# projects

application_id: 9503257
project_number: 1P30GM127607-01
project_title: Imaging and Physiology Core
administering_ic: NIGMS
award_notice_date: 2018-06-22
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127607
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
subproject_number: 5794
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
budget_end_date: 2019-06-30
project_terms:
Address;Affect;Area;Attention;Businesses;Cardiovascular Diseases;Cardiovascular Physiology;Cells;Centers of Research Excellence;Charge;Collaborations;Communication;Communities;Complications of Diabetes Mellitus;Counseling;Data Analyses;Development;Diabetes Mellitus;Disease;Disease model;Echocardiography;Education;Effectiveness;Ensure;Extramural Activities;Faculty;Felis catus;Fruit;Funding;Future;Goals;Grant;Growth;Health;Human Resources;Image;Individual;Instruction;Investigation;Investments;Mentors;Mentorship;Microscopy;Mission;Modeling;Monitor;Mus;Obesity;Operative Surgical Procedures;Phase;Physiology;Policies;Procedures;Protocols documentation;Publications;Research;Research Design;Research Infrastructure;Research Personnel;Resources;Role;Services;Surgical Models;Techniques;Tissue imaging;Training;Training and Education;United States National Institutes of Health;Universities;Work;cardiometabolism;consumer product;flexibility;fluorescence imaging;heart function;imaging approach;imaging modality;improved;in vivo imaging;innovation;instrumentation;investigator training;meetings;member;non-invasive imaging;protocol development;sound;success;technological innovation;theories


application_id: 9503256
project_number: 1P30GM127607-01
project_title: Animal Models and Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2018-06-22
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127607
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
subproject_number: 5793
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
budget_end_date: 2019-06-30
project_terms:
Animal Model;Animals;Capital;Cardiovascular system;Centers of Research Excellence;Complex;Complications of Diabetes Mellitus;Consultations;Continuing Education;Core Facility;Country;Detection;Development;Diabetes Mellitus;Disease;Educational workshop;Equipment;Evaluation;Fees;Funding;Future;Grant;Human Resources;Institution;Instruction;Insulin Resistance;Investments;Learning;Marshal;Metabolic;Metabolism;Methods;Modeling;Molecular;National Heart Lung and Blood Institute;National Institute of Environmental Health Sciences;Obesity;Phase;Phenotype;Procedures;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Series;Services;Standardization;Structure;Study models;Superfund;Techniques;Technology;Time;Training;Training Activity;Universities;animal imaging;base;cardiometabolism;career;career development;expectation;experience;instrument;investigator training;lectures;member;metabolomics;pre-clinical;programs;success;user-friendly


application_id: 9503255
project_number: 1P30GM127607-01
project_title: Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2018-06-22
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127607
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
subproject_number: 5792
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
budget_end_date: 2019-06-30
project_terms:
Acetylcysteine;Address;Alkaloids;Analytical Biochemistry;Applications Grants;Area;Atherosclerosis;Benzene;Biological Assay;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Charge;Chemicals;Chromatography;Clinical Chemistry;Collaborations;Communities;Complete Blood Count;Complications of Diabetes Mellitus;Continuing Education;Data Analyses;Detection;Diabetes Mellitus;Directed Molecular Evolution;Educational workshop;Ensure;Equipment;Evolution;Experimental Designs;Extramural Activities;Faculty;Fee-for-Service Plans;Fostering;Functional disorder;Funding;Future;Glucose;Goals;Grant;Hepatic;Human Resources;Kidney;Lipids;Maintenance;Malondialdehyde;Mass Chromatography;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Methods;Molecular Weight;Neurotransmitters;Obesity;Participant;Pathologic;Pathology;Pathway Analysis;Phase;Pilot Projects;Plasma;Play;Procedures;Program Research Project Grants;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Science;Scientist;Services;Specimen;Stable Isotope Labeling;Structure;Superfund;Technical Expertise;Techniques;Tobacco;Training;United States National Institutes of Health;Universities;Volatile Fatty Acids;Work;Xenobiotic Metabolism;combat;cost;design;diabetic;experience;experimental study;instrument;interest;investigator training;knowledge base;mass spectrometer;member;metabolomics;monoamine;muconic acid;non-diabetic;novel;operation;oxidation;ranpirnase;research facility;stable isotope;symposium;toxicant;urinary;vascular inflammation;volatile organic compound;webinar


application_id: 9503252
project_number: 1P30GM127607-01
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2018-06-22
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127607
program_official: GOROSPE, RAFAEL
project_start_date: 2018-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Animal Model;Animals;Area;Arts;Award;Basic Science;Biomedical Research;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Centers of Research Excellence;Clinical;Complement;Core Facility;Country;Data;Development;Diabetes Mellitus;Discipline;Disease;Endocrine;Ensure;Environment;Environmental Exposure;Epidemic;Event;Faculty;Flow Cytometry;Fostering;Foundations;Funding;Goals;Grant;Growth;Health;Human;Image;Individual;Inflammation;Institution;Insulin Resistance;Interdisciplinary Study;Investigation;Laboratories;Lead;Learning;Medicine;Mentors;Mentorship;Metabolic;Metabolism;Molecular;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathology;Phase;Phenotype;Physiology;Pilot Projects;Postdoctoral Fellow;Public Health Schools;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Risk Factors;Science;Seeds;Services;Solid;Stroke;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;Vascular Diseases;Work;base;cardiometabolism;cardiovascular disorder risk;career;career development;clinical investigation;diabetic;graduate student;innovation;interdisciplinary approach;interest;member;mortality;multidisciplinary;novel;prevent;programs;recruit;stem cell biology;sudden cardiac death


application_id: 9503084
project_number: 5F31NS093892-03
project_title: Defining the Role of Laforin in Glycogen Metabolism and Lafora Disease
administering_ic: NINDS
award_notice_date: 2018-06-20
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: NS
serial_number: 093892
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-01
project_end_date: 2019-05-18
study_section: Special Emphasis Panel[ZRG1-F04B-D(20)L]
contact_pi_person_id: 12497153
contact_pi: BREWER, MARY KATHRYN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract The goal of this proposal is to use the unique window offered by Lafora disease (LD) to understandhow laforin regulates glycogen metabolism and define the molecular perturbation of LD patientmutations. Lafora disease (LD) one of the five major progressive myoclonus epilepsies is a fatal geneticneurological disorder that manifests during adolescence and invariably leads to neurodegeneration and death.Patients with LD display accumulations of hyperphosphorylated aberrantly branched glycogen-like particlescalled Lafora bodies (LBs). LBs are found in most tissues but neurological symptoms predominate in LDpatients. Mutations in the gene encoding the glycogen phosphatase laforin cause approximately 70% of LDcases. LD largely centers on glycogen metabolism. Glycogen is the most important carbohydrate storagemolecule in mammals and misregulation of glycogen is implicated in many diseases. Recent studies show thatglycogen plays a dynamic role in brain function and that neurons are highly sensitive to glycogen perturbations.Although glycogen has been studied for many years gaps in our understanding of its regulation remain. TheGentry lab established laforin as the founding member of the glucan phosphatase family (i.e. enzymes thatrelease phosphate from carbohydrates) and studies on LD show that the absence of laforin triggers thetransformation of glycogen into the neurotoxic carbohydrate that makes up LBs. As the only glucanphosphatase in humans laforin is the lynchpin of glycogen regulation by phosphorylation. We recently determined the crystal structure of laforin. This proposal will couple insights from the structurewith biochemical and biophysical tools to define how laforin functions as a glucan phosphatase and regulatesglycogen metabolism. Further the 33 LD-associated missense mutations are scattered throughout thestructure and have different effects on laforin activity. A goal in our lab is to define the effect of all of thesemutations. Aim 1A will address the nature of the dimer interface which has been controversial in the field andthe molecular effect of LD mutations in this region. Aim 1B will define how laforin cooperatively binds theglucan chains in glycogen and the effects of length and branching. Aim 2 will establish the role of theinterdomain region of laforin (i.e. between the phosphatase and carbohydrate-binding domains) in maintainingC3- and C6-specific dephosphorylation of glycogen. A number of LD mutations fall in this region and this aimwill demonstrate their functional effects. In summary this proposal utilizes cross-disciplinary techniques tostudy glycogen homeostasis and the mechanisms of LD studies that will provide insights into brain metabolismand pave the way for patient-specific diagnoses and treatments.

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

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


application_id: 9501780
project_number: 5R21MH109844-02
project_title: Exploring Anatomical and Circuit Plasticity Deficits in Fmr1 Mice During Tactile Learning
administering_ic: NIMH
award_notice_date: 2018-05-04
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: MH
serial_number: 109844
program_official: BUHRING, BETTINA D
project_start_date: 2017-07-01
project_end_date: 2020-04-30
study_section: Developmental Brain Disorders Study Section[DBD]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: HIRES, SAMUEL ANDREW
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:
Project AbstractFragile X Syndrome (FXS) is a leading inheritable cause of mental impairment. There is no known cure forFXS or treatment that reverses the collective pathology. There is a fundamental gap in our knowledge of howFXS causes mental impairments through alteration of neural circuitry. The long-term goal of this research is todevelop an understanding of FXS that links learning impairments to specific changes in neural circuits.Characteristic symptoms of FXS include reduced intellectual abilities learning deficits and hypersensitivity tosensory stimuli. FXS arises from a loss-of-function in the FMR1 gene; mice lacking a functional fmr1 geneexhibit several phenotypes similar to FXS. Fmr1 mutant mice display an intriguing deficit on both the gap crosstask a freely-behaving whisker-dependent tactile learning task as well as a head-fixed whisker-dependenttactile learning task. The central hypothesis is that impairments in tactile learning are driven by reduceddendritic spine stability and hypersensitive touch responses in primary somatosensory cortex resulting fromattenuated activity of somatostatin-expressing (SOM) interneurons. Experiments in this proposal will determinethe extent to which loss of the fmr1 gene disrupts spine stability tactile learning and circuit dynamics duringtask performance. Guided by our strong preliminary data we will pursue this hypothesis in two related specificaims. In Aim 1 longitudinal two-photon in vivo imaging is combined with an automated head-fixed whisker-dependent tactile learning task to evaluate if reduced activity of SOM interneurons in fmr1 mutant micedecreases dendritic spine stability and impairs learning. In Aim 2 sophisticated electrophysiology is combinedwith high-speed tracking of whisker position during this same head-fixed object localization to quantify theextent to which tactile discrimination and cortical representations of afferent sensory activity in somatosensorycortex are abnormal fmr1 mutant mice and if attenuated function of SOM interneurons contributes to thisdeficit. This approach is particularly innovative because the synaptic changes that underlie learning aremeasured longitudinally throughout task acquisition. Furthermore breaking from the anesthetized status quothe cortical circuit dynamics that represent touch are quantified during active perceptual behavior. Theproposal is significant because it vertically advances our knowledge of FXS mechanisms across levels ofanalysis from synapse to circuit to behavior. Additionally it opens new horizons for these advancedtechniques to be applied to other cortical layers and brain regions to build a comprehensive understanding ofneural circuit defects in a premier FXS model system. This proposal squarely meets the key mission objectivesof the NINDS and NIMH to provide detailed and integrated knowledge of how the function of synapses andcircuits is disrupted in neurological disorders. Ultimately the resulting improved understanding of circuitdysfunction has the potential to lead to therapies that improve the quality of life for the roughly 1 in 5000people born with Fragile X Syndrome.

project_terms:
Address;Anatomy;Area;Attenuated;Behavior;Behavioral;Biological Models;Brain;Brain region;Characteristics;Data;Defect;Dendrites;Dendritic Spines;Detection;Discrimination;Disease;Electrophysiology (science);Exhibits;FMR1;Fragile X Syndrome;Functional disorder;Genetic;Goals;Head;Hypersensitivity;Impairment;Inherited;Interneurons;Knowledge;Lead;Learning;Learning Disabilities;Link;Measures;Mediating;Mental disorders;Mission;Molecular Abnormality;Mus;Mutant Strains Mice;National Institute of Mental Health;National Institute of Neurological Disorders and Stroke;Neurons;Neurophysiology - biologic function;Pathology;Patients;Performance;Phenotype;Positioning Attribute;Psyche structure;Public Health;Quality of life;Regulation;Research;Sensory;Slice;Somatosensory Cortex;Somatostatin;Speed;Stimulus;Symptoms;Synapses;Tactile;Task Performances;Techniques;Testing;Therapeutic Intervention;Touch sensation;Training;Vertebral column;Vibrissae;Wild Type Mouse;associated symptom;barrel cortex;designer receptors exclusively activated by designer drugs;excitatory neuron;experimental study;gene function;hippocampal pyramidal neuron;improved;in vivo two-photon imaging;innovation;learned behavior;loss of function;motor learning;mouse model;mutant;nervous system disorder;neural circuit;neurotransmission;novel therapeutic intervention;relating to nervous system;response;sensory stimulus;synaptic function;targeted treatment

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because knowledge of how genetic abnormalities in FragileX Syndrome (FXS) alter the function of neural circuits during learning and behavior is ultimately expected toimprove our understanding of circuit targets for therapeutic intervention. Thus the proposed research isrelevant to the mission of the both the NIMH and NINDS to provide detailed and integrated knowledge of howsynapses and circuits function in connection with mechanisms underlying the causes of psychiatric andneurologic disorders.


application_id: 9501748
project_number: 5R01GM109195-04
project_title: Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy
administering_ic: NIGMS
award_notice_date: 2018-05-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 109195
program_official: FABIAN, MILES
project_start_date: 2015-06-01
project_end_date: 2021-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7876821
contact_pi: YOKEL, ROBERT ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The technological development of nanomaterials has been underway for decades. Only in the past decade has serious attention been paid to their potential unwanted health and environmental effects. Many nanomaterials do not readily dissolve or disintegrate in biological and environmental milieu. As a result they can persist where they are sequestered (in mammals mostly in mononuclear phagocyte system organs such as the liver spleen and bone marrow) for months possibly years often associated with inflammatory/oxidative stress responses including granuloma. These unwanted effects have been seen with nanoceria (nanoscale cerium dioxide). On the other hand nanoceria has been shown to be an effective anti-inflammatory/antioxidant in numerous cellular cell and whole animal models of inflammation/oxidative stress. Nanoceria's pro- and antioxidant effects result from its auto-catalytic redox behavior (oxidation from Ce (III) to Ce (IV) and reduction back to Ce(III)). The first specific aim of this project will determine if nanoceria can produce inflammatory/pro- oxidant effects in the absence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effects when inflammation/oxidative stress is elevated and determine the lowest observed adverse dose and lowest observed beneficial dose. Four nanoceria will be studied: a 5 and a 30 nm nanoceria extensively studied for their distribution persistence and effects in the rat (preliminary findings) and a third that others have demonstrated produces beneficial inflammatory/pro-oxidant effects. These three will be synthesized and extensively characterized in-house. The fourth will be NM-212 a commercial nanoceria that is being extensively studied by the inhalation route by others. Due to the very low oral and pulmonary absorption of nanomaterials nanoceria will be delivered by intravenous injection to establish sufficient levels in multiple organs to study its biodistribution persistene biotransformation and effects. Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammalian cells over months to a more stable form. This appears to occur via dissolution and formation of very small nanoceria particles. These very small nanoceria particles have a greater enrichment of Ce (III) on their surface; therefore they are expected to have enhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhanced benefit over time associated with nanoceria's persistence and bioprocessing. The second specific aim will test the hypothesis that the distribution form and effects of nanoceria change over time due to its bioprocessing in the liver to smaller more antioxidant forms. The third specific aim will identify factors that contribute to nanoceria dissolution and precipitation and mediate its bioprocessing and precipitation in the liver. The proposed studies will identify nanoceria doses that maximize its efficacy relative to its unwanted effects elucidate nanoceria's long term fate in a model mammal the rat and provide the insight into its biotransformation that may enable safer by design nanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.

project_terms:
3-Dimensional;Address;Adverse effects;Affect;Animal Model;Anti-inflammatory;Antiinflammatory Effect;Antioxidants;Area;Attention;Back;Behavior;Biodistribution;Biological;Biological Availability;Bone Marrow;Buffers;Cells;Characteristics;Chemicals;Coculture Techniques;Development;Diesel Fuels;Dose;Family;Future;Goals;Granuloma;Health;Industrialization;Inflammasome;Inflammation;Inflammatory;Inhalation;Lipopolysaccharides;Liver;Lung;Mammalian Cell;Mammals;Measures;Mechanics;Mediating;Medical;Metabolic Biotransformation;Modeling;Mononuclear;Morphology;Oral;Organ;Oxidation-Reduction;Oxidative Stress;Phagocytes;Physiological;Pilot Projects;Polishes;Precipitation;Property;Rattus;Reactive Oxygen Species;Recycling;Reporting;Research;Research Personnel;Route;Safety;Spleen;Stress;Surface;System;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;absorption;base;biological adaptation to stress;biological systems;bioprocess;body system;catalyst;ceric oxide;design;insight;interest;intravenous injection;metal oxide;nanomaterials;nanoscale;nanotherapy;novel;oxidation;particle;public health relevance;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cerium dioxide nanomaterials (nanoceria) have many current commercial uses including as a diesel fuel additive to catalyze combustion and in chemical-mechanical polishing to manufacture integrated circuits with future applications expected in fuel cells and batteries. Nanocerias have been shown to produce adverse effects as well as beneficial antioxidant/anti-inflammatory effects the latter suggesting potential medical applications. The proposed research will determine the influence of dose and biotransformation on long-term nanoceria effects with the goal of minimizing its adverse and maximizing its beneficial effects supporting its design for safe use for its many potential applications.


application_id: 9501693
project_number: 5R03AI133056-02
project_title: Borrelia burgdorferi responses to antibiotic stresses
administering_ic: NIAID
award_notice_date: 2018-05-10
opportunity_number: PA-16-162
application_type: 5
activity_code: R03
ic: AI
serial_number: 133056
program_official: ILIAS, MALIHA R
project_start_date: 2017-06-06
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTLyme disease which is caused by the spirochete Borrelia burgdorferi is generally treatable by a 2-4 weekcourse of antibiotics. However there is strong evidence from studies of human patients and experimentalanimals that antibiotics do not always clear B. burgdorferi infections. Studies of other bacterial species haverevealed genetically-encoded physiological adaptations to antibiotic stresses such as altering expressionlevels of target proteins or metabolic enzymes. To gain insight on whether the Lyme spirochete also adapts toantibiotic stresses we will examine the transcriptomes and proteomes of B. burgdorferi that are exposed tosub-lethal and lethal concentrations of antibiotics that are commonly used to treat human Lyme diseaseinfections. Results of these studies will reveal whether B. burgdorferi possesses genetically-encoded adaptivemechanisms which can then be targeted for development of improved therapeutics.

project_terms:
Address;Animals;Antibiotics;Bacteria;Borrelia burgdorferi;Development;Enzymes;Escherichia coli;Exhibits;Exposure to;Gene Expression;Genes;Genetic Transcription;Human;Individual;Infection;Laboratory Animals;Laboratory Study;Lyme Disease;Metabolic;Molecular;Order Spirochaetales;Patients;Physiological Adaptation;Production;Proteins;Proteome;Research Personnel;Residual state;Staphylococcus aureus;Stress;Symptoms;Therapeutic;Ticks;Tissues;base;chronic infection;improved;insight;pathogen;pathogenic bacteria;response;transcriptome

public_health_relevance:
PROJECT NARRATIVEEvidence exists that the spirochete bacterium Borrelia burgdorferi the agent of Lyme disease may possessmechanisms to avoid killing by antibiotics during human infection. Some other pathogenic bacteria undergogenetically-encoded physiological adaptations to antibiotic stresses such as altering expression levels oftarget proteins or metabolic enzymes. We hypothesize that the Lyme disease spirochete also adapts toantibiotic stresses which we will address by comparing the transcriptomes and proteomes of B. burgdorferithat are exposed to antibiotics which are commonly used to treat human Lyme disease.


application_id: 9500808
project_number: 1R01DC016957-01
project_title: Behavioral Parent Training for Families with Deaf and Hard of Hearing Preschoolers
administering_ic: NIDCD
award_notice_date: 2018-06-04
opportunity_number: PA-17-118
application_type: 1
activity_code: R01
ic: DC
serial_number: 016957
program_official: KING, KELLY ANNE
project_start_date: 2018-06-06
project_end_date: 2023-05-31
study_section: Psychosocial Development, Risk and Prevention Study Section[PDRP]
contact_pi_person_id: 8804342
contact_pi: STUDTS, CHRISTINA RUTH
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:
PROJECT SUMMARYThe prevalence of disruptive behavior problems among deaf or hard of hearing (DHH) children is double that ofnormal hearing children but this underserved population rarely receives behavioral interventions. Behavioralproblems in DHH children often are attributed to delays in language development yet even when languageoutcomes improve in response to early intervention behavioral problems frequently persist. Although parentingbehaviors have been largely overlooked in the literature investigating the etiology and maintenance of disrup-tive behavior problems in young DHH children their effects on child behavior are well-established in the normalhearing population. Behavioral parent training (BPT) programs have consistently demonstrated efficacy andeffectiveness in reducing disruptive behavior problems comorbidities parental stress and depression andlong-term costly consequences in children with normal hearing especially when delivered in early childhood.The hearing healthcare setting is ideal as a delivery venue for behavioral services because of consistent con-tacts from infancy through adolescence; parents trust and familiarity with the setting and providers; and lack ofstigma. This type 1 hybrid effectiveness-implementation trial will be conducted in 10 state-funded hearinghealthcare clinics testing an evidence-based BPT adapted to meet the needs of parents of underserved DHHchildren. The specific aims are: (1) To systematically adapt an evidence-based BPT by incorporating the pref-erences and perspectives of the target population and key stakeholders; (2) using a cluster-randomized trialdesign to test the effects of the adapted BPT on parent behaviors child behaviors adherence to wearinghearing rehabilitation devices and language development outcomes; and (3) based on the ConsolidatedFramework of Implementation Research to identify factors within the domains of the inner setting outer set-ting intervention characteristics process and provider characteristics influencing implementation of the inter-vention in each clinic as well as implementation outcomes (i.e. acceptability adoption recruitment/retentionfidelity and costs). The ADAPT-ITT framework will guide the systematic adaptation process. Examples of pos-sible adaptations include modifications to content (e.g. incorporation of scenarios relevant to DHH children inmaterials and activities inclusion of facilitative language techniques in skills training) and context (e.g. deliveryin hearing healthcare settings incorporation of language and hearing data in behavioral assessments). If theadapted BPT is effective behavioral problems among DHH children could be successfully addressed in hear-ing healthcare. The use of a type I hybrid design will allow us to simultaneously test effectiveness and gatherinformation on multilevel factors influencing the quality of implementation. Results of this study will inform hear-ing healthcare systems regarding resources and strategies needed to deliver this intervention in new settingsto a new population. This project could inform a transformation of care in hearing healthcare settings to scaleup the integration of much-needed behavioral services into their already-interdisciplinary clinics.

project_terms:
Address;Adherence;Adolescence;Adoption;Adult;Behavior;Behavior Therapy;Behavior assessment;Behavioral;Caring;Characteristics;Child;Child Behavior;Child Rearing;Clinic;Cluster randomized trial;Communities;Comorbidity;Criminal Justice;Data;Device or Instrument Development;Early Intervention;Educational Intervention;Effectiveness;Environment;Etiology;Failure;Familiarity;Family;Funding;Healthcare;Healthcare Systems;Hearing;Hearing Impaired Persons;Hybrids;Intervention;Intervention Studies;Language;Language Development;Literature;Maintenance;Mental Depression;Methods;Modification;Outcome;Parents;Phase;Population;Prevalence;Problem behavior;Process;Provider;Rehabilitation device;Research Personnel;Resources;Schools;Services;Stress;Substance abuse problem;Target Populations;Techniques;Testing;Time;Training;Training Programs;Translating;Translational Research;Translations;Trust;Underserved Population;base;checkup examination;cost;cost outcomes;design;early childhood;effectiveness trial;evidence base;experience;health care settings;health related quality of life;implementation research;implementation trial;improved;improved outcome;infancy;innovation;pilot trial;preference;prevent;primary outcome;recruit;research to practice;response;scale up;skills training;social stigma;treatment as usual;trial design

public_health_relevance:
PROJECT NARRATIVEDespite being more likely than normal hearing children to experience disruptive behavior problems childrenwho are deaf and hard of hearing (DHH) rarely receive behavioral interventions to prevent the long-term costlyoutcomes of behavior problems. This project will systematically adapt an evidence-based parent trainingintervention to increase its acceptability and relevance for parents of young DHH children. Effectiveness of theadapted intervention and its implementation in real world hearing healthcare clinics will be assessed.


application_id: 9498456
project_number: 1R01DA045700-01
administering_ic: NIDA
award_notice_date: 2018-07-23
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DA
serial_number: 045700
program_official: RAMEY, TANYA S
project_start_date: 2018-08-01
project_end_date: 2022-05-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 8906159
contact_pi: BABALONIS, SHANNA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-08-01
project_terms:
Absence of pain sensation;Accidents;Acute;Address;Age;Agonist;Analgesics;Animals;Attenuated;Automobile Driving;Autopsy;Behavior;Behavioral;Biochemical;CNR1 gene;Cannabinoids;Chemosensitization;Cognitive;Data;Dose;Double-Blind Method;Dronabinol;Drug Interactions;Drug Modelings;Enrollment;Epidemic;Evaluation;Funding;Heroin;Human;Illicit Drugs;Individual;Inpatients;Intake;Laws;Legal;Marijuana;Measures;Medical Marijuana;Mus;Opioid;Opioid Receptor;Opioid user;Outcome;Oxycodone;Oxymorphone;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Population;Public Health;Randomized;Recording of previous events;Reporting;Research;Risk;Safety;Sampling;Self Administration;Series;Specimen;Statutes and Laws;System;THC concentration;Taxes;Therapeutic;Time;Ventilatory Depression;cannabinoid receptor;clinical practice;design;drug discrimination;drug misuse;endogenous cannabinoid system;endogenous opioids;epidemiologic data;functional outcomes;human data;innovation;marijuana smoke;marijuana use;meetings;mortality;neurochemistry;neurophysiology;nonhuman primate;opioid misuse;opioid mortality;opioid overdose;opioid use;opioid use disorder;pain outcome;pain relief;prescription opioid;prescription opioid misuse;receptor;response;substance use prevention;young adult


application_id: 9498362
project_number: 1R37CA227656-01
project_title: The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia
administering_ic: NCI
award_notice_date: 2018-04-06
opportunity_number: PA-16-160
application_type: 1
activity_code: R37
ic: CA
serial_number: 227656
program_official: JHAPPAN, CHAMELLI
project_start_date: 2018-04-06
project_end_date: 2023-03-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Lymphocytic Leukemia;Adult;Adverse effects;Apoptosis;Binding Sites;Biochemical;Biotin;Cancer Patient;Cells;Cessation of life;Child;Clinic;Clinical Trials;Cytotoxic Chemotherapy;DNA-Binding Proteins;Data;Defect;Development;Developmental Delay Disorders;Diagnosis;Disease;Disease Progression;Drug Targeting;Enhancers;FDA approved;Family;Gene Chips;General Population;Genes;Genetic Transcription;Growth;Human;Human Cell Line;In Vitro;Kinetics;Knowledge;Life;Ligase;Link;MYC gene;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Methods;Mission;Modeling;Molecular Target;Normal Cell;Nucleic Acid Regulatory Sequences;Oncogenes;Oncogenic;Organ;Outcomes Research;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Play;Preclinical Testing;Protein Array;Protein Tyrosine Phosphatase;Public Health;Regimen;Relapse;Research;Role;Sampling;Second Primary Cancers;Signal Pathway;Single Nucleotide Polymorphism;TP53 gene;Testing;Therapeutic;Transcriptional Regulation;Transplantation;Tumor Suppressor Proteins;Xenograft procedure;Zebrafish;base;cancer type;chemotherapy;in vivo;inhibitor/antagonist;innovation;knock-down;leukemia;member;molecular targeted therapies;novel;outcome forecast;pediatric patients;phosphatase inhibitor;preclinical trial;small molecule;targeted cancer therapy;targeted treatment;therapeutic target;transcription factor;translational impact;tumor progression


application_id: 9497819
project_number: 5R01HL107326-07
project_title: Sex Differences in Angiotensin-Induced Vascular Diseases
administering_ic: NHLBI
award_notice_date: 2018-06-13
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_abstract:
Abdominal aortic aneurysms (AAAs) exhibit pronounced sexual dimorphism. Similar to humans wedemonstrated previously that testosterone is a primary contributor to a 4-fold higher incidence of angiotensin II(AngII)-induced AAAs in male compared to female mice. In addition to sex hormones sex chromosomes havebeen suggested to contribute to sexual dimorphism of cardiovascular diseases. Preliminary data demonstratethat changing the sex chromosome complement from XX to XY in female mice results in an AAA incidence thatis similar to males. As testosterone promotes AngII-induced AAAs in XY males we administered testosteroneto neonatal (1 dose) and adult XY females. Testosterone caused aneurysm rupture in 73% of adult XYfemales. These results demonstrate that sex chromosome complement has a striking impact on AAA severityand that these effects are augmented by testosterone. Gene arrays on smooth muscle cells from XX versusXY females incubated with AngII or testosterone identified neprilysin and heme oxygenase 1 (HO1) as genetargets that may contribute in a sex-specific manner to higher AAA incidences severity and progression inmales compared to females. The central hypothesis of this proposal is that an interplay between sexhormones and chromosomes promotes the incidence and severity of AAAs. Moreover we hypothesize that aPrecision Medicine approach to therapeutically target specific pathways influenced by sex hormoneschromosomes or AngII will provide sex-specific efficacy against AAA formation and progression. Aim 1 willtest the hypothesis that an XY sex chromosome complement increases susceptibility to AngII-induced AAAsdue to the presence of genes on the Y chromosome. We will use a novel mouse model (XY*) that when bredto XX females enables delineation of whether XX XO XXY or XY sex chromosome complement influencesthe development and/or progression of AngII-induced AAAs. Aim 2 will test the hypothesis that sex-specifictherapeutic approaches targeting neprilysin inhibition in males versus HO1 stimulation in females will provideefficacy against the formation and/or progression of AngII-induced AAAs. These studies will increase basicknowledge of sex chromosome influences on the vasculature identify sex-specific therapies that may havetherapeutic applicability against AAAs and increase cardiovascular knowledge for the use of sex hormones inthe growing trans-gender population.

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;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

public_health_relevance:
The proposed studies will define the role of sex chromosomes on the development of abdominal aorticaneurysms (AAAs). Our approach is to identify interactions between one's sex hormones (e.g. testosterone)and sex chromosomes (XX versus XY) on genes expressed in the aorta that may contribute to AAAdevelopment and progression. We also propose to tailor drug therapies using this information to be moreeffective in males versus females to treat AAAs and other cardiovascular diseases.


application_id: 9497816
project_number: 5T32HL091812-10
project_title: Clinical Scholars In Cardiovascular Science
project_terms: Cardiovascular system;Clinical;Science
administering_ic: NHLBI
award_notice_date: 2018-05-04
opportunity_number: PA-11-184
application_type: 5
activity_code: T32
ic: HL
serial_number: 091812
program_official: HUANG, LI-SHIN
project_start_date: 2008-06-01
project_end_date: 2020-05-31
study_section: NHLBI Institutional Training Mechanism Study Section[NITM(JA)]
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
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky Training Program for Clinical Scholars in Cardiovascular Science (hereafter referred to as "the Program") prepares clinical scholars to assume leadership positions directing research in the field of cardiovascular medicine. In the last several years we have leveraged our cardiovascular science strengths to provide a unique multidisciplinary training program that horizontally integrates trainees across the disciplines of Medicine Nursing and Pharmacy. With this approach we have achieved our goal of increasing the pipeline of investigators who bridge the gap between basic science advances and their application to clinical medicine. This has been achieved by providing a highly collaborative training environment that combines strong science with the study of cardiovascular biology and disease in clinical populations. As described in this application our program features substantial collaborations between faculty mentors a talented pool of qualified applicants and solid infrastructure and institutional support. The success of our trainees in the first funding cycle demonstrates our ability to achieve our aims which are: 1) To provide a rigorous and solid research education in the basic sciences related to cardiovascular research 2) To prepare new researchers for translational and clinical science in a highly interdisciplinary environment 3) To provide training in the efficient and ethical conduct of high quality laboratory management and science 4) To create an environment that will incubate scholars and mentors with an innovative and nurturing structure

public_health_relevance:
The University of Kentucky Clinical Scholars in Cardiovascular Science Training Program prepares fellows toassume positions at the forefront of cardiovascular discovery. By doing so we have increased the pipeline ofphysicians and scientists that contribute at the highest levels to advancing the cardiovascular health of thenation.


application_id: 9495662
project_number: 5R21AI130756-02
project_title: Innate immune mechanisms regulating silicosis
administering_ic: NIAID
award_notice_date: 2018-05-10
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AI
serial_number: 130756
program_official: MINNICOZZI, MICHAEL
project_start_date: 2017-06-05
project_end_date: 2021-05-31
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
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:
ABSTRACT Exposure to irritant crystals such as crystalline silica (CS) induces inflammation of lungs leading tochronic irreversible disease-silicosis. Silicosis is incurable due to impaired particle clearance resulting in chroniclung inflammation and may eventually lead to many inflammatory diseases such as arthritis and lung cancer. CSexposure leads to recruitment of inflammatory cells to lungs of which neutrophils are key mediators of thepathophysiology of silicosis. Our results in mouse models showed that CS-induced pulmonary inflammation isattenuated in leukotriene B4 receptor1 (BLT1-/-) deficient. Extensive in vivo studies in CS exposed mice and exvivo studies in isolated bone marrow derived mast cells and macrophages suggested an intricate interplay ofmediators such as LTB4 IL-1 and neutrophil active chemokines regulate silicosis. Moreover our results suggestthat CS-induced LTB4 production by mast cells sets the pace of sterile neutrophilic inflammation in the lung. Suchinflammation is further perpetuated by IL-1 and CXC and CC neutrophil chemokines. The hypothesis of thisproposal is that CS-induced lipidosome and inflammasome pathways function in consort with chemokinesto coordinate sustained chronic sterile inflammation in silicosis. In the proposed research plan in twospecific aims we will perform studies to 1) delineate the molecular links between phagosome lipidosome andinflammasome pathways in regulating the CS-induced production of neutrophil chemoattractants (LTB4 IL-1 andCXCL1). Signaling intermediates unique to each of these pathways will be identified as they can serve as potentialdrug targets to block neutrophil recruitment into silicotic lungs. In aim2 we will identify the cellular mechanismsthat integrate the lipid/cytokine/chemokine (LTB4 IL-1 and CXCL1) responses into chronic inflammation in vivo.Select inhibitors of the leukotriene pathway will be tested for their efficacy in controlling CS-induced neutrophilicinflammation in preclinical mouse models. This knowledge will facilitate development of immunotherapeuticstrategies to fight silicosis.

project_terms:
Actins;Acute;Arthritis;Attenuated;Bone Marrow;CCR;CXC Chemokines;CXCL1 gene;CXCR;Cells;Chemotactic Factors;Chronic;Chronic Disease;Chronic lung disease;Clinical Trials;Complex;Crystallization;Cytoskeleton;Data;Development;Disease;Dominant-Negative Mutation;Drug Targeting;Epithelial Cells;Exposure to;Fibrosis;Functional disorder;G-Protein-Coupled Receptors;Glass;Health;Immune;Immunotherapeutic agent;Impairment;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inhalation;Interleukin-1;Interleukin-1 beta;Irritants;Knockout Mice;Knowledge;LTB4R gene;Lead;Leukotriene B4;Leukotriene Production;Leukotrienes;Link;Lipids;Lung;Lung Inflammation;MAPK8 gene;Malignant neoplasm of lung;Mediating;Mediator of activation protein;Methods;Microscopy;Mining;Modeling;Molecular;Mus;Neutrophil Infiltration;Occupational;Pathway interactions;Phagocytosis;Phagosomes;Pharmacology;Phase;Production;Pulmonary Inflammation;Research;Risk;Role;Signal Transduction;Silicon Dioxide;Silicosis;Small Interfering RNA;Sterility;Testing;base;beta-Chemokines;cell type;chemokine;chemokine receptor;crystallinity;cytokine;experimental study;fighting;in vivo;inhibitor/antagonist;knock-down;macrophage;mast cell;mouse model;neutrophil;novel strategies;novel therapeutic intervention;overexpression;particle;pre-clinical;rab GTP-Binding Proteins;recruit;response;treatment choice;uptake

public_health_relevance:
PROJECT NARRATIVE Chronic exposure of crystalline silica (CS) often encountered in occupational settings such asconstruction mining glass and concrete production is a worldwide problem with tens of millions of people at risk.Such exposure is well known to induce lung inflammation and eventually causes an incurable irreversibledisease of lung-silicosis. Silicosis has now been shown to promote many inflammatory diseases includingarthritis and lung cancer. The research proposed in this project will identify the molecular and cellular basis forCS-mediated lung inflammation in mouse models. These studies will lead to new approaches to treat silicosis.


application_id: 9494529
project_number: 5R18HS024047-04
project_title: Dissemination of Computer-assisted Cognitive-behavior Therapy for Depression in Primary Care
administering_ic: AHRQ
award_notice_date: 2018-05-07
opportunity_number: PA-14-290
application_type: 5
activity_code: R18
ic: HS
serial_number: 024047
program_official: NOURJAH, PARIVASH
project_start_date: 2015-08-01
project_end_date: 2020-08-31
study_section: Healthcare Information Technology Research[HITR]
contact_pi_person_id: 9075017
contact_pi: WRIGHT, JESSE H.
other_pis: Not Applicable
congressional_district: 03
department: PSYCHIATRY
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): Dissemination of Computer-assisted cognitive-behavior therapy (CCBT) for depression in primary care will be evaluated in a trial with 320 patients randomly assigned to CCBT or treatment as usual (TAU). The study will disseminate a therapy method found to be effective in psychiatric settings into primary care - a setting where there have been significant problems in delivery of adequate evidence-based treatment for depression. The study will include a high percentage of disadvantaged patients - a population that has been largely ignored in previous research in CCBT. There have been no previous studies of CCBT for depression in primary care that have enrolled large numbers of disadvantaged patients. The form of CCBT used in this study is designed to increase access to effective therapy provide a cost-effective method and be a sustainable model for wide-spread use in primary care.  In order to deliver therapy in a practical manner that can be replicated in other primary care practices patients with significant symptoms of depression will receive treatment with an empirically supported computer program that builds cognitive-behavior therapy skills. Support for CCBT will be provided by telephone and/or e-mail contact with a care coordinator instead of the face-to-face treatment with a cognitive-behavior therapist that has been a part of CCBT delivery in mental health settings. Novel features of this treatment program include: 1) fully detailed and replicable method for integrating clinician support with CCBT in primary care; 2) delivery of CCBT to a population with high percentage of disadvantaged patients; 3) integration of CCBT into the primary care delivery model; 4) highly interactive multimedia computer program with adaptations for persons who may have lower levels of education or computer experience; 5) advanced cost-benefit analysis including data on actual health care utilization and costs; 6) exploration of moderators and predictors of treatment outcome.  Outcome will be assessed by measuring CCBT completion rate comprehension of CBT concepts and satisfaction with treatment; in addition to ratings of depressive symptoms negative thoughts and quality of life. The cost-effectiveness analysis and exploration of possible predictors of outcome should help clinicians health care organizations and others plan further dissemination of CCBT in primary care.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Computer-assisted cognitive-behavior therapy a treatment that has been shown to be effective in previous studies in psychiatric settings will be disseminated into primary care - a health care setting where there are significant problems in receiving adequate treatment for depression. Computer-assisted cognitive- behavior therapy will feature a low-cost method of delivering therapy designed to be replicated and sustained in other primary care settings. Feasibility and effectiveness will be tested by randomly assigning 320 primary care patients with depression to receive either computer-assisted cognitive-behavior therapy or treatment as usual.


application_id: 9494145
project_number: 1S10OD025130-01
project_title: High-Pressure Freezing / Freeze-Substitution System
administering_ic: OD
award_notice_date: 2018-06-15
opportunity_number: PAR-17-074
application_type: 1
activity_code: S10
ic: OD
serial_number: 025130
program_official: WANG, GUANGHU
project_start_date: 2018-06-15
project_end_date: 2019-06-14
study_section: Special Emphasis Panel[ZRG1 IMST-K (30)]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The proposed equipment would benefit at least nine R01 and one R21 NIH-funded projectscarried out in the University of Kentucky. These projects cover wide range of health-relatedbiomedical research including studies on Alzheimer disease viral infection noise-inducedhearing loss spinal cord injury hereditary forms of epilepsy thrombosis alcohol-inducedneurotoxicity chronic weakness and diabetes. Collectively these projects have generated morethan 230 publications only in the last 5 years. The current application is in response to asignificant need of NIH-funded Users to obtain excellent preservation of ultrastructural featuresin different cells/tissues without artifacts of fixation and dehydration. All these users exploreintracellular or plasma membrane events that could be significantly compromised by chemicalfixation and dehydration which are inherent to classical techniques of sample preparation fortransmission electron microscopy (TEM). Therefore the goal of this proposal is to acquire Leicahigh-pressure freezing (HPF) / freeze-substitution (FS) system. As of today there is no singleHPF system available either in Lexington campus or in general in the large neighboring region(~200 miles in radius) that includes Kentucky Ohio Vest Virginia and the parts of Tennesseeand Indiana. The proposed HPF/FS equipment will be installed and maintained in the ElectronMicroscopy Center (EMC) of the University of Kentucky a core facility that operates as arecharge center. The PI on this application Dr. Frolenkov has a decades-long experience withvarious electron microscopy techniques including HPF/FS techniques. The Director of EMC Dr.Balk has a decades-long experience in TEM and runs EMC since 2010. The everydayoperation of the equipment will be supported by a skilled TEM technician. The operational costof the equipment will be covered by moderate user fees. NIH-funded Major Users on thisproposal will require ~80% of the accessible user time of the proposed equipment. The financialplan includes a commitment from the Vice President of Research of the University of Kentuckyto cover 50% of the cost of the service contract. In addition the Vice Dean of Research of theCollege of Medicine provides commitments for covering installation and initial start-up costs aswell as five-year back-up of the financial plan if service fees fall short of the anticipated costs ofoperating the system. Thus the operation and maintenance of the proposed HPF/FS equipmentare well supported. The proposed HPF/FS system will provide entirely new opportunities for thelarge group of NIH-funded researchers in the University of Kentucky in one of the most hard-hitregion of US economy and help their numerous health-related projects.

project_terms:
Alcohol-Induced Neurotoxicity;Alzheimer's Disease;Back;Biomedical Research;Cell membrane;Cells;Chronic;Contract Services;Core Facility;Dehydration;Diabetes Mellitus;Electron Microscopy;Epilepsy;Equipment;Event;Fee-for-Service Plans;Fees;Freeze Substitution;Freezing;Funding;Goals;Health;Indiana;Inherited;Intracellular Membranes;Kentucky;Maintenance;Medicine;Morphologic artifacts;Noise-Induced Hearing Loss;Ohio;Operating System;Preparation;Publications;Radial;Research;Research Personnel;Running;Sampling;Spinal cord injury;System;Techniques;Tennessee;Thrombosis;Time;Tissues;Transmission Electron Microscopy;United States National Institutes of Health;Universities;Virginia;Virus Diseases;chemical dehydration;chemical fixation;college;cost;experience;falls;operation;preservation;pressure;response;sample fixation

public_health_relevance:
Project NarrativeThe requested high-pressure freezing / freeze-substitution system will allow scientists in theUniversity of Kentucky to prepare samples for electron microscopy observations without artifactsof chemical fixation and dehydration. This is very important for the range of NIH-funded health-related project carried out in the University of Kentucky including studies on Alzheimer diseaseviral infection noise-induced hearing loss spinal cord injury hereditary forms of epilepsythrombosis alcohol-induced neurotoxicity chronic weakness and diabetes.


application_id: 9493177
project_number: 1S10OD025033-01
project_title: Acquisition of a BioSorter PRO and a Vast BioImager for small animal model organisms
administering_ic: OD
award_notice_date: 2018-04-20
opportunity_number: PAR-17-075
application_type: 1
activity_code: S10
ic: OD
serial_number: 025033
program_official: WANG, GUANGHU
project_start_date: 2018-04-20
project_end_date: 2019-04-19
study_section: Special Emphasis Panel[ZRG1 IMST-K (30)]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
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:
AbstractThis proposal requests funding for the purchase of a BIOSORTER PRO and VAST BioImagerwhich will be housed in the new core facility operated by the College of Arts and Sciences at theUniversity of Kentucky. These complementary instruments are needed for automated handlingand high-throughput sorting imaging and analysis of small model organisms such as zebrafishlarvae or fly. The acquisition of VAST BioImager and BIOSORTER PRO would significantlyenhance research capabilities at the University of Kentucky and establish best practices forreliable and reproducible biomedical science utilizing small model organisms. Theseinstruments would be the first of their kind in the state of Kentucky and would be an importantaddition to the region. The BIOSORTER large particle cytometer will replace manual sorting ofsmall model organisms (i.e. fly and zebrafish) and experimental models such as tissuespheroids/organoids pancreatic islets and other large cell clusters with a fast sensitivereproducible automation for gentle sorting and high throughput screens. The VAST BioImagerwill eliminate manual manipulation of zebrafish larvae by automatically precisely andreproducibly orienting larvae for high throughput high-resolution fluorescent and bright-fieldimaging while maintaining viability of the organism for further testing. This equipment cluster willserve a growing group of NIH-funded investigators in the Colleges of Art and SciencesMedicine and Agriculture at the University of Kentucky (UK) who successfully utilize small modelorganisms to study molecular mechanisms underlying disease organ and tissue formation andrepair. The potential major users conduct NIH sponsored research in areas including studies oforgan system development tissue regeneration circadian rhythms the role of scaffoldingproteins in hematopoiesis the regulation of signaling pathways during developmenttumorigenesis and neurodegeneration. Minor users with relevant interests and qualifyingsupport are also included. The facility core at UK employs a manager with broad experience inimaging and support of the core facility that will be responsible for a routine oversight upkeepand operation of the requested instruments. Dr Galperin the PI of this application hasextensive record of accomplishment in the development and application of imaging methods inbiomedical research. The acquisition of this cluster of instruments will significantly enhanceresearch efforts aiming to study organ system development tissue regeneration circadianrhythms the role of scaffolding proteins in hematopoiesis the regulation of signaling pathwaysduring development and carcinogenesis.

project_terms:
Agriculture;Animal Model;Area;Arts;Automation;Biomedical Research;Cells;Circadian Rhythms;Core Facility;Development;Disease;Equipment;Experimental Models;Funding;Hematopoiesis;Image;Image Analysis;Islets of Langerhans;Kentucky;Larva;Manuals;Medicine;Minor;Molecular;Nerve Degeneration;Organ;Organism;Organoids;Qualifying;Regulation;Reproducibility;Request for Proposals;Research;Research Personnel;Resolution;Role;Scaffolding Protein;Science;Signal Pathway;Sorting - Cell Movement;Systems Development;Testing;Tissues;United States National Institutes of Health;Universities;Zebrafish;body system;carcinogenesis;college;experience;fly;high throughput screening;imaging modality;instrument;interest;operation;particle;repaired;tissue regeneration;tumorigenesis

public_health_relevance:
Relevance to public healthStudies in small model organisms provide great insight into the cellular and molecularmechanisms of development processes that go amiss in disease. In this proposal funding isrequested to enable the purchase of a cluster of equipment that will permit automated handlingand consistent imaging of fragile small model organisms. These instruments will significantlyimprove research aimed at understanding organ system development and regeneration cell-cellsignaling circadian rhythms neurobiology and cancerogenesis among many other areas.


application_id: 9492587
project_number: 5R01HL130174-03
project_title: Metabolic optimization of cell therapy
administering_ic: NHLBI
award_notice_date: 2018-05-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 130174
program_official: SCHWARTZ, LISA
project_start_date: 2016-06-01
project_end_date: 2021-05-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTType 2 diabetes is an independent risk factor for the development of heart failure. It contributes to adversecardiac remodeling and it increases heart failure mortality. While cell therapy offers promise for treating heartfailure in nondiabetic patients the efficacy of cell therapy in diabetic hearts remains uncertain. Our preliminarystudies show that diabetes impairs cardiac progenitor cell (CPC) growth survival and differentiation and thatCPCs isolated from diabetic hearts fail to promote myocardial recovery after myocardial infarction (MI). We findthat CPCs express Glut1 and that their rate of glucose utilization increases in the presence of high extracellularglucose independently of insulin. Moreover CPCs isolated from diabetic mice exhibit a marked and sustainedincrease in aerobic glycolysis accompanied by an elevated level of 6-phophofructo-2-kinase/fructose-26-bisphosphatase 3a phosphofructokinase 2 isoform known to sustain high rates of glycolysis. Our studiesalso show that increased glycolytic activity in diabetic CPCs is associated with lower glucose-derived carbonflux through the pentose phosphate and hexosamine biosynthetic pathways but higher flux through theglycerolipid biosynthetic pathway. These results indicate that high rates of glycolysis in CPCs alter the activityof ancillary pathways of glucose metabolism which are important for biosynthetic reactions maintaining redoxbalance and for resistance to stress. That such changes in glucose metabolism affect CPC function isindicated by our observation that increasing glycolysis at the PFK step is sufficient to decrease CPCproliferation in vitro. Informed by these observations we suspect that diabetic dysfunction in CPCs is at leastin part caused by a dysregulation of glucose metabolism and that correcting this metabolic defect will be aviable approach to optimize cell therapy for the diabetic heart. We propose to test the hypothesis that diabetesleads to an increase in the glycolytic activity in CPCs which diminishes flux through key ancillary pathways ofglucose metabolism. This metabolic dysregulation decreases CPC proliferation survival and secretory activityand impairs the capacity of CPCs to promote myocardial repair. To test this hypothesis we will: (1) examinehow diabetes affects CPC competence and therapy; (2) elucidate the role of glucose metabolism in mediatingCPC dysfunction in diabetes; and (3) determine whether rescuing defects in glucose metabolism improves celltherapy in the diabetic heart. Successful completion of the project will provide new understanding of themetabolic pathways that regulate stem/progenitor cell function and how they affect the outcomes of celltherapy for heart failure. These findings would facilitate the optimization of cell therapy protocols and informongoing and future cell therapy trials for the treatment of heart failure in both nondiabetic and diabetic patients.

project_terms:
6-Phosphofructo-2-kinase;Affect;Attenuated;Biochemical;Carbon;Cardiac;Cause of Death;Cell Proliferation;Cell Survival;Cell Therapy;Cell Transplants;Cell physiology;Cells;Cicatrix;Clinical Treatment;Competence;Defect;Development;Diabetes Mellitus;Diabetic mouse;Enzymes;Equilibrium;Exhibits;Fatty acid glycerol esters;Fibrosis;Fructose-26-bisphosphatase;Functional disorder;Future;Glucose;Glycolysis;Heart;Heart failure;Hexosamines;Impairment;In Vitro;Inflammation;Injury;Insulin;Intervention;Measurement;Mediating;Metabolic;Metabolic Pathway;Modeling;Mus;Myocardial;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Oxidation-Reduction;Pathway interactions;Patients;Pentosephosphate Pathway;Pentosephosphates;Pharmacology;Phosphoric Monoester Hydrolases;Phosphotransferases;Property;Protein Isoforms;Protocols documentation;Radiolabeled;Reaction;Recovery;Resistance;Risk Factors;Role;Stem cells;Stress;Testing;Tissues;Tracer;Transplantation;aerobic glycolysis;cardiogenesis;cell growth;cellular transduction;db/db mouse;diabetic;diabetic patient;extracellular;glucose metabolism;heart function;impaired capacity;improved;inhibitor/antagonist;metabolomics;mortality;non-diabetic;novel therapeutic intervention;repaired;stable isotope;stem

public_health_relevance:
PROJECT NARRATIVEHeart failure is a leading cause of death and is prominent in patients with diabetes. In this project we willexamine the mechanisms by which diabetes impairs cell therapy and how cell therapy can be improved toameliorate heart failure. These studies could lay the groundwork for the development of novel therapeuticinterventions to improve cardiac function in both nondiabetic and diabetic patients with heart failure.


application_id: 9492363
project_number: 5F32DE027277-02
project_title: Retinoic Acid Signaling in Salivary Gland Organogenesis
administering_ic: NIDCR
award_notice_date: 2018-05-03
opportunity_number: PA-16-307
application_type: 5
activity_code: F32
ic: DE
serial_number: 027277
program_official: FRIEDEN, LESLIE A
project_start_date: 2017-07-01
project_end_date: 2020-06-30
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11005944
contact_pi: METZLER, MELISSA 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:
AbstractUnderstanding how an embryo builds an organ during development is essential to inform studies intoregenerating tissue in vitro. There is currently a clinical need to regenerate salivary glands for patients whohave suffered permanent gland damage due to radiation therapy or autoimmune disease. The resulting chronicxerostomia (dry mouth) leads to a sharp decline in oral health and quality of life. The ability to constructfunctioning gland for these patients would restore saliva to the oral cavity which includes many beneficialcomponents involved in functions such as antimicrobial protection pH balance digestion lubrication andremineralization. Many current studies in salivary gland development have elucidated the signaling molecules necessaryfor several important processes such as branching morphogenesis lumen formation cell differentiation andprogenitor cell maintenance. Studies in the field have also shown that early salivary gland development isdependent on both the epithelium and enervation from the closely associated parasympathetic ganglion (PSG).However very little is known about the earliest stages of gland development and no studies have been doneon the signaling molecules needed to control salivary gland initiation or PSG formation. The gap in knowledgeis likely due to the lack of experimental models for the earliest phases of gland organogenesis. In preparation for this proposal I have established a novel ex vivo culture system utilizing mouseembryo tissues to assay salivary gland initiation. This is an important development for the field in that it allowsresearchers to answer questions they could not before. With this system I have generated preliminary datashowing that RA signaling is required for submandibular gland (SMG) initiation and development of theparasympathetic ganglion (PSG). Blocking RA signaling represses gland bud initiation and converselysupplementation with retinol (vitamin A) enhances initiation. Moreover I have identified that the size of theinitial PSG is reduced with a fewer number of cells when RA signaling is blocked. In this proposal I willinvestigate the role of vitamin A metabolism by the retinol oxidizing enzyme RDH10 in initiation of the SMGepithelium and the role of RA signaling on PSG formation.

project_terms:
All-Trans-Retinol;Alleles;Autoimmune Diseases;Biological Assay;Biomedical Research;Cell Count;Cell Differentiation process;Cell Maintenance;Chemicals;Chronic;Clinical;Communication;Data;Development;Digestion;Embryo;Embryonic Development;Enzymes;Epithelial;Epithelium;Equilibrium;Experimental Models;Future;Gene Expression;Genes;Gland;Growth;In Vitro;Investigation;Kidney;Knock-out;Knowledge;LacZ Genes;Ligands;Lubrication;Lung;Mandible;Mediating;Metabolism;Monitor;Morphogenesis;Mus;Natural regeneration;Nerve;Neural Crest;Neurons;Nuclear Family;Nuclear Receptors;Oral cavity;Oral health;Organ;Organogenesis;Oxides;Pancreas;Patients;Phase;Physical condensation;Preparation;Process;Production;Quality of life;Radiation therapy;Reaction;Reporter;Research;Research Personnel;Retinoic Acid Receptor;Retinol Metabolism Pathway;Role;Saliva;Salivary;Salivary Glands;Schwann Cells;Signal Transduction;Signaling Molecule;Stem cells;Structure of parasympathetic ganglion;Submandibular gland;Supplementation;Surface;System;Testing;Tissues;Training;Transgenic Organisms;Tretinoin;Vitamin A;Xerostomia;antimicrobial;career;chorda tympani;embryo tissue;experience;gland development;hindbrain;in vitro Assay;inhibitor/antagonist;innovation;migration;neuron development;neuronal survival;novel;oxidation;remineralization;salivary assay

public_health_relevance:
Project NarrativeUnderstanding how an embryo builds an organ during development is essential to inform studies intoregenerating tissue in vitro. I have developed a novel assay for submandibular salivary gland initiation andearly formation of the associated parasympathetic ganglion two previously unstudied stages in salivary glanddevelopment. Using this assay I will investigate the essential role of vitamin A metabolism and retinoic acidsignaling in these processes.


application_id: 9492298
project_number: 1P30GM127211-01
project_title: Pilot Projects Program
administering_ic: NIGMS
award_notice_date: 2018-07-27
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127211
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
subproject_number: 5343
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
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: 2018-08-01
budget_end_date: 2019-07-31
project_terms:
Advisory Committees;Appalachian Region;Applications Grants;Area;Biomedical Research;Cardiovascular Diseases;Categories;Centers of Research Excellence;Clinical Sciences;Clinical and Translational Science Awards;Consultations;Core Facility;Data;Development;Diabetes Mellitus;Disease;Extramural Activities;Floor;Funding;Funding Opportunities;Generations;Goals;Grant;Head;Health;Institution;Kentucky;Link;Malignant Neoplasms;Mentors;Modernization;Names;Nerve Degeneration;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Peer Review;Phase;Pilot Projects;Process;Program Research Project Grants;Publications;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Risk Factors;Secure;Services;Standardization;Substance abuse problem;Talents;Translational Research;United States National Institutes of Health;Universities;base;biomedical facility;cancer type;design;driving force;experience;health disparity;human disease;member;multidisciplinary;operation;programs;recruit;success;translational study


application_id: 9492297
project_number: 1P30GM127211-01
project_title: Core D - Energy Balance and Body Composition Core
administering_ic: NIGMS
award_notice_date: 2018-07-27
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127211
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
subproject_number: 5342
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: 2018-08-01
budget_end_date: 2019-07-31
project_terms:
Acclimatization;Adipose tissue;Animals;Area;Blood Pressure;Body Composition;Body Water;Body Weight;Cardiovascular Diseases;Cells;Chronic;Collaborations;Communities;Conscious;Consultations;Coupled;Data;Diabetes Mellitus;Diet;Eating;Energy Metabolism;Epidemic;Equipment;Exercise;Experimental Models;Fatty acid glycerol esters;Fees;Food Energy;Fostering;Funding;Genetic;Genome;Growth;Health care facility;Human Resources;Indirect Calorimetry;Individual;Institution;Intervention;Kentucky;Laboratories;Longitudinal Studies;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Metabolism;Methods;Modernization;Mus;Neurodegenerative Disorders;Obese Mice;Obesity;Obesity associated disease;Phase;Physical activity;Pilot Projects;Principal Investigator;Proteins;Recommendation;Regulation;Research;Research Design;Research Personnel;Resources;Running;Services;Standardization;Structure;Study models;System;Therapeutic;Thinness;Time;Tissues;Training;United States National Institutes of Health;Water consumption;Weight;animal care;base;cardiovascular risk factor;energy balance;experience;feeding;health disparity;improved;insight;mid-career faculty;obesity development;operation;outreach program;programs;time use


application_id: 9492295
project_number: 1P30GM127211-01
project_title: Core B - Analytical Core
administering_ic: NIGMS
award_notice_date: 2018-07-27
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127211
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
subproject_number: 5340
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: 2018-08-01
budget_end_date: 2019-07-31
project_terms:
Adipose tissue;Analytical Chemistry;Animals;Area;Award;Biological Assay;Biological Markers;Blood;Cardiovascular Diseases;Centers of Research Excellence;Clinical;Collaborations;Complex Mixtures;Core Facility;Coupled;Data;Development;Diet;Diet and Nutrition;Dietary Carbohydrates;Dietary Fats;Disease;Ecology;Ensure;Fees;Funding;Glucose;Goals;Grant;High Pressure Liquid Chromatography;Human;Incidence;Individual;Institution;Journals;Kentucky;Laboratories;Link;Lipids;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Measures;Medicine;Methods;National Institute of Environmental Health Sciences;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Obesity associated disease;Peer Review;Phase;Phospholipids;Pre-Clinical Model;Publications;Reporting;Research;Research Personnel;Research Support;Resolution;Resources;Risk Factors;Rural;Services;Structure;Testing;Time;Tissues;Tracer;Training and Education;Triglycerides;United States National Institutes of Health;Urine;analytical method;base;biomarker development;cardiovascular risk factor;cohort;college;disorder risk;energy balance;fatty acid metabolism;human disease;human subject;instrumentation;interest;lipid metabolism;metabolic abnormality assessment;metabolic phenotype;obesity development;operation;programs;small molecule;stable isotope;western diet


application_id: 9492293
project_number: 1P30GM127211-01
project_title: Center of Research on Obesity and Cardiovascular Disease
administering_ic: NIGMS
award_notice_date: 2018-07-27
opportunity_number: PAR-17-249
application_type: 1
activity_code: P30
ic: GM
serial_number: 127211
program_official: FRINCU, CRINA
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZGM1 RCB-3 (C3)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adipose tissue;Advisory Committees;Aging;Alzheimer's Disease;Area;Award;Basic Science;Body Composition;Cardiovascular Diseases;Cardiovascular system;Center for Translational Science Activities;Centers of Research Excellence;Chronic Disease;Clinical Research;Clinical Sciences;Comorbidity;Core Facility;Death Rate;Development;Diabetes Mellitus;Diet;Disease;Equipment;Etiology;Evaluation;Extramural Activities;Fostering;Funding;Gills;Goals;Growth;High Prevalence;Hypertension;Institutes;Institution;Kentucky;Limb structure;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mentors;Morphology;Mus;Neurodegenerative Disorders;Neurosciences;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathology;Phase;Physicians;Pilot Projects;Prevalence;Publications;Publishing;Request for Applications;Research;Research Infrastructure;Research Personnel;Research Support;Risk;Risk Factors;Scientist;Services;Strategic Planning;System;Technology;Tissues;Translating;Translational Research;United States National Institutes of Health;Universities;cancer research center director;cardiovascular risk factor;clinical care;energy balance;experience;health disparity;human disease;improved;obesity development;programs;research facility;small molecule;success;targeted treatment;therapy development;voucher


application_id: 9492039
project_number: 1R01HL141081-01
administering_ic: NHLBI
award_notice_date: 2018-03-14
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: HL
serial_number: 141081
program_official: WONG, RENEE P
project_start_date: 2018-04-01
project_end_date: 2023-02-28
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 12204790
contact_pi: MOORE IV, JOSEPH B
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
project_terms:
Affect;Azacitidine;Biological;Bone Marrow;Cardiac;Cardiovascular system;Cell Lineage;Cell Survival;Cell Therapy;Cell Transplantation;Cells;Characteristics;Chronic;Clinical Trials;Competence;Congestive Heart Failure;Dependence;Development;Exhibits;Future;GATA4 gene;Genetic;Goals;Heart;Heart failure;Human;In Vitro;Infarction;Injections;Injury;Left Ventricular Function;Light;Link;Mediating;Mediator of activation protein;Mesenchymal;Methods;Modality;Modeling;Modification;Muscle Cells;Myocardial Infarction;Nude Rats;Paracrine Communication;Pathway interactions;Patients;Pharmacology;Phase;Population;Production;Rattus;Research;Role;Signal Transduction;Stem cells;Testing;Therapeutic;Tissues;Treatment Efficacy;Variant;Ventricular;Ventricular Remodeling;Work;arteriole;cardiac regeneration;cardiac repair;cell type;cytokine;extracellular vesicles;heart function;improved;neovascularization;novel;pre-clinical;release factor;repaired;retention rate;transcription factor


application_id: 9491689
project_number: 5U19AI113182-05
project_title: Project 3: PREVENT: A first-in-human clinical trial of Griffithsin an HIV entry
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6667
contact_pi_person_id: 1921448
contact_pi: BRAND, RHONDA METTER
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
The overarching goal of the PREVENT Program is to develop a Griffithsin (GRFT) rectal gel that could be used prior to receptive anal intercourse (RAI) to reduce the risk of HIV infection by men who have sex with men (MSM). Project 3 will conduct a randomized placebo-controlled pre-Phase 1 human study to measure GRFT safety pharmacokinetics (PK) and pharmacodynamics (PD). We will recruit 18 healthy men to participate in a prospective trial to evaluate GRFT carbopol gel versus a matched placebo in a 2:1 randomization design. The study will address traditional product safety and PK parameters but we will also evaluate the effect of the product on adaptive immunity to GRFT by conducting a three stage study. The first stage will involve a single drug exposure. In Stages 2 and 3 men will receive 5 doses of gel product on consecutive days separated by a two week washout period. Rectal biopsies and other samples taken at baseline and during Stages 1-3 will be used to characterize mucosal responses to GRFT including enumeration of HIV target cells and detection of representative HIV receptors and epithelial junction proteins in the rectumby immunohistochemistry and flow cytometry. The biopsies will also be used for a PD assessment by ex vivo challenge of the tissue with HIV-1. Additionally we will employ a systems biology approach including transcriptomics proteomics and microbiome analysis to analyze the global impact of GRFT treatment on the mucosal environment in the rectum.

project_terms:
AIDS prevention;Address;Affinity;Animals;Antigens;Antiviral Agents;Anus;Awareness;Binding;Biopsy;Carbopol;Cell surface;Cells;Clinical Trials;Community Health;Data;Data Set;Detection;Dimensions;Dose;Drug Exposure;Drug Kinetics;Environment;Epithelial;Epithelial Cells;Exposure to;Flow Cytometry;Formulation;Gel;Gene Expression;Goals;HIV;HIV Entry Inhibitors;HIV Infections;HIV Receptors;HIV-1;HIV-2;Health;Hepatitis C virus;Human Development;Immune;Immune response;Immunohistochemistry;In Vitro;Incidence;Inflammatory;Laboratories;Laboratory Animals;Lectin;Link;Lymphocyte;Measures;Metagenomics;Mucous Membrane;Mus;Natural Immunity;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase;Phase I Clinical Trials;Placebos;Plants;Polysaccharides;Prevention;Proteins;Proteomics;Randomized;Rectum;Risk;Safety;Sampling;Simplexvirus;Structure;Surface;Systems Biology;T-Lymphocyte;Techniques;Tissues;Toxic effect;Vagina;Viral;adaptive immune response;adaptive immunity;base;crosslink;cytokine;design;first-in-human;healthy volunteer;human study;immunotoxicity;inhibitor/antagonist;men;men who have sex with men;microbial community;microbicide;microbiome;microbiome analysis;novel;preclinical safety;prevent;programs;prospective;rRNA Genes;recruit;rectal;rectal microbicide;rectal microbiota;response;transcriptomics;transmission process;trial design;volunteer

public_health_relevance:
There is now evidence that rectal microbicides based on entry inhibitors can successfully block HIV transmission in high incidence settings and provide an invaluable addition to HIV prevention packages. This project describes the initial human development of a new anti-HIV rectal microbicide griffithsin (GRFT). If GRFT were shown to be effective it would have significant advantages over current microbicides.


application_id: 9491688
project_number: 5U19AI113182-05
project_title: Project 2: PREVENT Preclinical safety and efficacy studies
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6666
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
The antiviral lectin Griffithsin (GRFT) has broad spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2 herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV) (1-4). Griffithsin-based topical microbicide formulations offer the potential for use as a multipurpose non- antiretroviral based method to prevent HIV-1 and epidemiologically linked infections. The Project 2 objective is to show that GRFT containing rectal microbicide products are safe and effective in the Rhesus macaque model of rectal HIV transmission. These studies are designed to be complementary to the human clinical studies proposed in Project 3. We have three specific aims: Aim 1 is to evaluate the safety pharmacokinetics and pharmacodynamics (PK/PD) of GRFT carbopol gel. We will conduct a three stage placebo controlled PK/PD study in adult male Rhesus macaques with the GRFT rectal gel formulation and matched placebo gel supplied by Core B. The proposed macaque study is designed to address specific translational questions concerning immunotoxicity and health of the mucosal environment after GRFT exposure. Favorable stage 1 outcomes include detection of active HIV-1 inhibitory concentrations of GRFT in rectal fluids and acceptable clinical safety metrics which allows progression to the efficacy Stage 2. Using a cohort of GRFT treatment experienced animals will allow us to determine whether pre-existing immunity to GRFT affects product efficacy. Stage 3 will test the GRFT and placebo products in SHIV infected animals where we will compare amounts of virus shed in experimental versus control animals providing an additional safety metric. Aim 2 is to assess the impact of GRFT treatment on the mucosal immune environment. We will use multiplexed immunoassays and gene expression arrays to measure markers of inflammatory immune responses. The highly sensitive immunohistochemistry (IHC) techniques refined in Prof. Kristina Broliden's laboratory will be applied to compare the number distribution and activation state of HIV target cells and expression of HIV receptor targets CD4 CCR5 DC-SIGN and Langerin plus markers of epithelial integrity in rectal biopsies from animals treated with GRFT active drug or matched placebo. Flow cytometry analyses will also enumerate and phenotype lymphocytes in biopsy tissues. Aim 3 is to assess the impact of GRFT treatment on the mucosal environment in the rectum using a systems biology approach that utilizes modern mass spectrometry proteomics assays to compare tissues and rectal secretions from animals that receive active drug versus placebo and to evaluate the effect of GRFT treatment on the rectal microbiota of treated animals.

project_terms:
Address;Adult;Affect;Affinity;Anal Sex;Animals;Antiviral Agents;Anus;Attention;Awareness;Binding;Biological Assay;Biopsy;CCR5 gene;CD209 gene;Carbopol;Cell surface;Cells;Clinical;Clinical Research;Clinical Trials;Colorectal;Communities;Community Health;Control Animal;Data;Data Set;Detection;Development;Dose;Drug Kinetics;Effectiveness;Environment;Enzyme-Linked Immunosorbent Assay;Epidemiology;Epithelial;Epithelial Cells;Exposure to;Female;Flow Cytometry;Formulation;Gel;Gene Chips;Gene Expression;Goals;HIV;HIV Receptors;HIV-1;Health;Hepatitis C virus;Heterosexuals;Human;Human Herpesvirus 2;Human Volunteers;Immune;Immune response;Immunity;Immunoassay;Immunohistochemistry;Incidence;Infection;Laboratories;Lectin;Link;Liquid substance;Local Microbicides;Lymphocyte;Macaca;Macaca mulatta;Mass Spectrum Analysis;Measures;Metagenomics;Methods;Modeling;Modernization;Mucous Membrane;Mus;Outcome;Pharmaceutical Preparations;Pharmacodynamics;Phenotype;Placebos;Polysaccharides;Population;Prevention;Proteins;Proteomics;Rectum;Reporting;Safety;Stigmatization;Structure;Surface;Systems Biology;Techniques;Testing;Tissues;Trauma;Vagina;Viral;Virus Diseases;Virus Shedding;Woman;base;cohort;crosslink;design;efficacy study;experience;immunotoxicity;in vivo;inflammatory marker;langerin;male;men who have sex with men;microbial community;microbicide;microbiome analysis;novel;placebo controlled study;preclinical safety;prevent;product development;protective efficacy;rRNA Genes;rectal;rectal microbicide;rectal microbiota;research clinical testing;response;safety study;safety testing;sexual HIV transmission;simian human immunodeficiency virus;transcriptomics;transmission process;trial design

public_health_relevance:
The global incidence of HIV-1 infection is declining but not in populations that practice unprotected anal intercourse (URAI) highlighting urgent need for attention to the preventative health needs in communities where men who have sex with men are especially stigmatized. Our rectal gel formulations have potential to prevent HIV-1 transmission via URAI but must first be tested for safety and effectiveness in animals. Our studies aim to provide a comprehensive set of data in support of further product development and clinical testing of the griffithsin gel product in the PREVENT clinical trial.


application_id: 9491687
project_number: 5U19AI113182-05
project_title: Project 1: PREVENT Program Critical Path Project
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6665
contact_pi_person_id: 8752851
contact_pi: TUSE, DANIEL
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP- compliant Drug Substance and Drug Product manufacture and release manage preclinical safety and efficacy studies and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA) in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT) a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV such as HSV-2. Through our collaborators in the PREVENT Program we have produced more than 200 g of GRFT for research use and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2 the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species with endpoints to include topical and systemic safety tolerability irritation sensitivity and immunotoxicity. Preliminary Chemistry Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application activation of which by FDA will allow us to initiate a first-in-humans clinical trial of the GRFT microbicide in Project 3.

project_terms:
AIDS prevention;Animals;Biological Assay;Carbopol;Characteristics;Chemistry;Clinic;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Development;Documentation;Dosage Forms;Ensure;Feedback;Formulation;Gel;Goals;Guidelines;HIV;HIV vaccine;HIV-1;Human;Human Herpesvirus 2;Investigational Drugs;Investigational New Drug Application;Licensure;Marines;Methodology;Methods;Mus;Nicotiana;Oryctolagus cuniculus;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology Study;Phase;Plants;Prevention;Production;Proteins;Published Comment;Rattus;Recombinants;Recovery;Regulation;Research;Risk;Rodent;Route;Safety;Skin;Suggestion;System;Toxicology;Training;United States Food and Drug Administration;Vagina;Viral;Virus;base;cGMP production;clinical efficacy;efficacy study;first-in-human;genotoxicity;immunotoxicity;in vivo;inhibitor/antagonist;irritation;manufacturing process;meetings;microbial;microbicide;novel;pre-clinical;preclinical safety;preclinical study;programs;prototype;rectal;rectal microbicide;safety study;transmission process

public_health_relevance:
Without a preventative HIV vaccine microbicides may offer a powerful option for the prevention of HIV transmission through the rectal and vaginal routes. This Project manages the key development tasks to bring to the clinic a novel microbicide candidate protein griffithsin which could be economically manufactured at a market-relevant scale using our plant-based production system.


application_id: 9491685
project_number: 5U19AI113182-05
project_title: Core D: PREVENT Program Regulatory Affairs Core
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6664
contact_pi_person_id: 9074577
contact_pi: FUQUA, JOSHUA L
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
The purpose of Core D is to provide an infrastructure of regulatory and technical expertise to maintain and manage consistent compliance with the regulatory requirements for all projects in the PREVENT Program. The Core includes two separate but complementary components: (i) oversight of the preclinical work required to support a successful IND including interactions with the FDA and (ii) management and oversight of regulatory compliance training and implementation of a pre-Phase 1 clinical trial. The Core will manage track develop and provide coordinated responses to all regulatory submissions and Agency interactions. This will include the transition from pre-GMP to cGMP drug substance and drug product manufacture pilot and GLP preclinical toxicology strategic interactions with external regulatory agencies and IND development and submissions with a focus on regulatory training and education and the goal of standardizing the Program's regulatory practices. The Core will also provide an overall Quality Management Plan and implement and monitor quality control and quality assurance activities as needed throughout all program projects and cores. The Core will coordinate and direct all required self-monitoring activities and will serve as a central document control repository.

project_terms:
Accelerometer;Blinded;Clinical;Clinical Data;Clinical Trials;Code;Cyclic GMP;Data;Development;Drug Kinetics;Ensure;Gel;Goals;Human;Monitor;Peer Review;Pharmaceutical Preparations;Pharmacodynamics;Phase I Clinical Trials;Practice Management;Prevention;Process;Publications;Quality Control;Randomized;Regulation;Regulatory Affairs;Reporting;Research;Research Infrastructure;Sampling;Site;Standardization;Systems Biology;Technical Expertise;Time;Toxicology;Training;Training and Education;Viral;Work;base;innovation;microbicide;pre-clinical;programs;quality assurance;rectal;rectal microbicide;repository;response;symposium;volunteer

public_health_relevance:
PREVENT Program Regulatory Affairs Core (Core D) will ensure that the overall PREVENT program complies with regulatory requirements. The core will oversee activities relating to product manufacture regulations as well as clinical trial regulations.


application_id: 9491684
project_number: 5U19AI113182-05
project_title: Core C: PREVENT Program Pharmacokinetics and Pharmacodynamics Services Core
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6663
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
The objective of the Pharmacokinetics and Pharmacodynamics (PK/PD) Services Core will be to provide centralized support for the PK and key PD analyses common to preclinical macaque studies in Project 2 and human clinical studies in Project 3 thereby ensuring Program's research integrity and comparability between the preclinical and clinical studies proposed. To this end we will provide the following functions. (1) We will validate the quality of a griffithsin (GRFT) reference standard. A series of biochemical biophysical and virological assays will be used to validate the quality of GRFT. (2) We will develop an immunoassay to validate the potency of GLP/GMP-manufactured GRFT. Upon validation of the assay at OCRP its standard operating procedure will be transferred to Project 1 and Core B. (3) We will detect and quantify GRFT active pharmaceutical ingredient (API) and GRFT-binding antibodies in biological fluids to support PK/PD analysis in Projects 2 and 3. In addition to conventional methods based on enzyme-linked immunosorbent assays we will develop surface plasmon resonance-based analytical methods to detect low-affinity rapidly dissociating antibodies. As part of PK assessment we will use HIV-1 neutralization and cell-cell fusion assays to measure the anti-HIV-1 capacity of rectal fluid samples. (4) We will analyze the impact of GRFT gel treatment on the mucosal environment to support in vivo safety assessment. To this end we will employ a systems biology approach to comprehensively reveal the changes in the mucosal environment that may occur upon rectal administration of GRFT and GRFT combination gels. The induction of innate and adaptive immune responses in the mucosal and systemic immune compartments will be assessed using proteomic techniques. We will also use highly sensitive immunohistochemistry techniques to compare the number and location of HIV target cells and epithelial junction proteins in rectal tissue. Additionally the structure of rectal microbiota throughout the course of GRFT and combination gel treatment will be monitored by barcoded 16S rRNA genes sequencing to reveal the effect of microbicides formulation on the taxonomic structure of the rectal microbiota.

project_terms:
16S ribosomal RNA sequencing;Adverse effects;Affinity;Anti-HIV Agents;Antibodies;Binding;Biochemical;Biological;Biological Assay;Biological Markers;Biophysics;Blood specimen;Body Fluids;Cell Line;Cell fusion;Cells;Clinical Research;Complement;Complex;Cyclic GMP;Detection;Development;Drug Kinetics;Ensure;Environment;Enzyme-Linked Immunosorbent Assay;Epithelial;Evaluation;Fluorescence;Formulation;Gel;Gene Expression Profiling;Giant Cells;Glycoproteins;HIV;HIV Envelope Protein gp120;HIV-1;Hela Cells;High Pressure Liquid Chromatography;Histopathology;Human;Human Herpesvirus 2;IgE;Immune;Immunoassay;Immunoblotting;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;Immunohistochemistry;Lead;Liquid substance;Location;Macaca;Macaca mulatta;Measures;Methods;Molecular Sieve Chromatography;Monitor;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Prevention;Procedures;Proteins;Proteomics;Reagent;Rectal Administration;Reference Standards;Reporter Genes;Research;Safety;Sampling;Series;Services;Standardization;Structure;Surface Plasmon Resonance;Systems Biology;Taxonomy;Techniques;Technology Transfer;Testing;Tissues;Toxicology;Validation;Viral;adaptive immune response;analytical method;base;immunogenicity;in vivo;microbicide;pre-clinical;pre-clinical research;preclinical study;programs;rectal;rectal microbicide;rectal microbiota;virology

public_health_relevance:
Pharmacokinetics and Pharmacodynamics Services Core will facilitate preclinical and clinical research by developing and providing key assays and reagents to other components of the U19 PREVENT Program Project investigating the potent anti-HIV protein griffithsin as a candidate rectal microbicide.


application_id: 9491683
project_number: 5U19AI113182-05
project_title: Core B: PREVENT Product Development Core
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6662
contact_pi_person_id: 6194125
contact_pi: ROHAN, LISA CENCIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
Given the significant anatomical and physiological differences in the rectal and vaginal compartments it is essential to design rectal specific microbicide products to effectively inhibit rectal transmission of HIV. The overall goal of the Product Development Core (Core B) is in the provision of formulated Griffithsin (GRFT) gel products and quality physiochemical safety and efficacy assessments for these products. Specifically Core C will provide preformulation data formulation development efforts and formulation assessment evaluations in support of Projects 1 2 and 3 as well as Cores C and D. Formulation strategies within the scope of Core activities will be initiated utilizing knowledge obtained from previously developed rectal and vaginal GRFT gel products. Product attributes will be modified to obtain defined target specifications suitable for rectal application. The rectal specific GRFT product will be tested for safety and efficacy using an excised mucosal tissue explant model. A final formulation will be chosen based on successful achievement of defined target product profiles. Once the newly developed rectal GRFT formulation is obtained it will be scaled up and manufactured to support GLP animal safety testing studies and other preclinical assessments planned within Projects 1 and 2. Manufacture of GMP quality material will be achieved through a contract research organization within Project 1. Core B will be responsible for methods transfer provide assistance with development of batch records generated assist in protocol development for product assessment methods established for GMP product release and review stability results obtained. Additionally Core B will design a rectal specific GRFT combination product with enhanced potency as a second generation product. Efforts toward this end will be initiated through application of a screening algorithm to identify the most effective combination. Lead secondary antiretroviral candidates include tenofovir (TFV) and dapivirine(DPV). TFV and DPV are the lead ARV candidates currently being evaluated in the clinic. Quantitative assays to support formulation efforts have been developed in the laboratory for GRFT TFV and Dapivirine. This Core plays a critical role in the activities described within the PREVENT Program. The products and testing parameters developed within this core will be utilized by all projects and cores within the program.

project_terms:
Achievement;Algorithms;Anatomy;Animals;Anti-Retroviral Agents;Biological Assay;Carbopol;Characteristics;Chemicals;Chemistry;Clinic;Clinical Research;Clinical Trials;Critical Pathways;Cyclic GMP;Data;Development;Documentation;Dose;Drug Combinations;Drug Kinetics;Ensure;Evaluation;Formulation;Gel;Generations;Goals;HIV;Human;Investigational New Drug Application;Knowledge;Laboratories;Lead;Macaca;Methods;Modeling;Modification;Mucous Membrane;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Play;Preparation;Prevention;Procedures;Production;Property;Proteins;Records;Rectal Administration;Regulation;Regulatory Affairs;Research Contracts;Role;Safety;Series;TMC120-R147681;Technology Transfer;Tenofovir;Testing;Toxic effect;Toxicology;Vagina;Vaginal Gel;Viral;analytical method;base;chemical stability;clinical development;condoms;design;dosage;efficacy study;immunogenicity;microbicide;oxidation;packaging material;pre-clinical;preclinical safety;preclinical study;product development;programs;protocol development;prototype;rectal;rectal microbicide;safety study;safety testing;scale up;screening;transmission process

public_health_relevance:
Product Development Core (Core B) will provide formulation development focused on the development of the anti-HIV protein griffithsin single entity and combination products. This Core will also conduct activities to ensure the safety of gels advancing to clinical trials.


application_id: 9491682
project_number: 5U19AI113182-05
project_title: Core A: PREVENT Program Administrative Core
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
project_end_date: 2020-06-30
study_section: ZAI1-BP-A
subproject_number: 6661
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-07-01
project_abstract:
The overall objective of the PREVENT Program is to advance into clinical trials a candidate microbicide gel containing griffithsin (GRFT) that is designed to prevent rectal transmission of HIV-1. The primary responsibility of the Administrative Core (Core A) is to monitor direct and coordinate activities of the three research projects and three scientific cores to ensure that this objective is achieved efficiently as quickly as possible and in compliance with regulatory and sponsor requirements. The overarching goal of Core A is to provide scientific support to the PREVENT program's projects and cores to enable progression into the PREVENT clinical trial. Specific Aim 1 is to ensure effective PREVENT Program leadership through coordinated efforts of a Steering Committee (SC). Aim 2 is to provide administrative support for the effective functioning of the entire GRFT PREVENT program. Aim 3 is to provide centralized fiscal management of projects and cores and Aim 4 is to provide an internal structure for both internal and external review of scientific progress.

project_terms:
AIDS prevention;Archives;Award;Biometry;Calendar;Clinic;Clinical Trials;Collaborations;Communication;Consensus;Consult;Decision Making;Ensure;Experimental Designs;Gel;Goals;Grant;HIV-1;Information Dissemination;Leadership;Methods;Monitor;Online Systems;Paper;Prevention;Preventive vaccine;Problem Solving;Progress Reports;Proteins;Protocols documentation;Research Project Grants;Secure;Sexual Transmission;Site;Structure;TimeLine;United States National Institutes of Health;Universities;Viral;Work;base;condoms;design;meetings;microbicide;novel;posters;prevent;programs;rectal;rectal microbicide;transmission process

public_health_relevance:
In the absence of a preventative vaccine microbicides offer an alternative to condoms as a feasible method for prevention of HIV-1 sexual transmission. This Core manages the key administrative and fiscal tasks to bring to the clinic a novel candidate microbicide gel containing the potent anti-HIV01 protein griffithsin.


application_id: 9491681
project_number: 5U19AI113182-05
project_title: Griffithsin-based Rectal Microbicides for PREvention of Viral ENTry (PREVENT)
administering_ic: NIAID
award_notice_date: 2018-05-08
opportunity_number: RFA-AI-13-023
application_type: 5
activity_code: U19
ic: AI
serial_number: 113182
program_official: MATHIAS, CHERLYNN
project_start_date: 2014-07-01
project_end_date: 2020-06-30
study_section: ZAI1-BP-A(M2)
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): PREVENT (Pre-exposure prevention of viral entry) is an Integrated Preclinical/Clinical Program with the overall goal to provide a comprehensive set of data to facilitate an informed decision on whether the antiviral lectin Griffithsin (GRFT) shoul progress in the topical microbicides pipeline. GRFT has broad-spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2 herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV). Our product target is a rectal microbicide gel containing GRFT as the primary Active Pharmaceutical Ingredient (API). People who practice unprotected receptive anal intercourse (URAI) represent the population most vulnerable to HIV-1 transmission due to the high preponderance of HIV target cells in the rectal mucosa and mucosal trauma commonly associated with RAI. As a small protein unlikely to be widely used in antiretroviral therapy the GRFT PREVENT program stands apart from pre-exposure prophylaxis (PREP) strategies that involve small molecule antiretrovirals (ARV) which bear the potential risk of selecting for viral resistance. Broad spectrum antiviral prophylaxis that is offered by lubricant gels containing GRFT offer a much needed option for HIV infected people who require effective PREP against superinfection with HIV as well as HSV-2 HCV and other enveloped viruses that are transmitted by URAI. Three Projects and four Cores will all contribute to the Specific Aims of the Overall Program. Aim 1: Provide a comprehensive set of safety and efficacy data to facilitate a Go/No-Go decision on progression of GRFT rectal microbicides into later stage clinical studies. Aim 2: Manage and integrate the PREVENT U19 Program with the goals and expectations of the NIH sponsor and future sponsors and investors in GRFT microbicide gel products.

project_terms:
Address;Affect;Animals;Anti-Retroviral Agents;Antiviral Agents;Anus;Cells;Characteristics;Chemistry;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Colorectal;Critical Pathways;Cyclic GMP;Data;Data Set;Development;Documentation;Dosage Forms;Dose;Drug Delivery Systems;Drug Kinetics;Ensure;Epidemic;Epithelium;Feedback;Formulation;Future;Gel;Goals;Guidelines;HIV;HIV-1;Hepatitis C virus;Human;Human Herpesvirus 2;Immune response;Immunoassay;Immunohistochemistry;Institution;Investigational Drugs;Investigational New Drug Application;Laboratories;Lead;Lectin;Licensure;Local Microbicides;Lubricants;Macaca mulatta;Manufacturer Name;Marines;Measures;Methodology;Methods;Modeling;Mucous Membrane;Nucleosides;Participant;Peptides;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Phase I Clinical Trials;Placebos;Population;Practice Management;Pre-Clinical Model;Preclinical Testing;Prevention;Process;Prophylactic treatment;Proteins;Proteomics;Randomized;Recombinants;Recovery;Regulation;Research;Reverse Transcriptase Inhibitors;Risk;Safety;Sampling;Services;Superinfection;System;TMC120-R147681;Techniques;Technology Transfer;Tenofovir;Topical application;Toxicology;Trauma;United States Food and Drug Administration;United States National Institutes of Health;Universities;Ursidae Family;Vagina;Viral;Virus;analytical method;antiretroviral therapy;base;clinical efficacy;condoms;design;efficacy study;efficacy testing;expectation;first-in-human;immunotoxicity;inhibitor/antagonist;innovation;irritation;manufacturing process;medical schools;meetings;microbicide;microbiome analysis;next generation;non-nucleoside reverse transcriptase inhibitors;novel;novel therapeutics;pre-clinical;pre-exposure prophylaxis;preclinical safety;preclinical study;prevent;product development;programs;prototype;public health relevance;recruit;rectal;rectal microbicide;safety study;safety testing;small molecule;transcriptomics;transmission process;viral resistance;virus envelope;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: PREVENT is an integrated preclinical/clinical project that aims to determine whether a gel based drug delivery system for a potent broad spectrum antiviral protein Griffithsin is safe in preclinical models and a pre-phase I clinical trial. Preclinical studies are also designed to predict whether the microbicide we develop might be effective against HIV-1 transmission. A safe and effective rectal microbicide gel would have significant impact on preventing expansion of the domestic and global HIV-1 epidemic.   
   
Project 1: PREVENT Program Critical Path Project   
Project Leader (PL): Tuse Daniel   
   
DESCRIPTION (as provided by applicant): The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP-compliant Drug Substance and Drug Product manufacture and release manage preclinical safety and efficacy studies and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA) in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT) a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV such as HSV-2. Through our collaborators in the PREVENT Program we have produced more than 200 g of GRFT for research use and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2 the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species with endpoints to include topical and systemic safety tolerability irritation sensitivity and immunotoxicity. Preliminary Chemistry Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application activation of which by FDA will allow us to initiate a first-in-humans clinical trial f the GRFT microbicide in Project 3.


application_id: 9491591
project_number: 5F31ES028982-02
project_title: Polychlorinated biphenyls act through EGFR to worsen NAFLD
administering_ic: NIEHS
award_notice_date: 2018-05-08
opportunity_number: PA-16-309
application_type: 5
activity_code: F31
ic: ES
serial_number: 028982
program_official: SCHUG, THADDEUS
project_start_date: 2017-06-01
project_end_date: 2018-09-30
study_section: ZDK1-GRB-2(J1)L
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
arra_indicator: N
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 disease;nonalcoholic steatohepatitis;phosphoproteomics;prevent;receptor;receptor binding;receptor function;targeted 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: 9488161
project_number: 6R43HL135918-02
project_title: Vagus Nerve Stimulation Treatment for Asthmatic Bronchoconstriction
administering_ic: NHLBI
award_notice_date: 2017-07-21
opportunity_number: PA-15-269
application_type: 6
activity_code: R43
ic: HL
serial_number: 135918
program_official: NOEL, PATRICIA
project_start_date: 2017-02-01
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1-CVRS-H(11)B]
contact_pi_person_id: 10459031
contact_pi: BATES, MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079829394
duns_number: 079829394
fips: US
organization_id: 10039078
organization_name: PULSUS MEDICAL, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111162
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-25
budget_end_date: 2018-01-31
project_abstract:
Project Summary The Specific Aim of this proposal is to test the feasibility of using vagus nerve stimulation (VNS) fortreating asthma related airway constriction that is refractory to current treatments. There are approximately 25million people with asthma in the US. About 15% percent of these asthma sufferers experience early and latephase severe asthmatic bronchoconstriction that is refractory to current medication. These patients account formore than half of health related asthma costs and the majority of its mortality. This patient population accountsfor 4700 emergency department visits per day 1200 hospitalizations per day and more than 3300 deathsannually. There is currently no treatment for people who suffer from uncontrolled asthma. Other percutaneous devices have proven effective for blocking the early phase of asthma attacks thatare refractory to current therapy in an ED setting; but there is currently no effective VNS device for outside ofthe ED setting. In addition the efficacy of their device for blocking the later phase of the asthma response isunknown. The late phase occurs in 50% of individuals and may account for extended stand and returns to theED. Our goal is to provide patients with VNS for on-demand treatment of both the early- and late-asthmaresponses in order to drastically improve quality of life prevent death and to obviate the need for visiting theED.However before evaluating our method in humans we must first determine if VNS is effective for haltingboth the early and the late phase of asthma. In this Phase I study we will achieve our Specific Aim byevaluating the efficacy of VNS for blocking both early and late asthma responses in an ovalbumin (OVA)-sensitized guinea pig model of asthma. Guinea pigs are anesthetized with urethane (1.8 g/kg i.p.). Heart rate and blood pressure are measuredvia a carotid artery cannula. Both jugular veins are also cannulated for administration of drugs. The left vagusnerve will be isolated and immersed in a pool of mineral oil and bipolar cuff electrode will be placed around theleft cervical vagus. Animal's body temperature will be maintained at 37C using a heating blanket. Animals areparalyzed with succinylcholine (10 ml/kg/min i.v.) and ventilated (tidal volume 1 ml/100 g body weight at 100breaths per minute) via a tracheal cannula (using a constant volume pump Harvard Apparatus Co SouthNatick MA). Bronchoconstriction (measured as an increase in pulmonary inflation pressure (Ppi) via apressure transducer on a sidearm of the tracheal cannula) will be measured at stated time intervals afterovalbumin inhalation. Test of Feasibility: We must observe  35% (mean) reduction of max respiratory system resistancewhen OVA is combined with VNS in comparison to sham VNS. This value was chosen because it is bothdirectly related to previously demonstrated pulmonary pressure change in guinea pigs and predictive of laterclinically meaningful responses in humans.

project_terms:
Accident and Emergency department;Adrenal Cortex Hormones;Air;American;Animals;Asthma;Blood Pressure;Body Temperature;Body Weight;Breathing;Bronchoconstriction;Cannulas;Carotid Arteries;Cavia;Cervical;Cessation of life;Classification;Clinical;Clinical Trials;Data;Devices;Diabetes Mellitus;Dyspnea;Economic Inflation;Electrodes;Emergency department visit;Enrollment;Epilepsy;FDA approved;Goals;Grant;Guinea;Hand;Health;Heart Rate;Heating;Hospitalization;Human;Hunger;Implant;Individual;Intractable Epilepsy;Investigation;Left;Life;Link;Lipids;Lung;Measures;Medical;Mental Depression;Methods;Mineral Oil;Modeling;Morbidity - disease rate;Nocturnal Asthma;Obesity;Osteopenia;Ovalbumin;Paralysed;Patients;Pharmaceutical Preparations;Phase;Physical activity;Physicians;Population;Pressure Transducers;Pump;Quality of life;Refractory;Resistance;Respiratory System;Safety;Seizures;Severity of illness;Source Code;Structure of jugular vein;Succinylcholine;Symptoms;System;Target Populations;Testing;Tidal Volume;Urethane;Vagus nerve structure;Visit;asthmatic;cohort;constriction;cost;disabling symptom;early experience;efficacy study;experience;human study;improved;mortality;patient population;phase 1 study;pressure;prevent;response;time interval;treatment response;vagus nerve stimulation

public_health_relevance:
Project NarrativeThis is a proposal to develop an on-demand treatment for both immediate and long-lasting symptoms ofasthma using vagus nerve stimulation. There are 25 million Americans with asthma and approximately 15% donot respond to current methods of treatment. The proposed therapy seeks to mitigate debilitating symptomsand restore quality of life to patients suffering from uncontrolled asthma.


application_id: 9487946
project_number: 5R01CA188354-05
project_title: Non-peptide proteasome inhibitors as a novel anticancer agent
administering_ic: NCI
award_notice_date: 2018-05-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 188354
program_official: VERMA, SHARAD KUMAR
project_start_date: 2014-07-07
project_end_date: 2020-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 8152159
contact_pi: KIM, KYUNG BO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The long-term goal of this project is to develop next-generation proteasome inhibitors that will serve as effective therapies 1) for multiple myeloma (MM) patients refractory to the existing proteasome-targeting drugs bortezomib and carfilzomib as well as 2) for patients with solid cancers. In the last decade the FDA has approved the proteasome-targeting drugs bortezomib (Velcade(R)) and carfilzomib (Kyprolis(R)) for the treatment of MM patients. These agents have greatly improved the prognosis of MM and firmly validated the proteasome as an important anticancer target. However many patients eventually develop resistance after prolonged proteasome inhibitor therapy and few effective treatment options exist for such patients. In addition the potential of proteasome-targeting drugs remain untapped for the treatment of solid cancers despite their promising anticancer activities in preclinical models of solid cancers. Thus it is critically important to develop novel proteasome inhibitors which can overcome the limitations of existing proteasome inhibitors and deliver the therapeutic benefits of proteasome inhibitor therapy to cancer patients of all types including solid cancers. We hypothesize that a new class of proteasome inhibitors with non-peptide scaffolds will provide new therapeutic options for MM patients refractory to bortezomib or carfilzomib and solid cancer patients. This is based on the drawbacks arising from the structural features shared among bortezomib carfilzomib and nearly all proteasome inhibitors in drug development pipelines. Specifically the structural features of peptide backbones and reactive pharmacophores contribute to a high susceptibility to chemical/metabolic inactivation and off-target interactions causing unwanted toxicities and an inability to achieve sufficient drug penetration within solid cancer sites. Using step-wise screening approaches combining virtual screen and in vitro enzyme kinetics we identified several promising hits with diverse non-peptide scaffolds and proteasome inhibitory potencies. G4-1 a 135-substitutive pyrazole derivative is our current lead candidate displaying its anticancer activity in multiple cancer cel lines including cell lines resistant to bortezomib or carfilzomib. In addition to having excellentmetabolic stability G4-1 displayed promising anticancer efficacy and safety profiles in vivo. Withthe goal of further improving the potency and other pharmacokinetic properties of G4-1 to be suitable for oral dosing we propose the following aims: 1) to extend our lead optimization effortsin developing more potent proteasome inhibitors with improved drug-like properties 2) to investigate the cytotoxic mechanism of action of optimized non-peptide proteasome inhibitors and 3) to evaluate the in vivo anticancer efficacy safety and pharmacokinetic profiles of selected lead non-peptide proteasome inhibitors. Successful completion of the proposed work will yield novel non-peptide proteasome inhibitors that can advance to next stages of drug development efforts and ultimately lead to effective therapies for patients with MM and solid cancers.

project_terms:
Active Sites;Bioavailable;Bortezomib;Cancer Patient;Cancer cell line;Cell Line;Chemicals;Clinic;Clinical;Clinical Trials;Data;Dose;Drug Kinetics;Drug Stability;Drug Targeting;Drug resistance;Effectiveness;Enzyme Kinetics;Evaluation;FDA approved;Goals;Hematologic Neoplasms;Human;In Vitro;Lead;Libraries;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic;Mind;Molecular;Multiple Myeloma;Mus;Oral;Patients;Penetration;Peptides;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pre-Clinical Model;Predisposition;Property;Proteasome Inhibitor;Pyrazoles;Refractory;Relapse;Research;Resistance;Resistance development;Safety;Solid;Specificity;Structure-Activity Relationship;Therapeutic;Toxic effect;Translating;Velcade;Vertebral column;Work;Xenograft procedure;anti-cancer;anticancer activity;base;cancer cell;cancer site;cell killing;chymotrypsin;cytotoxic;design;drug candidate;drug development;effective therapy;human model;improved;in vitro testing;in vivo;in vivo Model;inhibitor/antagonist;intraperitoneal;lead candidate;lead optimization;molecular dynamics;multicatalytic endopeptidase complex;next generation;novel;novel anticancer drug;novel therapeutics;outcome forecast;pharmacophore;pre-clinical;public health relevance;scaffold;screening;small molecule;small molecule libraries;success;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  With the remarkable success of the two proteasome inhibitor drugs bortezomib and carfilzomib in treating multiple myeloma patients extensive efforts have been under way to extend their therapeutic benefits to a larger number of patients with refractory multiple myeloma and those with solid cancers. However the effectiveness of the currently available proteasome inhibitors is limited by poor in vivo stability and unwanted toxicit arising from their structural features. In the proposed study we will develop proteasome inhibitors with novel structural scaffolds thus achieving improved stability efficacy and safety profiles against human multiple myeloma and solid cancers.


application_id: 9487928
project_number: 5R01CA177679-05
project_title: The role of adipocyte/macrophage fatty acid binding protein in breast cancer deve
administering_ic: NCI
award_notice_date: 2018-05-03
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 177679
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2015-07-09
project_end_date: 2020-05-31
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 9620088
contact_pi: LI, BING
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):  Despite recent improvements in survival rates breast cancer still kills nearly half-a-million women worldwide annually. As the two most predominant populations in breast cancer stroma macrophages and adipocytes play central roles in breast tumorigenesis and progression. Thereby modifications in these cells can greatly influence tumor behavior. The objectives of this proposal are to determine the role of adipocyte/macrophage fatty acid binding protein (A-FABP) in promoting breast cancer development through simultaneously targeting both macrophages and adipocytes and to develop inhibitors to modulate A-FABP activity for breast cancer therapy. A-FABP abundantly expressed in macrophages and adipocytes has been identified as a central regulator of metabolic and inflammatory pathways in these cells. Our preliminary studies demonstrate that A- FABP is significantly upregulated in human and murine breast/mammary cancers. In response to tumor stimulation cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs) whereas circulating A-FABP is mainly released by adipocytes. More importantly A-FABP deficiency alters macrophage phenotype and protects mice against mammary tumor growth and metastasis. While obesity is associated with poor prognosis and increased mortality in patients with breast cancer the mechanistic basis for this association remains unclear. We found that obesity increases A-FABP in both cytosol and the circulation and promotes breast cancer progression. It is likely that A-FABP links obesity and breast cancer via regulating macrophage and adipocyte functions. Thus we hypothesize that A-FABP as an unidentified link underlying the obesity-breast cancer association promotes the development of breast cancer through enhancing pro-tumor functions of macrophages and adipocytes. Therefore modulating A-FABP activity will represent a novel strategy for breast cancer therapy. Specific Aim 1 will answer how cytoplasmic A-FABP regulates macrophage functions for breast cancer progression. We hypothesize that upregulation of cytoplasmic A-FABP in TAMs reprograms the macrophages to promote a pro-tumor environment. Specific Aim 2 will delineate how circulating A-FABP released by adipocytes contributes to breast cancer invasion. Experiments will designed to test the hypothesis that circulating A-FABP released by adipocytes favors breast cancer progression by inducing oncogenic signaling in tumor cells to increase their aggressiveness. Specific Aim 3 will address whether obesity promotes breast cancer through increasing A-FABP expression. We propose that A-FABP represents an unidentified factor in obesity to promote breast cancer risk and inhibition of A-FABP with inhibitors may suppress breast cancer development and progression. In conclusion the data collected will help us unravel the critical role of A-FABP in breast cancer development and identify specific A- FABP inhibitors for potential breast cancer therapy.

project_terms:
Address;Adipocytes;Animal Model;Basic Science;Behavior;Biopsy;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Risk Factor;Breast Cancer Treatment;Breast Cancer therapy;Cell Cycle Regulation;Cells;Clinical;Cytosol;Data;Development;Environment;Human;Infiltration;Inflammatory;Link;Mammary Neoplasms;Mediating;Metabolic;Modification;Molecular;Mus;Neoplasm Metastasis;Obesity;Oncogenic;Pathway interactions;Patients;Phenotype;Physiological;Play;Population;Protein Deficiency;Role;Signal Transduction;Survival Rate;Testing;Tissues;Treatment Efficacy;Tumor-associated macrophages;Up-Regulation;Woman;Women's Health;anticancer research;breast cancer progression;breast tumorigenesis;design;experimental study;fatty acid-binding proteins;immunoregulation;in vivo;inhibitor/antagonist;link protein;macrophage;malignant breast neoplasm;mortality;mouse model;neoplastic cell;novel strategies;outcome forecast;protein expression;public health relevance;response;tumor;tumor growth;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Breast cancer poses a major threaten to women's health. Uncovering new mechanisms of breast cancer development represents a critically important focus for breast cancer research. This proposal will establish A-FABP as a new player in breast cancer development. The data obtained will not only have basic science ramifications for understanding mechanisms of how A-FABP promotes breast tumorigenesis and progression but will also have clinical impact for treatment of breast cancer.


application_id: 9487280
project_number: 5R01HL123358-04
project_title: A novel mechanism for ART-associated dyslipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2018-05-07
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 123358
program_official: FLEG, JEROME L
project_start_date: 2015-08-01
project_end_date: 2019-07-31
study_section: AIDS Discovery and Development of Therapeutics Study Section[ADDT]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
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_abstract:
DESCRIPTION (provided by applicant): The rise in long-term HIV survivorship as a result of the introduction of effective antiretroviral therapy (ART) over the past decades has generated new awareness of the sequelae of both HIV infection and of the therapeutics used to treat HIV patients. Accumulating evidence of comorbidities associated with HIV infection and treatment with antiretroviral (ARV) drugs includes significant dyslipidemia and elevated risk of developing atherosclerotic cardiovascular disease (CVD). The goal of this project is to investigate a novel mechanism of ART-associated dyslipidemia and cardiovascular disease (CVD). Several ARV drugs have been identified as potent agonists for the pregnane X receptor (PXR) a nuclear receptor activated by numerous drugs xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. In the past decade the function of PXR in the regulation of drug and xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well established. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Preliminary studies demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild- type mice but not in PXR-deficient mice; furthermore follow-up study of currently used first-line ARV drugs subsequently found that these drugs activated PXR and induced PXR-mediated gene expression. The goal of this project is to generate novel mechanistic insights into ART-associated dyslipidemia and risk of CVD. Our central hypothesis is that long-term treatment with ARV drugs that activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on lipid homeostasis; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on macrophage functions and atherosclerosis development. These studies will provide critical mechanistic insights and new understandings of ART-associated dyslipidemia and CVD risk and will have direct clinical consequences for patients undergoing long-term treatment with PXR agonistic drugs.

project_terms:
Adverse effects;Agonist;Amprenavir;Animal Model;Anti-Retroviral Agents;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Awareness;CD36 gene;Cardiovascular Diseases;Cells;Chemicals;Cholesterol;Chronic;Clinical;Comorbidity;Development;Diet;Disease;Dose;Drug Regulations;Dyslipidemias;Foam Cells;Follow-Up Studies;Gene Expression;Generations;Goals;HIV;HIV Infections;HIV Protease Inhibitors;HIV therapy;Health;Heart;Homeostasis;Hyperlipidemia;In Vitro;Individual;Infection;Inflammation;Intestines;Knockout Mice;Laboratories;Lipids;Liver;Long-Term Survivors;Longevity;Lopinavir;Mediating;Modeling;Molecular;Morbidity - disease rate;Mus;Nuclear Receptors;Pathway interactions;Patients;Pharmaceutical Preparations;Pilot Projects;Protease Inhibitor;Receptor Activation;Regulation;Risk;Ritonavir;Role;SXR receptor;Signal Pathway;Testing;Therapeutic Uses;Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;antiretroviral therapy;atherogenesis;base;cardiovascular disorder risk;cholesterol transporters;defined contribution;drug metabolism;efavirenz;experimental study;in vivo;insight;macrophage;mortality;mouse model;non-nucleoside reverse transcriptase inhibitors;novel;pregnane X receptor;public health relevance;receptor function;scavenger receptor;sensor;survivorship;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Infection with HIV is known to elevate the risk for serious heart and arterial disease. With the advent of new generations of drugs for HIV infection the number of long-term HIV-infected patients has brought new recognitions of drug-related side effects including altered lipid profiles and even more greatly increased risk for heart and arteril disease. This study will provide important new information about the impact of HIV therapy on cardiovascular disease in patients undergoing long-term treatment with these drugs.


application_id: 9486995
project_number: 5R01HL122676-04
project_title: Cardiovascular Toxicity of Tobacco Products and Constituents
administering_ic: NHLBI
award_notice_date: 2018-04-27
opportunity_number: RFA-OD-13-011
application_type: 5
activity_code: R01
ic: HL
serial_number: 122676
program_official: ITURRIAGA, ERIN
project_start_date: 2015-07-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1-AARR-J(56)R]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
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): Cardiovascular Toxicity of Tobacco Products The Family Smoking Prevention and Tobacco Control Act grants the FDA the authority to regulate tobacco products to protect public health. However to set standards for tobacco products it is important to know which components of conventional new and emerging tobacco products induce cardiovascular injury so as to provide toxicity thresholds for harmful and potentially harmful constituents (HPHC) in tobacco products. However to identify HPHC toxicity it is important to determine how this toxicity could be identified and associated with disease risk and what assays best compare the toxic properties of different tobacco products. Although for toxicological profiling a high-throughput in vitro method is preferable CVD is a complex disease that develops from the dysfunction of several organ systems. Therefore the cardiovascular toxicity of tobacco products cannot be estimated in simple in vitro systems. Hence we will use an animal model and determine the relative toxicity of major HPHCs in cigarette smoke and electronic cigarette aerosol determine the toxicity profile of individual HPHCs specifically aldehydes and assess how the toxicity of an individual HPHC is modified by other HPHCs and nicotine. To validate this toxicity profile in humans we will examine the relationship between exposure to different HPHCs and cardiovascular toxicity in a well-characterized cohort. Successful completion of this project will lead to quantitative and rigorous evaluation of the cardiovascular toxicity of the major HPHCs in tobacco products and to the validation of an association between exposure to individual HPHCs and cardiovascular toxicity in humans. These findings will provide new information regarding the contribution of individual aldehydes in HPHC mixtures to the cardiovascular toxicity of tobacco smoke and as such will be useful in developing informed threshold limits and the policies needed to regulate HPHC levels in cigarettes electronic cigarettes smokeless tobacco as well as in other emerging tobacco-derived products.

project_terms:
Acetaldehyde;Acrolein;Address;Adult;Aerosols;Affect;Aldehydes;Animal Model;Animals;Biological Assay;Biological Markers;C57BL/6 Mouse;Cardiovascular Diseases;Cardiovascular system;Chronic Disease;Cigarette;Complex;Complex Mixtures;Cotinine;Creatinine;Data;Disease;Dose;Dyslipidemias;Electronic cigarette;Evaluation;Exposure to;Family Smoking Prevention and Tobacco Control Act;Female;Formaldehyde;Functional disorder;Future;Grant;Guidelines;Human;In Vitro;Individual;Injury;Insulin Resistance;Knowledge;Lead;Lipids;Measures;Mediating;Metabolism;Methods;Modification;Mus;Nicotine;Plasma;Policies;Property;Public Health;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoker;Smoking;System;Thrombosis;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Toxicology;Validation;Variant;authority;body system;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;cohort;disorder risk;environmental tobacco smoke exposure;experimental study;male;non-smoker;preventable death;primary endpoint;primary outcome;public health relevance;response;secondary endpoint;secondary outcome;smokeless tobacco use;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular Toxicity of Tobacco Products Project Narrative Although the rates of smoking have declined in the recent past nearly 1 billion people continue to smoke and cigarette smoking remains the most important cause of preventable deaths worldwide. Smoking and the use of tobacco products are associated with increased risk of developing multiple chronic diseases; however roughly half of all smoking-related illnesses are due to cardiovascular disease (CVD). Cigarette smoking and potentially the use of smokeless tobacco are associated with an increase in CVD risk factors. Nonetheless tobacco constituents that mediate the cardiovascular toxicity of tobacco use remain unknown and therefore it is unclear how tobacco products could be regulated to reduce cardiovascular injury or how Potential Reduced Exposure Tobacco Products (PREPs) such as electronic cigarettes could be evaluated for cardiovascular toxicity. This project will address this gap in knowledge regarding the toxicity of harmful and potentially harmful constituents (HPHCs) in tobacco products.


application_id: 9485347
project_number: 5R01GM113087-04
project_title: Deciphering the molecular mechanisms underlying active scaffolding
administering_ic: NIGMS
award_notice_date: 2018-05-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 113087
program_official: KODURI, SAILAJA
project_start_date: 2015-08-01
project_end_date: 2020-05-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway plays an essential role in several critical steps of embryonic development and tumor progression. It also controls critical cellular functions such as apoptosis motility and differentiation. Kinases and phosphatases of this pathway have been extensively studied and targeted therapeutically. However the mechanisms that determine the signal specificity and orchestrate the diverse biological outcomes of ERK1/2 signaling are still poorly understood. Scaffold proteins are key players in the ERK1/2 signaling pathway that are thought to integrate incoming signals and deliver signaling specificity and yet their role in signal propagation and the mechanisms of their action are still unknown. The long-term goal of our research is to reveal how scaffold proteins are involved in the biological processes regulated by the ERK1/2 cascade. In this way new therapeutic strategies can be developed to more specifically target this cascade without affecting other essential biological functions.  The objective of this proposal is to determine the mechanisms underlying the ability of the key scaffold protein Shoc2 to regulate ERK1/2-mediated cell motility. Shoc2 is essential for embryonic development and a critical regulator of ERK1/2 activity. We have shown that depletion of Shoc2 in zebrafish results in defects in hematopoiesis. We also found that Shoc2 integrates endocytic and ubiquitin machineries to regulate ERK1/2 signaling. Based on this preliminary data the central hypothesis of this proposal is that Shoc2 creates a signaling hub that regulates ERK's developmental signals in a spatio-temporal manner.  Our hypothesis will be tested by pursuing three specific aims: Aim 1 will determine the spatio-temporal organization and dynamics of Shoc2 scaffold complexes. Aim 2 will reveal the molecular mechanism by which the E3 ligase HUWE1 controls Shoc2 function and assembly of the Shoc2 scaffold complexes. Aim 3 will determine the signaling events mediated through the Shoc2 scaffold complexes that control embryonic development. The proposed Aims therefore are expected to provide a detailed understanding of how Shoc2 is involved in determining the specificity of ERK1/2 signaling outcomes. These studies will employ state-of-the-art innovative microscopy genetic molecular and cellular techniques and will provide critical insights into our understanding of the spatial-temporal control of signaling by scaffold proteins. This research has significance for contributing to the advancement of novel therapeutic strategies and biomarker innovations for developmental disorders and cancer progression. Thus the proposed studies are relevant to the NIH's mission to increase understanding of biological processes and to lay the foundation for advances in disease diagnosis treatment and prevention.

project_terms:
Address;Affect;Apoptosis;Biochemical;Biological;Biological Markers;Biological Process;Blood;Cell Adhesion;Cell membrane;Cell model;Cell physiology;Cells;Cognitive deficits;Complex;Cultured Cells;Data;Defect;Development;Disease;Effectiveness;Embryo;Embryonic Development;Endocytosis;Endosomes;Ensure;Event;Face;Fluorescence Resonance Energy Transfer;Foundations;Genetic;Genetic Models;Goals;Growth;Heart Abnormalities;Hematopoiesis;Hematopoietic;Income;Lead;Link;MAP Kinase Gene;MAPK3 gene;MEKs;Mediating;Microscopy;Mission;Modeling;Molecular;Mus;Mutation;Outcome;Pathology;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiological;Play;Prevention;Prognostic Marker;Protein Biochemistry;Proto-Oncogene Proteins c-raf;Ras/Raf;Regulation;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Spatial Distribution;Specificity;Study models;System;Techniques;Testing;Ubiquitin;Ubiquitination;United States National Institutes of Health;Work;Zebrafish;base;cell motility;cellular transduction;chromophore;developmental disease;disease diagnosis;imaging approach;imaging study;in vivo;innovation;insight;novel;novel therapeutic intervention;novel therapeutics;public health relevance;scaffold;spatiotemporal;targeted treatment;therapeutic development;transmission process;tumor;tumor progression;ubiquitin-protein ligase;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Deregulation of the MAPK signaling cascade is found in 30% of all tumors and multiple cardiac abnormalities and virtually every component of the cascade is target for therapeutic development. The effective targeting of this pathway in disease relies upon a clear understanding of all the intricacies in modulating numerous signaling components. Understanding the molecular mechanisms underlying the role of Shoc2 in MAPK signaling propagation potentially may lead to the development of specific prognostic markers and will enhance the effectiveness of targeted treatment.


application_id: 9483599
project_number: 5R00AG044445-05
project_title: Involvement of myelin integrity in Alzheimer's disease pathogenesis
administering_ic: NIA
award_notice_date: 2018-04-18
opportunity_number: PA-11-197
application_type: 5
activity_code: R00
ic: AG
serial_number: 044445
program_official: OPANASHUK, LISA A
project_start_date: 2016-05-01
project_end_date: 2019-05-31
study_section: NSS
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
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): This K99/R00 application provides career development training and a research plan to further the understanding of glial responses in white matter in the context of Alzheimer's disease (AD). The hypothesis to be tested is that a progressive loss of myelin integrity occurs in AD activating microglia towards a proinflammatory feed-forward loop which mediates hyperphosphorylation of the microtubule-associated protein tau and traditional AD pathology: neuritic plaques (NP) and neurofibrillary tangles (NFTs). Conventionally considered a disease of the CNS gray matter AD also has pronounced and progressive deterioration of cerebral white matter. Recent evidence suggests that changes in myelin integrity could be an early factor driving AD pathology through stimulation of inflammatory microglia activation and subsequent axonal damage. Extensive work has been done to understand the glial response in AD gray matter yet very little is known about microglia activation in AD white matter despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD white matter compared to gray matter. No studies have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression. Our project will fill this gap by using human autopsy tissue and a mouse model that exhibits loss of myelin integrity to test our hypothesis. Our specific aims are: 1) Quantify the relationship between myelin integrity microglia activationproinflammatory cytokine levels and traditional measures of AD burden (NPs and NFTs) in the white matter of autopsy samples; 2) Determine if loss of myelin integrity induced by mutation in PLP in hTau mice will accelerate hyper-phosphorylated tau pathology and if this pathology can be rescued by suppressing the chronic neuroinflammation using a glia cytokine inhibitor. This project takes advantage of a strong scientific environment and extensive resources at the University of Kentucky including the Alzheimer's Disease Center clinically well-characterized autopsy cases that span the disease pathology continuum and renowned scientific expertise of an enthusiastic and committed mentoring team. A comprehensive training and career development plan has been developed for the K99 phase that includes further scientific training in oligodendrocyte/myelin biology and human neuropathology; formal coursework and participation in local national and international scientific meetings; evaluative meetings with th mentoring team; and activities designed to improve communication writing teaching and management skills. Overall there is an outstanding intellectual environment and access to relevant expertise in the applicant's project area multiple opportunities for career growth and substantial institutional commitment. This rich and supportive environment will enable a highly promising young scientist to further develop his research expertise pursue his structured training and career development plan and launch his career as an independent academic investigator.

project_terms:
Alzheimer's Disease;Amyloid beta-Protein Precursor;Animal Model;Area;Automobile Driving;Autopsy;Biochemistry;Biology;Brain;Brodmann's area;Central Nervous System Diseases;Cerebrum;Chronic;Clinical;Cognitive;Communication;Data;Deterioration;Development Plans;Diffusion Magnetic Resonance Imaging;Disease;Disease Progression;Educational process of instructing;Environment;Enzyme-Linked Immunosorbent Assay;Event;Exhibits;Genes;Genetic;Goals;Growth;Health;Human;Immunohistochemistry;Induced Mutation;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1 beta;International;Kentucky;Late Onset Alzheimer Disease;MAPT gene;Measures;Medial;Mediating;Mental disorders;Mentors;Methods;Microglia;Mus;Mutation;Myelin;Myelin Proteins;Neocortex;Neuregulin 1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Oligodendroglia;Pathogenesis;Pathologic;Pathology;Pathway interactions;Phase;Research;Research Personnel;Research Project Grants;Resources;Role;Sampling;Scientist;Senile Plaques;Structure;Synapses;TNF gene;Temporal Lobe;Testing;Tissues;Training;Universities;White Matter Disease;Work;Writing;amnestic mild cognitive impairment;axon injury;beta-site APP cleaving enzyme 1;brain tissue;burden of illness;career;career development;collaborative environment;cytokine;design;digital;frontal lobe;genetic risk factor;gray matter;hTau Mice;human tissue;hyperphosphorylated tau;improved;inhibitor/antagonist;insight;lipid transport;meetings;mouse model;myelination;neuroinflammation;neuron loss;neuropathology;pre-clinical;public health relevance;response;skills;white matter;white matter change;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This research project will provide fundamental insights regarding the role of microglia dysregulated neuroinflammation and white matter integrity in the temporal onset of Alzheimer's disease. Recent data suggest white matter involvement in a variety of neurodegenerative and psychiatric disease. Therefore the understanding of oligodendrocyte - microglia - neuron interaction in Alzheimer's disease could have a broad impact on our understanding of cognitive health and disease.


application_id: 9481503
project_number: 1R21DA044251-01A1
project_title: Examining Social Influences on Syringe Exchange Uptake among Rural PWID at Risk for HIV
administering_ic: NIDA
award_notice_date: 2017-09-26
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: DA
serial_number: 044251
suffix: A1
program_official: JENKINS, RICHARD A
project_start_date: 2017-09-30
project_end_date: 2019-08-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The proposed study will conduct targeted formative research to identify key social-ecological factorsinfluencing the uptake of newly implemented syringe exchange programs (SEPs) among people who injectdrugs (PWID) in rural Appalachian Kentucky (KY). The recent initiation of SEPs in this rural resource poorarea provides a unique opportunity to examine social drivers impacting uptake of an evidence-based structurallevel HIV prevention intervention among a highly vulnerable and understudied population of PWID and todevelop complementary intervention strategies for enhancing SEP utilization. Serious health consequencesassociated with opioid injection are at crisis levels: KY has the highest rate of acute hepatitis C (HCV) in thenation particularly among persons aged 30 years residing in non-urban areas with a risk factor of injectiondrug use. In addition a recent analysis by the CDC identified 8 counties in Appalachian KY as among thenation's top 10 most vulnerable to the rapid dissemination of HIV and HCV among PWID. Despite well-documented rural-urban differences in drug use patterns and social characteristics there is a critical gap in ourknowledge of social drivers of SEP uptake and utilization among PWID in rural communities. Theimplementation of structural level HIV prevention programming has been virtually absent in rural locations andthe applicability of research findings from urban SEPs is largely unknown. Such data are urgently needed toinform the continued refinement of SEP policies and practices for vulnerable rural PWID and to developcomplementary multi-level prevention strategies to enhance access and utilization of rurally located SEPs.Guided by Social Ecological Theory the Specific Aims of this exploratory mixed methods study are to: 1)Examine the uptake of SEPs in three Appalachian county HDs (Clark Knox and Pike) through structuredinterviews with 350 PWID (175 SEP utilizers and 175 non-utilizers) to identify and compare the key differencesbetween utilizers and non-utilizers in social ecological domains including intrapersonal (e.g. HIV /HCVknowledge rural identity) interpersonal (e.g. kinship peer norms social isolation); institutional (e.g. justicesystem involvement law enforcement activity); community (e.g. community stigma geographic distance); andpublic policy factors (e.g. SEP policies and practices (privacy/anonymity hours locations distribution modelsecondary exchange)) that influence SEP uptake and utilization; and 2) Identify priority interventiontargets and develop strategies to enhance uptake of SEPs among rural PWID by conducting in-depthqualitative interviews with a strategically selected sample of PWID from Aim 1 as well as key healthdepartments directors and SEP staff local substance treatment providers law enforcement and othercommunity stakeholders to assess multi-level barriers to SEP utilization acceptability and feasibility ofcomplementary intervention strategies and to develop recommendations for intervention priorities and practicechanges to improve SEP uptake.

project_terms:
AIDS prevention;Acute Hepatitis C;Appalachian Region;Area;Centers for Disease Control and Prevention (U.S.);Communities;County;Data;Disease Outbreaks;Drug usage;Drug user;Economics;Epidemic;Geography;Growth;HIV;HIV risk;HIV/HCV;Health;Health Personnel;Health Services Accessibility;Heroin;Hour;Indiana;Infection;Injectable;Injecting drug user;Injection of therapeutic agent;Intervention;Interview;Justice;Kentucky;Knowledge;Law Enforcement;Location;Methods;Modeling;Morbidity - disease rate;Needle-Exchange Programs;Opioid;Overdose;Pattern;Perception;Persons;Pharmaceutical Preparations;Pike fish;Policies;Population;Prevention strategy;Preventive Intervention;Privacy;Program Accessibility;Public Health;Public Policy;Recommendation;Research;Resources;Risk;Risk Behaviors;Risk Factors;Rural;Rural Community;Sampling;Services;Social Characteristics;Social Values;Social isolation;Structure;Syringes;System;Time;aged;disorder prevention;evidence base;experience;high risk;improved;injection drug use;mortality;peer;prescription opioid;prescription opioid abuse;rural area;social;social norm;social stigma;stressor;substance abuse treatment;theories;uptake;virtual

public_health_relevance:
The proposed study will conduct targeted formative research to identify key social-ecological factorsinfluencing the uptake of newly implemented syringe exchange programs (SEPs) among people who injectdrugs (PWID) in rural Appalachian Kentucky (KY). Serious health consequences associated with opioidinjection are at crisis levels: KY has the highest rate of acute hepatitis C (HCV) in the nation and a recentanalysis by the CDC identified 8 counties in Appalachian KY as among the nation's top 10 most vulnerable tothe rapid dissemination of HIV among PWID. The significant public health impact of the study is indicated bythe potential to understand SEP uptake patterns in rural resource poor areas and to develop complementaryintervention strategies for enhancing access to evidence-based structural HIV prevention interventions forhighly vulnerable rural PWID.


application_id: 9481379
project_number: 4R33DA038817-03
project_title: Single molecule determination of nAChR structural assembly for therapeutic targeting
administering_ic: NIDA
award_notice_date: 2017-07-20
opportunity_number: PAR-13-350
application_type: 4
activity_code: R33
ic: DA
serial_number: 038817
program_official: HILLERY, PAUL
project_start_date: 2017-08-01
project_end_date: 2019-06-30
study_section: NSS
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
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:
DESCRIPTION (provided by applicant): The consumption of tobacco products leads to the elevation of several health risks. Smokers have a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. As a result approximately 20% of all deaths in the United States are associated with tobacco products. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. One of the primary barriers to decreasing the number of smokers is that nicotine a component of tobacco is highly addictive. We propose a novel approach to elucidate the mechanism of nicotine addiction and to identify target nAChR assemblies and phenotypes for nicotine cessation therapeutics. In the R21 phase we will focus on the development of a novel approach to monitor the assembly and trafficking of nicotinic receptors at the single molecule level. Nicotinicreceptors cannot be purified outside of the cellular environment making them inaccessible to common single molecule techniques that require the purification and reconstitution of proteins. We will utilize receptors isolated in cell derived vesicles. Isolation of vesicles from different organelles will allow us to determine nicotine and therapeutic ligands affect the assembly and trafficking of nAChRs. Identification of the specific structural assemblies targeted by existing therapeutics will allow us to identify specific targets for cessation therapeutics. In the R33 phase we will extend studies to receptors generated in live animals by isolating vesicles from different regions of the brain of nicotinic receptor GFP knock-mice. These will be the first singlemolecule studies of nicotinic receptors generated in live animals. We will be able to correlate theassembly of different receptor subtypes to specific brain regions. These studies will for the firsttime allow us to perform single molecule fluorescence studies on brain derived nAChRs. Understanding how existing therapeutics alter structural assembly in specific brain regions will provide an understanding of which nAChRs to target and the structural assembly they should induce. This will provide insight into the mechanism of nicotine addiction and on the receptor phenotypes optimally induced by cessation therapeutics.

project_terms:
Adult;Affect;Animals;Brain;Brain imaging;Brain region;Cardiovascular Diseases;Cell membrane;Cells;Cessation of life;Development;Environment;Exposure to;Fluorescence;Goals;Golgi Apparatus;Health;Knock-in Mouse;Label;Ligands;Lung diseases;Measures;Mediating;Membrane;Molecular Chaperones;Monitor;Mus;Nicotine;Nicotine Dependence;Nicotinic Receptors;Organelles;Pharmacology;Phase;Phenotype;Play;Risk;Role;Series;Smoker;Structure;Synapses;Synaptosomes;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tobacco;Tobacco use;United States;Vesicle;addiction;cancer type;experimental study;fluorescence imaging;hazard;in vivo;innovation;insight;molecular imaging;novel;novel strategies;novel therapeutics;presynaptic;protein reconstitution;public health relevance;receptor;single molecule;stoichiometry;targeted treatment;therapeutic target;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The consumption of tobacco products leads to a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. The proposed studies will help to elucidate the underlying mechanism of nicotine addiction and will identify specific structural targets for therapeutic targeting.


application_id: 9481317
project_number: 5R01HL127682-04
project_title: Specific Lysis for Large-Volume High-Purity Endothelial Progenitor Cell Isolates
administering_ic: NHLBI
award_notice_date: 2018-04-28
opportunity_number: PAR-13-137
application_type: 5
activity_code: R01
ic: HL
serial_number: 127682
program_official: LEE, ALBERT
project_start_date: 2015-07-15
project_end_date: 2020-04-30
study_section: Instrumentation and Systems Development Study Section[ISD]
contact_pi_person_id: 10218003
contact_pi: BERRON, BRADLEY JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
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:
DESCRIPTION:  Ischemic heart disease is the primary cause of death in both men and women globally. Ischemic heart conditions including angina and myocardial infarction are characterized by loss of blood flow to the heart tissue and reduced cardiac function both reducing quality of life and increasing mortality. Improved recovery of cardiac function following a myocardial infarction has been observed in several studies upon the injection of high concentrations of endothelial progenitor cells (EPCs) to the ischemic area. Multiple types of EPCs have been shown to play pivotal roles in the formation of new blood vessels and are promising candidates for accelerated and increased repair of ischemic tissues. Follow up studies indicate both high purity and quantity of EPCs are critical to recovery of function yet current technologies for sorting of EPCs are incapable of isolating these cells in the purity and speed required for widespread clinical use. This research grant will develop a novel technique for the isolation of EPCs which yields a high-purity isolate at high throughput. The developed technology Antigen Specific Lysis (ASL) is capable of being performed in a typical research lab setting where batches exceeding 200 mL (>1010 cells) are completed in under an hour. The proposed work will develop high speed selection modalities for the isolation of high purity functional EPCs. ASL uses targeted coatings to selectively protect EPCs while all other cells are lysed. Preliminary results demonstrate 1) antibody- initiator conjugates are capable of selectively forming a ~100 nm polymer coating on the exterior of only antigen expressing cells 2) these coatings stabilize cells in harsh environments (5% SDS) and 3) viable cells are released at high purity (>99% purity for antigen positive cells spiked into blood). This research grant drives new advances in wavelength specific polymerization and degradation for the selective protection of targeted cells and the subsequent release of cells with increased viabilityand proliferative capacity. Sequential selection for CD133+ and CD34+ cells is expected yielding a >99% pure population of EPCs. This system will also have the capability to process multiple smaller batches at one time using only standard disposable labware for cell- contacting materials. Finally the functional properties of clinically-relevant EPC populations isolated fluorescently or by ASL will be evaluated through in vitro and in vivo assays. ASL shows considerable promise as a powerful isolation technique that can be applied both clinically for the treatment of acute myocardial infarctions and in individual research settings for the analysis of rare cellular species in blood. This project is significant because in-lab isolation of large volums of cells will enable the widespread use of EPC therapy for improved cardiac function following acute myocardial infarctions. Future directions of this work include the use of ASL in the isolation of other rare cell populations (other progenitor cells circulating tumor cells) emergingin clinical research diagnostics prognostics and treatment.

project_terms:
Acute myocardial infarction;Antibodies;Antigens;Area;Automobile Driving;Biological;Biological Assay;Blood;Blood Vessels;Blood flow;CD34 gene;Capital;Cardiac;Cause of Death;Cell Separation;Cell Survival;Cell Therapy;Cells;Clinical;Clinical Research;Clinical Treatment;Cytolysis;Data;Deterioration;Diagnostic;Environment;Follow-Up Studies;Future;Goals;Growth;Heart;Hemorrhage;Home environment;Hour;In Vitro;Individual;Injections;Leukocytes;Life;Light;Magnetism;Medical;Methodology;Methods;Modality;Morbidity - disease rate;Mus;Myocardial Infarction;Myocardial Ischemia;Neoplasm Circulating Cells;Patient-Focused Outcomes;Patients;Perfusion;Play;Polymers;Polystyrenes;Population;Procedures;Process;Property;Quality of life;Recovery;Recovery of Function;Research;Research Project Grants;Risk;Role;Sampling;Science;Site;Sorting - Cell Movement;Source;Speed;Stem cells;Sterilization;System;T-Lymphocyte;Technical Expertise;Techniques;Technology;Time;Tissues;Training;Translations;Tube;Umbilical Cord Blood;Woman;Work;base;cardiac repair;cell type;clinical application;clinically relevant;cost;heart damage;heart function;hospital laboratories;improved;in vivo;irradiation;magnetic beads;matrigel;men;migration;mortality;new technology;novel;novel strategies;peripheral blood;polymerization;preservation;prognostic;prototype;public health relevance;repaired;scale up;subcutaneous;time use

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project develops a new approach to isolating a rare type of cell capable of repairing heart damage. This approach promises to deliver cells with fewer contaminants faster and at a lower cost than is possible today. This technology is also expected to both accelerate and reduce the cost of research across a broad spectrum of biological and medical sciences.


application_id: 9481262
project_number: 5R01AI129959-02
project_title: Enhanced diagnostic assessment in lupus using differential scanning calorimetry
administering_ic: NIAID
award_notice_date: 2018-04-04
opportunity_number: PAR-16-242
application_type: 5
activity_code: R01
ic: AI
serial_number: 129959
program_official: RICE, JEFFREY S
project_start_date: 2017-05-05
project_end_date: 2022-04-30
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 11129807
contact_pi: GARBETT, NICHOLA C.
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:
Address;Affect;Albumins;Amyotrophic Lateral Sclerosis;Antibodies;Attention;Autoantibodies;Autoimmune Diseases;Autoimmune Process;Biochemical;Biological Markers;Characteristics;Classification;Clinical;Clinical Trials;Comorbidity;Cross-Sectional Studies;Data;Degenerative polyarthritis;Development;Diagnosis;Diagnostic;Diagnostic Procedure;Diagnostic tests;Differential Scanning Calorimetry;Disease;Disease remission;Early Diagnosis;Emerging Technologies;Goals;Immunologics;Insulin-Dependent Diabetes Mellitus;Investments;Laboratories;Laboratory Study;Lead;Liquid substance;Lupus;Lyme Disease;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mass Spectrum Analysis;Medical Technology;Molecular;Monitor;Organ;Pathology;Patient Monitoring;Patients;Performance;Plasma;Post-Translational Protein Processing;Process;Property;Protein Denaturation;Proteome;Recording of previous events;Rheumatoid Arthritis;Sampling;Sensitivity and Specificity;Serologic tests;Serological;Severity of illness;Source;Systemic Lupus Erythematosus;Technology;Testing;Therapeutic Intervention;Thermodynamics;Urine;base;diagnostic accuracy;diagnostic assay;diagnostic biomarker;effective therapy;human disease;improved;infancy;melanoma;novel diagnostics;novel marker;outcome forecast;personalized medicine;serological marker;targeted treatment;therapy development;tool;treatment response


application_id: 9480847
project_number: 5R01CA207538-02
project_title: Addressing ELSI Issues in Unregulated Health Research Using Mobile Devices
administering_ic: NCI
award_notice_date: 2018-05-08
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 207538
program_official: CAGA-ANAN, EMILIE CHARLISSE F
project_start_date: 2017-05-04
project_end_date: 2020-04-30
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: WILBANKS, JOHN
congressional_district: 03
department: SOCIAL SCIENCES
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYHealth research using mobile devices such as smartphones and tablets is becoming more common. Newhardware and software can transform a mobile device into a sophisticated data collection and analyticalplatform. These technologies are fundamentally changing health research because the recruitment datacollection and data sharing are conducted online without any face-to-face interaction between researchers andresearch participants.Increasingly this research also is being conducted by researchers who do not receive any federal funding andare not subject to the Common Rule the FDA research regulations and the HIPAA Privacy Rule. Yetunregulated health research using mobile devices raises numerous important ethical issues including externalreview recruitment inclusion and exclusion criteria informed consent privacy and security incidental findingsand data sharing.This project has the following three aims:Aim 1: Conduct in-depth qualitative interviews to elicit thought leaders' perspectives on the risks andappropriate protections for participants in unregulated health research using mobile devices.Aim 2: Develop a detailed analysis of the ELSI issues through a series of 4 meetings by a diverseexpert working group and use a consensus-building methodology to develop recommendations.Aim 3: Devise and implement educational programs and translation of the consensusrecommendations. Sub-aim 3-1: Because app developers play a key role in mobile health innovations we will hold 2 workshops exclusively for app developers on ethical issues in designing mobile health apps with video highlights posted on the internet. Sub-aim 3-2: We will hold a conference in Washington DC on policy issues of interest to the NIH FDA OHRP FTC Congressional staffs state governments professional organizations researchers IRBs patient groups and other stakeholders. Sub-aim 3-3: Members of the working group will draft 20 articles containing consensus policy recommendations for publication in a special symposium issue of the Journal of Law Medicine &Ethics. Sub-aim 3-4: We will present our findings and recommendations at meetings of consumers professionals and policy makers.

project_terms:
Address;Categories;Cellular Phone;Child;Computer software;Consensus;Data;Data Analytics;Data Collection;Educational workshop;Ensure;Ethical Issues;Ethics;Exclusion Criteria;Funding;Government Agencies;Grant;Health;Health Insurance Portability and Accountability Act;Health Technology;Incidental Findings;Informed Consent;Institutional Review Boards;Internet;Interview;Journals;Laws;Measures;Medicine;Methodology;Mobile Health Application;Nonprofit Organizations;Participant;Patients;Play;Policies;Policy Maker;Precision Medicine Initiative;Privacy;Professional Organizations;Publications;Recommendation;Regulation;Research;Research Ethics;Research Personnel;Risk;Security;Series;State Government;Tablets;Technology;Translations;United States National Institutes of Health;Washington;cancer care;citizen science;common rule;design;handheld mobile device;inclusion criteria;innovation;interest;mHealth;meetings;member;novel;patient advocacy group;programs;recruit;sharing data;symposium;welfare;working group

public_health_relevance:
PROJECT NARRATIVEHealth research using mobile devices such as smartphones and tablets is becoming increasingly common.Because some of this research is not subject to the federal research regulations it raises novel ethical andpolicy issues such as independent review informed consent and privacy. The proposed study will developand disseminate recommendations for the ethical conduct of this emerging research.


application_id: 9479300
project_number: 5R01NS092680-02
project_title: ER Ca2+ store mediated white matter injury
administering_ic: NINDS
award_notice_date: 2018-01-16
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 092680
program_official: JAKEMAN, LYN B
project_start_date: 2017-05-01
project_end_date: 2022-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11601659
contact_pi: STIRLING, DAVID PAUL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
AVIL gene;Area;Atrophic;Axon;Behavioral;Binding Proteins;Calcium;Data;Degenerative Disorder;Distal;Dyes;Electron Microscopy;Elements;Event;FDA approved;Fiber;Gait;Generations;Goals;Human;ITPR1 gene;Image;Imagery;Imaging Techniques;Injury;Inositol;Intervention;Kainic Acid Receptors;Knockout Mice;Mediating;Microscopy;Modeling;Molecular;Morphology;Multiple Sclerosis;Mus;Myelin;Nature;Neurologic Deficit;Pathologic;Pathology;Patients;Pharmacology;Process;Recovery;Recovery of Function;Reproducibility;Research;Reticulum;Role;Ryanodine Receptors;Secondary to;Signal Pathway;Signal Transduction;Site;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stroke;Swelling;System;Technology;Testing;Therapeutic;Time;Transgenic Mice;Wallerian Degeneration;Work;axonal degeneration;carvedilol;clinically relevant;effective therapy;functional outcomes;genetic approach;improved;in vivo;injured;innovation;kinematics;lipophilicity;loss of function;nervous system disorder;neurological recovery;new therapeutic target;novel;novel therapeutics;oxidation;prevent;receptor;spinal tract;two-photon;white matter;white matter injury


application_id: 9479183
project_number: 5P30GM110787-05
project_title: Pilot Grant Program
administering_ic: NIGMS
award_notice_date: 2018-03-21
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
project_end_date: 2021-04-30
study_section: ZGM1-TWD-C
subproject_number: 6094
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
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: 2018-05-01
project_abstract:
The long-term goal of the Pilot Grant Program is to provide resources to COBRE investigators so that they can generate new preliminary data for extramural grant applications and thus expand their research programs. The Pilot Grant Program was begun in Phase I continued in Phase II and its success will be built upon in Phase III. During Phase I and II the Program was extremely successful. Awardees produced -200 publications and the success rate for gaining independent extramural funding was -80%. Many of the initial awardees have now been granted tenure. This successful program will continue in Phase III. The Pilot Grant Program will feature three grant categories all designed to further the goals of the COBRE Center for Molecular Medicine and to promote innovation by allowing meritorious investigators to explore novel ideas and develop new technologies. Category 1 grants are for newly-independent non-tenured tenure-track research faculty with no prior NIH ROI or equivalent external grant support as a principal investigator. A strong mentoring component is associated with this class of grant. Category 2 grants are for more established faculty who wish to pursue a new research area for which they do not currently have an NiH R01 or equivalent. These grants are meant to promote innovation and allow investigators to expand their research programs into new areas. Category 3 grants are available to groups of investigators planning to submit a multi-PI or Program Project grant application working collaboratively on a specific research problem and can be comprised of both junior and more established investigators. These grants are meant to promote synergistic collaborations. The grants are designed for 2 years of funding ($50000 per year) with the second year contingent on demonstrated progress. Evaluation of the grant applications and funding decisions will be made by the External Advisory Board in consultation with the Program Coordinator. All applicants regardless of funding decisions will receive a review of their proposals with a full evaluation of NIH's five criteria so that their future proposals can be improved. This Pilot Grant program has had a highly successful past and its philosophy of operation will be carried into Phase III.

project_terms:
Animal Model;Applications Grants;Area;Award;Basic Science;Categories;Cellular biology;Centers of Research Excellence;Clinical;Collaborations;Consultations;DNA;Data;Development;Diagnostic;Discipline;Evaluation;Evolution;Extramural Activities;Faculty;Feasibility Studies;Fostering;Foundations;Funding;Future;Generations;Goals;Grant;Growth;Kentucky;Knowledge;Mentors;Molecular;Molecular Medicine;Neurodegenerative Disorders;Participant;Patients;Phase;Philosophy;Pilot Projects;Positioning Attribute;Principal Investigator;Program Research Project Grants;Publications;RNA;Research;Research Personnel;Research Project Grants;Resources;Science;Signal Pathway;Sum;Technology;Therapeutic;Translational Research;United States National Institutes of Health;Universities;career;data submission;design;experience;faculty research;human disease;improved;innovation;interest;new technology;novel;operation;programs;success;tenure track;tool;trafficking;translational study

public_health_relevance:
The Pilot Grant Program promotes innovation by supporting COBRE investigators in the exploration of novel ideas and in the development of new technologies. This new knowledge will be the foundation for developing the future diagnostics tools and clinical therapeutics needed in the treatment of human disease.


application_id: 9479182
project_number: 5P30GM110787-05
project_title: Genetic Technologies Core
administering_ic: NIGMS
award_notice_date: 2018-03-21
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
project_end_date: 2021-04-30
study_section: ZGM1-TWD-C
subproject_number: 6093
contact_pi_person_id: 1893692
contact_pi: MENDENHALL, MICHAEL D.
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: 2018-05-01
project_abstract:
The Genetic Technologies Core evolved from the Viral Core that began with funding from an ARRA supplement grant in 2009 and was incorporated into the COBRE in 2011. It was initially conceived as a central service facility for the preparation purification and titering of recombinant lentlviruses adenoviruses and adeno-associated viruses for the use of investigators associated with the Center for Molecuair Medicine and for other investigators interested in the use of recombinant viruses as a delivery tool for nucleic acids. Over the past four years the Core has steadily grown in the number of individual viral preparations that it produced and the number of investigators it served. There has evolved an interest from users for services in addition to those associated with viral production and the Core has adapted by increasing the scope of services provided necessitating the change to its new designation as the Genetic Technologies Core. At present the Genetic Technologies Core provides a broad range of services related to the manipulation and analysis of recombinant DNAs especially for those laboratories with clinical/translational interests that are not equipped for recombinant DNA work. Evolution of the Core continues as it adds capacity in genomic manipulation through the development and use of "recombineering" TALEN and piggybac technologies. These technologies will be especially valuable for the creation of cellular and animal models of human diseases that can be exploited by members of the Center for Molecular Medicine. In addition to its scientific development the Core is also expanding its outreach programs by interfacing with the expanding Masters of Medical Science program (currently over 30 students) to provide hands-on and didactic instruction in recombinant DNA technologies including viral production and assay mammalian genomic manipulation tissue culture techniques and federal regulatory and safety requirements for up to three students each semester. A parallel didactic-only class is being developed for PhD graduate students. These courses will serve as additional revenue sources to sustain this core beyond COBRE funding.

project_terms:
Adenoviruses;American;Animal Model;Biological Assay;Cell model;Cells;Centers of Research Excellence;Clinical;Complex;Consultations;DNA;DNA Sequence Alteration;DNA laboratory;Dependovirus;Development;Disease model;Doctor of Philosophy;Evolution;Exposure to;Fee-for-Service Plans;Fees;Funding;Genetic Engineering;Genome;Genomics;Grant;Individual;Institution;Instruction;Investments;Kentucky;Laboratories;Leadership;Master of Science;Medical;Medicine;Modeling;Molecular;Molecular Medicine;Nucleic Acids;Phase;Plasmids;Positioning Attribute;Preparation;Production;Reagent;Recombinant DNA;Recombinants;Recovery;Research;Research Personnel;Resources;Safety;Science;Service delivery model;Services;Source;Speed;Students;System;Techniques;Technology;Time;Tissue Culture Techniques;Training;Training Activity;Training Programs;United States National Institutes of Health;Universities;Viral;Work;base;cost;design and construction;genetic technology;graduate student;human disease;human model;interest;mammalian genome;member;nucleic acid delivery;operation;outreach program;programs;recombinant virus;tool;transcription activator-like effector nucleases

public_health_relevance:
The Genetic Technologies Core provides a wide range of services relating to the manipulation of recombinant DNAs and mammalian genomes for investigators associated with the Center for Molecular Medicine. Of particular importance are the production of recombinant viruses for the delivery of nucleic acids for experimental use and the manipulation of mammalian genomes for creation of cell-based and animalbased human disease models.


application_id: 9479181
project_number: 5P30GM110787-05
project_title: Organic Synthesis Core
administering_ic: NIGMS
award_notice_date: 2018-03-21
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
project_end_date: 2021-04-30
study_section: ZGM1-TWD-C
subproject_number: 6092
contact_pi_person_id: 1964895
contact_pi: WATT, DAVID STEWART
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
project_abstract:
The Organic Synthesis Core prepares novel specialized organic compounds that are not readily obtainable from commercial sources for faculty in the Center for Molecular Medicine as well as other investigators at the University of Kentucky other Kentucky universities. The core has all of the appropriate equipment needed to prepare small organic compounds (< 2 kDa) along with access to appropriate analytical techniques including NMR and mass spectrometry for confirming structural assignments to characterize the final product(s) an essential element of any synthesis project. The core has synthesized and characterized novel probes for more than twenty-five investigators including photoactive drug analogs fluorescent compounds used as molecular probes modified natural products unnatural peptides and compounds used for the affinity purification of proteins. The core has developed small molecule libraries that have been effectively used for ligand and drug screening leading to the identification of novel targets and the development of therapeutics. In Phase III this core will continue to provide novel small-molecule probes for disease-relevant studies further develop and expand its libraries of small-molecules for biological screening and promote and facilitate the use of small-molecule approaches in our translational research efforts. In addition the core will provide training opportunities for students and researchers who seek to learn synthetic organic chemical techniques and apply them to their research projects. An important but potentially overlooked aspect of the Organic Synthesis Core is that it does not compete with pharmaceutical companies rather the services provided by the core complement what private enterprises do. Generally a potentially valuable new compound developed by the core in collaboration with an investigator will be patented and then licensed to a pharmaceutical company for development and testing leading ultimately to clinical trials.

project_terms:
Affinity Chromatography;Biological;Businesses;Centers of Research Excellence;Clinical Trials;Collaborations;Complement;Consult;Consultations;Detection;Deuterium;Development;Disease;Drug Industry;Drug Screening;Elements;Equipment;Extramural Activities;Faculty;Fees;Funding;Grant;Health;Human;Institution;Investigation;Investigational Drugs;Investments;Kentucky;Label;Learning;Legal patent;Ligands;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Medicine;Molecular;Molecular Medicine;Molecular Probes;Monitor;NMR Spectroscopy;National Center for Research Resources;National Institute of General Medical Sciences;Natural Products;Nature;Neurodegenerative Disorders;Organic Chemicals;Organic Synthesis;Outcome;Peptide Nucleic Acids;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacy facility;Phase;Polymers;Positioning Attribute;Postdoctoral Fellow;Private Enterprises;Proteins;Publications;Research;Research Personnel;Research Project Grants;Research Support;Resources;Services;Source;Structure;Students;Techniques;Testing;Time;Training;Translating;Translational Research;Universities;X-Ray Crystallography;analog;base;college;cost;design;drug candidate;functional group;graduate student;human disease;improved;industry partner;instrumentation;molecular mass;novel;novel therapeutics;operation;outreach;programs;protein purification;radiotracer;screening;small molecule;small molecule libraries;therapeutic development;training opportunity;undergraduate student

public_health_relevance:
This Organic Synthesis core synthesizes small organic molecule use by investigators for their research projects related to understanding the molecular basis of human disease.


application_id: 9479180
project_number: 5P30GM110787-05
project_title: Protein Core
administering_ic: NIGMS
award_notice_date: 2018-03-21
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
project_end_date: 2021-04-30
study_section: ZGM1-TWD-C
subproject_number: 6091
contact_pi_person_id: 7875214
contact_pi: RODGERS, DAVID W
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: 2018-05-01
project_abstract:
The Protein Core in the University of Kentucky Center for Molecular Medicine works with biomedical investigators to facilitate the expression purification and characterization of recombinant proteins and other macromolecules. It makes available equipment instrumentation and expertise not normally be found within individual research laboratories. The Core has fermentors bioreactors and tissue culture facilities for expressing recombinant protein in bacteria yeast insect or mammalian cells as required. It also maintains cell cracking equipment and an extensive facility for the purification of recombinant proteins. In addition a range of analytical instruments for biophysical characterization are available in the Core including dynamic light scattering spectropolarimetry fluorescence isothermal titration calorimetry high performance liquid chromatography analytical ultracentrifugation and X-ray crystallography. Crystallography facilities include instruments for automated crystallization trials in house data collection equipment and membership in a group (SER-CAT) operating a state-of-the-art data collection facility at the Advanced Photon Source located within Argonne National Laboratory. A Core staff member maintains the equipment provides training and works with researchers on their individual projects. Experienced users have direct access to Core facilities while new users are first trained by Core personnel and assisted in initial experiments. Users with more difficult projects receive additional assistance from the Core personnel. Service projects are undertaken selectively for users who lack the expertise or personnel to carry out the work on their own. The Core is used by investigators representing 50-70 research groups each year with over 4200 individual uses of instruments or facilities documented for the first four years of Phase II COBRE funding. Outreach activities include the Core web site talks given by Core associated faculty individual and group training sessions a monthly research talk series and participation in graduate courses and an NSF REU summer program. The Core is active in obtaining new instrumentation and introducing new techniques. Transition to a selfsustaining regional facility is planned over the course of Phase III COBRE funding.

project_terms:
Area;Bacteria;Behavior;Biological;Biomedical Research;Bioreactors;Calorimetry;Cells;Centers of Research Excellence;Chromatography;Collaborations;Communities;Consult;Core Facility;Core Protein;Crystallization;Crystallography;Data Collection;Equipment;Fees;Fluorescence;Fostering;Funding;Goals;Grant;Growth;High Pressure Liquid Chromatography;Human Resources;Individual;Insecta;Institution;Kentucky;Laboratories;Laboratory Research;Mammalian Cell;Mission;Molecular Medicine;Phase;Photons;Production;Protein Chemistry;Proteins;Recombinant Proteins;Research;Research Personnel;Resources;Schedule;Series;Services;Source;Structural Biologist;Structure;Techniques;Time;Titrations;Training;Universities;Work;X-Ray Crystallography;Yeasts;analytical ultracentrifugation;biophysical properties;cell type;design;equipment acquisition;experience;experimental study;instrument;instrumentation;light scattering;macromolecule;member;mid-career faculty;operation;outreach;outreach program;recruit;structural biology;summer program;tissue culture;web site

public_health_relevance:
This Protein Core in the Center for Molecular Medicine provides a variety of services aimed at the production and characterization of proteins for investigator inflated biomedical research. The Core makes available well maintained instruments and facilities not generally found in individual research labs and provides both training in their use and expert guidence. In addition service projects carried out by Core personnel are undertaken.


application_id: 9479179
project_number: 5P30GM110787-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2018-03-21
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
project_end_date: 2021-04-30
study_section: ZGM1-TWD-C
subproject_number: 6090
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
budget_start_date: 2018-05-01
project_abstract:
The Administrative Core will provide the administrative oversight for the Center for Molecular Medicine and the COBRE resources designed to build and strengthen the Center. The Administrative Core under the direction of Lou Hersh the COBRE PI and Sidney Whiteheart Program Coordinator will provide leadership oversight and coordination of the various activities associated with the Ceriter and it COBRE resources. The Administrative Core will facilitate and implement the goals and objectives of this COBRE and facilitate the transition of the Center for Molecular Medicine and its associated Cores to a sustainable independent status. The Administrative Core will provide oversight of the various activities associated with the COBRE grant including its voucher program its pilot grant program its mentoring activities and its scientific cores. The Administrative Core will work with the Intemal and External Advisory Committees and the Core directors and to meet our goals and objectives. The Administrative Core will oversee the budgets associated with the COBRE coordinate the various mentoring and Advisory Board meetings track core usage prepare reports etc. The specific objectives of the Administrative Core include enhancing and sustaining the infrastructure of the Center for Molecular Medicine including its research core facilities increasing the critical mass of investigators whose research focuses on the molecular basis of human disease fostering new collaborative and novel research in the Center providing a foundation for investigators to obtain extramural research support and to expand and develop educational activities through the scientific cores. The Administrative Core will use a number of approaches to facilitate faculty mentoring especially for junior untenured faculty to enhance educational initiatives associated with the Center and its cores to optimally use the pilot grant program to enhance competitive research to facilitate programmatic grant development and to develop collaborations with other IDeA centers and institutions in the region.

project_terms:
Achievement;Advisory Committees;Basic Science;Biochemistry;Budgets;Centers of Research Excellence;Collaborations;Core Facility;Data;Department chair;Development;Educational Activities;Equipment;Extramural Activities;Faculty;Fostering;Foundations;Goals;Grant;Head;Institution;Kentucky;Leadership;Medicine;Mentors;Mission;Molecular;Molecular Medicine;Performance;Phase;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Resources;Running;Services;Solid;Techniques;Technology;Universities;Work;college;design;faculty mentor;human disease;meetings;new technology;novel;programs;recruit;tool;voucher

public_health_relevance:
This Administrative Core will oversee all of the activities of this COBRE including the scientific cores the voucher program and the pilot grant program.


application_id: 9479172
project_number: 5P30GM110787-05
project_title: COBRE for the Center for Molecular Medicine
administering_ic: NIGMS
award_notice_date: 2018-03-21
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110787
program_official: FRINCU, CRINA
project_start_date: 2014-07-01
project_end_date: 2021-04-30
study_section: ZGM1-TWD-C(3C)
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This COBRE Phase III proposal aims to further develop the Center for Molecular Medicine at the University of Kentucky. This Center focuses on research aimed at understanding the molecular mechanisms associated with human disease with emphases on cancer neurodegenerative diseases diabetes and cardiovascular diseases. We propose to transition to independence the research infrastructure developed during previous COBRE funding. Our COBRE funded Center for Molecular Medicine has had a number of successes. During the previous funding period 30 junior faculty from 12 different departments and centers were funded as COBRE project or pilot grant PIs. These mentored faculty received 27 NIH ROI grants 11 other NIH grants and 41 other peer-reviewed extramural grants. The COBRE-supported junior faculty published more than 400 research papers. These and other successes can in large part be attributed to a strong mentoring program excellent institutional support and the availability of the scientific cores associated with the Center. For this application we propose to transition the Center for Molecular Medicine and its three scientific cores to independence of NIH/NIGMS support and to enhance and upgrade core technologies. 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 COBRE supported Imaging core is soon to become a department supported core. During the proposed five-year transition period we will increase the critical mass of faculty associated with the Center and continue to enhace its Cores. The use of vouchers will promote core usage and pilot grants will develop research collaborations and competitive grant submissions. The Administrative Core will serve as the focal point of the grant and in conjunction with the Program Coordinator and Internal Advisory Committee will serve as the operational arm of the Center. An External Advisory Committee consisting of world-renown scientists will provide ongoing assessment and evaluation of the Center. Continuing Institutional commitments will ensure programmatic growth and long-term sustainability.

project_terms:
Advisory Committees;Cardiovascular Diseases;Centers of Research Excellence;Collaborations;Diabetes Mellitus;Ensure;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Funding;Grant;Growth;Image;Institution;Kentucky;Malignant Neoplasms;Mentors;Molecular;Molecular Medicine;National Institute of General Medical Sciences;Neurodegenerative Disorders;Paper;Peer Review;Phase;Proteomics;Publishing;Research;Research Infrastructure;Scientist;Technology;Translational Research;United States National Institutes of Health;Universities;arm;faculty mentor;human disease;mid-career faculty;programs;public health relevance;success;voucher

public_health_relevance:
PUBLIC HEALTH RELEVANCE: 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 research at the University of Kentucky and other regional institutions.


application_id: 9479159
project_number: 5P30ES026529-02
project_title: Pilot Project Program
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7095
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: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Advertisements;Advertising;Appalachian Region;Area;Award;Budgets;Categories;Clinical Sciences;Collaborations;Communities;Data;Development;Dimensions;Discipline;Disease;Ecology;Electronic Mail;Emerging Technologies;Ensure;Environmental Exposure;Environmental Health;Environmental Medicine;Evaluation;Faculty;Fostering;Funding;Funding Opportunities;Generations;Goals;Grant;Human Biology;IACUC;Institutional Review Boards;Investigation;Kentucky;Leadership;Legal patent;Manuscripts;Mission;Monitor;National Institute of Environmental Health Sciences;Pilot Projects;Publishing;Research;Research Personnel;Research Support;Resources;Scientist;Supervision;System;Time;Translational Research;United States National Institutes of Health;Universities;Work;career;community organizations;design;early-career faculty;electronic data;experience;faculty support;health science research;high risk;improved;innovation;interest;meetings;new technology;next generation;novel;programs;research study;success;synergism;web site


application_id: 9479158
project_number: 5P30ES026529-02
project_title: Community Outreach and Engagement Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7094
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN 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: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Academic Training;Acute;Address;Advocacy;Air;Appalachian Region;Area;Area Health Education Centers;Awareness;Basic Science;Cardiovascular Diseases;Chemicals;Child Health;Chronic Obstructive Airway Disease;Colorectal Cancer;Communication;Communities;Community Health;Community Outreach;Complex;Decision Making;Development;Diabetes Mellitus;Disease;Ecology;Educational Background;Educational workshop;Employment;Enrollment;Ensure;Environmental Exposure;Environmental Health;Environmental Risk Factor;Event;Exposure to;Focus Groups;Goals;Healthcare;Heavy Metals;Interest Group;Kentucky;Knowledge;Laws;Lead;Link;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic Diseases;Mining;Mission;Modality;Modeling;Nature;Obesity;Outcome;Particulate;Plague;Positioning Attribute;Poverty;Pulmonary Heart Disease;Radon;Recording of previous events;Research;Research Personnel;Resources;Rivers;Rural;Science;Trust;Voice;Work;career development;dissemination research;early life exposure;health literacy;malignant breast neoplasm;member;operation;organizational structure;outreach;population health;programs;research data dissemination;self reliance;social media;success;water quality;web site;working group


application_id: 9479156
project_number: 5P30ES026529-02
project_title: Integrative Health Sciences Facility Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7092
contact_pi_person_id: 6457660
contact_pi: BAUER, JOHN ANTHONY
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: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Address;Affect;Air;Analytical Chemistry;Animal Model;Animals;Appalachian Region;Area;Basic Science;Biological;Biological Models;Biometry;Cancer Center;Cell Culture Techniques;Cells;Clinical;Clinical Informatics;Clinical Research;Clinical Sciences;Coal;Communication;Communities;Complex;Core Facility;Development;Disadvantaged;Disease;Ecology;Elements;Environmental Health;Environmental Risk Factor;Evaluation;Exposure to;Fostering;Funding;Gases;Geology;Goals;Health;Health Sciences;Heavy Metals;High Prevalence;Institution;Integrative Medicine;Interest Group;Intervention Studies;Kentucky;Life;Link;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic Diseases;Mining;Modeling;Outcome;Particulate;Pediatric Hospitals;Pilot Projects;Poisons;Population;Population Research;Population Sciences;Population Study;Public Health;Public Health Practice;Pulmonary Heart Disease;Radon;Research;Research Activity;Research Design;Research Infrastructure;Research Personnel;Research Project Grants;Research Proposals;Resources;Rivers;Rural Health;Rural Population;Sampling;Scientist;Services;Specimen;Structure;Support System;Time;Tobacco smoke;Tobacco use;Toxicology;Translational Research;United States;Universities;Work;base;career;clinical practice;data management;design;early life exposure;epidemiology study;flexibility;hazard;health disparity;improved;instrumentation;interest;laboratory equipment;lung injury;member;patient oriented;pre-clinical research;programs;recruit;research and development;success;tobacco exposure;translational study


application_id: 9479155
project_number: 5P30ES026529-02
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2018-03-23
opportunity_number: RFA-ES-16-001
application_type: 5
activity_code: P30
ic: ES
serial_number: 026529
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 7091
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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: 2018-04-01
budget_end_date: 2019-03-31
project_terms:
Affect;Appalachian Region;Applications Grants;Area;Award;Clinical;Collaborations;Communication;Communication Research;Communities;Community Outreach;Core Facility;Data;Decision Making;Development;Disadvantaged;Disease;Ecology;Effectiveness;Employment;Ensure;Environment;Environmental Health;Environmental Impact;Environmental Risk Factor;Event;Goals;Group Meetings;Health;Health education;Individual;Interest Group;Journals;Kentucky;Leadership;Life;Malignant Neoplasms;Measures;Medicine;Metabolic Diseases;Mission;Monitor;Newsletter;Outcome;Pilot Projects;Play;Population;Process;Productivity;Program Development;Publications;Pulmonary Heart Disease;Records;Research;Research Infrastructure;Research Personnel;Resource Sharing;Resources;Retreatment;Role;Rural Population;Science;Scientist;Series;Socioeconomic Status;Strategic Planning;Time;Training;Translations;Universities;career;career development;citizen science;college;design;innovation;interest;meetings;member;operation;programs;skills;success


application_id: 9478869
project_number: 5P50AA024337-03
project_title: Mechanisms of Alcohol-Induced Lung and Liver Injury
administering_ic: NIAAA
award_notice_date: 2018-05-25
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8305
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
Chronic ethanol abuse leads to increased susceptibility to acute lung injury (ALI) and mortality in the setting of sepsis. We believe that this is due in part to alterations in the expression of tissue remodeling genes that prime the lung to disrepair after injury. This is supported by our own findings showing that lungs harvested from rodents treated with ethanol show increased expression of fibronectin matrix metalloproteinases and transforming growth factor ; we also demonstrated activation of matrix remodeling in alcoholics. Together with changes in oxidative stress and epithelial cell dysfunction these alterations represent key features of what has been termed the alcoholic lung phenotype. Despite the above advances we still do not understand the mechanisms that lead to these changes nor the role of matrix remodeling in the alcoholic lung. Importantly the mechanisms by which these changes render the lung susceptible to disrepair after injury remain unclear. We hypothesize that chronic ethanol promotes redox stress that triggers extracellular matrix (ECM) remodeling resulting in the `re-pavement' of the lung with a `pro-inflammatory' ECM characterized by increased expression of fibronectin EDA and collagen V two molecules implicated in tissue disrepair. Upon injury of the alcoholic lung epithelial cells trying to populate denuded areas become exposed to this aberrant ECM resulting in increased permeability while incoming immune cells exposed to this ECM experience exaggerated activation. Together these processes enhance inflammation and epithelial cell dysfunction leading to disrepair and ultimately ALI. We have observed similar derangements in the aging lung and speculate that ethanol-induced redox stress promotes accelerated aging of the lung through epigenetic modifications that drive ECM remodeling. Our hypothesis is supported by several in vivo studies demonstrating a role for the ECM in the lung's response to injury. Second we showed that primary lung cells harvested from ethanol-treated animals deposit a pro-inflammatory matrix. Third we found that alveolar epithelial cells cultured on different matrices show alterations in their expression of claudins resulting in barrier dysfunction. Fourth like ethanol we found that aging also promotes ECM remodeling and this defect is associated with epigenetic histone modifications that drive fibronectin gene expression; we speculate that similar mechanisms are taking place here. Finally recent studies in our laboratory suggest that the above effects might be dependent on ethanol-induced redox stress and could potentially be ameliorated by dietary interventions targeting redox stress. We aim to test the hypothesis in specific aims designed to: 1) Examine the effects of ethanol-induced ECM remodeling on immune cells and epithelial cells in vitro and explore its role in susceptibility to ALI in vivo; 2) Examine ethanol- dependent gene-specific promoter-associated epigenetic modifications regulating ECM gene expression in lung fibroblasts; and 3) Investigate how ethanol-induced redox stress promotes ECM remodeling and determine the effect of anti-oxidant dietary interventions on ethanol-induced ECM remodeling and susceptibility to ALI.

project_terms:
Acute Lung Injury;Aging;Alcohol abuse;Alcohols;Alveolar;Animals;Antioxidants;Area;Cell surface;Cells;Chronic;Collagen;Complement Factor B;Cultured Cells;Defect;Deposition;Development;Dietary Intervention;Epigenetic Process;Epithelial Cells;Ethanol;Ethanol dependence;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Functional disorder;Gene Expression;Genes;Glycoproteins;Growth Factor;Harvest;Immune;In Vitro;Income;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Laboratories;Lead;Lung;Matrix Metalloproteinases;Modeling;Modification;Mus;Nicotinic Receptors;Organ;Organ Transplantation;Oxidation-Reduction;Oxidative Stress;Permeability;Phenotype;Play;Predisposition;Process;Production;Rodent;Role;Sepsis;Stress;Testing;Tissues;Transforming Growth Factors;Work;alcohol effect;cytokine;design;experience;histone modification;in vivo;indium-bleomycin;injury and repair;liver injury;lung injury;monocyte;monolayer;mortality;nutrition;problem drinker;programs;promoter;response to injury;sensor


application_id: 9478867
project_number: 5P50AA024337-03
project_title: HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis
administering_ic: NIAAA
award_notice_date: 2018-05-25
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8303
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
There is increasing evidence that demonstrates a critical pathogenic role for the gut-liver axis in the development of alcoholic liver disease (ALD). The major goal of this proposal is to conduct studies that determine the mechanisms underlying chronic alcohol induced pathogenic changes in the gut-liver axis leading to ALD. Chronic alcohol consumption-mediated enteric microbiota (dysbiosis) and impairment of the gut barrier function leads to increased intestinal permeability and exposes the liver to gut-derived microbial products including endotoxin. The consequent hepatic steatosis and inflammation can in turn promote gut dysfunction. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiome and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Significantly the alcohol-induced intestinal and hepatic pathogenic changes were markedly attenuated by supplementation with the probiotic Lactobacillus rhamnosus Gorbach-Goldin (LGG).  There is gathering evidence and increasing interest regarding the contributory role of epigenetic mechanisms in the development of ALD. In this regard it has been observed that histone associated epigenetic modifications play a significant role in the development of hepatic pathology induced by chronic as well as binge alcohol exposure. Our recent work showed that binge alcohol treatment decreases hepatic class I II and IV HDACs with a sole increase in HDAC3 and a correspondent increase in the global hepatic histone H3 acetylation (H3Ac) status. Subsequently we demonstrated that increased HDAC3 plays a critical role in the binge alcohol-induced suppression of the carnitine palmitoyltransferase 1 (Cpt1a) gene expression and development of hepatic steatosis. Besides altered hepatic HDAC expression our recent preliminary data also show that chronic ethanol feeding leads to a significant increase in the intestinal HDAC1 expression. Accordingly the current proposal examines the unifying hypothesis that chronic alcohol induced alterations in the intestinal as well as hepatic HDACs and histone modifications constitute critical epigenetic mechanisms driving the abnormal gut-liver axis and liver disease. Importantly the proposal also pursues translational studies that examine the efficacy of nutrition based therapeutic interventions targeted at intestinal dysbiosis and HDAC inhibition in mitigating alcohol-induced gut-liver axis changes and liver disease. The specific aims of the proposal are: Aim 1 - Determine the effect of chronic alcohol on intestinal and hepatic HDAC expression and global histone modifications underlying gut-liver axis changes in ALD; Aim 2 - Determine the impact of alcohol-induced HDAC alterations on gene-specific histone modifications and consequent pathogenic expression affecting the gut-liver axis in ALD and; Aim 3 - Evaluate the efficacy of nutrition-based therapeutic interventions in ALD. We expect that the results of our study will provide critical molecular insights and facilitate the development of therapeutic interventions for ALD.

project_terms:
Acetylation;Affect;Alcoholic Liver Diseases;Alcohols;Attenuated;Automobile Driving;Bacteria;Butyrates;Carnitine O-Palmitoyltransferase;Chronic;Data;Development;Diet;Endotoxemia;Endotoxins;Enteral;Epigenetic Process;Ethanol;Fatty Acids;Fatty Liver;Functional disorder;Gene Expression;Genes;Goals;Gram-Negative Bacteria;HDAC1 gene;HDAC3 gene;Hepatic;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Impairment;Inflammation;Injury;Intestinal permeability;Intestines;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Liver;Liver diseases;Mass Spectrum Analysis;Mediating;Modification;Molecular;Organ;Pathogenesis;Pathogenicity;Pathology;Permeability;Play;Prevention strategy;Probiotics;Prodrugs;Proteomics;Role;Testing;Therapeutic Intervention;Work;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;dysbiosis;epigenetic regulation;feeding;gut microbiome;gut microbiota;gut-liver axis;histone modification;insight;interest;lipid metabolism;metabolomics;microbial;nutrition;probiotic supplementation;programs;promoter;therapeutic development;translational study;treatment strategy;tributyrin


application_id: 9478866
project_number: 5P50AA024337-03
project_title: Role of Dietary Fat in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2018-05-25
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8302
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the US and worldwide. Although substantial progress has been made in ALD pathogenesis the specific mechanism(s) responsible for ALD development and progression remain incompletely understood. Importantly there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others demonstrated that dietary unsaturated fat rich in linoleic acid (LA) increased intestinal permeability to gut-derived endotoxins and exacerbated liver inflammation and injury in an experimental animal model of ALD. In addition our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs) specifically 9- and 13-hydroxy- octadecadienoic acids (9-and 13-HODEs) and concomitant up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) the key enzyme involved in the oxidation of LA. These findings suggest that OXLAMs which act as natural ligands to the transient receptor potential vanilloid 1 (TRPV1 subfamily V member 1) contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of interleukin-1 (IL-1) and interleukin-18 (IL-18) is an important pro- inflammatory response in ALD. Many factors are involved in inflammasome priming and activation network including gut-derived endotoxin lipopolysaccharide (LPS). These findings in conjunction with our preliminary data have led us to hypothesize that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol- mediated liver inflammation and injury via oxidized linoleic acid metabolites that induce gut barrier disruption and hepatic inflammasome activation. To address our hypothesis we propose the following four specific aims: Aim 1. Determine the role of dietary unsaturated fat specifically linoleic acid and its oxidation products in the development and/or progression of ALD. Aim 2. Assess whether hepatic inflammasome activation is mediated by OXLAMs-TRPV1-Ca2+ pathway in an animal model of ALD. Aim 3. Evaluate the molecular mechanism(s) by which dietary saturated fat attenuates and unsaturated fat exacerbates alcohol- mediated gut barrier disruption endotoxemia and liver injury. Aim 4. Explore the role of OXLAMs 12/15-LO and TRPV1 in monocyte inflammasome activation in human alcoholic hepatitis. The proposed studies will lead to a better understanding of the molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to better understand alcohol-diet interactions which may lead to identification of new drug targets and potential dietary interventions for treating ALD as well as help to explain why only some people who drink heavily develop clinically important ALD. This proposal extensively interacts with other projects pilots and cores and it incorporates the ULARC theme of nutrition and alcohol-induced organ injury.

project_terms:
Address;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Clinical;Data;Development;Diet;Dietary Fats;Dietary Intervention;Down-Regulation;Endotoxemia;Endotoxins;Enzymes;Experimental Animal Model;FDA approved;Genetic;Heavy Drinking;Hepatic;Human;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Injury;Interleukin-1 beta;Interleukin-18;Intestinal permeability;Intestines;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Lipopolysaccharides;Mediating;Molecular;Morbidity - disease rate;Oral;Organ;Oxides;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Permeability;Pharmacology;Play;Production;Proteins;Role;Severities;Signal Pathway;Supplementation;TRPV1 gene;Testing;Tight Junctions;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;fecal metabolome;gut microbiome;human study;liver inflammation;liver injury;member;monocyte;mortality;new therapeutic target;nutrition;octadecadienoic acid;overexpression;oxidation;peripheral blood;prevent;programs;receptor;saturated fat


application_id: 9478865
project_number: 5P50AA024337-03
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2018-05-25
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8301
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
Abstract: The primary function of Omics Core is to provide members of the ULARC with the expertise resources and facilities needed for metabolomic proteomic and bioinformatic analyses of biological samples collected to study liver injury nutrition gut:liver interactions and liver:environment/toxicant/drug interactions. OMICS Core personnel will assist with the design of sample collection protocols will drive the development and the execution of novel and robust chromatographic methods for sample separation and mass spectrometric methods for the analysis of proteins peptides and metabolites with a goal of providing a greater understanding of the evolution of molecular mechanisms that correlate with or participate in liver dysfunction. The core will ensure uniformity and standardization in sample preparation method development instrument performance data collection data reporting and data sharing. The Core endeavors to contribute to the overall success and utility of the ULARC and to enhance the infrastructure and the technical and academic capabilities of the institution as a whole. In addition to its function as a service core we will also promote the education and training of the ULARC members with regards to state-ofthe-art Omics and Bioinformatics methods; with particular attention to the ULARC junior investigators.

project_terms:
Acids;Acrolein;Affinity;Alcoholic Liver Diseases;Alcohols;Animals;Attention;Attenuated;Automobile Driving;Bioinformatics;Biological;Biotin;Blood;Blood specimen;Body Weight;Cell Line;Cells;Chronic;Complex Mixtures;Curcumin;Data;Data Collection;Data Reporting;Data Set;Development;Drug Interactions;Embryo;Endotoxemia;Ensure;Environment;Epigenetic Process;Exposure to;Extracellular Matrix;Feces;Fibroblasts;Gas Chromatography;Ginger;Goals;Grapefruit;Hepatic;High Pressure Liquid Chromatography;Histone Acetylation;Histones;Human Resources;Inflammation;Injury;Institution;Interleukin-2;Intestines;Lactobacillus casei rhamnosus;Liquid substance;Liver;Liver Dysfunction;Liver diseases;Lung;Lysine;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Methodology;Methods;Molecular;Molecular Evolution;Mus;Neural Crest Cell;Oral;Organ;Pathogenicity;Pattern;Peptides;Performance;Post-Translational Protein Processing;Preparation;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Sampling;Science;Services;Standardization;Sulforaphane;Techniques;Technology;Time;Tissue Sample;Tissues;Training and Education;Transcriptional Regulation;Unsaturated Fats;Urine;alcohol effect;design;exosome;histone methylation;histone modification;instrument;liquid chromatography mass spectrometry;liver injury;long chain fatty acid;male;member;metabolomics;method development;multiple reaction monitoring;nanoparticle;novel;nutrition;phosphoproteomics;programs;response;sample collection;saturated fat;sharing data;success;toxicant;tributyrin;two-dimensional


application_id: 9478562
project_number: 5F30DE025543-04
project_title: Characterization of P. gingivalis minor fimbrial accessory proteins
administering_ic: NIDCR
award_notice_date: 2018-05-11
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: DE
serial_number: 025543
program_official: FRIEDEN, LESLIE A
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11948429
contact_pi: LEE, JAE YONG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease affecting around half the adults over 35 in the United States. Clinical outcomes include damage to periodontal tissues and alveolar bone loss with eventually exfoliation of the teeth. Porphyromonas gingivalis is a keystone pathogen in adult periodontitis and the organism possesses a number of virulence factors that enable colonization of the periodontal area confer resistance to host immunity and mediate destruction of periodontal tissues. P. gingivalis colonization of antecedent oral communities is facilitated by binding to common oral bacteria such as S. gordonii. Attachment of P. gingivalis to S. gordonii is mediated by the short/minor fimbriae of P. gingivalis which interact with the SspA/B streptococcal surface proteins. Communities of P. gingivalis and S. gordonii are more pathogenic in a mouse model of alveolar bone loss compared to either organism alone. The minor/short fimbriae are comprised of the Mfa1 structural subunit and the mfa1 gene is part of a cluster that contains mfa1 mfa2 mfa3 pgn0290 and pgn0291. Mfa2 is an anchoring and length regulating protein. Mfa3 is an accessory protein localized to the fimbrial tip and necessary for the integration of proteins derived from pgn0290 and pgn0291 (which we designate Mfa4 and Mfa5 respectively) into the fimbrial structure. Beyond this however little is known regarding protein interactions supramolecular structure and the functions of Mfa3 4 and 5. We propose 3 specific aims to address these topics: To determine the location of Mfa4 and Mfa5 on the Mfa fimbriae and characterize the binding interactions among Mfa3 4 and 5; to determine the role of Mfa3 Mfa4 and Mfa5 in P. gingivalis co-adhesion to S. gordonii; and to determine the role of Mfa3 Mfa4 and Mfa5 in polymicrobial synergy in vivo. The findings from this study will provide novel structural and functional detail of an important virulence factor of P. gingivalis. This has the potential to lead to the design of new therapeutics to target the effector molecules of P. gingivalis colonization and prevent the accumulation of P. gingivalis into polymicrobially synergistic communities.

project_terms:
Address;Adhesions;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Animals;Area;Binding;Binding Proteins;Biogenesis;Biological Assay;Cell surface;Chronic;Chronic Disease;Clinical;Communities;Complement;Complex;Development;Disease;Electron Microscopy;Epithelial Cells;Exhibits;Filament;Gene Cluster;Genes;Goals;Homeostasis;Immune;Immune response;Immunity;Individual;Infection;Inflammatory;Lead;Left;Length;Location;Mediating;Membrane Proteins;Minor;Molecular;Mouth Diseases;Oral;Oral cavity;Oral health;Organism;Outcome;Pathogenesis;Pathogenicity;Periodontitis;Population;Porphyromonas gingivalis;Process;Protein Subunits;Proteins;Recombinant Proteins;Research;Resistance;Role;Severities;Streptococcus gordonii;Structure;Surface;Testing;Therapeutic Studies;Tissues;Tooth Exfoliation;Tooth Loss;United States;Virulence Factors;bone loss;co-infection;design;dysbiosis;immunoregulation;improved;in vivo;mouse model;mutant;new therapeutic target;novel;novel therapeutics;oral bacteria;pathogen;prevent;protein complex;public health relevance;synergism;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontitis is a prevalent oral disease that can ultimately lead to tooth loss. In this project we shall study the means by which one of major causative agents of periodontitis establishes itself in the mouth. This has the potential to identify therapeutic targets which in turn can be included in oral health products designed to mitigate the severity of periodontitis.


application_id: 9478181
project_number: 5R25ES027684-02
project_title: Summer Research in Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2018-04-26
opportunity_number: PAR-15-184
application_type: 5
activity_code: R25
ic: ES
serial_number: 027684
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-05-01
project_end_date: 2022-04-30
study_section: ZES1-LKB-J(R)1
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
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:
Address;Affect;Appalachian Region;Area;Communities;Critical Thinking;Development;Ecology;Economics;Educational workshop;Elevator;Engineering;Environment;Environmental Health;Ethics;Evaluation;Faculty;Film;Future;Goals;Individual;Interview;Kentucky;Laboratories;Life;Measures;Mentors;Mission;National Institute of Environmental Health Sciences;Nature;Oral;Outcome;Play;Population Heterogeneity;Postdoctoral Fellow;Professional Competence;Reporting;Research;Research Project Grants;Research Training;Role;Safety;Science;Scientist;Speech;Students;Surveys;Technology;Training;Training Programs;Underrepresented Students;United States;Universities;Work;career;collaborative environment;college;design;experience;experimental study;faculty mentor;global health;hands on research;health science research;improved;interest;member;movie;multidisciplinary;outreach;peer;posters;programs;recruit;research facility;retention rate;skills;social;stem;student mentoring;student participation;success;summer program;summer research;undergraduate education;undergraduate research;undergraduate student


application_id: 9478006
project_number: 261201300013I-4-26100005-3
administering_ic: NCI
project_start_date: 2015-05-01
project_end_date: 2018-04-30
contact_pi_person_id: 14511283
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF CORE INFRASTRUCTURE SUPPORT FOR SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PERIOD OF PERFORMANCE: 05/01/2015 TO 04/30/2017

project_abstract:
The aim of this Task Order modification is to support a pilot test to obtain medical claims data from Unlimited System a medical claims aggregator (also referred to as a clearinghouse). Medical claims aggregators receive edits and submit insurance claims from medical practices. Working through a medical claims aggregator will ensure that this pilot test is conducted in the most efficient and cost effective manner because the desired oncology practice will be able to be recruited directly through the aggregator and once recruited the aggregator will directly submit their claims data. Also since oncology practices are required to by law to submit data on newly diagnosed cases of cancer it is hoped that the option of claims aggregator submitted data will prove appealing. The goal of this pilot is to evaluate the feasibility of utilizing medical claims data to obtain longitudinal treatment data.

project_terms:
Data;Ensure;Goals;Insurance;Laws;Malignant Neoplasms;Medical;Modification;Newly Diagnosed;Recruitment Activity;Research Infrastructure;SEER Program;System;Testing;cost effective;oncology


application_id: 9478005
project_number: 261201300013I-4-26100005-2
administering_ic: NCI
project_start_date: 2015-05-01
project_end_date: 2018-04-30
contact_pi_person_id: 14511283
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
IGF::OT::IGF CORE INFRASTRUCTURE SUPPORT FOR SURVEILLANCE EPIDEMIOLOGY AND END RESULTS (SEER) PERIOD OF PERFORMANCE: 05/01/2015 TO 04/30/2017

project_abstract:
The SEER Program was initiated in 1972 in response to requirements of the National Cancer Program for assessing the magnitude of the cancer burden in the United States and for identifying factors related to cancer risk and/or patient survival. The SEER Program has among its objectives: 1.         To assemble and report on a periodic basis estimates of cancer incidence. 2.         To monitor annual cancer incidence trends to identify unusual changes in specific forms of cancer occurring in population subgroups defined by geographic demographic and social characteristics. 3.         To provide continuing information on changes over time in extent of disease at diagnosis trends in therapy and changes in cancer patient survival. 4.         To identify the occurrence of possible iatrogenic cancers i.e. cancers that are caused by cancer therapy. 5.         To serve as a research resource to the National Cancer Institute and conduct studies dealing with current cancer control issues as well as problems related to the operation of the SEER Program.

project_terms:
Cancer Burden;Cancer Control;Cancer Etiology;Cancer Patient;Diagnosis;Disease;Geography;Incidence;Malignant Neoplasms;Monitor;National Cancer Institute;National Cancer Program;Patients;Periodicity;Population;Reporting;Research Infrastructure;Resources;SEER Program;Social Characteristics;Subgroup;Time;Treatment-Related Cancer;United States;cancer risk;cancer therapy;operation;response;trend


application_id: 9477243
project_number: 1U18FD006228-01
project_title: Conformance with the Manufactured Food Regulatory Program Standards (MFRPS) (U18)
administering_ic: FDA
award_notice_date: 2017-08-01
opportunity_number: RFA-FD-17-005
application_type: 1
activity_code: U18
ic: FD
serial_number: 006228
program_official: WEED, BRETT
project_start_date: 2017-08-05
project_end_date: 2019-07-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 15008074
contact_pi: GILLIS, REBECCA
other_pis: HENDREN, PAMELA
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
KENTUCKYCABINETFORHEALTHANDFAMILYSERVICESDEPARTMENTFORPUBLICHEALTHRFAFD17005CONFORMANCEWITHTHEMANUFACTUREDFOODREGULATORYPROGRAMSTANDARDS(MFRPS)(U18)SUMMARYThegoaloftheKentuckyFoodSafetyBranchcontinuestobeanactiveparticipantinthenationallyintegratedfoodprotectionsystem.ChiefinaccomplishingthisgoalaswellasthegoalofcontinuingprogramimprovementisparticipationintheMFRPS.ThefiveyearCooperativeFundingAgreementhasallowedourstatefoodprotectionprogramtoaddressmanyoftheidentifiedgapsandobstaclesidentifiedandhasallowedouragencytoimplementafullyfunctionalMFRPSprograminKentuckyandwillultimatelyallowourstatetoachieveandsustainsignificanttofullconformancewiththeMFRPS.InsummarytheintendedoutcomeoftheCooperativeAgreementFundingApplicationistofurtheradvanceeffortsforanationallyintegratedfoodsafetysystembyutilizingavailablefederal(FDA)fundingassistancetoallowKentucky'sStateManufacturedFoodRegulatoryProgramtoachieveandmaintainfullconformancewiththeManufacturedFoodRegulatoryProgramStandards(MFRPS).TheMFRPSprogramfundingwillbeutilizedtoensurethatKentucky'smanufacturedfoodregulatoryprogramsdevelopandmaintainbestpracticesforahighqualityregulatoryprogram.FullparticipationinMFRPSprogramwillassistourfederal(FDA)partnersinestablishingauniformbasisformeasuringandimprovingtheperformanceofmanufacturedfoodregulatoryprogramsintheUnitedStates.

public_health_relevance:
TheintendedoutcomeoftheCooperativeAgreementFundingApplicationistofurtheradvanceeffortsforanationallyintegratedfoodsafetysystembyutilizingavailablefederal(FDA)fundingassistancetoallowKentucky'sStateManufacturedFoodRegulatoryProgramtoachieveandmaintainfullconformancewiththeManufacturedFoodRegulatoryProgramStandards(MFRPS).TheMFRPSprogramfundingwillbeutilizedtoensurethatKentucky'smanufacturedfoodregulatoryprogramsdevelopandmaintainbestpracticesforahighqualityregulatoryprogram.FullparticipationinMFRPSprogramwillassistourfederal(FDA)partnersinestablishingauniformbasisformeasuringandimprovingtheperformanceofmanufacturedfoodregulatoryprogramsintheUnitedStates.


application_id: 9477020
project_number: 5P20GM103436-18
project_title: UK Program Evaluation Budget
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 6139
contact_pi_person_id: 10372051
contact_pi: STONE, RAMONA-ELENA FLOREA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
The Kentucky INBRE serves a statewide mission to build a sustainable infrastructure with a capacity forbiomedical and health-related research and research training. In this application the two research intensiveinstitutions the University of Louisville and the University of Kentucky will partner with our regionalcomprehensive affiliates including Eastern Kentucky University Morehead State University NorthernKentucky University and Western Kentucky University and with a number of outreach institutions tocontinue the development of a highly collaborative and successful network. The goal of our network is tobuild competitive research which will serve as the foundation for excellent training of our students in thebiomedical and health-related sciences. We plan to develop and grow our multi-disciplinary researchnetwork with an overarching theme of functional genomics. With an emphasis on sustainability we willcontinue to fund developmental research projects for our junior investigators while providing criticalmentoring as well as the requisite infrastructure support for genomics and bioinformatics Our centralizedgenomics core facility will provide access to state-of-the-art equipment for microarray and next generationsequencing technologies along with qualified technical support. Similarly we will continue to build a criticalmass of expertise and infrastructure in bioinformatics to provide data analysis services for high contentand/or high throughput data. We have built undergraduate and graduate training programs in bioinformatics.In the rapidly changing world of biomedical research these facilities and services are essential to providing apathway to independence for our next generation of investigators. We will provide junior faculty with ail of thetools necessary to become independent investigators thereby building network sustainability and at thesame time provide for high quality research training experiences for our students. In summary our strategyis designed to build a sustainable infrastructure with capacity for biomedical and health-related research aridresearch training. This strategy will aid the development of a highly skilled workforce in the Commonwealthof Kentucky.

project_terms:
Bioinformatics;Biomedical Research;Budgets;Core Facility;Data;Data Analyses;Development;Equipment;Faculty;Foundations;Funding;Genomics;Goals;Health;Institution;Instruction;Interdisciplinary Study;Kentucky;Mentors;Mission;Pathway interactions;Program Evaluation;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Science;Services;Students;Technology;Time;Training;Training Programs;Universities;design;experience;functional genomics;next generation;next generation sequencing;outreach;programs;research facility;tool;undergraduate student

public_health_relevance:
RELEVANCE (See instructions):This INBRE program is designed to build infrastructure and support activities to enhance biomedicalresearch and research training in Kentucky.


application_id: 9477019
project_number: 5P20GM103436-18
project_title: Morehead State Lead Faculty Award
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 6137
contact_pi_person_id: 1973824
contact_pi: DENNIS, DOUGLAS E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
The Kentucky INBRE serves a statewide mission to build a sustainable infrastructure with a capacity forbiomedical and health-related research and research training. In this application the two research intensiveinstitutions the University of Louisville and the University of Kentucky will partner with our regionalcomprehensive affiliates including Eastern Kentucky University Morehead State University NorthernKentucky University and Western Kentucky University and with a number of outreach institutions tocontinue the development of a highly collaborative and successful network. The goal of our network is tobuild competitive research which will serve as the foundation for excellent training of our students in thebiomedical and health-related sciences. We plan to develop and grow our multi-disciplinary researchnetwork with an overarching theme of functional genomics. With an emphasis on sustainability we willcontinue to fund developmental research projects for our junior investigators while providing criticalmentoring as well as the requisite infrastructure support for genomics and bioinformatics Our centralizedgenomics core facility will provide access to state-of-the-art equipment for microarray and next generationsequencing technologies along with qualified technical support. Similarly we will continue to build a criticalmass of expertise and infrastructure in bioinformatics to provide data analysis services for high contentand/or high throughput data. We have built undergraduate and graduate training programs in bioinformatics.In the rapidly changing world of biomedical research these facilities and services are essential to providing apathway to independence for our next generation of investigators. We will provide junior faculty with ail of thetools necessary to become independent investigators thereby building network sustainability and at thesame time provide for high quality research training experiences for our students. In summary our strategyis designed to build a sustainable infrastructure with capacity for biomedical and health-related research aridresearch training. This strategy will aid the development of a highly skilled workforce in the Commonwealthof Kentucky.

project_terms:
Award;Bioinformatics;Biomedical Research;Core Facility;Data;Data Analyses;Development;Equipment;Faculty;Foundations;Funding;Genomics;Goals;Health;Institution;Instruction;Interdisciplinary Study;Kentucky;Lead;Mentors;Mission;Pathway interactions;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Science;Services;Students;Technology;Time;Training;Training Programs;Universities;design;experience;functional genomics;next generation;next generation sequencing;outreach;programs;research facility;tool;undergraduate student

public_health_relevance:
RELEVANCE (See instructions):This INBRE program is designed to build infrastructure and support activities to enhance biomedicalresearch and research training in Kentucky.


application_id: 9477018
project_number: 5P20GM103436-18
project_title: Morehead State KBRIN INBRE Project Coordinator
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 6136
contact_pi_person_id: 9258139
contact_pi: MATTINGLY, BRUCE A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_terms:
Bioinformatics;Biomedical Research;Core Facility;Data;Data Analyses;Development;Equipment;Faculty;Foundations;Funding;Genomics;Goals;Health;Institution;Instruction;Interdisciplinary Study;Kentucky;Mentors;Mission;Pathway interactions;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Science;Services;Students;Technology;Time;Training;Training Programs;Universities;design;experience;functional genomics;next generation;next generation sequencing;outreach;programs;research facility;tool;undergraduate student

public_health_relevance:
RELEVANCE (See instructions):This INBRE program is designed to build infrastructure and support activities to enhance biomedicalresearch and research training in Kentucky.


application_id: 9477014
project_number: 5P20GM103436-18
project_title: EKU Lead Faculty Award
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7046
contact_pi_person_id: 10574352
contact_pi: CALIE, PATRICK JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
The KBRIN-Centralized Core Facility otherwise known at the Uofl as the Uofl GG enomics Core Facility has been operating as a merged INBRE-COBRE operation since 2008 although certain individual components were available separately from either the INBRE or COBRE awards since 2001. Its objectives are to provide state of the art genomic related technologies including microarray and deep sequencing services to Uofl researchers as well as to investigators in the KBRIN-affiliated institutions and its outreach institutions across the Commonwealth of Kentucky. Its services are centered around the most advanced and comprehensive platforms of high-density oligonucleotide array technologies offered by Affymetrix Inc. and Agilent Inc as well as the next generation sequencing capabilities of the Jon Torrent PGM platform. These platforms allow standardized analyses of RNA or miRNA expression profiles splice patterns and variations DNA mutations and single nucleotide polymorphism profiles. The Facility ensures that all investigators including clinical faculty and basic science groups will be able to adopt such state-of-the-art technologies for their investigative goals using clinical specimen or animal model or cell culture materials.  Since its inception the Facility has experienced a rapid growth in personnel user numbers and diversity of experimental platforms allocated space attendance in training events and resources for data analysis and mining. It has been an integral part of several funded and/or currently pending individual and multi-investigator Center and Training grant applications the strongest case for its longevity and its continued utility. The Facility is currently a key component of COBRE 8P20GM103482-10 Center of Biomedical Research Excellence in Molecular Targets (D. Miller P.l.) COBRE 8P20GM103453-10 Molecular Determinants of Developmental Defects (R. Greene P.l.) NIGMS- KY-INBRE P20GM103436 KY-IDeA Networks of Biomedical Research Excellence award (N. Cooper P.l.) and training grant NIEHS T32 ES11564 Uofl EElnvironmental Health Sciences Training Program (D. Hein P.l.).

project_terms:
Adopted;Animal Model;Applications Grants;Award;Basic Science;Bioinformatics;Biomedical Research;Biometry;Biotechnology;Cell Culture Techniques;Centers of Research Excellence;Clinical;Computer software;Core Facility;DNA;DNA Sequence Alteration;Data Analyses;Data Collection;Defect;Development;Educational workshop;Ensure;Event;Experimental Designs;Faculty;Funding;Gene Expression;Genetic Transcription;Genomic DNA;Genomics;Genotype;Goals;Grant;Health Sciences;Human;Human Resources;Hybridization Array;Individual;Information Sciences;Institution;Internet;Kentucky;Lead;Libraries;Logistics;Longevity;Manuscripts;Microarray Analysis;Molecular;Molecular Target;Mus;National Institute of Environmental Health Sciences;National Institute of General Medical Sciences;Nursing Faculty;Oligonucleotide Microarrays;Pattern;Preparation;Procedures;Provider;Public Health Schools;RNA;RNA Splicing;RNA amplification;RNA analysis;Research Personnel;Resources;Sample Size;Sampling;Scanning;Services;Single Nucleotide Polymorphism;Specimen;Standardization;Technology;Training;Training Programs;Variant;base;data mining;data resource;deep sequencing;density;experience;medical schools;miRNA expression profiling;next generation sequencing;operation;outreach;rapid growth;tool;transcriptome


application_id: 9477013
project_number: 5P20GM103436-18
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7045
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
Over a decade ago the development of our bioinformatics infrastructure and capabilities was a new focus for the 2 major research institutions in KY because they had clearly recognizable needs associated with the blossoming of the 'omics' era in the life sciences. More recently health-related and biomedical informatics are seen as challenging necessities for clinical and translational research. The recognition of the importance of bioinformatics is being expressed now in the regional institutions because bioinformatics is seen to be an important requirement in the undergraduate science curriculum especially in biology and computer science classes. We will continue to encourage our KBRIN-affiliated regional institutions to integrate bioinformatics into their research and educational missions. In addition we propose to incorporate our KBRIN-outreach institutions into this 'movement' so that a larger proportion of the state's undergraduate student body can be engaged in our overall integrated genomics/bioinformatics research training/education mission.  Our operational model for bioinformatics (Table 10 above) shows that each of our 6 KBRIN primary networked institutions have resources committed to some aspect of bioinformatics whether it be in research training or education. For example Uofils committed to eliminating the bottlenecks in the data-analyses pipeline that currently hold up progress in research. UK similarly is developing a Clinical Translational Science Award (CTSA) supported bioinformatics center in support of translation/clinical research. A most impressive development in bioinformatics infrastructure among our network has to be the 50 member strong Bioinformatics and Information Science Center (BISC) at WKU. The integration of bioinformatics across departments into a Center-like organization at a regional institution has to be a first. Two faculty members associated with this center have participated for several years in the HHMI's SEA-PHAGE program a unique vehicle for introducing genomics/bioinformatics research training/education to undergraduate students. We intend to make use of their experience and expertise together with the core facilities and resources at the 2 research intensive universities to establish a KBRIN-centric genomics/bioinformatics training exercise in our outreach institutions. This will bring our functional genomics theme to an expanded network of undergraduate students (see administrative core). The bioinformatics core narrative is described under the following headings:   (1) Infrastructure (2) Research (3) Education and Training (4) The Next Five Years. (1) Infrastructure: At Uofl we initially had a major problem building interest and collaborations between interdisciplinary/multi-disciplinary investigators on multiple campuses. These include investigators in Anatomical Science and Neurobiology Biochemistry and. Molecular Biology Bioinformatics and Biostatistics on the Health Sciences campus and Chemistry Computer Engineering and Computer Science Biology Psychology and Mathematics on the main/undergraduate campus geographically separated by several miles. To enhance collaboration between these researchers and engage more biomedical researchers a bioinformatics the PI negotiated with the EVPRI and the Dean oUhe School of Medicine to develop a dedicated 1900 ft2 space and a state-of-the-art videoconferencing facility on the University of Louisville's Health Science Campus (Figure 20) in this past 5 year funding cycle. This space is fully operational and allows for KBRIN to further develop bioinformatics research capability and provide a mechanism for keeping close contact with bioinformatics researchers across campus and throughout the state. It is currently inhabited by KBRIN-affiliated researchers and can accommodate visiting faculty from other campuses and/or KBRIN institutions. We hope to grow this space as additional needs and resources become available.

project_terms:
Anatomy;Biochemistry;Bioinformatics;Biological Sciences;Biology;Biomedical Research;Biometry;Chemistry;Clinical Research;Clinical and Translational Science Awards;Collaborations;Computer software;Computers;Core Facility;Data Analyses;Development;Education;Educational Curriculum;Engineering;Exercise;Faculty;Flowers;Funding;Genomics;Geography;Health;Health Sciences;Informatics;Information Sciences;Institution;Mathematics;Mediation;Mission;Modeling;Molecular Biology;Movement;Neurobiology;Output;Psychology;Research;Research Infrastructure;Research Personnel;Research Training;Resources;Science;Training;Training and Education;Translational Research;Universities;Videoconferencing;Visit;biomedical informatics;clinical translation;computer science;experience;functional genomics;interest;medical schools;member;multidisciplinary;outreach;programs;service providers;undergraduate student


application_id: 9477012
project_number: 5P20GM103436-18
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
study_section: ZGM1-TWD-7
subproject_number: 7043
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-05-01
budget_end_date: 2019-04-30
project_abstract:
(1) Purpose of the Core: The purpose of the administrative core is to provide sound management of the INBRE-award on behalf of the network and to provide the network with structure direction and leadership to help grow and expand the network to develop ideas - that often originate from network members - into viable projects and to provide logistical support oversight and evaluation functions and also to aid the development of suitable research training and research mentoring activities (Table 3).

project_terms:
Award;Biomedical Research;Development;Evaluation;Health;Leadership;Logistics;Mentors;Research;Research Infrastructure;Research Training;Structure;Training;Workforce Development;member;sound


application_id: 9477005
project_number: 5P20GM103436-18
project_title: KY IDeA Networks of Biomedical Research Excellence
administering_ic: NIGMS
award_notice_date: 2018-04-26
opportunity_number: PAR-12-205
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
program_official: ARORA, KRISHAN
project_start_date: 2001-09-30
project_end_date: 2019-04-30
study_section: ZGM1-TWD-7(IN)
contact_pi_person_id: 1866398
contact_pi: COOPER, NIGEL G.F.
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Kentucky INBRE serves a statewide mission to build a sustainable infrastructure with a capacity for biomedical and health-related research and research training. In this application the two research intensive institutions the University of Louisville and the University of Kentucky will partner with our regional comprehensive affiliates including Eastern Kentucky University Morehead State University Northern Kentucky University and Western Kentucky University and with a number of outreach institutions to continue the development of a highly collaborative and successful network. The goal of our network is to build competitive research which will serve as the foundation for excellent training of our students in the biomedical and health-related sciences. We plan to develop and grow our multi-disciplinary research network with an overarching theme of functional genomics. With an emphasis on sustainability we will continue to fund developmental research projects for our junior investigators while providing critical mentoring as well as the requisite infrastructure support for genomics and bioinformatics. Our centralized genomics core facility will provide access to state-of-the-art equipment for microarray and next generation sequencing technologies along with qualified technical support. Similarly we will continue to build a critical mass of expertise and infrastructure in bioinformatics to provide data analysis services for high content and/or high throughput data. We have built undergraduate and graduate training programs in bioinformatics. In the rapidly changing world of biomedical research these facilities and services are essential to providing a pathway to independence for our next generation of investigators. We will provide junior faculty with ail of the tools necessary to become independent investigators thereby building network sustainability and at the same time provide for high quality research training experiences for our students. In summary our strategy is designed to build a sustainable infrastructure with capacity for biomedical and health-related research arid research training. This strategy will aid the development of a highly skilled workforce in the Commonwealth of Kentucky.

project_terms:
Bioinformatics;Biomedical Research;Core Facility;Data;Data Analyses;Development;Equipment;Faculty;Foundations;Funding;Genomics;Goals;Health;Institution;Interdisciplinary Study;Kentucky;Mentors;Mission;Pathway interactions;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Science;Services;Students;Technology;Time;Training;Training Programs;Universities;design;experience;functional genomics;next generation;next generation sequencing;outreach;programs;public health relevance;research facility;tool;undergraduate student

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This INBRE program is designed to build infrastructure and support activities to enhance biomedical research and research training in Kentucky.


application_id: 9474293
project_number: 6R44HL129870-03
administering_ic: NHLBI
award_notice_date: 2017-07-07
opportunity_number: PA-14-071
application_type: 6
activity_code: R44
ic: HL
serial_number: 129870
program_official: LEE, ALBERT
project_start_date: 2015-08-01
project_end_date: 2019-02-28
study_section: Special Emphasis Panel[ZRG1-CVRS-C(10)]
contact_pi_person_id: 10459031
contact_pi: BATES, MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079829394
duns_number: 079829394
fips: US
organization_id: 10039078
organization_name: PULSUS MEDICAL, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111162
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-07-05
budget_end_date: 2019-02-28
assistance_listing_number: 93.837
project_title:
Development of a microperforated nanocomposite balloon for intravascular anti-restenotic drug delivery

project_abstract:
Hemodialysis is the most common treatment for kidney failure requiring the passing of blood out of the bodythrough a filter and back into the body. Almost 30% of hemodialysis patients undergo arteriovenous graftprocedures involving the insertion of prosthetic shunts (i.e. synthetic tubes) between artery and veinparticularly in the forearm. With the hemodialysis patient population estimated to reach over 500000 by 2020the number of patients requiring grafts will reach over 150000 (30% of 500000) and most of these grafts willeventually clot. Clotting occurs in these grafts due to blockages that occur in the blood vessel at the outflowsite of the graft. As a result many hemodialysis patients require intervention to open up the narrowing orstenosis of the blood vessel.Currently interventions for clotted grafts involve removal of the clot with a device followed by angioplasty of thevein. Once angioplasty is needed the lesion will keep restenosing and often the patients need additional declotprocedures and repeat angioplasty. While stents are routinely used to open up narrowed arteries they cannotbe implemented in this case. A more mechanically compliant structure is needed. Relatively new drug-coatedballoons (DCBs) are a possible solution. However DCBs inherently exhibit sporadic and unpredictable drugdelivery. Furthermore DCB drug delivery is currently quite inefficient with much of the drug being lostdownstream. This increases the potential for systemic toxicity. In addition chemical agents (excipients) areneeded to control diffusion of the drug coating. These excipients pose a risk of downstream embolism for thepatient. A more efficient safer method of intravascular anti-restenotic drug delivery is needed to improveefficacy and reduce risk of embolism.We propose to develop a nanocomposite-based polymer balloon with microperforations to enable pulsed-flowdrug delivery to the lesion. Using our approach drugs can be efficiently delivered directly to the diseased sitereducing the potential for systemic toxicity. Our intravascular drug delivery system is capable of deliveringdrugs of almost any form from lipophilic drugs to hydrophilic drugs and even combinations thereof.-1-

project_terms:
Adverse reactions;Angioplasty;Animals;Arteries;Back;Biological;Blood;Blood Vessels;Carbon Nanotubes;Caring;Catheters;Chemical Agents;Chemistry;Coagulation Process;Development;Devices;Dialysis procedure;Diffusion;Dimensions;Disease;Drug Delivery Systems;Dysbarism;Embolism;Evaluation;Excipients;Excision;Exhibits;FDA approved;Family suidae;Fee-for-Service Plans;Forearm;Health;Hemodialysis;In Situ;Intervention;Kidney Failure;Laboratories;Lesion;Liquid substance;Manufacturer Name;Measures;Mechanics;Medical;Medical Device;Methods;Modeling;Modification;Monitor;Nylons;Organ Transplantation;Output;Paclitaxel;Patients;Pharmaceutical Preparations;Phase;Physiologic pulse;Polymers;Procedures;Process;Prosthesis;Research Institute;Risk;Safety;Shunt Device;Site;Stenosis;Stents;Structure;Surface;Technology;Testing;Therapeutic Effect;Toxic effect;Tube;Twin Multiple Birth;Validation;Veins;aqueous;base;biocompatible polymer;biomaterial compatibility;common treatment;cost;design;hydrophilicity;improved;in vivo;individualized medicine;lipophilicity;mortality;nanocomposite;novel therapeutics;patient population;polymerization;pressure;restenosis;scale up;systemic toxicity

public_health_relevance:
Project NarrativeThe major challenge for hemodialysis patients is the eventual blockage of arteries occurring near the site in theforearm where the dialysis tubing is inserted. We propose to develop a drug delivery system that will eliminatethese blockages. Our drug delivery system will lower the added care costs currently required to managehemodialysis patients and reduce their mortality risk.-1-


application_id: 9474223
project_number: 5R01NS070899-09
project_title: Regulation signaling and dynamics of glucan phosphatases
administering_ic: NINDS
award_notice_date: 2018-04-25
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 070899
program_official: LEENDERS, MIRIAM
project_start_date: 2010-07-01
project_end_date: 2020-04-30
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The goal of this project is to utilize the unique window into cellular metabolism that Lafora disease offers to define both normal glycogen metabolism and disease implications when the process is disrupted. Lafora disease (LD) one of five major progressive myoclonic epilepsies is a fatal recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic hyperphosphorylated water-insoluble glycogen-like particles called Lafora bodies. These inclusions occur throughout the body but disease results from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. LD is the result of loss of function mutations or mutations that cause aberrant function in either of the genes encoding the glucan phosphatase laforin or E3 ubiquitin ligase malin.  We established laforin as the founding member of the glucan phosphatase family i.e. phosphatases that dephosphorylate glycogen or starch. A laforin structure is needed to determine how reversible glycogen phosphorylation impacts glycogen metabolism and define why laforin mutations result in LD. We also demonstrated that malin is an E3 ubiquitin ligase and reported that malin ubiquitinates proteins involved in glycogen synthesis. However malin does not promote degradation of these enzymes and it has remained unknown as to how malin impacts glycogen metabolism and why mutations in malin result in LD. While mutations in the laforin or malin gene result in LD it is increasingly recognized that multiple mechanisms lead to LD and that a spectrum of mutations yields different degrees of disease progression. Because our work has defined the molecular function of laforin and malin we are uniquely poised to define the clinical biochemistry of LD mutations in both laforin and malin. Therefore we propose to: 1. Determine the structural mechanism of laforin. We will utilize X-ray crystallography combined with structure-guided mutagenesis and functional assays to determine how laforin binds to glycogen how phosphorylated glycogen is dephosphorylated laforin's role in glycogen metabolism and laforin's role in LD. 2. Define the role of malin in LD and glycogen metabolism. Using multiple methods we have identified malin substrates and established the type of ubiquitination as well as defined the consequences of ubiquitination for one substrate. We will define the signaling events that drive ubiquitination of malin substrates the dynamics of the events the functional consequences and how misregulation leads to LD. We will utilize cell culture and mouse models to determine the role of malin in glycogen metabolism and LD. 3. Translate current insights into patient-specific diagnosis and treatment. LD results from both missense mutations as well as Premature Termination Codons. Our initial analysis revealed that not all point mutations abolish activity. We will utilize our biochemical tools to define mutation specific mechanisms for laforin and malin LD mutations and explore therapeutic options using our recently developed bioassay.

project_terms:
Acute;Affect;Aminoglycosides;Binding;Biochemical;Biochemistry;Biological Assay;Biology;Carbohydrates;Cell Culture Techniques;Cells;Cellular Metabolic Process;Clinical;Complex;Comprehension;Diagnosis;Disease;Disease Progression;Energy Metabolism;Enzymes;Epilepsy;Event;Family;Fibroblasts;Genes;Glucans;Glycogen;Glycogen Phosphorylase;Glycogen Storage Disease;Goals;Inherited;Knockout Mice;Lafora Disease;Lead;Life;Link;Liver;Metabolism;Methods;Missense Mutation;Modeling;Molecular;Muscle;Mutagenesis;Mutation;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Point Mutation;Process;Progressive Myoclonic Epilepsies;Proteins;Proteome;Protocols documentation;Regulation;Reporting;Role;Signal Transduction;Starch;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Tissues;Translating;Ubiquitin;Ubiquitination;Water;Work;X-Ray Crystallography;biochemical tools;cell type;design;disease-causing mutation;gene product;glycogen metabolism;in vivo;insight;loss of function mutation;member;mouse model;neuron apoptosis;neurotoxicity;novel;novel therapeutics;particle;potency testing;premature;public health relevance;screening;tool;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The focus of our work is to determine how mutations in either of two gene products lead to the fatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveries and uses complementary approaches to advance our understanding of the intertwined events of cell metabolism neurodegeneration and epilepsy. Completion of this work will yield a better comprehension of these complex events and will allow us to translate our insights into diagnoses bioassays and treatments.


application_id: 9473778
project_number: 5R01ES021771-05
project_title: Apoptosis resistance and Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2018-04-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 021771
program_official: REINLIB, LESLIE J
project_start_date: 2014-08-01
project_end_date: 2019-04-30
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: SHI, XIANGLIN
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): Chromate (Cr (VI)) compounds are toxic and carcinogenic on humans. Our preliminary studies show that exposure of human lung bronchial epithelial (BEAS-2B) cells to Cr (VI) generated reactive oxygen species (ROS). Through ROS reactions Cr(VI) caused cell transformation leading to tumorigenesis. However once cells were transformed the capability of those cells to generate ROS was decreased. Expressions of antioxidant regulative nuclear factor Nrf2 its positive regulator p62 and several major antioxidant enzymes were increased. Apoptosis eliminates DNA-damaged or mutated cells. When cells acquire apoptosis resistance they continue to proliferate leading to carcinogenesis. Cr(VI)-transformed cells developed apoptosis resistance as indicated by reductions of cleaved poly(ADP-ribose) polymerase (C-PARP) and cleaved caspase 9 (C-caspase 9) and by elevation of anti- apoptotic protein Bcl-2. Binding of Nrf2 to antioxidant response element (ARE) of Bcl-2 gene was increased indicating the possibility of Nrf2 in up-regulation of Bcl-2. In Cr (VI)-transformed cells inhibition of p62 by its shRNA reduced Nrf2 expression leading to induction of apoptosis. These results provide a linkage among p62 Nrf2 Bcl- 2 and apoptosis resistance. The central hypothesis of this application is that due to up-regulations of p62 and Nrf2 and decreased generation of ROS Cr (VI)-transformed cells develop apoptosis resistance and increase cell survival invasion and migration contributing to overall mechanism of Cr (VI)-induced carcinogenesis. Aim 1 will investigate the mechanism of decreased ROS generation of Cr(VI)-transformed cells. We will carry out comparative studies using non-transformed and Cr(VI)- transformed cells to study each key step of major Cr(VI)- induced ROS generation pathway and identify the specific step responsible for decreased ROS generation in Cr(VI)-transformed cells. We will also investigate the contribution of elevated antioxidant level by focusing on Nrf2 and Nrf2 targeting antioxidants. Aim 2 will investigate apoptosis resistance and its role in enhanced proliferation invasion and migration of Cr(VI)-transformed cells. We will alter ROS production by up-regulation of key proteins involved in ROS generation pathway and by down-regulation of key antioxidant enzymes to study the role of ROS in apoptosis resistance. We will investigate whether Nrf2-regulated Bcl-2 induction is a key event. We will alter apoptosis resistance by modifying Bcl-2 Bcl-xL Mcl-1 or Bax expression to investigate the role of apoptosis resistance in Cr(VI)-enhanced cell proliferation invasion and migration. Aim 3 will investigate the role of apoptosis resistance in Cr(VI)-induced tumorigenesis and metastasis using animal models. We will investigate the role of ROS by altering ROS generation including modification of antioxidant enzymes and Nfr2. The role of p62 will be investigated by inhibiting its expression. The role of apoptosis resistance will be investigated by alternation of apoptosis regulative proteins Bcl-2 Bcl-xL Mcl-1 or Bax. The same approaches will be used to investigate the role of ROS p62 and apoptosis resistance in metastasis of Cr(VI)-transformed cells using animal models.

project_terms:
Animal Model;Antioxidants;Apoptosis;Apoptotic;BCL2 gene;Binding;CASP9 gene;Carcinogens;Caspase;Cell Nucleus;Cell Proliferation;Cell Survival;Cells;Chromates;Cleaved cell;Comparative Study;DNA Damage;Down-Regulation;Epithelial;Equilibrium;Event;Exhibits;Generations;Heme;Human;Induction of Apoptosis;Industry;Lung;Malignant - descriptor;Mediating;Modification;Mutate;NQO1 gene;Neoplasm Metastasis;Normal Cell;Nuclear;Oxidases;Oxidoreductase;Oxygenases;Pathway interactions;Play;Poisons;Poly(ADP-ribose) Polymerases;Process;Production;Proliferating;Promoter Regions;Proteins;Quinine;Reaction;Reactive Oxygen Species;Regulation;Resistance;Response Elements;Role;Superoxide Dismutase;System;Testing;Up-Regulation;antioxidant enzyme;carcinogenesis;carcinogenicity;catalase;cell transformation;chromium hexavalent ion;exposed human population;genetic regulatory protein;migration;overexpression;public health relevance;small hairpin RNA;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cr(VI)-containing compounds are human carcinogens. The mechanism of their carcinogenesis remains to be investigated. This application will study the roles of p62 Nrf2 reactive oxygen species and apoptosis resistance in Cr(VI)-induced carcinogenesis.


application_id: 9473414
project_number: 1R21NS103433-01A1
project_title: Glial-specific gene expression after contusive spinal cord injury
administering_ic: NINDS
award_notice_date: 2017-09-12
opportunity_number: PA-16-161
application_type: 1
activity_code: R21
ic: NS
serial_number: 103433
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2017-09-15
project_end_date: 2019-08-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: WHITTEMORE, SCOTT R
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
No clinically applicable treatments exist to improve functional outcome after spinal cord injury (SCI). In partsuch a lack of progress is due to poor understanding of the complex pathology of this injury. The SCI responseis cell type-specific and evolves with time post-injury. Acutely after injury oligodendrocytes (OL) displaydisruption of proteostasis including endoplasmic reticulum stress (ERSR) and integrated stress (ISR)responses. The ISR leads to apoptosis and white matter loss that underlies many deficits of sensation andlocomotion. Later oligodendrocyte precursor cells (OPCs) proliferate in an attempt to repair lost myelin.However that response is limited by inhibitory signals that block OPC differentiation. While global spinal cordtranscriptomics have enabled a systematic knowledge about the SCI response conclusions from these effortsare limited by technological barriers and the complexity of spinal cord anatomy. Thus SCI-associated changesin mRNA levels may not translate into parallel effects on protein expression. Moreover homogenizedfragments of whole spinal cord used for traditional transcriptomic experiments make identification of novelcomponents of the cell-specific injury response challenging. These limitations may be overcome by TranslatingRibosome Affinity Purification (TRAP) technology which isolates and analyzes only mRNAs that are associatedwith ribosomes (i.e. being likely translated) from specific cell populations that were marked genetically with aribosomal tag. Thus we propose to apply TRAP to test the hypothesis that after SCI both transcriptional andtranslational reprogramming regulate the expression of critical components of the injury response in a cell type-specific manner. Furthermore translational regulation will be of particular significance to launch proteostasisresponses in OPCs and OLs. We also propose that in the context of OPC/OLs that respond to SCI identifyingtranslated mRNAs for transcription factors will uncover new targets that can be targeted for OL protectionand/or remyelination. Focusing on the injury epicenter we will characterize translated transcriptome profiles ofOPC/OLs at 2 10 and 42 days after moderate mouse contusive SCI inOPC/OLs from transgenic mice thatexpress EGFP-L10 ribosome tag in a Cre dependent manner selectively in these cells (specific aim 1). Inaddition we will use the resulting data sets to identify transcription factors (TF) that orchestrate OPC/OLresponses to SCI (specific aim 2). We expect to characterize SCI-associated gene expression events inOPC/OLs with unprecedented accuracy. By focusing on ribosome-associated transcripts our data will paint alandscape of complete gene expression events that reach the protein level. Such a landscape is unavailablefor SCI-challenged OPC/OLs on a whole genome scale. Therefore this high risk/high reward proposal mayredefine the SCI response of OPC/OLs and identify novel targets for white matter protection and/orremyelination therapies.

project_terms:
ATF6 gene;Acute;Affect;Affinity Chromatography;Alpha Cell;Anatomy;Apoptosis;Binding Sites;Biological Assay;Biological Process;Cell Differentiation process;Cells;Cellular Structures;Cessation of life;Chest;Chronic;Clinical;Complex;Data;Data Set;Esthesia;Event;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic Transcription;Immunohistochemistry;In Situ Hybridization;Injury;Knowledge;Label;Locomotion;Mediating;Messenger RNA;Molecular Profiling;Motor;Mus;Myelin;Neuroglia;Nucleic Acid Regulatory Sequences;Oligodendroglia;Ontology;Outcome;Paint;Pathogenesis;Pathology;Pathway Analysis;Population;Post-Transcriptional Regulation;Principal Component Analysis;Proliferating;Proteins;Proteolipids;Publishing;Rattus;Recovery of Function;Research;Resolution;Ribosomal Proteins;Ribosomes;Role;Signal Transduction;Site;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stress;System;Tamoxifen;Technology;Testing;Therapeutic Intervention;Time;Transcript;Transgenic Mice;Translating;Translational Regulation;Untranslated RNA;Up-Regulation;Work;XBP1 gene;biological adaptation to stress;cell type;clinical application;differential expression;effective therapy;endoplasmic reticulum stress;experimental study;functional outcomes;genome-wide;high reward;high risk;improved;improved outcome;injured;insight;knock-down;new technology;new therapeutic target;novel;oligodendrocyte precursor;overexpression;precursor cell;protein expression;proteostasis;remyelination;repaired;response;response to injury;sensor;transcription factor;transcription factor CHOP;transcriptome;transcriptome sequencing;transcriptomics;white matter;white matter damage;whole genome

public_health_relevance:
Project narrativeCurrently there are no clinically effective treatments to improve outcome after traumatic spinal cord injury(SCI). This proposal will use a novel technology known as translating ribosome affinity purification assay toobtained unprecedented insight into gene expression changes in specific populations of spinal cord glia withwell established roles in the pathogenesis of SCI. This research may identify new targets for therapeuticinterventions after SCI.


application_id: 9472996
project_number: 5R01AG033649-09
project_title: A healthy brain aging strategy to restore insulin signaling and Ca homeostasis
administering_ic: NIA
award_notice_date: 2018-04-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 033649
program_official: WISE, BRADLEY C
project_start_date: 2009-08-01
project_end_date: 2020-03-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 8361727
contact_pi: THIBAULT, OLIVIER
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    Peripheral metabolic dysregulation appears to increase the risk for cognitive decline with aging and susceptibility to dementing neurodegenerative disorders such as Alzheimer's disease. However the pathways and mechanisms underlying the relationship between metabolic dysregulation and age-related cognitive impairment are not clearly defined. Here we propose that insulin resistance in the brain can destabilize tightly regulated processes which maintain normal calcium homeostasis in neurons resulting in neuronal dysfunction and impaired cognition. Age-related neuronal calcium dysregulation is a well-recognized mechanism contributing to neurologic dysfunction and cognitive decline and we and others have extensively characterized this dysfunction in brain structures important for learning and memory. Interestingly peripheral tissues that are insulin resistant also show calcium dysregulation and provide supporting evidence for a similar relationship in the brain. In the prior funding cycle weidentified a previously unrecognized link between metabolic dysregulation and altered calcium signaling in hippocampal neurons. Together these findings provide support for the notion that overcoming insulin resistance in the hippocampus with insulin-raising strategies will reestablish neuronal calcium homeostasis. Several innovative approaches will be used to increase brain insulin signaling in aging. Specifically we will 1) utilize intranasal insulin delivery to increas insulin availability at the brain insulin receptor in vivo 2) increase insulin receptor signaling n the brain via AAV-mediated expression of a constitutively active human insulin receptor mutant ( subunit) and 3) increase endogenous insulin receptor trafficking through the use of a novel pharmacologic strategy. Using these approaches in the F344 rat model of aging we will investigate cognitive functions using different behavioral paradigms. In hippocampal tissue from these animals we will use single cell electrophysiology/imaging to directly measure calcium status (recordings of calcium-dependent potentials and calcium imaging) and complement these studies with molecular/biochemical assays. To determine whether increasing insulin in the brain affects other pathways independent of Ca2+ we will also quantify p-Akt signaling tyrosine phosphorylation glucose homeostasis (glucose imaging) and adiponectin levels. Type 2 diabetes has reached epidemic proportions among older adults accounting for approximately 26 million people and a $175 billion dollar toll to our health care system (CDC statistics). Our studies are designed to determine whether enhancing insulin action in the brain reduces the burden of cognitive decline in aging and helps to maintain healthy cognitive function. The outcomes from our studies will inform related clinical studies and may have significant impact for the aging population especially for those at increased risk for neurodegenerative diseases such as Alzheimer's disease. This work is clinically-oriented and directly addresses one of the missions of the NIA by establishing novel targets for the treatment of cognitive decline and/or dementia in brain aging.

project_terms:
Accounting;Address;Affect;Age;Age-associated memory impairment;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Animal Model;Animals;Area;Behavior;Behavioral;Behavioral Paradigm;Biochemical;Biological Assay;Brain;Calcium;Calcium Signaling;Cell membrane;Cells;Centers for Disease Control and Prevention (U.S.);Clinical;Clinical Research;Complement;Dementia;Diabetes Mellitus;Disease;Dorsal;Elderly;Electrophysiology (science);Epidemic;Event;Exhibits;Formulation;Functional disorder;Funding;Gap Junctions;Glucose;Healthcare Systems;Hippocampus (Brain);Homeostasis;Human;Hypothalamic structure;Image;Imaging Techniques;Impaired cognition;Inbred F344 Rats;Insulin;Insulin Receptor;Insulin Resistance;Intervention;Kinetics;Learning;Ligands;Link;Measures;Mediating;Memory;Metabolic;Metabolic dysfunction;Mission;Modeling;Modification;Molecular;Neurodegenerative Disorders;Neurologic Dysfunctions;Neuronal Dysfunction;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Measure;Pathologic;Pathway interactions;Patients;Peripheral;Pharmacology;Physiological;Positioning Attribute;Predisposition;Process;Receptor Signaling;Regulation;Research;Risk;Role;Satiation;Signal Transduction;Slice;Structure;Synapses;Techniques;Testing;Time;Tissues;Tyrosine Phosphorylation;Viral;Visceral;Work;adeno-associated viral vector;adiponectin;age related;aged;aging brain;aging population;animal tissue;base;blood glucose regulation;clinical effect;clinically relevant;cognitive function;cognitive performance;cognitive process;design;feeding;improved;in vivo;innovation;insight;insulin sensitivity;insulin signaling;male;morris water maze;mutant;neuronal excitability;novel;novel therapeutics;pre-clinical research;public health relevance;receptor;response;sensory cortex;sigma-2 receptor;statistics;trafficking;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    Our work will test if the mechanism of insulin actions in the brain modulates calcium-related functions inside cells. We will focus on one area of the brain that is known for its role in memoryfunction the hippocampus. We propose new ways to increase insulin signals in the brain.


application_id: 9472983
project_number: 5R37AG004542-29
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2018-04-30
opportunity_number: PA-10-067
application_type: 5
activity_code: R37
ic: AG
serial_number: 004542
program_official: DIBATTISTA, AMANDA
project_start_date: 1998-01-01
project_end_date: 2021-03-31
study_section: NSS
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
FK506-Binding Protein 12.6/1b (FKBP1b) stabilizes intracellular calcium release in heart cells but its role inbrain neurons has been unknown. During the preceding phase of this project we conducted systematic testsof our working hypothesis that an aging-related decline in FKBP1b underlies many calcium-mediatedaspects of unhealthy brain aging. These studies showed that reproducing the proposed pathogenic declinewith FKBP1b knockdown in the hippocampus recapitulated the calcium dysregulation brain aging syndromein young rats. Conversely counteracting the aging-related hippocampal FKBP1b decline by using virally-mediated FKBP1b overexpression fully reversed calcium dysregulation and cognitive impairment in agedrats (Gant et al 2011; 2014; 2015) thereby providing strong support for this novel hypothesis on themolecular basis of unhealthy brain aging. Subsequent long term studies using behavioral and geneexpression assessment revealed that cognitive rescue was similarly effective after 7 months and after 2months of FKBP1b overexpression. Further cognitive aging changes and rescue by FKBP1b correlated withage related changes in calpain gene and protein expression and with cytoskeletal gene expression (Gant etal in prep.). Based on these findings we propose the following specific aims for the next phase of research: Aim 1. Corticosterone and vitamin D are steroid hormones that regulate calcium related biomarkers ofhippocampal aging in opposite directions. Therefore we will test the hypothesis that these two naturallyoccurring hormonal factors act on brain aging processes by modulating FKBP1b. Aim 2. Based on findings in the preceding phase we will test the hypothesis that downstream negativeeffects of declining FKBP1b are mediated in part by the calpain pathway. Aim 3. We will use rodent models to test aspects of the intriguing hypothesis that aging related changesin hippocampal and entorhinal FKBP1b expression link normal brain aging to increased risk of Alzheimer'sdisease.

project_terms:
Affect;Age of Onset;Age-Years;Aging;Aging-Related Process;Alzheimer's Disease;Alzheimer's disease risk;Behavioral;Biological Markers;Brain;Calcium;Calpain;Cognitive;Cognitive aging;Corticosterone;Cytoskeletal Proteins;FKBP1B gene;Gene Expression;Glucocorticoids;Goals;Healthcare;Hippocampus (Brain);Hormonal;Hormones;Impaired cognition;Instruction;Intervention;Link;Longitudinal Studies;Mediating;Metabolism;Molecular;Neurons;Outcome;Pathogenicity;Pathologic;Pathway interactions;Performance;Peripheral;Phase;Play;Population;Predisposition;Quality of life;Rattus;Research;Rodent Model;Role;Structure;Synapses;Syndrome;Tacrolimus Binding Proteins;Techniques;Testing;Viral;Vitamin D;age effect;age related;aged;aging brain;aging population;base;care burden;gene therapy;heart cell;knock-down;novel;overexpression;prevent;protein expression;steroid hormone

public_health_relevance:
RELEVANCE (See instructions):The increasing aging population in the U.S. (20% of the population will be >65 years of age by the year2030) often has cognitive decline that can significantly affect quality of life and profoundly add to health careburden. Our results indicate that a specific pathway (FKBP-Ca2+) plays a critical role in brain aging andcognitive decline; thus the goal of this project is to use gene therapy techniques to determine whether suchinterventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial


application_id: 9472296
project_number: 5R01AI128818-02
project_title: Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasis
administering_ic: NIAID
award_notice_date: 2018-03-27
opportunity_number: RFA-AI-16-006
application_type: 5
activity_code: R01
ic: AI
serial_number: 128818
program_official: ROTHERMEL, ANNETTE L
project_start_date: 2017-04-20
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1-IDM-W(50)R]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Biology;CCL20 gene;Cells;Chronic;Chronic small plaque psoriasis;Clinical;Data;Dermal;Dermis;Development;Disease;Health;Homeostasis;Human;Immune;Immunologic Surveillance;In Vitro;Individual;Infection;Infiltration;Inflammation;Inflammatory;Interleukin-1;Interleukin-1 beta;Interleukin-12;Interleukin-17;Interleukins;Laboratories;Leukocytes;Memory;Modeling;Monoclonal Antibodies;Mus;Pathogenesis;Pathogenicity;Patients;Phase II Clinical Trials;Phenotype;Play;Population;Production;Psoriasis;Recurrent disease;Regulation;Role;SCID Mice;Signal Pathway;Signal Transduction;Skin;Source;Streptococcal Infections;T cell regulation;T-Cell Activation;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Treatment Efficacy;Xenograft Model;base;chemokine;chronic inflammatory skin;cytokine;individual patient;insight;interleukin-23;keratinocyte;microbial;microorganism;neglect;novel;pathogen;peripheral blood;receptor;skin disorder;skin lesion;skin microbiota;trafficking; T cells


application_id: 9471717
project_number: 5F31AG055233-02
administering_ic: NIA
award_notice_date: 2018-05-13
opportunity_number: PA-16-309
application_type: 5
activity_code: F31
ic: AG
serial_number: 055233
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)L]
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
budget_start_date: 2018-05-14
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;Normal Range;Obsessive compulsive behavior;Obsessive-Compulsive Personality;Outcome;Patient Self-Report;Personality;Personality Assessment;Personality Disorders;Personality Traits;Prevention;Process;Property;Psychometrics;Reporting;Research;Research Domain Criteria;Risk;Sampling;Science;Stress;Symptoms;Syndrome;System;TNF gene;Testing;Time;Training;Variant;base;immune function;informant;longitudinal dataset;mortality;novel;physical conditioning;professor;service providers;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: 9471522
project_number: 1R13DC016831-01
project_title: International Society of Neurogastronomy Annual Meeting
administering_ic: NIDCD
award_notice_date: 2017-09-26
opportunity_number: PA-16-294
application_type: 1
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2020-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is a new society whose composition of scientists clinicians nutritionists foodservice professionals and chefs naturally predisposes it to focus on translational issuesfundamental to how the chemical senses impact human health. The first two specificobjectives are to provide a venue and opportunity that brings these groups together andfacilitates the synergies that arise when distinctly different fields interact productively. Thethird specific objective is to attract and stimulate the young scientists that are the future ofthe field of neurogastronomy. The fourth specific objective is to ensure that this new fieldembraces a culture of diversity weaving this principle into its early development byrecruiting persons of diverse backgrounds to the conference. !

project_terms:
Agriculture;Appalachian Region;Area;Chemicals;Clinical;Development;Diet Habits;Disabled Persons;Eating;Education;Ensure;Environment;Equation;Equilibrium;Event;Food;Food Services;Fostering;Funding;Future;Goals;Grant;Health;Human;International;Knowledge;Life;Mission;Neurosciences;Nutritional;Nutritionist;Perception;Persons;Policies;Quality of life;Recruitment Activity;Rural;Science;Scientist;Societies;Stimulus;Structure;Training;Underrepresented Groups;Veterans;Work;design;drinking;ethnic minority population;experience;food consumption;improved;interest;meetings;member;multisensory;nutrition;preference;racial and ethnic;social;sound;symposium;synergism

public_health_relevance:
PROJECT NARRATIVEA major part of the mission of the International Society of Neurogastronomy (ISN) is topromote the study of flavor and its use to enhance the quality of human life channeling ourgrowing knowledge of neurogastronomy and chemosensory science into translationalaction needed to overcome the ways in which flavor preferences are often hijacked tocause unhealthy eating habits. ISN promotes cooperation between scientists and foodprofessionals towards altering the balance of this equation in our culture. ISNs annualmeeting provides an important mechanism for facilitating the interactions betweenchemosensory scientists neuroscientists clinicians nutritional scientists agriculturalscientists and food professionals needed to develop strategies for using flavor properly -strategies that are both practical and scientifically sound. !


application_id: 9471366
project_number: 5R21CA216090-02
administering_ic: NCI
award_notice_date: 2018-03-23
opportunity_number: RFA-CA-15-009
application_type: 5
activity_code: R21
ic: CA
serial_number: 216090
program_official: KONDAPAKA, SUDHIR B
project_start_date: 2017-04-12
project_end_date: 2021-03-31
study_section: ZCA1-SRB-8(J2)
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
project_title:
PQ-10: Microbial metabolite Urolithin A is  a potent immunomodulator and chemosensitizing adjuvant in treating colon cancer.

project_abstract:
Abstract Colon cancer is the third leading cause of cancer related deaths in United States of America.Chemoresistance (drug resistance) of tumors is the primary reason for the failure of chemotherapy and the majorcause of mortality in colon cancer. The molecular mechanisms involved in chemoresistance or approaches toresensitize cancer cells to chemotherapy remain elusive. Recent studies suggest that gut microbiota andmicrobial metabolites play a crucial role in the development and progression of colon cancer but their role inchemoresistance remains unknown. Towards this goal we investigated the influence of commensal microbialmetabolite Urolithin A (UroA) on cancer chemotherapy. UroA is a microbial metabolite derived from ellagic acidand ellagitannins which are major components of berries and pomegranate. Our preliminary data showed thatUroA significantly reduced bacteria induced inflammation in macrophages and protected from lipopolysaccharideinduced barrier dysfunction by upregulating junctional proteins in colon epithelial cells. More importantly UroAsignificantly increased the chemosensitization of colon cancer cells to 5florouracil (5FU) by down regulating drugtransporters and modulating epithelial-mesenchymal transition (EMT) pathways. The combination therapysignificantly reduced colony formation of colon cancer cells as well as blocked cancer cell migration. By screeningseveral novel structural analogues of UroA we have identified a potent compound UAS03 which displayedincreased chemosensitizing activities compared to UroA. Based on these observations we hypothesize thatUroA and UAS03 act as chemosensitizing adjuvants in 5-FU therapies through regulation of drugtransporters and cancer stemness. The goal of the proposal is to determine the effects of microbial derivedmetabolites (UroA and its analogue UAS03) on colon cancer chemotherapy especially 5FU resistant cancers.In aim1 we propose to identify the molecular target of UroA using bioactive biotinylated UroA; to determine themolecular mechanisms of UroA and UAS03 mediated chemosensitization of 5FU-resistance (5FUR) coloncancer cells. In aim 2 we will evaluate the therapeutic efficacies of UroA or UAS03 in combination with 5 FU inpreclinical colon cancer models. We will utilize both implantable (tumors generated by 5FUR colon cancer cells)and azoxymethane-DSS models. The successful completion of these studies will delineate regulatorymechanisms of microbial metabolite (UroA) mediated chemosensitization and offer better therapeutic options forcolon cancer.

project_terms:
ABCG2 gene;Address;Adjuvant;Adopted;Affect;Americas;Anti-inflammatory;Area;Azoxymethane;Bacteria;Berry;Cancer Etiology;Cancer Model;Cell Survival;Cessation of life;Chemopreventive Agent;Chemosensitization;Chemotherapy-Oncologic Procedure;Colitis;Colon;Colon Carcinoma;Combined Modality Therapy;Custom;Data;Development;Diet;Drug Efflux;Drug Regulations;Drug resistance;E-Cadherin;Ellagi-Tannins;Ellagic Acid;Epithelial;Epithelial Cells;Failure;Fluorouracil;Functional disorder;Genes;Goals;High-Throughput Nucleotide Sequencing;Immunomodulators;Inflammation;Inflammatory disease of the intestine;Interleukin-6;Knowledge;Lipopolysaccharides;Malignant Neoplasms;Mediating;Mesenchymal;Methods;Modeling;Molecular;Molecular Target;Mus;Oral Administration;P-Glycoprotein;Pathway interactions;Pharmaceutical Preparations;Play;Pomegranate;Population;Pre-Clinical Model;Proteins;Resistance;Role;Sodium Dextran Sulfate;TLR4 gene;TNF gene;Therapeutic;Therapeutic Effect;Treatment Efficacy;United States;Xenograft Model;Xenograft procedure;analog;anticancer activity;base;cancer cell;cancer therapy;cell motility;chemosensitizing agent;chemotherapy;clinically relevant;colon cancer cell line;colon cancer patients;colon cancer progression;colon cancer treatment;colon tumorigenesis;gut microbiota;immunoregulation;improved;indexing;innovation;iron metabolism;macrophage;microbial;microbiota;mortality;mouse model;neoplastic cell;novel;occludin;pre-clinical;response;screening;stemness;synergism;three dimensional cell culture;translational impact;tumor

public_health_relevance:
Project NarrativeChemoresistance of tumors is a major cause of mortality in colon cancer patients. Mechanisms responsible forchemoresistance and factors to improve the chemosensitization are not completely understood. Here weidentified microbial metabolite urolithin A (UroA) and its novel structural analogue (UAS03) significantlychemosensitized the colon cancer cells to 5florouracil (5FU). Current proposal investigates effects of microbialmetabolite UroA on colon cancer chemotherapy by utilizing cellular and preclinical colon cancer mouse models.Successful completion of these studies will have tremendous translational impact on utilization of microbialmetabolites along with existing chemotherapeutic drugs in colon cancer.


application_id: 9471160
project_number: 2R13CA168316-06A1
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2018-03-30
opportunity_number: PA-16-294
application_type: 2
activity_code: R13
ic: CA
serial_number: 168316
suffix: A1
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZCA1 PCRB-G (O1)]
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Area;Award;Behavioral Sciences;China;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communicable Diseases;Communication;Communication Programs;Communication Research;Communities;Country;Decision Making;Developing Countries;Development;Diabetes Mellitus;Discipline;Disease;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Foundations;Funding;Germany;Goals;Government;Government Agencies;Growth;Health;Health Communication;Health Personnel;Health Promotion;Health Sciences;Healthcare;Human Resources;Interdisciplinary Study;International;Internet;Intervention;Kentucky;Knowledge;Life;Malignant Neoplasms;Mentors;Mission;Netherlands;Nonprofit Organizations;Participant;Patients;Personal Satisfaction;Public Health;Publications;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Role;Russia;Schedule;Scientist;Series;Social Sciences;Structure;Students;Substance abuse problem;Switzerland;Training;Translational Research;Underrepresented Groups;Underserved Population;United States National Institutes of Health;Universities;base;behavioral/social science;cancer risk;career;career development;design;disability;disorder prevention;experience;graduate student;health disparity;health information technology;health knowledge;health literacy;innovation;new technology;prevent;recruit;skills;substance abuse prevention;symposium;therapy design;tool


application_id: 9471128
project_number: 1R01NS101752-01A1
project_title: Interleukin-1 alpha as a novel treatment for ischemic stroke
administering_ic: NINDS
award_notice_date: 2018-05-16
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: NS
serial_number: 101752
suffix: A1
program_official: BOSETTI, FRANCESCA
project_start_date: 2018-07-01
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1 BDCN-K (02)]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
other_pis: PINTEAUX, EMMANUEL
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
project_abstract:
PROJECT SUMMARY/ABSTRACTStroke is a major cause of death and disability worldwide and more effective therapies are urgently needed.Unfortunately all clinical trials that have targeted the primary mechanisms of neuronal injury caused by cerebralischemia (CI) (i.e. oxidative stress and excitotoxicity) have failed. CI also induces a potent local inflammatoryresponse that leads to progressive damage in the ischemic penumbra. However emerging evidence suggestthat inflammation may also initiate key post-stroke repair processes including angiogenesis leading to long-termfunctional recovery. For these reasons we propose that inflammation is an attractive therapeutic target for strokerecovery. In support of this we have recently shown that endogenous post-stroke brain upregulation of theproinflammatory cytokine interleukin-1 (IL-1) isoform IL-1 is tightly regulated in a cell-specific fashion (microgliaacutely and platelets chronically) suggesting that it could play important roles in both injury and repairrespectively. Furthermore we now demonstrate that delayed (3 day) post-stroke administration of IL-1promoted post-stroke angiogenesis in mice. This may occur at least in part as the result of IL-1-inducedgeneration of the proangiogenic extracellular matrix fragment perlecan LG3. Furthermore as LG3 has knownneuroprotective actions we hypothesize that IL-1 could be both neuroprotective and neurorestorative inischemic stroke. In support of this hypothesis preliminary results suggest that IL-1 administered systemically(IV) or intra-arterially (IA) immediately after reperfusion in mice subjected to transient middle cerebral arteryocclusion is well tolerated profoundly neuroprotective and functionally restorative. Therefore we hypothesizethat IL-1 may represent a novel neuroprotective agent for ischemic stroke.To investigate the neuroprotective potential and mechanism(s) of action of IL-1 in experimental ischemic strokewe propose the following aims:Aim 1: Determine the role of acute and chronic endogenous IL-1 in ischemic stroke.Aim 2: Determine the therapeutic potential of IL-1 in experimental ischemic stroke.Aim 3: Determine the neuroprotective mechanism(s) of IL-1 action.Successful completion of these studies will increase our understanding of the role of endogenous IL-1 atdifferent stages after stroke determine its therapeutic potential and mechanism(s) of action and support IL-1as a promising novel stroke therapy.

project_terms:
Acute;Acute Brain Injuries;Adverse effects;Animals;Biochemical;Biochemical Genetics;Blood Platelets;Blood Vessels;Brain;Brain imaging;Cause of Death;Cells;Cerebral Ischemia;Chronic;Clinical Trials;Cre-LoxP;Dose;Encephalitis;Endothelial Cells;Endothelium;Enterobacteria phage P1 Cre recombinase;Exposure to;Extracellular Matrix;Gender;Generations;Genetic Techniques;Glucose;Goals;Impairment;In Vitro;Infarction;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1;Interleukin-1 Receptors;Interleukin-1 alpha;Ischemic Penumbra;Ischemic Stroke;Knockout Mice;LoxP-flanked allele;Magnetic Resonance Imaging;Microglia;Middle Cerebral Artery Occlusion;Mus;Neuronal Injury;Neurons;Neuroprotective Agents;Outcome Assessment;Oxidative Stress;Oxygen;Pathway interactions;Phase;Physiologic pulse;Play;Process;Protein Isoforms;Publishing;Recovery of Function;Reperfusion Therapy;Role;Signal Transduction;Source;Stroke;Techniques;Therapeutic;Up-Regulation;Vital Statistics;age effect;angiogenesis;base;cytokine;deprivation;disability;effective therapy;excitotoxicity;functional outcomes;hemodynamics;in vivo;inhibitor/antagonist;injury and repair;male;neuroprotection;neurorestoration;novel;perlecan;post stroke;repaired;spatiotemporal;stroke model;stroke recovery;stroke therapy;therapeutic target;young adult

public_health_relevance:
Project NarrativeStroke is a major cause of death and disability worldwide and effective therapies are urgently needed. Emergingevidence suggest that inflammation may play key potentially beneficial roles in the brain after stroke making itan attractive therapeutic target. We have recently demonstrated that a key inflammatory cytokine Interleukin-1alpha (IL-1) promotes angiogenic neurorepair in experimental stroke models and new results suggest that IL-1 is also profoundly neuroprotective. In this project we propose to determine the role of IL-1 after experimentalstroke its therapeutic potential and mechanism(s) of action with the goal of developing it as a novel stroketherapy.


application_id: 9469994
project_number: 1F32AG058456-01
administering_ic: NIA
award_notice_date: 2017-09-15
opportunity_number: PA-16-307
application_type: 1
activity_code: F32
ic: AG
serial_number: 058456
program_official: OPANASHUK, LISA A
project_start_date: 2018-02-01
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 11123177
contact_pi: BRAUN, DAVID JAMES
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-02-01
project_title:
Vascular-associated neuroinflammation in Alzheimer's disease: differential effects on disease progression modulated by underlying amyloid burden

project_abstract:
PROJECT SUMMARY Of the modifiable factors that collectively account for over half of Alzheimers disease (AD) cases themajority are vascular risk factors (VRFs). Given that the number of AD patients is expected to double by 2040this situation presents an important opportunity to reduce negative impacts on public health. Clearerunderstanding of the precise temporal and mechanistic alterations linking VRFs to AD may enable developmentof therapeutic approaches to sever that link. The overall goal of this proposal is therefore to elucidate potentiallytargetable mechanisms underlying the connection between early vascular damage and subsequent ADpathology. Vascular inflammation is one unifying feature of many VRFs and this can induce or propagateneuroinflammatory changes in the brain. Considering the established role of neuroinflammation in ADpathogenesis it may be clinically useful to target neuroinflammatory alterations secondary to vascular insult.This proposal will therefore test the hypothesis that vascular risk factors contribute to AD primarily by increasingneuroinflammatory responses and altering subsequent amyloid pathology. For these studies I will use a well-characterized amyloid beta (Ab) overexpression mouse model of AD (APPswe/PS1dE9) along with a dietaryhyperhomocysteinemia (HHcy) model to induce vascular damage and inflammation. In Aim 1 I will induce HHcyin AD mice within a period corresponding to prodromal AD and in Aim 2 within a period corresponding to earlyAD. In both aims l will acutely treat the vascular-associated neuroinflammation in half of the animals. I willcharacterize how vascular damage and associated neuroinflammation interact with underlying Ab pathology toproduce additive cognitive deficits at different stages of AD progression. In addition both aims will includeclinically relevant neuroimaging measures to connect pathological alterations with detectable alterations incerebral blood flow (arterial spin labeling) and metabolic changes (magnetic resonance spectroscopy).Successful completion of this project will provide clinically-relevant insight into the links between VRFs and AD.Further it will provide proof-of-concept of the utility of targeting neuroinflammation secondary to vasculardamage as a means of preventing or delaying future cognitive decline. Ideally such an approach will somedaybe incorporated into a comprehensive strategy of managing AD risk. A carefully designed career developmentplan has also been formalized that includes participation in specialty workshops regular presentation of dataparticipation in scientific meetings and enhancement of non-technical science proficiencies. An experiencedmentoring group of senior scientists in a well-established institution for AD research ensure that I will haveoptimal opportunity to grow into a successful independent investigator devoted to AD therapeutic development.

project_terms:
Abeta synthesis;Acute;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrum;Clinical;Cognitive;Cognitive deficits;Comorbidity;Data;Deposition;Development Plans;Diet;Disease Progression;Educational workshop;Ensure;Functional disorder;Future;Goals;Hyperhomocysteinemia;Hypertension;Impaired cognition;Inflammation;Inflammatory;Injury;Institution;Link;Magnetic Resonance Spectroscopy;Measures;Mediating;Memory impairment;Mentors;Metabolic;Modeling;Mus;Neuroglia;Obesity;Pathogenesis;Pathogenicity;Pathologic;Pathology;Patients;Pattern;Pharmaceutical Preparations;Process;Public Health;Research;Research Personnel;Risk;Risk Factors;Role;Science;Secondary to;Senior Scientist;Spin Labels;Testing;Training;Translating;Vascular Diseases;abeta accumulation;abeta deposition;amyloid pathology;beta amyloid pathology;brain metabolism;career development;cerebral hypoperfusion;clinically relevant;cytokine;design;epidemiology study;experience;glial activation;hypercholesterolemia;inflammatory marker;insight;medical specialties;meetings;middle age;modifiable risk;mouse model;neuroimaging;neuroinflammation;overexpression;prevent;response;stem;therapeutic development;tool;treatment strategy;vascular inflammation

public_health_relevance:
PROJECT NARRATIVEThe most prevalent modifiable risk factors for Alzheimers disease (AD) are vascular risk factors and there isstrong evidence that neuroinflammation is a crucial aspect of this risk. Successful completion of this project willclarify this relationship advance anti-inflammatory treatment strategies and hopefully help to stem the tide ofnew AD cases projected to occur in the coming decades.


application_id: 9469852
project_number: 1R01DA043938-01A1
project_title: Cardiovascular Immune and Psychosocial Benefits of Reduced Cocaine Use
administering_ic: NIDA
award_notice_date: 2017-09-01
opportunity_number: PA-16-160
application_type: 1
activity_code: R01
ic: DA
serial_number: 043938
suffix: A1
program_official: CHAND, NARESH
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7577019
contact_pi: STOOPS, WILLIAM WALTON
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Abnormal Cell;Abstinence;Adopted;Adoption;Aftercare;Alcohol dependence;Atherosclerosis;Behavior;Behavioral;Biochemical;Biological Markers;Blood Platelets;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Cellular Immunity;Chronic;Clinical;Clinical Trials;Cocaine;Cognitive;Comorbidity;Contracts;Control Groups;Counseling;Data;Delayed Hypersensitivity;Diagnosis;Disease;Dose;Drug Use Disorder;Drug usage;Eating;Endothelin-1;Fatty acid glycerol esters;Foundations;Frequencies;Health;Heart Rate;Heavy Drinking;Hypertension;Immune;Immunologic Markers;Incentives;Individual;Infection;Inflammatory;Intervention;Knowledge;Life Style;Measures;Mediating;Medical;Mental Health;Myocardial Infarction;Outcome;Patient Self-Report;Physiological;Problem behavior;Randomized;Research;Risk;Risk Behaviors;Standardization;Stress Tests;TNF gene;TNFSF5 gene;Toxic effect;Treatment Efficacy;Unemployment;Vasospasm;active method;alcohol use disorder;behavioral pharmacology;biopsychosocial;clinical practice;cocaine use;expectation;experience;financial incentive;fitness;follow-up;immune function;improved;innovation;prevent;prospective;psychosocial;response;stroke;success;therapy development;treadmill;vasoconstriction;week trial


application_id: 9469462
project_number: 5R21AA025563-02
project_title: The role of exosomes on brain inflammation and microglia activation in alcohol use disorders
administering_ic: NIAAA
award_notice_date: 2018-03-26
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AA
serial_number: 025563
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2017-04-10
project_end_date: 2020-09-30
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
arra_indicator: N
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;Apoptosis;Attention;Brain;Brain Injuries;Cells;Characteristics;Clinical;Communication;Data;Elements;Encephalitis;Enzyme-Linked Immunosorbent Assay;Ethanol;Exposure to;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: 9469038
project_number: 1F31DE027585-01
project_title: Exploitation of the host immune response by Aggregatibacter actinomycetemcomitans mediated by QseBC
administering_ic: NIDCR
award_notice_date: 2017-09-05
opportunity_number: PA-16-308
application_type: 1
activity_code: F31
ic: DE
serial_number: 027585
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-01-01
project_end_date: 2022-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14913835
contact_pi: OZUNA, HAZEL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Anaerobic Bacteria;Animal Model;Antibodies;Asses;Binding;Catecholamines;Complex;Cytoplasmic Granules;Development;Endocrinology;Enterobactin;Environment;Enzyme-Linked Immunosorbent Assay;Foundations;Future;Gene Expression;Genes;Growth;Homeostasis;Hormones;Human;Immune response;Infection;Infiltration;Inflammatory;Iron;Kinetics;Knowledge;Ligands;Location;Measures;Mediating;Membrane;Metabolism;Microbial Biofilms;Nutrient;Operon;Organism;Outcome;Periodontal Diseases;Periodontitis;Phagocytes;Play;Process;Proteins;Regulation;Research Design;Respiration;Role;Siderophores;Signal Transduction;Stress;Surface Plasmon Resonance;System;Testing;Therapeutic;Transferrin;Virulence;Virulence Factors;Work;design;enteric pathogen;environmental change;macrophage;microbial;mutant;neutrophil;periplasm;receptor;response;sensor;therapeutic target;uptake


application_id: 9468570
project_number: 1F31AR071748-01A1
project_title: IRE1/XBP1 signaling in skeletal muscle growth
administering_ic: NIAMS
award_notice_date: 2018-02-27
opportunity_number: PA-16-309
application_type: 1
activity_code: F31
ic: AR
serial_number: 071748
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2018-03-01
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1 F10B-B (20)]
contact_pi_person_id: 14655709
contact_pi: BOHNERT, KYLE R
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:
AbstractThis project is designed to obtain research training in the area of skeletal muscle biology usingvarious genetic and molecular biology approaches. Loss of skeletal muscle mass is a devastatingconsequence of a number of chronic disease states and conditions. However the cellular andmolecular mechanisms which regulate skeletal muscle mass and function in various physiologicaland pathophysiological conditions remain less understood. Recent studies have suggested thatEndoplasmic Reticulum (ER) stress-induced Unfolded Protein Response (UPR) pathways play animportant role in skeletal muscle homeostasis and metabolic function. However the role of theindividual arms of the UPR in the regulation of skeletal muscle mass and function has not yet beeninvestigated using genetic mouse models or molecular approaches. Our preliminary studies havesuggested that the IRE1/XBP1 arm of the UPR is required for the maintenance of skeletal musclemass and may have a critical role in post-natal skeletal muscle growth and overload-inducedmuscle hypertrophy. However the specific role and the mechanisms of action of the IRE1/XBP1pathway in the regulation of skeletal muscle mass remains completely unknown. To understandthe role the IRE1/XBP1 arm of the UPR in the regulation of skeletal muscle mass we will addressfollowing two specific aims. AIM 1: Establish the role and investigate the cellular mechanisms bywhich the IRE1/XBP1 arm of the UPR promotes skeletal muscle growth. In this aim we will test thehypothesis that the IRE1/XBP1 pathway mediates skeletal muscle growth through a cell-autonomous and/or a non-cell autonomous manner. AIM 2: Investigate the molecular mechanismsby which the IRE1/XBP1 axis promotes muscle growth. In this aim we will test the hypothesis thatthe activation of the IRE1/XBP1 arm of the UPR promotes skeletal muscle growth throughaugmenting protein synthesis mitochondrial biogenesis and inducing the expression of certainmyokines. The proposed studies will identify a novel molecular pathway which will significantlyimprove our understanding of the mechanisms involved in growth and maintenance of skeletalmuscle mass. Moreover this project will provide me outstanding training in the field of skeletalmuscle biology.

project_terms:
70-kDa Ribosomal Protein S6 Kinases;ATF6 gene;Address;Adult;Area;Atrophic;Binding Proteins;Biogenesis;Biology;Breathing;Cell Death;Cells;Chronic;Chronic Disease;Cues;Development;Embryo;Endoplasmic Reticulum;Enzymes;Eukaryotic Initiation Factors;FRAP1 gene;Gene Targeting;Genetic;Growth;Health;Homeostasis;Human body;Hypertrophy;Individual;Inositol;Integral Membrane Protein;Introns;Knock-out;Lead;Locomotion;Maintenance;Malignant Neoplasms;Mediating;Membrane;Messenger RNA;Metabolic;Metabolism;Mitochondria;Molecular;Molecular Biology;Mus;Muscle;Muscle Fibers;Muscle function;Muscular Atrophy;Organelles;Pathway interactions;Pharmacology;Phosphotransferases;Physiological;Physiological Adaptation;Play;Prokaryotic Initiation Factor-2;Protein Biosynthesis;Proteins;Publishing;RNA Splicing;Regulation;Research Training;Role;Signal Transduction;Skeletal Muscle;Stress;Testing;Time;Tissues;Training;Transcriptional Regulation;angiogenesis;arm;base;cancer cachexia;design;eIF-2 Kinase;endoplasmic reticulum stress;experimental study;extracellular;improved;mRNA Decay;mRNA Transcript Degradation;misfolded protein;molecular targeted therapies;mouse model;muscle form;muscle hypertrophy;novel;overexpression;prevent;protein activation;protein folding;protein transport;response;skeletal muscle growth;skeletal muscle wasting

public_health_relevance:
Project NarrativeSkeletal muscle loss or wasting is a devastating problem in a wide range of chronic diseased statesincluding cancer. We have identified the IRE1/XBP1 arm of the Unfolded Protein Response as anovel regulator of skeletal muscle growth. We will investigate the cellular and molecularmechanisms by which the IRE1/XBP1 pathway promotes skeletal muscle growth and preventsatrophy. Our proposed studies will provide strong basis to determining whether IRE1/XBP1 can beused as a novel molecular target for treatment of skeletal muscle wasting in diverse conditions.


application_id: 9468401
project_number: 5R01HL122581-05
project_title: Cardiac pathophysiology of histidyl dipeptides
administering_ic: NHLBI
award_notice_date: 2018-04-19
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 122581
program_official: ADHIKARI, BISHOW B
project_start_date: 2014-06-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1-CVRS-Q(02)]
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Myocardial ischemia and reperfusion (I/R) results in increased glycolysis changes in internal pH inflammation and elevated levels of reactive oxygen species (ROS) that contribute to I/R injury and its clinical outcomes. However a common biochemical feature of myocardial I/R is increased formation of reactive carbonyls which are generated in high abundance in the ischemic heart and their concentration is further increased upon reperfusion. Previous work has shown that increased enzymatic detoxification of these carbonyls decreases myocardial I/R injury. Nevertheless it remains unclear which carbonyls are generated during I/R and how they contribute to tissue injury. As a result the general contribution of carbonyls to myocardial I/R injury remains unclear and no specific carbonyl quenching interventions have been developed to limit I/R injury. The current project is designed to understand the role of endogenous histidyl dipeptides synthesized by the heart in preventing carbonyl toxicity during I/R. Histidyl dipeptides such as carnosine and anserine react avidly with structurally-diverse carbonyls we propose that these peptides represent a general carbonyl detoxification pathway. To test this hypothesis we will elucidate the role of histidyl dipeptides in myocardial I/R injury. Using both in situ and ex vivo models of myocardial I/R injury we will examine whether increasing myocardial levels of histidyl dipeptides either by overexpression of histidyl dipeptide synthase (HDS) in the heart or exogenous delivery will diminish tissue injury. To assess whether the cardioprotective effects of these peptides are due to increased carbonyl detoxification we will determine whether increased myocardial levels of these peptides are associated with increased carbonyl removal and excretion Our studies will also delineate the mechanism by which histidyl dipeptides affect myocardial I/R injury. Specifically we will examine whether histidyl dipeptides generated during I/R inhibit the proteasome and induce ER stress and that histidyl dipeptides decrease myocardial damage by preventing protein carbonylation and thereby attenuating proteasomal dysfunction and ER stress. Finally we will examine the relative efficacy of endogenous and synthetic histidyl dipeptides against myocardial I/R injury. For this we will compare the relative efficacy of differet endogenous histidyl dipeptides and their synthetic analogs against carbonyl toxicity and investigate whether enhanced carbonyl quenching properties of these peptides result in greater protection against myocardial I/R injury. Completion of this project will lead to the identificatio and assessment of a novel antioxidant system present in the heart and how components of this system (histidyl peptides HDS) prevent critical features of ischemia injury (carbonyl toxicity). We expect that these studies will lead to the identification of specific carbonyls that mediate I/Rinjury and how they contribute to myocardial damage. These findings might lead to the development of robust and effective interventions that could be used clinically to limit ischemic and oxidative injury in the heart as well as in other tissues.

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

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


application_id: 9464624
project_number: 7R01EY021580-06
project_title: Deciphering Inhibition of Visual Plasticity by NgR1
administering_ic: NEI
award_notice_date: 2017-08-24
opportunity_number: PA-16-285
application_type: 7
activity_code: R01
ic: EY
serial_number: 021580
program_official: GREENWELL, THOMAS
project_start_date: 2012-05-01
project_end_date: 2018-08-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
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:
Project Summary/Abstract The functional connectivity within primary visual cortex exhibits heightenedsensitivity to visual experience during an interval late in development termed the criticalperiod. Abnormal visual experience during the critical period is the cause of amblyopia aprevalent childhood visual disorder. Treatment is most effective in children before theclose of the critical period. Subsequently plasticity diminishes and effective therapy ismore difficult. In a mouse model of amblyopia monocular deprivation during the criticalperiod but not thereafter both shifts the relative responsiveness of neurons in visualcortex and decreases visual acuity. Analogous to clinical findings these deficits persist ifnormal vision is restored after the close of the critical period. The nogo-66 receptor (NgR1) is required to close the critical period. In micelacking NgR1 plasticity during the critical period is normal but it continues such thatadult mice display the same plasticity as during the critical period. This proposalinvestigates how NgR1 closes the critical period. Specific Aim 1 dissects where NgR1expression is required with cortical circuitry to close the critical period and limit furtherOD plasticity with a combination of mouse genetics and electrophysiological recordings.Specific Aim 2 exploits the unique plasticity phenotype of NgR1 mutant mice to studyhow structural synaptic plasticity contributes to OD plasticity with repeated two-photon invivo imaging. Specific Aim 3 explores whether blocking NgR1 function after the criticalperiod will reactivate OD plasticity and improve visual acuity in amblyopic mice. The goalof this proposal is to improve understanding of how cortical plasticity is governed in thedeveloping and mature visual system.

public_health_relevance:
Project NarrativeAbnormal vision during a sensitive or 'critical' period in childhood is the cause ofamblyopia also known as lazy eye. Treatment for amblyopia is most effective during thecritical period. This research investigates how the critical period closes and explores howto 'reopen' the critical period in adults.


application_id: 9464522
project_number: 5R01DA043519-02
administering_ic: NIDA
award_notice_date: 2018-02-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 043519
program_official: SIROCCO, KAREN
project_start_date: 2017-05-01
project_end_date: 2022-02-28
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 3100162
contact_pi: BADA, HENRIETTA S.
other_pis: LEGGAS, MARKOS
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
project_terms:
Abstinence;Adrenergic Agonists;Affect;Aftercare;Age;Analgesics;Brain;Cells;Child;Child Behavior Checklist;Chloral Hydrate;Chronic;Clinic;Clinical;Clonidine;Cognitive;Collaborations;Data;Development;Drug Kinetics;Drug Withdrawal Symptoms;Effectiveness;Epidemic;Exposure to;Genetic;Goals;Growth;Health;Health Care Costs;Hospitals;Infant;Informal Social Control;Injury;Laboratory Study;Language;Length of Stay;Life;Metabolic;Methadone;Mission;Modeling;Morphine;Mothers;Motor;Narcotics;Neonatal;Neonatal Abstinence Syndrome;Neurons;Newborn Infant;Norepinephrine;Opioid;Opioid Receptor;Outcome;Performance;Pharmaceutical Preparations;Pharmacogenetics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Pilot Projects;Population;Pregnancy;Problem behavior;Property;Public Health;Randomized Clinical Trials;Reflex action;Reporting;Research;Stress;Testing;Time;United States National Institutes of Health;Withdrawal;Withdrawal Symptom;assault;brain size;brain volume;cost;drug withdrawal;early childhood;fetal opioid exposure;heroin use;improved;individual response;neonate;neurobehavioral;neurogenesis;noradrenergic;opioid exposure;opioid use;pharmacodynamic model;postnatal;prevent;prospective;response;standard of care;synaptogenesis;treatment duration;treatment optimization;treatment response


application_id: 9464496
project_number: 1R41NS102118-01A1
project_title: Commercialization of a Rapid Blood Test for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2018-03-06
opportunity_number: PA-16-303
application_type: 1
activity_code: R41
ic: NS
serial_number: 102118
suffix: A1
program_official: CAPORELLO, EMILY LAURA
project_start_date: 2018-04-01
project_end_date: 2020-03-31
study_section: Special Emphasis Panel[ZRG1 ETTN-P (13)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079138197
primary_uei: PNN2MU8LSPR3
duns_number: 079138197
uei: PNN2MU8LSPR3
fips: US
organization_id: 10042949
organization_name: FAWKES BIOTECHNOLOGY, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
project_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 injuryubiquitinated visinin like protein 1 (ubVILIP-1) that is released into blood rapidly after injury. To facilitate rapidon-field point-of-care (POC) measurement of circulating ubVILIP-1 we developed a lateral flow device (LFD)that provides detection of the biomarker in less than 20 min from a single drop of blood from a finger stick.Although initial testing in human TBI patients in a small clinical trial in the Emergency Department of theUniversity of Kentucky is promising we have observed variability in the lab produced devices related to limitedconstruction capacity that would likely limit further clinical trials. Therefore there is a need for conversion ofour lab produced devices to a commercial vendor for optimization of device architecture and production ofanalytically reproducible devices for future clinical trials. The aim of the current Phase I STTR proposal is towork with DCN Diagnostics to optimize antibody conjugation and device architecture and to produce prototypedevices for comparison to lab produced devices and evaluation of performance characteristics of DCNproduced devices. Analytical performance characteristics for prototype devices to be evaluated includeaccuracy precision limit of detection (LOD) limit of quantification (LOQ) linearity of response concentrationrange and device robustness. Results of the analytical validation will be compared to our lab produced devicesparticularly for LOD and LOQ. If successful the proposed studies will verify that our lab produced device cantransition to a commercial platform to allow analytically reproducible large scale production of devicesnecessary for larger clinical trials and pave the way for further commercialization.

project_terms:
Accident and Emergency department;Acute;Affect;Afghanistan;Antibodies;Architecture;Biological Assay;Biological Markers;Blood;Blood Tests;Brain Injuries;Cells;Cellulose;Cerebrospinal Fluid;Characteristics;Clinical Trials;Coma;Computers;Contracts;Craniocerebral Trauma;Data;Data Analyses;Detection;Development;Devices;Diagnosis;Diagnostic;Diagnostic radiologic examination;Diffuse;Drops;Early identification;Enzymes;Evaluation;Filament;Fingers;Fracture;Future;Gold Colloid;Healthcare;Hemorrhage;Hospitals;Hour;Human;Image;Immunoassay;Incidence;Injury;Iraq;Ischemic Stroke;Kentucky;Label;Laboratories;Laboratory Research;Lateral;Legal patent;Link;Measurement;Membrane;Methods;Migration Assay;Military Personnel;Modeling;Myelin Basic Proteins;Neuron-Specific Enolase;Neuronal Injury;Neurons;Operative Surgical Procedures;Patients;Performance;Phase;Population;Preparation;Production;Proteins;Rattus;Recombinants;Reference Standards;Reporter;Reproducibility;Research;Scanning;Serum;Small Business Technology Transfer Research;Specificity;Sports;Stroke;TBI Patients;Temperature;Testing;Time;Traumatic Brain Injury;Universities;Validation;Variant;Vendor;Visual;Whole Blood;Work;antibody conjugate;circulating biomarkers;commercialization;controlled cortical impact;experience;falls;interest;large scale production;male;mild traumatic brain injury;nanoGold;neurotrophic protein S100beta;novel marker;point of care;point-of-care diagnostics;prototype;response;scale up;screening;sensor;tomography;tool;vehicular accident;visinin

public_health_relevance:
Traumatic brain injury (TBI) is a substantial health care issue affecting both civilian and militarypopulations and there remains substantial need for development of a point-of-care (POC) diagnostictool that will allow rapid identification of patients with mild to moderate TBI (mmTBI). We recentlydeveloped a lateral flow device (LFD) that quantifies ubiquitinated visinin like protein 1 (ubVILIP-1) apost-translationally modified neuron specific Ca2+-sensor protein released into blood following TBI thatwas effective in the identification of mmTBI patients from normal controls in a small clinical trial.Although our preliminary data are promising there is a need to transition our lab produced devices to acommercial platform for optimization and to compare analytical figures of merit for commercial devicesrelative to our lab produced devices paving the way for larger scale production of analyticallyreproducible devices necessary for further clinical trials and further commercialization.


application_id: 9464243
project_number: 5UC2FD005049-05
project_title: Development and distribution of a certified reference cigarette suitable for rese
administering_ic: FDA
award_notice_date: 2018-03-08
opportunity_number: RFA-FD-14-001
application_type: 5
activity_code: UC2
ic: FD
serial_number: 005049
program_official: STATON, JILL
project_start_date: 2014-04-01
project_end_date: 2020-03-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 12031375
contact_pi: CHAMBERS, ORLANDO
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL 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:
Project Summary/Abstract : Since 1968 the University of Kentucky has provided referencecigarettes as the standard for non-clinical investigational purposes by tobacco manufacturerscontract and government laboratories and academic institutions. The University of KentuckyReference Cigarette Program (UKRCP) is committed to continue providing standards fortobacco product research and to work with the FDA to develop new products as necessary forregulation and analytical testing. The project will produce and characterize 50 million high-quality reference cigarettes representative of an American blended cigarette that aremanufactured in one manufacturing run with certified physical and chemical characteristics toallow for proficiency testing instrument calibration employee/student training method validationand for investigational purposes. A process for the design analysis and approval of prototyperesearch cigarettes is included to ensure the new reference cigarette meets the specified goals.Quality control and sample testing parameters are defined and substantial chemical analyseswill be conducted by the manufacturer and independent testing labs to allow for certification ofproduct physical parameters and constituent levels.A center of excellence in tobacco product analysis and reference tobacco products will beestablished to collaborate and coordinate studies with stakeholders including Tobacco Centersfor Regulatory Science product testing laboratories tobacco product manufacturers andtobacco researchers. This proposal outlines significant improvements to the current UKRCP interms of operational efficiency planning for new reference cigarette products establishingresearch capability and new services that will benefit the tobacco research community includingestablishing a proficiency testing program. A web-based interface will be developed to allow forsecure transmission and storage of data for the proficiency program. As an academic institutionour proposal to coordinate and administer inter-laboratory comparison studies on tobaccoreference products and mechanisms to provide various tobacco reference products as a serviceto the entire tobacco research community is an improvement over current programs. Thedevelopment of a high-quality reference cigarette and using this to help establish the center ofexcellence will strengthen the CTP's effort to develop the science of tobacco regulation andprovide a much needed basic resource for tobacco product research and regulation.

public_health_relevance:
Project NarrativeReference cigarettes are a necessary tool for measuring and reporting harmful and potentiallyharmful constituents in tobacco products as required under the Family Smoking Prevention andTobacco Control Act. Fifty million well-characterized and consistent certified referencecigarettes will be produced to allow for a proficiency testing program instrument calibrationemployee/student training method validation and for investigational purposes. The currentUniversity of Kentucky Reference Cigarette Program will establish a center of excellence fortobacco analysis and reference tobacco products to provide the foundation for establishing anaccredited laboratory proficiency testing system improved constituent analysis storagemanufacture and distribution of tobacco reference products with significant proposedimprovements and development in all of these areas.


application_id: 9463637
project_number: 5R01HL056652-19
project_title: Molecular Mechanism of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2018-03-23
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2021-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
World-wide spurious thrombosis accounts for 1 in 4 non-communicable disease deaths.Normally platelets respond to vascular damage and secrete granule cargo that are essential forrecruiting more platelets their adhesion and thrombosis. This releasate promotes normalsequelae but can also contribute to disease. Do platelets actively control what they release?How much releasate is enough? These are key questions to understand how platelets affecttheir vascular microenvironments. Membrane proteins (v- and t-SNAREs) fuse granule andplasma membranes to allow cargo release. In platelets VAMPs SNAP-23 and Syntaxin-11form a membrane-spanning complex that mediates fusion. Formation of this complex requirespost-translational modifications and a host of SNARE-regulators. This controls the complexity ofthe platelet release reaction: its rate extent and content. We hypothesize that bymanipulating the platelet secretory machinery we can modulate thrombosis with onlymodest effects on hemostasis. We propose three Aims: 1) Determine how alterations inplatelet exocytosis affect thrombosis and hemostasis. Using our unique collection oftransgenic mice we will genetically titrate platelet secretory machinery to determine how muchsecretion is needed for thrombosis and hemostasis. 2) Determine if platelet exocytosis canbe controlled by targeting post-translational modifications of t-SNAREs. We will examinetwo post-translational modifications: SNAP-23 phosphorylation by IB kinase and t-SNAREacylation. We will test inhibitors to determine if they can be repurposed as anti-thrombotics. t-SNARE acylation is highly dynamic in platelets. We will alter its cycling with acyl transferase andthioesterase inhibitors to define its importance to secretion and whether acylation can betargeted to affect platelet exocytosis. 3) Determine the roles of new elements of the plateletexocytosis machinery. We will probe the roles of two novel secretory elements: -synucleinand RalA/B. Our proposal expands our knowledge of the molecular requirements and thesequence of protein-protein interactions controlling platelet exocytosis. Our work is significantbecause it provides the needed mechanistic insights to identify potential targets for therapeuticintervention and to evaluate the relevance of the increasing volume of gene/risk associations.

project_terms:
Acylation;Address;Adhesions;Affect;Agonist;Amino Acid Sequence;Biochemical;Biological Assay;Blood Coagulation Disorders;Blood Platelets;Blood Vessels;Cell membrane;Cessation of life;Clinical;Coagulation Process;Collection;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Defect;Disease;Elements;Equilibrium;Event;Exocytosis;Fatty Acids;Funding;Goals;Health;Hemorrhage;Hemostatic function;Hyperactive behavior;Kinetics;Knowledge;Mediating;Membrane;Membrane Fusion;Membrane Proteins;Molecular;Mus;Myocardial Infarction;Pathology;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physicians;Post-Translational Protein Processing;Process;Proteins;Public Health;Reaction;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Serine;Stroke;Testing;Therapeutic;Therapeutic Intervention;Thrombosis;Transferase;Transgenic Animals;Transgenic Mice;Transmembrane Domain;Work;active control;alpha synuclein;alpha-SNAP;base;design;experimental study;genetic analysis;genetic manipulation;genetic regulatory protein;in vivo;inhibitor/antagonist;insight;kinase inhibitor;novel;protein protein interaction;recruit;response;risk variant;syntaxin 11;target SNARE proteins;targeted treatment;therapeutic target;vesicle-associated membrane protein;vesicular SNARE proteins

public_health_relevance:
NarrativeRelevance of the Project to Public Health:Worldwide thrombotic events e.g. strokes and heart attacks account for 1 of 4 deaths not caused bycommunicable diseases. Platelet secretion is essential for clot formation and thus is a target forcontrolling thrombosis; however we need to know more about the process before we can manipulate it.This proposal will yield the knowledge necessary to understand the process of platelet secretion andwill identify strategies to control it.


application_id: 9463337
project_number: 5F30EY026792-02
administering_ic: NEI
award_notice_date: 2018-01-18
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: EY
serial_number: 026792
program_official: AGARWAL, NEERAJ
project_start_date: 2017-03-01
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-F02B-D(20)L]
contact_pi_person_id: 14147214
contact_pi: CAMPBELL, PETER W
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
project_title:
Formation and Maturation of Projections Between Thalamic Reticular Nucleus and Dorsal Lateral Geniculate Nucleus

project_abstract:
Project SummaryOne of the preeminent models used to study the development of thalamic circuitry is the mouse visualthalamus. Most studies on this system have focused on the retinogeniculate pathway that connects retinalaxons with relay neurons of the dorsal lateral geniculate nucleus (dLGN). These relay neurons transmit visualinformation to the visual cortex via their axonal projection to primary visual cortex but this projection also sendsaxon collaterals to the thalamic reticular nucleus (TRN). The TRN is a GABAergic nucleus that projects to thedorsal thalamus including dLGN and is the main inhibitory projection to these brain regions. Thus there is afeedback loop between dLGN and TRN which is known to mediate visual attention select thalamocorticalrhythms and is involved in multiple diseases processes. However when this loop is formed and how itdevelops is currently not known. Furthermore it is unknown whether the development of these projections areregulated like other nonretinal projections to dLGN by retinal signaling. These questions will be addressed inthree specific aims: Aim 1 will determine when TRN terminals arrive in dLGN when synapses onto relayneurons become functional and how both terminal expanse and synaptic responses mature; Aim 2 willinvestigate similar parameters for the innervation of TRN by dLGN determining when terminals arrive whensynapses are made and how synaptic responses change over early development; Aim 3 will compare thedevelopmental time course of these projections TRN and dLGN in the presence and absence of retinal input tocentral visual structures in order to determine if retinal terminals coordinate the developmental timing ofinnervation. These experiments will utilize transgenic mice that specifically label either the projections fromTRN or those from dLGN. Specifically the GAD65 mouse will be used to visualize TRN innervation of dLGNwith EGFP while the somatostatin-cre mouse will be crossed to a channelrhodopsin-2 mouse in order tophotoactivate TRN terminals in electrophysiological recordings (aim 1). The corticotropin releasing hormonecre-recombinase mouse will be used to both stimulate and visualize dLGN inputs to TRN with crosses to eitherthe channelrhodopsin-2 mouse or an Ai9 reporter line that will label this projection with TdTomato (aim 2).Finally these experiments will be repeated after crossing all these mice into a math 5 null background togenetically remove retinal inputs (aim 3). Together these experiments will determine how an importantcomponent of the visual system develops and they will test the hypothesis that retinal terminals in dLGNcoordinate the innervation of non-retinal projections to dLGN as well as the axonal projections of dLGN relayneurons. These studies will not only advance the current understanding of the visual system but will haveimplications for circuit development in the thalamus as a whole.

project_terms:
Acute;Address;Adopted;Anatomy;Attention;Autistic Disorder;Axon;Biological Models;Brain;Brain region;CRH gene;Cell Nucleus;Cells;Corticotropin-Releasing Hormone;Data;Development;Disease;Dorsal;Electrophysiology (science);Enterobacteria phage P1 Cre recombinase;Epilepsy;Feedback;Imagery;Knock-in Mouse;Knock-out;Knowledge;Label;Lateral Dorsal Nucleus;Lateral Geniculate Body;Light;Mathematics;Mediating;Modeling;Mus;Mutant Strains Mice;Neurons;Optic Nerve;Output;Pathway interactions;Presynaptic Terminals;Process;Reporter;Retina;Retinal;Retinal Ganglion Cells;Signal Transduction;Slice;Somatostatin;Source;Structure;Synapses;System;Testing;Thalamic Nuclei;Thalamic structure;Time;Transgenic Mice;Visual;Visual Cortex;Visual attention;Visual system structure;area striata;experimental study;loss of function;mouse Cre recombinase;nerve supply;optogenetics;postnatal;postsynaptic;response;retinal axon;retinogeniculate;synaptogenesis;transcription factor;transmission process;visual information

public_health_relevance:
Project NarrativeInhibitory circuits of the thalamus are involved in multiple disease states includingepilepsy and autism but they also direct our attention in normal situations. Sinceunderstanding the development of a circuit is critical for determining its function wepropose to determine when these connections are formed and how they mature duringearly development. This study will determine when an important inhibitory feedback loopdevelops in the visual thalamus - a structure that has been used to discover much ofwhat we currently understand about thalamic circuitry.


