# projects

application_id: 10382687
project_number: 2R42MD015915-02
administering_ic: NIMHD
award_notice_date: 2022-02-11
opportunity_number: PA-20-265
application_type: 2
activity_code: R42
ic: MD
serial_number: 015915
program_official: DAGHER, RADA K
project_start_date: 2020-09-23
project_end_date: 2023-11-30
study_section: Special Emphasis Panel[ZRG1 EMNR-D (11)]
contact_pi_person_id: 16414967
contact_pi: SHAH, SWATI
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 081302037
primary_uei: D263NL49YK14
duns_number: 081302037
uei: D263NL49YK14
fips: US
organization_id: 10059076
organization_name: FETAL LIFE, LLC
organization_city: PROSPECT
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400598112
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-02-11
project_title:
Portable Affordable Innovative and Smart Device-Coupled Electronic Fetal Monitoring System to Improve Rural Access to Obstetrics Services and Improve Outcomes in Rural Communities

project_abstract:
PROJECT SUMMARYTo ensure fetal well-being obstetricians monitor fetal heartrate (FHR) and uterine contractions on a weekly tobi-weekly basis towards the end of pregnancy and during labor. Such monitoring is performed with an electronicfetal monitor (EFM) to decrease the development of complications while minimizing the need for unnecessaryobstetric interventions. This is especially important for women with high-risk pregnancies. Inadequate monitoringincreases the risk of morbidity mortality and poor infant outcomes. Unfortunately many women especially inrural and minority communities face many barriers like sufficient time and resources to adequate prenatal carelike EFM. Furthermore EFMs used in hospitals are not portable and can be prohibitively expensive for mid- tolow-resource communities. On the other hand monitors for home use measure only 1 parameter and thereforenot approved for clinical decision making. Fetal Lifes solution is a novel EFM system based on a patent-pendingengineering design. Our innovation enables us to manufacture an EFM system as accurate as a hospital EFMbut at a fraction of the cost while maintaining a portable size with telemonitoring capabilities. Commercializingthis system will increase accessibility to necessary healthcare by reducing the cost and time required for prenatalcare for patients and healthcare providers.In a successful Phase I program Fetal Life met all Phase I milestones resulting in: 1) development of a prototypeof the system (devices plus patient-facing mobile app) and 2) confirmation that the system is usable by pregnantpatients and can detect contraction and FHR signals. Completion of the Phase I program was critical tosupporting the proposed Phase II program that will focus on completing and validating the EFM system withtelemonitoring capabilities for 510(k) clearance. Phase II efforts will include completing the system with theaddition of the healthcare provider-facing app and validating its accuracy with in vitro testing (Aim 1)manufacturing and completing standard safety testing (Aim 2) and validating accuracy and usability of thesystem in a statistically powered study with pregnant subjects (Aim 3). Successful completion of the Phase IIprogram will provide critical performance and safety data necessary for a 510(k) filing and key data supportingits use for telehealth both of which are required for successful market deployment.

project_terms:
3D Print;Address;Appointment;Biological;Caring;Charge;Clinic;Clinical;Code;Companions;Computer software;County;Coupled;Data;Data Set;Development;Device Designs;Devices;Diabetes Mellitus;Discipline of obstetrics;Engineering;Ensure;Evaluation;Face;Fetal Monitoring;Fetal health;Frequencies;Funding;Gel;Gynecology;Health Personnel;Healthcare;High-Risk Pregnancy;Home;Hospitals;Improve Access;In Vitro;Intervention;Legal patent;Life;Low income;Manikins;Maternal Health Services;Measurement;Measures;Medical Device;Minority;Monitor;Morbidity - disease rate;Mothers;Outpatients;Participant;Patient Care;Patients;Performance;Personal Satisfaction;Phase;Pregnancy;Pregnancy Complications;Pregnant Women;Prenatal care;Procedures;Resource-limited setting;Resources;Risk;Risk Factors;Rural;Rural Community;Rural Minority;Safety;Services;Signal Transduction;Small Business Technology Transfer Research;Study Subject;Surveys;System;Technology;Testing;Time;United States National Institutes of Health;Universities;Uterine Contraction;Woman;barrier to care;base;biomaterial compatibility;clinical decision-making;clinical practice;cohort;commercialization;cost;cytotoxicity;data exchange;data sharing;engineering design;fetal;health care availability;health care quality;human subject;improved;improved outcome;in vitro testing;infant outcome;innovation;minority communities;mobile application;monitoring device;mortality;novel;obstetric care;portability;pregnant;programs;prototype;remote health care;remote monitoring;rural underserved;safety testing;skin irritation;telehealth;telemonitoring;underserved community;usability;vibration

public_health_relevance:
PROJECT NARRATIVEMeasuring fetal heartrate and uterine contractions is a common procedure performed by obstetricians to ensuremother and fetal health during pregnancy and labor. However many pregnant mothers especially in rural andminority communities do not have the resources or time to reach an obstetrician and currently available at-homeproducts are not used to make clinical decisions. Fetal Health will lower the barriers to healthcare access forrural mothers by developing a portable and affordable telemonitoring product that can measure fetal heartrateand uterine contractions and simultaneously send both sets of data to a remote doctor to make critical decisionsin real time that will ultimately improve mother and fetal health.


application_id: 10382267
project_number: 5R01DE028883-02
project_title: Topical Vitamin D and Periodontal Disease
administering_ic: NIDCR
award_notice_date: 2022-03-31
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 028883
program_official: CHANDER, PREETHI
project_start_date: 2021-04-02
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-MOSS-V(02)M]
contact_pi_person_id: 1891127
contact_pi: DIAMOND, GILL
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_terms:
3-Dimensional;Actinobacillus actinomycetemcomitans;Address;Affect;Anti-Bacterial Agents;Apical;Bacteria;Bioinformatics;Bone Development;Bone Resorption;Calcium;Cells;Cholecalciferol;Chronic;Clinical;Clinical Trials;Complex;Conflict (Psychology);Data;Development;Epigenetic Process;Epithelial;Epithelial Cells;Feedback;Genes;Genetic;Gingiva;Growth;Health;Health Status;Homeostasis;Host Defense;Human;Immune;Immunity;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Inflammatory Response Pathway;Kinetics;Lead;Link;Mechanics;Mediating;Mixed Function Oxygenases;Molecular;Mus;Natural Immunity;Operative Surgical Procedures;Oral;Oral cavity;Outcome;Pathway interactions;Peptides;Periodontal Diseases;Periodontitis;Population;Porphyromonas gingivalis;Preventive therapy;Production;Publishing;Regulation;Reporting;Role;Signal Pathway;Surface;Tissues;Tooth Loss;Topical application;Toxic effect;Vitamin D;Vitamin D Deficiency;Vitamin D supplementation;Vitamin D3 Receptor;Vitamins;absorption;antimicrobial;bone loss;commensal microbes;cytokine;cytotoxicity;dysbiosis;mouse model;oral cavity epithelium;oral infection;oral microbial community;oral microbiome;oral supplementation;pathogenic bacteria;periodontopathogen;prevent;response;supervitaminosis;three dimensional cell culture;transcription factor


application_id: 10382018
project_number: 3P42ES023716-05S1
administering_ic: NIEHS
award_notice_date: 2021-07-16
opportunity_number: PA-20-272
application_type: 3
activity_code: P42
ic: ES
serial_number: 023716
suffix: S1
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2023-03-31
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-07-16
project_title:
KC Donnelly ExternshipPromotion of Translational/Transdisciplinary Efforts in Graduate & Post-Doctoral Research

project_abstract:
AbstractThe overarching goal of my research is to investigate the role of volatile organiccompound (VOC) exposure on the development of cardiovascular disease (CVD).Volatile organic compounds are gaseous chemicals present in industrial solventspetroleum products automobile exhaust tobacco smoke and household chemicals.VOCs are abundant at several Superfund and hazardous waste sites. Population basedstudies at the University of Louisville SRP show that VOCs such as 13-butadiene (BD)used in the production of synthetic rubber are positively associated with sub-clinicalmarkers of cardiopulmonary injury (endothelial cell and lung microparticles) andproinflammatory cytokines. These associations are also accompanied by a decrease inendothelial progenitor cells reflecting an impaired endothelial repair capacity. Studiesperformed by Dr. Arthur Penn (LSU SRP) have demonstrated that exposure to 13-butadiene via inhalation exacerbated atherosclerosis in cockerels.1 It is unclear whethercardiovascular injury of 13-butadiene is due to direct effects of the chemical orsecondary effects of 13-butadiene-induced pulmonary toxicity. We will be assessing thetoxicity of BD using a state of the art air-liquid interface (ALI) cell exposure system(Vitrocell).

project_terms:
13-Butadiene;Air;Arterial Injury;Atherosclerosis;Automobile Exhaust;Butadiene;Cardiopulmonary;Cardiovascular Diseases;Cell Differentiation process;Cell Survival;Cells;Chemicals;Development;Electrical Resistance;Endothelial Cells;Endothelium;Epithelial;Exposure to;Gene Expression;Generations;Goals;Hazardous Waste Sites;Household;Impairment;In Vitro;Industrialization;Inhalation;Injury;Liquid substance;Lung;Nitric Oxide;Petroleum;Population Study;Postdoctoral Fellow;Production;Reactive Oxygen Species;Research;Role;Signal Recognition Particle;Solvents;Superfund;Synthetic Rubber;System;Tobacco smoke;Toxic effect;Universities;cardiovascular injury;cytokine;cytotoxicity;dosimetry;endothelial stem cell;externship;improved;lung injury;repaired;transcriptome sequencing;volatile organic compound

public_health_relevance:
NarrativeOur proposed project will provide an improved approach for studying lung and arterial injury invitro. This will generate a better understanding of how exposure to 13-butadiene and othervolatile organic compounds VOCs contribute to the development of cardiovascular diseases.


application_id: 10381502
project_number: 5R01HD101508-03
project_title: Noninvasive Noncontact High-Density Optical Imaging of Neonatal Intraventricular Hemorrhage
administering_ic: NICHD
award_notice_date: 2022-04-12
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HD
serial_number: 101508
program_official: KING, TRACY
project_start_date: 2020-04-10
project_end_date: 2025-03-31
study_section: Imaging Technology Development Study Section[ITD]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
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:
ABSTRACTGerminal matrix-intraventricular hemorrhage (GM-IVH) is a major complication of premature birth occurring inup to 45% of very low birthweight neonates (<1500 g) due to fragility of immature blood vessels within thegerminal matrix. GM-IVH can also lead to hydrocephalus (HCP) and increased intracranial pressure whichfurther induces inflammation and brain tissue injury. Though neonatal GM-IVH and HCP are increasinglycommon due to the rising survival rate of preterm births there are no established biomarkers or guidelines fortheir treatments to prevent brain injury. Preterm infants with GM-IVH/HCP are vulnerable to alterations in cerebralblood flow (CBF) because they have impaired cerebrovascular autoregulation. However there are no reliablefunctional imaging methods at the bedside of neonatal intensive care units (NICUs) for repeatedly assessingeither degree of cerebral injury or effectiveness of interventions. Near-infrared spectroscopy and tomographytechnologies have been used for decades as noninvasive bedside tools for continuous monitoring of cerebralblood oxygen saturation (StO2). However most systems lack the combination of spatial resolution and wide field-of-view (FOV) to image distributed brain functions and discriminate the brain signal from overlaying scalp andskull. A few high-density tomographic systems use numerous discrete sources and detectors coupled with fiberbundles to a head cap. However adjusting and maintaining a stable optical coupling of numerous fibers to asmall fragile neonatal head (i.e. a contact measurement) is labor-intensive and poses great challenges to headcap design with safety concern. To overcome these limitations we propose to develop a novel noncontacthigh-density-detection (using a CCD/CMOS camera) multi-wavelength speckle contrast diffuse correlationtomography (MW-scDCT) system to accommodate fast high-resolution functional imaging of both CBF andStO2 over a large FOV on the neonatal head. The MW-scDCT will be rigorously calibrated and optimized usingstandard tissue phantoms (Aim 1). In vivo calibration/evaluation will be conducted against MRI and histologicalexamination in an IVH/HCP model of neonatal piglets who preserve great similarities with human neonates (Aim2). A pilot clinical observational study will be performed in preterm neonates with GM-IVH/HCP under standardof care in the NICU (Aim 3). Cerebral hemodynamics/metabolism cerebrovascular autoregulation and cerebralfunctional connectivity will be analyzed from serial functional images taken over several weeks after birth. Wehypothesize that cerebral hemodynamic/metabolic alterations detected by MW-scDCT correlate withprogression of brain injury after GM-IVH/HCP and recovery after treatment. Multiple parameters will providemore comprehensive assessments of neonatal brain injury/recovery compared to a single parameter alone. Thisstudy will fulfill a critical need in the field of neonatology to provide objective measures/biomarkers to guide timingof treatment for GM-IVH and HCP. We anticipate that noninvasive repeated and longitudinal cerebral monitoringfor the guidance of interventions could be eventually implemented as standard of care in NICUs.

project_terms:
Acute;Aftercare;Autopsy;Biological Markers;Birth;Blood;Blood Vessels;Brain;Brain Injuries;Brain imaging;Calibration;Case Study;Cephalic;Cerebral Ventricles;Cerebrospinal Fluid;Cerebrospinal fluid shunts procedure;Cerebrovascular Circulation;Cerebrum;Chronic Phase;Clinical;Complication;Coupled;Coupling;Critical Care;Critical Illness;Detection;Development;Devices;Diffuse;Effectiveness of Interventions;Evaluation;Fiber;Functional Imaging;Goals;Guidelines;Head;Histologic;Homeostasis;Human;Hydrocephalus;Image;Imaging Device;Imaging Techniques;Impairment;Inflammation;Injury;Intervention;Intracranial Hypertension;Intracranial Pressure;Ischemic Brain Injury;Laboratories;Lead;Legal patent;Low Birth Weight Infant;Magnetic Resonance Imaging;Measurement;Measures;Medical;Metabolic;Metabolism;Methods;Modeling;Monitor;Multi-modal optical imaging;Mus;Near-Infrared Spectroscopy;Neonatal;Neonatal Brain Injury;Neonatal Intensive Care Units;Neonatology;Neurologic Deficit;Neurological outcome;Neurosciences Research;Observational Study;Optics;Outcome;Outcome Measure;Outcome Study;Oxygen;Oxygen Consumption;Premature Birth;Premature Infant;Property;Rattus;Recovery;Research;Resolution;Safety;Scalp structure;Signal Transduction;Source;Survival Rate;System;Technology;Testing;Three-Dimensional Imaging;Time;Tissues;Ultrasonography;algorithmic methodologies;brain health;brain tissue;cerebral hemodynamics;cerebrovascular;clinical application;clinical outcome assessment;cranium;density;design;detector;functional disability;high risk;human imaging;imager;imaging modality;improved;in vivo;injury recovery;innovation;intraventricular hemorrhage;metabolic rate;multimodality;neonatal brain;neonate;neuroimaging;novel;optical imaging;portability;pre-clinical;premature;preservation;preterm newborn;prevent;standard care;standard of care;tissue injury;tissue phantom;tomography;tool

public_health_relevance:
PROJECT NARRATIVEPreterm infants are at high risk for brain injuries due to alterations in brain blood flow and oxygenation especiallyafter the occurrence of intraventricular hemorrhage and currently there is no reliable bedside method to monitorthese functional parameters continuously in premature brains. This project will develop and test a newnoncontact fast high-resolution and portable optical device which enables immediate and continuous imagingof brain blood flow oxygenation metabolism and functional connectivity in neonatal piglets and preterm infants.Compared to currently available technologies this noninvasive multi-parameter functional imager will providea more comprehensive and accurate assessment of neonatal brain health/injury which may help optimize carefor critically ill neonates and reduce harm to their brains.


application_id: 10381281
project_number: 3R21CA251042-01S1
project_title: Supplement: Bio CaRGOS: Capture and release gels for optimized storage of Cancer Biospecimens
administering_ic: NCI
award_notice_date: 2021-09-20
opportunity_number: PA-21-071
application_type: 3
activity_code: R21
ic: CA
serial_number: 251042
suffix: S1
program_official: AGRAWAL, LOKESH
project_start_date: 2021-08-01
project_end_date: 2022-07-31
contact_pi_person_id: 15717479
contact_pi: GUPTA, GAUTAM
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Biomarkers play a central role in the detection diagnosis management and monitoring of patientswith cancer. Factors such as analytical sensitivity and reproducibility are critical to the clinicalutility of plasma-based biomarkers in the setting of longitudinal surveillance and early detection ofdisease and or recurrence. Currently the state of preservation of biospecimens is accomplishedprimarily using sub freezer techniques and it is cost prohibitive and certainly not practical in mostscenarios. There is clearly a dearth of techniques that can preserve the biospecimens at roomtemperature for long periods of time. Therefore there is a critical unmet clinical need for storing aplethora of biospecimens acquired routinely.In the parent grant we proposed to demonstrate stability and integrity of Pancreatic CancerSpecific biomarkers (CA-A19 miRNA21 and ctDNA) in buffers as well as plasma for extendedperiods of time at room temperature utilizing a 1-step microwave based sol-gel process. Thespecific aims were:The specific aims of this research were: (A) Achieve complete integrity and stability of cancerbiomarkers in physiologic electrolytes at room temperature. (B) Demonstrate integrity and stabilityof cancer biomarkers in presence the major plasma proteins (albumin globulin and fibrinogen). (C)Investigate the integrity of induced cancer biomarkers and native biomarkers present in plasmaSolutes such as glucose uric acid and other nominal proteins can have an effect on CaRGOS.In the Supplement Grant Lindsay will develop a reverse engineering approach and will workclosely with the PIs and students to directly stabilize biomarkers in plasma. Lindsay started workingon this approach and have observed critical challenges including: (i) biocompatibility of the processdue to even minimal presence of methanol (ii) possible interference of silica with characterizationtechniques such as dd PCR. (iii) intensive extraction protocols for extraction of biomarkers fromplasma and their compatibility with the silica. These three major hurdles form the basis of thesupplement grant where we will need to advance our fundamental understanding of the nature ofinteractions of silica precursors with a complex matrix such as plasma. The specific aims of theSupplement grant are:(A) Elimination of methanol from the precursor sol prior to addition of biomarker/plasma. (B) Develop robust protocols to separate silica from the biomarkers at the point of downstreamprocessingDuring the first year Lindsay will be an undergraduate researcher and obtain her B.S. in ChemicalEngineering. During the second year she will obtain her masters in engineering enabling her toenrich her skill set in this area. This focused project will allow Lindsay to become an independentand confident researcher in future that aligns with her goals to obtain a MD/PhD.

project_terms:
Achievement;Albumins;Amylases;Antigens;Area;Biological Markers;Buffers;Cancer Model;Cell Line;Chemical Engineering;Clinical;Complex;Cryopreservation;Detection;Diagnosis;Disease;Doctor of Philosophy;Due Process;Early Diagnosis;Electrolytes;Engineering;Equipment;Experimental Designs;Fibrinogen;Formulation;Freezing;Future;Gel;Globulins;Glucose;Goals;Grant;Immunoassay;Individual;Ionic Strengths;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Methanol;Methodology;Methods;Modeling;Monitor;Nature;Patient Monitoring;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Phosphate Buffer;Physiological;Plasma;Plasma Proteins;Play;Polymerase Chain Reaction;Process;Property;Proteins;Protocols documentation;RNA vaccine;Recovery;Recurrence;Reproducibility;Research;Research Personnel;Reverse Transcription;Role;Saline;Sampling;Silicon Dioxide;Students;Techniques;Technology;Temperature;Time;Uric Acid;Virus;Work;anticancer research;aqueous;base;biomaterial compatibility;cancer biomarkers;cost;digital;innovation;insight;interest;microwave electromagnetic radiation;parent grant;preservation;skills;solute;specific biomarkers;undergraduate student;user-friendly


application_id: 10381267
project_number: 3P42ES007380-23S3
project_title: K.C. Donnelly Externship Admin Supplement for Erin Molly Frazar P42ES007380 UKSRC
administering_ic: NIEHS
award_notice_date: 2021-07-23
opportunity_number: PA-20-272
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S3
program_official: HENRY, HEATHER F
project_start_date: 2021-06-01
project_end_date: 2022-01-31
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
KC Donnelly Abstract for E. Molly Frazar My current UK-SRP funded research seeks to develop inexpensive reusable polymericsorbents for PFAS capture and removal. Specifically polymeric sorbents that can selectively bindand release PFAS contaminants are designed developed and optimized thereby providing alow-cost sustainable alternative to the current commercially available water remediation sorbents.In order to better inform my PFAS based research the proposed KC Donnelly Externship projectwill provide educational opportunities in the development of human health and ecological riskassessment. Under the direction of Dr. Amanda Persad in the U.S. Environmental ProtectionAgency Center for Public Health and Environmental Assessment I will learn how to conductenvironmental impact assessments which will consists of hazard identification mode of actionanalysis dose-response analysis systematic review and computational tools used for evidenceanalysis. Through this externship I will gain a deeper understanding of how to best applyenvironmental research in order to support legislative action related to risk assessment.Specific Aim 1. To learn how to conduct environmental impact assessments consisting of hazardidentification and systemic review. In order to learn how to bridge the gap between the researchcommunity and regional offices who make regulatory enforcement and remedial actiondecisions I will learn to determine how pollutants or other stressors may impact human healthand the environment.Specific Aim 2. To gain hands on experience in an EPA research facility through onsite visitsIn person visits will equip me with professional networking opportunities while developinghuman health and ecological risk assessments and using robust scientific processes to determinehow pollutants or other stressors may impact human health and the environment.

project_terms:
Binding;Communities;Development;Dose;Environment;Environmental Impact;Environmental Pollution;Excision;Face;Funding;Future;Hazard Identification;Health;Human;Learning;Long-Term Effects;Mollies;Persons;Polychlorinated Biphenyls;Polymers;Process;Public Health;Regulation;Research;Risk Assessment;Signal Recognition Particle;United States Environmental Protection Agency;Visit;Water;base;career networking;computerized tools;cost;design;experience;externship;organic contaminant;pollutant;remediation;research facility;response;stressor;systematic review

public_health_relevance:
KC Donnelly Project Narrative for E.Molly Frazar Perfluorinated alkylated substances (PFAS) are a recently recognized group of emergingorganic environmental contaminants that have been used for decades in products that are still onthe market today presenting grave concern for remediation efforts. Unfortunately the challengeswe face today with PFAS are similar to those we have faced in the past with other pervasiveorganic contaminants such as polychlorinated biphenyls (PCBs) and will be similar to those thatwe will certainly face in the future with unrecognized pollutants we are currently producing andusing without full understanding of long-term effects or proper regulation and/or oversite. Theproposed KC Donnelly Externship project will provide educational opportunities in thedevelopment of human health and ecological risk assessment equipping me with a deeperunderstanding of how to best apply environmental research in order to support legislative actionrelated to risk assessment.


application_id: 10381183
project_number: 3P20GM135004-02S1
administering_ic: NIGMS
award_notice_date: 2021-05-28
opportunity_number: PA-18-935
application_type: 3
activity_code: P20
ic: GM
serial_number: 135004
suffix: S1
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2025-01-31
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2021-06-01
project_title:
Surveillance and identification of variants of concern within circulating SARS-CoV-2 across Kentucky

project_abstract:
PROJECT SUMMARYThe emergence and circulation of SARS-CoV-2 the virus that causes COVID-19 disease has led to >125 millioninfections and more than 2.5 million deaths worldwide in just over 1 year. Global sequencing efforts haveidentified several viral variants of concern (VOC) and interest (VOI) that result in increased transmission ratesand/or increased mortality for those infected with the new SARS-CoV-2 strains. Despite the development ofmultiple robust and effective vaccines further viral evolution may result in resistance to current levels of vaccine-mediated protection. Ongoing viral genomic surveillance is necessary to identify and characterize known andnew viral variants to inform both ongoing public health efforts and future vaccine design strategies. This is aparticularly urgent need for Institutional Development Award (IDeA) states for which knowledge of circulatingSARS-CoV-2 variants is extremely limited. The mechanistic forces driving SARS-CoV-2 diversification andvariant emergence are certainly multifactorial. Effective natural and vaccine antiviral protection is thought to bemediated by potent broadly reactive neutralizing antibodies (nAbs). Recently developed genotyping assays havecharacterized the extensive diversity within immunoglobulin (IG) loci with increasing evidence suggesting thatthe collective array of genes that encode antibody repertories differ widely across ethnic populations. Moreoverrecent reports suggest that biological sex may impact immunopathogenesis and individual resilience and thatgeographically restricted circulation and transmission of variants along with pre-existing social vulnerabilitiesmay also impact SARS-CoV-2 variant dynamics. It is well documented that COVID-19 disproportionately impactsunderrepresented populations including Black Indigenous and people of color (BIPOC) and Latinx peoples.Data regarding SARS-CoV-2 circulation and variant profiling in these populations in also underreported inongoing viral surveillance efforts. Evaluating how viral VOC and VOI are impacted by differential geneticbiological and social backgrounds will be critical for providing equitable representation of the frequency andcharacteristics of SARS-CoV-2 variants and act as a first step towards mechanistic hypothesis generation forfuture studies. Using a robust high throughput and cost-effective single molecule real-time sequencingapproach we propose to perform large scale SARS-CoV-2 genomic surveillance from ~7000 samples sourcedacross Kentucky (KY) to (1) substantially improve data availability regarding SARS-CoV-2 dynamics and variantcirculation (2) evaluate biological and social correlates of variant emergence and evolution and (3) leveragethis pipeline to develop a unique curriculum in pathogen surveillance. To achieve this we have built a multi-institutional collaborative effort developing key partnerships among a deep network of academic healthcareand industrial stakeholders positioning this team to establish a pathogen surveillance center for ongoing andfuture efforts.

project_terms:
2019-nCoV;Address;Age;Antibodies;Antiviral Agents;Award;Biological;Biological Assay;Black Indigenous People of Color;Blood Circulation;Brazil;COVID-19;COVID-19 severity;COVID-19 surveillance;Cessation of life;Characteristics;Collaborations;Color;Communicable Diseases;Communities;Complement;Country;County;Custom;Data;Data Set;Databases;Deposition;Detection;Development;Diagnostic;Disease;Educational Curriculum;Ensure;Ethnic Origin;Ethnic group;Etiology;Evolution;Female;Frequencies;Future;Future Generations;Genes;Genetic;Genomics;Genotype;Geographic Locations;Geography;Government Agencies;Health Care Research;Healthcare;Immune response;Immunoglobulins;Individual;Industrialization;Infection;Informatics;Institution;Kentucky;Knowledge;Laboratories;Latinx;Mediating;Methods;Mutation;Outcome Study;Pathogenicity;Phylogenetic Analysis;Population;Positioning Attribute;Privatization;Public Health;RNA;Race;Reporting;Resistance;SARS-CoV-2 genome;SARS-CoV-2 infection;SARS-CoV-2 variant;Sampling;Secure;Source;South Africa;Specimen;Surveillance Program;Time;Training;Underrepresented Populations;United Kingdom;Universities;Vaccine Design;Vaccines;Variant;Viral;Viral Genome;Viral Pathogenesis;Virus;base;biological sex;cost effective;design;driving force;genomic signature;graduate student;health inequalities;improved;infection rate;informatics tool;interest;male;molecular sequence database;mortality;neutralizing antibody;next generation;novel;pandemic disease;pathogen;population based;prospective;resilience;single molecule real time sequencing;skills;social;social vulnerability;surveillance data;transmission process;undergraduate student;variants of concern;viral genomics;viral transmission

public_health_relevance:
PROJECT NARRATIVEThe emergence of the SARS-CoV-2 virus the etiologic agent of COVID-19 has resulted in a global pandemicleading to >125 million infections and >2.5 million deaths thus far. Global viral sequencing efforts have identifiedmultiple variants of concern that result in increased viral transmission and/or mortality; expansion of thissurveillance is urgently needed in Institutional Development Award (IDeA) states which are vastlyunderrepresented in public SARS-CoV-2 databases. We are proposing a large scale SARS-CoV-2 genomicsurveillance effort from samples (n=7000) sourced across Kentucky (KY) to substantially improve publiclyavailable KY data evaluate genetic biological and social correlates of variant emergence and leverage thispipeline to develop a unique curriculum for pathogen surveillance training.


application_id: 10380864
project_number: 5R01NS079507-09
administering_ic: NINDS
award_notice_date: 2023-05-25
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 079507
program_official: LEENDERS, MIRIAM
project_start_date: 2012-09-30
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
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
budget_start_date: 2023-04-01
project_title:
Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy

project_abstract:
Blood-brain barrier dysfunction is recognized as both a cause and consequence of seizures in epilepsy. Two keycharacteristics of barrier dysfunction in epilepsy include 1) neurovascular inflammation and 2) barrier leakageboth of which have been linked to seizures. In spite of increasing evidence supporting that glutamate causesblood-brain barrier dysfunction knowledge of the associated underlying mechanisms remain to be fully defined.Moreover therapeutic options for restoring barrier function are currently not available. Thus there is an unmetcritical need to determine how glutamate promotes blood-brain barrier inflammation and leakage and to developtargeted strategies to restore barrier function. The consequence of this unmet need is that development of noveltreatments to improve seizure control in epilepsy will likely remain a clinical challenge. The long-term goal of theinvestigator is to contribute toward the development of mechanism-based strategies to repair blood-brain barrierdysfunction in brain diseases. The overall objective in this application is to establish the efficacy of a mechanism-based intervention to treat blood-brain barrier dysfunction in epilepsy thereby vertically extending what has beenlearned under current funding. Based on preliminary data the central hypothesis of this project is that glutamatesignaling mediates blood-brain barrier dysfunction and that therapeutic intervention targeting this mechanismwill resolve seizure-induced neurovascular inflammation repair barrier leakage and reduce seizure burden. Therationale for the proposed research is that its successful completion will provide a robust framework for thecontinued development and clinical translation of a novel evidence-based therapeutic intervention to help treatseizures in patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identifysignaling steps responsible for seizure-induced inflammation of the blood-brain barrier. 2) Determine themechanism responsible for capillary leakage at the human blood-brain barrier and 3) Develop a therapeuticintervention to reduce seizure burden in a chronic epilepsy model. Under Aim 1 signaling steps that lead toseizure-mediated neuroinflammation will be determined in capillaries isolated from knockout mouse models andverified in vivo. Under Aim 2 key signaling steps that trigger barrier leakage will be determined in human braincapillaries from seizure-free control individuals and from patients with epilepsy. Under Aim 3 an interventiontherapy designed to repair barrier dysfunction will be developed and the therapeutic benefit of this strategy onreducing seizure burden will be evaluated in a rat chronic epilepsy model. The proposed research is innovativebecause it represents a substantive departure from the status quo by shifting the focus to molecular targets atthe blood-brain barrier to resolve neurovascular inflammation restore barrier function and improve epilepsysymptoms. The proposed research is significant because it holds the promise of a novel therapeutic approachto repair barrier dysfunction that has translational potential for clinical use to advance treatment of patients withepilepsy and other seizure disorders with underlying barrier dysfunction.

project_terms:
Agonist;Arachidonate 5-Lipoxygenase;Attenuated;Automobile Driving;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Blood capillaries;Brain Diseases;Cell Adhesion Molecules;Characteristics;Chronic;Clinical;Combined Modality Therapy;Data;Data Reporting;Development;Disease;Endothelium;Epilepsy;Extracellular Matrix Proteins;Extravasation;FPR2 gene;Feedback;Functional disorder;Funding;Glutamates;Goals;Human;Individual;Inflammation;Intervention;Knockout Mice;Knowledge;LOX gene;Lead;Learning;Leukocytes;Leukotrienes;Link;Lipoxygenase;Matrix Metalloproteinases;Mediating;Mission;Modeling;Molecular Target;Mus;National Institute of Neurological Disorders and Stroke;Neurons;PTGS2 gene;Pathway interactions;Patients;Prostaglandins;Proteins;Public Health;Publishing;Rattus;Research;Research Personnel;Seizures;Signal Transduction;Symptoms;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;cerebral capillary;clinical translation;cyclooxygenase 2;evidence base;expectation;glutamatergic signaling;improved;in vivo;innovation;mouse model;nervous system disorder;neuroinflammation;neurotransmitter release;neurovascular;new therapeutic target;novel;novel therapeutic intervention;repaired;therapy design;translational potential;vascular inflammation

public_health_relevance:
The proposed research is relevant to public health because it is expected to identify molecular targets that can be exploited to repair the blood-brain barrier after seizure-induced neuroinflammation and dysfunction. Thistherapeutic strategy is expected to improve seizure control in patients with epilepsy. Thus the proposed research is relevant to the part of the NIH/NINDS mission that pertains to developing fundamental knowledge that will help reduce the burden of neurological disease.


application_id: 10380862
project_number: 5R25HD106831-02
project_title: Team-Based Design of Assistive Technology Devices
administering_ic: NICHD
award_notice_date: 2022-04-18
opportunity_number: PAR-19-215
application_type: 5
activity_code: R25
ic: HD
serial_number: 106831
program_official: NITKIN, RALPH M
project_start_date: 2021-04-01
project_end_date: 2022-12-19
study_section: ZEB1-OSR-B(J1)S
contact_pi_person_id: 10388308
contact_pi: BAZRGARI, BABAK
other_pis: BARD, CHRISTINA ESPINOSA;HUBER, JUSTIN
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThe goal of this proposed educational program is to train and create a biomedical engineering workforcecapable of identifying and addressing the assistive technology device needs of persons with disabilities.Training will revolve around the design and development of assistive technology devices that satisfy the needsof persons with disabilities are not abandoned by the user and which demonstrate an understanding of thesocial ethical environmental and technical challenges associated with the use of assistive technologydevices. We propose a unique educational program aimed at enabling undergraduate Biomedical Engineeringstudents to design such assistive technology devices in a team-based environment. Implementing twoundergraduate courses a summer clinical immersion and several community immersion activities we willachieve our goal by completing three specific aims: 1) To provide a multidisciplinary team-based designexperience 2) To provide a unique holistic biomedical training associated with adoption and use of assistivetechnology devices 3) To provide training in assistive technology device needs through clinical and communityimmersion experiences. This educational program will be offered in a partnership between the University ofKentucky F. Joseph Halcomb III MD Department of Biomedical Engineering the Department of PhysicalMedicine and Rehabilitation and the Human Development Institute (a statewide extension network for personswith disabilities in Kentucky). Each cycle of the program will take one year and will start with a spring semestercourse on social technical ethical and economic challenges associated with design and use of assistivetechnology devices. With the Human Development Institute as a program partner participating students will beable to complete several community immersion activities as a part of this course wherein they will closelyobserve the interactions between practitioners persons with disabilities and their family members. A summerclinical immersion will also be offered as a part of the proposed program wherein 12 undergraduateengineering students (10 from Biomedical Engineering) will complete 200 hours of clinical observation activitiesat a local rehabilitation hospital (Cardinal Hill Rehabilitation Hospital). Participants will be trained to identifyunaddressed assistive technology device needs during clinical and community immersion experiences.Trainees will then be coached to design and prototype biomedical engineering solutions for a select number ofthe identified assistive technology needs. A special consideration will be given to user needs when guidingstudent teams in their projects. The proposed educational program will be led by a team of three programdirectors with complementary engineering clinical and community expertise who have piloted a successful runof the proposed program during the 2019-2020 academic year. Participation of non-engineering studentsstudents with disabilities and minority students will be encouraged. Finally program evaluation will be led bythe Evaluation Unit of the Human Development Institute.

project_terms:
Address;Adopted;Adoption;Affect;Applications Grants;Biomedical Engineering;Caregivers;Caring;Clinical;Collaborations;Communication;Communities;Development;Device Designs;Devices;Disabled Persons;Economics;Educational Activities;Engineering;Environment;Environmental Risk Factor;Ethics;Evaluation;Family member;Fostering;Future;Goals;Health Personnel;Health Professional;Hospitals;Hour;Human;Human Development;Immersion;Institutes;Kentucky;Medical Device;Needs Assessment;Outcome;Participant;Patients;Performance;Physical Medicine;Physical Rehabilitation;Problem Solving;Process;Program Evaluation;Quality of life;Rehabilitation therapy;Reporting;Resources;Running;Rural;Self-Help Devices;Societal Factors;Structure;Students;Testing;Thinking;Training;Universities;Work;Writing;base;design;disability;disabled students;engineering design;experience;falls;holistic approach;improved;lectures;minority student;multidisciplinary;optimism;physically handicapped;programs;prototype;satisfaction;skills;social;student participation;undergraduate student;user centered design

public_health_relevance:
Project NarrativeWe propose a team-based educational program to train and develop a biomedical engineering workforcecapable of not only identifying unaddressed assistive technology needs of persons with disabilities but alsocapable of developing engineering solutions from a holistic approach that accounts for personal social andenvironmental needs of the user.


application_id: 10380761
project_number: 5F32AA027950-03
project_title: RvD1-FPR2 signaling ameliorates alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2022-05-05
opportunity_number: PA-19-188
application_type: 5
activity_code: F32
ic: AA
serial_number: 027950
program_official: LIN, LI
project_start_date: 2020-05-01
project_end_date: 2022-09-30
study_section: ZAA1-GG(32)
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
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:
Alcoholic hepatitis (AH) is a morbid condition with poor prognosis that is primarily driven by alteredimmune cell function in response to endotoxemia but the mechanisms are not fully known orunderstood. Resolvin D1 (RvD1) is a pro-resolution lipid mediator that signals through formylpeptide receptor 2 (FPR2) in mice eliciting M2 polarization in macrophages and antibacterialfunctions in neutrophils. Plasma RvD1 levels and hepatic FPR2 expression are decreased in AHpatients suggesting this pathway is impeded in AH. Animal models suggest RvD1 treatmentameliorates alcohol induced liver injury inflammation fibrosis and endotoxemia while Fpr2-/- micedevelop exacerbated liver injury inflammation fibrosis and endotoxemia. Studies characterizingthe RvD1-FPR2 signaling pathway in alcoholic liver disease (ALD) are nonexistent but arewarranted based on preliminary data. Aim 1: This aim will determine if RvD1 acts solely throughFPR2 to elicit protection in an animal of alcoholic liver disease (ALD). Aim 2: Aim 2a will determineif the RvD1-FPR2 signaling pathway is essential for M2 polarization of Kupffer cells. Aim 2b willestablish if RvD1-FPR2 signaling is required for neutrophil-mediated defense responses againstpathogenic threats. Aim 3: AH patient and healthy control acquired neutrophils and monocyteswill be treated with or without RvD1 ex vivo followed by flow cytometry and proteomic andphosphoproteomic analysis to measure receptor activation and to characterize the signalingpathway respectively. Collectively this study will generate data that could identify RvD1 or FPR2agonists as a therapeutic approach for ALD. Due to the severity of AH and the analysis of AHpatient samples this study it is immediately impactful and informative for future treatmentstrategies. Novel biomarkers and therapeutic interventions are expected to come from theconclusion of the proposed study. Basic biology of the RvD1-FPR2 signaling pathway inneutrophils and monocytes is expected from this work as well.

project_terms:
Aftercare;Agonist;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic steatohepatitis;Alcohols;Animal Model;Animals;Anti-Bacterial Agents;Bacteria;Biology;Cell Extracts;Cell physiology;Cells;Cessation of life;Chronic;Cirrhosis;Data;Disease model;Dopamine D1 Receptor;Endotoxemia;Ethanol;Exposure to;FPR2 gene;Fatty Liver;Fibrosis;Flow Cytometry;Future;Genes;Hepatic;Histologic;Human;Immune;Immune response;Immunology;Infection;Inflammation;Inflammatory Response;Kupffer Cells;Label;Lead;Ligands;Liver;Liver diseases;Measures;Mediating;Modeling;Morbidity - disease rate;Mus;Pathogenesis;Pathogenicity;Pathology;Pathway interactions;Patients;Phagocytes;Phagocytosis;Plasma;Play;Population;Prognosis;Proteomics;Receptor Activation;Receptor Cell;Regimen;Resolution;Respiratory Burst;Role;Sampling;Sampling Studies;Serum;Severities;Signal Pathway;Signal Transduction;Stimulus;Therapeutic;Tissues;Work;alcohol exposure;antimicrobial;base;chronic liver disease;cytokine;defense response;feeding;healthy volunteer;lipid mediator;liver inflammation;liver injury;macrophage;monocyte;mortality;neutrophil;novel marker;novel therapeutic intervention;phosphoproteomics;prevent;response;standard care;treatment strategy

public_health_relevance:
Project Narrative: Findings from this study will demonstrate whether enhanced RvD1-FPR2signaling is a therapeutic option for alcoholic liver disease. These results will immediately impactthe treatment strategies for alcoholic hepatitis patients who have high mortality rates under thecurrent standard care. Advancements in the field of immunology and host-bacteria interactionsand the RvD1-FPR2 signaling pathway are expected from this work as well.


application_id: 10380633
project_number: 5R13CA168316-10
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2022-04-01
opportunity_number: PA-16-294
application_type: 5
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2023-03-31
study_section: ZCA1-PCRB-G(O1)
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract This R13 renewal application requests support to continue the highly successful Kentucky Conference onHealth Communication (KCHC)District of Columbia Health Communication (DCHC) scientific conferenceseries. The overall goal of the annual KCHC-DCHC conferences is to promote health communicationresearch and practice to advance our knowledge and understanding of communication and related social-behavioral sciences; such advances will through translational research subsequently enhance theeffectiveness of interventions designed to promote health and prevent illness. The specific aims are toexpand the impact and scholarly excellence of KCHC-DCHC by 1) enhancing dissemination through moreformal conference proceedings and an innovative online networking initiative; 2) increasing participation byearly career scientists graduate students and underrepresented groups through targeted recruitment andreduced registration rates for students; 3) enhancing training by building in structured mentoring sessions withsenior scholars; 4) increasing innovation and opportunities for research translation by scheduling specialsessions to promote academic and clinical research collaborations; 5) increasing international impact throughopportunities for discussion built into conference programming and increased promotion in internationalarenas; and 6) continuing emphasis on scholarly excellence by inviting distinguished speakers and makingscholarly awards. Across all six aims our goal is to positively influence the field of health communication andincrease its impact by promoting the career development of early career scientists encouraginginterdisciplinary research collaborations and enhancing dissemination and implementation of leading research.Our 2.5-day international interdisciplinary conference involves several disciplines representing communicationpublic health and other social behavioral and health sciences. Topics addressed include interventionsdesigned for health risk behavior reduction in areas such as cancer substance abuse and infectious disease;issues related to underserved populations health disparities and health literacy; interventions throughinterpersonal community media and new technology channels; and international health concerns includingpromoting the development of health communication programs in developing nations. Such communication-focused inquiry is now recognized as instrumental in promoting public health. Past conference attendance hasaveraged 250 participants. The audience primarily includes graduate postdoctoral and academic facultyresearchers as well as healthcare practitioners clinical researchers and representatives from non-profitorganizations and government agencies. We emphasize participation by graduate students and early careerscientists. This audience composition allows the conference series to support one of NIH's goals: to developmaintain and renew scientific humanresources that will ensure the Nation's capability to prevent disease.

project_terms:
Address;Area;Award;Behavioral Sciences;China;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communicable Diseases;Communication;Communication Programs;Communication Research;Communities;Country;Decision Making;Developing Countries;Development;Diabetes Mellitus;Discipline;Disease;Dissemination and Implementation;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Foundations;Funding;Germany;Goals;Government;Government Agencies;Growth;Health;Health Personnel;Health Promotion;Health Sciences;Healthcare;Human Resources;Interdisciplinary Study;International;Internet;Intervention;Kentucky;Knowledge;Life;Malignant Neoplasms;Mentors;Mission;Netherlands;Nonprofit Organizations;Participant;Patients;Personal Satisfaction;Persons;Public Health;Publications;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Role;Russia;Schedule;Scientist;Series;Social Sciences;Structure;Students;Substance abuse problem;Switzerland;Training;Translational Research;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;base;behavioral/social science;cancer risk;career;career development;design;disability;disorder prevention;experience;graduate student;health communication;health disparity;health goals;health information technology;health knowledge;health literacy;innovation;new technology;prevent;recruit;skills;substance abuse prevention;symposium;therapy design;tool

public_health_relevance:
Project NarrativeThe Kentucky Conference on Health Communication (KCHC)District of Columbia HealthCommunication (DCHC) conference series will advance health communication research andpractice to reduce the burden of pressing public health problems such as cancer diabetessubstance abuse and infectious disease. The conferences will advance health communicationresearch and practice through structured researcher and practitioner networking andcollaboration opportunities. The conferences will promote career development in the social andbehavioral sciences through involvement of early career scientists and graduate studentsincreasing the number of professionals with expertise in health communication.


application_id: 10380581
project_number: 5R01AR072061-06
project_title: Myostatin Alters Muscle Composition as The Result of an ACL Injury
administering_ic: NIAMS
award_notice_date: 2023-01-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 072061
program_official: CARIFI, EMILY FORAN
project_start_date: 2018-03-26
project_end_date: 2025-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 11267737
contact_pi: FRY, CHRISTOPHER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractAnterior cruciate ligament (ACL) reconstruction surgery results in protracted quadriceps weakness that isassociated with poorer outcomes altered biomechanics and heightened risk of subsequent injuries. Littleprogress has been made in improving quadriceps strength and functional outcomes in the past decade.Alterations in the cellular and morphological composition of the knee extensor muscles contribute to weaknessfollowing an ACL reconstruction. ACL reconstruction induces expression of myostatin a negative regulator ofmuscle growth locally within the quadriceps. In addition to mitigating muscle regrowth myostatin alsopromotes connective tissue synthesis through activation of figrogenic cells within muscle. The objective ofthis proposal is to determine the time course of deleterious changes to the injured ligament and limb muscleand identify myostatin as integral in the etiology of protracted muscle weakness in individuals following an ACLtear. Aim 1 will evaluate the timeframe of myostatin induction within the injured ACL and quadriceps. Aim 2will determine the deleterious changes within the muscle using a mouse model of ACL injury and the efficacyof follistatin and a soluble form of the myostatin receptor (activin 2B receptor) to mitigate these maladaptations.Experiments in aim 3 will determine if the competitive inhibition of myostatin is capable of rescuing ACL injury-induced skeletal muscle weakness. Finally aim 4 will define if the acute induction of myostatin signalingfollowing an ACL injury in human subjects predicts reductions in muscle strength connective tissue infiltrationand dysregulation of skeletal muscle progenitor cells. The identification of myostatin as a therapeutic targetwill establish the basis for further research to mitigate myostatin signaling after ACL and other ligamentousinjuries to improve rehabilitative efforts and patient recovery.

project_terms:
Activins;Acute;Anabolism;Animals;Anterior Cruciate Ligament;Atrophic;Biomechanics;Biopsy;Cell Proliferation;Cells;Chronic;Clinical Trials;Collagen;Connective Tissue;Data;Degenerative polyarthritis;Development;Diffusion;Etiology;Extensor;Extracellular Matrix;Fc Receptor;Fibroblasts;Fibrosis;Follistatin;GDF8 gene;Goals;Growth;Human;Individual;Infiltration;Injury;Joints;Knee;Ligaments;Limb structure;Link;Measures;Modeling;Molecular;Morphology;Mus;Muscle;Muscle Fibers;Muscle Weakness;Muscle satellite cell;Muscular Atrophy;Operative Surgical Procedures;Outcome;Pathway interactions;Patients;Pharmaceutical Preparations;Physical therapy;Physiological;Procedures;Public Health;Quality of life;Randomized;Reconstructive Surgical Procedures;Recovery;Rehabilitation therapy;Research;Risk;Saline;Signal Transduction;Skeletal Muscle;Testing;Time;Up-Regulation;antagonist;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;disability;efficacy evaluation;experimental study;functional outcomes;healing;human subject;improved;ligament injury;limb injury;mouse model;muscle strength;premature;prevent;progenitor;quadriceps muscle;receptor;reconstruction;response;satellite cell;skeletal muscle weakness;stem cells;therapeutic target

public_health_relevance:
Project NarrativeAnterior cruciate ligament reconstructions are a common procedure resulting in significant quadriceps musclestrength loss which is linked to poorer functional outcomes. Increases in myostatin following anterior cruciateligament injury can impede muscle recovery by promoting alterations in the cellular and morphologicalcomposition of the muscle. The goal of this proposal is to determine the time course of deleterious changeswithin the injured limb muscle and identify myostatin as integral in the etiology of protracted muscle weaknessin individuals following an ACL tear and reconstruction.


application_id: 10380355
project_number: 1UG1HD107649-01
project_title: Neonatal Opioid Withdrawal Syndrome (NOWS) in Kentucky: Improving Outcomes for Infants
administering_ic: NICHD
award_notice_date: 2021-09-17
opportunity_number: RFA-HD-21-031
application_type: 1
activity_code: UG1
ic: HD
serial_number: 107649
program_official: BREMER, ANDREW
project_start_date: 2021-09-17
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZHD1 DSR-T (50)]
contact_pi_person_id: 8880455
contact_pi: DEVLIN-PHINNEY, LORI ANN
other_pis: TELANG, SUCHETA
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_terms:
Accounting;Address;Adjuvant Analgesic;Affect;Caring;Child;Childhood;Clinic;Clinical;Clinical Nursing Research;Clinical Pharmacology;Clinical Practice Guideline;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Community Healthcare;Confounding Factors (Epidemiology);Country;Data Analyses;Development;Dose;Enrollment;Ensure;Evaluation;Family;Female of child bearing age;Fetal Development;Frequencies;Geography;Goals;Health;Health Personnel;Healthcare Systems;Hospitalization;Hospitals;Infant;Infant Care;Infrastructure;Kentucky;Leadership;Length of Stay;Life;Medical;Medical Care Team;Mothers;Multi-Institutional Clinical Trial;Multi-site clinical study;Neonatal;Neonatal Abstinence Syndrome;Neonatal Intensive Care Units;Newborn Infant;Opioid;Outcome;Patient Recruitments;Patients;Pharmacological Treatment;Pharmacology;Play;Population;Population Heterogeneity;Pregnancy;Prevalence;Psychotropic Drugs;Public Health;Randomized;Randomized Controlled Clinical Trials;Recording of previous events;Research;Research Design;Research Personnel;Role;Rural;Sample Size;Scientist;Site;Solid;Standardization;Stress;Time;Treatment Protocols;United States;United States National Institutes of Health;Universities;Variant;Visit;Withdrawal;Work;behavioral outcome;care outcomes;clinical care;clinical practice;clinical research site;clinically relevant;comparative effectiveness trial;compare effectiveness;control trial;data sharing;design;effective therapy;evidence base;experience;follow-up;high risk;improved;improved outcome;infant outcome;member;neonate;opioid epidemic;opioid misuse;opioid use;opioid use in pregnancy;optimal treatments;outreach;pediatric department;pediatrician;prenatal exposure;programs;prospective;recruit;rural area;rural underserved;standard of care;suburb;underserved area;urban underserved


application_id: 10380091
project_number: 5R01DE012505-25
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2022-04-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: DE
serial_number: 012505
program_official: MCNEALY, TAMARA L
project_start_date: 1998-09-01
project_end_date: 2023-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
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:
Polymicrobial infections are inherently more complex than mono-species infections and this complexity hasbeen a significant barrier to both a fuller appreciation of pathogenic mechanisms and to the development ofeffective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases andare among the most common infections of humans. Although certain organisms such as Porphyromonasgingivalis are considered key pathogens it is the polymicrobial community as a whole that initiates and drivesthe disease. While interspecies interactions within communities shape overall pathogenic potential study ofvirulence mechanisms has been largely restricted to individual organisms in monoculture. In this proposal wewill molecularly dissect the mechanistic basis of polymicrobial interactions in a model community of P. gingivaliswith the antecedent colonizer S. gordonii. Our preliminary data have established multimodal interactionsbetween P. gingivalis and S. gordonii. Detection of the streptococcal metabolite 4 aminobenzoate (pABA) by P.gingivalis or interactions between the Mfa1 fimbriae and the streptococcal SspA/B surface protein incitedisparate signaling events that are transduced through a tyrosine kinase/phosphatase signal integration hub. Invivo colonization is enhanced by pABA-dependent signaling but virulence in a murine bone loss model isdiminished. In contrast interspecies coadhesion increases pathogenic potential in this model. Our data furthersuggest that that the synergistic pathogenicity of P. gingivalis-S. gordonii communities arises from upregulationof genes controlled by the RprY response regulator including sufBCD which encode Fe-S clusters important inresistance to oxidative stress and oxidative killing in neutrophils.The Aims of the project are thus to 1) Characterize the P. gingivalis tyrosine kinase/phosphatase signaling axis.In vitro and in vivo mutational approaches will be adopted to decipher the operational mode of the P. gingivalistyrosine kinase Ptk1 and the molecular basis of control of signal transduction. 2) Characterize tyrosine cross-phosphorylation of the RprY response regulator in P. gingivalis. The functional consequences of tyrosinephosphorylation of RprY and the integration of this response regulator into the streptococcal induced signalinghub will be determined. 3) Determine the role of the Suf complex of P. gingivalis in polymicrobial synergy. Therole of the RprY-controlled suf genes in mediating resistance to neutrophil killing and determining polymicrobialsynergy in the murine alveolar bone loss model will be established.Successful completion of this project will provide fundamental novel information regarding the regulation ofsynergistic pathogenicity displayed by P. gingivalis and S. gordonii which could ultimately be translated intotherapeutic strategies designed to target the community-based pathogenesis that underlies periodontal disease.

project_terms:
Adhesions;Adopted;Alveolar Bone Loss;Animal Model;Bacteria;Bacterial Adhesins;Communication;Communities;Complex;Cues;Data;Detection;Development;Disease;Event;Exhibits;Fimbrial Adhesins;Genes;Genetic Transcription;Goals;Grant;Human;In Vitro;Individual;Infection;Inflammatory;Investigation;Measures;Mediating;Membrane Proteins;Metabolic;Modeling;Molecular;Mus;Mutation;Organism;Oxidative Stress;Pathogenesis;Pathogenicity;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteome;Regulation;Regulon;Resistance;Role;Shapes;Signal Transduction;Streptococcus;Streptococcus gordonii;System;Therapeutic;Translating;Tyrosine;Tyrosine Phosphorylation;Up-Regulation;Virulence;base;bone loss;design;in vivo;insight;microbial community;multimodality;neutrophil;novel;oral infection;oral plaque;pathogen;polymicrobial disease;prevent;response;small molecule;synergism;transcriptome

public_health_relevance:
Diseases caused by mixtures of bacteria are often more serious and harder to treat that those caused by a singleorganism. Periodontal (gum) diseases are caused by mixtures of organisms that communicate with each otherto become more aggressive. In this proposal we shall study the communication mechanisms that allow groupsof periodontal bacteria to increase in number and resist killing by the host.


application_id: 10379950
project_number: 5R01NS116990-03
project_title: Elucidating the role of placental growth factor in diffuse white matter disease
administering_ic: NINDS
award_notice_date: 2022-03-28
opportunity_number: RFA-NS-19-039
application_type: 5
activity_code: R01
ic: NS
serial_number: 116990
program_official: CORRIVEAU, RODERICK A
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: ZNS1-SRB-O(04)
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
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:
AbstractDiffuse white matter disease (DWD) is a common manifestation of small-vessel cerebrovascular pathology anda key subtype of vascular contributions to cognitive impairment and dementia (VCID). However themechanistic underpinnings of DWD remain incompletely characterized. Based on assessment of extensivedata in humans and animal models we have identified angiogenic mediators in particular placentalgrowth factor (PlGF) as being strongly associated with diffuse white matter disease. Much like the pathologic angiogenesis that occurs in retinopathies pathologic angiogenesis in the brainresults in blood-brain barrier leakage and counterintuitively tissue ischemia. We have exciting preliminarydata indicating robust relationships between PlGF and human DWD. We have also identified PlGF as beingincreased in association with blood-brain barrier leakage. We hypothesize that PlGF and relatedangiogenic mediators result in pathologic angiogenesis with leaky tortuous vessels and surroundinginflammation leading to diffuse white matter disease. Importantly these pathologic changes alsorepresent a potentially targetable mechanism to improve cognition in aging. To test these hypotheseswe propose focused studies in an extensively characterized human cohort and a mouse model of small vesseldisease. We answer the what where why questions surrounding PlGF. What cell type is responsible forPlGF; where is PlGF being expressed; why is PlGF upregulated and can it be modulated. To test thesehypotheses we propose focused studies in an extensively characterized human autopsy cohort and a mousemodel of small vessel disease:Specific Aim 1: Determine contributions to plasma PLGF and related angiogenic proteins using cell-specific exosomes and their association with periventricular and deep white matter pathologies.Specific Aim 2: Ascertain the regional expression of PLGF and related angiogenic proteins withinadjacent to and distant from periventricular and DWD and the association with aberrant angiogenesis.Specific Aim 3: Test the potential to manipulate PLGF related small vessel pathology in response tohyperhomocysteinemia (HHcy)-induced small vessel disease.

project_terms:
Acute;Address;Aging;Algorithms;Angiogenic Proteins;Animal Model;Antibodies;Astrocytes;Autopsy;Biochemical;Biological Markers;Blood - brain barrier anatomy;Blood Circulation;Blood Vessels;Brain;Caliber;Cells;Cerebrovascular system;Chronic;Clinical;Cognition;Data;Dementia;Diet;Diffuse;Distant;Endothelial Cells;Extravasation;Histologic;Histology;Human;Human Characteristics;Hyperhomocysteinemia;Impaired cognition;Individual;Inflammation;Ischemia;Kentucky;Knockout Mice;Length;Longitudinal cohort;Magnetic Resonance Imaging;Mediating;Mediator of activation protein;Microglia;Microvascular Dysfunction;Modeling;Molecular;Morphology;Mus;Neurons;Oligodendroglia;PGF gene;Pathologic;Pathologic Neovascularization;Pathology;Plasma;Proteins;Quantitative Reverse Transcriptase PCR;Research Personnel;Resources;Retinal Diseases;Rodent;Role;Sampling;Series;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Universities;Western Blotting;White Matter Disease;Wild Type Mouse;angiogenesis;base;cell type;cerebrovascular;cerebrovascular pathology;cohort;digital;digital pathology;exosome;gray matter;human model;human tissue;improved;innovation;interest;intravital imaging;mouse model;neurovascular;novel;response;targeted treatment;vascular cognitive impairment and dementia;white matter

public_health_relevance:
Proposal Narrative Vascular contributions to cognitive impairment and dementia (VCID) are known to be common causesof dementia yet remain poorly understood. Diffuse white matter disease (DWD) is a common manifestation ofsmall-vessel cerebrovascular pathology and a key subtype of VCID. In these series of studies we propose todetermine how placental growth factor (PlGF) causes DWD via formation of new immature and leaky bloodvessels in the brain.


application_id: 10379384
project_number: 5R01DK123712-03
administering_ic: NIDDK
award_notice_date: 2022-03-24
opportunity_number: PAR-19-294
application_type: 5
activity_code: R01
ic: DK
serial_number: 123712
program_official: NGUYEN, KHOA DINH DANG
project_start_date: 2020-06-20
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-F(50)R]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_title:
Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy

project_abstract:
PROJECT SUMMARYCurrently there is no curative medication available for ulcerative colitis (UC) a type of inflammatory boweldisease affecting the innermost mucosal layer of the rectum and the colon. Although mucosal healing is a majortreatment goal many patients fail to achieve mucosal healing with available UC drugs such as anti-inflammatoryimmuno-modulatory and anti-TNF agents. Since epithelial repair is a critical process towards mucosal healingan agent facilitating this process will provide a novel therapeutic strategy differentiating from existing clinical carefor UC. Our therapeutic lead is a variant of the oral cholera vaccine antigen cholera toxin B subunit (CTB) whichwas modified with a C-terminal extension including an endoplasmic reticulum retention motif (CTBSEKDEL). Wehave recently shown that oral administration of CTBSEKDEL but not native CTB facilitates colon epithelial repairand mucosal healing in a dextran sodium sulfate (DSS)-induced acute colitis mouse model. Moreover biweeklyoral administration of CTBSEKDEL significantly reduced tumorigenesis in the azoxymethane/DSS model of colitis-associated cancer. Based on these findings we hypothesize that CTBSEKDEL provides a prototype oral biologicfacilitating mucosal healing in UC. The goal of this translational R01 project is to optimize and validate thetherapeutic potential of CTBSEKDEL in preclinical UC models. Since CTBSEKDEL has already shown feasibility in anacute colitis model we will immediately proceed with further validation in chronic colitis models. In parallel inAim 1 we will create CTBSEKDEL variants with modifications in the C-terminal sequence (CTB(X)H/KDEL) to improvemolecular stability upon spray dry for enteric-coated formulations. We will produce these proteins using aNicotiana benthamiana plant transient overexpression system and screen them based on a series of biochemicaland biophysical assays as well as a mouse acute DSS colitis model. In Aim 2 we will validate the efficacy andsafety of CTBSEKDEL and a selected CTB(X)H/KDEL in two chronic colitis models based on repeated DSS exposurein C57bl/6 mice and piroxicam-exposed IL-10 knockout mice in comparison to an anti-TNF antibody.Therapeutic efficacy and safety will be determined by disease activity index histopathologyimmunohistochemistry and molecular biological analysis of inflammation crypt regeneration epithelial barrierrecovery and fibrosis. In Aim 3 we will employ a human colon explant model to further validate the mucosalhealing potential of CTBSEKDEL and CTB(X)H/KDEL. Colon biopsy and colectomy tissues will be obtained frompatients with different disease history and biological backgrounds. Efficacy will be evaluated based on woundhealing-related gene expression and immunohistochemistry for epithelial proliferation/regeneration markers. Celltype-specific responses will be investigated in colon lamina propria mononuclear cells and colonic organoids.Collectively the project will generate pivotal preclinical data supporting the development of a first-in-class oralbiologic candidate inducing colon epithelial repair for UC treatment towards a Phase I clinical trial.

project_terms:
Acute;Affect;Affinity;Anti-Inflammatory Agents;Antibodies;Azoxymethane;Binding;Biochemical;Biological;Biological Assay;Biological Response Modifier Therapy;Biophysics;Biopsy;C-terminal;C57BL/6 Mouse;Caco-2 Cells;Cells;Cholera Toxin Protomer B;Cholera Vaccine;Chronic;Clinical Trials;Colectomy;Colitis;Colon;Crohn's disease;Data;Detection;Development;Disease;Disease remission;Dose;Dysplasia;E-Cadherin;Endoplasmic Reticulum;Endoscopy;Enteral;Enzyme-Linked Immunosorbent Assay;Epithelial;Epithelial Cells;Excision;Exposure to;Fibrosis;Formulation;Frequencies;Ganglioside GM1;Gene Expression;Genes;Goals;High Pressure Liquid Chromatography;Histopathology;Human;Immune;Immune System Diseases;Immunohistochemistry;Immunologic Surveillance;Immunosuppressive Agents;Impairment;In Vitro;Individual;Inflammation;Inflammatory Bowel Diseases;Interleukin-10;Intestines;Knock-out;Knockout Mice;Lamina Propria;Lead;Malignant Neoplasms;Mass Spectrum Analysis;Modeling;Modification;Molecular;Monitor;Mononuclear;Mucous Membrane;Mus;Natural regeneration;Nicotiana;Oral;Oral Administration;Organoids;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Piroxicam;Plants;Postoperative Complications;Process;Proteins;Recombinants;Recording of previous events;Recovery;Rectum;Refractory;Relapse;Research;Safety;Scanning;Series;Sodium Dextran Sulfate;Specimen;System;TNF gene;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Tissues;Treatment Efficacy;Ulcerative Colitis;Vaccine Antigen;Validation;Variant;analog;base;cell type;clinical care;colitis associated cancer;comparative efficacy;curative treatments;dextran sulfate sodium induced colitis;efficacy study;efficacy validation;epithelial injury;epithelial repair;first-in-human;gut inflammation;healing;holotoxins;immunoregulation;improved;indexing;infection risk;inflammatory marker;mouse model;murine colitis;mutant;novel;novel therapeutic intervention;overexpression;pre-clinical;prototype;response;retrograde transport;safety study;screening;tissue culture;translational goal;tumorigenesis;wound healing

public_health_relevance:
NARRATIVEThe objective of the proposed research is to optimize and validate the therapeutic potential of a novel orallyactive recombinant mucosal healing protein for the treatment of ulcerative colitis. We will test the proteinsefficacy and safety in well-established mouse models of chronic colitis and in ex vivo human colon tissue culture.The proposed research will generate pivotal preclinical feasibility data towards a first-in-human clinical trial.


application_id: 10379089
project_number: 5R01DE028916-03
project_title: Biosynthesis structure and function of cell wall in Streptococcus mutans
administering_ic: NIDCR
award_notice_date: 2022-02-16
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 028916
program_official: MCNEALY, TAMARA L
project_start_date: 2020-04-08
project_end_date: 2025-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
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:
The cell wall of many species of Lactobacillales consists of multiple peptidoglycan layersdecorated with serotype-specific polysaccharides that are characterized by the presence ofrhamnose. Streptococcus mutans is a key etiological agent of human dental caries and hasalso been implicated in bacteremia and infective endocarditis. Based on the chemical structuresof serotype-specific carbohydrates S. mutans is classified into serotypes c e f and k withapproximately 70-80% of strains found in the oral cavity classified as serotype c. The serotypec-specific carbohydrate (SCC) of S. mutans is composed of a polyrhamnose backbone with -linked glucose side-chains. Although carbohydrate structures have been reported for allS. mutans serotypes our recent insights into the structure of these glycopolymers indicate thatthe functionally important modification glycerol phosphate was overlooked possibly due to itsloss during the purification steps. This new finding justifies a re-examination of the chemicalstructures of serotype-specific carbohydrates. One of the goals of the proposed study is todetermine the molecular structure of SCC isolated from S. mutans using mild non-destructivemethods. Moreover little is known about the multienzyme processes involved in attachment ofthe glucose side-chains to the polyrhamnose backbone of SCC and the function of the glycerolphosphate modification in S. mutans. Our preliminary findings revealed that the glycerolphosphate modification plays important roles in S. mutans morphology autolysis resistance toantimicrobials and biofilm formation. We propose to identify and functionally characterize theenzymes involved in glucose side-chain attachment to polyrhamnose and investigate themolecular mechanisms underlying the functions of glycerol phosphate modification inmorphology autolysis and biofilm formation. To accomplish our goals we will employstreptococcal genetics in vitro enzymology NMR spectroscopy of polysaccharides analyticalchemistry mass spectrometric analysis of phospholipids and various methods of microscopyincluding AFM-based nanomechanics. The cell wall biosynthetic machinery is an historicallypreferred target for the development of novel antimicrobials. In order to validate the pathway ofSCC decoration with glycerol phosphate as a potential drug target we will determine the role ofthis modification in a rat caries model. Successful outcomes will guide future studies of cell wallbiogenesis in other important Gram-positive bacteria and the development of novel strategies totreat S. mutans infections.

project_terms:
Adherence;Affect;Anabolism;Analytical Chemistry;Antibiotics;Antimicrobial Resistance;Autolysin;Autolysis;Bacteremia;Bacteria;Biochemical;Biogenesis;Biology;Carbohydrates;Cell Wall;Cell division;Cell physiology;Cell surface;Cellular Morphology;Charge;Chemical Structure;Collaborations;Defect;Dental caries;Development;Divalent Cations;Drug Design;Drug Targeting;Enzymatic Biochemistry;Enzymes;Etiology;Future;Genetic;Glucose;Glycerol;Goals;Gram-Positive Bacteria;Human;In Vitro;Infection;Infective endocarditis;Knowledge;Lead;Light;Link;Mass Spectrum Analysis;Mechanics;Methods;Microbial Biofilms;Microscopy;Modeling;Modification;Molecular;Molecular Genetics;Molecular Structure;Morphology;NMR Spectroscopy;Oral cavity;Outcome;Outcomes Research;Pathogenesis;Pathway interactions;Peptidoglycan;Permeability;Phenotype;Phospholipase A2;Phospholipids;Play;Polysaccharides;Predisposition;Preparation;Process;Property;Proteins;Publishing;Rattus;Regulation;Reporting;Research;Resistance;Rhamnose;Role;Septal Region;Serotyping;Side;Signal Transduction;Spatial Distribution;Streptococcus;Streptococcus mutans;Streptococcus pyogenes;Structure;Surface;Techniques;Testing;Transferase;Vertebral column;Virulence;Work;antimicrobial;antimicrobial drug;base;carbohydrate biosynthesis;carbohydrate structure;cell envelope;drug development;extracellular;improved;inorganic phosphate;insight;lipoteichoic acid;mutant;nanomechanics;neutrophil;novel;novel strategies;pathogen;quorum sensing;recruit;targeted treatment;therapeutic target;therapeutically effective

public_health_relevance:
The cell wall of Streptococcus mutans the primary etiological agent of human dentalcaries is composed of peptidoglycan decorated with serotype-specific glycopolymers. Theproposed research investigates the structure biosynthesis and function of the serotype c-specific glycopolymer. The outcomes of this research are expected to have a positive impact onthe development of highly targeted therapeutics to control S. mutans infections.


application_id: 10378844
project_number: 3F31DC017660-03S1
project_title: Connectivity of periperal taste neurons
administering_ic: NIDCD
award_notice_date: 2021-04-06
opportunity_number: PA-20-272
application_type: 3
activity_code: F31
ic: DC
serial_number: 017660
suffix: S1
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2018-09-01
project_end_date: 2021-11-30
contact_pi_person_id: 15039557
contact_pi: OHMAN, LISA 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:
Project Summary/AbstractWhile the function of taste neurons (that connect taste receptor cells to the brain) has been well-studied almost nothing is known about individual taste neuron morphology or peripheralconnectivity. Specifically it is unclear how many taste receptor cells provide input to a singleneuron or even if those receptor cells are all the same type. This lack of knowledge contributesto our relatively poor understanding of peripheral taste coding mechanisms. This project will usea combination of sparse cell genetic labeling and serial blockface scanning electron microscopy(SBF-SEM) to 1) examine the number of taste receptor cells likely contacted by chorda tympanineurons of differing complexity 2) determine if individual neurons contact receptor cells of thesame type or more than one type. I will accomplish these goals via three specific Aims. In Aim1 I will determine if there are any structural motifs present at synapses or non-synapticstructural connections using SBF-SEM which can also be identified in 3-D confocal images ofsparsely labeled nerve fibers and taste receptor cells. The goal is to permit better interpretationof the anatomical relationships between receptor cells and nerve fibers at the light level. In Aim2 I will reconstruct separate fibers entering the taste bud using SBF-SEM which will determinethe rules of connectivity of simply vs. sparsely branched fibers within the fungiform taste bud.These data will be compared with the contacts identified using image analysis software at thelight level between individual fibers entering the taste bud. In Aim 3 I will analyze themorphology of whole chorda tympani nerve fibers innervating anywhere from 1 to 7 taste budsand relate their branching complexity to the number and types of peripheral contacts made withtaste receptor cells. Together these experiments will test the hypothesis that heavily branchedneurons contact many more taste receptor cells of multiple types compared to simply branchedneurons which will contact only a few receptor cells of a single type. This project will be the firstto examine the peripheral connectivity of individual chorda tympani neurons and may reveal ananatomical substrate for the physiological finding that some neurons are narrowly tuned(respond to one taste stimulus) whereas others are broadly tuned (respond to multiple tastestimuli). Determining the peripheral connectivity of individual neurons will likely inform futureexperiments designed to look at taste coding. These baseline data for the normal connectivity ofthe peripheral taste system can be used to compare the potential disruption of connectivity thatmay result from disease states or manipulations of molecular factors regulating the formation ofthese connections.

project_terms:
3-Dimensional;Anatomy;Axon;Brain;Cells;Characteristics;Code;Complex;Computer software;Data;Defect;Disease;Electron Microscopy;Face;Fiber;Future;Ganglia;Genetic;Goals;Image Analysis;Immunohistochemistry;Individual;Knowledge;Label;Laboratories;Length;Light;Location;Maps;Mentors;Methodology;Molecular;Morphology;Mus;Nerve Fibers;Neurons;Peripheral;Peripheral Nerves;Pharmaceutical Preparations;Physiological;Quality of life;Receptor Cell;Role;Scanning Electron Microscopy;Signal Transduction;Structure;Structure of geniculate ganglion;Synapses;Taste Buds;Taste Disorders;Taste Perception;Testing;Variant;Work;base;cell type;chemotherapy;chorda tympani;confocal imaging;design;experimental study;fiber cell;light microscopy;novel;taste stimuli;taste system

public_health_relevance:
Project NarrativeTaste disorders impact quality of life yet little is known about the underlying defects andmechanisms that result in these perceptual deficits. Diseases and drugs (i.e. chemotherapies)that disrupt taste function could have their effects by disturbing taste receptor cell neuronperipheral connectivity. This project will develop a baseline connectivity map of peripheral nervefibers with taste receptor cells; both the map and novel methodological approach can be used todissect the role of connectivity in taste disorders.


application_id: 10378081
project_number: 5R01DC017770-04
project_title: Communities Helping the Hearing of Infants by Reaching Parents: The CHHIRP Navigator Trial
administering_ic: NIDCD
award_notice_date: 2022-03-31
opportunity_number: PA-18-385
application_type: 5
activity_code: R01
ic: DC
serial_number: 017770
program_official: KING, KELLY ANNE
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYAs the most common neonatal sensory disorder in the United States infant hearing loss has an incidence of1.7 per 1000 births. The consequences of delayed diagnosis and failure to obtain timely intervention includesignificant communication impairment and negative socioeconomic effects. The overall lifetime medicaleducational and occupational costs due to deafness is estimated to be over $2.1 billion. Early detection ofhearing may prevent language development and learning disorders. National standards dictate that all infantsshould be screened by 1 month of age diagnosed by 3 months of age and initiate treatment by 6 months ofage (1-3-6 rule) and no more than 10% of infants should be non-adherent to diagnosis within 3 months afterbirth. In 2015 59.4% of U.S. infants failed to obtain a diagnosis within 3 months after abnormal screening.There is a need for the development and implementation of interventions that promote adherence to timelydiagnosis and treatment standards. Early infant hearing detection and intervention (EHDI) programs arecoordinated on a state level and the diagnostic process is complex and difficult for parents to navigate.Families of children with hearing loss report that they lack confidence and support in obtaining care for theirchild. Patient navigator (PN) programs have improved adherence to recommended diagnostic testing in cancercare after the detection of a screening abnormality resulting in substantial healthcare system cost savings.PNs are trained individuals who mitigate barriers to promote healthcare adherence by educating patients andimproving self-efficacy. We have recently demonstrated the PN efficacy to decrease non-adherence with infanthearing diagnostic care; however PN has yet to be tested in diverse communities or implemented into EHDIprograms and there is a gap in this field regarding effectiveness and implementation research on interventionsto reduce non-adherence. The proposed research is a community-engaged type 1 hybrid effectiveness-implementation trial of a PN intervention aimed at decreasing infant hearing diagnosis non-adherence afterfailed newborn hearing screening delivered in state-funded EHDI clinics. Guided by our community advisoryboard and partners we aim to 1) to test the effectiveness of PN to decrease non-adherence to receipt of infanthearing diagnosis within 3 months after birth using a stepped-wedge trial design 2) investigate implementationoutcomes and factors influencing implementation and 3) determine the cost-effectiveness of PN from theperspective of third party payers. This study is significant because it aims to reduce non-adherence to timelyinfant diagnostic hearing testing to prevent life-long negative consequences. This research is innovative intesting an intervention not previously assessed in hearing healthcare within a state-funded EHDI program andin integrating implementation research and cost-effectiveness methods with our effectiveness aim. Our resultswill impact the field by partnering with communities to inform the scale-up of this and other innovative patientsupportive interventions to create efficient and effective EHDI programs and maximize public health impact.

project_terms:
Address;Adherence;Adoption;Advisory Committees;Age-Months;Behavior Disorders;Birth;Caring;Characteristics;Child;Clinic;Collaborations;Communication impairment;Communities;Community Health;Complex;Congenital Disorders;Consolidated Framework for Implementation Research;Cost Savings;Cost effectiveness research;Data;Detection;Development;Diagnosis;Diagnostic;Diagnostic tests;Early Diagnosis;Early Intervention;Education;Effectiveness;Emotional;Employment;Environment;Failure;Family;Feedback;Funding;Health Services Accessibility;Healthcare;Healthcare Systems;Hearing;Hearing Tests;Impairment;Improve Access;Incidence;Individual;Infant;Intervention;Joints;Kentucky;Language Development;Learning;Learning Disorders;Life;Measures;Medical;Methods;Modality;Neonatal Screening;Newborn Infant;Occupational;Outpatients;Parents;Patient Care;Patients;Penetration;Preventive service;Process;Public Health;Randomized Controlled Trials;Recording of previous events;Reporting;Research;Research Methodology;Research Personnel;Self Efficacy;Sensory;Social Development;Speech;System;Testing;Third-Party Payer;Time;Training;Translational Research;United States;cancer care;care systems;childhood hearing loss;cognitive development;community clinic;community intervention;community setting;cost;cost effective;cost effectiveness;cost estimate;deafness;disparity reduction;early childhood;economic cost;effectiveness implementation design;effectiveness implementation study;effectiveness implementation trial;effectiveness research;effectiveness testing;effectiveness trial;falls;hearing impairment;hearing loss treatment;hearing screening;hybrid type 1 trial;implementation cost;implementation determinants;implementation evaluation;implementation intervention;implementation outcomes;implementation research;implementation strategy;improved;innovation;intervention program;navigator intervention;neonatal sensory disorder;peer support;prevent;programs;randomized trial;recruit;research to practice;scale up;screening;social;socioeconomics;standard care;standard of care;trial design

public_health_relevance:
PROJECT NARRATIVEHearing loss is the most common sensory congenital disorder and this condition is diagnosable and treatable.Infants who are born with hearing loss must undergo several hearing tests to diagnose the condition and manyfamilies are delayed in receiving this testing or never obtain the necessary testing and treatment. This studyevaluates (1) whether patient navigation in state-funded clinics throughout Kentucky increases parents' follow-through with testing (2) factors that promote or impede its delivery and (3) cost-effectiveness of this approach. !


application_id: 10377959
project_number: 5R35HL150818-03
project_title: Platelet Exocytosis and Endocytosis in Thrombosis and Immunity
administering_ic: NHLBI
award_notice_date: 2022-04-06
opportunity_number: RFA-HL-20-011
application_type: 5
activity_code: R35
ic: HL
serial_number: 150818
program_official: KINDZELSKI, ANDREI L
project_start_date: 2020-04-01
project_end_date: 2027-03-31
study_section: ZHL1-CSR-R(O1)
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;Area;Blood Platelets;Blood Vessels;Cell physiology;Cellular biology;Cessation of life;Chronic;Coagulation Process;Cytoplasmic Granules;Data;Detection;Endocytosis;Exocytosis;Growth;HIV-1;Hemostatic function;Immune response;Immune system;Immunity;Innate Immune Response;Knowledge;Link;Membrane;Modeling;Molecular;Mouse Strains;Natural Immunity;Pathway interactions;Physiological;Process;Publications;Reagent;Research;Risk;Role;Signal Transduction;Sorting - Cell Movement;Technology;Therapeutic;Thrombosis;Thrombus;Transgenic Mice;Viremia;Virus;Work;holistic approach;human disease;innovation;insight;pathogen;programs;tool;trafficking


application_id: 10377950
project_number: 5K01HS025494-05
administering_ic: AHRQ
award_notice_date: 2022-04-13
opportunity_number: PA-16-223
application_type: 5
activity_code: K01
ic: HS
serial_number: 025494
program_official: WILLIS, TAMARA
project_start_date: 2018-05-01
project_end_date: 2023-04-30
study_section: Healthcare Effectiveness and Outcomes Research[HEOR]
contact_pi_person_id: 12011666
contact_pi: HOGG, RACHEL A.
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-05-01
project_title:
Examining the Integration of Hospitals Public Health and Social Services to Target the Social Determinants of Health Using Patient-Centered and Comparative Effectiveness Research Methods

project_abstract:
Abstract This is an application for a K01 award for Dr. Rachel Hogg an Assistant Professor at the University OfKentucky College Of Health Sciences. Dr. Hogg is establishing herself as a young investigator who usesPatient Centered Outcomes Research (PCOR) and Comparative Effectiveness Research (CER) methods toexamine the effect models of clinical and community collaboration around the health-related socialdeterminants of health have on improved health care quality and reduced hospitalizations and readmissions.This K01 award will provide Dr. Hogg with the support necessary to achieve the following goals: (1) developexpert knowledge in the types of models being used to integrate clinical and community organizations toaddress not only health care but also the health-related social determinants of health (2) establish herself asan independent researcher with mastery of using advanced Comparative Effectiveness Research methods todetermine effect heterogeneity in how clinical-community models address diverse population needs and (3) Tosecure R01 level funding using the Public Health and Social Service Sensitive Admission Measures as anoutcome. Dr. Hogg has assembled a mentoring team comprised of primary mentor Dr. Glen Mays and Co-Mentors Drs. Patrick Kitzman Danielle Varda and Mark Williams. Addressing the health-related social determinants of health has emerged as a leading strategy tocombat the increasing economic and financial burden of preventable hospitalizations and readmissions. Dr.Hoggs study will use a mixed methods approach to examine in greater detail the models being used acrossthe US to integrate public health and social services with clinical care provided in hospitals as a mechanism totarget the social behavioral and environmental factors that contribute to hospitalizations and readmissions(Aims 1 and 2). Dr. Hoggs project will also engage patients caregivers and community stakeholders todetermine the extent to which patient caregiver and provider experiences with health care are influenced bythe surrounding delivery systems for public health and social services (Aim 3). The findings will cumulate in atemplate model that will be proposed for pilot testing as part of a R01 application to be submitted before theend of the K award.

public_health_relevance:
Project NarrativeThis study has the potential to reveal how health care system organization and delivery policies can be used toimprove health and lower health care costs across the US by examining the benefits of integration betweenhospitals and other community organizations to address patient needs. Results have the potential of leading tobeneficial changes in policy at the local state and federal level that impact individual health. The value of theknowledge to be gained from this research is considerable given its potential health and economic implicationson a broad population-wide basis.


application_id: 10377899
project_number: 5P20GM113226-07
project_title: Project 4 - Smita Ghare PhD
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6814
contact_pi_person_id: 11468892
contact_pi: GHARE, SMITA S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Attenuated;Binding;Biological Models;Biopsy;Butyrates;CXC Chemokines;CXCL2 gene;Centers of Research Excellence;Chronic;Clinical;Cytokine Activation;DNA Binding;Data;Deacetylation;Development;Doctor of Philosophy;Epigenetic Process;Ethanol;FDA approved;Fatty acid glycerol esters;Genes;Genetic Transcription;Goals;HDAC3 gene;Hepatic;Hepatocyte;Histone Acetylation;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;IL8 gene;Inflammation;Inflammatory;Injury;Intervention;Knockout Mice;Ligands;Liver diseases;Macrophage Activation;Mediating;Modification;Molecular;Morbidity - disease rate;Mus;Myeloid Cells;Neutrophil Infiltration;Organ;Oxidative Stress;Pathogenicity;Pathology;Patients;Plasma;Play;Post-Translational Protein Processing;Preventive treatment;Prodrugs;Regulation;Role;Serum;Severity of illness;Stimulus;Testing;Therapeutic;Therapeutic Intervention;Toxicology;Transactivation;Transcriptional Activation;Up-Regulation;Work;alcohol effect;alcohol exposure;base;beta-Chemokines;chemokine;chromatin remodeling;cohort;cytokine;dietary;histone acetyltransferase;histone modification;in vitro Model;in vivo;insight;liver inflammation;liver injury;mortality;non-histone protein;nucleocytoplasmic transport;nutrition;p65;prevent;promoter;recruit;response;therapeutic development;transcription factor;translational study;tributyrin


application_id: 10377898
project_number: 5P20GM113226-07
project_title: Project 3 - Ming Song
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6813
contact_pi_person_id: 10972280
contact_pi: SONG, MING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Title: Metabolic effect of fructose in intestine induces gut microbiota dysbiosisAbstract. Emerging evidence has demonstrated that gut microbiota dysbiosis plays a causative role in thedevelopment of obesity type 2 diabetes and NAFLD. Gut physiologic hypoxia is key to maintaining a balancedgut microbiota and gut barrier function. Disturbance of gut physiologic hypoxia namely oxygenation results ingut microbiota dysbiosis. Our preliminary studies have shown that chronic feeding with either fructose or glucoseinduces gut microbiota dysbiosis in a similar manner in rats and mice. Moreover both daily gavage and chronicfeeding with fructose or glucose results in intestinal oxygenation as shown by HIF-1 alpha reporter (ODD-luc)mice and this effect is more robust with glucose. Given that fructose is preferentially metabolized under hypoxiaand glucose can be rapidly converted to fructose via the polyol pathway the proposed studies will test thehypothesis that fructose metabolism in the intestine results in metabolic reprogramming which switches the hostmetabolic pathway from mitochondrial -oxidation to glycolysis and consumes less oxygen. This in turn leadsto intestinal oxygenation subsequent inhibiting the growth of obligate anaerobic bacteria and facilitating theexpansion of pathogenic bacteria. The hypothesis will be tested in three specific aims: Aim 1. Determinewhether fructose induces metabolic reprogramming in intestinal epithelial cells and determine if this results ingut microbiota dysbiosis. We will test the hypothesis that fructose metabolism in the intestine results in metabolicreprogramming and leads to intestinal oxygenation which in turn results in gut microbiota dysbiosis. Aim 2.Determine whether modulation of glycolytic activity in intestinal epithelial cells alters gut microbiota composition.We hypothesize that genetic modulation of glycolytic activity via 6-phosphofructo-2-kinase/fructose-26-bisphosphatase (PFK2) in intestinal epithelial cells results in altered oxygen consumption rate which in turn leadsto the alteration of gut microbiota. Aim 3. Determine whether the metabolic effect of fructose in intestinecontributes to the development of NAFLD. We will test the hypothesis that the metabolic effects of fructose inintestine on the development of NAFLD is mediated by gut microbiota dysbiosis.

project_terms:
6-Phosphofructo-2-kinase;Acute;Anaerobic Bacteria;Antibiotics;Butyrates;Centers of Research Excellence;Chronic;Clinical;Consumption;Development;Economic Burden;Energy Supply;Epithelial Cells;FDA approved;Feedback;Female;Fructose;Fructose-26-bisphosphatase;Gastrointestinal tract structure;Genetic;Glucose;Glycolysis;Growth;HIF1A gene;Health;Hyperglycemia;Hypoxia;Insulin Resistance;Intestines;Ketohexokinase;Liver;Liver diseases;Luciferases;Maintenance;Malignant Neoplasms;Mediating;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;Mitochondria;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Organ;Oxygen;Oxygen Consumption;Pathogenesis;Pathway interactions;Perfusion;Pharmacotherapy;Physiological;Play;Prevalence;Proteobacteria;Rattus;Reporter;Risk Factors;Rodent;Role;Site;Solid;Stress;Testing;Tight Junctions;Toxicology;United States;Upper digestive tract structure;cardiovascular disorder risk;cross-species transmission;dietary;drinking water;dysbiosis;fecal transplantation;feeding;gut microbiome;gut microbiota;intestinal epithelium;male;mortality;non-alcoholic fatty liver disease;obesity development;oxidation;pathogenic bacteria;polyol;preservation


application_id: 10377897
project_number: 5P20GM113226-07
project_title: Project 2 - Joshua Hood PhD
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6812
contact_pi_person_id: 7170643
contact_pi: HOOD, JOSHUA L.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-Dimensional;Adjuvant;Antigen Presentation;Attenuated;Autologous;BAY 54-9085;Bee Venoms;Bees;Biological Assay;Blood;Cancer Etiology;Cancer Vaccines;Cell Line;Cells;Centers of Research Excellence;Cirrhosis;Coupled;Development;Doctor of Philosophy;Effector Cell;Enzyme-Linked Immunosorbent Assay;FDA approved;Growth;Harvest;HepG2;Hepatitis;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune response;Immunity;Immunocompetent;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;In Vitro;Inflammatory;Injections;Investigation;Kupffer Cells;Liver;Liver Fibrosis;Liver diseases;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;MicroRNAs;Modeling;Modernization;Mononuclear;Mus;Myeloid-derived suppressor cells;Neoplasm Metastasis;Nivolumab;Participant;Pathogenicity;Pathologic;Patients;Peptides;Phagocytes;Phenotype;Plasma;Population;Primary carcinoma of the liver cells;Process;Proteins;Quantitative Reverse Transcriptase PCR;Reporting;Research;Role;Source;Sting Injury;System;Testing;Therapeutic;Time;Toxic effect;Toxicology;Treatment Efficacy;Tyrosine Kinase Inhibitor;Vaccine Adjuvant;arginase;cancer therapy;checkpoint therapy;exosome;extracellular vesicles;hepatocellular carcinoma cell line;in vivo;light scattering;macrophage;melanoma;mortality;nanocarrier;nanomaterials;nanomedicine;nanovesicle;neoplastic cell;non-alcoholic;nonalcoholic steatohepatitis;polarized cell;problem drinker;recruit;response;tumor;tumor growth;zeta potential


application_id: 10377896
project_number: 5P20GM113226-07
project_title: Project 1 - Yan Li PhD
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6811
contact_pi_person_id: 9527186
contact_pi: LI, YAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Non-alcoholic steatohepatitis (NASH) a potential precursor of hepatocellular carcinoma (HCC) currently has noFDA-approved treatment. Recent studies of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggestthat endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic condi-tions including NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studiedin clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities pro-gression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithe-lial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosis-cirrhosis-HCC sequence in patients. Recent studies indicated that FGF21 down-regulates the Th17-IL-17 axissuppresses NF-B but activates p53 pathways which are the critical anti-cancer mechanism(s). However thereis no evidence demonstrating the specific anticancer effect of FGF21 on the NASH associated HCC. It is alsounknown whether FGF21 could negatively affect the Th17-IL-17 axis and the carcinogenetic signaling to abolishthe carcinogenetic transformation from NASH to HCC. Our central hypothesis is that FGF21 and FGF15/19prevent NASH-HCC through in turn controlling lipolysis clearing excessive FFAs and inhibiting the IL-17A signaling mediated inflammation and carcinogenesis. The hypothesis will be tested in the followingSpecific Aims. Aim 1: Investigate lipid metabolic disorder and IL-17A mediated inflammation during NASH-HCCtransition. Establishing NASH-HCC mice to 1) determine FFA pools (plasma adipose liver and feces) and FAmetabolites by metabolomics; 2) determine metabolic enzymes and components of IL-17A signaling by targetingproteomics. Aim 2: Evaluate the efficacy of FGF21 (LY2405319) and FGF19 (NGM282) against NASH-HCCtransition. Administrating LY2405319/NGM282 in NASH-HCC mice to 1) evaluate NASH score HCC incidencehepatic injury and HCC lesion; 3) determine IL-17A-mediated inflammation/carcinogenesis and tumor-initiatingcells. Aim 3: Explore the preventive mechanism(s) of FGF21/FGF15/19 against NASH-HCC transition. Repro-ducing NASH-HCC in FGF21 knockout (KO) FGF15KO and IL-17A mutation mice to investigate the feedbackloop of FGF21/FGF15/19-IL-17A on molecular target(s) linking to carcinogenetic pathways. The importance ofthis proposal is: 1) to explore pharmacological use of FGF21/FGF15/19 against the NASH-HCC transition; and2) to reveal therapeutic targets and mechanism(s) especially the IL-17 signaling linked carcinogenetic pathwaysduring NASH-HCC transition.

project_terms:
Adipose tissue;Agonist;Attention;Biological Process;Cell Adhesion Molecules;Cells;Centers of Research Excellence;Chimeric Proteins;Cirrhosis;Development;Disease Progression;Doctor of Philosophy;Early treatment;Endocrine;Enzymes;FDA approved;FGF19 gene;FGF21 gene;Fatty Liver;Feces;Feedback;Fibroblast Growth Factor;Goals;Hepatocyte;Hormones;Human;Incidence;Infiltration;Inflammation;Inflammatory;Insulin Resistance;Interleukin-17;Interleukins;Investigation;Knock-out;Knowledge;Lesion;Link;Lipids;Lipolysis;Liver;Malignant neoplasm of liver;Mediating;Metabolic;Metabolic Diseases;Metabolism;Molecular Target;Mus;Mutation;Neurons;Nonesterified Fatty Acids;Obesity;Orthologous Gene;Pathway interactions;Patients;Pharmacology;Phase;Phase II Clinical Trials;Plasma;Population;Preventive;Primary carcinoma of the liver cells;Production;Proteomics;Publishing;Research;Risk Factors;Signal Transduction;TLR4 gene;TP53 gene;Testing;Toxicology;Variant;advanced disease;anti-cancer;blood glucose regulation;cancer stem cell;carcinogenesis;clinical application;efficacy evaluation;fatty acid metabolism;fibroblast growth factor receptor 4;high risk;ileum;insight;lipid metabolism;liver cancer model;liver injury;markov model;metabolomics;negative affect;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;polypeptide;prevent;therapeutic target;therapeutically effective;tumor;uptake


application_id: 10377895
project_number: 5P20GM113226-07
project_title: Biorepository and Animal Core
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6810
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Alcoholic Liver Diseases;Animal Experimentation;Animal Model;Animals;Autopsy;Biological;Biology;Centers of Research Excellence;Characteristics;Data;Development;Ensure;Equipment and supply inventories;Evaluation;Experimental Animal Model;Experimental Models;Fees;Fostering;Future;Germ-Free;Gnotobiotic;Goals;Hepatocyte;Histology;Human;Human Resources;IACUC;In Vitro;Individual;Infrastructure;Institution;Institutional Review Boards;Liver;Liver diseases;Maintenance;Malignant neoplasm of liver;Measures;Mission;Modeling;Mus;Occupational;Operative Surgical Procedures;Phenotype;Procedures;Protocols documentation;Research;Research Personnel;Resources;Sampling;Service delivery model;Services;Specimen;Standardization;Structure;System;Techniques;Tissue Banks;Toxicology;Training;Training and Education;Translational Research;biobank;biological specimen archives;career development;design;experimental study;flexibility;gut microbiome;human subject;interest;investigator training;meetings;member;metabolic phenotype;sample collection;success;sustainable resource


application_id: 10377894
project_number: 5P20GM113226-07
project_title: Bioanalytical Core
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6809
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Area;Attention;Award;Biochemical;Biological;Biological Assay;Cells;Centers of Research Excellence;Clinical Research;Communities;Computer software;Continuing Education;Core Facility;Core Grant;Data Analyses;Development;Drug Interactions;Ensure;Environment;Equipment;Evaluation;Extramural Activities;Faculty;Fee-for-Service Plans;Felis catus;Fostering;Funding;Future;Genus Hippocampus;Goals;Grant;HIV;Immunologics;Individual;Infrastructure;Institution;Instruction;Investigation;Journals;Laboratories;Liver;Liver diseases;Maintenance;Methodology;Mission;Molecular;Molecular Target;Pathogenicity;Performance;Phase;Play;Protocols documentation;Reagent;Research;Research Personnel;Resources;Role;Services;Signal Pathway;Specimen;System;Techniques;Technology;Time;Tissues;Toxicology;Training and Education;Translational Research;United States National Institutes of Health;Universities;Whole Organism;career development;cost;cytokine;experience;experimental study;innovation;instrument;instrumentation;investigator training;liver injury;meetings;member;microscopic imaging;multidisciplinary;novel;programs;protocol development;research facility;square foot;success;toxicant


application_id: 10377893
project_number: 5P20GM113226-07
project_title: Omics Core
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6808
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Applications Grants;Attention;Award;Bioinformatics;Biological;Biological Assay;Centers of Research Excellence;Chemicals;Clinical Research;Communities;Complex Mixtures;Continuing Education;Data;Data Analyses;Data Collection;Data Reporting;Development;Disease;Drug Interactions;Ensure;Environment;Equipment;Fee-for-Service Plans;Felis catus;Funding;Future;Goals;Health Sciences;Human Resources;Individual;Infrastructure;Institution;Intervention Studies;Leadership;Liver;Liver Dysfunction;Liver diseases;Malignant neoplasm of liver;Mass Spectrum Analysis;Methods;Modality;Modeling;Modification;Molecular Evolution;Peptides;Performance;Phase;Preparation;Procedures;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;RNA;Reagent;Research;Research Activity;Research Personnel;Research Support;Resources;S10 grant;Sampling;Science;Services;Standardization;Statistical Data Interpretation;Techniques;Technology;Toxicology;Training;Training and Education;Translational Research;United States National Institutes of Health;Universities;base;career;career development;clinical infrastructure;data sharing;design;epitranscriptomics;experimental study;fatty liver disease;innovation;instrument;liver development;liver injury;meetings;member;metabolomics;method development;molecular marker;non-alcoholic;novel;nutrition;operation;problem drinker;programs;sample collection;small molecule;success;theories;tool;toxicant


application_id: 10377891
project_number: 5P20GM113226-07
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6807
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Hepatobiology and Toxicology COBRE is a multidisciplinary group ofinvestigators focusing on the liver and liver injury gut:liver interactions and liver:environment/toxicant/druginteractions alcoholic and non-alcoholic liver injury infectious liver diseases liver cancer and new livertherapies. The purpose of the administrative core is to provide administrative fiscal and scientific oversight forthis Phase II COBRE. This includes the overall career development and research goals of the Phase IICOBRE (including formative and summative evaluation and specific milestones); the career development plansfor junior faculty (including plans for transitioning to independence); plans for replacing key personnel (e.g.Project PIs Core leaders overall PI pilot project PIs); oversight of the pilot projects; oversight of thebiostatistical support services; and disseminating information to the lay and scientific communities. Liver diseases are some of the most common rapidly increasing and poorly recognized healthproblems afflicting Americans. For example Non-alcoholic fatty liver disease/non-alcoholic steatohepatitisis the most common cause of abnormal liver enzymes in the US affecting about 25% of adults and about 10%of children. Alcoholic Liver Disease is an increasing problem among those who drink. Importantly there is noFDA-approved therapy for either NASH or ALD. Toxicant-Induced Liver Injury is an increasingly recognizedindustrial/environmental problem. Viral Liver Diseases (Hepatitis A B and C) remain major health problemsrelated to drug abuse and homelessness. Hepatocellular carcinoma and Hepatitis C are major causes for liverrelated morbidity and liver transplantation in the US. Drug-Induced Liver Injury is the major reason new drugsdo not come to market and the major cause of fulminant liver failure in the US. Personalized Medicine isincreasingly recognized as an important aspect of drug therapy; and most drugs are metabolized in the liver. Building on the success of the Phase I COBRE Administrative Core the specific aims of this Phase IICOBRE Administrative Core are: 1. continue to provide overall administrative fiscal and scientific oversight 2. enhance and grow the career development enterprise for project PIs 3. enhance and grow the career development/mentor development enterprise for the mentors 4. enhance and grow the research goals of the COBRE 5. continue to provide a process for replacing key personnel 6. continue to provide and enhance a summative and formative evaluation process for the COBRE including specific milestones 7. continue to provide a robust pilot project program to grow the overall research goals of the COBRE 8. disseminate pertinent information to the scientific and lay community

project_terms:
Acute Liver Failure;Adult;Affect;Alcoholic Liver Diseases;Alcohols;American;Area;Bioinformatics;Biometry;Budgets;Cancer Grant Supplements (P30);Centers of Research Excellence;Child;Clinical Trials;Communities;Community Outreach;Conflict (Psychology);Country;Development;Development Plans;Diabetes Mellitus;Drug Interactions;Drug abuse;Ensure;Environment;Environmental Health;Enzymes;Evaluation;FDA approved;Faculty;Funding;Goals;Grant;Health;Hepatitis A;Hepatitis C;Homelessness;Human Resources;Individual;Industrialization;Italy;Kentucky;Letters;Liver;Liver diseases;Malignant neoplasm of liver;Mentors;Morbidity - disease rate;National Institute of Environmental Health Sciences;National Institute on Alcohol Abuse and Alcoholism;Obesity;Overweight;Pharmaceutical Preparations;Pharmacology and Toxicology;Pharmacotherapy;Phase;Physicians;Pilot Projects;Population;Primary carcinoma of the liver cells;Process;Public Health;Research;Research Infrastructure;Research Personnel;Rural;Scientist;Services;Structure;Superfund;Teacher Professional Development;Text;Toxicology;United States National Institutes of Health;Universities;Viral hepatitis;career development;drug induced liver injury;faculty mentor;faculty research;formative assessment;improved;liver injury;liver metabolism;liver transplantation;microbiome;microbiome research;multidisciplinary;non-alcoholic;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel therapeutics;opioid abuse;personalized medicine;problem drinker;programs;ranpirnase;recruit;research and development;senior faculty;success;toxicant;tumor immunology;viral liver disease


application_id: 10377890
project_number: 5P20GM113226-07
project_title: Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2022-04-11
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3(C2)
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:
Acute Liver Failure;Address;Adult;Affect;Alcoholic Liver Diseases;American;Area;Basic Science;Biomedical Research;Centers of Research Excellence;Child;Cirrhosis;Collaborations;Communication;Communities;Complex;Core Facility;Data Analyses;Development;Diabetes Mellitus;Discipline;Drug Interactions;Drug abuse;Ensure;Environment;Enzymes;FDA approved;Fostering;Funding;Goals;Grant;Health;Hepatitis A;Hepatitis B;Hepatitis C;Home;Homelessness;Industrialization;Industry;Injury;International;Kentucky;Laboratories;Link;Liver;Liver Failure;Liver diseases;Mentors;Metabolic syndrome;Metabolism;Molecular Target;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Obesity;Organ;Overweight;Pharmaceutical Preparations;Pharmacotherapy;Phase;Phase I Clinical Trials;Prevention;Primary carcinoma of the liver cells;Process;Program Sustainability;Publications;Research;Research Infrastructure;Research Personnel;Research Project Grants;Resources;Scientist;Structure;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translational Research;United States National Institutes of Health;Universities;University resources;biobank;career development;clinical practice;drug induced liver injury;education research;experience;liver injury;liver transplantation;member;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;nutrition;personalized medicine;prevent;programs;recruit;success;toxicant;viral liver disease


application_id: 10377585
project_number: 5T35DK072923-17
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2022-05-27
opportunity_number: PA-20-162
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: CASTLE, ARTHUR
project_start_date: 2006-05-01
project_end_date: 2026-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Authorship;Cardiovascular system;Clinical;Complications of Diabetes Mellitus;Conflict of Interest;Data;Diabetes Mellitus;Diabetic Nephropathy;Educational Curriculum;Endocrine;Endocrinology;Environment;Funding;Goals;IACUC;Institutional Review Boards;International;Journals;Laboratories;Malignant Neoplasms;Medical Students;Mentors;Mentorship;Metabolism;Methods;NCI Scholars Program;National Institute of Diabetes and Digestive and Kidney Diseases;Obesity;Outcome;Peer Review;Persons;Physicians;Pituitary Gland;Plagiarism;Publications;Publishing;Regulation;Reproducibility;Research;Research Personnel;Research Project Grants;Research Training;Scientist;Structure;Student recruitment;Students;Training;Training Programs;Training Support;Translational Research;Universities;Vertebrates;Work;career;disadvantaged background;experience;faculty mentor;faculty research;hormone regulation;human subject;medical schools;meetings;non-alcoholic fatty liver disease;peer coaching;peptide hormone;posters;programs;responsible research conduct;skills;stem cell biology;summer research;summer student;underrepresented minority student


application_id: 10377508
project_number: 5R01NS121193-02
project_title: Functional Diversity of Reactive Astrocytes in Spinal Cord Repair
administering_ic: NINDS
award_notice_date: 2022-03-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 121193
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9380335
contact_pi: CHEN, MEIFAN
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Area;Astrocytes;Attenuated;Axon;CSF1 gene;Cells;Chest;Chronic;Cicatrix;Corticospinal Tracts;Data;Diffuse;Distal;Functional disorder;Genetic;Glial Fibrillary Acidic Protein;Goals;Hindlimb;Human;Injury;Knock-out;Knowledge;Lateral;Lesion;Leucine Zippers;Location;Macrophage Colony-Stimulating Factor;Maintenance;Mediating;Microglia;Microinjections;Modeling;Molecular;Motor;Mus;Outcome;Paralysed;Pathologic;Pathway interactions;Phenotype;Phosphotransferases;Primary Lesion;Recovery;Regulation;Research;Role;Sensory;Site;Spinal;Spinal Cord;Spinal cord injury;Tamoxifen;Testing;Therapeutic;Tissues;Translating;Traumatic CNS injury;United States;Work;astrogliosis;axon growth;axonal degeneration;axonal sprouting;base;cellular targeting;central nervous system injury;disability;genetic manipulation;in vivo;injury and repair;injury recovery;insight;macrophage;monocyte;neural repair;novel;overexpression;promoter;relating to nervous system;repair strategy;repaired;response to injury;restoration;spinal cord repair;targeted treatment;tool;translational approach


application_id: 10377459
project_number: 5R01AI152258-04
administering_ic: NIAID
award_notice_date: 2022-03-11
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 152258
program_official: MENDEZ, SUSANA
project_start_date: 2020-04-16
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1-CVRS-R(03)]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_terms:
Acute Disease;Affect;Age;Age-Years;Aged 80 and over;Aging;American;Animal Diseases;Antibiotic Therapy;Antibiotics;Antibodies;Area;Biological Assay;Biology;Cells;Censuses;Chronic;Chronic Disease;Chronic lung disease;Communities;Coupled;Cytokine Gene;Defect;Development;Disease;Elderly;Environment;Female;Genetic Transcription;Genomics;Genus Mycobacterium;Health;Immune;Immune response;Immunity;Immunologics;Immunology;Immunology procedure;Incidence;Individual;Infection;Interferon Type II;Interleukin-12;Kinetics;Lead;Life;Lower respiratory tract structure;Lung;Lung diseases;Lung infections;Macaca mulatta;Mediating;Modeling;Morbidity - disease rate;Mucociliary Clearance;Mutation;Mycobacterium Infections;Mycobacterium avium;Mycobacterium avium Complex;Mycobacterium avium-intracellulare Infection;Mycobacterium tuberculosis;Oral;Pathogenesis;Patient Care;Patients;Peripheral Blood Mononuclear Cell;Physiological;Play;Population;Predisposition;Prevalence;Prospective Studies;Pulmonology;Relapse;Research;Risk;Role;Severities;Severity of illness;Statistical Models;Structure;T-Lymphocyte;TNF gene;Testing;Tuberculosis;United States;age effect;age related;aged;aging population;clinical care;cytokine;disorder prevention;disorder risk;exposed human population;genome wide association study;human old age (65+);immune activation;inflammatory marker;inhibitor;insight;juvenile animal;lung microbiome;lung microbiota;mathematical model;microbial community;microbiome;next generation sequencing;non-tuberculosis mycobacteria;nonhuman primate;novel;pathogen;pathogenic bacteria;probiotic therapy;pulmonary function;respiratory microbiome;response;virtual


application_id: 10377419
project_number: 5R01DK124774-02
administering_ic: NIDDK
award_notice_date: 2022-02-08
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 124774
program_official: SILVA, CORINNE M
project_start_date: 2021-04-01
project_end_date: 2026-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-02-01
project_terms:
Age;Agonist;Behavior;Biological;Body Weight;Body Weight Changes;Cardiometabolic Disease;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical;Clinical Trials Design;Complex;Control Groups;Cost of Illness;Cues;Data;Diabetes Mellitus;Disease;Eating;Eating Behavior;Estradiol;Estrogen Receptor alpha;Estrogen Receptor beta;Estrogen Receptors;Estrogen Therapy;Estrogens;Excision;Exposure to;Fasting;Fatty acid glycerol esters;Feeding behaviors;Female;Food;Functional disorder;GTP-Binding Proteins;Glucose Intolerance;Health;Heart Diseases;Hepatocyte;High Fat Diet;Hour;Incidence;Insulin Resistance;Intervention;Knockout Mice;Life;Light;Liver;Measures;Menopause;Metabolic;Metabolic dysfunction;Metabolic syndrome;Metabolism;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Ovariectomy;Overweight;Pattern;Phase;Physiology;Postmenopause;Pre-Clinical Model;Prediabetes syndrome;Predisposition;Premenopause;Randomized;Randomized Controlled Clinical Trials;Research;Resistance;Rest;Risk;Risk Behaviors;Risk Factors;Sex Differences;Signal Transduction;Stroke;System;Testing;Text;Therapeutic;Time-restricted feeding;Tissues;United States;Woman;Women's Role;actigraphy;arm;base;cancer risk;cancer type;cardiometabolism;circadian;circadian biology;circadian pacemaker;circadian regulation;comorbidity;diet-induced obesity;estrophilin;experimental study;feeding;heart disease risk;high risk;improved;insulin sensitivity;male;men;molecular clock;mouse model;obesity risk;primary outcome;protective factors;receptor expression;therapeutic target;time use


application_id: 10376861
project_number: 5R37CA227656-05
project_title: The phosphatase PRL3 as a MYC target and pro-survival oncogene in Acute Lymphoblastic Leukemia
administering_ic: NCI
award_notice_date: 2022-04-15
opportunity_number: PA-16-160
application_type: 5
activity_code: R37
ic: CA
serial_number: 227656
program_official: JHAPPAN, CHAMELLI
project_start_date: 2018-04-06
project_end_date: 2023-03-31
study_section: Cancer Molecular Pathobiology Study Section[CAMP]
contact_pi_person_id: 10310607
contact_pi: BLACKBURN, JESSICA S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThere is a great need for the development of molecularly targeted therapies in Acute Lymphoblastic Leukemia(ALL). The lack of targeted therapies for this disease is an important problem because ALL is primarily apediatric cancer and intensive rounds of general cytotoxic chemotherapy have severe and long-term adverseeffects in children. Additionally adults and children whose ALL does not respond to cytotoxic chemotherapy orwho develop relapse have a universally poor prognosis due to limited treatment options. The well-knowndrivers of ALL are mis-expressed transcription factors such as MYC which are not easily therapeuticallytargeted without undesirable side-effects on normal cells. Preliminary data which built on a novel in vivotransplantation screen in a MYC-induced ALL model in zebrafish demonstrated that the tyrosine phosphatasePRL3 collaborated with MYC to enhance leukemia progression. In vitro and in vivo studies using human cellsshowed that PRL3 is linked with MYC expression and plays a critical role in ALL survival. Phosphatases likePRL3 are most well-known as tumor suppressors and despite emerging evidence that some phosphataseshave oncogenic abilities there are currently no phosphatase inhibitors used in the clinic for cancer patientsand only one in clinical trial. The overall objective of this application is to clearly define the oncogenic role ofthe tyrosine phosphatase PRL3 in MYC-driven ALL and to establish that it is a novel molecular target in thisdisease. The central hypothesis is that PRL3 is a direct transcriptional target of MYC and synergizes withMYC to promote a pro-survival phenotype in ALL cells. The rationale for this research is that PRL3 belongs toa unique family of phosphatases that can be selectively inhibited; defining the mechanisms through whichPRL3 promotes ALL survival will provide a strong scientific rationale for the development of PRL and otherphosphatase inhibitors for use as targeted therapy for cancer patients. This hypothesis will be tested bypursuing three specific aims: 1) Define a mechanism through which MYC regulates PRL3 expression by usingenChIP and biochemical approaches to assess MYC interaction with a novel enhancer region near PRL3; 2)determine the pro-survival mechanisms that are controlled by PRL3 by utilizing an unbiased biotin ligaseapproach to identify PRL3 substrates in ALL cells; and 3) establish that small molecule inhibition of the PRLfamily is a potent therapeutic strategy in ALL by completing comprehensive pre-clinical testing of three newPRL inhibitors and a panel of FDA-approved tyrosine phosphatase inhibitors. This research is innovativebecause it departs from the status quo to use new methods to define an oncogenic role for a phosphatase incancer. The proposed research is also significant because it is expected to vertically advance and expandunderstanding of the role that phosphatases play in cancer progression. Ultimately this knowledge has thepotential to drive the development of a new class of targeted therapy for patients with acute lymphoblasticleukemia and other MYC-driven cancers.

project_terms:
Acute Lymphocytic Leukemia;Adult;Adverse effects;Apoptosis;Binding Sites;Biochemical;Biotin;Cancer Patient;Cells;Cessation of life;Child;Clinic;Clinical Trials;Cytotoxic Chemotherapy;DNA-Binding Proteins;Data;Defect;Development;Developmental Delay Disorders;Diagnosis;Disease;Disease Progression;Drug Targeting;Enhancers;FDA approved;Family;Gene Chips;General Population;Genes;Genetic Transcription;Growth;Human;Human Cell Line;In Vitro;Kinetics;Knowledge;Leukemic Cell;Life;Ligase;Link;MYC gene;Maintenance;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Methods;Mission;Modeling;Molecular Target;Normal Cell;Nucleic Acid Regulatory Sequences;Oncogenes;Oncogenic;Organ;Outcomes Research;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Play;Preclinical Testing;Prognosis;Protein Array;Protein Tyrosine Phosphatase;Public Health;Regimen;Relapse;Research;Role;Sampling;Second Primary Cancers;Signal Pathway;Single Nucleotide Polymorphism;TP53 gene;Testing;Therapeutic;Transcriptional Regulation;Transplantation;Tumor Suppressor Proteins;Zebrafish;acute lymphoblastic leukemia cell;antileukemic activity;base;cancer type;chemotherapy;in vivo;inhibitor;innovation;knock-down;leukemia;member;molecular targeted therapies;novel;patient derived xenograft model;pediatric patients;phosphatase inhibitor;preclinical trial;side effect;small molecule;targeted cancer therapy;targeted treatment;therapeutic target;transcription factor;translational impact;tumor progression

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


application_id: 10376254
project_number: 5R01DK121797-04
project_title: Novel Liver Signaling Pathways Controlling Adiposity
administering_ic: NIDDK
award_notice_date: 2022-03-23
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 121797
program_official: BURGESS-BEUSSE, BONNIE L
project_start_date: 2020-07-03
project_end_date: 2025-03-31
study_section: Molecular and Cellular Endocrinology Study Section[MCE]
contact_pi_person_id: 9293438
contact_pi: HINDS, TERRY D
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:
Adenovirus Vector;Adipocytes;Adipose tissue;Adult;Affect;Antioxidants;Attenuated;Bile fluid;Bilirubin;Biliverdin reductase;Biliverdine;Binding;Blood;Blood Glucose;Body Weight;Body Weight decreased;Cardiovascular Diseases;Cardiovascular system;Categories;Cell Size;Crigler-Najjar Syndrome;Data;Deposition;Diabetes Mellitus;Energy Intake;Energy Metabolism;Enzymes;Event;Excretory function;Expenditure;Fatty Liver;Fatty acid glycerol esters;Fenofibrate;Genes;Genetic;Genetic Polymorphism;Gilbert Disease;Glucose;Glucose Intolerance;Health;Hepatic;Hepatocyte;Hepatotoxicity;High Fat Diet;Hormones;Human;Hyperbilirubinemia;Icterus;Inflammatory;Inherited;Insulin;Insulin Resistance;Intestines;Investigation;Knock-out;Knockout Mice;Knowledge;Lead;Ligands;Lipids;Liver;Liver diseases;LoxP-flanked allele;Measures;Mediating;Medical;Metabolic;Metabolic hormone;Metabolism;MicroRNAs;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Receptors;Obese Mice;Obesity;Obesity Epidemic;Obesity associated disease;Outcome;Overweight;Oxidative Stress;PPAR alpha;Pathologic;Pathway interactions;Patients;Peripheral;Peroxisome Proliferator-Activated Receptors;Physiological;Plasma;Population Study;Process;Protein Isoforms;Publications;Resistance;Risk;Rodent;Serum;Signal Pathway;Signal Transduction;Signaling Molecule;Testing;Therapeutic;Tissues;Transactivation;UDP-Glucuronosyltransferase 1A1;Uncertainty;United States;Visceral fat;Weight Gain;carbohydrate metabolism;clinically relevant;cost;cytokine;fatty liver disease;fibroblast growth factor 21;hormonal signals;humanized mouse;improved;insulin sensitivity;lipid metabolism;mouse model;non-alcoholic fatty liver disease;novel;novel therapeutics;obese patients;oxidation;preference;promoter;recruit;transcription factor


application_id: 10376209
project_number: 5R01NS116058-03
administering_ic: NINDS
award_notice_date: 2022-04-06
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 116058
program_official: CORRIVEAU, RODERICK A
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_title:
The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)

project_abstract:
Alzheimer's disease (AD) is the most common cause of cognitive impairment but diseases of cerebral bloodvessels particularly the small blood vessels that supply all cells of the brain are also major contributors. Noeffective therapies exist and innovative approaches are needed. The proposed study introduces two conceptualinnovations to identify novel therapeutic strategies. First the study focuses on cerebral small vessel ischemicdisease (SVID) induced by dyshomeostasis of amylin an endocrine hormone that participates in the centralregulation of satiety and also known to form pancreatic amyloid in patients with type-2 diabetes. Recent empiricalfindings advanced in part by our group suggest that axonal degeneration and maladaptation of small vesselssuch as gliosis are linked by vascular deposits of amylin. Our preliminary data also show that amylin depositionin brain capillaries correlates with accumulation of amylin in red blood cells. Working in non-AD rats we showedthat pancreatic expression of human amylin (rat amylin is non-amyloidogenic) promotes vascular amylindeposition leading to microhemorrhages axonal degeneration and late-life onset neurological deficits. Secondthe study introduces a new paradigm that amylin dyshomeostasis modulates brain amyloid composition. Severallaboratories (including ours) report the presence of mixed amylin- amyloid (A) plaques in brains of individualswith pathological AD. To study the amylin-A interaction in vivo we crossed AD rats with human amylin-expressing rats. Our preliminary data indicate that human amylin-expressing AD rats have accelerated agingand behavioral changes whereas genetic or pharmacological suppression of amylin is protective. Here wepropose to test these hypotheses by using red blood cell lysates cerebrospinal fluid samples and clinical datafrom the MarkVCID study along with mechanistic studies and amylin-centric therapeutic interventions in ratmodels of amylin dyshomeostasis-related dementia. Data derived from the proposed specific aims can directlylead to human clinical translational studies for the prevention and treatment of vascular cognitive impairmentand/or mixed pathologic disease states that currently lack effective treatments.

project_terms:
Acids;Adherence;Adhesions;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimers disease biomarker;Amyloid;Amyloid beta-42;Amyloid beta-Protein;Arteries;Axon;Behavioral;Biopsy;Blood;Blood Vessels;Blood capillaries;Brain;Cardiovascular system;Carrying Capacities;Cerebral small vessel disease;Cerebrospinal Fluid;Cerebrovascular Circulation;Cerebrovascular system;Cerebrum;Clinical;Clinical Data;Data;Dementia;Deposition;Development;Diabetes Mellitus;Disease;Disease Marker;Elderly;Endocrine;Enrollment;Enzymes;Epoxide hydrolase;Erythrocytes;Genetic;Gliosis;Glucose;Hemoglobin;Hormone Antagonists;Hormones;Human;Hypersensitivity skin testing;Hypoxia;Hypoxic-Ischemic Brain Injury;Impaired cognition;Individual;Insulin;Isomerism;Laboratories;Lead;Link;Magnetic Resonance Imaging;Measures;Mediating;Mediator of activation protein;Metabolic dysfunction;Microspheres;Modeling;National Institute of Neurological Disorders and Stroke;Neurologic;Neurologic Deficit;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pancreas;Participant;Pathologic;Pathologic Processes;Pathology;Pathway interactions;Patients;Pharmacology;Phenotype;Prevention;Prevention strategy;Proteins;Rattus;Regulation;Reporting;Research Project Grants;Sampling;Satiation;Senile Plaques;Signal Pathway;Skin;Techniques;Testing;Therapeutic Intervention;Vascular Cognitive Impairment;Vascular Endothelial Cell;axonal degeneration;beta amyloid pathology;brain cell;brain dysfunction;cerebral capillary;cerebrovascular;cohort;comorbidity;effective therapy;hypoxic ischemic injury;in vivo;inhibitor;innovation;islet amyloid polypeptide;mild cognitive impairment;neuroinflammation;novel therapeutic intervention;tau Proteins;tool;translational study;vascular cognitive impairment and dementia

public_health_relevance:
Most patients with late-life onset Alzheimer's disease (AD) have cerebral small vessel ischemic disease;currently there is no treatment or effective prevention strategies. We will focus on a specific endocrine hormonewhich when hypersecreted causes diabetes and interaction with AD pathology. If our study demonstrates thatthe specific hormone we are studying causes cerebral small vessel disease then new inhibitors of this hormoneshould help protect the brain in aging and diabetes.


application_id: 10375465
project_number: 5K08DK123381-02
administering_ic: NIDDK
award_notice_date: 2022-03-23
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: DK
serial_number: 123381
program_official: SASLOWSKY, DAVID E
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 9291843
contact_pi: JOPHLIN, LORETTA L.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_title:
Interaction of the Microtubule Cytoskeleton and Perilipin-2 Regulates Hepatic Lipid Droplets - a Potential Therapeutic Target for Fatty Liver Disease

project_abstract:
PROJECT SUMMARY/ABSTRACTThe overall objective of this research is to target hepatocyte lipid droplets (LDs) for the development oftherapeutic interventions for fatty liver disease. Hepatic steatosis fat accumulation within hepatocyte LDs is a keyprecursor for steatohepatitis which can lead to cirrhosis and hepatocellular cancer necessitating livertransplantation. Unfortunately hepatic steatosis also limits the number of donor livers acceptable for transplant asdonor livers with severe steatosis have a high risk of primary nonfunction. As such therapeutic strategies toreverse fatty liver are important for patients at risk for steatohepatitis and cirrhosis as well as to increase thedonor pool of viable livers for transplantation. Our work focused on hepatocyte LDs herein shows three keyobservations: a) perilipin-2 (PLIN2) a LD-associated protein which regulates fat storage and utilization co-localizes with and co-immunoprecipitates microtubules; b) microtubule disruption with nocodazole a bluntmicrotubule targeting agent (MTA) uncouples PLIN2 from the LD promotes LD fusion and yields delipidation (i.e.exocytotic secretion of LD contents) of steatotic hepatocytes with minimal cytotoxicity; and c) nocodazolepromotes fat loss from ex vivo liver tissue with no effect on tissue viability. Based on these preliminary data wepropose the CENTRAL HYPOTHESIS that hepatocyte LDs are regulated by an interaction between PLIN2 andthe microtubule cytoskeleton and that this interaction is a potential therapeutic target to decrease the lipid burden ofhepatocytes in fatty liver disease. Our SPECIFIC AIMS will test three hypotheses. FIRST we will test thehypothesis that microtubules directly interact with LD-associated PLIN2. SECOND we will test the hypothesisthat microtubule perturbation increases lipolysis and leads to delipidation of steatotic hepatocytes. FINALLY wewill test the hypothesis that treatment of ex vivo steatotic liver tissue and ex vivo perfusion of steatotic livers withMTAs will lead to delipidation of hepatocytes and improved liver function in a pre-clinical model of organ salvageand rehabilitation. This work will provide foundational information to the emerging field of LD biology and isprojected to demonstrate a novel cellular mechanism controlling hepatocyte LD dynamics and to identifytherapeutic strategies to defat steatotic livers. The candidate is a basic scientist and transplant hepatologistdedicated to improving the lives of patients with liver disease using a basic science approach. She is an AssistantProfessor of Medicine at Mayo Clinic with a mentorship team consisting of Drs. Vijay Shah and Greg Gores. She hasprotected time for research and training activities dedicated institutional funding for equipment and supplies anda robust career development plan with specific activities and benchmarks that will position her for anindependent research career. The comprehensive training plan will allow for the candidate to complete hercurrent research plan and seek independent investigator status where she will translate these and future studiesto human trials and future therapeutic interventions for patients.

project_terms:
Affect;Aftercare;Alcohols;American;Basic Science;Benchmarking;Binding;Biogenesis;Biology;Catabolism;Cell Survival;Cessation of life;Cirrhosis;Clinic;Co-Immunoprecipitations;Coupled;Cytoskeleton;Data;Development Plans;Disease;Dynein ATPase;Equipment and Supplies;Fatty Liver;Fatty acid glycerol esters;Foundations;Funding;Future;Goals;Hepatic;Hepatocyte;Human;Imaging Techniques;Lead;Lipids;Lipolysis;Liver;Liver Failure;Liver diseases;Malignant neoplasm of liver;Measures;Medicine;Mentorship;Metabolism;Microtubules;Modeling;Mus;Mutation;Nocodazole;Organ;Organ Model;Organelles;Patient-Focused Outcomes;Patients;Positioning Attribute;Post-Translational Protein Processing;Pre-Clinical Model;Prevalence;Primary carcinoma of the liver cells;Process;Proteins;Regulation;Rehabilitation therapy;Research;Research Activity;Research Personnel;Risk;Scientist;Steatohepatitis;Structure;Testing;Therapeutic;Therapeutic Intervention;Time;Tissue Viability;Tissues;Training;Training Activity;Translating;Transplantation;Tubulin;Work;base;career;career development;cytotoxicity;ex vivo perfusion;fatty liver disease;high risk;improved;improved outcome;knock-down;liver function;liver transplantation;mutant;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;perilipin;primary outcome;professor;targeted agent;therapeutic development;therapeutic evaluation;therapeutic target;trafficking;western diet

public_health_relevance:
PROJECT NARRATIVENon-alcoholic fatty liver disease (NAFLD) affects millions of Americans and can lead to cirrhosis liver cancerneed for liver transplantation and death. Excess fat stored within lipid droplets (LDs) of liver cells is responsiblefor this disease and this project aims to better understand LDs as a potential therapeutic target for NAFLD.


application_id: 10374861
project_number: 5R01AG066653-03
project_title: Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2022-04-05
opportunity_number: PAR-17-031
application_type: 5
activity_code: R01
ic: AG
serial_number: 066653
program_official: BARRETT, PAUL JOHN
project_start_date: 2020-04-15
project_end_date: 2022-10-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 11838914
contact_pi: SUN, RAMON C.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:The onset of Alzheimer's disease (AD) increases in incidence with age and an increasing aging demographicmeans the number of individuals suffering from AD is expanding rapidly. Changes in cerebral metabolism arehallmarks of aging therefore it is reasonable to hypothesize that age-associated change in metabolism playmajor roles in AD progression. AD brains show clear metabolic impairments and studies suggest that alteredmetabolism drives a cascade of events leading to AD onset. The mechanisms initiating these metabolicimpairments remain a critical knowledge gap in AD research. We recently discovered that aberrant glycogenaggregates (AD-glycogen) are a universal feature of AD in both human and mice. Increases in AD-glycogencorrelated with higher Braak staging and lower glucose levels in patient specimens. AD-glycogen is bothhyper-phosphorylated and hyper-branched making them architecturally distinct from normal glycogen. Wepresent strong evidence showing that AD-glycogen modulate brain metabolism through direct binding andinactivation of the AMP-activated protein kinase (AMPK) a master regulator of central carbon metabolism. Wewill first elucidate the molecular events leading to abnormal AD-glycogen formation in vitro and in vivo (Aim 1)then we will interrogate the impact of AD-glycogen on cerebral metabolism during aging (Aim 2). Finally wewill assess the efficacy of a novel glycogen-clearing enzyme therapy on brain metabolism cognition and ADneuropathology in vivo (Aim 3). The PI has assembled a multi-disciplinary team of investigators withcomplementary skillsets and state-of-art high resolution and Omic-based techniques to discover potentialtherapeutic options and possibly treat the onset of AD.

project_terms:
5'-AMP-activated protein kinase;Ablation;Age;Aging;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease patient;Anabolism;Antibodies;Architecture;Astrocytes;Autopsy;Behavior;Binding;Biochemical;Brain;Carbon;Cerebrum;Characteristics;Clinical;Cognition;Cyclic AMP-Dependent Protein Kinases;Data;Disease Progression;Enzymes;Event;Glucose;Glycogen;Glycogen Storage Disease;Human;Impairment;In Vitro;Incidence;Individual;Kentucky;Knowledge;Lead;Learning;Mass Spectrum Analysis;Measures;Memory;Metabolic;Metabolic Pathway;Metabolism;Methods;Molecular;Mus;Nerve Degeneration;Neurons;Onset of illness;Pathogenesis;Pathologic;Patients;Play;Polysaccharides;Positioning Attribute;Premature aging syndrome;Process;Protein Kinase;Reporting;Research;Research Personnel;Resolution;Rodent;Role;Sampling;Severities;Specimen;Staging;Symptoms;System;Tauopathies;Techniques;Testing;Therapeutic;Transgenes;Universities;age related;aging brain;aging demographic;aging population;amyloid pathology;base;brain metabolism;design;enzyme therapy;glucose metabolism;glycogen metabolism;improved;in vitro Model;in vivo;metabolomics;mouse model;multidisciplinary;mutant;neuropathology;novel;novel therapeutics;pre-clinical;stable isotope;therapeutic target

public_health_relevance:
Project NarrativeCerebral glucose hypometabolism is now considered one of the hallmarks of Alzheimers disease (AD) clinicalAD symptoms almost never occur in the absence glucose hypometabolism and the extent of the metabolicchanges measured strongly correlate with the severity of clinical symptoms. The mechanism(s) that driveglucose hypometabolism remain a critical knowledge gap in AD research. This proposal aims to examine age-related changed in cerebral glucose metabolism in both healthy and AD mouse models to 1) improve ourunderstanding in the metabolic aging process and 2) to identify divergent events that result in the onset of ADfrom the aging population.


application_id: 10374099
project_number: 5R01HL151419-03
project_title: Biophysical Mechanisms of Hyperoxia-Induced Lung Injury
administering_ic: NHLBI
award_notice_date: 2022-04-27
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 151419
program_official: ZHOU, GUOFEI
project_start_date: 2020-04-15
project_end_date: 2024-03-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
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:
Acute lung injury and its more severe form acute respiratory distress syndrome(ARDS) are devastating illnesses with high rates of incidence and mortality. Patientswith acute lung injury are typically provided supplemental oxygen using positivepressure mechanical ventilation but this can lead to additional injury termed ventilator-induced lung injury (VILI). The long term objective of this proposal is to improveunderstanding of the mechanisms by which the combination of exposure to high levelsof oxygen (hyperoxia) and overdistention (or stretch) of lung cells contributes toventilator-induced lung injury. The central hypothesis of this application is thathyperoxia induces structural changes in alveolar epithelial and endothelial cells as wellas macrophages that alter their mechanical properties making them more susceptibleto injury caused by mechanical stretch. Mechanisms of the initiation of cell injury will beinvestigated using primary cultures of mouse alveolar type II (AT2) epithelial cellsprimary human lung endothelial cells mouse alveolar and bone marrow-derivedmacrophages cultures of mouse lung slices and a mouse model of combinedhyperoxia and VILI. In Aim 1 we will test the hypothesis that exposure of cells or lungslices causes changes in cell structural elements that increase the elastic modulus ofthe cells through activation of RhoA. We will measure the Youngs modulus anindication of an objects ability to deform using atomic force microscopy in theindentation mode and we will determine how hyperoxia changes cytoskeletal structuresincluding f-actin microtubules and focal adhesions. In Aim 2 we will investigate howhyperoxia increases stretch-induced cell detachment and injury. In Aim 3 we will testthe hypothesis that RhoA-mediated changes in structure and mechanical propertiesincreases lung injury in mice in a combined model of hyperoxia and VILI. The proposedstudies will investigate the biophysical mechanisms that contribute to lung injury duringmechanical ventilation and provide new insights into mechanotransduction the processof converting mechanical signals to biological signals.

project_terms:
Actins;Acute Lung Injury;Acute Respiratory Distress Syndrome;Alveolar;Animal Model;Antioxidants;Apoptosis;Atomic Force Microscopy;Bacterial Pneumonia;Basement membrane;Biological;Biophysical Process;Biophysics;Bone Marrow;Cell Adhesion;Cell Death;Cell membrane;Cells;Clinical;Cultured Cells;Disease;Elements;Endothelial Cells;Endothelium;Epithelial;Epithelial Cells;Exposure to;F-Actin;Focal Adhesions;Gelsolin;Guanosine Triphosphate Phosphohydrolases;Human;Hyperoxia;Incidence;Inflammasome;Inflammation;Inflammatory;Influenza;Injury;Intensive Care Units;Investigation;Knock-out;Lead;Light;Lung;MYLK gene;Masks;Measures;Mechanical ventilation;Mechanics;Mediating;Microtubules;Modeling;Modulus;Mus;Myosin ATPase;Myosin Light Chains;Necrosis;Oxygen;Pathway interactions;Patients;Phosphotransferases;Predisposition;Preparation;Process;Proteins;Resistance;Rho-associated kinase;Rupture;Severities;Signal Pathway;Signal Transduction;Slice;Stretching;Structure;Structure of parenchyma of lung;Testing;Therapeutic Intervention;Tidal Volume;Ventilator-induced lung injury;Work;alveolar bone;alveolar epithelium;biophysical properties;cell injury;ezrin;hyperoxia induced lung injury;improved;injured;insight;keratinocyte growth factor;lung injury;macrophage;mechanical pressure;mechanical properties;mechanical signal;mechanotransduction;moesin;mortality;mouse model;myosin phosphatase;prevent;radixin protein;response;supplemental oxygen;targeted treatment

public_health_relevance:
Bacterial pneumonia and influenza are common diseases that can lead to severeacute lung injury. Patients with severe acute lung injury require mechanical ventilationand supplemental oxygen and often require extended stays in the intensive care unit.The proposed studies will investigate the biophysical mechanisms that contribute tolung injury during mechanical ventilation and will identify potential targets for therapeuticintervention to reduce injury.


application_id: 10374051
project_number: 5R01CA249734-02
project_title: Targeting Lipid Metabolism in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2022-03-18
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 249734
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
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:
Biological;Biological Assay;Biological Sciences;CD36 gene;Cancer Etiology;Cancer Patient;Cause of Death;Cecum;Cell Survival;Cessation of life;Clinical;Collaborations;Colorectal Cancer;Data;Development;Disease;Drug Evaluation;Drug Targeting;Environment;Enzymes;Fatty Acids;Fatty-acid synthase;Goals;Growth;Human;In Vitro;Incidence;Injections;Knowledge;Lipids;Literature;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic to;Microarray Analysis;Modeling;Molecular;Morbidity - disease rate;Mus;Neoplasm Metastasis;Oncology;Organ;Organoids;Outcome;Palmitates;Pathway interactions;Patients;Pharmacology;Phase I/II Clinical Trial;Phase II Clinical Trials;Pre-Clinical Model;Prognosis;Public Health;Recurrence;Regulation;Research;Role;Sampling;Signal Pathway;Solid;Solid Neoplasm;Specimen;Sphingolipids;Sphingosine;Testing;Therapeutic;Tissue Microarray;Tumor Angiogenesis;United States;Up-Regulation;Validation;Woman;analog;antibody inhibitor;base;cancer cell;colorectal cancer metastasis;colorectal cancer progression;disorder risk;fatty acid metabolism;genetic approach;high risk;in vivo;in vivo Model;inhibitor;lipid biosynthesis;lipid metabolism;men;metabolomics;mortality;mouse model;neutralizing antibody;new therapeutic target;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;preclinical study;prevent;resistance mechanism;response;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;therapeutic target;transcriptome sequencing;translational impact;translocase;tumor;tumor metabolism;uptake


application_id: 10374023
project_number: 5R01ES019217-10
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2022-03-29
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 019217
program_official: NADADUR, SRIKANTH
project_start_date: 2011-09-23
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTMultiple epidemiological and experimental studies report that acute or chronic exposure to air pollution isassociated with adverse cardiovascular events including myocardial ischemia stroke arrhythmias heart failuresudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fineparticulate matter (PM2.5) fraction which is generated directly from the combustion of fossil fuels and is found inautomobile exhaust wood or coal smoke and industrial emissions. However the mechanisms by which PM2.5induces cardiovascular injury remain unclear and the pathophysiological conditions and co-exposures thatdetermine individual susceptibility to PM2.5 toxicity have not been identified. Our previous work has shown thatin young healthy adults exposure to PM2.5 is associated with inflammation decreases in vascular reparativecirculating angiogenic cells (CACs) and changes in cytokine/growth factor profiles consistent with an inhibitionof angiogenesis. In addition we found increased levels of circulating endothelial microparticles evidence ofsubclinical vascular injury. We obtained similar results in mouse exposure studies which show that exposure toconcentrated ambient particles depletes circulating angiogenic cells and leads to defective hematopoiesis andfunctional defects in bone marrow-derived cells. In pilot experiments we have found that these PM2.5-induceddefects in mice could be prevented by treatment with the endogenous nucleophile carnosine which quenchesreactive oxygen species and removes toxic products of lipid peroxidation. Furthermore in a human cohort withmild-to-moderate CVD risk we also found that those with high CVD risk are more susceptible to the effects ofPM2.5 and that individuals with high carnosine levels are relatively impervious to the adverse cardiovasculareffects of PM2.5 exposure. Thus we hypothesize that individual risk factors determine cardiovascular susceptibilityto PM2.5 and that means to limit electrophiles/oxidative stress will mitigate the adverse consequences of PM2.5exposure. These ideas will be tested in three Aims. In the first we will assess the impact of PM2.5 exposure onvascular function (arterial stiffness flow-mediated dilation peripheral artery tone) in a population with mild-to-moderate CVD risk and determine whether exposure exacerbates composite CVD risk and whether changesinflammation oxidative stress or thrombosis are associated with PM2.5-induced vascular dysfunction. In thesecond Aim we will determine whether the relationship between vascular injury and dysfunction is mediated byindividual-level demographic characteristics (e.g. sex age ethnicity) co-exposure to gaseous pollutants orsystemic levels of carnosine. In the third Aim we will enroll a subset of individuals with inherently low carnosinelevels and determine whether daily oral supplementation with carnosine attenuates the association betweenPM2.5 exposure and vascular dysfunction as well as PM2.5 -induced changes in biomarkers of cardiovascularinjury and indices of cardiovascular function. The results of this project will provide better estimates of CVDburden due to PM2.5 exposure identify specific risk factors that increase susceptibility to PM2.5-induced injuryand assess the efficacy of carnosine in attenuating PM2.5 toxicity. Findings of this project could potentially leadto the development of a novel and practical therapeutic intervention to prevent PM2.5 toxicity.

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

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


application_id: 10373964
project_number: 5F31CA260840-02
project_title: Exploring the Role of Drp1 in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2022-03-14
opportunity_number: PA-20-246
application_type: 5
activity_code: F31
ic: CA
serial_number: 260840
program_official: BIAN, YANSONG
project_start_date: 2021-04-01
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1-F09A-R(20)L]
contact_pi_person_id: 16493761
contact_pi: HASANI, SUMATI RAJ
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract - Exploring the Role of Drp1 in Colorectal Cancer. Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately150000 new cases and 50000 deaths are predicted for the year 2020. Emerging research suggests that thedysregulation of mitochondrial fitness due to an imbalance in mitochondrial dynamics can lead to metabolicreprogramming in various cancer types. A number of epidemiological studies indicate that obesity is as a majorrisk factor for several types of cancer including colorectal cancer. Our group and others have shown thatincreased uptake of fatty acids promotes the development and progression of difference cancers by alteringmetabolic pathways to favor mitochondrial fatty acid oxidation. However the molecular mechanisms by whichfatty acid consumption influences mitochondrial fitness to promote tumor cell survival and progression is poorlyunderstood. In this proposed study I plan to investigate the signaling crosstalk between mitochondrial dynamicsand fatty acid metabolism in colorectal cancer. In my preliminary experiments I discovered that fatty acid uptakepromotes mitochondrial fragmentation by activating Drp1 a small GTPase required for mitochondrial fission byincreasing the phosphorylation at the S616 site and its interaction with mitochondria. Importantly silencing Drp1inhibits cancer stem cell functions by attenuating Wnt signaling in colon cancer cells. The central hypothesis isthat Drp1-dependent mitochondrial fission is required for fatty acids to promote tumor progression in coloncancer. Specifically I will determine how fatty acid uptake alters Drp1 activity and how mitochondrial dynamicsaugments cancer stem cell functions to drive tumorigenesis in vivo. The following specific aims are proposed:1) to delineate the molecular mechanism by which fatty acid uptake enhances Drp1 activity; 2) to determine thefunctional importance of Drp1 in promoting CSC functions in colorectal cancer; and 3) to define the role of Drp1in regulating tumorigenesis using in vivo colon cancer models. Results from this study will provide novel insightsinto the role of mitochondrial dynamics in connecting cellular metabolic pathways with cancer stem cell signaling.Dr. Gao has extensive experience in studying the regulation of signaling pathways and mitochondrial metabolismin colorectal cancer. I will also benefit from additional expertise provided by my committee members and state-of-the-art facilities of the Markey Cancer Center at the University of Kentucky. A comprehensive training planhas been developed to fit my research background and career goals. Based on my strong preliminary data withmy mentors knowledge and training and the excellent research environment at the Department of Molecularand Cellular Biochemistry and the Markey Cancer Center I am confident that this project will be successful.Ultimately this study will help develop personalized treatment options by targeting mitochondrial dynamics toeradicate cancer stem cells.

project_terms:
Acetylation;Address;Animal Model;Attenuated;Biochemical;Biochemistry;Bioenergetics;Cancer Center;Cancer Etiology;Cancer Model;Cell Communication;Cell Survival;Cellular biology;Cessation of life;Colon Carcinoma;Colorectal Cancer;Committee Members;Consumption;Data;Development;Disease;Down-Regulation;Environment;Fatty Acids;Fatty acid glycerol esters;Goals;High Fat Diet;Homeostasis;Image;Immunofluorescence Immunologic;Immunoprecipitation;Incidence;Kentucky;Knock-out;Knockout Mice;Knowledge;Lead;Malignant Neoplasms;Mediating;Mentors;Metabolic;Metabolic Pathway;Mitochondria;Modeling;Molecular;Monomeric GTP-Binding Proteins;Mus;Nuclear;Obesity;Organelles;Organoids;Phosphorylation;Play;Property;Regulation;Research;Risk Factors;Role;Signal Pathway;Signal Transduction;Site;Stress;Testing;Tissues;Training;United States;Universities;Up-Regulation;WNT Signaling Pathway;Western Blotting;base;beta catenin;cancer cell;cancer stem cell;cancer type;career;epidemiology study;experience;experimental study;fatty acid metabolism;fatty acid oxidation;in vivo;insight;mitochondrial fitness;mitochondrial metabolism;mortality;mouse model;neoplastic cell;novel;novel therapeutics;personalized medicine;receptor;recruit;stem cell function;tumor;tumor initiation;tumor microenvironment;tumor progression;tumorigenesis;uptake;western diet

public_health_relevance:
PROJECT NARRATIVEColorectal cancer mortality is predominantly due to the development of disseminated disease. My study focuseson developing a mechanistic understanding of mitochondrial retrograde signaling in mediating the metabolicinteraction between cancer cells and fatty acids in the tumor microenvironment. Results from my studies will helpto identify new therapeutic options by targeting fatty acid-cancer cell interaction.


application_id: 10373927
project_number: 5F32HL149140-02
project_title: Deciphering the Relationship Between Cardiomyocyte Metabolic Configuration and Cell Cycle Re-entry
administering_ic: NHLBI
award_notice_date: 2021-12-31
opportunity_number: PA-19-188
application_type: 5
activity_code: F32
ic: HL
serial_number: 149140
program_official: WANG, WAYNE C
project_start_date: 2021-01-01
project_end_date: 2023-12-31
study_section: Special Emphasis Panel[ZRG1-F10A-K(20)L]
contact_pi_person_id: 15737705
contact_pi: ABOULEISA, RIHAM RAAFAT ELGHARIB
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:
Myocardial infarction causes irreversible loss of cardiomyocytes (CMs) and often leads to heart failure. Toreplace the lost cells we identified a combination of cell-cycle regulators that induces stable cytokinesis in adultpost-mitotic cells. Overexpression of cyclin-dependent kinase 1 (CDK1) CDK4 cyclin B1 and cyclin D1 (referredto as 4F) promotes cell division in post-mitotic mouse rat and human cardiomyocytes. The high efficiency ofthis protocol in inducing myocyte renewal provides new opportunities for understanding the mechanisms involvedin cardiomyocyte proliferation. One of the most interesting findings related to this discovery was the confirmationof a link between metabolic reprogramming and cardiomyocyte proliferation. Although in proliferating cells thereis a strong correlation between metabolic changes and cellular proliferation it remains unclear how metabolisminfluences the proliferative potential of cardiomyocytes. During the past 2 years in collaboration with Dr. Hillsgroup I have generated preliminary data which indicate that cardiomyocyte proliferation is associated withmarked reprogramming in energy metabolism. In proliferating cardiomyocytes isolated from lineage tracing(MADM) mice RNA-seq data indicate profound downregulation of fatty acid oxidation genes and upregulation ofbiosynthetic pathway enzyme expression; in human iPSC-derived cardiomyocytes (hiPSC-CMs) 4F expressiondecreases mitochondrial respiration and catabolic activities. Using stable isotope-resolved metabolomics(SIRM) we demonstrate that 4F-infected hiPS-CMs show significant elevation in 13C labeled intermediates orend products of the hexosamine biosynthetic pathway (HBP) serine biosynthesis pathway (SBP) and pentosephosphate pathway (PPP). In line with these findings our results also demonstrate that augmenting the carbonavailability for these biosynthetic pathways by overexpressing phosphoenolpyruvate carboxykinase (PCK1 orPCK2) augments the ability of cardiomyocytes to proliferate. These data suggest that higher biosyntheticpathway flux may be required for cardiomyocyte proliferation. Informed by these results we propose the generalhypothesis that activation of ancillary biosynthetic pathways of glucose metabolism are required forcardiomyocyte proliferation. We suggest that higher biosynthetic pathway flux is required for building blocksynthesis and may be important for regulating pro-proliferative gene programs. During this project we willdelineate the importance of each biosynthetic pathway in influencing cardiomyocyte proliferation. First usingpharmacological and virus-based approaches we will determine the specific contribution of the HBP SBP andPPP pathways to myocyte proliferation. In addition we will investigate the influence of increasing the carbon fluxin biosynthetic pathway through overexpression of PCK1 or PCK2 on cardiac function and repair in vivo. Theaims of this project are: Specific Aim 1: Delineate the contribution of each biosynthetic pathway on cardiomyocyteproliferation. Specific Aim 2: Investigate the functional efficacy of increasing carbon flux in biosynthetic pathwayson cardiac repair in vivo.

project_terms:
Adult;Affect;Anabolism;CDC2 gene;CDK4 gene;Carbon;Cardiac Myocytes;Cell Cycle;Cell Cycle Regulation Pathway;Cell Proliferation;Cell division;Cells;Collaborations;Cyclin D1;Cytokinesis;Data;Development;Down-Regulation;Echocardiography;Energy Metabolism;Fetus;Foundations;Genes;Heart;Heart Diseases;Heart failure;Hexosamines;Hip region structure;Histology;Human;Knowledge;Label;Link;Metabolic;Metabolism;Mitochondria;Mitotic;Modeling;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;Pathway interactions;Patients;Pentosephosphate Pathway;Pharmacology;Phosphoenolpyruvate Carboxylase;Proliferating;Protocols documentation;Rattus;Respiration;Salamander;Serine;Technology;Up-Regulation;Viral;Virus;Zebrafish;base;cardiac repair;cyclin B1;enzyme pathway;fatty acid oxidation;glucose metabolism;heart function;in vivo;induced pluripotent stem cell derived cardiomyocytes;metabolomics;mouse model;novel strategies;novel therapeutics;overexpression;programs;stable isotope;transcriptome sequencing

public_health_relevance:
The muscle cells in the adult heart are not able to regenerate themselves which made itdifficult to treat heart disease; however in human fetuses zebrafish and salamanderthe heart muscle is able to regenerate. Here we are using cutting edge technologies tounderstand why the fetuses but not adults are able to regenerate their hearts. Thisunderstanding will allow the development of novel therapies to regenerate the deadheart muscle in heart failure patients.


application_id: 10372632
project_number: 1R21AR078447-01A1
project_title: Magnetic nanocomplexes-induced immunomodulation for fracture healing
administering_ic: NIAMS
award_notice_date: 2022-02-10
opportunity_number: PAR-19-173
application_type: 1
activity_code: R21
ic: AR
serial_number: 078447
suffix: A1
program_official: MARQUITZ, ARON
project_start_date: 2022-02-10
project_end_date: 2023-12-31
study_section: Musculoskeletal Tissue Engineering Study Section[MTE]
contact_pi_person_id: 14078198
contact_pi: TIRUVANNAMALAI ANNAMALAI, RAMKUMAR
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Non-healing fractures are a cause of severe disability and have devastating effects on the quality of life.Currently there are no reliable first-line therapies that stimulate healthy bone formation and prevent nonunion.There is a growing body of evidence supporting the indispensable role of macrophages in fracture healing.Also macrophage dysfunction is a critical component in the pathogenesis of non-healing or poorly healingfractures. Immunomodulatory strategies that apply biochemical factors are gaining traction to regulatemacrophage phenotypes. However they have limited success due to complications with specificity efficacyand systemic toxicity. Here we propose to develop a magnetic iron-oxide nanocomplexes (MNC)-based therapy for promotingfracture healing. The cytoskeletal dynamics of macrophages are intricately linked to their inflammatoryresponse. Our studies confirmed that the cytoskeletal dynamics of macrophages are determined by theirphenotype. Studies also show that mere manipulation of cytoskeletal dynamics using physical cues withoutany exogenous factors is shown to transform macrophage phenotype. This phenotype modulation is due tothe nuclear translocation of the transcription factor MRTF-A and changes in chromatin compaction caused bycytoplasmic-to-nuclear redistribution of histone deacetylase-3 (HDAC3). We hypothesize that intracellularmagnetic force can elicit transcriptional control of macrophage phenotype and promote fracture healing viaMRTF-A release and HDAC3 redistribution. In SA1 we will engineer magnetic nanocomplexes for targeted internalization and mechanisticallyelucidate intracellular force-induced modulation of the cytoskeleton and corresponding change in macrophagephenotype. In SA2 we will validate macrophage targeting of MNC and elucidate their therapeutic potential in amurine critical-sized femoral defect. The proposed research will be a paradigm shift in wound healing and willalso provide crucial insights into the mechanobiology of macrophages that are valuable for diagnostic andtherapeutic interventions.

project_terms:
Actins;Acute;Adopted;Area;Biochemical;Biocompatible Materials;Biomechanics;Bone Regeneration;Bone Resorption;Cells;Chromatin;Chronic;Cues;Cytoskeleton;Defect;Endothelium;Engineering;Exhibits;Exogenous Factors;Exposure to;F-Actin;Fostering;Fracture;Functional disorder;G Actin;Gene Expression;Genes;HDAC3 gene;Immune response;Infiltration;Inflammation;Inflammatory Response;Injury;Kinetics;Lead;Link;Macrophage Activation;Magnetism;Metabolic;Methodology;Methods;Modeling;Morphology;Multipotent Stem Cells;Mus;Natural regeneration;Nuclear;Nuclear Translocation;Organ failure;Osteogenesis;Pathogenesis;Pathology;Peptides;Pharmaceutical Preparations;Phenotype;Process;Quality of life;Regenerative Medicine;Research;Role;Signal Transduction;Site;Specificity;Surface;TLR4 gene;TNF gene;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;Time;Traction;Transcriptional Regulation;Trauma;Traumatic injury;Up-Regulation;Work;age related;base;bone;bone fracture repair;bone healing;cancer imaging;clinically translatable;cyclooxygenase 2;density;design;diagnostic value;disability;immunomodulatory therapies;immunoregulation;inflammatory modulation;insight;iron oxide;macrophage;magnetic field;nanocomplexes;nanomaterials;polymerization;prevent;regenerative therapy;success;systemic toxicity;tissue regeneration;transcription factor;uptake;wound healing

public_health_relevance:
Regenerative medicine holds much promise for treating various ailments including organ failures age-related pathologies and trauma-related injuries. While most of the current research focus is on developingbiomaterials and methods for controlling the fate of multipotent stem cells little is known about the hostresponse primarily due to macrophages and the interconnectivity between inflammation and functionalintegration. This proposed research will investigate the mechanobiology of macrophages and developmethodologies that harness the bodys natural processes for augmenting bone regenerative therapies.


application_id: 10372241
project_number: 3R01GM138882-02S2
administering_ic: NIGMS
award_notice_date: 2021-08-10
opportunity_number: PA-19-056
application_type: 3
activity_code: R01
ic: GM
serial_number: 138882
suffix: S2
program_official: BARSKI, OLEG
project_start_date: 2020-09-01
project_end_date: 2024-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: HEIDARY, DAVID ;RICHARDS, CHRISTOPHER I
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:
AbstractCYP1B1 is absent or expressed at very low levels in the liver and healthy tissues while being overexpressed intumors giving it the title of universal tumor antigen. Evidence from basic science clinical and epidemiologicalstudies demonstrate that CYP1B1 is involved in cancer initiation progression and resistance to a wide range ofchemotherapeutics. In addition several point mutations have been discovered within CYP1B1 that areassociated with other disease states particularly hereditary congenital glaucoma and metabolic disorders.However there is currently no known molecular mechanism that explains how mutations altered protein levelsand environmental conditions impact the function and dysfunction of this enzyme. We hypothesize that CYP1B1subcellular localization oligomerization protein:protein assembly degradation and small molecule binding arealtered in cancer cells as a result of specific single nucleotide polymorphisms or environmental features.Trafficking of CYP1B1 from the ER to the mitochondria association into multimeric states or generation ofabnormal protein:protein assemblies could result in damaging levels of the protein and consequently metabolicproducts including ROS and mutagens that facilitate malignant progression. This work will demonstrate how theprotein:protein interactions of a cytochrome P450 enzyme impacts enzyme activity and protein lifecycle. Singlemolecule microscopy methods and fluorescence lifetime microscopy imaging will be used to gain high resolutioninformation on protein assembly and activity in live cells. Additionally paradigm-shifting inhibitors of this enzymewill be developed that act though two distinct mechanisms: long-residence-time coordinative inhibition andactivation of CYP1B1 degradation. Reduction of CYP1B1 protein levels and activity should suppress its role incancer progression and is anticipated to facilitate restoration of efficacy for a variety of chemotherapeutics.

project_terms:
3-Dimensional;Affect;Aromatase;Aromatase Inhibitors;Basic Science;Binding;Biology;CYP17A1 gene;CYP1B1 gene;Cell Line;Cell physiology;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Cisplatin;Clinical Research;Conflict (Psychology);Cytochrome P450;Cytochrome a;Data;Disease;Dose;Drug resistance;Environment;Environmental Risk Factor;Enzyme Inhibitor Drugs;Enzymes;Functional disorder;Generations;Genetic;Genetic Polymorphism;Goals;Half-Life;Heme;Hemeproteins;Homo;Hormones;Hydrophthalmos;Hypoxia;Immune response;In Vitro;Inherited;Iron;Liver;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Medical;Membrane;Metabolic;Metabolic Diseases;Methods;Microscopy;Mitochondria;Modeling;Molecular;Molecular Conformation;Mutagens;Mutation;Mycoses;Nucleotides;Paclitaxel;Patients;Pharmacology;Phase I Clinical Trials;Phenotype;Photobleaching;Physiologic pulse;Play;Point Mutation;Population;Population Distributions;Proteins;Proteolysis;Resistance;Resolution;Role;Scanning;Single Nucleotide Polymorphism;Testing;Thermodynamics;Time;Tissues;Tumor Antigens;Vesicle;Work;cancer cell;cancer initiation;chemotherapy;enzyme activity;epidemiology study;experimental study;fluorescence lifetime imaging;improved;in vivo;inhibitor/antagonist;knock-down;malignant breast neoplasm;mitochondrial membrane;nanoscale;novel;overexpression;protein degradation;protein protein interaction;residence;response;restoration;single molecule;small molecule;small molecule inhibitor;trafficking;tumor;tumor progression


application_id: 10372099
project_number: 5R34MH124799-02
administering_ic: NIMH
award_notice_date: 2022-02-25
opportunity_number: RFA-MH-18-706
application_type: 5
activity_code: R34
ic: MH
serial_number: 124799
program_official: VILLATTE, JENNIFER L
project_start_date: 2021-03-15
project_end_date: 2024-02-29
study_section: ZMH1-ERB-K(09)
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-03-01
project_title:
A Pilot Randomized Control Trial of a Relapse Prevention Online Exposure Protocol for Eating Disorders and Mechanisms of Change

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are chronic and disabling; most individuals never achieve full remissioneven after intensive treatment and 50% of those who access intensive treatment will relapsewithin 6-months of discharge. These high relapse rates occur often and contribute to the pooroutcomes seen in EDs. Importantly existing treatments to not differ from control treatments inthe ability to alter cognitive ED pathology which is the primary remaining symptomatology atdischarge from intensive care. ED relapse-prevention treatments are urgently needed that candisrupt the persistent cycle of admission and discharge from intensive treatment and that areexplicitly targeted at core cognitive-affective pathology. Our scientific premise developed fromour past work is that the application of an online exposure protocol will engage fear extinction -improving outcomes enhancing full recovery and decreasing the likelihood of relapse. Ourstudy goals are to (1) develop and test the acceptability feasibility and preliminary efficacy of arandomization of an online exposure relapse-prevention protocol that can be delivered post-acute treatment versus a writing control treatment and (2) to test if this treatment targets fearextinction which is a core aspect of ED cognitive-affective pathology. These goals will ultimatelylead to a highly deployable and accessible online treatment targeted at core ED mechanisms.The proposed research uses highly innovative methods; we will use an all remote technology-based approach combining an online treatment with mobile technology that assesses the targetof fear extinction. The combination of an online treatment with mobile assessment allows forthe first time the creation of an engaged and targeted treatment which can rapidly bedisseminated during a critical period of care. Specific aims are to (1) collect preliminary data onthe feasibility and acceptability of the randomization of two treatment conditions after dischargefrom intensive ED treatment: a relapse-prevention online exposure protocol (n=65; ROEP) anda control treatment writing condition (n=65) (2) To test for differences between ROEP andcontrol treatment for the prevention of relapse and preliminary change on clinical ED outcomes(3) To examine if ROEP targets fear extinction and if fear extinction is associated with relapseand ED outcomes and (3b) To test if baseline differences in fear conditioning relate to changein ED outcomes across treatment. The proposed research has clinical impact. Ultimately thisproposal will lead directly to the creation and dissemination of a highly user-friendly easilyaccessible and deployable intervention that can prevent relapse in the EDs which will decreasemortality morbidity and the high costs associated with chronic treatment.

project_terms:
Acute;Address;Admission activity;Adult;Affective;Aftercare;Anorexia Nervosa;Anxiety;Behavior;Behavioral;Bulimia;Caring;Cellular Phone;Chronic;Clinical;Cognition;Cognition Disorders;Cognitive;Communities;Data;Diagnosis;Diagnostic;Dimensions;Disease remission;Eating Disorders;Exhibits;Extinction (Psychology);Food;Fright;Goals;Hospitalization;Hospitals;Individual;Inpatients;Intensive Care;Intervention;Lead;Learning;Literature;Measures;Medical;Methods;Morbidity - disease rate;Outcome;Participant;Pathology;Prevention Protocols;Prevention program;Protocols documentation;Randomized;Randomized Controlled Trials;Recovery;Relapse;Research;Service delivery model;Severities;Shapes;Symptoms;Technology;Testing;Time;Treatment Efficacy;Treatment outcome;United States National Institutes of Health;Validation;Variant;Weight;Weight Gain;Work;Writing;acceptability and feasibility;base;conditioned fear;cost;cost outcomes;critical period;dietary restriction;disorder later incidence prevention;evidence base;hospital readmission;improved outcome;individual variation;innovation;medical complication;mobile computing;mortality;prevent;public health relevance;recruit;relapse prediction;remote therapy;severe mental illness;smartphone Application;smartphone based assessment;symptomatology;targeted treatment;therapy design;user-friendly

public_health_relevance:
PROJECT NARRATIVEThis project will collect data on the feasibility acceptability efficacy and target engagement andvalidation of an online relapse-prevention treatment for eating disorders delivered afterdischarge from acute treatment. The proposed research has significant public health relevanceas it will directly lead to a highly accessible and deployable treatment that can decrease eatingdisorder relapse and the high societal burden associated with eating disorders. The proposedresearch is relevant to NIHs strategic aim 4.3 as it will lead to the creation of an innovativeevidence-based service delivery model using technology that can be easily disseminated tocommunities in need during a critical period of transition of care.


application_id: 10372094
project_number: 5R21AI156332-02
project_title: F-18 fluorodeoxysorbitol for detecting response of bacterial infection to treatment
administering_ic: NIAID
award_notice_date: 2022-01-26
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 156332
program_official: XU, ZUOYU
project_start_date: 2021-03-16
project_end_date: 2024-02-29
study_section: Imaging Guided Interventions and Surgery Study Section[IGIS]
contact_pi_person_id: 7606517
contact_pi: NG, CHIN K
other_pis: Not Applicable
congressional_district: 03
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project summary (Abstract):Bacterial infections cause significant mortality and morbidity worldwide despite the availability of antibiotics.Antibiotic resistance is one of the most urgent threats to the public's health. Klebsiella microbes are gram-negative bacteria that have the inherent adaptive ability to resist treatment and also pass along genetic materialthat facilitates drug resistance in other bacteria. Klebsiella pneumoniae (Kp) infection has created a tremendousclinical problem for many hospitals worldwide. As of today none of the current convention methods can provideearly specific diagnosis and rapid monitoring of infections in the clinic. Consequently treatment is often delayedor indefinite. The long-term goal is to develop a novel pathogen-specific and non-invasive whole-body imagingtechnique to guide patient management monitor treatment efficacy and speed drug development.The objective of this proposal is to validate F-18 fluorodeoxysorbitol (FDS) as an imaging tool for monitoringtreatment efficacy and identifying drug resistant Kp from drug sensitive Kp. The central hypothesis is that FDSis a promising PET imaging agent with simple chemistry optimal pharmacokinetics and high specificity andsensitivity for predicting treatment response to bacterial infection. The rationale underlying this proposal is thatits completion will contribute to accurate diagnosis for guiding effective treatment. The central hypothesis will betested by pursuing two specific aims: 1) Identify the optimal imaging time of FDS for 2 drug-resistant and 2 drug-sensitive Kp strains in a clinically relevant preclinical mouse model of lung infection 2) Determine the ability ofFDS PET imaging to differentiate treatment response between drug-resistant Kp strains and drug-sensitive onesin mice of lung infection. We will pursue these aims by using novel and more clinically relevant Kp mouse modelsof lung infection and a double-blinded strategy to mimic actual clinical patient situation.The proposed studies are significant and innovative because FDS PET imaging can be validated to be a usefultool to triage drug options by predicting early treatment response to bacterial infection and thus avoiding themisuse and overuse of antibiotics. The results will have an important positive impact immediately in that they willestablish an imaging technique for better understanding of bacterial infection guiding patient management andassisting drug development because they lay the groundwork to develop a suite of techniques for bettertreatment of Kp drug-resistant infections.

project_terms:
Antibiotic Resistance;Antibiotics;Bacteria;Bacterial Antibiotic Resistance;Bacterial Infections;Bacterial Pneumonia;Bioluminescence;Biopsy;Carbapenems;Categories;Ceftriaxone;Chemistry;Clinic;Clinical;Clinical Trials;Communicable Diseases;Development;Diagnosis;Discipline of Nuclear Medicine;Disease Progression;Double-Blind Method;Drug Kinetics;Drug resistance;Early treatment;Escherichia coli;Future;Genetic Materials;Goals;Gram-Negative Bacteria;Health;Hospitals;Human;Image;Imaging Device;Imaging Techniques;Imaging technology;Infection;Inflammation;Klebsiella;Klebsiella pneumoniae;Knowledge;Label;Leukocytes;Location;Lung;Lung infections;Magnetic Resonance Imaging;Methods;Microbe;Modeling;Monitor;Morbidity - disease rate;Multi-Drug Resistance;Mus;Outcome;Oxyquinoline;Patient imaging;Patients;Persons;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Positron-Emission Tomography;Pre-Clinical Model;Prediction of Response to Therapy;Public Health;Publishing;Reporting;Research;Research Proposals;Rodent;Sensitivity and Specificity;Signal Transduction;Site;Source;Specialist;Speed;Sterility;Stress;Techniques;Testing;Thigh structure;Time;Treatment Cost;Treatment Efficacy;Treatment outcome;Triage;Work;X-Ray Computed Tomography;accurate diagnosis;antibiotic resistant infections;antimicrobial;base;carbapenem resistance;cellular imaging;clinically relevant;diagnostic platform;dosage;drug development;drug-sensitive;effective therapy;emerging pathogen;evidence base;fluorodeoxyglucose;imaging agent;improved;innovation;interest;microbial;mortality;mouse model;non-invasive imaging;novel;novel therapeutics;pathogen;pre-clinical;resistant Klebsiella pneumoniae;resistant strain;response;symposium;tool;treatment planning;treatment response;whole body imaging

public_health_relevance:
Project NarrativeThis research proposal is directly relevant to public health and would advance the capability of infectious diseasespecialists to detect early response to treatment for patients with bacterial infection. This proposal to furthervalidate F-18 fluorodeoxysorbitol (FDS) as a potential PET imaging agent for gram-negative bacteria byunderstanding its ability to triage drug options could potentially allow clinicians to quickly change the treatmentplan thereby minimizing patient stress improving survival and reducing treatment costs.


application_id: 10372039
project_number: 5R01AA028246-02
administering_ic: NIAAA
award_notice_date: 2022-01-31
opportunity_number: PA-18-390
application_type: 5
activity_code: R01
ic: AA
serial_number: 028246
program_official: FREEMAN, ROBERT
project_start_date: 2021-03-15
project_end_date: 2026-01-31
study_section: Interventions to Prevent and Treat Addictions Study Section[IPTA]
contact_pi_person_id: 14470701
contact_pi: RAY, ANNE ELIZABETH
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-02-01
project_terms:
Alcohol consumption;Alcohols;Area;Behavior;Behavior Therapy;Behavioral;Clinical;Data;Data Collection;Development;Effectiveness;Ensure;Event;Feedback;Focus Groups;Future;Gold;Health;Heavy Drinking;Hybrids;Individual;Intervention;Link;Literature;Mind;Monitor;Motivation;National Institute on Alcohol Abuse and Alcoholism;Nature;Outcome;Participant;Pathway interactions;Pattern;Persons;Prevention strategy;Process;Public Health;Randomized Controlled Trials;Reporting;Research;Research Design;Risk;Sampling;Self Efficacy;Sex Behavior;Site;Students;System;Target Populations;Technology;Testing;Time;Universities;Unsafe Sex;Work;alcohol misuse;alcohol prevention;base;behavior change;binge drinking;college;design;diaries;drinking;eHealth;effectiveness evaluation;effectiveness implementation design;effectiveness implementation study;effectiveness implementation trial;evidence base;experience;flexibility;follow-up;formative assessment;group intervention;high intensity drinking;high risk;high risk sexual behavior;implementation determinants;implementation intervention;improved;innovation;intervention effect;post implementation;programs;response;scale up;sex;sexual victimization;sexually active;success;university student;usability;web-based assessment


application_id: 10371713
project_number: 3P30CA177558-09S1
project_title: UK MCC CCSG: GMaP Supplement
administering_ic: NCI
award_notice_date: 2021-09-23
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S1
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2023-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
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
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) was established more than 35 years ago as a university-based matrixcancer center at the University of Kentucky (UK) Kentucky's flagship institution of higher education. MCC isthe only National Cancer Institute (NCI)-designated Cancer Center in Kentucky a state of 4.4 million that leadsthe nation for all-site cancer incidence and mortality and serves as the MCC's catchment area. Over $347M instate institutional and philanthropic investment since recruitment of MCC Director Dr. B. Mark Evers (CS) in2009 have supported significant research and resource expansion enabling substantial new facultyrecruitment program development renovation of clinical and shared resource space and new state-of-the artinstrumentation as well as statewide education and community outreach efforts. The 119 MCC members drawfrom 28 departments in 8 UK colleges with 28 new faculty recruited since 2013. Cancer-relevant researchfunding to MCC investigators exceeds $38.7M in total annual costs an increase of $10.3M since 2012. Overthe last 4 years 9357 subjects have been accrued to interventional trials. Members have published 851cancer-focused publications since 2013 reflecting 28% intra-programmatic 16% inter-programmatic and 58%inter-institutional collaborations. Research is conducted within 4 MCC Research Programs: Cancer CellBiology and Signaling; Cancer Prevention and Control; Drug Discovery Delivery and TranslationalTherapeutics; and Genomic Instability Epigenetics and Metabolism. Five Shared Resource Facilities (SRFs)facilitate cutting-edge research by providing robust infrastructure for specialized expertise and advancedmethods: Biospecimen Procurement and Translational Pathology; Biostatistics and Bioinformatics; CancerResearch Informatics; Flow Cytometry and Cell Sorting; and Redox Metabolism. Two new SRFs (Behavioraland Community-Based Research and Oncogenomics) are in development. Significant achievements include:development of an NCI-sponsored early therapeutics program including an active Molecular Tumor Board andPrecision Medicine Center; expansion of the MCC Network from 8 to 24 sites; establishment of a regionalMetabolomics Center (U24); award of 2 new cancer-related centers  a Center of Biomedical ResearchExcellence (COBRE) in Cancer and Metabolism and a Center for Appalachian Research in EnvironmentalSciences; and expansion of community outreach/education initiatives across the state. MCC research focuseson Kentucky's most serious cancer burdens with emphasis on the distressed Appalachian Kentucky regionwhere cancer incidence and mortality rates surpass those for the entire state. The MCC brings unique basicclinical and population research strengths to this mission. These strengths are integral to all MCC programsand collectively provide robust capacity to deliver transformative interventional research to an importantunderserved priority population thereby contributing to national efforts to conquer cancer through discoveryand clinical translation cancer prevention and community outreach.

project_terms:
Achievement;Address;Administrative Supplement;Appalachian Region;Award;Basic Science;Behavioral Research;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Cell Separation;Cellular biology;Centers of Research Excellence;Clinical;Clinical Research;Clinical Trials;Collaborations;Community Outreach;Development;Distress;Ecology;Education;Education and Outreach;Epigenetic Process;Faculty Recruitment;Flow Cytometry;Funding;Galanin;Genomic Instability;Geography;Healthcare;Incidence;Informatics;Infrastructure;Institution;Intervention Studies;Intervention Trial;Investments;Kentucky;Malignant Neoplasms;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Outcome;Oxidation-Reduction;Pathology;Patients;Population;Population Research;Population Sciences;Prevention;Program Development;Publications;Publishing;Research;Research Personnel;Research Training;Resource Sharing;Resources;Signal Transduction;Site;Therapeutic;Translational Research;Universities;Validation;anticancer research;authority;base;bench to bedside;cancer genomics;cancer health disparity;cancer prevention;cancer research center director;cancer site;clinical development;clinical translation;college;community based research;community engagement;cost;drug discovery;health disparity;higher education;instrumentation;inter-institutional;member;metabolomics;mortality;precision medicine;programs;ranpirnase;recruit;tumor;tumor metabolism

public_health_relevance:
PROJECT NARRATIVE The Markey Cancer Center the only NCI-designated Cancer Center serving 4.4 million Kentuckians in itsstatewide catchment area has the institutional authority for all cancer-relevant activities at the University ofKentucky (UK) and within the UK HealthCare enterprise. The center's mission is to reduce cancer incidenceand mortality through an integrated comprehensive program of cancer research treatment educationprevention and community engagement. Thus the Markey Cancer Center delivers in-depth and impactfulresearch programs in basic translational and population science including the development of clinical trials toaddress Kentucky's unique cancer burden and to accelerate bench-to-bedside translational outcomes thatwill reduce serious health disparities and significantly impact patients the state and the nation.


application_id: 10371341
project_number: 1K23MH126211-01A1
project_title: A Precision Medicine Approach to Target Engagement for Emotion Regulation
administering_ic: NIMH
award_notice_date: 2021-12-23
opportunity_number: PA-20-206
application_type: 1
activity_code: K23
ic: MH
serial_number: 126211
suffix: A1
program_official: CHAVEZ, MARK RAY
project_start_date: 2022-01-01
project_end_date: 2025-12-31
study_section: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]
contact_pi_person_id: 14333057
contact_pi: SOUTHWARD, MATTHEW WAYNE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Aftercare;Algorithms;Anger;Anxiety;Behavioral;Behavioral Model;Borderline Personality Disorder;Characteristics;Clinical;Consensus;Data;Development;Disease;Disease remission;Ecological momentary assessment;Educational process of instructing;Emotional;Emotional disorder;Emotions;Experimental Designs;Explosion;Goals;Influentials;Intervention;Investigational Therapies;Learning;Machine Learning;Maintenance;Mediating;Mental Health;Mental disorders;Mentored Patient-Oriented Research Career Development Award;Multimedia;National Institute of Mental Health;Nature;Outcome;Participant;Patient Representative;Patient Self-Report;Patient-Focused Outcomes;Patients;Persons;Phase;Population;Process;Productivity;Psychopathology;Randomized;Reporting;Research;Research Domain Criteria;Research Training;Role;Sampling;Scientist;Signal Transduction;Statistical Methods;Strategic Planning;Symptoms;Techniques;Testing;Therapeutic;Time;Training;Trauma;Work;base;behavior measurement;behavioral health;career;cost;depressive symptoms;design;efficacious intervention;emotion dysregulation;emotion regulation;emotional experience;emotional functioning;evidence base;experience;functional outcomes;health care availability;health care service;improved;in vivo;indexing;individual patient;novel;precision medicine;predictive test;prospective;response;skills;time use


application_id: 10370306
project_number: 5P20GM130456-03
project_title: Immunomodulatory Therapy for Bone Regeneration
administering_ic: NIGMS
award_notice_date: 2022-02-09
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: MCGUIRL, MICHELE
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9
subproject_number: 6618
contact_pi_person_id: 14078198
contact_pi: TIRUVANNAMALAI ANNAMALAI, RAMKUMAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Inflammation plays a vital role during bone formation resorption and fracture healing. The process of fracture healing is biologically entangled with that of acute inflammation and innate immunity. A proper sequence and dose of inflammatory signals are critical for proper bone healing. Macrophages one of the first cells that infiltrate the fracture site are indispensable for fracture healing as they promote osteoblastic differentiation and vascularization. Also it is well recognized that mechanical conditions influence callus development and the type and extent of osteogenesis during fracture. But most work on the macrophage response in the context of fracture healing has focused on activation mediated by biochemical signals. The biophysical parameters of the fracture microenvironment especially matrix mechanics and their influence on macrophage immunophenotypes are largely overlooked. Our overall goal is to elucidate the influence of biophysical cues on macrophage function to develop an immunomodulatory platform reducing the burden of bone diseases in patients.  Macrophages respond to changes in extracellular matrix mechanics through actin-cytoskeletal reorganization nuclear deformation and gene expression. We hypothesize that biophysical forces in the form of substrate mechanics elicit transcriptional control of macrophages via a transcriptional activator MRTF-A release (during actin polymerization) and redistribution of a cell signaling mediator HDAC3 (chromatin compaction). The two independent aims for this project are: 1) Elucidate the actin cytoskeleton-mediated transcriptional control in macrophages in a murine fracture model 2) Engineer immunomodulatory materials with suitable viscoelastic mechanics to guide the transcriptional machinery of macrophages to promote bone regeneration.  Overall our proposed research provides insights into the role of the innate immune response in fracture healing and develops next-generation immunomodulatory materials for therapeutic bone regeneration. Hence our research aligns well with the CPRI COBRE mission to facilitate translational chemical biology research to advance treatments and strategies to address significant health challenges.

project_terms:
Actins;Acute;Address;Biochemical;Biology;Biophysics;Bone Diseases;Bone Regeneration;Bone callus;Cells;Centers of Research Excellence;Chemicals;Chromatin;Cues;Cytoskeletal Modeling;Cytoskeleton;Development;Dose;Engineering;Extracellular Matrix;Fracture;Gene Expression;Genetic Transcription;Goals;HDAC3 gene;Health;Immunophenotyping;Inflammation;Inflammatory;Innate Immune Response;Mechanics;Mediating;Mediator of activation protein;Mission;Modeling;Mus;Natural Immunity;Nuclear;Osteogenesis;Patients;Pharmacologic Substance;Play;Process;Research;Role;Signal Transduction;Site;Therapeutic;Transcription Coactivator;Transcriptional Regulation;Vascularization;Work;biophysical properties;bone fracture repair;bone healing;immunomodulatory therapies;immunoregulation;innovation;insight;macrophage;next generation;osteoblast differentiation;polymerization;response;treatment strategy;viscoelasticity


application_id: 10369893
project_number: 1R21AI159194-01A1
project_title: Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection
administering_ic: NIAID
award_notice_date: 2021-09-22
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 159194
suffix: A1
program_official: BAQAR, SHAHIDA
project_start_date: 2021-09-22
project_end_date: 2023-08-31
study_section: Immunity and Host Defense Study Section[IHD]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Enterotoxigenic Bacteroides fragilis (ETBF) has been associated with acute diarrhealinflammatory bowel disease and colorectal cancer (CRC). ETBF oncogenesis requires thecoordinated action of its toxin BFT and an inflammatory response to orchestrate the recruitmentof myeloid cells but how ETBF recruits colonic myeloid cells remains poorly understood. S1p actsas bioactive sphingolipid messengers influencing the myeloid cells migration and regulatingcolonic inflammation. However whether ETBF integrates sphingolipid metabolites to determinethe metabolism of colonic myeloid cells needs to be explored. Recent evidence indicates thatremodeling of myeloid cells metabolism is central to the induction of innate immune response.We found ETBF infection alters the activity of sphingosine kinase which is linked to metabolicremodeling histone acetylation and PGE2 production in myeloid cells. Two integrated specificaims are proposed to test: Aim 1 will determine how ETBF infection regulates inflammatorymyeloid cells accumulation in the colon. Aim 2 will determine if ETBF alteration of acetyl-CoAcontributes to metabolic remodeling in myeloid cells via PPAR activation. Deeper understandingof the proper role of sphingolipids and their enzymes in controlling the intestinal immuneproperties and in promoting the pathogenesis and progression of colitis will generate newperspectives in the development of sphingolipid-centered therapeutic strategies that control theonset and perpetuation of the ETBF-induced gut inflammation.

project_terms:
Acetyl Coenzyme A;Acute Diarrhea;Anaerobic Bacteria;ApcMin/+ mice;Bacteroides fragilis;Cell Proliferation;Cell physiology;Cells;Cellular Metabolic Process;Ceramidase;Ceramides;Colitis;Colon;Colorectal Cancer;Data;Development;Diet;Dinoprostone;Disease;Environment;Enzymes;Epithelial;Epithelial Cells;Fatty Acids;General Population;Genes;Histone Acetylation;Human;ITGAM gene;Immune;Infection;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Innate Immune Response;Interleukin-17;Intestines;Lead;Link;Lipids;Liver;Lymphocyte Function;Metabolic;Metabolism;Modeling;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Nuclear;PPAR gamma;PTGS2 gene;Pathogenesis;Pathway interactions;Phosphorylation;Production;Property;Proteins;Reaction;Regulation;Role;Shapes;Signal Transduction;Sphingolipids;Sphingosine;Steroids;Testing;Therapeutic;Toxin;Translating;blood glucose regulation;cell motility;colon tumorigenesis;dietary sphingolipids;extracellular;gene induction;granulocyte;gut bacteria;gut dysbiosis;histone modification;inflammatory disease of the intestine;intestinal epithelium;lipid metabolism;microbial;migration;monocyte;new therapeutic target;polarized cell;promoter;recruit;response;sphingosine 1-phosphate;sphingosine kinase;tumorigenesis

public_health_relevance:
Project NarrativeThis proposal provides the basis for a better understanding of the mechanisms for enterotoxigenic Bacteroidesfragilis-triggered gut inflammation and may lead to the identification of novel therapeutic targets.


application_id: 10369846
project_number: 3R34MH123601-01S1
project_title: Increasing Treatment Efficiency Using SMART Methods for Personalize Care
administering_ic: NIMH
award_notice_date: 2021-06-25
opportunity_number: PA-21-071
application_type: 3
activity_code: R34
ic: MH
serial_number: 123601
suffix: S1
program_official: VILLATTE, JENNIFER L
project_start_date: 2020-07-20
project_end_date: 2023-06-30
contact_pi_person_id: 9522329
contact_pi: SAUER-ZAVALA, SHANNON E
other_pis: LANGER, DAVID A
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractAnxiety and depressive disorders are highly prevalent costly and debilitating representing a serious publichealth concern. Although time-limited efficacious interventions have been developed for these commonconditions these treatment protocols often require more sessions than patients in community practice typicallyattend. Thus it is critical to increase the efficiency of our interventions such that the skills that drive therapeuticchange are presented as early as possible. Transdiagnostic interventions designed to directly target coreprocesses implicated in the development of a range of conditions may increase treatment efficiency bysimultaneously leading to improvements across comorbid conditions. However transdiagnostic treatmentscontain multiple treatment elements (modules) and it is possible that some skills may be better suited for targetengagement based on each patients clinical presentation; prioritization of those modules may lead to earlier andmore robust symptom improvements. Unfortunately we lack empirical evidence to guide treatment planning sothat care is personalized to the patients unique strengths and weaknesses. Additionally evidence-baseddecision rules regarding when to terminate treatment based on promising early markers of improvement ratherthan complete symptom remission may also improve treatment efficiency making care available to a greaternumber of individuals. It is also possible that engagement of core processes may serve as an early indicationthat a sufficient dose of treatment has been received aiding decisions about when to discontinue care. Theproposed study will determine the feasibility tolerability and acceptability of a study that tests: 1) personalizedtreatment delivery (i.e. module sequencing and treatment discontinuation timing) aimed at increasing theefficiency of care and 2) the research protocol designed to evaluate the effects of this personalized care. Asample of 60 participants with heterogeneous anxiety disorders (and comorbid conditions including depression)will be enrolled in a pilot sequential multiple assignment randomized trial (SMART). Patients will be randomlyassigned to one of three sequencing conditions: transdiagnostic treatment administered in its standard moduleorder module sequences that prioritize capitalizing on relative strengths and module sequences that prioritizecompensating for relative weaknesses. Next after 6 sessions participants will be randomly assigned to eithercontinue or discontinue treatment to evaluate post-treatment change at varying levels of target engagement.This proposal will enable us to 1) test the feasibility acceptability and tolerability of the research protocoltreatment sequencing conditions and early treatment discontinuation 2) determine whether a preliminary signalthat capitalization or compensation module sequencing improves treatment efficiency exists and 3) explorepreliminary associations between core process engagement at treatment discontinuation and later symptomimprovement. The proposed study and the subsequent research it will support will inform evidence-baseddecision rules to make existing treatments more efficient ultimately reducing patient costs and increasing themental health service systems capacity to address the needs of more individuals.

project_terms:
Achievement;Address;Aftercare;Anxiety Disorders;Caring;Clinical;Common Core;Community Practice;Data;Data Collection;Depressive disorder;Development;Disease remission;Dose;Early treatment;Effectiveness;Elements;Enrollment;Financial compensation;Goals;Individual;Intervention;Lead;Mental Depression;Mental Health Services;Methods;National Institute of Mental Health;Outcome;Participant;Patients;Process;Protocols documentation;Public Health;Randomized;Reaction;Research;Research Design;Research Domain Criteria;Sampling;Sequential Multiple Assignment Randomized Trial;Signal Transduction;Symptoms;System;Testing;Therapeutic;Time;Training;Treatment Protocols;Work;anxiety symptoms;base;comorbidity;cost;design;dosage;efficacious intervention;emotional experience;evidence base;feasibility testing;improved;novel;personalized care;personalized medicine;psychologic;recruit;research study;response;service intervention;skills;standard care;symptomatic improvement;therapy design;therapy development;treatment of anxiety disorders;treatment planning

public_health_relevance:
Increasing the efficiency of existing treatments for anxiety and depressive disorders is critical for substantiallyimproving the treatments impact on public health. This project assesses the feasibility acceptability andtolerability of a research study that (1) compares the efficiency of multiple sequencing approaches to treatmentand (2) tests if core process engagement (avoidant reactions to emotional experiences) can serve as an indicatorof sufficient treatment dose.


application_id: 10369811
project_number: 1K23DK128562-01A1
administering_ic: NIDDK
award_notice_date: 2021-12-08
opportunity_number: PA-20-205
application_type: 1
activity_code: K23
ic: DK
serial_number: 128562
suffix: A1
program_official: GREER, RAQUEL CHARLES
project_start_date: 2022-01-01
project_end_date: 2026-11-30
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 16335091
contact_pi: FLANNERY, ALEXANDER H
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_title:
Classical and Alternative Renin-Angiotensin System Dysregulation in Sepsis-Associated AKI: A Reverse Translation Approach

project_abstract:
PROJECT SUMMARY/ABSTRACTThis proposal includes a five-year research career development program to study classical and alternativerenin-angiotensin system (RAS) dysregulation in sepsis-associated acute kidney injury (SA-AKI). Thecandidate is currently an Assistant Professor at the University of Kentucky College of Pharmacy. The proposalbuilds on the candidates strong background in clinical research on AKI and integrates mentorship fromestablished investigators in sepsis AKI RAS therapeutics and murine models of SA-AKI. The proposedcareer development activities will equip the candidate with the skills necessary to become established as anindependent clinical and translational scientist conducting patient-oriented research on SA-AKI. Over 4 millionpatients are hospitalized annually with AKI and sepsis is estimated to contribute to 26-50% of all cases.Current therapy is limited to supportive care and kidney replacement therapy. Recent evidence suggestssepsis causes a disruption in angiotensin converting enzyme (ACE) and ACE2 that could severely dysregulatethe RAS. This disruption may ultimately result in local excess of the proinflammatory classical RAS anddeficiencies in the counter-regulatory anti-inflammatory alternative RAS (Alt-RAS). An intra-renal RASoperating independently from the circulatory RAS may drive pathophysiology and urinary RAS biomarkershave been proposed as surrogate markers of intra-renal RAS activation. Using a bedside-to-bench approachour overall objective is to quantify the classical and Alt-RAS disturbances present at the circulatory and tissuelevel in SA-AKI and evaluate the relationship between the extent of this disturbance and major adverse kidneyevents. Our central hypothesis is that a deficiency of the regenerative RAS or Alt-RAS exists relative to theclassical RAS in SA-AKI at the circulatory and tissue level and that the degree of this imbalance differentiallyassociates with outcomes in patients with SA-AKI. We propose three specific aims to accomplish this: (1) Todetermine the relationship between RAS dysregulation kidney biomarkers of tubular injury and function andmajor adverse kidney events within 30 days (MAKE-30) in SA-AKI (2) To assess the relationship betweenurinary biomarkers of intra-renal RAS activation and MAKE outcomes out to one year in critically ill patientswith SA-AKI and heterogenous AKI and (3) To test the hypothesis that the kidney RAS peptide metabolomeand receptor expression profile shift to a regenerative or Alt-RAS deficiency in a murine model of SA-AKI andthat the degree of Alt-RAS deficiency (relative to classical RAS) corresponds to the degree of kidney injury andintra-renal RAS activation. Career development activities that align with this research include: training inapplication of laboratory assays including mass spectrometry advancement of statistical analysis skills withlongitudinal data and introductory machine learning and learning pre-clinical models of SA-AKI. This proposalsupports the mission of NIDDK by furthering the understanding of SA- AKI a leading cause of AKI and kidneycomplications impacting the publics health and quality of life.

project_terms:
ACE2;Acute;Acute Renal Failure with Renal Papillary Necrosis;Angiotensin II;Angiotensinogen;Angiotensins;Anti-Inflammatory Agents;Biological Assay;Biological Markers;Cecum;Chronic Disease;Chronic Kidney Failure;Classification;Clinical;Clinical Research;Critical Illness;Data;Development;End stage renal failure;Etiology;Event;Evolution;Frequencies;Functional disorder;Future;Health;Infection;Injury;Injury to Kidney;Kentucky;Kidney;Laboratories;Learning;Machine Learning;Mass Spectrum Analysis;Measurement;Measures;Mentorship;Mission;Modeling;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Outcome;Patient-Focused Outcomes;Patients;Peptides;Peptidyl-Dipeptidase A;Pharmacy facility;Pre-Clinical Model;Program Development;Prospective cohort;Proteins;Public Health;Quality of life;Recovery;Renal Replacement Therapy;Renin;Renin-Angiotensin System;Research;Research Personnel;Risk;Risk Marker;Role;Sepsis;Septic Shock;Statistical Data Interpretation;Supportive care;Surrogate Markers;Testing;Therapeutic;Tissues;Training;Translational Research;Translations;Tubular formation;Universities;Up-Regulation;Urine;bench to bedside;biobank;career development;clinical care;cohort;college;complex biological systems;improved;metabolome;metabolomics;molecular marker;mortality;mouse model;patient oriented research;patient subsets;professor;receptor;receptor expression;regenerative;renal damage;response;skills;translational model;translational scientist;urinary

public_health_relevance:
PROJECT NARRATIVESepsis a dysregulated response to infection is the leading cause of acute kidney injury impacting millions ofpatients every year and has no proven therapy aside from supportive care. The proposed research willinvestigate the role of a complex biologic system the renin-angiotensin system and its relationship with kidneyinjury in sepsis. By increasing our understanding future therapies may be developed that help treat patientswith this condition and improve meaningful short- and long-term patient outcomes.


application_id: 10369724
project_number: 5R01NS112304-02
project_title: Propriopsinal neuron function in normal and post-SCI locomotion
administering_ic: NINDS
award_notice_date: 2022-02-04
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 112304
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2026-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: DANNER, SIMON MICHAEL
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits many ofthe functional details of those circuits and their contributions to recovery following spinal cord injury (SCI)remain to be determined. Recent development of powerful molecular tools enables functional dissection ofneural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling. We will combine thesetools with sophisticated gait and kinematic analyses that includes the full repertoire of speed dependent gaitsto provide the functional and anatomical information necessary for building and refining an advanced neuro-biomechanical computer model of the rat spinal cord body and limbs. We will focus on two classes of spinalcord interneurons the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons thatinterconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements andinvestigate their role in the intact spinal cord and after SCI using both hemisection and contusion models. Ourpreliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gaitexpression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisinglysilencing these neurons after an incomplete contusion injury results in better overground locomotion a resultthat is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-basedtrans-synaptic labeling we will determine the sensory descending and propriospinal inputs onto both LAPNsand LDPNs. We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as newanatomical data (Aim 2) to build and refine our computational model (Aim 3). Then in vivo experiments andcomputer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissuralLAPNs and LDPNs play in locomotor behavior including the full range of locomotor gaits and in recoveredfunction after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of longpropriospinal neurons represents an important step towards the development of new therapeutic tools forrecovery after SCI.

project_terms:
Adult;Anatomy;Animals;Axon;Behavior;Biomechanics;Cervical;Characteristics;Computer Models;Computer Simulation;Contusions;Data;Data Set;Development;Dissection;Forelimb;Gait;Goals;Hindlimb;Injury;Interneurons;Ipsilateral;Knowledge;Label;Lateral;Left;Limb structure;Locomotion;Mediating;Modeling;Molecular;Movement;Musculoskeletal System;Neurons;Physiological;Play;Population;Publishing;Rattus;Recovery;Reverse engineering;Role;Running;Sensory;Source;Speed;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Structure;Structure-Activity Relationship;Synapses;Techniques;Testing;Thoracic spinal cord structure;Validation;Viral;Virus;Walking;animal data;base;biomechanical model;central pattern generator;design;experimental study;in silico;in vivo;kinematics;model development;neural circuit;neurotransmission;novel;novel therapeutics;predictive modeling;sensory input;tool

public_health_relevance:
Project Narrative This multi-PI project focuses on the role of the long ascending and descending propriospinalneurons (LAPNs LDPNs) in the control of locomotion and recovery after a spinal cord injury. We will use acombination of viral based synaptic silencing retrograde and trans-synaptic tracing and comprehensive gaitand kinematic analysis to aid the development of a neuro-biomechanical computer model and to generateimportant new knowledge of spinal locomotor circuitry.


application_id: 10369658
project_number: 5R01HL141191-04
project_title: The role of bioactive lipids in CMC-induced myocardial repair.
administering_ic: NHLBI
award_notice_date: 2022-03-17
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141191
program_official: WONG, RENEE P
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11176762
contact_pi: WYSOCZYNSKI, MARCIN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
A variety of sterile diseases including myocardial infarction (MI) and subsequent repair involve theimmune system. Although unresolved inflammation exacerbates heart failure depletion of macrophages in theinfarcted myocardium leads to left ventricular (LV) rupture and death. Thus indiscriminate immunosuppressionis not a viable approach. Nevertheless persistent inflammation in the failing heart must be addressed.Unfortunately significant barriers to progress remain because we do not know how immune cells regulatemyocardial repair and what determines their harmful versus salutary actions. Cell therapy provides a uniqueopportunity for understanding how immune cells contribute to myocardial repair and recent findings implicatemacrophages as direct contributors to cell therapy-mediated myocardial repair. Although few injected cellssurvive long-term in the recipient common benefits include reduction of fibrosis enhanced angiogenesis andimprovement in LV function. These improvements occur independently of differentiation of the injected cellsinto cardiomyocytes suggesting that cell therapy must recruit endogenous repair mechanisms; however thesemechanisms remain unidentified. Our preliminary data show that injection of cardiac mesenchymal cells(CMCs) into the infarcted heart promotes accumulation of reparative macrophages decreases fibrosis andimproves LV function. Co-culture of CMCs with macrophages favors a reparative macrophage program and itmay be due to CMC-derived bioactive lipidssuch as prostaglandins leukotrienes and resolvins which offertestable explanations of the `paracrine hypothesis' of cell-mediated repair. Thus we propose that CMCs recruitmonocytes and activate reparative macrophages which promote favorable anti-fibrotic cardiac remodeling andimprove cardiac function in the infarcted heart. In the current project we will determine the capacity for thebioactive lipid synthesis and secretion in CMCs. Mass spectrometry will be performed to explore the role ofCox and Lox pathways in bioactive lipid synthesis in CMCs. Moving forward we will ascertain the role bioactivelipids in macrophage recruitment and their reparative function with the particular focus on macrophage BLT-1receptor and its CMC-derived ligands. Finally we will determine the reparative effect of CMCs with enhancedbioactive lipid synthesis in mouse model of HF. This project will be the first systematic analysis of bioactivelipid synthesis profile in reparative CMCs. This project will provide novel insights into not only pathways ofbioactive lipid synthesis in CMC but also the mechanisms regulating cell therapy-mediated myocardial repair.

project_terms:
Acute;Address;Affect;Arachidonate 5-Lipoxygenase;Cardiac;Cardiac Myocytes;Catheterization;Cell Therapy;Cells;Cellular Structures;Cessation of life;Coculture Techniques;Data;Disease;Echocardiography;Fibrosis;Genes;Genetic;Heart;Heart failure;Homeostasis;Immune;Immune response;Immune system;Immunohistochemistry;Immunosuppression;In Vitro;Infarction;Inflammation;Inflammatory Response;Injections;Kinetics;LTB4R gene;Left;Left Ventricular Function;Left ventricular structure;Leukotriene B4;Leukotrienes;Ligands;Link;Lipid Synthesis Pathway;Lipids;Lipoxygenase;Mass Spectrum Analysis;Mediating;Mesenchymal;Mus;Myocardial;Myocardial Infarction;Myocardium;Pathway interactions;Phenotype;Production;Property;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Regulation;Research Personnel;Role;Rupture;Severities;Sterility;Testing;Ventricular;angiogenesis;cyclooxygenase 1;cyclooxygenase 2;genetic manipulation;heart function;heart preservation;immunoregulation;improved;in vivo;in vivo Model;insight;knock-down;lipid metabolism;macrophage;monocyte;mouse model;novel;novel strategies;paracrine;preservation;programs;receptor;recruit;repair function;repaired;reparative capacity

public_health_relevance:
R01 Project narrativeThe immune system is an important component of myocardial repair after myocardial infarction. In this projectwe will examine how cardiac mesenchymal cell treatment affects immune system and delineate mechanismdictating myocardial repair.


application_id: 10369462
project_number: 1RF1NS122028-01A1
project_title: Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease
administering_ic: NINDS
award_notice_date: 2022-01-31
opportunity_number: PAR-19-070
application_type: 1
activity_code: RF1
ic: NS
serial_number: 122028
suffix: A1
program_official: YIN, XILING
project_start_date: 2022-02-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZRG1 MDCN-M (91)]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: WANG, DANNY JJ
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
project_abstract:
Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel DiseaseVascular cognitive impairment and dementia (VCID) is common in older adults and is a majorpublic health risk. VCID affects the network of small blood vessels that supply all parts of thebrain resulting in cognitive decline. Clinical trials have been hampered by the lack of non-invasive tools to detect early stages of VCID. Consequently innovative tools for theidentification of early-stage VCID have become a major research priority. The blood-brainbarrier (BBB) may be a key system affected early in the course of VCID. Recent advances inthe development of a novel diffusion-weighted ASL (DW-ASL) sequence and post-processinganalyses have made it possible to quantify water exchange rate across the BBB a metric ofBBB functioning. Our preliminary results using this novel sequence suggest that low waterexchange across the BBB (low kw) is associated with high concentrations of plasma vascularinflammatory markers and poor cognitive performance suggesting that it may represent anearly marker of VCID. Longitudinal research is required to test this possibility. This proposalseeks to assess the accuracy of low kw as a predictor of subsequent neurocognitive declines.We will also test the possibility that low kw is associated with oxidative stress assessed viacerebrospinal fluid (CSF) isoprostane levels. We propose to study 140 healthy older adults atbaseline using DW-ASL plasma inflammatory markers and CSF measures of isoprostanes Ap-tau and t-tau. In addition structural neuroimaging measures will be obtained and quantifiedincluding regional volumes white matter hyperintensity (WMH) volumes diffusion tensorimaging for quantification of regionally distributed white matter abnormalities and susceptibilityweighted imaging for quantification of cerebral microbleeds. A subset of participants willcomplete the same neuroimaging and biofluid measures approximately 3 years later. We aim toidentify the relationship between baseline BBB water exchange and subsequent WMH growth(Aim 1); cognitive declines (Aim 2) and biofluid indices of oxidative stress (Aim 3). The overallhypothesis we will test is that that low water exchange rate assessed with a novel DW-ASLsequence represents an early marker BBB dysfunction associated with later WMH growthcognitive declines and oxidative stress.

project_terms:
Affect;Amino Acids;Amyloid beta-Protein;Biological;Biological Markers;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrospinal Fluid;Clinical Trials;Cognitive;Data;Development;Diffusion Magnetic Resonance Imaging;Disease Progression;Early Diagnosis;Early identification;Elderly;Extravasation;Functional disorder;Glucose;Goals;Growth;Image;Impaired cognition;Individual;Isoprostanes;MRI Scans;Magnetic Resonance Imaging;Measures;Methods;Microvascular Dysfunction;Modeling;Monitor;Neurocognitive Deficit;Neuropsychology;Outcome Study;Oxidative Stress;Participant;Plasma;Predisposition;Public Health;Regression Analysis;Research;Research Priority;Risk;Risk Factors;Sampling;Serum Albumin;System;Testing;Therapeutic Intervention;Water;White Matter Hyperintensity;arterial spin labeling;blood-brain barrier function;cerebral microbleeds;cerebrovascular;cognitive performance;dementia risk;diffusion weighted;early detection biomarkers;executive function;follow-up;high risk;improved;indexing;inflammatory marker;innovation;neuroimaging;neuroimaging marker;novel;novel marker;pre-clinical;response;tau Proteins;tau-1;tool;vascular cognitive impairment and dementia;vascular risk factor;white matter

public_health_relevance:
Project NarrativeNovel markers of vascular cognitive impairment and dementia (VCID) are neededfor early identification of individuals at high risk for developing VCID. This study willtest the accuracy of a new neuroimaging marker of blood-brain-barrier function asa predictor of VCID-related neurocognitive declines. It is anticipated that findingsfrom this study may improve the ability to detect early VCID and track changes incognitive status during disease progression.


application_id: 10369013
project_number: 5R21AI146542-02
project_title: Antimicrobial peptide mimetic activity against Candida auris
administering_ic: NIAID
award_notice_date: 2022-01-31
opportunity_number: PA-19-053
application_type: 5
activity_code: R21
ic: AI
serial_number: 146542
program_official: LIU, BAOYING
project_start_date: 2021-03-11
project_end_date: 2024-02-29
study_section: Special Emphasis Panel[ZRG1-IDM-Y(82)S]
contact_pi_person_id: 1891127
contact_pi: DIAMOND, GILL
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary / AbstractCandida auris is a recently emerged pathogenic fungus whose infections lead to high mortality in invasivenosocomial infections world-wide. The fungus can persist long-term and thus can often cause outbreaks. Inaddition C. auris exhibits high levels of resistance to all classes of antifungal drugs. Even those strains whichare initially susceptible to echinochandins the treatment of choice rapidly develop resistance. Thus there is anurgent need to develop new antifungal drugs to treat this pathogen. Antimicrobial peptides (AMPs) are naturallyoccurring broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeuticantibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance tothem. Unfortunately they are expensive to produce and are often sensitive to protease digestion. We haverecently demonstrated the potent antifungal activity of a series of inexpensive nonpeptidic compounds that mimicAMPs in both structure and activity. These AMP mimetics exhibit strong activity against C. albicans in bothplanktonic and biofilm forms as well as against drug-resistant non-albicans Candida clinical isolates. The activityis rapid and fungicidal against both blastoconidia and hyphal forms and resistant strains of Candida have failedto be generated suggesting that they are attractive candidates as drugs to treat C. auris infections. Most recentlyit was demonstrated that these mimetics exhibit potent in vivo activity in two mouse models of oral candidiasisand in a model of invasive candidiasis with low in vivo systemic toxicity. Indeed preliminary data show potentactivity of newly designed mimetics against C. auris in vitro. These initial results support the hypothesis thatthese compounds are active and non-toxic and can be developed into novel therapeutic antifungal agents totreat C. auris infections. In order to obtain sufficient data to investigate this in depth this exploratory studyproposes to examine the activity of AMP mimetics against C. auris. To address this two aims are proposed: 1)Quantify the antifungal activity of select AMP mimetics against C. auris clinical isolates and evaluatethe development of resistance in vitro; 2) Quantify the kinetics and activity of select AMP mimetics inmouse models of C. auris infection. Successful completion of these aims will provide the basis for futurestudies of these mimetic compounds as a treatment for C. auris and potentially other emerging fungalpathogens.

project_terms:
Address;Antibiotics;Antifungal Agents;Candida;Candida albicans;Candida auris;Candidiasis;Cations;Characteristics;Chemistry;Clinical;Communicable Diseases;Dangerousness;Data;Development;Digestion;Disease Outbreaks;Drug Kinetics;Drug resistance;Environment;Exhibits;Future;Goals;Hour;Immunocompromised Host;In Vitro;Individual;Industrial fungicide;Infection;Kidney;Kinetics;Lead;Membrane;Microbe;Microbial Biofilms;Modeling;Multi-Drug Resistance;Nosocomial Infections;Oral candidiasis;Peptide Hydrolases;Pharmaceutical Preparations;Publishing;Research;Resistance;Resistance development;Series;Structure;Testing;Therapeutic;Toxic effect;Toxicology;antimicrobial drug;antimicrobial peptide;base;design;dosage;effective therapy;experimental study;fungus;immunosuppressed;in vivo;mimetics;mortality;mouse model;multi-drug resistant pathogen;novel therapeutics;pathogen;pathogenic fungus;peptidomimetics;resistant strain;small molecule;synergism;systemic toxicity;treatment choice;treatment response

public_health_relevance:
Project NarrativeCandida auris is a recently identified often fatal fungal pathogen that is resistant to many standard antifungaldrugs. We hypothesize that a new class of molecules based on naturally occurring antimicrobial peptides whichexhibits potent activity against other species of Candida and to which fungi do not readily develop resistancecan be developed as a new treatment for this dangerous infectious disease. We propose to test these moleculesagainst C. auris to identify ones that could be further developed into new antifungal drugs.


application_id: 10368994
project_number: 5R03CA259670-02
project_title: Statistical methods for cancer progression delineation and subtype identification
administering_ic: NCI
award_notice_date: 2022-07-01
opportunity_number: PAR-20-052
application_type: 5
activity_code: R03
ic: CA
serial_number: 259670
program_official: MILLER, DAVID J
project_start_date: 2021-07-01
project_end_date: 2024-06-30
study_section: ZCA1-SRB-2(J2)P
contact_pi_person_id: 10631406
contact_pi: WANG, CHI
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 Carcinogenesis is a complex process involving somatic mutations in a number of key biological pathwaysand processes. Full study of the temporal order of somatic mutation occurrences is very important tounderstand biological mechanisms of cancer development and to inform new therapeutic targets and treatmentoptions. The first and most recognized example of order of mutations is from colon cancer which is frequentlyinitiated by mutations that affect the Wnt signaling pathway and then progress upon subsequent mutations ingenes involved in MAPK PI3K TGF-beta and p53 signaling pathways. However for many other cancer typestemporal orders of mutations are still largely unknown. Somatic mutation profiling via high throughput DNAsequencing has provided an unprecedented opportunity for using statistical/computational methods to studycancer progression. We and others have developed methods to infer temporal order of somatic mutationsbased on combining mutation profile data from a cohort of patients. However one major limitation of currentmethods is that they only consider presence or absence of mutations in a patients tumor but do not take intoaccount intra-tumoral heterogeneity (ITH). The ITH refers to the presence of multiple cell populations i.e.subclones with distinct mutation profiles within a patients tumor. The ITH which can be inferred from eithersingle-/multi-region bulk sequencing or single cell sequencing is usually characterized by a phylogenetic treewith nodes in the tree indicating different subclones and edges indicating the evolutionary relationships ofsubclones. As a phylogenetic tree describes the temporal order of mutations within an individual patientstumor incorporating such in-depth intra-patient information into the tumor progression analysis across patientsis likely to substantially increase the power and accuracy of the analysis. Another important priority in cancerresearch is to identify molecular subtypes. As cancer is a complex disease patients of the same cancer typemay have very different prognoses and responses to therapy. Further classifying patients into subtypes allowsclinicians to better predict a patients clinical outcomes and design more personalized treatment strategies. Byharnessing omics profiling data statistical/machine learning has emerged as a powerful tool to identifymolecular cancer subtypes. However due to the high complexity of cancer omics data and limited sample sizeit is still challenging to obtain stable and biologically interpretable results. Recently it has been advocated thatincorporating biological knowledge and structure into the construction of statistical/machine learning models isa viable approach to improve the mechanistic interpretability and robustness of the models. To advancecurrent capabilities we propose to develop new statistical methods to better estimate the temporal order ofpathway mutations by integrating ITH pathway and mutational functional annotation information and therebyto classify patients into biologically meaningful subtypes.

project_terms:
Adenocarcinoma Cell;Advocate;Affect;Algorithms;Appalachian Region;Basic Science;Biological;Cancer Cluster;Cancer Patient;Cells;Clinical;Clinical Research;Colon Carcinoma;Complex;Computing Methodologies;DNA sequencing;Data;Development;Disease;Future;Genes;Genomics;High-Throughput DNA Sequencing;Knowledge;Lung Adenocarcinoma;MAP Kinase Gene;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Modeling;Molecular;Mutation;Outcome;Pathway interactions;Patients;Phylogenetic Analysis;Population;Process;Prognosis;Publications;Research;Resolution;Sample Size;Somatic Mutation;Squamous cell carcinoma;Statistical Methods;Structure;The Cancer Genome Atlas;Transforming Growth Factor beta;Trees;WNT Signaling Pathway;anticancer research;base;cancer classification;cancer subtypes;cancer type;carcinogenesis;clinical practice;cohort;design;drug development;genomic data;improved;individual patient;insight;machine learning model;molecular subtypes;new therapeutic target;p53 Signaling Pathway;personalized medicine;single cell sequencing;statistical and machine learning;success;tool;treatment response;treatment strategy;tumor;tumor heterogeneity;tumor progression;tumorigenesis

public_health_relevance:
Project NarrativeThis project aims to develop new statistical methods to delineate temporal order of pathway mutations duringtumorigenesis and identify cancer subtypes with different cancer progression mechanisms. The success of thisproject will enhance our understanding of the biological mechanisms of cancer progression and enable betterclassification of cancer patients into subtypes which can potentially impact drug development and clinicalpractice.


application_id: 10368338
project_number: 1UF1NS125488-01
administering_ic: NINDS
award_notice_date: 2021-09-22
opportunity_number: RFA-NS-21-005
application_type: 1
activity_code: UF1
ic: NS
serial_number: 125488
program_official: MCGAVERN, LINDA
project_start_date: 2021-09-29
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZNS1 SRB-O (15)]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: WILCOCK, DONNA M
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
budget_start_date: 2021-09-29
project_title:
The University of Kentucky MarkVCID Biomarker Validation Cohort: Development of a Toolbox to Advance VCID Interventional Studies

project_abstract:
ABSTRACTThe MarkVCID consortium was established to discover and cross-site validate biomarkers of cerebral small vessel disease (cSVD) with an ultimate goal of developing a toolbox of biomarkers that will have diagnostic disease stratification and longitudinal tracking utility for future vascular contributions to cognitive impairment and dementia (VCID) clinical trials. The University of Kentucky (UK) was selected as one of the seven MarkVCID sites in its initial funding period in 2016. Being in the heart of the stroke belt Kentucky is a state with a high prevalence of cardiovascular and cerebrovascular disease and the University of Kentucky is a Center of Excellence for Stroke and Dementia with UK being a designated Comprehensive Stroke Center and has an NIA Alzheimer's Disease Research Center (ADRC). During our current funding period we successfully recruited a cohort of 126 individuals (exceeding our originally proposed 120) with varying levels of cardiovascular risk factors and a large proportion of whom have defined subjective memory complaints (SMCs) with some defined as mild cognitive impairment (MCI). All participants underwent the MarkVCID MRI battery blood collection and neuropsychological and clinical assessment while one quarter also contributed CSF. Importantly all participants have consented to autopsy; a requirement we initiated at the beginning of our MarkVCID recruitment. UK MarkVCID has fully participated in the validation of every biomarker kit except the OCT-A kit. We have also led two biomarker kits: the White Matter Growth and Regression kit and the CSF PlGF kit.  In this renewal connected to UH3NS100606 under RFA-NS-16-020 we propose to expand our cohort to 200 individuals with a particular focus on expanding recruitment of diverse populations and individuals with SMCs and MCI. Having participated in the harmonization instrumental validation and now biological validation of all MRI and fluid biomarker kits we are poised to make significant contributions in the continuation of the consortium. We have proposed three Specific Aims to achieve the goals laid out in RFA- NS-21-005: Specific Aim 1: Retain and expand a diverse cohort enriched for individuals with subjective memory complaints and cognitive impairment at high risk for cerebral small vessel disease. Specific Aim 2: Work with the consortium to facilitate data imaging and fluid sharing and accelerate our validation of the MarkVCID candidate biomarkers in our cohort. Specific Aim 3: Fully engage in leadership roles within the consortium and serve in a consulting capacity for both internal and external researchers seeking to explore biomarkers and or develop new clinical trials and interventional studies for the treatment of VCID.

project_terms:
Alzheimer's Disease;Autopsy;Biological;Biological Markers;Blood;Blood Platelets;Cardiovascular Diseases;Cardiovascular system;Cerebral small vessel disease;Cerebrovascular Disorders;Cessation of life;Clinical;Clinical Data;Clinical Trials;Clinical assessments;Collection;Consent;Consult;Data;Dementia;Development;Diagnostic;Disease stratification;Dropout;Enrollment;Environment;Foundations;Funding;Future;Gait;Goals;Gold;Growth;Heart;High Prevalence;Image;Impaired cognition;Individual;Infrastructure;Intervention Studies;Kentucky;Lead;Leadership;Lesion;Liquid substance;Magnetic Resonance Imaging;Memory;Minority;Multi-Institutional Clinical Trial;Neuropsychology;Outcome Measure;PGF gene;Participant;Plasma;Population;Population Heterogeneity;Procedures;Process;Protocols documentation;Reader;Research;Research Personnel;Research Support;Risk Factors;Role;Sampling;Schedule;Site;Standardization;Strategic Planning;Stratification;Stroke;Stroke Belt;Testing;Universities;Validation;Visit;Work;base;biomarker validation;candidate marker;cardiovascular risk factor;cerebrovascular;clinical Diagnosis;clinical biomarkers;cohort;coronavirus disease;design;digital;experience;follow-up;high risk;imaging biomarker;innovation;instrument;lifestyle data;member;mild cognitive impairment;operation;racial and ethnic;recruit;vascular cognitive impairment and dementia;white matter

public_health_relevance:
PROJECT NARRATIVE The MarkVCID consortium was established to discover and cross-site validate biomarkers of VascularCognitive Impairment and Dementia (VCID) with an ultimate goal of developing a toolbox of biomarkers thatwill be useful for future clinical trials. The University of Kentucky (UK) was selected as one of the sevenMarkVCID sites in its initial funding period in 2016 and being in the heart of the stroke belt Kentucky is a statewith high prevalence of cardiovascular and cerebrovascular disease. We are currently following 126participants for their VCID biomarkers and propose to increase this number to 200 in this renewal application.


application_id: 10368329
project_number: 5P20GM130456-02
project_title: Immunomodulatory Therapy for Bone Regeneration
administering_ic: NIGMS
award_notice_date: 2021-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: MCGUIRL, MICHELE
project_start_date: 2021-03-08
project_end_date: 2025-01-31
study_section: ZGM1-RCB-9(C1)
subproject_number: 6618
contact_pi_person_id: 14078198
contact_pi: TIRUVANNAMALAI ANNAMALAI, RAMKUMAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Inflammation plays a vital role during bone formation resorption and fracture healing. The process of fracture healing is biologically entangled with that of acute inflammation and innate immunity. A proper sequence and dose of inflammatory signals are critical for proper bone healing. Macrophages one of the first cells that infiltrate the fracture site are indispensable for fracture healing as they promote osteoblastic differentiation and vascularization. Also it is well recognized that mechanical conditions influence callus development and the type and extent of osteogenesis during fracture. But most work on the macrophage response in the context of fracture healing has focused on activation mediated by biochemical signals. The biophysical parameters of the fracture microenvironment especially matrix mechanics and their influence on macrophage immunophenotypes are largely overlooked. Our overall goal is to elucidate the influence of biophysical cues on macrophage function to develop an immunomodulatory platform reducing the burden of bone diseases in patients.  Macrophages respond to changes in extracellular matrix mechanics through actin-cytoskeletal reorganization nuclear deformation and gene expression. We hypothesize that biophysical forces in the form of substrate mechanics elicit transcriptional control of macrophages via a transcriptional activator MRTF-A release (during actin polymerization) and redistribution of a cell signaling mediator HDAC3 (chromatin compaction). The two independent aims for this project are: 1) Elucidate the actin cytoskeleton-mediated transcriptional control in macrophages in a murine fracture model 2) Engineer immunomodulatory materials with suitable viscoelastic mechanics to guide the transcriptional machinery of macrophages to promote bone regeneration.  Overall our proposed research provides insights into the role of the innate immune response in fracture healing and develops next-generation immunomodulatory materials for therapeutic bone regeneration. Hence our research aligns well with the CPRI COBRE mission to facilitate translational chemical biology research to advance treatments and strategies to address significant health challenges.

project_terms:
Actins;Acute;Address;Biochemical;Biological;Biology;Biophysics;Bone Diseases;Bone Regeneration;Bone callus;Cells;Centers of Research Excellence;Chemicals;Chromatin;Cues;Cytoskeletal Modeling;Cytoskeleton;Development;Dose;Engineering;Extracellular Matrix;Fracture;Fracture Healing;Gene Expression;Genetic Transcription;Goals;HDAC3 gene;Health;Immunophenotyping;Inflammation;Inflammatory;Innate Immune Response;Mechanics;Mediating;Mediator of activation protein;Mission;Modeling;Mus;Natural Immunity;Nuclear;Osteogenesis;Patients;Pharmacologic Substance;Play;Process;Research;Role;Signal Transduction;Site;Therapeutic;Transcription Coactivator;Transcriptional Regulation;Vascularization;Work;biophysical properties;bone healing;immunomodulatory therapies;immunoregulation;innovation;insight;macrophage;next generation;osteoblast differentiation;polymerization;response;treatment strategy;viscoelasticity


application_id: 10367780
project_number: 1K01DK128022-01A1
project_title: Elucidating Molecular Mechanisms Linking Fructose to Cholesterol Metabolism
administering_ic: NIDDK
award_notice_date: 2021-12-20
opportunity_number: PA-20-190
application_type: 1
activity_code: K01
ic: DK
serial_number: 128022
suffix: A1
program_official: SASLOWSKY, DAVID E
project_start_date: 2022-01-01
project_end_date: 2026-12-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 11480537
contact_pi: HELSLEY, ROBERT NATHANIEL
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acetyl Coenzyme A;Acetylation;Advisory Committees;Affect;Aging;Animals;Atherosclerosis;Biological Assay;Biopsy;Carbon;Cardiometabolic Disease;Cardiovascular Diseases;Carnitine Palmitoyltransferase I;Catabolism;Cells;Cholesterol;Cholesterol Homeostasis;Citrates;Clustered Regularly Interspaced Short Palindromic Repeats;Collaborations;Committee Members;Communication;Consumption;Coupled;Data;Development;Development Plans;Dietary Sugars;Dyslipidemias;Educational workshop;Ensure;Enzymes;Epigenetic Process;Exhibits;Fat-Restricted Diet;Female;Food;Fructose;Funding;Genes;Genetic;Genetic Transcription;Goals;Hepatic;Hepatocyte;Human;Image;Impairment;In Vitro;Isotope Labeling;Kentucky;Ketohexokinase;Knock-out;Knockout Mice;Laboratory Study;Learning;Link;Lipids;Liver;LoxP-flanked allele;Lysine;Mass Spectrum Analysis;Measures;Mediating;Mentored Research Scientist Development Award;Mentors;Messenger RNA;Metabolic;Metabolic Diseases;Metabolism;Methodology;Mitochondria;Modification;Molecular;Monosaccharides;Mus;Mutagenesis;Nuclear;Obesity;Obesity associated liver disease;Observational Study;PPAR alpha;Pathway interactions;Patients;Persons;Phenotype;Phosphorylation;Prevalence;Process;Production;Proteins;Proteomics;Radiolabeled;Reducing diet;Regulation;Reporter;Research;Research Institute;Research Personnel;Risk Factors;Rodent;Role;SRE-2 binding protein;Serum;Signal Pathway;Signal Transduction;Small Interfering RNA;Stable Isotope Labeling;Sterols;Techniques;Testing;Tracer;Training;Transcriptional Regulation;Triglycerides;Universities;Water;Woman;acylcarnitine;cardiometabolic risk;cardiovascular disorder risk;career development;cholesterol biosynthesis;cohort;dietary;fast protein liquid chromatography;fatty acid oxidation;fatty acid-transport protein;feeding;hypercholesterolemia;in vivo;innovation;insight;knock-down;lipid biosynthesis;liquid chromatography mass spectrometry;male;men;metabolomics;mortality;mouse model;non-alcoholic fatty liver disease;novel therapeutics;nutrient metabolism;overexpression;protein expression;response;skills;stable isotope;sugar;sweetened beverage;symposium


application_id: 10366053
project_number: 5R01HL141343-04
project_title: Transcriptional Regulation of KCNH2
administering_ic: NHLBI
award_notice_date: 2022-02-04
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141343
program_official: SHI, YANG
project_start_date: 2019-03-08
project_end_date: 2024-02-29
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7001509
contact_pi: DELISLE, BRIAN P
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:
SummaryCircadian rhythms help to match the optimal function of the cardiovascular system to the daily changes in theenvironment. Normal cardiovascular rhythms provide a physiological advantage to people. Unfortunatelynormal circadian signaling can also unmask a time-of-day pattern in adverse events like heart attack strokeand sudden death in patients with underlying cardiovascular disease.Emerging data now show that abnormal or unhealthy daily rhythms can create a negative impact on normalhealth too. For example shiftwork which repeatedly causes shifts in endogenous circadian rhythms is anindependent risk factor for cardiovascular disease.In mammals the suprachiasmatic nucleus (SCN) in the brain is the primary circadian pacemaker that helps toentrain endogenous rhythms to the environment. SCN rhythms are synchronized to the environment via lightand its signaling helps to coordinate the molecular rhythms in cells throughout the body. What is new aboutthis application is we determine how repeated changes in light cycle will impact molecular circadian signaling inthe heart.Most cells have a molecular clock signaling mechanism that cycles with a periodicity of ~24 hours. We foundgenetic disruptions in the molecular clock mechanism of heart cells (cardiomyocytes) primarily causesabnormal changes in cardiac electrophysiology by disrupting the regulation of ion channel function.The goal of this application is to determine how repeated shifts in the light cycle impact molecular clocksignaling in the mouse heart and its regulation on ion channel function.Aim 1. To identify new mechanisms with which the cardiac molecular clock regulates different ion channels.Aim 2. To determine how repeated changes in light impact molecular clock signaling in the heart and ionchannel regulation.This project creates new knowledge at the interface between chronobiology and cardiac electrophysiology.

project_terms:
ARNTL gene;Action Potentials;Adverse event;Arrhythmia;Biological Assay;Bioluminescence;Brain;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cells;Cessation of life;Chemistry;Chronic;Chronobiology;Circadian Rhythms;Cues;Data;Electrophoretic Mobility Shift Assay;Elements;Environment;Gene Expression;Genes;Genetic;Genetic Transcription;Goals;Half-Life;Health;Heart;Hour;Human;Hypothalamic structure;Incidence;Ion Channel;Knowledge;Kv channel-interacting protein 2;Label;Length;Light;Long QT Syndrome;Mammals;Measures;Messenger RNA;Molecular;Molecular Target;Mus;Myocardial Infarction;Patients;Pattern;Periodicity;Persons;Phase;Phenotype;Physiological;Potassium Channel;Premature Mortality;Proteins;RNA;Regulation;Reporter Genes;Role;Signal Transduction;Stroke;Sudden Death;Telemetry;Testing;Time;Tissues;Transcript;Transcriptional Regulation;Transgenic Mice;Uridine;cardiovascular risk factor;chromatin immunoprecipitation;circadian;circadian pacemaker;heart cell;in vivo;induced pluripotent stem cell;insight;mRNA Stability;molecular clock;mouse model;premature;promoter;shift work;suprachiasmatic nucleus;transcription factor

public_health_relevance:
Project NarrativeThe molecular clock mechanism serves a ubiquitous cellular time-keeping function and it regulates the tissue-specific expression of many genes. Molecular clock signaling in cardiomyocytes controls the expression ofseveral K+ channel genes that are important for normal cardiac excitability. We are applying approachesdeveloped in chronobiology to study the regulation of cardiac K+ channels at an entirely new level.


application_id: 10366028
project_number: 5R01CA259580-02
project_title: Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2022-04-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 259580
program_official: WATSON, JOANNA M
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Aging;Anchorage-Independent Growth;Animal Model;Brain;Breast Cancer Cell;Breast cancer metastasis;CRISPR library;Cancer Biology;Cancer Cell Growth;Cell Nucleus;Cell model;Clinical;Code;Complex;Cytoplasm;Data;Development;Diabetes Mellitus;Diagnosis;Disease;Drug resistance;Environment;Enzymes;Event;Exhibits;Extravasation;FOXC1 gene;Family;Gatekeeping;Genetic Transcription;Goals;Homeostasis;Human;In Vitro;Knock-out;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methyltransferase;Mitochondria;NADH;NADP;Neoplasm Metastasis;Niacinamide;Nicotinamide N-Methyltransferase;Nicotinamide adenine dinucleotide;Oncogenic;Oxidation-Reduction;Oxidative Stress;Pathologist;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;Prognosis;Prognostic Marker;Proliferating;Property;Reactive Oxygen Species;Regimen;Regulation;Research;Respiration;Rodent;Role;Signal Pathway;Site;Specimen;Suspensions;Talents;Testing;Therapeutic;Transcriptional Regulation;Up-Regulation;Vertebral column;Xenograft Model;arginine methyltransferase;base;breast cancer progression;coactivator-associated arginine methyltransferase 1;druggable target;experimental study;extracellular;in vivo;inhibitor;innovation;knock-down;malignant breast neoplasm;mammary gland development;metabolomics;mouse model;multidisciplinary;novel therapeutic intervention;oxidative damage;patient derived xenograft model;prevent;screening;stem-like cell;success;therapeutically effective;therapy resistant;transcription factor;tumor growth;tumor progression;uptake


application_id: 10365990
project_number: 5R01HL147921-03
administering_ic: NHLBI
award_notice_date: 2022-03-17
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 147921
program_official: TJURMINA, OLGA A
project_start_date: 2020-04-22
project_end_date: 2025-03-31
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 15587997
contact_pi: MOHAMED, TAMER M 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
budget_start_date: 2022-04-01
project_title:
Induction of Cardiomyocyte Proliferation via Transient Expression of Cell Cycle Factors as a Promising Therapy for Heart Failure

project_abstract:
Heart failure kills 1 in 10 people over the age of 65 in the USA. We recently identified a combination of four cell-cycle regulators that induces stable cytokinesis in adult cardiomyocytes to replace their loss following myocardialinfarction. Specifically adenoviral overexpression of cyclin-dependent kinase 1 (CDK1) CDK4 cyclin B1 andcyclin D1 (collectively known as 4F i.e. four factors) efficiently induced cell division in post-mitotic mouse ratand human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products in cardiomyocytes. In vivo lineage tracing using the MosaicAnalysis of Double Marker (MADM) mouse model revealed that 1520% of adult cardiomyocytes expressing the4F underwent stable cell division with significant improvement in cardiac function after acute or subacutemyocardial infarction. Currently our approach is the most robust method to induce cardiomyocyte proliferation;however clinical applicability in humans is limited by concerns for tumorigenic potential in other organs. Ourpreliminary data in vitro shows that in other cell types (e.g. neurons) 4F induce cell proliferation continuously for5-6 successive rounds over 7 days. Therefore in this proposal we will focus on approaches to make cell cycleinduction in cardiomyocytes more clinically applicable and avoid any oncogenic potential.We hypothesize that a transient and cardiomyocyte-specific expression is needed to induce one cycle ofcardiomyocyte proliferation to avoid any potential adverse effects on other tissues. Our preliminary data showsthat TNNT2 derived 4F expression in NIL is robustly inducing proliferation in vitro and in vivo and improvedcardiac function after myocardial infarction. Here we will rigorously demonstrate the efficacy and safety of thispolycistronic NIL encoding 4F expression driven by the cardiac specific promoter of TNNT2 (TNNT-4F-NIL) ininducing cardiomyocyte division and improving cardiac function after myocardial infarction in vivo in rat and pigmodels as well as in situ in human heart slices from healthy and infarcted hearts. Here we aim first to fullydemonstrate the efficacy and specificity of TNNT-4F-NIL to induce proliferation only in cardiomyocytes in vivo.Secondly we will test the functional efficacy and perform initial safety studies for TNNT-4F-NIL in rat and pigmodels of heart failure. Lastly we will demonstrate the efficacy of TNNT-4F-NIL in inducing adult humancardiomyocyte proliferation in situ in human heart slices and improving contractile function of failing human heartslices. This study will address all preclinical efficacy testing and perform initial safety studies for one of the mostpromising approaches to regenerate the heart. The successful completion of this study will allow the start of firstin human clinical trial.

project_terms:
Acute;Address;Adenoviruses;Adult;Adverse effects;Area;Blood;CDC2 gene;CDK4 gene;Calcium;Cardiac;Cardiac Myocytes;Cell Cycle;Cell Proliferation;Cell division;Cells;Clinical Trials;Contracts;Cyclin D1;Cytokinesis;Data;Daughter;Disease;Electrophysiology (science);Event;Family suidae;Gene Expression Profile;Generations;Heart;Heart failure;Hip region structure;Human;In Situ;In Vitro;Infarction;Ischemia;Kidney;Lentivirus;Liver;Mediating;Methods;Mitotic;Modeling;Mosaicism;Mus;Muscle Cells;Myocardial Infarction;Natural regeneration;Neurons;Oncogenic;Organ;Pancreas;Parents;Persons;Proliferation Marker;Property;Rattus;Recording of previous events;Reperfusion Therapy;Reporter;Rest;Rodent;Safety;Slice;Specificity;System;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Treatment Failure;Troponin T;cell type;clinical application;cyclin B1;dosage;efficacy evaluation;efficacy testing;first-in-human;gene therapy;healing;heart function;human old age (65+);improved;in vivo;mouse model;multicatalytic endopeptidase complex;novel;novel strategies;overexpression;porcine model;preclinical efficacy;promoter;protein degradation;safety study;tool;transcriptome sequencing;translational potential;tumorigenic

public_health_relevance:
After heart attack the heart loses many muscle cells which leads to the loss of ability to bump blood tothe rest of the body. The muscle cells in the heart are not able to regenerate themselves which madeit difficult to treat such disease. Here we are developing new transient gene therapy approach toregenerate these muscle cells in the heart and make them able to heal the heart.


application_id: 10364661
project_number: 5R01DA053070-02
project_title: Functional and Genomic Signatures of Escalated Fentanyl Use
administering_ic: NIDA
award_notice_date: 2022-01-12
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DA
serial_number: 053070
program_official: POLLOCK, JONATHAN D
project_start_date: 2021-03-15
project_end_date: 2025-12-31
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10484112
contact_pi: TURNER, JILL R.
other_pis: BARDO, MICHAEL T;ORTINSKI, PAVEL IVANOVICH
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Agonist;Animal Behavior;Animal Model;Animals;Astrocytes;Awareness;Behavior;Behavior Therapy;Behavioral;Behavioral Model;Biology;Biometry;Brain;Calcium;Calcium Signaling;Cells;Centers for Disease Control and Prevention (U.S.);Cessation of life;Chronic;Clinical;Clinical Research;Consumption;Coupled;Data;Databases;Dependence;Development;Diagnosis;Drug Targeting;Drug usage;Economic Burden;Electrophysiology (science);Evaluation;Family;Fentanyl;Genetic Databases;Genetic Markers;Genomics;Goals;Heroin;Human;Individual;Individual Differences;Intake;Joints;Laboratory Animals;Life;Link;Literature;Maintenance;Microglia;Modeling;Modernization;Molecular;Molecular Profiling;Monitor;Morphine;Motivation;Neurobiology;Neurons;Nucleus Accumbens;Opiate Addiction;Opioid;Outcome;Output;Patch-Clamp Techniques;Pathway interactions;Pattern;Permeability;Persons;Pharmaceutical Preparations;Pharmacogenomics;Pharmacology;Phenotype;Play;Policies;Population;Potassium;Potassium Channel;Prefrontal Cortex;Prevention;Probability;Protein Family;Publishing;Rattus;Regulation;Relapse;Rewards;Role;Sampling;Self Administration;Shapes;Source;Statistical Models;Structure;Substance Use Disorder;Sucrose;System;Testing;Therapeutic;Training;United States National Center for Health Statistics;antagonist;base;behavioral pharmacology;behavioral phenotyping;big-data science;cancer therapy;cell type;drug abstinence;fentanyl abuse;functional genomics;gene product;genomic biomarker;genomic profiles;genomic signature;imaging approach;individual variation;interdisciplinary approach;medication-assisted treatment;mu opioid receptors;neural circuit;non-drug;novel;novel therapeutics;opioid misuse;opioid mortality;opioid overdose;opioid use;opioid use disorder;opioid user;personalized approach;personalized cancer therapy;pre-clinical;reinforcer;success;synthetic opioid;targeted treatment;transcriptome sequencing;transcriptomics;whole genome


application_id: 10363931
project_number: 2R01DC007176-17
project_title: Regulation of taste neuron morphology and function
administering_ic: NIDCD
award_notice_date: 2022-02-22
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2027-02-28
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Anatomy;Axon;Brain;Brain-Derived Neurotrophic Factor;Calcium;Characteristics;Chemicals;Citric Acid;Development;Disease;Epithelial;Fibrinogen;Food;Functional Imaging;Ganglia;Gene Expression;Genetic;Goals;Health;Hour;Image;Individual;Intrinsic factor;Label;Link;Longevity;Measurement;Measures;Methods;Morphology;Mus;Nerve Fibers;Neurons;Pattern;Peripheral;Persons;Population;Process;Quality of life;Receptor Cell;Regulation;Role;Structure;Taste Bud Cell;Taste Buds;Taste Disorders;Taste Perception;Temperature;Time;Variant;Wild Type Mouse;base;cell type;cellular transduction;experimental study;functional plasticity;in vivo;insight;intravital imaging;neurotrophic factor;overexpression;preproenkephalin;reconstruction;sensory system;taste stimuli;taste system;two photon microscopy


application_id: 10363829
project_number: 1R01HL156957-01A1
project_title: Role of miR-146a in Abdominal Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2021-12-07
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 156957
suffix: A1
program_official: GALIS, ZORINA S
project_start_date: 2022-01-01
project_end_date: 2022-08-31
study_section: Atherosclerosis and Vascular Inflammation Study Section[AVI]
contact_pi_person_id: 10792635
contact_pi: SUBRAMANIAN, VENKATESWARAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta with a high mortalitygreater than 80% after rupture. Aortic vascular smooth muscle cells (SMCs) are pivotal in maintaining aorticstructural integrity and function and SMC-rich aortic medial stability is highly disrupted in AAA. Currentlybesides surgical interventions no alternative therapeutics are available to blunt AAA progression and rupture.Consequently there is a dire need to identify novel strategies for development of effective non-surgicaltherapeutics. MicroRNA-146a (miR-146a) a well-known regulator of inflammation and auto-immunity is highlyexpressed in aneurysmal tissue of AAA patients. However the role of miR-146a in SMC homeostasis andAAA remains to be explored. In preliminary studies by in-situ hybridization we observed that miR-146a isupregulated in SMC-rich aortic media of human and mouse AAAs; miR-146a deficiency significantly promotedAngiotensin II (AngII) -induced AAA formation in normolipidemic mice co-administered with Lysyl oxidase inhibitor-aminopropionitrile (BAPN); and mimetics-mediated miR-146a overexpression abolished AngII-induced AAAs inboth hypercholesterolemic LDLr-/- mice and normolipidemic mice co-infused with BAPN. To elucidate underlyingmechanisms by RNA sequencing we identified novel targets from miR-146a deficiency experiments: TFIID-31a TATA binding protein associated factor involved in transcriptional activation and repression is significantlyupregulated; whereas Beclin-1 a gene indispensable for autophagy induction and USP9X a deubiquitinasecritical for Beclin-1 stabilization are significantly downregulated. Autophagy a self-regulatory process bywhich cells digest and recycle their cytoplasmic materials for energy purposes under stress. Our preliminarystudy also showed an increased Beclin-1 in mouse AAAs as observed in human AAAs and Tat-peptidemediated Beclin-1 activation suppressed AngII-induced AAA formation in mice. In addition miR-146aoverexpression significantly suppressed TFIID-31 promoted USP9X and Beclin-1 and ShRNA-mediatedsilencing of TFIID-31 increased USP9X in cultured aortic SMCs. Based on these observations we will test ourcentral hypothesis that miR-146a activation protects against AAA formation and progression by promotingBeclin-1-mediated aortic SMC homeostasis. By utilizing our unique mice models generated specifically forthese studies we propose 3 aims. Aim 1 will test our working sub-hypothesis that miR-146a promotes Beclin-1stability in aortic SMCs via a TFIID-31-USP9X dependent manner. Aim 2 will test our working sub-hypothesisthat miR-146a activation protects against AAA through activation of SMC-Beclin-1-derived autophagy. Aim 3will determine the effect of miR-146a / Beclin-1 activation on progression of established AAAs. In summary wewill delineate the protective role of Beclin-1 in AAA and establish miR-146a activation as a novel therapeuticstrategy against AAA by targeting SMC-Beclin-1. This mechanistic research will set solid preclinical evidencethat targeting miR-146a represents a novel therapeutic strategy for treatment and prevention of AAA.

project_terms:
3' Untranslated Regions;Abdominal Aortic Aneurysm;Angiotensin II;Aorta;Autoimmunity;Autophagocytosis;Binding;Binding Sites;Bone Marrow Transplantation;Cardiovascular system;Cell Survival;Cells;Clinical;Deubiquitination;Development;Disease;Event;Genes;Goals;Homeostasis;Human;In Situ Hybridization;Inflammation;Inflammatory;Infusion procedures;Knowledge;Leukocytes;Low Density Lipoprotein Receptor;Medial;Mediating;Medical;MicroRNAs;Modeling;Mus;Operative Surgical Procedures;Outcome;Patients;Peptides;Pharmacology;Plasma;Prevalence;Prevention;Process;Protein-Lysine 6-Oxidase;Proteins;Research;Role;Rupture;Smooth Muscle Myocytes;Solid;Stress;TAF1 gene;TATA-Binding Protein Associated Factors;Testing;Therapeutic;Tissues;Transcriptional Activation;Untranslated RNA;Vascular Smooth Muscle;Western Blotting;abdominal aorta;base;beta Aminopropionitrile;experimental study;gene repression;in silico;inhibitor;insight;mimetics;monocyte;mortality;mouse model;new therapeutic target;novel;novel strategies;novel therapeutic intervention;overexpression;peripheral blood;pre-clinical;prevent;small hairpin RNA;therapeutic development;transcriptome sequencing;treatment strategy

public_health_relevance:
Project Narrative Abdominal aortic aneurysm a permanent dilation of the abdominal aorta with a high mortalityrate of over 80% after rupture. Using novel mouse models that we have developed our goals are toelucidate mechanisms responsible for AAA formation and identify new targets for therapeuticdevelopment against AAAs.


application_id: 10363388
project_number: 1R01DK128033-01A1
project_title: Mirabegron and tadalafil effectiveness for treatment of prediabetes
administering_ic: NIDDK
award_notice_date: 2021-11-26
opportunity_number: PAS-20-160
application_type: 1
activity_code: R01
ic: DK
serial_number: 128033
suffix: A1
program_official: LAUGHLIN, MAREN R
project_start_date: 2021-12-01
project_end_date: 2024-11-30
study_section: Human Studies of Diabetes and Obesity Study Section[HSDO]
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:
Approximately 84 million Americans have prediabetes and progression to type 2 diabetes occurs at a rateof 5% to 10% per year and is a risk factor for heart disease. Although lifestyle change is effective mostprediabetic individuals cannot achieve the changes necessary to reverse prediabetes or prevent diabetes. In recent studies we treated obese insulin-resistant humans with the -adrenergic receptor (3AR) agonistmirabegron and this resulted in improved oral glucose tolerance lower HbA1c and increased insulinsensitivity and -cell function. These changes occurred in the absence of weight loss. Although brownadipose tissue did not increase mirabegron treatment increased beige fat reduced adipose inflammation andincreased type 1 fibers and capillary density in skeletal muscle. Beige adipocytes have beneficial effects onglucose metabolism and are postulated to act as a glucose sink. Mirabegron stimulates the 3AR which stimulates the cAMP-mediated activation of PKA and the activationof p38 map kinase which induces UCP1 and adipose beiging. Recent studies showed that cGMP activation ofprotein kinase G (PKG) acted in a similar fashion to improve glucose metabolism and increase white adiposebeiging. Indeed cGMP is stimulated by natural ligands (ANP BNP nitric oxide); the phosphodiesterase 5(PDE5) inhibitor drugs sildenafil and tadalafil prevent breakdown of cGMP activating PKG and this results inincreased UCP1 in adipocytes. Therefore we hypothesize that treatment of prediabetic subjects withmirabegron or tadalafil will improve glucose metabolism. We further hypothesize that the combined treatmentwith mirabegron and tadalafil will have additive improvements in glucose metabolism likely due to their parallelactions of stimulating the cyclic nucleotides cAMP and cGMP and inducing adipose beiging. Specific Aim 1. We hypothesize that a 4 month treatment with the 3 agonist mirabegron will result inimproved glucose metabolism in obese prediabetic human research participants and this improvement inglucose metabolism will be further improved by combination therapy with mirabegron plus tadalafil. Specific Aim 2. We will identify underlying mechanisms of the improved glucose homeostasis in responseto mirabegron and tadalafil by characterizing insulin sensitivity insulin secretion adipose tissue beigingmuscle fiber type and muscle capillaries.Clinical relevance: Other than weight loss we have only limited methods for improving prediabetes. Drugsthat target white adipose beiging improve glucose metabolism in both rodents and humans and we proposethat this can be exploited to attenuate prediabetes. This application addresses the effectiveness of two drugsthat are widely prescribed well tolerated but which have not been extensively studied for their metaboliceffectiveness in subjects with prediabetes and have never been studied in combination. Results from thisstudy could lead to a larger trial which could considerably alter our approach to the treatment of prediabetes.

project_terms:
Address;Adipocytes;Adipose tissue;Adrenergic Receptor;Agonist;American;Attenuated;Beta Cell;Bladder;Blood capillaries;Body Weight decreased;Brown Fat;Cell physiology;Clinical Trials;Combined Modality Therapy;Consumption;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cyclic GMP;Cyclic GMP-Dependent Protein Kinases;Cyclic Nucleotides;Data;Diabetes Mellitus;Disease;Drug Combinations;Drug Targeting;Effectiveness;Exercise;FDA approved;Fatty acid glycerol esters;Fiber;Glucose;Glycosylated hemoglobin A;Goals;Heart Diseases;Human;Individual;Inflammation;Insulin Resistance;Lead;Life Style;Ligands;Link;Lipids;Lipolysis;Mediating;Metabolic;Methods;Mission;Multicenter Trials;Muscle;Muscle Fibers;National Institute of Diabetes and Digestive and Kidney Diseases;Nitric Oxide;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oral;Overactive Bladder;Participant;Pathway interactions;Pharmaceutical Preparations;Prediabetes syndrome;Research;Research Project Grants;Risk Factors;Rodent;Skeletal Muscle;Smooth Muscle;Thinness;Treatment Effectiveness;Woman;beta-adrenergic receptor;blood glucose regulation;clinical efficacy;clinically relevant;comorbidity;density;design;diabetes prevention program;effectiveness evaluation;glucose metabolism;glucose tolerance;heart disease risk;improved;inhibitor;inhibitor therapy;insulin secretion;insulin sensitivity;oral glucose tolerance;p38 Mitogen Activated Protein Kinase;phosphodiesterase V;placebo controlled trial;prevent;protein activation;response;side effect;sildenafil;subcutaneous;tadalafil;uncoupling protein 1

public_health_relevance:
This research grant is designed to examine the importance of repurposing two drugs that holdpromise for improving glucose metabolism. Mirabegron and tadalafil augment levels of cAMPand cGMP respectively and we will determine whether mirabegron tadalafil or a combinationof these drugs improve glucose homeostasis. These drugs both cause induction of beigeadipose and this study will also explore mechanisms for their effects.


application_id: 10362691
project_number: 5R01NS116068-02
project_title: Macrophage Depletion Therapy for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2021-12-01
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 116068
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2025-11-30
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: ALILAIN, WARREN JOSEPH
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;American;Americas;Animal Model;Animals;Anti-Inflammatory Agents;Applications Grants;Autonomic Dysreflexia;Basic Science;Biodistribution;Biological Assay;Bone Marrow;Breathing;Cell Death;Cells;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chronic;Clinical;Clinical Trials;Congresses;Contusions;Data;Dichloromethylene Diphosphonate;Distal;Dose;Encapsulated;FDA approved;Flow Cytometry;Forelimb;Frustration;Funding;Goals;Grant;Hand functions;Hindlimb;Hour;Human;Immune;Immune Targeting;Immunologic Deficiency Syndromes;Impairment;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Laboratories;Lead;Lesion;Leukocytes;Liposomes;Liver;Locomotion;Locomotor Recovery;Mediating;Minocycline;Modeling;Modification;Motor;Multiple Trauma;Myelopoiesis;Neuroglia;Organ;Outcome;Outcome Measure;Output;Pain;Pathology;Persons;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Population;Production;Publishing;Quality of life;Rattus;Recovery;Recovery of Function;Regulation;Reporting;Research;Research Personnel;Respiration;Rodent;Rodent Model;Sensory;Site;Spinal Cord;Spinal Cord Contusions;Spinal Cord Plasticity;Spinal Injuries;Spinal cord injury;Spleen;Steroids;Testing;Therapeutic;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Translating;Translations;Treatment Efficacy;United States;United States National Institutes of Health;Visceral pain;Voice;arm;axonal sprouting;base;care outcomes;central pattern generator;clinically relevant;functional disability;functional outcomes;improved;improved outcome;indexing;innovation;macrophage;meetings;monocyte;novel therapeutic intervention;pain sensation;pre-clinical;preclinical evaluation;recruit;repaired;respiratory;response;side effect;synaptogenesis;tissue repair;translational impact


application_id: 10362208
project_number: 3R01ES029846-04S1
project_title: Diversity supplement to Urban Greenness and Cardiovascular Health
administering_ic: NIEHS
award_notice_date: 2021-06-24
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: ES
serial_number: 029846
suffix: S1
program_official: SCHUG, THADDEUS
project_start_date: 2021-06-25
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
project_abstract:
ABSTRACTThe Green Heart Project is a rigorously defined clinical controlled trial on the effect of residential vegetation oncardiovascular health and disease risk. The project evaluates cardiovascular health and disease as well asneighborhood characteristics before and after increasing greenspaces in neighborhoods in LouisvilleKentucky. The results of this project will elucidate the contribution of greenness to cardiovascular health andprovide new insights into the effects of urban vegetation on community environments. These findings will bedirectly relevant to the development of new public health policies and optimization of ongoing planting efforts incities around the world to enhance public health. Collectively the Green Heart Project will contribute to theformulation of an imitable paradigm a model that could be readily replicated in other cities in both developedand developing countries.The proposed diversity supplement (parent grant R01 ES029846-03) will support a junior-level assistantprofessor Dr. Natasha DeJarnett who is an environmental health researcher with expertise in air qualityclimate-health and cardiovascular disease risk. This diversity supplement will contribute to the proposedGreen Heart Project by strengthening its community engagement and outreach activities and by providingadditional input into its neighborhood characteristics assessment. Meaningful participation of communitymembers in activities that affect their environmental health is key toward achieving environmental justice andavoiding unintended consequences like gentrification and displacement. Dr. DeJarnetts experience withstakeholder engagement at national membership associations and her passion for health equity ensure thatshe will be a strong contributor toward effective community engagement collaborating with members of thecommunity and collecting community-informed data. Dr. DeJarnetts expertise in air quality and climateadaptation will expand the robustness of the air quality assessment in the parent grant by incorporating localtemperature gradients a key factor of air quality. Examining temperature gradients through a lens of equity willmore accurately define the relationship between greenness air quality and cardiovascular health. Thus theoverarching hypothesis of the supplement is that equity-informed temperature gradients and expanded datacollection of community perceptions on equity will enhance the air quality and community assessments tobetter explain the relationship between increasing greenness and resulting air quality and cardiovascularhealth outcomes.The specific aims are to: 1. Support the community engagement initiatives of the Green Heart Project anddevelop new approaches to community engagement and assessment and 2. Examine how an increase inarea greenness affects temperature gradients within an urban neighborhood. Successful completion of theseaims will enhance and enrich the parent project while at the same time enable participation and training of anew junior investigator in environmental health science research.

project_terms:
Address;Administrative Supplement;Affect;Air;Air Pollutants;Air Pollution;Area;Biological Markers;Blood;COVID-19;Carbon Black;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Characteristics;Cities;Climate;Clinical Trials;Collaborations;Collection;Communities;Community Outreach;Community Participation;Controlled Clinical Trials;Data;Data Analyses;Data Collection;Developed Countries;Developing Countries;Development;Discrimination;Ecosystem;Ensure;Environment;Environmental Health;Evaluation;Excision;Exposure to;Formulation;Goals;Grant;Green space;Hair;Health;Health Policy;Heart;Heart Diseases;Housing;Individual;Kentucky;Learning;Measures;Mediating;Modeling;Nail plate;National Institute of Environmental Health Sciences;Neighborhoods;Nitrogen Oxides;Outcome;Ozone;Participant;Perception;Persons;Plants;Pollution;Population Heterogeneity;Psychosocial Stress;Public Health;Race;Research Personnel;Risk Factors;Role;Sampling;Seasons;Socioeconomic Status;Sulfate;Surveys;Temperature;Testing;Time;TimeLine;Training;Trees;Urine;Work;built environment;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;climate adaptation;cohort;community engagement;community involvement;data acquisition;environmental justice;ethnic minority population;evidence base;experience;falls;foot;health equity;health science research;insight;land use;lens;meetings;member;novel strategies;parent grant;parent project;pollutant;professor;racial minority;recruit;research clinical testing;social;social cohesion;ultrafine particle

public_health_relevance:
NARRATIVEThis administrative supplement is to support Dr. Natasha DeJarnetts involvement in the communityengagement and exposure assessment activities of the on-going NIEHS supported project - Urban Greennessand Cardiovascular Health (ES 029846-03). Work supported by the supplement will test the role ofdiscrimination in modifying the relationship between the urban greenspaces and cardiovascular disease riskand will examine whether the health effects of increasing greenness are mediated by changes in areatemperature and temperature gradients.


application_id: 10360011
project_number: 2R15GM085722-04
project_title: Mechanisms of Action of UmuD in Regulating DNA Damage-Induced Genes in a umuC-Deficient Bacterium
administering_ic: NIGMS
award_notice_date: 2021-12-29
opportunity_number: PAR-18-714
application_type: 2
activity_code: R15
ic: GM
serial_number: 085722
program_official: REDDY, MICHAEL K
project_start_date: 2009-08-01
project_end_date: 2025-12-31
study_section: Special Emphasis Panel[ZRG1 GGG-X (81)]
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Multi-drug resistant bacteria such as the ESKAPE pathogens are difficult to treat; finding new drugtargets and alternate methods of interfering with cell growth are crucial to infectious disease control. AGram-negative nosocomial ESKAPE pathogen Acinetobacter baumannii has multiple antibiotic-resistancegenes and a mutagenic response to DNA damage that antibiotics can cause. The PIs undergraduate researchteam has uncovered a novel DNA damage response (DDR) system in this pathogen that uses a non-canonical repressor UmuDAb and a small protein coregulator DdrR to repress mutagenic error-pronepolymerases. Typical DDR regulators namely the LexA repressor of SOS genes and the SulA cell divisioninhibitor are not encoded by the non-enteric Acinetobacter genus yet they possess a checkpoint response offilamentation after DNA damage. There is increasing interest in targeting cell division and controlcheckpoints to control bacterial infections and novel mechanisms of cell division inhibition are recentrefinements to Escherichia coli and Bacillus DDR models. Staphylococcus aureus (also an ESKAPE pathogen)and other Gram-positive and non-enteric bacteria that lack SulA instead use small proteins lacking inter-genus homologies to inhibit cell division after DNA damage. Our teams evidence suggests that the DdrRcomponent of SOS regulation mimics the actions of SulA and these Gram-positive growth inhibitors afterDNA damage: ddrR mutants have growth sensitivity to DNA damage and cannot inhibit cell division after it. This projects long-term goal is to construct a new model of inhibiting cell division in Gram-negativeGammaproteobacteria such as A. baumannii which could help find non-antibiotic means of inhibiting itsgrowth and treating infectious disease. Our objectives are to identify how UmuDAb and DdrR directly andindirectly control error-prone polymerase production and cell division checkpoints as part of theAcinetobacter DDR. We hypothesize that the UmuDAb and DdrR regulators physically interact to control thisLexA-deficient pathogen's SOS response. Our objectives will be achieved using complementary approachesto determine whether their phenotype of cell division inhibition results from directly interacting withdivisome proteins or occurs through co-regulatory actions. Specifically we will: (Aim 1) use biochemicalmethods to identify UmuDAb-DdrR interactions; (Aim 2) establish these proteins' roles in inhibiting celldivision with fluorescence microscopy localization experiments two-hybrid and growth inhibition assays;and (Aim 3) examine previously obtained transcriptome data for targets of DdrR and UmuDAb regulatoryactivities that may control DNA damage checkpoints and growth after DNA damage. The PIs previouslydemonstrated mutant strains purified proteins and expertise in microbiology molecular biologybiochemistry and bioinformatics will allow her team of undergraduate students to complete these objectiveswhile producing authentic scientific knowledge and gaining a wide range of knowledge and skills.

project_terms:
Acinetobacter;Acinetobacter baumannii;Antibiotic Resistance;Antibiotics;Bacillus;Bacteria;Bacterial Infections;Biochemical;Biochemistry;Bioinformatics;Biological Assay;Cell Division Process;Cell division;Cells;Collection;Communicable Diseases;DNA Damage;DNA damage checkpoint;Data;ESKAPE pathogens;Escherichia coli;Filament;Fluorescence Microscopy;Gammaproteobacteria;Gene Expression;Genes;Goals;Gram-Negative Bacteria;Growth;Growth Inhibitors;Immune checkpoint inhibitor;Knowledge;Learning;Membrane;Methods;Microbiology;Microscopic;Modeling;Molecular Biology;Multiple Bacterial Drug Resistance;Mutation;Nature;Phenotype;Polymerase;Polymerase Gene;Process;Production;Proteins;Regulation;Research;Role;SOS Box;SOS Response;Son of Sevenless Proteins;Staphylococcus aureus;System;Testing;Two-Hybrid System Techniques;cell fixing;cell growth;crosslink;disorder control;drug resistant pathogen;experimental study;inhibitor;interest;mutant;new therapeutic target;novel;overexpression;pathogen;repaired;resistance gene;response;skills;stoichiometry;transcriptome;transcriptome sequencing;undergraduate research;undergraduate student;yeast two hybrid system

public_health_relevance:
Project Narrative The purpose of this research is to understand how Acinetobacter baumannii an antibiotic-resistant pathogen responds to DNA damage to learn how to inhibit this pathogens growth withoutusing antibiotics. The typical bacterial repair response to DNA damage causes a pause in growth whilethe cell fixes the damage but can also cause mutations. Our research will test for interactions betweenproteins that regulate the production of these mutations and proteins used to halt cell division afterDNA damage.


application_id: 10359979
project_number: 1R15GM144954-01
project_title: Telomere and telomerase evolution in S. cerevisiae
administering_ic: NIGMS
award_notice_date: 2021-12-28
opportunity_number: PAR-18-714
application_type: 1
activity_code: R15
ic: GM
serial_number: 144954
program_official: VATAKIS, DIMITRIOS NIKOLAOS
project_start_date: 2022-01-01
project_end_date: 2025-12-31
study_section: Special Emphasis Panel[ZRG1 GGG-X (81)]
contact_pi_person_id: 15800518
contact_pi: MEFFORD, MELISSA ANNE
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT ABSTRACTTelomeres composed of repetitive DNA sequences at the termini of linearchromosomes serve as protective caps. However telomeres cannot be fullycopied during replication without the ribonucleoprotein enzyme telomerase.Understanding the delicate balance between telomere length and telomeraseactivity has important implications for two of the biggest human health concerns:aging and cancer. Telomeres have been shown to shorten with age acting as abiological clock limiting the rounds of division a cell can undergo. To circumventthis proliferative limit over 85% of cancers aberrantly up-regulate telomeraseexpression. The long-term goal of this work is to understand the evolution oftelomeres and telomerase and how these cellular components contribute to thehealth and lifespan of an organism. To begin unraveling these broad fundamentalquestions two specific lines of inquiry will be undertaken harnessing the powerfulgenetic manipulability of Saccharomyces cerevisiae. First a screen for gain-of-function mutations in telomerase RNA will identify novel alleles that lengthentelomeres by increasing enzyme activity. Such gain-of-function mutants will shednew light on how the essential RNA component of telomerase contributes to theoverall action of the enzyme. More active telomerase will also permit explorationof whether longer telomeres alter total fitness of the organism. Second yeaststrains will be genetically engineered to circularize each of their 16 linearchromosomes allowing novel experimental investigation of the advantages anddisadvantages of circular chromosomes in a eukaryotic organism. These novelyeast strains will build a foundation for creating an innovative eukaryoticorganism with all linear chromosomes circularized opening the door to explorebig picture questions of telomere and telomerase evolution.

project_terms:
Address;Age;Aging;Alleles;Architecture;Behavior;Biological;Biological Clocks;Cardiovascular Diseases;Cell Cycle Arrest;Cell Proliferation;Cell division;Cells;Chromosome Structures;Chromosomes;Costs and Benefits;DNA;DNA Sequence;DNA cassette;Disadvantaged;Disease;Enzymes;Equilibrium;Eukaryota;Evolution;Exhibits;Foundations;Genes;Genetic;Genetic Engineering;Genetic Recombination;Goals;Health;Human;Investigation;Knowledge;Length;Light;Link;Longevity;Malignant Neoplasms;Mental Depression;Mutation;Organism;Positioning Attribute;RNA;Research;Ribonucleoproteins;Role;Saccharomyces cerevisiae;Shapes;Structure;Structure-Activity Relationship;Telomerase;Telomerase RNA Component;Telomere Maintenance;Telomere Shortening;Telomere-Binding Proteins;Testing;Work;Yeasts;arm;design;enzyme activity;enzyme structure;fitness;gain of function;gain of function mutation;innovation;insight;loss of function mutation;mutant;novel;prevent;public health relevance;senescence;telomere;tool;uncontrolled cell growth

public_health_relevance:
PROJECT NARRATIVE/PUBLIC HEALTH RELEVANCETelomeres are repeated sequences at the ends of linear chromosomes that actas biological clocks shortening as cells divide and preventing the uncontrolledcellular proliferation seen in cancers. The evolutionary costs and benefits oftelomeres and the telomerase enzyme that maintains their length are not fullyunderstood. This work aims to experimentally address fundamental questionsregarding the mechanism of telomerase enzyme function and the necessity oflinear chromosome structure which will shed light on the basic biologicalunderpinnings of both aging and cancer.


application_id: 10359325
project_number: 3R01ES016893-14S1
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2021-06-30
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: ES
serial_number: 016893
suffix: S1
program_official: TYSON, FREDERICK L
project_start_date: 2021-07-01
project_end_date: 2021-10-31
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY OF THE FUNDED PARENT GRANTLung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combatingit is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major publichealth concern because exposure to it is common in the workplace and in the general environment. Our studyfocuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which are currently unknown. Inparticular this work focuses on the particulate Cr(VI) compounds because they are the most potent Cr(VI)carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells toevade DNA double strand break repair which are hallmarks of human lung cancer. Thus this research focuseson how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosomeinstability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts theeffector arm of homologous recombination (HR repair) disrupting RAD51 nucleoprotein filament formation lossof which can cause chromosome instability. Therefore the goal of this research is to characterize this impact onHR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is:particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivatingHR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test thishypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2 DSS1RAD51B RAD51C RAD51D RPA and XRCC2 to disrupt RAD51 nucleoprotein filament formation in humanlung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation inhuman lung cells neoplastically transformed by Cr(VI) and the protein levels of BRCA2 DSS1 RAD51BRAD51C RAD51D RPA and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impactof Cr(VI) on protein levels of BRCA2 DSS1 RAD51B RAD51C RAD51D RPA and XRCC2 in the lungs andlung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of theinteractions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the firstcharacterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers.Results will also show which changes are transient and depend on exposure and which changes persist in cellsthat escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1)An understanding of Cr(VI)s carcinogenic mechanism; 2) Essential information to better assess exposure riskto particulates; and 3) A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Address;Affect;Animals;Anti-Inflammatory Agents;Antiinflammatory Effect;Antioxidants;Automobile Driving;BRCA2 gene;Beets;Betaine;Biological Markers;Breast Cancer Cell;Cancer Etiology;Carcinogens;Cell Death;Cells;Cessation of life;Chromium Compounds;Chromosomal Instability;DNA;DNA Double Strand Break;Data;Double Strand Break Repair;Endothelial Cells;Environment;Epithelial Cells;Event;Exposure to;Fibroblasts;Filament;Food;Funding;Goals;Hazardous Substances;Health Benefit;Heritability;Human;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Investments;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Metals;Molecular;Mus;National Institute of Environmental Health Sciences;Natural Products;Neoplastic Cell Transformation;Nucleoproteins;Outcome;Particulate;Pathway interactions;Property;Proteins;Public Health;RAD51C gene;Rattus;Regulatory Pathway;Reporting;Research;Risk;Risk Assessment;Risk Management;Role;Signal Transduction;Structure of parenchyma of lung;Testing;Toxicology;Translating;Umbilical vein;United States;Work;Workplace;XRCC2 gene;anti-cancer;arm;cancer cell;carcinogenesis;carcinogenicity;chromium hexavalent ion;genotoxicity;homologous recombination;improved;in vivo;insight;neoplastic;neoplastic cell;novel strategies;parent grant;potential biomarker;prevent;response;targeted biomarker;therapeutic target;tumor;tumor progression

public_health_relevance:
PROJECT NARRATIVE OF THE FUNDED PARENT GRANTLung cancer is the number one cause of cancer death in the United States. Our study focuses on two hallmarksof lung cancer chromosome instability and evading DNA double strand break repair and advances our basicunderstanding of the cellular and molecular mechanisms underlying how Cr(VI) causes these outcomes as partof its carcinogenic mechanism. Our findings will help identify new mechanistic insights which can spur newpotential treatment targets new approaches to reduce and prevent Cr(VI)-induced lung cancer and new insightsto better determine safer exposure levels for this major public health concern.


application_id: 10359109
project_number: 5R01HD096077-04
project_title: The Role of FOS in the Ovary
administering_ic: NICHD
award_notice_date: 2023-03-28
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HD
serial_number: 096077
program_official: TAYMANS, SUSAN
project_start_date: 2019-05-06
project_end_date: 2025-02-28
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
arra_indicator: N
project_abstract:
Abstract Understanding the cellular events underlying ovulation and subsequent corpus luteum (CL) formation iscritically important because these biological processes provide the foundation of our ability to regulate femalefertility. A fundamental cornerstone of the cellular events induced by the preovulatory gonadotropin surge vitalfor ovulation and CL formation is the expression of specific transcription factors. However our knowledge ofthe identity and regulatory actions of gonadotropin-induced key transcription factors remains limited. A recent study has shed light on a member of the activator protein-1 (AP-1) transcription factor family FOS(a.k.a. c-fos) as a key transcription factor involved in follicular development ovulation and luteal formation.Fos-deficient mice failed to ovulate and form CL even when exogenous gonadotropins were administered (1)indicating that the ovarian expression of Fos is necessary for normal ovulation and luteinization. However littleto nothing is known exactly how the FOS/AP-1 transcription factor affects these processes in the ovary. Ourpreliminary study revealed for the first time that the expression of FOS is highly up-regulated in dominantfollicles collected after hCG administration from normally cycling women and in preovulatory follicles after hCGadministration in mice. Moreover we demonstrated that FOS regulated the hCG-induced increase in theexpression of key ovulatory genes in human granulosa cells by directly binding to the promoters of thesegenes. Based on these novel findings we hypothesized that FOS/AP-1 plays essential roles in ovulation andluteal formation/function both in humans and mice. Fos null mice displayed a pleiotropic phenotype with significant loss of viability at birth. To determine theovary-specific function/action of FOS/AP-1 we propose to establish novel transgenic mouse models in whichFos expression is ablated in an ovarian cell-specific manner. These mutant mice will be used to assess theovarian phenotype including follicular development ovulation luteal development and fertility as well as toidentify downstream target genes of FOS/AP-1 in ovarian cells (Specific Aim #1). To relate and compare thefindings from mice to humans we will first characterize the spatiotemporally regulated expression of all FOSand JUN family members in ovulatory follicles obtained before and throughout the periovulatory period fromnormally cycling women. The specific role of FOS/AP-1 in human ovaries will also be determined by identifyingdownstream target genes of FOS/AP-1 and assessing the cellular impact(s) of FOS' action (Specific Aim #2). The information obtained from the proposed studies will not only advance our understanding of themechanism necessary for successful ovulation and luteinization but also be instrumental for futuretranslational/clinical application thus leading to improved management of fertility in vivo and in vitro.

project_terms:
Ablation;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;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;System;Time;Transcription Factor AP-1;Transgenic Mice;Woman;clinical application;corpus luteum;design;female fertility;granulosa cell;human tissue;improved;in vivo;insight;jun Oncogene;member;mouse model;novel;prevent;promoter;spatiotemporal;transcription factor

public_health_relevance:
Narrative Successful ovulation and subsequent corpus luteum formation and development are essential for femalefertility. In the present proposal we will demonstrate for the first time that the FOS/AP-1 transcription factorplays an essential role in ovulation and corpus luteum formation in both humans and mice. Information derivedfrom the present proposal will provide novel insights into the mechanism(s) underlying ovulation and lutealformation and can be applied for promoting and inhibiting the critical facet of ovarian physiology therebyallowing us to effectively manage fertility in women.


application_id: 10358917
project_number: 1R15DA051833-01A1
administering_ic: NIDA
award_notice_date: 2022-03-18
opportunity_number: PAR-19-133
application_type: 1
activity_code: R15
ic: DA
serial_number: 051833
suffix: A1
program_official: MITCHELL, SHANNON GWIN
project_start_date: 2022-04-01
project_end_date: 2026-03-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 12257283
contact_pi: TEETERS, JENNI
other_pis: Not Applicable
congressional_district: 02
department: NONE
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: UNIVERSITY-WIDE
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Evaluation of an Interactive Mobile Phone-Based Brief Intervention to Reduce Substance-Impaired Driving among Emerging Adults

project_abstract:
PROJECT SUMMARY/ABSTRACTDriving after cannabis use (DACU) and driving after simultaneous alcohol and cannabis use representsignificant public health concerns. Rates of substance-impaired driving remain especially high amongemerging adults and traffic accidents remain the leading cause of substance-related death among thispopulation. Brief Interventions (BIs) have been shown to reduce alcohol and cannabis use in emerging adultsbut to date no study has selected emerging adults on the basis of recent DACU and evaluated the efficacy of amobile-based substance-impaired driving BI. The present study will be the first to examine whether a mobilephone-based substance-impaired driving BI including interactive text-messaging significantly decreasesDACU among emerging adult substance users compared to personalized feedback only. Research participantswill be 160 emerging adults (ages 18-25) who endorse driving after cannabis use and/or simultaneouscannabis and alcohol use at least three times in the past 3 months. After completing baseline measuresparticipants will be randomly assigned to receive either: a) substance-impaired driving personalized feedbackor b) a substance-impaired driving personalized feedback intervention plus interactive text messages.Participants will complete comprehensive follow-ups 3- and 6-months post-intervention. Repeated measuresmixed modeling analyses will be used to determine whether the intervention significantly reduces DACU overtime. The project has two specific aims: 1) to evaluate a mobile phone-based substance-impaired drivingintervention in a randomized clinical trial and 2) to determine whether cognitive factors identified in previousresearch (e.g. perceived dangerousness and consequences peer norms expectancies) mediate interventionoutcomes. This study is innovative because it utilizes cutting-edge technology to deliver the entire interventionenabling the study to reach a large number of emerging adults in a short time period in a cost-effectivemanner. The study is significant because it will contribute substantially to the substance-impaired drivingliterature by identifying an intervention that can decrease substance-impaired driving among this high-riskpopulation. Additionally this study will add to the rapidly growing technology-based intervention literature byincluding mobile-based assessment personalized feedback and interactive text-messaging.

project_terms:
Age;Alcohol consumption;Alcohols;Automobile Driving;Behavior;Belief;Cannabis;Car Phone;Cessation of life;Cognition;Cognitive;Communities;Dangerousness;Drunk driving;Effectiveness of Interventions;Electronic Mail;Elements;Evaluation;Expectancy;Feedback;Female;Goals;High Prevalence;Impairment;Individual;Intervention;Literature;Measures;Mediating;Mediator of activation protein;Meta-Analysis;Minority Recruitment;Modeling;Outcome;Participant;Perception;Persons;Population;Populations at Risk;Public Health;Questionnaires;Randomized;Randomized Clinical Trials;Reporting;Research;Research Personnel;Risk;Risk Behaviors;Sampling;Series;Southeastern United States;Technology;Telephone;Testing;Text;Text Messaging;Therapeutic;Time;Traffic accidents;Training;Universities;age group;base;brief intervention;community center;cost effective;driving behavior;efficacy evaluation;emerging adult;follow-up;high risk population;impaired driving performance;improved;improved outcome;innovation;intervention effect;live text;marijuana use;marijuana user;meetings;mobile computing;motivational enhancement therapy;peer;pilot trial;post intervention;prevention service;public health relevance;recruit;reduced alcohol use;response;substance use;substance user;treatment services;university student

public_health_relevance:
PUBLIC HEALTH RELEVANCE:Rates of substance-impaired driving remain especially high among emerging adults andsubstance-related traffic accidents remain the leading cause of substance-related death amongthis age group. Though brief interventions have been shown to effectively reduce impaireddriving behaviors it is often not economically feasible for universities and community centers tohire and train staff to deliver in-person interventions to all impaired drivers leading researchersto develop innovative ways of delivering targeted interventions. This proposal seeks to improveintervention access and engagement by using a mobile-based personalized feedbackintervention and interactive text-messaging to reduce substance-impaired driving amongemerging adults.


application_id: 10358879
project_number: 1R01ES033767-01
project_title: Phthalate-Induced Dysregulation of Prostaglandin and Angiogenic Function During Ovulation in Women
administering_ic: NIEHS
award_notice_date: 2021-12-24
opportunity_number: RFA-ES-21-001
application_type: 1
activity_code: R01
ic: ES
serial_number: 033767
program_official: SCHUG, THADDEUS
project_start_date: 2022-01-01
project_end_date: 2026-10-31
study_section: Special Emphasis Panel[ZES1 LAT-S (R1)]
contact_pi_person_id: 12252020
contact_pi: HANNON, PATRICK RYAN
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Agonist;Angiogenic Factor;Animal Model;Award;Biological Assay;Blood capillaries;Cell Proliferation;Cell model;Cells;Chemicals;Couples;Cyclic AMP;Cyclooxygenase Inhibitors;Data;Defect;Dose;Endocrine Disruptors;Endothelial Cells;Ensure;Environmental Health;Environmental Impact;Exhibits;Exposure to;FGF2 gene;Failure;Female infertility;Fertility;Fertility Rates;Foundations;Functional disorder;Goals;Healthcare;Housing;Human;Impairment;In Vitro;Infertility;Link;Literature;Mediator of activation protein;Medical;Mental Health;Metabolism;Modeling;Mus;Nature;Non-Steroidal Anti-Inflammatory Agents;Oocytes;Outcome;Ovarian;Ovarian Follicle;Ovarian Granulosa Cell;Ovary;Ovulation;Ovulation Inhibition;PTGS2 gene;Parents;Pathway interactions;Pregnant Women;Prevalence;Process;Production;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Public Health;Quality of life;Reproductive Health;Research;Rodent Model;Sampling;Signal Transduction;Signaling Molecule;Social Functioning;Societies;Stress;Supplementation;Testing;Time;Toxic effect;VEGFA gene;Woman;Women's Health;Work;angiogenesis;cost;critical period;exposed human population;granulosa cell;human model;in vivo;migration;mouse model;novel;personal care products;phthalates;physical conditioning;prevent;receptor;reproductive;translational approach;urinary


application_id: 10358590
project_number: 5R01DK095662-11
project_title: The Role of Crypt Fissioning in IBD Ulcer Healing
administering_ic: NIDDK
award_notice_date: 2022-04-14
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 095662
program_official: SENGER, STEFANIA
project_start_date: 2021-02-24
project_end_date: 2025-01-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Program Director/Principal Investigator (Barrett Terrence A):The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data thatdemonstrate it to be a predictor of remission1. Thus ulcer healing predicts the capacity for therapies to preventunwanted clinical sequelae (i.e. surgery). Unfortunately many IBD patients remain refractory or loseresponsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show thatreduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC)2. These findingswere supported by Kugathasan et al who found that increased expression of mitochondrial respiratory chaingenes predicted favorable (B1 protected) Crohns disease (CD) outcomes3. Based on these results and ourown data we hypothesize that a critical driver of chronic ulceration in IBD is the failure of intestinalepithelial cells (IEC) to increase mitochondrial respiration with ROS generation. We posit that chronicmucosal inflammation suppresses mitochondrial respiration needed for crypt fissioning (in ulcer healing) inIBD. This hypothesis will be tested in the following studies: Aim 1. Determine the impact ofmitochondrial respiration for mucosal healing. These studies benefit from strikingly novel Prelim.Data using VilCre/mTmG/TFAMfl/fl mice where mitochondrial respiration was shown to be required forcrypt fissioning in ulcer healing. In Aim 2 we will determine the requirement of mitochondrial-derived ROS in IEC crypt division using primary human colonoids. Aim 3 studies will determinethe impact of chronic inflammation on ulcer healing in patients. IEC transcriptomics from ulceredges from CD and ulcerative colitis will be compared to normal ulcer healing. Normal ulcer healingwill be interrogated using a novel biopsy of a biopsy (Bx/Bx) approach (IEC will be isolated fromBx/Bx sites 4-6day after initial biopsies). ScRNAseq results have already shown that mitochondrialbiogenesis (PGC1) increases in Bx/Bx ulcers whereas levels drop in IBD IEC. In summary: Studieswill investigate the cause of non-healing ulceration in IBD by interrogating novel murine humanand in vitro colonoid culture models of determining the impact of suppressed mitochondrial respirationon IEC responses (crypt fissioning). The studies will test the notion that chronic mucosalinflammation (as in IBD) suppresses mitochondrial respiration which impedes ROS-inducedPI3K signaling and crypt fissioning. Our goal is to identify therapeutic targets to allow for enhancedmitochondrial respiration to aide mucosal repair in IBD.OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

project_terms:
Biochemical;Biogenesis;Biopsy;Childhood;Chronic;Clinical;Clinical Data;Clinical Research;Colitis;Crohn's disease;Data;Disease;Disease Outcome;Disease remission;Drops;Epithelial Cells;Failure;Gene Expression;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Human;In Vitro;Inflammation;Inflammatory Bowel Diseases;Injury;Intestines;Investigation;Knockout Mice;Leukocyte L1 Antigen Complex;Maintenance;Measures;Mitochondria;Modeling;Monoclonal Antibodies;Mucositis;Mucous Membrane;Mus;Operative Surgical Procedures;Outcome;Oxidation-Reduction;PTEN gene;Pathogenesis;Patients;Phosphatidylinositols;Phosphotransferases;Principal Investigator;Procedures;Refractory;Respiration;Respiratory Chain;Role;Signal Transduction;Site;TNF gene;Tattooing;Testing;Treatment Efficacy;Ulcer;Ulcerative Colitis;Visualization;WNT Signaling Pathway;Work;base;beta catenin;chronic ulcer;clinical phenotype;crypt cell;dextran sulfate sodium induced colitis;drug development;experience;healing;infliximab;intestinal epithelium;new therapeutic target;novel;novel strategies;prevent;programs;prospective;repaired;response;single-cell RNA sequencing;stem cells;therapeutic biomarker;therapeutic target;transcriptomics

public_health_relevance:
The importance of understanding the role of mitochondrial respiration in ulcer healing and determiningclinical phenotypes in inflammatory bowel disease has been recently strengthened by major prospectiveclinical studies in pediatric Crohns (Kugathasan et al Lancet) and ulcerative colitis (Haberman) patients.Studies proposed here use a novel genetically-engineered mouse model of mitochondrial deficiency incombination with single cell RNAseq analysis of normal and diseased (CD/UC) patients. We posit thiswork will identify key mechanisms that underlie the cause of nonhealing ulceration in IBD with the goalof identifying targets for new drug development.


application_id: 10358516
project_number: 5K08DK124566-02
project_title: Muscle bone interaction and its role in diabetic bone disease of Type I diabetes
administering_ic: NIDDK
award_notice_date: 2021-12-21
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: DK
serial_number: 124566
program_official: MALOZOWSKI, SAUL N
project_start_date: 2021-03-01
project_end_date: 2025-12-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 14779143
contact_pi: KALAITZOGLOU, EVANGELIA
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
20 year old;Activin Receptor;Address;Affect;Age;Animal Model;Antibodies;Basic Science;Biopsy;Bone Density;Bone Marrow Stem Cell;Bone Resorption;Cell Line;Cells;Childhood;Clinical;Clinical Research;Communication;Complication;Complications of Diabetes Mellitus;Data;Development;Diabetes Mellitus;Disease;Endocrine;Endocrinology;Environment;Equipment;Exhibits;FRAP1 gene;Foundations;Fracture;Functional disorder;Future;GDF8 gene;Gene Expression;Gene Proteins;General Population;Genes;Health;Hip Fractures;Hip region structure;Human;Hyperglycemia;Impairment;In Vitro;Incidence;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Knowledge;Laboratories;Lead;Life;MAP Kinase Gene;Measures;Mechanics;Mediating;Mediator of activation protein;Mentors;Mus;Muscle;Muscle function;Musculoskeletal;Musculoskeletal Diseases;Musculoskeletal System;Nurses' Health Study;Osteoblasts;Osteocalcin;Osteocytes;Osteogenesis;Outcome;Pathway interactions;Pediatrics;Pharmacology;Phenotype;Physical Capacity;Population;Population Study;Positioning Attribute;Prevalence;Prevention;Program Development;Relative Risks;Research;Resources;Risk;Roentgen Rays;Role;Sampling;Scientist;Serum;Signal Pathway;Signal Transduction;Skeletal Muscle;Skeletal bone;Time;Trabecular Bone Score;Translational Research;Universities;Upper Extremity Fracture;Work;bone;bone cell;bone fracture repair;bone imaging;bone mass;bone turnover;career;career development;clinically significant;cost;diabetic;diabetic bone disease;diabetogenic;fracture risk;high risk;improved;in vivo;mineralization;mouse model;muscle form;negative affect;novel;osteoblast differentiation;paracrine;prevent;professor;prospective;receptor;reduced muscle mass;reduced muscle strength;skills;young adult


application_id: 10357944
project_number: 5R01DA047368-04
project_title: A Translational Determination of the Mechanisms of Maladaptive Choice in Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2022-02-07
opportunity_number: PA-18-060
application_type: 5
activity_code: R01
ic: DA
serial_number: 047368
program_official: FEDOTA, JOHN RAPHAEL
project_start_date: 2019-04-15
project_end_date: 2024-02-29
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
other_pis: BECKMANN, JOSHUA ;WESLEY, MICHAEL J
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Opioid use disorder (OUD) is characterized by the decision to use opioids at the expense of other activities.Lab-based efforts to address this problem have therefore included opioid choice self-administration proceduresthat incorporate a non-drug alternative to model this defining feature. Studies using these procedures havetypically scheduled competing reinforcers so that the probabilities are certain. However such deterministicoutcomes are not representative of real-world experiences in which the consequences from drug-related choicesare often unpredictable. Importantly decision-making in a dynamic uncertain context significantly alters thevalue of choice options and requires continuous updating of option values which engages learning processesand related corticostriatal networks that function abnormally in OUD. Decision-making in dynamic environmentshas been successfully modeled using probabilistic reinforcement-learning choice (PRLC) tasks. The integrationof these tasks with reinforcement-learning (RL) computational modeling has been used to capture moment-to-moment changes in the mechanisms of dynamic choice and the application of neuroscience techniques hasbegun to identify the underlying neurobiology. This approach has uncovered biologically-based decision-makingabnormalities in multiple brain disorders but has yet to be systematically applied to the experimental study ofOUD The translation of combined RL and neuroscience approaches to OUD is logical considering themaladaptive choice behavior that typifies the disorder the varying reinforcement probabilities in opioid usersnatural environments and the learning impairments that have been documented in individuals with OUD. Thusthere are critical gaps in our understanding of the mechanisms underlying dynamic opioid use decisions and astrong scientific premise for applying an RL framework to fill these gaps. This project proposes rigorous PRLCtasks RL modeling neurorecording/fMRI neuroimaging techniques and complementary translational studydesigns in rats and humans. The first set of cross-species experiments will demonstrate the impact of opioidexposure and withdrawal on dynamic decision-making and reveal the neurobehavioral and neurobiologicalprocesses underlying abnormal task performance. The second set of experiments will use a PRLC task in whichintravenous remifentanil a prototypical opioid agonist with a favorable safety profile is available as an alternativeto a non-drug reinforcer to determine the behavioral and neural profiles associated with drug choice as well asthe increases and decreases in drug choice that occur during withdrawal and in the presence of a largemagnitude alternative reinforcer respectively. This project will have a significant impact on the field byestablishing the experimental application of reinforcement-learning theory to the study of maladaptive dynamicdrug-use decision-making in OUD to reveal behavioral and neural mechanisms that can be targeted for futureprevention and treatment development.

project_terms:
Abate;Abstinence;Address;Animals;Area;Back;Behavioral;Behavioral Mechanisms;Brain Diseases;Brain region;Choice Behavior;Chronic;Clinical;Cognition;Computer Models;Cues;Decision Making;Disease;Drug usage;Environment;FDA approved;Fibrinogen;Food;Foundations;Functional Magnetic Resonance Imaging;Future;Half-Life;Human;Impairment;Individual;Intravenous;Knowledge;Learning;Mental disorders;Methods;Modeling;Neurobiology;Neurologic;Neurosciences;Opioid;Opioid agonist;Outcome;Oxycodone;Performance;Pharmaceutical Preparations;Postdoctoral Fellow;Prevention;Prevention strategy;Probability;Procedures;Process;Psychological reinforcement;Rattus;Research;Research Design;Safety;Schedule;Self Administration;Signal Transduction;Task Performances;Techniques;Time;Translating;Translations;Update;Withdrawal;base;experience;experimental study;human subject;innovation;neuroadaptation;neurobehavioral;neuroimaging;neuromechanism;non-drug;novel;opioid exposure;opioid use;opioid use disorder;opioid user;opioid withdrawal;participant safety;reinforcer;relating to nervous system;remifentanil;theories;therapy development;translational study;treatment strategy

public_health_relevance:
PROJECT NARRATIVE Opioid use disorder (OUD) is characterized by the decision to use opioids at the expense of other activitiesbut lab-based studies have not modeled naturalistic dynamic decision-making. This translational rat and humanproject will use an innovative reinforcement-learning approach and neuroscience methods to uncover themechanisms of maladaptive dynamic choice in OUD in order to reveal novel prevention and treatment targets.


application_id: 10357570
project_number: 5R01AR071789-04
project_title: Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide
administering_ic: NIAMS
award_notice_date: 2022-01-28
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: AR
serial_number: 071789
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2018-09-21
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)S]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Children born with severe homocystinuria due to homozygous cystathionine beta synthase deficiency (CBS-/-)exhibit poor body weights skeletal muscle myopathy and die in teenage. Although mice with homozygous CBSmutation die shortly after birth the heterozygous CBS-/+ survives. Our preliminary data suggests thatenzymes CBS and cystathionine gamma-lyase (CSE) that irreversibly remove homocysteine (Hcy) byconverting to hydrogen sulfide (H2S) are decreased in skeletal muscle. Although lowering of Hcy levels andgeneration of H2S is beneficial the mechanism by which HHcy causes of skeletal muscle wasting and frailty isunknown. The long-term goal of this project is to understand the mechanism of muscle wasting in HHcy andevaluate the potential beneficial effects of H2S signaling in reversing skeletal muscle wasting and myopathy.The central hypothesis of this proposal is that HHcy causes skeletal muscle deterioration bycompromising vasculogenesis by enhancing muscle atrophy and by limiting skeletal muscleregeneration and H2S reverses these changes. We will test this hypothesis by following three specific aims:Specific Aim #1: To determine whether the HHcy inhibits muscle specific AKT HIF-1 and AMPKsignaling and impairs vasculogenesis and H2S reverses impaired vasculogenesis.Specific Aim #2: To determine whether the HHcy attenuates PGC-1 signaling and instigates atrogeneexpression and causes muscular atrophy and H2S mitigates muscle atrophy.Specific Aim #3: To determine whether the HHcy enhances TGF-1 signaling and myostatin levelsthereby suppresses muscle regeneration and H2S ameliorates these changes.

project_terms:
Angiography;Atrophic;Attenuated;Biological Assay;Birth;Body Weight;CRISPR/Cas technology;Caliber;Cell Differentiation process;Cell Line;Cell Proliferation;Child;Chronic;Collagen;Cystathionine beta-Synthase;Cysteine Desulfhydrase;Data;Deposition;Deterioration;Endothelial Cells;Enzymes;Exhibits;FOXO1A gene;Fatigue;GDF8 gene;Generations;Genes;Genetic Transcription;Goals;Homocysteine;Homocystinuria;Hydrogen Sulfide;Hyperhomocysteinemia;Hypoxia;Image;Immunohistochemistry;Impairment;In Vitro;Ischemia;Isolated limb perfusion;Lasers;Lead;Ligation;Measures;Mediating;Metabolic;Modality;Mus;Muscle;Muscle Fibers;Muscular Atrophy;Mutation;Myopathy;Natural regeneration;Phosphorylation;Plasma;Predisposition;Proto-Oncogene Proteins c-akt;Roentgen Rays;Role;Signal Transduction;Signaling Molecule;Skeletal Muscle;Starvation;Teenagers;Testing;Therapeutic;Tissues;Transcript;Transduction Gene;Transgenic Organisms;Vascular Endothelial Growth Factors;attenuation;density;design;femoral artery;frailty;hypoxia inducible factor 1;in vivo;knock-down;limb ischemia;muscle regeneration;novel;prevent;response;satellite cell;skeletal muscle wasting;small molecule;tissue oxygenation;vasculogenesis

public_health_relevance:
Narrative: This proposal is aimed to understand the mechanistic role of metabolic alterations (i.e.HHcy) in muscular damage and to evaluate the therapeutic potential of this novel gaseous signalingmolecule H2S. This study will also reveal that the H2S generation itself is enough to counter the HHcymediated detrimental effects necessary to benefit therapeutic modalities.


application_id: 10356813
project_number: 5R01HL141081-05
administering_ic: NHLBI
award_notice_date: 2022-02-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 141081
program_official: WONG, RENEE P
project_start_date: 2018-04-01
project_end_date: 2024-02-29
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 12204790
contact_pi: MOORE IV, JOSEPH B
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-03-01
project_title:
The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

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

project_terms:
Affect;Azacitidine;Biological;Bone Marrow;Cardiac;Cardiovascular system;Cell Lineage;Cell Survival;Cell Therapy;Cell Transplantation;Cells;Characteristics;Chronic;Clinical Trials;Competence;Congestive Heart Failure;Dependence;Development;Exhibits;Future;GATA4 gene;Genetic;Goals;Heart;Heart failure;Human;In Vitro;Infarction;Injections;Injury;Left Ventricular Function;Light;Link;Mediating;Mediator of activation protein;Mesenchymal;Methods;Modality;Modeling;Modification;Muscle Cells;Myocardial Infarction;Nude Rats;Paracrine Communication;Pathway interactions;Patients;Pharmacology;Population;Production;Rattus;Research;Role;Signal Transduction;Testing;Therapeutic;Tissues;Treatment Efficacy;Variant;Ventricular;Ventricular Remodeling;Work;arteriole;cardiac regeneration;cardiac repair;cell type;cytokine;directed differentiation;early phase clinical trial;extracellular vesicles;heart function;improved;neovascularization;novel;pre-clinical;release factor;repaired;reparative capacity;retention rate;stem cells;transcription factor

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


application_id: 10356591
project_number: 3R21AI151482-02S1
project_title: Defining the Intracellular Growth Niche of Foodborne Listeria monocytogenes
administering_ic: NIAID
award_notice_date: 2021-03-31
opportunity_number: PA-19-053
application_type: 3
activity_code: R21
ic: AI
serial_number: 151482
suffix: S1
program_official: BAQAR, SHAHIDA
project_start_date: 2020-03-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-IDM-B(81)]
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:
Ingestion of Listeria monocytogenes (Lm)-contaminated food results in human disease ranging in severityfrom mild self-limiting gastroenteritis to life-threatening septicemia and meningoencephalitis. The specificfactors that influence disease severity are not well understood and our knowledge of the intestinal phase oflisteriosis in particular is severely limited. We recently developed a mouse model of foodborne infection tostudy the interaction of Lm with intestinal innate immune cells. In preliminary studies we found that themajority of Lm in the gut were extracellular. This was an unexpected result because intracellular growthand spread from cell-to-cell without encountering the extracellular milieu are generally regarded as theprimary virulence strategies for these facultative intracellular bacteria. LplA1-deficient Lm that were unableto replicate intracellularly could readily invade the gut mucosa and establish infection in the underlyinglamina propria but did not persist as well as wildtype Lm and by three days post-infection had a severedefect in spreading to the mesenteric lymph nodes (MLN). This suggests that intracellular growth is notrequired for the initial stages of intestinal infection but replication in some as-yet-unidentified cell type in thegut becomes increasingly more important as the infection proceeds. Multicolor flow cytometry candiscriminate eight different subsets of myeloid-derived phagocytes that are unique to the gut. Preliminarydata provided here verified that intestinal tissue contained at least one cell type that could supportintracellular growth of Lm and ruled out Ly6Chi monocytes and all three subsets of conventional dendriticcells as the intracellular niche. The primary goal of this proposal is to identify the cell type(s) in the gut thatsupport intracellular growth of Lm and to define the innate immune response of intestinal cell types that thatinteract primarily with either intracellular or extracellular Lm. We hypothesize that Lm initially interactprimarily with cell types that that they cannot efficiently invade or survive in and that later in the course ofinfection the bacteria shift to a cell type that serves as a protected intracellular growth niche.!In Aim 1 fourcandidate intestinal myeloid cell types will be sort purified infected directly ex vivo and assayed for bothintracellular localization and replication. In Aim 2 flow cytometry will be used to identify Lm-associated cellsin the lamina propria and submucosa of the ileum and colon as well as the MLN that drain each of thesetissues (SI-MLN and LI-MLN) to track the fate of Lm that invade the gut mucosa in mice. In Aim 3 we willdefine the initial response of all eight subsets of intestinal myeloid cells by measuring the production ofcytokines known to be triggered by either host cell surface bound or cytosolic receptors. These exploratorystudies will fill a key knowledge gap in the field by defining the early events that occur in the gut duringfoodborne transmission of Lm. !

project_terms:
Anatomy;Bacteremia;Bacteria;Biological Assay;Blood;Bypass;C57BL/6 Mouse;Cell surface;Cells;Colon;Cytosol;Data;Defect;Dendritic Cells;Dependence;Disease Outbreaks;E-Cadherin;Eating;Elderly;Environment;Epithelial;Event;Exposure to;Feces;Flow Cytometry;Food;Food Contamination;Food Supply;Gastroenteritis;Gastrointestinal tract structure;Gentamicins;Goals;Growth;Gut Mucosa;Hospitalization;Immune;Immune system;Immunoassay;In Vitro;Incidence;Individual;Infection;Ingestion;Innate Immune Response;Interleukin-12;Interleukin-18;Interleukin-6;Intestinal Diseases;Intestines;Intravenous;Invaded;Knowledge;Lamina Propria;Large Intestine;Lead;Life;Ligation;Listeria monocytogenes;Listeriosis;M cell;Measures;Mediating;Meningoencephalitis;Minor;Modeling;Mus;Myelogenous;Myeloid Cells;Neuraxis;Phagocytes;Phase;Population;Process;Production;Resistance;Route;Sepsis;Septicemia;Severities;Severity of illness;Small Intestines;Stains;Submucosa;Surface;Symptoms;Systemic infection;Therapeutic Intervention;Time;Tissues;Virulence;Work;cell type;cytokine;cytosolic receptor;design;draining lymph node;enteric infection;experience;experimental study;extracellular;feeding;foodborne;foodborne infection;foodborne pathogen;human disease;ileum;in vivo;macrophage;mesenteric lymph node;monocyte;mortality;mouse model;neonate;pathogen;prevent;response;transmission process

public_health_relevance:
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 how this pathogen is able to survive in the gutand avoid being killed by the immune system. A better understanding of this process could lead to newstrategies to prevent systemic infection particularly in susceptible populations such as neonates and theelderly.!


application_id: 10354697
project_number: 2P42ES023716-06
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5061
contact_pi_person_id: 11775218
contact_pi: HEBERLE, LAUREN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Air;Area;Awareness;Cardiometabolic Disease;Chronic;Chronic Disease;Communities;Development;Diabetes Mellitus;Elements;Ensure;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Science;Equipment and supply inventories;Ethnic Origin;Exposure to;Face;Farm;Geographic Locations;Goals;Green space;Hazardous Substances;Hazardous Waste;Health;Health Food;Health Sciences;Heart Diseases;Home;Housing;Hypertension;Industry;Intervention;Kentucky;Knowledge;Natural Sciences;Neighborhoods;Obesity;Outcome;Patient Recruitments;Persons;Plant Roots;Play;Policy Maker;Population;Poverty;Prevention;Race;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Science;Site;Social Sciences;Source;Structural Racism;Superfund;Syndrome;Toxic effect;Toxin;Training;Transcend;Transportation;Ursidae Family;base;biological systems;cardiometabolic risk;cardiometabolism;community center;community engagement;community involvement;empowerment;fatty liver disease;health disparity;interest;landfill;meetings;member;pollutant;social;superfund site;therapy design

public_health_relevance:
Relevance:We are beginning to understand that toxin exposure can initiate/exacerbate multiple adverse health outcomesespecially cardiometabolic diseases. Kentuckians are disproportionately affected by many chronic diseasesincluding obesity hypertension heart disease diabetes fatty liver disease etc. which are all aspects ofcardiometabolic syndrome. Certain communities are more highly impacted than others and it is critical tounderstand why. We hypothesize that exposure to toxics specifically VOCs initiates/exacerbates theseconditions. It is fundamental to our understanding of the effects of these toxics to engage the communities mostdeeply affected by exposure to these pollutants and to try to mitigate the effects of these exposures. Thusdetermining the influence of pollutant exposures on the development/progression of these chronic conditions isvital. Also vital is examining this influence within the proposed areas within West and Southwest LouisvilleKentucky that face added social environmental health burdens including an uneven distribution of race andethnicity a traumatic introduction into the racial reckoning historic redlining and poverty. Bidirectional researchin this community will support understanding of the impacts of VOCs on cardiometabolic disease and communityempowerment.


application_id: 10354696
project_number: 2P42ES023716-06
project_title: Metabolism and Toxicity Core
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5060
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
project_terms:
Address;Analytical Chemistry;Animals;Bile Acids;Biochemical;Biological Assay;Biological Markers;Biology;Blood;Bone Marrow;Cardiometabolic Disease;Cardiovascular system;Catecholamines;Cells;Chemical Exposure;Clinical;Clinical Pathology;Communities;Complex;Continuing Education;Data;Data Analyses;Data Reporting;Deposition;Detection;Development;Ensure;Environmental Exposure;Environmental Health;Equipment;Exposure to;Extramural Activities;Faculty;Felis catus;Flow Cytometry;Foundations;Functional disorder;Future;Goals;Growth;Health;Hepatic;Hepatotoxicity;Histologic;Human;Human Resources;Individual;Infrastructure;Injury;Laboratories;Mass Fragmentography;Measurement;Measures;Metabolic;Metabolism;Methodology;Methods;Mus;Pathologic;Pathology;Physiological;Population;Postdoctoral Fellow;Procedures;Property;Protocols documentation;Quality Control;Research;Research Personnel;Research Project Grants;Resolution;Resources;Risk;Sampling;Scientist;Services;Signal Transduction;Students;Superfund;Techniques;Technology;Testing;Toxic effect;Toxicology;Training;Universities;Urine;blood glucose regulation;cardiometabolism;career development;data dictionary;data harmonization;data management;flexibility;graduate student;indexing;innovation;interest;investigator training;liquid chromatography mass spectrometry;liver function;meetings;member;next generation;novel;operation;response;superfund chemical;systemic toxicity;urinary;volatile organic compound


application_id: 10354695
project_number: 2P42ES023716-06
project_title: Research Experience and Training Coordination Core
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5059
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary. The RETCC has played a coordinating role in the success of ULSRC since its inception inSeptember 2017. By working closely with other NIEHS-supported training programs at the UofL (T32ES011564;T35ES014559) the RETCC has developed a rich diverse and comprehensive training program that is bothmultidisciplinary and inclusive. In addition to the course work and on the bench training activities RETCCroutinely organizes participatory field trips to the Lees Lane Superfund site to better understand and appreciatehealth concerns of residents in the adjacent community of Riverside Gardens; facilitates the meeting of traineeswith regional Superfund site coordinators and officials and the Metro Louisville Public Health and WellnessDepartment. Our training core in collaboration with Superfund Research Centers at Duke University Universityof Kentucky and University of Pennsylvania organized a trip to Washington D.C. so trainees could attend aScience and Policy Institute meeting that included interactions with congressional leaders and their staff. Suchactivities have been instrumental in the well-rounded growth of our trainees. Moreover these trainees not onlyprovide the force that turns the wheel but also are the focus and hub of intellectual crosstalk and fertilizationacross projects cores other SRCs and the National SRP. To date ULSRC success is the product of our traineessuccesses through their many accomplishments including publications presentations awards degreesfellowships interactions with community partners and environmental health sciences-related careeropportunities. Thus although we are proud of our current success via integration of trainee activities across theULSRC we continue to strive to build on these successes by implementing innovative and unifying features intoRETCC-directed activities that focus on fulfilling the goals and furthering the success of our trainees.

project_terms:
Advisory Committees;Age;Arts;Award;Awareness;Cardiometabolic Disease;Chemistry;Collaborations;Communication Research;Communities;Community Health Education;County;Data;Data Analyses;Dentistry;Development;Discipline of Nursing;Engineering;Environmental Exposure;Environmental Health;Exposure to;Fellowship;Fertilization;Fostering;Gardenal;Goals;Government;Growth;Hazardous Substances;Health;Health Professional;Human;Institutes;Institution;Kentucky;Laboratories;Medicine;Metals;Mission;National Institute of Environmental Health Sciences;Pennsylvania;Phase;Play;Postdoctoral Fellow;Program Research Project Grants;Public Health;Publications;Research;Research Project Grants;Role;Schools;Science;Science Policy;Scientist;Signal Recognition Particle;Statistical Data Interpretation;Students;Superfund;Training;Training Activity;Training Programs;Training Support;Translational Research;Universities;Washington;Work;base;cardiometabolism;career;career development;cohort;college;community based participatory research;community engagement;data management;experience;field trip;graduate student;health science research;innovation;interdisciplinary approach;knowledge base;meetings;multidisciplinary;next generation;pre-doctoral;programs;skills;success;superfund site;training opportunity

public_health_relevance:
Relevance: The overall goal of the Research Experience and Training Coordination Core(RETCC) is to direct successful training of graduate students and post-doctoral fellows(designated trainees) in the University of Louisville Superfund Research Center (ULSRC). Thisincludes scientific interdisciplinary training within defined ULSRC projects and cores as well aspromoting development of a broad knowledge base and the skills needed to communicate andengage with relevant community partners government liaisons and health-care professionalsregarding the importance of environmental health sciences research in the Superfund Program.


application_id: 10354694
project_number: 2P42ES023716-06
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5058
contact_pi_person_id: 9753394
contact_pi: RAI, SHESH N.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe primary objective of the Sample and Data Management Core (DMAC) is to provide statistical support anddata management and storage capabilities to all components of the University of Louisville Superfund ResearchCenter (ULSRC). The functions of the Core are matched to the needs of each project and cover a full range ofservices from collaboration and routine service to protocol preparation to procedural review and oversight. TheCore will provide two main services: it will establish a repository for the long-term storage and archiving of data;and it will assist Center investigators in the statistical analysis of their results. The core will assure the authenticityand quality of these specimens and it will prepare these samples for long-term storage or dispense samples asneeded. The Core will also provide scientifically valid and rigorous statistical analysis of data and support thedevelopment of innovative methods to enhance the basic and translational research efforts of Centerinvestigators. It will provide state-of-the-art biostatistics and bioinformatics expertise and analytical support. Corebiostatisticians will also develop new statistical methods such as quantitative risk assessment modelsmultipollutant exposure analysis and land-use regression models for estimating cardiometabolic disease risk inexposed populations and for the analysis and evaluation of exposures and health effects. In collaboration withother projects and cores DMAC statisticians will harmonize the data by defining standards (e.g. creatingsearchable data dictionaries and defining variables relevant for each project. In the next funding cycle we willcontinue to use these procedures. The core will serve as a unique educational resource for training graduatestudents post-doctoral fellows residents and junior faculty and in collaboration with the Training andAdministration Cores. This Core will allow Center investigators easy access to high quality centralized datamanagement and statistical services and thereby will strengthen the organizational cohesion of the Center. Thiscomprehensive and integrated service permits one or more biostatisticians to be involved from the initial planningstage of a project (when statistical consultation is most beneficial) throughout its implementation analysis andcompletion. The Core will provide a stable and collegial environment that fosters long-term working relationshipsbetween biostatisticians and investigators and continues to promote sophisticated approaches to experimentaldesign and analysis. The biostatisticians of this Core are knowledgeable about clinical research and have broadexpertise in statistical applications for epidemiological investigations clinical trials pre-clinical studies andprevention and control research. Their interdisciplinary interactions with basic scientists and clinical investigatorswill add a new dimension to the interpretation of experimental results one that is only possible when collaboratorsshare a mutual appreciation of problems and issues.

project_terms:
Anacondas;Animals;Artificial Intelligence;Basic Science;Bioinformatics;Biological Assay;Biometry;Cardiometabolic Disease;Characteristics;Clinical Investigator;Clinical Research;Clinical Trials;Code;Collaborations;Consultations;Data;Data Analyses;Data Collection;Data Files;Data Set;Data Storage and Retrieval;Databases;Development;Dimensions;Disease;Educational workshop;Ensure;Environment;Environmental Exposure;Evaluation;Experimental Designs;Exposure to;FAIR principles;Faculty;Fostering;Funding;Future;Gases;Geography;Hazardous Chemicals;Health;Human;Human Resources;Individual;Institution;Linux;Machine Learning;Manuscripts;Maps;Mass Spectrum Analysis;Measurement;Methods;Modeling;Molecular;Operating System;Output;Participant;Population Analysis;Postdoctoral Fellow;Preparation;Prevention;Privacy;Procedures;Process;Protocols documentation;Pythons;Quality Control;Research;Research Design;Research Personnel;Resources;Risk;Risk Assessment;Sampling;Scientist;Secure;Series;Services;Site;Source;Spatial Distribution;Specimen;Statistical Data Interpretation;Statistical Methods;Study Subject;Superfund;Testing;Toxic effect;Training;Translational Research;Universities;Validation;Variant;Work;archive data;archived data;base;cardiometabolism;central database;cohesion;computing resources;data curation;data dictionary;data exchange;data harmonization;data hub;data interoperability;data management;data quality;data sharing;data streams;data structure;design;detection limit;disorder risk;education resources;efficacy testing;epidemiology study;experience;experimental analysis;graduate student;improved;innovation;land use;large datasets;lipidomics;meetings;metabolomics;novel;novel strategies;operation;platform-independent;portability;preclinical study;quality assurance;repository;statistical service;tool;transcriptomics;usability;volatile organic compound

public_health_relevance:
RELEVANCEBy ensuring proper study designs and supporting appropriate data analysis and by providing efficient andorganized data management and storage capabilities the core will further our understanding of risk sources andcardiometabolic disease risk estimation due to exposure to hazardous chemicals. Well annotated data basescreated and supported by the core will facilitate data sharing and collaborative projects within the Center andwith other Superfund Centers and academic institutions.


application_id: 10354693
project_number: 2P42ES023716-06
project_title: Administrative Core
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5057
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Achievement;Administrator;Advisory Committees;Cardiometabolic Disease;Collaborations;Communication;Communities;Consultations;Core Facility;Counseling;Data;Development;Development Plans;Diabetes Mellitus;Discipline;Emergency response;Ensure;Environment;Environmental Exposure;Evaluation;Focus Groups;Funding;Future;Goals;Hazardous Chemicals;Health;Health Professional;Heart Diseases;Human Resources;IACUC;Individual;Institutional Review Boards;Knowledge;Leadership;Link;Liver diseases;Logistics;Medical emergency;Mentors;Monitor;National Institute of Environmental Health Sciences;Nongovernmental Organizations;Policies;Policy Maker;Productivity;Progress Reports;Protocols documentation;Public Health;Quality Control;Reagent;Regulation;Research;Research Personnel;Research Project Grants;Research Training;Resource Sharing;Resources;Scientific Evaluation;Scientist;Selection Criteria;Signal Recognition Particle;Specimen;Students;Superfund;Time;Training;Training Activity;Training and Education;Translational Research;Universities;Work;community engagement;effectiveness research;experimental study;federal policy;meetings;member;operation;participant enrollment;programs;tool;training opportunity;web site


application_id: 10354692
project_number: 2P42ES023716-06
project_title: Project 4 - Advancing VOC Treatment with Novel Materials and Processes
administering_ic: NIEHS
award_notice_date: 2022-08-31
opportunity_number: RFA-ES-20-014
application_type: 2
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZES1 LAT-S (SF)]
subproject_number: 5056
contact_pi_person_id: 15792674
contact_pi: FORTNER, JOHN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3-Dimensional;Area;Benign;Carbon;Carbon Dioxide;Cardiometabolic Disease;Catalysis;Chemicals;Complex;Data Analyses;Development;Electromagnetics;Engineering;Environmental Exposure;Exclusion;Film;Filtration;Gases;Generations;Geometry;Goals;Health;Health Benefit;Heating;Hybrids;In Situ;Library Materials;Lighting;Liquid substance;Magnetism;Membrane;Mission;Modeling;Nature;Outcome;Oxides;Pathway interactions;Performance;Phase;Predisposition;Process;Production;Property;Reaction;Reactive Oxygen Species;Recovery;Research;Resistance;Risk;Series;Shapes;Source;Specificity;Structure;Superfund;Surface;Techniques;Technology;Temperature;Thinness;Training;Universities;Water;advanced analytics;analog;base;catalyst;cost;data sharing;design;disorder risk;flexibility;graphene;improved;innovation;insight;irradiation;membrane assembly;metal oxide;microwave electromagnetic radiation;nanocomposite;nanomaterials;nanoparticle;nanoscale;novel;operation;oxidation;radio frequency;reaction rate;remediation;self assembly;titanium dioxide;treatment strategy;ultraviolet irradiation;volatile organic compound


