# projects

application_id: 9756256
project_number: 5P30AG028383-14
project_title: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2019-07-11
opportunity_number: RFA-AG-16-018
application_type: 5
activity_code: P30
ic: AG
serial_number: 028383
program_official: ELLIOTT, CERISE
project_start_date: 2006-07-15
project_end_date: 2021-06-30
study_section: ZAG1-ZIJ-G(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: OverallThis application seeks to renew the University of Kentucky Alzheimers Disease Core Center (UK-ADC) anexperienced and collaborative ADC originally funded in 1985. Our principal mission is to serve as the focalpoint for all AD-related activities at UK and this region of the United States by providing an environment andcore resources that catalyze innovative research outreach education and clinical programs. Our signatureresources include: 1) a cognitively normal group of ~500 subjects followed longitudinally with all committed tobrain autopsy upon death; 2) a strong program in clinical-neuropathological correlations and short postmorteminterval autopsies; 3) a maturing program studying the early preclinical biological emergence of pathology thatmay lead to dementia states with an increasing focus on antemortem imaging and CSF biomarker collection;4) an integrated centralized database and innovative biostatistical expertise to characterize clinical andbiological transitions; and 5) a successful and close partnership with the African-American community andincreased participation of underrepresented individuals in our longitudinal cohort and ADC-affiliated researchstudies and clinical trials. The overall scientific emphasis of the UK-ADC continues to be on our interrelatedthemes: Transitions & Translation. Our well-characterized longitudinal cohort and historically strongneuropathology program focused on normal aging preclinical disease states and early cognitive transitionshave been central to our success in defining early pathogenic mechanisms underlying the transitions fromnormal cognitive aging to impairment. The depth of expertise and collaborative nature of our investigators havealso resulted in substantial progress on translation of that knowledge into new targets and novel therapeuticstrategies. The UK-ADC will continue to provide the infrastructure and resources to focus on these integratedthemes and advance innovative AD research through the pursuit of four overarching specific aims.Aim 1. Facilitate and enhance basic translational and clinical research in AD and related dementias.Aim 2. Provide the necessary resources and interactive environment to support and create new opportunitiesfor innovative research.Aim 3. Maintain and grow educational opportunities and community partnerships to promote awarenessincrease participation in research and provide an innovative and interdisciplinary training environment.Aim 4. Contribute to the national efforts to advance AD research education and care.The UK-ADC provides an infrastructure and environment that focuses on these integrated themes andadvances AD research education outreach and clinical programs through six highly interactive and effectivecomponents: Administrative Core Clinical Core Data Management and Statistics Core Neuropathology CoreOutreach and Recruitment Core and Research Education Component.

project_terms:
African American;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Outreach;Comorbidity;Dementia;Disease;Education;Education and Outreach;Environment;Funding;Goals;Health Professional;Image;Impaired cognition;Impairment;Individual;Industry;Infrastructure;Intervention;Kentucky;Lead;Longitudinal cohort;Mission;Nature;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Pilot Projects;Research;Research Personnel;Research Support;Resources;Risk;Training;Translating;Translational Research;Translations;United States;Universities;Work;aging brain;biomarker development;central database;clinical practice;cognitive development;cohesion;collaborative environment;community partnership;data management;education research;experience;healthcare community;innovation;knowledge translation;neuropathology;new therapeutic target;next generation;normal aging;novel therapeutics;outreach;pre-clinical;prevent;programs;recruit;research study;statistics;success

public_health_relevance:
NARRATIVE: OVERALLThe University of Kentucky Alzheimers Disease Center facilitates and supports research efforts to identify theearly manifestations of disease and the pathogenic mechanisms underlying the transitions from normal agingto the development of cognitive impairment with an overall goal of more rapid translation of that knowledgeinto new therapies to delay or prevent AD. We are also dedicated to training the next generation ofresearchers and to educating the lay and healthcare community to increase awareness of AD and relateddisorders and the importance of research and research participation.


application_id: 9755244
project_number: 5U01HL143508-02
administering_ic: NHLBI
award_notice_date: 2019-07-15
opportunity_number: RFA-HL-18-018
application_type: 5
activity_code: U01
ic: HL
serial_number: 143508
program_official: EINHORN, PAULA T
project_start_date: 2018-08-15
project_end_date: 2021-07-31
study_section: ZHL1-CSR-H(M3)
contact_pi_person_id: 14537492
contact_pi: LI, JING
other_pis: WILLIAMS, MARK V
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
project_title:
Project MISSION: Developing a multicomponent Multilevel Implementation Strategy for Syncope OptImalCare thrOugh eNgagement

project_abstract:
Project Abstract Syncope is a complex presenting symptom that requires thoughtful and efficient evaluation todetermine the etiology of a patient's loss of consciousness. Prevalence rates of syncope have been reportedas high as 41% with recurrent syncope occurring in 13.5%. A common symptom approximately 1% to 3% ofall emergency department (ED) visits (as many ED visits as atrial fibrillation) and up to 6% of all hospitaladmissions are due to syncope. The prognosis among patients with syncope depends on the etiology andunderlying cardiovascular condition. A cardiac etiology of syncope is associated with significantly higher ratesof morbidity and mortality than other causes such as vasovagal reflex mediated or orthostatic hypotension. TheFramingham study documented a doubling of the risk of death among participants with cardiac syncopecompared with those with non-cardiac syncope. Notably experiencing syncope affects patients' quality of life(QoL) and those with more frequent syncope report poorer QoL with perceptions of low overall physical andmental health and impairment in activities of daily living. The QoL among patients with recurrent syncopeappears equivalent to severe rheumatoid arthritis and chronic low-back pain in an adult population. Thoughresearch in the past 25 years provides substantial understanding of the pathophysiology of particular etiologiesof syncope the diagnostic approach to such a perplexing symptom remains difficult and efficient diagnosisremains elusive. The major challenge in the evaluation of patients with syncope is that most patients are asymptomaticat the time of their presentation. Because of concerns that patients presenting with syncope are at risk for animpending catastrophic event overuse and inappropriate use of testing and hospital admission are common.Aiming to provide guidance on optimizing the evaluation and management of syncope a collaboration of theAmerican College of Emergency Physicians Society for Academic Emergency Medicine American College ofCardiology (ACC) American Heart Association (AHA) and Heart Rhythm Society (HRS) issued a Guideline forthe Evaluation and Management of Patients with Syncope in 2017. Adopting a standardized approach tosyncope based on this guideline offers an effective opportunity for delivering high value care to patientssuffering this distressing and potentially dangerous event. Aiming for more rapid translation from guideline toclinical practice and improved health the proposed study will identify barriers and facilitators forimplementation of an evidence-based high value approach to diagnosis and management of patientspresenting with syncope. The research team will develop a multi-level multi-component implementationstrategy for evidence-based syncope evaluation and management and plan for a subsequent hybrideffectiveness-implementation trial guided by the Consolidated Framework for Implementation Research(CFIR).

project_terms:
Academic Medical Centers;Accident and Emergency department;Activities of Daily Living;Adherence;Adopted;Adoption;Adult;Affect;American;American Heart Association;Assessment tool;Atrial Fibrillation;Attitude;Cardiac;Cardiology;Cardiovascular system;Caring;Characteristics;Chronic low back pain;Climate;Clinical;Clinical Practice Guideline;Collaborations;Community Hospitals;Complex;Dangerousness;Data;Diagnosis;Diagnostic;Distress;Effectiveness;Emergency Department Physician;Emergency Medicine;Emergency department visit;Etiology;Evaluation;Event;Functional disorder;Goals;Guidelines;Health;Hospitalization;Hospitals;Hybrids;Impairment;Interview;Knowledge;Mediating;Medicine;Mental Health;Morbidity - disease rate;Organizational Culture;Orthostatic Hypotension;Participant;Patient-Focused Outcomes;Patients;Perception;Population;Prevalence;Process;Provider;Public Health;Quality of life;Readiness;Recommendation;Recurrence;Reflex action;Reporting;Research;Rheumatoid Arthritis;Risk;Social Environment;Societies;Standardization;Structure;Surveys;Symptoms;Syncope;System;Testing;Time;Translations;Unconscious State;Vasovagal;Work;adverse outcome;base;clinical care;clinical practice;college;common symptom;design;evidence base;experience;heart rhythm;high risk;implementation research;implementation strategy;implementation trial;improved;mortality;mortality risk;novel;outcome forecast;physical conditioning;social organization;tool

public_health_relevance:
Project NarrativeA growing and burdensome public health issue approximately 1% to 3% of all emergency department (ED)visits as many ED visits as atrial fibrillation and 6% of all hospital admissions were due to syncope. Thoughresearch in the past 25 years achieved substantial understanding of the pathophysiology of particularetiologies of syncope the diagnostic approach to such a perplexing symptom remains difficult and efficientdiagnosis remains elusive. Project MISSION (Developing a multicomponent Multilevel ImplementationStrategy for Syncope OptImalCare thrOugh eNgagement) will develop a multi-level multi-componentimplementation strategy for evidence-based syncope evaluation and management and plan for a subsequenthybrid effectiveness-implementation trial guided by Consolidated Framework for Implementation Research(CFIR).


application_id: 9754152
project_number: 5R01EY021580-08
project_title: Deciphering Inhibition of Visual Plasticity by NgR1
administering_ic: NEI
award_notice_date: 2019-07-24
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 021580
program_official: GREENWELL, THOMAS
project_start_date: 2012-05-01
project_end_date: 2021-07-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 10356866
contact_pi: MCGEE, AARON W
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe visual system exhibits a heightened sensitivity to the quality visual experience during an interval late indevelopment termed the `critical period'. Discordant vision during the critical period is the cause of amblyopia aprevalent visual disorder in children. Treatment of amblyopia is most effective in children before the close ofthe critical period. Subsequently the flexibility with brain circuitry diminishes in adulthood and effective therapyis more difficult. In a mouse model of amblyopia disrupting normal vision by closing one (monoculardeprivation MD) for the duration of the critical period but not thereafter decreases visual acuity and perturbsthe normal eye dominance of neurons in visual cortex. The nogo-66 receptor gene (ngr1) is required to close the critical period. In ngr1 mutant mice plasticityduring the critical period is normal but it is retained in adult mice. Importantly ngr1 mutant mice spontaneouslyrecover visual acuity in this model of amblyopia. Our overall hypothesis is that recovery of acuity and eyedominance are independent. In the proposed research we take advantage of this extended critical period inngr1 mice to identify with location and mechanisms of plasticity that mediate recovery of acuity and eyedominance with a combination of conditional mouse genetics behavioural assays electrophysiologysophisticated repeated in vivo calcium imaging and laser-scanning photostimulation circuit mapping. We willbegin to unravel how plasticity within visual circuitry mediates recovery of visual function following earlyabnormal vision (MD) as well as how this plasticity is restricted to the critical period with these experiments. Inaddition to improving understanding of how experience-dependent plasticity changes the function of braincircuits these studies may reveal new avenues for developing therapeutic approaches to treat amblyopia..

project_terms:
Address;Adult;Alleles;Amblyopia;Behavioral;Behavioral Assay;Binocular Vision;Brain;Calcium;Child;Childhood;Data;Development;Disease;Disinhibition;Electrophysiology (science);Exhibits;Eye;Frequencies;Genetic;Head;Image;Interneurons;Knowledge;Lasers;Lateral Geniculate Body;Lazy Eyes;Location;Maps;Measures;Mediating;Mission;Modeling;Modification;Mus;Mutant Strains Mice;Neurons;Ocular Dominance;Parvalbumins;Phenotype;Population;Public Health;Receptor Gene;Recovery;Research;Scanning;Strabismus;Synapses;Synaptic plasticity;Testing;Thalamic structure;Therapeutic;Therapeutic Intervention;Time;Vision;Vision Disorders;Visual;Visual Acuity;Visual Cortex;Visual impairment;Visual system structure;Water;brain circuitry;critical period;effective therapy;excitatory neuron;experience;experimental study;flexibility;improved;in vivo calcium imaging;inhibitory neuron;monocular deprivation;mouse model;neural circuit;optogenetics;postsynaptic;programs;response;spatial vision;targeted treatment;visual deprivation;visual plasticity;visual processing

public_health_relevance:
Project NarrativeAbnormal vision only during a critical period in childhood induces amblyopia also known as lazy eye adisorder comprising several deficits in spatial vision including poor acuity. The proposed research is relevant topublic health because knowledge of the neural circuits that mediate recovery of acuity and eye dominance willimprove our understanding of targets for therapeutic intervention. Thus the proposed research is relevant tothe mission of the both the NEI to increase understanding of the critical period in order to determine howexperience alters connectivity in the developing visual system.


application_id: 9754089
project_number: 5UH3DA041115-05
project_title: Development of Long-acting Cocaine Hydrolase as a Treatment for Cocaine Abuse
administering_ic: NIDA
award_notice_date: 2019-08-07
opportunity_number: RFA-DA-15-017
application_type: 5
activity_code: UH3
ic: DA
serial_number: 041115
program_official: KLINE, RICHARD
project_start_date: 2015-09-15
project_end_date: 2022-07-31
study_section: ZDA1-JXR-D(12)R
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine abuse is a major public health problem that directly or indirectly affects most communities and families. There is still no FDA-approved medication specific for cocaine addiction or overdose. Disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. Accelerating cocaine metabolism that produces biologically inactive metabolites via a route similar to the principal cocaine-metabolizing pathway-cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) in plasma-is recognized as the most efficient treatment strategy for cocaine overdose and addiction. Since the catalytic efficiency (kcat/KM) of wild-type BChE against the naturally occurring (-)-cocaine is low (kcat = 4.1 min and KM = 4.5 M) we have recently designed and discovered a set of BChE -1 mutants known as cocaine hydrolases (CocHs) with at least 1000-fold improved catalytic efficiency against (- )-cocaine compared to wild-type BChE. In vivo and clinical data for the first one of our discovered and patented CocHs demonstrate the promise of enzyme therapy for cocaine abuse. In addition to improved efficacy our recently designed discovered and patented new CocH entities have not only significantly higher catalytic efficiency against (-)-cocaine but also possess much longer biological half-lives Built on our success in rational design and discovery of the highly efficient CocHs and their long-acting forms (LAFs or CocH-LAFs) this investigation will focus on further optimization manufacturing process development formulation development and preclinical testing of the most promising CocH-LAF as a novel therapeutic candidate for cocaine addiction treatment. The specific aims are: (1) to optimize a promising CocH-LAF which has not only a high catalytic efficiency against (-)-cocaine but also a long biological half-life; (2) to test feasibility of lage- scale expression of promising CocH-LAF entities; (3) to develop large-scale manufacturing processes for the most promising CocH-LAF selected in Aim 2; (4) to characterize the detailed pharmacology and toxicology profiles of the most promising CocH-LAF in animal models with the CocH-LAF material produced in Aim 3. The most promising CocH-LAF entity developed in this investigation is expected to be highly effective and safe as a novel exogenous enzyme suitable for a monthly dosing schedule for treatment of cocaine addiction in humans. This investigation will make the best possible CocH-LAF entity ready for the cGMP (current Good Manufacturing Practices) protein manufacturing Investigational New Drug (IND)-enabling studies and subsequent clinical trials. Thus this investigation will move a promising therapeuticcandidate closer toward FDA approval for cocaine addiction treatment.

project_terms:
Affect;Albumins;Animal Model;Animals;Antibodies;Binding;Binding Sites;Biological;Biological Assay;Butyrylcholinesterase;Cell Line;Clinical Data;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependence;Communities;Computer Simulation;Data;Development;Dose;Drug Kinetics;Enzymes;Evaluation;FDA approved;Family;Formulation;Half-Life;Human;Hydrolase;Hydrolysis;Immunoglobulins;In Vitro;Injections;Investigation;Investigational Drugs;Legal patent;Medical;Metabolic;Metabolism;Monkeys;Monoclonal Antibodies;Neuraxis;Neurons;Pathway interactions;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology and Toxicology;Plasma;Preclinical Testing;Process;Production;Proteins;Public Health;Rattus;Route;Self Administration;Serum Albumin;Technology;Testing;Toxic effect;Treatment Protocols;Vaccines;Work;base;cell bank;clinical development;cocaine overdose;design;drug of abuse;enzyme therapy;expression cloning;immunogenicity;improved;in vivo;innovation;manufacturing process;manufacturing process development;mutant;novel;novel therapeutics;off-patent;public health relevance;small molecule;social;success;therapeutic candidate;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE The long-acting cocaine hydrolase developed in this project will be a promising candidate for therapeutic treatment of cocaine addiction.


application_id: 9753735
project_number: 5R01CA195573-05
project_title: Novel pRNA Nanoparticle Delivery as Directed Therapy for Colorectal Cancer Metastasis
administering_ic: NCI
award_notice_date: 2019-07-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 195573
program_official: FU, YALI
project_start_date: 2015-09-25
project_end_date: 2020-11-30
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GUO, PEIXUAN ;THORSON, JON SCOTT
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Although progress has been made in survival of patients with earlier stage colorectal cancer (CRC) only minimal improvement has been noted in patients with systemic metastases (Stage IV disease). Current chemotherapeutic agents while highly effective at killing CRC cells are limited by their systemic toxicity. If advances ar to be made in the survival of cancer patients highly innovative strategies are required for more targeted delivery of anti-cancer agents directly to CRC metastases. Our ultimate translational goal is to develop a highly effective and less toxic approach to specifically deliver anti-cancer agents to CRC metastases. To achieve this goal we have assembled a multidisciplinary and highly collaborative team who are at the forefront of molecular signaling pathways in CRC CRC treatment modalities medicinal chemistry novel nanoparticle synthesis and delivery systems. Over the last two years we have made significant progress to achieve our goals: (i) using a novel three-way junction (3WJ) motif we have constructed thermodynamically and chemically stable three-branched RNA nanoparticles with an aptamer against receptors that can deliver a small molecule inhibitor or chemotherapeutic agent specifically to CRC metastases in the liver (ii) we have constructed a variety of RNA nanoparticles using the pRNA-3WJ motif as a scaffold and have demonstrated in critical experiments that the resulting RNA constructs retained their folding and independent functionalities for specific cell binding cell entry and cancer targetingboth in vitro and in vivo (iii) we have shown that the RNA nanoparticles remain intact after systemic injection into mice and strongly bind to tumors with little accumulation in normal organs or tissues; these RNA constructs are non- toxic non-immunogenic and display favorable pharmacological profiles in mice and (iv) we have demonstrated localized in vivo delivery of pRNA-3WJ to CRC xenografts and liver metastases. Thus the central hypothesis of our proposal is that CRC receptor-specific delivery of chemotherapeutic agents using our pRNA-3WJ nanoparticles will provide a safe effective strategy to selectively target and inhibit CRC metastasis. To address our hypothesis we have designed experiments with the following Specific Aims: 1) to construct pRNA-3WJ nanoparticles coupled with anti-cancer agents and analyze their stability cellular uptake and anti-proliferative effects in vitro; 2) to determine te pharmacokinetics stability safety and drug delivery of pRNA-drug conjugates in vivo; and 3) to evaluate the selective delivery and in vivo anti-tumor effect of pRNA- 3WJ nanoparticles coupled with anti-cancer agents. In summary our enthusiasm for our current proposal is driven not only by its inherent scientific importance but also by its translational potential clinical impact and the possibility to provide a more effective and less toxic delivery system targeting CRC metastases.

project_terms:
Address;Antineoplastic Agents;Binding;Biodistribution;Biological Models;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cells;Cessation of life;Chemicals;Clinical;Colorectal Cancer;Coupled;Disease;Distant;Drug Delivery Systems;Drug Kinetics;Early treatment;Epithelial Cells;Excision;FOLR1 gene;Goals;Growth;Human;In Vitro;Injections;Intestines;Kentucky;Laboratories;Liver;Malignant Neoplasms;Metastatic Neoplasm to the Liver;Modality;Molecular;Motor;Mucous Membrane;Mus;Nanotechnology;Neoplasm Metastasis;Organ;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Process;RNA;Research;Resistance;Safety;Signal Pathway;Submucosa;System;Technology;Thermodynamics;Tissues;Tumor Tissue;Universities;Xenograft procedure;antitumor effect;aptamer;base;cancer cell;cancer survival;chemotherapeutic agent;colorectal cancer metastasis;colorectal cancer treatment;design;experimental study;improved;in vivo;innovation;metastatic colorectal;mortality;multidisciplinary;nanoparticle;nanoparticle delivery;nanotechnology platform;novel;overexpression;public health relevance;receptor;scaffold;small molecule inhibitor;systemic toxicity;targeted delivery;targeted treatment;tumor;uptake

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


application_id: 9753486
project_number: 1R01ES029838-01A1
project_title: The role of p62 in the mechanism of Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2019-05-08
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: ES
serial_number: 029838
suffix: A1
program_official: REINLIB, LESLIE J
project_start_date: 2019-05-08
project_end_date: 2019-08-22
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: SHI, XIANGLIN
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Although reactive oxygen species (ROS) are considered important in Cr(VI)-induced malignant celltransformation the underlying mechanism remains to be investigated. Recent studies show that ROS areimportant in the induction of autophagy and subsequently upregulation of p62. Our preliminary results showthat chronic exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) upregulated p62 and that chronicexposure of animals to Cr(VI) particles upregulated this protein in the lung. Forced expression of p62 in BEAS-2B cells caused malignant transformation of these cells and generated tumor in xenograft model. Thus it islikely that in BEAS-2B cells ROS upregulate p62 and its downstream leading to cell transformation. Ourpreliminary studies show that in Cr(VI)-transformed cells p62 was upregulated. Among six maindomains/regions of p62 we will study (a) the TRAF6-binding domain which binds to TRAF6 and causes itsphosphorylation leading to activation of NF-B and (b) the Keap-interacting region which binds to Keap1(Nrf2 inhibitor) and causes constitutive activation of Nrf2. The central hypothesis is that in normal cells Cr(VI)activates NADPH oxidase generates ROS and then upregulates p62 leading to malignant cell transformationand that in Cr(VI)-transformed cells p62 activates NF-B through TRAF6-binding domain and causesconstitutive Nrf2 activation through Keap-interacting region and subsequently upregulates its downstream anti-inflammatory antioxidant and anti-apoptotic proteins resulting in increased survival and tumorigenesis ofthese transformed cells. Aim 1 will test the hypothesis that in normal cells Cr(VI) activates NADPH oxidasegenerates ROS and upregulates p62 leading to malignant cell transformation. We will carry out the followingstudies. (a) ROS generated by Cr(VI) upregulate p62. We will inhibit ROS to show the decrease of p62. (b) Wewill inhibit ROS or p62 to demonstrate the inhibition of Cr(VI)-induced malignant cell transformation. (c) We willuse whole transcriptome (RNA Seq) analysis to identify p62 downstream genes responsible for Cr(VI)-inducedmalignantly transformation. Aim 2 will test the hypothesis that p62 upregulates NF-B through its TRAF6-binding domain and that p62 causes constitutive Nrf2 activation through its Keap-interacting region resulting inthe generation of microenvironment favorable for survival of Cr(VI)-transformed cells and subsequenttumorigenesis. We will show (a) the role of TRAF6-binding domain in NF-B activation; (b) the role of Keap-interacting region in constitutive Nrf2 activation and upregulation of its downstream inflammatory antioxidantand anti-apoptotic proteins; and (c) the role of p62 and its downstream NF-B and Nrf2 pathways intumorigenesis of Cr(VI)-transformed cells. Aim 3 will investigate the role of p62 in the mechanism of Cr(VI)carcinogenesis using p62 wildtype and knockout mice. We will measure p62 and its downstream proteins inlung issues of animals chronically exposed to Cr(VI) and of workers occupationally exposed to Cr(VI) tostrengthen the cellular and animal Cr(VI) exposure studies.

project_terms:
Animals;Anti-inflammatory;Antioxidants;Apoptosis;Apoptotic;Autophagocytosis;BCL2 gene;Binding;Cell Survival;Cells;Chronic;Development;Drug resistance;Epithelial;Epithelial Cells;Exhibits;Exposure to;Generations;Genes;Inflammation;Inflammatory;Investigation;Knockout Mice;Laboratories;Lung;Malignant - descriptor;Malignant Neoplasms;Measures;Mus;NADPH Oxidase;Normal Cell;Occupational Exposure;Oncogenic;Oxidative Stress;Pathway interactions;Phosphorylation;Play;Poison;Process;Property;Proteins;Reactive Oxygen Species;Response Elements;Role;Signal Pathway;Signal Transduction;Structure of parenchyma of lung;TNF gene;TRAF6 gene;Testing;Up-Regulation;Xenograft Model;animal tissue;cancer cell;carcinogenesis;carcinogenicity;catalase;cell transformation;chromium hexavalent ion;exposed human population;human tissue;inhibitor/antagonist;particle;promoter;transcription factor;transcriptome;transcriptome sequencing;tumor;tumorigenesis

public_health_relevance:
NARRATIVE This application investigates the role of p62 in the mechanisms of malignant cell transformation and oftumorigenesis induced by Cr(VI) at cellular animal and human tissue levels. If aims are achieved the studywill demonstrate that in normal cells Cr(VI) activates NADPH oxidase generates ROS and upregulates p62leading to malignant cell transformation and that in Cr(VI)-transformed cells p62 activates NF-B throughTRAF6-binding domain and causes constitutive Nrf2 activation through Keap-interacting region andsubsequently upregulates its downstream anti-inflammatory antioxidant and anti-apoptotic proteinsresulting in increased survival of Cr(VI)-transformed cells and tumorigenesis.


application_id: 9753472
project_number: 1R56AI137020-01
project_title: Rules for penetrating the Gram-negative bacterial envelope
administering_ic: NIAID
award_notice_date: 2018-08-14
opportunity_number: PA-16-160
application_type: 1
activity_code: R56
ic: AI
serial_number: 137020
program_official: XU, ZUOYU
project_start_date: 2018-08-15
project_end_date: 2020-07-31
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 10386925
contact_pi: WEI, YINAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The development of new antimicrobials has drastically lagged behind the fast growth of drug resistantpathogenic microbes especially for Gram-negative (GN) bacteria. To be effective in GN bacteria entering andstaying in the cells is a challenge. Insight into the physicochemical properties that enable the entrance ofcompounds is critical to direct future effort in the development of effective treatment against GN pathogens.Toward this goal we will develop methods to accurately quantify the accumulation of small moleculecompounds without requiring fluorescence or other properties for detection and independent of theirantibacterial activity. In addition we will develop a novel computational algorithm to describe and predictphysicochemical properties that favors entry and evade efflux in GN bacteria. The computer model will bevalidated and refined through the selection and characterization of ~1500 of compounds. Specifically we willpursue the following aims: Aim 1) To develop and validate LC-MS/MS based assays to quantify compoundpartition. We will use a panel of antibiotics as "gold standards" to develop and validate assays to accuratelydetermine the accumulation of small molecule compounds in different cellular compartments. We will developLC-MS/MS assays and experiment with the kinetics of entrance optimizing the conditions to enablereproducible and accurate quantification. We will use a CRE strain of E. coli and a MDR strain of Acinetobacterbaumannii in this study. Aim 2) To develop a computational algorithm for predicting compounds that arepotentially good penetrators for GN bacteria. We will develop a new and highly accurate computationalalgorithm through machine learning which can systematically recognize all favorable structural factors of thecompounds effective for GN bacteria. Selected compounds will be experimentally characterized in Aim 3 theknowledge from which will be incorporated back into refining the computational algorithm to generate a newround of learning/prediction. This cycle will be repeated with the testing of ~1500 compounds in total. Aim 3)To measure the accumulation and subcellular distribution of selected compounds and to validate rules oncompound accumulation. With the assays from Aim 1 we will measure the accumulation data of compoundsselected through Aim 2. Data from these analyses will be used to polish the computer model in Aim 2. Finallythe models will be evaluated through measurement of accumulation data of selected compounds and examineif the experimental data match the prediction. The knowledge gap about penetrating the cellular envelope hasbecome the biggest hurdle to the rational design of new classes of antimicrobials against all GN pathogens.Outcome from the proposed study will help bridge the gap between a potent inhibitor and an effectiveantibacterial drug. The combined use of the detailed experimental assays and the new computational algorithmwill empower drug discovery efforts that aim to identify promising drug candidates targeting GN bacteria.

project_terms:
Acinetobacter baumannii;Anti-Bacterial Agents;Antibiotics;Back;Biological Assay;Cells;Chemicals;Collection;Computational algorithm;Computer Simulation;Cytoplasm;Data;Data Analyses;Detection;Development;Drug resistance;Drug-sensitive;Escherichia coli;Experimental Models;Exposure to;Fluorescence;Future;Goals;Gold;Gram-Negative Bacteria;Growth;In Vitro;Kinetics;Knowledge;Learning;Machine Learning;Measurement;Measures;Membrane;Methods;Microbe;Modeling;Obstruction;Outcome;Pathogenicity;Performance;Pharmaceutical Preparations;Polishes;Production;Property;Reproducibility;Testing;Validation;antimicrobial;assay development;base;design;drug candidate;drug discovery;effective therapy;experimental study;inhibitor/antagonist;insight;mutant;novel;pathogen;periplasm;prediction algorithm;small molecule

public_health_relevance:
The development of new antimicrobials has drastically lagged behind the fast growth of drug resistantpathogenic microbes especially for Gram-negative (GN) bacteria. Insight into the physicochemical propertiesthat enable the entrance of compounds is critical to direct future effort in the development of effective treatmentagainst GN pathogens. Outcome from the proposed study using the combination of detailed experimentalassays and new computational algorithms will empower drug discovery efforts that aim to identify promisingdrug candidates targeting GN bacteria.


application_id: 9753340
project_number: 5R01HL138488-03
project_title: Lysophosphatidic Acid Mediates Cardiac Inflammation After Acute Infarction
administering_ic: NHLBI
award_notice_date: 2019-07-14
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 138488
program_official: SOPKO, GEORGE
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11330155
contact_pi: ABDEL LATIF, AHMED
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTIschemic heart disease is the leading cause of morbidity and mortality in the U.S. population and is often causedby acute myocardial infarction (AMI). AMI initiates an inflammatory response leading to increased circulatinginflammatory bone marrow cells (BMCs) particularly monocytes (monocytosis). This response is crucial forremoving dead tissue and initiating the healing process. However exacerbated inflammatory response followingAMI can be detrimental and is associated with infarct expansion poor cardiac remodeling and adverse clinicaloutcomes. While most studies focus on monocyte production following AMI the mechanism(s) of monocyteegress from the bone marrow and early cardiac infiltration after AMI are poorly understood. Our preliminary datademonstrate the role of the signaling bioactive lipid lysophosphatidic acid (LPA) in the post-AMI mobilization ofBMCs. LPA produced by the enzyme autotaxin (ATX) plays a key role in activating inflammatory monocytesregulating their peripheral blood count and homing them to sites of inflammation. Preliminary studies alsoindicated that LPA levels are elevated early in PB and cardiac tissues after AMI in humans and mice. The long-term goal is to contribute to development of new clinically useful therapies for AMI injury. The overall objectiveof this application is to define LPA mediated signaling pathways linking AMI to the inflammatory BM response.The rationale for the proposed research is its potential to offer new approaches to reduce inflammation andimprove cardiac recovery after AMI. The central hypothesis is that LPA plays a key role in initiating andmaintaining the post-AMI inflammatory response thus impairing cardiac recovery. This hypothesis will be testedby pursuing three specific aims: 1) Identify the molecular mechanism(s) that result in elevated plasma LPA afterAMI 2) Determine the signaling systems by which ATX/LPA axis promotes monocytosis after AMI and 3) definethe association between LPA levels heritable genetic variability in LPA receptor 1 that predicts receptorexpression and monocytosis after AMI in humans. Results of these studies are expected to provide newmechanistic understanding of AMI-induced ATX/LPA signaling their contribution to AMI-associated systemicmonocytosis and cardiac inflammation and the role of heritable genetic mutations in monocytosis andinflammation in humans. To attain this goal the proposed project will combine human studies with animal modelswith genetic manipulation of key components of the ATX/LPA signaling. This group has extensive experience instudying heart/BM signaling after AMI as well as ATX/LPA signaling pathways. The overall impact of thesestudies derives from an innovative focus on the ATX/LPA signaling nexus as a critical mechanism in AMI-induc edinflammation and the potential to control post-AMI infarct expansion and subsequent heart failure by dampeningthis pathological response.

project_terms:
Acute;Acute myocardial infarction;Address;Adhesions;Affect;Animal Model;Atherosclerosis;Blood;Blood Vessels;Bone Marrow;Bone Marrow Cells;Cardiac;Cardiac Myocytes;Cells;Cessation of life;Chemotactic Factors;Clinical;Complement;Coupled;DNA Sequence Alteration;Data;Development;Endothelial Cells;Endothelium;Enzymes;Frequencies;GTP-Binding Proteins;Gap Junctions;Genetic;Goals;Healthcare;Heart;Heart failure;Heritability;Homing;Human;Impairment;Infarction;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Knowledge;Link;Lipids;Lysophosphatidic Acid Receptors;Lysophospholipids;Mass Spectrum Analysis;Mediating;Metabolism;Mission;Modeling;Molecular;Monocytosis;Morbidity - disease rate;Mus;Myelopoiesis;Myocardial;Myocardial Ischemia;Myocarditis;Outcome;Pathologic;Pathway interactions;Patients;Pharmacology;Phosphoric Monoester Hydrolases;Plasma;Play;Population;Process;Production;Proteins;Public Health;Recovery;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Source;Spleen;System;Testing;Therapeutic;Tissues;Tracer;United States National Institutes of Health;Variant;base;cardiogenesis;chemokine;cytokine;experience;genetic manipulation;genetic variant;gustin;healing;improved;inhibitor/antagonist;innovation;lysophosphatidic acid;monocyte;mortality;mouse model;novel strategies;peripheral blood;progenitor;receptor;receptor expression;repaired;response;role model;stable isotope

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. The bone marrowresponds to myocardial injury by the production and mobilization of inflammatory cells that can exacerbate theinjury and our proposal aims at reducing this pathological inflammation and subsequent development of heartfailure. The proposed research is relevant to the NIHs mission pertaining to developing and applyingfundamental knowledge to protect and improve the health of the public.


application_id: 9753077
project_number: 5R21AA026344-02
project_title: Mechanisms for alcohol-induced pancreatic damage
administering_ic: NIAAA
award_notice_date: 2019-07-29
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AA
serial_number: 026344
program_official: GAO, PETER
project_start_date: 2018-08-01
project_end_date: 2020-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alcohol abuse is the major risk factor for pancreatitis. It has been shown that the drinking pattern affects theimpact of alcohol-induced organ damage. However the underlying cellular and molecular mechanisms remainunclear. The progress in this line of research has been hindered by the lack of appropriate animal models. Wehave recently developed a paradigm of chronic plus binge alcohol exposure in which alcohol caused pancreaticdamage characteristic of acute pancreatitis. We showed neither chronic nor binge alcohol exposure alonecaused significant pancreatic damage. However chronic plus binge alcohol exposure induced drastic pancreaticdamage and inflammation which was accompanied by endoplasmic reticulum (ER) stress. ER is the site forprotein folding modification and transport and calcium storage. ER stress is caused by the alterations in ERhomeostasis such as increased protein synthesis accumulation of misfolded proteins or changes in the calciumlevels. ER stress triggers unfolded protein response (UPR) which functions to restore ER homeostasis. Howeversustained ER stress exceeds UPRs ability to restore ER homeostasis resulting in cell death. We further showedthat chronic alcohol exposure inhibited the expression of MANF a key ER stress responsive protein which wasoriginally identified as a neurotrophic factor and functions primarily to maintain ER homeostasis. We hypothesizethat MANF is a critical UPR component that can alleviate ER stress in response to alcohol exposure and chronicalcohol exposure impairs MANF resulting in increased susceptibility to ER stress. We propose two specific aimsto test these hypotheses. Specific Aim 1 determines the role of MANF in chronic/binge alcohol exposure-induceddamage to the pancreas. Specific Aim 2 determines whether ER stress plays a critical role in chronic/bingealcohol exposure-induced damage to the pancreas. As a unit the proposal will use novel animal models toinvestigate the mechanisms underlying chronic/binge alcohol exposure-induced pancreatic damage. The studywill not only gain insight into cellular/molecular mechanisms of alcoholic pancreatitis but also establish aprotective role of MANF. It therefore may offer a potential new therapeutic target for the treatment of alcoholicpancreatitis.

project_terms:
Acinar Cell;Affect;Alcohol abuse;Alcohol-Induced Disorders;Alcoholic Pancreatitis;Alcohols;Animal Model;C57BL/6 Mouse;Calcium;Cell Death;Characteristics;Chronic;Cicatrix;Clinical;Control Groups;Data;Diabetes Mellitus;Diagnosis;Diet;Disease;Endoplasmic Reticulum;Ethanol;Exocrine pancreas;Gastrointestinal Diseases;Homeostasis;Hospitalization;Hospitals;Impairment;Inflammation;Inflammatory;Liquid substance;Modification;Molecular;Morbidity - disease rate;Mus;Organ;Pain;Pancreas;Pancreatitis;Pattern;Play;Predisposition;Protective Agents;Protein Biosynthesis;Proteins;Research;Resistance;Risk Factors;Role;Site;Symptoms;Testing;United States;Wild Type Mouse;acute pancreatitis;alcohol effect;alcohol exposure;alcohol response;chronic pancreatitis;drinking;endoplasmic reticulum stress;inhibitor/antagonist;insight;misfolded protein;mortality;neurotrophic factor;new therapeutic target;novel;novel therapeutic intervention;protein folding;response;restoration

public_health_relevance:
Alcohol abuse is the major risk factor for pancreatitis. This proposal aims to investigate the cellular/molecularmechanisms of alcoholic pancreatitis and identify protective agents. It may provide a new therapeutic approachfor the treatment of alcoholic pancreatitis.


application_id: 9753076
project_number: 5R21AA025724-02
project_title: Gut extracellular vesicles promote alcohol-induced liver injury via TLR4-regulated miRNAs
administering_ic: NIAAA
award_notice_date: 2019-07-15
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: AA
serial_number: 025724
program_official: WANG, JOE
project_start_date: 2018-08-01
project_end_date: 2022-07-31
study_section: Biomedical Research Study Section[AA-1]
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 explore the mechanisms that lead to immune regulation of alcoholicliver disease (ALD). We will focus on extracellular vesicles (EVs) of gut and hepatic macrophages. Specificallywe will examine how microbial antigen stimulates the production of gut EVs through TLR4 signaling and theconsequences of these events in the development of ALD via gut-liver axis. Novel in vitro and in vivo approacheswill be used to address mechanisms of action with the goal of identifying new targets for intervention. Wepropose that gut-derived EVs regulate the accumulation and polarization of hepatic macrophages duringalcohol-induced chronic inflammation via TLR4 signaling. We specifically propose that TLR4-activatedextracelluar miRNAs production is the key to the activation of macrophages. Based on our published workand other preliminary data this proposal will test the hypothesis that microbial antigen regulates the productionof gut extracellular miRNAs through TLR4 signaling which initiates a crosstalk among macrophages andhepatocytes in ALD. Moreover we will determine whether diet-associated nanoparticles carrying inflammatorymiRNAs inhibitor have potential therapeutic implications in ALD. These hypotheses will be tested in the followingSpecific Aims: Aim 1: Determine the role of TLR4-regulated gut EVs on alcohol-induced liver inflammationand injury. Aim 2: Determine whether alteration of IEC miRNAs via TLR4 modulation affects the severityof alcohol-induced liver inflammation and injury in ALD. Following the successful completion of the aboveSpecific Aims our novel studies will (i) validate TLR4 activated EVs is directly relevant to the activation of hepaticmacrophages in ALD (ii) define the preventive potential of TLR4-extracellular miRNAs axis in a mouse model ofALD and (iii) provide a foundation for future mechanistic investigation of gut EVs and extracellular miRNA in ALDtherapy.

project_terms:
Address;Affect;Alcoholic Liver Diseases;Alcohols;Antigens;Attenuated;Automobile Driving;Cell physiology;Cells;Chronic;Colitis;Colon Carcinoma;Data;Development;Diet;Distant;Epithelial;Epithelial Cells;Event;Foundations;Future;Goals;Hepatic;Hepatocyte;Hypoxia;Immune;Immune signaling;Immunotherapy;Impairment;In Vitro;Inflammation;Inflammatory;Inflammatory disease of the intestine;Injury;Intervention;Intestinal permeability;Intestines;Investigation;Kupffer Cells;Lead;Link;Liver;Liver diseases;Macrophage Activation;Mediating;MicroRNAs;Molecular;Myeloid Cells;Outcome;Pathogenicity;Patients;Play;Preventive;Production;Proteins;Publishing;Regulation;Role;Severities;Signal Transduction;TLR4 gene;Testing;Therapeutic;Tumor Angiogenesis;Ulcerative Colitis;Work;antimicrobial;base;chronic alcohol ingestion;exosome;extracellular;extracellular vesicles;gut microbiota;gut-liver axis;immunoregulation;improved;in vivo;inhibitor/antagonist;interest;liver development;liver inflammation;liver injury;macrophage;microbial;microorganism antigen;migration;mouse model;nanoparticle;nanovesicle;novel;nutrition;overexpression;prevent;recruit;response;therapeutic target;translational study;vesicular release

public_health_relevance:
Project NarrativeThis proposal underscores the importance of investigating TLR4- associated extracellular miRNAs as a criticalIECs-derived factor for the development of ALD by regulating the function of hepatic macrophages. Weanticipate that we can abrogate their local and/or distant activities by targeting extracellular vesicles associatedmiRNAs.


application_id: 9752532
project_number: 5R01DK116591-02
project_title: miRNA Mechanism of Acute Kidney Injury in Aging
administering_ic: NIDDK
award_notice_date: 2019-06-05
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 116591
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2018-07-31
project_end_date: 2023-05-31
study_section: Special Emphasis Panel[ZRG1-VH-C(02)]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryIschemia/reperfusion (I/R)-induced acute kidney injury (AKI) remains a major clinical problem in olderpopulation. Although I/R-induced AKI occurs in a variety of clinical situations such as shock renaltransplantation sepsis and renal artery stenosis the mechanism is multifactorial complex and poorlyunderstood. Under normal physiological conditions kidney produces hydrogen sulfide (H2S) with the aid of fourenzymes: cystathionine -synthase (CBS) cystathionine -lyase (CSE) 3-mercaptopyruvate sulfurtransferase(3MST) and cysteine aminotransferase (CAT). In recent years H2S has been shown to regulate severalphysiological functions and its decrease has been implicated in diseases such as hypertension inflammationatherosclerosis and renal disease progression and failure. MicroRNAs (miRNAs) are small non-coding RNAswhich has the ability to inhibit mRNA transcripts by inducing degradation or blocking protein translation. In I/R-induced AKI several miRNAs have been reported to be differentially expressed. Furthermore in I/R-inducedAKI macrophages play a key role in inflammatory and reparative process. While M1 subset macrophage isinvolved in inflammation subset M2 is involved in repair mechanism. Our preliminary results suggested that inI/R-induced AKI in aging miRNA-21 is upregulated and miRNA-194 is down regulated. The injured kidney alsoshowed decreased expression of CBS and 3MST enzymes leading to diminished H2S production. Theincreased ratio of M1/M2 further suggested prolonged inflammatory phase. In addition expression of matrixmetalloproteinase-9 (MMP-9) and their regulatory molecules EMMPRIN and Meprin-A were also upregulatedin AKI. These changes in concert with endothelial to mesenchymal transition (EndoMT) led us to stronglybelieving a detrimental remodeling in I/R-induced old kidney. Interestingly H2S treatment mitigated remodelingand improved renal function in I/R-induced AKI in old mice. We obtained similar results through miR-21inhibitor treatments. Based on these preliminary findings we hypothesize that H2S is a protective agent againstI/R-induced damage in aging kidney. In further substantiating our concept both male and female old vs youngwild type (WT C57BL/6J) mice will be used to compare severity of I/R-induced kidney injury and dysfunctionand beneficial effects of H2S treatment will be assessed. The gained knowledge will not only help to betterunderstand mechanisms of AKI in aging but will also shed lights on future diagnostic and therapeuticstrategies which will be applicable to older patients suffering from AKI.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Acute Renal Failure with Renal Papillary Necrosis;Aging;Angiography;Animals;Anti-Inflammatory Agents;Antioxidants;Atherosclerosis;Barium;Bilateral;Blood flow;Cardiac Surgery procedures;Clinical;Collagen;Complex;Creatinine;Cystathionine;Cystathionine beta-Synthase;Cysteine;Deposition;Diagnostic;Disease;Disease Progression;Down-Regulation;Endothelium;Enzymes;Equilibrium;Extracellular Matrix;Failure;Female;Fibrosis;Flow Cytometry;Fluorescein-5-isothiocyanate;Functional disorder;Future;Gelatin Zymography;Gelatinase B;Generations;Glomerular Filtration Rate;Goals;Health;Histology;Hydrogen Sulfide;Hypertension;Impairment;Infection;Inflammation;Inflammation Mediators;Inflammatory;Injury;Ischemia;Kidney;Kidney Diseases;Kidney Transplantation;Knowledge;Lasers;Lead;Lyase;Matrix Metalloproteinases;Measures;Mediating;Meprin;Mesenchymal;Messenger RNA;Metabolic;Methods;MicroRNAs;Mus;Older Population;Organ Transplantation;Outcome;Peritoneal;Phase;Physiological;Plasma;Play;Population;Prevention strategy;Process;Production;Protective Agents;Proteins;Quality of life;Renal Artery Stenosis;Renal Blood Flow;Renal function;Reperfusion Injury;Reperfusion Therapy;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Sepsis;Severities;Shock;Testing;Therapeutic;Transaminases;Transcript;Translations;Transplantation Surgery;Ultrasonography;Untranslated RNA;Up-Regulation;Vascular Diseases;Western Blotting;base;density;design;differential expression;experimental study;improved;inhibitor/antagonist;injured;kidney dysfunction;kidney fibrosis;kidney vascular structure;macrophage;male;older patient;prevent;renal ischemia;repaired;treatment strategy

public_health_relevance:
Project NarrativeIschemia-reperfusion (I/R) is the cut off and re-establishment of blood flow and is a commoncause of acute kidney injury (AKI) in a variety of health conditions including shock infectionorgan transplantation and cardiac surgery. Understanding of I/R mechanism is incomplete andtherefore treatment strategies for AKI are insufficient. This proposal is designed to delineate theunderlying mechanism of kidney I/R injury in older population and to effectively counter AKI witha hydrogen sulfide releasing compound GYY4137.


application_id: 9752421
project_number: 5U01AA026980-02
project_title: Alcoholic Hepatitis Network 3/9 University of Louisville
administering_ic: NIAAA
award_notice_date: 2019-07-25
opportunity_number: RFA-AA-18-002
application_type: 5
activity_code: U01
ic: AA
serial_number: 026980
program_official: GAO, PETER
project_start_date: 2018-08-01
project_end_date: 2023-06-30
study_section: ZAA1-JJ(01)R
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_terms:
Adrenal Cortex Hormones;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collection;Conduct Clinical Trials;Consumption;Data;Data Coordinating Center;Data Set;Databases;Development;Disease;Economic Burden;Educational workshop;Eligibility Determination;FDA approved;Foundations;Funding;Future;Goals;Granulocyte Colony-Stimulating Factor;Hepatitis B;Infection;Inflammasome;Inflammation;Informatics;Institution;Interleukin-1 Receptors;Interleukin-1 beta;Label;Laboratories;Life;Light;Literature;Liver;Liver diseases;Medical;Mission;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Observational Study;Oral cavity;Outcome;Pathogenesis;Patient Care;Patient Recruitments;Patients;Pentoxifylline;Pharmaceutical Preparations;Phase;Pilot Projects;Positioning Attribute;Predisposition;Prednisone;Public Health;Randomized;Recording of previous events;Research Design;Research Personnel;Resources;Role;Sampling;Severities;Systems Biology;Testing;Therapeutic;Therapeutic Studies;Translational Research;Treatment Efficacy;Universities;Validation;Work;Zinc;active method;anakinra;base;catalyst;drug testing;effective therapy;efficacy trial;evidence base;improved;insight;interest;liver injury;longitudinal database;meetings;mortality;new therapeutic target;novel;primary endpoint;prospective;receptor;repository;research study;secondary endpoint;standard of care;targeted treatment;therapeutic development;translational study;treatment arm


application_id: 9752193
project_number: 3R01NS070899-09S1
project_title: Regulation Signaling and Dynamics of Glucan Phosphatases
administering_ic: NINDS
award_notice_date: 2018-08-24
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: NS
serial_number: 070899
suffix: S1
program_official: LEENDERS, MIRIAM
project_start_date: 2018-09-01
project_end_date: 2019-08-31
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The goal of this project is to utilize the unique window into cellular metabolism that Lafora diseaseoffers to define both normal glycogen metabolism and disease implications when the process isdisrupted. Lafora disease (LD) one of five major progressive myoclonic epilepsies is a fatal recessiveneurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is theaccumulation of cytoplasmic hyperphosphorylated water-insoluble glycogen-like particles called Lafora bodies.These inclusions occur throughout the body but disease results from acute neurotoxicity due to the sensitivityof neurons to energy perturbations. LD is the result of loss of function mutations or mutations that causeaberrant function in either of the genes encoding the glucan phosphatase laforin or E3 ubiquitin ligase malin. We established laforin as the founding member of the glucan phosphatase family i.e. phosphatases thatdephosphorylate glycogen or starch. A laforin structure is needed to determine how reversible glycogenphosphorylation impacts glycogen metabolism and define why laforin mutations result in LD. We alsodemonstrated that malin is an E3 ubiquitin ligase and reported that malin ubiquitinates proteins involved inglycogen synthesis. However malin does not promote degradation of these enzymes and it has remainedunknown as to how malin impacts glycogen metabolism and why mutations in malin result in LD. Whilemutations in the laforin or malin gene result in LD it is increasingly recognized that multiple mechanisms leadto LD and that a spectrum of mutations yields different degrees of disease progression. Because our work hasdefined the molecular function of laforin and malin we are uniquely poised to define the clinical biochemistry ofLD mutations in both laforin and malin. Therefore we propose to:1. Determine the structural mechanism of laforin. We will utilize X-ray crystallography combined withstructure-guided mutagenesis and functional assays to determine how laforin binds to glycogen howphosphorylated glycogen is dephosphorylated laforin's role in glycogen metabolism and laforin's role in LD.2. Define the role of malin in LD and glycogen metabolism. Using multiple methods we have identifiedmalin substrates and established the type of ubiquitination as well as defined the consequences ofubiquitination for one substrate. We will define the signaling events that drive ubiquitination of malin substratesthe dynamics of the events the functional consequences and how misregulation leads to LD. We will utilizecell culture and mouse models to determine the role of malin in glycogen metabolism and LD.3. Translate current insights into patient-specific diagnosis and treatment. LD results from both missensemutations as well as Premature Termination Codons. Our initial analysis revealed that not all point mutationsabolish activity. We will utilize our biochemical tools to define mutation specific mechanisms for laforin andmalin LD mutations and explore therapeutic options using our recently developed bioassay.

project_terms:
Acute;Binding;Biochemistry;Biological Assay;Cell Culture Techniques;Cellular Metabolic Process;Clinical;Complex;Comprehension;Diagnosis;Disease;Disease Progression;Enzymes;Epilepsy;Event;Family;Genes;Glucans;Glycogen;Goals;Lafora Disease;Lead;Life;Metabolism;Methods;Missense Mutation;Molecular;Mutagenesis;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Point Mutation;Process;Progressive Myoclonic Epilepsies;Proteins;Regulation;Reporting;Role;Signal Transduction;Starch;Structure;Terminator Codon;Therapeutic;Translating;Ubiquitination;Water;Work;X-Ray Crystallography;biochemical tools;gene product;glycogen metabolism;insight;loss of function mutation;member;mouse model;neurotoxicity;particle;premature;ubiquitin-protein ligase

public_health_relevance:
The focus of our work is to determine how mutations in either of two gene products lead to thefatal neurodegenerative epilepsy called Lafora disease. Our proposal is built on our past discoveriesand uses complementary approaches to advance our understanding of the intertwined events of cellmetabolism neurodegeneration and epilepsy. Completion of this work will yield a bettercomprehension of these complex events and will allow us to translate our insights into diagnosesbioassays and treatments.


application_id: 9751917
project_number: 5P30GM127211-02
project_title: Pilot Projects Program
administering_ic: NIGMS
award_notice_date: 2019-07-23
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
study_section: ZGM1-RCB-3
subproject_number: 5343
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
budget_end_date: 2020-07-31
project_terms:
Advisory Committees;Appalachian Region;Applications Grants;Area;Biomedical Research;Cardiovascular Diseases;Categories;Centers of Research Excellence;Clinical Sciences;Clinical and Translational Science Awards;Consultations;Core Facility;Data;Development;Diabetes Mellitus;Disease;Extramural Activities;Floor;Funding;Funding Opportunities;Generations;Goals;Grant;Head;Health;Infrastructure;Institution;Kentucky;Link;Malignant Neoplasms;Mentors;Modernization;Names;Nerve Degeneration;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Peer Review;Phase;Pilot Projects;Process;Program Research Project Grants;Publications;Research;Research Personnel;Research Support;Resources;Risk Factors;Secure;Services;Standardization;Substance abuse problem;Talents;Translational Research;United States National Institutes of Health;Universities;base;biomedical facility;cancer type;design;driving force;experience;health disparity;human disease;member;multidisciplinary;operation;programs;recruit;success;translational study


application_id: 9751915
project_number: 5P30GM127211-02
project_title: Core C - Pathology
administering_ic: NIGMS
award_notice_date: 2019-07-23
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
study_section: ZGM1-RCB-3
subproject_number: 5341
contact_pi_person_id: 1879534
contact_pi: KATZ, WENDY S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
budget_end_date: 2020-07-31
project_terms:
Adipose tissue;Aging;Basic Science;Cardiovascular Diseases;Cell Count;Cell Size;Cellularity;Characteristics;Clinical Sciences;Collaborations;Collection;Communities;Computer software;Data;Diabetes Mellitus;Disease;Equipment;Fees;Fostering;Funding;Goals;Histologic;Histology;Human;Human Characteristics;Image;Image Analysis;Individual;Inflammation;Institution;Laboratory Research;Light Microscope;Link;Location;Malignant Neoplasms;Manuals;Microscope;Microtome - medical device;Morphology;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Paraffin;Paraffin Embedding;Pathologic;Pathology;Patients;Peripheral;Phase;Procedures;Protocols documentation;Reagent;Research;Research Personnel;Risk Factors;Sampling;Services;Sirius Red F3B;Slide;Specimen;Speed;Stains;Standardization;Structure;Techniques;Tissue Sample;Tissue Stains;Tissues;Training;Translational Research;Trichrome stain method;United States National Institutes of Health;Update;biobank;cardiovascular risk factor;design;experience;finesse;health assessment;high resolution imaging;histological specimens;human tissue;interest;mid-career faculty;operation;outreach program;programs;quantitative imaging;tissue processing;translational study


application_id: 9751912
project_number: 5P30GM127211-02
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2019-07-23
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
study_section: ZGM1-RCB-3
subproject_number: 5339
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
budget_end_date: 2020-07-31
project_terms:
Accounting;Achievement;Adherence;Advisory Committees;Animal Welfare;Area;Cardiovascular Diseases;Caring;Centers of Research Excellence;Comorbidity;Core Facility;Diabetes Mellitus;Ensure;Evolution;Extramural Activities;Funding;Guidelines;Kentucky;Leadership;Malignant Neoplasms;Monitor;Neurodegenerative Disorders;Obesity;Organization administrative structures;Output;Performance;Phase;Pilot Projects;Policies;Procedures;Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Risk Factors;Services;Structure;Universities;human disease;human subject protection;implementation strategy;improved;meetings;programs;research facility;success


application_id: 9751910
project_number: 5P30GM127211-02
project_title: Center of Research on Obesity and Cardiovascular Disease
administering_ic: NIGMS
award_notice_date: 2019-07-23
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127211
program_official: FRINCU, CRINA
project_start_date: 2018-08-01
project_end_date: 2023-07-31
study_section: ZGM1-RCB-3(C3)
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adipose tissue;Advisory Committees;Aging;Alzheimer's Disease;Area;Award;Basic Science;Body Composition;Cardiovascular Diseases;Cardiovascular system;Center for Translational Science Activities;Centers of Research Excellence;Chronic Disease;Clinical Research;Clinical Sciences;Comorbidity;Core Facility;Death Rate;Development;Diabetes Mellitus;Diet;Disease;Equipment;Etiology;Evaluation;Extramural Activities;Fostering;Funding;Gills;Goals;Growth;High Prevalence;Hypertension;Infrastructure;Institutes;Institution;Kentucky;Limb structure;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mentors;Morphology;Mus;Neurodegenerative Disorders;Neurosciences;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathology;Phase;Physicians;Pilot Projects;Prevalence;Publications;Publishing;Request for Applications;Research;Research Infrastructure;Research Personnel;Research Support;Risk;Risk Factors;Scientist;Services;Strategic Planning;System;Technology;Tissues;Translating;Translational Research;United States National Institutes of Health;Universities;cancer research center director;cardiovascular risk factor;clinical care;energy balance;experience;health disparity;human disease;improved;obesity development;programs;research facility;small molecule;success;targeted treatment;therapy development;voucher


application_id: 9751862
project_number: 5R01EY021769-07
project_title: Vertebrate photoreceptor development and regeneration
administering_ic: NEI
award_notice_date: 2019-07-16
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 021769
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2023-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adoption;Animal Model;Biochemical;Biology;Blindness;Cell Differentiation process;Cell Proliferation;Cell Transplantation;Cell Transplants;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Cone;Data;Defect;Development;Developmental Biology;Disease;Embryo;Event;Evolution;Eye diseases;Family;Gene Targeting;Genetic;Genetic Diseases;Genetic Transcription;Goals;Health;Homologous Gene;Human;Image;In Vitro;Inherited;Injury;Laboratories;Mammals;Mediating;Microphthalmos;Modeling;Molecular;Molecular Genetics;Molecular Target;Morphogenesis;Morphology;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Optics;Pathway interactions;Photoreceptors;Protocols documentation;Regulator Genes;Retina;Retinal;Retinal Cone;Retinal Degeneration;Retinal Dystrophy;Retinitis Pigmentosa;Role;SOX11 gene;SOX4 gene;Signal Pathway;Signal Transduction;Suggestion;System;Therapeutic;Time;Transcription Repressor/Corepressor;Transgenic Organisms;Transplantation;Vascular Endothelial Growth Factors;Vertebrate Photoreceptors;Visual;Visual impairment;Visual system structure;Work;Zebrafish;base;cellular imaging;clinical application;dosage;experimental study;gene therapy;genetic approach;genome editing;imaging modality;improved;in vivo;loss of function;member;mouse genome;mutant;neurogenesis;notch protein;novel;optic cup;photoreceptor degeneration;precursor cell;response;retinal neuron;retinal progenitor cell;retinal rods;stem cell differentiation;therapy development;transcription factor


application_id: 9751356
project_number: 5R01HG008988-04
project_title: Addressing Ethical Challenges in Networked Biorepositories
administering_ic: NHGRI
award_notice_date: 2019-07-26
opportunity_number: PA-14-276
application_type: 5
activity_code: R01
ic: HG
serial_number: 008988
program_official: LOCKHART, NICOLE C
project_start_date: 2016-09-28
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZRG1-SEIR-R(01)Q]
contact_pi_person_id: 10692185
contact_pi: BROTHERS, KYLE BERTRAM
other_pis: GOLDENBERG, AARON J
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTIndividual institutions across the country have worked to support research in a wide variety of areas includingprecision medicine research by developing large biorepositories comprised of biospecimens and health datacollected from local patients and controls. However these local cohorts rarely provide the diversity and sizeneeded to identify and study subsets of patients who share biological mechanisms for their disease and arethus more likely to respond to the same targeted therapies. To address this need researchers have begun topromote the networking of multiple repositories within or across multiple institutions. This networkedbiorepository approach makes it possible for researchers to access larger more diverse sets of data andbiospecimens in a way that leverages the research relationships that local institutions have built with their owncommunities of donors. In order for this approach to be successful networked biorepositories need to addressimportant ethical legal and social challenges. Networked biorepositories are comprised of diverse sets ofspecimens and data from different institutions each with their own governance structures and donor needs.For these reasons they encounter complex issues related to consent and donor permission privacy and datasecurity and data access. These novel challenges have not previously been examined in detail and bestpractices for addressing these issues through governance and oversight processes are lacking. This study willaddress these important needs through a rigorous mixed-methods study of the perspectives and experiencesof stakeholders currently engaged in designing operating and governing networked biorepositories. It will alsoaim to develop approaches to consent and donor permission privacy and data security data accessgovernance and oversight that are most appropriate and effective for a variety of networked biorepositoryconfigurations.

project_terms:
Address;American;Area;Authorization documentation;Biological;Collection;Communities;Complex;Consent;Country;Data;Data Security;Data Set;Development;Disease;Elements;Ethics;Focus Groups;Future;Genetic Variation;Health;Human Resources;Individual;Institution;Interview;Knowledge;Link;Literature;Medical;Methods;National Human Genome Research Institute;Participant;Patients;Persons;Policies;Precision Medicine Initiative;Privacy;Problem Solving;Process;Rare Diseases;Recommendation;Research;Research Personnel;Research Support;Resources;Sampling;Specimen;Structure;Time;Work;biobank;cohort;data access;data sharing;design;ethical legal social implication;experience;health data;informant;interest;meetings;network models;novel;patient subsets;personalized health care;precision medicine;preservation;prospective;repository;structural genomics;symposium;targeted treatment;tool

public_health_relevance:
PROJECT NARRATIVENetworked biorepositories make it possible for investigators in a wide variety of research domains to accesslarge diverse collections of biospecimens and health data across multiple institutions. At the same time theyalso raise complex issues related to consent and donor permission privacy and data security and dataaccess. Developing a detailed account of these challenges and identifying appropriate solutions includingeffective governance and oversight processes will enable new and developing networked biorepositories tosupport important health research while at the same time meeting the needs of donors and protecting theinterests of contributing institutions.


application_id: 9751303
project_number: 5R21ES028752-02
project_title: Role of EHMT2 in tobacco smoke-induced epithelial barrier dysfunction
administering_ic: NIEHS
award_notice_date: 2019-07-22
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: ES
serial_number: 028752
program_official: TYSON, FREDERICK L
project_start_date: 2018-08-01
project_end_date: 2022-07-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
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 SummaryEpithelial barrier dysfunction contributes to the pathogenesis of infection inflammation andinjury. E-Cadherin a component of epithelial adherens junctions plays an essential role inmaintaining epithelial barrier function. Cigarette smoke exposure has been reported todownregulate E-Cadherin expression in epithelial cells. However molecular mechanisms ofcigarette smoke-induced suppression of E-Cadherin expression and epithelial barrierdysfunction remain largely unknown. In this project we will investigate the role of a histonemethyltransferase euchromatic histone-lysine N-methyltransferase 2 (EHMT2 or G9a) incigarette smoke-induced E-cadherin downregulation and epithelial barrier dysfunction. EHMT2specifically methylates Histone H3 at lysine 9 (H3K9). Methylation of H3K9 by EHMT2 regulatesgene expression by silencing euchromatin. Our preliminary data demonstrate that EHMT2expression is robustly up-regulated in cigarette smoke-exposed normal human bronchialepithelial cells (NHBEs). The up-regulation of EHMT2 is associated with high levels of H3K9methylation and E-Cadherin downregulation. EHMT2 knockdown or selective inhibition was ableto restore E-Cadherin expression in cigarette smoke-exposed NHBEs. Furthermore in a mousemodel of cigarette smoke exposure lung EHMT2 expression and H3K9 methylation wereincreased which was associated with E-cadherin downregulation and epithelial barrierdisruption in lung tissues. In the proposed studies we will test we will test the hypothesis thatEHMT2 up-regulation by chronic tobacco smoke exposure leads to epigeneticsuppression of E-Cadherin expression and epithelial barrier dysfunction. Our specificaims are: (1) To determine the role of EHMT2 in epigenetic suppression of E-Cadherinexpression and epithelial barrier dysfunction in tobacco smoke-exposed humanbronchial epithelial cells. (2) To explore therapeutic mechanisms of EHMT2 inhibitionagainst tobacco smoke-induced epithelial barrier dysfunction in vivo. Our studies couldreveal new therapeutic targets to treat environmental tobacco smoke-induced epithelial celldysfunction.

project_terms:
Adherens Junction;Cardiovascular Diseases;Cells;Cellular Structures;Chronic;Data;Defect;Disease;Down-Regulation;E-Cadherin;Environmental Tobacco Smoke;Epigenetic Process;Epithelial;Epithelial Cells;Euchromatin;Exposure to;Functional disorder;Gene Expression;Gene Expression Regulation;Histone H3;Histone-Lysine N-Methyltransferase;Human;Infection;Inflammation;Injury;Intercellular Junctions;Lung;Lung diseases;Lysine;Methylation;Modification;Molecular;Pathogenesis;Play;Reporting;Role;Structure of parenchyma of lung;Testing;Therapeutic;Tobacco smoke;Toxic Environmental Substances;Up-Regulation;airway epithelium;cadherin 10;cigarette smoke;cigarette smoke-induced;environmental tobacco smoke exposure;exposed human population;exposure to cigarette smoke;histone methyltransferase;histone modification;in vivo;interstitial;knock-down;mouse model;new therapeutic target;novel;prevent;promoter;recruit;therapeutic target

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal epigenetic induction of epithelial barrier dysfunctionby EHMT2 as a novel mechanism of tobacco smoke-induced diseases. The results will validate the potentialof EHMT2 as a therapeutic target to treat epithelial barrier dysfunction induced by environmental tobaccosmoke exposure.


application_id: 9750847
project_number: 5R01NS094741-05
project_title: Mechanisms controlling distinct modes of adult axon growth
administering_ic: NINDS
award_notice_date: 2019-07-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 094741
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2015-09-01
project_end_date: 2021-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Affecting axonal growth as a means to enhance recovery and alleviate pathology in conditions of nervous system injury insult or disease is a major goal for the healthcare and biomedical research endeavors. Significant effort is directed at inducing neural plasticity to enhance axonal growth to establish functionally- adaptive connections. However these efforts must also prevent and not induce maladaptive plasticity a balance which requires a clear understanding of the processes regulating axon growth. A major factor confounding efforts to understand neural plasticity is that the traumatically-injured nervou system contains both directly-injured axons and the NON-injured axons. This project examines the long-standing question and controversy regarding the mechanisms of the two major forms of axon growth in the adult nervous system - growth of injured axons (Regeneration) and that of non-injured axons (Collateral Sprouting - CS). We aim to objectively determine the degree to which the intrinsic molecular mechanisms controlling these processes are similar or different. Doing so will enable identification of sets of genes which control a specific mode and may thus be targeted to affect just that one mode or may be shared between modes and thus targeted to affect both and could identify an entire new set of genes capable of regulating adult axonal plasticity.  Axonal Regeneration and CS are both relatively robust in the PNS and the injured and non-injured neurons can be clearly separated. Nerve crush provides a model of successful axon regeneration. Using the spared dermatome model (where intact non-injured neurons of a single dorsal root ganglion are induced to grow by denervating the skin bordering their dermatome) we have generated a transcriptomic profile of genes regulated during CS. Bioinformatic analyses indicate that the genes involved in regeneration and CS are highly distinct. Preliminary data using mice with genetic deletion of transcription factors (TFs) that appear to be specific for each axon growth mode supports the concept that the growth modes involve separate genetic programs. Aim 1 will use mice with mode-specific-TF knockout to thoroughly examine the impact of the gene- deletions on the different modes of axon growth using behavioral and histological assessments of axon growth. This will determine if the flagship mode-specific-TFs are indeed responsible for controlling that single mode.  We have data demonstrating 1) a mutually-exclusive expression of the mode-specific TFs and 2) that "conditioning" with one mode of growth appears to influence the functional execution of the other mode. This is rational considering that there must be a large change in which genes are expressed and proper orchestration of such a significant change could be delayed or prevented. Aim 2 will test the hypothesis that the modes negatively-influence each other and involve mutually-exclusive genetic programs by alternately applying the different models to the same neurons (i.e. regeneration-then-sprouting or sprouting-then-regeneration). This will determine how execution of one mode influences the other.  For both Aims experimental outcomes in accord with preliminary data would strongly support the concept that there are indeed two different growth modes each with distinct genetic control. Outcomes contrary to preliminary data could include 1) effects on some neural populations but not others which would suggest that there may still be distinct modes with distinct genetic control but that these modes may be based not on injury- status but on cell-type and/or 2) that the apparent mode-specific genetic control systems act as facilitators but are not necessary (i.e. in their absence the processes occur anyway but much more slowly) which would suggest that there are not necessarily two fully-distinct modes. All outcomes will serve to address both the conceptual framework and the specific molecular control regarding axon growth in the adult nervous system.

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

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


application_id: 9750769
project_number: 5R01ES026151-05
project_title: The epigenetic mechanism of hexavalent chromium carcinogenesis
administering_ic: NIEHS
award_notice_date: 2019-08-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: ES
serial_number: 026151
program_official: TYSON, FREDERICK L
project_start_date: 2016-09-01
project_end_date: 2021-08-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9719630
contact_pi: YANG, CHENGFENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTHexavalent chromium [Cr(VI)] is one of the most common environmental pollutants causing lung and othercancer. The mechanism of Cr(VI) carcinogenesis has not been elucidated. The long-term goal of this study is todetermine the mechanism of Cr(VI) carcinogenicity and identify targets for better treatment and prevention oflung cancer resulting from Cr(VI) exposure. Epigenetics refers to heritable changes in the pattern of geneexpression that are not caused by changes in DNA sequence but are mediated by DNA methylation histoneposttranslational modifications microRNAs and long noncoding RNAs. Cancer stem cells (CSCs) are cancercells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiatingcells. Genomic imprinting refers to an epigenetic mechanism by which certain genes are expressed in a parent-of-origin-specific manner restricting their expression from only one of the two parental chromosomes. Manystudies demonstrated that deregulation of epigenetics and genomic imprinting plays key roles in carcinogenesis.Accumulating evidence shows that Cr(VI) also causes epigenetic effects such as changing DNA methylation andhistone posttranslational modifications. However the mechanisms by which Cr(VI) triggers these epigeneticmodifications remain largely unknown and whether these epigenetic modifications play a causal role in Cr(VI)carcinogenesis are not clear. Our preliminary studies found: (i) Chronic Cr(VI) exposure induces CSC-likeproperty and cell malignant transformation; (ii) Chronic Cr(VI) exposure increases the levels of several HMTaseswhich play a causal role in Cr(VI)-induced CSC-like property and cell transformation; (iii) Higher levels of H3repressive methylation marks and their related HMTases are also detected in lung cancer tissues of humansexposed to chromium; (iv) Up-regulation of HMTases plays a crucial role in chronic Cr(VI) exposure-causedderegulation of Dlk1-Dio3 genomic imprinting cluster; (v) miR-494 down-regulation plays a causal role in Cr(VI)-induced cell transformation; and (vi) Oxidative stress increases the levels of HMTases. Based on literature andour preliminary data we hypothesize: (i) Cr(VI) exposure generates oxidative stress which increases the levelsof HMTases; (ii) Up-regulation of HMTases deregulates the Dlk1-Dio3 genomic imprinting cluster whichdecreases the level of miR-494; and (iii) Down-regulation of miR-494 increases the levels of its targets and keyCSC factors c-Myc and BMI1 which produce CSC-like property promoting Cr(VI)-induced cell transformation andtumorigenesis. This proposed study not only fills the knowledge gap of epigenetics and Cr(VI) carcinogenesisbut also provides novel mechanistic insights for the crucial role of oxidative stress in Cr(VI) carcinogenesis. Threeaims are proposed: Aim 1: Induction of CSC-like property by down-regulating miR-494 of Dlk1-Dio3 imprintingcluster and its role in Cr(VI)-induced cell transformation and tumorigenesis. Aim 2: Down-regulation of miR-494by chronic Cr(VI) exposure-induced HMTases through deregulating Dlk1-Dio3 genomic imprinting cluster. Aim 3:Up-regulation of HMTases by chronic Cr(VI) exposure through oxidative stress.

project_terms:
Affect;BMI1 gene;Cancer Etiology;Cells;Characteristics;Chromium;Chromosomes;Chronic;Country;Cultured Cells;DNA Methylation;DNA Modification Methylases;DNA Sequence;Data;Down-Regulation;EZH2 gene;Elements;Environmental Health;Environmental Pollutants;Epigenetic Process;Epithelial Cells;Exposure to;Gene Expression Profile;Genes;Genomic Imprinting;Goals;Heritability;Histone H3;Histones;Human;Impairment;Inherited;Knowledge;Literature;Lung;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Methylation;MicroRNAs;Modification;Occupational;Oxidative Stress;Parents;Play;Post-Translational Protein Processing;Promoter Regions;Property;Rattus;Reactive Oxygen Species;Regulation;Role;Stem Cell Factor;Stem cells;Tumor Suppressor Genes;Tumor Tissue;United States;Untranslated RNA;Up-Regulation;base;c-myc Genes;cancer cell;cancer stem cell;carcinogenesis;carcinogenicity;cell transformation;chromium hexavalent ion;genotoxicity;histone methyltransferase;human tissue;imprint;insight;lung cancer prevention;novel;overexpression;pollutant;recruit;stem-like cell;tumorigenesis;tumorigenic

public_health_relevance:
PROJECT NARRATIVEHexavalent chromium [Cr(VI)] is one of the most common environmental and occupational pollutants andexposure to Cr(VI) is a major environmental health concern affecting millions of people in the United States aswell many other countries. The goal of this study is to determine the epigenetic mechanism by which Cr(VI)exposure causes cancer.


application_id: 9750758
project_number: 5R01DK074720-12
project_title: Novel mechanisms involving complement cascade in stem cell trafficking
administering_ic: NIDDK
award_notice_date: 2019-07-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: ROY, CINDY
project_start_date: 2007-03-01
project_end_date: 2021-06-30
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
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:
Modified Project Summary/Abstract SectionThe main hypothesis of this competing renewal is based on new exciting data that further supports the pivotalrole of the complement cascade (ComC) and other elements of innate immunity in the mobilization ofhematopoietic stem/progenitor cells (HSPCs). The ComC is activated by the i) classical ii) mannan-bindinglectin (Mbl) and iii) alternative pathways and as we already reported mice that lack the common distalcomponent of the ComC (C5/ mice) are poor mobilizers. To our surprise however we found that mice thatdo not activate the classical ComC (C1q/ mice) are normal mobilizers. This discrepancy is now explained byour latest results that show the pivotal involvement of the Mbl-dependent ComC pathway and not the classicalpathway in mobilization. We also recently found that two stress-induced enzymes heme oxygenase 1 (HO-1)and inducible nitric oxide synthetase (iNOS) are negative regulators of cell migration. Based on these findingswe have assembled a proposal that in a comprehensive way addresses the involvement of elements of innateimmunity (ComC Gr-1+ granulocytes/monocytes naturally occurring antibodies) in the mobilization of HSPCs.In three interrelated specific aims we address the crucial: i) inititation ii) amplification and execution phases ofmobilization. Specific Aim 1. The initiation phase of mobilization is explained by Mbl-mediated ComCactivation. We have maintained that the classical ComC activation pathway plays a crucial role in triggeringmobilization. However as we discovered recently it is not the classical but the Mbl pathway that is crucial inthis process. The main target cells for mobilizing agents are Gr-1+ cells which in addition to proteolytic andlipolytic enzymes also secrete ROS and danger-associated molecular pattern molecules (DAMPs). Whileproteolyic and lipolytic enzymes perturb the retention of HSPCs in bone marrow (BM) niches ROS-exposedneoepitope antigens bound by naturally occurring IgM antibodies and DAMPs released from Gr-1+ cells arerecognized by the circulating pattern recognition receptor (PRR) Mbl which via mannan-binding lectin serineproteases (MASPs) activates the ComC and coagulation cascade (CoaC). Specific Aim 2. The amplificationphase of mobilization - the generation of C5 convertase. Since C5 cleavage is crucial for egress of HSPCsfrom BM the main function of this phase is generation of C5 convertase activity. This enzyme is generated asa result of C3 cleavage which provides elements of classical C5 convertase and additionally by thrombinwhich has C5 convertase-like activity. The amplification phase is also modulated by a spontaneousamplification loop of C3 activation and by possible involvement of an alternative pathway of ComC activationand will be studied in detail in this aim. Specific Aim 3. Execution phase of ComC-mediated mobilization.Our recent results show that egress of HSPCs from BM is negatively controlled by HO-1 and iNOS which arenegative regulators of cell migration. We will focus on the molecular mechanisms of this phenomenon. It isexpected that these results will be translated into the development of better mobilization protocols.1

project_terms:
Address;Alternative Complement Pathway;Animal Model;Antibodies;Blood Circulation;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell physiology;Cells;Chemotactic Factors;Circadian Rhythms;Coagulation Process;Complement;Complement 1q;Complement 3 Convertase;Complement Activation;Complement Factor H;Data;Defect;Development;Distal;Elements;Engraftment;Enzymes;Generations;Growth Factor;Hematology;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Immunoglobulin M;Integrin alpha4beta1;Integrins;Ligands;Mannose Binding Lectin;Mediating;Molecular;Mus;Natural Immunity;Nitric Oxide;Nitric Oxide Synthase;Pathway interactions;Patients;Pattern;Pattern recognition receptor;Pharmacology;Phase;Physiological;Play;Process;Properdin;Protocols documentation;Reporting;Research;Role;Stem cells;Stress;Testing;Thrombin;Translating;Transplantation;Vascular Cell Adhesion Molecule-1;antigen binding;base;cell motility;conditioning;granulocyte;heme oxygenase-1;leukemia;mannose-binding protein-associated serine proteases;monocyte;neoantigens;novel;novel therapeutics;peripheral blood;pre-clinical;public health relevance;reconstitution;small molecule inhibitor;trafficking

public_health_relevance:
Modified Public Health Relevance SectionIn this proposal we will focus on the role of a major component of innate immunity namely the complementcascade in the trafficking of hematopoietic stem/progenitor cells. This application will allow us to betterunderstand this process and will lead to the development of novel therapeutic strategies to treat patients withleukemia and inborn defects of hematopoiesis by employing hematopoietic stem cell transplants.2


application_id: 9750673
project_number: 5U01DA043908-02
project_title: Development of Novel Therapeutics for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2019-06-14
opportunity_number: PAR-16-431
application_type: 5
activity_code: U01
ic: DA
serial_number: 043908
program_official: ACRI, JANE
project_start_date: 2018-08-01
project_end_date: 2021-07-31
study_section: ZDA1-IXN-O(09)S
contact_pi_person_id: 1878605
contact_pi: DWOSKIN, LINDA P
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Methamphetamine (METH) use disorder is linked to dire health and societal consequences. Effective treat-ments for METH addiction are not available. METH interacts with the vesicular monoamine transporter-2(VMAT2) promoting dopamine (DA) release into the cytosol and reversal of the DA transporter to increase ex-tracellular DA resulting in abuse liability. This project focuses on VMAT2 as a novel therapeutic target with theoverall goal of obtaining a treatment for METH use disorder. Phase 1b studies with lobeline the initial leadwere completed; however bitter taste and multiple daily doses were expected to reduce compliance. Lobelinewas modified to obtain GZ-793A which had the desired pharmacology but also had hERG toxicity. We nextidentified novel small molecules GZ-11608 and JPC-077 with greatly reduced hERG interaction and with po-tent and selective inhibition of VMAT2 function and METH-evoked DA release. These new leads specificallydecrease METH self-administration and METH-induced reinstatement in rats at doses that do not alter foodreinforcement suggesting efficacy against relapse. Tolerance does not develop upon repeated dosing. Theseanalogs protect against or do not exacerbate METH-induced striatal DA neurotoxicity. Despite this favorablepharmacologic profile these analogs have low oral bioavailability. Thus this proposal focuses on the discov-ery/development of optimized GZ-11608 and JPC-077 analogs with increased oral bioavailability. First we willsubstitute deuterium for hydrogen at sites of metabolic liability. If deuterium substitution is not successful wewill use rational design to synthesize a focused library based on each lead. Chemoinformatics incorporatingrefined models based on our library of ~520 VMAT2-targeted compounds was used to predict optimized ana-logs with decreased metabolic liability and desirable drug-like properties. Each analog from deuterium substi-tution and medchem approaches will be synthesized and evaluated for selective inhibition of VMAT2 as wellas metabolism. We will then assess the pharmacokinetics (PK) to determine oral bioavailability plasma andbrain concentrations and estimate PK parameters following IV PO and SC dosing. Metabolites exceeding 10%will be synthesized and evaluated for toxicity and potential use as active pharmaceutical ingredient. We willthen determine the dose-related inhibition of METH self-administration and reinstatement. Development of tol-erance following repeated administration will be determined. We will conduct abbreviated toxicology studiesand assess the potential for off-target interactions and CYP450 inhibition/induction. We will relate the pharma-cokinetics of optimized analogs to pharmacodynamic effects and determine the maximum tolerated dose ther-apeutic index and behavioral specificity. Completion of this optimization program will allow for immediate tran-sition of our leads into IND-enabling studies. Successful completion of the project should have a tremendouslybeneficial health and socioeconomic impact on society since currently there are no available treatments forMETH use disorder.

project_terms:
Acute;Animal Model;Back;Behavioral;Biological Assay;Biological Availability;Brain;Chemical Structure;Clinical Research;Corpus striatum structure;Cytosol;Data;Deuterium;Development;Disease;Dopamine;Dose;Drug Kinetics;Epidemic;Exhibits;Female;Food;Formulation;Gender;Goals;Health;Human;Hydrogen;Investigational Drugs;Kinetics;Lead;Libraries;Link;Liver Microsomes;Lobeline;Maximum Tolerated Dose;Metabolic;Metabolism;Methamphetamine;Methamphetamine dependence;Modeling;Molecular Bank;Norepinephrine;Oral;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Phase;Plasma;Process;Property;Psychological reinforcement;Rattus;Relapse;Self Administration;Serotonin;Site;Slice;Societies;Specificity;Structure;Synaptic Vesicles;Taste Perception;Therapeutic Index;Toxic effect;Toxicology;Training;Translations;Treatment Efficacy;analog;base;design;dopamine transporter;drug development;drug discovery;effective therapy;extracellular;inhibitor/antagonist;lead optimization;methamphetamine abuse;methamphetamine use;methamphetamine user;neurotoxicity;new therapeutic target;novel;novel therapeutics;programs;scaffold;small molecule;socioeconomics;uptake;vesicular monoamine transporter 2

public_health_relevance:
Methamphetamine use disorder is linked to dire health and societal consequences. The goal of this project is todevelop a treatment for methamphetamine use disorder by focusing on the vesicular monoamine transporter-2as a novel therapeutic target and by completing an optimization program that will allow for immediate transitionof our lead compounds into late stage Investigational New Drug enabling studies. Successful completion of theproject should have a tremendously beneficial health and socioeconomic impact on society since currently thereare no available treatments for METH use disorder.


application_id: 9750672
project_number: 5R01DK112136-03
project_title: Community to Clinic Navigation to Improve Diabetes Outcomes
administering_ic: NIDDK
award_notice_date: 2019-08-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 112136
program_official: THORNTON, PAMELA L
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTReducing adverse outcomes from Type 2 Diabetes Mellitus (T2DM) requires optimal self-management andappropriate clinical care.1 Combining an evidence-based intervention to improve diabetes self-managementwith individually-tailored patient navigation to improve appropriate clinical care holds great promise. Only oneknown randomized controlled trial has been tested that combines these two most essential components ofdiabetes control. That trial resulted in improvements to glycemic control blood pressure and diabetes self-management but was implemented in a clinical setting.2 We aim to enhance this work by recruiting from andlocating most research activities in community-based settings to insure involvement of the most vulnerablehardest to reach populations who may not be receiving regular health care and by leveraging CommunityHealth Workers and Patient Navigators who are essential and sustainable outreach workers in health careprofessional shortage areas.We propose testing a refined intervention Community to Clinic Navigation (CCN) shown to be promisingfeasible and acceptable in our pilot study. Given that Appalachian and rural residents maintaindisproportionately high rates of T2DM and suffer tremendous burdens from diabetic complications3 this settingprovides a perfect opportunity to test the intervention with a hard to reach population while addressing healthinequities. We will administer a 3 arm group randomized design including (1) Diabetes Self-managementProgram DSMP only; (2) tailored Patient Navigation PN only; and (3) the combined DSMP + PN: Communityto Clinic Navigation program CCN. Outcomes include biometrics (HbA1c BMI blood pressure lipids waistcircumference); diabetes self-management and clinic attendance as mediators of the primary outcomes; costeffectiveness and participant satisfaction. Persons with diabetes will be recruited through churches and othercommunity venues. Our project leverages sustainable assets available in most health disparity communities--faith organizations community centers federally qualified health clinics strong social ties and talented locallay people who can be trained to educate and navigate those diagnosed with T2DM. Our sustainedinvolvement in Appalachian Kentucky positions our team to appropriately and efficiently test this promisingprogram with strong potential for future dissemination to other traditionally underserved environments.

project_terms:
Address;Affect;American;Appalachian Region;Biometry;Blood Pressure;Church;Clinic;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Data;Diabetes Mellitus;Diagnosis;Education;Environment;Epidemic;Evidence based intervention;Focus Groups;Future;Glycosylated hemoglobin A;Goals;Health;Health care facility;Healthcare;Individual;Influentials;Intervention;Interview;Kentucky;Lipids;Low income;Mediator of activation protein;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Positioning Attribute;Prediabetes syndrome;Protocols documentation;Randomized;Randomized Controlled Trials;Recruitment Activity;Research;Research Activity;Rural;Rural Population;Self Management;Social support;Talents;Testing;Training;Vulnerable Populations;Work;adverse outcome;arm;base;behavioral outcome;clinical care;community center;community setting;cost effectiveness;design;diabetes control;evidence base;glycemic control;health care quality;health care service organization;health disparity;health professional shortage areas;improved;improved outcome;innovation;low socioeconomic status;meetings;member;outreach;primary outcome;programs;randomized trial;recruit;relative cost;rural dwellers;satisfaction;self-management program;social;theories;waist circumference

public_health_relevance:
PROJECT NARRATIVESince diabetes has reached epidemic proportions in the US especially among low income and rural residentswe aim to test a refine and promising program called Community to Clinic Navigation (CCN) that combinesdiabetes self-management education with tailored patient navigation to improve clinical care. To ourknowledge no one has ever combined these two approaches which is surprising because these are the mostimportant ways to manage and control diabetes. If this theory-based culturally appropriate intervention showsimprovement in physical and behavioral outcomes then CCN can easily be applied to other communities withhealth disparities.1


application_id: 9750566
project_number: 5U01AA022618-04
project_title: Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation
administering_ic: NIAAA
award_notice_date: 2019-09-05
opportunity_number: PAR-13-133
application_type: 5
activity_code: U01
ic: AA
serial_number: 022618
program_official: WANG, JOE
project_start_date: 2016-08-15
project_end_date: 2021-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Long-term excessive use of alcohol is capable of damaging nearly every organ and system in the body. The adverse effects of chronic alcohol consumption on the brain include not only psychiatric disorders but also severe alcohol-related neuroinflammation and brain damage. Work done by us and others has shown that chronic alcohol exposure causes intestinal oxidative stress epithelial barrier disruption enhancement of gut leakiness and consequent systemic endotoxemia and inflammation. Our recent work has begun to identify specific alcohol-induced alterations in enteric microbiota (dysbiosis) and shows that chronic alcohol consumption leads to a significant expansion of pathogenic gram-negative bacteria that may lead to the development of systemic endotoxemia. Moreover our earlier work has shown that chronic alcohol exposure increases the expression and activity of phosphodiesterase-4 (PDE4) decreases cellular cAMP and primes monocytes/macrophages leading to exaggerated expression of endotoxin-inducible inflammatory cytokines such as TNFa. Additionally alcohol exposure leads to a deficiency in brain docosahexanoeic acid (DHA) which likely contributes to the development/augmentation of cerebral inflammation and neurodegenerative pathologies. We hypothesize that alcohol-mediated enteric dysbiosis systemic endotoxemia and elevated inflammatory responses induce/exacerbate alcohol-associated neuropathologies via TLR4- and PDE4-mediated signaling DHA deficiency microglial activation neuroinflammation and injury. The proposed study is an intramural-extramural collaborative effort that combines the relevant expertise to investigate the complex interactive mechanisms involving intestinal dysbiosis systemic endotoxemia and inflammatory responses (UofL) and cerebral DHA deficiency in alcohol-induced neuropathologies (NIAAA). Moreover a translational aspect will examine the therapeutic potential of specific mechanism-based strategies in mitigating alcohol-induced injury. The Specific aims of the application are: Aim 1: Determine alcohol mediated changes in the gut bacterial composition and intestinal permeability and correlate these changes to the development of peripheral endotoxemia and brain inflammation. Aim 2: Examine the role of PDE4 in alcohol-induced brain inflammatory signaling associated with DHA deficiency and injury. Aim 3: Evaluate the therapeutic efficacy of three intervention strategies targeting (i) enteric dysbiosis (ii) PDE4 activity and (iii) DHA deficiency in attenuating alcohol mediated brain inflammation and injury.

project_terms:
16S ribosomal RNA sequencing;Acids;Adverse effects;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcohols;Animals;Anti-inflammatory;Astrocytes;Attenuated;Bacteria;Brain;Brain Injuries;Cells;Cerebrum;Chronic;Complex;Cyclic AMP;Data;Development;Diet;Encephalitis;Endotoxemia;Endotoxins;Enteral;Epithelial;Ethanol;Extramural Activities;Feedback;Functional disorder;Gene Expression;Gram-Negative Bacteria;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intervention;Intestinal permeability;Intestines;Knockout Mice;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Leaky Gut;Link;Mediating;Membrane;Mental disorders;Microglia;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Omega-3 Fatty Acids;Oxidative Stress;PDE4B;Pathogenicity;Pathology;Peripheral;Permeability;Play;Populations at Risk;Preventive;Probiotics;Process;Production;Proteins;Proteobacteria;Role;Rolipram;Signal Transduction;Supplementation;TLR4 gene;TNF gene;Therapeutic;Tight Junctions;Treatment Efficacy;Universities;Work;alcohol effect;alcohol exposure;bacterial community;base;body system;brain cell;chronic alcohol ingestion;cytokine;dysbiosis;feeding;gut microbiome;gut microbiota;immune activation;inhibitor/antagonist;macrophage;metagenomic sequencing;monocyte;neuroinflammation;neuropathology;next generation sequencing;phosphodiesterase IV;prevent;probiotic supplementation;public health relevance;sequencing platform;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Recent work indicates that the brain is an important target for alcohol-induced damage and is often associated with gut-generated signals. Findings from this project could provide important mechanisms by which alcohol-induced pathology in the gut influences the brain inflammatory responses often observed in alcohol abuse. Moreover the findings from this study would be significant in the development of successful preventive and therapeutic strategies in most-at-risk populations.


application_id: 9750082
project_number: 5R01AG055359-03
project_title: Mechanisms mediating severity of acute pancreatitis in the aged
administering_ic: NIA
award_notice_date: 2019-05-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AG
serial_number: 055359
program_official: WILLIAMS, JOHN
project_start_date: 2017-09-01
project_end_date: 2022-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this project is to understand the mechanisms leading to the development of severe acutepancreatitis (sAP) a life-threatening illness with high mortality characterized by necrotizing pancreas severesystemic inflammation coagulation multiple organ dysfunction syndrome (MODS). AP is a particularly seriousdisease among the elderly as both incidence and the likelihood for progression to sAP increases dramaticallywith advancing age. Despite recognition of this clinical problem little is known regarding the underlyingbiological mechanisms of this disease or why progression to sAP is more common among elderly patients. Werecently developed an aged mouse model of AP in which only aged mice exhibit sAP that parallels clinicalobservations including prolonged systemic inflammation coagulation MODS and fatality. Our observationswith this mouse model include a dramatic age-dependent increase in tissue damage and cytokine geneexpression within visceral adipose tissue and elevated levels of free fatty acids in the ascitic fluid. Collectivelythese findings suggest that visceral adipose tissues are key mediators promoting the progression of AP to sAPin the aged. The central hypothesis of this project is that aged animals are more prone to develop sAP due topronounced visceral adipose tissue inflammation caused by leakage of pancreas-derived digestive enzymesinto the peritoneum from the damaged pancreas. AP-induced adipose tissue inflammation results in release offree fatty acids inflammatory cytokines and pro-thrombotic factors all promoting MODS. Our hypothesis willbe tested in the following three specific aims: To determine features of visceral adipose tissue inflammation inaged animals with sAP (Aim 1); To demonstrate that increased visceral adipose tissue inflammation promotesthe progression of AP to sAP in the aged (Aim 2); and To develop strategies to prevent the progression of APto sAP in aged animals by suppressing adipose tissue inflammation (Aim 3).

project_terms:
Adipocytes;Adipose tissue;Affect;Age;Agonist;Animal Model;Animals;Antibodies;Area;Biological;Blood Circulation;Cells;Cessation of life;Characteristics;Clinical;Coagulation Process;Creatinine;Cytokine Gene;Development;Diagnostic;Disease;Elderly;Enzymes;Excision;Exhibits;Extravasation;Foundations;Gene Expression;Immune;Incidence;Infiltration;Inflammation;Inflammatory;Injury;Interleukin-6;Intraperitoneal Injections;Kidney;Life;Link;Lipase;Lipolysis;Lung;Mediating;Mediator of activation protein;Modeling;Multiple Organ Failure;Mus;Mutant Strains Mice;Necrosis;Nonesterified Fatty Acids;Organ;PPAR alpha;Pancreas;Pathologic;Peritoneal;Peritoneal Fluid;Peritoneum;Phase;Plasminogen Activator Inhibitor 1;Prevention strategy;Production;Public Health;Research;Risk;Severities;Source;Testing;Therapeutic;Thrombosis;Tissues;Visceral;Visceral fat;acute pancreatitis;age related;aged;cytokine;effective therapy;experimental study;inhibitor/antagonist;mortality;mouse model;older patient;prevent;release factor;therapeutic development;treatment strategy

public_health_relevance:
PROJECT NARRATIVEThis project is relevant to public health because it will enhance our understanding of how visceral adiposetissue inflammation contributes to increased severity of acute pancreatitis in the elderly. This project will alsoprovide information for the development of diagnostic and treatment strategies to decrease incidence rates anddeaths related to severe acute pancreatitis in the aged. The development of effective therapies for preventingprogression to severe acute pancreatitis of which there are currently none available will be beneficial toelderly patients who suffer from acute pancreatitis.


application_id: 9749509
project_number: 3R01NS097722-02S1
project_title: Neurovascular astrocyte dysfunction in VCID
administering_ic: NINDS
award_notice_date: 2018-09-19
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: NS
serial_number: 097722
suffix: S1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2017-08-01
project_end_date: 2022-05-31
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract This application is being submitted in response to PA-18-591 in accordance with NOT-OD-18-194. Down syndrome (DS) individuals develop Alzheimer's disease (AD) neuropathology by 40 years of agewith clinical dementia typically observed at ages over 50 years. Due to the genetic underpinning of AD in DSthere has been an assumption in the field that DS individuals represent pure cases of AD and this assumptionhas been made in the absence of evidence to that fact. Neuropathological studies in DS have focused on ADpathologies; plaques and tangles as well as neurodegeneration. Based on data we generated several yearsago exploring neuroinflammatory states in the DS brain using autopsy tissue we have generated ahypothesis that DS brain also exhibits early cerebrovascular damage leading to vascular contributionsto cognitive impairment and dementia (VCID) in DS. At the University of Kentucky we have outstanding resources to study DS. We have both autopsy braintissue for DS at different ages and we have a longitudinal clinical cohort where we have been following DSindividuals over the age of 25 for eight years. These individuals undergo cognitive testing and MRI imaging aswell as giving blood samples for fluid biomarker studies. Novel findings already published from the longitudinalstudy include early white matter disruptions unique neuroinflammatory responses and altered brainmetabolism. Recent findings from the study highlight early cerebrovascular changes in the DS brain. As aresult of these recent exciting findings we propose to explore neurovascular astrocyte changes in the DSbrain and explore some recently identified novel fluid biomarkers that we find associate significantly with smallvessel ischemic disease and vascular cognitive impairment. These data will further add to the parent RO1grant. Our overarching hypothesis is that DS brains show similar VCID changes to the neurovascularastrocytes leading to astrocytic degeneration early in the disease process and this is accompanied bychanges in endothelial and microglial cell activation. To test our hypotheses we will leverage our autopsy braintissue and plasma from our longitudinal clinical cohort. We propose two specific aims for this supplement:Specific Aim 1: Test the hypothesis that neurovascular astrocyte degeneration is present early in the DS brainand is associated with cerebrovascular pathology.Specific Aim 2: Test the hypothesis that endothelial activation and a neuroinflammatory response accompaniescerebrovascular pathologies in a longitudinally followed DS cohort.

project_terms:
Age;Age-Years;Alzheimer's Disease;Amyloid beta-Protein;Astrocytes;Autopsy;Biological Markers;Blood - brain barrier anatomy;Blood specimen;Brain;Cerebellum;Cerebrovascular system;Characteristics;Clinical;Clinical Trials;Data;Dementia;Development;Disease;Down Syndrome;Endothelial Cells;Exhibits;Extravasation;Functional disorder;Future;Gelatinase B;Genetic;Grant;Image;Immunotherapy;Impaired cognition;Individual;Inflammatory Response;Kentucky;Liquid substance;Longitudinal Studies;Magnetic Resonance Imaging;Methods;Microglia;Microvascular Dysfunction;Nerve Degeneration;Neurofibrillary Tangles;Occipital lobe;Outcome;Parents;Pathology;Plasma;Prevalence;Process;Publishing;Resources;Severities;Testing;Time;Tissues;Universities;Vascular Cognitive Impairment;base;brain metabolism;brain tissue;cerebrovascular;cerebrovascular pathology;cognitive testing;cohort;foot;frontal lobe;neuroimaging;neuroinflammation;neuropathology;neurovascular;novel;novel marker;response;vascular cognitive impairment and dementia;white matter


application_id: 9749466
project_number: 3R01HD064993-09S1
project_title: Aging and Dementia in Down Syndrome: Connectivity Inflammation and Cerebrovascular Contributions
administering_ic: NICHD
award_notice_date: 2018-09-12
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: HD
serial_number: 064993
suffix: S1
program_official: PARISI, MELISSA
project_start_date: 2009-09-30
project_end_date: 2020-01-31
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: HEAD, ELIZABETH
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
7. Project Summary/AbstractThis application is being submitted to PA-18-591 in accordance with NOT-OD-18-195. Down syndrome (DS) isthe major cause of intellectual disability in humans and it is estimated there are over 300000 individuals withthis genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for adiagnosis of Alzheimer disease (AD) in their 40th year. However dementia may not develop until up to a decadelater and some people remain cognitively intact. Imaging studies reveal early neuropathology within the striatumand frontal lobes. Given these regions are involved in motor and cognitive function we hypothesize that gait willbe associated with changes in cognition and prodromal dementia. We will follow up with an initial cohort of DSindividuals who had gait assessed three years ago to assess whether the degree of change in gait associateswith prodromal dementia. Next we will use a dual-task gait paradigm to elucidate subtle gait impairment andcompare spatial and temporal gait characteristics from people with DS over a wide range of ages. Finally wewill use structural neuroimaging to identify underlying neural substrates associated with changes in gait andprodromal dementia. Determining whether gait indicates early pathogenesis of AD in DS will initiate earlytreatment improving quality of life. Furthermore earlier detection of prodromal dementia will facilitate researchinvestigating pathogenesis and subsequently may provide novel targets for a preventative approach to slow orhalt the development of AD neuropathology.

project_terms:
Adult;Age;Aging;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Amyloid beta-Protein Precursor;Area;Attention;Behavioral;Brain;Characteristics;Chromosomes Human Pair 21;Clinical;Clinical Trials;Cognition;Cognitive;Cognitive deficits;Corpus striatum structure;Data;Dementia;Development;Diagnosis;Disease;Disease Progression;Down Syndrome;Early Diagnosis;Early treatment;Elderly;Exhibits;External Capsule;Financial compensation;Funding;Future;Gait;Genetic Diseases;Human;Impaired cognition;Impairment;Individual;Inflammation;Intellectual functioning disability;Intervention;Length;Life Expectancy;Link;Longevity;Longitudinal cohort;Magnetic Resonance Imaging;Measurable;Measurement;Measures;Memory;Motor;Nerve Degeneration;Neurofibrillary Tangles;Neurons;Outcome;Outcome Measure;Pathogenesis;Pathway interactions;Performance;Persons;Pittsburgh Compound-B;Population;Positron-Emission Tomography;Quality of life;Research;Resources;Risk;Role;Senile Plaques;Structure;Symptoms;System;Testing;United States;Walking;brain size;cerebrovascular;cognitive change;cognitive function;cognitive testing;cohort;computerized;follow-up;frontal lobe;hyperphosphorylated tau;imaging study;improved;mortality;neuroimaging;neuropathology;novel;overexpression;parent grant;pre-clinical;progressive neurodegeneration;relating to nervous system;resilience;therapy development;virtual;white matter

public_health_relevance:
8. Project NarrativeThe proposed study will use gait identify early clinical signs of dementia reflecting Alzheimer disease (AD) inadults with Down syndrome (DS). Using magnetic resonance imaging and the GAITRite system to quantitativelymeasure gait we will identify whether matter integrity losses are associated with gait and whether those regionsare associated with early dementia symptoms. Identifying dementia earlier and resilience indicators providesopportunities to better track the progression of AD in DS and develop targeted interventions to improve thequality of life of DS individuals who are vulnerable to neurodegeneration.


application_id: 9749295
project_number: 3R01CA166499-05S1
project_title: A role for c-Abl/Arg in melanoma progression
administering_ic: NCI
award_notice_date: 2018-08-15
opportunity_number: PA-11-260
application_type: 3
activity_code: R01
ic: CA
serial_number: 166499
suffix: S1
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2012-09-12
project_end_date: 2019-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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_abstract:
DESCRIPTION (provided by applicant): Despite 35 years of clinical trials there has been little improvement in five-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma. Here we demonstrate a previously unrecognized role for Abl kinases in melanoma cells. We found that c-Abl/Arg non-receptor tyrosine kinases are activated in primary melanomas and in melanoma cell lines and promote proliferation survival cell-cell adhesion migration invasion and lung colonization/metastasis. In addition c-Abl/Arg promote matrigel invasion via STAT3 and MMP-dependent pathways; increase cell-cell adhesion; and dramatically induce degradation of a metastasis suppressor. Moreover drugs targeting c-Abl/Arg and Raf/MEK/ERK pathways cooperate to decrease melanoma viability. Based on these novel findings we hypothesize that c-Abl/Arg activate novel pathways that cooperate with B-Raf to promote melanoma cell-cell adhesion migration invasion and metastasis. We propose a comprehensive hypothesis-driven experimental design that will establish Abl kinases as novel and exploitable drug targets for metastatic melanoma. Aim 1 will define molecular pathways by which Abl kinases promote cell-cell adhesion migration and invasion. To achieve our objective we will combine biochemical molecular and cell biological approaches using RNAi pharmacological inhibitors constitutively active forms of c-Abl/Arg rescue experiments 2D/3D cell culture and melanoma- endothelial co-cultures to identify migration invasion and cell-cell adhesion signaling pathways driven by c- Abl/Arg. Aim 2 will test the prediction that c-Abl/Arg cooperates with Abl-independent pathways (e.g. B-Raf) to promote melanoma cell-cell adhesion migration and invasion. Finally three complementary approaches will be utilized in Aim 3 to identify mechanisms by which c-Abl/Arg promote metastasis. A novel GEM model that develops metastatic UV-induced melanomas and lung colonization and spontaneous metastasis xenograft models will be used to test the prediction that blocking c-Abl/Arg-dependent signaling pathways inhibits metastatic progression. We also will test whether B-Raf and c-Abl/Arg inhibitors cooperate to prevent metastasis of melanomas harboring B-Raf mutations. The data obtained from this proposal not only will allow us to gain insight into the fundamental mechanisms by which c-Abl/Arg drive invasion and metastasis but also will lead to clinical studies testing the efficacy of c-Abl/Arg inhibitors for treating metastatic disease.

project_terms:
ABL1 gene;Anoikis;Biochemical;Biological;Cathepsins;Cell Adhesion;Cell Communication;Cell Line;Cell Survival;Cell-Cell Adhesion;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Coculture Techniques;Data;Dermal;Detection;Development;Disease;Disease remission;Drug Combinations;Drug Targeting;Endothelial Cells;Environment;Experimental Designs;Extravasation;FDA approved;Fibroblasts;Genetic Transcription;Genetically Engineered Mouse;Goals;Imatinib;In Vitro;Lead;MEKs;Matrix Metalloproteinases;Mean Survival Times;Mediating;Melanoma Cell;Metastatic Melanoma;Molecular;Mouse Strains;Mutation;N-Cadherin;NME1 gene;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Peptide Hydrolases;Pharmacology;Phosphotransferases;Play;Positioning Attribute;Prevention;RNA Interference;Ras/Raf;Regimen;Research;Residual state;Resistance;Role;STAT3 gene;STI571;Scientist;Seminal;Signal Pathway;Signal Transduction;Solid Neoplasm;Survival Rate;Testing;Transcriptional Activation;Treatment Protocols;UV-induced melanoma;Universities;Xenograft Model;base;beta catenin;chemotherapeutic agent;design;efficacy testing;experimental study;gain of function;inhibitor/antagonist;innovation;insight;leukemia;loss of function;lung colonization;matrigel;melanoma;migration;mutant;new therapeutic target;novel;novel drug combination;novel therapeutics;prevent;three dimensional cell culture;tool

public_health_relevance:
Melanomas are essentially untreatable if they metastasize because they are resistant to all known chemotherapeutic agents. This proposal will solidify Abl kinases as novel druggable targets in melanoma by identifying mechanisms by which Abl kinases promote invasion and metastasis; determining which type of melanomas contain active Abl kinases; and testing whether Abl inhibitors cooperate with B-Raf inhibitors to kill melanoma cells and prevent metastatic progression. Data obtained from this proposal are likely to lead to the initiation of a clinical trial to test these novel drug combinations for treatment of metastati disease.


application_id: 9749097
project_number: 5R01DA045700-02
administering_ic: NIDA
award_notice_date: 2019-05-24
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DA
serial_number: 045700
program_official: RAMEY, TANYA S
project_start_date: 2018-08-01
project_end_date: 2022-05-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 8906159
contact_pi: BABALONIS, SHANNA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-06-01
project_title:
Evaluation of Marijuana and Opioid Drug Interactions: Assessment of the Safety Profile Abuse-Related Pharmacodynamic Effects and Models of Drug Intake

project_abstract:
Abstract Misuse of prescription opioids and heroin is a global epidemic with an estimated 33 million peoplemisusing opioids worldwide and 2.6 million individuals in the U.S. meeting criteria for an opioid use disorder.This public health crisis is occurring on the background of a precipitous increase in the availability of marijuanaboth in the U.S. and worldwide. Marijuana use is at peak levels in the U.S.  in 2014 22.2 million individuals 12years and older reported past month marijuana use and 8.4 million individuals reported daily/near-dailymarijuana use. Marijuana and opioids are the two most commonly misused illicit drug classes (with manymore taking these drugs therapeutically); however despite these high rates of use there are no carefullycontrolled human data available on their co-use specifically in regard to drug response abuse-relatedmeasures and safety outcomes. Thus the current project aims to explore the 1) safety/physiological effects ofmarijuana and opioid combinations 2) impact of marijuana use on opioid response and opioid drug-taking 3)effects of opioid use on marijuana drug-taking and 4) behavioral and cognitive effects of combined opioid-cannabinoid use. Two independent inpatient studies will be conducted during this 4-year project and each willutilize a randomized within-subject double-blind double-dummy placebo-controlled design and will enrollsamples of non-physically dependent recreational opioid users with histories of marijuana use. Study 1 willexamine the effects of smoked marijuana pre-treatment over a range of THC concentrations (0 5 &15% THC)on intranasal oxycodone (0 15 & 30 mg) response using a full battery of pharmacodynamic outcomesincluding safety/physiological response and abuse-related subjective and observer-rated effects. Secondaryaims will examine the psychomotor/cognitive effects across the dose conditions. Study 2 will explore 1) theeffects of smoked marijuana pre-treatment (0 15% THC) on intranasal oxycodone (0 15 & 30 mg) self-administration and 2) intranasal oxycodone pre-treatment (0 30 mg) on smoked marijuana (0 5 & 15% THC)self-administration. Overall these studies will provide some of the first empirical data on the interaction effectsof the two most commonly misused drug classes providing information on the safety impact physiologicaleffects and abuse-related effects of their co-use. These findings will be highly relevant to public healthconsiderations will help determine the risk profile of marijuana and opioid interactions and will provide newcontrolled information relevant to clinical practice prescribing and public safety.

project_terms:
Absence of pain sensation;Accidents;Acute;Address;Age;Agonist;Analgesics;Animals;Attenuated;Automobile Driving;Autopsy;Behavior;Behavioral;Biochemical;CNR1 gene;Cannabinoids;Chemosensitization;Cognitive;Data;Dose;Double-Blind Method;Dronabinol;Drug Interactions;Drug Modelings;Enrollment;Epidemic;Evaluation;Funding;Heroin;Human;Illicit Drugs;Individual;Inpatients;Intake;Laws;Legal;Marijuana;Measures;Medical Marijuana;Mus;Opioid;Opioid Receptor;Opioid user;Outcome;Oxycodone;Oxymorphone;Pharmaceutical Preparations;Pharmacodynamics;Physiological;Placebos;Population;Public Health;Randomized;Recording of previous events;Reporting;Research;Risk;Safety;Sampling;Self Administration;Series;Specimen;Statutes and Laws;System;THC concentration;Taxes;Therapeutic;Time;Ventilatory Depression;cannabinoid receptor;clinical practice;design;drug discrimination;drug misuse;endogenous cannabinoid system;endogenous opioids;epidemiologic data;functional outcomes;human data;innovation;marijuana smoke;marijuana use;meetings;mortality;mu opioid receptors;neurochemistry;neurophysiology;nonhuman primate;opioid misuse;opioid mortality;opioid overdose;opioid use;opioid use disorder;pain outcome;pain relief;prescription opioid;prescription opioid misuse;receptor;response;safety assessment;substance use prevention;young adult

public_health_relevance:
PROJECT NARRATIVEThis research will provide important public health and safety information regarding the interaction effects ofopioids and smoked marijuana on a full range of pharmacodynamic safety and abuse-related outcomes.


application_id: 9749072
project_number: 5R13DC016831-03
project_title: International Society of Neurogastronomy Annual Meeting
administering_ic: NIDCD
award_notice_date: 2019-08-09
opportunity_number: PA-16-294
application_type: 5
activity_code: R13
ic: DC
serial_number: 016831
program_official: SULLIVAN, SUSAN L
project_start_date: 2017-09-26
project_end_date: 2020-08-31
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe objective of this conference grant request is to provide support for certain aspects ofthe annual meeting of the International Society of Neurogastronomy (ISN) for the next fiveyears. ISN is a new society whose composition of scientists clinicians nutritionists foodservice professionals and chefs naturally predisposes it to focus on translational issuesfundamental to how the chemical senses impact human health. The first two specificobjectives are to provide a venue and opportunity that brings these groups together andfacilitates the synergies that arise when distinctly different fields interact productively. Thethird specific objective is to attract and stimulate the young scientists that are the future ofthe field of neurogastronomy. The fourth specific objective is to ensure that this new fieldembraces a culture of diversity weaving this principle into its early development byrecruiting persons of diverse backgrounds to the conference. !

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

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


application_id: 9749021
project_number: 5R24AI138963-02
administering_ic: NIAID
award_notice_date: 2019-06-14
opportunity_number: PAR-16-412
application_type: 5
activity_code: R24
ic: AI
serial_number: 138963
program_official: BREEN, JOSEPH J
project_start_date: 2018-07-23
project_end_date: 2022-06-30
study_section: ZAI1-JTS-I(M1)
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: SMITH, MELISSA LAIRD
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
budget_start_date: 2019-07-01
project_abstract:
Project Summary/AbstractThere is a fundamental gap in our understanding of how germline variation in immunoglobulin (IG) heavy (IGH)and light chain (IGK; IGL) loci in the human population impacts the development of the functional antibody (Ab)response in health and disease. However there is a growing appreciation that IG polymorphism contributes tovariability in the Ab repertoire indicating that the integration of IG genetic data has the potential to inform ourunderstanding of Ab function in various clinical contexts. A critical barrier to progress has been that existinggenomic resources for IG loci are lacking and poorly represent diversity found across human populations. IGregions are structurally complex consisting of large segmental duplications and are among the mostpolymorphic in the genome with large copy number variants (CNVs) elevated nucleotide diversity andpopulation-specific haplotype variants. These complexities have long made IG loci difficult to study at thegenomic and population level using standard high-throughput methods with direct negative impacts on geneticdisease association studies and more recently the analysis of expressed Ab repertoire data. As a result ourknowledge of human IG germline diversity (particularly in non-Caucasians) and its contribution to disease lagsfar behind that of other well studied immune loci. This highlights a direct need for publically available well-characterized IG haplotype references and accurate variant catalogues from diverse ethnic backgrounds tofacilitate the design and integration of more accurate genotyping tools analysis pipelines and their interpretation.To meet this need we have developed several robust approaches which we will utilize here to establish criticalcommunity resources for the IG loci. We will first enumerate up to 16 novel IGH/K/L haplotype referenceassemblies from an existing set of 8 fosmid libraries from individuals of African Asian and European descent.We will also use a novel multi-haplotype informed genotyping pipeline to profile IGH/K/L genetic variation in acohort of 180 familial and unrelated individuals from these same three populations. This will represent the mostcomprehensive population survey of IG germline diversity including descriptions of variable diversity joiningand constant gene variation and locus-wide single nucleotide polymorphisms (SNPs) and CNVs allowing forfine-scale assessment of variant imputation panels for disease association studies. Finally to facilitate theutility of these data as long-term resources all sequences tools/methods and analysis pipelines will be madepublically available. We will work with established databases to ensure all sequences are deposited in both rawand annotated form. This will include the integration of assemblies into future releases of the human genomereference for use by the genomics community as well as updates to existing germline gene/allele databasescritical to expressed Ab repertoire analysis. This project establishes desperately needed genomic resources forthe human IG loci which will better serve the immunology community for years to come. These will stand as afoundation for future efforts to define the role of IG germline variation in Ab function health and disease.

project_terms:
African;Alleles;Antibodies;Antibody Repertoire;Antibody Response;Asians;Autoimmunity;B-Lymphocytes;Biological Assay;Catalogs;Clinical;Communities;Complex;Copy Number Polymorphism;Data;Data Analyses;Data Set;Databases;Deposition;Development;Diploidy;Disease;Ensure;European;Evaluation;Foundations;Future;Genbank;Genes;Genetic;Genetic Diseases;Genetic Polymorphism;Genetic Research;Genetic Variation;Genome;Genomics;Genotype;Haplotypes;Health;Human;Human Resources;IGL@ gene cluster;Immune;Immune System Diseases;Immunogenetics;Immunoglobulins;Immunology;Individual;Infection;Information Systems;International;Knowledge;Libraries;Light;Link;Malignant Neoplasms;Methods;Nucleic Acid Regulatory Sequences;Nucleotides;Outcome;Population;Positioning Attribute;Resolution;Resources;Role;Sampling;Single Nucleotide Polymorphism;Structure;Update;Variant;Work;adaptive immunity;analysis pipeline;cohort;design;direct application;ethnic diversity;genetic association;high standard;human reference genome;immunoglobulin light chain locus;improved;insight;inter-individual variation;novel;novel strategies;personalized medicine;population survey;precision medicine;reference genome;tool;vaccine response

public_health_relevance:
Project NarrativeGenomic resources for the human immunoglobulin loci are lacking and poorly represent diversity amonghuman populations hindering our understanding of the role of antibody genetic variation in health and disease.This project will result in a set of genomic resources that will have transformative impacts on the fields of B cellimmunology and immunogenetics allowing for a better integration of antibody germline data at the genomicand population level. These will have direct applications in genetic association and antibody repertoire profilingstudies with implications for a range of immunological diseases and personalized medicine approaches.


application_id: 9748337
project_number: 5F31NS105443-02
administering_ic: NINDS
award_notice_date: 2019-06-13
opportunity_number: PA-16-309
application_type: 5
activity_code: F31
ic: NS
serial_number: 105443
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2018-07-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 14385763
contact_pi: KOPPER, TIMOTHY JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
project_title:
Contributions of Myelin Derived Arachidonic Acid to Macrophage Polarization and Secondary Damage after Spinal Cord Injury

project_abstract:
Project summary/Abstract Spinal cord injury (SCI) produces a chronic inflammatory state primarily mediated by resident microgliaand infiltrating monocytes (here collectively referred to as macrophages). These chronically activated SCImacrophages adopt a pro-inflammatory pathological state that continues to cause additional damage after theinitial injury and inhibits recovery. Myelin debris generated after SCI can directly stimulate macrophages toadopt these maladaptive functions; however the mechanisms by which this stimulation occur are poorlyunderstood. Myelin contains an inflammatory lipid molecule arachidonic acid stored in an inactive form withinmyelin's extensive membranes. After injury macrophages clear and accumulate myelin debris long after injury.Here we propose that the inflammatory environment within the SCI lesion induces the expression of theenzyme cytosolic phospholipase A2 (cPLA2) within macrophages. cPLA2 releases arachidonic acid fromcellular membranes. Free active arachidonic acid invokes direct pro-inflammatory functions or throughsynthesis forms various eicosanoids with pro-inflammatory properties. This is the basis for the centralhypothesis that increased cPLA2 activity in SCI macrophages releases arachidonic acid from myelindebris thereby driving chronic SCI inflammation and tissue damage. . Using in-vitro and in-vivo approaches Aim 1 of this proposal will identify cPLA2 as the regulator ofmyelin-mediated inflammation in macrophages. We will thereby demonstrate the importance of myelin-derivedarachidonic acid in these critical inflammatory responses. Aim 2 will utilize cPLA2-/- bone marrow chimeric miceto interrogate the importance and influence of macrophage cPLA2 in the pathogenesis of SCI. Chronic pro-inflammatory macrophage activation is a key mediator of secondary damage and impaired recovery after SCIyet the mechanisms behind this process are poorly understood. Here I propose a novel mechanism by whichmyelin debris and subsequent processing by macrophage cPLA2 continuously produces free arachidonic acidthereby driving the chronic inflammation observed after SCI.

project_terms:
Address;Adopted;Affect;Anatomy;Animals;Arachidonic Acids;Automobile Driving;Behavioral;Biological Assay;Bone Marrow;Cellular Membrane;Chest;Chimera organism;Chronic;Cytosolic Phospholipase A2;Data;Eicosanoids;Environment;Enzyme-Linked Immunosorbent Assay;Enzymes;Fatty Acids;Genes;Health Care Costs;Immunohistochemistry;Impairment;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Injury;Knock-out;Lesion;Lipids;Macrophage Activation;Mass Fragmentography;Measures;Mediating;Mediator of activation protein;Membrane;Microglia;Molecular;Mus;Myelin;Nerve Degeneration;Paralysed;Pathogenesis;Pathologic;Pathology;Patients;Peripheral;Phagocytes;Phagocytosis;Phenotype;Phospholipase;Phospholipids;Process;Property;Proteins;Publishing;Reactive Oxygen Species;Recovery;Reporting;Role;Spinal Cord Contusions;Spinal cord injury;Stimulus;Tissues;base;cytokine;in vivo;inflammatory milieu;inhibitor/antagonist;macrophage;membrane model;monocyte;novel;repaired

public_health_relevance:
Project NarrativeAfter spinal cord injury (SCI) there is incomplete recovery often resulting in chronic paralysis and expensivehealth care costs for patients. One major contributor to this inability to recover is a chronic inflammatoryresponse that inhibits the normal repair process. While the negative effects of this inflammatory response havebeen well studied the molecular mechanisms that drive this inflammation long after the initial injury remainunclear; to address this this proposal will examine the mechanisms by which the cellular debris generatedafter injury can be continuously broken down into a potent inflammatory stimulus.


application_id: 9748149
project_number: 3R01AA017226-11S1
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2018-08-23
opportunity_number: PA-13-302
application_type: 3
activity_code: R01
ic: AA
serial_number: 017226
suffix: S1
program_official: MURRAY, GARY
project_start_date: 2008-03-05
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness the p38. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38 which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT) increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims. Specific Aim 1 will determine the role of p38 in alcohol- induced aggressiveness in vitro. Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38 activation as well as the mechanisms how p38 mediates aggressiveness of breast cancer cells. Specific Aim 3 will investigate the role of p38 in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.

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

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


application_id: 9747423
project_number: 3UL1TR001998-03S1
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2018-08-30
opportunity_number: PAR-15-304
application_type: 3
activity_code: UL1
ic: TR
serial_number: 001998
suffix: S1
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2020-05-31
study_section: ZTR1-SRC(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Contact PD/PI: Kern Philip APROJECTSUMMARYTheUniversityofKentucky(UK)CenterforClinicalandTranslationalScience(CCTS)hascreatedanintegratedhomeforclinicalandtranslationalresearchtopromotescientificprogressanddiscoveriesateveryphaseofthetranslationalcontinuum.TheCCTShasfundamentallytransformedtheresearchenvironmentnotonlyatUKbutthroughoutCentralAppalachiathroughthedevelopmentofastrongresearchnetworktheAppalachianTranslationalResearchNetwork(ATRN)withintegratedresearchpartnershipsincludingotherCTSAhubs.Whencombinedwithanin-depthunderstandingoftheuniqueandserioushealthchallengesfacedbyCentralAppalachianresidentstheUKCCTSispositionedtoleadlocalregionalandnationalresearcheffortsthatfocusonthesignificanthealthdisparitiesinthispopulation.OuroverarchinggoalasaCTSAhubistocontinuetochampioninnovationinthefullspectrumofclinicalandtranslationalresearchwhileeducatingtheworkforceofthefutureengagingourcommunitiesinbiomedicalscienceandworkingwiththenationalnetworktoadvancecohesivemulti-centerclinicaltrialswhichwillultimatelyelevatethehealthandqualityoflifeofthepopulaceofCentralAppalachia.SpecificallytheUKCCTSwill:1)Leadinstitutionalinnovationinthedeliveryofefficienteffectiveclinicalandtranslationalresearch.2)Developadiverseworkforceacrossmultipledisciplinesthatadvancestranslationalresearchandexcelsinteam-basedscience.3)MeettheuniqueneedsofCentralAppalachianresidentsbyextensivelyengagingandcollaboratingwithourregionalruralandcommunity-basedpartners.4)Catalyzeinnovativeresearchincludingnoveldrugdevelopmentandinformaticsmethodologieswithparticularfocusonbringinginnovationtospecialpopulationsandacrossthelifespan.5)CreateanefficientclinicaltrialsnetworkcenteredatUKandextendingintoourpartnerhealthcaresystemsthatwillbeanessentialandleadingcomponentoftheCTSAconsortiuminvolvingparticipantsthroughoutafourstateregionofruralCentralAppalachia.TheUKCCTSbenefitsfromacollaborativeenvironmentfoundononlyafewuniversitycampuses.UKhas16collegeswith11involvedintheUKCCTS(includingsixbiomedicalcolleges)ononecentralcampus.ThisphysicalproximityofouracademicandhealthcarecommunitiesalongwithacultureofcollaborationcreatesacloselyknitunifiedacademiccommunityandpositionstheUKCCTStodemonstratetheimpactofcollaborativetranslationalresearchandleadershipinteamscience.OureffortshavealreadybeensuccessfulattransformingthecultureoftheUKacademicmedicalcentertoonethatmorekeenlyappreciatesscholarshipinnovationandtranslationalscience.Wenowplantobuildonthesestrengthstoadvancetranslationalsciencetothenextlevelwithfurtherdevelopmentofourclinicaltrialnetworksdevelopmentofnovelinformaticsprogramsandcontinueddevelopmentoftheworkforcethroughouttheregion.TheseeffortswillbenefitthemedicallyunderservedresidentsofCentralAppalachiaandwillsignificantlycontributetothenationalCTSAprogram.  1 Project Summary/Abstract Page 287Contact PD/PI: Kern Philip A

project_terms:
Abbreviations;Academic Medical Centers;Affect;Agriculture;Appalachian Region;Arts;Clinical;Clinical Research;Clinical Sciences;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Community Healthcare;Data;Development;Discipline;Diverse Workforce;Education;Engineering;Environment;Fostering;Future;Goals;Health;Healthcare;Healthcare Systems;Home environment;Informatics;Institutes;Institution;Interdisciplinary Study;Kentucky;Lead;Leadership;Longevity;Medical center;Methodology;Mission;Multi-Institutional Clinical Trial;Participant;Patient Recruitments;Personal Satisfaction;Phase;Population;Positioning Attribute;Quality of Care;Quality of life;Research;Research Training;Role;Rural;Rural Community;Rural Population;Scholarship;Science;Solid;Target Populations;Translational Research;Trust;Universities;West Virginia;Workforce Development;base;biomedical informatics;catalyst;cohesion;collaborative environment;college;data management;data warehouse;drug development;food environment;health care service organization;health disparity;healthcare community;improved;innovation;medical schools;medically underserved;named group;novel;novel therapeutics;programs;success

public_health_relevance:
PROJECT NARRATIVEThe University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) is strategicallypositioned in Central Appalachia to catalyze efforts to connect the populace of this medically underservedregion with significant health disparities to the national CTSA network. The UK CCTS is recognized locallyand regionally for affecting change and building robust partnerships across the CTSA network in CentralAppalachia and at UK creating an efficient platform for clinical and translational research and training all toimprove quality of care health and well-being for the rural populations of this region.1Project Narrative Page 288


application_id: 9747214
project_number: 5R01CA208343-03
project_title: Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment
administering_ic: NCI
award_notice_date: 2019-07-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 208343
program_official: TIMMER, WILLIAM C
project_start_date: 2017-08-01
project_end_date: 2022-07-31
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: GAO, TIANYAN
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Altered cellular metabolism has been widely recognized as an emerging hallmark of cancer. Althoughrecent advances in cancer metabolism research have begun to elucidate how metabolic changes supportcancer cell growth and survival alterations in fatty acid (FA) metabolism in cancer cells have received lessattention. Increasing evidence has suggested that increased FA biosynthesis is needed not only toaccommodate high rates of proliferation by providing building blocks for membrane synthesis but also toenhance the ability of cancer cells to defend against oxidative stress- or chemotherapy-induced cell death bychanging membrane lipid composition. Studies from our laboratories and others have demonstrated that FAsynthase (FASN) a key enzyme of de novo lipid biosynthesis is significantly upregulated in colorectal cancer(CRC). Our in vivo studies demonstrate that RNAi-mediated inhibition of FASN markedly reduces lung andhepatic CRC metastases and inhibits tumor angiogenesis. Collectively our studies indicate FASN may serveas a potential target for novel therapeutic agents. Recently several orally-available reversible potent andselective FASN small molecule inhibitors have been developed by our collaborator 3-V Biosciences. Theseagents have excellent pharmaceutical profiles and achieve antitumor effects at tolerated doses in a broadrange of tumors including non-small cell lung cancer ovarian and triple negative breast cancers. Thetranslational goal of our project is to define the metabolic adaptations that occur in colon cancer and toconduct a clinical trial to evaluate the effect of FASN inhibitor TVB-2640 on modulating cellular metabolismand proliferation in colon cancer patients. The central hypothesis for our proposal is that upregulation ofFASN expression and activity occurs in a subset of colon cancer patients; therefore these individuals wouldbenefit from a therapeutic approach that includes targeted inhibition of de novo lipogenesis. The followingSpecific Aims are proposed: 1) to determine the effect of altered FASN expression on metabolic reprogramingin colon cancer; 2) to delineate the anti-proliferative effect of FASN inhibition using patient-derived xenograft(PDX) models of colon cancer; and 3) to perform a pilot clinical trial in collaboration with 3-V Biosciences toassess pharmacodynamic effects on metabolic endpoints following short-term treatment with a novel FASNinhibitor (TVB-2640) prior to colon resection. Our highly collaborative group has the requisite expertiseinnovative model systems state-of-the-art technology and novel inhibitors to make rapid progress that willsignificantly advance our understanding of the FASN-mediated metabolic alterations of colon cancers andpotentially provide novel treatment strategies based on a more focused and personalized approach.

project_terms:
Acute;Address;Apoptosis;Attention;Behavior;Benign;Biological;Biological Models;Biological Sciences;Cancer Cell Growth;Cancer Etiology;Carnitine;Cell Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Colorectal Cancer;Controlled Clinical Trials;DNA Sequence Alteration;Development;Dose;Enzymes;Epithelial Cells;Etiology;Excision;Fatty Acids;Fatty-acid synthase;Future;Glucose;Glycolysis;Goals;Growth;Hepatic;Individual;Laboratories;Lead;Lipids;Lung;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Membrane Lipids;Metabolic;Metabolism;Mitochondria;Mucous Membrane;Non-Small-Cell Lung Carcinoma;Oncogenic;Oral;Ovarian;Oxidative Stress;Palmitates;Patients;Pharmacodynamics;Pharmacologic Substance;Phospholipids;Placebos;Production;RNA Interference;Randomized;Research;Resected;Respiration;Signal Pathway;Slice;Techniques;Technology;Therapeutic;Therapeutic Agents;Tissues;Triglycerides;Tumor Angiogenesis;United States;Up-Regulation;Warburg Effect;Xenograft Model;Xenograft procedure;antitumor effect;base;beta catenin;cancer cell;cell growth;cell transformation;chemotherapy;colon cancer patients;colon cancer treatment;colorectal cancer metastasis;colorectal cancer progression;experimental study;extracellular;fatty acid biosynthesis;fatty acid metabolism;in vivo;inhibitor/antagonist;innovation;lipid biosynthesis;lipid metabolism;membrane synthesis;metabolomics;multidisciplinary;neoplastic;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;patient subsets;personalized approach;response;secondary endpoint;small molecule inhibitor;stable isotope;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor metabolism;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEColorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Alteredcellular metabolism is required to drive tumorigenesis and progression. Our study will define the metabolicadaptations associated with increased fatty acid synthase (FASN) expression in colon cancer patients anddelineate the subset of patients who may benefit from treatment with FASN inhibitors.


application_id: 9746863
project_number: 1R01HL147343-01
project_title: The Role of E-cigarette Characteristics and Constituents in Cardiac Dysfunction
administering_ic: NHLBI
award_notice_date: 2019-05-20
opportunity_number: RFA-OD-18-002
application_type: 1
activity_code: R01
ic: HL
serial_number: 147343
program_official: POSTOW, LISA
project_start_date: 2019-05-20
project_end_date: 2022-04-30
study_section: Special Emphasis Panel[ZRG1 BST-T (55)]
contact_pi_person_id: 11702638
contact_pi: CARLL, ALEX PERROW
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_terms:
Acute;Adverse effects;Aerosols;Affect;Aldehydes;Animals;Area;Arrhythmia;Biochemical;Biochemistry;Biological Assay;Biological Markers;Blood Pressure;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac health;Cardiotoxicity;Cardiovascular system;Characteristics;Chronic;Data;Devices;Echocardiography;Electric Stimulation;Electrocardiogram;Electrodes;Electronic cigarette;Electrophysiology (science);Exposure to;Failure;Female;Functional disorder;Gap Junctions;Gene Expression;Generations;Glycerol;Goals;Harm Reduction;Health;Health Policy;Heart;Heart Atrium;Histologic;Histopathology;Human;Inhalation;Ion Channel;Mainstreaming;Measures;Mission;Molecular;Monitor;Mus;Myocardial dysfunction;Nicotine;Outcome;Particulate Matter;Pattern;Periodicity;Physiology;Policies;Predisposition;Production;Propylene Glycols;Public Health;Refractory;Regimen;Research;Research Personnel;Research Priority;Risk;Role;Safety;Smoking;Solvents;Stimulus;Structure;Telemetry;Testing;Time;Tissues;Toxic effect;United States National Institutes of Health;Vegetables;Ventricular;Western Blotting;Work;aerosolized;air filter;atrioventricular node;authority;cardiovascular health;cigarette smoke;cigarette smoking;combustible cigarette;design;disability;electronic cigarette use;heart function;heart rate variability;hemodynamics;insight;interest;male;novel;sex;urinary


application_id: 9746324
project_number: 1R21DE028070-01A1
administering_ic: NIDCR
award_notice_date: 2019-08-21
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: DE
serial_number: 028070
suffix: A1
program_official: LUMELSKY, NADYA L
project_start_date: 2019-09-01
project_end_date: 2021-08-31
study_section: Arthritis, Connective Tissue and Skin Study Section[ACTS]
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_title:
Characterizing T cell contribution to the injury microenvironment during tissue regeneration in African spiny mouse

project_abstract:
It remains evident that most injuries caused by surgery trauma or disease heal by fibrosis and formation ofscar tissue. Therapy to stimulate regeneration of musculoskeletal tissue in situ would alleviate much of theemotional and economic burden associated with imperfect therapies but mammalian epimorphic regenerationcontinues to be an elusive target. Multiple labs including our own have shown that immune cells are essentialfor regeneration where they orchestrate the injury response. Identifying specific immune cell subpopulationsthat regulate regeneration and how they direct resident cells to polarize the healing response are key areas ofresearch. The long-term goal of our research is to understand the mechanistic basis for mammalianmusculoskeletal regeneration in order to catalyze therapies that inhibit fibrosis and stimulate regenerationwhere it does not naturally occur. The objectives of this proposal are to characterize regulatory T (TREG) cellphenotypes associated with regenerating and scarring microenvironments functionally test the role of TREGcells for regeneration and to test how T cell paracrine factors drive local fibroblast behavior. Our centralhypothesis is that a regeneration-specific population of TREG cells are required for musculoskeletalregeneration. TREG cells represent fundamental dominant-negative immune cells that coordinate inflammation.Despite the importance of TREG cells during the inflammatory response how they contribute to regeneration inmammals remains unknown. Completing Aim 1 will enhance our understanding of whether TREG cells haveregeneration-specific phenotypes through single-cell RNAseq. Additionally it will test the functionalrequirement of these cells for musculoskeletal regeneration by generating a transgenic spiny mouse.Completing Aim 2 will illuminate how secreted T cell factors regulate fibroblast behavior and drive aregenerative phenotype by performing intra- and inter-species co-cultures of isolated T cells and primaryfibroblasts. The rationale for pursuing this work is that these results will provide the necessary foundation foran in-depth interrogation to test how specific T cell interactions and the factors they produce regulate blastemaformation in mammals.

project_terms:
Acomys;Affect;African;Animal Model;Area;Behavior;Cell Communication;Cell Cycle Progression;Cells;Cicatrix;Clinical;Coculture Techniques;Data;Development;Disease;Dominant-Negative Mutation;Ear;Economic Burden;Emotional;Enzyme-Linked Immunosorbent Assay;Extracellular Matrix;FOXP3 gene;Fibroblasts;Fibrosis;Foundations;Future;Gene Transfer Techniques;Genetic;Goals;House mice;Human;Immune;Immune response;Immunotherapy;In Situ;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Investigation;Laboratory mice;Lymphocyte Subtypings;Mammals;Medicine;Menstruation;Modeling;Mus;Musculoskeletal;National Institute of Dental and Craniofacial Research;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Operative Surgical Procedures;Outcome;Pathway interactions;Phenotype;Physiological;Physiology;Population;Pregnancy;Process;Production;Proteomics;Regenerative Medicine;Regulatory T-Lymphocyte;Research;Role;Salamander;Skeletal Muscle;T-Lymphocyte;TCF Transcription Factor;Testing;Tissues;Transgenic Organisms;Trauma;Vision;Work;Wound Healing;Zebrafish;blastema;cell type;craniofacial;diphtheria toxin receptor;external ear auricle;healing;improved;in utero;macrophage;muscle regeneration;novel therapeutic intervention;paracrine;programs;regenerative;repaired;research clinical testing;response;response to injury;single-cell RNA sequencing;time use;tissue regeneration;tissue trauma;transcriptome;transcriptome sequencing;wound

public_health_relevance:
One of the goals for the NIDCR 2030 vision is to develop clinical interventions that modulate themicroenvironment of an injury to stimulate regeneration by taking advantage of the body's innate regenerativeability. In completing the proposed research we will provide a detailed characterization of what T lymphocytesubtypes an immune cell that coordinates changes in the microenvironment of a wound are unique andnecessary for mammalian regeneration. By comparing the healing process after creating a 4 mm hole in theear pinna of two mammals one that heals by fibrosis followed by formation of a scar (Mus musculus) and onethat endogenously regenerates musculoskeletal tissue (Acomys cahirinus) we will increase our understandingof what factors are necessary to stimulate tissue regeneration in situ and catalyze future therapies.


application_id: 9745597
project_number: 5R01DK115406-02
project_title: CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis
administering_ic: NIDDK
award_notice_date: 2019-04-11
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_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;Inflammatory disease of the intestine;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;interest;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


application_id: 9745337
project_number: 3R01HL135158-01A1S1
project_title: Effect of early life stress on obesity-induced hypertension in mice
administering_ic: NHLBI
award_notice_date: 2018-09-14
opportunity_number: PA-16-160
application_type: 3
activity_code: R01
ic: HL
serial_number: 135158
suffix: A1S1
program_official: MCDONALD, CHERYL
project_start_date: 2017-12-01
project_end_date: 2022-11-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353675
contact_pi: LORIA, ANALIA
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:
Acute;Adipose tissue;Adult;Affect;Afferent Neurons;American;Angiotensin II;Angiotensinogen;Autonomic ganglion;Baroreflex;Biological Assay;Birth;Blood Pressure;Body mass index;Capsaicin;Cardiovascular Diseases;Catecholamines;Child;Chronic;Comorbidity;Diet;Dose;Exposure to;Feedback;Female;Functional disorder;Gene Expression;Generations;Glomerular Filtration Rate;Glucocorticoids;Health;High Fat Diet;Homeostasis;Hormones;Hypertension;Hypothalamic structure;Immediate-Early Genes;Kidney;Knockout Mice;Leptin;Life;Link;Longevity;Mediating;Mediator of activation protein;Metabolic;Microinjections;Modeling;Morbidity - disease rate;Mus;Myocardial Ischemia;Nerve;Nerve Fibers;Neuraxis;Neurons;Nociception;Norepinephrine;Obesity;Organ;Outcome Study;Pathway interactions;Personal Satisfaction;Plasma;Procedures;Reflex action;Renin-Angiotensin System;Resiniferatoxin;Risk Factors;Role;Scheme;Sensory;Signal Transduction;Source;Stimulus;Sympathetic Nervous System;Tamoxifen;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Visceral;Weaning;abuse neglect;afferent nerve;analog;base;blood pressure reduction;blood pressure regulation;brain tissue;cardiovascular risk factor;chromatin immunoprecipitation;early life stress;epidemiologic data;epidemiology study;experimental study;hypertension prevention;in vivo;indexing;leptin receptor;male;maternal obesity;maternal separation;modifiable risk;molecular marker;mortality;mouse model;neglect;neonate;neurotransmission;next generation;novel;paraventricular nucleus;postnatal;prevent;promoter;response;somatosensory;stressor;urinary


application_id: 9745172
project_number: 1R21AG059123-01A1
project_title: SLC9A1 and Neurodegenerative Disease
administering_ic: NIA
award_notice_date: 2019-03-21
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AG
serial_number: 059123
suffix: A1
program_official: OPANASHUK, LISA A
project_start_date: 2019-04-01
project_end_date: 2021-01-31
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
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 related dementia;Amyloid;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;Functional disorder;Future;Genes;Genetic;Glial Fibrillary Acidic Protein;Gliosis;Human;Immunoglobulin G;Impaired cognition;Individual;Injury;Ions;Knowledge;Late Onset Alzheimer Disease;Link;Magnetic Resonance Imaging;Mediating;Membrane;Modeling;Mus;NHE1;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuronal Injury;Neurons;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 remodeling;Viral;Virus;Work;age related;age related neurodegeneration;axon injury;base;cerebrovascular;cerebrovascular pathology;cognitive function;cresyl violet;dementia risk;immunohistochemical markers;improved;innovation;insight;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;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: 9744817
project_number: 5R01NS081125-05
project_title: Aurora-A is a novel therapeutic target in glioblastoma
administering_ic: NINDS
award_notice_date: 2019-01-23
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 081125
program_official: FOUNTAIN, JANE W
project_start_date: 2014-09-01
project_end_date: 2021-01-31
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 7041152
contact_pi: LEHMAN, NORMAN
other_pis: Not Applicable
congressional_district: 03
department: PATHOLOGY
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):  Aurora-A (AURKA) is an exciting new drug target for the treatment of glioblastoma (GB). GB is a highly malignant mostly adult brain tumor for which only marginal improvement in survival time has been achieved. AURKA is a serine-threonine kinase that drives mitotic progression and cytokinesis. It also positively regulates several proproliferative signaling pathways including c-Myc cyclin B/CDK1 NF-kB and Wnt signaling and negatively regulates p53. AURKA is oncogenic when overexpressed in cultured cells and its altered expression promotes genomic instability and malignancy.  Our preliminary data show that the selective AURKA inhibitor MLN8237 potently inhibits proliferation of GB cells in vitro and extends animal survival in a GB orthotopic xenograft model. We will study the efficacy of MLN8237 against GB patient-derived neurosphere tumor stem-like cells in vitro and in GB orthotopic xenograft mouse models using neurosphere stem-like cells from multiple patients. Alternate AURKA inhibitors and anti-AURKA RNAi will also be used to verify the efficacy of inhibiting this kinase and to distinguish off-target effects respectively. These in vitro and animl studies will also investigate the possible synergistic effects of MLN8237 with other GB therapies e.g. temozolomide radiation angiogenesis inhibitors and other chemotherapeutic drugs. We will perform experiments to determine if activated AURKA expression or candidate important interacting proteins e.g. Bora and TPX2 predict sensitivity to MLN8237 an important step toward understanding which GB patients would likely benefit most from AURKA inhibition. We will determine the mechanisms of AURKA inhibition of tumor growth by examining effects of inhibitors on GB cell apoptosis differentiation senescence and genomic stability as well as the regulation of biochemical pathways mediating these responses.  Tumor hypoxia and angiogenesis are important mechanisms of tumor progression in gliomas. AURKA is induced by hypoxia and may itself increase angiogenic factors such as VEGF. We will study the effects of AURKA knockin and knockdown on important angiogenic signaling proteins e.g. HIF-1 GSK-3 and VEGF in cultured cells to investigate possible direct and indirect roles of AURKA in GB angiogenesis. Since AURKA is induced by hypoxia we will test the ability of AURKA inhibitors to potentiate bevacizumab which may potentially optimize the latter's clinical usefulness. We will also examine measurable biological effects of AURKA inhibition on angiogenesis tumor invasion and genomic stability using in vitro and animal models.

project_terms:
Adult;Angiogenesis Inhibitors;Angiogenic Factor;Animal Model;Animals;Apoptosis;Applications Grants;Astrocytes;Biochemical Pathway;Biological;Biological Assay;Brain;Brain Neoplasms;CDC2 Protein Kinase;Carboplatin;Caspase;Cell Culture Techniques;Cell physiology;Cells;Clinical;Clinical Trials;Combined Modality Therapy;Cultured Cells;Cyclic AMP-Dependent Protein Kinases;Cyclin B;Cytokinesis;DNA;Data;Diagnosis;Differentiation Antigens;Effectiveness;Exhibits;Flow Cytometry;Genome Stability;Genomic Instability;Glial Fibrillary Acidic Protein;Glioblastoma;Glioma;Goals;HIF1A gene;Human;Hypoxia;In Situ Nick-End Labeling;In Vitro;Knock-in;Laboratories;Lead;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Measurable;Mediating;Messenger RNA;MicroRNAs;Mitosis;Mitotic;Mus;NF-kappa B;Oncogenic;Patient Monitoring;Patients;Perfusion;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Ploidies;Protein Family;Protein-Serine-Threonine Kinases;Proteins;RNA Interference;Radiation;Recurrent tumor;Regulation;Resistance;Role;STK6 gene;Sampling;Signal Pathway;Signal Transduction;Signaling Protein;Slice;Stains;Subfamily lentivirinae;TP53 gene;Testing;Time;Tumor Angiogenesis;Tumor Cell Invasion;Vascular Endothelial Growth Factors;Vascular Proliferation;WNT Signaling Pathway;Xenograft Model;Xenograft procedure;angiogenesis;annexin A5;aurora-A kinase;beta catenin;beta-Galactosidase;bevacizumab;brain endothelial cell;brain tissue;c-myc Genes;cancer type;cell motility;chemotherapy;comparative genomic hybridization;cytotoxicity;efficacy study;efficacy testing;experimental study;glycogen synthase kinase 3 beta;hypoxia inducible factor 1;in vitro testing;in vivo;in vivo Model;inhibitor/antagonist;irinotecan;kinase inhibitor;knock-down;migration;molecular marker;mouse model;neoplastic cell;new therapeutic target;novel;novel therapeutics;overexpression;patient response;public health relevance;radiation response;response;senescence;small hairpin RNA;small molecule;stem-like cell;stemness;targeted treatment;taxane;temozolomide;therapy resistant;tumor;tumor growth;tumor hypoxia;tumor progression;vasculogenesis;weapons

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Glioblastoma is the most common type of brain cancer in adults. It is a very malignant tumor and most patients survive only about one year after diagnosis. Aurora-A inhibitors are a new type of chemotherapy drug that have shown promise against several types of cancer. The purpose of this grant proposal is to perform laboratory testing in cell cultures and mice to confirm that one of these new drugs is an effective weapon against glioblastoma. The ultimate goal of these studies is that this drug will be used to treat glioblastoma patients and allow them to survive longer.


application_id: 9744795
project_number: 5R01HL135000-03
project_title: Role of myocyte Na+ dysregulation in diabetic heart disease
administering_ic: NHLBI
award_notice_date: 2019-07-24
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 135000
program_official: BUXTON, DENIS B
project_start_date: 2017-08-01
project_end_date: 2021-07-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
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:
ABSTRACTType-2 diabetes (T2D) heightens the risk of heart failure arrhythmias and sudden cardiac death even in theabsence of vascular complications. However the underlying mechanisms are poorly understood. We proposethat a critical contributor to diabetic heart disease involves myocyte Na+ dysregulation. Maintenance of cardiacNa+ homeostasis is vital for preserving heart function. Elevated myocyte Na+ concentration ([Na+]i) causesoxidative stress and augments the sarcoplasmic reticulum (SR) Ca2+ leak thus amplifying the risk forarrhythmias and promoting heart dysfunction. Using a rat model of late-onset T2D (the HIP rat) that displaysmyocardial dysfunction and arrhythmias we recently found that [Na+]i is increased in T2D hearts.Unexpectedly higher [Na+]i seems to be caused by enhanced Na+ entry through the Na+-glucose cotransporterisoform 1 (SGLT1) a previously ignored player in cellular Na+ homeostasis. Furthermore we found higherSGLT1 expression in hearts from patients with T2D compared to lean non-diabetic individuals and in heartsfrom diabetic HIP rats vs. control rats. Cardiac-specific SGLT1 overexpression was recently shown to causehypertrophy and left-ventricular dysfunction while SGLT1 activation has been linked to the cardiomyopathycaused by mutations in the gene encoding the 2 subunit of AMP-activated protein kinase. Thus the evidencethat enhanced SGLT1 activity damages the heart is mounting but little is known about the underlyingmechanisms and its role in diabetic cardiomyopathy. Based on these findings we hypothesize that SGLT1upregulation contributes to the multifactorial mechanism driving cardiac remodeling in T2D by perturbingmyocyte Na+ dyshomeostasis. To test this overall hypothesis we will i) assess the role of SGLT1 activation inthe myocyte [Na+]i rise and consequent oxidative stress larger SR Ca2+ leak and spontaneousafterdepolarizations in T2D ii) test whether SGLT1 upregulation is a maladaptation of the myocardium toimpaired insulin-dependent glucose uptake and iii) assess whether SGLT1 and [Na+]i are elevated in heartsfrom humans with T2D. Experiments will combine fluorescence imaging electrophysiology biochemistry invivo assessment of heart function pharmacological tools T2D and transgenic animal models and humanstudies. By integrating physiological and pharmacological analyses in rat and human hearts this project willestablish whether SGLT1 activation and Na+ overload are key events in the pathology of diabetic heart diseaseand will identify SGLT1 as a new therapeutic target for cardiac complications in T2D patients.

project_terms:
5'-AMP-activated protein kinase;Animal Model;Animals;Arrhythmia;Automobile Driving;Biochemistry;Blood Vessels;Cardiac;Cardiomyopathies;Diabetes Mellitus;Electric Stimulation;Electrophysiology (science);Event;Genes;Glucose;Heart;Heart Diseases;Heart failure;Homeostasis;Human;Hyperglycemia;Hypertrophy;Impairment;Individual;Insulin;Insulin Resistance;Kidney;Left Ventricular Dysfunction;Link;Maintenance;Mediating;Messenger RNA;Mitochondria;Modeling;Mus;Muscle Cells;Mutation;Myocardial;Myocardial dysfunction;Myocardium;Na(+)-K(+)-Exchanging ATPase;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxidative Stress;Pathology;Patients;Pharmacology;Phase;Physiological;Prediabetes syndrome;Protein Isoforms;Proteins;Rattus;Regulation;Rest;Risk;Role;Sarcoplasmic Reticulum;Structure;Testing;Thinness;Tissues;Transgenic Animals;Transgenic Mice;Translating;Up-Regulation;Work;base;cardioprotection;db/db mouse;diabetic;diabetic cardiomyopathy;experimental study;fluorescence imaging;glucose uptake;heart damage;heart function;heart preservation;improved;in vivo;injured;insulin sensitizing drugs;insulin signaling;new therapeutic target;non-diabetic;overexpression;prevent;sudden cardiac death;tool

public_health_relevance:
NARRATIVEType-2 diabetes heightens the risk of heart failure arrhythmias and sudden cardiac death but the underlyingmechanisms are poorly understood and there is no specific treatment for heart disease in patients withdiabetes. Proposed work seeks to test the hypothesis that enhanced activity of the Na+-glucose cotransporter 1and myocyte Na+ dysregulation are critical contributors to diabetic cardiomyopathy. Thus this work mayidentify novel therapeutic targets for cardioprotection that are specifically tailored to patients with type-2diabetes.


application_id: 9744766
project_number: 5U01HL133359-03
project_title: Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
administering_ic: NHLBI
award_notice_date: 2019-07-18
opportunity_number: PAR-15-085
application_type: 5
activity_code: U01
ic: HL
serial_number: 133359
program_official: ADHIKARI, BISHOW B
project_start_date: 2017-08-03
project_end_date: 2022-07-31
study_section: ZEB1-OSR-C(M1)S
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: WENK, JONATHAN F
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Affect;Algorithms;American;Biological Assay;Biology;Cardiac;Cardiac Death;Cardiomyopathies;Cardiovascular Diseases;Cells;Chronic;Computer Simulation;Computer software;Coupled;DNA Sequence Alteration;Data;Data Analyses;Development;Drug usage;Elements;Engineering;Fiber;Future;Genetic;Geometry;Goals;Growth;Heart;Heart Abnormalities;Heart Diseases;Heart Hypertrophy;Heart failure;Histology;Hypertrophy;Inherited;Intervention;Kinetics;Laws;Magnetic Resonance Imaging;Mathematics;Measurement;Measures;Modeling;Molecular;Motor;Mutation;Myocardial;Myosin ATPase;Myosin Regulatory Light Chains;Organ;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Proteins;Records;Research;Research Personnel;Sarcomeres;Scientist;Structure;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Transgenic Animals;Transgenic Mice;Treatment Failure;Validation;Ventricular;Ventricular Remodeling;Wild Type Mouse;Work;cell motility;drug testing;experience;experimental study;genetic regulatory protein;heart function;improved;inherited cardiomyopathy;innovation;interest;mathematical model;model development;molecular scale;multi-scale modeling;novel therapeutics;personalized medicine;predictive modeling;response;simulation;skills;software development;treatment optimization;treatment planning


application_id: 9744677
project_number: 5T32DK007778-20
project_title: Pharmacology and Nutritional Sciences: Multidisciplinary Approaches for Metabolic Disease
project_terms: Metabolic Diseases;Nutritional Science;Pharmacology;interdisciplinary approach
administering_ic: NIDDK
award_notice_date: 2019-07-08
opportunity_number: PA-14-015
application_type: 5
activity_code: T32
ic: DK
serial_number: 007778
program_official: DENSMORE, CHRISTINE L
project_start_date: 2000-08-15
project_end_date: 2021-07-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
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_abstract:
DESCRIPTION (provided by applicant): This is a competing renewal of a training program that was initially funded in 1999. Since its inception the primary goal of this training program has been to prepare promising pre-doctoral students for successful careers in nutritional sciences with a focus on nutrition as a modulator of metabolic disease (obesity diabetes) cancer neurodegenerative disease and cardiovascular disease. In this renewal we capitalize upon our unique academic structure of a recently merged Department of Pharmacology and Nutritional Sciences to provide a multi-disciplinary program where graduate students are trained to develop nutritional and/or pharmacologic approaches towards the prevention and treatment of chronic diseases. The need for highly trained scientists capable of conducting multidisciplinary research in this area has become critical with the increased prevalence of metabolic diseases in the U.S. and the growing recognition that metabolic disorders underlie chronic diseases including cancer neurodegenerative disease and cardiovascular disease. We envision that scientists who receive cross-training in nutrition and pharmacology through this multidisciplinary program will have the necessary skill set to tackle these common yet complex disease processes. Twenty-nine training faculty who routinely employ nutritional and/or pharmacologic approaches to understand the metabolic basis of disease will provide training around 4 theme areas (obesity/diabetes cardiovascular disease cancer neuroscience/aging). The goals of the Multidisciplinary Approaches for Metabolic Diseases Training Program are to provide support to a talented and diverse population of graduate students through stipends and individual development plans (IDPs) to prepare them for biomedical careers in the area of metabolic diseases; to provide innovative multidisciplinary education to promote the essential skills for conducting outstanding research using nutrition and pharmacology-based approaches; to provide a core faculty of established and productive researchers who will serve as mentors and role models for the trainees; to provide a broad-based yet cohesive research environment for trainees thus fostering further interdisciplinary research; and to provide training in the ethcal conduct of high quality research.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Disorders in metabolism are a common feature of most chronic diseases especially those on the rise in prevalence in the US. We propose to train future scientists to identify ways to use pharmacological (drugs) and nutritional approaches to prevent and treat metabolic disease based-disorders including obesity/diabetes cancer cardiovascular disease and neurodegenerative disease.


application_id: 9744473
project_number: 5R01CA217934-03
project_title: (PQ9)A redox-mediated mechanism of chemotherapy-induced cognitive impairment
administering_ic: NCI
award_notice_date: 2019-07-24
opportunity_number: RFA-CA-15-008
application_type: 5
activity_code: R01
ic: CA
serial_number: 217934
program_official: CHEN, WEIWEI
project_start_date: 2017-09-15
project_end_date: 2022-07-31
study_section: ZCA1-RTRB-E(M2)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: BONDADA, SUBBARAO ;BUTTERFIELD, D. ALLAN
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 SummaryThis application addresses the Provocative Question 9: "What are the molecular and/or cellular mechanismsthat underlie the development of cancer therapy-induced severe adverse sequelae?" focusing onChemotherapy-induced cognitive impairments (CICI). CICI is now a recognized toxicity syndrome that includesloss of executive function (confusion; memory issues) inability to multitask and impaired intellectualreasoning. While CICI caused by central nervous system (CNS)-directed therapies (such as radiation andintrathecal chemotherapy) is readily understood the mechanisms underlying a critical and shared toxicity ofchemotherapy that occurs after systemic cancer treatment with drugs that did not direct at the brain areunclear. The number of patients at risk for CICI from systemic therapy far exceeds the number of patientsexposed to CNS therapy but little is known about the mechanisms mediating the effect of systemic therapy onCICI and there is no clear vision of how to prevent this condition. We have previously shown that generationof reactive oxygen species (ROS) by cytotoxic chemotherapeutic drugs is an essential mediator of brain injuryeven though the drug itself did not get into the brain. It is also imperative to note that anticancer medicationsdesigned specifically to target cancer cells with specialized features such as the family of Bcl2 inhibitors alsogenerate ROS. However the effect of targeted therapy on CICI has never been addressed andconsequently their mechanisms of action are entirely unknown. The goal of this proposal is to test the overallhypothesis that therapy-induced ROS production in the target tissues leads to increased circulating TNFthrough extracellular vesicles (EVs)-mediated reactions and this pro-inflammatory cytokine crosses the bloodbrain barrier to elicit mitochondrial dysfunction and consequent neuronal injury leading to CICI. The followingspecific aims are designed to test the ROS hypothesis gain an understanding of the EVs-mediatedmechanisms and test the proof-of-concept in an experimental cancer therapy setting using two prototypechemotherapy agents (Doxorubicin and Venetoclax) that represent standard cytotoxic and experimentaltargeted drugs in a lymphoma model. Aim 1 will investigate the fundamental role of TNF in therapy-inducedneuronal injury to gain insights into mechanisms of CICI in the brain and demonstrate efficacy of chemotherapyin the presence of redox-active antioxidants. Aim 2 will determine the mechanistic links between circulatingextracellular vesicles and therapy-induced CICI. Aim 3 will define the cell(s) of origin of TNF produced duringchemotherapy that leads to cognitive impairment. These aims will be accomplished in vitro and in vivo usingstate-of-the-art technologies including magnetic resonance spectroscopy redox proteomics unique animalmodels and novel mitochondria targeting anti-oxidant MnP to ameliorate CICI without reducing the efficacy ofthe anti-cancer drugs. The results from this project will lay important groundwork for future clinical trials toimprove the quality of lives of cancer patients exposed to cytotoxic or targeted therapies.

project_terms:
4 hydroxynonenal;Address;Animal Model;Antibodies;Antineoplastic Agents;Antioxidants;Apoptotic;BCL2 gene;Biochemical;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain Injuries;Cancer Patient;Cancer Survivor;Cells;Choline;Clinical;Clinical Trials;Cognition;Confusion;Cytotoxic Chemotherapy;Development;Doxorubicin;Drug Targeting;Drug usage;Etiology;Exposure to;Family;Functional disorder;Future;Generations;Goals;Immune;Impaired cognition;Impairment;In Vitro;Inflammatory;Injury;Intrathecal Chemotherapy;Knockout Mice;Link;Lymphoma;Magnetic Resonance Spectroscopy;Mediating;Mediator of activation protein;Memory;Mitochondria;Modeling;Molecular;Mus;Neuraxis;Neuronal Injury;Nitrates;Oxidation-Reduction;Oxidative Stress;Pathology;Patients;Peripheral;Permeability;Pharmaceutical Preparations;Plasma;Prevention;Production;Proteins;Proteomics;Publishing;Quality of life;Radiation;Reaction;Reactive Oxygen Species;Recommendation;Research;Respiration;Risk;Role;SOD2 gene;Symptoms;Syndrome;Systemic Therapy;TNF gene;Technology;Testing;Therapeutic Effect;Therapeutic Uses;Tissues;Toxic effect;Toxicity due to chemotherapy;Treatment Efficacy;United States;Vision;anti-cancer;antioxidant enzyme;cancer cell;cancer therapy;chemobrain;chemotherapy;cytokine;cytotoxic;design;executive function;experience;extracellular vesicles;improved;in vivo;inhibitor/antagonist;insight;macrophage;mimetics;mitochondrial dysfunction;multitask;neuron loss;nitration;novel;prevent;prototype;specific biomarkers;targeted treatment;tumor

public_health_relevance:
Project NarrativeChemotherapy-induced cognitive impairment (CICI) is a serious threat to the quality of life. This project isdesigned to identify practice-changing therapy by establishing a new paradigm which recognizes that ROS isthe initiator of CICI caused by both cytotoxic and targeted drugs. Results from these studies will lead to veryconcrete information potentially offering a specific course of action to develop effective clinical approachesspecifically designed to prevent CICI without reducing chemotherapeutic efficacy.


application_id: 9743618
project_number: 5K01CA197073-05
project_title: Intestinal phosphatidylcholine exposure and breast cancer risk
administering_ic: NCI
award_notice_date: 2019-06-25
opportunity_number: PAR-12-050
application_type: 5
activity_code: K01
ic: CA
serial_number: 197073
program_official: TILAHUN, MULUALEM ENYEW
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10392720
contact_pi: ONONO, FREDRICK ONYANGO
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): Diet-dependent obesity is a risk factor for many cancers including postmenopausal breast cancer. Obesity is also associated with more aggressive breast cancer subtypes and poorer clinical outcomes in breast cancer patients. The increasing prevalence of overweight and obese postmenopausal breast cancer patients makes it critical to identify the mechanisms that underlie this link between obesity and breast cancer risk and prognosis. A better understanding of the link between diet obesity and breast cancer risk might then lead to improvements in healthful nutrition for obese or overweight patients or identify markers for breast cancer risk assessment or targets for pharmacological intervention to mitigate breast cancer risk associated with obesity. The aim of this K01 application is to support mentored training in advanced mass spectrometry/metabolomics and preclinical models that will enable me to become an independent investigator working at the interface of obesity and cancer research. A broad hypothesis to explain the link between obesity and cancer risk is that consumption of a high fat diet and/or increased synthesis and storage of fats is associated with the production of bioactive lipids or lipid-derived molecules that themselves promote disease. I propose to investigate the possibility that intestinal exposure to the phospholipid phosphatidylcholine (PC) constitutes a link between diet and breast cancer risk by promoting the synthesis of a PC derived bioactive lipid lysophosphatidic acid (LPA). Breast cancer cells are acutely responsive to LPA which stimulates their migration growth and survival in vitro. Genetic and pharmacological targeting of LPA synthesis and signaling attenuate breast cancer tumor growth and metastasis in mouse models. We propose that dietary consumption of foods rich in PC or secretion of PC into the stomach as bile in response to a fatty meal results in uptake of this lipid as its lyso derivative lysoPC (LPC) that is transported in the blood as a component of intestinally derived lipoproteins where is serves as a substrate for production of LPA by the secreted lysophospholipase D autotaxin. In support of this idea we show that plasma LPA levels in mice and humans are acutely sensitive to fasting and re-feeding and that in mice dietary PC can be converted to LPA in the blood. To address our hypothesis we will use mass spectrometry to monitor metabolism of dietary PC in mice and develop mouse diets with defined PC composition that we propose will lead to alterations in plasma LPA levels. The information in this aim will then be exploited to determine the impact of manipulations of dietary PC and pharmacological inhibition of the LPA generating enzyme autotaxin on breast cancer metastasis in mouse models. Completion of these studies will provide important new information about how a specific dietary constituent could contribute to breast cancer metastasis in humans and might also provide an impetus for future translational studies exploring the possibility that pharmacological inhibition of LPA synthesis and signaling could be a viable strategy to mitigate human breast cancer risk particularly in obese subjects.

project_terms:
Acute;Address;Adipose tissue;Animals;Attenuated;Award;Bile fluid;Bioavailable;Blood;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Risk Factor;Breast cancer metastasis;Calories;Cancer Patient;Cancer Prognosis;Chylomicrons;Clinical;Consumption;Data;Diet;Dietary Fats;Disease;Enterocytes;Enzymes;Exposure to;Fasting;Fatty acid glycerol esters;Food;Funding;Future;Genetic;Growth;High Fat Diet;Human;Hydrolysis;In Vitro;Incidence;Individual;Intervention;Intestinal Absorption;Intestines;Lead;Lecithin;Link;Lipids;Lipoproteins;Low-Density Lipoproteins;Lymphatic System;Lysophospholipase;Lysophospholipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediator of activation protein;Mentors;Metabolic;Metabolism;Metastatic Neoplasm to the Bone;Modernization;Monitor;Mus;Neoplasm Metastasis;Nonesterified Fatty Acids;Obesity;Oral;Outcome;Overweight;Pathway interactions;Patients;Pharmacology;Phospholipase A2;Phospholipase D;Phospholipids;Plants;Plasma;Postmenopause;Pre-Clinical Model;Prevalence;Process;Production;Reaction;Request for Proposals;Research;Research Personnel;Research Support;Research Training;Risk Assessment;Risk Factors;Signal Transduction;Stomach;Testing;Tracer;Training;Underrepresented Minority;United States;United States National Institutes of Health;Weight;Woman;Work;anticancer research;cancer risk;cancer subtypes;career development;diet and cancer;dietary constituent;dietary manipulation;disorder risk;experience;feeding;food consumption;inhibitor/antagonist;lysophosphatidic acid;malignant breast neoplasm;metabolomics;migration;minority scientist;mouse model;nutrition;obesity risk;particle;public health relevance;response;sedentary lifestyle;skills;stable isotope;translational study;tumor growth;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Being obese or overweight dramatically increases cancer risk particularly in women and obese or overweight cancer patients often experience worse clinical outcomes than normal weight individuals. However the basis for this association of obesity with cancer risk and prognosis is not well understood. This proposal requests funds to support research training and career development for a promising underrepresented minority scientist who proposes to investigate a potential mechanism linking obesity to cancer risk and clinical outcomes.


application_id: 9743221
project_number: 5R01HL142710-02
project_title: Regulation of Coronary Blood Flow
administering_ic: NHLBI
award_notice_date: 2019-07-03
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 142710
program_official: OH, YOUNGSUK
project_start_date: 2018-07-20
project_end_date: 2023-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10920880
contact_pi: NYSTORIAK, MATTHEW A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Affinity;Animals;Binding;Biochemistry;Biosensor;Blood;Blood Vessels;Blood flow;Caliber;Cardiac;Cardiovascular system;Catalysis;Cells;Comorbidity;Complex;Contrast echocardiography procedure;Coronary;Coronary Arteriosclerosis;Coronary Vessels;Coronary artery;Coronary heart disease;Couples;Coupling;Cues;Data;Dependence;Development;Electrophysiology (science);Exercise;Family;Genetically Engineered Mouse;Genetically Modified Animals;Goals;Heart;Heart Contractilities;Heart Diseases;Heart Rate;Hyperemia;Image;Impairment;In Vitro;Ischemia;Link;Measurement;Measures;Mediating;Mediator of activation protein;Membrane Potentials;Metabolic;Metabolism;Molecular;Molecular Biology;Monitor;Myocardial;Myocardial Ischemia;Myocardial perfusion;Myocardium;Myography;NADH;Norepinephrine;Oxidation-Reduction;Oxides;Oxidoreductase;Oxygen;Patients;Physiological;Play;Process;Property;Proteins;Protocols documentation;Pump;Recurrence;Regulation;Resistance;Rest;Role;Running;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stress;Structural Protein;Testing;Transgenic Animals;Treatment Efficacy;Vascular Smooth Muscle;Vasodilation;Voltage-Gated Potassium Channel;Work;Workload;arteriole;base;conditioning;coronary artery occlusion;exercise capacity;exercise regimen;exercise training;heart function;heart metabolism;hypoperfusion;in vivo;insight;member;novel;novel imaging technique;novel therapeutics;patch clamp;prevent;pyridine nucleotide;reconstitution;response;sedentary;tool;treadmill;voltage


application_id: 9742454
project_number: 5R03DE028031-02
project_title: A novel role for NADPH oxidase in modulating neutrophil functions in periodontal disease
administering_ic: NIDCR
award_notice_date: 2019-06-06
opportunity_number: PAR-16-409
application_type: 5
activity_code: R03
ic: DE
serial_number: 028031
program_official: CHANDER, PREETHI
project_start_date: 2018-07-10
project_end_date: 2020-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11377419
contact_pi: BAGAITKAR, JUHI
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:
ABSTRACTPeriodontal diseases are caused by host inflammatory responses to dysbiotic oral microbiota resultingin the progressive destruction of supporting hard and soft tissues of the peridontium. It is estimated thatapproximately 50% of the US population will suffer from some form of periodontal disease. Neutrophilsare the most common anti-microbial effector myeloid cells recruited to the oral cavity under bothphysiological and pathological conditions. Although neutrophils are associated with the initiation andprogression of periodontal diseases we know little about the specific immune pathways that driveneutrophil recruitment or activation at the gingival barrier. The NADPH oxidase enzyme complex ishighly expressed in neutrophils. On activation the NADPH oxidase generates superoxide which isenzymatically or spontaneously converted to reactive oxygen species (ROS) that have antimicrobialand immuno-regulatory functions. Our preliminary data demonstrates a key role for NADPH oxidasederived-ROS in limiting neutrophilic effector functions in response to periodontal pathogens. Oxidasenull neutrophils generated excessive amounts of inflammatory mediators in response to oral bacteria.Oxidase deficiency in mice resulted in profound inflammation characterized by excessive mobilizationand tissue accrual of neutrophils. These data support a somewhat counterintuitive role for ROS inlimiting host inflammation. Our central hypothesis is that the NADPH oxidase derived-ROSindependent of their antimicrobial functions play key roles in redox modulation of neutrophil effectorfunctions in vitro and in vivo. Further we hypothesize that while excessive amounts of ROS areassociated with the pathophysiology of periodontal diseases low-level localized ROS responses areimmuno-regulatory. These hypotheses will be tested in two specific aims. 1) We will determine thespecific intracellular signaling pathways modulated by oxidants that limit neutrophil degranulation andtranscriptional responses to oral bacteria. 2) We will also investigate the role of sentinel macrophagesand ROS from microbial sources in modulating neutrophilic inflammation in vivo. The use of conditionalknockout mice that specifically lack NADPH oxidase activity in neutrophils will enable us to specificallydetermine the role of oxidants in regulation of neutrophil effector functions in a cell intrinsic manner invivo. The data generated by these studies will not only shed key mechanistic insights in neutrophilbiology but also enhance our understanding of immune pathways relevant in gingival inflammation andtheir regulation by oxidants. Further our studies are also highly relevant in understanding theimmunopathology of chronic granulomatous disease a life-threatening pediatric immuno-deficiencycaused by inherited mutations in NADPH oxidase genes.

project_terms:
Alleles;Antibiotic Therapy;Autoimmune Diseases;Biology;Cell membrane;Cell physiology;Cells;Childhood;Chronic;Chronic Granulomatous Disease;Conflict (Psychology);Data;Dendritic Cells;Diagnosis;Disease;Effector Cell;Enzymes;Functional disorder;Fusobacterium nucleatum;Generations;Genes;Genetic;Genetic Transcription;Gingiva;Goals;Immune;Immune response;Immunologic Deficiency Syndromes;In Vitro;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Inherited;Injury;Knockout Mice;Leukocytes;Life;Literature;Microbe;Multienzyme Complexes;Mus;Mutation;Myelogenous;Myeloid Cells;NADPH Oxidase;Nature;Neutrophil Activation;Neutrophil Infiltration;Oral cavity;Oral mucous membrane structure;Outcome;Oxidants;Oxidases;Oxidation-Reduction;Pathologic;Pathway interactions;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontium;Physiological;Play;Population;Porphyromonas gingivalis;Production;Reactive Oxygen Species;Regulation;Reporting;Resolution;Role;Sentinel;Signal Pathway;Source;Sterility;Stimulus;Superoxides;Testing;Tissues;Tooth structure;antimicrobial;chemokine;cytokine;dysbiosis;immunopathology;immunoregulation;in vivo;insight;macrophage;microbial;mouse model;neutrophil;novel;null mutation;oral bacteria;oral microbial community;periodontopathogen;prevent;recruit;release of sequestered calcium ion into cytoplasm;response;soft tissue;superoxide-generating NADPH oxidase

public_health_relevance:
PROJECT NARRATIVEAberrant host inflammatory responses to microbial infections or sterile injury can cause tissue damage and isan underlying factor in multiple chronic inflammatory and autoimmune disorders. The proposed studies willdetermine how oxidants generated by leukocytes play a role in dampening host inflammatory responses in theoral mucosa independent of their antimicrobial function. These studies will not only elucidate entirely novelpathways regulated by oxidants during host inflammatory responses but also shed key mechanistic insightsinto understanding the basis of profound inflammatory complications observed in chronic granulomatousdisease patients; a severe immunodeficiency caused by inherited mutations in NADPH oxidase genes.!


application_id: 9741969
project_number: 1R56AI135021-01
project_title: Biogenesis and Function of Lancefield Group A Carbohydrate Expressed by Streptococcus Pyogenes
administering_ic: NIAID
award_notice_date: 2018-08-06
opportunity_number: PA-16-160
application_type: 1
activity_code: R56
ic: AI
serial_number: 135021
program_official: GU, XIN-XING
project_start_date: 2018-08-06
project_end_date: 2020-07-31
study_section: Bacterial Pathogenesis Study Section[BACP]
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
project_abstract:
Group A Streptococcus (GAS Streptococcus pyogenes) is a leading bacterial pathogen of thehuman pharynx and skin. In most cases the pathogen causes self-limiting infections such aspharyngitis and impetigo. However in recent years a striking resurgence in severe invasiveGAS infections has been observed worldwide. GAS infections account for more than 650000cases of invasive disease annually. Although this pathogen is susceptible to antibiotic therapysevere invasive GAS infections are often difficult to treat. The ability of GAS to cause infectionsis associated with pathogen resistance to killing by the host innate immune system. The cell wallof GAS consists of peptidoglycan sacculus decorated with a carbohydrate comprising apolyrhamnose backbone with immunodominant N-acetylglucosamine side-chains the Group ACarbohydrate (GAC). GAC plays a major role in the bacterial physiology of GAS by protectingthe cell envelope from environment stress and innate immunity assault. To evade immunerecognition GAS deploys post-synthetic modifications of GAC sugars. The goal of this proposalis to re-examine GAC structure and characterize GAC biosynthesis regulation and function. Tohelp answer these important biological questions we will use a range of biochemical andstructural approaches including NMR x-ray crystallography and atomic force microscopy. Thebiological function of GAC sugar modifications will be studied in different models of GASinfection. The proposed study is significant because GAC is a promising candidate for auniversal GAS vaccine and the enzymes of the GAC biosynthesis pathway are attractive drugtargets.

project_terms:
Acids;Affect;Anabolism;Anti-Bacterial Agents;Antibiotic Therapy;Atomic Force Microscopy;Bacteria;Bacterial Physiology;Binding;Biochemical;Biochemistry;Biogenesis;Biological;Biological Process;Carbohydrates;Cell Shape;Cell Wall;Cells;Chemical Structure;Control Groups;Defect;Development;Diagnostic;Disease;Disease Outbreaks;Drug Targeting;Environment;Enzymes;Gene Cluster;Genetic;Glycerophosphates;Goals;Gram-Positive Bacteria;Group Structure;Growth;Heme;Human;Hydrolysis;Immune;Impetigo;Infection;Innate Immune System;Knowledge;Life;Link;Lipid Biochemistry;Measurement;Mediating;Membrane Proteins;Methods;Minor;Modeling;Modification;Molecular;Morbidity - disease rate;Mutagenesis;N-acetylmuramic acid;Natural Immunity;Osmolalities;Outcomes Research;Pathogenesis;Pathway interactions;Peptidoglycan;Pharyngeal structure;Pharyngitis;Physiology;Play;Polymyxin B;Polysaccharides;Positioning Attribute;Process;Proteins;Publishing;Regulation;Research;Research Personnel;Resistance;Rhamnose;Role;Side;Site;Skin;Streptococcal Infections;Streptococcus pyogenes;Streptococcus vaccine;Stress;Structure;Surface Properties;Techniques;Thick;Transferase;Vaccines;Vertebral column;Virulence;X-Ray Crystallography;amidase;antimicrobial;antimicrobial peptide;assault;carbohydrate biosynthesis;carbohydrate structure;cell envelope;improved;insight;interest;mortality;mouse model;mutant;neutrophil;novel;pathogen;structural biology;sugar;targeted treatment;tool;vaccine development

public_health_relevance:
Streptococcus pyogenes is a human bacterial pathogen that causes high morbidity andmortality. S. pyogenes cell wall is composed of peptidoglycan and the covalently attachedrhamnose-containing group A-specific carbohydrate (GAC). The proposed research investigatesGAC structure biosynthesis pathway regulation and function. The outcomes of this researchare expected to have a positive impact on the development of highly targeted therapeutics tocontrol S. pyogenes infections.


application_id: 9741653
project_number: 5P30CA177558-07
project_title: Leadership Planning and Evaluation
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5638
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Advisory Committees;Area;Basic Science;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Clinical;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Consultations;Decision Making;Department chair;Development;Doctor of Philosophy;Education;Ensure;Evaluation;Faculty Recruitment;Feedback;Fostering;Foundations;Funding;Funding Mechanisms;Future;Goals;Grant;Growth;Infrastructure;Kentucky;Lead;Leadership;Maps;Medicine;Mentors;Mission;NCI Center for Cancer Research;National Cancer Institute;Outcome;Phase;Policies;Population Research;Precision Medicine Initiative;Prevention education;Process;Reporting;Research;Resource Sharing;Resources;Review Committee;Science;Strategic Planning;Training and Education;Translational Research;Translations;Universities;Update;Vision;Work;anticancer research;base;cancer education;cancer prevention;cancer research center director;career development;clinical care;clinical translation;college;experience;inter-institutional;meetings;member;mentoring community;operation;outreach;precision medicine;programs;recruit;training opportunity;translational scientist


application_id: 9741649
project_number: 5P30CA177558-07
project_title: Drug Discovery Delivery and Translational Therapeutics Research Program
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5634
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Adjuvant;Appalachian Region;Automobile Driving;Basic Science;Binding Proteins;Bioinformatics;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Cancer Patient;Carcinogen exposure;Catchment Area;Cellular biology;Characteristics;Clinic;Clinical Cancer Center;Clinical Data;Clinical Pathology;Clinical Protocols;Clinical Trials;Collaborations;Colon;Colon Carcinoma;Community Outreach;Complex;DNA;Development;Devices;Diagnosis;Diagnostic Trial;Direct Costs;EIF4EBP1 gene;Early Therapeutic-Clinical Trials Network;Early identification;Engineering;Enrollment;Environmental Carcinogens;Epigenetic Process;Eukaryotic Initiation Factors;Evaluation;Ewings sarcoma;Fatty Acids;Fli-1 protein;Frequencies;Funding;Genomic Instability;Geography;Goals;Grant;Health Services Accessibility;High-Risk Cancer;Hydroxychloroquine;Informatics;Infrastructure;International;Intervention;Investigation;Investigational New Drug Application;Investments;Kentucky;Knowledge;Laboratory Research;Lead;Libraries;Ligands;Ligase;Link;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Metabolism;Mission;Molecular;Molecular Abnormality;Molecular Target;Mutation;Natural Product Drug;Natural Products;Ovarian;PAWR gene;Participant;Pathology;Patients;Pharmacologic Substance;Pharmacy facility;Phase;Phenotype;Phosphorylation;Physicians;Population;Precision Medicine Initiative;Preclinical Testing;Protocols documentation;Publications;Publishing;Reporting;Research;Research Personnel;Resources;Role;Science;Scientist;Signal Transduction;Socioeconomic Status;Squamous Cell Lung Carcinoma;Therapeutic;Therapeutic Agents;Therapeutic Human Experimentation;Therapeutic Trials;Translating;Translations;Universities;Vision;Work;Writing;anticancer activity;anticancer research;anticancer treatment;biomarker discovery;cancer biomarkers;cancer cell;cancer clinical trial;cancer genomics;cancer prevention;cancer subtypes;cancer therapy;clinical development;clinical implementation;cohesion;college;cross disciplinary program;data management;design;drug candidate;drug development;drug discovery;druggable target;evidence base;exome sequencing;individual patient;inhibitor/antagonist;innovation;inter-institutional;malignant breast neoplasm;member;metabolomics;molecular marker;mutational status;neoplasm registry;new therapeutic target;novel;novel anticancer drug;novel marker;novel therapeutics;phenotypic biomarker;pre-clinical;precision medicine;programs;recruit;repository;research facility;screening;senior faculty;synergism;targeted agent;targeted biomarker;targeted treatment;translational study;treatment response;treatment trial;tumor


application_id: 9741648
project_number: 5P30CA177558-07
project_title: Cancer Prevention and Control Research Program
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5633
contact_pi_person_id: 9152491
contact_pi: HE, CHUNYAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Age;Appalachian Region;Area;Behavioral;Behavioral Genetics;Biological Markers;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Control Research Program;Cancer Patient;Catchment Area;Collaborations;Colon Carcinoma;Colorectal Cancer;Communities;Country;County;Data Linkages;Data Set;Development;Diagnosis;Direct Costs;Early Diagnosis;Education;Effectiveness of Interventions;Environmental Carcinogens;Environmental Exposure;Environmental Risk Factor;Epidemiologist;Evaluation;Evidence based intervention;Exposure to;Funding;Genetic;Goals;Incidence;Informatics;Intervention;Intervention Studies;Kentucky;Laboratories;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Measures;Metals;Methods;Mission;Molecular;Morbidity - disease rate;National Cancer Institute;Natural Language Processing;Obesity;Outcomes Research;Pathology;Pathology Report;Patients;Pattern;Play;Policy Developments;Population;Population Research;Poverty;Prevalence;Prevention;Process;Productivity;Program Research Project Grants;Provider;Publications;Registries;Reporting;Research;Research Personnel;Resources;Risk Factors;Role;Rural;Rural Appalachia;Rural Population;Sampling;Site;Smoking;Social Identification;Testing;Time;Tissues;Translational Research;United States;Universities;Vulnerable Populations;Work;anticancer research;base;cancer health disparity;cancer prevention;cancer recurrence;cancer risk;cancer site;carcinogenesis;college;design;disadvantaged population;experience;federal poverty level;high risk;high risk behavior;high school;innovation;insight;inter-institutional;intervention program;low socioeconomic status;malignant breast neoplasm;member;mortality;neoplasm registry;novel;population based;programs;protein expression;recruit;repository;smoking cessation;social;social media;socioeconomics;survivorship;tool;trait;virtual


application_id: 9741647
project_number: 5P30CA177558-07
project_title: Cancer Cell Biology and Signaling Research Program
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5632
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Achievement;Adhesions;Adipocytes;Animal Model;Anoikis;Apoptosis;Appalachian Region;Area;Bacteria;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Cell Survival;Cellular biology;Chloroquine;Climate;Clinic;Clinical Trials;Collaborations;Cytoskeleton;Development;Diabetes Mellitus;Direct Costs;Drosophila genus;Drug Combinations;Engineering;Ensure;Environment;Epithelial;Extracellular Matrix;FDA approved;Faculty;Funding;Future;Gene Proteins;Genes;Goals;Grant;Group Meetings;Growth Factor;Immune checkpoint inhibitor;Immunologist;Incidence;Individual;Institutes;Interdisciplinary Study;Intestinal Hormones;Joints;Kentucky;Legal patent;Link;Malignant Neoplasms;Malignant neoplasm of gastrointestinal tract;Medicine;Mentors;Mesenchymal;Mission;Morbidity - disease rate;NCI Center for Cancer Research;National Cancer Institute;Nature;Neoplasm Metastasis;Neurotensin;Obesity;Oral;PAWR gene;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Postdoctoral Fellow;Process;Program Description;Public Health;Publications;Publishing;Regulation;Research;Research Personnel;Research Project Grants;Role;Science;Signal Pathway;Signal Transduction;Stem cells;Stilbenes;System;Testing;Therapeutic;Transitional Cell;Translational Research;Translations;Tumor Cell Invasion;Tumor Suppressor Genes;Tumor Suppressor Proteins;Underserved Population;Universities;Zebrafish;base;breast cancer progression;cancer cell;cancer education;cancer initiation;cancer stem cell;cell motility;clinical translation;cohesion;collaborative environment;college;colon cancer treatment;cytokine;drug discovery;inhibitor/antagonist;insight;inter-institutional;leukemic stem cell;melanoma;member;mortality;neoplastic cell;new therapeutic target;novel;novel drug combination;novel therapeutics;off-patent;programs;recruit;resistance mechanism;response;smoothened signaling pathway;stem cell division;success;targeted treatment;therapy resistant;tool;tumor;tumor microenvironment;tumor progression


application_id: 9741646
project_number: 5P30CA177558-07
project_title: Redox Metabolism Shared Resource Facility
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5631
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Affect;Appalachian Region;Area;Australia;Basic Science;Bioenergetics;Biological;Biological Assay;Biology;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control Research;Catchment Area;Cell Respiration;Cells;Centers of Research Excellence;Chemotherapy-Oncologic Procedure;Clinical;Comprehensive Cancer Center;Consultations;Development;Education;Educational workshop;Equipment;Europe;Experimental Designs;Faculty;Free Radicals;Funding;Future;Genomics;Genus Hippocampus;Goals;Immunotherapy;Incidence;Injury;Institution;International;Investments;Kentucky;Knowledge;Leadership;Malignant Neoplasms;Mass Spectrum Analysis;Measurement;Mentors;Metabolic;Metabolic Pathway;Metabolism;Methodology;Methods;Mission;Mitochondria;Molecular;Morphologic artifacts;NCI Center for Cancer Research;National Cancer Institute;Neoplasm Metastasis;Normal tissue morphology;Nuclear Magnetic Resonance;Obesity;Oxidation-Reduction;Oxidative Stress;Oxides;Patients;Peer Review;Phase;Population;Post-Translational Protein Processing;Preparation;Principal Investigator;Protein Array;Proteins;Proteomics;Research;Research Personnel;Resource Sharing;Resources;Role;Sampling;Science;Services;Signal Transduction;Strategic Planning;System;Techniques;Technology;Tissues;Training;Training and Education;Translational Research;United States;United States National Institutes of Health;Universities;bench to bedside;biological systems;biomarker discovery;biomarker validation;cancer prevention;cancer therapy;data integration;differential expression;high risk population;improved;innovation;insight;interest;lens;member;metabolomics;metabolomics resource;mortality;nitrosative stress;oxidative damage;precision medicine;programs;recruit;response;service utilization;side effect;stable isotope;tumor metabolism


application_id: 9741644
project_number: 5P30CA177558-07
project_title: Flow Cytometry and Cell Sorting Shared Resource Facility
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5630
contact_pi_person_id: 1878476
contact_pi: COHEN, DONALD A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Animals;Antibodies;Apoptosis;Applications Grants;Basic Science;Bioinformatics;Biological Assay;Biological Markers;Biometry;Blood;Cancer Center;Cancer Center Support Grant;Cancer Immunology Science;Cancer Science;Catchment Area;Cell Cycle;Cell Separation;Cell physiology;Cells;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Cloning;Collaborations;Complex;Computers and Advanced Instrumentation;Consult;Consultations;Core Facility;Cryopreservation;Data;Data Analyses;Dendritic Cells;Development;Doctor of Philosophy;Enzyme-Linked Immunosorbent Assay;Experimental Designs;Faculty;Flow Cytometry;Flow Cytometry Shared Resource;Fresh Tissue;Funding;Generations;Goals;Grant;Growth Factor;Health;Human;Immune;Immune system;Immunologic Monitoring;Immunologics;Immunology procedure;Individual;Informatics;Kentucky;Laboratories;Leadership;Malignant Neoplasms;Mentors;Mentorship;Mission;Monitor;National Cancer Institute;Necrosis;Pathology;Peer Review;Phenotype;Ploidies;Population;Production;Publications;Research;Research Design;Research Personnel;Research Support;Resource Sharing;Sampling;Services;Signal Transduction;Speed;Surface;System;T-Cell Proliferation;T-Lymphocyte;Techniques;Tissue Expansion;Training;Tumor Tissue;United States National Institutes of Health;Universities;anticancer research;antigen-specific T cells;base;cancer biomarkers;cancer immunotherapy;career;cell bank;cost effective;cytokine;cytotoxicity;design;enzyme linked immunospot assay;improved;innovation;instrument;instrumentation;macrophage;meetings;member;multidimensional data;novel;operation;phenotypic biomarker;pre-clinical;pre-clinical research;programs


application_id: 9741643
project_number: 5P30CA177558-07
project_title: Cancer Research Informatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5629
contact_pi_person_id: 9276771
contact_pi: DURBIN, ERIC B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Adopted;Appalachian Region;Basic Science;Big Data;Bioinformatics;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cellular biology;Clinical;Clinical Cancer Center;Clinical Sciences;Clinical Treatment;Clinical Trials;Collaborations;Communities;Computational Science;Computer software;Data;Data Quality;Data Reporting;Data Set;Data Sources;Data Storage and Retrieval;Databases;Development;Ecosystem;Educational workshop;Ensure;Epigenetic Process;Evaluation Research;Faculty;Foundations;Funding;Genomic Instability;Goals;Grant;Healthcare;High Performance Computing;Human;Informatics;Information Technology;Infrastructure;Institutes;Kentucky;Knowledge;Knowledge Discovery;Leadership;Machine Learning;Maintenance;Malignant Neoplasms;Medicine;Mentors;Mentorship;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Natural Language Processing;Outcome Measure;Pathology;Patient-Focused Outcomes;Patients;Peer Review;Phenotype;Population Research;Preparation;Research;Research Personnel;Resource Informatics;Resources;Role;SEER Program;Science;Scientist;Services;Signal Transduction;Source;Supporting Cell;Technology;Therapeutic;Therapeutic Studies;Tissue Microarray;Training and Education;Translational Research;Treatment outcome;United States;Universities;analytical method;anticancer research;biomedical informatics;cancer cell;cancer genomics;cancer prevention;clinical decision support;clinical decision-making;cohort;data exchange;data management;data sharing;data warehouse;design;drug discovery;evidence base;genomic biomarker;handheld mobile device;improved;informatics shared resource;informatics tool;innovation;interoperability;learning strategy;member;mortality;multidimensional data;national surveillance;neoplasm registry;next generation sequencing;novel;population based;precision medicine;programs;recruit;research and development;research data dissemination;response;screening;surveillance data;tumor


application_id: 9741642
project_number: 5P30CA177558-07
project_title: Biostatistics and Bioinformatics Shared Resource Facility
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5628
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Adoption;Appalachian Region;Applications Grants;Area;Basic Science;Bioinformatics;Bioinformatics Shared Resource;Biological;Biological Markers;Biometry;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Immunology Science;Cancer Surveillance Research;Cell Separation;Cellular biology;Classification;Clinical;Clinical Cancer Center;Clinical Research;Clinical Trials;Collaborations;Communities;Community Outreach;Comprehensive Cancer Center;Computer software;Consultations;Data;Data Analyses;Data Quality;Data Science;Databases;Development;Disease;Dose;Early Therapeutic-Clinical Trials Network;Education;Education and Outreach;Ensure;Epigenetic Process;Evaluation;Experimental Designs;Faculty;Flow Cytometry;Funding;Genomic Instability;Genomics;Grant;Growth;Hand;Human Resources;Immunologic Monitoring;Informatics;Journals;Kentucky;Lead;Leadership;Malignant neoplasm of lung;Malignant neoplasm of pancreas;Mentors;Mentorship;Metabolism;Methodology;Methods;Mission;Modeling;Molecular;Monitor;Multicenter Trials;NCI Center for Cancer Research;National Cancer Institute;Oxidation-Reduction;Pathology;Peer Review;Phase;Play;Population;Population Research;Population Study;Positioning Attribute;Precision medicine trial;Process;Quality Control;Reproducibility;Research;Research Design;Research Personnel;Research Priority;Research Support;Resource Sharing;Resources;Risk Factors;Role;Sample Size;Science;Series;Service provision;Services;Signal Transduction;Site;Statistical Data Interpretation;Statistical Methods;Survival Analysis;Technical Expertise;Testing;Therapeutic;Toxic effect;Training;Training Activity;Training Programs;Training and Education;Translational Research;Universities;Work;Writing;analysis pipeline;anticancer research;base;biomarker-driven;cancer cell;cancer health disparity;cancer immunotherapy;cancer prevention;computerized data processing;cost effective;data management;design;drug discovery;early phase trial;exosome;experience;genomic platform;health disparity;high throughput analysis;improved;innovation;investigator-initiated trial;lectures;malignant breast neoplasm;meetings;member;metabolomics;multidisciplinary;neoplasm registry;next generation sequencing;novel;population based;precision medicine;precision medicine clinical trials;programs;research study;skills;statistics;success;targeted treatment;translational clinical trial;translational study;working group


application_id: 9741641
project_number: 5P30CA177558-07
project_title: Biospecimen Procurement and Translational Pathology Shared Resource Facility
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5627
contact_pi_person_id: 8368087
contact_pi: JENNINGS, DARRELL
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Ambulatory Care Facilities;Animals;Appalachian Region;Archives;Area;Award;Back;Basic Science;Bioinformatics;Biological Assay;Biological Markers;Biological Models;Biometry;Blood;Cancer Center;Cancer Center Support Grant;Cancer Immunology Science;Clinical;Clinical Cancer Center;Clinical Data;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Collection;Communities;Comprehensive Cancer Center;Computer software;Consent;Consultations;Custom;DNA;Data;Databases;Department chair;Development;Education;Ensure;Evaluation;Faculty;Familiarity;Formalin;Fostering;Freezing;Fresh Tissue;Funding;Future;Genetic;Genetic Markers;Genomics;Goals;Growth;Guidelines;Histologic;Histology;Histopathology;Hospitals;Human;Immunohistochemistry;In Situ;In Situ Hybridization;Informatics;Institutional Review Boards;Kentucky;Laboratories;Laboratory Research;Lasers;Leadership;Liquid substance;Malignant Neoplasms;Medicine;Metabolic;Microscopy;Mission;Modeling;NCI Center for Cancer Research;Names;Obesity associated cancer;Operative Surgical Procedures;Organoids;Outcome;Paraffin Embedding;Pathologic;Pathologist;Pathology;Patient Care;Patients;Peer Review;Play;Population;Procedures;Protocols documentation;RNA;Research;Research Design;Research Personnel;Research Training;Resistance;Resource Sharing;Resources;Retrospective Studies;Role;SEER Program;Sampling;Science;Scientist;Services;Site;Slice;Specimen;Standardization;Structure;Students;Therapeutic Clinical Trial;Therapeutic Human Experimentation;Time;Tissue Banks;Tissue Embedding;Tissue Microarray;Tissues;Training;Training and Education;Translating;Translational Research;Tumor Tissue;United States Office of Research Integrity;Universities;Work;Xenograft procedure;anticancer research;biomarker evaluation;cancer health disparity;cancer immunotherapy;clinical investigation;cohort;consent capacity;digital imaging;direct patient care;faculty support;histological stains;human tissue;imaging system;innovation;interest;investigator-initiated trial;member;metabolomics;molecular pathology;neoplasm registry;next generation;novel;operation;patient population;patient privacy;population based;precision medicine clinical trials;preservation;professor;programs;prospective;repository;response;sample collection;tissue biomarkers;tumor;tumor metabolism


application_id: 9741640
project_number: 5P30CA177558-07
project_title: Career Enhancement
administering_ic: NCI
award_notice_date: 2019-06-21
opportunity_number: PAR-17-095
application_type: 5
activity_code: P30
ic: CA
serial_number: 177558
study_section: Cancer Centers Study Section (A)[NCI-A]
subproject_number: 5626
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Appalachian Region;Award;Cancer Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Catchment Area;Clinical;Clinical Trials;Communities;Complement;County;Data;Dedications;Development;Direct Costs;Education;Educational Curriculum;Ensure;Evolution;Extramural Activities;Faculty;Fostering;Funding;Geography;Goals;Grant;Growth;High School Student;Immersion Investigative Technique;Incidence;Individual;Investments;K-12 student;Kentucky;Lead;Link;Malignant Neoplasms;Mentors;Mentorship;Mission;Modernization;NCI Center for Cancer Research;National Cancer Institute;National Cancer Program;Outcome;Physicians;Population;Research;Research Personnel;Research Training;Resources;Rural Appalachia;Scientist;Series;Surgeon;Time;Training;Training Programs;Training and Education;Translational Research;Underrepresented Minority;Universities;Writing;anticancer research;base;cancer education;career;career development;clinical practice;cohesion;early-career faculty;education research;educational atmosphere;elementary school;experience;faculty research;health disparity;health management;high school;higher education;improved;innovation;interest;meetings;member;mortality;next generation;oncology;outreach;pre-doctoral;programs;symposium;undergraduate student


application_id: 9741094
project_number: 5R21CA216722-02
project_title: NOVEL PAN-RALGEF INHIBITORS TO BLOCK PANCREATIC CANCER.
administering_ic: NCI
award_notice_date: 2019-07-01
opportunity_number: PAR-16-176
application_type: 5
activity_code: R21
ic: CA
serial_number: 216722
program_official: CHEN, WEIWEI
project_start_date: 2018-07-06
project_end_date: 2021-06-30
study_section: ZCA1-TCRB-Q(M1)
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY 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
project_abstract:
Background: Pancreatic cancer exhibits almost 100% morbidity and is almost 100% associated withactivation of the Ras oncoprotein. Therefore targeting Ras is the most logical approach to developingenhanced therapy for this disease. So far all attempts at inhibiting Ras directly have failed in the clinic. Rasacts in large part by binding and activating the oncogenic effectors Raf PI3 Kinase and RalGEFs. Inhibitorsfor Raf and PI3 kinase have been developed but have yet to show efficacy in the clinic against pancreaticcancer. To date no inhibitors of the third arm of the Ras effector system the RalGEFs have been described inthe literature. We have developed what appears to be the first pan-RalGEF inhibitor.Specific Aims: 1. To characterize the binding and action of novel specific inhibitors of RalGEFs. 2. To determine if suppression of the RalGEF pathway prevents tumorigenesis andmetastasis in pdx and transgenic models of cancer in vivo.Objective: To define the mechanism of action on suppression of the tumorigenic phenotype in vitro of novelsmall molecules that inhibit the Ras/RalGEF pathway. To determine if the molecule/s exhibit anti-tumor effectsin an in vivo model of pancreatic cancer.Hypotheses: Targeting multiple RalGEFs will be an effective strategy for inhibiting Pancreatic cancer.Significance: There is no effective treatment for pancreatic cancer. Pancreatic cancer is driven by Rasactivation. Ras driven cancers are highly dependent upon the Ras/RalGEF pathway. We describe the firstinhibitor of this pathway.Relevance to public health: Pancreatic cancer has no effective therapies. This proposal seeks to develop anovel therapeutic small molecule for Pancreatic cancer.Unique features and innovation: The project used a combination of in silico and in vitro assays to identifyand optimize novel inhibitors of RalGEF. As no such inhibitors have yet been reported the project isintrinsically innovative.Methodology: In silico computer screens of large molecular libraries were used to identify potential RalGEFbinding compounds based on the known structure of the Ras binding domain of RalGDS. The compoundswere bioassayed to identify those that act as anticipated. The interaction of the compounds with their targetwill be defined by NMR and bioassays perfomed to determine their main biological modes of action in vitro.They will then tested in highly physiological animal models of human pancreatic cancer.Expected results: We will identify the first pan-RalGEF inhibitor and it will inhibit pancreatic cancer.Affects on other research areas: The molecules we identify may serve as powerful scientific tools toinvestigate Ras/RalGEF function in vivo and may lead to novel therapeutics for Ras driven cancer.

project_terms:
1-Phosphatidylinositol 3-Kinase;Affect;Agar;Animal Model;Animals;Area;Binding;Biological;Biological Assay;Biological Models;Cancer Model;Cancer cell line;Clinic;Collaborations;Computer Simulation;Computers;Development;Disease;Disseminated Malignant Neoplasm;Exhibits;Genetic;Goals;Growth;Human;In Vitro;KRAS2 gene;Lead;Literature;Malignant Neoplasms;Malignant neoplasm of pancreas;Methodology;Molecular Bank;Morbidity - disease rate;Mutation;Neoplasm Metastasis;Oncogenic;Oncoproteins;Pathway interactions;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phenotype;Physiological;Point Mutation;Positioning Attribute;Primary Neoplasm;Proteins;Public Health;RALGDS gene;Raf Kinase Inhibitor;Ras Inhibitor;Reporting;Research;Signal Pathway;Structure;Structure of parenchyma of lung;Survival Rate;System;Testing;Therapeutic;Toxic effect;Transgenic Mice;Transgenic Model;Treatment Efficacy;Variant;Xenograft procedure;advanced pancreatic cancer;antitumor effect;arm;base;cell transformation;drug development;effective therapy;experience;experimental study;human model;in vitro Assay;in vivo;in vivo Model;inhibitor/antagonist;innovation;kinase inhibitor;molecular modeling;neglect;novel;novel therapeutics;pancreatic cancer cells;pancreatic cancer model;physiologic model;prevent;raf Kinases;ral A GTP-Binding Protein;ras Oncogene;screening;small molecule;small molecule inhibitor;small molecule therapeutics;tool;tumor;tumor growth;tumorigenesis;tumorigenic

public_health_relevance:
Ras is the most frequently activated oncoprotein found in human cancer. No effective anti-Ras drugs are yetavailable in the clinic. This proposal seeks to validate novel small molecules that block the ability of Ras topromote cancer/metastasis by inhibiting its ability to interact with the RalGEF class of Ras effector proteins.


application_id: 9740723
project_number: 2R01DE022597-06
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2019-03-05
opportunity_number: PA-18-484
application_type: 2
activity_code: R01
ic: DE
serial_number: 022597
program_official: CHANDER, PREETHI
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-Induced 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: 9740266
project_number: 1R01HD096077-01A1
project_title: The Role of FOS in the Ovary
administering_ic: NICHD
award_notice_date: 2019-05-03
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: HD
serial_number: 096077
suffix: A1
program_official: TAYMANS, SUSAN
project_start_date: 2019-05-06
project_end_date: 2024-02-29
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Affect;Albers-Schonberg disease;Binding;Binding Sites;Biological Process;Birth;Cell Culture Techniques;Cells;DNA Binding;Data;Development;Event;Exhibits;FOS gene;Family;Family member;Fertility;Foundations;Future;Gene Expression;Genes;Gonadotropins;Hour;Human;Human Chorionic Gonadotropin;In Vitro;JUNB gene;Knockout Mice;Knowledge;Light;Luteinization;Mediating;Mus;Mutant Strains Mice;Ovarian;Ovarian Tissue;Ovary;Ovulation;PMSG (Gonadotropins);Pathway interactions;Phenotype;Physiological;Physiology;Pilot Projects;Play;Process;Progesterone Receptors;Prostaglandins;Reporting;Reproductive Health;Role;Time;Transcription Factor AP-1;Transgenic Mice;Woman;activator 1 protein;base;clinical application;corpus luteum;design;female fertility;granulosa cell;human tissue;improved;in vivo;insight;jun Oncogene;member;mouse model;novel;prevent;promoter;recombinase-mediated cassette exchange;spatiotemporal;transcription factor


application_id: 9739902
project_number: 1R01HL142640-01A1
project_title: Inflammasome Activation Triggers Systemic Coagulation in Sepsis
administering_ic: NHLBI
award_notice_date: 2019-05-09
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: HL
serial_number: 142640
suffix: A1
program_official: AGRAWAL, NITIN
project_start_date: 2019-05-15
project_end_date: 2023-04-30
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
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:
AbstractSeptic shock is invariably associated with systemic coagulation leading to thrombus formation. Sepsis-relatedorgan dysfunction has been attributed to microvascular thrombosis. Mortality rate doubles in septic patientswith disseminated intravascular coagulation (DIC). DIC is even considered as a sign that death is coming.Previous studies have demonstrated the important roles of tissue factor (TF) in sepsis-associated DIC.However the mechanism leading to TF release which triggers systemic coagulation in sepsis is unknown.Recent in vitro studies revealed that bacterial components (flagellin the rod protein of the type III secretionsystem (T3SS) or LPS) induce programmed cell death (called pyroptosis) of macrophages through activationof inflammasome pathways. We show that intravenous injection of a T3SS rod protein E. coli EprJ induceddepletion of peripheral monocytes and macrophages in tissues. Importantly injection of EprJ or LPS whichelicit canonical and noncanonical inflammasome activation respectively induced systemic coagulationactivation as evident by prolonged prothrombin time (PT) due to increased consumption of coagulation factorsthrombocytopenia increased plasma levels of thrombin-antithrombin complex (TAT) and reduced plasmafibrinogen levels. Thus our findings made connections between the in vitro and in vivo observations andsuggested monocyte/macrophage pyroptosis as a trigger of DIC in sepsis. The goal of this application is todelineate the underlying mechanisms by which inflammasome activation and pyroptosis trigger DIC in sepsis.Specific Aim 1 will establish inflammasome activation and pyroptosis as a common mechanism for DICinduced by bacterial infection. The working hypothesis is that bacteria and bacterial components from differentstrains elicit DIC through Inflammasome activation and pyroptosis. We will use a combination of variousdeficient mice to elucidate the role of inflammasome activation and pyroptosis in DIC elicited by Gram-negativebacteria. Specific Aim 2 is to identify the molecular mechanism of TF release from macrophages followinginflammasome activation. We will also use the myeloid-specific TF knockout mice and a low TF mouse modelto elucidate whether DIC elicited by the bacterial components depends on release of TF from macrophages.Specific Aim 3 will demonstrate the role of inflammasome activation in sepsis-associated coagulopathy. We willuse the cecal ligation and puncture (CLP) sepsis model and bacterial infusion sepsis model to investigate therole of inflammasome activation and pyroptosis in coagulation. Completion of the proposed studies willdemonstrate the molecular mechanism of systemic coagulation is sepsis. Such findings would have profoundramifications for the identification of new drug targets for DIC the deadly complication of sepsis.

project_terms:
Apoptosis;Bacteria;Bacterial Infections;Blood Coagulation Disorders;Blood Coagulation Factor;Bone Marrow;Burkholderia;CASP1 gene;Cells;Cessation of life;Clinical;Coagulation Process;Complication;Consumption;Data;Development;Disease;Disseminated Intravascular Coagulation;Escherichia coli;Family;Fibrinogen;Flagellin;Functional disorder;Goals;Gram-Negative Bacteria;In Vitro;Infection;Inflammasome;Infusion procedures;Injections;Intervention;Knockout Mice;Lead;Link;Modeling;Molecular;Morbidity - disease rate;Mus;Myelogenous;Needles;Organ;Outcome;Pathway interactions;Patients;Peripheral;Phagocytosis;Physiological;Plasma;Play;Proteins;Prothrombin time assay;Pseudomonas aeruginosa;Reagent;Research Project Grants;Role;Salmonella;Sepsis;Septic Shock;Testing;Thrombocytopenia;Thromboplastin;Thrombosis;Thrombus;Tissues;Type III Secretion System Pathway;Work;antithrombin III-protease complex;base;cecal ligation puncture;driving force;in vivo;insight;intravenous injection;macrophage;monocyte;mortality;mouse model;multidisciplinary;new therapeutic target;protein E;release factor;retinal rods;septic patients;targeted treatment

public_health_relevance:
Project NarrativeSystemic coagulation is a major driving force for morbidity and mortality in sepsis. This research projectseeks to understand the mechanism of coagulation in sepsis. Completion of this work will provide newinsights into the molecular mechanisms eliciting coagulation during sepsis that could lead to targetedtherapies to treat this deadly disease.


application_id: 9739518
project_number: 1R01HL141191-01A1
project_title: The role of bioactive lipids in CMC-induced myocardial repair.
administering_ic: NHLBI
award_notice_date: 2019-02-20
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: HL
serial_number: 141191
suffix: A1
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
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;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: 9739365
project_number: 5R21DA046551-02
project_title: Using Mindfulness Training to Reduce Delay Discounting in Rural Adult Smokers
administering_ic: NIDA
award_notice_date: 2019-06-17
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: DA
serial_number: 046551
program_official: AKLIN, WILL
project_start_date: 2018-07-15
project_end_date: 2021-02-28
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 7740063
contact_pi: REYNOLDS, BRADY A
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAs a Trans-Disease Behavioral Process delay discounting is related to almost all addictive behaviorsincluding addition to tobacco alcohol cannabis stimulants opiates & gambling. Delay discounting is alsoassociated with treatment outcomes and relapse to addictive behaviors obesity attention-deficit/hyperactivitydisorder and even risky behaviors like texting while driving. To increase the public-health impact of researchinvolving delay discounting it is of critical importance to identify innovative methods of improving discountingthat are also scalable and accessible In response we are proposing to use a mindfulness training app(Headspace) to reduce delay discounting perceived stress and depression in rural adult smokers. We havechosen mindfulness training as our intervention because it has been shown to reduce cigarette smoking incollege students and because of demonstrated effects on many of the cognitive and neural systems thatunderlie delay discounting. Furthermore by using a web-based/app version of mindfulness training weincrease program flexibility for difficult-to-reach populations such as rural adult smokers. To explore use of thisapproach we will utilize a two-arm single blinded randomized control design. For the active treatmentcondition (n = 50) participants will complete a 30 day foundational program of mindfulness training(Headspace). In the control condition (n = 50) participants will listen to an audio book about mindfulnesstraining that is read by the same person guiding the mindfulness training for the active condition. This audiobook has been divided into 30 sections that are time-matched with the 30 sessions of the active Headspaceprogram and these audio book sections will be accessed by participants through the Headspace site just asthe active training program will be accessed by participants in that condition. Delay discounting depressionperceived stress mindfulness and tobacco use will be assessed before starting either of these two conditionsand also after every 10 days during the programs (days 10 20 and 30) to track the time course of anychanges. To conclude we will collect all of these data again 30 days post intervention to evaluate stability ofany observed effects. We hypothesize that in rural adult smokers mindfulness training will reduce delaydiscounting perceived stress and depression as well as cigarette smoking compared to the audio book controlcondition. If these hypotheses are confirmed online mindfulness training can be readily adapted as an adjunctto existing prevention and treatment programs to improve their outcomes. This research addresses asignificant public health issue by directly engaging central behavioral targets for cigarette smoking in a difficult-to-reach population.

project_terms:
Addictive Behavior;Address;Adult;Affect;Alcohols;Area;Attention deficit hyperactivity disorder;Automobile Driving;Behavioral;Books;Brain;Brain region;Cannabis;Cognitive;Data;Disease;Effectiveness;Female;Foundations;Gambling;Health Services Accessibility;Home environment;Human;Intervention;Lead;Link;Mediating;Mental Depression;Methods;Mindfulness Training;Obesity;Online Systems;Opioid;Outcome;Participant;Persons;Population;Prevention program;Process;Public Health;Randomized;Relapse;Research;Risk Behaviors;Role;Rural;Short-Term Memory;Single-Blind Study;Site;Smoker;Smoking;Stress;System;Text;Text Messaging;Time;Tobacco;Tobacco use;Training;Training Programs;Treatment outcome;Work;active method;addiction;arm;base;cigarette smoking;density;design;discount;discounting;executive function;flexibility;follow-up;gray matter;improved;innovation;male;mindfulness;perceived stress;post intervention;programs;relating to nervous system;response;rural area;suburb;treatment program;university student

public_health_relevance:
PROJECT NARRATIVEDelay discounting perceived stress and depression are important behavioral targets related to cigarettesmokingwhich represents a significant threat to public health. This study will use and evaluate a mindfulnesstraining app to reduce delay discounting perceived stress and depression in rural adult smokers. If successfulmindfulness training can be added to prevention and treatment programs to improve their efficacy and reducesmoking in this difficult-to-reach population.


application_id: 9739083
project_number: 5R01AR071398-03
project_title: Mechanistic assessment of blood flow restricted training for an ACL injury
administering_ic: NIAMS
award_notice_date: 2019-07-11
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 071398
program_official: WASHABAUGH, CHARLES H
project_start_date: 2017-07-22
project_end_date: 2022-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-Dimensional;Address;Anterior Cruciate Ligament;Architecture;Area;Attenuated;Biomechanics;Biopsy;Blood flow;Clinical;Data;Degenerative polyarthritis;Development;Effectiveness;Electric Stimulation;Evidence based intervention;Extensor;Extracellular Matrix;Fatty acid glycerol esters;Fiber;Fibrosis;Frequencies;Generations;Goals;Imaging Techniques;Individual;Infiltration;Injury;Knee;Lead;Limb structure;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mediating;Microscopic;Morphology;Multi-Institutional Clinical Trial;Muscle;Muscle Fibers;Muscle Weakness;Muscle satellite cell;Outcome;Patient Care;Patients;Phenotype;Physical therapy;Physiological;Physiological Adaptation;Population;Positioning Attribute;Procedures;Property;Quality of life;Randomized;Reconstructive Surgical Procedures;Recovery;Rehabilitation therapy;Resistance;Risk;Stem cells;Techniques;Testing;Thigh structure;Time;Training;Work;alternative treatment;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;base;functional outcomes;improved;injured;knee mechanics;ligament injury;muscle strength;novel;novel strategies;premature;prevent;progenitor;quadriceps muscle;reconstruction;rehabilitation strategy;satellite cell;stem;strength training;treatment as usual;treatment strategy;vastus lateralis


application_id: 9738650
project_number: 2R01AG038651-06A1
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2019-03-26
opportunity_number: PA-18-484
application_type: 2
activity_code: R01
ic: AG
serial_number: 038651
suffix: A1
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2024-01-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: ABNER, ERIN ;YU, LEI
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Academic Medical Centers;Adult;Affect;Age;Age of Onset;Aging;Agreement;Alzheimer's Disease;Alzheimer's disease risk;Americas;Area;Autoimmune Diseases;Autopsy;Brain;Cerebrovascular Disorders;Cessation of life;Chronic Disease;Clinical;Cognitive;Comorbidity;Conflict (Psychology);Data;Databases;Dementia;Diabetes Mellitus;Diagnosis;Elderly;Factor Analysis;Female;Funding;Future;Goals;Grant;Health Sciences;Hypertension;Impaired cognition;Impairment;Individual;Infarction;Investments;Kentucky;Kidney Diseases;Knowledge;Life;Link;Longitudinal Studies;Lung diseases;Medical Genetics;Medical History;Medicare;Medicare claim;Memory;Microvascular Dysfunction;National Institute on Aging;Non-Insulin-Dependent Diabetes Mellitus;Oregon;Paper;Participant;Pathology;Patient Self-Report;Population;Primary Prevention;Probability;Public Health;Records;Research;Research Personnel;Risk;Risk Factors;Role;Sample Size;Secondary Prevention;Severities;Statistical Models;Universities;Update;Washington;age related;care costs;cerebrovascular pathology;clinical Diagnosis;cognitive testing;data integration;dementia risk;disorder prevention;follow-up;human old age (65+);improved;mild cognitive impairment;mixed dementia;multiple chronic conditions;neuropathology;sex;trend


application_id: 9737946
project_number: 5R01GM115261-04
project_title: Platform technologies for understanding and exploiting methylation
administering_ic: NIGMS
award_notice_date: 2019-06-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 115261
program_official: BOND, MICHELLE RUEFFER
project_start_date: 2016-08-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1-BCMB-W(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL
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): Methyltransferase (MT)-catalyzed S-adenosyl-L-methionine (AdoMet)-dependent methylation is essential to all walks of life and alterations in methylation-dependent processes have direct relevance to microbial/fungal/viral pathogenesis and human disease. Yet for many MTs there is a lack of correlative fundamental knowledge regarding specific MT function and corresponding impact upon cellular fate and/or pathogenesis/disease. In addition while simple chemical or MT-catalyzed methylation of a drug/drug lead can dramatically impact its corresponding ADMET (absorption distribution metabolism excretion and/or toxicity) the structural complexity of many natural products often prohibits doing so in the context of natural products-based drugs/lead development. This proposal seeks to develop general chemoenzymatic alkylation strategies and reagents for that are expected to broadly facilitate the fundamental study annotation and application of MTs. A centerpiece to the proposed universal platform development is the study engineering and application of permissive methionine adenosyltransferases (MATs) and MTs where the model MTs selected represent broad catalytic diversity (C-methylation O-methylation and N-methylation) and directly act upon a selected set of complex natural product-based drugs validated clinical candidates or marketed agricultural products. The proposed studies will integrate the chemical synthesis and application of unique methionine (Met) analogs MAT/MT structure determination high throughput MAT/MT assay development/application structure-guided MAT/MT directed evolution microbial strain engineering complex natural product (NP) structure elucidation and bioactivity assessment for NP analogs generated. The anticipated outcomes of this study include highly permissive/proficient MATs/MTs engineered for medicinal chemistry applications novel functional AdoMet orthologs designed as alternative alkyl donors and/or with improved stability an expanded understanding of MAT/MT structure-activity relationships of potential relevance to MAT/MT inhibitor design single vessel chemoenzymatic strategies to enable complex NP differential alkylation engineered microbial strains to enable complex NP differential alkylation and functional MT annotation and unprecedented differentially-alkylated NP analogs with potential therapeutic and/or agricultural applications. Within this context the proposed studies will also provide the first bioorthogonal strategy to functionally annotate interrogate or exploit a single MT within a cell containing a full complement of competing native MTs. While NP methylation has been selected as the model for platform development it is important to note that reagents and concepts developed will likewise enable the similar study annotation and application of other class I MTs relevant to cellular development human disease or microbial/fungal/viral pathogenesis.

project_terms:
Agriculture;Alkylation;Anabolism;Ansamycin Antineoplastic Antibiotic;Anti-Infective Agents;Biological Assay;Biological Process;Catalysis;Cells;Chemicals;Complement;Complex;Development;Directed Molecular Evolution;Disease;Elements;Engineering;Enzymes;Escherichia coli;Eukaryota;Evolution;Excretory function;Gene Deletion;Goals;Human;Immunosuppressive Agents;In Vitro;Insecticides;Isotope Labeling;Knowledge;Lead;Life;Ligands;Metabolism;Methionine;Methylation;Methyltransferase;Modeling;Mutation;Natural Products;Orthologous Gene;Outcome Study;Pathogenesis;Pharmaceutical Chemistry;Pharmaceutical Preparations;Polyketide Macrolides;Process;Prokaryotic Cells;Reaction;Reagent;S-Adenosylmethionine;Series;Sirolimus;Small Interfering RNA;Specificity;Structure;Structure-Activity Relationship;Substrate Specificity;System;Technology;Therapeutic;Toxic effect;Translating;Viral Pathogenesis;Walking;absorption;actionable mutation;analog;anti-cancer;assay development;base;catalyst;cellular development;chemical genetics;chemical synthesis;clinical candidate;design;flexibility;high throughput screening;human disease;improved;in vivo;inhibitor/antagonist;innovation;loss of function;methionine adenosyltransferase;methylome;microbial;novel;patient response;practical application;prototype;public health relevance;tool;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Enzyme-catalyzed methylation is essential to normal function and development of all species. However disproportionate or aberrant methylation can also serve as a causative element in pathogenesis human disease and directly impact a patient's response to treatment. This proposal seeks to develop a universal platform and innovative reagents to facilitate the fundamental study and practical application of enzyme-catalyzed methylation and will also provide novel natural product analogs with potential anticancer immunosuppressant anti-infective and/or insecticide activities.


application_id: 9737058
project_number: 3R01AG047297-04S1
project_title: Asthma in Older Adults: Identifying Phenotypes and Factors Impacting Outcomes
administering_ic: NIA
award_notice_date: 2018-09-11
opportunity_number: PA-18-751
application_type: 3
activity_code: R01
ic: AG
serial_number: 047297
suffix: S1
program_official: ZIEMAN, SUSAN
project_start_date: 2015-02-01
project_end_date: 2019-01-31
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 11844758
contact_pi: POLIVKA, BARBARA J
other_pis: FOLZ, RODNEY J
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Asthma is a common chronic inflammatory disorder of the distal airways characterized by recurring symptomsairway inflammation and reversible airflow constriction. It is considered a collection of various phenotypes(characteristics) instead of a single disease. Currently there is no comprehensive phenotyping specific to olderadults with asthma that considers multiple factors relevant to this population. Divergent asthma phenotypesand exposure to unique environmental triggers may effect asthma control in the elderly. In addition factorscontributing to asthma quality of life in the elderly have not been well explored. The aims of our study are to:(1) develop and systematically implement a phenotyping algorithm in older adults with asthma; (2)longitudinally investigate the effects of asthma phenotypes and volatile organic compounds (VOCs) exposureson asthma control in older adults with asthma; and (3) develop a predictive model for asthma quality of life forolder adults with asthma. Sub-aims are to explore the impact on moving from community-based to congregateliving settings (e. g assisted living) on the course of asthma in older adults and to identify barriers tosuccessful asthma medication management. One hundred ninety participants 60 years of age or older will beenrolled. Inclusion criteria are: meet standard diagnostic criteria for asthma non-smokers have no otherchronic respiratory diseases do not reside in a skilled nursing facility and have not recently had a major amedical illness. At baseline participants will complete spirometry bronchodilator responsiveness fractionalexhaled nitric oxide methacholine challenge (if not completed within past 5 years) allergic sensitizationImmunoglobulin E (IgE) and sputum analysis as well as standardized questionnaires to assess asthmacontrol quality of life knowledge and self-efficacy. Within 30 days an in-home environmental assessment willbe conducted to obtain data on VOCs air particulates moisture temperature humidity pests and an asthmahome environment checklist. At 9 and 18 months in-home data will be collected on participants' pulmonarystatus asthma control and asthma quality of life. At 9-months participants will also complete the measures ofmedication management. At 18-months we will conduct follow-up in-home environmental assessmentscollecting the same data we collected at baseline. Participants who have moved to congregate living facilitieswill be asked open-ended questions about their perception of the effects of the move on the course of theirasthma. Using factor analysis we will perform a comprehensive phenotypic characterization that will include awide range of demographics asthma-specific knowledge and self-efficacy and biomarkers. Predictive modelsfor asthma control and asthma quality of life will be identified using generalized linear mixed-effects modeling.The findings of this study will be used in future research to develop and test the efficacy of patient-centeredinterventions for older adults with asthma to improve asthma control and enhance quality of life.

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

public_health_relevance:
Project NarrativeThis study will develop a method of categorizing asthma in older adults longitudinally investigate the effects ofthese categorizations on asthma control and identify factors such as environmental exposures and type ofliving arrangements that impact asthma quality of life for older adults. As the population ages and thepercentage of older adults with asthma increases the information obtained from this study is needed to developand test patient-centered interventions that will improve asthma control and quality of life in older adults withasthma.


application_id: 9736986
project_number: 3R01DA043519-02S1
administering_ic: NIDA
award_notice_date: 2018-09-12
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: DA
serial_number: 043519
suffix: S1
program_official: SIROCCO, KAREN
project_start_date: 2017-05-01
project_end_date: 2022-02-28
contact_pi_person_id: 3100162
contact_pi: BADA, HENRIETTA S.
other_pis: LEGGAS, MARKOS
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-03-01
project_title:
Non-opiate treatment after prenatal opiate exposure to Prevent Postnatal Injury to the Young Brain (No-POPPY)

project_abstract:
ABSTRACT (R01 DA043519):The number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal AbstinenceSyndrome (NAS) in the US has increased to epidemic proportions. The pharmacologic treatment of NAS withmorphine or methadone is highly concerning as it corresponds with a timeframe of rapid postnatal braindevelopment. The negative effects of opioids on the developing brain include decreased neurogenesissynaptogenesis and corticogenesis decreased brain size and decreased brain volumes in older children withprenatal opiate exposure. Furthermore response of neonates to treatment is highly variable and limitedpharmacogenetic and metabolic activity data which can be used to optimize therapy in this population poseadditional challenges in using any drug to treat NAS. Collectively these issues present a critical need to evaluateand optimize the use of a non-opioid drug for treatment of NAS. The long-term goals of our research are toestablish the best pharmacological treatment for NAS and determine how pharmacologic treatment of NASaffects long-term developmental outcomes. The objective of this application is to evaluate the effectiveness ofclonidine an 2 adrenergic receptor agonist as a treatment for neonates with NAS in a randomized clinical trial.Our central hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates.Preliminary clinical evidence supports this hypothesis. Clonidine has previously been reported by us and othersas a single drug therapy for NAS in small number of infants with relief of withdrawal symptoms and as an effectiveadjunctive treatment when giving chloral hydrate or morphine. The rationale for the proposed research is thatonce we understand how clonidine can be used optimally in the clinic to treat NAS a safe medication will beavailable and it could potentially minimize complications associated increased length-of-stay in the hospitalhealthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiateadministration. To test our central hypothesis and accomplish the objective of this application we plan to pursuethe following three specific aims: 1) To determine whether the treatment of NAS with a non-opiate medicationclonidine will be more effective than morphine. 2) To determine whether treatment of NAS with clonidine willresult in better early childhood outcomes than those treated with morphine. 3) To determine how infants withNAS metabolize morphine and clonidine. With respect to expected outcomes this proposal will provideprospective evidence: a) regarding the potential of clonidine treatment to treat NAS; b) regarding how opioid andnon-opioid exposure affect early childhood development; c) regarding factors that influence response totreatment. These results are expected to have an important positive impact because they have the potential toprovide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs and mostimportantly to improve the long-term outcomes of children born to addicted mothers.

project_terms:
Abstinence;Adrenergic Agonists;Affect;Aftercare;Age;Analgesics;Brain;Cells;Child;Child Behavior Checklist;Chloral Hydrate;Chronic;Clinic;Clinical;Clonidine;Cognitive;Collaborations;Data;Development;Drug Kinetics;Drug Withdrawal Symptoms;Effectiveness;Epidemic;Exposure to;Genetic;Goals;Growth;Health;Health Care Costs;Hospitals;Infant;Informal Social Control;Injury;Laboratory Study;Language;Length of Stay;Life;Metabolic;Methadone;Mission;Modeling;Morphine;Mothers;Motor;Narcotics;Neonatal Abstinence Syndrome;Neurons;Newborn Infant;Norepinephrine;Opioid;Opioid Receptor;Outcome;Performance;Pharmaceutical Preparations;Pharmacogenetics;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Pilot Projects;Population;Pregnancy;Problem behavior;Property;Public Health;Randomized Clinical Trials;Reflex action;Reporting;Research;Stress;Testing;Time;United States National Institutes of Health;Withdrawal;Withdrawal Symptom;assault;brain size;brain volume;cost;drug withdrawal;early childhood;fetal opioid exposure;heroin use;improved;individual response;neonate;neurobehavioral;neurogenesis;noradrenergic;opioid exposure;opioid use;pharmacodynamic model;postnatal;prevent;prospective;response;standard of care;synaptogenesis;treatment duration;treatment optimization;treatment response

public_health_relevance:
PROJECT NARRATIVE (R01 DA043519):The proposed research is relevant to public health because it will investigate the treatment of newborn drugwithdrawal or neonatal abstinence syndrome afflicting infants born to mothers who used heroin or opioid painkillers (prescribed or non-prescribed) during pregnancy. Instead of treating infants with opioids to alleviateintense drug withdrawal symptoms the project will test the effectiveness of a non-opioid medication and inaccompanying laboratory studies it will determine how genetics and metabolic maturity of neonates affectindividual response to treatment. This study is relevant to NIH's mission because it has the potential to improvethe short- and long-term health outcomes of these neonates.


application_id: 9736333
project_number: 5R01NR016824-04
project_title: Rural Intervention for Caregivers' Heart Health (RICHH)
administering_ic: NINR
award_notice_date: 2019-06-19
opportunity_number: RFA-NR-16-003
application_type: 5
activity_code: R01
ic: NR
serial_number: 016824
program_official: HUSS, KAREN
project_start_date: 2016-09-26
project_end_date: 2021-06-30
study_section: ZNR1-REV-M(25)
contact_pi_person_id: 1906318
contact_pi: MOSER, DEBRA KAY
other_pis: CHUNG, MISOOK LEE
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT In the patient-family caregiver dyad emphasis traditionally has been on the patient or on helping thecaregiver take care of the patient. This approach ignores the health of the caregiver. Family caregivers ofpatients with chronic disease are at uniquely high risk for development of cardiovascular disease (CVD).Because of the environment they share with the patient lack of time for personal care due to caregivingdemands and persistent psychological distress caregivers of patients with chronic illness have substantiallyhigher risk for CVD than non-caregivers. To reduce this risk cardiovascular health interventions aimed at (1)CVD risk reduction (2) improving adherence to self-management of CVD risk reducing behaviors and (3)preventing and managing depressive symptoms are required. Rural caregivers are particularly at risk for poorhealth. Most rural areas are characterized by marked health disparities including elevated CVD risk persistentpoverty and lack of social and healthcare resources. As such innovative intervention programs are needed toimprove cardiovascular health among rural caregivers while overcoming personal and environmental barriersto achieving this goal. The Rural Intervention for Caregivers Heart Health (RICHH) program proposed in this study willaddress the important components of CVD risk reduction for rural caregivers of patients with chronic illness most notably improved self-management of CVD risk reduction efforts including prevention and managementof depressive symptoms. We propose an innovative delivery modality designed to overcome environmentalbarriers in socioeconomically austere rural areas. The purpose of the proposed 2-group (RICHH vs control)randomized clinical trial is to examine short- and long-term effects of the RICHH intervention on CVD risk (i.e.lipid profile body mass index and blood pressure) self-care behaviors (i.e. diet quality physical activity levelself-reported adherence to health behaviors) and depressive symptoms compared to usual care control inrural caregivers of persons with chronic disease. A total of 280 caregivers of patients with chronic illness will beenrolled. Rural caregivers will be randomly assigned to either the RICHH intervention group or a usual carecontrol group. We will stratify caregivers by gender in order to examine the moderating effect of gender onintervention outcomes given the many differences between male and female caregivers. The RICHHintervention (6 interactive modules) will be delivered for 12 weekly sessions (30- to 45 minutes per session). Inorder to enhance maintenance of behaviors we will also deliver 8 biweekly (every other week) boostersessions (20-30 minutes per sessions) for 2 months and then 6 monthly sessions. All sessions are deliveredindividually using a video-conferencing program on a multimedia digital device (i.e. mini iPad). Data onoutcomes will be collected at baseline 4 months and 12 months.

project_terms:
Address;Adherence;Adult;American;Behavior;Blood Pressure;Body mass index;Cardiac health;Cardiovascular Diseases;Caregivers;Caring;Cessation of life;Chronic Disease;Chronically Ill;Communication;Computer software;Data;Development;Devices;Diagnostic;Diet;Distress;Economically Deprived Population;Enrollment;Environment;Epidemic;Family;Family Caregiver;Family member;Female;Fibrinogen;Gender;Goals;Health;Health Personnel;Health Policy;Health Promotion;Health Resources;Health behavior;Healthcare;Heart Diseases;High Prevalence;Individual;Intervention;Kentucky;Light;Lipids;Long-Term Effects;Maintenance;Major Depressive Disorder;Mental Depression;Mental Health;Methods;Modality;Multimedia;Outcome;Patient Care;Patient Self-Report;Patients;Personal Satisfaction;Persons;Physical activity;Physically Handicapped;Policy Maker;Population;Poverty;Prevention;Psyche structure;Quality of life;Randomized;Randomized Clinical Trials;Randomized Controlled Trials;Reporting;Research;Resources;Risk;Risk Factors;Risk Reduction;Rural;Rural Health;Self Care;Self Management;Skilled Nursing Facilities;Symptoms;Tablets;Technology;Testing;Time;United States Health Resources and Services Administration;Videoconferencing;Work;associated symptom;cardiogenesis;cardiovascular disorder risk;cardiovascular health;caregiver interventions;caregiving;clinically significant;depressive symptoms;design;digital;efficacy testing;evidence base;group intervention;health care availability;health disparity;high risk;improved;informal caregiver;innovation;intervention effect;intervention program;male;mortality;physical conditioning;prevent;primary caregiver;primary outcome;programs;psychological distress;rural America;rural area;rural dwellers;rural environment;rural setting;self-management program;social;socioeconomics;treatment as usual;usual care arm

public_health_relevance:
PROJECT NARRATIVE Rural caregivers of individuals with chronic illness are at uniquely high risk for development of heartdisease. We propose to test the Rural Intervention for Caregivers Heart Health program an innovative self-management program designed to lower heart disease and depression risk and overcome environmental andpersonal barriers to self-management. This innovative intervention program will improve physical andpsychological health for rural caregivers of chronically ill patients in rural Kentucky.


application_id: 9736110
project_number: 1U18FD006560-01
project_title: Vet-LIRN Network Capacity Building Projects
administering_ic: FDA
award_notice_date: 2018-09-11
opportunity_number: PAR-18-604
application_type: 1
activity_code: U18
ic: FD
serial_number: 006560
program_official: CERIC, OLGICA
project_start_date: 2018-09-10
project_end_date: 2020-01-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 15010137
contact_pi: REED, DEBBIE CAROL
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Breathitt Veterinary Center Vet-LIRN Network Capacity-Building ProjectFunding Opportunity Announcement Number PAR-18-604 As a part of the Breathitt Veterinary Centers Vet-LIRN Network Capacity Building it has beenidentified that new CO2 incubators are necessary. CO2 incubators are an important part of themicrobiology section protocols. Microbiology and molecular diagnostics both depend heavily on thegrowth and reproduction of organisms recovered from a diseased animal. All of these organisms growmore efficiently under controlled environments where temperature humidity and CO2 levels are atoptimum levels. A CO2 incubator is used to keep these parameters at constant optimal levels forspecified times necessary to grow bacteria.

public_health_relevance:
Research StrategyVet-LIRN Network Capacity-Building ProjectsPAR-18-604 The Breathitt Veterinary Center (BVC) is a part of the Vet-LIRN network and seeks to ensure thatthe laboratory is well equipped to meet the public health and safety goals of the network. In an effortto be better prepared to meet any potential needs BVC seeks to purchase a CO2 incubator for use inmicrobiology. A CO2 incubator is recommended for growing bacterial cultures in several situations. CO2incubators are typically heated to 37C and maintain 95% relative humidity and a CO2 level of 5 percent.Microbiological incubators are essentially temperature-controlled ovens that work within the biologicalrange of 5C to 70C and are mostly used for growing and storing bacterial cultures. Most incubatorunits are water-jacketed air-jacketed or use direct heat to maintain the temperature around the culturechamber. When attempting to isolate bacteria that are suspected of contaminating animal food sourcesthe use of the CO2 incubator is recommended in several situations. Brucella species grow well underthe effects of CO2. Brucellosis affects both man and animals and while not usually a feed contaminantis a significant biological hazard. Salmonella Shigella Escherichia Listeria and Klebsiella species all ofwhich are common food contaminants are facultative anaerobes growing well under CO2supplementation in the CO2 incubator. A CO2 incubator allows for a increase in the levels of CO2 in the incubation chamber comparedto normal CO2 concentration in the atmosphere. This elevated level more naturally mimics theconcentration of CO2 in the body. The increase in CO2 along with special media allows for an increase recovery of food pathogenssuch as Staph. Aureus Brucella E. coli Salmonella Shigella and Listeria.


application_id: 9735655
project_number: 1U18FD006566-01
project_title: Microwave Accelerated Reaction System for sample preparation for metal analyses
administering_ic: FDA
award_notice_date: 2018-09-11
opportunity_number: PAR-18-604
application_type: 1
activity_code: U18
ic: FD
serial_number: 006566
program_official: CERIC, OLGICA
project_start_date: 2018-09-10
project_end_date: 2019-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11450267
contact_pi: GASKILL, CYNTHIA LYNN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Gaskill 2018 Project Summary/AbstractThe objective of this Food and Drug Administration (FDA) Veterinary Laboratory Response Network (Vet-LRN)Capacity Building project is to support enhanced human and animal food safety by strengthening the capacitycollaboration and integration of food-safety laboratories and networks thereby facilitating an effective andcoordinated response to future human and animal food safety issues. The overall goal of the program is tocomplement develop improve and use university state and federal veterinary diagnostic laboratory testingcapabilities.The goal of this specific application is to obtain funding for microwave digestion equipment used to preparebiological feed and other samples for metal analyses used to diagnose metal intoxication or deficiency casesassociated with feeds or drugs. This will expand the laboratory's capability ad capacity to perform food-safetyrelated testing for the FDA Vet-LIRN program and investigate potential animal foodborne illness outbreaks.

public_health_relevance:
Gaskill 2018 Project NarrativeThis FDA Vet-LRN Network Capacity Building project will strengthen the overall food safety system bydeveloping increased capacity and capabilities to detect adulteration which could affect animals raised forhuman consumption or companion animals consuming ingredients used in both animal and human foodproducts.


application_id: 9735311
project_number: 5R01ES029846-02
project_title: Urban Greenness and Cardiovascular Health
administering_ic: NIEHS
award_notice_date: 2019-03-28
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;Sunlight;Surface;Surveys;Testing;Trees;Ultrafine;Unspecified or Sulfate Ion Sulfates;Urine;Vascular Plant;Wood material;Work;air filtration;built environment;cardiovascular disorder prevention;cardiovascular disorder risk;cardiovascular health;cohesion;cohort;demographics;design;fine particles;foot;insight;land use;mortality;pollutant;premature;prevent;psychologic;recruit;residence;social;trial design;urinary;volatile organic compound


application_id: 9735170
project_number: 5R21DA045101-02
administering_ic: NIDA
award_notice_date: 2019-07-10
opportunity_number: PA-16-161
application_type: 5
activity_code: R21
ic: DA
serial_number: 045101
program_official: KAUTZ, MARY A
project_start_date: 2018-07-15
project_end_date: 2022-09-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 8906159
contact_pi: BABALONIS, SHANNA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
project_title:
Evaluating Recreational and Medical Marijuana Strains for Impairing Effects on Simulated Driving Performance

project_abstract:
Abstract:Driving under the influence of drugs of abuse is an epidemic in the United States (U.S.) and has been identifiedas a priority area of research by the National Institute on Drug Abuse and the White House Office of NationalDrug Control Policy. This public health crisis is occurring on the background of a precipitous increase in theavailability of marijuana across the U.S. However it is not clear how smoked marijuana particularly highpotency products that are commonly used for medical and recreational purposes affect driving performance.The aim of this study is to employ driving simulator methodology to characterize the impairing effects of severaltypes of smoked marijuana in a tightly controlled laboratory setting by utilizing a randomized placebo-controlled outpatient within-subject design enrolling healthy occasional marijuana smokers (n=24completers 12 M 12 F). This study will examine smoked marijuana containing: 1) high concentrations of THC(20% THC trace CBD) 2) high concentrations of CBD (10% CBD trace THC) and 3) moderateconcentrations of both CBD and THC (5% CBD 10% THC) in comparison to inactive marijuana (0% THC 0%CBD; negative control) and a dose of alcohol known to produce driving impairment (0.8 g/kg [which produces0.08% breath alcohol concentration]; positive control) on performance in a driving simulator a model that ispredictive of on-road driving ability. Secondary aims include examining the abuse liabilitycognitive/psychomotor performance and physiological effects across the dose conditions; sex differences willalso be explored. Overall this study will use state-of the-art technology to yield new empirical data ondrugged-driving performance following exposure to the most commonly abused illicit drug marijuana. Thesefindings will be highly relevant to public health and may directly inform recommendations for medical marijuanapatients and public safety regulations.

project_terms:
Accidents;Acute;Adult;Affect;Age;Alcohols;American;Area;Automobile Driving;Behavior;Body Fluids;Canada;Cannabinoids;Chronic;Cognitive;Consensus;Data;Dose;Driving While Intoxicated;Drug Controls;Drug usage;Enrollment;Epidemic;Exposure to;Formulation;Guidelines;Health;Household;Human;Illicit Drugs;Impairment;International;Intoxication;Laboratories;Laboratory Study;Lateral;Lead;Legal;Link;Liquid substance;Marijuana;Measures;Medical;Medical Marijuana;Methodology;Methods;Modeling;National Institute of Drug Abuse;Outcome;Outpatients;Participant;Patients;Performance;Pharmaceutical Preparations;Physiological;Placebos;Policies;Population;Positioning Attribute;Psychomotor Performance;Public Health;Randomized;Reaction Time;Recommendation;Recording of previous events;Regulation;Reporting;Research;Risk;Safety;Sampling;Sex Differences;South Africa;Speed;Statutes and Laws;Surveys;THC concentration;Technology;Testing;United States;Variant;Waxes;behavioral outcome;breath alcohol measurement;cognitive task;design;driving under influence;drug of abuse;drugged driving;epidemiology study;experience;illicit drug use;impaired driving performance;marijuana smoke;marijuana smoker;marijuana use;response

public_health_relevance:
PROJECT NARRATIVEThis research will provide important public health and safety information regarding the acute effects ofcommonly used medical and recreational marijuana doses on driving performance.


application_id: 9734430
project_number: 1R56AI132410-01A1
project_title: Role of Intracellular Growth in Dissemination of Listeria from the Gut
administering_ic: NIAID
award_notice_date: 2018-07-19
opportunity_number: PA-16-160
application_type: 1
activity_code: R56
ic: AI
serial_number: 132410
suffix: A1
program_official: BAQAR, SHAHIDA
project_start_date: 2018-08-01
project_end_date: 2021-07-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
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_abstract:
Humans who ingest Listeria monocytogenes (Lm)-contaminated food develop infections that range inseverity from mild self-limiting gastroenteritis to life-threatening sepsis and meningoencephalitis. Strainlineage dose and host susceptibility factors are all likely to influence infection outcomes but ourunderstanding of the intestinal phase of infection is still severely limited. To overcome this obstacle werecently developed a murine model of foodborne listeriosis that can be used to study both virulencedeterminants and immune responses in animals that vary in their susceptibility or resistance to infection.Using this model we found that the vast majority of Lm in the gut were extracellular. This result wasunexpected because Lm are facultative intracellular pathogens and most research efforts over the pastfew decades have focused on Lm factors that promote invasion survival and growth in culturedmammalian cells. Mutant Lm that were unable to replicate inside host cells established infection in themurine gut normally and persisted for a few days but had a severe defect in disseminating from theintestinal lamina propria (LP) to the mesenteric lymph nodes (MLN). These observations suggest thatintracellular growth is not needed to cause gastroenteritis; however further systemic spread requiresreplication inside an as-yet-unidentified cell type in the gut. The central hypothesis of this proposal is thatexponential replication in a permissive cell type is needed to evade innate clearance mechanisms in thegut and to increase the number of Lm above a critical threshold that can promote dissemination by one ofthree distinct mechanisms. In Aim 1 ex vivo flow cytometry and microscopy approaches will be used toidentify all of the cell types that can be productively infected with Lm in the ileum colon and the MLN thatdrain these tissues. In Aim 2 we test the hypothesis that Lm can use one of three potentially redundantmechanisms to spread from the gut LP to the MLN: 1) attached to migratory cells that are not efficientlyinvaded; 2) stealth transport in the cytosol of other migratory cells; and 3) extracellular Lm traffickingfree-flowing in lymphatic vessels. Building on the knowledge gained from Aims 1 & 2 Aim 3 seeks toaddress the paradox that mechanisms exist for Lm to spread extracellularly yet intracellular replication isneeded at some point in the infection cycle for efficient dissemination to the MLN. The replication rate inthe gut will be altered by eliminating the cell types permissive for intracellular growth and the clearancerate will be altered by depleting neutrophils and inflammatory monocytes. A key strength of this proposal isthe interdisciplinary nature of the approaches that capitalize on recent advances in understandingmononuclear phagocyte differentiation pathways in the steady state and applying those findings to aphysiologically relevant infection model. This study will advance the field by revealing how Lm survive andreplicate in the gut and by identifying the bottlenecks they face in order to cause systemic disease.

project_terms:
Address;Anatomy;Animals;Bacteria;Binding;Blood;Bypass;Caco-2 Cells;Cells;Colon;Confocal Microscopy;Cytosol;Defect;Disease Outbreaks;Dose;E-Cadherin;Eating;Elderly;Enterocytes;Environment;Epithelial;Epithelium;Face;Feces;Flow Cytometry;Food;Food Contamination;Food Supply;Gastroenteritis;Gastrointestinal tract structure;Goals;Growth;Gut Mucosa;Hospitalization;Human;Immune;Immune response;Immune system;In Vitro;Individual;Infection;Inflammatory;Intestinal Diseases;Intestines;Intravenous;Invaded;Knockout Mice;Knowledge;Lamina Propria;Large Intestine;Life;Listeria;Listeria monocytogenes;Listeriosis;Lymph;Lymph Node Subcapsular Sinus;Lymphatic vessel;M cell;Mammalian Cell;Mediating;Membrane Proteins;Meningoencephalitis;Mesentery;Metabolic Clearance Rate;Microscopy;Minor;Modeling;Mononuclear;Mus;Myelogenous;Natural Immunity;Nature;Neuraxis;Oral;Outcome;Output;PTPRC gene;Pathway interactions;Phagocytes;Phase;Physiological;Population;Predisposition;Process;Research;Resistance;Resistance to infection;Role;Route;Sepsis;Severities;Severity of illness;Site;Small Intestines;Stains;Symptoms;Systemic disease;Testing;Time;Tissues;Treatment Efficacy;Virulence;Work;adaptive immunity;cell motility;cell type;experience;extracellular;feeding;foodborne;foodborne infection;foodborne pathogen;human disease;ileum;immune clearance;in vivo;lymph nodes;monocyte;mouse model;mutant;neonate;neutrophil;pathogen;podoplanin;prevent;receptor;trafficking;transmission process

public_health_relevance:
Project Narrative:Human disease caused by eating food that is contaminated with the bacterium Listeria monocytogenesranges in severity from mild gastroenteritis to severe life-threatening infections of the blood and centralnervous system. The goal of this proposal is to understand the pathways used by the bacteria to spreadfrom the gut to other sites in the body with a long-term goal of developing an effective therapeutic thatmight limit this process particularly in susceptible populations such as neonates and the elderly.!


application_id: 9731776
project_number: 1R15ES030541-01
project_title: Genetic Susceptibility to Developmental Benzo[a]pyrene Neurotoxicity
administering_ic: NIEHS
award_notice_date: 2019-05-09
opportunity_number: PA-18-504
application_type: 1
activity_code: R15
ic: ES
serial_number: 030541
program_official: HOLLANDER, JONATHAN
project_start_date: 2019-05-15
project_end_date: 2023-04-30
study_section: Special Emphasis Panel[ZRG1 DKUS-J (82)]
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary. Traffic-related air pollution (TRAP) is a mixture of particulates gases and organic moleculesprimarily polycyclic aromatic hydrocarbons (PAHs). Although the effects of TRAP on lung function and hearthealth are well known there is emerging evidence that TRAP also harms the developing brain with effects on IQand behavior persisting into school age. These studies are limited because they can only identify correlationsand not the specific causative factor. Extensive animal studies have strongly implicated aryl hydrocarbonreceptor (AHR) agonists including PAHs in developmental neurotoxicity. Many of these studies focused on theprototypical PAH benzo[a]pyrene (BaP) and found deficits in learning and memory behavior and dopaminergicpathways. Those studies however did not take into account genetic variations that could affect BaP metabolismand its resultant effects on neurodevelopment and brain function. The studies proposed here will address thelimitations of prior human and animal studies by using a mouse model with allelic differences in the AHR-CYP1pathway previously shown to alter susceptibility to BaP carcinogenesis. All three genes of interest (AHRCYP1A1 and CYP1A2) vary in the human population and have been linked to adverse effects following exposureto TRAP. Therefore our studies will help identify those at highest risk of adverse effects. We will use mice withallelic differences at the Ahr Cyp1a1 and Cyp1a2 loci to test the over-arching hypothesis that the AHR pathwaymediates neurotoxicity. Aim 1: Determine how genetic differences in the AHR-CYP1 pathway alter theseverity of developmental BaP neurotoxicity using validated tests of learning & memory behavior and motorfunction. Together we will determine if BaP also affects motor function while testing the hypothesis that the lossof CYP1A1 increases the severity of developmental BaP neurotoxicity. Aim 2: Compare neurotransmitterlevels in the cortex cerebellum striatum and hippocampus in adult mice exposed to BaP during earlybrain development. Developmental neurotoxicants often act by permanently disrupting normal neuronalsignaling. Using HPLC and UPLC to quantify neurotransmitters in multiple brain regions we are likely to identifythe critical pathways affected by developmental BaP exposure. This will be important in identifying the specificmechanism of neurotoxicity. Aim 3: Compare BaP metabolism in exposed dams and their offspring duringlate gestation and lactation. Our over-arching hypothesis is based on prior studies demonstrating differentialmetabolism of BaP in mice with variations in CYP1 genes. By including mice with variation in AHR affinity forBaP we will be able to examine both gene-gene and gene-environment interactions and more closely modelhuman genetic variation. As an AREA-R15 application this will strengthen the research environment at NorthernKentucky University a predominantly undergraduate institution in the Greater Cincinnati area serving a largepercentage of diverse and disadvantaged students.

project_terms:
Address;Adult;Adverse effects;Affect;Affinity;Agonist;Alleles;Animals;Area;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Award;Behavior;Behavioral Sciences;Benzo(a)pyrene;Biological Assay;Biology;Blood;Brain;Brain region;CYP1A1 gene;CYP1A2 gene;Cancer Etiology;Cardiac health;Cerebellum;Chemicals;Chemistry;Cigarette;Corpus striatum structure;Critical Pathways;DNA Adducts;Data;Data Analyses;Development;Embryo;Environment;Exposure to;Female;Food;Gases;Genes;Genetic;Genetic Predisposition to Disease;Genetic Variation;Grant;Half-Life;High Pressure Liquid Chromatography;Hippocampus (Brain);Human;Impairment;Individual;Institution;Kentucky;Knockout Mice;Laboratories;Lactation;Learning;Life;Link;Measures;Mediating;Memory;Mentors;Metabolism;Motor;Mus;Neurosciences;Neurotoxins;Neurotransmitters;Orthologous Gene;Particulate;Pathway interactions;Phenotype;Population;Predisposition;Pregnancy;Psychology;Reporting;Reproducibility;Research;Research Methodology;Respiratory physiology;Risk;School-Age Population;Severities;Signal Transduction;Societies;Students;System;Teratology;Testing;Time;Tissues;Toxicokinetics;Toxicology;Training;Universities;Variant;Weight Gain;base;behavior change;brain abnormalities;carcinogenesis;career;developmental neurotoxicity;disadvantaged student;experience;exposed human population;gene environment interaction;high risk;human model;interest;male;maternal weight;mouse model;neurodevelopment;neurotoxicity;neurotoxicology;neurotransmission;offspring;prenatal;pup;symposium;traffic-related air pollution;undergraduate student

public_health_relevance:
Project Narrative. Traffic-related air pollution cigarettes and grilled food all contain asignificant concentration of polycyclic aromatic hydrocarbons (PAHs). These chemicals areknown to cause cancer but more recently were associated with developmental neurotoxicity inhighly exposed human populations. We will test mice with differing genetic backgrounds toidentify genes that increase susceptibility to prenatal and early life PAH exposure and the risk ofabnormal brain development.


application_id: 9731422
project_number: 5R01CA196835-05
project_title: Treatment of Castration-resistant Prostate Cancer (CRPC)
administering_ic: NCI
award_notice_date: 2019-05-31
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 196835
program_official: FORRY, SUZANNE L
project_start_date: 2019-01-15
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-BMCT-C(01)S]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)  Androgen ablation (castration) is one major approach to treat prostate cancer (PCa) as androgen receptor (AR) signaling is essential for PCa development and growth. Enough evidence supports the notion that AR signaling continues to be active in castration-resistant prostate cancer (CRPC). Consequently abiraterone and enzalutamide two androgen signaling inhibitors (ASI) are becoming the major drugs to treat CRPC post- docetaxel. Unfortunately ASI can only improve the overall patient survival for 2-5 months. Therefore it is urgent to identify new targets and develop novel approaches to treat ASI-resistant CRPC. Accumulating data suggests that the -catenin pathway is a good target for CRPC because the -catenin pathway was identified as one of the top signaling pathways with significant genomic alterations in CRPC and activation of the - catenin pathway contributes to elevation of AR signaling. However how the -catenin pathway can be targeted in CRPC is still elusive. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the -catenin pathway thus AR signaling and to exploit this unique pathway as a novel therapeutic target for CRPC patients. Axin2 a key regulator of the -catenin pathway was identified as a novel Plk1 substrate. The central hypothesis is that a combination of inhibition of Plk1 with BI2536 and the -catenin pathway with IWR1 is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing three Specific Aims - (1) to determine whether a combination of inhibition of Plk1 and -catenin pathway is a novel approach to treat ASI-resistant CRPC using patient- derived xenografts; (2) to test whether inhibition of Plk1 activates the -catenin pathway in genetically engineered mice; and (3) to dissect how Plk1 phosphorylation of Axin2 regulates the -catenin pathway and AR signaling. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with PCa mouse models culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the -catenin and AR signaling and to examine whether a combination of inhibition of Plk1 and the -catenin pathway is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will () define the molecular mechanism by which Plk1 regulates the -catenin and AR signaling; and (ii) validate Plk1 as a critical therapeutic target to enhance the efficacy of inhibitors that targt the -catenin pathway. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the -catenin and AR signaling that is critical for generating and maintaining the CRPC phenotype.

project_terms:
Ablation;Affect;Androgen Receptor;Androgens;Biochemical;Cancer Patient;Castration;Cell Death;Cell Death Inhibition;Cells;Clinical Research;DNA Sequence Alteration;Data;Development;Disease;Event;Fostering;Genetic;Genetically Engineered Mouse;Goals;Growth;Growth and Development function;Health;Human;Investigation;Knock-out;Lead;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Methodology;Mission;Mitotic;Modeling;Molecular;Nuclear;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phenotype;Phosphorylation;Prevention;Prognostic Marker;Prostate;Public Health;Receptor Signaling;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Work;Xenograft Model;Xenograft procedure;abiraterone;beta catenin;castration resistant prostate cancer;design;diagnostic biomarker;docetaxel;effective therapy;improved;in vivo;inhibitor/antagonist;innovation;knock-down;mouse model;new therapeutic target;next generation sequencing;novel;novel strategies;prostate cancer cell;prostate cancer progression;public health relevance;success;therapeutic target;transgenic adenocarcinoma of mouse prostate;tumor growth;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE  The proposed research is relevant to public health because it focuses on discovery of novel signaling pathways that drive castration-resistant prostate cancer. These studies will establish new avenues of investigation to develop improved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus the proposed research is relevant to NCI's mission of fostering creative discoveries and innovative research strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 9731300
project_number: 5R01HL141356-02
project_title: Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction
administering_ic: NHLBI
award_notice_date: 2019-06-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 141356
program_official: ZHOU, GUOFEI
project_start_date: 2018-07-01
project_end_date: 2022-05-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: CALLAHAN, LEIGH A
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:
Severe ICU acquired diaphragm dysfunction is present in the majority of mechanically ventilated MICUpatients. Importantly recent work indicates that patients with weak diaphragms have a much longerrequirement for mechanical ventilation and a markedly higher mortality. As a result therapies that increasediaphragm function have the potential to improve MICU patient outcomes. These recent studies also suggestthat a major risk factor for ICU acquired diaphragm weakness is infection. Infections elicit a marked increasein diaphragm mitochondrial free radical production and these free radicals contribute to weakness andfatigue. The present proposal therefore will test the hypothesis that pharmacological therapiesdesigned to either inhibit mitochondrial free radical generation or induce mitochondrial repair willprevent and/or reverse sepsis mediated diaphragm dysfunction. This theory will be tested in fourgroups of studies:Aim 1 studies will test the hypothesis that sepsis induced diaphragm dysfunction can be reduced by usingagents which inhibit mitochondrial free radicals. Experiments will utilize the cecal ligation puncture sepsismodel (CLP) and compare diaphragm function in sham operated CLP CLP plus drug and sham plus druggroups. Drugs to be tested include mitoTEMPOL SKQ1 and necrostatin.Aim 2 studies will test the hypothesis that administration of activators of mitochondrial biogenesis canimprove infection induced diaphragm dysfunction. Sepsis will again be produced with CLP and we willexamine the ability of three treatments (i.e. AICAR+PQQ PQQ and AICAR+GW1506) to prevent CLPinduced diaphragm dysfunction.Aim 3 studies will evaluate the mechanisms by which Aim 1 and Aim 2 drugs produce their effects onmuscle cells. These experiments will also test the hypothesis that these agents induce release of myokineswhich have autocrine effects to attenuate cytokine induced muscle cell damage.Aim 4 studies will test the hypothesis that myokine administration can be used as a pharmacologicaltreatment to attenuate sepsis induced diaphragm dysfunction in animals. Myokines to be tested include irisinand other proteins found in Aim 3 studies to block cytokine induced muscle cell damage in vitro.

project_terms:
Animal Model;Animals;Antioxidants;Attenuated;Biogenesis;Cell Size;Clinical;Contractile Proteins;Critical Illness;Development;Electron Transport;Fatigue;Free Radicals;Functional disorder;Generations;In Vitro;Infection;Intensive Care Units;Ligation;Mechanical ventilation;Mechanics;Mediating;Medical;Mitochondria;Modeling;Morbidity - disease rate;Muscle;Muscle Cells;Muscle Mitochondria;Muscle Weakness;Muscle function;Muscular Atrophy;Outcome;Pathway interactions;Patient-Focused Outcomes;Patients;Peritonitis;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Process;Production;Proteins;Puncture procedure;Reactive Oxygen Species;Research;Respiratory Diaphragm;Risk Factors;Saline;Sepsis;Skeletal Muscle;Testing;Work;autocrine;base;cecal ligation puncture;cell injury;cytokine;design;experimental study;improved;improved outcome;indexing;inhibitor/antagonist;mortality;muscle strength;neuromuscular function;paracrine;prevent;repaired;response;targeted treatment;theories;therapy design

public_health_relevance:
Diaphragm muscle weakness is a major contributor to morbidity and mortality in critically ill MICU patients butcurrently there is no drug therapy available to treat this problem. The studies in this proposal are designed toidentify treatments to prevent and/or restore muscle function in these patients. We believe this work has thepotential to define new treatments that can have a major impact to improve the clinical outcomes of critically illpatients.


application_id: 9730622
project_number: 5R01NS091582-05
project_title: The role of macrophage phenotype and age in spinal cord injury
administering_ic: NINDS
award_notice_date: 2019-07-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 091582
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2015-09-30
project_end_date: 2021-07-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a heterogeneous neuroinflammatory response consisting of macrophages with the potential to both aggravate tissue damage and promote wound healing and repair. These macrophages have been identified as pro-inflammatory pathological "M1" macrophages or anti-inflammatory alternatively activated pro-reparative "M2" macrophages. There is published evidence that driving M2 macrophage activation improves SCI recovery. The mechanisms underlying the reparative effects of M2 macrophages however are not well understood. As a result the development of clinically viable pharmacological interventions that harness the reparative potential of activated macrophages remains a critical challenge that is compounded by a changing SCI demographic. The incidence of SCI among older individuals has increased in recent years with a more equal balance of SCI across sexes. The purpose of this proposal is to investigate the mechanisms of M2 macrophage-mediated SCI repair and determine the effects of age and sex on SCI macrophage activation. Aim 1 will determine the role of arginase in M2 macrophage-mediated SCI repair processes through the use of genetically engineered mice with macrophages that lack arginase-1 (Arg1) and a newly identified treatment that increases M2-mediated arginase production. Parallel in vivo and in vitro SCI models of neurotoxicity axon growth/dieback and remyelination will test the hypothesis that the effects of M2 macrophages are dependent upon Arg1 production. In Aim 2 mice of different ages and sex will be used to determine the effect of these physiological factors on the acute SCI macrophage response. The macrophage response over time will be evaluated using newly developed focused gene profiling and flow cytometry techniques. The hypothesis to be tested is that aged males will have impaired M2 macrophage activation. In Aim 3 the effect of age and sex on M2 macrophage-mediated SCI repair and recovery will be evaluated using a clinically relevant mouse SCI model and a newly developed immunomodulatory SCI treatment. Forms of M2 macrophage activation occur in most CNS pathologies; therefore the current work is significant because it is expected to have broad translational impact on a wide range of neuroinflammatory conditions. This project is both conceptually and technically innovative. It will employ creative use of Arg1 knockout mice and a novel immunomodulatory agent. The investigation of the effects of age and sex on the macrophage response to SCI using a comprehensive focused gene array approach is novel. Collectively the completion of the proposed research will improve scientific knowledge regarding macrophage biology as it specifically relates to age and sex. This knowledge will improve clinical practice by leading to sophistication of treatment strategies that include sex andage as potential influences in the context of SCI treatment and recovery.

project_terms:
Acute;Affect;Age;Age Factors;Animals;Anti-inflammatory;Automobile Driving;Azithromycin;Biology;Cell Proliferation;Cells;Chronic;Clinical;Clinical Data;Data;Development;Dose;Effectiveness;Equilibrium;Estradiol;Female;Flow Cytometry;Genes;Genetically Engineered Mouse;Goals;Gonadal Steroid Hormones;Health Care Costs;Human;Immunomodulators;Impairment;In Vitro;Incidence;Individual;Inflammatory;Inflammatory Response;Intervention;Investigation;Knockout Mice;Knowledge;Macrolide Antibiotics;Macrophage Activation;Mediating;Modeling;Mus;Outcome Measure;Paralysed;Pathologic;Pathology;Patients;Pharmacology;Phenotype;Physiological;Process;Production;Progesterone;Publishing;Recovery;Recovery of Function;Research;Rodent;Role;Spinal Cord Contusions;Spinal cord injury;Techniques;Testing;Time;Tissues;United States;Work;Wound Healing;age effect;aged;arginase;axon growth;axon regeneration;base;clinical development;clinical practice;clinically relevant;female sex hormone;functional disability;gain of function;immunomodulatory therapies;immunoregulation;improved;in vivo;injury and repair;innovation;loss of function;macrophage;male;middle age;mouse model;neuroinflammation;neuropathology;neuroprotection;neurotoxic;neurotoxicity;novel;pre-clinical;public health relevance;remyelination;repaired;response;sex;translational impact;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The injured spinal cord does not heal properly resulting in chronic paralysis and expensive health care costs for patients with spinal cord injuries (SCI). The average age at the time of SCI in the United States is increasing but most clinical SCI therapies are being examined in individuals regardless of age and are based upon pre-clinical data generated almost exclusively using young female animals. The physiological factors of age and sex influence the inflammatory response to SCI therefore this proposal will examine treatment and inflammatory mechanisms in SCI models using both young and middle-aged male and female subjects in order to generate data of relevance to all SCI individuals.


application_id: 9730521
project_number: 5P30GM127607-02
project_title: Pilot Projects Program
administering_ic: NIGMS
award_notice_date: 2019-06-28
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5795
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Advisory Committees;Affect;Applications Grants;Area;Award;Basic Science;Biology;Cardiovascular Diseases;Cardiovascular system;Cell physiology;Centers of Research Excellence;Complex;Custom;Data;Development;Diabetes Mellitus;Disease;Effectiveness;Ensure;Environment;Environmental Pollution;Etiology;Extramural Activities;Faculty;Fostering;Funding;Genetic;Goals;Grant;Growth;Health;Institution;Insulin Resistance;Investments;Knowledge;Life Style;Manuscripts;Mentors;Mentorship;Metabolic;Metabolic Diseases;Methodology;Mission;Molecular Chaperones;Monitor;Obesity;Phase;Pilot Projects;Probability;Publishing;Recommendation;Regulation;Research;Research Personnel;Research Project Grants;Resources;Role;Social status;Stem cells;Time;Translational Research;United States National Institutes of Health;Universities;Vocational Guidance;base;cardiometabolism;cardiovascular health;career;career development;innovation;interest;mid-career faculty;novel;novel therapeutics;progenitor;programs;recruit;senior faculty;success;synergism


application_id: 9730517
project_number: 5P30GM127607-02
project_title: Flow Cytometry Core
administering_ic: NIGMS
award_notice_date: 2019-06-28
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
study_section: ZGM1-RCB-3
subproject_number: 5791
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: 2019-07-01
budget_end_date: 2020-06-30
project_terms:
Address;Adipocytes;Adipose tissue;Adopted;Antigens;Apoptotic;Area;Award;Biological Assay;Blood Cell Count;Blood Platelets;Cardiovascular system;Cell Therapy;Cells;Centers of Research Excellence;Chemicals;Clinical Research;Color;Communities;Continuing Education;Coupled;Data;Data Analyses;Detection;Diabetes Mellitus;Dyes;Epidemic;Equipment;Event;Extramural Activities;Fee-for-Service Plans;Fees;Felis catus;Flow Cytometry;Foundations;Funding;Future;Generations;Goals;Grant;Health Hazards;Human Resources;Immune;Individual;Institutes;Institution;Metabolism;Monitor;Nature;Obesity;Patients;Phase;Population Analysis;Procedures;Protocols documentation;Reagent;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Sampling;Services;Signal Transduction;Structure;Techniques;Tissues;Training;Universities;Work;analytical tool;base;career development;cell determination;clinical investigation;diabetic;event cycle;experience;experimental study;innovation;instrument;interest;investigator training;macrophage;meetings;member;mitochondrial membrane;monocyte;novel;operation;peripheral blood;programs;rapid detection;stem cell population;synergism;theories


application_id: 9729094
project_number: 5P01NS097197-04
administering_ic: NINDS
award_notice_date: 2019-08-05
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8557
contact_pi_person_id: 1888145
contact_pi: ROACH, PETER J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
funding_mechanism: Non-SBIR/STTR
project_title:
Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to Lafora Disease

project_abstract:
Project Summary Suppressing glycogen storage with small molecule inhibitors as a therapeutic approach to Lafora disease Lafora disease is a fatal childhood-onset progressive epilepsy caused by mutations at either the EPM2A or EPM2B genes and for which no cure is currently available. Much has been learned of the disease in the last decade that can help guide new approaches to effective therapies. A consistent feature is the accumulation of insoluble deposits called Lafora bodies in many tissues and of special significance in neurons in the brain. Lafora bodies contain polyglucosan an abnormal glycogen-like compound that is less branched and less soluble than normal glycogen. In mouse models of Lafora disease laforin-/- and malin-/- mice genetic depletion or elimination of glycogen was shown to decrease the formation of Lafora bodies and to alleviate indicators of the disease. Therefore current thinking is that the formation of Lafora bodies is causative of the disease and suppression of their formation would represent a promising approach as a therapy. In this project we propose to reduce glycogen stores in the brain by developing small molecule inhibitors of its accumulation. Aim 1: Identification and validation of small molecule glycogen synthase inhibitors. We are searching for active site and allosteric site inhibitors of glycogen synthase by high-throughput screens (HTS) using novel assays. Positives from the above screens will be validated in vitro and analyzed by the Medicinal Chemistry Core for favorable ADME their potential to cross the blood brain barrier (BBB). Aim 2. Medicinal chemistry optimization. Prioritized hits from Aim 1 will be further validated for activity through direct synthesis and a limited set of related analogs will either be purchased or synthesized to evaluate a range of sub-structures substituents and/or substitution patterns for activity by the in vitro analyses described in Aim 1. Preliminary structure-activity relationships (SAR) will inform on the potential for further pre-clinical development. Aim 3: Cell-based assay of glycogen accumulation toxicity and preliminary pharmacokinetics. We have developed two novel plate-based assays to monitor cellular glycogen levels in glycogen accumulating cell lines. The assays will be applied to evaluate and validate glycogen synthase inhibitors identified in Aim 1 and could also be developed as an alternative for HTS of compound libraries to identify novel inhibitors at the cellular level. The most promising candidates will be advanced for toxicology and pharmacokinetic analyses in mice. Aim 4: Testing inhibitors of glycogen accumulation in mouse models of Lafora disease. Compounds identified in previous Aims that show most promise will be tested in laforin-/- and malin-/- mice to assess their effects on Lafora body formation neurodegeneration and behavioral impairment associated with the disease. Any compounds making it to this stage will be candidates for further development via NINDS drug development programs of the IGNITE/BLUEPRINT initiatives such as PAR-15-071.

project_terms:
Active Sites;Age-Months;Allosteric Site;Animals;Biochemical;Biological;Biological Assay;Blood - brain barrier anatomy;Brain;Cell Line;Cells;Chemicals;Childhood;Core Facility;Data;Deposition;Development;Disease;Dose;Drug Kinetics;Enzyme Kinetics;Epilepsy;Evaluation;Genes;Genetic;Genomics;Glucose-6-Phosphate;Glycogen;Glycogen (Starch) Synthase;Histologic;Human Cell Line;Impairment;In Vitro;Investigation;Laboratories;Lafora Disease;Lead;Libraries;Long-Term Effects;Measurement;Monitor;Mus;Mutation;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Nervous System Physiology;Neurologic Symptoms;Neurons;Pathology;Pattern;Penetration;Pharmaceutical Chemistry;Prevention;Program Development;Property;Protocols documentation;Radioactive;Series;Structure;Structure-Activity Relationship;Testing;Therapeutic;Thinking;Tissues;Toxic effect;Toxicology;Validation;Weaning;analog;base;behavioral impairment;cohort;drug development;effective therapy;high throughput screening;human disease;in vitro activity;inhibitor/antagonist;lead candidate;mouse model;novel;novel strategies;phosphatase inhibitor;polyglucosan;preclinical development;response;small molecule;small molecule inhibitor


application_id: 9729091
project_number: 5P01NS097197-04
project_title: Personalized diagnosis - defining how glycogen metabolism and proteostasis impact LD
administering_ic: NINDS
award_notice_date: 2019-08-05
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8555
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_abstract:
Lafora disease (LD) is a fatal recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic hyperphosphorylated water- insoluble glycogen-like particles called Lafora bodies (LBs). LD results from mutations in either of the genes encoding laforin a glycogen phosphatase or malin an E3 ubiquitin ligase and mutations in either gene results in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. Associated with LB formation cells display multiple markers indicating perturbations in critical cellular pathways including increased endoplasmic reticulum stress autophagy ROS production and others.  The overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): which is an international collaboration devoted to the Diagnosis Treatment and Cure of LD. The goals of this project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options. To achieve these goals we will define the molecular basis of LD utilizing structural biochemistry cellular biology and mouse models and translate our insights into mutation-specific diagnoses and novel therapeutic approaches to ameliorate LD induced epilepsy and cure LD.  We will first utilize integrated structural and functional tools to define the physical and cellular perturbations caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and treat LD patients. We will define the role of neurotransmitter transporters affected in LD. Further we will determine how laforin and malin affect transporter homeostasis and how LD mouse models respond to treatment of symptoms with antiepileptic drugs. Lastly we will establish the beneficial effect of pharmacological intervention novel compounds that promote read-through of premature termination codons. Embedded in these approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of molecular sub-types of the disease key to each of the LECI Center projects. Further these results have significant broader implications since LD is one of five major progressive myoclonic epilepsies and the connection between metabolic dysfunction and epilepsy is an emerging theme.  Cumulatively these results will allow personalized therapeutic options that are developed to promote recovery of molecular and cellular function as a means of treating and curing LD.

project_terms:
Acute;Address;Affect;Antiepileptic Agents;Apoptosis;Area;Astrocytes;Autophagocytosis;Biochemical;Biochemistry;Biochemistry and Cellular Biology;Biological Assay;Brain;Cell Culture Techniques;Cell physiology;Cells;Cessation of life;Clinical;Collaborations;Cystic Fibrosis;Data;Defect;Development;Diagnosis;Disease;Disease Progression;Energy Metabolism;Epilepsy;Event;Family;Functional disorder;Genes;Glucans;Glycogen;Goals;Homeostasis;International;Intervention;Ion Channel;Knowledge;Lafora Disease;Life;Metabolic dysfunction;Modeling;Molecular;Mutation;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Neurotransmitters;Outcome;Oxidative Stress;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phosphoric Monoester Hydrolases;Production;Program Research Project Grants;Progressive Myoclonic Epilepsies;Proteins;Recovery;Research;Role;Sampling;Structural Biochemistry;Structure;Symptoms;Terminator Codon;Testing;Therapeutic;Toxic effect;Translating;Translations;Water;clinical application;design;disease-causing mutation;drug efficacy;endoplasmic reticulum stress;glycogen metabolism;in vitro Model;induced pluripotent stem cell;insight;member;misfolded protein;molecular subtypes;mouse model;neuron apoptosis;neurotoxicity;new therapeutic target;novel;novel therapeutic intervention;overexpression;particle;personalized approach;personalized diagnostics;personalized therapeutic;potency testing;premature;protein degradation;protein expression;proteostasis;receptor;restoration;small molecule;symptom treatment;tool;trafficking;ubiquitin-protein ligase


application_id: 9729090
project_number: 5P01NS097197-04
project_title: Biological Core
administering_ic: NINDS
award_notice_date: 2019-08-05
opportunity_number: PAR-14-183
application_type: 5
activity_code: P01
ic: NS
serial_number: 097197
study_section: Neurological Sciences and Disorders C Study Section[NSD-C]
subproject_number: 8554
contact_pi_person_id: 9487963
contact_pi: WORBY, CAROLYN ANN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
budget_end_date: 2020-06-30
project_abstract:
AbstractEpilepsy is one of the most common neurological disorders with a lifetime cumulative incidence of nearly 4%.Amongst the epilepsies Lafora Disease (LD) is the one most ready for personalized treatment. The molecularbasis of LD is known with 65-70% of LD cases due to mutations in the EPM2A gene encoding the glycogenphosphatase laforin and 25-30% of LD cases due to mutations in EPM2B the gene encoding the E3 ubiquitinligase malin. The hallmark of LD is the accumulation of starch-like polyglucosans called Lafora bodies (LBs)which present clinically as an intractable fatal epilepsy. To support the work proposed in this grant theBiological Core will generate transgenic cell culture and mouse models to both study LD mechanisms andevaluate putative therapeutics. The core will use CRISPR technilogy to genetically manipulate SY5Y (humannueronal cell line) and induced pluripotent stem cells (iPSc) to harbor a LD missense mutation and apremature stop codon in both the lafonin and malin genes (8 cell lines total). These cells will be evaluated fortheir ability to differentiate into neurons and produce LBs . These cell lines will be used in high throughput drugscreens and testing of lead compounds. The core will also generate 4 mouse models by introducing the sameLD mutations for laforin and malin used in the cell culture models. Video-EEG and behavioral studies willdocument drug effects on epilepsy and behavior of LD transgenic mice. These mouse models will be used byin Projects 1-4 to determine the efficacy of promising drugs obtained from the high throughput screens anddefine the window of opportunity for treatment. The ultimate goal of the PIs associated with this programproject grant is to combine our efforts to cure Lafora Disease.

project_terms:
Aftercare;Antisense Oligonucleotides;Ataxia;Basic Science;Behavior;Biochemical;Biological;CRISPR/Cas technology;Cell Culture Techniques;Cell Line;Cell model;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communities;Consensus;Cytoplasm;Deterioration;Development;Diagnosis;Disease;Disease Progression;Disease model;Drug Screening;Educational workshop;Electroencephalography;Ensure;Epilepsy;Funding;Genes;Glycogen;Goals;Grant;Hormonal;Human;Impaired cognition;Incidence;Intractable Epilepsy;Knock-in Mouse;Lafora Disease;Lead;Missense Mutation;Modeling;Molecular;Mutation;Myoclonic Epilepsies;Neurologic;Neurons;Nonsense Codon;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Plants;Program Research Project Grants;Progressive Myoclonic Epilepsies;Reagent;Research;Research Personnel;Side;Starch;Stimulus;Structure;Techniques;Teenagers;Therapeutic;TimeLine;Transgenic Mice;Transgenic Organisms;United States National Institutes of Health;Work;behavioral study;drug testing;epileptic encephalopathies;genome editing;high throughput screening;induced pluripotent stem cell;innovation;meetings;member;mouse model;multidisciplinary;nervous system disorder;patient advocacy group;personalized diagnostics;personalized medicine;polyglucosan;prevent;small molecule;success;ubiquitin-protein ligase


application_id: 9726115
project_number: 5R24OD010435-19
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2019-07-05
opportunity_number: PAR-13-253
application_type: 5
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2022-03-14
study_section: Special Emphasis Panel[ZRG1-BBBP-Y(45)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis application proposes to develop fundamental genomic and bioinformatic resources that willbetter enable studies of a model amphibian the Mexican axolotl (Ambystoma mexicanum). Theaxolotl is used in several areas of biomedical research including regenerative medicine and stem cellbiology. Axolotls show a remarkable ability to regenerate damaged body parts including whole limbsspinal cord and brain. Understanding how axolotls regenerate complex tissues may revealmechanisms to achieve endogenous regeneration in humans. Specific Aim 1 will continue efforts tosequence the large axolotl genome which is 10x larger than the human genome. An innovativechromatin capture approach (Hi-C) will be used to develop DNA libraries that contain information forscaffolding unordered genomic fragments. Accomplishment of this aim will yield a highly contiguousand annotated genome assembly an essential resource for any model organism. Specific Aim 2 willperform the first epigenetic studies of the axolotl genome. These studies will characterize changes inhistone modifications whole genome methylation patterns and local chromatin interactions duringlimb regeneration leveraging an existing transcriptional dataset that provides robust temporalresolution of gene expression. These studies will identify chromatin modifications and interactions thatarise or are remodeled during critical phases of limb regeneration. Specific Aim 3 will developgenomic sequence for a second salamander model the red-spotted newt (Notophthalamusviridescens). The newt is a logical choice for sequencing because it too serves as a model organismin tissue regeneration research and its phylogenetic distance from axolotl is ideal for identifyingconserved and lineage-specific non-coding sequences that may function to regulate transcriptionduring regeneration. Thus the proposed newt genomic sequence will broaden the salamander toolkitincreasing the likelihood for future clinical applications in biomedicine. Broad impact will be achievedby sharing genomic and epigenetic data from all three Specific Aims through an existing publicwebsite (Sal-Site). Overall the project will greatly enhance salamander models for biomedicalresearch.

project_terms:
Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Area;Bacterial Artificial Chromosomes;Biomedical Research;Body part;Brain;ChIP-seq;Chromatin;Chromosomes;Complex;DNA;DNA Library;DNA Methylation;DNA Sequence;Data;Data Set;Distal;Enhancers;Epigenetic Process;Erythroblasts;Funding;Future;Gene Expression;Gene Structure;Genetic;Genetic Transcription;Genome;Genomics;Human;Human Genome;Libraries;Limb structure;Location;Maps;Meiosis;Methods;Modeling;Molecular;Natural regeneration;Newts;Nucleic Acid Regulatory Sequences;Partner in relationship;Phase;Phylogenetic Analysis;Red-Spotted Newts;Regenerative Medicine;Regulatory Element;Research;Research Personnel;Resources;Salamander;Sampling;Site;Spinal Cord;Structural Genes;Testing;Tissues;Transcript;Untranslated RNA;Vision;Work;bioinformatics resource;chromatin modification;clinical application;design;epigenetic variation;histone modification;improved;innovation;limb amputation;limb regeneration;methylation pattern;promoter;scaffold;stem cell biology;temporal measurement;tissue regeneration;transcriptome;transcriptome sequencing;web site;whole genome

public_health_relevance:
The project will develop critical genomic resources to enhance research efforts using the Mexicanaxolotl. Studies using the axolotl may reveal strategies to achieve endogenous tissue regeneration inhumans.


application_id: 9725949
project_number: 5R01DA036550-05
project_title: Human Laboratory Screening of Pregabalin and Tiagabine for Cannabis Dependence
administering_ic: NIDA
award_notice_date: 2019-05-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 036550
program_official: HAMPSON, AIDAN
project_start_date: 2014-09-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZRG1-RPIA-N(09)F]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cannabis use disorders are a significant public health concern and the absence of effective medications is a critical barrier to overcome. This application is founded on promising results from our laboratory suggesting that drugs that act at a2d-1 subunit containing voltage-dependent calcium channels (VDCCs) and/or elevate g- aminobutyric acid (i.e. GABA) will be effective medications for cannabis-use disorders. Our laboratory results are supported by a recent pilot clinical trial showing that gabapentin which isa VDCC ligand and elevates GABA reduced cannabis use in dependent treatment-seeking adults. The goal of the present proposal is to build upon these promising laboratory and clinical findings by determining the ability of outpatient maintenance on pregabalin a "next generation" VDCC ligand and tiagabine a GABA reuptake inhibitor to attenuate the reinforcing effects of cannabis. Pregabalin will be tested because although their mechanism of action is the same the pharmacokinetic profile of pregabalin is improved compared to gabapentin and clinical results suggest that this translates into greater pharmacotherapeutic effectiveness. Tiagabine will be tested because its effects overlap with gabapentin and pregabalin GABA elevation is a possible mechanism for gabapentin's effects on cannabis use and our recent data demonstrated that tiagabine produced a profile of effects that was comparable to gabapentin when tested in combination with D9-THC. Outpatient maintenance dosing will be tested because it more closely resembles the clinical treatment situation. Cannabis self-administration using a concurrent progressive-ratio drug-money choice procedure will be the primary outcome because drug seeking and drug taking behaviors and the choice to use drugs to the exclusion of other behaviors are defining characteristics of drug dependence and drug self-administration procedures are predictive of therapeutic efficacy. Cannabis use in the natural environment will also be monitored during drug maintenance as a secondary outcome to optimize resource management and quicken the pace of intervention development. Our preliminary data with the proposed procedures support the feasibility of the project the assembled research team is highly qualified and the environment will significantly contribute to the success of the research. The proposed project is innovative because it employs a novel hybrid procedure to study the impact of medication maintenance on direct cannabis effects in the laboratory as well as cannabis use in the natural environment the effects of pregabalin and tiagabine on cannabis self-administration have not been tested previously and a novel real-time medication maintenance compliance technology will be implemented. Positive findings will exert an immediate and sustained impact by rapidly advancing currently available medications for the treatment of cannabis-use disorders promoting novel pharmacological targets for further medications development and providing valuable basic science information about the mechanisms underlying cannabis reinforcement.

project_terms:
Abstinence;Acute;Admission activity;Adult;Attenuated;Award;Basic Science;Behavior;Behavior Therapy;Calcium Channel;Cannabis;Characteristics;Clinical;Clinical Treatment;Clinical Trials;Cost Savings;Data;Dependence;Development;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Drug usage;Effectiveness;Environment;Exclusion;Goals;Human;Hybrids;Illicit Drugs;Incentives;Independent Scientist Award;Intervention;Laboratories;Ligands;Maintenance;Marijuana Dependence;Measures;Methods;Modeling;Monitor;Motivation;Outpatients;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacology;Pharmacotherapy;Placebos;Principal Investigator;Procedures;Process;Psychological reinforcement;Public Health;Randomized;Relapse;Research;Resources;Role;Schedule;Self Administration;Statistical Data Interpretation;Statistical Models;Study Subject;Techniques;Technology;Testing;Therapeutic Effect;Time;Translating;Treatment Efficacy;United States;career development;cost effectiveness;drug maintenance;experience;gabapentin;gamma-Aminobutyric Acid;illicit drug use;improved;inhibitor/antagonist;innovation;marijuana use;marijuana use disorder;marijuana user;next generation;novel;pregabalin;primary outcome;public health relevance;reinforcer;response;reuptake;screening;secondary outcome;side effect;success;therapy development;tiagabine;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence treatment admission and relapse that are comparable to other illicit drugs that are often perceived as more harmful. Currently there are no effective pharmacological treatments for cannabis-use disorders. This project will evaluate pregabalin and tiagabine for cannabis-use disorders using state-of-the-art human laboratory methods.


application_id: 9724559
project_number: 5R01NS095215-05
project_title: Regulation of cilia by ceramide
administering_ic: NINDS
award_notice_date: 2019-06-26
opportunity_number: PAS-15-029
application_type: 5
activity_code: R01
ic: NS
serial_number: 095215
program_official: LAVAUTE, TIMOTHY M
project_start_date: 2016-09-30
project_end_date: 2021-06-30
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:
Cilia are protrusions of the cell membrane with sensory (primary cilia) or motor (motile cilia) function. Inastrocytes and ependymal cells primary and motile cilia regulate cell division and migration and propelcerebrospinal fluid (CSF) respectively. Ciliary dysfunction leads to astrocytic overgrowth (astrogliosis) orependymal cell malfunction and hydrocephalus. It is vital for the function of cilia in cell signaling and motilitythat cilium number length and intraciliary or intraflagellar transport (IFT) of cargo proteins are dynamicallyregulated. A critical barrier in understanding this regulation is the lack of knowledge on dynamically activatedfactors in ciliogenesis and cilium function. Although cilia are membrane structures research so far has focusedon the role of proteins in the regulation of cilia and little is known about the role of lipids in this process. Ourresearch goals are to determine how membrane lipids and proteins interact in the regulation of cilia and howmodulation of lipid metabolism can be utilized to support the function of cilia in astrocytes and ependymal cells.Our central hypothesis is that the sphingolipid ceramide regulates cilium length and IFT which is critical forthe function of cilia in astrocytes and ependymal cells. Our objectives are to 1) test that cilia are regulated byceramide-associated protein complexes; 2) define these complexes by using a novel technique to pull downceramide enriched- and cilium-derived membrane vesicles and covalently crosslink a bifunctional ceramideanalog to its interacting proteins to identify ceramide binding domains; 3) test that induction of receptors in ciliais regulated by ceramide; and 4) test that astroglial activation and ependymal cell function is regulated byceramide in vitro and in vivo. Our expected outcomes include 1) determining ceramide species that promoteciliogenesis and support cilium function and how the generation of ciliogenic ceramide is regulated; 2) defininga mechanism of cilium extension and IFT regulation by interaction of ceramide with atypical PKC GSK-3 andHDAC6; 3) defining SMase activation in vesicle transport pathways and their function for ceramide flux to thecilium; 4) identifying proteins and protein domains that associate with ceramide; 5) determining that transportand activation of signaling proteins in cilia in particular of the sonic hedgehog pathway are regulated byceramide; and 6) defining a mechanism by which ceramide regulates astrocyte activation and ependymal cell-driven CSF flow. The impact of this project is on defining a fundamental and novel mechanism in basicneuroscience and membrane biology which has broad implications for our understanding of the regulation ofcilia by lipid-protein interaction and the importance of this regulation for the function of astrocytes andependymal cells during brain development and aging. Aim 1 will test the hypothesis that ceramide stabilizescilia in astrocytes and ependymal cells. Aim 2 will test the hypothesis that ceramide regulates IFT andreceptor activation in cilia. Aim 3 will test the hypothesis that ciliogenic ceramide regulates astrocyte andependymal cell function.

project_terms:
AGFG1 gene;Aging;Apical;Astrocytes;Binding;Brain;Carrier Proteins;Cell Surface Extensions;Cell division;Cell physiology;Ceramides;Cerebrospinal Fluid;Cilia;Complex;Development;Enzyme Activation;Ependymal Cell;Fatty acid glycerol esters;Functional disorder;Generations;Glycogen (Starch) Synthase;Goals;Growth Factor;Growth Factor Receptors;HDAC6 gene;Hydrocephalus;Impairment;In Vitro;Inflammatory;Kinesin;Knowledge;Laboratories;Length;Lipids;Liquid substance;Mediating;Membrane;Membrane Biology;Membrane Lipids;Membrane Proteins;Motor;Neuroglia;Neurons;Neurosciences;Outcome;Process;Proteins;Receptor Activation;Regulation;Research;Role;SHH gene;Sensory;Signal Pathway;Signal Transduction;Signaling Protein;Sonic Hedgehog Pathway;Sphingolipids;Sphingomyelinase;Techniques;Tertiary Protein Structure;Testing;Tubulin;Vesicle;Vesicle Transport Pathway;Work;aging brain;analog;astrogliosis;base;cell motility;cell type;cerebrospinal fluid flow;cilium biogenesis;cilium motility;crosslink;cytokine;glycogen synthase kinase 3 beta;in vivo;lipid metabolism;novel;prevent;protein complex;protein transport;receptor;transcription factor

public_health_relevance:
Cilia are protrusions of the cell membrane that work like antenna or whips. Antenna-like primary cilia sensegrowth factors that regulate activation and proliferation of astrocytes and other neural cells in the brain. Whip-like motile cilia of ependymal cells move fluids that contain growth factors such as the cerebrospinal fluid.Therefore primary and motile cilia are vital for brain development and function. The P.I.'s laboratory has foundthat a fat-like substance (lipid) called ceramide is critical for cilia. In the present study the P.I. will determinehow ceramide regulates cilia in the brain a fundamental and novel mechanism in basic neuroscience andmembrane biology.


application_id: 9724211
project_number: 5R01CA215095-03
project_title: Roles of RORalpha in breast cancer development and progression
administering_ic: NCI
award_notice_date: 2019-06-17
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 215095
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: Tumor Microenvironment Study Section[TME]
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_terms:
3-Dimensional;Agonist;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Cell Polarity;Cellular Metabolic Process;Chronic;Coculture Techniques;Complex;Development;Down-Regulation;Epithelial Cells;Expression Profiling;Gene Expression;Gene Expression Profiling;Generations;Glutathione Disulfide;Goals;Human;Hydrogen Peroxide;Immunocompetent;Infiltration;Inflammation;Knockout Mice;Knowledge;Lead;Link;Malignant Neoplasms;Mammary gland;Measurement;Mediating;Metabolic;Metformin;Mitochondria;Modeling;Molecular;Mus;NADP;Nature;Neoplasm Metastasis;Nuclear Orphan Receptor;Oxidation-Reduction;Pathway interactions;Positioning Attribute;Production;Reactive Oxygen Species;Research;Role;Scheme;Source;Structure;Superoxides;System;TP53 gene;Testing;Tissue Microarray;Tissues;Tumor Suppressor Proteins;base;breast cancer progression;cancer cell;cancer prevention;cancer therapy;cytokine;druggable target;healing;improved;inhibitor/antagonist;insight;knock-down;loss of function;macrophage;malignant breast neoplasm;metabolomics;monocyte;multidisciplinary;novel;novel strategies;stable isotope;transcriptome;tumor;tumor microenvironment;tumor progression


application_id: 9724047
project_number: 1R21EY030186-01
project_title: The effect of cannabidiol and the role of GPR3 in experimental autoimmune uveitis
administering_ic: NEI
award_notice_date: 2019-03-21
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: EY
serial_number: 030186
program_official: MCKIE, GEORGE ANN
project_start_date: 2019-04-01
project_end_date: 2021-03-31
study_section: Special Emphasis Panel[ZRG1 BDCN-J (81)]
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;Anti-inflammatory;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;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.


