# projects

application_id: 9917668
project_number: 5P50AA024337-05
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2020-05-29
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: 2020-05-01
budget_end_date: 2021-04-30
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;Histone Deacetylase;Histones;Human Resources;Inflammation;Infrastructure;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;Pathogenicity;Pattern;Peptides;Performance;Post-Translational Protein Processing;Preparation;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Research;Research Personnel;Resolution;Resources;Role;Sampling;Science;Services;Standardization;Sulforaphane;Techniques;Technology;Tissue Sample;Tissues;Training and Education;Transcriptional Regulation;Unsaturated Fats;Urine;alcohol effect;data sharing;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;organ injury;phosphoproteomics;programs;response;sample collection;saturated fat;success;time of flight mass spectrometry;toxicant;tributyrin;two-dimensional


application_id: 9917667
project_number: 5P50AA024337-05
project_title: Pilot Project Core
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8300
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN 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: 2020-05-01
budget_end_date: 2021-04-30
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) was created to serve as a regional/national resource to investigate mechanisms of alcohol induced organ injury and to develop new agents/interventions to prevent/treat this organ injury both of which represent important unmet research needs. The theme of the center is unique among alcohol centers: the role of nutrition in the development/progression and potential prevention/treatment of alcohol-induced organ injury. The Pilots Core will contribute to this program by funding new projects dedicated to this theme of research. We will do this by supporting Young Investigators as well as recruiting Established Investigators who propose projects that represent a change in direction for their research. The goal of the Pilot Core is to provide support for promising clinical and translational research in alcohol-induced organ injury. This support will be targeted mainly at new investigators those newly entering alcohol clinical and translational research and alcohol clinical/translational investigators collaborating across departments and institutions. We will provide an environment that encourages development of pilot projects by providing alcohol researchers with the information resources and mentoring needed to perform innovative clinical/translational research that meets the demands of 21st century science. In addition we will improve the flow of information about existing and new opportunities and resources for pilot projects among University components and our affiliates. The ULARC will provide a clear entry point for investigators seeking to conduct alcohol research. We will reach our goal through the following Specific Aims: 1) To request potential pilot projects that coordinate with the overall theme of the ULARC: Nutrition and Alcohol-Induced Organ Injury; 2) To coordinate evaluation of new pilot project applications which conform to the criteria and goals of the ULARC pilot program; 3) To assist pilot project recipients to achieve extramural funding. This Pilot Program will build on UofL's already outstanding record of identifying promising pilot projects for support. Establishment of the ULARC and the Pilot Program will provide a significant boost to the currently available pilot program funding and greatly stimulate novel alcohol research at UofL.

project_terms:
Address;Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Awareness;Chronic Disease;Clinical;Clinical Research;Development;Educational Status;Environment;Evaluation;Extramural Activities;Funding;Goals;Health;Heart Diseases;Individual;Institution;Intervention;Kentucky;Lung diseases;Malignant Neoplasms;Mentors;Mission;Modeling;New Agents;Obesity;Patients;Peer Review;Pilot Projects;Prevention;Research;Research Personnel;Resources;Role;Rural;Schools;Science;Secure;Stroke;Study Section;Substance abuse problem;Translational Research;United States National Institutes of Health;Universities;alcohol abuse therapy;alcohol research;base;black lung;health disparity;improved;innovation;medically underserved;novel;nutrition;organ injury;prevent;programs;recruit;translational scientist


application_id: 9917666
project_number: 5P50AA024337-05
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
study_section: ZAA1-GG
subproject_number: 8308
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: 2020-05-01
budget_end_date: 2021-04-30
project_abstract:
The University of Louisville Alcohol Research Center (ULARC) is a multidisciplinary group of investigators focusing on nutrition gut flora/intestinal dysfunction and alcohol-induced organ injury and therapeutic interventions. The ULARC investigators come from 13 departments across 6 schools. The Administrative Core will provide oversight and coordination to the ULARC. The Administrative Core will support education opportunities a biostatistician and a tissue handling/archiving technician. The PI will be assisted by a the Steering and Program Advisory committees and a part-time assistant. The Specific Aims of the Administrative Core are to: 1) provide a formal governance structure for the coordination implementation direction and prioritization of activities including budget issues and resolving any conflicts as they arise ensuring the quality of all functions and evaluating progress; 2) provide a mechanism to replace any key individuals who may leave; 3) provide educational/training opportunities for students at all levels and junior faculty members; 4) provide biostatistical support for investigators; 5) provide `chain of custody' tissue/sample handling and storage; and 6) disseminate pertinent information to the scientific and lay community. All projects pilots and cores will be using the Administrative Core.

project_terms:
Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Archives;Area;Arts;Basic Science;Bioinformatics;Biometry;Budgets;Cancer Center;Clinical;Clinical Investigator;Collaborations;Communities;Conflict (Psychology);Consultations;Country;Development;Education;Engineering;Ensure;Epigenetic Process;Faculty;Functional disorder;Funding;Grant;Health;Health Sciences;Individual;International;Intervention;Lead;Leadership;Letters;Medicine;Pilot Projects;Proteomics;Public Health Nursing;Reporting;Research;Research Personnel;Research Proposals;Resources;Role;Schools;Science;Social Work;Specialized Center;Structure;Students;Therapeutic Intervention;Time;Tissue Sample;Tissues;Universities;alcohol research;body system;cohesion;gut microbiota;high school;innovation;interest;intestinal barrier;medical schools;member;metabolomics;multidisciplinary;next generation;novel;nutrition;organ injury;programs;training opportunity


application_id: 9917663
project_number: 5P50AA024337-05
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2020-05-29
opportunity_number: RFA-AA-15-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
program_official: DUNTY, JR, WILLIAM
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: ZAA1-GG(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Louisville Alcohol Research Center (ULARC) was created to serve as a regional/national resource to investigate mechanisms of alcohol induced organ injury and to develop new agents/interventions to prevent/treat this organ injury both of which represent important unmet research needs. The theme of the center is unique among alcohol centers: the role of nutrition and alcohol-induced organ injury. The approach is highly translational. Our investigators include faculty from 13 departments and 6 colleges. The Specific Aims of the ULARC are to:  1) facilitate interdisciplinary approaches and serve as a regional/national resource for the study of nutrition and alcohol-induced organ injury; 
2) provide a robust pilot project program and comprehensive education and research training in order to develop the next generation of alcohol investigators; and  3) develop potential therapeutic targets/interventions for alcohol induced organ injury based on the mechanistic research of the ULARC and translate knowledge/interventions to the community.  We will explore interactions of nutrition and alcohol abuse in the development of alcohol-induced organ dysfunction and we will evaluate diverse potential nutritional therapeutic interventions. Project  (McClain/Kirpich) evaluates the role of dietary unsaturated fat in the development/progression of alcoholic liver disease. Project 2 (Barve/Feng) evaluates alcohol-induced alterations in the gut-liver axis. They study the role of histone deacetylases (HDACs) in both the intestine and liver in gut-barrier dysfunction and steatohepatitis and the role of probiotics and dietary HDAC inhibitor in preventing/treating experimental ALD. Project 3 (Chen/Arteel) determines mechanisms by which maternal alcohol consumption causes mental retardation in the offspring. They evaluate epigenetic mechanisms by which alcohol induces apoptosis and teratogenesis and by which the nutraceutical sulforaphane provides epigenetic protection. Project 4 (Roman/Watson) evaluates mechanisms by which alcohol causes increased susceptibility to acute lung injury. They postulate that chronic alcohol intake triggers extracellular matrix remodeling resulting in "repavement" of lung tissue with a proinflammatory extracelluar matrix and that this process can be modulated by dietary intervention. We propose 3 pilots that evaluate nutrition:alcohol interactions on the A) liver B) immune system and C) the gut:liver axis and we have a novel "omics" core (metabolomics/proteomics) that will be utilized by all projects and pilots as well as
outside alcohol investigators/centers. Together these projects form a cohesive and interactive approach to investigate the effects of nutrition and nutritional interventions on alcohol-induced organ injury.

project_terms:
Acute Lung Injury;Alcohol Nutrition;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Apoptosis;Area;Award;Biomedical Engineering;Carnosine;Cause of Death;Chronic;Clinical Research;Collaborations;Communities;Development;Diet;Dietary Intervention;Education;Epigenetic Process;Extracellular Matrix;FDA approved;Faculty;Functional disorder;Funding;Goals;Health Care Costs;Histone Deacetylase;Histone Deacetylase Inhibitor;Immune system;Industry;Injury;Institution;Intervention;Intestines;Knowledge;Laboratories;Lead;Lipids;Liver;Mental Retardation;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;New Agents;Nutraceutical;Nutritional;Organ;Pilot Projects;Predisposition;Prevention;Probiotics;Process;Proteomics;Research;Research Personnel;Research Training;Resources;Rewards;Role;S-Adenosylmethionine;Steatohepatitis;Structure of parenchyma of lung;Sulforaphane;Therapeutic Intervention;Training and Education;Translating;Translational Research;United States;United States National Institutes of Health;Universities;Unsaturated Fats;alcohol abuse therapy;alcohol intervention;alcohol research;base;cohesion;college;gut-liver axis;high school;improved;interdisciplinary approach;interest;intestinal barrier;metabolomics;mortality;multidisciplinary;new therapeutic target;next generation;novel;nutrition;offspring;organ injury;prevent;programs;public health relevance;success;teratogenesis;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcohol abuse exacts a major toll on health and health costs in the United States and is the 3rd leading preventable cause of death in the U.S. There is no FDA-approved therapy for most forms of alcohol-induced organ injury such as alcoholic liver disease. Our focus on nutrition and alcohol-induced organ injury should lead to new therapeutic targets new nutritional preventions/treatments and improved mortality and morbidity.


application_id: 9917380
project_number: 1R01HL149351-01A1
project_title: Atherogenic Mechanisms of Electronic Nicotine Delivery Systems
administering_ic: NHLBI
award_notice_date: 2020-01-07
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: HL
serial_number: 149351
suffix: A1
program_official: CHEN, JUE
project_start_date: 2020-01-01
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1 VH-J (02)]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Acetaldehyde;Acrolein;Aerosols;Affect;Aldehydes;Animal Model;Animals;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Blood Vessels;Cardiovascular Diseases;Carnosine;Cells;Cessation of life;Characteristics;Chemicals;Chronic;Chronic Disease;Cigar;Cigarette;Collagen;Data;Devices;Dipeptides;Disease;Dose;Electronic Nicotine Delivery Systems;Electronic cigarette;Emerging Tobacco Products;Endothelium;Excision;Exposure to;Fatty acid glycerol esters;Formaldehyde;Glycerol;Human;In Vitro;Inflammation;Inflammatory;JUUL;Knockout Mice;Lesion;Life;Low Density Lipoprotein Receptor;Macrophage Activation;Matrix Metalloproteinases;Measures;Mediating;MicroRNAs;Molecular;Mus;Myeloid Cells;Myocardial Infarction;Nature;Necrosis;Nicotine;Nitrosamines;Oral;Pathway interactions;Play;Process;Propylene Glycols;Proteins;Risk;Role;Signal Transduction;Smoke;Smokeless Tobacco;Smoker;Smoking;Smooth Muscle Myocytes;Stroke;Supplementation;Testing;Thromboplastin;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;Toxin;Trees;Untranslated RNA;Urine;Vegetables;adduct;air filter;alpha-bungarotoxin receptor;atherogenesis;atherosclerosis risk;base;chronic inflammatory disease;cigarette smoke;cigarette smoking;cigarillos;combustible cigarette;combustion product;cytokine;electronic hookah;electronic liquid;feeding;heart disease risk;hookah;insight;macrophage;mortality risk;novel;overexpression;premature;prevent;recruit;response;sex;tobacco products;toxicant


application_id: 9917162
project_number: 1R01DK124112-01
administering_ic: NIDDK
award_notice_date: 2020-01-10
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: DK
serial_number: 124112
program_official: SADUSKY, ANNA BURKART
project_start_date: 2020-01-10
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1 DKUS-P (02)]
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-10
project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Apoptosis;Autophagocytosis;Biochemistry;Cancer Patient;Carboplatin;Cell Cycle;Cells;Cellular Stress;Ceramidase;Ceramides;Chronic;Chronic Kidney Failure;Cisplatin;Clinic;Data;Deterioration;Development;Diabetes Mellitus;Dialysis procedure;Dose;Dose-Limiting;Elderly;Electrolytes;Ensure;Enzymes;FDA approved;Fibrosis;Foundations;Future;Goals;Grant;Homeostasis;Hour;In Vitro;Inflammation;Injury;Injury to Kidney;Kidney;Knowledge;Laboratories;Lead;Lipids;Liquid substance;Long-Term Effects;Magnesium;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Medical;Metabolic;Metabolism;Methodology;Modeling;Mus;Necrosis;Oncologist;Patients;Phase;Process;Publishing;Recording of previous events;Recurrent disease;Regimen;Renal Replacement Therapy;Renal function;Reproducibility;Research;Risk;Role;Sodium Chloride;Sphingolipids;Supportive care;Testing;Therapeutic;Toxic effect;Treatment Efficacy;Treatment Protocols;Up-Regulation;analog;base;cancer type;comorbidity;design;drug development;in vivo;innovation;kidney cell;mortality;new therapeutic target;novel;novel therapeutics;stressor;wasting


application_id: 9914617
project_number: 1R21AI150085-01
administering_ic: NIAID
award_notice_date: 2020-03-17
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AI
serial_number: 150085
program_official: MCGUGAN, GLEN C
project_start_date: 2020-03-20
project_end_date: 2022-02-28
study_section: Special Emphasis Panel[ZRG1 IDM-M (02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-03-20
project_title:
Extragenic adaptation to the loss of a deubiquitinase affecting the T. gondii cell cycle and development

project_abstract:
Project SummaryThe cell cycle of protozoan parasite Toxoplasma gondii an important opportunistic pathogen in HIV-AIDSpatients is fundamentally distinct from that of typical eukaryotes. Replication in the actively growingtachyzoites in acute infection and within bradyzoites associated with chronic infection occurs by an internalbudding process termed endodyogeny. With endodyogeny each mother parasite produces 2 daughters percycle. In contrast the sexual cycle of the parasite a stage restricted to the feline gut occurs by a hybrid ofschizogony and endopolygeny which are typically associated with the malaria parasite and members of thegenus Sarcocystis respectively. These cell cycle architectures are associated with the generation of multipleprogeny per replicative cycle. We recently characterized a cell cycle regulated deubiquitnase TgOTUD3A(TgGT1_258780) the targeted disruption of which relaxed the restriction of tachyzoites replication toendodyogeny (2 progeny per cycle) to exhibit characteristics of both schizogony and endopolygeny-oftenwithin the same clonal vacuole. These mutant parasites generate 34 or 5 progeny per cycle to define themulti-daughter phenotype. In addition over 70% of TgOTUD3A tachyzoites ectopically express markersassociated with bradyzoites and induce the expression of genes typically associated with merozoties thestage associated with entry into the sexual cycle in cats. Complementation of the TgOTUD3A-KO failed torestore any of these phenotypes with whole genome sequencing revealing no credible mutations at thegenomic level. This suggested that a compensatory adaptation had occurred. Examination of the otherTgOTU family members revealed a selective transcriptional upregulation of two closely related familymember TgOTUD1B (TgGT1_237894) and TgOTUD1C (TgGT1_323200). It is likely that TgOTUD1A(TgGT1_207650) is similarly upregulated. This presents the possibility that one or more of the cell cycle anddevelopmental phenotypes attributed to the loss of TgOTUD3A may in fact be due to the upregulation of theClade D1 TgOTU members. To address this specific question we propose to functionally characterize theClade D1 TgOTU members and establish the consequence of both their ablation and regulatedoverexpression in the wild type and TgOTUD3A-KO background. In doing so we expect to gain insights intohow these deubiquitinases govern the selection of cell cycle architecture and control aspects of keydevelopmental transitions cementing an emerging association between these fundamental processes.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Affect;Architecture;Biochemical;CRISPR screen;Cell Cycle;Cell Cycle Regulation;Cell Nucleus;Characteristics;Chronic Phase;Cloning;Clustered Regularly Interspaced Short Palindromic Repeats;Complement;Cytokinesis;Daughter;Development;Dissection;Dolichos;Ectopic Expression;Enzyme Kinetics;Epitopes;Eukaryota;Exhibits;Family;Family Felidae;Family member;Felis catus;Gap Junctions;Gene Expression;Generations;Genes;Genetic Transcription;Genomics;Growth;HIV;Hybrids;In Situ;Individual;Infection;Investigation;Lectin;Light;Link;Malaria;Mediating;Metabolism;Mitotic;Morphology;Mothers;Mutation;Nuclear;Organism;Parasites;Patients;Phenotype;Polyploidy;Process;Production;Quantitative Reverse Transcriptase PCR;Recombinants;Reporting;Role;Sarcocystis;Substrate Specificity;Surface;Toxoplasma;Toxoplasma gondii;Ubiquitin;Up-Regulation;Vacuole;Work;acute infection;asexual;chronic infection;fitness;genome sequencing;genome-wide;head-to-head comparison;insight;member;mutant;ovarian neoplasm;overexpression;pathogen;promoter;scaffold;whole genome

public_health_relevance:
Project NarrativeThe loss of the deubiquitinase TgOTUD3A in Toxoplasma gondii tachyzoites initiates both thedysregulation of the cell cycle and a developmental shift characterized by a partial induction ofbradyzoite and merozoite activities. Dissection of the role of the induced Clade D1 OTUdeubiquitinases in these unusual phenotypes will be established.


application_id: 9914613
project_number: 1R13DE029404-01
project_title: PgLouisville2020: International Conference on P. gingivalis and Related Species
administering_ic: NIDCR
award_notice_date: 2020-03-09
opportunity_number: PA-18-648
application_type: 1
activity_code: R13
ic: DE
serial_number: 029404
program_official: MCNEALY, TAMARA L
project_start_date: 2020-04-01
project_end_date: 2022-09-30
study_section: Special Emphasis Panel[ZDE1 YM (08)]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTRecent methodological advances have accelerated research on periodontitis and the role of the dysbioticmicrobiota on the tooth surface below the gum line in the development and maintenance of chronicinflammation of the periodontium. Concurrently we have learned much about communication between bacteriain the dental plaque community and how they can corrupt host immune responses. Also our knowledge ofmechanisms causing erosion of the periodontium has increased exponentially. In all respects Porphyromonasgingivalis is in the center of the pathobiology of periodontitis. Therefore the purpose of this meeting is to bringtogether specialists investigating different host and bacterial aspects of the disease to present their majorrecent achievements. This is essential for continued progress in research into periodontitis and its associatedco-morbidities since the exchange of ideas will open new avenues in basic studies as well as discoveries ofnovel prophylactic and treatment measures. The conference will also serve as a venue to educate PhDstudents and postdoctoral associates who have entered this field of research in the most recent majorbreakthroughs in periodontitis-related research including: (i) structural and functional characterization of thenovel type IX secretion system (T9SS) used by periodontal pathogens to secrete their proteinaceous virulencefactors; (ii) advances in characterization of virulence factors structure on the atomic structure level(iii) understanding molecular mechanisms of dysbiotic community development on the tooth surface;(iv) elucidation of host signaling pathways manipulated by P. gingivalis; (v) implication of P. gingivalis as apotentially causative factor in such diseases such as esophageal cancer rheumatoid arthritis and Alzheimer'sdisease; and (vi) identification and characterization of new targets for development of novel strategies toprevent/treat periodontitis.

project_terms:
Achievement;Alkaloids;Alzheimer's Disease;Aspiration Pneumonia;Automobile Driving;Bacteria;Chronic;Communication;Communities;Community Developments;Dental Plaque;Development;Disease;Estrogens;Evaluation;Faculty;Funding;Future;Goals;Grant;Homeostasis;Immune response;In Situ;Infection;Inflammation;Inflammatory;International;Investigation;Knowledge;Light;Link;Maintenance;Malignant Neoplasms;Malignant neoplasm of esophagus;Measures;Metabolic;Methodology;Microbial Biofilms;Molecular;Mouth Diseases;National Institute of Dental and Craniofacial Research;Oral;Organism;Pathogenesis;Periodontitis;Periodontium;Physiology;Porphyromonas gingivalis;Postdoctoral Fellow;Predisposing Factor;Pregnancy Complications;Prophylactic treatment;Prothrombin;Reaction;Research;Rheumatoid Arthritis;Role;Scientist;Seminal;Signal Pathway;Specialist;Structure;Students;System;Systemic disease;Tissues;Tobacco;Tooth structure;Travel;Virulence;Virulence Factors;chronic inflammatory disease;commensal microbes;comorbidity;doctoral student;dysbiosis;environmental stressor;genetic risk factor;innovation;insight;meetings;microbial;microbiota;multidisciplinary;novel;novel strategies;oral microbiome;oral pathogen;periodontopathogen;posters;prevent;symposium;synergism;tooth surface

public_health_relevance:
NARRATIVERecent seminal findings have opened new research directions on molecular mechanism of initiation andprogression of periodontitis and associated systemic chronic inflammatory diseases. This conference proposesfunding for the 4th International Conference on Porphyromonas gingivalis and Related Species in Oral andSystemic Diseases with the goals to promote on innovative approaches to study periodontal pathogens anddevelopment of ground-breaking approaches to prevent and/or treat periodontitis and related comorbidities.


application_id: 9914108
project_number: 5T35DK072923-15
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2020-04-02
opportunity_number: PA-14-016
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: CASTLE, ARTHUR
project_start_date: 2006-05-01
project_end_date: 2021-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This is a competing renewal application for a T35 summer medical student training program in endocrine research that has been funded by NIDDK for 10 years. The 2 Specific Aims are 1) To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. 2) To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The program has supported the training of 6-7 second year medical students each summer in endocrine research topics including diabetes - with a particular focus on diabetic kidney disease endocrine malignancies pituitary regulation of peptide hormone expression LHR in brain non-alcoholic fatty liver disease and hormonal regulation of metabolism. Trainees are selected from the first year class at University of Louisville School of Medicine (SOM) applying for the summer research scholar program (SRSP). A successful effort has been made to recruit students from ethnic minorities and disadvantaged backgrounds. Students review the available projects submitted by 22 faculty research mentors and enter their 1st-3rd choices allowing matching of trainees with mentors. In-person meetings between trainees and mentors assures the 'fit' in the middle of the Spring semester. During the 10 week summer training students work with mentors on research projects in clinical or laboratory settings complete training in the Responsible Conduct of Research including managing scientific data fabrication and falsification of data plagiarism publication practices and responsible authorship mentorship stewardship and conflict of interest. Trainees working with human subjects complete human subject and IRB training. Trainees who use vertebrate animals in their research complete animal training courses and successfully pass tests to be certified. All trainees attend a weekly "Endocrine Seminar" designed to introduce clinical/translational research in endocrinology as led by mentors in this T35 program which culminates with each trainee presenting his/her research project to peers and mentors. Trainees also present the results of their research as posters with peers at a SOM-wide week-long celebration of research that includes nationally recognized physician scientists as keynote speakers. Winners from the poster contest have the opportunity to attend the National Student Research Forum the following Spring. Trainees may choose to continue research as part of the Distinction in Research (DIR) track enrichment program that provides research experiences throughout the medical school curriculum including in the third and fourth years toward the goal of developing clinician-researchers. Trainees have published their research in peer-reviewed journals and outcomes of trainees are being tracked to assess the impact of this T35 program on careers as physician- scientists.

project_terms:
Animals;Authorship;Brain;Clinical;Conflict of Interest;Data;Diabetes Mellitus;Diabetic Nephropathy;Educational Curriculum;Endocrine;Endocrinology;Environment;Funding;Goals;Institutional Review Boards;Journals;Laboratories;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Metabolism;NCI Scholars Program;National Institute of Diabetes and Digestive and Kidney Diseases;Outcome;Peer Review;Persons;Physicians;Pituitary Gland;Plagiarism;Publications;Publishing;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Scientist;Structure;Student recruitment;Students;Testing;Training;Training Programs;Training Support;Translational Research;Universities;Vertebrates;Work;base;career;design;ethnic disadvantage;ethnic minority population;experience;faculty research;hormone regulation;human subject;medical schools;meetings;non-alcoholic fatty liver disease;peer;peer coaching;peptide hormone;posters;programs;responsible research conduct;skills;summer research

public_health_relevance:
PUBLIC HEALTH RELEVANCE   Understanding the aberrant hormonal and genetic regulation of cellular homeostasis is the key to unraveling chronic disease and to the development of new treatment strategies. The major goal of this project is to provide medical students who have completed at least one year of medical school with a hands-on summer research experience in NIDDK-focused research on endocrine-related health concerns to stimulate their interest in a research career.


application_id: 9913998
project_number: 5R01DK115406-03
project_title: CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis
administering_ic: NIDDK
award_notice_date: 2020-04-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 115406
program_official: GARCIA, MARTHA
project_start_date: 2018-07-20
project_end_date: 2023-04-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
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:
The overarching theme of this project is to address the mechanisms underlying gut derived extracellular vesicles(EVs)-induced liver inflammation/injury in Non-alcoholic fatty liver disease (NAFLD). We will determine the roleof sphingolipid metabolites specifically; Sphingosine 1-phosphate (S1P)-enriched gut EVs and pathwayCSN8/SphK1 in the development of NAFLD. The current proposal links gut-derived EVs to macrophage-mediated inflammation by proposing that extracellular vesicles from gut recruit macrophages to the liverresulting in liver injury and inflammation. Our recent work has begun to identify intestinal inflammation-inducedalterations in EVs and shows that gut-derived EVs play a critical role in the regulation of NKT cells and Th17cells in the development of liver inflammation and colon cancer via gut-liver axis. Our preliminary data showsthat LPS promotes Intestinal epithelial cells (IECs) release sphingolipid metabolites-enriched pro-inflammatoryEVs including ceramide and S1P. Our preliminary findings also indicate that CSN8/SphK1 signaling pathwayplays a crucial role in the production of S1P-enriched EVs. Chronic high fat diet consumption leads to increasedgut permeability and expose the liver to gut-derived products including EVs of IECs. Increased S1P-enrichedEVs activate its receptor S1P1 on hepatic macrophages which may promote macrophage chemotaxis into theliver. This has led to the central hypothesis that gut microbiota regulate sphingolipid metabolites-enriched EVs biogenesis and release via gut CSN8/SphK1 pathway and gut EVs carrying sphingolipidmetabolites (ceramide and S1P) translocate to liver which in turn attract macrophages into the liverpromoting liver injury in NAFLD. Importantly the proposal also pursues translational studies that examine theefficacy of nutrition-nanoparticles based therapeutic interventions targeted at gut microbiota and SphK1-S1PR1inhibition in mitigating gut-liver axis changes. To address our hypothesis we propose the following specific aims:Aim 1: Determine whether gut-derived EVs-S1P regulate liver inflammation and injury via CSN8/SphK1 pathwayin NAFLD. Aim 2: Determine whether gut-derived EVs-S1P contribute to liver macrophagesrecruitment/activation by S1PR1-STAT3 in NAFLD. Aim 3: Define molecular mechanisms underlying CSN8 andSphK1 reciprocal regulation and modulation of the CSN8/S1P-S1PR1 signal will prevent macrophagesmediated-liver injury in NAFLD. The proposal will provide a better understanding of diet-gut-liver interactions andmolecular mechanisms contributing to the pathogenesis of EVs-S1P-induced liver inflammation and injury. Thestudy will lead to identification of new therapeutic targets and potential dietary interventions for treating NAFLD.

project_terms:
Address;Affect;Biogenesis;Cell physiology;Cells;Ceramides;Chemotaxis;Chronic;Colitis;Colon Carcinoma;Consumption;Data;Development;Diet;Dietary Intervention;Distant;Enzymes;Epithelial Cells;Hepatic;High Fat Diet;Immune;Inflammation;Inflammatory;Injury;Intestinal permeability;Intestines;Kupffer Cells;Link;Lipids;Liver;Lymphocyte;Macrophage Activation;Mediating;Molecular;Pathogenesis;Pathogenicity;Pathway interactions;Play;Production;Property;Regulation;Role;SPHK1 enzyme;STAT3 gene;Severities;Signal Pathway;Signal Transduction;Sphingolipids;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Up-Regulation;Work;base;ceramide 1-phosphate;edg-1 Protein;exosome;extracellular vesicles;gut microbiota;gut-liver axis;inflammatory disease of the intestine;interest;intestinal epithelium;liver development;liver inflammation;liver injury;macrophage;microorganism antigen;nanoparticle;new therapeutic target;non-alcoholic fatty liver disease;nutrition;prevent;recruit;sphingosine 1-phosphate;trafficking;translational study

public_health_relevance:
Project NarrativeThis proposal underscores the importance of investigating S1P-enriched extracellular vesicles as a critical gut-derived factor for the development of nonalcoholic fatty liver diseases by regulating the recruitment/activation ofhepatic macrophages. We anticipate that we can abrogate their local and/or distant activities by targetingCSN8/SphK1-S1PR1/Stat3 pathway.


application_id: 9913569
project_number: 5R00HL129193-05
project_title: Protein S Anticoagulant Activity: Biochemical Mechanisms and Structural Studies
administering_ic: NHLBI
award_notice_date: 2020-03-19
opportunity_number: PA-14-042
application_type: 5
activity_code: R00
ic: HL
serial_number: 129193
program_official: SARKAR, RITA
project_start_date: 2015-09-15
project_end_date: 2021-09-30
study_section: NSS
contact_pi_person_id: 9231243
contact_pi: WOOD, JEREMY P
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Project Summary/Abstract Thrombosis is a leading cause of death in the United States. It is caused by excessive production of the blood clotting factor thrombin. During normal hemostasis thrombin generation is tightly regulated by several anticoagulant proteins including protein S (PS). PS is an important anticoagulant protein in humans with total deficiency producing severe life-threatening thrombosis at birth. However the biochemical mechanism(s) by which PS mediates its anticoagulant activity are poorly understood. PS is a cofactor for two other endogenous anticoagulants tissue factor pathway inhibitor alpha (TFPIa) and activated protein C (APC). PS/TFPIa inhibits coagulation factor Xa (FXa) while PS/APC proteolytically inactivates factor Va (FVa). FVa and FXa combine to form prothrombinase the powerful enzymatic complex that converts prothrombin to thrombin. Prothrombinase is resistant to inactivation by either PS/APC or PS/TFPIa during the propagation phase of blood clotting yet its activity is clearly regulated because thrombi do not spread throughout the entire vasculature during normal hemostasis. PS promotes the inactivation of both protein components of prothrombinase FVa (as an APC cofactor) and FXa (as a TFPIa cofactor) suggesting that it may modulate prothrombinase activity. We hypothesize that coordinated action of the PS/TFPIa and PS/APC anticoagulant systems will produce efficient inhibition of prothrombinase. This hypothesis will be tested via complimentary biochemical and structural studies. The K99 will focus on biochemical studies using assays established during my post-doctoral research. They will further define the mechanism by which PS enhances TFPIa inhibitory activity (Specific Aim 1.1) and determine how FXa inhibition by PS/TFPIa alters the ability of PS/APC to proteolytically inactivate FVa and vice versa (Specific Aim 1.2). The R00 will extend this work further by assessing the contribution of different physiologic membrane surfaces to the regulation of thrombin generation (Specific Aim 1.3). These functional studies will be correlated with structural studies. The K99 will focus on development of molecular models of the PS/TFPIa and PS/APC complexes (Specific Aim 2.1). The R00 will extend this work by producing crystal structures of individual domains of PS TFPIa and APC separately and in complex (Specific Aims 2.2 and 2.3). These studies will coincide with career development training which will include a focus on training in structural biology through a combination of courses and work in the laboratory of Dr. Stephen Everse. This will differentiate my work from that of my mentor and enable me to establish an independent research career studying the biochemistry of hemostatic proteins.

project_terms:
Amino Acids;Anticoagulants;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Birth;Blood Coagulation Disorders;Blood Coagulation Factor;Blood Platelets;Blood Proteins;Blood coagulation;Cause of Death;Coagulation Process;Complex;Crystallization;Data;Development;Endothelial Cells;Factor Va;Factor Xa;Generations;Hemophilia A;Hemostatic Agents;Hemostatic function;Human;Individual;Injury;Laboratories;Length;Life;Lipoproteins;Mediating;Membrane;Mentors;Modeling;Molecular Conformation;Myocardial Infarction;Patients;Phase;Physiological;Plasma;Postdoctoral Fellow;Production;Property;Protein S;Proteins;Prothrombin;Regulation;Research;Resistance;Risk;Site;Stroke;Structure;Surface;System;TFPI;Testing;Thrombin;Thromboplastin;Thrombosis;Thrombus;Training;United States;Work;X-Ray Crystallography;activated Protein C;base;career;career development;cofactor;design;inhibitor/antagonist;innovation;molecular modeling;platelet function;prevent;protein protein interaction;structural biology;tubulin-specific chaperone C

public_health_relevance:
Project NarrativeBlood clots are a leading cause of death in the United States every year. Protein S keeps blood from clottingbut we don't understand how it works. This project is designed to determine how protein S interacts with otherblood proteins to prevent clotting and the results will have applications for the treatment of patients withbleeding or clotting disorders.


application_id: 9911775
project_number: 1F31HL151111-01
project_title: Bronchiolar Dysplasia in COPD is Governed by Loss of Polycomb Repressive Complex 2
administering_ic: NHLBI
award_notice_date: 2020-03-15
opportunity_number: PA-19-196
application_type: 1
activity_code: F31
ic: HL
serial_number: 151111
program_official: TIGNO, XENIA
project_start_date: 2020-03-15
project_end_date: 2021-10-14
study_section: Special Emphasis Panel[ZRG1 F10A-R (20)]
contact_pi_person_id: 11938641
contact_pi: BYRD, ARIA
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:
PROJECT SUMMARYFuture Research QuestionsAs a graduate student in the Toxicology and Cancer Biology Department of University of Kentucky I seek tounderstand the complex molecular processes that drive development of lung diseases. The goal of mydissertation research is to determine how the role of Polycomb Repressive Complex 2 (PRC2) directs properlung stem cell fate and how this process is dysregulated in lung disease. My central hypothesis is that PRC2normally represses basal and goblet cell fates in bronchiolar epithelium and that loss of PRC2-mediatedrepression of these lineages leads to phenotypes observed in bronchiolar epithelium of Chronic ObstructivePulmonary disease (COPD) including basal cell and goblet cell metaplasia.Background and MethodologyPolycomb Repressive Complex 2 (PRC2) modulates gene expression through histone modification. Recentunpublished data from the Brainson lab suggests that PRC2 activity is dysregulated in chronic obstructivepulmonary disease (COPD). These findings fit with others in the field that demonstrated loss of PRC2 indeveloping lung causes aberrant expression of basal cell markers including KRT5 and p63 in distal lung airwaysin mice. Together these data suggest that improper PRC2 activity is important for cell development fate andfunction. They also warrant further investigation into PRC2's role in disease development and propagationparticularly those involving lung functions.MethodologyThe Aims of my proposal are to: 1) Elucidate the cellular changes in bronchiolar epithelial cells observed in invitro and in vivo after genetic modulation of the PRC2 complex and 2) Confirm that loss of proper PRC2 genesilencing leads to expansion of basal cell and goblet cell fates in human bronchiolar epithelial cells. For Aim 1I am knocking out one or two alleles of Ezh2 the gene encoding the enzyme for PRC2 in adult mouse lung forfour months and challenging the mice with ovalbumin to induce goblet cell metaplasia. My hypothesis that lossof PRC2 will prevent cells from resolving allergic response will be tested by lung histology. In parallel I will uselung organoid cultures and single cell RNA-sequencing to examine lung cell fates when PRC2 is dysregulatedin mouse lung cells. For Aim 2 I will use an EZH2 inhibitor short hairpin RNAs against PRC2 components andcigarette smoke extract on human bronchial epithelial cells in air-liquid interphase cultures to examine howperturbation of PRC2 changes lung cell fate decisions. I will also establish new cultures from COPD patientsand finally explore the transcriptional changes in these cultures and how PRC2 influences these changes bychromatin immunoprecipitation experiments.Career PotentialMy ultimate goal is to influence national and global health policy by effectively investigating the physiologicalchanges that are currently taking and have taken place as a result of environmental changes. My personalinterest in stem cell biology and epigenetic manipulation coincides with Dr. Brainson's objective to elucidate lungstem cell fate and annotate the epigenome of diseased versus normal human and mouse lung epithelium.

project_terms:
Ablation;Adult;Air;Alleles;Allergens;Area;Back;Basal Cell;Basal Cell Hyperplasia;Cancer Biology;Cell Differentiation process;Cells;Chromatin;Chronic Bronchitis;Chronic Obstructive Airway Disease;Coal;Complex;DNA;Data;Deposition;Development;Disease;Distal;Doxycycline;Dust;Dysplasia;EZH2 gene;Embryo;Environmental Risk Factor;Enzymes;Epigenetic Process;Epithelial;Epithelial Cells;Epithelium;Future;Gene Expression;Gene Expression Regulation;Gene Silencing;Genetic;Genetic Transcription;Genetically Engineered Mouse;Goals;Goblet Cells;Health Policy;Histology;Histone H3;Histones;Human;In Vitro;Infiltration;Inflammatory;Interphase;Investigation;Kentucky;Knock-out;Laboratories;Liquid substance;Lung;Lung diseases;Lysine;MUC5AC gene;Measures;Mediating;Mentors;Metaplastic Cell;Methodology;Methods;Molecular;Mucous body substance;Mus;Organoids;Ovalbumin;Oxidative Stress;Patients;Phenotype;Physiological;Polycomb;Process;Progressive Disease;Repression;Research;Respiration;Respiratory physiology;Reverse Transcriptase Polymerase Chain Reaction;Role;Smoker;Smoking;Stains;Structure of parenchyma of lung;Testing;Toxicology;Universities;allergic response;bronchial epithelium;career;chromatin immunoprecipitation;cigarette smoke;design;effective therapy;environmental change;epigenome;experimental study;exposure to cigarette smoke;gene repression;global health;graduate student;histone modification;in vivo;inhibitor/antagonist;interest;knock-down;lung development;mouse model;novel;prevent;respiratory;response;single-cell RNA sequencing;small hairpin RNA;stem cell biology;stem cell fate;treatment strategy

public_health_relevance:
NARRATIVEChronic obstructive pulmonary disease (COPD) is a progressive disease with no effective treatments and oftenthe disease persists well after the initial drivers such as coal dust or smoking are eliminated. My researchfocuses on understanding how DNA organization is altered in the lung cells of COPD patients. If my hypothesisabout how normal DNA organization is changed in lung cells of COPD patients is supported by our data thisresearch may suggest novel treatments strategies to reverse these changes during COPD.


application_id: 9911525
project_number: 1F31HL151120-01
project_title: Cardiomyocyte phenotype drives enhanced AMI recovery in spiny mice
administering_ic: NHLBI
award_notice_date: 2020-03-20
opportunity_number: PA-19-196
application_type: 1
activity_code: F31
ic: HL
serial_number: 151120
program_official: HUANG, LI-SHIN
project_start_date: 2020-06-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 F10A-R (20)]
contact_pi_person_id: 15924998
contact_pi: PENG, HSUAN
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:
Project Summary/Abstract Approximately every 40 seconds there is an incident of heart attack (acute myocardial infarction AMI).This injury causes necrosis of heart leading to cardiac arrhythmia and reduced cardiac contractility renderingprogression of heart failure (HF) in many patients within five years of initial AMI. Unfortunately the human heartdoes not regenerate after injury and there is no approved clinical treatment that facilitates cardiac repair.Moreover no regenerative mammalian models are established to identify molecular targets for bona fide cardiacrepair. This proposal will address these limitations by studying regenerate mammal with a non-regeneratorsimultaneously. Acomys (African Spiny mice) is a mammal closely related to Mus (laboratory mouse). Recentlyindependent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs.Most importantly after AMI Acomys demonstrated significant cardiac protection with a higher survival rate thanmice. Our preliminary studies revealed that Acomys is capable of rescuing cardiac function after AMI. Thisproposal will further dissect the effect of these alternative injury responses seen in Acomys. Based on our preliminary results I proposed to explore the alternative injury response seen in Acomys.I hypothesized that pro-regenerative cellular signals in Acomys heart after AMI stimulate adult cardiomyocyteproliferation and result in enhanced myocardium recovery and survival. I will test this hypothesis by implementingthe following two aims. Aim 1 will investigate the extent of cardiac repair and the role of cardiomyocyteproliferation in Acomys after a heart attack with direct comparison to Mus. I will examine cardiomyocyteproliferation in both species after AMI. Scar size functional recovery and angiogenesis will also be characterized.Aim 2 of this proposal will investigate the effect of macrophage-derived signals on Acomys cardiac repair. Sincecellular cross-talk between cardiac cells are important in both cardiac homeostasis and post-injury repaircardiomyocyte proliferation after AMI is likely controlled by both intrinsic and extrinsic signals. Macrophagesinfiltrate the injured heart in abundance early after AMI and have been shown to influence cardiac repair. Ourpreliminary data suggest that macrophage polarization in Acomys is different with more anti-inflammatorymacrophages compared to Mus. I hypothesized that Acomys macrophage release extracellular signals that aremore pro-regenerative than Mus macrophages. To test my hypothesis I will employ both in vivo and in vitrotechniques to enrich macrophage secretome and examine its effect on Mus cardiac repair. This proposal willestablish Acomys as a novel mammalian model for studying cardiac recovery after ischemic injury. I anticipatethe outcome of this study to provide a blueprint for the future development of novel cardiac therapies for cardiacpatients.

project_terms:
Acomys;Acute myocardial infarction;Address;Adult;African;Animals;Anti-Inflammatory Agents;Apoptotic;Arrhythmia;Biological Process;Biology;Bone Marrow;Cardiac;Cardiac Myocytes;Career Choice;Cell Proliferation;Cell Therapy;Cells;Cessation of life;Cicatrix;Clinical;Clinical Treatment;Cultured Cells;Data;Development;Echocardiography;Enzyme-Linked Immunosorbent Assay;Failure;Fellowship;Fibroblasts;Flow Cytometry;Future;Goals;Healthcare;Heart;Heart Injuries;Heart failure;High Prevalence;Homeostasis;Human;Immunization;Immunohistochemistry;In Vitro;Inflammatory;Injections;Injury;Knowledge;Label;Laboratory mice;Ligation;Mammals;Medicine;Methods;Modeling;Molecular;Molecular Target;Mononuclear;Morbidity - disease rate;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Necrosis;Neonatal;Organ;Outcome Study;Patients;Pattern;Peptides;Phenotype;Production;Recovery;Recovery of Function;Recurrence;Reperfusion Injury;Reporting;Research;Research Personnel;Role;Side;Signal Transduction;Study models;Survival Rate;Techniques;Testing;Tissues;Training;Translating;United States;Vision;Western Blotting;angiogenesis;base;cardiac repair;cardioprotection;clinical development;clinically relevant;comparative;cytokine;exosome;extracellular;extracellular vesicles;heart function;in vivo;injured;injury and repair;intravenous injection;ischemic injury;mRNA Expression;macrophage;mortality;mouse model;myocardial injury;nano;new therapeutic target;novel;novel therapeutic intervention;regenerative;repaired;response to injury;small molecule;treatment group

public_health_relevance:
The proposed research is relevant to health care in that Ischemic heart disease following acute myocardialinfarction (AMI) continues to be the leading cause of mortality and morbidity in the U.S. with no approved clinicaltherapies to replace the damaged myocardium. The goal of this proposal is to elucidate cardiac protectivemechanisms that enhance recovery after AMI using the novel regenerative mammal Acomys as adult mousemodel. Our results will identify new therapeutic targets for the future development of clinically relevant cardiactherapies for human patients.


application_id: 9911167
project_number: 1F30AG063422-01A1
administering_ic: NIA
award_notice_date: 2019-09-11
opportunity_number: PA-19-192
application_type: 1
activity_code: F30
ic: AG
serial_number: 063422
suffix: A1
program_official: DIBATTISTA, AMANDA
project_start_date: 2019-09-29
project_end_date: 2023-06-28
study_section: Special Emphasis Panel[ZRG1 F03A-N (20)]
contact_pi_person_id: 15251375
contact_pi: FARMER, BRANDON CHARLES
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_title:
Astrocyte Lipid Droplets as a Novel Mechanism for Impaired Glucose Metabolism in the E4 and AD Brain

project_abstract:
PROJECT SUMMARY Alzheimers disease (AD) is a societal burden costing the nation 277 billion dollars per year and is thesixth leading cause of death. As the search for disease modifying therapies for AD continues a deeperunderstanding of cellular metabolism in the AD brain is critical to guide research. The apolipoprotein E (APOE)gene is the strongest genetic predictor of late onset AD (LOAD). In humans there are three major isoforms ofapoE: E2 E3 and E4. E3 is the major isoform expressed in humans (~60% of population). E4 confers betweena 2 (heterozygous) to 15-fold (homozygous) increase in risk of LOAD compared to E3. Apolipoprotein E (apoE)is primarily secreted by astrocytes as a primary lipid carrier in the brain and has gained traction as a regulatorof cerebral metabolism. For example E4 carriers exhibit decreased glucose uptake as measured by 18fludeoxy-glucose positron emission tomography (FDG-PET). FDG-PET is similarly lower in AD individuals however E4carriers show low FDG-PET decades before the onset of symptomatic cognitive decline. We recently showedthat E4 expressing astrocytes accumulate significantly more lipid in the form of lipid droplets (LDs) compared toE3 an intriguing finding in light of the initial 1907 report from Alzheimer that implicated glial lipid accumulationas a hallmark of disease. Since LDs have been shown to be involved in metabolic disease  including regulationof glucose uptake  we hypothesize that over accumulation of astrocyte LDs drive the impaired glucose uptakeseen in E4 and AD brains. Therefore this proposal tests a mechanism by which an LD-associated proteinsequesters a critical mediator of glucose transporter trafficking leading to a decrease in astrocyte glucoseuptake. We will test this mechanism (Aim 1A) in vivo in mice homozygous for human E3 and E4 and (Aim 1B-C) in vitro in primary astrocytes that express human E3 and E4. We will also translate our findings (Aim 2) bycharacterizing LD formation in APOE genotyped human post-mortem brain tissue correlating lipid abundancewith clinical data from the UK Alzheimers Disease Center cohort. The key focus of this fellowship is to uncovera cellular mechanism driving impaired glucose uptake in E4 astrocytes as well as equip the trainee with skills inmass spectrometry confocal microscopy immunohistochemistry radioactive tracing translational humanspecimen handling data analysis and more. These skills and excellent mentorship will be instrumental in thetrainees path to become an independent physician-scientist.

project_terms:
Address;Adipose tissue;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Amyloid;Apolipoprotein E;Astrocytes;Attention;Automobile Driving;Autopsy;Biological Assay;Brain;Brain Diseases;Cause of Death;Cell membrane;Cells;Cerebrum;Characteristics;Clinical;Clinical Data;Cognitive;Cognitive deficits;Confocal Microscopy;Cytosol;Data;Data Analyses;Development;Dietary Intervention;Disease;Etiology;Exhibits;Fellowship;Genes;Genetic;Genotype;Glucose;Glucose Transporter;High Fat Diet;Human;Immunohistochemistry;Impaired cognition;Impairment;In Vitro;Individual;Label;Late Onset Alzheimer Disease;Lead;Ligation;Light;Link;Lipids;Location;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Mentorship;Metabolic;Metabolic Diseases;Metabolism;Mus;Neuroglia;Neurons;Pathogenesis;Patients;Physicians;Population;Positron-Emission Tomography;Process;Protein Isoforms;Proteins;Radioactive;Reporting;Research;Resolution;Risk;Role;SLC2A1 gene;SNAP23 gene;Saccule structure;Scientist;Source;Specimen;Specimen Handling;Testing;Tracer;Traction;Translating;apolipoprotein E-4;biobank;blood glucose regulation;brain tissue;cell type;clinically relevant;cohort;cost;fluorodeoxyglucose positron emission tomography;genetic predictors;genetic risk factor;glucose metabolism;glucose uptake;impaired driving performance;in vivo;insight;neuropathology;non-demented;novel;perilipin;skills;therapeutic target;trafficking;uptake

public_health_relevance:
PROJECT NARRATIVE The strongest genetic risk factor for the development of late-onset Alzheimers Disease (AD) isapolipoprotein E4 (E4) and research into how E4 contributes to this risk is critical to find therapeutictargets. Glial lipid droplet (LD) accumulation and glucose hypometabolism are shared characteristicsof the AD and non-AD E4 brain. This project characterizes an E4-associated astrocyte LDaccumulation and its clinical relevance in post-mortem human brain tissue presenting a novelmechanism underlying E4-driven glucose hypometabolism.


application_id: 9908078
project_number: 5R01ES028268-03
project_title: Effects of Air Pollution on Stem Cell Health
administering_ic: NIEHS
award_notice_date: 2020-04-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028268
program_official: SCHUG, THADDEUS
project_start_date: 2018-08-15
project_end_date: 2023-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: HILL, BRADFORD GUY
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:
ABSTRACTExtensive evidence indicates that exposure to ambient particulate matter (PM) contributes to the global burdenof disease. Worldwide air pollution is linked with seven million premature deaths; and in the US PM isassociated with 200000 deaths per year most of which are due to cardiovascular disease (CVD).Nevertheless the mechanisms by which PM exposure induces cardiovascular injury remain unclear.Understanding such mechanisms is important to develop mechanistically validated biomarkers of PM-inducedsubclinical injury and to develop effective therapeutic interventions. Mechanistic studies in individuals with mildto moderate CVD risk have implicated endothelial dysfunction and inflammation as critical mediators of PM-induced injury; however because these mediators are also key features of CVD it is unclear whether PMdirectly affects endothelial function or whether these changes are secondary to the exacerbation of CVD byPM. We found that in young healthy individuals exposure to elevated levels of fine PM (PM2.5) suppressescirculating levels of endothelial progenitor cells (EPCs). Chronic suppression of EPCs is indicative of earlyendothelial injury and in prospective studies predictive of CVD mortality. Nevertheless the mechanisms bywhich PM2.5 suppress EPC levels remain obscure and it is unclear whether PM2.5 affects EPC function andtheir ability to promote tissue repair and angiogenesis. Our preliminary data show that exposure toconcentrated PM2.5 decreases the metabolic activity of EPCs and reduces their ability to repair vascular tissue.We have also found that the effects of PM2.5 are attenuated by overexpressing extracellular superoxidedismutase in the lung. Based on these observations we propose that upon PM2.5 inhalation pulmonarygeneration of superoxide impairs EPC signaling and metabolism which compromises their ability to maintain ahealthy endothelium and to promote angiogenesis. To test this hypothesis we will determine the effects ofPM2.5 exposure on EPC metabolism; assess the impact of PM2.5 exposure on EPC function; and elucidate themechanisms by which PM2.5 exposure induces metabolic and functional changes in EPCs. Completion of thisproject will not only lead to a better understanding of how PM causes EPC dysfunction but could also identifyselective specific and mechanistically validated biomarkers of PM2.5-induced cardiovascular injury. Overallour results would further a new conceptthat PM2.5-induced cardiovascular injury is due to defective EPCmetabolismand could lead to the development of a novel approach that could be readily tested in futureclinical studies to attenuate PM2.5-induced CVD mortality and morbidity.

project_terms:
Affect;Aging;Air;Air Pollution;Angiogenic Factor;Animal Model;Atherosclerosis;Attenuated;Biological Markers;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cardiovascular system;Cell Aging;Cell physiology;Cells;Cellular Metabolic Process;Cessation of life;Chronic;Clinical;Clinical Research;Competence;Data;Defect;Development;Endothelium;Exposure to;Flow Cytometry;Functional disorder;Future;Generations;Glycolysis;Goals;Health;Hypertension;Impairment;In Vitro;Individual;Inflammation;Inhalation;Injury;Insulin;Intervention;Isotopes;Lead;Link;Lung;Mediator of activation protein;Metabolic;Metabolic dysfunction;Metabolism;Morbidity - disease rate;Mus;Nose;Outcome;Oxidative Phosphorylation;Oxidative Stress;Particulate Matter;Pathologic Processes;Phenotype;Proliferating;Prospective Studies;Research;Resistance;Risk;Secondary to;Signal Pathway;Signal Transduction;Superoxide Dismutase;Superoxides;Techniques;Testing;Therapeutic Intervention;Tissues;Treatment Efficacy;Tube;Vascular Endothelial Growth Factors;Work;air filter;angiogenesis;base;burden of illness;cardiovascular disorder risk;cardiovascular injury;endothelial dysfunction;endothelial stem cell;extracellular;fine particles;improved;in vivo;limb ischemia;mortality;novel strategies;overexpression;premature;prevent;repaired;response;stem cells;tissue repair

public_health_relevance:
NARRATIVEThe goal of this project is to determine the mechanisms by which air pollution contributes to cardiovasculardisease. In particular the proposed research focuses on how inhalation of particulate matter contributes toprogenitor cell dysfunction and defects in vascular repair.


application_id: 9907005
project_number: 1F31AR075364-01A1
administering_ic: NIAMS
award_notice_date: 2020-02-24
opportunity_number: PA-19-195
application_type: 1
activity_code: F31
ic: AR
serial_number: 075364
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2020-02-24
project_end_date: 2020-07-25
study_section: Special Emphasis Panel[ZRG1 F10B-K (20)]
contact_pi_person_id: 15358539
contact_pi: ENGLUND, DAVIS A.
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: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Determining the fiber type-specific requirements for satellite cells during skeletal muscle hypertrophy

project_abstract:
PROJECT SUMMARY/ABSTRACT Physical inactivity advancing age limb immobilization degenerative diseases and various systemicdiseases (many cancers sepsis HIV COPD kidney disease) all lead to skeletal muscle wasting. The loss ofmuscle mass is of major clinical importance because it leads to an increased risk for morbidity disability andthe loss of independence; collectively contributing to a substantive increase in healthcare utilization and cost. Arapidly aging U.S population will undoubtedly lead to an increase in the prevalence of sarcopenia and the age-related systemic diseases that cause cachexia. In order to reduce concomitant increases in healthcare costsdeveloping interventional strategies that promote healthy aging and extend functional independence is critical. Gaining a fundamental understanding for the role of muscle stem cells (satellite cells) during musclehypertrophy will increase the feasibility of targeting these cells and increasing their ability to promote musclegrowth. Our lab previously showed that while a lack of satellite cells does not limit short-term muscle growthsatellite cells are required to support sustained growth at least in type 2 (fast twitch) fibers. The compensatorypathways activated in the absence of satellite cell fusion to enable short-term muscle growth in type 2 fibersare of interest. In line with this the mechanism precipitating a shift in the requirement for satellite cells duringsustained muscle growth is unknown. Due to the method of overload used in previous studies ourunderstanding for satellite cell-mediated muscle growth is currently restricted to muscles comprised exclusivelyof type 2 muscle fibers. Emerging evidence suggests that these findings may not extend to type 1 (slow twitch)fibers. As type 1 fibers comprise ~50% of human skeletal muscle and are known to positively influencephysical function and health determining the role of satellite cells during type 1 fiber growth is of clinicalimportance. In order to address these critical gaps in our understanding of the regulation of muscle growth thePax7-DTA mouse strain will be used allowing for the inducible depletion of satellite cells and a short and longterm weighted wheel running model will be used to induce hypertrophy in the plantaris (100% type 2) and thesoleus (50% type 1 and 50% type 2) muscles in satellite cell deplete (SC-) and replete (SC+) mice. This designwill allow me to determine (1) the fiber type-specific requirements for satellite cells during muscle growth and(2) elucidate the intracellular mechanisms regulating satellite cell independent and dependent muscle growthover a time course of muscle hypertrophy. The findings from this study will provide information necessary toevaluate the therapeutic potential of satellite cell targeted approaches and potentially identify compensatorymechanisms enabling growth in the absence of satellite cells that may also be potential therapeutic targets.Moreover the completion of this project will provide an outstanding training opportunity for a promising youngscientist.

project_terms:
Address;Adult;Aging;Cachexia;Cell Nucleus;Cell fusion;Cells;Chemistry;Chronic Obstructive Airway Disease;Clinical;Clinical Research;Data;Degenerative Disorder;Development;Dissociation;Elderly;Expression Profiling;Fast-Twitch Muscle Fibers;Fiber;Future;Gene Expression;Genetic Transcription;Goals;Growth;HIV;Health;Health Care Costs;Human;Hypertrophy;Immobilization;Intervention;Kidney Diseases;Knowledge;Label;Lead;Limb structure;Malignant Neoplasms;Mechanics;Mediating;Metabolic;Metabolism;Methods;Modeling;Molecular and Cellular Biology;Morbidity - disease rate;Mouse Strains;Mus;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Muscular Atrophy;Output;Pathway interactions;Personal Satisfaction;Phase;Physical Function;Plantaris muscle;Population;Prevalence;RNA;Regulation;Research;Risk;Role;Running;Scientist;Sepsis;Skeletal Muscle;Soleus Muscle;Stimulus;Systemic disease;Tamoxifen;Techniques;Testing;Therapeutic;Time;Training;Transcriptional Regulation;Transgenic Mice;Uridine;Wild Type Mouse;Work;age related;base;bench to bedside;design;disability;functional independence;genome-wide;health care service utilization;healthy aging;improved;interest;mouse model;muscle form;muscle hypertrophy;novel;physical conditioning;physical inactivity;response;restoration;sarcopenia;satellite cell;skeletal muscle wasting;skills;targeted treatment;therapeutic target;training opportunity;transcriptome sequencing;translational scientist;treatment strategy

public_health_relevance:
PROJECT NARRATIVEThe loss of muscle mass leads to an increased risk for morbidity disability and the loss of independence;collectively contributing to a substantive increase in healthcare utilization and cost. The primary goal of theproposed research is to gain an in depth understanding for the role of muscle stem cells (satellite cells) duringmuscle hypertrophy. Gaining this knowledge will increase the feasibility of targeting these cells and increasingtheir ability to promote muscle growth as a therapeutic strategy.


application_id: 9906926
project_number: 5R01ES027881-04
project_title: Air Pollution Circadian Rhythm Disruption and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2020-04-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 027881
program_official: SCHUG, THADDEUS
project_start_date: 2017-05-01
project_end_date: 2022-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
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:
AbstractExposure to ambient air pollution has been linked to annually 7 million premature deathsworldwide and 200000 in the US and the global burden of air pollution is likely to increase dueto increasing urbanization and industrialization. Extensive research has shown that exposure toparticulate air pollution and specifically fine particulates (PM2.5) increase the risk ofcardiovascular disease and diabetes. However despite this extensive evidence it is unclearhow PM2.5 exposure increases the cardiometabolic risk and which susceptible states increasethe sensitivity to vascular and cardiometabolic injury due to PM2.5 exposure. In our proposedstudies we attempt to disentangle the mechanism leading to the toxicity of PM2.5 by testing thenovel hypothesis that PM2.5 disrupts vascular circadian rhythms and that this contributes to thedevelopment of cardiometabolic disease in a new susceptibility state of circadian dyssynchrony.This hypothesis is supported by our preliminary data showing that that exposure to concentratedambient PM2.5 (CAP) alters the rhythmic expression of clock genes in the murine aorta andincreases insulin resistance in mice with the disturbed light/dark cycle (circadian dyssynchrony).As this models a real-world scenario in which individuals with disturbed light cycle (e.g. due tolight pollution sleep deprivation) are exposed to air pollution it is of high relevance to ourmodern urban 24 h lifestyle associated with air and light pollution and changes in sleepbehavior. Successful completion of this project will identify new targets of and novelsusceptibility states (circadian dyssynchrony and chronotoxicity) for PM2.5 toxicity. Results oftheses studies will be of significance in understanding the adverse health effects originated fromour modern lifestyle and could ultimately lead to the development of evidence-based guidelinesand policies to minimize the cardiometabolic effects of urbanization and pollutant exposure.

project_terms:
ARNTL gene;Aerosols;Affect;Air;Air Pollution;Animal Model;Aorta;Attenuated;Biochemical Process;Biological;Biological Availability;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Characteristics;Circadian Dysregulation;Circadian Rhythms;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Eating;Endothelium;Exposure to;Gene Expression;Genes;Goals;Health;Human;Individual;Industrialization;Injury;Insulin Resistance;Knockout Mice;Laboratories;Lead;Life Style;Light;Link;Lung;Mediating;Metabolism;Modeling;Modernization;Mus;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Oxidation-Reduction;Oxidative Stress;Particulate;Periodicity;Peripheral;Phase;Physiological Processes;Policies;Pollution;Post-Translational Protein Processing;Predisposition;Prevention strategy;Research;Sleep Deprivation;System;Testing;Toxic effect;Transcriptional Regulation;Urbanization;Work;air filter;ambient air pollution;atherogenesis;base;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;chemical property;circadian;diabetes risk;epidemiologic data;evidence based guidelines;mortality;mouse model;novel;overexpression;particle;physical property;pollutant;premature;prevent;response;sleep behavior;vascular injury

public_health_relevance:
NarrativeGoal of this project is to test the novel hypothesis that air pollution exposure a major healthconcern worldwide that increase the risk of cardiovascular disease and diabetes disruptsvascular circadian rhythms and that this exacerbates cardiometabolic injury in the newsusceptibility state of circadian dyssynchrony. Results of this project will be of significance inunderstanding and preventing the adverse health effects originated from air pollution exposure.


application_id: 9906759
project_number: 5F32NS111241-02
project_title: Role of Age on Anti-oxidant Defense in Spinal Cord Injury: Physiological Changes and Intervention
administering_ic: NINDS
award_notice_date: 2020-04-14
opportunity_number: PAR-16-458
application_type: 5
activity_code: F32
ic: NS
serial_number: 111241
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2019-04-01
project_end_date: 2021-10-31
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 15507155
contact_pi: STEWART, ANDREW NATHANIEL
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:
Since the 1970s the average age that a spinal cord injury (SCI) occurs has shifted towards older populationsfrom age 29 to 42. Further both clinical and pre-clinical reports reveal age as an important predictor offunctional recovery following SCI. Despite this the use of younger adult animals prevails in pre-clinical SCImodels. Increasingly age-dependent inflammatory responses and reactive oxygen species-mediated damageare implicated in the pathophysiology of SCI deficits. Although not yet explored in the context of SCI agereduces cellular anti-oxidant capacity through diminished levels of glutathione a critical anti-oxidant regulatingredox balance within all cells. Collectively an increase in ROS production with a decrease in anti-oxidantdefense leaves aged cells more susceptible to ROS-mediated damage and can result in cell death.Characterization of redox balance within the aged spinal cord before and after injury is needed to evaluate thetherapeutic potential of strategies aimed at increasing cellular anti-oxidant defense. One such strategy istreatment using N-acetylcysteineamide (NACA) which increases intracellular glutathione and results in anti-oxidant protection against ROS. Treatment using NACA or similar analogs have demonstrated therapeuticefficacy in animal models of SCI when used to treat young SCI conditions. The proposed work will determinethe anti-oxidant capabilities and redox state of aged and young spinal cords before and after SCI as well astest the efficacy of NACA as a free radicle scavenging treatment to restore function and improve outcomes in acontusive mouse model of SCI. The specific hypotheses are two-fold: 1) intracellular anti-oxidant capacitywithin the spinal cord diminishes with age and is further reduced as a consequence of SCI and 2) treatmentefficacy using NACA is age-dependent following SCI and will elicit a larger therapeutic response in aged mice.Aim 1 will determine the extent that intracellular anti-oxidant defense mediates protection against ROS in agedand young spinal cords. Aim 2 will determine the extent to which the therapeutic efficacy of ROS scavengingafter spinal cord contusion is age-dependent. Collectively the data from these studies will aid in thedevelopment of therapies to treat SCI individuals of all ages. Further elucidating the mechanisms of age-related neurodegeneration will advance the fields of aging and neuroscience.

project_terms:
Affect;Age;Aging;Animal Model;Animals;Antioxidants;Biochemical Process;Biological Assay;Buthionine Sulfoximine;Cell Death;Cells;Clinical;Contusions;Data;Defense Mechanisms;Dependence;Dose;Enzymes;Equilibrium;Exposure to;Fostering;Functional disorder;Glutathione;Histologic;Homeostasis;Human;Individual;Inflammation;Inflammatory Response;Injury;Intervention;Knowledge;Laboratories;Measures;Mediating;Mediator of activation protein;Mission;Modeling;Motor;Mus;N-Acetylcysteinamide;NADPH Oxidase;Neurosciences;Older Population;Outcome;Oxidation-Reduction;Physiological;Pre-Clinical Model;Production;Public Health;Rattus;Reactive Oxygen Species;Recovery of Function;Reduced Glutathione;Reporting;Research;Role;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;United States National Institutes of Health;Work;acetovanillone;age effect;age related;age related neurodegeneration;aged;analog;base;cell age;disability;efficacy testing;experience;experimental study;functional outcomes;functional restoration;improved;improved outcome;inhibitor/antagonist;juvenile animal;mature animal;mouse model;nervous system disorder;neuropathology;neuroprotection;pre-clinical;targeted treatment;therapy development;translational impact;treatment response;young adult

public_health_relevance:
The proposed research is relevant to public health because determining the extent to which age affect the efficacy of therapies for SCI will facilitate the successful translation of treatments to a growing aging SCI demographic. Moreover understanding the mechanisms that contribute to age-related neurodegeneration is important for a number of neuropathologies. Therefore the proposed research is relevant to the part of the NIH mission that pertains to developing fundamental knowledge and applying that knowledge to foster research strategies to reduce the burden of human disabilities.


application_id: 9905466
project_number: 5R21AG061551-02
project_title: Novel misfolded proteins in ADRD: proteomics genetics and clinical-pathological correlations
administering_ic: NIA
award_notice_date: 2020-02-12
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AG
serial_number: 061551
program_official: PETANCESKA, SUZANA
project_start_date: 2019-04-15
project_end_date: 2022-01-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
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
project_abstract:
The heterogeneous pathologies of Alzheimer's disease and related dementias (ADRD) are stillincompletely understood. There is no perfect animal model to study these diseases. Four known aberrantlymisfolded proteins are commonly detected via neuropathologic examination of brains with ADRD: A TauTDP-43 and/or -Synuclein. Our preliminary data indicate that there are more pathogenic proteinspecies awaiting identification. Characterization of these proteins may be relevant to the development ofboth diagnostic and therapeutic strategies for ADRD. The goals of this research project are to identifypreviously uncharacterized misfolded and aberrantly processed proteins in ADRD; to resolve gene variantsthat modulate the severity and heterogeneity of dementia through the novel misfolded proteins; and toperform clinical-pathological correlation focusing on these novel proteins to identify new disease-associatedpathologic biomarkers. We will leverage the resources of the University of Kentucky AD Center (UK-ADC)biobank and the University of Kentucky Proteomics Core Facility to execute the following Specific Aims:Specific Aim 1. Analyse detergent-insoluble protein extracts from human amygdala (snap-frozenat autopsy) to investigate whether as yet uncharacterized misfolded proteins are detectable in ADRD.Polypeptides from the detergent-insoluble urea-soluble protein fractions of amygdala will be interrogatedusing mass spectrometry. We have on-hand amygdalae from 40 UK-ADC subjects which incorporate aspectrum of clinical and pathologic features. Immunohistochemistry and biochemical studies will beperformed to determine the best candidate proteins for additional studies (Aims 2 and 3). Specific Aim 2. Construct a robust and harmonized database with exonic sequencing to localizegenetic regions associated with novel misfolded proteins in ADRD. We will test the association betweendementia and rare exonic (`mis-sense') genetic variants in genes that encode candidate misfolded proteins(Aim 1). Genetics data augmented with rich neuropathologic endophenotypes and longitudinal clinical data willenable insights into novel mechanisms that drive dementia. Large-scale datasets (NACC ADGC ADSP) willbe aggregated and harmonized to test the genetic drivers of clinical and neuropathology-basedendophenotypes focusing on novel candidate genes. Candidate target genes have already been identified. Specific Aim 3. Establish the clinical-pathologic correlation for the novel misfoldedproteinopathies in ADRD. We will test the association between the potential novel proteinopathies (fromAim 1) with cognitive impairment factoring in known markers A tau -Synuclein and TDP-43 as well ascerebrovascular pathologies. We have 370 samples available for analyses (both sexes) from the UK-ADCwhich should be statistically powered to test our hypothesis that the presence and severity of novelmisfolding protein pathologies are associated with cognitive impairment.

project_terms:
Age;Alzheimer's disease pathology;Alzheimer's disease related dementia;Amygdaloid structure;Amyloid beta-Protein;Animal Model;Automobile Driving;Autopsy;Biochemical;Biochemistry;Biological Markers;Brain;Brain Diseases;Candidate Disease Gene;Cessation of life;Chromosome Mapping;Clinical;Clinical Data;Core Facility;Correlation Studies;Data;Databases;Dementia;Detergents;Development;Diagnostic;Disease;Education;Elderly;Electrospray Ionization;Freezing;Funding Mechanisms;Future;Genes;Genetic;Genetic study;Genie;Genomics;Goals;Hand;Heterogeneity;Human;Image;Immunohistochemistry;Impaired cognition;Impairment;Individual;Kentucky;Knowledge;Liquid Chromatography;Mass Spectrum Analysis;Mutation;Neurodegenerative Disorders;Neurofibrillary Tangles;Pathogenicity;Pathologic;Pathology;Persons;Process;Proteins;Proteome;Proteomics;Public Health;Reporting;Research;Research Project Grants;Sampling;Seasons;Series;Severities;Statistical Data Interpretation;Statistical Models;TDP-43 aggregation;Testing;Therapeutic;Universities;University resources;Urea;Work;aged;aging brain;alpha synuclein;base;biobank;cerebrovascular pathology;clinical Diagnosis;cohort;demented;endophenotype;frontotemporal lobar dementia-amyotrophic lateral sclerosis;genetic risk factor;genetic variant;insight;large scale data;misfolded protein;multidisciplinary;neuropathology;novel;polypeptide;protein TDP-43;protein misfolding;sex;synuclein;tandem mass spectrometry;tau Proteins

public_health_relevance:
Project NarrativeAlzheimer's disease and related dementias are an enormous public health problem. Itis challenging to develop optimal diagnostic or therapeutic strategies because we havenot yet identified the full spectrum of misfolded proteins that commonly underlie theclinical state of dementia. Here we plan to perform a study that identifies a list ofmisfolded proteins in dementia that is more comprehensive than ever before as anecessary prerequisite for future work aimed at finding cures.


application_id: 9905377
project_number: 5R37AG004542-31
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2020-04-14
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: 2022-03-31
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;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;Process;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: 9905374
project_number: 5R01AG026307-14
project_title: Self-Regulation and Brain and Cognitive Health in Older Adults
administering_ic: NIA
award_notice_date: 2020-07-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 026307
program_official: KING, JONATHAN W
project_start_date: 2006-07-15
project_end_date: 2023-03-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Summary The typical older adult experiences declines in brain structure and cognitive function but these mean declines occur in the context of what can be very different individual trajectories. The purpose of this project is to measure individual differences and changes in self-regulation (control of thoughts emotions behaviors and impulses) over time in older adults and to link self-regulation to physical activity inflammation and trajectories of neurocognitive health relevant to development of Alzheimers disease. This is a competing renewal of this longitudinal study which began in 2001 and received R01 funding in 2006 submitted by a research team with expertise in aging self-regulation exercise science neuropsychology neuroimaging Alzheimers disease and longitudinal design and analysis. The previous renewal period focused on relationships among facets of self-regulation and their relationship to immunological and cardiovascular health. The renewal continues assessment of these measures to provide continuity in this longitudinal dataset and adds innovation in the inclusion of repeated neuroimaging and assessment of infectious disease burden. Specifically the aims of the study are: (1) to test the effects of facets of self-regulation (conscientiousness self-regulation executive cognitive function and heart rate variability) on measures of neurocognitive health associated with aging and risk for Alzheimers disease; (2) to test the degree to which the relationship between self-regulation and neurocognitive health is mediated by physical activity and inflammation; (3) to test whether neurocognitive health associated with executive cognitive functions (e.g. dorsolateral frontal lobe volume) contributes to better self-regulation higher physical activity and lower inflammation; and (4) to test effects of infectious disease burden (latent viruses Toxoplasma gondii) on self-regulation inflammation and neurocognitive health and risk for Alzheimers disease. At 6-month intervals older adults (N = 175) will complete measures of self-reported self-regulation; executive cognitive functions including inhibition shifting and working memory; and resting HRV. Physical activity BMI and waist circumference will be measured at each visit. Blood draws will be synchronized with these visits and assays performed on these samples will capture serum proinflammatory cytokines and antibodies against latent infections. The sample has follow-back data on many of these measures from 1-15 years and an eligible subset (N = 90) will already have baseline neuroimaging. Neuroimaging will be repeated twice at 2-year intervals. This renewal will be innovative in its longitudinal assessment of a dynamic system that includes brain behavior and immunity; integration of neuroimaging measures with other domains of healthy and unhealthy aging; and multimodal assessment of neurocognitive health including measures associated with risk for Alzheimers disease and other dementias: subjective cognitive health cognitive function volumetric imaging measures connectivity fractional anisotropy and resting cerebral blood flow.

project_terms:
Adult;Affect;Age;Aging;Alzheimer's Disease;Alzheimer's disease risk;Anisotropy;Antibodies;Back;Behavior;Biological Assay;Blood;Brain;Cerebrovascular Circulation;Cognition;Cognitive;Communicable Diseases;Cytomegalovirus;Data;Dementia;Development;Elderly;Emotions;Episodic memory;Exercise;Failure;Funding;Goals;Health;Hippocampus (Brain);Image;Immunity;Immunologic Factors;Impaired cognition;Individual;Individual Differences;Infection;Inflammation;Informal Social Control;Knowledge;Link;Longevity;Longitudinal Studies;Longitudinal cohort;Maintenance;Measures;Mediating;Mental Health;Motivation;Neurocognitive;Neuropsychology;Outcome;Parasites;Pathway interactions;Patient Self-Report;Physical activity;Prefrontal Cortex;Psychological Factors;Psychoneuroimmunology;Research;Rest;Risk;Risk Factors;Role;Sampling;Science;Serum;Short-Term Memory;Structure;Testing;Time;Toxoplasma gondii;Virus Latency;Visit;brain behavior;brain health;burden of illness;cardiovascular health;cognitive function;cohort;cytokine;dynamic system;executive function;experience;frontal lobe;heart rate variability;immune health;inflammatory marker;innovation;interest;latent infection;longitudinal analysis;longitudinal dataset;longitudinal design;multimodality;nervous system disorder;neuroimaging;physical conditioning;prospective;success;thought control;waist circumference

public_health_relevance:
NarrativeWith age come changes in the brain that can increase the risk of cognitive decline and neurological disease.However not all older adults experience these changes to the same degree. This project will continue to tracka cohort of older adults examining psychological and immunological factors that may be protective for brainand cognitive health and vice versa.


application_id: 9904707
project_number: 5P20GM113226-05
project_title: Pathogenic role of PDE4 in hepatic stellate cell activation and TGF signaling
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6173
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
Liver injury of different etiologies leads to a wound healing process involving activation of hepatic stellate cells(HSCs). However an ongoing hepatocyte injury and inflammation results in an uncontrolled activation andproliferation of HSCs and development of hepatic fibrosis leading to cirrhosis and even hepatocellular cancer.Despite the advances made gaps remain in our understanding of the mechanisms involved in the process ofHSC transformation from quiescent to activated phenotype. Recently we discovered that thephosphodiesterase 4 (PDE4) subfamily of enzymes play a pathogenic role in the development of cholestaticliver injury and fibrosis. Notably PDE4s are not present in quiescent HSCs and are rapidly induced uponactivation in vitro. Further the PDE4 specific inhibitor rolipram effectively attenuates SMA collagenexpression and accompanying morphological changes in HSCs. PDE4 is the largest sub-family among cAMP-hydrolyzing PDEs which tightly regulate the levels of cellular cAMP. cAMP through its effector moleculesprotein kinase A (PKA) and Exchange Protein directly Activated by cAMP (EPAC) has been shown to down-regulate cytokine induced fibrogenic genes in non-hepatic cells. Hence we hypothesize that induction of PDE4expression and activity plays a causal role in HSC activation by decreasing cAMP-PKA/EPAC activities andpromoting fibrogenic signaling. We postulate that during HSC activation promoter associated epigeneticchanges and post-translational modifications play a significant role in the regulation of PDE4 expression andactivity. We also postulate that PDE4 inhibition will restore PKA/EPAC activities and attenuate TGF-Smadsignaling through: (i) inactivation of relevant MAPKs; and (ii) de-repressing PPAR leading to decreasedexpression of SMA and Col1A1. Importantly inhibition of PDE4 activity may be a significant therapeuticapproach for liver fibrosis. The specific aims of this proposal are to: 1) Determine the role of PDE4 in theregulation of fibrogenic signaling in HSCs; 2) Determine promoter-associated epigenetic modificationscontributing to the induction of PDE4 isoforms during HSC activation; and 3) Determine the post-translationalmodifications (PTMs) relevant for PDE4 isoform function during HSC activation. Importantly the results of thisCOBRE-funded project will provide proof-of-principle and mechanistic rationale for in vivo translational studies(R01) to examine PDE4 targeted strategies for prevention and treatment of hepatic fibrosis.

project_terms:
Address;Attenuated;Centers of Research Excellence;Cirrhosis;Collagen;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;DNA Modification Process;Development;Enzymes;Epigenetic Process;Etiology;FDA approved;Family;Fibrosis;Funding;Genes;Genetic Transcription;Hepatic Stellate Cell;In Vitro;Inflammation;Knockout Mice;Liver Fibrosis;MAP Kinase Gene;Mass Spectrum Analysis;Mediating;Modeling;Modification;Morphology;Myofibroblast;PDE4B;PPAR gamma;Pathogenicity;Phenotype;Phosphorylation;Play;Post-Translational Protein Processing;Prevention strategy;Primary carcinoma of the liver cells;Process;Promoter Regions;Protein Isoforms;Proteins;Proteomics;Rattus;Regulation;Role;Rolipram;Second Messenger Systems;Signal Transduction;Therapeutic;Toxicology;Transcriptional Activation;Transforming Growth Factor beta;base;cell transformation;cytokine;experimental analysis;hepatocyte injury;histone modification;in vivo;inhibitor/antagonist;liver injury;member;phosphodiesterase IV;promoter;translational study;wound healing

public_health_relevance:
As per Opportunity Announcement PAR-14-035 the Project Narrative for this component is not requested forthis proposal.


application_id: 9904704
project_number: 5P20GM113226-05
project_title: ANIMAL MODEL AND BIOREPOSITORY CORE
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6171
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN 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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
The primary function of Core D is to provide members of the Hepatobiology and Toxicology COBRE with theexpertise resources and facilities needed for animal husbandry necropsy and histological services for animalmodels of liver disease. The Core provides essential services by addressing the needs of COBRE-supportedjunior investigators COBRE members and other UofL investigators interested in liver disease research. Corepersonnel will ensure uniformity of husbandry and phenotyping so that the same set of characteristics ismeasured in each model. This uniformity ensures that the data generated within the COBRE are consistentand that results of one experiment will be directly comparable with the results of another. The Core will isolateprimary hepatic cells (parenchymal Kupffer stellate sinusoidal endothelial cells) for ex vivo and in vitrostudies. The Core will assist COBRE members in developing new mouse models of liver disease. The Corewill also facilitate cataloging and storage of animal and clinical samples in a biorepository that will providebiobanking infrastructure and support so that other researchers may share the tissue generated by COBRE-supported projects. The Core endeavors to contribute to the overall success and utility of the COBRE and toenhance the infrastructure and the technical and academic capabilities of the institution as a whole. In additionto its function as a service core Core D will also promote the education and training of the COBRE memberswith particular attention to the COBRE junior investigators. Core D will specifically communicate with COBREjunior investigators regarding their experimental requirements on a continual basis and appropriatelyparticipate in the planning execution and data analysis. To function as a vital integrative component of theCOBRE providing services not only for its members but also for the Institution as a whole Core D has thefollowing Specific Aims:1) To foster the development and success of current and future COBRE projects. 2) To educate andtrain investigators.3) To develop new protocols and techniques:4) To become an integral and self-sustaining component of the COBRE.

project_terms:
Address;Animal Husbandry;Animal Model;Animals;Attention;Autopsy;Basic Science;Biological Assay;Cataloging;Catalogs;Centers of Research Excellence;Characteristics;Clinical;Data;Data Analyses;Development;Endothelial Cells;Ensure;Equipment;Fee-for-Service Plans;Fostering;Future;Goals;Hepatic;Hepatocyte;Histologic;Human;Human Resources;In Vitro;Individual;Infrastructure;Institution;Libraries;Liver;Liver diseases;Maintenance;Measurement;Measures;Methods;Mission;Modeling;Operative Surgical Procedures;Phenotype;Physiology;Procedures;Protocols documentation;Research;Research Activity;Research Personnel;Resolution;Resources;Sampling;Services;Techniques;Tissue Banks;Tissues;Toxicology;Training;Training and Education;Translational Research;Translations;biobank;career;career development;design;experience;experimental study;flexibility;interest;investigator training;liver injury;meetings;member;mouse model;operation;success

public_health_relevance:
As per Opportunity Announcement PAR-14-035 the Project Narrative for this component is not requested forthis proposal.


application_id: 9904703
project_number: 5P20GM113226-05
project_title: ANALYTICAL CORE
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6170
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
The University of Louisville Hepatobiology and Toxicology COBRE is a multidisciplinary group of investigatorsfocusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/drug interactions.The Bioanalytical Core is an integral part of the COBRE and will play a key role in the implementation andfuture development of COBRE-funded projects. The Core will provide the necessary expertise and state-of-the-art equipment for rigorous and comprehensive experimental evaluation of cell and tissue specimens toinvestigate the pathogenic mechanisms of liver disease. Besides providing requisite analytical services amajor goal of the Bioanalytical Core is to promote the education and training of the Center members withparticular attention to the COBRE junior investigators. The Bioanalytical Core will specifically communicatewith COBRE junior investigators regarding their experimental requirements on a continual basis andappropriately participate in the planning execution and data interpretation. The Bioanalytical Core will alsointeract with other COBRE Cores on a regular basis in order to avoid duplication of equipment orinstrumentation and to foster innovative protocol development and refinement exchange of ideas andintegrative analysis of data. The Core will provide technical and analytical expertise with centralized state-of-the-art equipment including Cellomics ArrayScan(R) VTI HCS Reader for automated microscope based highcontent screening and the Seahorse XF96 extracellular flux analyzer for cellular bioenergetics and metabolismstudies in real time. The Core facility is located in Clinical and Translational Research Building with 2500 sq.ftof operating space which is contiguous with the 20000 sq.ft laboratory space of the Hepatobiology andToxicology COBRE. Dr. Barve the Director of the Core has extensive experience in various analytical andexperimental approaches in the areas of liver injury and pathogenic mechanisms of liver disease. Before hismove to the University of Louisville he served for nearly a decade as the Director of the Molecular andCytokine Core Laboratory of the NIH-funded GCRC at the University of Kentucky and has considerableexperience in running a core laboratory. Also in this role he supported the career development of severaljunior faculty. To function as a vital integrative component of the Center providing services not only for itsmembers but also for the Institution as a whole the Bioanalytical Core has the following specific aims: 1) Tofoster the development and success of proposed COBRE projects and future pilots; 2) To play an active andsignificant role in the education and training of the investigators; 3) To assist and participate in thedevelopment of new experimental protocols and techniques; and 4) To become an integral and self-sustainingcomponent of the COBRE.

project_terms:
Address;Area;Attention;Award;Bioenergetics;Biological;Biological Assay;Cells;Centers of Research Excellence;Clinical Research;Communities;Continuing Education;Core Facility;Core Grant;Data Analyses;Detection;Development;Drug Interactions;Ensure;Environment;Equipment;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Felis catus;Fostering;Funding;Future;Genus Hippocampus;Glutathione;Goals;HIV;High Pressure Liquid Chromatography;In Vitro;Individual;Infrastructure;Institution;Instruction;Journals;Kentucky;Laboratories;Liver;Liver diseases;Measurement;Measures;Metabolism;Methodology;Microscope;Mission;Molecular;Molecular Target;Pathogenicity;Performance;Phase;Play;Population;Proteins;Protocols documentation;Reader;Reagent;Research;Research Personnel;Research Support;Resources;Role;Running;S-Adenosylmethionine;Sampling;Services;Signal Pathway;Specimen;System;Techniques;Technology;Time;Tissues;Toxicology;Training and Education;Translational Research;United States National Institutes of Health;Universities;Whole Organism;base;career development;complex biological systems;cytokine;design;experience;experimental study;extracellular;innovation;instrumentation;interest;investigator training;liver injury;meetings;member;metabolic abnormality assessment;multidisciplinary;novel;programs;protocol development;research facility;screening;square foot;success;time use;toxicant

public_health_relevance:
The Bioanalytical Core is an integral part of the COBRE and will play a key role in the implementation andfuture development of COBRE-funded projects. The Core will provide the necessary expertise and state-of-the-art equipment for rigorous and comprehensive experimental evaluation of cell and tissue specimens toinvestigate the pathogenic mechanisms of liver disease.


application_id: 9904702
project_number: 5P20GM113226-05
project_title: OMICS CORE
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6169
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
High-throughput 'omics analysis platforms are the technologies of choice for analyzing complex mixturesderived from tissues and biological matrices such as liver feces intestine blood and urine. To maximize ourcapability for deciphering the mechanism and therapy for liver injury nutrition and gut:liver interactions andliver:environment/toxin/drug interactions we propose an OMICS Core in this Hepatobiology and ToxicologyCOBRE proposal. Our OMICS Core is composed of three major components including Metabolomics CoreProteomics Core and Bioinformatics. The overarching goal of the OMICS Core is to support the proposedCOBRE research. This goal will be met through application of state of the art separations science and massspectrometry techniques to analyze research samples containing complex mixtures of metabolites proteinsand protein fragments. This goal is achieved through the following aims:Specific Aim 1: Application of liquid chromatography mass spectrometry (LC-MS) comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC/TOF-MS) and integrated laserablation inductively coupled plasma mass spectrometry (LA-ICP-MS) platforms for quantitative analysis ofmetabolites metal ions and metal-protein complex in biological samples.Specific Aim 2: Application of high-resolution multidimensional liquid chromatography mass spectrometry(MDLC-MS) and affinity enrichment methods for targeted protein quantification.

project_terms:
Ablation;Acetylation;Affinity;Alcohols;Arsenic;Binding;Bioinformatics;Biological;Blood;Cecum;Centers of Research Excellence;Chemicals;Complex Mixtures;Curcumin;Cysteine;DNA Binding Domain;Diet;Dimensions;Drug Interactions;Environment;Ethanol;Event;Feces;Gas Chromatography;Gel;Goals;Hepatic;Hepatic Stellate Cell;High Fat Diet;Immunoprecipitation;Inductively Coupled Plasma Mass Spectrometry;Inflammation;Injury;Intestines;Iodoacetamide;Iodoacetic Acid;Ions;Label;Lactobacillus casei rhamnosus;Large Intestine;Lasers;Linoleic Acids;Liquid Chromatography;Liver;Mass Spectrum Analysis;Measurement;Measures;Mediating;Metals;Methods;Methylation;Mus;Oxides;Pathology;Phenotype;Phosphopeptides;Phosphorylation;Plasma;Post-Translational Protein Processing;Production;Protein Fragment;Protein Isoforms;Proteins;Proteomics;Recombinant Proteins;Regulation;Research;Resolution;Role;Sampling;Science;Site;Small Intestines;Stable Isotope Labeling;Steatohepatitis;Techniques;Technology;Time;Tissue Sample;Tissues;Toxicology;Toxin;Tumor Promotion;Unsaturated Fatty Acids;Urine;Volatile Fatty Acids;Zinc;exosome;experimental study;feeding;liquid chromatography mass spectrometry;liver inflammation;liver injury;mass spectrometer;metabolomics;non-alcoholic fatty liver disease;novel;nutrition;oxidation;phosphodiesterase IV;protein complex;recombinant peptide;response;time of flight mass spectrometry;transcription factor;tumor growth;two-dimensional;zinc-binding protein

public_health_relevance:
As per Opportunity Announcement PAR-14-035 the Project Narrative for this component is not requested forthis proposal.


application_id: 9904701
project_number: 5P20GM113226-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
study_section: ZGM1-TWD-A
subproject_number: 6168
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
The University of Louisville Hepatobiology and Toxicology COBRE is a multidisciplinary group of investigatorsfocusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/drug interactions.UofL is uniquely poised to investigate these problems in a coordinated and efficient fashion. UofL has thelargest academic hepatology section in the region with 6 clinical hepatologists and multiple PhD investigatorsacross campus and collaborators across the nation. The Hepatobiology group has strong research andtraining interactions with the Dept. of Pharmacology & Toxicology and other basic science programs acrosscampus. We have an established record of federal funding mentoring and interactions with UofL traininggrants. This application is led by a PI who is highly qualified. We have five outstanding PI-mentees with wellestablished funded senior mentoring teams. Our proposed COBRE will have a major positive impact onresearch and community outreach at UofL and in the region. The Hepatobiology and Toxicology COBRE willfacilitate the recruitment/ development of faculty in the Department of Pharmacology and Toxicology andassociated critical areas (e.g. personalized medicine; drug metabolism). This COBRE will develop cores whichwill benefit all of UofL and will help recruit/retain critical faculty. Liver diseases have a major impact on publichealth and especially so in Kentucky. Our population is poor rural and among the most overweight in thecountry and Kentucky is a leader in the distillation of alcoholic spirits. Thus this COBRE will have wide impacton development of researchers and research infrastructure focused on hepatic metabolism as well as liverdiseases and their treatments and it will enhance the health of Kentucky residents and beyond. The Administrative Core will provide overall governance and will ensure that the COBRE projects and coreswork together in a cohesive and coordinated manner. All projects and cores will utilize the Administrative Core.The Specific Aims are to:1) provide a formal governance structure to provide coordination direction and prioritization ofactivities including budget issues and resolving any conflicts as they arise ensuring the quality of allfunctions and evaluating progress;2) provide a formalized process for mentoring junior faculty and developing senior faculty mentors;3) provide a mechanism to replace mentees as they become independent;4) provide a mechanism to replace any key individuals who may leave;5) provide pilot funding for junior faculty or senior faculty coming into the Hepatobiology andToxicology area;6) provide biostatistical and bioinformatics support; and7) disseminate pertinent information to the scientific and lay community.

project_terms:
Adult;Affect;Alcoholic Liver Diseases;Alcohols;Area;Basic Science;Bioinformatics;Biometry;Budgets;Centers of Research Excellence;Child;Cirrhosis;Clinical;Clinical Trials;Communities;Community Outreach;Complex;Conflict (Psychology);Country;Development;Diabetes Mellitus;Disease;Doctor of Philosophy;Drug Delivery Systems;Drug Interactions;Ensure;Environment;Environmental Health;Extramural Activities;Faculty;Funding;Grant;Health;Healthcare;Hepatitis B;Hepatitis C;Hepatology;Individual;Industry;Intellectual Property;Kansas;Kentucky;Leadership;Link;Liver;Liver Failure;Liver diseases;Malignant Neoplasms;Malignant neoplasm of liver;Mentors;Metabolic syndrome;Metabolism;Names;National Institute of Environmental Health Sciences;National Institute on Alcohol Abuse and Alcoholism;Nuclear Receptors;Obesity;Organ;Overweight;Pharmaceutical Preparations;Pharmacology and Toxicology;Population;Positioning Attribute;Primary carcinoma of the liver cells;Process;Public Health;Research;Research Infrastructure;Research Personnel;Research Training;Retirement;Rural;Structure;Superfund;Teacher Professional Development;Toxic Environmental Substances;Toxicology;Training;United States National Institutes of Health;Universities;Work;cancer transplantation;cohesion;drug development;drug metabolism;faculty mentor;improved;liver injury;liver metabolism;liver transplantation;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel therapeutics;personalized medicine;problem drinker;programs;ranpirnase;recruit;senior faculty;toxicant


application_id: 9904694
project_number: 5P20GM113226-05
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2020-03-09
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2021-03-31
study_section: ZGM1-TWD-A(C1)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
?   DESCRIPTION (provided by applicant): The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic research center. The UofL COBRE scientists comprise a multidisciplinary group senior mentors and junior investigators focusing on the mechanisms and therapy for liver injury nutrition and gut:liver interactions and liver:environment/toxin/dru interactions. The liver is the largest internal organ in the body and is possibly the most complexorgan in terms of metabolism. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) is the most common liver disease affecting about 1/3 of adults and over 10% of children in the US. NAFLD arises most commonly among overweight/obese individuals and is highly linked to the Metabolic Syndrome. Alcoholic Liver Disease (ALD) remains a common problem among those who drink. Environmental Toxicant Induced Liver Injury is an increasingly recognized problem and Louisville has been a leader in this area. Hepatitis B and C remain important causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Personalized Medicine is an increasingly important factor in medication efficacy. Drug-Induced Liver Injury (DILI) is the most common reason drugs are removed from the market and an important cause of liver failure. This COBRE brings together experienced senior mentors and promising junior investigators from across UofL in collaboration with scientists across the U.S./World to perform cross-cutting research on the unique topics of Hepatobiology and Toxicology. The Specific Aims of the Hepatobiology and Toxicology COBRE are to: 1. Develop a thematically-focused program in Hepatobiology and Toxicology that strengthens the overall research infrastructure at UofL. 2. Create a multidisciplinary program in research education mentoring and career development in Hepatobiology and Toxicology. 3. Provide the necessary research resources and translational science/basic technologies to support and sustain state-of-the-art research in Hepatobiology and Toxicology. 4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liver diseases/toxicant exposures and communicate our findings to the public.

project_terms:
Acute Liver Failure;Address;Adult;Affect;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;American;Area;Back;Basic Science;Blood Circulation;Carbohydrates;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communities;Complex;Core Facility;County;Data Analyses;Development;Diabetes Mellitus;Drug Interactions;Endotoxins;Environment;Enzymes;Evaluation;FDA approved;Fatty acid glycerol esters;Fostering;Goals;Government;Health;Hepatitis B;Hepatitis C;Hepatotoxicity;Home environment;Immune Tolerance;Individual;Industrialization;Industry;Infrastructure;Kentucky;Link;Liver;Liver Failure;Liver diseases;Medical History;Mentors;Metabolic syndrome;Metabolism;Micronutrients;Molecular Target;Monitor;National Institute on Alcohol Abuse and Alcoholism;Neighborhoods;Obesity;Organ;Overweight;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Prevention;Primary carcinoma of the liver cells;Process;Production;Proteins;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Role;Scientist;Site;Specimen;Strategic Planning;Structure;Technology;Toxic Environmental Substances;Toxicant exposure;Toxicology;Toxin;Translational Research;United States National Institutes of Health;Universities;biobank;career development;education research;experience;liver injury;liver transplantation;medical complication;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;public health relevance;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE (provided by applicant): The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic research center. The UofL COBRE scientists comprise a multidisciplinary group senior mentors and junior investigators focusing on the mechanisms and therapy for liver injury nutrition and gut:liver interactions and liver:environment/toxin/drug interactions.


application_id: 9904690
project_number: 5P42ES023716-04
project_title: Superfund Training Core
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2020-04-01
project_end_date: 2022-03-31
study_section: ZES1-LKB-K
subproject_number: 7663
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID 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:
Abstract: Interdisciplinary research remains an important feature of the NIH Roadmap. An integrated investigation of chemicals in Louisville will address the effects of exposure on health outcomes related to cardiometabolic disease. The central hypothesis of the UofL Superfund Hazardous Substance Research and Training Project is that exposure to the environmental chemicals volatile organic compounds (VOCs) causes/exacerbates insulin resistance leading to cardio-metabolic disease. Preliminary results from our biomedical projects provide evidence that obesity places individuals at higher risk to adverse health outcomes related to VOCs exposures while our non-biomedical projects will address the lack of methods to systematically measure exposure to these chemicals in residents distal and proximal to industrial areas. This Training Core will train our pre- and post-doctoral fellows not only in laboratory-based research but also in effective communication of the research findings to others in the Superfund Research Projects as well as to the Community at large. The Training Core will develop graduate courses for our Trainees to be shared with the UofL Schools of Engineering Dentistry Medicine and Nursing and the College of Arts & Sciences providing the latest information about the chemistry and human health effects of volatile organic compounds. The Training Core also will contribute to the professional and undergraduate training programs by providing our trainees as seminar speakers or lecturers to UofL undergraduate Biology & Chemistry honors students to nursing dentistry and medical students and to teachers and high school students in the Jefferson County School System to communicate the role of chemical exposure in human disease. Finally our trainees will participate in meetings with the West Louisville Task Force and the Metro Louisville Public Health and Wellness Department with our Community Engagement and Research Translation Cores to engage in discussion and answer questions about the Superfund research projects. Each trainee will be assigned a specific project that each trainee will develop in order to experience how to translate research findings into concepts that can be transmitted effectively to the community various local/state agencies and university audiences alike.

project_terms:
Address;Advisory Committees;Area;Arts;Biology;Chemical Exposure;Chemicals;Chemistry;Communication Research;Communities;County;Dentistry;Discipline of Nursing;Disease;Distal;Engineering;Environmental Exposure;Exposure to;Hazardous Substances;Health;High School Student;Human;Individual;Industrialization;Insulin Resistance;Interdisciplinary Study;Investigation;Laboratories;Measures;Medical Students;Medicine;Methods;Obesity;Outcome;Postdoctoral Fellow;Public Health;Research;Research Project Grants;Role;Schools;Science;Students;Superfund;System;Training;Training Programs;Translating;Translational Research;United States National Institutes of Health;Universities;base;cardiometabolism;college;environmental chemical;experience;high risk;human disease;lecturer;meetings;pre-doctoral;teacher;training project;undergraduate student;volatile organic compound


application_id: 9904689
project_number: 5P42ES023716-04
project_title: Characterizing Urban- and Finer-Scale Spatial Variability for Select VOC Superfund Compounds
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5123
contact_pi_person_id: 10828196
contact_pi: TURNER, JAY ROBERT
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
SUMMARY  Project 4 Hazardous volatile organic compounds (VOC) have adverse impacts on human health.These compounds likely exhibit high spatial variability in urban areas because of the numerousemission sources (e.g. industrial commercial residential traffic) and complex dispersionpatterns. Thus tools are needed to characterize the small-area variation of intra-urban VOCconcentrations. Land use regression (LUR) modeling is a powerful tool for assessing spatialvariability. It relies upon ambient measurements at a large number of sites and has beenextensively used for pollutants such as nitrogen dioxide and particulate matter. Howeverrelatively few studies have built LUR models for VOCs and in most cases the focus was trafficrelated emissions of benzene and other compounds emitted by vehicles. Mobile platformmeasurements have recently been used to collect air quality data for LUR model-building.However mobile monitoring of VOCs has not been used in LUR modeling because ofmeasurement challenges. This project will develop a portable VOC monitor suitable for mobileplatform measurements. Field studies will be conducted at urban- and neighborhood scales andthe VOC data will be used for LUR model-building. LUR results will be used by another Centerproject to evaluate relationships between ambient VOCs and cardiometabolic disease. LURresults will also be used to examine relationships between VOC air quality and proximity togreen space which might be an effective VOC remediation strategy. New tools will bedeveloped to use mobile platform measurements to identify the location and strength ofemission sources. This project is closely coupled to the Centers primary objective to examinecardiometabolic effects of exposure to VOC Superfund chemicals. It will also have broaderimpacts on air quality monitoring and exposure assessment.

project_terms:
Air;Automobile Driving;Benzene;Categories;Complex;Coupled;Data;Data Analyses;Development;Disease;Disease Progression;Ecology;Environment;Environmental Engineering technology;Environmental Exposure;Equipment and supply inventories;Etiology;Exhibits;Exposure to;Future;Gases;Geography;Goals;Green space;Health;Heart;Housing;Human;Industrialization;Location;Measurement;Modeling;Monitor;Neighborhoods;Nitrogen Dioxide;Participant;Particulate Matter;Pattern;Proxy;Research Project Grants;Resolution;Route;Sampling;Scheme;Seasons;Site;Small-Area Variations;Source;Superfund;Testing;Time;Variant;Work;cardiometabolism;density;design;design and construction;field study;insight;land use;metropolitan;miniaturize;mobile computing;model building;novel;pollutant;portability;remediation;sample collection;spatial relationship;study population;superfund chemical;tool;urban area;urinary;volatile organic compound

public_health_relevance:
RELEVANCE  Project 4This environmental science and engineering research project will develop a novel portablevolatile organic compound (VOC) monitor suitable for mobile platform measurements andconduct monitoring for land use regression model-building. The project will determine the small-scale variation of intra-urban VOC concentrations which will be used by another Center projectto examine the impact of VOCs on cardiometabolic disease. Relationships between VOCconcentrations and proximity to green space will be examined towards evaluating whethergreening could be an effective remediation strategy. Tools will be developed to use mobilemonitoring data to identify emission sources of ambient VOCs.


application_id: 9904688
project_number: 5P42ES023716-04
project_title: Development of Novel Ultrasensitive Devices for the Measurement of VOCs
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5122
contact_pi_person_id: 9972311
contact_pi: NANTZ, MICHAEL H
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
Hazardous volatile organic compounds (VOCs) in environmental air have both acute andchronic effects on human health. Gas chromatography coupled with a mass spectrometer (GC-MS) is the most common technology used for analysis of airborne VOCs. However GC-MS isnot effective for on-site measurement of trace VOCs at Superfund sites. The overall goal of thisenvironmental science research project is to develop novel technologies for quantitativeanalysis of trace VOCs in both the lab and for on-site measurement of toxic airborne VOCs.We will focus on measurements of acrolein vinyl chloride benzene and 13-butadiene. Theapproach is to investigate chemoselective microreactors for capture of Superfund VOCs.Microreactors provide superior advantages of miniaturized device size very low cost and fastdetection over current sorbent-based tube preconcentrators. We also will develop thiol-modifiedgold nanoparticle gas sensor arrays for on-site detection of these VOCs. Functionalized thiolswill be synthesized to detect target VOCs at a concentration range from sub-ppb to a few ppm.The thiols proposed for modification of gold nanoparticles will have functional groups andstructural motifs to specifically promote interaction with and recognition of target VOCs thussignificantly increasing sensing selectivity and sensitivity. The sensors will work at ambienttemperature. This research project will lead to transformational technologies for quantitativeanalysis of trace VOCs. The research is directly related to the overall goals of the Center forinvestigating the effects of exposure to VOCs on inducing/exacerbating cardiometabolicdisease. The project will also have significant broader impacts on monitoring environmental airand on promoting homeland security.

project_terms:
13-Butadiene;Acrolein;Acute;Adsorption;Air;Benzene;Biomedical Research;Butadiene;Chemicals;Chronic;Complex;Coupled;Custom;Detection;Development;Devices;Disease;Ecology;Electrodes;Engineering;Environmental Exposure;Environmental Monitoring;Environmental Pollutants;Exposure to;Face;Gas Chromatography;Gases;Goals;Gold;Group Structure;Health;High Pressure Liquid Chromatography;Human;Insulin Resistance;Ions;Liquid substance;Mass Spectrum Analysis;Measurement;Measures;Methods;Modification;Normal Range;Oxidants;Pattern;Process;Research;Research Project Grants;Security;Signal Transduction;Silicon;Site;Sulfhydryl Compounds;Superfund;Surface;System;Techniques;Technology;Temperature;Tube;Vinyl Chloride;Work;adduct;air sampling;base;carbonyl compound;cardiometabolism;cost;design;functional group;glycolaldehyde;improved;liquid chromatography mass spectrometry;mass spectrometer;metal oxide;microsensor;miniaturize;nanoGold;new technology;novel;sensor;simulation;superfund site;vascular inflammation;volatile organic compound

public_health_relevance:
NarrativeThe overall goal of this environmental science research project is to develop novel microsensorsfor quantitation of volatile organic compounds (VOCs) for on-site measurement of toxic airborneVOCs. The research is directly related to the overall goals of the Superfund Center forinvestigating the effects of exposure to VOCs on inducing/exacerbating cardiometabolicdisease.


application_id: 9904686
project_number: 5P42ES023716-04
project_title: Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5121
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
SUMMARYExposure to toxicants has been linked to the development or exacerbation of chronic disease. While the healthof effects of ubiquitous environmental substances such as tobacco smoke and particulate matter are morewell-studied less is known about how volatile organic chemicals (VOC)a class of toxicants associated withhigher prevalence of type 2 diabetes (T2D) and strokepromote the development of cardiometabolic disease(CMD). Understanding how VOC affect CMD is important because obesity and T2D are rapidly growing globalhealth crises. Accordingly the overarching goals of this Superfund project are to determine the mechanisms bywhich VOCs negatively impact cardiovascular health and metabolism identify biomarkers for VOC exposureand vascular injury and test therapeutic strategies to minimize VOC-induced CMD. Our preliminary datasuggest that VOC such as acrolein promote endoplasmic reticulum (ER) stress and trigger the unfolded proteinresponse (UPR) in endothelial cells resulting in insulin resistance. In addition we find that individuals exposedto VOC such a vinyl chloride develop symptoms of CMD that could be instigated at the molecular level byVOC-induced ER stress. Specifically we hypothesize that aldehyde metabolites of VOC which are generallymore toxic than their parent compound diminish insulin sensitivity in vascular tissues by inducing ER stresswhich triggers metabolic changes that accelerate ectopic lipid deposition and promote cardiometabolicdysfunction. To test this hypothesis we will: (1) examine the effects of VOC exposure on endothelial functionand insulin resistance; (2) delineate the contribution of endothelial UPR to the cardiometabolic toxicity of VOC;and (3) elucidate the role of VOC-derived aldehydes in exacerbating CMD. The design of these studiesincludes molecular and pharmacological interventions designed to detoxify or quench the reactiveintermediates evoked by VOC exposure as well as studies that could lead to the identification of novelsensitive and robust biomarkers of both VOC exposure and vascular injury. These studies were designed tosynergize with and provide biological plausibility for the associations identified in Project 1. Successfulcompletion of this project will lead to identification of the underlying cellular and molecular mechanisms bywhich VOC affect insulin sensitivity and cardiometabolic function and provide insights into how VOC toxicitycould be prevented or therapeutically minimized by targeting aldehydes or protein-folding pathways.

project_terms:
ATF6 gene;Acids;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Apoptosis;Atherosclerosis;Attenuated;Benzene;Biochemical Pathway;Biological;Biological Markers;Blood Vessels;Body Burden;Butyric Acids;Cardiovascular Diseases;Cardiovascular system;Carnosine;Cell Respiration;Chemical Exposure;Chemical Injury;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Diet;Disease;Disease Resistance;Dyslipidemias;Endoplasmic Reticulum;Endothelial Cells;Endothelium;Environmental Exposure;Environmental Impact;Enzymes;Exposure to;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Goals;Hazardous Chemicals;Hazardous Substances;Health;Hepatic;High Prevalence;Individual;Inflammatory;Insulin Resistance;Investigation;Lead;Link;Lipids;Measures;Mediator of activation protein;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Oxidative Stress;Parents;Particulate;Particulate Matter;Pathway interactions;Pharmacology;Phase;Plants;Plasma;Poison;Polyvinyl Chloride;Process;Production;Proteins;Protocols documentation;Reporting;Risk;Role;Series;Signal Transduction;Stress;Stroke;Superfund;Surveys;Symptoms;Testing;Therapeutic;Tissues;Tobacco smoke;Toxic effect;Vinyl Chloride;Work;aldehyde dehydrogenases;ambient air pollution;cardiometabolism;cardiovascular disorder risk;cardiovascular health;design;endoplasmic reticulum stress;global health;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;oxidized lipid;prevent;protein folding;response;superfund site;tauroursodeoxycholic acid;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;vascular injury;volatile organic compound;western diet

public_health_relevance:
PROJECT NARRATIVEExposure to hazardous substances has been linked to the development or worsening of chronic disease. Thepurposes of this Superfund project are to understand how a particular class of compounds i.e. volatile organiccompounds affect cardiovascular health and the onset or progression of insulin resistance obesity anddiabetes as well as to develop therapeutic strategies to minimize these affect after exposure to toxiccompounds.


application_id: 9904685
project_number: 5P42ES023716-04
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5120
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
The overall goal of this project is to examine whether exposure to environmental pollutants specifically volatileorganic compounds (VOCs) induces/exacerbates cardiometabolic disease (CMD) by causing systemic insulinresistance and low grade inflammation. Insulin is a master regulator of metabolism and energy disposition anddysregulation of insulin signaling is associated with the development of obesity and Type 2 diabetes (T2D)which are robust contributors to atherogenesis and heart disease. Recent research has identified a pathogeniccontinuum between the development of insulin resistance hepatic steatosis dyslipidemia and cardiovasculardisease. We postulate that environmental pollutants/toxins can either directly cause CMD or interact withobesity and poor nutrition to cause/exacerbate CMD. We have published initial experimental human/rodentdata to support this concept and further preliminary animal data are presented in Project #2. Here we presentimportant human preliminary results from a unique database/specimen bank of plant workers exposed to highlevels of certain VOCs especially vinyl chloride. The Toxicology Specimen and Databank provides theopportunity for a novel cross-sectional study evaluating the effects of vinyl chloride and other VOCs on thedevelopment of insulin resistance and fatty liver (Aim 1a). We will examine our death certificate data toevaluate the effects of VOC exposure on all cause and cardiac deaths (Aim 1b). We will also perform aretrospective/prospective study using samples obtained over a ~40-year period of time to correlate thedevelopment of insulin resistance with outcome measures of the CMD and predictors of risk (includingoccupational exposure personal exposure and novel markers of metabolic injury that we have developedAim 1c). We will also be able to enroll residents from VOC "hot spots" including the Lees Lane superfund sitein a prospective longitudinal evaluation of the impact of lower levels of exposure and the impact ofobesity/nutrition on the progression of CMD (Aim 2). We are able to perform these studies because of anestablished database continued linkages with industry for nearly 40 years and ongoing interactions withcommunity leaders and residents which provide a highly-novel opportunity to assess the cardiometaboliceffects of VOCs over a range of exposures.

project_terms:
Air;Area;Arsenic;Attention;Benzene;Biochemical Pathway;Biological Markers;Biological Specimen Banks;Blood;Blood Coagulation Factor;Blood Platelets;Cardiac Death;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell physiology;Cessation of life;Chronic;Clinical;Collaborations;Communities;Controlled Study;Cross-Sectional Studies;Cytokeratin 18;Data;Databases;Death Certificates;Development;Disease;Disease Progression;Dyslipidemias;Endocrine Disruptors;Endothelial Cells;Endothelium;Enrollment;Environment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Event;Exposure to;Fatty Liver;Geography;Glucose Intolerance;Goals;Heart;Heart Diseases;Hot Spot;Human;Hydroxyeicosatetraenoic Acids;Impact evaluation;Individual;Industrialization;Industry;Inflammation;Injury;Insulin;Insulin Resistance;Lipids;Liver diseases;Longitudinal prospective study;Measures;Medical;Medical History;Metabolic;Metabolic Marker;Metabolism;Modeling;Monitor;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Nutritional status;Obesity;Occupational;Occupational Exposure;Outcome Measure;Participant;Particulate;Pathogenicity;Pathway interactions;Plants;Plasma;Population;Prevalence;Process;Prospective Studies;Publishing;Research;Resources;Retrospective Studies;Risk;Rodent;Role;Sampling;Serum;Severities;Specimen;Superfund;Testing;Time;Toxicology;Toxin;Urine;Vinyl Chloride;Work;adipokines;animal data;atherogenesis;base;biobank;blood glucose regulation;cardiometabolism;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;data management;data warehouse;endoplasmic reticulum stress;endothelial dysfunction;exposed human population;insulin signaling;monocyte;novel;novel marker;nutrition;obesity development;pollutant;primary outcome;prospective;stem cells;superfund chemical;superfund site;translational study;urinary;volatile organic compound

public_health_relevance:
The overall goal of this project is to examine whether exposure to environmental pollutants particularly volatileorganic compounds (VOCs) causes or makes worse a group of disease processes known as cardiometabolicdisease (CMD). These processes include type 2 diabetes cardiovascular disease and fatty liver disease. Allof these conditions seem to be regulated through insulin resistance. We hypothesize that environmentalpollutants/toxins can either directly cause CMD or interact with obesity and poor nutrition to cause CMD ormake it worse. In this project we will investigate subjects from two ongoing studiesOccupational ToxicologyData and Specimen Bank and the Louisville Healthy Heart Studyto determine if exposure to pollutants leadsto insulin resistance and subsequent CMD. We are able to perform these studies because of an establisheddatabase continued linkages with industry for nearly 40 years and ongoing interactions with communityleaders and residents which provide a highly-novel opportunity to assess the effects of pollutants in bothworkers and a residential population from the same West Louisville area.


application_id: 9904684
project_number: 5P42ES023716-04
project_title: Sample and Data Management Core
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5119
contact_pi_person_id: 9753394
contact_pi: RAI, SHESH N.
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
ABSTRACTThe primary objective of the Sample and Data Management Core (SDMC) is to provide support to each of thefour projects of the Louisville Superfund Center. The functions of the Core are matched to the needs of eachproject and cover a full range of services from collaboration and routine service to protocol preparation toprocedural review and oversight. The Core will provide two main services: it will establish a repository for thelong-term storage and archiving of samples and data; and it will assist Center investigators in the statisticalanalysis of their results. The core will assure the authenticity and quality of these specimens and it will preparethese samples for long-term storage or dispense samples as needed. The Core will also provide scientificallyvalid and rigorous statistical analysis of data and support the development of innovative methods to enhance thebasic and translational research efforts of Center investigators. The Core will provide state-of-the-art biostatisticsand bioinformatics expertise and analytical support. Core biostatisticians will also develop new statisticalmethods such as quantitative risk assessment models for estimating cardiometabolic disease risk in exposedpopulations and for the analysis and evaluation of exposures and health consequences. In addition the corewill develop novel methods for the analysis of multi-pollutant exposures as they relate to health outcomes. Thecore will serve as a unique educational resource for training graduate students post-doctoral fellows residentsand junior faculty and in collaboration with the Training and Administration Cores. This Core will allow Centerinvestigators easy access to high quality centralized data management and statistical services and thereby willstrengthen the organizational cohesion of the Center. This comprehensive and integrated service permits oneor more biostatisticians to be involved from the initial planning stage of a project (when statistical consultation ismost beneficial) throughout its implementation analysis and completion. The Core will provide a stable andcollegial environment that fosters long-term working relationships between biostatisticians and investigators andcontinues to promote sophisticated approaches to experimental design and analysis. The biostatisticians of thisCore are knowledgeable about clinical research and have broad expertise in statistical applications forepidemiological investigations clinical trials pre-clinical studies and prevention and control research. Theirinterdisciplinary interactions with basic scientists and clinical investigators will add a new dimension to theinterpretation of experimental results one that is only possible when collaborators share a mutual appreciationof problems and issues.

project_terms:
Animals;Annual Reports;Archives;Basic Science;Bioinformatics;Biological;Biometry;Biostatistical Methods;Cataloging;Catalogs;Clinical Investigator;Clinical Research;Clinical Trials;Collaborations;Collection;Communities;Consultations;Continuing Education;Data;Data Analyses;Development;Dimensions;Disease;Educational workshop;Elements;Ensure;Environment;Environmental Exposure;Evaluation;Experimental Designs;Exposure to;Faculty;Fostering;Future;Goals;Hazardous Chemicals;Hazardous Substances;Health;Human Resources;Individual;Journals;Metabolism;Methods;Modeling;Outcome;Population Analysis;Postdoctoral Fellow;Preparation;Prevention;Procedures;Productivity;Protocols documentation;Publications;Records;Reproducibility;Research;Research Activity;Research Design;Research Personnel;Resources;Risk;Risk Assessment;Sampling;Scientist;Services;Signal Recognition Particle;Source;Specimen;Statistical Data Interpretation;Statistical Methods;Students;Superfund;System;Technology;Testing;Tissues;Toxic effect;Training;Translational Research;Universities;Work;base;biobank;cardiometabolism;career development;cohesion;cohort;data archive;data exchange;data management;design;disorder risk;education resources;efficacy testing;epidemiology study;experience;experimental analysis;graduate student;innovation;meetings;member;novel;operation;pollutant;preclinical study;programs;quality assurance;radio frequency;repository;statistical service;tool;usability

public_health_relevance:
RELEVANCEBy ensuring proper study designs and supporting appropriate data analysis the core will help in theunderstanding of risk sources and cardiometabolic disease risk estimation due to exposure to hazardouschemicals. Long-term storage and archiving of data and samples within the Core will facilitate future studies.


application_id: 9904683
project_number: 5P42ES023716-04
project_title: Metabolism and Toxicity Core
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5118
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY 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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
ABSTRACTThe function of the Metabolism and Toxicity Core is to provide intellectual input high quality analytical servicesand validated data in support of all projects in this Superfund Center. Furthermore its support and interactionwith all other components of this Center will assure the overall success of these endeavors. While it is chargedto satisfy the existing needs of the current projects the scope of the Core services will not be limited to therequirements of these projects. The Core will endeavor to develop leading edge technologies and use them toestablish a variety of validated endpoints including exposure biomarkers disease prognosticators andtherapeutic interventions. This Core will be comprised of three discrete technology-centric components includingFlow Cytometry Metabolism and Pathology that nevertheless will function seamlessly and efficiently together toensure that the projects progress smoothly. In addition this Core will strive to educate and train its users throughtechnical seminars and hands-on operation. It will also organize informal meetings which will serve as forumsfor bringing together users to initiate discussion of novel procedures applications and approaches. Finally theMetabolism and Toxicity Core intends to expand its operations not only to support the multidimensional needsof the proposed projects but also to facilitate interactions with additional UofL faculty investigators and with otherSuperfund Centers. Thus the highly diverse yet integrated services and expertise of this Core are essential toachieve the goals of the Superfund center and help make progress with regards to understanding the likelydiverse pathological consequences of VOC exposures and the mitigation of these consequences.

project_terms:
Address;Analytical Chemistry;Animals;Biochemistry;Biological Assay;Biological Markers;Biology;Cells;Charge;Chemical Exposure;Clinical;Communities;Complex;Continuing Education;Data;Detection;Development;Disease;Ensure;Environmental Exposure;Equipment;Extramural Activities;Faculty;Felis catus;Flow Cytometry;Future;Goals;Histologic;Human;Human Resources;Informatics;Infrastructure;Measurement;Metabolic;Metabolism;Mission;Mus;Pathologic;Pathology;Physiological;Population;Postdoctoral Fellow;Procedures;Property;Proteomics;Protocols documentation;Research;Research Personnel;Resolution;Resources;Role;Sampling;Services;Signal Transduction;Superfund;Techniques;Technology;Testing;Therapeutic Intervention;Toxic effect;Toxicology;Toxin;Training;Universities;Validation;cardiometabolism;career development;flexibility;graduate student;interest;investigator training;meetings;member;metabolomics;novel;operation;response;success;superfund chemical;systemic toxicity;volatile organic compound

public_health_relevance:
NARRATIVEThe primary role of the Metabolism and Toxicity Core is to provide high quality validated data in support of allprojects in this Superfund Center. This Core has appropriate state-of-the art equipment and highly trainedtechnical personnel to carry out this mission. In addition this Core will strive to educate and train its users throughtechnical seminars and hands-on operational training. The highly diverse yet integrated services and expertiseof this Core are essential to achieve the goals of the Superfund center and help make progress with regards tounderstanding the diverse pathological consequences of VOC exposures.


application_id: 9904682
project_number: 5P42ES023716-04
project_title: Research Translation Core
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5117
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
ABSTRACTThe overall goal of the Research Translation Core (RTC) is to disseminate scientific knowledge acquired fromthe Louisville Superfund Basic Research Program (SBRP) in a timely manner to key constituencies in formsthat are targeted and useful to our audience. Our primary target audience are: (a) our local community andcommunity-based groups involved in protecting human health and the environment; (b) scientists and publichealth professionals working at other academic institutions and at local and federal agencies including theNIEHS itself and the broader SBRP community; (c) local state and federal policy makers and non-governmental organizations that contribute to the development of environmental regulations and policies; and(d) local media and press. We will tailor messages to appropriate audiences and use conventional andinnovative tools such as social media blogs and tweets to communicate with our audience aboutenvironmental issues of mutual interest. Our intent is to cultivate an informed participatory audience as well asto enhance awareness and understanding of our Superfund team of environmental issues of interest andconcern to both local and national stakeholders. Serving as a multi-directional bridge the RTC will facilitatemaximize and optimize interactions between our Superfund team and its wider audience. This arrangementwill ensure that environmental issues particularly those related to VOC exposure and cardiometabolic healthinform our research activities and that the findings of our research are appropriately disseminated. It will alsoensure that knowledge generated by our program contributes substantially to practices and policies relevant toenvironmental health across Kentucky and the nation. The RTC will serve as bidirectional bridge between thecommunity and the Louisville Superfund Program and develop effective and contextually appropriatecommunication strategies and tools. The core personnel will communicate routinely with policy makers andpublic health organizations and assist Center investigators in their efforts in disseminating research findingsand facilitate intellectual and technology transfer of promising scientific and engineering applications topromote timely application of research. The RTC will working closely with the Community Engagement Core tofurnish educational information to be incorporated in their community and trainee education activities andprovide a venue for Training Core participants to experience and learn research translation and regulatoryscience. The Core will also evaluate its effectiveness in facilitating communication between the program andits broad audience and in facilitating technology transfer and enabling educational activities.

project_terms:
Administrator;Affect;Area;Awareness;Basic Science;Cardiovascular Diseases;Chemical Exposure;Chemicals;Collaborations;Communication;Communities;Consequentialism;Data;Decision Making;Detection;Development;Devices;Diabetes Mellitus;Disease;Education;Educational Activities;Educational Materials;Educational Technology;Effectiveness;Emergency response;Engineering;Ensure;Environment;Environmental Exposure;Environmental Health;Evaluation;Exposure to;Federal Government;General Population;Goals;Government;Government Agencies;Government Officials;Health;Health Policy;Health Professional;Human;Human Resources;Information Dissemination;Institution;Intellectual Property;Kentucky;Knowledge;Learning;Link;Liver diseases;Local Government;Medical emergency;Methods;National Institute of Environmental Health Sciences;Newsletter;Nongovernmental Organizations;Participant;Pathway interactions;Policies;Policy Maker;Population;Process;Public Health;Regulation;Research;Research Activity;Research Personnel;Risk Estimate;Science;Scientist;State Government;Students;Superfund;Technology;Technology Transfer;Time;Training;Translating;Translational Research;Work;base;cardiometabolism;effectiveness evaluation;experience;federal policy;health organization;innovation;interest;meetings;member;news;novel;programs;public health relevance;social media;superfund chemical;superfund site;symposium;tailored messaging;tool;volatile organic compound;web site;webinar

public_health_relevance:
Project Narrative:The Research Translational Core (RTC) will provide a communication pathway linking the community atSuperfund site and other areas of high exposure to volatile organic chemicals (VOCs) with investigators at theLouisville Superfund Center (LSC). Working with both the Community Engagement Core and theAdministrative Core the RTC will organize Town Hall Meeting symposia informal meeting round tablediscussions between the community residents and leaders subject matter experts LSC researchers membersof governmental agencies and other stakeholders. The Core will develop communication strategies to targetspecific audiences and disseminate research findings and environmental health relevant information incontextually appropriate formats. Core personnel will communicate regularly with governmental organizationsand other interested parties to Louisville Superfund Center to provide assessments and risk estimates of VOCexposure in affected communities. The RTC will strive to identify the barriers to communication betweenresearchers and policy makers and work toward eliminating or ameliorating those barriers. The Core will alsofacilitate transfer of intellectual property and technology to ensure that the research and technology developedby LSC members finds appropriate and timely application. In collaboration with the Community EngagementCore and the Training Core the RTC will develop educational material for community forums and for traineesand students. The Core will gather data on its effectiveness in enabling communication between the programand its broad audience and provide an evaluation of its activities.Public Health RelevanceLittle is known about the health effects of volatile organic chemicals (VOCs) an important class of SuperfundChemicals on cardiovascular disease liver disease or diabetes. The Core will assist in understanding theimpact of these chemicals in affected populations facilitate the dissemination of this information and translatethis knowledge into formats that would be readily accessible to policy makers and regulators. During thisprocess the Core will ensure that the technologies and research developed by LSC researcher finds timelyapplications and that the activities of the Center are fully understood by its participants trainees governmentagencies and the general public.


application_id: 9904681
project_number: 5P42ES023716-04
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2020-04-02
opportunity_number: RFA-ES-15-019
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
study_section: ZES1-LKB-K
subproject_number: 5116
contact_pi_person_id: 11775218
contact_pi: HEBERLE, LAUREN
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: 2020-04-01
budget_end_date: 2021-03-31
project_abstract:
Abstract: Residents of Kentucky suffer disproportionately from many chronic diseases and exposure to toxics in theirenvironment. Dangerously high rates of obesity hypertension diabetes and cancer in Kentucky have beenwell documented. Our areas of focus are West Louisville encompassing six zip codes within the larger Metroarea. In West Louisville neighborhoods 61.1% of residents are black/African Americans and 55% of childrenunder age 18 live in poverty. Our preliminary assessments suggest that residents living near the Lees Lanelandfill in West Louisville Rubbertown a heavily industrialized residential area and Oakdale a neighborhoodnear Churchill Downs have high in VOC exposures. The Louisville medical community has a long history of bi-directional interactions with active communityinvolvement in health care delivery and research. These interactions date back to the creation of the MarineHospital in 1823 to treat riverboat workers continues in the 1970s with partnerships with industries to establishthe ongoing surveillance program of workers with hepatic hemeangiosarcoma associated with their exposureto vinyl chloride and more recently is highlighted by the partnership between Louisville Metro Department ofPublic Health and Wellness along with UofL and other community partners to fight obesity and chronic diseaseunder the CDC Communities Putting Prevention To Work (CPPW) grant and to mitigate the effects of airpollution exposure by planting trees under the Funders Network for Smart Growth and Livable CommunitiesPartner-for-Places grant. The overarching goal of the CEC is to support community and academicscientists/educators in transdisciplinary research that incorporates best practices in community engagement byfacilitating beneficial and bidirectional interactions between residents industry policy makers and SuperfundCenter interdisciplinary investigators. We will achieve this through the following Specific Aims: 1. Augment community and investigator capacity for transdisciplinary research focused on exposure to Superfund contaminants through facilitating Community Environmental Quality Resource Exchange Sessions (CEQRES) and establishing a Sustainable InstitutionalizedCollaborative Framework through the Louisville Superfund Center Community Advisory Board (LSC-CAB). 2. Support and facilitate project- and core-specific community engagement activities 3. Support a community project aimed at mitigating the effects of exposures to Superfund VOCs 4. Assess change in perception and knowledge of community participants and investigators as a result of engaging in specific Superfund Center activities.Through regular public forums and board meetings support of specific Superfund research projects andtraining community engaged intervention assessment of community and investigator perceptions andknowledge and substantive interactions with other project Cores particularly the Research Translation Core(RTC) the CEC will provide content and structural support necessary for ongoing community engagedresearch aimed at evaluating the health effects of pollutant exposure and reducing exposures to and negativeimpacts of Superfund toxic emissions.

project_terms:
Address;Adult;Affect;African American;Age;Air;Air Pollution;Area;Awareness;Back;Belief;Centers for Disease Control and Prevention (U.S.);Child;Chronic;Chronic Disease;Code;Communities;Dangerousness;Data;Death Rate;Development;Diabetes Mellitus;Disease;Elements;Ensure;Environment;Environmental Exposure;Environmental Health;Equipment;Evaluation;Exposure to;Fatty Liver;Feedback;Future;Goals;Government;Grant;Green space;Growth;Health;Health Food;Health Sciences;Heart Diseases;Hepatic;Home environment;Hospitals;Hot Spot;Housing;Hypertension;Industrialization;Industry;Intervention;Kentucky;Knowledge;Liver diseases;Love;Malignant Neoplasms;Measures;Medical;Monitor;Natural Sciences;Neighborhoods;Obesity;Participant;Patient Recruitments;Perception;Plants;Play;Policy Maker;Population;Poverty;Prevention;Preventive Intervention;Process;Public Health;Recording of previous events;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Scientist;Social Sciences;Source;Structure;Superfund;Surveillance Program;Syndrome;Testing;Toxic effect;Training;Transcend;Translational Research;Transportation;Trees;Vinyl Chloride;Work;attributable mortality;biological systems;cardiometabolism;community center;community involvement;fighting;health care delivery;health disparity;landfill;meetings;member;pollutant;public health relevance;racial disparity;social;superfund site;therapy design;toxicant

public_health_relevance:
Project Narrative:Residents of Kentucky are disproportionately affected by many chronic diseases and exposure to toxics in theirenvironment. Dangerously high rates of obesity hypertension diabetes and cancer in Kentucky have beenwell documented. Health disparities by race and class persist across Louisville Metro. Our areas of focus areWest Louisville neighborhoods where 61% of the population is black/African American. This area includesboth the Lees Lane Superfund site and Rubbertown. A nearby neighborhood Oakdale also is a hot spot.All of these areas have excessive exposure to Superfund VOCs. Within the West Louisville neighborhoods thepercentage of children under age 18 who live in poverty is 55% and the rates of deaths attributable to povertyfor adults over 25 are 4%-24% higher than in other Louisville Metro neighborhoods. West Louisville is alsohome to a very high number of industries (located very near residential areas) that are major sources of toxicair emissions numerous brownfields and a superfund designated land-fill. In addition area residents strugglewith poor access to greenspace inadequate transportation lack of affordable safe housing and limited accessto healthy food options. The CEC goal is to support transdisciplinary research that incorporates best practicesin community engagement by facilitating beneficial bi-directional interactions between residents industrypolicy makers and Superfund Center interdisciplinary investigators building all stakeholders capacities tocollaboratively understand reduce exposure to and address the negative impacts of contaminants initiallyfocused on VOCs from Superfund sites and industrial activities in West Louisville.Public Health Relevance:We are beginning to understand that exposure to toxicants can initiate/exacerbate multiple health problemsespecially cardiometabolic diseases. Kentuckians are disproportionately affected by many chronic diseasesincluding obesity hypertension heart disease diabetes fatty liver disease etc. which are all aspects of thecardiometabolic syndrome. Certain communities are more highly impacted than others and it is critical tounderstand why. It is our hypothesis that exposure to toxics specifically VOCs initiates/exacerbates theseconditions. It is fundamental to our understanding of the effects of these toxics to engage the communitiesmost deeply affected by exposure to these pollutants and to try to mitigate the effects of these exposures.Thus determining the influence of pollutant exposure on the development/progression of these chronicconditions is vital.


application_id: 9904600
project_number: 5R01DC017770-02
project_title: Communities Helping the Hearing of Infants by Reaching Parents: The CHHIRP Navigator Trial
administering_ic: NIDCD
award_notice_date: 2020-03-29
opportunity_number: PA-18-385
application_type: 5
activity_code: R01
ic: DC
serial_number: 017770
program_official: KING, KELLY ANNE
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: 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;Adherence;Adoption;Advisory Committees;Age-Months;Behavior Disorders;Birth;Caring;Characteristics;Child;Clinic;Collaborations;Communication impairment;Communities;Community Health;Complex;Congenital Disorders;Cost Savings;Cost effectiveness research;Data;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Early Diagnosis;Early Intervention;Education;Effectiveness;Emotional;Employment;Environment;Failure;Family;Feedback;Funding;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Tests;Hybrids;Impairment;Improve Access;Incidence;Individual;Infant;Intervention;Joints;Kentucky;Language Development;Learning;Learning Disorders;Life;Measures;Medical;Methods;Modality;Neonatal;Neonatal Screening;Newborn Infant;Occupational;Outcome;Outpatients;Parents;Patient Care;Patients;Penetration;Preventive service;Process;Public Health;Randomized Controlled Trials;Recording of previous events;Reporting;Research;Research Methodology;Research Personnel;Self Efficacy;Sensory;Sensory Disorders;Social Development;Speech;System;Testing;Third-Party Payer;Time;Training;Translational Research;United States;cancer care;care systems;childhood hearing loss;cognitive development;community clinic;community intervention;community setting;cost;cost effective;cost effectiveness;cost estimate;deafness;design;disparity reduction;early childhood;economic cost;effectiveness implementation study;effectiveness implementation trial;effectiveness research;effectiveness testing;effectiveness trial;falls;hearing impairment;hearing loss treatment;hearing screening;implementation research;implementation strategy;improved;innovation;intervention program;navigator intervention;peer support;prevent;programs;randomized trial;recruit;research to practice;scale up;screening;social;socioeconomics;standard care;standard of care;trial design


application_id: 9904131
project_number: 5R37CA227656-03
project_title: The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia
administering_ic: NCI
award_notice_date: 2020-03-17
opportunity_number: PA-16-160
application_type: 5
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_abstract:
PROJECT SUMMARYThere is a great need for the development of molecularly targeted therapies in Acute Lymphoblastic Leukemia(ALL). The lack of targeted therapies for this disease is an important problem because ALL is primarily apediatric cancer and intensive rounds of general cytotoxic chemotherapy have severe and long-term adverseeffects in children. Additionally adults and children whose ALL does not respond to cytotoxic chemotherapy orwho develop relapse have a universally poor prognosis due to limited treatment options. The well-knowndrivers of ALL are mis-expressed transcription factors such as MYC which are not easily therapeuticallytargeted without undesirable side-effects on normal cells. Preliminary data which built on a novel in vivotransplantation screen in a MYC-induced ALL model in zebrafish demonstrated that the tyrosine phosphatasePRL3 collaborated with MYC to enhance leukemia progression. In vitro and in vivo studies using human cellsshowed that PRL3 is linked with MYC expression and plays a critical role in ALL survival. Phosphatases likePRL3 are most well-known as tumor suppressors and despite emerging evidence that some phosphataseshave oncogenic abilities there are currently no phosphatase inhibitors used in the clinic for cancer patientsand only one in clinical trial. The overall objective of this application is to clearly define the oncogenic role ofthe tyrosine phosphatase PRL3 in MYC-driven ALL and to establish that it is a novel molecular target in thisdisease. The central hypothesis is that PRL3 is a direct transcriptional target of MYC and synergizes withMYC to promote a pro-survival phenotype in ALL cells. The rationale for this research is that PRL3 belongs toa unique family of phosphatases that can be selectively inhibited; defining the mechanisms through whichPRL3 promotes ALL survival will provide a strong scientific rationale for the development of PRL and otherphosphatase inhibitors for use as targeted therapy for cancer patients. This hypothesis will be tested bypursuing three specific aims: 1) Define a mechanism through which MYC regulates PRL3 expression by usingenChIP and biochemical approaches to assess MYC interaction with a novel enhancer region near PRL3; 2)determine the pro-survival mechanisms that are controlled by PRL3 by utilizing an unbiased biotin ligaseapproach to identify PRL3 substrates in ALL cells; and 3) establish that small molecule inhibition of the PRLfamily is a potent therapeutic strategy in ALL by completing comprehensive pre-clinical testing of three newPRL inhibitors and a panel of FDA-approved tyrosine phosphatase inhibitors. This research is innovativebecause it departs from the status quo to use new methods to define an oncogenic role for a phosphatase incancer. The proposed research is also significant because it is expected to vertically advance and expandunderstanding of the role that phosphatases play in cancer progression. Ultimately this knowledge has thepotential to drive the development of a new class of targeted therapy for patients with acute lymphoblasticleukemia and other MYC-driven cancers.

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;Leukemic Cell;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;acute lymphoblastic leukemia cell;antileukemic activity;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;side effect;small molecule;targeted cancer therapy;targeted treatment;therapeutic target;transcription factor;translational impact;tumor progression

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because the discovery of the mechanisms through whichthe tyrosine phosphatase PRL3 drives leukemia progression is expected to re-define the roles thatphosphatases can have in cancer. The proposed research is therefore relevant to the NCI mission because itwill provide a strong impetus for the development of phosphatase inhibitors which will be a new class oftargeted therapy for cancer patients.


application_id: 9903243
project_number: 5R01AI087849-09
project_title: Biosynthesis of nucleoside antibiotics targeting bacterial translocase I
administering_ic: NIAID
award_notice_date: 2020-04-01
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 087849
program_official: XU, ZUOYU
project_start_date: 2011-06-15
project_end_date: 2021-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 9509796
contact_pi: VAN LANEN, STEVEN GARY
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
New antibiotics are needed particularly those that can be considered as new chemical entitiesand have novel targets relative to the current clinical armament of antibiotics. Highly modifiednucleoside antibiotics that inhibit bacterial translocase I (TL1) involved in cell wall biosynthesis fitboth these descriptions and have excellent potential in part because they are (i) nanomolarinhibitors of TL1 (ii) inhibit a target that has been proven to be essential for the survival of mostif not all bacteria (iii) are effective antibiotics in both in vitro and in vivo models and (iv) have noapparent toxicity in mice. We have defined the biosynthetic mechanism leading to the coredisaccharyl-nucleoside structure of several promising nucleoside antibiotics including A-90289from Streptomyces sp. SANK 60405 muraminomicin from Streptosporangium sp andmuraymycin from Streptomyces sp. LL-AA896 using a combined in vivo and in vitro approach.The results have defined a multi-enzyme pathway highlighted by divergence from the primarybuilding block UMP and reconvergence to form the core nucleoside. This data was utilized to scanthe wealth of genomic information to identify a new lead antibiotic sphaerimicin which wasisolated and revealed to share the nucleoside core structure but have several unique featuresincluding a dihydroxylated piperidine ring of unknown origin. We will now accomplish the followingspecific aims: (i) to define the mechanism for the attachment of the 3-amino-3-carboxypropyl(3A3CP) moiety that generates the last shared intermediate in the biosynthesis of A-90289muraminomicin muraymycin and sphaerimicin which is hypothesized to occur via a new enzymestrategy catalyzed by a pyridoxal-5-phosphate-dependent protein and (ii) to delineate thebiosynthetic mechanism for divergence from the last shared intermediate to generate uniquenucleoside core scaffolds that are further decorated by fatty acids polyketides nonribosomalpeptides and/or saccharides. A biosynthetic mechanism for the diazepanone ring for A-90289and the highly unusual fused piperidine ring system in sphaerimicin will be defined.

project_terms:
AIDS/HIV problem;Aldehydes;Amides;Anabolism;Anti-Bacterial Agents;Antibiotics;Bacteria;Cell Wall;Cessation of life;Chemicals;Clinic;Clinical;Data;Decarboxylation;Development;Dioxygenases;Disease;Drug resistance;Drug resistance in tuberculosis;Enzymes;Fatty Acids;Genetic Engineering;Genome;Genomics;Goals;Health;Hospitals;Human;In Vitro;Lead;Logic;Methodology;Mining;Modality;Molecular;Multiple Bacterial Drug Resistance;Mus;Natural Product Drug;Nucleosides;Oxidoreductase;Pathway interactions;Peptides;Peptidoglycan;Pharmaceutical Preparations;Phosphotransferases;Process;Proteins;Public Health;Pyridoxal Phosphate;Research;S-Adenosylmethionine;Scanning;Side;Staphylococcus aureus infection;Streptomyces;Structure;System;Time;Toxic effect;Transaldolase;Transketolase;Tuberculosis;United States;Uridine;Uridine Monophosphate;World Health Organization;alpha ketoglutarate;analog;clinical application;community setting;drug discovery;enzyme pathway;expectation;improved;in vivo;in vivo Model;inhibitor/antagonist;member;methicillin resistant Staphylococcus aureus;multi-drug resistant pathogen;nanomolar;novel;nucleophilic substitution;pathogen;piperidine;prevent;scaffold;synthetic biology;tool;translocase

public_health_relevance:
Diseases caused by multidrug resistant bacteria are becoming a significant threat to humanhealth worldwide. The goal of this proposal is to study nucleoside antibiotics that represent anew structural class of antibiotics have a different mode of action than clinically usedantibacterial drugs are effective antibiotics in both in vitro and in vivo models and are ingeneral not toxic to mice.


application_id: 9902454
project_number: 5R01ES029846-03
project_title: Urban Greenness and Cardiovascular Health
administering_ic: NIEHS
award_notice_date: 2020-03-11
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 029846
program_official: SCHUG, THADDEUS
project_start_date: 2018-07-01
project_end_date: 2023-03-31
study_section: Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]
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:
Adopted;Affect;Air;Air Pollutants;Air Pollution;Area;Biochemical;Biological Markers;Blood;Carbon Black;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Characteristics;Chronic Disease;Cities;Communities;Data;Developed Countries;Developing Countries;Development;Ecosystem;Environment;Evaluation;Exposure to;Formulation;Grasslands;Green space;Hair;Health;Health Policy;Heart;Hospital Mortality;Hospitalization;Human;Individual;Intervention;Intervention Trial;Kentucky;Lead;Life Expectancy;Link;Location;Maintenance;Measurement;Measures;Mediating;Modeling;Neighborhoods;Noise;Outcome;Ozone;Particulate;Perception;Physiological;Plants;Poaceae;Pollution;Population;Prevalence;Prevention strategy;Psychosocial Stress;Public Health;Questionnaires;Reporting;Research;Risk;Risk Factors;Sampling;Severities;Stress;Sulfate;Sunlight;Surface;Surveys;Testing;Trees;Ultrafine;Urine;Vascular Plant;Wood material;Work;air filtration;built environment;cardiovascular disorder prevention;cardiovascular disorder risk;cardiovascular health;cohort;demographics;design;fine particles;foot;insight;land use;mortality;pollutant;premature;prevent;psychologic;recruit;residence;social;social cohesion;trial design;urinary;volatile organic compound


application_id: 9902340
project_number: 5R01CA131075-10
project_title: Defining the contribution of ATR to MC1R-enhanced DNA repair in melanocytes
administering_ic: NCI
award_notice_date: 2020-03-04
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 131075
program_official: JOHNSON, RONALD L
project_start_date: 2010-07-01
project_end_date: 2022-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 8508402
contact_pi: D'ORAZIO, JOHN A
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Melanoma the most lethal skin malignancy is a significant cause of cancer mortality often affecting men and women in their prime. The melanocyte-stimulating hormone (MSH)-melanocortin-1 receptor (MC1R) signaling axis is an inducible cutaneous pathway that regulates ultraviolet (UV) responses in melanocytes. Loss-of- function polymorphisms of MC1R signaling affecting millions in the United States alone more than double lifetime melanoma risk . Signaling through the MC1R a Gs-coupled membrane receptor leads to activation of adenylyl cyclase production of cAMP and enhancement of the ability of melanocytes to repair UV-damaged DNA that if left unrepaired causes "UV signature" mutations that fuel progression of melanocytes into melanoma. As a result MC1R-defective individuals with blunted DNA repair responses accumulate more mutations after UV exposure and are predisposed to melanoma. Our laboratory identified a critical molecular pathway linking MC1R/cAMP signaling to nucleotide excision repair (NER) the genome maintenance pathway responsible for removing UV-damaged bases from DNA. Activated by MC1R signaling and cAMP generation cAMP-dependent protein kinase (PKA) phosphorylates the ataxia and rad3 related (ATR) protein on the S435 residue. This post-translational modification causes ATR to associate with the NER factor xeroderma pigmentosum A (XPA) accelerating its interaction with nuclear photodamage and enhancing DNA repair. Compelling findings during the previous funding cycle indicate that A-kinase anchoring protein 12 (AKAP12) integrates PKA-ATR-XPA interactions. We hypothesize that through AKAP-regulated PKA-mediated ATR phosphorylation MC1R signaling protects melanocytes from UV mutagenesis by enhancing NER. The overall goal of this project is to determine how the PKA-ATR-XPA DNA repair axis is regulated and to understand how it impacts NER. Experiments proposed in the first Aim will determine how AKAP12 regulates MC1R-enhanced NER in melanocytes using co-localization kinase assays proximity ligation assay (PLA) proteomics and a UV-inducible mouse melanoma model. Studies proposed in the second Aim will identify how pS435 ATR impacts NER by focusing on mechanisms of DNA binding and strand incision using co-immunoprecipitation PLA fluorescent strand incision assay and oligonucleotide retrieval assay (ORA) as a functional measure of NER. Finally since we have determined that dysregulated pS435 signal profoundly sensitizes cells to genotoxic agents the third aim will define how p-S435 ATR is inactivated in melanocytes focusing on the role of PP2A phosphatase in pS435 ATR inactivation and determining how persistent pS435 ATR sensitizes melanoma cells to DNA damaging agents. Together these studies will define how MC1R signaling promotes NER and UV resistance and will serve as a platform for the development of rational melanoma-preventive strategies among high-risk MC1R-defective populations.

project_terms:
A kinase anchoring protein;ATR gene;Address;Adenylate Cyclase;Affect;American;Ataxia;Binding;Biological Assay;Cancer Etiology;Cells;Cessation of life;Co-Immunoprecipitations;Complex;Coupled;Coupling;Cutaneous;Cyclic AMP;Cyclic AMP Receptors;Cyclic AMP-Dependent Protein Kinases;DNA;DNA Binding;DNA Damage;DNA Repair;Defect;Development;Diagnosis;ERCC1 gene;Event;Funding;GTP-Binding Protein alpha Subunits Gs;Generations;Genetic Polymorphism;Genome;Goals;Gravin;Incidence;Individual;Inherited;Laboratories;Left;Ligation;Link;Maintenance;Malignant Neoplasms;Measures;Mediating;Melanins;Melanocortin 1 Receptor;Melanocyte stimulating hormone;Melanoma Cell;Membrane;Modeling;Molecular;Mus;Mutagens;Mutation;Nuclear;Nucleotide Excision Repair;Oligonucleotides;Pathway interactions;Pharmacology;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Pigmentation physiologic function;Population;Positioning Attribute;Post-Translational Protein Processing;Prevention strategy;Preventive therapy;Production;Protein Kinase;Protein Phosphatase 2A Regulatory Subunit PR53;Proteomics;Public Health;Radiation therapy;Receptor Signaling;Regulation;Repair Complex;Reporting;Resistance;Retrieval;Risk;Risk Factors;Role;Seminal;Signal Transduction;Skin;Skin Cancer;Surface;Surgical incisions;Time;Tissues;UV Mutagenesis;UV Radiation Exposure;UV induced DNA damage;UV response;Ultraviolet Rays;United States;Woman;Xeroderma Pigmentosum;anti-cancer;base;cell injury;cell type;chemotherapy;defined contribution;design;experimental study;high risk;loss of function;melanocyte;melanoma;men;mortality;prevent;receptor;recruit;repaired;response;therapy development;ultraviolet;ultraviolet damage

public_health_relevance:
PUBLIC HEALTH RELEVANCEL: Melanoma the deadliest form of skin cancer affects nearly 80000 individuals in the United States each year. The proposed study focuses on the role of a receptor known as the melanocortin 1 receptor (MC1R) that is important in normal pigmentation. Inherited defects in MC1R affect millions of Americans who are at elevated risk from ultraviolet light damage and mutations and as a result have a high risk for melanoma. By discovering how MC1R protects against melanoma formation our goal is to develop therapies to prevent melanoma.


application_id: 9900578
project_number: 5U01DE025833-05
project_title: Oral Health Promotion (OHPROM) Strategy for Persons with Intellectual & Developmental Disabilities
administering_ic: NIDCR
award_notice_date: 2020-03-31
opportunity_number: PAR-15-059
application_type: 5
activity_code: U01
ic: DE
serial_number: 025833
program_official: SHUM, LILLIAN
project_start_date: 2016-04-01
project_end_date: 2023-03-31
study_section: ZDE1-CF(05)
contact_pi_person_id: 16476700
contact_pi: DUKKA, HIMABINDU
other_pis: JOHNSON, KNOWLTON WILLIAM
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): People with intellectual and/or developmental disabilities (IDD) living in group homes are more likely to have poor oral hygiene poor dietary practices increased decay periodontal disease and total tooth loss than the general population-a significant health disparity. To improve the oral health care of this population we are conducting a stratified cluster Phase 2 randomized controlled trial to test for the efficacy ofan oral health promotion (OHPROM) strategy on persons with IDD living in group homes. This intervention is based on behavioral and public health theory derived from the literature and includes features to enhance sustainability.  The sample of consented participants is projected to be about 23 home managers 258 caregivers and 258 persons with IDD who reside in 86 group homes. Assuming the attrition rate observed in a pilot study it is projected that the final participants will be 20 managers 240 caregivers and 240 persons with IDD residing in 80 group homes. The homes are managed by three nonprofit partnering organizations and three sites of ResCare the nation's largest provider of residential services to persons with IDD in or near the Metro Louisville area in Kentucky and Southern Indiana. Managers are responsible for the conduct of caregivers in a small cluster of group homes are generally former caregivers and are paid staff. Caregivers are responsible for ensuring daily personal hygiene and dietary guidance for persons with IDD and are paid staff of the partner organizations. The OHPROM strategy is comprised of (a) planned action that entails caregivers signing a behavioral contract and engaging in oral health action planning for persons with IDD (b) caregiver capacity- building that includes didactic and observational learning as well as oral health devices (c) environmental adaptations with reminder posters and change of oral hygiene location (physical environment) and administrative oral health support (social environment) and (d) reinforcement through caregiver coaching.  The primary study objective is to assess change in oral health status of persons with IDD living in group homes. A second objective is to assess change in proximal and intermediate outcomes (i.e. mechanisms of change) and the extent to which these outcomes moderate the intervention effects on the oral health of persons with IDD. As a third objective the study will assess implementation quality as delivered to home managers and caregivers and the association of intervention components with the mechanisms of change.  The study results are intended to affect the fields of dentistry and behavioral research by demonstrating whether a theory-based prevention strategy can improve the oral health of persons with IDD living in group homes and may also improve the oral health of other at-risk dependent populations. Ultimately the study may produce changes in service organizations oral health care policies and practices of the study organizations. Diffusion of the tested oral health strategy if proven efficacious is also important; thus creating infrastructure for diffuson is also a study priority.

project_terms:
Affect;Applications Grants;Area;Behavior;Behavioral;Behavioral Research;Caregivers;Caring;Classification;Cognitive;Communities;Consent;Contracts;Data;Dementia;Dental;Dental General Practice;Dental Hygiene;Dentistry;Dentists;Developmental Disabilities;Devices;Diagnosis;Diet;Dietary Practices;Diffusion;Disabled Persons;Elderly;Ensure;Evaluation;Exhibits;Expectancy;Future;General Anesthesia;General Population;Group Homes;Health;Health Care Costs;Health Policy;Health Promotion;Health Status;Health behavior;Healthcare;Home environment;Hygiene;Impaired cognition;Indiana;Individual;Infrastructure;Intellectual functioning disability;Intervention;Journals;Kentucky;Learning;Link;Literature;Location;Longitudinal Studies;Medical Records;Modeling;Oral;Oral health;Organizational Policy;Outcome;Parents;Participant;Periodontal Diseases;Persons;Phase;Physical environment;Pilot Projects;Pneumonia;Population;Prevention strategy;Preventive;Procedures;Process;Provider;Psychological reinforcement;Public Health;Publishing;Randomized;Randomized Controlled Trials;Research;Risk;Risk Factors;Sampling;Self Efficacy;Services;Severities;Site;Social Environment;Systemic disease;Target Populations;Testing;Tissues;Tooth Extraction;Tooth Loss;United States;base;behavioral health;community setting;design;developmentally disabled;dosage;effective intervention;efficacy study;efficacy testing;efficacy trial;environmental adaptation;health disparity;health literacy;health plan;health related quality of life;improved;intervention effect;member;post intervention;posters;programs;public health relevance;recruit;service organization;social;theories

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People with intellectual and/or developmental disabilities (IDD) living in group homes are more likely to have poor oral hygiene poor dietary practices increased decay periodontal disease and total tooth loss than the general population-a significant health disparity. In the short term the effects of a Phase II stratified cluster randomized controlled efficacy trial can provide evidence that argues for public health and organizational policies that include oral health promotion (OHPROM) strategies for persons with IDD. In the long term this study is expected to demonstrate that the OHPROM strategy targeting caregivers and persons with IDD may potentially be generalized to other organizations that provide services to persons with IDD. Assuming future studies also show that oral health outcomes are positively affected by this intervention the overall health care cost could be reduced because persons with IDD will have less need for expensive procedures resulting from lack of proper oral health behaviors.


application_id: 9899102
project_number: 5R01ES019217-08
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2020-04-14
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 019217
program_official: NADADUR, SRIKANTH
project_start_date: 2011-09-23
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
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:
ABSTRACTMultiple epidemiological and experimental studies report that acute or chronic exposure to air pollution isassociated with adverse cardiovascular events including myocardial ischemia stroke arrhythmias heart failuresudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fineparticulate matter (PM2.5) fraction which is generated directly from the combustion of fossil fuels and is found inautomobile exhaust wood or coal smoke and industrial emissions. However the mechanisms by which PM2.5induces cardiovascular injury remain unclear and the pathophysiological conditions and co-exposures thatdetermine individual susceptibility to PM2.5 toxicity have not been identified. Our previous work has shown thatin young healthy adults exposure to PM2.5 is associated with inflammation decreases in vascular reparativecirculating angiogenic cells (CACs) and changes in cytokine/growth factor profiles consistent with an inhibitionof angiogenesis. In addition we found increased levels of circulating endothelial microparticles evidence ofsubclinical vascular injury. We obtained similar results in mouse exposure studies which show that exposure toconcentrated ambient particles depletes circulating angiogenic cells and leads to defective hematopoiesis andfunctional defects in bone marrow-derived cells. In pilot experiments we have found that these PM2.5-induceddefects in mice could be prevented by treatment with the endogenous nucleophile carnosine which quenchesreactive oxygen species and removes toxic products of lipid peroxidation. Furthermore in a human cohort withmild-to-moderate CVD risk we also found that those with high CVD risk are more susceptible to the effects ofPM2.5 and that individuals with high carnosine levels are relatively impervious to the adverse cardiovasculareffects of PM2.5 exposure. Thus we hypothesize that individual risk factors determine cardiovascular susceptibilityto PM2.5 and that means to limit electrophiles/oxidative stress will mitigate the adverse consequences of PM2.5exposure. These ideas will be tested in three Aims. In the first we will assess the impact of PM2.5 exposure onvascular function (arterial stiffness flow-mediated dilation peripheral artery tone) in a population with mild-to-moderate CVD risk and determine whether exposure exacerbates composite CVD risk and whether changesinflammation oxidative stress or thrombosis are associated with PM2.5-induced vascular dysfunction. In thesecond Aim we will determine whether the relationship between vascular injury and dysfunction is mediated byindividual-level demographic characteristics (e.g. sex age ethnicity) co-exposure to gaseous pollutants orsystemic levels of carnosine. In the third Aim we will enroll a subset of individuals with inherently low carnosinelevels and determine whether daily oral supplementation with carnosine attenuates the association betweenPM2.5 exposure and vascular dysfunction as well as PM2.5 -induced changes in biomarkers of cardiovascularinjury and indices of cardiovascular function. The results of this project will provide better estimates of CVDburden due to PM2.5 exposure identify specific risk factors that increase susceptibility to PM2.5-induced injuryand assess the efficacy of carnosine in attenuating PM2.5 toxicity. Findings of this project could potentially leadto the development of a novel and practical therapeutic intervention to prevent PM2.5 toxicity.

project_terms:
Acute;Adult;Adverse effects;Affect;Age;Air Pollution;Angiogenesis Inhibition;Animal Model;Antioxidants;Arrhythmia;Arteries;Atherosclerosis;Attenuated;Automobile Exhaust;Biological Markers;Blood Vessels;Bone Marrow;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Carnosine;Cell physiology;Cells;Characteristics;Chronic;Clinical Trials;Coal;Defect;Development;Dipeptides;Double-Blind Method;Endothelium;Enrollment;Ethnic Origin;Event;Exposure to;Fossil Fuels;Grant;Growth Factor;Guidelines;Health;Heart Arrest;Heart failure;Hematopoiesis;Human;Impairment;Individual;Industrialization;Inflammation;Inflammatory Response;Injury;Insulin Resistance;Intervention;Lead;Link;Lipid Peroxidation;Measures;Mediating;Mediator of activation protein;Mus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Participant;Particulate;Particulate Matter;Peripheral;Placebos;Population;Populations at Risk;Predisposing Factor;Predisposition;Reactive Oxygen Species;Reporting;Risk;Risk Factors;Smoke;Socioeconomic Status;Stroke;Testing;Therapeutic Intervention;Thrombosis;Toxic effect;Vascular Diseases;Wood material;Work;adverse outcome;ambient particle;arterial stiffness;atherogenesis;base;biological adaptation to stress;burden of illness;cardiovascular disorder risk;cardiovascular injury;cohort;cytokine;design;endothelial stem cell;epidemiology study;experimental study;fine particles;indexing;mortality;novel;oral supplementation;pollutant;prevent;randomized trial;repaired;sex;sudden cardiac death;vascular injury;volatile organic compound

public_health_relevance:
PROJECT NARRATIVEAcute exposure to particulate matter (PM) air pollution produces oxidative stress and inflammatory responsesin young healthy adults and chronic exposures are strongly correlated with the progression of atherosclerosisincreased thrombosis myocardial infarction and stroke. In this proposal we determine if the effects of PM aremore pronounced in unhealthy at risk populations with impaired anti-oxidant capacity and whether theseeffects can be limited by a simple anti-oxidant intervention.


application_id: 9898375
project_number: 5R21EY030186-02
project_title: The effect of cannabidiol and the role of GPR3 in experimental autoimmune uveitis
administering_ic: NEI
award_notice_date: 2020-03-19
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: EY
serial_number: 030186
program_official: MCKIE, GEORGE ANN
project_start_date: 2019-04-01
project_end_date: 2022-09-30
study_section: Special Emphasis Panel[ZRG1-BDCN-J(81)S]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
other_pis: SONG, ZHAO-HUI
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract Non-infectious autoimmune uveitis is a sight-threatening inflammatory eye disease which accountsfor 10% of preventable blindness despite currently available therapies. There is a high demand formedications which not only provide anti-inflammatory efficacy but are well tolerated by the patient. Cannabinoid (CBD) is one of the major components of marijuana without psychotropic effects. It isbeing explored for treating a number of pathological conditions in animal models and in patients includingcancer inflammatory diseases neuro-degenerative diseases substance abuse disorders etc. Currentlyevidence supports CBD as an immune-modulating agent affecting T cells B cells monocytes andmicroglia cells causing an overall reduction in pro-inflammatory cytokine expression and an increase inanti-inflammatory cytokines. However CBD has not been studied in animal models of autoimmune uveitisor the patients with uveitis. G protein-coupled receptor 3 (GPR3) belongs to a family of closely related orphan receptors.Although it has been reported to play important roles in many normal physiological functions and beinvolved in a variety of pathological conditions until recently we found that CBD is an inverse ligand forGPR3. This discovery highlights this orphan receptor as a potential new molecular target for CBD with anovel mechanism of CBD action. In our pilot study we discovered that GPR3 is expressed at low levels inthe spleen and barely detectable in the eye in nave mice. The expression however is dramaticallyincreased during intraocular inflammation. Further we identified that T cells and antigen presenting cells(APCs) of B cells and dendritic cells (DCs) express GPR3. The role of GPR3 on these cells is unknown. Itis also unknown whether CBD produces GPR3-mediated therapeutic effects in EAU. In this application we will use our well-established T cell-mediated experimental autoimmuneuveitis (EAU) models to test the potential therapeutic effects of CBD on EAU (Aim 1) and the functionalimpact of GPR3 on EAU development (Aim 2) and whether the therapeutic effects of CBD on EAU ismediated by GPR3 in vivo and in vitro (Aim 3) These studies will provide a preclinical proof for CBD as a potent anti-inflammatory photoreceptorprotective and analgesic drug for patients with uveitis and advance our understanding of CBD GPR3interaction in the development of autoimmune uveitis.

project_terms:
Adoptive Transfer;Adverse effects;Affect;Agonist;Analgesics;Animal Model;Anti-Inflammatory Agents;Antigen-Presenting Cells;Autoimmune Diseases;Autoimmune Process;B-Lymphocytes;Biological Assay;Blindness;Cannabidiol;Cannabinoids;Cannabis;Cell Proliferation;Cells;Clinical Trials;Coculture Techniques;Cyclic AMP;Dendritic Cells;Development;Disease;Eye;Eye diseases;Family;Fibromyalgia;Flow Cytometry;Future;GPR3 gene;Goals;Immune;Immunization;Immunize;Immunomodulators;In Vitro;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Knockout Mice;Lead;Ligands;Local Therapy;MHC Class II Genes;Malignant Neoplasms;Marijuana;Measures;Mediating;Microglia;Modeling;Molecular Target;Multiple Sclerosis;Mus;Neoplasms;Neurodegenerative Disorders;Orphan;Pathologic;Patients;Peptides;Pharmaceutical Preparations;Phase;Photoreceptors;Physiological;Pilot Projects;Play;Production;Protective Agents;Reporting;Retinol Binding Proteins;Role;Severities;Spleen;Substance abuse problem;Systemic Therapy;T-Lymphocyte;Testing;Therapeutic;Therapeutic Effect;Uveitis;Vision;Visual;Western World;Wild Type Mouse;autoimmune uveitis;cannabinoid treatment;cell injury;cytokine;disability;immunomodulatory therapies;in vivo;monocyte;novel;novel therapeutics;phytocannabinoid;pre-clinical;receptor;recruit

public_health_relevance:
NarrativeAutoimmune uveitis is one of the leading causes of blindness in the Western world despite awide range of local and systemic therapies. We propose to use experimental autoimmuneuveitis models to explore a potential anti-inflammatory therapy of cannabinoid (CBD) on uveitisfunctional impacts of its receptor (GPR3) on disease development and the importance of CBD-GPR3 interactions to uveitis.


application_id: 9898214
project_number: 5R21AG059123-02
project_title: SLC9A1 and Neurodegenerative Disease
administering_ic: NIA
award_notice_date: 2020-03-16
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AG
serial_number: 059123
program_official: OPANASHUK, LISA A
project_start_date: 2019-04-01
project_end_date: 2022-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BACHSTETTER, ADAM D
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:
Age-related neurologic disease is a significant and growing burden on our society. Although the largest shareof research effort has typically been devoted to the common neurodegenerative illnesses (such as Alzheimer'sdisease or AD) the reality is that nearly all cases of neurodegenerative disease possess elements of mixedpathology. Individuals diagnosed with AD frequently harbor neuropathologic hallmarks common in otherdiseases. For example tau pathology is also found in some forms of frontotemporal dementia ALS and otherforms of neurodegenerative disease and is also believed to be a key form of neuropathology that developsfollowing traumatic brain injury. Cerebrovascular disease (CVD) is abundant in individuals with a history ofobesity (and type 2 diabetes or T2D) which have a well known elevated risk of dementia. In general it isactually quite rare to identify AD cases lacking elements of co-morbid cerebrovascular pathology. It is unclearas to whether these elements of pathology contribute to dementia in an additive or synergistic manner. Inrecent studies in our lab we have observed an intriguing relationship between various aspects ofneuropathology that could potentially connect to AD and CVD. We have identified a membrane ion exchangerNHE1 (SLC9A1) as potentially involved in both pathologic processes. NHE1 has been shown to be involvedwith neuronal injury and tau pathology as our preliminary data indicates. This project seeks to determinewhether the function of this exchanger is important for either or both of these pathologies. This projectcombines both genetic and pharmacologic approaches to explore this exciting new target that has notpreviously been examined as a major player in age-related neurodegenerative disease. In specific aim 1(SA1) we will investigate the mechanism of the membrane ion exchanger NHE1 in a unique mouse modelcombining AD- and CVD-related pathology using a highly specific pharmacologic agent. In SA2 we willinvestigate how this membrane ion exchanger drives the formation of tau pathology by over expressing tau ona background of NHE1 genetic reduction. Efficacy will be determined using a range of immunohistochemicalmolecular and biochemical markers of pathology as well as gauging changes in cognitive function. Wehypothesize that NHE1 will be responsible for multiple aspects of neurodegenerative disease pathology andthat interfering with its activity will ameliorate these problems and will alleviate cognitive dysfunction. This is ahighly innovative hypothesis that to our knowledge has not been previously explored. Another strength of thisproposal is the use of a novel mouse model with unique features. This project has the capacity to significantlyimprove our understanding of co-morbid neuropathologies and could have significant implications for thetreatment and prevention of age-related neurodegenerative disease.

project_terms:
Acute;Address;Affect;Age-Months;Albumins;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Amyloid;Amyloid beta-42;Animal Model;Attenuated;Biochemical Markers;Blood Vessels;CD34 gene;Cerebrovascular Disorders;Cytoskeleton;Data;Dementia;Development;Diagnosis;Diet;Disease;Disease model;Elements;Ensure;Experimental Designs;Extravasation;Frontotemporal Dementia;Future;Genes;Genetic;Glial Fibrillary Acidic Protein;Gliosis;Human;Immunoglobulin G;Impaired cognition;Individual;Ions;Knowledge;Late Onset Alzheimer Disease;Link;Magnetic Resonance Imaging;Mediating;Membrane;Modeling;Mus;NHE1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuronal Injury;Non-Insulin-Dependent Diabetes Mellitus;Obesity;PHF-1;Palliative Care;Pathologic;Pathologic Processes;Pathology;Pathway interactions;Pharmacology;Prevention;Prussian blue;PubMed;Recording of previous events;Research;Risk;Role;Societies;Therapeutic;Trauma;Traumatic Brain Injury;VWF gene;Vascular Diseases;Vascular remodeling;Viral;Virus;Work;age related;age related neurodegeneration;axon injury;base;cerebrovascular;cerebrovascular pathology;cognitive function;comorbidity;cresyl violet;dementia risk;immunohistochemical markers;improved;innovation;insight;ischemic injury;mixed dementia;molecular marker;morris water maze;mouse model;nervous system disorder;neuron loss;neuropathology;novel;preclinical study;prevent;primary endpoint;small molecule inhibitor;stroke model;tau Proteins;therapeutic target;vascular cognitive impairment and dementia;vascular injury;vector control;virtual

public_health_relevance:
Mixed dementia is a form of neurologic disease with no defined treatment and no accepted animal model. Thisdisorder involves the interplay of co-morbid neuropathologies including elements of both cerebrovascular andAlzheimer's disease. This project will explore a novel mechanism that may drive the mixed dementia state andstudy putative therapeutic strategies based on this pathway in an innovative mouse model of the disease.


application_id: 9896561
project_number: 1R34AT010370-01A1
administering_ic: NCCIH
award_notice_date: 2019-12-23
opportunity_number: PAR-18-417
application_type: 1
activity_code: R34
ic: AT
serial_number: 010370
suffix: A1
program_official: MURRAY, PETER DANIEL
project_start_date: 2020-01-01
project_end_date: 2022-12-31
study_section: Special Emphasis Panel[ZAT1 PJ (06)]
contact_pi_person_id: 14550427
contact_pi: JACOBS, CALE
other_pis: VRANCEANU, ANA-MARIA
congressional_district: 06
department: ORTHOPEDICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Development of a Mind Body Program to Reduce Knee Pain in Obese Osteoarthritis Patients with Comorbid Depression

project_abstract:
PROJECT SUMMARYDevelopment of a mind body program to reduce cartilage breakdown and knee pain in obese osteoarthritispatients with comorbid depression This is a R34 application that follows the recently released IMMPACT criteria and the InternationalClassification of Functioning Disability and Health (ICF) framework to adapt a multimodal theory groundedmind body program (The Relaxation Response Resilience Program; 3RP) with prior success in patients withmedical illness in pilot and effectiveness studies for the needs of obese patients with knee osteoarthritis (OA)and depression and to specifically target increased physical activity (p3RP-OA). Depression obesity and OAexacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines reflecting a complex mind-body interaction. Current treatments for knee OA offerlittle to no benefit over a placebo and do not emphasize mind-body practices or physical activity to target theunderlying pathophysiology. Physical activity alone has shown benefit in the treatment of depression obesityand OA individually but adequate implementation remains challenging. Our guiding hypothesis is that thesynergistic interaction between mindfulness adaptive thinking positive psychology and healthy living skills ofthe 3RP adapted for the needs of OA patients and to target increased physical activity reduces pro-inflammatory cytokine expression while also promoting optimal mechanical loading of the cartilage will slowthe progression of symptomatic knee OA. Toward this goal this R34 proposal aims to 1) adapt the 3RP for theneeds of knee OA patients with depression (PHQ-910) and obesity (BMI30 kg/m2) with a focus of increasingphysical activity; and 2) establish the feasibility credibility and acceptability of the programs and researchprocedures. Using the R34 NCCIH mechanism we propose to use an iterative mixed methods strategy to adaptthe 3RP for the specific needs of obese OA patients with depression including increased activity to maximizetheir feasibility acceptability and credibility. This R34 grant will set the stage for us to conduct a fully poweredRCT through the R61/R33 mechanisms to assess the biopsychosocial mechanisms associated with OAprogression.

project_terms:
Accelerometer;Address;Adherence;Age;Attention;Biochemical;Biological;Biological Markers;Blood;Blood specimen;Body Weight;Body Weight decreased;Cartilage;Catabolism;Classification;Clinic;Clinical;Clinical Trials;Complex;Data;Data Collection;Degenerative polyarthritis;Detection;Development;Effectiveness;Eligibility Determination;Focus Groups;Functional disorder;Goals;Grant;Health;Individual;Inflammation;Inflammatory;Instruction;Interleukin-1;Interleukin-1 beta;International;Intervention;Interview;Kentucky;Knee;Knee Osteoarthritis;Link;Logistics;Manuals;Measures;Mechanics;Medical;Mental Depression;Methods;Mind-Body Intervention;Obesity;Pain;Participant;Patient Preferences;Patient Self-Report;Patients;Phase;Physical Function;Physical activity;Placebos;Population;Procedures;Program Acceptability;Protocols documentation;Psychology;Relaxation;Reporting;Research;Secure;TLR4 gene;Testing;Thinking;Time;Travel;Universities;Urine;Walking;arthropathies;articular cartilage;biopsychosocial;body-mind;cartilage degradation;chronic pain patient;comorbid depression;comorbidity;coping;cytokine;depressive symptoms;disability;high risk;improved;knee pain;mechanical load;medical schools;mind body interaction;mindfulness;multimodality;osteoarthritis pain;overexpression;pilot trial;programs;psychologic;recruit;resilience;response;sample collection;satisfaction;screening;skills;statistics;success;symptomatology;telehealth;theories

public_health_relevance:
Project Narrative The proposed feasibility clinical trial will adapt the Relaxation Response ResiliencyProgram (3RP) for telehealth delivery to meet the needs of obese osteoarthritis patients withdepression. We will finalize study procedures necessary for a fully powered RCT through theR61/R33 mechanisms to assess the biopsychosocial mechanisms associated with osteoarthritisprogression.


application_id: 9890996
project_number: 5R01AG054130-05
administering_ic: NIA
award_notice_date: 2020-03-12
opportunity_number: PAR-16-365
application_type: 5
activity_code: R01
ic: AG
serial_number: 054130
program_official: MCLINDEN, KRISTINA
project_start_date: 2016-07-15
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1-BBBP-V(55)R]
contact_pi_person_id: 10700978
contact_pi: MOGA, DANIELA CLAUDIA
other_pis: JICHA, GREGORY A
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
budget_start_date: 2020-04-01
project_title:
INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimers Symptomatic Expression: The INCREASE study

project_abstract:
Alzheimer's disease (AD) represents one of the most important public health issues our society is facing today.An estimated 5 million people age 65 and older in the United States (US) are currently living with AD and thisnumber may nearly triple by 2050. To address this impeding population burden the National Alzheimer's ProjectAct (NAPA) 2015 report emphasized the need for identifying preventive strategies that can delay symptomaticdisease onset. While much emphasis has been placed on developing and testing effective disease-modifyingstrategies targeting this asymptomatic preclinical phase of AD (pAD) little emphasis has been placed oncurrently available strategies that target cognitive reserve resulting in (1) delaying symptom onset (2) shorteningthe overall course of symptomatic disease and (3) substantially reducing the financial and societal impact of AD.We hypothesize that targeted reductions in inappropriate medication use (Beers Criteria 2015) will bolstercognitive reserve in subjects at risk for AD delaying the onset of clinical symptoms and reducing the prevalenceand duration of symptomatic disease. The impact of this strategy if successful includes a dramatic reduction inoverall health care expenditures for the millions affected by AD by delaying the symptomatic phase of diseasein accord with NAPA aims. Our specific aims are:Specific Aim 1. Conduct a 12-month randomized placebo-controlled trial to evaluate the impact of our patient-centered pharmacist-physician team MTM intervention in reducing unnecessary and inappropriate medicationuse in community-dwelling elderly non-demented subjects. Primary outcome measures will include pre- to post-intervention measures of: (1) use of inappropriate medications as measured by the Medication AppropriatenessIndex (MAI); 2) Cognitive Reserve Change Score (CRCS) defined as the difference in the scopolamine-challenged vs unchallenged measures on the neurocognitive score.Specific Aim 2 Evaluate the impact of preclinical amyloid burden on cognitive reserve deficits and decline(measured as CRCS) to evaluate efficacy of delaying symptomatic disease progression in pAD.While not eliminating AD or shortening duration of biological disease the delay in symptom onset andprogression to functional decline resulting from reduction in inappropriate medication use could lessen ADprevalence and significantly reduce healthcare expenditures related to not only AD but potentially all forms ofdementia involving a prodromal asymptomatic period. Study results would enable the larger implementation ofsimilar medication management strategies in clinical practice to address the need for multifaceted preventivestrategies to maintain cognitive health in the aging population.

project_terms:
Address;Adverse drug effect;Aerobic Exercise;Affect;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;American;Amyloid beta-Protein;Anti-Cholinergics;Beer;Biological;Brain;Clinical;Cognitive;Communities;Complex;Data;Dementia;Diet;Disease;Disease Progression;Drug usage;Elderly;Enrollment;Health;Health Care Costs;Health Expenditures;Impaired cognition;Intervention;Intervention Trial;Measures;Medical;Medication Management;Neurocognitive;Neurofibrillary Tangles;Onset of illness;Outcome Measure;Pathologic;Patients;Pharmaceutical Preparations;Pharmacists;Pharmacology;Pharmacy facility;Phase;Physicians;Population;Positron-Emission Tomography;Prevalence;Prevention strategy;Public Health;Reporting;Research;Scopolamine;Senile Plaques;Societies;Standardization;Symptoms;Testing;Time;United States;aging population;base;clinical practice;cognitive reserve;comorbidity;disability;exhaust;functional decline;human old age (65+);indexing;insight;non-demented;older patient;patient oriented;placebo group;post intervention;pre-clinical;preservation;primary outcome;psychosocial;public health relevance;randomized placebo controlled trial;randomized trial;stressor;therapy design;uptake;-amyloid burden

public_health_relevance:
Public Health Relevance StatementThe study will examine the impact on cognitive reserve of a pharmacist-physician patient-centered medicationtherapy management intervention to address inappropriate medication use as identified by the Beers 2015 list.By bolstering cognitive reserve our project will directly address the National Alzheimer's Project Act 2015priorities serving to delay onset of symptoms in preclinical dementia. The results of this study will providevaluable insights on how to expand this intervention to reduce the prevalence and associated healthcare costsof symptomatic Alzheimer's disease.


application_id: 9889908
project_number: 5R01CA203257-05
project_title: Natural product-based modulators of 4E-BP1 phosphorylation
administering_ic: NCI
award_notice_date: 2020-03-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 203257
program_official: FU, YALI
project_start_date: 2016-04-01
project_end_date: 2023-03-31
study_section: Special Emphasis Panel[ZRG1-BCMB-D(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: SHE, QING-BAI
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): Metastatic colorectal cancer (CRC) is difficult to treat and patients have few long term effective therapeutic options. The aggressiveness of this disease is in part driven by the aberrant expression of oncoproteins. At the molecular level cap-dependent translation of the precursor oncogenic mRNAs is frequently activated. Specifically this occurs via 4E-BP1 phosphorylation which when not phosphorylated functions as a mRNA translation repressor downstream from mTOR. We recently discovered that activated signaling via the PI3K/AKT and RAS/RAF/MEK/ERK pathways cooperate to promote CRC progression by convergent phosphorylation of 4E-BP1. Our work further demonstrated that 4E-BP1 phosphorylation-mediated oncogene translation functions as a critical node that integrates oncogenic signals of the AKT and ERK pathways for CRC tumorigenesis and metastasis. Moreover we found that CRC resistance to upstream kinase targeted therapy is associated with incomplete inhibition of 4E-BP1 phosphorylation. Notably genetic blockade of cap-dependent translation by a dominant active and non-phosphorylated 4E-BP1 mutant can effectively suppress tumor growth and metastasis in the mouse models of CRC. Our overarching hypothesis is that directly targeting 4E-BP1 phosphorylation- mediated oncogene translation represents a novel strategy for cancer drug development and therapy. Using a cap-dependent translation-based reporter assay we recently identified naturally occurring pyranonaphthoquinones that act as selective inhibitors of 4E-BP1 phosphorylation in a manner that is mechanistically distinct to existing mTOR inhibitors. The primary goals of the proposed studies are to determine the fundamental mechanism of pyranonaphthoquinone-based inhibition of 4E-BP1 phosphorylation and identify optimized analogs with suitable in vitro and in vivo potency and selectivity. Cumulatively the proposed studies offer high potential for the identification and development of structurally and functionally novel agents to target the translational control of CRC progression and metastasis with the potential to define new molecular probes and early stage leads for first-in-class targeted therapies to treat CRC.

project_terms:
Antineoplastic Agents;Binding;Biological Assay;CCI-779;Colorectal Cancer;Complex;Development;Disease;Disease Progression;Drug Kinetics;Drug resistance;EIF4EBP1 gene;FRAP1 gene;Generations;Genetic;Genetic Translation;Goals;In Vitro;Knowledge;MEKs;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Messenger RNA;Modeling;Molecular;Molecular Probes;Mutation;Naphthoquinones;Natural Products;Neoplasm Metastasis;Oncogenes;Oncogenic;Oncoproteins;PI3K/AKT;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Pharmacotherapy;Phosphorylation;Phosphotransferases;Production;Property;Protein Inhibition;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Ras/Raf;Reactive Oxygen Species;Reporter;Research;Resistance;Ribosomes;Signal Pathway;Signal Transduction;Structure;Testing;Therapeutic;Therapeutic Index;Toxic effect;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Work;Xenograft procedure;analog;base;cancer cell;cancer therapy;cell growth;clinical efficacy;colorectal cancer progression;colorectal cancer treatment;drug development;effective therapy;expectation;in vitro Assay;in vivo;inhibitor/antagonist;interest;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;mouse model;mutant;novel;novel strategies;novel therapeutic intervention;pharmacokinetics and pharmacodynamics;pre-clinical;prevent;public health relevance;targeted treatment;tumor;tumor growth;tumor xenograft;tumorigenesis;upstream kinase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal seeks to identify and optimize unique natural product-based modulators of 4E-BP1-regulated cap-dependent translation. The agents developed as part of this work offer potential as unique molecular probes to advance the understanding 4E-BP1 in tumorigenesis and metastasis and as early first-in-class preclinical leads to treat advanced colorectal cancers (CRCs) for which there currently are few if any effective therapies.


application_id: 9887301
project_number: 1R01MH119119-01A1
project_title: Estrogen Effects on ADHD and Cognition
administering_ic: NIMH
award_notice_date: 2019-09-06
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: MH
serial_number: 119119
suffix: A1
program_official: PACHECO, JENNIFER LYNN
project_start_date: 2019-09-10
project_end_date: 2023-08-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 8204810
contact_pi: MARTEL, MICHELLE M
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:
Adolescence;Adult;Affect;Age;Animals;Attention;Attention deficit hyperactivity disorder;Back;Basic Science;Biological;Biological Assay;Childhood;Clinic;Clinical;Cognition;Cognitive;Communities;Comorbidity;Data;Deltastab;Diagnosis;Disease;Dopamine;Estradiol;Estrogens;Evaluation;Exclusion Criteria;Exhibits;Experimental Designs;Feasibility Studies;Female;Goals;Gonadal Steroid Hormones;Health;Hormonal;Hormone use;Hormones;Human;Impairment;Impulsivity;Laboratories;Link;Longitudinal Studies;Measurement;Measures;Menstrual cycle;Menstruation;Neurocognitive;Ovarian hormone;Ovulation;Participant;Persons;Pharmaceutical Preparations;Phase;Prevalence;Progesterone;Psychology;Puberty;Publishing;Rattus;Research Design;Risk;Risk Factors;Role;Saliva;Sampling;Short-Term Memory;Symptoms;Test Result;Testing;Thinking;Translating;Universities;Visit;Withdrawal;Woman;Work;animal data;base;clinical practice;clinical predictors;clinically significant;cognitive function;cognitive performance;cognitive testing;design;falls;hypothalamic pituitary gonadal axis;improved;inattention;innovation;male;multilevel analysis;perimenstrual;personalized approach;proliferative phase Menstrual cycle;recruit;response;sex;social media;treatment response;virtual;young adult;young woman


application_id: 9887287
project_number: 1R01GM132443-01A1
project_title: A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages
administering_ic: NIGMS
award_notice_date: 2019-09-18
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: GM
serial_number: 132443
suffix: A1
program_official: DUNSMORE, SARAH
project_start_date: 2019-09-20
project_end_date: 2023-06-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
other_pis: WEI, YINAN
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:
Sepsis is a life-threatening condition that affects more than 1 million patients a year in the United States.Growing evidence indicates that immunosuppression is a major driving force for mortality in sepsis.Macrophages play essential roles in immune response to pathogens. Previous clinical studies have shown thatperipheral monocytes are depleted in septic patients through apoptosis. Recent in vitro studies revealed thatbacterial components flagellin the rod protein of the type III secretion system (T3SS) or LPS inducepyroptosis of macrophages through activation of inflammasome pathways. In this proposal we provideconvincing evidence that both peripheral monocytes and tissue macrophages are depleted due to pyroptosis inmouse sepsis models including the cecal ligation and puncture (CLP) model. We show that intravenousinjection of flagellin or the rod proteins induced depletion of peripheral monocytes and macrophages in tissues.We further demonstrate that depletion of these cells in mice impaired immune response and increasedmortality rate by subsequent challenged with E. coli. Importantly our data indicate that tissue factor releasedfrom pyroptotic monocytes and macrophages triggers disseminated intravascular coagulation (DIC). Thus ourfindings identified monocyte/macrophage depletion as a novel mechanism of immunosuppression and DIC insepsis. The goal of this application is to delineate the underlying mechanisms of monocyte/macrophagedepletion and its contribution to immunosuppression in sepsis. Aim 1 is to delineate the mechanisms ofpyroptotic monocyte and macrophage death during sepsis. The working hypothesis is that inflammasomeactivation and subsequent pyroptosis play a critical role in monocyte/macrophage depletion during sepsis.Mouse models deficient in caspase-1 caspase-11 caspase-1/11 double or GSDMD (whole-body andmacrophage-specific) will be used to elucidate the detailed mechanism of inflammasome activation andpyroptosis in monocyte/macrophage depletion. Aim 2 is to identify the mechanism by which rod protein andflagellin induce pyroptosis leading to monocyte/macrophage depletion. We recently identified an intracellularbinding partner of EprJ the acyl-CoA dehydrogenase family member type 9 (ACAD9) in macrophages. We willuse different approaches to test the hypothesis that the ACAD9-dependent pathway contributes tomacrophage depletion. Aim 3 is to identify the contribution of monocyte/macrophage depletion toimmunosuppression during sepsis. We will use a combination of sepsis models to investigate the role ofmonocyte/macrophage depletion in immunosuppression during sepsis. Peripheral monocyte depletion in septicpatients will also be investigated. Completion of the proposed studies will reveal a novel molecular mechanismof immunosuppression induced by Gram-negative bacteria. Such findings will significantly advance ourunderstanding about the pathogenesis of sepsis and identify new drug targets for this deadly disease.

project_terms:
Affect;Apoptosis;B-Lymphocytes;Bacteria;Binding;CASP1 gene;Caspase;Cell Death;Cell membrane;Cells;Cessation of life;Cleaved cell;Clinical Research;Data;Dendritic Cells;Disease;Disseminated Intravascular Coagulation;Effector Cell;Escherichia coli;Family member;Flagellin;Goals;Gram-Negative Bacteria;Gram-Negative Bacterial Infections;Immune;Immune response;Immunosuppression;Impairment;In Vitro;Infection;Inflammasome;Inflammatory;Lead;Life;Modeling;Molecular;Morbidity - disease rate;Mus;N-terminal;Pathogenesis;Pathway interactions;Patients;Peripheral;Phagocytosis;Play;Proteins;Reporting;Research Project Grants;Role;Rupture;Sepsis;T-Cell Depletion;Testing;Thromboplastin;Tissues;Type III Secretion System Pathway;United States;Work;acyl-CoA dehydrogenase;cecal ligation puncture;driving force;insight;intravenous injection;macrophage;monocyte;mortality;mouse model;new therapeutic target;novel;pathogen;release factor;response;retinal rods;septic patients

public_health_relevance:
Project NarrativeCumulative data indicate that immunosuppression is a major driving forcefor morbidity and mortality in sepsis. This research project seeks tounderstand the mechanism of monocyte and macrophage depletion which maycontribute to sepsis-associated immunosuppression. Completion of the work willprovide new insights into molecular mechanism of immunosuppression by Gram-negative bacteria that could be targeted to treat this deadly disease.


application_id: 9887193
project_number: 1R01ES030380-01A1
project_title: Radon on the RADAR
administering_ic: NIEHS
award_notice_date: 2020-02-19
opportunity_number: PA-18-260
application_type: 1
activity_code: R01
ic: ES
serial_number: 030380
suffix: A1
program_official: O'FALLON, LIAM
project_start_date: 2020-02-20
project_end_date: 2024-11-30
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Adoption;Advocate;Awareness;Back;Charcoal;Collaborations;Communities;County;Data;Data Analyses;Data Collection;Detection;Disease;Effectiveness;Environmental Health;Environmental Risk Factor;Equipment;Feedback;Gases;Geological Survey;Geology;Geoscience;Health;Home environment;Information Dissemination;Kentucky;Knowledge;Libraries;Low income;Maintenance;Malignant neoplasm of lung;Maps;Marketing;Measurement;Monitor;Outcome;Precipitation;Procedures;Property;Provider;Radar;Radon;Reporting;Risk;Rural;Rural Community;Sampling;Self Efficacy;Smoking;Soil;Technology;Temperature;Testing;Time;Tobacco smoke;Training;Translating;atmospheric conditions;base;cancer risk;citizen science;cost;design;detector;digital;environmental tobacco smoke exposure;health literacy;improved;information seeking behavior;interest;member;novel;programs;time use;usability;web site


application_id: 9886997
project_number: 2R01CA175105-06A1
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2019-11-28
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: CA
serial_number: 175105
suffix: A1
program_official: AULT, GRACE S
project_start_date: 2013-04-01
project_end_date: 2024-11-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Binding Proteins;Biological Markers;Biology;Cancer Etiology;Cell Line;Cessation of life;Clinical;Colorectal Cancer;Dependence;Development;Disease;Down-Regulation;EIF4EBP1 gene;Effectiveness;Electron Transport Complex III;Environment;Epigenetic Process;FRAP1 gene;Fostering;Foundations;Funding;Genes;Genetic Transcription;Genetic Translation;Goals;Immune Evasion;Immunity;Immunologic Surveillance;Immunologist;Immunotherapy;Internal Ribosome Entry Site;Knowledge;Left;Malignant Neoplasms;Mediating;Messenger RNA;Molecular;Monoclonal Antibodies;Neoplasm Metastasis;Oncogenic;Oncologist;Outcome Study;Pathogenesis;Pathologist;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Polyribosomes;Positioning Attribute;Process;Property;Protein Biosynthesis;Proteins;Public Health;RNA;RNA Helicase;Reporting;Research;Resistance;Role;Signal Pathway;Signal Transduction;Snails;T-Lymphocyte;Testing;Therapeutic;Transact;Translating;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Tumor Immunity;Tumor-Infiltrating Lymphocytes;United States;Woman;Work;Xenograft procedure;anti-PD-1;base;cancer cell;clinically relevant;colon cancer patients;colorectal cancer progression;colorectal cancer treatment;effective therapy;experience;genetic corepressor;improved;in vivo;inhibitor/antagonist;innovation;insight;kinase inhibitor;mTOR Inhibitor;men;metastatic colorectal;metastatic process;mouse model;novel;novel strategies;novel therapeutics;polysome profiling;programmed cell death ligand 1;protein complex;recruit;response;silvestrol;targeted treatment;therapeutic target;treatment response;tumor;tumor growth


application_id: 9886316
project_number: 2R01DE024509-06
project_title: Filifactor alocis interactions with neutrophils
administering_ic: NIDCR
award_notice_date: 2019-09-13
opportunity_number: PA-19-056
application_type: 2
activity_code: R01
ic: DE
serial_number: 024509
program_official: MELILLO, AMANDA A
project_start_date: 2014-07-01
project_end_date: 2024-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8652094
contact_pi: URIARTE, SILVIA M
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;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Apoptosis;Apoptotic;Bacteria;Biology;Bone Marrow;Cells;Chemotaxis;Chronic;Communities;Complex;Cytoplasmic Granules;Data;Development;Disease;Disease Progression;Etiology;Exocytosis;Experimental Models;Focal Infection;Foundations;Fusobacterium nucleatum;Gene Expression;Generations;Gingiva;Goals;Health Status;High-Throughput Nucleotide Sequencing;Human;Immune;Immune response;In Vitro;Indigenous;Infection;Inflammation;Inflammatory;Inflammatory Response;Intention;Knowledge;Laboratories;Leukocytes;Longevity;Mediating;Molecular;Mus;NF-kappa B;Oral;Oral health;Organism;Pathogenesis;Pathogenicity;Pathology;Periodontal Diseases;Periodontal Pocket;Periodontitis;Phagocytes;Phagosomes;Play;Porphyromonas gingivalis;Process;Proteins;Publishing;Reactive Oxygen Species;Regulation;Research;Research Personnel;Role;Secure;Signal Pathway;Signal Transduction;Site;Stimulus;TLR2 gene;Techniques;Testing;Tissues;United States;Virulence;Work;antimicrobial;bactericide;bone loss;combat;cytokine;defined contribution;density;dysbiosis;extracellular;host-microbe interactions;in vivo;in vivo Model;innovation;microbial;microbial community;microbicide;microbiota;neutrophil;novel therapeutic intervention;oral bacteria;oral biofilm;oral pathogen;pathogenic bacteria;periodontopathogen;preservation;prevent;programs;recruit;response;retinal rods;trafficking;transcriptome;transcriptome sequencing


application_id: 9886230
project_number: 5R01DE022597-07
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2020-02-25
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DE
serial_number: 022597
program_official: MCNEALY, TAMARA L
project_start_date: 2013-02-01
project_end_date: 2024-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affinity;Alleles;Alveolar Bone Loss;Animal Model;Antibodies;Antibody Formation;Antigens;Arginine deiminase;Autoantibodies;Autoantigens;Autoimmune Process;B-Lymphocytes;Bacteria;Bacterial Proteins;Binding;Bone Resorption;C-terminal;Carrier Proteins;Cells;Characteristics;Chronic;Citrulline;Clinical;Collaborations;Collagen Arthritis;Communities;Complex;Crystallization;Data;Development;Diagnosis;Dinoprostone;Disease;Enzymes;Epitopes;Etiology;Event;Fibrinogen;Fibroblasts;GTP-Binding Proteins;Genes;Gingiva;Gingival Crevicular Fluid;Grant;HLA-DR4 Antigen;Haptens;Human;Immune response;Immunize;Inbred C3H Mice;Individual;Inflammation;Inflammatory Arthritis;Inflammatory Response;Link;Mammals;Mediator of activation protein;Mucous Membrane;Norway;Pathogenesis;Pathogenicity;Pathologic;Patients;Peptide Hydrolases;Peptides;Periodontal Ligament;Periodontitis;Periodontium;Play;Porphyromonas;Porphyromonas gingivalis;Prevalence;Process;Production;Protein Isoforms;Protein-arginine deiminase;Proteins;Research;Rest;Rheumatoid Arthritis;Role;Saliva;Self Tolerance;Serum;Severities;Site;Solid;Specimen;Structure;Surface;Symptoms;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Universities;Variant;Virulence;Virulence Factors;arthropathies;base;biobank;citrullinated protein;cohort;dysbiosis;enolase;gingipain;joint destruction;mouse model;novel;novel strategies;oral bacteria;pathogen;periodontopathogen;preference;response


application_id: 9885797
project_number: 1R01EY030060-01A1
project_title: Role of MRTF signaling in proliferative vitreoretinopathy
administering_ic: NEI
award_notice_date: 2019-12-17
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: EY
serial_number: 030060
suffix: A1
program_official: NEUHOLD, LISA
project_start_date: 2020-01-01
project_end_date: 2024-12-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 9182746
contact_pi: TAMIYA, SHIGEO
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractProliferative vitreoretinopathy (PVR) is a fibrotic complication affecting the retina. In PVR loss of visualacuity and in severe cases blindness is caused by contraction of scar tissue that form on the retinalsurface. PVR is found in ~50% of posterior segment ocular trauma cases and about 5% of cases aftersurgical repair of rhegmatogenous retinal detachment. Reliable treatment for PVR is currently unavailableand therefore prevention is important. The overall goal of this project is to unravel molecular mechanismsinvolved in PVR development to identify targets for potential intervention. The trigger for fibrosis such asPVR is sustained presence of myofibroblasts a cell type specialized ECM deposition and woundcontraction. Recent studies show that stiff ECM activates intracellular signaling essential for differentiationof myofibroblasts. Myofibroblasts in turn feeds back to further enhances ECM stiffness via aberrant ECMdeposition and crosslinking. This positive feedback loop between myofibroblasts and ECM rigidity sustainsmyofibroblast presence and its inhibition successfully prevented lung and liver fibrosis in animal models.However the underlying detailed mechanisms and molecules involved are both tissue and cell typedependent and the role of this positive feedback loop is yet to be examine in PVR. Past studies show thepresence of molecules involved in ECM stiffening in samples from PVR patients. Our preliminary data showtwo key molecules known to be affected by ECM stiffness transient receptor potential vanilloid 4 (TRPV4)channel and myocardin-related transcription factor (MRTF) are required for myofibroblasttransdifferentiation of retinal pigment epithelial (RPE) and Mller glia cells two resident cell types that giverise to myofibroblasts in PVR. Further data also show another molecule regulated by stiffness and known toalter MRTF target expression TAZ interacts with MRTF. We propose studies to determine molecularmechanisms activated by ECM stiffness leading to myofibroblast differentiation and PVR. In Aim1 the effectof ECM stiffening molecules on myofibroblast differentiation and PVR will be examine. Detailed molecularmechanism of regulating MRTF which is key to myofibroblast differentiation by TRPV4 and TAZ will bedetermined in Aim2 and 3 respectively. The project has the potential to uncover key molecular therapeutictargets for the prevention of PVR and possibly other fibrotic diseases.

project_terms:
Actins;Affect;Animal Model;Atomic Force Microscopy;Back;Blindness;Calcium;Cell Nucleus;Cells;Characteristics;Cicatrix;Collagen;Complication;Contracts;Cultured Cells;Data;Deposition;Development;Disease;Enzymes;Epiretinal Membrane;Extracellular Matrix;Family;Family suidae;Feedback;Feeds;Fibronectins;Fibrosis;Gene Expression;Goals;In Vitro;Intervention;Literature;Liver Fibrosis;Measures;Modeling;Molecular;Muller's cell;Myofibroblast;Myosin Light Chain Kinase;Nuclear;Nuclear Translocation;Operative Surgical Procedures;PTK2B gene;Patients;Phosphotransferases;Prevention;Production;Proliferative Vitreoretinopathy;Protein Inhibition;Protein-Lysine 6-Oxidase;Publishing;Pulmonary Fibrosis;Retina;Retinal Detachment;Role;Sampling;Series;Serum Response Factor;Signal Transduction;Small Interfering RNA;Structure of retinal pigment epithelium;Surface;Testing;Time;Tissues;Traction;Transforming Growth Factor beta;Transglutaminases;Trauma;Vanilloid;Visual Acuity;base;cell type;crosslink;cytokine;fibrillogenesis;in vivo;knock-down;molecular targeted therapies;myocardin;polymerization;prevent;receptor;repaired;rho;small hairpin RNA;src-Family Kinases;therapeutic target;transcription factor;transdifferentiation;wound

public_health_relevance:
Project NarrativeProliferative vitreoretinopathy (PVR) is a fibrotic complication that causes retinal folds and/or traction retinaldetachment resulting in loss of visual acuity and in severe cases blindness. We propose to study signalingmechanisms involving both cells and the fibrotic extracellular matrix that creates a positive feedback loopthat results in PVR. The ultimate aim is to identify key molecules that can become therapeutic targets for theprevention of PVR.


application_id: 9885698
project_number: 1C06OD028340-01
project_title: Healthy Kentucky Research Building Fit-up for Vascular Research
administering_ic: OD
award_notice_date: 2019-09-19
opportunity_number: PAR-19-128
application_type: 1
activity_code: C06
ic: OD
serial_number: 028340
program_official: CHEN, YONG
project_start_date: 2019-09-23
project_end_date: 2021-10-31
study_section: Special Emphasis Panel[ZOD1 STOD-X (02)]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentucky (UK) requests support to fit-up the first floor of the new Healthy Kentucky ResearchBuilding (HKRB also referred to as RB2) for vascular researchers within an overall 6 floor facility that isdedicated to research addressing and eradicating health disparities that disproportionately influence the livesof Kentuckians especially those living in rural Appalachia. The proposed fit-up will complete 17350 squarefeet of laboratory shell space for investigators performing vascular (both central and peripheral blood vessels)research across a variety of disciplines to detect mechanistically define and treat a broad array of diseasesinfluenced by blood vessel function including aortopathies atherosclerosis and Alzheimer's disease andrelated dementias. To facilitate integration of research approaches and translation of basic and appliedresearch within the fit-up first floor UK will fit-up an imaging core facility within the basement of HKRB that willbe used by these and other investigators within the facility and across the institution. The focus on vascularresearch within the first floor of HKRB builds upon existing research strengths in this area across theinstitution an ability to engage multiple disciplines and academic units long-term sustainability and thesignificance of the research for the health of Kentucky. Specifically this project will (1) Fit-up the first floor(17350 sq ft) of HKRB creating two neighborhoods with 6 benches/neighborhood (total of 12 laboratorybenches) fixed casework and equipment (2) Fit-up of a linear equipment hall spanning the length of wetlaboratory neighborhoods that includes one autoclave and one cold room (3) Fit-up 16 procedure rooms (200sq ft/procedure room) within the wet laboratory neighborhood design two of which have 3 fume hoods/eachand (4) Fit-up associated technical personnel space investigator space and collaborative spaces.Construction of 60% of HKRB was supported from the State legislature for health disparities research and thebuilding design has many attributes that should facilitate the research of investigators on the fit-up first floorincluding adjacent location of dry laboratory researchers approaching the problem from a different perspectivetwo connected research buildings with a biomedical focus a full vivarium with several core facilities (includingthe imaging service core) open neighborhood laboratory design to promote collaborative vascular researchand other elements (e.g. indoor bike room) that promote a healthy lifestyle. Vascular research within the fit-upfirst floor of HKRB is an institutional priority that is targeted for additional growth which will be achievedthrough support of this project. The fit-up of the first floor of HKRB provides high quality collaborativebiomedical research and core facility space to attract and retain outstanding vascular researchers acrossmultiple disciplines who use a variety of imaging approaches.

project_terms:
Address;Alzheimer's disease related dementia;Applied Research;Area;Atherosclerosis;Basic Science;Biomedical Research;Blood Vessels;Core Facility;Discipline;Disease;Elements;Equipment;Floor;Growth;Health;Human Resources;Image;Institution;Kentucky;Laboratories;Length;Location;Neighborhoods;Procedures;Research;Research Personnel;Rural Appalachia;Services;Translations;Universities;building design;design;health disparity;healthy lifestyle;imaging approach;peripheral blood vessel;research facility;square foot


application_id: 9885360
project_number: 1R01AI144126-01A1
project_title: SpoVG and PlzA Regulation of Lyme Disease Spirochete Infection Processes
administering_ic: NIAID
award_notice_date: 2020-03-30
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: AI
serial_number: 144126
suffix: A1
program_official: BOWDEN, NADINE
project_start_date: 2020-04-01
project_end_date: 2024-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
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
project_terms:
Affect;Affinity;Anti-Bacterial Agents;Antibiotic Therapy;Antibiotics;Back;Bacteria;Bacterial Infections;Bacterial Physiology;Binding;Binding Proteins;Binding Sites;Biology;Borrelia;Borrelia burgdorferi;Centers for Disease Control and Prevention (U.S.);Cessation of life;ChIP-seq;Collaborations;Cues;DNA;DNA Binding;Data;Development;Environment;Failure;Gene Expression;Genes;Genetic Transcription;Genome;Human;Immunocompetent;Impairment;Infection;Infection Control;Infectious Agent;Invaded;Investigation;Joints;Knowledge;Lyme Disease;Mammals;Maps;Mechanics;Membrane Proteins;Mus;Nature;North America;Order Spirochaetales;Organism;Pathogenesis;Pathogenicity;Patients;Periodicity;Physiology;Preventive therapy;Process;Production;Property;Proteins;Proteomics;RNA;RNA Sequences;RNA immunoprecipitation sequencing;RNA-Binding Proteins;Recording of previous events;Regulation;Regulatory Pathway;Regulon;Research Personnel;Role;Site;Specificity;Spirochaetales Infections;Ticks;Ursidae Family;Vertebrates;Virulence;Virulence Factors;Work;arthropod-borne;curative treatments;genetic regulatory protein;human disease;human pathogen;improved;insight;member;microbial;mutant;novel therapeutics;nucleic acid binding protein;pathogen;pathogenic bacteria;protein expression;response;stem;tick feeding;transcriptome;transcriptomics;transmission process;vector-borne pathogen


application_id: 9882789
project_number: 1UG1DA050069-01
project_title: Kentucky Women's Justice Community Opioid Innovation Network (WJCOIN)
administering_ic: NIDA
award_notice_date: 2019-07-15
opportunity_number: RFA-DA-19-025
application_type: 1
activity_code: UG1
ic: DA
serial_number: 050069
program_official: MULFORD, CARRIE FRIED
project_start_date: 2019-07-15
project_end_date: 2024-04-30
study_section: Special Emphasis Panel[ZDA1 HXO-H (05)]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Benefits and Risks;Caring;Climate;Clinical;Clinical Research;Communities;Cost Analysis;Criminal Justice;Death Rate;Development;Drug abuse;Drug usage;Effectiveness;Exposure to;Funding;Goals;Health Services Accessibility;High Risk Woman;Hybrids;Imprisonment;Intervention;Jail;Justice;Kentucky;Lead;Leadership;Life;Link;Maintenance;Methods;Modeling;National Institute of Drug Abuse;Opioid;Outcome;Overdose;Perception;Pharmaceutical Preparations;Physicians;Positioning Attribute;Public Health;Quality of Care;Randomized;Readiness;Recording of previous events;Recovery;Relapse;Reporting;Research;Research Personnel;Rewards;Safety;Savings;Self Medication;Services;Site;System;Time;Treatment Cost;United States National Institutes of Health;Universities;Woman;arm;base;community reentry;compare effectiveness;comparison group;cost;cost effectiveness;cost-effectiveness ratio;effectiveness trial;experience;follow-up;high risk;implementation trial;improved;incremental cost-effectiveness;innovation;innovative technologies;intervention cost;member;men;opioid epidemic;opioid exposure;opioid injection;opioid mortality;opioid use disorder;overdose death;pain sensitivity;peer;prescription opioid;programs;recidivism;telehealth;treatment as usual


application_id: 9882235
project_number: 5R25CA203637-04
project_title: Training in Interprofessional Education for Palliative Care in Oncology
administering_ic: NCI
award_notice_date: 2020-03-25
opportunity_number: PAR-15-151
application_type: 5
activity_code: R25
ic: CA
serial_number: 203637
program_official: RADAEV, SERGEY
project_start_date: 2017-03-14
project_end_date: 2022-06-30
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 8126973
contact_pi: PFEIFER, MARK P
other_pis: HEAD, BARBARA A
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Excellent oncology care requires the close collaboration of numerous professionals. Extending andenhancing interdisciplinary care will require interprofessional education (IPE)for students which develops theirunderstanding of the strengths capabilities skills roles and cultures of other professionals and teaches thecommunication and collaboration skills essential for effective teamwork. Integration of palliative care is nowrecommended at the time of a cancer diagnosisregardless of prognosisand palliative care by its verynature requires interdisciplinary patient-centered care to meet the complex needs of oncology patients. Thisproject will develop a critical mass of competent equipped oncology educators skilled in the development andimplementation of IPE for palliative oncology care. Through faculty development webinars and materials atrain-the-trainer workshop ongoing educational activities and mentoring by experienced interprofessionaleducators 160 health science educators (representing the fields of medicine nursing social work andchaplaincy) from 35-50 institutions will develop the skills knowledge and resources to overcome barriers toIPE and teach oncology palliative care and teamwork to students of multiple disciplines. Guided by thisprojects faculty the trainees will work in interprofessional faculty teams to develop a plan for implementing anIPE curriculum in palliative oncology at their site. Trainee and institutional outcomes will be evaluated usingvalidated instruments and a pre/post-test design. A national summit on interdisciplinary palliative oncologyeducation will be held at the completion of the project; sites will share their experiences and other interestededucators will be invited to attend and present their own initiatives.

project_terms:
Accreditation;Address;Cancer Patient;Caring;Collaborations;Communication;Complex;Crowding;Development;Diagnosis;Discipline;Discipline of Nursing;Education;Educational Activities;Educational Curriculum;Educational workshop;Faculty;Future;Goals;Health Sciences;Infrastructure;Institution;Knowledge;Lead;Learning Skill;Length;Logistics;Malignant Neoplasms;Medicine;Mentors;Modeling;Nature;Nurses;Oncology;Outcome;Palliative Care;Patient Care;Patient-Centered Care;Patients;Physicians;Pre-Post Tests;Program Sustainability;Quality of life;Resources;Role;Site;Social Work;Social Workers;Students;Teacher Professional Development;Time;Trainers Training;Training;Training Programs;Work;base;cancer care;cancer diagnosis;cancer education;cancer palliative treatment;design;experience;health care service utilization;improved;instrument;interest;method development;outcome forecast;palliative;patient oriented;pedagogy;practice setting;programs;science teacher;skills;student training;success;symposium;webinar

public_health_relevance:
Project Narrative (Relevance)Excellent care of patients diagnosed with cancer requires the integration of palliative care and the closecollaboration of professionals from many disciplines including physicians nurses chaplains and socialworkers. Through faculty development webinars online modules and a train-the- trainer program this projectwill train 160 health science educators to provide interprofessional education in oncology palliative care at 35-50 institutions across the nation. As a result students of the health sciences at these institutions will learn theskills and knowledge essential for providing effective team-based patient-centered palliative oncology care.


application_id: 9881742
project_number: 3R21HD091118-02S1
administering_ic: NICHD
award_notice_date: 2019-08-29
opportunity_number: PA-18-591
application_type: 3
activity_code: R21
ic: HD
serial_number: 091118
suffix: S1
program_official: WALSH, MICHELE CATHERINE
project_start_date: 2019-09-01
project_end_date: 2022-01-31
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-09-01
project_title:
A Multiscale Multimodal Diffuse Optical Device for Early Detection of Preclinical Alzheimers Disease

project_abstract:
ABSTRACTPreclinical Alzheimers disease (pre-AD) is a newly defined stage of AD reflecting current evidence thatmeasurable biomarker changes in the brain may occur years before symptoms affecting memory thinking orbehavior can be detected. Current noninvasive and low-cost technologies/biomarkers for diagnosis of pre-ADare still being developed and not ready for use in general practice. Genetic studies have identified an associationbetween the presence of apolipoprotein 4 allele (APOE4) and the common form of AD. However the APOE4genotype alone is not a valuable biomarker for predicting AD because many without APOE4 will develop ADand many with APOE4 will not. Neuroimaging studies using fMRI and PET have shown that cognitively normalAPOE4 carriers develop cerebrovascular and metabolic alterations decades before any clinical symptoms occur.Thus these early cerebral functional alterations may serve as sensitive biomarkers for assessment ofpathological progress and therapeutic interventions for AD at early stage. Supported by an existing parent R21award that is not currently focused on AD we have developed a noninvasive low-cost wearable near-infrareddiffuse speckle contrast flow-oximetry (DSCFO) device for simultaneous measurements of cerebral blood flow(CBF) cerebral oxygen saturation (StO2) and cerebral oxidative metabolism (CMRO2) in newborn infants. In thissupplement application we propose to investigate DSCFO measurements of cerebrovascular and metabolicalterations as noninvasive and low-cost biomarkers for early diagnosis of pre-AD. We will conduct a randomizedcontrolled single-blinded (investigator) biomarker validation trial of DSCFO measurements of cerebralhemodynamic and metabolic alterations throughout a novel Bluegrass memory task in cognitively normal oldersubjects (65 yrs) with equal distributions of APOE4 carriers and noncarriers. Given its high temporal resolutionand quantitative multi-parameter outputs DSCFO is excellent for detecting dynamic alterations in cerebralhemodynamics and metabolism which are strongly related to early cerebrovascular and neurological problemsbefore developing AD and dementia. Thus we expect that the patterns of brain functional responses to memory-induced tasks quantified by DSCFO measurements of StO2 CBF and CMRO2 will differ in APOE4 carriers andnoncarriers. As subjects with AD generally suffer from multiple neurovascular problems multiple functionalparameters are expected to provide a more comprehensive assessment of neurovascular impairments than asingle parameter alone. If successful clinicians will have a low-cost continuous and wearable technology forcontinual and longitudinal monitoring of cerebral hemodynamics and metabolism potentially obviating theextensive use of expensive and cumbersome technologies such as fMRI and PET. This pilot study would enableus to acquire preliminary data for the application of larger funds with longer durations (e.g. R01) to supportvalidation of the noninvasive and low-cost optical biomarkers for screening classification and longitudinalmonitoring of progression and interventions in AD with a focus on the preclinical stage.

project_terms:
Administrative Supplement;Affect;Algorithms;Alleles;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Animals;Apolipoproteins;Behavior;Biological Markers;Blood;Brain;Brain scan;Cell Respiration;Cerebrovascular Circulation;Cerebrum;Classification;Clinic;Clinical;Cognitive;Conscious;Data;Data Analyses;Dementia;Devices;Diagnosis;Diagnostic;Diffuse;Disease;Early Diagnosis;Education;Elderly;Ensure;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;Forehead;Functional Magnetic Resonance Imaging;Funding;General Practices;Genetic study;Genotype;Grant;Guidelines;Head;Human;Impairment;Intervention;Kentucky;Lasers;Measurable;Measurement;Memory;Metabolic;Metabolism;Methods;Monitor;Mus;National Institute of Child Health and Human Development;Neurologic;Newborn Infant;Optics;Outcome;Output;Oxygen;Oxygen Consumption;Oxygen saturation measurement;Parents;Pathologic;Patients;Pattern;Pilot Projects;Poa plant;Positron-Emission Tomography;Randomized;Rattus;Research;Research Personnel;Resources;Rest;Rodent;Single-Blind Study;Source;Standardization;Symptoms;Techniques;Technology;Testing;Therapeutic Intervention;Thinking;Time;United States National Institutes of Health;Universities;Validation;Variant;abeta accumulation;age group;biomarker validation;cerebral hemodynamics;cerebrovascular;clinical practice;consumption measures;cost;detector;early detection biomarkers;flexibility;genetic risk factor;high risk;imaging modality;innovation;metabolic rate;mild cognitive impairment;miniaturize;multimodality;neonate;neuroimaging;neurovascular;novel;optical sensor;pre-clinical;predictive marker;response;screening;tau aggregation;temporal measurement;translational study;wearable technology

public_health_relevance:
PROJECT NARRATIVESince cerebrovascular and metabolic alterations are strongly associated with early neurovascular problemsyears before developing Alzheimers disease (AD) they may serve as sensitive biomarkers for screeningclassification and continual monitoring of progression and interventions in AD at the preclinical stage. Supportedby an existing parent R21 award that is not currently focused on AD we have developed a noninvasive low-cost wearable optical sensor for simultaneous measurements of cerebral blood flow oxygenation andmetabolism in newborn infants. In this supplement application we propose to investigate the use of thisinnovative technique for noninvasive measurements of cerebral hemodynamic and metabolic alterationsthroughout a memory-induced task as noninvasive and low-cost biomarkers for discriminating between a groupof cognitively normal older subjects (65 yrs) at higher risk for AD (APOE4 carriers) and a group ofage/education-matched control subjects at lower risk for AD (APOE4 noncarriers).


application_id: 9881258
project_number: 5R01CA205400-05
project_title: Distinct Redox Mechanism in Normal and Cancer Cells as a Novel Therapeutic Target
administering_ic: NCI
award_notice_date: 2020-03-04
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 205400
program_official: PRASANNA, PAT G
project_start_date: 2016-04-01
project_end_date: 2022-09-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ST CLAIR, WILLIAM H
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of male cancer deaths in the U.S. but it is the most frequently diagnosed cancer in men. Although current therapeutic radiation strategies are successful in treating the initial cancer there are fw effective therapeutic options for patients with aggressive prostate cancer. Addition of cytotoxic or hormone therapy offers some benefit but each is associated with unwanted side effects to normal tissues. The goal of this research project is to develop an anticancer regimen that improves the efficacy of radiation therapy by sensitizing tumor tissue to radiation while simultaneously protecting normal tissue against the side effects of radiation therapy. It addresses the critical gap in scientific knowledge of how the intrinsic differences in the redox conditions of normal and tumor cells trigger differential adaptive responses to prooxidants and demonstrates the outcome of the proposed approach in a preclinical setting with the expectation that changes in clinical practice could result. We propose that the differences in redox homeostasis in normal and cancer cells create a therapeutic window for pushing cancer cells towards oxidative stress overload and death while stimulating adaptive responses in normal cells to enhance survival. Our preliminary data show that dimethylaminoparthenolide (DMAPT) a lactone water soluble prodrug of parthenolide selectively sensitizes prostate cancer cells to ionizing radiation (IR) but protects normal prostate epithelial cells against IR-induced injury. W screened a library of 760 FDA-approved compounds for drugs that can radiosensitize tumor cells but radioprotect normal cells and identified betamethasone (BET) a steroid as a lead compound with these properties. Interestingly both DMAPT and BET exhibit opposing effects in normal vs cancer cells on RelB a member of the NF-B alternative pathway. These results are very important as they allow us to focus on testing a concept and pathway rather than on a specific agent.  This proposed study involves proof-of-concept studies in experimental animal models coupled with in-depth mechanistic molecular and cellular studies using DMAPT and BET. Aim 1 will test the concept that aberrant redox conditions of cancer cells enables a redox-based approach that enhances radiation therapy efficacy by sensitizing cancer cells to radiation treatment while protecting normal cells from the side effects of radiation therapy of prostate cancer. Aim 2 will test the hypothesis that RelB mediates the effect of DMAPT and BET in protecting normal cells but sensitizing prostate cancer cells to IR.  The results of this study wil facilitate the translation of novel radiation sensitizers for clinical use and will fill in critica gaps in scientific knowledge of how the differences in redox conditions of normal and tumor cells trigger differential responses to pro-oxidants. Translation of this paradigm-shifting concept will have a major impact on the efficacy and morbidity of radiation therapy.

project_terms:
Acute;Address;Affinity Chromatography;Amino Acids;Apoptosis;Autophagocytosis;Autopsy;Betamethasone;Biochemical;Biological Markers;Cancer Survivor;Cell Culture Techniques;Cell Line;Cells;Cessation of life;Clinical;Clinical Treatment;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Coupled;Couples;Cultured Cells;Cytotoxic Chemotherapy;Data;Development;Disulfides;Dose;Electron Spin Resonance Spectroscopy;Epithelial Cells;Exhibits;Experimental Animal Model;FDA approved;Family;Gene-Modified;Genetic Transcription;Goals;Histology;Homeostasis;In Vitro;Inflammatory;Ionizing radiation;Knowledge;Lactones;Lead;Libraries;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Mediator of activation protein;Messenger RNA;Methods;Modeling;Molecular;Molecular Biology;Morbidity - disease rate;Mus;Necrosis;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Outcome;Oxidation-Reduction;Oxidative Stress;PC3 cell line;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Primary Neoplasm;Prodrugs;Property;Prostate;Prostate Cancer therapy;Prostate carcinoma;Proteins;Proteomics;Quality of life;Radiation;Radiation Tolerance;Radiation exposure;Radiation therapy;Radiation-Sensitizing Agents;Radiodermatitis;Radiosensitization;Reactive Oxygen Species;Recurrence;Regimen;Research Project Grants;Role;Sesquiterpenes;Small Interfering RNA;Stable Isotope Labeling;Steroids;Sulfhydryl Compounds;Testing;Therapeutic;Tissues;Translations;Treatment Efficacy;Tumor Tissue;United States;Water;Work;advanced prostate cancer;anti-cancer;base;cancer cell;cancer diagnosis;clinical practice;cytotoxic;expectation;fractionated radiation;gene product;hormone refractory prostate cancer;hormone therapy;improved;in vivo;in vivo evaluation;in vivo imaging;luminescence;male;member;men;morphometry;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;parthenolide;personalized therapeutic;pre-clinical;prostate cancer cell;public health relevance;radiation resistance;radiation response;radiation-induced injury;response;side effect;tissue injury;treatment response;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This application will test a paradigm-shift concept for the development of novel therapeutic strategies that aim to increase radiation therapy efficacy while protecting normal tissue injury against the side effects of radiation therapy. We will test this concept by employing a lactone: dimethylaminoparthenolide which is in early stage clinical trials; and a steroid betametazone which is FDA approved for inflammatory related conditions. Results from these studies will lead to very concrete information potentially offering a specific course of action to improve radiation therapy efficacy and quality of life for cancer survivors.


application_id: 9881253
project_number: 5T32CA165990-08
project_title: Interdisciplinary Research Training in Cancer Biology
project_terms: Cancer Biology;Interdisciplinary Study;Research Training
administering_ic: NCI
award_notice_date: 2020-03-06
opportunity_number: PA-14-015
application_type: 5
activity_code: T32
ic: CA
serial_number: 165990
program_official: LIM, SUSAN E
project_start_date: 2012-04-01
project_end_date: 2022-03-31
study_section: Institutional Training and Education Study Section (F)[NCI(J1)-F]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: EVERS, BERNARD MARK
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: 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): Our interdisciplinary program will focus on training pre-doctoral students and post-doctoral fellows in cancer biology so they can effectively decipher important research questions associated with human cancer. We will accomplish this objective by integration of the already established and successful programs in Signal Transduction and Mechanisms of Cancer Cell Survival Cancer Progression and Metastasis Tumor Microenvironment Metabolomics and Oxidative Stress and DNA Damage with clinical exposure into one cohesive program. Trainees will receive both didactic and non-didactic instruction laboratory-based basic science research training in cancer research and cutting-edge clinical applications and career development as independent cancer biologists. To further their growth as important members of the scientific community students and fellows will receive ample training to articulate their ideas and communicate them effectively evaluate biomedical research and mentor others in scientific excellence.       This program assembles a cohesive group of basic science and clinical faculty from 8 departments at the College of Medicine. In the past 10 years our program faculty trained 89 doctoral students and 95 post-doctoral students; our faculty have the experience and interdisciplinary focus to guide this group of trainees to function in research teams pursuing multidisciplinary investigations. We mentor trainees to be proficient at utilizing hypothesis-drive approaches as well as discovery-oriented research design to address key problems. All trainees are required to complete foundation courses in graduate-level Genetics Biochemistry Immunology Pharmacology Physiology Cell Biology Molecular Biology Biostatistics Ethics and Cancer Signaling and Cancer Biology and Therapy which emphasize cancer in the context of human disease. Training also involves participation in the weekly Markey Cancer Center Seminars a monthly Metastasis Journal Club and a monthly Cancer Biology Journal Club. A unique feature of this program is the interdisciplinary training emphasizing bench to bedside (and vice versa) research topics to provide a bridge between the fundamental biology of cancer and clinical cancer. The ultimate objective is to develop a cadre of future scientists who can become leaders in integrative team approaches and understand the complex issue of cancer as it relates to potential prevention and treatment strategies. To help ensure our commitment to the clinical translation of basic science discoveries Markey Cancer Center Associate Director Vivek Rangnekar Ph.D. and Director B. Mark Evers M.D. will continue to be PIs for this team-based training program. The University of Kentucky places a significant emphasis on training minority students post-doctoral researchers and physicians and this program will continue to ensure the inclusion of individuals with under-represented racial and ethnic background to better serve our diverse society. Accordingly this training program will train the next generation of cancer researchers to better understand and treat cancers using an interdisciplinary team approach.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This multidisciplinary training program represents a team-approach involving multiple PIs to mentor pre- doctoral students and post-doctoral fellows in fundamental aspects of cancer biology translational science of cancer and therapeutics and prepare them as independent investigators who can become fully integrated in multidisciplinary cancer care teams.


application_id: 9881062
project_number: 3R01DC014468-04S1
project_title: AD supplement to In vivo patterns of receptor activation by odorants
administering_ic: NIDCD
award_notice_date: 2019-06-14
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: DC
serial_number: 014468
suffix: S1
program_official: SULLIVAN, SUSAN L
project_start_date: 2015-12-01
project_end_date: 2020-11-30
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:
PROJECT SUMMARY/ABSTRACTThe parent award for this administrative supplement request investigates the patterns of odorant receptorresponses evoked by odors and the cell and molecular biology of the olfactory sensory neurons that expressthese odorant receptors. Deficits in olfactory performance are an early symptom for many patients sufferingfrom Alzheimers Disease (AD) and AD patients typically show neuropathology in brain regions that processolfactory information including the loss of olfactory sensory neurons. This susceptibility of olfactory sensoryneurons to AD-related neurodegeneration is a fundamental reason they are advantageous models forinvestigating the onset and progression of AD-related neurodegeneration. Another fundamental reason is ourhighly detailed understanding of the biology of these neurons such as knowing the identity of all genes theyexpress. Other reasons include their accessibility for experimental manipulation their homogeneity and largepopulation size (>5 million per mouse) and the numerous genetically modified mouse strains that have beenmade to study these neurons. Investigating the onset of AD is critical given that therapies targeting late stagesof the disease have been unsuccessful. Olfactory sensory neurons are particularly well-suited for determiningthe onset and order of progression of events responsible for AD-related neurodegeneration. We propose to takeadvantage of our ongoing study of olfactory sensory neuron function to carefully and deeply investigatephenotypic changes in olfactory sensory neurons in two types of mouse models of AD. We expect to identifymajor events in the early stages of AD-related neurodegeneration and thereby demonstrate that olfactorysensory neurons are a powerful model for study of the onset of AD.

project_terms:
Abbreviations;Administrative Supplement;Affect;Age-Months;Alleles;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Amyloid beta-Protein Precursor;Apolipoprotein E;Award;Axon;Behavior;Biology;Bipolar Neuron;Brain;Brain Diseases;Brain region;Cellular biology;Cessation of life;Characteristics;Cholesterol;Dementia;Deoxyglucose;Deoxyuridine;Development;Disease;Electron Transport;Endoplasmic Reticulum Degradation Pathway;Event;Functional disorder;Gene Targeting;Genes;Glucose;Green Fluorescent Proteins;Human;Human Amyloid Precursor Protein;Intervention;Knowledge;Late Onset Alzheimer Disease;Life;Link;MAPT gene;Modeling;Molecular Biology;Mouse Strains;Mus;Nature;Nerve Degeneration;Neurofibrillary Tangles;Neuronal Dysfunction;Neurons;Odorant Receptors;Odors;Olfactory Pathways;Onset of illness;Oxygen Consumption;Parents;Patients;Pattern;Performance;Phenotype;Physiology;Population Sizes;Predisposition;Preventive measure;Process;Proteins;Receptor Activation;Risk;Senile Plaques;Smell Perception;Stem cells;Stimulus;Study models;Suggestion;Symptoms;Synapses;System;Tauopathies;Testing;Tetracyclines;Thinness;Trans-Activators;Transgenes;Tricarboxylic Acids;age related;apolipoprotein E-4;familial Alzheimer disease;human model;in vivo;mouse model;mutant;neuroinflammation;neuron loss;neuropathology;olfactory bulb;olfactory sensory neurons;promoter;relating to nervous system;response;targeted treatment

public_health_relevance:
NARRATIVEAlzheimers Disease (AD) is the most common type of dementia estimated to affect more than 5 million U.S.citizens and more than 25 million people worldwide. Therapies targeting late-stage AD neuropathology haveproven unsuccessful and lack of understanding of disease onset has hampered development of betterinterventions and preventive measures. This proposal describes the development and initial study of the onsetand progression of AD-related neurodegeneration in olfactory sensory neurons already known to besusceptible to AD and having numerous advantages for deeply investigating the changes in phenotyperesponsible for AD-related neurodegeneration.


application_id: 9880513
project_number: 3R01AG019223-13S1
project_title: The Interaction of Interleukin 1b and Glucocorticoid Signaling Pathways in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2019-06-06
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: AG
serial_number: 019223
suffix: S1
program_official: PEREZ MONTES, VIVIANA
project_start_date: 2002-08-01
project_end_date: 2023-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Affinity;Aging;Agonist;Alzheimer's Disease;Animals;Asses;Cause of Death;Cell Aging;Cell physiology;Cells;Ceramides;ChIP-seq;Chronic;Clinical;Complex;Diet;Disease;Dose;Drug Prescriptions;Elderly;Enzymes;FOXO1A gene;Fatty Liver;Funding;Gene Delivery;Gene Expression Regulation;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gluconeogenesis;Goals;Grant;Health;Hepatic;Hepatocyte;Histologic;Homeostasis;Hypersensitivity;IGFBP1 gene;IRAK1 gene;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Insulin Signaling Pathway;Interleukin-1 beta;Interleukins;Lead;Link;Liver;MAPK8 gene;Medical;Messenger RNA;Metabolic syndrome;Minor;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Organ;Organism;Oxidation-Reduction;Pain;Pathway interactions;Pattern;Pharmacology;Phosphorylation;Play;Population;Process;Progress Reports;Protein Phosphatase 2A Regulatory Subunit PR53;Public Health;Rattus;Receptor Signaling;Regulation;Research;Role;Series;Signal Pathway;Signal Transduction;Sphingomyelinase;Stress;Testing;Transcriptional Regulation;Trauma;Ubiquitination;Work;adenoviral-mediated;aged;experimental study;genome-wide;genome-wide analysis;in vivo;in vivo evaluation;insulin sensitivity;lipid biosynthesis;mouse model;non-alcoholic fatty liver disease;novel;novel strategies;response;senescence;side effect;stressor;transcription factor;transcriptome sequencing


application_id: 9880416
project_number: 5R01DA018151-16
project_title: Investigation of Neoclerodanes as Novel Opioid Ligands
administering_ic: NIDA
award_notice_date: 2020-02-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 018151
program_official: HILLERY, PAUL
project_start_date: 2019-08-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-MDCN-B(05)M]
contact_pi_person_id: 7842243
contact_pi: PRISINZANO, THOMAS EDWARD
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): Addiction to cocaine and methamphetamine highly addictive psychostimulants is associated with substantial neuropsychiatric co-morbidity and also enhances transmission of HIV-1 hepatitis B and C and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. Growing evidence shows that that  opioid (KOP) receptors (and their endogenous high-efficacy agonist neuropeptides the dynorphins) are involved in the modulation of major abuse-related effects of psychostimulants and particularly relapse. The plant-derived hallucinogen salvinorin A (a neoclerodane) from the mint Salvia divinorum is a structurally unique KOP-agonist. Reference KOP-r agonists and salvinorin A can decrease certain psychostimulant-induced effects but these desirable actions are accompanied by undesirable effects including the aforementioned hallucinations sedation and dysphoria/aversion. Selected novel semi-synthetic neoclerodanes from the previous period of this Project have potential as "lead" pharmacotherapeutic agents for psychostimulant addiction as shown by their in vitro and in vivo profiles in translational modelsincluding a reduced burden of undesirable behavioral effects. The central hypothesis of this proposal is that iterative structural modification of these neoclerodane "leads" will generate novel opioid receptor ligands with the potential to treat psychostimulant addiction relapse and co-morbid neuropsychiatric disorders. The Specific Aims of this proposal are (1) optimize the activity of novel neoclerodanes including innovative synthetic trans-decalin analogs at KOP receptors; (2) determine and optimize the in vivo activity of novel neoclerodanes as KOPr ligands in mice and for their ability to decrease cocaine-induced effects; and (3) determine and optimize the activity of novel neoclerodanes prioritized from Aims 1 and 2 in translational non- human primate models. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design synthesis evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically useful KOP-r targeted medications for the treatment of drug addiction.

project_terms:
Affinity;Agonist;Anxiety;Behavioral;Biological Assay;Biological Markers;Central Nervous System Diseases;Chemicals;Clinical;Cocaine;Development;Dose;Drug Addiction;Dynorphins;Effectiveness;Evaluation;FDA approved;Funding;Generations;Genus Mentha;Goals;HIV-1;Hallucinations;Hallucinogens;Health Care Costs;Hepatitis B;Hepatitis C;In Vitro;Investigation;Laboratories;Lead;Ligands;Literature;Mediating;Mental Depression;Methamphetamine;Modeling;Modification;Motor Activity;Mus;Neuropeptides;Neurosecretory Systems;Opioid;Opioid Receptor;Parents;Pharmaceutical Preparations;Pharmacology;Plants;Post-Traumatic Stress Disorders;Preparation;Progress Reports;Property;Psychostimulant dependence;Public Health;Relapse;Reporting;Research;Research Personnel;Rewards;Salvia;Sedation procedure;Signal Transduction;Structure;Terpenes;Testing;Toxic effect;Work;addiction;analog;base;comorbidity;decalin;design;dysphoria;experience;improved;in vivo;innovation;kappa opioid receptors;nanomolar;neoclerodane;neuropsychiatric disorder;neuropsychiatry;nonhuman primate;novel;pharmacophore;preference;psychostimulant;public health relevance;receptor;salvinorin A;stress related disorder;targeted treatment;translational model;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project seeks develop neoclerodane-derived  opioid (KOP) receptor ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse as well as neuropsychiatric disorders (including anxiety depression and stress-related disorders such as PTSD). The design synthesis and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically usefu opioid- targeted drugs for the treatment of drug addiction and major neuropsychiatric disorders.


application_id: 9878864
project_number: 5F30EY026792-04
administering_ic: NEI
award_notice_date: 2020-02-28
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: 2020-03-01
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;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;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 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;Visualization;area striata;autism spectrum disorder;experimental study;loss of function;mouse Cre recombinase;nerve supply;optogenetics;postnatal development;postsynaptic;response;retinal axon;retinal neuron;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.


application_id: 9878728
project_number: 5R01AG053585-04
project_title: Reversing Microvascular Dysfunction in Advancing Age
administering_ic: NIA
award_notice_date: 2020-02-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 053585
program_official: KERR, CANDACE L
project_start_date: 2017-03-01
project_end_date: 2022-02-28
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 8957618
contact_pi: LEBLANC, AMANDA JO
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Coronary blood flow (BF) reserve (or the ability of the small coronary vessels to increase BF inresponse to increased workload) declines in senescent animals and humans and may contribute in theincreased risk for cardiovascular disease (CVD) as a person ages. In addition to this baselinedeterioration of coronary microvascular function there are some distinct gender-related symptoms ofCVD that have gone untreated. As many as 50% of women referred for evaluation of myocardialischemia do not have obstructive coronary disease (like most men) but are frequently associated withcoronary microvascular dysfunction/ischemia. Unfortunately most traditional therapeutic treatments ofCVD and myocardial ischemia were designed to address symptoms displayed by a majority of men(with obstructive large coronary vessels) but these methods are not applicable to treating women withmicrovascular ischemia. To address the clinical need for an effective microvessel-targeted therapy wedeveloped an adipose-derived stromal vascular fraction (SVF) cell therapy and demonstrated that thecells improved the microvascular coronary blood flow (CBF) and vasoactivity in aged rats. Furthermorethe therapeutic use of SVF cells improves tissue perfusion independent of vessel density. Building onthis observation additional findings have determined that the intravenous (i.v.) delivery of autologousSVF cells reduced the resting tone of peripheral vasoactive arteries due to the injected SVF cellsspontaneously populating the walls of these arteries in a hydrogen-peroxide-dependent manner.Therefore we hypothesize that the i.v. delivery of freshly isolated adipose SVF cells will improve CBFin aged female rats by populating the walls of small coronary arteries/arterioles promoting vesselrelaxation. To test this we will use an aged female rat model combined with transgenic reporter-basedcell tracking and functional assessment approaches to determine if coronary microvascular dysfunctioncan be reversed through SVF cell injection (Aim 1) to determine the effect of SVF cell incorporation onvascular network function (Aim 2) and which cell population from the SVF is contributing to the reversalof coronary microvascular dysfunction (Aim 3). To date there a lack of cellular therapy designed totreat dysfunctional coronary microvessels as a result of advanced age and this particular autologouscellular therapy has high clinical potential with findings applicable to a broad array of othermicrovascular disorders. In addition we foresee our findings to have broad therapeutic relevance andprovide new insight into the dynamics of vessel wall homeostasis and microvascular disease.

project_terms:
Address;Adipocytes;Adipose tissue;Age;Aging;Animals;Arteries;Autologous;Blood Pressure;Blood Vessels;Blood flow;Cardiac;Cardiovascular Diseases;Catheters;Cell Fraction;Cell Therapy;Cell physiology;Cells;Clinical;Coronary;Coronary Arteriosclerosis;Coronary Vessels;Coronary artery;Coronary heart disease;Deterioration;Disease;Elderly;Endothelial Cells;Evaluation;Exhibits;Female;Functional disorder;Gender;Heart;Homeostasis;Human;Hydrogen Peroxide;ITGAM gene;Impairment;Individual;Injections;Intravenous;Ischemia;Mediating;Mediator of activation protein;Methods;Microspheres;Microvascular Dysfunction;Modeling;Molecular;Monitor;Mus;Muscle Tonus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Pathway interactions;Patient-Focused Outcomes;Perfusion;Peripheral;Persons;Pharmaceutical Preparations;Pharmacology;Population;Postmenopause;Publishing;Rattus;Reactive Oxygen Species;Regulation;Relaxation;Reporter;Rest;Role;Safety;Signal Transduction;Skin;Stromal Cells;Surface;Symptoms;Telemetry;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Transgenic Organisms;Trees;Tunica Adventitia;Ultrasonography;Vascular Diseases;Vascular Smooth Muscle;Woman;Workload;age related;aged;arteriole;base;cardiovascular disorder risk;cell type;coronary vasculature;density;design;effective therapy;experimental study;heart function;improved;improved outcome;in vivo;insight;intravital microscopy;juvenile animal;macrophage;macrovascular disease;men;molecular drug target;older men;older women;pressure;regenerative;repaired;response;senescence;targeted treatment;therapy design

public_health_relevance:
NarrativeTo date there are no known treatments to improve coronary microvascular dysfunction that occurs inadvancing age. The purpose of this study is to evaluate the safety and efficacy of a regenerative cell-based therapy to repair or restore coronary microvascular function potentially through theincorporation of injected regenerative cells into the vascular wall. This study will improve ourunderstanding of age-related cell therapy and the mechanism for which cell type in adipose tissuemediates vascular dysfunction reform upon incorporation.


application_id: 9878198
project_number: 1R21CA245560-01
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NCI
award_notice_date: 2019-12-06
opportunity_number: PAR-18-020
application_type: 1
activity_code: R21
ic: CA
serial_number: 245560
program_official: SOMMERS, CONNIE L
project_start_date: 2019-12-07
project_end_date: 2021-11-30
study_section: Special Emphasis Panel[ZCA1 SRB-A (O1)]
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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:
PROJECT SUMMARY/ABSTRACT Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy usingimmune checkpoint inhibitors (ICIs; e.g. anti-PD-1antibody) has revolutionized the treatment of metastatic lungcancer resulting in long-term complete responses for many patients. Nevertheless there remains an urgentneed for new strategies because not all patients respond to ICIs; moreover resistance can occur in those thatdo. Myeloid-derived suppressor cells (MDSCs) in particular monocytic MDSCs (M-MDSCs) are potentimmunosuppressive innate immune cells that actively inhibit CD8+ T cell tumor homing and activation. SinceM-MDSC levels are elevated in multiple human cancers and correlate with decreased patient survival wepostulate that these cells contribute to anti-PD-1 resistance. The purine nucleoside adenosine is produced incopious amounts within the tumor microenvironment (TME) where it serves to suppress the immune systemand promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediateresistance to ICIs. Immune suppressive adenosine is produced via the enzymatic conversion of extracellularAMP by the cell surface enzyme CD73 (ecto-5-nucleotidase; AMP  adenosine). Our preliminary studiesdemonstrate that tumor cell-derived prostaglandin E2 (PGE2) maintains M-MDSC suppressive activity in largepart by directly inducing cell surface CD73 expression leading to increased immune suppressive adenosinewithin the TME. The overall hypothesis of this proposal is that tumor cell-derived PGE2 dictates CD73expression in M-MDSCs leading to substantial increases in adenosine-dependent inhibition of anti-tumor CD8+T cell activation resulting ultimately in anti-PD-1 immunotherapeutic resistance. A major goal of this proposalis to test the anti-tumor efficacy of a novel cancer immunotherapy involving systemic administration ofadenosine deaminase (ADA)an enzyme that irreversibly converts adenosine into inosine a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA) is already FDA-approved foruse as an enzyme replacement therapy in children with severe combined immunodeficiency (ADA-SCID). Wehypothesize that depletion of adenosine-mediated T cell immune suppression by PEG-ADA sensitizes tumorsto PD-1 inhibitor therapy and improves clinical outcomes for NSCLC patients. To fulfill the stated objectivesthe following aims are proposed: 1) Investigate intra-tumoral M-MDSC functional maintenance in the context ofa PGE2  CD73+ M-MDSC  adenosine dependent pathway; 2) Determine if loss/inhibition of extracellularadenosine-dependent pathway attenuates anti-PD-1 resistance in mouse models of lung cancer; and 3)Validate PGE2  CD73+ M-MDSC  adenosine mediated anti-PD-1 resistance pathway in lung cancerpatients receiving pembrolizumab therapy. Our proposed study will provide important insights towardsdeveloping a safe and novel immunotherapy to attenuate ICI resistance in lung cancer patients.

project_terms:
5'-Nucleotidase;Ablation;Adenosine;Adopted;Advanced Malignant Neoplasm;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Model;Cancer Patient;Cattle;Cell physiology;Cell surface;Cells;Child;Clinical;Consumption;Data;Dinoprostone;Disease;Effectiveness;Enzymes;FDA approved;Frequencies;Generations;Goals;Health;Health Care Costs;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In complete remission;Inosine;Life;Lung Adenocarcinoma;Lung Neoplasms;Maintenance;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nucleosides;Outcome;PD-1 inhibitors;Pathway interactions;Patients;Pharmaceutical Preparations;Polyethylene Glycols;Production;Purine Nucleosides;Resistance;Scheme;Severe Combined Immunodeficiency;Signal Transduction;T cell response;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;Transgenic Model;Tumor Immunity;Tumor-Derived;adenosine deaminase;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer cell;cancer immunotherapy;clinically relevant;effector T cell;enzyme replacement therapy;extracellular;improved;inhibitor/antagonist;insight;monocyte;mouse model;neoplastic cell;novel;objective response rate;prevent;programmed cell death ligand 1;response;therapeutic target;therapy development;therapy resistant;tumor;tumor growth;tumor microenvironment

public_health_relevance:
Project NarrativeCancer immunotherapy using immune checkpoint inhibitors (ICIs) to target molecules that prevent the immunesystem from attacking cancer cells (e.g. anti-PD-1 antibody) has revolutionized the treatment of metastatic lungcancer resulting in long-term complete responses for many patients. Regardless of these encouraging resultsimmunotherapeutic resistance continues to occur in a significant proportion of patients. A critical determinant ofunresponsiveness in these patients is due to the intra-tumoral accumulation of adenosine which activelysuppresses the effectiveness of immunotherapies. In order to therapeutically deplete the intra-tumoraladenosine we have explored the use of an FDA approved drug [PEGylated]-Adenosine Deaminase (PEG-ADA). We propose to investigate if adenosine depletion with PEG-ADA therapy can induce anti-tumorimmunity and sensitize lung tumors to immunotherapy. Such a therapeutic strategy will reduce health carecosts and loss of life from a disease that is now a major health problem worldwide.


application_id: 9878126
project_number: 5R01HL141191-02
project_title: The role of bioactive lipids in CMC-induced myocardial repair.
administering_ic: NHLBI
award_notice_date: 2020-03-05
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141191
program_official: WONG, RENEE P
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11176762
contact_pi: WYSOCZYNSKI, MARCIN
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;Address;Affect;Arachidonate 5-Lipoxygenase;Cardiac;Cardiac Myocytes;Catheterization;Cell Therapy;Cells;Cellular Structures;Cessation of life;Coculture Techniques;Data;Disease;Echocardiography;Fibrosis;Genes;Genetic;Heart;Heart failure;Homeostasis;Immune;Immune response;Immune system;Immunohistochemistry;Immunosuppression;In Vitro;Infarction;Inflammation;Inflammatory Response;Injections;Kinetics;LTB4R gene;Left;Left Ventricular Function;Left ventricular structure;Leukotriene B4;Leukotrienes;Ligands;Link;Lipid Synthesis Pathway;Lipids;Lipoxygenase;Mass Spectrum Analysis;Mediating;Mesenchymal;Mus;Myocardial;Myocardial Infarction;Myocardium;Pathway interactions;Phenotype;Production;Property;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Regulation;Research Personnel;Role;Rupture;Severities;Sterility;Testing;Ventricular;angiogenesis;cyclooxygenase 1;cyclooxygenase 2;genetic manipulation;heart function;heart preservation;immunoregulation;improved;in vivo;in vivo Model;insight;knock-down;lipid metabolism;macrophage;monocyte;mouse model;novel;novel strategies;paracrine;preservation;programs;receptor;recruit;repaired


application_id: 9878117
project_number: 5P20GM125504-03
project_title: Modulation of respiratory melioidosis inflammation
administering_ic: NIGMS
award_notice_date: 2020-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8246
contact_pi_person_id: 10426217
contact_pi: WARAWA, JONATHAN MARK
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: 2020-03-01
budget_end_date: 2021-02-28
project_abstract:
Burkholderia pseudomallei (Bp) is an antibiotic resistant Select Agent bacterial pathogen and the causativeagent of the disease melioidosis with endemicity in tropical regions worldwide. Bp is infectious by several routesof entry into a host with inhalation representing an important route of entry and furthermore Bp exhibit a stronglung tropism regardless of the route of entry. Respiratory melioidosis is an acute inflammatory disease of thelung which progresses into a fatal systemic disease involving all major organs. Bp is a facultative intracellularpathogen which employs the Type 3 Secretion System cluster 3 (T3SS3) to mediate vacuolar escape of Bp fromphagocytes allowing for subsequent outgrowth of the bacteria in the host cytoplasm. Importantly the specifichost cells which support the intracellular lifestyle of Bp have not been well characterized.A critical gap in our understanding of Bp pathogenesis is the identification of which host cell types facilitate areplicative niche for Bp. Identification of these host environments will further provide key insights into which hostcells mount an inflammatory response against Bp. It is furthermore poorly understood as to whether the cytokinestorm mounted as a response to respiratory melioidosis contributes to morbidity as recent evidence suggeststhat excessive neutrophil recruitment is associated with reduced host survival. This suggests thatimmunomodulation of the innate immune response may represent an excellent method of providing noveltherapeutics for a disease which has no licensed vaccine and minimal treatment options due to inherentgenome-encoded antibiotic resistance. We provide preliminary data which demonstrate the therapeutic efficacyof inhaled slow-release IL-12 particles to provide full protection against a lethal Bp respiratory challengeOur central hypothesis is that the host innate immune response to lethal respiratory melioidosis is driven by apoorly-controlled intracellular bacterial proliferation where immunomodulation represents an effective method ofcombating disease. In Specific Aim 1 we will identify the replicative niche of Bp in the lung. We hypothesize thatspread of Bp to secondary phagocytes is the leading cause of sepsis/death associated with respiratorymelioidosis. In Specific Aim 2 we will determine the contribution of host innate immune cells to inflammation. Wehypothesize that the late-arriving myeloid component causes lethality via the inflammatory mediators theyproduce. In Specific Aim 3 we will determine the mechanism of microparticulate IL-12 therapeutic efficacy ofrespiratory melioidosis.Modification of the state of inflammation of respiratory melioidosis may provide effective control of disease byeither encouraging early clearance of pathogen through promoting early inflammation or by improving outcomethrough modulating late inflammation.

project_terms:
Acute;Antibiotic Resistance;Bacteria;Burkholderia pseudomallei;Cells;Cessation of life;Cytoplasm;Data;Disease;Environment;Exhibits;Genome;Immune;Inflammation;Inflammation Mediators;Inflammatory Response;Inhalation;Innate Immune Response;Interleukin-12;Life Style;Lung;Mediating;Melioidosis;Methods;Modification;Morbidity - disease rate;Myelogenous;Neutrophil Infiltration;Organ;Pathogenesis;Pathogenicity;Phagocytes;Route;Secondary to;Sepsis;Systemic disease;Treatment Efficacy;Tropism;Type III Secretion System Pathway;Vaccines;cell type;combat;cytokine release syndrome;disorder control;immunoregulation;improved outcome;inflammatory lung disease;insight;microbiome research;novel therapeutics;particle;pathogen;pathogenic bacteria;respiratory;response


application_id: 9878113
project_number: 5P20GM125504-03
project_title: Novel synthetic analogue of microbial metabolite Urolithin A mitigates inflammatory bowel diseases
administering_ic: NIGMS
award_notice_date: 2020-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8243
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
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: 2020-03-01
budget_end_date: 2021-02-28
project_abstract:
Project Summary/Abstract Inflammatory Bowel Diseases (IBDs) which include f ulcerative colitis and Crohns disease affect asmany as 1.4 million people in the USA. Chronic inflammation and microbial dysbiosis are major features of IBDs.Beneficial effects rendered by healthy dietary practices are not uniform among individuals and are attributed tovariations in gut microbiota and their active metabolites. To overcome the challenge of inter-individual differencesin gut microbiota their metabolites and poor bioavailability here we propose direct usage of microbialmetabolites to maintain gut immune homeostasis to mitigate IBDs. Urolithin A (UroA) is one of such beneficialmicrobial metabolite derived from ellagic acid and ellagitannins major polyphenolic components of berries andpomegranate. Based on UroA structure we developed novel potent structural analogue UAS03 which exhibitedincreased anti-inflammatory and gut barrier functional activities compared to parent UroA compound. Thecurrent proposal investigates the molecular and cellular mechanisms of UAS03 and its therapeutic efficacies inIBD pre-clinical models. Our preliminary results showed that the oral administration of UAS03 mitigated colitis in dextran sodiumsulphate (DSS)- or 246-Trinitrobenzenesulfonic acid (TNBS) induced murine colitis even at 10 fold lower dosecompared to UroA. UAS03 significantly inhibited lipopolysaccharide (LPS)-induced increase in inflammatorymediators in immune cells and epithelial cells with 10 fold higher efficacy than UroA. Further treatment withUAS03 reduced intestinal permeability by up-regulating junctional proteins through activation of nuclear factor(erythroid-derived 2)-like 2 (Nrf2)-hemoxygenase (HO1) pathways in epithelial cells. Based on these results wepropose two-pronged beneficial activities of UAS03 and UroA where these compounds protect the host fromexternal challenges by protecting gut barrier function and dampening inflammatory activities. In this proposal wewill test the hypothesis that treatment with UAS03 an effective analogue of a microbial metabolite protectsfrom IBD development by reducing barrier dysfunction and inflammation. In Aim 1 we will investigate howUSA03/UroA increase gut barrier function in a Nrf2-dependent manner by upregulating junctional proteins aswell as molecular events involved anti-inflammatory activities of UAS03. In Aim 2 therapeutic efficacies ofUAS03 and UroA will be examined in acute chronic and spontaneous IBD pre-clinical models. In Aim 3 wepropose to identify the bacteria responsible for UroA production and test their pro-biotic activities in colitis models.The successful completion of proposed studies will allow understanding of UAS03 and UroA mechanisms ofactions and establishes the basis for therapeutic usage in IBDs.

project_terms:
Acids;Acute;Affect;Anti-Inflammatory Agents;Bacteria;Benzopyrans;Berry;Biological;Biological Availability;Cells;Chemopreventive Agent;Chronic;Clinical;Colitis;Crohn's disease;Data;Development;Diet;Dietary Intervention;Dietary Practices;Disease;Disease model;Dose;Down-Regulation;Ellagi-Tannins;Ellagic Acid;Epithelial Attachment;Epithelial Cells;Erythroid;Event;Exhibits;Functional disorder;Glycols;Goals;Heme;Homeostasis;Human;Ileitis;Immune;In Vitro;Indigenous;Individual;Individual Differences;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Bowel Diseases;Interleukin-1;Interleukin-6;Intestinal permeability;Lipopolysaccharides;Measures;Mediating;Modeling;Molecular;Mus;Nuclear;Oral Administration;Oxygenases;Parents;Pathogenicity;Pathway interactions;Phenotype;Phytochemical;Pilot Projects;Pomegranate;Pre-Clinical Model;Probiotics;Production;Proteins;Risk;Role;Sampling;Sodium Dextran Sulfate;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic;Therapeutic Uses;Tight Junctions;Time;Treatment Efficacy;Trinitrobenzenesulfonic Acid;Ulcerative Colitis;Variant;Wild Type Mouse;analog;bacterial metabolism;base;chemokine;comparative efficacy;dysbiosis;gastrointestinal epithelium;gut bacteria;gut microbiota;in vivo;in vivo Model;inter-individual variation;microbial;microbiome research;microbiota metabolites;molecular targeted therapies;novel;preservation;protective effect


application_id: 9878110
project_number: 5P20GM125504-03
project_title: COBRE-Administrative Core
administering_ic: NIGMS
award_notice_date: 2020-02-20
opportunity_number: PAR-16-415
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
study_section: ZGM1-RCB-3
subproject_number: 8241
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD 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: 2020-03-01
budget_end_date: 2021-02-28
project_abstract:
The University of Louisville (UofL) COBRE in Functional Microbiomics Inflammation and Pathogenicitycomprises a multidisciplinary group of investigators addressing thematic aspects of microbiome inflammationand pathogenicity studies. The UofL is uniquely poised to investigate these problems in a coordinated andefficient fashion and the COBRE is horizontally integrated with a number of UofL funded initiatives and grantapplications in related areas. The departments of Oral Immunology and Infectious Diseases Microbiology andImmunology and Bioengineering all contribute to the cross-disciplinary nature of the center. These units haveestablished records of federal funding mentoring junior faculty graduate student training and collaborativeinteractions across campus. This application is led by well-qualified and well-funded Center Directors. There arefive outstanding PI-mentees with senior established funded mentoring teams. Our proposed COBRE will havea major positive impact on research throughout UofL and will help recruit and retain faculty. The germ freeanimal facility to be established will be one of only a few in the country. Many of the projects address chronicinflammatory diseases that occur at disproportionately high incidence in minority communities. Other projectsinvolving plague and melioidosis have national and international significance. The Administrative Core willprovide overall governance and will ensure that the COBRE projects and cores work together in a cohesive andcoordinated manner. All projects and cores will utilize the Administrative Core. The Specific Aims are: to providea formal governance structure to allow coordination direction and prioritization of activities including budgetissues ensuring the quality of all functions; to evaluate progress; to resolve any conflicts as they arise; to providea formalized process for mentoring junior faculty; to provide a mechanism to replace mentees as they becomeindependent; to provide a mechanism to replace any key individuals who may leave; to provide pilot funding forjunior faculty to ensure a pipeline of investigators; to provide biostatistical and bioimaging support; and todisseminate pertinent information resulting from the COBRE activities.

project_terms:
Acute;Address;Applications Grants;Area;Biological Warfare;Biomedical Engineering;Biometry;Bubonic Plague;Budgets;Burkholderia pseudomallei;Centers of Research Excellence;Communicable Diseases;Communities;Conflict (Psychology);Country;Disease;Disease Outcome;Ensure;Faculty;Funding;Germ-Free;Goals;Guidelines;Health;Human;Human Microbiome;Immunology;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Interdisciplinary Study;International;Location;Melioidosis;Mentors;Microbiology;Minority;Modality;Natural Immunity;Pathogenicity;Plague;Play;Population;Process;Records;Regulation;Research;Research Personnel;Role;Structure;Universities;Work;Yersinia pestis;animal facility;bioimaging;chronic inflammatory disease;cohesion;graduate student;host-microbe interactions;immune system function;microbiome;microbiome research;microbiota;minority communities;multidisciplinary;nature center;new technology;new therapeutic target;oral immunology;oral infection;pathogen;recruit;student training


application_id: 9878059
project_number: 5R25CA134283-09
project_title: University of Louisville Cancer Education Program
administering_ic: NCI
award_notice_date: 2020-03-18
opportunity_number: PAR-15-152
application_type: 5
activity_code: R25
ic: CA
serial_number: 134283
program_official: RADAEV, SERGEY
project_start_date: 2011-09-14
project_end_date: 2023-03-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: KIDD, LA CREIS RENEE
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:
Cancer incidence morbidity and mortality in the Commonwealth of Kentucky are among thehighest in the nation. The University of Louisville Cancer Education Program recruits andmotivates outstanding undergraduate and health professional students to pursue further trainingand careers in cancer research. The program consistently recruits the best and brightestundergraduate and health science professional students from the University of Louisville andprestigious universities across the country. An impressive number of University of Louisvillefaculty members among its many colleges and schools contribute to this program. The Universityof Louisville Cancer Education program has surpassed all of its five year goals. The renewalapplication proposes an aggressive plan to reach even higher goals over the next five years. Wepropose to accomplish the objectives described in our renewal proposal via completion of six aims1) Recruit outstanding health professional and undergraduate students including targetenrollment of students from groups underrepresented in cancer research; 2) Provide hands-onparticipation in cancer research through the development completion and presentation of cancerresearch projects under the mentorship of research-intensive faculty members of the JamesGraham Brown Cancer Center; 3) Enrich the student participation with professional developmentand cancer research training activities and research seminars; 4) Require student presentation oftheir cancer research project to faculty judges and fellow students at annual scientificconferences; 5) Motivate students to attend and present their cancer research project at regionaland national scientific meetings; and 6) Evaluate student recruitment participation satisfactionplacement and other student outcomes against explicit benchmarks.

project_terms:
Benchmarking;Cancer Center;Cancer Research Project;Country;Development;Enrollment;Faculty;Goals;Health Professional;Health Sciences;Incidence;Kentucky;Malignant Neoplasms;Mentorship;Morbidity - disease rate;Outcome;Research;Schools;Student recruitment;Students;Training;Training Activity;Underrepresented Groups;Universities;anticancer research;cancer education;career;college;meetings;member;mortality;programs;recruit;research and development;satisfaction;science teacher;student participation;symposium;undergraduate student;university student

public_health_relevance:
Project NarrativeCancer incidence morbidity and mortality in the Commonwealth of Kentucky are among thehighest in the nation. The objective of the University of Louisville Program Cancer EducationProgram is to recruit train and motivate outstanding undergraduate and professional studentsto engage and present an outstanding cancer research project and to pursue further trainingand careers in cancer research.


application_id: 9877445
project_number: 1R21AI149366-01
administering_ic: NIAID
award_notice_date: 2020-04-06
opportunity_number: PA-19-053
application_type: 1
activity_code: R21
ic: AI
serial_number: 149366
program_official: GU, XIN-XING
project_start_date: 2020-04-06
project_end_date: 2022-03-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (81)]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
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
budget_start_date: 2020-04-06
project_title:
Identification of the factors contributing to resistance of Group A Streptococcus to human group IIA secreted phospholipase A2

project_abstract:
Human Group IIA secreted phospholipase A2 (hGIIA) is a highly cationic small protein!important for the innate immune defense against Gram-positive bacteria. The enzyme traversesthe thick peptidoglycan layer of Gram-positive bacteria to reach the phospholipid membranewhere it catalyzes the hydrolysis of phosphatidylglycerol ultimately leading to bacterial deaththrough lysis. In comparison to other Gram-positive bacteria Group A Streptococcus (GAS) orStreptococcus pyogenes is remarkably resistant to hGIIA activity. GAS transposon libraryscreens designed to identify the genes that provide susceptibility/resistance to hGIIAuncovered a number of genes involved in biosynthesis and modification of Lancefield group Acarbohydrate (GAC) and lipoteichoic acid (LTA) two crucial cell envelope constituents of GAS.GAC is a rhamnose-containing glycopolymer covalently attached to peptidoglycan. Modificationof GAC with negatively charged glycerol phosphate as well as the absence of positively-chargedD-alanine modifications in LTA drastically compromise GAS survival when challenged withhGIIA. This project seeks to identify the functions of two previously uncharacterized proteinsidentified by an hGIIA sensitivity screen a putative GAC hydrolase GacM and a GT-C typemembrane glycosyltransferase PgtC. Additionally we uncovered a GT-A type membraneglycosyltrasferase PgtA that might participate together with PgtC in a protein glycosylationpathway in GAS. We will define the biological functions of these three proteins and their roles inantimicrobial resistance and virulence using a range of genetic biochemical and analyticalapproaches. Functional characterization of these novel targets will lead to an increasedunderstanding of how antimicrobial resistance is regulated in all Gram-positive bacteria and howresistance to antimicrobials is emerging among Gram-positive pathogens.

project_terms:
Acute;Affect;Affinity Chromatography;Alanine;Anabolism;Anti-Bacterial Agents;Antibiotics;Antimicrobial Resistance;Bacteria;Binding;Biochemical;Biological;Biological Process;Body Fluids;Carbohydrates;Cations;Cell Wall;Cell membrane;Cells;Cessation of life;Charge;Complex;Control Groups;Cytolysis;Data;Development;Divalent Cations;Enzymes;Eukaryota;Gene-Modified;Genes;Genetic;Glycerol;Glycopeptides;Glycoproteins;Glycoside Hydrolases;Goals;Gram-Positive Bacteria;Grouping;Histones;Human;Hydrolase;Hydrolysis;Immune;Infection;Inflammation;Ions;Lectin;Libraries;Mediating;Membrane;Modification;Muramidase;Outcome;Outcome Study;Pathway interactions;Penetration;Peptidoglycan;Permeability;Phase;Phosphatidylglycerols;Phospholipase A2;Phospholipids;Polysaccharides;Predisposition;Protein Family;Protein Glycosylation;Proteins;Proteome;Publishing;Regulation;Research Personnel;Resistance;Rhamnose;Role;Serological;Serum;Side;Skin;Stains;Streptococcal Infections;Streptococcus;Streptococcus Group B;Streptococcus pyogenes;Structure;Thick;Transcription Repressor;Transgenic Mice;Vaccine Design;Virulence;antimicrobial;antimicrobial peptide;base;cell envelope;cell type;design;extracellular;glycosylation;glycosyltransferase;human pathogen;improved;in vivo;inorganic phosphate;link protein;lipoteichoic acid;mouse model;mutant;neutrophil;novel;novel strategies;pathogen;resistance mechanism

public_health_relevance:
The goal of this project is to identify the functions of two enzymes that provide resistance ofGroup A Streptococcus (GAS) to Human Group IIA secreted phospholipase A2. Understandingthe resistance mechanisms used by GAS will allow developing the novel strategies against GASinfections.


application_id: 9876524
project_number: 1R61NS111081-01A1
project_title: Treatment of Lafora disease with an antibody-enzyme fusion
administering_ic: NINDS
award_notice_date: 2019-12-05
opportunity_number: PAR-18-761
application_type: 1
activity_code: R61
ic: NS
serial_number: 111081
suffix: A1
program_official: ROOF, REBECCA
project_start_date: 2019-12-15
project_end_date: 2022-11-30
study_section: Neurological Sciences and Disorders A Study Section[NSD-A]
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: PAULY, JAMES R
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Lafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with notreatment or cure. Over the last 15 years we and others have defined the molecular underpinnings of LD thatposition the field to cure this horrific disease. A hallmark of LD is cytosolic aberrant glycogen-like inclusionsknown as Lafora bodies (LBs) that accumulate in cells of most tissues including the brain. Like patients LDmouse models present with LBs and neurodegeneration. Reduced glycogen synthesis via genetic methodseliminates LB formation and rescues the neurological phenotype in LD mouse models. Thus a current focusin the field is to decrease LBs with the goal of treating LD. Valerion Therapeutics has engineered a cell delivery platform utilizing antibody fragments allowing theirantibody-enzyme fusions (AEFs) to deliver a protein into a myriad of cells. In collaboration with Valerion werecently identified therapeutic strategies to clear LBs. This involves use of a novel targeting functionalityfused to active LB-degrading amylases called VAL-0417 and VAL-1221. We have completed in vitro proof ofconcept experiments and found that VAL-0417 and VAL-1221 degrade LBs. Further in situ experimentsdemonstrate that they penetrate cells and they are active in cells. Strikingly we see thatintracerebroventricular (ICV) injection of VAL-0417 and VAL-1221 efficiently degrade LBs in LD mousemodels lowering total glucan levels of LD mouse brains to near WT levels. Pompe disease is a classical glycogen storage disease caused by lack of the lysosomal enzyme acid -glucosidase (GAA) that normally degrades glycogen. Valerion has completed pre-clinical studies with VAL-1221 and initiated a Phase 1/2 clinical trial. This trail involves IV administration of VAL-1221. However thecurrent VAL-1221 formulation is not suitable for human ICV injections. Therefore this proposal will:Specific Aims for the R61 phase of the grant (1 year)Specific Aim 1  Reformulate VAL-1221 for ICV delivery. A series of go/no-go studies will be performed tooptimize the activity and stability of VAL-1221. We will also determine the brain biodistributionpharmacokinetic (PK) and pharmacodynamic (PD) parameters of ICV VAL-1221.Specific Aims for the R33 phase of the grant (2 years)Specific Aim 2  Establish the optimal in vivo dosing strategy for ICV VAL-1221. We will perform a doseescalation study to determine the maximum tolerated dose of ICV VAL-1221 along with studies that willassess the duration and frequency of ICV VAL-1221 administration that most efficaciously improves glucanclearance from the brains of Laforin knockout mice that have extensive pathological load i.e. LBs. We are poised to perform the preclinical research required to translate this therapy into the clinic.Additionally VAL-1221 is a novel approach with potential beyond LD.

project_terms:
Adolescence;Affect;Age;Alpha-glucosidase;Amylases;Animal Diseases;Antibodies;Ataxia;Binding;Biochemical;Biodistribution;Brain;Cells;Cessation of life;Chemicals;Child;Clinic;Collaborations;Convulsions;Data;Dementia;Development;Diagnosis;Disease;Disease Progression;Disease model;Dose;Drug Kinetics;Drug Targeting;Engineering;Enzymes;Epilepsy;Etiology;Formulation;Frequencies;Genes;Genetic;Glucan 14-alpha-Glucosidase;Glucans;Glycogen;Glycogen Storage Disease;Glycogen storage disease type II;Goals;Grant;Half-Life;Human;Immunoglobulin Fragments;Impaired cognition;In Situ;In Vitro;Incidence;Inclusion Bodies;Infusion procedures;Injections;Intractable Epilepsy;Kentucky;Knockout Mice;Lafora Disease;Left;Legal patent;Life;Maximum Tolerated Dose;Medicine;Methods;Molecular;Mus;Mutation;Myoclonic Epilepsies;Myoclonus;Nerve Degeneration;Neurologic;Outcome;Pancreas;Pathologic;Patient-Focused Outcomes;Patients;Periodic acid Schiff stain method;Pharmacodynamics;Phase;Phase I/II Clinical Trial;Phase I/II Trial;Phenotype;Phosphoric Monoester Hydrolases;Physicians;Positioning Attribute;Proteins;Pulmonary Inflammation;Rare Diseases;Research;Safety;Scientist;Seizures;Series;Status Epilepticus;Symptoms;Technology;Teenagers;Therapeutic;Tissues;Translating;Treatment Efficacy;Universities;Vegetative States;Vision;Work;alpha-amylase;childhood epilepsy;clinical translation;drug development;drug discovery;experimental study;glucosidase;glycogen metabolism;immunogenicity;improved;in vivo;interest;liquid formulation;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;pharmacokinetics and pharmacodynamics;pre-clinical research;preclinical safety;preclinical study;side effect;therapy development;ubiquitin-protein ligase;uptake

public_health_relevance:
Lafora disease (LD) is a catastrophic epilepsy that strikes healthy teenagers and leads to constant ever-worsening seizures until it results in death after 10 years. The collaboration in this proposal brings togetherscientists at the University of Kentucky and Valerion Therapeutics that have identified a cure for LD in mousemodels. Our vision is that one day a physician having diagnosed a child with this horrendous epilepsy wouldhave the medicines and technologies to stop the disease in its tracks so that the child is able to resumedevelopment and life a healthy and normal life.!


application_id: 9873166
project_number: 1R03AI148828-01
project_title: Examination C. pneumoniae-specific Incs by employing C. trachomatis L2 genetic tools
administering_ic: NIAID
award_notice_date: 2020-02-06
opportunity_number: PA-19-052
application_type: 1
activity_code: R03
ic: AI
serial_number: 148828
program_official: VINCENT, LEAH REBECCA
project_start_date: 2020-02-06
project_end_date: 2022-01-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 9776107
contact_pi: WOLF, KATERINA
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:
AbstractMembers of the genus Chlamydia are Gram-negative bacteria that cause various acute as wellas chronic diseases in humans. Although chlamydiae share numerous aspects of their typicalbacterial life style such as intracellular developmental cycle and the preference to primarilyinvade epithelial cells these human pathogens employ sophisticated species-specific strategiescontributing to an extraordinary diversity in tissue tropism and disease manifestation. C.trachomatis infects mucosal surfaces of the human urogenital tract or columnar epithelial cellsof the eye. Chlamydia-mediated genital infections represent the leading cause of bacterial STDsin the United States with 1708569 infections reported to the CDC in 2017. C. pneumoniaeinfects mucosal surfaces of the human respiratory tract causing pneumonia bronchitispharyngitis and sinusitis. Epidemiological data suggest that most people are infected andreinfected throughout life. Infections with both chlamydial species can often lead to thedevelopment of various chronic diseases. Genome sequencing of several members of thegenus Chlamydia revealed that there are only a few C. trachomatis genes with no homologs inthe genome of C. pneumoniae whilst C. pneumoniae contains ~200 genes not found in C.trachomatis. It is highly likely that those genes unique to C. pneumoniae significantly contributeto the particular tissue tropism of this organism. In this grant we propose to utilize C.trachomatis L2 as a surrogate microorganism together with recently developed approaches forgenetic manipulation of this chlamydial species in investigating unique host-cell interactions ofthree C. pneumoniae-specific inclusion membrane proteins (Incs). Initially we would focus onCP0641 CP0401 and CP0707 putative Incs because our preliminary data demonstrated that adomain(s) of each proposed Inc is exposed to the eukaryotic host cytoplasm. Due to theunavailability of reliable genetic manipulation tools for generating mutations in C. pneumonaieemploying C. trachomatis L2 as a surrogate microorganism may prove useful for studying notonly C. pneumonaie-specific genes but also genes from other chlamydial species.

project_terms:
Acute;Alzheimer's Disease;Animal Model;Asthma;Atherosclerosis;Biotinylation;Bronchitis;Cell Communication;Cells;Centers for Disease Control and Prevention (U.S.);Chimeric Proteins;Chlamydia;Chlamydia trachomatis;Chlamydiaceae;Chlamydophila pneumoniae;Chronic Disease;Chronic Obstructive Airway Disease;Columnar Epithelium;Communities;Complex;Cytoplasm;Data;Detection;Development;Disease;Endometritis;Epithelial Cells;Eukaryotic Cell;Exposure to;Eye;Family;Genes;Genetic;Genome;Goals;Gram-Negative Bacteria;Grant;Human;Immune Sera;Infection;Invaded;Investigation;Label;Laboratories;Lead;Life;Life Style;Mass Spectrum Analysis;Mediating;Medical;Membrane;Membrane Proteins;Mucous Membrane;Multiple Sclerosis;Mutation;Organ;Organism;Oryctolagus cuniculus;Pelvic Inflammatory Disease;Peroxidases;Pharyngitis;Play;Pneumonia;Protein Analysis;Proteins;Reiter Disease;Reporting;Reproducibility;Respiratory System;Role;Salpingitis;Sarcoidosis;Sinusitis;Streptavidin;Subcellular structure;Surface;System;Tetracyclines;Tissues;United States;Woman;Work;Yeasts;acute infection;comparative;epidemiologic data;genetic approach;genetic manipulation;genital infection;genome sequencing;human pathogen;hydrophilicity;member;microorganism;mutant;novel strategies;pathogen;pathogenic bacteria;preference;promoter;tissue tropism;tool;urogenital tract;vector;yeast two hybrid system

public_health_relevance:
PROJECT NARRATIVE (RELEVANCE)Organisms of the family Chlamydiaceae include significant human pathogens C. pneumoniaeand C. trachomatis. In this proposal we intend to utilize recently developed genetic manipulationapproaches for C. trachomatis L2 in investigation of C. pneumonaie-specific Incs where C.trachomatis L2 will be employed as a surrogate organism for identification and characterizationof eukaryotic target molecules interacting with CP0401 CP0641 and CP0707 putative Incs.


application_id: 9872960
project_number: 5R01AG034389-11
project_title: Function of ceramide in neurodegenerative disease
administering_ic: NIA
award_notice_date: 2020-02-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 034389
program_official: YANG, AUSTIN JYAN-YU
project_start_date: 2010-09-01
project_end_date: 2022-02-28
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by progressive neurodegeneration and build-up of A peptides amyloid plaques and neurofibrillary tau tangles. Current strategies to prevent A formation or secretion are not successful. Preventing A build-up while enhancing A uptake and clearance is an alternative approach to minimize the effect of A peptides. A critical barrier to progress in the development of novel drugs that prevent A build-up and improve clearance is the lack of a thorough understanding of how A amyloid plaques are nucleated and proliferate instead of A being taken up and cleared by glial cells. Our goal is to interrupt amyloid plaque nucleation and propagation to enhance A clearance and delay the onset and reduce neurodegeneration in AD. Our central hypothesis is that ceramide-enriched exosomes secreted by astrocytes form complexes with A (A/Exos) that function as "seeds" to catalyze nucleation and propagation of neurotoxic plaques instead of facilitating A transport and clearance by microglia. Secretion aggregation and neurotoxicity of A/Exos is enhanced by elevation of ceramide levels in particular by neutral sphingomyelinase 2 (nSMase2) an enzyme generating ceramide when activated by A. Drug (e.g. nSMase2 inhibitor)-induced reduction of ceramide will prevent A/Exo build-up/spreading and protect neurons which is a novel treatment option for AD. Our objectives are to 1) test key regulatory factors that control secretion of exosomes and their association with A; 2) test a novel molecular mechanism by which A/Exos induce plaque formation tau hyperphosphorylation and neuronal cell death; 3) test pharmacological drugs that prevent exosome secretion A/Exo-induced plaque formation tau hyperphosphorylation and neuronal cell death in vitro and in vivo; and 4) test if A/Exos in serum and cerebrospinal fluid from AD model mice and AD patients can be used as a novel diagnostic tool for monitoring plaque and tangle build-up and treatment success. Our expected outcomes include 1) determining an exosome composition that induces association with A plaque nucleation and propagation tau hyperphosphorylation and neuronal cell death; 2) identifying ceramide- modulating drugs that prevent A/Exo-induced plaque formation tau hyperphosphorylation and neuronal cell death; and 3) defining a level of A/Exos in serum that indicates severity of AD and success of treatment. The impact of this project on public health will include knowledge needed for the development of new strategies and treatments that could delay and reduce the onset of progressive neurodegeneration in AD. We will test by which mechanism ceramide promotes association and aggregation of A42 (Aim 1) how A42/Exos induce plaque formation and neurodegeneration (Aim 2) and which treatment prevents exosome-induced amyloid aggregation plaque formation and AD pathology (Aim 3).

project_terms:
Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Apoptosis;Apoptotic;Astrocytes;Behavior;Binding;Brain;Ceramides;Cerebrospinal Fluid;Cholesterol;Complex;Development;Disease Progression;Enzymes;Genetic;Goals;Impaired cognition;In Vitro;Interruption;Knowledge;Lipids;Mediating;Microglia;Molecular;Monitor;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Neurons;Outcome;PAWR protein;Peptides;Pharmaceutical Preparations;Pharmacology;Proliferating;Prostate;Public Health;Seeds;Senile Plaques;Serum;Severities;Sphingomyelinase;Testing;Vesicle;amyloid peptide;exosome;improved;in vivo;inhibitor/antagonist;mouse model;neurofibrillary tangle formation;neuron loss;neurotoxic;neurotoxicity;novel;novel diagnostics;novel marker;novel therapeutics;prevent;progressive neurodegeneration;public health relevance;response;small molecule;success;tau Proteins;tau aggregation;tau phosphorylation;tool;treatment strategy;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Development of novel drugs to treat Alzheimer's disease (AD) by preventing amyloid plaque formation and neurodegeneration is being impeded by lack of knowledge of how neurotoxic plaques are nucleated and propagated. Our goal is to interrupt amyloid plaque nucleation and propagation to enhance amyloid peptide clearance and delay the onset and reduce neurodegeneration in AD. The impact of this project on public health will include knowledge needed for the development of new strategies and treatments that could delay and/or reduce the onset of progressive neurodegeneration in Alzheimer's disease.


application_id: 9872210
project_number: 5R01NS101105-04
project_title: Promoting and understanding recovery of breathing after chronic spinal cord injury
administering_ic: NINDS
award_notice_date: 2020-02-19
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 101105
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-03-15
project_end_date: 2022-02-28
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8838438
contact_pi: ALILAIN, WARREN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT More than 50% of all spinal cord injuries occur at the cervical level. At this level are the phrenic motorneurons which innervate the diaphragm. Therefore injuries at this level can lead to the inability to breathe.The overall objective of this grant proposal is to examine the changes which take place chronically in thephrenic circuitry of the cord in response to cervical spinal cord injury and investigate and optimize potentialtherapies that can restore breathing long after injury. Through these studies an effective intervention can betranslated to a significant population of the spinal cord injured community. In this proposal we will utilizechronic cervical spinal cord-hemisected animals which have half of the diaphragm paralyzed. In our earlierstudies we observed that enzymatic (chondroitinase ABC) removal of extracellular matrix molecules calledchondroitin sulfate proteoglycans which block plasticity regeneration and sprouting led to restoration offunction of the once paralyzed hemidiaphragm when administered at or near the time of injury. Recovereddiaphragmatic activity was rhythmic and synchronized. In stark contrast when the spinal cord of chronicallyinjured animals was stimulated with chondroitinase ABC and intermittent hypoxia training chaotic andunstructured activity resulted suggesting slowly developing and potentially maladaptive responses to injury.However the use of chondroitinase alone at chronic stages can promote normal rhythm and dramaticallyenhance properly patterned functional recovery. This grant proposal seeks to: 1) understand the time courseand carefully describe the maladaptive processes that take place; 2) understand the mechanisms underlyingthe production of this newly discovered atypical activity at chronic time points; and 3) learn how to overcomethese negative responses to injury so that interventions and rehabilitative strategies can become moreeffective thereby leading to improved functional outcomes. Overall these studies will provide insight on thebasic mechanisms that underlie maladaptive as well as functionally beneficial plasticity that can lead to robustfunctional respiratory motor recovery at chronic stages of spinal cord injury.

project_terms:
Acute;Americas;Anatomy;Animals;Applications Grants;Behavior;Breathing;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chondroitin ABC Lyase;Chondroitin Sulfate Proteoglycan;Chondroitinases;Chronic;Communities;Equilibrium;Excision;Extracellular Matrix;Health Care Costs;Hypersensitivity;Hypoxia;Injury;Intervention;Investigation;Knowledge;Lead;Learning;Length;Measures;Mechanical Ventilators;Mediating;Modeling;Motor;Motor Activity;Motor Neurons;Natural regeneration;Paralysed;Patients;Pattern;Periodicity;Play;Population;Positioning Attribute;Process;Production;Quality of life;Recovery;Recovery of Function;Regimen;Rehabilitation therapy;Research;Respiratory Diaphragm;Role;Saline;Serotonin;Spinal Cord;Spinal cord injury;Subgroup;Testing;Therapeutic Intervention;Time;Training;Translating;United States;Work;effective intervention;experimental study;functional outcomes;health management;improved;inhibitor/antagonist;injured;insight;motor recovery;motor rehabilitation;neurotransmission;novel therapeutics;optimal treatments;preservation;prevent;receptor;rehabilitation strategy;respiratory;response;response to injury;restoration;serotonin receptor;side effect;success

public_health_relevance:
PROJECT NARRATIVEPublic Relevance: There are near 260000 people in the United States of America that have a spinal cord injury with atleast 12000 new cases each year and more than half of all those injuries are at the cervical level which canresult in the patient's inability to breathe. Extreme measures such as the use of mechanical ventilators areoften needed to enable them to survive leading to millions of dollars in health care costs and a decreasedquality of life. The main objective of this grant proposal is to investigate and optimize novel therapies that canrestore the ability to breathe and improve functional outcomes in chronic cases of cervical spinal cord injury.


application_id: 9872133
project_number: 5R01CA207772-04
project_title: Roles of Hsp47 in breast cancer progression
administering_ic: NCI
award_notice_date: 2020-02-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 207772
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2022-02-28
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Despite recent advance in early diagnosis and adjuvant therapy treatment of triple negative breastcancer (TNBC) remains a significant challenge because of the high incidence of metastasis and relapse aftertreatment. Signaling from extracellular matrix (ECM) an essential component of the tumor microenvironmentis required for TNBC progression and metastasis. However it is not known how cancer cell-deposited ECMproteins and ECM signaling in cancer cells are regulated and promote TNBC metastasis/relapse. We recentlyidentified Hsp47 as a hub of the ECM transcription network. Hsp47 is a molecular chaperon that regulatessecretion and deposition of ECM proteins. Increased Hsp47 expression has been detected in TNBC and isassociated with cancer metastasis. Silencing Hsp47 restrains the aggressive phenotype of TNBC cells in 3Dculture and inhibits tumor growth and lung colonization in the xenograft model indicating that increased Hsp47expression is crucial for the TNBC progression. EMT promotes cancer progression by enhancing cancer celldissemination and endowing cancer cells with stemness properties that favor successful colonization indistant organs and contribute to chemoresistance. Platelet adhesion and activation are required for cancer cellcolonization at the distal sites. We found that silencing Hsp47 in metastatic breast cancer cells significantlyreduced platelet adhesion. These results suggest that Hsp47 promotes TNBC metastasis/relapse by inducingEMT and platelet recruitment. In Aim 1 we will investigate the molecular mechanism by which Hsp47 regulatesEMT and stemness properties. In Aim 2 we will determine the cellular mechanism by which Hsp47 promotescolonization of breast cancer cells at the secondary organs. In Aim 3 we will define the roles of Hsp47 inpromoting cancer metastasis and chemoresistance in TNBC. This investigation will change the currentconcept of ECM microenvironment in cancer metastasis by revealing new roles of cancer cell-derived collagenin inducing cancer cell-platelet interaction and metastasis. Characterization of Hsp47 as a hub ofcollagen/DDR2 signaling will identify a novel pathway to inhibit TNBC progression and chemoresistance.

project_terms:
Adhesions;Adjuvant Therapy;Aftercare;Binding;Biology;Blood Circulation;Blood Platelets;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Breast cancer metastasis;Cancer Relapse;Cell Survival;Cells;Clinical;Coculture Techniques;Collagen;Collagen Receptors;Deposition;Development;Disseminated Malignant Neoplasm;Distal;Distant;Early Diagnosis;Epithelial;Epithelium;Event;Extracellular Matrix;Extracellular Matrix Proteins;Extravasation;Gene Silencing;Genetic Transcription;Growth;Human;Incidence;Investigation;Knowledge;Lung;Mesenchymal;Metastatic breast cancer;Microfluidics;Migration Assay;Modeling;Molecular;Molecular Chaperones;Mus;Neoplasm Metastasis;Oncogenes;Organ;Pathologist;Pathway interactions;Phenotype;Platelet Activation;Positioning Attribute;Production;Prognostic Marker;Property;Proteins;Proteomics;Regulation;Relapse;Research;Role;Signal Transduction;Site;Stromal Cells;System;Techniques;Testing;Tissue Microarray;Tumor Tissue;Up-Regulation;Xenograft Model;base;breast cancer progression;cancer cell;carcinogenesis;chemotherapeutic agent;chemotherapy;discoidin domain receptor 2;experimental study;imaging system;in vivo;loss of function;lung colonization;malignant breast neoplasm;multidisciplinary;nano;novel;outcome forecast;protein expression;recruit;self-renewal;stemness;therapeutic target;three dimensional cell culture;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor microenvironment;tumor progression

public_health_relevance:
Defining roles of Hsp47 and collagen signaling in regulating platelet recruitment and cell plasticity will fill criticalgaps in our knowledge of the tumor microenvironment and cancer metastasis. The study of Hsp47 in regulatingDDR2 will identify a novel pathway regulating oncogene DDR2 and may characterize a potential strategy tosensitize TNBC to chemotherapy.


application_id: 9872023
project_number: 5F31HD096790-02
administering_ic: NICHD
award_notice_date: 2020-03-04
opportunity_number: PA-18-671
application_type: 5
activity_code: F31
ic: HD
serial_number: 096790
program_official: GRIFFIN, JAMES
project_start_date: 2019-02-03
project_end_date: 2020-08-01
study_section: Special Emphasis Panel[ZRG1-F02A-K(20)L]
contact_pi_person_id: 14376392
contact_pi: WHITE, HANNAH B
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: 2020-02-03
project_title:
The Role of Socioeconomic Status Cortisol and the Home Environment in the Development of Infants' Attentional Control

project_abstract:
The negative impacts of economic stress on infants' development persist across the lifespan (Melrose et al.2014). As such understanding how early deficits pertaining to socioeconomic status (SES) emerge and whatprocesses potentially underlie the development of such deficits is a critical step toward the creation of efficientand effective intervention programs. It has been proposed that negative outcomes related to lower-SES orpoverty are mediated by deficits in effortful control and a model has been proposed suggesting that the linkbetween SES and effortful control is mediated by allostatic load through processes such as a dysregulation ofthe hypothalamic-pituitary-adrenal axis resulting in maladaptive elevations in cortisol levels (Lengua 2012).While the importance of effortful control is not contested and the link between low-SES and decreasedeffortful control is well established the mediating effect of cortisol on the link between low-SES and anycognitive outcomes is severely lacking in direct empirical support (Piccolo et al. 2014) and the full model hasnever been tested as it relates to effortful control specifically. Additionally to my knowledge no study hasexamined this model or even components of this model within the first six months of life. This is surprisinggiven that cognitive outcomes pertaining to attentional control an early developing component of effortfulcontrol are significantly associated with SES by 6 months of age (Clearfield & Jedd 2013). Thus the currentinvestigation seeks to advance the field's understanding of the emergence of SES related cognitive deficits byfollowing infants at 3.5 5 and 6.5 months of age and examining their attentional control capabilities in thecontext of their SES and basal cortisol levels. Furthermore to establish a more complete picture of thedevelopmental context of these infants data about the stability of the home environment will be collected.Previous research has demonstrated significant mediating effects of factors of the home on the associationbetween SES and infant cognitive abilities (Rubio-Codina Attanasio Grantham-McGregor 2016). Accordinglyfactors of the home environment specifically chaos and adherence to routines will be examined as potentialmediators of the link between SES and basal cortisol levels. Given the fact that decreased effortful control isassociated with poorer coping strategies in the context of economic stress in adolescence (Taylor Widaman &Robins 2017) this project has the potential to greatly increase the mental health outcomes of economicallydisadvantaged youth by determining when and how such deficits emerge. This project would also be a greattraining opportunity as it would foster the development of an interdisciplinary research program incorporatingphysiological behavioral and environmental measures. This will be accomplished through supplementing myresearch skills and interdisciplinary background with 1) in-depth instruction and hands on experience with thecollection and analysis of physiological data 2) extensive training in longitudinal data collection and advancedstatistical methods 3) continued mentorship and explicit multi-faceted instruction in research ethics.

project_terms:
Adherence;Adolescence;Adolescent;Adult;Age;Age-Months;Attention;Behavioral;Child;Cognitive;Cognitive deficits;Collection;Data;Data Collection;Development;Economically Deprived Population;Economics;Environment;Family;Fostering;Future;Home environment;Hydrocortisone;Impaired cognition;Infant;Infant Development;Instruction;Interdisciplinary Study;Intervention;Investigation;Knowledge;Life;Link;Longevity;Low income;Measures;Mediating;Mediator of activation protein;Mental Health;Mentorship;Modeling;Outcome;Performance;Physiological;Poverty;Prevention;Process;Regulation;Reporting;Research;Research Ethics;Research Personnel;Rest;Role;Sampling;Socioeconomic Status;Source;Statistical Methods;Stress;Techniques;Testing;Time;Training;Youth;allostatic load;attentional control;cognitive ability;cognitive task;coping;economic impact;effective intervention;executive function;experience;hypothalamic-pituitary-adrenal axis;indexing;intervention program;low socioeconomic status;mental development;peer;programs;response;skills;social;thought control;tool;training opportunity

public_health_relevance:
The proposed investigation seeks to advance our understanding of the emergence of and potential interveningprocesses leading to socioeconomic status (SES) related cognitive deficits by following infants at 3.5 5 and 6.5months of age and examining their attentional control capabilities in the context of their SES and basal cortisollevels. Furthermore to examine a potential source of infants' stress factors of home the home environmentpertaining to stability will be examined as a mediator of the link between SES and basal cortisol levels. Inaddition to the clear implications for interventions seeking to better the social academic and mental healthoutcomes of economically disadvantaged youth this project would also serve as an invaluable training tool as itwould foster the development of an interdisciplinary research program incorporating physiological behavioraland environmental measures and advanced statistical techniques.


application_id: 9872018
project_number: 5R01AR070313-04
project_title: Macrophage phenotype orchestrates mammalian tissue regeneration
administering_ic: NIAMS
award_notice_date: 2020-02-20
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 070313
program_official: BELKIN, ALEXEY
project_start_date: 2017-03-13
project_end_date: 2022-02-28
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 10345749
contact_pi: SEIFERT, ASHLEY WINN
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT/PROJECT SUMMARYDespite clinical advances the fact remains that humans cannot regenerate injured tissue. Instead tissuetrauma stimulates inflammation which in turn induces fibrosis and ultimately the formation of scar tissue.Trauma-induced inflammation is primarily regulated by macrophages; key regulators of fibrosis. Althoughcurrent therapies to control human fibrotic diseases include agents that target macrophages new data indicatethese treatments negatively impact regenerative ability. This outcome results from our lack of knowledge abouthow macrophages regulate endogenous tissue regeneration. A mammalian model of tissue regeneration isnecessary to directly study how macrophages regulate the injury response to fill this knowledge gap. Thediscovery that African spiny mice (Acomys) can regenerate complex tissues of the external ear including skinhair follicles nerves muscle and cartilage provides such a model. Furthermore because laboratory miceproduce scar tissue in response to an identical injury this comparative system provides a unique opportunity todirectly study how macrophage phenotypes regulate regeneration and scarring. The long-term goal is todevelop clinical interventions that stimulate regeneration and inhibit fibrosis. The objective of this proposal is toidentify macrophage subtypes that regulate regeneration and manipulate inflammation to stimulateregeneration in response to injury. This proposal tests the central hypothesis that specific macrophagesubtypes stimulate a regenerative extracellular environment and that phenotype switching from one state toanother is critical to the outcome of injury. This hypothesis is based upon published and preliminary studiesindicating general macrophage phenotypes are associated with regeneration that Acomys and Mus exhibitdifferent cytokine and inflammatory gene profiles and that production of a regenerative or scarring extracellularenvironment corresponds to specific macrophage phenotypes observed in Acomys or Mus. Guided by strongpreliminary data this hypothesis will be tested by pursuing the following two specific aims: (1) identify specificmacrophage phenotypes that regulate tissue regeneration and scarring in Acomys and Mus. Parallel in vivoand in vitro studies will integrate the timing and extracellular influence of macrophage subtypes andmacrophage origin using newly developed regeneration assays; and (2) test the role of macrophage-producedarginase on tissue regeneration through the use of a newly identified immunomodulatory agent and geneticallyengineered mice with macrophages that lack arginase. The approach is innovative in the applicant's opinionbecause it departs from the status quo of investigating wound healing and instead focuses on understandingendogenous tissue regeneration in a unique model of mammalian tissue regeneration. The proposed researchis significant because it is expected to provide new and fundamental insight into how macrophages coordinatethe inflammatory and immune reaction to stimulate a regenerative response to injury.

project_terms:
Acomys;Address;African;Azithromycin;Biological Assay;Cartilage;Cicatrix;Clinical;Complex;Data;Disease;Ear;Environment;Epithelial;Epithelium;Exhibits;External Ear;Extracellular Matrix;Fibroblasts;Fibrosis;Genes;Genetic Transcription;Genetically Engineered Mouse;Genomics;Goals;Granulation Tissue;Hair follicle structure;Human;Immunomodulators;In Vitro;Inflammation;Inflammatory;Injury;Intervention;Knowledge;Laboratory mice;Mammals;Medicine;Modeling;Molecular;Mus;Muscle;Musculoskeletal structure;Natural regeneration;Nerve;Outcome;Pathology;Phenotype;Process;Production;Proteomics;Public Health;Publishing;Regenerative response;Research;Role;Skin;System;Testing;Time;Tissue Model;Tissues;Trauma;Work;Wound models;arginase;base;comparative;cytokine;disability;extracellular;healing;immunoreaction;improved functioning;in vivo;inhibitor/antagonist;injured;injury and repair;innovation;insight;macrophage;novel;organ regeneration;recruit;regenerative;response;response to injury;skin regeneration;stem;targeted agent;tissue regeneration;tissue trauma;wound;wound healing

public_health_relevance:
PROJECT NARRATIVEAlthough humans cannot regenerate damaged tissue the African spiny mouse can naturally regenerate skinhair follicles nerves muscle and cartilage. Thus the proposed research is relevant to public health becausestudying the cellular mechanisms that regulate endogenous regeneration is expected to generate novel clinicalapproaches to restore damaged tissue. Stimulating natural tissue regeneration greatly improves thefunctionality of injured tissue and will help reduce the burden human disability.


application_id: 9870949
project_number: 5R01HL141081-03
administering_ic: NHLBI
award_notice_date: 2020-02-01
opportunity_number: PA-16-160
application_type: 5
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: 2020-03-01
project_title:
The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

project_abstract:
Clinical trials for cell therapy reveal only modest benefits on cardiac function in heart failure (HF) patients leaving the future of this therapeutic modality uncertain. Despite years of research on the topic the celltherapy field remains engrossed in controversies regarding the mechanism(s) of action of donor cells and thecell type best suited to promote cardiac repair. Two competing hypotheses have been forwarded to explain themechanisms underlying cell therapy-mediated cardiac repair namely donor cell direct differentiation(contributing to new cardiac parenchyma) and paracrine signaling (promotion of endogenous repairmechanisms through cytokine and/or extracellular vesicle (EV) secretion). Given that donor cell populationsexhibit poor rates of retention and limited long-term persistence after delivery in HF models paracrine signalingis viewed as a major mechanism of cell-mediated cardiac repair. However there is also evidence implicating alink between therapeutic efficacy and donor cell cardiovascular fate decisions; although the mechanismsremain unknown. It is known that different cell types possess distinct trophic factor secretion profiles andparacrine signaling activities. Thus we posit that cardiovascular cell lineage commitment-dependent variationsin paracrine signaling are likely to have a significant impact on donor cell reparative capacity in cell-mediatedcardiac repair. Further as EVs have been identified as important mediators of progenitor cell-induced cardiacregeneration we hypothesize that donor cell cardiomyogenic lineage commitment regulates the expressionand synthesis of EV-resident cardiotrophic factors which mediate cardiac repair. To test this hypothesis wewill use genetic and pharmacologic approaches for enhancing cardiogenic factor expression to assess theeffects of cardiomyogenic lineage commitment on the reparative capacity of cardiac mesenchymal cells(CMCs) and lineage-dependent adaptations in CMC EV signaling. Aim 1 will interrogate the impact of genetic-and pharmacologic-mediated induction of cardiogenic factor expression on CMC cardiovascular lineagecommitment and EV paracrine signaling. Aim 2 will assess the effect of cardiomyogenic lineage commitmenton the reparative capacity of CMCs following administration in a chronic infarct model. Aim 3 will evaluate theconsequences of EV administration derived from nave and cardiomyogenic lineage-committed CMCs oncardiac repair. The results of this project will establish an unidentified link between progenitor cellcardiovascular lineage commitment and modifications in EV secretion/paracrine signaling as well as elucidatenovel targets and pathways that may be exploited to enhance the efficacy of cell therapy.

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;Population;Production;Rattus;Research;Role;Signal Transduction;Structure;Testing;Therapeutic;Tissues;Treatment Efficacy;Variant;Ventricular;Ventricular Remodeling;Work;arteriole;cardiac regeneration;cardiac repair;cell type;cytokine;early phase clinical trial;extracellular vesicles;heart function;improved;neovascularization;novel;pre-clinical;release factor;repaired;retention rate;stem cells;transcription factor

public_health_relevance:
Cell therapy is a promising approach to repair the human heart after a heart attack. Unfortunately ourunderstanding of how cell therapy actually works to repair dead or dying heart tissue after a heart attack islimited. This project seeks to identify the essential characteristics and/or reparative factors released fromdonor cells that contribute to their ability to improve heart function after injury.


application_id: 9870792
project_number: 5UC2FD005671-05
project_title: Smokeless Tobacco Reference Product Development Distribution and Research
administering_ic: FDA
award_notice_date: 2020-02-07
opportunity_number: RFA-FD-15-026
application_type: 5
activity_code: UC2
ic: FD
serial_number: 005671
program_official: WAKEFIELD, CHRISTI
project_start_date: 2016-03-01
project_end_date: 2022-02-28
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 referencetobacco products (including the most recent 1R6F reference cigarette) as standards for non-clinicalinvestigational purposes by tobacco manufacturers contract and government laboratories andacademic institutions. The University of Kentucky Center for Tobacco Reference Products(CTRP) is committed to supply certified standards for tobacco product research and to work withthe FDA to develop new certified reference products as necessary. This project will produce andcharacterize smokeless tobacco reference products representative of loose leaf chewing tobaccomoist snuff and pouched snus. These new certified reference products will be manufactured inone manufacturing run each to ensure product uniformity and will have certified physical andchemical characteristics to allow for proficiency testing instrument calibration employee/studenttraining and for method validation and investigational purposes. A process for the designanalysis and approval is included to ensure input from stakeholders and that the new referencesmokeless tobacco products meet the specified goals. Quality control and sample testingparameters are defined and substantial chemical analyses will be conducted to allow forcertification of product characteristics and constituent levels.The CTRP will advance efforts to collaborate and coordinate studies with stakeholders includingTobacco Centers for Regulatory Science commercial product testing laboratories tobacco productmanufacturers and academic researchers. This proposal outlines significant improvements tocurrent smokeless tobacco reference products in terms of product design and certification productdistribution product storage planning for new reference tobacco products establishing researchcapability and providing new services that will benefit the tobacco research community. A web-based interface for ordering reference tobacco products and for the secure transmission andstorage of collaborative data is under development and will be enhanced to include the smokelessreference products. As an academic institution our proposal to coordinate and administer inter-laboratory comparison studies on tobacco reference products and mechanisms to provide varioustobacco reference products as a service to the entire tobacco research community is animprovement over current programs. The development of high-quality smokeless tobaccoreference products and providing those through the CTRP will strengthen the FDAs effort todevelop the science of tobacco regulation and provide a necessary resource for tobacco productresearch and regulation.

public_health_relevance:
Project NarrativeReference tobacco products are a necessary tool for measuring and reporting harmful andpotentially harmful constituents in tobacco products as required under the Family SmokingPrevention and Tobacco Control Act. Four new certified reference products representative ofloose leaf chewing tobacco moist snuff and pouched snus will be manufactured in onemanufacturing run each to ensure product uniformity and will have certified characteristics toallow for a proficiency testing program instrument calibration employee/student trainingmethod validation and investigational purposes. The current University of Kentucky Center forTobacco Reference Products (CTRP) will expand our program for tobacco analysis andreference tobacco products to support collaborative studies improved constituent analysisstorage and stability research and the manufacture and distribution of smokeless tobaccoreference products with significant proposed improvements and development in all of theseareas.


application_id: 9869848
project_number: 5R21AI144648-02
project_title: Conditional Null Mutants in the Study Essential Gene Products of Chlamydia
administering_ic: NIAID
award_notice_date: 2020-01-15
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AI
serial_number: 144648
program_official: VINCENT, LEAH REBECCA
project_start_date: 2019-02-11
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(81)]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Chlamydia trachomatis represents a significant health concern world-wide. A substantialburden exists due to the prevalence and the combined health and socioeconomic impact ofacute and chronic disease. All Chlamydia species express a type III secretion system (T3SS)and this mechanism likely contributes significantly to overall pathogenesis. Chlamydiae areobligate intracellular parasites that undergo a complex developmental cycle and this biologyhas historically impeded rapid progress in understanding pathogenesis. The newly acquiredability to inactivate chlamydial genes via insertion or deletion mutagenesis has greatly facilitatedcharacterization of virulence factors. Unfortunately significant barriers remain in the applicationof genetics in elucidating molecular mechanisms of virulence. For example there is currentlyno mechanism to generate null strains for gene products that are absolutely essential forchlamydial propagation in cell culture. To this end we have adapted the fluorescence-reportedallelic exchange mutagenesis technique to facilitate creation of conditional null strains inessential genes. Preliminary data describing such a situation for a type III effector gene arepresented herein. We propose to validate and further develop our approach while revealing thefunction of a highly important effector protein. At the end of these studies we will haveestablished new approaches that will benefit the entire Chlamydia research community andadvance the understanding of how T3S manifests during chlamydial infection.

project_terms:
Acute Disease;Alleles;Biology;Carrier Proteins;Cell Culture Techniques;Cell Nucleus;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Code;Communities;Complement;Complex;Coupled;Data;Deletion Mutagenesis;Development;Engineering;Epithelial Cells;Essential Genes;Fluorescence;Gene Expression;Genes;Genetic;Goals;Growth;Health;Human;Infection;Insertional Mutagenesis;Label;Literature;Mass Spectrum Analysis;Modeling;Molecular;Mutagenesis;Nature;Pathogenesis;Phase;Phenotype;Precipitation;Prevalence;Protein Export Pathway;Proteins;Reporting;Research;Role;Sexually Transmitted Agents;Sexually Transmitted Diseases;Sorting - Cell Movement;Techniques;Type III Secretion System Pathway;Virulence;Virulence Factors;Work;design;gene product;genetic manipulation;hepatocyte growth factor-regulated tyrosine kinase substrate;interest;member;mutant;new technology;novel;novel strategies;obligate intracellular parasite;particle;protein expression;socioeconomics;success;tissue culture;tool

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease relies on a specializedsecretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis.This proposal contains work designed to use mutagenesis of specific genes that are essentialfor chlamydial survival to determine their specific contributions to chlamydial disease.


