healing;improved;innovation;inorganic phosphate;lymph nodes;male;meetings;novel strategies;phase 1 study;phase 2 study;programs;tissue regeneration;treatment strategy;wound

public_health_relevance:
NARRATIVE Our company has developed a new technique for intracellular ATP delivery to providethe diabetic wounds with much needed energy. The Phase I study has shown itssuperior healing capability than Regranex and no toxicity was found in local lymphnodes and the reproductive systems in both male and female rabbits. The Phase II willproduce the dressing in cGMP facility to make the package for easy application and totest its healing effects in 12-month diabetic plus ischemic wounds. This new approach isa potential game changer for diabetic foot ulcers.


application_id: 9337486
project_number: 5R01HL107326-06
project_title: Sex Differences in Angiotensin-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2017-06-05
opportunity_number: PA-13-302
application_type: 5
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;Cardiovascular Diseases;Cardiovascular system;Characteristics;Chromosomes;Chronic;Congenital chromosomal disease;DNA;Data;Development;Dissection;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;transgender


application_id: 9336929
project_number: 5R01EY026158-02
project_title: Cone Rescue in Retinitis Pigmentosa
administering_ic: NEI
award_notice_date: 2017-08-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 026158
program_official: NEUHOLD, LISA
project_start_date: 2016-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(04)S]
contact_pi_person_id: 1898524
contact_pi: KAPLAN, HENRY JERROLD
other_pis: DEAN, DOUGLAS CHASE;MCCALL, MAUREEN A
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_terms:
ARHGEF5 gene;Adult;Animal Model;Area;Binding;Birth;Blindness;Cell Differentiation process;Cell Transplants;Cells;Color Visions;Cone;Disabled Persons;Disease;Electrophysiology (science);Endoplasmic Reticulum;Evaluation;Face;Family member;Family suidae;Gene Transfer;Genes;Glucose;Inherited;Injectable;Label;Leber's amaurosis;Light;Mitochondria;Modeling;Molecular Conformation;Morphology;Mus;Mutation;Neuroprotective Agents;Night Blindness;North America;Opsin;Patients;Peripheral;Pharmacotherapy;Population;Prevention;Process;Reading;Resolution;Retina;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinal Pigments;Retinitis Pigmentosa;Rhodopsin;Rod Outer Segments;Series;Source;Starvation;Symptoms;TXN gene;Therapeutic;Time;Transplantation;Vertebrate Photoreceptors;Vision;Visual;Visual Fields;base;fetal;gene therapy;glucose transport;glucose uptake;hereditary blindness;in vivo;induced pluripotent stem cell;macula;man;mutant;neuroprotection;overexpression;prevent;restoration;retinal rods;sensor;synergism


application_id: 9336423
project_number: 1R56HL131782-01
project_title: Monomeric G-proteins and Cardioprotection from Heart Failure
administering_ic: NHLBI
award_notice_date: 2016-09-14
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: HL
serial_number: 131782
program_official: SCHWARTZ, LISA
project_start_date: 2016-09-15
project_end_date: 2017-08-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: ANDRES, DOUGLAS ALLEN
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): Monomeric G-proteins and Cardioprotection from Heart Failure Heart failure incidence in the United States is steadily increasing with annual costsin excess of $30 billion and the cost is expected to increase 127% between now and 2030. Heart failure with reduced ejection fraction (HFrEF) occurs in ~45% of HF patients and is associated with longer survival compared to HF with preserved ejection fraction; however treatment options are poor and are limited to increasing survival without improving systolic function. Success of agents such as -blockers to prolong lifespan (not necessarily quality of life) of HFrEF draws attention away from the fundamental principle that in HFrEF the heart defect is failure to contract with sufficient force to meet demand. This new proposal is motivated by our findings of a novel cardiac phenotype caused by deletion of the Rad-GTPase. Rad-null mice (Rad-/-) show increased cardiac contractility that persists well into senescence and out-performs age- and gender-matched animals. Rad-/- mice also show cardioprotection against chronic catecholamine stimulation and against chronic pressure overload. In this proposal we will test two classes of potentially related but mutually exclusive mechanistic hypothesis. First we will evaluate the contribution of altered Ca2+ homeostasis in response to Rad ablation; and second we will assess Rad contributions to the -adrenergic receptor (-AR) signaling axis. Three complementary Aims guide our studies. First we will test the hypothesis that Rad-ablation confers enhanced function via sarcolemmal Ca2+ influx. These experiments will traverse scales of function from molecular to whole organ. Cardiac magnetic resonance imaging (CMR) and echocardiography will also be used to measure in vivo heart function. Second we will evaluate the hypothesis that Rad deletion contributes to cardioprotection via enhancement of intracellular Ca2+ synchrony and preservation of -AR signaling. Again assessments of heart structure and function will traverse scales from molecular to cellular to organ level and i vivo function. Our third aim focuses on Rad-deletion as a potentially beneficial therapeutic approach. Overall this proposal tests a novel mechanism of augmentation of cardiac function that confers cardioprotection against sustained pressure overload and chronic stress signaling.

project_terms:
ADRBK1 gene;Ablation;Adrenergic Receptor;Age;Agonist;Animal Model;Animals;Arrhythmia;Attention;Biological Preservation;Cardiac;Cardiac Myocytes;Catecholamines;Chronic;Chronic stress;Contracts;Data;Development;Disease;EFRAC;Echocardiography;Failure;Gender;Goals;Guanosine Triphosphate Phosphohydrolases;Health;Hearing;Heart;Heart Abnormalities;Heart Hypertrophy;Heart failure;Homeostasis;Hypertrophy;Incidence;Injection of therapeutic agent;Knockout Mice;Laboratories;Longevity;Magnetic Resonance Imaging;Measures;Molecular;Monomeric GTP-Binding Proteins;Mus;Myocardial;Myocardium;Organ;Pathway interactions;Patients;Phenotype;Quality of life;RNA Interference;Receptor Signaling;Reducing Agents;Regulation;Risk Factors;Signal Transduction;Stress;Structure;Symptoms;System;Testing;Therapeutic;Time;Tissues;United States;Ventricular Remodeling;base;cost;genetic manipulation;heart function;improved;in vivo;innovation;meetings;molecular scale;novel;pressure;research study;response;senescence;success

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Heart failure is a major health problem in the United States and a major risk factor is old age. By definition heart failure involves the inability of the hear to generate sufficiently forceful contractions - defined as an insufficient inotropic response. This proposal tests a novel putative therapeutic direction that provides positive inotropic support to the failing myocardium along with protection against stress-induced remodeling.


application_id: 9336240
project_number: 5R01AR068313-03
project_title: MYD88 Signaling in Mammalian Myoblast Fusion
administering_ic: NIAMS
award_notice_date: 2017-08-22
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;Genetic Transcription;Goals;Growth;Hypertrophy;Impairment;In Vitro;Injury;Innate Immune Response;Interleukin-1;Knock-out;Knockout Mice;Knowledge;MAP Kinase Gene;Mediating;MicroRNAs;Molecular;Molecular and Cellular Biology;Mus;Muscle;Muscle Cells;Muscle Development;Muscle Fibers;Muscular Atrophy;MyD88 protein;Myelogenous;MyoD Protein;Myoblasts;Myogenic Regulatory Factors;Myogenin;Myopathy;Natural regeneration;Neonatal;Pathway interactions;Pattern;Play;Process;Promoter Regions;Recruitment Activity;Research;Role;Seminal;Signal Pathway;Signal Transduction;Skeletal Development;Skeletal Muscle;Small Interfering RNA;System;TLR3 gene;Testing;Therapeutic;Toll-like receptors;Transcript;Vertebrates;WNT Signaling Pathway;Wild Type Mouse;base;experimental study;improved;in vivo;insight;interleukin-18 receptor;knock-down;mouse model;muscle form;muscle hypertrophy;myogenesis;new therapeutic target;novel therapeutics;overexpression;promoter;public health relevance;receptor;repaired;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: 9336131
project_number: 272201000033I-0-27200005-1
administering_ic: NIAID
project_start_date: 2016-05-26
project_end_date: 2018-05-25
contact_pi_person_id: 14614836
contact_pi: JONATHON, WARAWA
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 A91: Development of a Murine Model of Subcutaneous (SC) Melioidosis for Use in Vaccine Evaluation

project_abstract:
This contract provides for the development and standardization of small animal models for infectious diseases and may include testing of candidate vaccines.

project_terms:
Animal Model;Communicable Diseases;Contracts;Development;Melioidosis;Standardization;Testing;Translational Research;animal model development;mouse model;subcutaneous;vaccine candidate;vaccine evaluation


application_id: 9335891
project_number: 5R01GM104123-05
project_title: Functional analysis of programmed genome rearrangement
administering_ic: NIGMS
award_notice_date: 2017-07-27
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 104123
program_official: AINSZTEIN, ALEXANDRA M
project_start_date: 2013-09-01
project_end_date: 2019-08-31
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;Experimental Designs;Fertility;Fertilization in Vitro;Gene Deletion;Genes;Genetic;Genetic Polymorphism;Genetic Recombination;Genome;Genome Stability;Genomics;Human;Human Biology;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;Phenotype;Play;Population;Property;Proteins;Regulation;Reproducibility;Research;Resistance;Resolution;Resources;Role;Site;Somatic Cell;Specificity;Study models;Synteny;Testing;Transcript;Vertebrate Biology;Vertebrates;Work;analog;comparative;design;developmental genetics;experimental study;gene function;genome-wide;genomic data;germline stem cells;insight;knock-down;novel;pleiotropism;pluripotency;programs;promoter;public health relevance;recombinational repair;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: 9335586
project_number: 3R21CA177359-02S1
project_title: Promoting Colorectal Cancer Screening in Rural Emergency Departments
administering_ic: NCI
award_notice_date: 2016-09-14
opportunity_number: PA-14-077
application_type: 3
activity_code: R21
ic: CA
serial_number: 177359
suffix: S1
program_official: BRESLAU, ERICA S
project_start_date: 2016-09-01
project_end_date: 2017-05-31
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
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
project_abstract:
DESCRIPTION (provided by applicant): Rural Appalachian Kentuckians suffer a disproportionate incidence and mortality from colorectal cancer (CRC) the second leading cause of cancer death. The Centers for Disease Control estimate that as many as 60 percent of CRC related deaths could be prevented if everyone age 50 and older were screened regularly. Rural Appalachian residents are currently being screened at suboptimal rates. The proposed intervention builds on our successful cancer prevention projects: Faith Moves Mountains: A CBPR Appalachian Wellness and Cancer Prevention Program and Promoting Mammography among African American Women Visiting the Emergency Departments. Both projects involve lay health advisor (LHA) delivered motivational interviewing interventions that have been culturally tailored. We propose to pilot test a culturally tailored intervention using brief motivational interviewing by LHAs to promote CRC screenings in an emergency department (ED) serving rural Appalachian Kentucky in order to (1) evaluate the feasibility of the intervention in this rurl Appalachian setting; and (2) assess the effects of the intervention on perceived barriers to CRC screening and subsequent cancer screening engagement.  Consistent with our current Faith Moves Mountains and Promoting Mammography projects we will train carefully selected community members (LHAs) to deliver a brief motivational interview while participants wait for non-urgent care in the ED or wait with a family member who is receiving care. Each participant in conjunction with the LHA will develop a written plan of action that addresses their identified barriers to screening. The brief intervention will take about 15 minutes and will be delivered in aprivate area of the ED. Control group participants will receive standard-of-care ED services that include brochure information identifying general cancer screening services provided by the hospital. Outcome measures will include assessment of barriers and receipt of CRC screening and will be measured at three and six months post intervention. The results will serve as preliminary data for a multisite rural ED-based clinical trial evaluating the cancer promotion intervention.

project_terms:
Accident and Emergency department;Address;Advisory Committees;Affect;African American;Age;Appalachian Region;Area;Cancer Burden;Cancer Etiology;Caring;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical Trials;Colorectal Cancer;Communities;Control Groups;County;Data;Education;Emergency department visit;Family member;Goals;Guidelines;Health;Healthcare Systems;Hospitals;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Malignant Neoplasms;Mammography;Measures;Outcome Measure;Pamphlets;Participant;Patients;Population;Prevention program;Preventive service;Primary Health Care;Provider;Randomized Controlled Trials;Readiness;Recommendation;Recruitment Activity;Research;Risk;Rural;Screening for cancer;Services;Staging;Survival Rate;Targeted Research;Testing;Training;Vulnerable Populations;Woman;Writing;base;behavioral/social science;brief intervention;cancer prevention;colorectal cancer screening;disorder prevention;experience;health care availability;health disparity;high risk;innovation;intervention effect;member;mortality;motivational enhancement therapy;post intervention;prevent;programs;screening;social science research;standard of care;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project will be the first to address the disproportionate incidence and mortality from CRC in rural Appalachia by providing an innovative CRC screening intervention in a rural ED.


application_id: 9334957
project_number: 3R01NS094741-02S1
project_title: Mechanisms controlling distinct modes of adult axon growth
administering_ic: NINDS
award_notice_date: 2016-08-19
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: NS
serial_number: 094741
suffix: S1
program_official: JAKEMAN, LYN B
project_start_date: 2015-09-01
project_end_date: 2020-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
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
project_abstract:
DESCRIPTION (provided by applicant): Affecting axonal growth as a means to enhance recovery and alleviate pathology in conditions of nervous system injury insult or disease is a major goal for the healthcare and biomedical research endeavors. Significant effort is directed at inducing neural plasticity to enhance axonal growth to establish functionally- adaptive connections. However these efforts must also prevent and not induce maladaptive plasticity a balance which requires a clear understanding of the processes regulating axon growth. A major factor confounding efforts to understand neural plasticity is that the traumatically-injured nervou system contains both directly-injured axons and the NON-injured axons. This project examines the long-standing question and controversy regarding the mechanisms of the two major forms of axon growth in the adult nervous system - growth of injured axons (Regeneration) and that of non-injured axons (Collateral Sprouting - CS). We aim to objectively determine the degree to which the intrinsic molecular mechanisms controlling these processes are similar or different. Doing so will enable identification of sets of genes which control a specific mode and may thus be targeted to affect just that one mode or may be shared between modes and thus targeted to affect both and could identify an entire new set of genes capable of regulating adult axonal plasticity.  Axonal Regeneration and CS are both relatively robust in the PNS and the injured and non-injured neurons can be clearly separated. Nerve crush provides a model of successful axon regeneration. Using the spared dermatome model (where intact non-injured neurons of a single dorsal root ganglion are induced to grow by denervating the skin bordering their dermatome) we have generated a transcriptomic profile of genes regulated during CS. Bioinformatic analyses indicate that the genes involved in regeneration and CS are highly distinct. Preliminary data using mice with genetic deletion of transcription factors (TFs) that appear to be specific for each axon growth mode supports the concept that the growth modes involve separate genetic programs. Aim 1 will use mice with mode-specific-TF knockout to thoroughly examine the impact of the gene- deletions on the different modes of axon growth using behavioral and histological assessments of axon growth. This will determine if the flagship mode-specific-TFs are indeed responsible for controlling that single mode.  We have data demonstrating 1) a mutually-exclusive expression of the mode-specific TFs and 2) that "conditioning" with one mode of growth appears to influence the functional execution of the other mode. This is rational considering that there must be a large change in which genes are expressed and proper orchestration of such a significant change could be delayed or prevented. Aim 2 will test the hypothesis that the modes negatively-influence each other and involve mutually-exclusive genetic programs by alternately applying the different models to the same neurons (i.e. regeneration-then-sprouting or sprouting-then-regeneration). This will determine how execution of one mode influences the other.  For both Aims experimental outcomes in accord with preliminary data would strongly support the concept that there are indeed two different growth modes each with distinct genetic control. Outcomes contrary to preliminary data could include 1) effects on some neural populations but not others which would suggest that there may still be distinct modes with distinct genetic control but that these modes may be based not on injury- status but on cell-type and/or 2) that the apparent mode-specific genetic control systems act as facilitators but are not necessary (i.e. in their absence the processes occur anyway but much more slowly) which would suggest that there are not necessarily two fully-distinct modes. All outcomes will serve to address both the conceptual framework and the specific molecular control regarding axon growth in the adult nervous system.

project_terms:
Address;Adult;Affect;Animals;Area;Autonomic Dysreflexia;Axon;Behavioral;Bioinformatics;Biomedical Research;Characteristics;Cutaneous;Data;Death Sudden Cardiac;Disease;Epilepsy;Equilibrium;Foundations;Future;Gene Deletion;Gene Expression;Genes;Genetic;Genetic Programming;Goals;Growth;Health;Health Care Research;Histology;Individual;Injury;Investigational Therapies;Knock-out;Knockout Mice;Literature;Maintenance;Modeling;Molecular;Molecular Genetics;Molecular Profiling;Mus;Natural regeneration;Nerve;Nerve Crush;Nervous System Trauma;Nervous system structure;Neuronal Plasticity;Neurons;Outcome;Pathology;Peripheral;Peripheral Nervous System;Population;Process;Productivity;Quality of life;Recovery;Recovery of Function;Reflex action;Regulation;Research Proposals;Role;Skin;Spinal Ganglia;Spinal cord injury;Structure;System;Testing;Therapeutic;Time;United States National Institutes of Health;Work;activating transcription factor 3;axon growth;axon regeneration;base;cell type;chronic pain;conditioning;design;functional restoration;improved;injured;nerve supply;neurological pathology;novel;prevent;programs;relating to nervous system;research study;screening;transcription factor;transcriptomics

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A major goal of the NIH is to support promote and maintain and/or improve the health independence quality of life and productivity of individuals with neurological pathologies throughout their lives. The current research proposal addresses these goals through animal studies of fundamental mechanisms by which the nervous system can adapt via growth of axons to establish new connections. This application seeks to clarify a long- standing conceptual controversy regarding different modes of axon growth which has hampered efforts to affect axon growth and restore function. We seek to demonstrate that distinct genetic programs control the axon growth of injured and non-injured neurons and that these programs are mutually exclusive. Determining if the mechanisms of axon growth and plasticity are separately-regulated by distinct sets of genes is a key step in designing and guiding future treatments which promote axonal growth with the goal of functional recovery following nervous system damage.


application_id: 9334216
project_number: 5R21EY027033-02
project_title: Yap1 is essential to maintain adult RPE differentiation
administering_ic: NEI
award_notice_date: 2017-08-14
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: EY
serial_number: 027033
program_official: NEUHOLD, LISA
project_start_date: 2016-09-01
project_end_date: 2019-08-31
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;Development;Disease;Down-Regulation;Embryo;Enterobacteria phage P1 Cre recombinase;Epithelial;Epithelial Cells;Equilibrium;Eye diseases;Functional disorder;Genes;Genetic Transcription;Human;Immunohistochemistry;In Vitro;Knock-out;Knockout Mice;Link;LoxP-flanked allele;Maintenance;Malignant Neoplasms;Mediating;Mesenchymal;Mitotic;Modeling;Morphogenesis;Morphology;Mus;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Oncogenes;Organ;Organ Size;Orthologous Gene;Pathologic;Pathway interactions;Phenotype;Phosphotransferases;Photoreceptors;Physiological;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;novel;novel therapeutics;overexpression;prevent;progenitor;promoter;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: 9333978
project_number: 5R01NS094741-03
project_title: Mechanisms controlling distinct modes of adult axon growth
administering_ic: NINDS
award_notice_date: 2017-07-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 094741
program_official: JAKEMAN, LYN B
project_start_date: 2015-09-01
project_end_date: 2020-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
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_terms:
Address;Adult;Affect;Animals;Area;Autonomic Dysreflexia;Axon;Behavioral;Bioinformatics;Biomedical Research;Characteristics;Cutaneous;Data;Death Sudden Cardiac;Disease;Epilepsy;Equilibrium;Foundations;Future;Gene Deletion;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Growth;Growth Factor;Health;Health Care Research;Histologic;Histology;Individual;Injury;Investigational Therapies;Knock-out;Knockout Mice;Literature;Maintenance;Modality;Modeling;Molecular;Molecular Genetics;Molecular Profiling;Mus;Natural regeneration;Nerve;Nerve Crush;Nervous System Trauma;Nervous system structure;Neuronal Plasticity;Neurons;Outcome;Pathology;Peripheral;Peripheral Nervous System;Population;Process;Productivity;Quality of life;Recovery;Recovery of Function;Reflex action;Regulation;Research Proposals;Role;Skin;Spinal Ganglia;Spinal cord injury;Structure;System;Testing;Therapeutic;Time;United States National Institutes of Health;Work;activating transcription factor 3;axon growth;axon regeneration;base;cell type;chronic pain;conditioning;dermatome;design;experimental study;functional restoration;improved;injured;nerve supply;nervous system disorder;neurological pathology;novel;prevent;programs;public health relevance;relating to nervous system;screening;transcription factor;transcriptomics


application_id: 9333812
project_number: 2R01NS062306-07A1
project_title: PPAR inhibition of spinal pain transmission
administering_ic: NINDS
award_notice_date: 2017-02-28
opportunity_number: PA-16-188
application_type: 2
activity_code: R01
ic: NS
serial_number: 062306
suffix: A1
program_official: OSHINSKY, MICHAEL L
project_start_date: 2008-12-18
project_end_date: 2022-01-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Diabetes affects 9% of the United States population and approximately one-third of these patients experiencechronic neuropathic pain commonly referred to as painful diabetic neuropathy (PDN). PDN is difficult tomanage as analgesic treatments are only effective in a small subset of PDN patients. The development ofanalgesics for pain associated with diabetes in particular type 2 diabetes is stalled by our incompleteunderstanding of the underlying mechanisms of PDN. An important new clue comes from the recent findingthat methylglyoxal (MG) a highly reactive dicarbonyl product of glycolysis that accumulates withhyperglycemia is particularly high in patients with PDN. MG causes non-enzymatic glycation of proteins. Theresulting protein adducts or advanced glycation end products (MG-AGEs) are toxic and contribute to diabeticcomplications including PDN. Our central hypothesis is that elevated MG in type 2 diabetes causes pain andthat this can be alleviated with new classes of drugs targeting MG itself TRPA1 AC1 Epac and PPAR. Totest the hypothesis that MG drives neuropathic pain (PDN) in type 2 diabetes Specific Aim 1 will firstdetermine whether elevations in MG and its metabolizing enzyme Glyoxalase-1 occur in pain processingtissues in the hereditary Leprdb/db (db/db) mouse and Zucker Diabetic Fatty (ZDF) rat models of type 2diabetes. We then ask whether a promising new class of MG-scavenging peptides will alleviate affective painand spinal pain transmission. Our preliminary data indicate that genetic deletion or pharmacological inhibitionof TRPA1 a glycation target of MG blocks MG-induced pain. Indeed TRPA1 is a leading target for thedevelopment of new analgesics for chronic pain but has not been tested in models of type 2 PDN. To fill thisgap Specific Aim 2 will test the hypothesis that TRPA1 antagonists reduce affective pain and spinal paintransmission in db/db mice and ZDF rats. Consequent to TRPA1 channel opening (e.g. by MG) the resultingCa2+ influx into the cell leads to the activation of Ca2+-sensitive proteins which includes adenylyl cyclase I(AC1). Our data indicate that selective inhibition of AC1 with NB001 blocks type 2 PDN. AC1 generates theintracellular second messenger cAMP which targets not only protein kinase A but also exchange proteindirectly activated by cAMP (Epac). Specific Aim 3 will use novel Epac1 and Epac2 small molecule inhibitors todetermine which of these targets drive PDN. Among the 33 original research articles reviews and a bookpublished during the previous funding cycle (22 with the PI as first or senior author) our Progress includes thediscovery that pioglitazone a peroxisome proliferator-activated receptor gamma (PPAR) agonist that is FDA-approved to treat diabetes acts at dorsal horn neurons to inhibit the chronic pain associated with cutaneousinflammation and traumatic nerve injury. Our new data indicate additional efficacy in PDN and MG-inducedpain with surprisingly robust analgesic effects in females. Specific Aim 4 proposes to study PPARmechanism of action in db/db and ZDF with a new focus on sex differences in spinal nociceptive transmission.

project_terms:
Adenylate Cyclase;Advanced Glycosylation End Products;Affect;Affective;Age;Agonist;Analgesics;Behavioral;Biological Assay;Blood;Books;Cations;Cells;Chemosensitization;Complications of Diabetes Mellitus;Conflict (Psychology);Cutaneous;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cytotoxin;Data;Development;Diabetes Mellitus;Diabetic Neuralgia;Diamond;Drug Targeting;Enzymes;Extracellular Signal Regulated Kinases;FDA approved;Female;Funding;Genetic;Glucose;Glycolysis;Hyperalgesia;Hyperglycemia;Inflammation;Inherited;Intracellular Second Messenger;Intrathecal Injections;Lactoylglutathione Lyase;Measures;Mechanics;Mediating;Metabolic;Modeling;Molecular;Motivation;Mus;Natural History;Nerve;Neurons;Nociception;Non-Insulin-Dependent Diabetes Mellitus;PPAR alpha;PPAR gamma;Pain;Patients;Peptides;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Pioglitazone;Plasma;Population;Posterior Horn Cells;Progress Reports;Proteins;Publishing;Pyruvaldehyde;Rattus;Research;Second Messenger Systems;Sex Characteristics;Signal Transduction;Spinal;Spinal Cord;Spine pain;Stimulus;Streptozocin;Structure of beta Cell of islet;TRPA1 Channel;Testing;Traumatic Nerve Injury;United States;adduct;adenylyl cyclase 1;chronic neuropathic pain;chronic pain;diabetic;dorsal horn;experience;glycation;inhibitor/antagonist;innovation;male;mouse model;new therapeutic target;novel;novel drug class;overexpression;pain behavior;painful neuropathy;preclinical study;public health relevance;receptor;small molecule;small molecule inhibitor;tissue processing;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTDiabetes affects almost 9% of the United States population and approximately one-third of thesepatients experience chronic pain termed painful diabetic neuropathy (PDN). Commercial analgesicdrugs do not work well in patients with advanced PDN yielding pain relief in less than 50% of patientsand of those the pain relief is less than 50%. This project explores a new mechanism of PDN that isdriven by the toxic by-product of high glucose  methylglyoxal (MG)  and evaluates four promisingnew drug targets (MG itself TRPA1 AC1 and PPAR) towards a new pharmacotherapy for thisdebilitating condition.


application_id: 9333688
project_number: 1R21AA025563-01A1
project_title: The role of exosomes on brain inflammation and microglia activation in alcohol use disorders
administering_ic: NIAAA
award_notice_date: 2017-04-10
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: AA
serial_number: 025563
suffix: A1
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2017-04-10
project_end_date: 2019-03-31
study_section: Neuroscience and Behavior Study Section[AA-4]
contact_pi_person_id: 9742546
contact_pi: PENG, HUI
other_pis: NIXON, KIMBERLY
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract Excessive alcohol consumption the defining characteristic of an alcohol use disorder (AUD) damages thenervous system producing the cognitive impairments observed in those afflicted with an AUD. Preclinical andclinical evidence from our lab and others suggest that microglia play a key role in alcohol-inducedneuroinflammation and neurotoxicity. Various types of microglia have been categorized based on their function:classically activated (M1) proinflammatory microglia and alternatively activated (M2) growth-promoting microglia.However the mechanisms responsible for alcohol activating microglia and polarizing them to either phenotypeare poorly understood. MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules thatplay an important role in the regulation of microglia polarization. Although miRNAs act mainly in a cell-autonomous manner accumulating evidence suggests that miRNAs can be packaged into exosomes forintercellular signaling. Exosomes are small 50-150 nm vesicles that are secreted into the extracellular spacefuse to neighboring cells and release their contents (proteins mRNAs and miRNAs) thus serving as a novelintercellular genetic regulatory mechanism. Many cells in the nervous systems have the capacity to releaseexosomes including neurons. Our preliminary data demonstrated that neuronal exosomes contain miRNAs thatcan alter microglia activation. Therefore we hypothesize that miRNA-containing exosomes derived fromalcohol-treated neurons transport messages namely miRNA to microglia and modulate their activationand function and thus potentially contribute to neuroinflammation in AUDs. We will test this hypothesiswith the following specific aims: Aim 1: Identify the miRNA elements that regulate microglia activation andfunction in alcohol-treated neuronal exosomes. Aim 2. Determine the role of brain exosomes derived from 4-daybinge alcohol-exposed rat brains in mediating brain inflammation and microglia activation. This proposal is novelin exploring the role of exosomes in cellular communication between neurons and microglia in AUDs. This uniqueand novel regulatory mechanism in neuron-to-microglia communication will provide new insight into miRNA-mediated microglia activation in pathological conditions such as AUDs.

project_terms:
Alcohols;Alpha Cell;Apoptosis;Attention;Brain;Brain Injuries;Cells;Characteristics;Clinical;Communication;Data;Elements;Encephalitis;Enzyme-Linked Immunosorbent Assay;Ethanol;Extracellular Space;Flow Cytometry;Future;Gene Expression;Genetic;Growth;Growth Factor;Heavy Drinking;Immune;Impaired cognition;Individual;Investigation;Macrophage Activation;Measures;Mediating;Messenger RNA;MicroRNAs;Microglia;Modeling;Nerve Degeneration;Nervous System Trauma;Nervous system structure;Neuraxis;Neurodegenerative Disorders;Neurons;Pathologic;Pathway interactions;Phagocytosis;Phenotype;Play;Production;Proteins;Protocols documentation;Rattus;Reactive Oxygen Species;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Role;Signal Pathway;Signal Transduction;Surface;Testing;Therapeutic Intervention;Time;Ultracentrifugation;Untranslated RNA;Vesicle;alcohol exposure;alcohol use disorder;base;chemokine;cytokine;exosome;genome-wide;insight;macromolecule;macrophage;neuroinflammation;neurotoxicity;novel;overexpression;pre-clinical;protein aggregate;therapeutic development;tissue repair

public_health_relevance:
Project Narrative Excessive alcohol consumption damages the nervous system producing the cognitive impairmentsobserved in those individuals with an alcohol use disorder (AUD). Microglia the immune cells of the centralnervous system (CNS) play a key role in alcohol-induced neuroinflammation and neurotoxicity but themechanisms responsible for microglia phenotype regulation under alcohol exposure are poorly understood. Inthis proposal we will explore the role of a new neuron-to-microglia intracellular signaling pathway: the exosome-mediated transfer of miRNA in exosomes and how they regulate microglia function.


application_id: 9333663
project_number: 1R01CA217255-01A1
project_title: Studies to understand and exploit 10-membered enediyne biosynthesis
administering_ic: NCI
award_notice_date: 2017-03-01
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: CA
serial_number: 217255
suffix: A1
program_official: FU, YALI
project_start_date: 2017-03-01
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1 BCMB-U (02)]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL;VAN LANEN, STEVEN GARY
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Achievement;Alkylation;Amination;Amines;Anabolism;Anthraquinones;Anti-Infective Agents;Antibodies;Antitumor Natural Products;Architecture;Biochemical;Biogenesis;Bioinformatics;Biotin;Chemicals;Chemistry;Clinical;Collaborations;Complement;Complex;Crystallization;Cyclization;Development;Dynemicin;Enzymatic Biochemistry;Enzymes;Family member;Foundations;Genetic;Hybrids;Hydroxylation;Iodination reaction;Ligands;Mixed Function Oxygenases;Modality;Modification;Molecular;Natural Products;Nucleotides;Polyenes;Proteins;Reaction;Reagent;Route;Series;Structural Protein;Structure;Sulfur;Trisaccharides;analog;base;cancer therapy;catalyst;chemical genetics;clinical development;design;enzyme pathway;glycosylation;glycosyltransferase;innovation;insight;non-Native;novel;novel strategies;oxidation;polyketide synthase;prototype;structural biology;structural genomics;sugar;targeted agent;thiosugar;tool;tumor


application_id: 9333410
project_number: 5R01HL120746-05
project_title: Tobacco Products and Atherosclerotic Disease
administering_ic: NHLBI
award_notice_date: 2017-08-18
opportunity_number: PAR-12-267
application_type: 5
activity_code: R01
ic: HL
serial_number: 120746
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2013-09-19
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-HDM-Q(54)R]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
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: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. Therefore regulation of cigarettes and other tobacco products could significant lower the global burden of cardiovascular disease (CVD). The Family Smoking Prevention and Tobacco Control Act gives the FDA the authority to regulate the manufacturing marketing and distribution of tobacco products to protect public health. However to set standards for tobacco products it is important to know how cardiovascular effects of new and emerging tobacco products could be measured and which components of tobacco products induce cardiovascular injury. Because CVD is a chronic disease that develops over several years biomarkers of tobacco-induced cardiovascular injury are urgently needed to assess CVD risk in a time-frame sufficient for product evaluation. Moreover to relate biomarkers of injury with exposure to specific harmful and potentially harmful (HPHC) tobacco constituents it is essential to identify biomarkers that reflect exposure to specific constituents of tobacco products. Elucidation of the relationship between biomarker of exposure and biomarkers of injury will enable comparisons between the toxicities of different tobacco products and inform the design of future human studies for evaluating the cardiovascular effects of tobacco product use. Accordingly the overall goal of our project is to identify biomarkers of exposure to tobacco products and to relate them to atherosclerosis the underlying cause of several cardiovascular diseases. To accomplish this goal we will examine tobacco-induced injury in apoE-null mice and apoE-null rats. We will expose animals to varying intensities of tobacco smoke and smokeless tobacco we will identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure as well as to atherosclerotic lesion formation and lesion stability and how the relationship between the biomarkers of injury and biomarkers of exposure is affected by gender and the species and duration of exposure. In these experiments we will identify specific indices of atherosclerosis and thrombosis and how these biomarkers of injury are related to the biomarkers of exposure. To delineate the contribution of HPHCs we will identify which constituents of tobacco and tobacco smoke contribute to atherogenesis we will examine atherogenesis in mice exposed to individual constituents of exposure - nicotine acrolein and crotonaldehyde and determine how removal of these constituents affects atherosclerosis due to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals exacerbate atherosclerosis. Successful completion of this project will lead to the development of validated animal models to establish standard toxicitychanges and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. The findings of this project will provide new information regarding the contribution of reactive aldehydes such as acrolein and crotonaldehyde to the cardiovascular toxicity of cigarette smoke and smokeless tobacco. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity in humans; assessing the extent of harm reduction in PREPs and in developing policies for regulating HPHCs in smokeless tobacco cigarettes and emerging tobacco products. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

project_terms:
2-butenal;Acrolein;Affect;Aldehydes;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological Markers;Blood Platelets;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Cholesterol Homeostasis;Chronic Disease;Cigarette;Development;Doctor of Philosophy;Evaluation;Excision;Exposure to;Family Smoking Prevention and Tobacco Control Act;Future;Gender;Goals;Harm Reduction;Heart Diseases;Heart failure;Human;Individual;Injury;Ischemia;Knockout Mice;Lesion;Link;Marketing;Measures;Mediating;Mus;Nature;Nicotine;Policies;Principal Investigator;Public Health;Rattus;Regulation;Reperfusion Therapy;Risk;Risk Factors;Smokeless Tobacco;Smoking;Surrogate Markers;Thrombosis;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;atherogenesis;authority;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;design;experimental study;indexing;mortality;novel marker;programs;public health relevance;stroke;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. In the proposed studies we will identify biomarkers of exposure to tobacco products and relate them to atherosclerosis in experimental animals the underlying cause of several cardiovascular diseases. These studies will lead to the development of validated animal models to establish standard toxicity changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 9333095
project_number: 5R01CA194409-04
project_title: sEcad as a novel target and therapy for IGF-1R expressing tumors
administering_ic: NCI
award_notice_date: 2017-09-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 194409
program_official: SALOMON, RACHELLE
project_start_date: 2015-09-01
project_end_date: 2021-08-31
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;Biophysics;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Carcinogenesis;Breast Oncology;Breast cancer metastasis;Cell Death;Cell Proliferation;Cell model;Cells;Cetuximab;Clinical Trials;Development;Disease;Disease-Free Survival;Drug Kinetics;E-Cadherin;EGF gene;ERBB2 gene;Effectiveness;Endocytosis;Epidermal Growth Factor Receptor;Evaluation;Exhibits;FRAP1 gene;Grant;Growth;Growth Factor;Hormone Receptor;Human;IGF1 gene;IGF1R gene;In Vitro;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;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;Tumorigenicity;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;novel;novel anticancer drug;novel therapeutics;overexpression;public health relevance;receptor;response;safety testing;targeted agent;targeted treatment;therapeutic target;therapy development;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: 9333085
project_number: 5U18FD004840-05
project_title: Assuring Radiation Protection
administering_ic: FDA
award_notice_date: 2017-07-20
opportunity_number: RFA-FD-13-002
application_type: 5
activity_code: U18
ic: FD
serial_number: 004840
program_official: ROBINSON, DENISE
project_start_date: 2013-09-15
project_end_date: 2018-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11755645
contact_pi: MCBURNEY, RUTH EVELYN
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 115963720
primary_uei: SBT5JJP6JP86
duns_number: 115963720
uei: SBT5JJP6JP86
fips: US
organization_id: 1565201
organization_name: CONFERENCE OF RADIATION CONTROL PROG DIR
organization_city: Frankfort
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406013717
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe objective of this cooperative agreement is to coordinate state and federal activities to achieveeffective solutions to present and future radiation control problems. The Conference of RadiationControl Program Directors (CRCPD) a professional organization whose membership includesrepresentatives of state radiation control programs and whose mission is dedicated to radiationprotection will provide a forum for development of coordinated national radiation policy modelregulations guidance and procedures for the control of sources of radiation in the United States andwill coordinate the interchange of radiation protection experience among the states and between thestates tribes and the federal government. CRCPD will establish and maintain approximately 65committees and other working groups made up of its state and local government members to addressspecific radiation control problems in the application of radiation in the healing arts education andindustry; the control and mitigation of radiation exposure from all sources including radiation in theenvironment and as a result of licensed activities and accidents and incidents; and preparedness forradiological emergencies and homeland security. Work products of the committees with oversight byan elected Board of Directors will include updates to the Suggested State Regulations for Control ofRadiation protocols for evaluation of x-ray trends practice guidelines and other model procedures andreports for use by state and local government agencies in maintaining effective radiation programs.CRCPD will also plan facilitate and provide travel assistance for state representatives for annualmeetings of the National Conference on Radiation Control as an opportunity for member States andother stakeholders to convene and exchange information on radiation issues and new technologies.The conference will include discussions lectures and workshops on radiation priorities as determinedby state and federal planners. CRCPD will also provide radiation protection training sessions inconjunction with the annual meeting and at other times outside of the annual meeting through state-federal workshops and web-based training sessions. We will also maintain various mechanisms foraccess to information for the benefit of the States and other interested parties including: a frequently-updated website for posting of working group products meetings services and opportunities forservice as well as a secure site for committees and state agency members to access sensitiveinformation; a periodic newsletter; liaison with other related organizations; broadcast e-mails for time-sensitive information; and conference calls for major concerns affecting a majority or all of the states.1


application_id: 9332721
project_number: 1R01AT009268-01A1
project_title: Mechanisms underlying anabolic effects of cyclic compressive loading in muscle
administering_ic: NCCIH
award_notice_date: 2017-03-13
opportunity_number: PA-14-168
application_type: 1
activity_code: R01
ic: AT
serial_number: 009268
suffix: A1
program_official: MUDD, LANAY MARIE
project_start_date: 2017-04-01
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1 MOSS-R (02)]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: BUTTERFIELD, TIMOTHY ALAN
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_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Adult;Aging;Animals;Atrophic;Attention;Attenuated;Biochemical Pathway;Biology;Clinical;Complex;Congestive Heart Failure;Contralateral;Data;Development;Devices;Disease;Disuse Atrophy;Elderly;Endocrine;Exercise;Extracellular Matrix;Focal Adhesion Kinase 1;Focal Adhesions;Growth;Immune response;Integrative Medicine;Intervention;Investigation;Knowledge;Lead;Limb structure;Maintenance;Malignant Neoplasms;Manipulative Therapies;Massage;Mechanical Stimulation;Mechanics;Mediating;MicroRNAs;Modality;Morbidity - disease rate;Muscle;Muscle Weakness;Muscular Atrophy;NIH Program Announcements;Neurons;Pain;Pathway interactions;Patients;Periodicity;Play;Protein Biosynthesis;Proteins;Quality of life;Rattus;Recovery;Reproducibility;Research;Rodent;Role;Skeletal Muscle;Standardization;Symptoms;Testing;Therapeutic Intervention;aged;cytokine;direct application;disability;exosome;functional decline;innovation;integrin-linked kinase;mechanotransduction;mortality;muscle form;novel;patient population;prevent;relating to nervous system;response;restoration;satellite cell;sensory feedback;skeletal muscle wasting


application_id: 9332496
project_number: 5KL2TR001996-02
project_title: Institutional Career Development Core
administering_ic: NCATS
award_notice_date: 2017-06-16
opportunity_number: PAR-15-304
application_type: 5
activity_code: KL2
ic: TR
serial_number: 001996
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1901822
contact_pi: KELLY, THOMAS H.
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:
PROJECT SUMMARYThe University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) proposes to establish aCareer Development Core to build upon the current KL2 program which is in its fifth year of NIH support. Thecurrent program provides two to three years of release time (75% effort) and research funding support formentored career development designed to accelerate academic growth of the next generation of clinical andtranslational scholars. This program has garnered strong institutional support with notable scholar productivity;in five years two NIH-supported training slots have been expanded to six slots. All eight program graduateshave each made important contributions to science through research and have successfully competed forextramural funding seven as PIs. The current KL2 cohort consists of six scholars. The scholar programsupports career development across the full spectrum of clinical and translational science includingtranslational clinical community/policy studies and novel methodology development (e.g. biomedicalinformatics) focusing on a broad array of health topics. Scholars and mentors represent a wide range ofcolleges and disciplines including Medicine Nursing Health Sciences Public Health Education Engineeringand Arts & Sciences (Health Psychology). To build on these achievements this new program requests NIHsupport for four KL2 scholars. The training of three additional institutionally sponsored early-career scholarswill be integrated with these NIH-supported scholars to establish a cohort of seven scholars. The foundation ofthe proposed program will continue to be practical research experiences within interdisciplinary teams guidedby experienced mentors. In addition to prepare future leaders of the evolving academic discipline of Clinicaland Translational Research (CTR) new efforts designed to promote program excellence are proposed. Theyinclude: 1) new Faculty Oversight and Workforce Integration Committee structures; 2) use of educationaltechnology to develop vigorous yet efficient new competency programs designed to strengthen thefoundational training for future leaders in CTR; and 3) developing a new institutionally sponsored ClinicalScientist Pipeline Program targeting residents fellows and early career clinical faculty to provide a strongerlinking of our successful undergraduate and early faculty career training programs. These initiatives aredesigned to accelerate the career development of future leaders of the biomedical research workforce who willbe prepared to address today's complex research challenges and spearhead advances in human health.

project_terms:
Academia;Achievement;Address;Aptitude;Arts;Behavioral;Biomedical Research;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Communication;Communities;Competence;Complement;Complex;Dentistry;Development;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Education;Educational Curriculum;Educational Technology;Engineering;Enhancement Technology;Ensure;Environment;Evaluation;Extramural Activities;Faculty;Foundations;Funding;Future;Good Clinical Practice;Growth;Health;Health Occupations;Health Psychology;Health Sciences;Healthcare;Human;Incubated;Industry;Instruction;Kentucky;Leadership;Link;Location;Medicine;Mentors;Methodology;NCI Scholars Program;Nurses;Nursing Faculty;Outcome;Pharmacy facility;Policies;Population;Process;Productivity;Program Development;Psychology;Public Health;Public Health Education;Recruitment Activity;Research;Research Training;Resource Development;Resources;Role;Scholarship;Science;Scientist;Self Efficacy;Social Work;Structure;Students;Talents;Teacher Professional Development;Time;Training;Training Programs;Training Support;Training and Education;Translational Research;United States National Institutes of Health;Universities;Work;base;biomedical informatics;career;career development;clinical development;clinical practice;cohort;college;design;early-career faculty;evidence base;experience;improved;interest;member;next generation;novel;programs;research and development;skills;training opportunity;translational medicine;undergraduate student;workforce needs


application_id: 9332495
project_number: 5UL1TR001998-02
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2017-06-15
opportunity_number: PAR-15-304
application_type: 5
activity_code: UL1
ic: TR
serial_number: 001998
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
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_terms:
Abbreviations;Academic Medical Centers;Affect;Agriculture;Appalachian Region;Arts;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Community Healthcare;Data;Development;Discipline;Diverse Workforce;Education;Engineering;Environment;Fostering;Future;Goals;Health;Healthcare;Healthcare Systems;Home environment;Informatics;Institutes;Institution;Interdisciplinary Study;Kentucky;Lead;Leadership;Longevity;Medical center;Methodology;Mission;Multi-Institutional Clinical Trial;Participant;Phase;Population;Positioning Attribute;Quality of Care;Quality of life;Recruitment Activity;Research;Research Training;Role;Rural;Rural Community;Rural Population;Scholarship;Science;Solid;Target Populations;Translational Research;Trust;Universities;West Virginia;Workforce Development;base;biomedical informatics;catalyst;cohesion;collaborative environment;college;data management;drug development;food environment;health care service organization;health disparity;healthcare community;improved;innovation;medical schools;medically underserved;named group;novel;novel therapeutics;programs;success


application_id: 9332493
project_number: 5TL1TR001997-02
project_title: NRSA Training Core
administering_ic: NCATS
award_notice_date: 2017-06-19
opportunity_number: PAR-15-304
application_type: 5
activity_code: TL1
ic: TR
serial_number: 001997
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
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:
PROJECTSUMMARYTheUniversityofKentucky(UK)CenterforClinicalandTranslationalScience(CCTS)TrainingPrograminClinicalandTranslationalScience(UKTL1program)willprepareprofessionalandpredoctoralstudentstoassumeleadershiprolestodirectteamscienceacrosstheclinicalandtranslationalresearch(CTR)spectrum.OverthelastfiveyearstheUKTL1programhasleveragedUKsCTRstrengthstoprovideamultidisciplinaryandtransdirectionaltrainingprogramthatintegratestraineesacrossdiversefieldstoprovidearigorousandsolidresearcheducationinCTR.Withthisapproachwehaveachievedourgoalofincreasingthenumberofinvestigatorswhobridgethegapbetweenbasicscienceadvancesandtheirapplicationtoclinicalmedicine.Thishasbeenaccomplishedbyprovidingahighlycollaborativetrainingenvironmentthatincubatesscholarsandmentorswithaninnovativeandnurturingstructuretodevelopresearchcompetenciesinateam-basedenvironment.ThesuccessoftraineesinthefirstfundingcycleandthedevelopmentofaninnovativetrainingprocesstoengageevengreaternumbersofstudentsinCTRarethefoundationforthefollowingSpecificAims:1)toincreasethepipelineofinvestigatorsengagedinCTR;2)totrainacrossthespectrumofCTR;and3)topreparescholarstoparticipateeffectivelyinteamscience.TomeetouraimsweproposetoincreasethenumberofpredoctoralTL1studentssupportedeachyearandtoincludeanew12-monthintensiveCTRexperiencetomeetanidentifiedneedamongprofessionalstudentsandmedicalprofessionalsinresidency.WewillcontinuetosolicitapplicationsbroadlyacrosscampusoffernewexperientialtrainingincommunityresearchinruralpopulationsinCentralAppalachiaanddevelopdoctoral-leveltraininginbiomedicalinformaticstakingadvantageoftherecentinfluxofleadershipandexpertiseinthisareaatUK.Finallywewillprovidetraineeswiththelatestskillsetstoparticipateeffectivelyininterdisciplinaryandcollaborativeteamscience.Theseinitiativeswillacceleratethecareerdevelopmentoffutureleadersofthebiomedicalresearchworkforcewhocanaddresstodayscomplexresearchchallengesandspearheadadvancesinhumanhealth.

project_terms:
Address;Anti-Retroviral Agents;Appalachian Region;Area;Basic Science;Biomedical Research;Certification;Clinical;Clinical Medicine;Clinical Research;Clinical Sciences;Collaborations;Communication;Communities;Competence;Complex;Dentistry;Development;Development Plans;Discipline;Discipline of Nursing;Doctor of Philosophy;Economics;Educational Status;Engineering;Environment;Ethics;Feedback;Fellowship;Foundations;Funding;Future;Goals;Grant;Growth;Health;Health Sciences;Healthcare;Human;Incubated;Individual;Interdisciplinary Study;Kentucky;Leadership;Learning;Manuscripts;Measures;Medical;Medicine;Mentors;Monitor;National Research Service Awards;Nurses;Oral;Outcome;Pathway Analysis;Pharmacy facility;Population;Positioning Attribute;Preparation;Process;Productivity;Psychology;Public Health;Publications;Research;Research Infrastructure;Research Personnel;Research Training;Residencies;Role;Rural Population;Science;Social Work;Solid;Structure;Students;TNFSF15 gene;Talents;Time Management;Training;Training Programs;Translational Research;Universities;Writing;base;biomedical informatics;career;career development;cohort;college;education research;experience;graduate student;innovation;instructor;multidisciplinary;patient oriented;posters;pre-doctoral;professor;programs;skills;success;training opportunity


application_id: 9332487
project_number: 5R21NS095299-02
project_title: The role of G3BP1 in mutant SOD1-mediated familial ALS
administering_ic: NINDS
award_notice_date: 2017-08-02
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 095299
program_official: GUBITZ, AMELIE
project_start_date: 2016-08-15
project_end_date: 2020-07-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 12058145
contact_pi: GAL, JOZSEF
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:
Abstract Amyotrophic lateral sclerosis also known as Lou Gehrig's disease or ALS is a progressive and fatalneurodegenerative disease with no cure available. In order to develop effective preventive measures or cureswe have to gain a better understanding of the molecular pathogenesis of ALS. A general symptom of ALS ismuscle wasting caused by motor neuron loss. In familial ALS the disease is caused by inherited genemutations. The first gene whose mutations were identified to cause ALS encodes the Cu/Zn superoxidedismutase SOD1. It is still not fully understood how the mutations in SOD1 cause toxicity in ALS. Several othergenes whose mutations cause ALS encode RNA metabolism regulators whose known functions are seeminglyunrelated to that of SOD1. The convergence of these two pathogenic pathways in ALS is still unclear. The Ras GTPase-activating protein-binding protein G3BP1 is known to regulate the stability andtranslation of messenger RNAs. It is also a critical regulator of stress granule dynamics. Stress granules formin response to challenges such as oxidative stress and heat shock. Stress granules sequester temporarilydispensable messenger RNAs in translationally inactive form freeing up ribosomes for the translation oftranscripts that are essential to survive the stress. ALS mutants of SOD1 form cytoplasmic inclusions. We found that the mutant SOD1 inclusionscontained G3BP1. We also found an RNA independent interaction between mutant SOD1 and G3BP1. Ourhypothesis is that G3BP1 represents a critical link between the ALS mutations in SOD1 and thepathological alterations in RNA metabolism. Aim 1 of the grant proposal will determine the molecular details of the ALS mutant SOD1-G3BP1interaction in cell culture and in vitro models. Aim 2 will determine the effect of ALS mutants of SOD1 on stressgranule dynamics and G3BP1 RNA binding in cell culture and transgenic mouse models. Aim 3 will test therole of G3BP1 and the Drosophila G3BP1 homolog Rasputin/Rin in the toxicity of transgenic human SOD1 in afly model. The findings are expected to provide important insight into the mechanism by which SOD1 mutationscause toxicity and perturb RNA metabolism.

project_terms:
ALS patients;Address;Amyotrophic Lateral Sclerosis;Appearance;Applications Grants;Binding Proteins;Biological Models;Cell Culture Techniques;Co-Immunoprecipitations;Collaborations;Cuprozinc Superoxide Dismutase;Cytoplasmic Granules;Cytoplasmic Inclusion;Data;Defect;Disease;Drosophila genus;Etiology;Future;G3BP1 gene;Gene Mutation;Genes;Genetic;Heat-Shock Response;Homologous Gene;Human;Immunoprecipitation;In Vitro;Inherited;Link;Mediating;Messenger RNA;Metabolism;Modeling;Molecular;Motor Neurons;Muscle Weakness;Muscular Atrophy;Mutagenesis;Mutate;Mutation;Neurodegenerative Disorders;Outcome;Oxidative Stress;Oxides;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Phenotype;Play;Preventive measure;Proteins;RNA;RNA Binding;Reagent;Reporting;Research;Resolution;Ribonucleosides;Ribosomes;Role;SCA2 protein;Sampling;Spinal Cord;Stress;Surface;Symptoms;Testing;Time;Toxic effect;Transcript;Transgenic Mice;Transgenic Organisms;Translations;base;crosslink;design;experimental study;fly;in vitro Model;in vivo;insight;matrin 3;motor neuron degeneration;mouse model;mutant;neuron loss;novel;overexpression;protein TDP-43;ras GTPase-Activating Proteins;response;superoxide dismutase 1

public_health_relevance:
Project narrative Amyotrophic lateral sclerosis or ALS is a fatal neurodegenerative disease with no known cure.Mutations in the SOD1 Cu/Zn superoxide dismutase are among the most frequent causes of the familial formof ALS. This project will determine the role of the G3BP1 protein in the toxicity of SOD1 mutants.


application_id: 9332298
project_number: 5U01AA022618-02
project_title: Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation
administering_ic: NIAAA
award_notice_date: 2017-08-01
opportunity_number: PAR-13-133
application_type: 5
activity_code: U01
ic: AA
serial_number: 022618
program_official: WANG, JOE
project_start_date: 2016-08-15
project_end_date: 2021-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acids;Adverse effects;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcohols;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Astrocytes;Attenuated;Bacteria;Brain;Brain Injuries;Cells;Cerebrum;Chronic;Communities;Complex;Cyclic AMP;Data;Development;Diet;Encephalitis;Endotoxemia;Endotoxins;Enteral;Epithelial;Ethanol;Extramural Activities;Feedback;Functional disorder;Gene Expression;Gram-Negative Bacteria;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intervention;Intestines;Knockout Mice;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Link;Mediating;Membrane;Mental disorders;Microglia;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Omega-3 Fatty Acids;Oxidative Stress;PDE4B;Pathogenicity;Pathology;Peripheral;Permeability;Play;Populations at Risk;Preventive;Probiotics;Process;Production;Proteins;Proteobacteria;Role;Rolipram;Signal Transduction;Supplementation;TLR4 gene;TNF gene;Therapeutic;Tight Junctions;Treatment Efficacy;Universities;Work;alcohol effect;alcohol exposure;base;body system;brain cell;chronic alcohol ingestion;cytokine;feeding;gut microbiome;gut microbiota;immune activation;inhibitor/antagonist;macrophage;metagenomic sequencing;microbiota;monocyte;neuroinflammation;neuropathology;next generation sequencing;phosphodiesterase IV;prevent;probiotic supplementation;public health relevance;rRNA Genes;sequencing platform;translational study


application_id: 9331553
project_number: 5K07CA181351-04
project_title: The Dynamics of Smoking Cessation After Cancer Diagnosis: A Naturalisitic Study
administering_ic: NCI
award_notice_date: 2017-08-17
opportunity_number: PAR-12-067
application_type: 5
activity_code: K07
ic: CA
serial_number: 181351
program_official: PERKINS, SUSAN N
project_start_date: 2014-09-01
project_end_date: 2019-08-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 9524802
contact_pi: BURRIS, JESSICA 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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The activities proposed in this NCI K07 application are designed to advance the career development of Dr. Jessica Burris whose long-term career goal is to sustain an independent innovative and meaningful clinical research program that focuses on tobacco use and cessation in cancer patients. Most clinicians view cancer diagnosis as a teachable moment and thus urge immediate smoking cessation after delivery of cancer diagnosis. However most quit attempts end in relapse and extant interventions for smoking cessation in cancer patients have limited success. A cancer diagnosis brings about many intra- and inter-personal changes (e.g. increase in emotional distress greater need for social support increase in saliency of personal risk) but there is very little understanding as to how such changes influence smoking cessation. With an eye toward intervention development the independent research proposed in this application will examine the naturalistic course of smoking cessation after cancer diagnosis as well as the dynamics that underlie changes in smoking behavior. Specific aims are 1) to describe key events in the process of smoking cessation and 2) to uncover cognitive and affective variables that promote or undermine the occurrence of a quit attempt lapse and relapse among newly diagnosed cancer patients. After a baseline assessment (N=120 head and neck cancer patients) participants will initiate a 30-day period of daily assessment via interactive voice response technology with a final assessment to occur three months after the baseline assessment. Biochemical verification of abstinence at the end of the 30-day daily IVR assessment and final assessment will be achieved through use of saliva cotinine samples. Statistical analysis will allow novel tests of how and to what extent day-to-day changes in cognitive and affective variables influence smoking cessation outcomes in newly diagnosed cancer patients. Innovation is achieved by: 1) a focus on the process of smoking cessation as opposed to the treatment of abstinence as a discrete outcome 2) equal attention given to cognitive and affective predictors of smoking cessation outcomes 3) use of mobile technology as the primary means of data collection among cancer patients and 4) proper application of longitudinal data analysis techniques to rich within-subjects data. A training plan that complements the independent research includes coursework seminars workshops mentored research journal clubs and conferences the combination of which will cover these topics: nicotine dependence; individual-level and public health approaches to tobacco control; longitudinal research design coordination and execution; advanced statistical techniques; research dissemination; grantsmanship; and ethical conduct of research. The strong support of an excellent team of mentors and the vast resources and outstanding scientific environment of the Medical University of South Carolina create an optimal training environment. Collectively the integrated research and training plan proposed in this NCI K07 application are an ideal mechanism to promote the career development of Dr. Burris.

project_terms:
Abstinence;Affective;Alcohol consumption;Attention;Behavior;Belief;Biochemical;Cancer Control;Cancer Model;Cancer Patient;Cancer Survivor;Cereals;Clinical;Clinical Investigator;Clinical Research;Cognitive;Complement;Complex;Cotinine;Data;Data Analyses;Data Collection;Distress;Educational workshop;Electronic cigarette;Ensure;Environment;Ethics;Event;Eye;Future;Goals;Head and Neck Cancer;Health;Health Status;High-Risk Cancer;Home environment;Hour;Individual;Intention;Intervention;Journals;Knowledge;Lead;Life;Measures;Medical;Mentors;Motivation;Nature;Newly Diagnosed;Nicotine Dependence;Outcome;Outcome Study;Participant;Perception;Play;Prevention;Process;Public Health;Recurrence;Relapse;Research;Research Design;Research Training;Resources;Risk;Risk Behaviors;Risk Factors;Role;Saliva;Sampling;Second Primary Cancers;Self Concept;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Cessation Intervention;Social Environment;Social support;South Carolina;Statistical Data Interpretation;Survival Rate;Techniques;Technology;Testing;Time;Tobacco;Tobacco Use Cessation;Tobacco use;Training;Universities;Voice;Withdrawal;Withholding Treatment;Work;behavioral outcome;cancer complication;cancer diagnosis;cancer prevention;cancer recurrence;cancer therapy;career;career development;cigarette smoking;craving;design;dissemination research;emotional distress;head and neck cancer patient;innovation;longitudinal design;mobile computing;novel;programs;psychologic;public health relevance;research data dissemination;response;skills;smoking cessation;smoking restriction;success;symposium;therapy development;tobacco control;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:Cigarette smoking after head and neck cancer diagnosis can lead to a number of significant health problems including a high risk of cancer recurrence and second primary cancer. The goal of this research is to uncover the process of smoking cessation in newly diagnosed head and neck cancer patients and to identify the dynamics of cognitive and affective variables that underlie quit attempts lapses and relapses. The results will inform the design of more effective smoking cessation treatments which has clear implications for the prevention of future threats to the health of cancer patients.


application_id: 9331426
project_number: 5R01AR067667-03
project_title: Mitigating mitochondrial epigenetics in bone remodeling by hydrogen sulfide
administering_ic: NIAMS
award_notice_date: 2017-08-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 067667
program_official: CHEN, FAYE H
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-U(90)S]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Clinical studies report that children born with severe hyperhomocysteinemia (HHcy) due to deficiency in cystathionine--synthase (CBS) gene resulting in an elevation in plasma homocysteine (Hcy) levels develop skeletal malformations with weaker bone. Although mitochondrial dysfunction has been involved in bone pathology altered mitochondrial (Mito) epigenetics and dynamics contributing to frailer bone have not been studied. The long term goal of this project is to understand the mechanisms of mito-epigenetic remodeling and changes in bone structure/function during genetic HHcy. Alterations in mitochondrial dynamics disturb bone cell (osteoclast/ osteoblast) differentiation and matrix metabolism. Studies have confirmed that type-I collagen (coll-1) a dominant protein of the organic bone matrix is homocysteinylated (N-Hcy-coll-1) during HHcy. Our preliminary data suggest that genetic HHcy affects mito-epigenetic remodeling by altering mito-redox stress mito-DNA methylation / hydroxymethylation fission-fusion and cause N-Hcy-coll-1 cross linking. These processes cumulatively disrupt bone matrix bone density bone blood flow and lead to mitophagy accompanying with significant bone loss. Interestingly hydrogen sulfide (H2S an anti-redox stress and Hcy lowering agent) mitigates bone damage. The central hypothesis of this proposal is that HHcy contributes to bone-matrix inferiority through N-Hcy-coll-1 in part byincreasing mito- epigenetic remodeling and altering mitochondrial dynamics. However treatment with H2S ameliorates HHcy-induced bone abnormalities. We will test this hypothesis by following three specific Aims: Specific Aim # 1: To determine whether the HHcy instigates mito-epigenetic remodeling and DNA methylation in part by altering mitochondrial fission and fusion and whether H2S mitigates mito-epigenetic remodeling. Specific Aim # 2: To determine whether the HHcy homocysteinylates bone type-I collagen activates MMP-1-3-13 disrupts bone matrix (MMP/TIMP axis; collagen/elastin ratio) and H2S ameliorates these changes. Specific Aim # 3: To determine whether the HHcy alters bone mineral density bone mineral content biomechanical load-bearing capacity bone blood flow and disrupts osteoblast/osteoclast differentiation and whether H2S alleviates these alterations.

project_terms:
Affect;Alkaline Phosphatase;Antibodies;Architecture;Attenuated;Azacitidine;Biomechanics;Blood Vessels;Blood flow;Bone Density;Bone Diseases;Bone Matrix;Bone Mineral Contents;Bone Resorption;Bone remodeling;Bone structure;C-terminal;Child;Chimeric Proteins;Clinical Research;Co-Immunoprecipitations;Collagen;Collagen Type I;Consumption;Cyclophosphamide;Cystathionine;DNA Methylation;DNA Modification Methylases;Data;Deformity;Elastin;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Event;Gel;Gelatin;Gelatinase B;Generations;Genes;Genetic;Goals;Homocysteine;Hydrogen Sulfide;Hyperhomocysteinemia;Immunohistochemistry;Impairment;In Situ;Inferior;Interstitial Collagenase;Knock-out;Knockout Mice;Lasers;MMP9 gene;MTHFR gene;Matrix Metalloproteinases;Measures;Mechanics;Metabolism;Mitochondria;Molecular;Mus;Osteoblasts;Osteocalcin;Osteoclasts;Osteocytes;Osteogenesis;Oxidation-Reduction;Oxidative Stress;Pathologic;Pathology;Pathway interactions;Peptides;Plasma;Process;Proteins;Proteome;Pyridoxal Phosphate;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Role;Staining method;Stains;Stress;Structure;Testing;Therapeutic;Therapeutic Agents;Weight-Bearing state;Western Blotting;blood lead;bone;bone cell;bone loss;bone strength;bone turnover;cortical bone;crosslink;density;femoral artery;inhibitor/antagonist;innovation;malformation;microCT;mitochondrial dysfunction;novel;osteoblast differentiation;public health relevance;skeletal;substantia spongiosa;tibia

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed project will delineate the novel molecular pathological and functional mechanisms for bone deformity by incorporating mitochondrial epigenetics and dynamics studies during hyperhomocysteinemia. The involvement of knockout (MMP9- /-) gene deficient (CBS+/-) double knockout (CBS+/-/MMP9-/-) mice and their various treatments (for example; 5'-azacytidine Mdivi-1 pyridoxal 5' phosphate) will come up with exciting results and innovative findings that have never been studied in bone pathology. Also the use of hydrogen sulfide throughout the study will not only validate the pathways but also confirm its therapeutic aspects in bone diseases.


application_id: 9331181
project_number: 1R01DE026963-01
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2017-08-18
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DE
serial_number: 026963
program_official: LUNSFORD, DWAYNE
project_start_date: 2017-09-01
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-S (02)]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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:
PROJECT SUMMARY Periodontitis a microbial-driven destructive disease of the tissues surrounding the teeth occurs in approximately50% of the population and is associated with several debilitating systemic conditions (including vascular and lung diseasesdiabetes mellitus and pre-term birth). Patients who smoke have increased susceptibility to periodontitis and are more likelythan non-smokers to display severe disease and to be refractory to treatment. Indeed the most recent epidemiological evidencesuggests that tobacco smoking accounts for the majority of destructive periodontal disease cases in developed nations. Smoking enhances infectionrates and enriches numbers of the keystone periodontal pathogen Porphyromonas gingivalis. However the mechanisms underlyingthis phenomenon are in need of elucidation. We plan to generate whole genome transposon sequencing (TnSeq) libraries for two P. gingivalis strains (ATCC 33277and W83) to be employed in order to (i) identify genes that are putatively essential for P. gingivalis to survive cigarette smokeexposure in vitro; (ii) to validate that TnSeq-identified genes are indeed essential by generating single gene deletion mutants andmonitoring their ability to grow planktonically and in biofilms under cigarette-induced stress; (iii) to determine the in vivorelevance of such mutations in a murine model of smoke-exacerbated periodontitis; (iv) to establish the distribution of essentialgenes in multiple low-passage clinical P. gingivalis isolates; (v) to characterize the function of those genes confirmed to be requisitefor survival of tobacco-induced stress both in vitro and in vivo and (vi) to identify in silico essential gene orthologues in otherbacteria whose virulence is also enhanced in tobacco smokers. There are several potential translational benefits to a successful R01 which include a better understanding of how P.gingivalis thrives in a tobacco-toxin rich environment; future therapeutic targeting of essential genes to control P. gingivalis infectionin smokers; potential identification of novel vaccine targets for prevention or control of P. gingivalis infection; alternate treatmentregimens for smokers based on mechanistic insight into smoke-induced and/or exacerbated periodontal diseases; and theestablishment of an essential gene database for tobacco-enhanced pathogens that will facilitate the identification of commonbacterial strategies for surviving tobacco smoke exposure thus broadening the significance of the research beyond the oralcavity.

project_terms:
Adult;Anaerobic Bacteria;Bacteria;Bacterial Model;Biochemical;Biological Assay;Chronic;Cigarette;Clinical;Collection;Communicable Diseases;Complex;Computer Simulation;Crystallography;Data;Databases;Deposition;Developed Countries;Developing Countries;Diabetes Mellitus;Disease;Dose;Economic Burden;Ensure;Environment;Epidemiology;Essential Genes;Exhibits;Exposure to;Future;Gene Deletion;Generations;Genes;Genome;Growth;Homologous Gene;Immune;In Vitro;Individual;Infection;Inflammation;Investigation;Laboratories;Libraries;Lung diseases;Microbial Biofilms;Modeling;Monitor;Mus;Mutation;New Zealand;Nicotine;Non-smoker;Oral;Oral cavity;Output;Pathogenicity;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Periodontium;Persons;Physiology;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Prevalence;Prevention;Preventive;Process;Refractory;Research;Resistance;Scandinavia;Smoke;Smoker;Smoking;Stress;Structural Models;Techniques;Testing;Time;Tissues;Tobacco;Tobacco smoke;Tobacco smoking;Tooth structure;Toxin;Treatment Protocols;Variant;Vascular Diseases;Virulence;Work;base;cigarette smoke;environmental tobacco smoke exposure;enzyme activity;fitness;in vivo;insight;microbial;mouse model;mutant;novel;novel vaccines;pathogen;periodontopathogen;prediction algorithm;screening;therapeutic target;whole genome

public_health_relevance:
PROJECT NARRATIVETobacco smoking is the leading environmental cause of chronic periodontal diseases. Many periodontal pathogens are highlyresistant to the plethora of toxic insults contained in cigarette smoke. One such important pathogen is Porphyromonas gingivalis.We will identify the P. gingivalis genes that are required for surviving smoke exposure; ensure in vivo relevance in a mouse modelof bacterial-induced periodontitis; and compare the presence or absence of confirmed essential genes in multiple strains of P.gingivalis as well as other oral and non-oral pathogens whose infectivity is known to be enhanced in tobacco smokers.


application_id: 9331009
project_number: 261201300013I-0-26100011-1
project_title: Patterns of Care/Quality of Care: Diagnosis Year 2015
administering_ic: NCI
project_start_date: 2016-08-15
project_end_date: 2017-08-14
contact_pi_person_id: 14661919
contact_pi: NEE, JACLYN
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: female breast colorectal and lung.

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


application_id: 9330929
project_number: 5R01NS089515-04
project_title: The Role of Perlecan Domain V in Vascular Dementia
administering_ic: NINDS
award_notice_date: 2017-08-25
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089515
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-09-01
project_end_date: 2019-07-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
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): Despite its prevalence VaD remains woefully understudied and poorly understood in part due to its diverse etiology. The outcome of these multiple causes of VaD however remains the same- disruption of the complex coupling between endothelial cells astrocytes pericytes neurons and the extracellular matrix the components of the neurovascular unit. We hypothesize that the extracellular matrix plays a critical role in the neurovascular disruption of VaD. In particular we have identified a biologicaly active fragment of one prominent matrix component the heparan sulfate proteoglycan perlecan to play a major role in regulating endothelial cell function after experimental ischemic stroke. This fragment termed domain V (DV) is actively generated in the stroked brain and appears to be important to the brain's response to injury inasmuch as its absence results in more significant stroke injury and worse outcome. Furthermore DV stroke treatment after stroke enhances peri-infarct new blood growth (angiogenesis) and important component of neurorepair. As extracellular matrix remodeling is likely to occur in the vascular pathology leading to VaD we hypothesize that DV is actively generated plays a key role in regulating brain endothelial cell function and may improve endothelial cell function and neurovascular coupling when administered in two experimental mouse models of VaD the BCAS and the DB/AD models which differentially impact white matter and gray matter respectively. This will allow us to determine both the impact of white and gray matter endothelial cell dysfunction on VaD and DV's potential impact on it. To investigate these hypotheses we propose three aims: Aim 1. Determine the extent and significance of DV generation in the BCAS and DB/AD mouse models. Aim 2. Determine the therapeutic potential of DV in the BCAS and DB/AD mouse models. Aim 3. Determine the extent and significance of DV generation in human autopsy brain from subjects with VaD. Successful completion of these studies will increase our understanding of the role of the extracellular matrix and angiogenesis in VaD and support the therapeutic potential for DV.

project_terms:
APP-PS1;Acute;Aftercare;Age;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Arteriovenous malformation;Astrocytes;Autopsy;Bilateral;Biochemical;Biological;Blood;Blood Vessels;Brain;Brain region;Carotid Stenosis;Cell Communication;Cell physiology;Cerebral Amyloid Angiopathy;Cerebrovascular Disorders;Cerebrovascular system;Cognitive;Complex;Coupling;Dementia;Development;Endothelial Cells;Etiology;Experimental Animal Model;Extracellular Matrix;Failure;Functional disorder;Gene Expression;Generations;Growth;Growth Factor;Heparan Sulfate Proteoglycan;Histologic;Homo;Human;Immunohistochemistry;Impaired cognition;Infarction;Injury;Integrin alpha5beta1;Ischemic Stroke;Knock-in Mouse;Methods;Mus;Neurons;Outcome;Pathologic;Pathology;Patients;Pericytes;Phenotype;Play;Prevalence;Process;Protein Fragment;Proteins;Replacement Therapy;Role;Therapeutic;Time;Vascular Dementia;angiogenesis;blood vessel development;brain abnormalities;brain endothelial cell;cerebrovascular;cognitive function;combat;diabetic;gray matter;hypoperfusion;improved;mouse model;neurovascular;neurovascular coupling;neurovascular unit;novel;perlecan;post stroke;prevent;public health relevance;receptor;response;response to injury;stroke;stroke treatment;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although vascular dementia is the second leading cause of dementia behind Alzheimer's disease it remains woefully understudied and poorly understood in part due to its diverse etiology. The gradual failure of compensatory new brain blood vessel formation (angiogenesis) in the face of ongoing cerebrovascular insult appears to contribute to vascular dementia regardless of the etiology. We propose to determine the role and therapeutic potential of an angiogenic extracellular matrix fragment in human and novel animal models of vascular dementia.


application_id: 9330910
project_number: 5R44HL129490-03
project_title: Development of Percutaneous DLC for Total Cavo-pulmonary Assistance
administering_ic: NHLBI
award_notice_date: 2017-07-20
opportunity_number: PA-15-269
application_type: 5
activity_code: R44
ic: HL
serial_number: 129490
program_official: LEE, ALBERT
project_start_date: 2016-08-15
project_end_date: 2019-07-31
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
arra_indicator: N
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;Congestive;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;Liquid substance;Low Cardiac Output;Lung;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;Savings;Scientist;Secure;Sheep;Small Business Innovation Research Grant;Superior vena cava structure;Surgeon;System;Technology;Testing;Thinness;Thrombosis;Transplantation;Universities;Validation;Velocimetries;Venous;Venous system;Ventricular;artificial lung;base;biomaterial compatibility;blood perfusion;blood pump;commercialization;congenital heart disorder;design;experience;in vivo;mortality;multidisciplinary;particle;performance tests;phase 1 study;prevent;prototype;public health relevance;reconstruction;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: 9330349
project_number: 1R13HL137316-01
project_title: Clinical & Translational Research in Pneumonia: Defining a Research Agenda for Today and Tomorrow
administering_ic: NHLBI
award_notice_date: 2017-04-01
opportunity_number: PA-16-294
application_type: 1
activity_code: R13
ic: HL
serial_number: 137316
program_official: CALER, ELISABET V
project_start_date: 2017-05-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZHL1 CSR-X (F1)]
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
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:
Pneumonia is a leading cause of infectious disease-related death in the United States.Generation of new knowledge in all aspects of pneumonia such as prevention andtreatment is critical to decreased morbidity and mortality.One important barrier to perform research and generate new knowledge is the paucity ofinternational forums with a primary focus on pneumonia research that facilitatesnetworking and generation of effective collaboration among pneumonia investigators.In an attempt to resolve this barrier we are proposing to bring together the pertinentresearch community into a two day meeting Clinical & Translational Research inPneumonia: Defining a Research Agenda for Today and Tomorrow. This researchsymposium will provide a unique opportunity to foster global clinical and translationalresearch in the field of pneumonia. During the symposium focused presentationsimmediately followed by brainstorming sessions will provide attendees with theopportunity to openly discuss innovative research ideas. This original approach will leadto significant tangible results including research proposals that will close importantknowledge gaps in the field of pneumonia.

project_terms:
Cessation of life;Clinical Research;Collaborations;Communicable Diseases;Communities;Computer software;Development;Fostering;Generations;Infection;International;Investigation;Knowledge;Lung;Measurable;Mentors;Morbidity - disease rate;Outcome;Pathway interactions;Pneumonia;Prevention;Publishing;Reporting;Research;Research Personnel;Research Project Grants;Research Proposals;Research Support;Translational Research;United States;Universities;experience;follow-up;improved;innovation;meetings;mortality;prevent;programs;symposium;virtual

public_health_relevance:
NarrativePneumonia is a lung infection with high mortality. We plan to bring together the most importantinvestigators from around the world working in the field of pneumonia. This meeting willgenerate new ideas to improve our capabilities to prevent and treat this serious infection.


application_id: 9330248
project_number: 5U01NS090408-05
project_title: The Center for SUDEP Research (CSR) Informatics and Data Analytics Core (IDAC)
administering_ic: NINDS
award_notice_date: 2017-08-01
opportunity_number: RFA-NS-14-004
application_type: 5
activity_code: U01
ic: NS
serial_number: 090408
program_official: LEENDERS, MIRIAM
project_start_date: 2016-02-27
project_end_date: 2019-07-31
study_section: ZNS1-SRB-B(40)
contact_pi_person_id: 7938505
contact_pi: ZHANG, GUO-QIANG
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): Project Summary The goal of SUTRA (SUDEP Translational Research Alliance) Center Without Walls is to better understand the brainstem mechanisms responsible for SUDEP and elucidate the role of cortical influences thereon using a data-driven systems-biology-based approach. This understanding requires a strategy that shares research resources and infrastructure to make good and efficient use of a spectrum of prospectively collected data encompassing clinical electrophysiological biochemical genetic and neuropathological domains. A critical aspect of SUTRA is the process and infrastructure facilitating the sharing of clinical and research data across centers. In our NINDS-funded center- planning award Prevention and Risk Identification of SUDEP Mortality (PRISM; 1P20- NS076965) a team of world-class epileptologists computer scientists biomedical informaticians and data analytics experts has developed an informatics infrastructure for sharing research data using the Multi-Modality Epilepsy Data Capture and Integration System (MEDCIS). The main goal of this Informatics and Data Analytics U01 Core (IDAC) is to build on the paradigm-changing progress already achieved through PRISM's MEDICS infrastructure and expand and broaden the sharing and utilization of research resources among SUTRA partners. With access to biospecimen materials and alliances with stakeholder organizations including Dup15q the North American SUDEP Registry Courtagen GW Pharma and CURE SUTRA will continuously boost materials and data collection. IDAC will promote and facilitate SUDEP research by expanding an integrated clinical and translation data resource for epilepsy; providing coordinated services and support for SUTRA members; empowering investigator with web-based cohort search interface for data mining and hypothesis generation; data analytics and statistical support for in-depth analyses of multi-modal data collected in the shared and expanding SUTRA Data Repository.

project_terms:
Address;Algorithmic Analysis;Algorithms;American;Animals;Award;Big Data;Biochemical Genetics;Biological;Blood Pressure;Brain;Brain Stem;Clinical;Clinical Research;Cloud Computing;Collection;Computers;Consultations;Coupling;Custom;Data;Data Analytics;Data Collection;Data Set;Databases;Development;Electrocardiogram;Electroencephalography;Electrophysiology (science);Enrollment;Epilepsy;Event;Feedback;Formalin;Freezing;Funding;Galvanic Skin Response;Generations;Goals;Imagery;Informatics;Institution;Intervention;Modality;Motion;National Institute of Neurological Disorders and Stroke;Online Systems;Ontology;Oxygen;Patients;Performance;Phenotype;Prevention;Prevention Measures;Process;Registries;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Respiration;Rest;Risk;Role;Scientist;Seizures;Services;Signal Transduction;Sleep;Statistical Data Interpretation;Structure;Surveys;System;Systems Biology;Systems Integration;Technology;Terminology;Translational Research;Visual;Work;base;clinical translation;cohort;computerized tools;crosslink;data management;data mining;data resource;demographics;design;empowered;evidence base;genetic resource;improved;informatics infrastructure;member;mortality;neuropathology;open source;phenotypic data;prospective;public health relevance;quality assurance;satisfaction;signal processing;sudden unexpected death in epilepsy;tool;user-friendly;webinar

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Project Narrative The main goal of this Informatics and Data Analytics Core a part of the SUDEP Translational Research Alliance is to expand and broaden the sharing and utilization of research resources across centers to accelerate the understanding of biological mechanisms responsible for SUDEP and to develop intervention and prevention measures to reduce SUDEP mortality.


application_id: 9330224
project_number: 5R01NS100093-02
project_title: Nrf2-Antioxidant Response Element Neuroprotection in TBI
administering_ic: NINDS
award_notice_date: 2017-05-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 100093
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-08-15
project_end_date: 2021-05-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
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:
3-nitrotyrosine;4 hydroxynonenal;Acute;Antioxidants;Attention;Attenuated;Biological Preservation;Brain;Brain Injuries;Broccoli - dietary;Buffers;Calcium;Calpain;Cell Culture Techniques;Chemicals;Chronic;Defense Mechanisms;Diffuse;Dose;Drops;Elements;Evaluation;Experimental Designs;Failure;Female;Free Radical Scavengers;Free Radical Scavenging;Free Radicals;Future;Gender;Gene Expression;Genes;Herb;Hippocampus (Brain);Histologic;Homeostasis;Injury;Lipid Peroxidation;Lipid Peroxides;Lipids;Mediating;Membrane Lipids;Messenger RNA;Mitochondria;Modeling;Motor;Mus;Nerve Degeneration;Nervous System Trauma;Neurodegenerative Disorders;Neurologic;Neurons;Nitrates;Nuclear;Oxidoreductase;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Proteins;Quinones;Reactive Oxygen Species;Recovery of Function;Respiratory physiology;Response Elements;Rosemary;Severities;Speed;Sulforaphane;Surrogate Endpoint;Surrogate Markers;Testing;Therapeutic;Time;Tissues;Transcriptional Activation;Traumatic Brain Injury;Treatment Efficacy;Water;Weight;base;body system;brain tissue;cognitive recovery;cohort;comparative;controlled cortical impact;design;drug discovery;expectation;experimental study;glutathione peroxidase;heme oxygenase-1;improved;injured;interest;male;motor recovery;mouse model;neuroprotection;nitration;novel;object recognition;oxidative damage;prevent;protective effect;prototype;respiratory;response;salvin;therapeutic target;transcription factor;young adult


application_id: 9330062
project_number: 5R01AR067188-03
project_title: Interplay of androgens microbiota and immunoregulation in lupus
administering_ic: NIAMS
award_notice_date: 2017-09-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 067188
program_official: MANCINI, MARIE
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Resubmission Systemic lupus erythematosus (SLE) is much more prevalent in females than males in humans and in the (NZBxNZW)F1 (BWF1) mouse model of lupus. Although estrogens can exacerbate disease in females considerable evidence suggests that androgens play a critical role in protecting males from lupus in both humans and mice. The gut microbiota is now thought to play a major role in host health and disease and microbiota dysbiosis is associated with development of autoimmune diseases. Interestingly androgens can have a significant impact on the microbiota and vice versa. Recent studies in a mouse model of type 1 diabetes (T1D) suggest that the microbiota and androgens collaborate in what is now being referred to as the "microgenderome" to protect male mice from disease via currently unknown mechanisms. However little is known about the relationship between androgens and the microbiota in lupus. In preliminary studies we have found that both the microbiota composition and metabolomic profile differ significantly between mature female and male BWF1 mice and transfer of male microbiota to female BWF1 mice protects female recipients from disease and significantly enhances survival. These data suggest that the male environment confers protective properties on the microbiota by altering microbiota composition and/or metabolome. Metabolites from commensal bacteria have been found to induce Treg differentiation both directly and through DC. The gut CD103+ dendritic cells (CD103DC) are highly tolerogenic and generate regulatory T cells in the periphery that can control systemic immune responses. Our preliminary data showing sex-based differences in CD103DC function and the requirement for CD103+ cells for protection in male BWF1 mice strongly support the notion that CD103DC function as a critical link between the male gut microbiota and the immune response and may therefore play an important role in protecting BWF1 male mice from disease. Moreover preliminary analysis of the microbiota metabolome has identified a metabolite that is increased in male BWF1 mice that may have an impact CD103DC function. We therefore hypothesize that the androgen-modified male microbiota and its metabolites protect against lupus by acting through the gut CD103DC. This novel hypothesis will be addressed in lupus-prone BWF1 mice by 1) examining the impact of androgens on the gut microbiota and its metabolites; 2) exploring the role of male microbiota and its metabolites in protection from disease; and 3) determining the role that CD103DC play in male microbiota- mediated protection from disease. The proposed project will fill the gaps in our knowledge about the role of the androgen-gut microbiota relationship in immunoregulation and lupus and will lead to the development of novel therapeutic strategies using the microbiota and/or its metabolites for the treatment of lupus and other autoimmune diseases.

project_terms:
Address;Affect;Agonist;Androgen Receptor;Androgens;Autoimmune Diseases;Castration;Cell physiology;Complex;Cytoprotection;Data;Defect;Dendritic Cells;Development;Diabetes Mellitus;Disease;Environment;Estrogens;Exhibits;Feces;Female;Gonadal Steroid Hormones;Health;Human;Immune response;Immune system;Immunologics;In Vitro;Inbred NOD Mice;Incidence;Inflammatory;Insulin-Dependent Diabetes Mellitus;Intestines;Knowledge;Lead;Link;Lupus;Mediating;Men's Role;Microbiological Techniques;Modeling;Mus;Pathogenesis;Phytol;Play;Prevention strategy;Production;Property;Puberty;RXR;Receptor Signaling;Regulatory T-Lymphocyte;Role;Severity of illness;Symbiosis;Systemic Lupus Erythematosus;Techniques;Therapeutic;Treatment Protocols;Tretinoin;Volatile Fatty Acids;Woman;autoreactivity;base;commensal microbes;disorder prevention;fecal transplantation;gender difference;gut microbiota;immunoregulation;imprint;in vivo;innovation;male;men;metabolome;metabolomics;microbiota;mortality;mouse model;next generation sequencing;novel;novel therapeutics;public health relevance;sex

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Systemic lupus erythematosus (SLE or lupus) is an insidious disease without many treatment options. Women have a much higher incidence of SLE than men and male sex steroids (androgens) appear to protect genetically susceptible men from disease. Recently a role for the intestinal natural (non-pathogenic) bacterial flora in health anddisease (including inflammatory and autoimmune diseases) has been demonstrated and an important relationship between the natural bacterial flora in the gut and male androgens in disease has been identified. We have found that fecal transplants from healthy male mice into lupus-susceptible female mice protected them from disease. In this application we propose to study the relationship between gut flora and androgens in lupus in order to develop novel therapies for the treatment of lupus.


application_id: 9329560
project_number: 3P20GM103492-09S1
project_title: Core A - Administrative Core
administering_ic: NIGMS
award_notice_date: 2016-08-17
opportunity_number: PAR-12-224
application_type: 3
activity_code: P20
ic: GM
serial_number: 103492
suffix: S1
program_official: CANTO, MARIA TERESA
study_section: ZGM1-TWD-Y
subproject_number: 5001
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Core A will continue to provide scientific fiscal administrative and logistic oversight to all aspects of the Center. As before. Core personnel will facilitate communication among investigators and the sharing of reagents tools specimens and data to ensure appropriate allocation and effective use of Center funds. The Core will also continue to: provide clerical support; coordinate interactions between facility cores and research projects; organize regular investigator meetings and; provide biostatistical support. In addition to these functions the Core will develop and implement a clear path for transition to and attainment of independent status and for the continued career development of early career investigators . The Core will provide leadership and administrative support needed to maintain the thematic focus of the Center and to achieve Center goal. It will provide mentorshp to early-career investigaotrs by expanding curernt mentoring activitis while continued to provide personalized mentoring. Core personnel will encourage the exploratoin of new research avenues and phase out unpromising resarch and maximize the intellectual environment of the Center. The Core will also provide statistical support to assist in study design and analysis and help in developing grant proposals. It will monitor evaluate overall Center progress in achieving specific milestones. Core personel will prepare annual scientific reports and financial statements and plan and organize symposia seminars and regulary-scheduled meetings. They will invite prominent scientists to present seminars and interact with Center members and communiate with University and NIH officials to report progress and discuss Center related issues. In consultation with the external and internal advisory committee the Program Director will recruit new faculty to replace graduating COBRE investigators and if required increase the critical mass of investiagtors working in the Center. If required Core A will adopt remedial measures for Principal Investigators who fail to satisfactory review by the External Advisory Committee. The Core will also maintain a Center Website and faciliate the dissemination of information about Center activities as well as diabetes and obesity.

project_terms:
Adopted;Advisory Committees;Applications Grants;Area;Centers of Research Excellence;Communication;Consultations;Core Facility;Data;Development;Diabetes Mellitus;Ensure;Environment;Faculty;Funding;Goals;Human Resources;Information Dissemination;Leadership;Logistics;Measures;Mentors;Monitor;Obesity;Phase;Prevention strategy;Principal Investigator;Progress Reports;Reagent;Recruitment Activity;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Schedule;Scientist;Specimen;Training;United States National Institutes of Health;Universities;Work;career;career development;meetings;member;next generation;programs;symposium;tool;web site

public_health_relevance:
The Core will provide administrative support to the Diabetes and Obesity Center at the University of Louisville and therefore contribute to the development of new and effective strategies for prevention and treatment of diabetes and obesity research by facilitating research in this area and by providing mentoring and training to the next generation of scientists.


application_id: 9329559
project_number: 3P20GM103492-09S1
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2016-08-17
opportunity_number: PAR-12-224
application_type: 3
activity_code: P20
ic: GM
serial_number: 103492
suffix: S1
program_official: CALDWELL, SHEILA
project_start_date: 2008-09-26
project_end_date: 2018-06-30
study_section: ZGM1-TWD-Y(C2)
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This proposal is for continued support for the multi-disciplinary Diabetes and Obesity Center at the University of Louisville. The central focus of the Center is to enable promote and support research on the cardiovascular causes and consequences of diabetes and obesity. The second major aim of the program is to continue to provide mentoring and guidance to junior investigators in the Center. Specific objectives of the program are to: (1) Enhance and expand a thematic multi-disciplinary research center focused on diabetes and obesity; (2) Foster the research careers of junior investigators leading to their development as independent principal investigators; (3) Develop a nationally-competitive program that will attract the best clinical and post-doctoral fellows graduate students and faculty; (4) Expand and bridge on-going research within the Center and further integrate current expertise into a thematically coherent program; (5) Promote collaborative interactions to build additional complementary research projects both individual and multi-investigator; (6) Build upon existing research capabilities and core facilities to provide state-of-the-art infrastructure support; (7) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease; (8) Discover new and effective means for preventing and treating diabetes and obesity; and (9) Develop and implement a plan for the transition from COBRE support to independent funding. The five related projects of the junior investigators will: (1) Examine the effects of dietary carnosine on diabetes and obesity; (2) Assess the impact of particulate air pollution on insulin resistance; (3)Elucidate the role of eNOS in obesity; (4) Assess stem cell dysfunction in diabetes; and (5) Develop biomarkers for detecting atherothrombotic events in patients with type 2 diabetes. These investigations will be supported by state-of-the-art core facilities in flow cytometry pathology and bioanalytical chemistry imaging and physiology and animal model development and phenotyping. Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide.

project_terms:
Address;Air Pollution;Biological Markers;Biomedical Research;Cardiology;Cardiovascular Diseases;Cardiovascular system;Carnosine;Centers of Research Excellence;Chemistry;Clinical;Core Facility;Data;Development;Diabetes Mellitus;Diet;Disease;Epidemiology;Event;Faculty;Flow Cytometry;Fostering;Foundations;Functional disorder;Funding;Goals;Health;Image;Individual;Insulin Resistance;Interdisciplinary Study;Investigation;Knowledge;Mentors;Modality;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Particulate;Pathology;Patients;Phase;Phenotype;Physiology;Postdoctoral Fellow;Prevention;Principal Investigator;Reagent;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Stem cells;Universities;Work;animal model development;career;clinical investigation;design;graduate student;novel;prevent;programs

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Research supported by the Diabetes and Obesity Center at the University of Louisville will address two of the most significant health concerns in the nation An established independent Diabetes and Obesity Center at the University of Louisville with a well-supported cadre of new and established investigators would create new knowledge and develop novel treatment and prevention modalities for these diseases.


application_id: 9329302
project_number: 5R01NR012967-04
administering_ic: NINR
award_notice_date: 2017-08-09
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NR
serial_number: 012967
program_official: HUSS, KAREN
project_start_date: 2014-09-26
project_end_date: 2019-07-31
study_section: Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]
contact_pi_person_id: 8446344
contact_pi: CHUNG, MISOOK LEE
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: 2017-08-10
project_title:
Effects of Family Sodium Watchers Program on Outcomes in Heart Failure Patient-Family Caregiver Dyads

project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) emerged as a significant public health threat in the 1990s and has now reached epidemic proportions. Despite advances in the medical treatment of HF patients with HF face frequent hospitalizations for acute exacerbations. Inadequate self-care strategies in particular non-adherence to a sodium restricted diet (SRD) are a main cause of these hospitalizations. Prior interventions to increase adherence have focused on increasing knowledge about restricting sodium in the diet have met with limited success. Unaddressed by these interventions are the major barriers of measuring and tracking daily sodium intake family members who continue to eat high sodium diets and a preference for salty foods-particularly in the elderly who have a decreased sense of taste. It is possible to retrain the taste buds to enjoy low salt foods by gradually reducing the amount of sodium in foods over the course of 16 weeks. This retraining works best with direct involvement and support from family members. The Family Sodium Watcher Program (Family Swap) proposed in this study incorporates the use of a unique electronic salt monitoring device that easily measures salt content in food-the major source of sodium. The intervention is designed to improve adherence to a SRDby both patients and family caregivers through education and strategies for gradual taste adaptation to low salt foods. The purpose of this 2-group randomized controlled repeated measures (baseline 4-month and 12-month) study is to examine effects of Family Swap on adherence (24-hour urine sodium excretion) to a SRD; knowledge attitudes and barriers about SRD; perceived control and perceived social support (in patient- caregiver dyads); caregiving burden (in caregivers only); and symptom distress and hospitalizations (in patients only). We will enroll a total of 220 patient-caregiver dyads. Dyads will be stratified as adherent and non-adherent using baseline patients' 24-hour urine sodium excretion (cut point = 3000 mg) and then randomly assigned to Family Swap intervention group or a usual care control group. The Family Swap intervention (6 weekly 45-minute sessions followed by 5 bi-weekly booster sessions) will be delivered remotely using a video- conferencing program on an iPad tablet. Patient-caregiver dyads will complete questionnaires (knowledge attitudes and barriers about diet; symptoms distress; perceived control; perceived social support; caregiving burden; and quality of life) and collect a 24-hour urine for sodium excretion at each assessment. Data will be analyzed using repeated measures ANOVA Cox regression and an innovative actor-partner interdependence model dyadic analysis for longitudinal data. This dyadic intervention study will provide rich data on the complex interpersonal relationships within patient-caregiver dyads that affect adherence and health outcomes in patients with HF and family caregivers. Given the recommendation that all individuals should consume a sodium restricted diet the intervention has the potential for expanded application beyond patients who need to follow a sodium restricted diet for cardiovascular reasons to everyone consuming a diet high in sodium.

project_terms:
Acute;Address;Adherence;Adult;Affect;Age;Analysis of Variance;Attitude;Behavior;Cardiovascular system;Caregivers;Chronic Care;Chronic Disease;Chronically Ill;Complex;Compliance behavior;Control Groups;Data;Desire for food;Diet;Dietary Intervention;Dietary Sodium;Distress;Eating;Education;Educational Intervention;Educational process of instructing;Elderly;Enrollment;Epidemic;Excretory function;Face;Family;Family Caregiver;Family member;Feeling;Food;Food Labeling;Food Preferences;Goals;Health;Health Care Costs;Health Status;Heart failure;Hospitalization;Hour;Individual;Intake;Interpersonal Relations;Intervention;Intervention Studies;Knowledge;Lead;Measures;Medical;Modeling;Monitor;Outcome;Patient Care;Patient-Focused Outcomes;Patients;Perception;Physiological;Play;Prevalence;Public Health;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Recommendation;Research;Research Personnel;Resources;Role;Self Care;Self Management;Sensory;Social support;Sodium;Sodium Chloride;Sodium-Restricted Diet;Source;Symptoms;Tablets;Taste Buds;Taste Perception;Testing;Time;Urine;Videoconferencing;Wit;Work;base;care giving burden;caregiving;design;family support;follow-up;group intervention;hedonic;high salt diet;improved;improved outcome;innovation;longitudinal analysis;member;monitoring device;outcome forecast;preference;prevent;programs;public health relevance;reduce symptoms;skills;success;treatment as usual;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With the rising costs of health care family members are playing a greater role in the care of chronically ill patients. This family-based intervention addresses the public health goal of improving the health status and quality of life of patients wit heart failure and their family caregivers through an innovative educational program focused on the self-care of sodium restricted diet.


application_id: 9329291
project_number: 5R01CA195573-03
project_title: Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
administering_ic: NCI
award_notice_date: 2017-08-21
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_abstract:
DESCRIPTION (provided by applicant):  Although progress has been made in survival of patients with earlier stage colorectal cancer (CRC) only minimal improvement has been noted in patients with systemic metastases (Stage IV disease). Current chemotherapeutic agents while highly effective at killing CRC cells are limited by their systemic toxicity. If advances ar to be made in the survival of cancer patients highly innovative strategies are required for more targeted delivery of anti-cancer agents directly to CRC metastases. Our ultimate translational goal is to develop a highly effective and less toxic approach to specifically deliver anti-cancer agents to CRC metastases. To achieve this goal we have assembled a multidisciplinary and highly collaborative team who are at the forefront of molecular signaling pathways in CRC CRC treatment modalities medicinal chemistry novel nanoparticle synthesis and delivery systems. Over the last two years we have made significant progress to achieve our goals: (i) using a novel three-way junction (3WJ) motif we have constructed thermodynamically and chemically stable three-branched RNA nanoparticles with an aptamer against receptors that can deliver a small molecule inhibitor or chemotherapeutic agent specifically to CRC metastases in the liver (ii) we have constructed a variety of RNA nanoparticles using the pRNA-3WJ motif as a scaffold and have demonstrated in critical experiments that the resulting RNA constructs retained their folding and independent functionalities for specific cell binding cell entry and cancer targetingboth in vitro and in vivo (iii) we have shown that the RNA nanoparticles remain intact after systemic injection into mice and strongly bind to tumors with little accumulation in normal organs or tissues; these RNA constructs are non- toxic non-immunogenic and display favorable pharmacological profiles in mice and (iv) we have demonstrated localized in vivo delivery of pRNA-3WJ to CRC xenografts and liver metastases. Thus the central hypothesis of our proposal is that CRC receptor-specific delivery of chemotherapeutic agents using our pRNA-3WJ nanoparticles will provide a safe effective strategy to selectively target and inhibit CRC metastasis. To address our hypothesis we have designed experiments with the following Specific Aims: 1) to construct pRNA-3WJ nanoparticles coupled with anti-cancer agents and analyze their stability cellular uptake and anti-proliferative effects in vitro; 2) to determine te pharmacokinetics stability safety and drug delivery of pRNA-drug conjugates in vivo; and 3) to evaluate the selective delivery and in vivo anti-tumor effect of pRNA- 3WJ nanoparticles coupled with anti-cancer agents. In summary our enthusiasm for our current proposal is driven not only by its inherent scientific importance but also by its translational potential clinical impact and the possibility to provide a more effective and less toxic delivery system targeting CRC metastases.

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;Chemicals;Clinical;Colorectal Cancer;Coupled;Disease;Distant;Drug Delivery Systems;Drug Kinetics;Early treatment;Epithelial Cells;Excision;FOLR1 gene;Goals;Growth;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;Pharmacology;Process;RNA;Research;Resistance;Safety;Signal Pathway;Submucosa;System;Technology;Thermodynamics;Tissues;Tumor Tissue;Universities;Xenograft procedure;antitumor effect;aptamer;base;cancer cell;cancer survival;cancer therapy;chemotherapeutic agent;design;experimental study;improved;in vivo;innovation;metastatic colorectal;mortality;multidisciplinary;nanoparticle;novel;overexpression;public health relevance;receptor;scaffold;small molecule inhibitor;systemic toxicity;targeted delivery;targeted treatment;tumor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Colorectal cancer is the second leading cause of cancer death in the U.S. When localized to the mucosa and submucosa of the bowel wall (Stage I) the five-year survival approaches 100% after resection; however systemic metastasis (Stage IV) usually to the liver is associated with a five-year survival that is less than 12%. Therefore mor selective highly innovative and better targeted therapies are required if we are to achieve an improved patient survival.


application_id: 9328955
project_number: 1F31AG055233-01A1
administering_ic: NIA
award_notice_date: 2017-03-30
opportunity_number: PA-16-309
application_type: 1
activity_code: F31
ic: AG
serial_number: 055233
suffix: A1
program_official: NIELSEN, LISBETH
project_start_date: 2017-05-14
project_end_date: 2020-05-13
study_section: Special Emphasis Panel[ZRG1 F16-L (20)]
contact_pi_person_id: 14276080
contact_pi: OLTMANNS, JOSHUA R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
A longitudinal investigation of maladaptive personality traits asreported by the self and others in the prediction of physical health

project_abstract:
Compared to traditional DSM personality disorder (PD) diagnostic categories dimensional representations ofPD provide a more comprehensive framework from which to understand and conceptualize maladaptivepersonality functioning (Clark 2007; Widiger & Trull 2007) consistent with the RDoC emphasis ondimensional models relative to traditional DSM syndromes. The five-factor model (FFM) of personality is widelyregarded as the leading dimensional model of personality and is supported by an extensive amount ofempirical support spanning over 30 years. The FFM consists of 30 lower-order facet scales (as conceptualizedby McCrae and Costa 2003) from which both high and low levels can be used to describe PD. FFMdescriptions of PD have been shown to account for the variance of all ten categorical DSM PD types (Livesley2001; Miller 2012). In addition personality science has demonstrated that "normal" range domains and facetsof the FFM significantly predict disease and mortality (Dixon-Gordon Whalen Layden & Chapman 2015;Friedman & Kern 2014; Smith & Mackenzie 2006). However symptoms of personality disorder have evenlarger associations with health outcomes (Gleason Weinstein Balsis & Oltmanns 2014). Recently FFM-based dimensional measures of PD have been developed (Widiger Lynam Miller & Oltmanns 2012)providing an exciting opportunity to measure PD within the comprehensive framework of the FFM. The presentline of research will incorporate this novel analytic and conceptual approach into an ongoing longitudinal studyof a representative sample of 1630 older adults in the St. Louis area. FFM-PD measures of neuroticismconscientiousness and extraversion (the Five-Factor Borderline Obsessive-Compulsive and AvoidantInventories respectively) which are most frequently associated with health (Smith Williams & Segerstrom2015) will be employed. Structural Equation Modeling will be used to compare the predictive and incrementalvalidity of FFM PD measures with and over DSM PD measures and normal personality measures in thelongitudinal prediction of self- and informant-reported general health status major disease (including cancerdiabetes and lung and heart disease) biological markers of stress and inflammation (e.g. cortisol interleukin-6 tumor necrosis factor- and C reactive protein) and mortality. The dimensional FFM PD measurementperspective will provide incremental validity over traditional measures of PD and normal personality measuresin the prediction of these both subjective and objective measures of health. Results will be imperative todeveloping a comprehensive framework for understanding the longitudinal relationship between maladaptivePD traits and risk of physical disease and mortality in older adults. This proposal will provide the PI with theopportunity to unite two cutting-edge personality research laboratories while advancing knowledge about therelationship between personality and health and developing research skills and clinical training that willfacilitate the goal of conducting and disseminating personality research as an academic professor.

project_terms:
Area;Biological Markers;Borderline Personality Disorder;C-reactive protein;Categories;Classification;Clinical;Clinical Treatment;Development;Diabetes Mellitus;Diagnostic;Dimensions;Disease;Elderly;Equation;Equipment and supply inventories;Evaluation;Goals;Health;Health Services;Health Status;Health behavior;Heart Diseases;Hydrocortisone;Individual;Inflammation;Interleukin-6;Intervention;Investigation;Knowledge;Laboratory Research;Link;Literature;Longevity;Longitudinal Studies;Lung diseases;Malignant Neoplasms;Measurement;Measures;Methodology;Methods;Modeling;Neurotic Disorders;Neurotics;Normal Range;Obsessive compulsive behavior;Obsessive-Compulsive Personality;Outcome;Patient Self-Report;Personality;Personality Assessment;Personality Disorders;Personality Traits;Prevention;Process;Property;Provider;Psychometrics;Reporting;Research;Research Domain Criteria;Risk;Sampling;Science;Stress;Symptoms;Syndrome;System;TNF gene;Testing;Time;Training;Variant;base;immune function;informant;knowledge base;longitudinal dataset;mortality;novel;physical conditioning;professor;skills;stress reactivity;tool;trait

public_health_relevance:
The present study examines the usefulness of a dimensional model of maladaptive personality traits incomparison to DSM personality disorder types for the prediction of important subjectively and objectivelymeasured health outcomes (such as physical disease stress reactivity health functioning and mortality) in anongoing longitudinal study of a representative sample of older adults in St. Louis. The goal of the project is todevelop scientific understanding of the relationships between maladaptive personality traits and health acrosstime. Implications of the present research include providing a more comprehensive knowledge of theconnection between personality and health testing the utility of a dimensional model of personality disorderand ultimately informing recent developing clinical treatments of maladaptive personality traits that couldpotentially reduce the long-term risk of deleterious health problems for many individuals.


application_id: 9328668
project_number: 1F31ES028982-01A1
project_title: Polychlorinated biphenyls act through EGFR to worsen NAFLD
administering_ic: NIEHS
award_notice_date: 2017-05-22
opportunity_number: PA-16-309
application_type: 1
activity_code: F31
ic: ES
serial_number: 028982
suffix: A1
program_official: SCHUG, THADDEUS
project_start_date: 2017-06-01
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZDK1 GRB-2 (J1)]
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and diabetes. The development of theNAFLD has previously been assumed to be due to excess calorie intake and genetic predisposition but ourrecent studies show that steatosis and steatohepatitis can be exacerbated upon exposure to polychlorinatedbiphenyls (PCBs). The Anniston AL cohort who have higher exposure to PCBs have significantincreases in steatohepatitis biomarkers and a prevalence of diabetes relative to healthy populations.Currently there is no well-established mechanism for exacerbated metabolic diseases due to PCB exposure.The literature and our preliminary data characterize PCBs as epidermal growth factor receptor (EGFR)antagonists that diminish activity of downstream effector kinases and transcription factors implicated inNAFLD/Diabetes. The literature and our preliminary data urges us to evaluate PCB-mediated EGFR inhibitionas a key feature in the progression of NAFLD/diabetes. As we hypothesize that genetic loss of EGFRfunction will make mice more susceptible to PCB-mediated NAFLD/diabetes and epidermal growthfactor (EGF) supplementation will ablate PCB-driven NAFLD/diabetes. Current risk assessment for PCB-mediated NAFLD/diabetes is limited. We recently characterized PCBs as EGFR antagonists which urges us toevaluate the binding affinities of PCB congeners for the EGFR extracellular domain to develop a EGFR toxicequivalency quotient (TEQ). Our preliminary data suggests that PCBs may outcompete epidermal growthfactor (EGF) for EGFR binding at environmental exposure concentrations. We hypothesize that PCBcongeners found in human serum directly antagonize the EGFR promoting NAFLD/diabetes. Preliminarydata demonstrates that many PCB congeners prevent EGF-mediated phosphorylation of EGFR but only thenon-dioxin like (NDL) PCBs are found in human serum at high concentrations. Preliminary proteomic dataindicate that while the EGFR pathway is highly affected so are other EGFR independent pathways. Toelucidate other hepatic aberrations due to PCB exposure we propose conducting a kinetic phosphoproteomicstudy in vitro. This will characterize what other pathways are altered due to PCB exposure. The proposedresearch aims to elucidate signaling pathways altered due to PCB exposure and if those alterationscontribute to the development of liver disease and diabetes observed in animals and humanpopulations. I plan to address these questions through genetic loss of function EGFR animal modelstherapeutic EGF animal studies binding assays and kinetic phosphoproteomic analysis. The proposedresearch will provide valuable information on altered cell signaling pathways due to PCB mediated NAFLD andelucidate potential therapeutic targets for treatment of organopollutant-induced liver disease.

project_terms:
Ablation;Address;Adolescent;Adult;Affect;Affinity;Animal Model;Animals;Binding;Biological Assay;Biological Markers;Calories;Cancer Patient;Chemicals;Competitive Binding;Data;Development;Diabetes Mellitus;Disease;Environmental Exposure;Epidemic;Epidermal Growth Factor;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Exposure to;Extracellular Domain;FRAP1 gene;Food Supply;Genetic;Genetic Predisposition to Disease;Goals;Growth;Hepatic;Hepatocyte;High Fat Diet;Human;In Vitro;Intake;Kinetics;Laboratories;Literature;Liver;Liver diseases;Mediating;Metabolic Diseases;Metabolism;Mus;Obesity;Pathway interactions;Phosphorylation;Phosphotransferases;Placenta;Play;Polychlorinated Biphenyls;Population;Predisposition;Prevalence;Production;Proteomics;Receptor Inhibition;Receptor Protein-Tyrosine Kinases;Receptor Signaling;Recombinant Epidermal Growth Factor;Research;Risk Assessment;Role;STAT3 gene;Serum;Signal Pathway;Signal Transduction;Steatohepatitis;Supplementation;Therapeutic;Time;Toxicology;Woman;Work;c-myc Genes;chemotherapy;chronic liver disease;cohort;constitutive androstane receptor;environmental stressor;in vivo;insight;liver development;liver function;liver injury;loss of function;mortality;non-alcoholic fatty liver;nonalcoholic steatohepatitis;phosphoproteomics;prevent;receptor;receptor binding;receptor function;therapeutic biomarker;therapeutic target;transcription factor

public_health_relevance:
The progression of non-alcoholic fatty liver disease (NAFLD) hasnt previously been associated withenvironmental stressors such as polychlorinated biphenyls (PCBs) until recently in our laboratory and others.This application investigates the altered cell signaling pathways due to PCB exposure in relation to liverdisease and diabetes.


application_id: 9328211
project_number: 3P30GM110787-03S1
project_title: Project-001
administering_ic: NIGMS
award_notice_date: 2016-08-17
opportunity_number: PAR-13-238
application_type: 3
activity_code: P30
ic: GM
serial_number: 110787
suffix: S1
program_official: ZLOTNIK, HINDA
study_section: ZGM1-TWD-C(3C)
subproject_number: 7545
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
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:
This COBRE Phase III proposal aims to further develop the Center for Molecular Medicine at the Universityof Kentucky. This Center focuses on research aimed at understanding the molecular mechanismsassociated with human disease with emphases on cancer neurodegenerative diseases diabetes andcardiovascular diseases. We propose to transition to independence the research infrastructure developedduring previous COBRE funding. Our COBRE funded Center for Molecular Medicine has had a number ofsuccesses. During the previous funding period 30 junior faculty from 12 different departments and centerswere funded as COBRE project or pilot grant PIs. These mentored faculty received 27 NIH ROI grants 11other NIH grants and 41 other peer-reviewed extramural grants. The COBRE-supported junior facultypublished more than 400 research papers. These and other successes can in large part be attributed to astrong mentoring program excellent institutional support and the availability of the scientific coresassociated with the Center. For this application we propose to transition the Center for Molecular Medicineand its three scientific cores to independence of NIH/NIGMS support and to enhance and upgrade coretechnologies. It is worth noting that two of our original cores have or soon will transition to independence;the Proteomics core developed by this COBRE is now a University fee-for-service core and the COBREsupported Imaging core is soon to become a department supported core. During the proposed five-yeartransition period we will increase the critical mass of faculty associated with the Center and continue toenhace its Cores. The use of vouchers will promote core usage and pilot grants will develop researchcollaborations and competitive grant submissions. The Administrative Core will serve as the focal point ofthe grant and in conjunction with the Program Coordinator and Internal Advisory Committee will serve as theoperational arm of the Center. An External Advisory Committee consisting of world-renown scientists willprovide ongoing assessment and evaluation of the Center. Continuing Institutional commitments will ensureprogrammatic growth and long-term sustainability.

project_terms:
Achievement;Advisory Committees;Aging;Anatomy;Area;Biochemistry;Cancer Center;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Collaborations;Core Facility;Department chair;Development;Diabetes Mellitus;Ensure;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Funding;Goals;Grant;Growth;Growth and Development function;Image;Immunology;Institution;Instruction;Internal Medicine;Kentucky;Malignant Neoplasms;Medicine;Mentors;Microbiology;Molecular;Molecular Genetics;Molecular Medicine;National Institute of General Medical Sciences;Neurobiology;Neurodegenerative Disorders;Organic Synthesis;Paper;Pathology;Patients;Pediatrics;Peer Review;Pharmacology;Phase;Physiology;Pilot Projects;Positioning Attribute;Proteins;Proteomics;Psychiatry;Publishing;Readiness;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Scientist;Signal Transduction;Staging;Technology;Toxicology;Translational Research;Translations;United States National Institutes of Health;Universities;Work;arm;base;clinical practice;college;faculty mentor;genetic technology;human disease;mid-career faculty;programs;success;therapeutic target;voucher

public_health_relevance:
RELEVANCE (See instructions):This COBRE funded Center for Molecular Medicine has as a focus the molecular basis of human disease.The COBRE scientific cores have supported and will continue to support and enhance translational researchat the University of Kentucky and other regional institiutions.


application_id: 9328096
project_number: 5R01EY023561-04
project_title: Mid-level mechanisms of surface and binocular perception
administering_ic: NEI
award_notice_date: 2017-07-24
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 023561
program_official: WIGGS, CHERI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
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:
DESCRIPTION (provided by applicant): Retinal images are inherently fragmentary and ambiguous because images of separate entities overlap. But the early visual mechanisms are not equipped to parse the overlapping 2-D retinal images into distinct 3-D entities. The job of parsing these images falls on the mid-level mechanisms whose main role is to represent the distinct entities as separate surfaces. The represented surface information then serves as inputs to the WHAT and WHERE systems that underlie our 3-D perception of objects and space respectively. As such the mid-level mechanisms are not just simple "conduits" of information between early and late level visual mechanisms but play a crucial role in determining the quality and reliability of the visual information conveyed. Compared to other aspects of visual processing less is known about the mid-level mechanisms. One of the biggest challenges is to discover how the often fragmentary and ambiguous retinal information is transformed into reliable surface representations presumably through a spreading-in operation. At times when an image belonging to the same entity is broken into parts due to occlusion a surface interpolation operation is required to integrate the parts into a global surface. Moreover inputs from the two eyes that contribute to these operations can be disparate in content and location. In the face of the myriad complexities of the visual inputs it is further proposed that the mid-level mechanisms must rely on internal assumptions (perceptual rules) and feedbacks from the higher visual levels for guidance in representing surfaces. But how these operations are accomplished is still unclear. Remedying it this proposal uses the human psychophysical approach to investigate the above issues by focusing on three specific aims. Aim 1 investigates how the spreading-in operation represents surfaces with texture patterns which is more complex than representing texture-free surfaces. It is proposed the principle of reducing coding redundancy that governs the spreading-in operation causes the global surface representation operation to be efficient but prone to poor resolution. The latter could be one basis of the well-known "crowding effect" phenomenon. Aim 2 investigates the texture-surface interpolation operation. Cognizant of the roles of attention and object knowledge the research investigates how these top-down factors influence surface integration. Aim 3 investigates the long-term plasticity of the mid-level mechanisms. Perceptual learning experiments will be conducted to reveal how extensive training modifies the perceptual rules implemented at the mid-level. The long-term goal of this proposal is to advance our knowledge of how visual information is processed and represented by the mid-level mechanisms. This knowledge helps us better understand how humans perceive the visual world and provides a clinical basis for behavioral diagnoses and treatments of visual dysfunctions related to amblyopia strabismus and aging.

project_terms:
3-Dimensional;Affect;Aging;Amblyopia;Attention;Behavioral;Clinical;Code;Color;Complex;Crowding;Diagnosis;Ensure;Environment;Eye;Feedback;Frequencies;Functional disorder;Goals;Grant;Human;Image;Knowledge;Link;Location;Measurement;Motion;Occupations;Ownership;Pattern;Perception;Perceptual learning;Play;Process;Property;Protocols documentation;Psychophysics;Research;Resolution;Retinal;Role;Space Perception;Strabismus;Surface;System;Testing;Texture;Time;Training;Visual;Visual Perception;Visual system structure;detector;experimental study;falls;feeding;imaging properties;improved;luminance;neurophysiology;noninvasive diagnosis;object perception;object shape;operation;public health relevance;visual information;visual processing;visual stimulus

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Early level visual information is often fragmentary and ambiguous because images of distinct entities overlap. A role of the mid-level mechanisms is to "make sense" of this information by representing the distinct entities as separate surfaces. Discovering how this is achieved leads to better scientific understanding of how humans perceive the visual world and provides a clinical basis for non-invasive diagnoses and treatments of visual dysfunctions related to amblyopia and strabismus.


application_id: 9327839
project_number: 5R01AA015407-13
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2017-04-10
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
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
arra_indicator: N
project_abstract:
Ethanol is a neuroteratogen and alcohol consumption during pregnancy causes Fetal Alcohol SpectrumDisorders (FASD). FASD are currently the leading cause of mental retardation in North America. The mostdevastating effect of developmental exposure to ethanol is the loss of CNS neurons which underlie manybehavioral deficits observed in FASD. We demonstrated that ethanol caused both oxidative stress andendoplasmic reticulum (ER) stress in the developing brain. We showed that ethanol induced the expression ofmonocyte chemoattractant protein-1 (MCP-1) and a specific ER stress-inducible protein mesencephalicastrocyte-derived neurotrophic factor (MANF). Our studies suggested that both MCP-1 and MANF wereinvolved in ethanol-induced ER stress and neuron death. The central hypothesis for this proposal is thatethanol-induced neurodegeneration in the developing brain is mediated by the interplay of oxidative stress andER stress. Three corollary hypotheses will be tested: 1) ethanol-mediated oxidative stress causes an earlyneuron death; the second phase of neuron death is mainly mediated by ethanol-induced ER stress or acombined action of both oxidative stress and ER stress; 2) the oxidative stress-induced neuron death is mainlyregulated by the mitochondrial intrinsic apoptotic pathway; while the ER stress-induced neuron death ismediated by the GSK3/calpain/caspase7/12 pathway; 3) activation of MCP-1 mediated signaling potentiatesethanol-induced ER stress and promotes an ER stress-initiated apoptotic program in neurons; contrarilyMANF is a neuroprotective protein which alleviates ethanol-induced ER stress and neuron death. We proposethree specific aims to test these hypotheses. Specific Aim 1 will test the hypothesis that ethanol-inducedneuron death is caused by the interplay of oxidative stress and ER stress in vitro. Specific Aim 2 willdetermine the role of MCP-1 signaling and MANF in ethanol-induced ER stress and neuron death in thedeveloping brain. Specific Aim 3 will determine whether simultaneous inhibition of oxidative stress and ERstress offers maximal protection and improves behavioral deficits in mice. As a unit this proposal willsystematically investigate the interplay of oxidative stress and ER stress and assess their contribution toethanol-induced neuron death. This study will therefore not only provide novel insight into the mechanisms ofethanol-induced damage to the developing CNS but also identify specific targets for developing effectivetherapeutic strategies.

project_terms:
Apoptotic;Astrocytes;Attention;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;Motor;Mus;Neonatal Alcohol Exposure;Nerve Degeneration;Neuraxis;Neurons;North America;Oxidative Stress;Pathway interactions;Phase;Play;Proteins;Research;Role;Signal Pathway;Signal Transduction;Testing;Third Pregnancy Trimester;Time;Treatment Efficacy;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

public_health_relevance:
Alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD). Bothoxidative stress and endoplasmic reticulum (ER) stress contributes to ethanol neurotoxicity. The study willexplore the underlying mechanisms and develop a new therapeutic approach by targeting both oxidative stressand ER stress.


application_id: 9326997
project_number: 5R01ES026151-03
project_title: The epigenetic mechanism of hexavalent chromium carcinogenesis
administering_ic: NIEHS
award_notice_date: 2017-08-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026151
program_official: TYSON, FREDERICK L
project_start_date: 2016-09-01
project_end_date: 2021-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9719630
contact_pi: YANG, CHENGFENG
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_terms:
Affect;BMI1 gene;Cancer Etiology;Cells;Characteristics;Chromium;Chromosomes;Chronic;Country;Cultured Cells;DNA Methylation;DNA Modification Methylases;DNA Sequence;Data;Down-Regulation;EZH2 gene;Elements;Environmental Health;Environmental Pollutants;Epigenetic Process;Epithelial Cells;Exposure to;Gene Expression Profile;Genes;Genomic Imprinting;Goals;Heritability;Histone H3;Histones;Human;Impairment;Inherited;Knowledge;Literature;Lung;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methylation;MicroRNAs;Modification;Occupational;Oxidative Stress;Parents;Play;Post-Translational Protein Processing;Promoter Regions;Property;Rattus;Reactive Oxygen Species;Recruitment Activity;Regulation;Role;Stem cells;Tumor Suppressor Genes;Tumor Tissue;Tumorigenicity;United States;Untranslated RNA;Up-Regulation;base;c-myc Genes;cancer cell;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;factor C;genotoxicity;histone methyltransferase;human tissue;imprint;insight;lung cancer prevention;novel;overexpression;pollutant;tumorigenesis;tumorigenic


application_id: 9326890
project_number: 5P30AG028383-12
project_title: Research Education Component (RL5)
administering_ic: NIA
award_notice_date: 2017-07-12
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
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: 2017-07-01
budget_end_date: 2018-06-30
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;Nurses;Occupational Therapist;Physician Assistants;Physicians;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;advanced dementia;aging population;bench to bedside;career;caregiver education;caregiving;clinical care;collaborative environment;design;disorder prevention;education research;interest;next generation;normal aging;novel;physical symptom;prevent;profession allied to medicine;programs;research study;screening;senior faculty;skills;student mentoring;success;symposium;training opportunity;translational scientist


application_id: 9326889
project_number: 5P30AG028383-12
project_title: Core E: Outreach and Recruitment Core
administering_ic: NIA
award_notice_date: 2017-07-12
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
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: 2017-07-01
budget_end_date: 2018-06-30
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 Trials;Cognitive;Collaborations;Communication;Communities;Community Actions;Consent;DNA;Data Collection;Databases;Dementia;Development;Disease;Education;Educational Activities;Effectiveness;Elderly;Enrollment;Event;Extramural Activities;Failure;Fostering;Future;Goals;Health Promotion;Healthcare;Individual;Intervention Trial;Kentucky;Lead;Link;Longitudinal cohort;Minority;Minority Groups;Minority Participation;Mission;Outcome Measure;Participant;Plasma;Play;Poa plant;Program Development;Protocols documentation;Recording of previous events;Recruitment Activity;Reporting;Research;Research Activity;Research Support;Resources;Risk Factors;Role;System;Therapeutic Trials;Time;Translational Research;Translations;Universities;Update;Work;cohort;dementia care;demographics;design;education research;health literacy;healthcare community;innovation;meetings;member;minority communities;neuroimaging;neuropathology;outreach;parity;programs;research study;response;success;volunteer;willingness


application_id: 9326887
project_number: 5P30AG028383-12
project_title: Core D: Neuropathology Core
administering_ic: NIA
award_notice_date: 2017-07-12
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
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: 2017-07-01
budget_end_date: 2018-06-30
project_terms:
Address;Aged 80 and over;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Amyloid beta-Protein;Area;Autopsy;Biological;Biological Markers;Biometry;Biostatistics Core;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrum;Clinical;Clinical Trials;Cognition Disorders;Cognitive;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;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;Serum;Services;Specimen;Staging;Standardization;Synaptosomes;Syndrome;Tauopathies;Therapeutic;Thinness;Time;Tissue Banks;Tissue Sample;Tissues;Universities;Work;abeta deposition;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: 9326886
project_number: 5P30AG028383-12
project_title: Core C: Data Management and Statistical Core
administering_ic: NIA
award_notice_date: 2017-07-12
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
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: 2017-07-01
budget_end_date: 2018-06-30
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;Data;Data Analyses;Data Collection;Data Element;Data Quality;Databases;Dementia;Elderly;Enrollment;Epidemiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Future;Generations;Genetic;Gerontology;Growth;Health Services Research;Image;Kentucky;Leadership;Literature;Manuscripts;Mentors;Methodology;Methods;Mission;Modeling;Neuroepidemiology;Online Systems;Paper;Participant;Pathologic;Pathology;Phase;Pilot Projects;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;Time;Training;Translational trial;Translations;Universities;Ursidae Family;Vision;cohort;data management;direct application;doctoral student;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;statistics;student training;success


application_id: 9326885
project_number: 5P30AG028383-12
project_title: Core B: Clinical Core
administering_ic: NIA
award_notice_date: 2017-07-12
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
study_section: ZAG1-ZIJ-G
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: 2017-07-01
budget_end_date: 2018-06-30
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;Foundations;Funding;Genetic Markers;Grant;Heart;Image;Impairment;Individual;Industry;Intervention Trial;Kentucky;Leadership;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Medical Genetics;Minority;Minority Participation;Mission;Pathogenesis;Pathologic;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;Standardization;Therapeutic Human Experimentation;Tissues;Translational Research;Translations;United States National Institutes of Health;Universities;Work;base;cohort;data management;innovation;meetings;minority communities;minority subjects;multidisciplinary;normal aging;novel therapeutics;operation;outreach;pre-clinical;prevent;programs;research and development;success;therapeutic development


application_id: 9326879
project_number: 5P30AG028383-12
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2017-07-12
opportunity_number: RFA-AG-16-018
application_type: 5
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: 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;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Health Education;Community Outreach;Comorbidity;Databases;Dementia;Disease;Education;Education and Outreach;Environment;Funding;Goals;Health Professional;Image;Impaired cognition;Impairment;Individual;Industry;Kentucky;Lead;Longitudinal cohort;Mission;Nature;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Pilot Projects;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Risk;Training;Translating;Translational Research;Translations;United States;Universities;Work;aging brain;biomarker development;clinical practice;cognitive development;cohesion;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;therapy development


application_id: 9326829
project_number: 5U18FD005015-05
project_title: Validation of LC-MS/MS analyses of animal tissue and feed matrices for toxicants
administering_ic: FDA
award_notice_date: 2017-08-02
opportunity_number: PA-13-244
application_type: 5
activity_code: U18
ic: FD
serial_number: 005015
program_official: REIMSCHUESSEL, RENATE
project_start_date: 2013-09-01
project_end_date: 2018-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11450267
contact_pi: GASKILL, CYNTHIA LYNN
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
2013 Gaskill Vet-LIRN Project Summary/AbstractThe Veterinary Laboratory Investigation and Response Network (Vet-LIRN) was developed by the FDA toincrease the safety of human and animal health by investigating potential adverse events involving animal feedor animal drug contamination or adulteration. The testing of diagnostic specimens adds insight intoinvestigations not routinely obtained from traditional food testing laboratories. Such investigations requiredetection methods that are validated for organs and diagnostic samples such as urine feces and blood whichare not typical food matrices.The objective of the proposed work is to expand the number of multi-laboratory validated analytical methodsthat can be used by the FDA Vet-LIRN cooperative laboratories during outbreaks or events of animal feed ordrug contaminations. The proposed project will also strengthen the collaborations and integration of thenetwork laboratories to encourage seamless interactions during actual emergency related testing.The specific aim of this proposal is to perform multi-laboratory validations of liquid chromatography-tandemmass spectrometry (LC-MS/MS) methods for detection and quantitation of anticoagulant rodenticides in animaltissues fluids and feeds and mycotoxins in animal tissues and feeds. Analytes and matrices for thesemethods will be expanded in the last year of the project as needed to address specific Vet-LIRN needs.Another major aim of this proposal is to provide collaborative support for other funded Vet-LIRN multi-laboratory method validation projects. We have agreed to collaborate and provide support of seven other Vet-LIRN network laboratory toxicology sections. This proposal will help ensure that the University of KentuckyVeterinary Diagnostic Laboratory has the necessary instrumentation and technical staff support to adequatelyhandle the collaborative analyses.The expected outcomes are to complete the multi-laboratory validation of the methods listed above anddisseminate the methods to Vet-LIRN collaborating laboratories and to the FDA Vet-LIRN. The impact of theproposed work will be to improve human and animal health by increasing the number of validated testingmethods available for collaborating Vet-LIRN laboratories to use during outbreaks or events of animal feed ordrug contamination or adulterations.

public_health_relevance:
2013 Gaskill Vet-LIRN Project NarrativeThis FDA Vet-LIRN program will expand the number of multi-laboratory validated analytical methods that canbe used by FDA Vet-LIRN cooperative laboratories during outbreaks or events of animal feed or drugcontaminations. The project will also strengthen collaboration and integration of the network laboratories toencourage seamless interactions during emergency related testing.


application_id: 9326350
project_number: 5UH3TR000875-05
project_title: Fruit exosome-like particles for therapeutic delivery of extracellular miRNAs
administering_ic: NCATS
award_notice_date: 2017-07-21
opportunity_number: RFA-RM-12-014
application_type: 5
activity_code: UH3
ic: TR
serial_number: 000875
program_official: TAGLE, DANILO A
project_start_date: 2013-08-01
project_end_date: 2019-07-31
study_section: Special Emphasis Panel[ZRG1-OBT-Z(50)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_abstract:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop exosome-like nanoparticles as a delivery vehicle for targetable delivery of extracellular RNA (exRNA) primarily focusing on miRNAs which modulate gene expression and induce immune responses upon delivery in mouse tumor models. Development of exRNA-based therapeutics must overcome challenges including issues of delivery potential off-target effects safety toxicity the cost of large scale production elimination of potential biohazards to the environmen and tissue specificity. Unlike the situation with artificially synthesized nanoparticles or liposomes naturally derived nanoparticle-size exosomes are released from many different types of cells. miRNAs and RNAs can be encapsulated in naturally derived exosomes and the RNAs are stable and a number of miRNAs can be naturally encapsulated simultaneously in these exosomes. Recently data published by ours and other groups have demonstrated that mammalian exosomes can deliver poorly soluble agents chemotherapeutic drugs and siRNA in vivo. A limitation of this mode is the need for large-scale production of exosomes and potential biosafety. Our preliminary data show that exosome-like nanoparticles can be isolated in large quantities from the tissue of edible plants including grapes. We have demonstrated that exosome-like nanoparticles from grapes are composed of small RNAs proteins and lipids. An edible plant-derived nano-vector (EPNV) assembled from grape exosome-like derived lipids is capable of encapsulating siRNAs. Co-delivery of folic acid with the chemotherapy drug paclitaxel by EPNVs results in an increased efficiency in tumor tissue targeting. Reducing the size of EPNVs by passing them through an appropriate pore size filter significantly enhances EPNV translocation to the brain and oral administration of the EPNVs results in their migration to the liver. Based on these preliminary data and the current literature we propose to: (1) Determine whether an EPNV can deliver therapeutic miR17 via oral administration to target metastatic colon tumor in the liver subsequently inducing NK cell activation to kill metastatic tumor cells; (2) Determine whether miR155 encapsulated in EPNV promotes differentiation of myeloid derived suppressor cells (MDSCs) into mature dendritic cells in mouse breast/brain tumor models; (3) Determine whether a therapeutic dose of miRNA17 or miRNA155 delivered by EPNV induces no side-effects in mouse tumor models; and (4) Determine whether EPNV can be produced in large scale amounts economically for use in clinical settings. Demonstration of using a EPNV-based delivery system loaded with a desired therapeutic extracellular RNA (exRNA) including microRNA to target to inflammatory cells and tumor cells in vivo would not only be a significant step forward in the treatment of cancer but also provide a powerful tool foridentifying the role and effects of each small RNA encapsulated in resident or circulating microvesicles on the recipient cells. We will accomplish this in our study by knock-out and knock-in strategies.

project_terms:
Adverse effects;Animals;Antibodies;Biohazardous Substance;Biological Assay;Brain;Brain Neoplasms;Breast;Cells;Clinic;Clinical;Colon Carcinoma;Colonic Neoplasms;Curcumin;DNA;Data;Dendritic Cells;Development;Disease;Dose;Down-Regulation;Edible Plants;Encapsulated;Environment;Evaluation;Folic Acid;Fruit;Gene Expression;Goals;Grapefruit;Grapes;Human;Hydrophobicity;Immune response;Immunotherapy;In Vitro;Inflammatory;Intranasal Administration;Killings;Knock-in;Knock-out;Laboratories;Light;Lipids;Liposomes;Literature;Liver;MHC Class I Genes;Malignant Neoplasms;Mammalian Cell;Metastatic Neoplasm to the Liver;MicroRNAs;Modality;Modeling;Mus;Myelogenous;Myeloid Cells;NK Cell Activation;Neoplasm Metastasis;Non-Viral Vector;Nucleic Acids;Oral Administration;Paclitaxel;Pharmaceutical Preparations;Phenotype;Play;Prevention;Production;Proteins;Protocols documentation;Publishing;RNA;Research Personnel;Role;Safety;Science;Signal Transduction;Small Interfering RNA;Small RNA;Specificity;Suppressor-Effector T-Lymphocytes;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Tomatoes;Toxic effect;Tumor Tissue;Viral;aqueous;base;cancer cell;cancer therapy;cell type;chemotherapy;cost;exosome;expression vector;extracellular;hydrophilicity;in vivo;intravenous administration;large scale production;microvesicles;migration;mouse model;nanoparticle;nanosized;nanovector;neoplastic cell;overexpression;particle;prevent;public health relevance;receptor;targeted delivery;therapeutic miRNA;tool;trafficking;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The concept that extracellular RNA (exRNA) may alter target cell phenotypes by way of intercellular signaling is becoming universally accepted in science. Whether exRNA can be used as a therapeutic agent is not known. The overall goal of this study is to develop grape lipid derived nano vectors for the delivery of exRNAs as therapeutic agents to target tumor cells as well as inflammatory cells in animal tumor models. Additionally we will assess the therapeutic potential of exRNA used in a clinical setting.


application_id: 9326113
project_number: 5R01AA017226-10
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2017-08-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 017226
program_official: MURRAY, GARY
project_start_date: 2008-03-05
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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): Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness the p38?. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38? which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT) increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims. Specific Aim 1 will determine the role of p38? in alcohol- induced aggressiveness in vitro. Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38? activation as well as the mechanisms how p38? mediates aggressiveness of breast cancer cells. Specific Aim 3 will investigate the role of p38? in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.

project_terms:
Alcohol consumption;Alcohols;Amino Acid Sequence;Animal Model;Animals;Attention;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Cancer Etiology;Cell Culture System;Cell Polarity;Cells;Cellular biology;Characteristics;DLG1 gene;Data;Development;Diet;ERBB2 Signaling Pathway;ERBB2 gene;Environmental Risk Factor;Epidermal Growth Factor Receptor;Etiology;Extracellular Signal Regulated Kinases;Family;Funding;Genes;Heavy Drinking;Human;In Vitro;Knockout Mice;Liquid substance;MAP2K6 gene;MAPK14 gene;MAPK8 gene;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Mediator of activation protein;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Molecular;Mus;Neoplasm Metastasis;Outcome;Patients;Phosphorylation;Phosphotransferases;Physiological;Play;Population;Production;Protein Tyrosine Kinase;Reactive Oxygen Species;Recruitment Activity;Risk;Role;Signal Transduction;Stream;Testing;Time;Transgenic Organisms;Tumor Promoters;Tumor Promotion;Xenograft Model;alcohol effect;alcohol exposure;alcohol sensitivity;anticancer research;cancer cell;cancer risk;cancer stem cell;cancer therapy;epidemiology study;epithelial to mesenchymal transition;experimental study;in vivo;indexing;malignant breast neoplasm;member;mitogen-activated protein kinase p38;novel;novel therapeutic intervention;outcome forecast;overexpression;public health relevance;stem-like cell;therapeutic target;tumor;tumor initiation;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Excessive alcohol consumption is associated with advanced and aggressive breast cancers suggesting that alcohol may enhance mammary tumor progression and metastasis. We found that p38? signaling is down stream of ErbB2 and hypothesize that alcohol activates p38? which promotes tumor aggressiveness and accelerates mammary tumor development. This proposal will elucidate the mechanisms by which alcohol promotes the progression of mammary tumors and identify therapeutic targets for alcohol-associated tumor promotion.


application_id: 9325888
project_number: 1F32DE026939-01
project_title: Phosphotyrosine Signaling of Porphyromonas gingivalis
administering_ic: NIDCR
award_notice_date: 2017-01-24
opportunity_number: PA-16-307
application_type: 1
activity_code: F32
ic: DE
serial_number: 026939
program_official: FRIEDEN, LESLIE A
project_start_date: 2017-03-01
project_end_date: 2020-02-29
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11206459
contact_pi: MILLER, DANIEL PATRICK
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:
Project SummaryPolymicrobial communities that exhibit synergistic pathogenicity cause periodontal disease one of the mostcommon infections of humans. As a model system for the study of polymicrobial synergy we are investigatingthe interactions of Porphyromonas gingivalis and Streptococcus gordonii. Heterotypic communities develop asphysiologically compatible organisms modulate their own and their partner's physiology resulting in enhancedfitness and virulence. S. gordonii is an early colonizer of the dental plaque biofilm and provides attachment andsupport for the more pathogenic keystone pathogen P. gingivalis. Contact-dependent and soluble metabolitesignaling regulates development of the dual species community. Initial development and ultimately constraintof community development depends upon a tyrosine phosphorylation-signaling cascade. The activities of thekinase and phosphatase Ptk1 and Ltp1 respectively signal upstream of the transcriptional regulator CdhR tocontrol gene expression of community effectors such as Mfa1 and LuxS. The objectives of this study are to: i)characterize the structure and function of the Ptk1 kinase activation domain that regulates kinase activity; ii)assess the complex balance of (de)phosphorylation by Ptk1 and Ltp1 that both regulates activity of eachprotein while controlling activity of downstream phosphorylation-dependent mediators; and iii) determine thesignaling network between tyrosine phosphorylation and CdhR that results in regulation of gene expression.The completion of this study will not only elucidate the mechanism of activation of Ptk1 but also provide criticalnew insights into the functional activation of BY-kinases. Additionally we will provide novel information aboutthe dynamic regulation of tyrosine phosphorylation between a BY-kinase and its cognate phosphatase. Finallywe will develop a detailed understanding of the tyrosine phosphorylation cascade that regulates communityformation and synergistic pathogenicity between P. gingivalis and S. gordonii. Our overall long-term goal is totranslate these novel molecular mechanisms into the development of future therapeutic approaches targetingpolymicrobial pathogenic communities. Additionally as BY-kinases are structurally distinct from eukaryoticprotein tyrosine kinases detailed molecular analysis of BY-kinase activation and regulation may provide criticalinsights for the identification of novel approaches targeting key bacterial signal transduction systems.

project_terms:
Affect;Antibiotic Resistance;Bacteria;Bacterial Infections;Binding;Biochemical;Biological Models;C-terminal;Cell physiology;Chronic;Communication;Communities;Community Developments;Complex;DNA Binding;Dental Plaque;Development;Disease;Disease model;Equilibrium;Eukaryota;Exhibits;Future;Gene Expression;Gene Expression Regulation;Genetic Transcription;Goals;Human;In Vitro;Infection;Inflammatory Response;Measurement;Measures;Mediator of activation protein;Microbial Biofilms;Molecular;Molecular Analysis;Mutate;Organism;Outcome;Pathogenicity;Pathway interactions;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Phosphotyrosine;Physiological;Physiology;Play;Population;Porphyromonas gingivalis;Production;Protein Dephosphorylation;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;Recombinants;Regulation;Role;Series;Signal Transduction;Streptococcus gordonii;Structure;Therapeutic;Tissues;Tooth structure;Translating;Tyrosine;Tyrosine Phosphorylation;Virulence;bone;fitness;genetic regulatory protein;in vivo;insight;mouse model;mutant;novel;novel strategies;pathogen;phosphoproteomics;prevent;protein function;response;stoichiometry;synergism

public_health_relevance:
Project NarrativePeriodontal diseases are one of the most common infections of humans and are caused by multiple bacterialspecies working synergistically to enhance pathogenicity. This study aims to understand the Porphyromonasgingivalis-signaling network that senses responds to and ultimately enhances virulence in response toStreptococcus gordonii. Understanding inter-bacterial communication and signaling is critical to development ofpotential therapeutics or approaches to prevent polymicrobial diseases.


application_id: 9325840
project_number: 1R21AI131427-01
project_title: RNAi methods for Zika virus vector control
administering_ic: NIAID
award_notice_date: 2017-02-14
opportunity_number: PAR-16-106
application_type: 1
activity_code: R21
ic: AI
serial_number: 131427
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2017-02-14
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZAI1 RRS-M (J5)]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Mosquitoes transmit zika virus as well as other pathogens that cause many deadly diseases. These vectors causemore human suffering than any other group of animals and are responsible for millions of deaths worldwide. Insecticidesprays use of repellents and insecticide-treated bed nets for adult control and use of larvicides are the most common methodsused to control disease vectors. However widespread resistance development to insecticides in mosquitoes human healthand environmental concern from the residual toxicity of these chemicals are limiting the use of these strategies. Thereforethere is an urgent need to develop novel strategies to control disease vectors. Many applications of RNA interference (RNAi)are being developed for use in human health. RNAi could also help with studies in vector biology as well as in developingadvanced vector control methods. RNAi efficiency is variable among insects; works very well in coleopteran insects butnot in insects belonging to order Diptera that includes mosquitoes. One of the main challenges in the widespread use ofRNAi technology in disease vectors is the lack of efficient and reliable dsRNA delivery method. We propose to developnovel formulations of double-stranded RNA (dsRNA) composited with polymers and/or particulate cores resulting innanostructured delivery vehicles or dsRNA nanocomposites (dsRNA-NCs). The major goal of these studies is to improveRNAi efficiency in mosquitoes that transmit Zika virus for applications in basic research as well as in the development ofvector control methods. In specific Aim 1 we will prepare dsRNA-NCs and determine their properties. We hypothesize thatbiodegradable and environmentally friendly biomaterials could be used to develop prototype dsRNA-NCs that could aid inenhancing RNAi efficiency in mosquitoes. We will prepare cores of Ca3(PO4)2 coated with chitosan Poly-L-Lysine or Poly-L-histidine. Additionally Au cores will be used as an insoluble probe. A number of analytical methods will be used todetermine the properties of synthesized dsRNA-NCs. We will also perform a comparative analysis of synthesized dsRNA-NCs by studying protection of dsRNA from dsRNases its uptake tissue distribution intracellular transport includingendosomal escape and dsRNA processing in Aeg-2 cells (a cell line developed from Aedes aegypti) Ae. aegypti larvae andadults as a model vector species. In Specific Aim 2 we will determine the efficacy and non-target effects of synthesizeddsRNA-NCs in Ae. aegypti larvae and adults. We will expose Aeg-2 cells or feed Ae. aegypti larvae and adults with dsRNA-NCs and determine their efficiency in knocking down target genes and causing mortality as well as their effect on theexpression of non-target genes. This application proposes to employ novel approaches including nanotechnology to improveRNAi for use in disease vectors. The proposal uses interdisciplinary approaches to exploit modern technology forimprovement in the health of citizens. Successful completion of proposed research will provide novel tools to study thebiology of vectors of Zika and other pathogens and develop modern vector control methods.

project_terms:
Adult;Aedes;Alpha Cell;Animals;Applied Research;Attenuated;Bacterial Toxins;Basic Science;Beds;Biochemistry;Biocompatible Materials;Biological Assay;Biology;Caenorhabditis elegans;Cell Line;Cells;Cellular biology;Cessation of life;Chemicals;Chemistry;Chitosan;Colorado;Confocal Microscopy;Culicidae;Dengue;Development;Diptera;Disease;Disease Vectors;Double-Stranded RNA;Drug or chemical Tissue Distribution;Effectiveness;Encephalitis;Filarial Elephantiases;Formulation;Gene Targeting;Genes;Goals;Health;Hemiptera;Histidine;Human;Inductively Coupled Plasma Mass Spectrometry;Insect Vectors;Insecta;Insecticides;Intracellular Transport;Knock-in;Label;Laboratories;Larva;Lepidoptera;Lysine;Malaria;Measurement;Methods;Modeling;Modernization;Molecular Biology;Nanostructures;Nanotechnology;Nematoda;Order Coleoptera;Particulate;Phase;Plants;Polymers;Potato;Powder dose form;Prevention;Principal Investigator;Problem Solving;Property;RNA Interference;RNA Processing;Research;Residual state;Resistance;Resistance development;Resolution;Small Interfering RNA;Spectroscopy Fourier Transform Infrared;Technology;Time;Toxic effect;Transmission Electron Microscopy;Vector-transmitted infectious disease;Work;X ray diffraction analysis;X-Ray Diffraction;Yellow Fever;Zika Virus;analytical method;base;chikungunya;comparative;design;disorder control;experimental study;feeding;fighting;gel electrophoresis;improved;interdisciplinary approach;knock-down;larval control;light scattering;mortality;nano;nanocomposite;nanoformulation;nanostructured;novel;novel strategies;pathogen;programs;prototype;tool;uptake;vector;vector control

public_health_relevance:
Project NarrativeMosquitoes transmit deadly diseases. The research proposed in this application will provide information and methods ofpotential importance for development of insecticides for vector control. The proposed studies will develop nano-formulations for delivery of dsRNA to improve RNAi efficiency in disease vectors. The methods developed will be usefulin both basic and applied research aimed at improving human health.


application_id: 9325388
project_number: 5R01AA023190-03
project_title: Mechanisms of Probiotics in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2017-08-14
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_abstract:
DESCRIPTION (provided by applicant): Severe alcoholic liver disease (ALD) has a high morbidity and mortality. Recent studies demonstrated that probiotics reversed alcohol-induced hepatic steatosis and inflammation and improved liver enzymes in animal models and in patients. Our laboratory showed that administration of a probiotic strain Lactobacillus rhamnosus Gorbach-Goldin (LGG) significantly improved liver enzymes and histology in alcohol treated mice. However the beneficial mechanisms of action of LGG either in viable bacteria form or in culture supernatant form are not clear. Our overall hypothesis is that LGG increases intestinal cathelicidin-related antimicrobial peptide (CRAMP) intestinal trefoil factor (ITF) expression and intestinal short chain fatty acids (SCFAs) leading to improved gut microbiota homeostasis intestinal barrier integrity and hepatic fat metabolism and these are likely the mechanisms by which LGG supplementation attenuates alcohol induced liver injury. We evaluate mechanisms of LGG action with 4 specific aims: Aim 1 will determine the role of CRAMP in the alcohol-mediated changes in gut microbiota and the role of CRAMP in the beneficial effects of LGG in experimental ALD. We will use CRAMP knockout mouse model of ALD to determine the role of CRAMP and LGG in alcohol-induced changes in gut microbiota using a metagenomic approach. Aim 2 will determine the role of LGG in promoting ITF expression and evaluate whether ITF positively modulates intestinal tight junctions as a mechanism for improved intestinal barrier integrity in experimental ALD. We will use an ITF-secreting goblet cell line to evaluate the role of LGG in the production of ITF and the role of ITFin the modulation of intestinal tight junctions in an epithelial cell line. We will also examine th strategy that oral administration of recombinant human ITF attenuates alcohol-induced intestinal barrier and liver injury. Aim 3 will determine the role and mechanisms of butyric acid in the beneficial effects of LGG on intestinal tight junctions in experimental ALD. A metabolomics approach will be used to analyze the changes in SCFAs induced by alcohol and LGG intervention in the intestinal lumen. We will explore the potential mechanisms underlying the role of butyric acid in the regulation of occludin expression involving intestinal histone deacetylases (HDACs) miR122a and HIF--mediated signaling in vitro and in vivo. Aim 4 will evaluate and compare the effectiveness of LGG supernatant (LGGs) with viable LGG (vLGG) and heat-inactivated LGG (hiLGG) in the prevention/therapy of ALD in mouse models. These three LGG preparations will be tested for the effectiveness in the prevention/therapy of ALD in three experimental models of ALD of steatosis steatohepatitis and fibrosis. This study will have a major impact on the development of probiotic-based new therapeutic strategy for the prevention and treatment of ALD.

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;Etiology;Experimental Models;Fatty Liver;Fibrosis;Functional disorder;Goals;Goblet Cells;Health;Hepatic;Histology;Histone Deacetylase;Homeostasis;Human;Hypoxia Inducible Factor;Immune response;Impairment;In Vitro;Inflammation;Injury;Intervention;Intestinal Diseases;Intestines;Knockout Mice;Laboratories;Lactobacillus casei rhamnosus;Liver;Mediating;Metagenomics;Morbidity - disease rate;Mucous body substance;Mus;Oral Administration;Outcome;Pathologic;Patients;Permeability;Pilot Projects;Plasma;Play;Preparation;Prevention strategy;Prevention therapy;Probiotics;Process;Production;Proteins;Recombinants;Regulation;Reporting;Role;Sampling;Signal Transduction;Steatohepatitis;Supplementation;Testing;Tight Junctions;Volatile Fatty Acids;alcohol exposure;antimicrobial peptide;bacterial metabolism;base;cathelicidin;cathelicidin antimicrobial peptide;comparative efficacy;compare effectiveness;gastrointestinal epithelium;gut microbiota;improved;in vivo;lipid metabolism;liver inflammation;liver injury;metabolomics;mortality;mouse model;novel therapeutic intervention;occludin;prevent;protective effect;public health relevance;repaired;transcription factor;trefoil factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goals of this project are to investigate the mechanisms of probiotic action on alcohol-induced liver injury. This study will have a major impact on the development of a probiotics-based new therapeutic strategy for the prevention and treatment of alcoholic liver disease.


application_id: 9325057
project_number: 5P01HD071875-04
project_title: Administrative Core
administering_ic: NICHD
award_notice_date: 2017-08-14
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7822
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The Administrative Core is the operational center behind the entire P01 program. The Core will facilitate the research goals of the program by:  * providing the organizational and administrative structure that insures maximally efficient use of resources among all investigators * providing a centralized location for the tracking of expenditures and compilation of budgets * insuring optimal dissemination of information among all investigators * overseeing usage of the Tissue Repository Core to insure efficient distribution of human  macaque and rat tissues to all investigators * directing usage of the Tissue Repository Core so that minimal numbers of animals are  utilized * funding new pilot projects in promising areas of research that complement the existing  P01 projects while also opening additional avenues of research collaboration or expertise arranging and coordinating the annual scientific retreat for the P01 program investigators * assisting with the preparation and submission of manuscripts reporting P01 program scientific advances and also providing for page charges to support publication of these manuscripts * interacting with NICHD and the Office of Sponsored Projects Administration at the University of Kentucky to ensure compliance with all federal regulations * insuring that each scientific project maintains regulatory compliance by coordinating and accounting for all aspects of personnel training protocol submission approval revision and continuing review (IACUC recombinant DNA biohazardous materials)

project_terms:
Accounting;Advisory Committees;Animals;Area;Budgets;Charge;Collaborations;Complement;Ensure;Expenditure;Faculty;Funding;Goals;Human;Human Resources;IACUC;Individual;Information Dissemination;Information Distribution;Institutional Review Boards;Instruction;Kentucky;Laboratories;Location;Macaca;Manuscripts;Monitor;Monkeys;National Institute of Child Health and Human Development;Organization administrative structures;Ovulation;Pilot Projects;Preparation;Program Research Project Grants;Protocols documentation;Publications;Rattus;Recombinant DNA;Regulation;Reporting;Research;Research Personnel;Resources;Retreatment;Rodent;Scientific Advances and Accomplishments;Secondary to;Services;Structure;Tissues;Training;Universities;Visit;Woman;Work;meetings;member;operation;programs;repository;success;synergism;web page

public_health_relevance:
RELEVANCE (See instructions): The Administrative core is responsible for carefully and closely monitoring the entire operation of the P01 program which is a multi-institutional program with 6 investigators at 3 different Universities. This core is the "command central" that deals with the day to day problems as well as insures that the long term research goals of the program are achieved.


application_id: 9325056
project_number: 5P01HD071875-04
project_title: CIPAR1 A Novel Modulator of Progesterone Accumulation in Periovulatory Follicle
administering_ic: NICHD
award_notice_date: 2017-08-14
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7820
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): In response to the preovulatory LH surge the preovulatory follicle rapidly increases progesterone production which is essential for ovulation and/or corpus luteum formation. Although this rise in progesterone level has been mainly linked to a few LH-induced genes involved in steroidogenesis (e.g. StAR Cypi 1 a l  and HSD3b) but there are many gaps in our understanding of periovulatory accumulation of progesterone. In this proposal we put forward a novel protein CIPAR1 (castration-induced prostatic apoptosis-related protein 1) as a vital mediator of progesterone accumulation in the periovulatory follicle. We have recently demonstrated the LH surge increases the expression of Ciparl in periovulatory follicles of rodent ovaries. More importantly our preliminary study using granulosa cell cultures showed that knockdown of Ciparl expression resulted in significant reduction of progesterone levels. Based on these novel findings we hypothesize that induction of CIPAR1 by the LH surge is crucial for progesterone accumulation in periovulatory follicles thus ovulation and luteinization. In specific Aim#1 we will demonstrate that the alteration of Ciparl expression by silencing or over-expression affects progesterone production in rat periovulatory follicles using both in vivo and in vitro models. As the first approach to pinpoint the functional contribution of C1PAR1 in periovulatory follicles we will identify the genes and proteins that are differentially expressed when Ciparl expression is silenced or over-expressed in periovulatory follicles. Because littie is known about cellular function of CIPAR1 Specific Aim #2 focuses on first determining the cellular location of CIPAR1 in periovulatory granulosa cells using confocal co-localization and/or subcellular fractionated protein analyses and then identifying CIPAR1 interacting proteins in periovulatory granulosa cells using immunoprecipitation followed by a proteomic approach. Other than our preliminary data detecting Ciparl expression in human granulosa cells nothing is known about CIPAR1 in human tissues. In collaboration with Drs. Brannstrum and Duffy specific Aim #3 will determine whether Ciparl expression is hormonally regulated during the periovulatory period and critical for LH-induced progesterone production in humans and/or macaques. Data obtain from the proposed studies will unravel the role of C1PAR1 as a novel and critical mediator of progesterone accumulation in periovulatory follicles of primates as well as rodents.

project_terms:
Affect;Antibodies;Apoptosis;Castration;Cell Culture Techniques;Cell Differentiation process;Cell physiology;Cells;Collaborations;Cytoprotection;Data;Development;Enzymes;Experimental Models;Female;Fertility;Future;Gene Proteins;Genes;Goals;Gonadotropins;Hormonal;Hormones;Human;Immunoprecipitation;In Vitro;Instruction;Link;Location;Luteinization;Macaca;Mediator of activation protein;Molecular;Monkeys;Ovary;Ovulation;Physiological;Play;Primates;Production;Progesterone;Prostaglandins;Prostate;Prostatic;Protein Analysis;Proteins;Proteomics;Rattus;Reproduction;Rodent;Role;Steroid biosynthesis;Testing;Tissues;Woman;base;corpus luteum;differential expression;experimental study;granulosa cell;hormone regulation;human tissue;improved;in vitro Model;in vivo;knock-down;novel;overexpression;response

public_health_relevance:
RELEVANCE (See instructions): Progesterone plays a vital role in many aspects of reproduction including ovulation and corpus function therefore female fertility. Identifying the cellular function of CIPAR1 will improve our understanding of mechanisms controlling progesterone production and may suggest a novel target for managing female fertility.


application_id: 9325055
project_number: 5P01HD071875-04
project_title: Mechanism of Periovulatory Leukocyte Infiltration into the Ovary
administering_ic: NICHD
award_notice_date: 2017-08-14
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7819
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG JAY
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): Crosstalk between the immune and reproductive systems dramatically impacts fertility. In particular studies have shown that a tight spatiotemporal control of leukocyte infiltration into the ovary is pivotal for successful ovulation. Once infiltrated the leukocytes differentiate into a cohort of pro- or anti-infiammatory cells in the preovulatory ovary and play critical roles in ovulation and luteal formation. In this study we will test the hypothesis that progesterone (P4) and prostaglandins (PG) play pivotal roles in recruiting leukocytes into the preovulatory ovary. Aim 1. To determine the mechanism(s) by which P4 and PG regulate WBC infiltration. We will first determine the roles of P4 and PG on WBC infiltration by treating cycling adult rats with RU486 indomethacin and vehicle and measuring the effect on the numbers populations and localization of infiltrating WBC by flow cytometry and immunohistochemistry together with a functional analysis of the expression of chemokines cytokines their receptors and cell adhesion molecules (CAMs) in serum on ovarian cells and WBC by ELISA and qPCR. Aim 2. To determine whether P4 and PG regulate WBC infiltration in primate ovary. In this Aim we will investigate P4 and PG regulated WBC infiltration in primates. Similar to rodents primates including humans also require P4 and PG for normal ovulation. Therefore we hypothesize that P4 and PG will regulate WBC infiltration in the primate ovary. The actions of P4 and PG will be inhibited by treating primates (Cynomolgous monkeys) with trilostane (3|3HSD inhibitor; inhibits progesterone synthesis) celecoxib (selective COX-2 inhibitor) or vehicle under ovarian stimulation. The effects on the numbers populations and localization of WBC together with the expression of infiammatory mediators will be determined. Upon the identification of the P4- and PG-regulated WBC subtypes and infiammatory mediators in the monkey the localization and expression patterns of their homologs will be determined in the human ovary. Aim 3. To determine the regulatory mechanism of preovulatory splenic WBC release. We will identify the trigger(s) and the mechanism of action of splenic WBC release from spleen. We hypothesize that either LH decreased concentration of circulating WBC or angiotensin-ll (the only known trigger of splenic leukocyte release) act as the trigger. To identify the trigger(s) ovariectomized rats will be treated with candidate triggers (LH and angiotensin-ll) or artificially reduce the concentration of circulating WBC by perfusing rats with plasma. The effects on splenic WBC release will be measured by counting WBC numbers in spleen and peripheral blood.

project_terms:
Adhesions;Adult;Affect;Age;Angiotensins;Animals;Anovulation;Biological Assay;Biological Process;Blood Circulation;Cell Adhesion Molecules;Cells;Chronic;Clinical Treatment;Cytokine Receptors;Cytometry;Data;Defect;Diagnosis;Disease;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Failure;Female;Fertility;Flow Cytometry;Human;Immune system;Immunohistochemistry;In Vitro;Indomethacin;Infiltration;Inflammation;Inflammation Mediators;Knockout Mice;Leukocyte Trafficking;Leukocytes;Measures;Mediator of activation protein;Mifepristone;Migration Assay;Monitor;Monkeys;Ovarian;Ovarian Stimulations;Ovary;Ovulation;PTGS2 gene;Pathway interactions;Pattern;Plasma;Play;Population;Primates;Procedures;Progesterone;Prostaglandins;Rattus;Receptor Cell;Recruitment Activity;Reproductive system;Rodent;Role;Serum;Signal Pathway;Spleen;Testing;Woman;celecoxib;chemokine;cohort;cytokine;inhibitor/antagonist;nonhuman primate;novel;novel strategies;peripheral blood;receptor;reproductive;spatiotemporal

public_health_relevance:
RELEVANCE (See instructions): Chronic anovulation affects up to 15% of the female US population many of the causes not being accounted for. This study will identify a novel cause of anovulation resulting from defective ovarian inflammation which will lead to develop a better treatment option for an ovulatory disorder.


application_id: 9325054
project_number: 5P01HD071875-04
project_title: Angiogenesis in the Primate Ovulatory Follicle
administering_ic: NICHD
award_notice_date: 2017-08-14
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7818
contact_pi_person_id: 1919355
contact_pi: DUFFY, DIANE M
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
Ovulation is essential for successful reproduction. The ovulatory luteinizing hormone (LH) surge stimulates periovulatory follicles to produce prostaglandin E2 (PGE2). Blockade of PGE2 production causes ovulation failure. LH-stimulated neovascularization of the follicle is also essential for ovulation as inhibition of follicular angiogenesis prevents ovulation. This proposal puts for the overall hypothesis that PGE2 mediates the ability of the ovulatory LH surge to regulate angiogenesis within the ovulatory follicle. Angiogenesis is regulated via vascular growth factors. In Aim 1 we will determine if LH acts at follicular granulosa cells to regulate production of vascular growth factors in a PGE2-dependent manner. Monkey ovaries with multiple follicles will be obtained before and after administration of an ovulatory dose of the LH-like hormone hCG; some monkeys will also receive concomitant administration of a prostaglandin (PG) synthesis inhibitor. Granulosa cells follicular fluid and whole ovaries will be assessed for vascular growth factor mRNAs by qPCR and proteins by western blotting ELISA and immunofiuorescent detection on tissue sections. In vitro studies will be performed to determine if PGE2 acts directiy at granulosa cells to regulate vascular growth factor mRNA and proteins. Vascular growth factors act at endothelial cells to promote the formation of new blood vessels. In Aim 2 we will determine if PGE2 and vascular growth factors act at endothelial cells of the follicle to stimulate angiogenesis. Using a novel proliferating population of monkey ovarian endothelial cells we will determine if PGE2 stimulates endothelial cell proliferation migration and formation of new capillaries. Similarly vascular growth factors produced by granulosa cells granulosa cell-conditioned media and coculture with granulosa cells will be used to determine if vascular growth factors stimulate endothelial cell functions necessary for angiogenesis. Finally monkey ovaries obtained after treatment in vivo with hCG hCG+PG synthesis inhibitor or hCG+PG synthesis inhibitor+PGE2 will be assessed histologically for neovascularization of the ovulatory follicle. The proposed studies will likely demonstrate that PGE2 and vascular growth factors act directly at endothelial cells to promote the neovascularization of the primate ovulatory follicle. Modulation of follicular PGE2 levels or PGE2 receptor activity may provide effective treatments for infertility or suggest targets for the development of novel contraceptives.

project_terms:
Aftercare;Antibodies;Area;Biopsy;Blood Vessels;Blood capillaries;Cell Count;Cell Proliferation;Cell physiology;Cells;Coculture Techniques;Contraceptive Agents;Data;Detection;Development;Diagnosis;Dinoprostone;Dose;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Exposure to;Failure;Fertility;Follicular Fluid;Gonadotropins;Growth Factor;Histologic;Hormones;Human;Human Chorionic Gonadotropin;In Vitro;Infertility;Injectable;Instruction;Laboratories;Lead;Luteinization;Luteinizing Hormone;Macaca;Mediating;Mediator of activation protein;Messenger RNA;Modeling;Monkeys;Ovarian;Ovarian Follicle;Ovarian Hyperstimulation Syndrome;Ovary;Ovulation;Population;Pregnancy;Primates;Production;Proliferating;Prostaglandin Antagonists;Prostaglandin Inhibition;Prostaglandins;Proteins;Reproduction;Rodent;Structure;Testing;Time;Tissues;Vascular Endothelial Growth Factors;Western Blotting;Woman;angiogenesis;capillary;effective therapy;experimental study;granulosa cell;in vivo;infertility treatment;inhibitor/antagonist;migration;neovascularization;novel;prevent;receptor;response

public_health_relevance:
RELEVANCE (See instructions): Formation of new blood vessels In the ovarian follicle is essential for ovulation and therefore fertility. Understanding how prostaglandins regulate angiogenesis in the ovarian follicle may identify new treatments for infertility or suggest targets for the development of novel contraceptives.


application_id: 9325053
project_number: 5P01HD071875-04
project_title: EMMPRIN: A Regulator of Angiogenesis and Leukocyte Trafficking During Ovulation
administering_ic: NICHD
award_notice_date: 2017-08-14
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7817
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
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: 2017-07-01
budget_end_date: 2018-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The preovulatory LH surge stimulates an increase in ovarian extracellular matrix metalloproteinase inducer (EMMPRIN) which is known as a classic regulator o fthe matrix metalloproteinases (MMPs). The paramount role of EMMPRIN in ovulation is evident from experiments in mice lacking EMMPRIN that display a decrease in oocyte release and fertilization. Yet other than our preliminary data nothing is known as to temporal expression patterns the regulation and potential function of EMMPRIN in the ovulatory process in the human. This question will be addressed in the proposed POI program through a collaborative approach utilizing the exceptional backgrounds technical expertise and models ofthe PIs. We will make use of a unique model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG (early late and postovulatory). The expression patterns of EMMPRIN in the human will be illuminated in Aim #1. Specific Aim #2 will build upon these findings to elucidate the role of EMMPRIN in ovarian angiogenesis in the human macaque and rat. The ability of EMMPRIN to stimulate proliferation migration and spouting of new vessels will be determined. To further characterize EMMPRIN's action. Specific Aim #3 will investigate the role of EMMPRIN in immune cell trafficking' Specifically studies will explore the impact of EMMPRIN on leukocyte expression of the MMP system and EMMPRIN's ability to regulate the invasive capacity of leukocytes. One novel aspect of this study is the use of well characterized human preovulatory follicles as a foundation to explore the expression and function of EMMPRIN in the process of human ovulation which has never been accomplished. Another major strength of this proposal is the collaborative interactions between different investigators to address the function of EMMPRIN in periovulatory events across multiple species. As such the proposed studies are extremely timely to elucidate the role that this exquisite proteolytic system plays in the coordinated processes of follicular rupture and oocyte release which are key aspects of normal human ovarian physiology.

project_terms:
Address;Blood Vessels;Cells;Data;Defect;Dinoprostone;EGF gene;Endothelial Cells;Event;Extracellular Matrix;Fertilization;Foundations;Gene Expression Profile;Genes;Glycoproteins;Human;Human Chorionic Gonadotropin;Immune;In Vitro;Infertility;Inflammatory;Instruction;Leukocyte Chemotaxis;Leukocyte Trafficking;Leukocytes;Macaca;Matrix Metalloproteinases;Mediator of activation protein;Modeling;Molecular Profiling;Monkeys;Motion;Mus;Oocytes;Ovarian;Ovarian Tissue;Ovary;Ovulation;Pattern;Peptide Hydrolases;Physiology;Play;Primates;Process;Production;Progesterone;Prostaglandins;Rattus;Regulation;Reporting;Research Personnel;Rodent;Rodent Model;Role;Rupture;Signal Pathway;Stimulus;System;Technical Expertise;Time;Tissue Model;Tissues;Vascular Endothelial Growth Factors;Woman;angiogenesis;collaborative approach;experimental study;granulosa cell;human tissue;implantation;in vitro Model;in vivo;migration;neoplastic cell;neovascularization;novel;programs;reproductive function;trafficking;tumor

public_health_relevance:
The proposed studies will use human tissues collected at carefully defined times prior to and immediately after ovulation to investigate the changes in gene expression patterns that may impact oocyte release. The changes in these genes and their regulation will be studied using both human tissues and rodent models to mimic the human. These studies will expand our understanding of ovulation in the human.


application_id: 9325051
project_number: 5P20GM103527-10
project_title: Role of Adipose Tissue TGF-b signaling on Adipose Dysfunction in Obesity
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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 adipocyte-macrophage 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;Heart Diseases;High Fat Diet;Human;Hypoxia;Immune;Impairment;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: 9325050
project_number: 5P20GM103527-10
project_title: Role of bioactive lipids in the protective pathways of obesity in ischemic cardi
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
project_abstract:
Obesity is approaching epidemic state in the western world 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 basis 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 of the obesity-associated alterations in AMI-induced stem cell mobilization pathways specially those involving bioactive lipids and devise therapies that harness 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;Pharmacology;Plasma;Play;Population;Positioning Attribute;Process;Recovery;Research;Review Literature;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Stem cells;System;Therapeutic;Thinness;Western World;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: 9325049
project_number: 5P20GM103527-10
project_title: Role of lipinl in skeletal muscle mitochondrial homeostasis and oxidative energy
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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. Lipin1 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- responsive genes. Lipin1 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. Lipin1 is also expressed in skeletal muscle and transgenic overexpression of lipin1 in this tissue reverses many of the phenotypes of lipin1 deficient fid mice. Interestingly humans with heritable lipin1 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 lipin1 is recruited to the mitochondrial surface where it promotes mitochondrial fission and remodels mitochondrial lipids suggesting that lipin1 deficiency impacts directly on mitochondrial function. Based on these observations we propose that lipin1 is poised to function as a link between fatty acid and carbohydrate metabolism in muscle and fat. Accordingly we hypothesize that recruitment of lipin1 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 lipin1 deficient mouse embryo fibroblasts and mitochondria isolated from skeletal muscle of lipin1 deficient mice. The broad goal of this research is to define the role of Lipin1 in mitochondrial function and skeletal muscle physiology. Aim 1 defines the role of muscle cell lipin1 PA phosphatase activity in regulating mitochondrial lipid composition and function while Aim 2 examines deletion of skeletal muscle lipin1 in lean and obese mice.

project_terms:
Activator Appliances;Acyltransferase;Adipose tissue;Alleles;Animals;Biological Preservation;Blood Pressure;Body Weight;Cardiovascular Diseases;Carnitine;Cell Culture System;Cell Respiration;Cells;Complement;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;Genetic Transcription;Glucose;Goals;Hepatic;Heritability;Homeostasis;Human;Hyperlipidemia;Impairment;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;PPAR alpha;Pathogenicity;Pathway interactions;Phenotype;Phosphatidate Phosphatase;Phosphoric Monoester Hydrolases;Play;Predisposition;Recruitment Activity;Regulation;Research;Respiratory Chain;Respiratory physiology;Rhabdomyolysis;Role;Seminal;Site;Skeletal Muscle;Small Interfering RNA;Surface;System;Thinness;Tissues;Transcription Coactivator;Transgenic Organisms;Transportation;Triglycerides;Variant;adipocyte differentiation;base;carbohydrate metabolism;experimental study;fatty acid metabolism;fatty acid oxidation;in vivo;insight;insulin sensitivity;inter-individual variation;mitochondrial dysfunction;muscle degeneration;muscle metabolism;muscle physiology;null mutation;overexpression;oxidation;skeletal muscle metabolism

public_health_relevance:
Lipin1 is emerging as a master regulator of metabolism. Inter-individual variation in lipin1 expression and alterations in lipin1 mRNA processing have been associated with human susceptibility to diet induced obesity. Our proposed studies promise to reveal a new facet of lipin1 function in skeletal muscle and to define the role of lipin1 as a link between fat storage in adipose tissue and consumption of mobilized fatty acids by skeletal muscle mitochondrial oxidative metabolism.


application_id: 9325048
project_number: 5P20GM103527-10
project_title: Quantifying the effect of obesity and comorbid hypertension on cardiac function
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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 dysfunction the underlying mechanisms of myocardial dysfunction in obesity and potential treatments have not been fully elucidated. Our preliminary data utilizing cardiac magnetic resonance imaging (MRI) show abnormalities in the magnitude of contraction 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 underlying 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;Comorbidity;Computer software;Data;Development;Diet;Fat-Restricted Diet;Fatty acid glycerol esters;Functional disorder;Heart;Heart Hypertrophy;High Fat Diet;Human;Hydralazine;Hypertension;Hypertrophy;Kentucky;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Mus;Myocardial;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;heart function;heart imaging;mortality;mouse model;normotensive;obesity in children;serial imaging;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: 9325047
project_number: 5P01HD071875-04
project_title: Ovulation and Luteal Formation in Rodents Monkeys and Women
administering_ic: NICHD
award_notice_date: 2017-08-14
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
program_official: TAYMANS, SUSAN
project_start_date: 2014-09-19
project_end_date: 2019-06-30
study_section: ZHD1-DRG-D(41)
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
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 unifying theme of this P01 proposal is to investigate one of the cornerstones of female fertility ovulation. Through this P01 project we will address key questions of the mechanisms associated with follicular rupture and the subsequent early changes in the postovulatory follicle. This will be accomplished through the scientific integration both experimentally and technically of 4 separate projects involving 5 investigators that will utilize ovarian tissues from women macaques and rodents. Project 1 (Curry/Brannstrom) will make use of an extremely novel model where human follicles are collected across the periovulatory period to examine the changes in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN). Project #2 (Duffy) will take advantage of Dr. Duffy's extensive experience with macaques to investigate the role of PGE2 in angiogenesis of the nonhuman primate periovulatory follicle. Project #3 (Ko) will study the mechanisms by which progesterone regulates leukocyte infiltration in the preovulatory ovary. Project #4 (Jo) will elucidate the cellular action of CIPAR1 in regulating the LH mediated induction of progesterone production. Translational interactions across the projects are readily evident as tissues from women (Project #1) and macaques (Project #2) will be available to extrapolate to rodent models (Projects 1 3 4). An Administrative core provides support for the research teams by overseeing the overall functioning of the program as well as coordinating shared tissues from women macaques and rodents across the different projects. A pilot project will also be supported to open additional avenues of research collaboration and expertise. The significance of this proposal lies in its truly unique translational potential to further our understanding of the pathways that are critical for ovulation and early luteal formation in the human. There can be no stronger translational potential than to use human follicles collected at defined times after hCG to truly comprehend the mechanisms of ovulation and luteinization. The proposed studies in both the human and macaque will make significant strides towards advancing our understanding and treatment of ovulatory associated infertility as well as providing therapeutic modalities to manipulate the ovulatory process in the human thereby providing an important relevance to human health.

project_terms:
Address;Collaborations;Contraceptive methods;Critical Pathways;Dinoprostone;Extracellular Matrix;Female;Fertility;Health;Human;Human Chorionic Gonadotropin;Infertility;Infiltration;Leukocytes;Luteinization;Macaca;Matrix Metalloproteinases;Mediating;Methods;Modality;Modeling;Monkeys;Oocytes;Ovarian Tissue;Ovary;Ovulation;Pilot Projects;Process;Production;Progesterone;Research;Research Personnel;Research Support;Rodent;Rodent Model;Role;Rupture;Therapeutic;Time;Tissues;Woman;angiogenesis;experience;nonhuman primate;novel;programs

public_health_relevance:
RELEVANCE: The proposed studies will examine the process of oocyte release using unique models and tissues from women monkeys and rodents. This will be accomplished by the integration of 4 synergistic and interactive research programs that will together provide a broader more comprehensive picture of the interrelated mechanisms of ovulation and luteal formation. This information can be used to treat infertility or conversely to explore novel methods of contraception.


application_id: 9325046
project_number: 5P20GM103527-10
project_title: The role of IKK in linking obesity to adipose tissue inflammation and adipogene
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
project_abstract:
The goal of this project is to investigate the role of IKB kinase beta (IKK) a central coordinator of innate immunity and inflammation through activation of NF-B 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-B is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKK is the predominant catalytic subunit of the IKK complex that is required for canonical activation of NF-B by inflammatory mediators. Given the defined role of IKK in regulating NF-B-mediated inflammation in several cell types it is unclear whether IKK contributes to obesity-induced inflammation in adipocytes. In the proposed studies we will define the role of adipocyte-derived IKK 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) IKK in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKK in SMCs we used SM22-Cre transgenic male mice carrying floxed IKK alleles that were mated to female LDLR-/- mice carrying floxed IKK alleles. During the course of these studies we made the novel finding that deficiency of IKK 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 IKK-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKK in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKK promotes adipocyte differentiation adipocyte inflammation and insulin resistance. In the proposed studies we will define mechanisms for IKK-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKK 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;Impairment;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;Muscle Cells;Natural Immunity;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Partner in relationship;Pathway interactions;Pharmacology;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;gain of function;lipid biosynthesis;loss of function;low density lipoprotein inhibitor;male;new therapeutic target;novel;nutrition;obesity treatment;overexpression;population health;progenitor;promoter;response;stem cell differentiation;therapeutic target;transcription factor

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: 9325045
project_number: 5P20GM103527-10
project_title: Pathology Core D
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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 paraffin microtomes microscope and stage for stitching paraffin sections together through imaging software.

project_terms:
Adipose tissue;Cardiovascular Diseases;Common Epitope;Equipment;Freezing;Histologic;Image Analysis;Inflammation;Kentucky;Link;Mentors;Microscope;Microtome - medical device;Obesity;Paraffin;Paraffin Embedding;Paraffin Tissue;Pathology;Pilot Projects;Research;Research Personnel;Sampling;Services;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: 9325044
project_number: 5P20GM103527-10
project_title: Physiologic Core C
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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 deposition 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;Closure by clamp;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;Services;Tail;Technical Expertise;Testing;Thinness;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: 9325043
project_number: 5P20GM103527-10
project_title: Analytical Core B
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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 specific 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;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;Research Support;Resolution;Series;Services;Suspensions;Training;United States National Institutes of Health;Universities;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: 9325042
project_number: 5P20GM103527-10
project_title: Administrative Core A
administering_ic: NIGMS
award_notice_date: 2017-08-01
opportunity_number: PAR-12-224
application_type: 5
activity_code: P20
ic: GM
serial_number: 103527
project_end_date: 2019-07-31
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: 2017-08-01
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 of the Program Director Administrative Assistant Financial Assistant Executive Committee Internal Advisory Committee COCVD Committee and Biostatistician. The Core will oversee all aspects of the 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;Retreatment;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.


