# projects

application_id: 10773046
project_number: 5R01NS116068-04
project_title: Macrophage Depletion Therapy for Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2023-12-18
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_abstract:
PROJECT SUMMARY/ABSTRACT. Spinal cord injury (SCI) is a devastating lifelong affliction that impairs anumber of functions including locomotion breathing autonomic regulation and sensation/pain. Unfortunatelythere is no current FDA approved therapy for SCI. Therefore there is a critical need to translate basic sciencediscoveries developed in the laboratory with promising effects after experimental SCI towards humanapplication. SCI elicits an intraspinal inflammatory response comprised of resident glia and infiltrating bloodleukocytes. Although subsets of resident and recruited immune cells have been implicated in CNS repair morethan 20 years of experimental data in different animal models of SCI indicate that acute monocyte depletion(MD) is consistently neuroprotective. Further there are clinically viable drugs such as clodronate that caneffectively deplete monocytes after SCI. However a number of fundamental questions must be answeredbefore successful translation including understanding the extent to which injury level impacts therapeuticefficacy as well as understanding the long-term consequences of MD on functional recovery and monocyterepopulation and fate. Therefore the goals of this proposal are to examine chronic and level-specific functionalchanges after acute MD using clinically relevant outcomes including pain autonomic dysreflexia respirationand forelimb/hand function. We will study the effects of acute liposome encapsulated clodronate treatment forup to one year in rodent models of cervical and thoracic SCI. Specifically this grant seeks to: Aim 1: evaluatethe dose-response effects of acute MD on myelopoiesis biodistribution and toxicity; Aim 2: determine theefficacy of acute MD on recovery of locomotor sensory and autonomic function in chronic SCI rats. Aim 3:determine the effects of acute MD on recovery of respiratory motor and forelimb function after cervical SCI.The combined approach of examining the effects of MD after both cervical and thoracic SCI will provideunprecedented preclinical data regarding the effects of monocyte function on sensory autonomic pain andrespiratory outcomes. The feasibility of clodronate (aka disodium dichloromethylene diphosphonate) treatmentin SCI individuals was reported almost 40 years ago therefore our proposal is significant as data from ourstudies could be adapted to treat human SCI and is expected to be of critical translational impact.

project_terms:
Acute;Affect;American;Animal Model;Animals;Anti-Inflammatory Agents;Applications Grants;Autonomic Dysreflexia;Basic Science;Biodistribution;Biological Assay;Bone Marrow;Breathing;Caring;Cell Death;Cells;Cervical;Cervical spinal cord injury;Cervical spinal cord structure;Chronic;Clinical;Clinical Trials;Contusions;Data;Dichloromethylene Diphosphonate;Distal;Dose;Encapsulated;Esthesia;FDA approved;Flow Cytometry;Forelimb;Frustration;Functional impairment;Funding;Goals;Grant;Hand functions;Hindlimb;Hour;Human;Immune;Immune Targeting;Immunologic Deficiency Syndromes;Impairment;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Injury;Laboratories;Lesion;Leukocytes;Liposomes;Liver;Locomotion;Locomotor Recovery;Macrophage;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;Voice;arm;axonal sprouting;central pattern generator;clinically relevant;efficacy evaluation;functional outcomes;improved;improved outcome;indexing;innovation;meeting reports;meetings;monocyte;neuroprotection;novel therapeutic intervention;pre-clinical;preclinical evaluation;recruit;repaired;respiratory;response;side effect;synaptogenesis;tissue repair;translational impact;translational therapeutics

public_health_relevance:
PROJECT NARRATIVE. There are near 290000 people in the United States of America that have a spinalcord injury (SCI) (with at least 18000 new cases each year) many with functional impairment. The mainobjective of this grant proposal is to investigate a novel therapeutic strategy which modifies the inflammatoryresponse and can potentially lead to protection of the spinal cord after injury as well as functional recovery.This dose-response experimental approach will be studied in multiple injury levels and functional outcomes aswell as tracked over time and collectively these studies will lead to better understanding of the impact ofinflammatory modification after injury and can potentially lead to improvement in human care and outcomes.


application_id: 10771220
project_number: 5P20GM135004-05
project_title: The role of ECM-mediated mechanosignaling on regional immunosuppression in GBM
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2024-06-26
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4
subproject_number: 7954
contact_pi_person_id: 12556833
contact_pi: CHEN, JOSEPH
other_pis: CHESNEY, JASON A.
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:
Recent studies reveal that immunosuppressive regions vary substantially throughout glioblastoma (GBM) tumors. These immune-restricted niches appear to correspond to specific extracellular matrix (ECM) components that are thought to drive regional mesenchymal transition. We hypothesize that these distinct GBM mesenchymal regions both coincide with and are responsible for monocytic myeloid-derived suppressor cell (M-MDSC) infiltration. Our project hypothesis predicts that changes in regional hyaluronic acid (HA) extracellular matrix (ECM) stiffness induces the activation of proneural GBM cell surface CD44 that in turn drives simultaneous mesenchymal transition and increases an M-MDSC recruiting/differentiation transcriptional program. Studies proposed in this application will rigorously delineate the mechanistic pathway and effectors involved by focusing on a hypothesized HACD44STAT3/ZEB1-dependent pathway and (2) delineate whether/how regional activation of this pathway results in a STAT3/ZEB1-dependent induction of IL-6/IL-17-mediated regional accumulation of M-MDSC-dependent immune suppression in GBM. We anticipate that results from this proposal will identify a novel targetable axis and address a critical gap in our understanding of the impact of biophysical changes in GBM TME.

project_terms:
Address;Biophysics;CD44 gene;Cancer Center;Cell surface;Extracellular Matrix;Genetic Transcription;Glioblastoma;Hyaluronic Acid;IL17 gene;Immune;Immunosuppression;Infiltration;Interleukin-6;Mediating;Mesenchymal;Myeloid-derived suppressor cells;Pathway interactions;Role;STAT3 gene;cancer immunotherapy;monocyte;novel;programs;recruit;tumor;tumor immunology


application_id: 10771219
project_number: 5P20GM135004-05
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4
subproject_number: 7953
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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:
Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy using immune checkpoint inhibitors (ICIs; e.g. anti-PD-1 anti-CTLA-4 antibodies) has revolutionized the treatment of metastatic lung cancer resulting in long-term complete responses for many patients. Nevertheless there remains an urgent need for new strategies because not all patients respond to ICIs; moreover resistance can occur in those that do. Myeloid-derived suppressor cells (MDSCs) in particular monocytic MDSCs (MMDSCs) are potent immunosuppressive innate immune cells that actively inhibit CD8+ T cell tumor homing and activation. Since M-MDSC levels are elevated in multiple human cancers and correlate with decreased patient survival we postulate that these cells contribute to anti-PD-1 resistance. The purine nucleoside adenosine is produced in copious amounts within the tumor microenvironment (TME) where it serves to suppress the immune system and promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediate resistance to ICIs. Immune suppressive adenosine is produced via the enzymatic conversion of extracellular AMP by the cell surface enzyme CD73 (ecto-5-nucleotidase; AMP  adenosine). Our preliminary studies demonstrate that tumor cell-derived prostaglandin E2 (PGE2) maintains M-MDSC suppressive activity in large part by directly inducing cell surface CD73 expression via a novel PGE2cAMPCREB/STAT3 pathway leading to increased immune suppressive adenosine within the TME. The overall hypothesis of this proposal is that tumor cell-derived PGE2 dictates CD73 expression in M-MDSCs leading to substantial increases in adenosine-dependent inhibition of anti-tumor CD8+ T cell activation resulting ultimately in anti-PD-1 immunotherapeutic resistance A major goal of this proposal is to test the antitumor efficacy of a novel cancer immunotherapy involving systemic administration of adenosine deaminase (ADA)an enzyme that irreversibly converts adenosine into inosine a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA) is already FDA-approved for use as an enzyme replacement therapy in children with ADA-associated severe combined immunodeficiency (ADA-SCID). We hypothesize that depletion of adenosine-mediated T cell immune suppression by PEG-ADA sensitizes tumors to PD-1 inhibitor therapy and improves clinical outcomes for NSCLC patients. To fulfill the stated objectives the following aims are proposed: 1) Delineate the signaling pathway and molecular mechanisms by which PGE2 induces CD73 expression in M-MDSCs; 2) Determine whether inhibition of the PGE2cAMPCREB/STAT3CD73adenosine pathway attenuates anti-PD-1 resistance in a mouse model of lung cancer; and 3) Validate PGE2  CD73+ M-MDSC  adenosine mediated anti-PD-1 resistance pathway in lung cancer patients receiving pembrolizumab therapy. Our proposed study will provide important insights towards developing a safe and novel immunotherapy to attenuate ICI resistance in lung cancer patients.

project_terms:
5'-Nucleotidase;Adenosine;Adopted;Advanced Malignant Neoplasm;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;CREB1 gene;Cancer Center;Cancer Model;Cancer Patient;Cattle;Cell Physiology;Cell surface;Cells;Child;Clinical;Consumption;Critical Pathways;Cyclic AMP;Data;Dinoprostone;Disease;Enzymes;FDA approved;Frequencies;Generations;Goals;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In Vitro;In complete remission;Infiltration;Inosine;Knock-out;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator;Molecular;Mus;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nucleosides;Outcome;PD-1 inhibitors;Pathway interactions;Patients;Polyethylene Glycols;Production;Prostaglandin Inhibition;Purine Nucleosides;Regulation;Resistance;STAT3 gene;Severe Combined Immunodeficiency;Signal Pathway;Signal Transduction;T-Cell Activation;T-Lymphocyte;Testing;Transgenic Model;Tumor Immunity;Tumor Promotion;Tumor-Derived;adenosine deaminase;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer immunotherapy;clinically relevant;conditional knockout;effector T cell;enzyme replacement therapy;extracellular;improved;in vivo;inhibitor;inhibitor therapy;insight;monocyte;mouse model;neoplastic cell;novel;objective response rate;pembrolizumab;programmed cell death ligand 1;response;therapeutic target;therapy development;therapy resistant;transcription factor;tumor;tumor growth;tumor immunology;tumor microenvironment


application_id: 10771217
project_number: 5P20GM135004-05
project_title: Mechanisms of resistance to immune therapy in NSCLC
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4
subproject_number: 7952
contact_pi_person_id: 14384874
contact_pi: LI, QINGSHENG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Despite having been approved as first and second line therapy for non-small cell lung cancer (NSCLC) anti-PD- 1 antibodies still fail in a substantial proportion of lung cancer patients. The mechanism that underlies the failure of anti-PD-1 therapy in the majority of NSCLC patients is not yet fully understood. We have discovered that in the anti-PD-1-resistant LSL-KrasG12D murine lung adenocarcinoma mouse model treatment induces a T-cell activation profile that favors Th17/T17 reinvigoration over CD8+ T cell activation. In contrast when administered in conjunction with an anti-IL-17 neutralizing antibody anti-PD-1 treatment results in a dramatic enhancement of CD8+ T-cell cytotoxicity with near-complete eradication of established disease. These findings provide the premise for our central hypothesis that in NSCLC the failure of anti-PD-1 is at least in part due to reinvigoration of PD-1+ type 17 T cells (Th17/T17) which actively undermine anti-PD-1-mediated restoration of cytotoxic function in CD8+ T-cells. Based on additional murine data we are also advancing the extended hypothesis that the severity of pre-existing T17 activity in the neoplastic lung is determined by commensal bacteria and that the lung microbiota signature can ultimately predict responsiveness to anti-PD-1 therapy. The goal of this proposal is to demonstrate the relevance of these findings to human prior to initiating an R01 application. Specifically in Aim 1 we will establish whether intrinsic lung T17/CTL ratio is predictive of anti-PD- 1 responsiveness in NSCLC patients independent of neoantigen burden. In Aim 2 we will determine whether specific human lung microbiota individually or in defined combinations drive the ontogeny of intrinsic T17 immunity and ultimately resistance to ICI therapy. The proposed study is conceptually impactful as it addresses an important clinical conundrum; is mechanistically novel; and has translational relevance since it introduces therapeutic/prognostic approaches that can rapidly move to the clinic.

project_terms:
Address;Bioinformatics;Biopsy Specimen;CD3 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Center;Cancer Model;Cancer Patient;Cells;Clinic;Clinical;Data;Disease;FDA approved;Failure;Generations;Germ-Free;Goals;Grant;Growth;Human;IL17 gene;Immune checkpoint inhibitor;Immunity;Immunotherapy;Individual;KRASG12D;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lymphocyte;Lymphocyte Activation;Macrophage;Macrophage Activation;Malignant neoplasm of lung;Mediating;Mus;Neoadjuvant Therapy;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Patients;Production;Progression-Free Survivals;Psoriasis;Resistance;Severities;Specimen;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer immunotherapy;checkpoint therapy;clinically relevant;commensal bacteria;cytotoxic;cytotoxicity;design;human microbiota;in vivo;interstitial;lung microbiota;microbiota;microbiota profiles;mouse model;neoantigens;neoplastic;neutralizing antibody;novel;predicting response;prognostic;prognostication;programmed cell death protein 1;prospective;resistance factors;resistance mechanism;response;restoration;standard of care;therapy outcome;tumor;tumor immunology;tumorigenic; T cells


application_id: 10771216
project_number: 5P20GM135004-05
project_title: Ongoing inflammation following chemotherapy induces immunosuppression
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4
subproject_number: 7951
contact_pi_person_id: 9855558
contact_pi: DING, CHUANLIN
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:
Conventional chemotherapy has been thought to act through the direct killing of tumor cells. Howeveraccumulating evidence indicates that immune competence is crucially required for chemotherapy efficacy. It isexpected that loss of this immunity during chemotherapy has a negative effect on its efficacy. Therefore theimpact of chemotherapy on anti-tumor immunity needs further investigation in order to rationally designcombinatorial regimens for conventional chemotherapy. In the preliminary studies we have demonstrated thatrepeated chemodrug gemcitabine (GEM) treatment promoted the expansion and differentiation ofimmunosuppressive Ly6Chigh monocytic-MDSC (M-MDSC). Tumor-derived soluble factors such as GM-CSF andsoluble ICAM-1(sICAM-1) were up-regulated upon chemo-drug treatment. In tumor-free nave mice GEMtreatment induced the immunosuppressive activity of Ly6Chigh myeloid cells in the bone marrow (BM). Thechemokine CX3CL1 and its receptor CX3CR1 expression levels were elevated in the BM. Higher levels ofmitochondrial reactive oxygen species (mtROS) were also observed in tumor cells and BM stromal cells followingchemotherapy. Furthermore chemotherapy induced NF-B activation leading to the hyperproduction of GM-CSFby tumor cells. Based on these preliminary data we hypothesize that chemotherapy enhances the production ofmtROS in tumor cells and BM stromal cells which increases the expressions of GM-CSF and sICAM-1 as wellas CX3CL1 leading to the enhanced immunosuppression of M-MDSC in the TME. These hypotheses will beaddressed by two Specific Aims. Aim 1 defines the roles of GM-CSF and sICAM-1 in chemotherapy-induceddifferentiation of immunosuppressive Ly6Chigh myeloid cells and the mechanisms underlying mtROS andupregulation of GM-CSF and sICAM-1 in tumor cells; Aim 2 determines the mechanisms by which host cell-derived chemokine CX3CL1 regulates the accumulation and immunosuppressive function of inflammatoryLy6Chigh myeloid cells in the BM. The findings from these studies will allow us to gain a better understanding theunderlying mechanisms by which ongoing inflammation following multi-dose clinical regimens of chemotherapymodulates anti-tumor immunity and rationally design a novel therapeutic approach by combining chemotherapywith mitochondria-targeted antioxidants for cancer treatment.

project_terms:
Address;Antioxidants;Bone Marrow;Breast Cancer Patient;Breast Cancer cell line;CX3CL1 gene;Cancer Center;Cells;Centers of Research Excellence;Chemotherapy-Oncologic Procedure;Clinical;Clinical Management;Combination Drug Therapy;Data;Dose;Fluorouracil;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;Hematopoiesis;Hematopoietic stem cells;Human;Immune response;Immune system;Immunity;Immunocompetence;Immunosuppression;In Vitro;Inflammation;Inflammatory;Intercellular adhesion molecule 1;Investigation;Mitochondria;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Oxidative Phosphorylation;Paclitaxel;Peripheral;Pharmaceutical Preparations;Pharmacotherapy;Production;Reactive Oxygen Species;Recruitment Activity;Regimen;Role;Side;Stromal Cells;Testing;Tissues;Treatment Efficacy;Tumor Immunity;Tumor-Derived;Tumor-associated macrophages;Up-Regulation;anti-tumor immune response;antitumor effect;cancer immunotherapy;cancer therapy;chemokine;chemotherapy;combinatorial;cytokine;gemcitabine;in vivo;monocyte;neoplastic cell;novel;novel therapeutic intervention;programs;rational design;receptor;response;tumor;tumor eradication;tumor immunology;tumor microenvironment;tumor progression


application_id: 10771215
project_number: 5P20GM135004-05
project_title: Functional Immunomics Core
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4
subproject_number: 7950
contact_pi_person_id: 9620088
contact_pi: LI, BING
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:
SUMMARY (Functional Immunomics Core)The primary goal of the Functional Immunomics Core (FIC) is to serve as the central infrastructure entity thatsupports all the investigators in the Center for Cancer Immunology and Immunotherapy (CCII) COBRE. FICwill utilize new equipment purchased with institutional funds and leverage existing facilities at the University ofLouisville to provide molecular/cellular immune profiling for mouse and human projects in the CCII. SpecificAim 1 is to build a functional immunomics facility at the University of Louisville. With the support of CCII wewill establish a streamlined state-of-the-art immunomics facility in a central location by incorporating theexisting resources of the University of Louisville. This unique resource will act as a vital integrative componentof the CCII through providing centralized services not only for its members but also for the Institution as awhole. Specific Aim 2 is to utilize the comprehensive and integrative FIC platform to ensure the success ofCCII-supported projects. The major goal of the FIC will be to support the development progress and successof proposed CCII projects in all phases of their research. Particularly the FIC will provide human sampleanalytics expertise and technical services to support the specific aims of the CCII projects. Specific Aim 3 isto facilitate translational cancer immunology/immunotherapy research and develop a self-sustaining entity ofthe CCII through University/region-wide services. In summary by integrating with the existing resources at theUofL the newly-established FIC will provide a comprehensive immunomics service center for the success ofthe proposed CCII projects and the translation of novel experimental discoveries to clinical applications.

project_terms:
Applications Grants;Area;Biological Specimen Banks;Blood;Cancer Center;Cancer Patient;Cell Separation;Cells;Centers of Research Excellence;Clinic;Clinical;Contract Services;Core Facility;Cytometry;DNA;Data;Databases;Decentralization;Dedications;Development;Education;Ensure;Extramural Activities;Fee-for-Service Plans;Flow Cytometry;Freezing;Funding;Future;Genomics;Goals;Human;Human Resources;Immune;Immune system;Immunofluorescence Immunologic;Immunologic Monitoring;Immunologics;Immunooncology;Immunotherapy;Infrastructure;Institution;Investments;Kentucky;Location;Malignant Neoplasms;Molecular;Mus;Paraffin Embedding;Patients;Phase;Phenotype;Process;Proteins;Protocols documentation;Publications;Qualifying;RNA;Research;Research Personnel;Research Support;Resources;Running;Sampling;Services;Site;Slide;Specimen;Stains;Technology;Tissues;Training;Training and Education;Translations;Tumor-Associated Process;Universities;University resources;Writing;cancer immunotherapy;clinical application;design;equipment acquisition;innovation;instrument;instrumentation;interest;member;new therapeutic target;novel;operation;prospective;success;tissue processing;tissue/cell preparation;transcriptomics;treatment strategy;tumor;tumor immunology


application_id: 10771211
project_number: 5P20GM135004-05
project_title: Center for Cancer Immunology and Immunotherapy (CCII)
administering_ic: NIGMS
award_notice_date: 2024-01-25
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2025-08-31
study_section: ZGM1-RCB-4(C1)
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
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
arra_indicator: N
project_abstract:
The objective of this program is to establish a thematic multidisciplinary research center of excellence at theUniversity of Louisville (UofL) named the Center for Cancer Immunology and Immunotherapy (CCII). Themission of the CCII is to conduct outstanding biomedical research that works towards harnessing the power ofthe immune system to eradicate cancer. There is currently a great deal of optimism about the prospects forcancer immunotherapies given the recent clinical successes of immune checkpoint inhibitors oncolytic virusesand adoptive cell transfer therapies. Immunotherapies have the potential to be used to treat all types of cancerand to induce long-lasting remissions or cures. However more research and development is needed forcancer immunotherapy to reach its full potential. The University of Louisville is exceptionally qualified to be thehome of the CCII for many reasons including our 10-year track record of conducting clinical trials ofimmunotherapeutic agents unique resources that include access to human specimens from these trials oursenior investigators expertise in cancer immunology our focus on translational research and the impact thatthis COBRE would have in a state with the highest cancer death rates in the nation. Importantly the Universityof Louisville is highly invested in making this proposed center a success as best evidenced by more than$16.8M in institutional commitments over five years. The two PIs of the CCII program are highly regardedexperts in the field who have made seminal contributions spanning from basic cancer immunology to pivotalclinical trials of cancer immunotherapies. Senior mentors with expertise in the thematic area and a stronghistory of funding publications mentoring and study section service will support the CCIIs mentoring missionas will a team of co-investigators with essential expertise (in administration biostatistics and bioinformatics)and Internal and External Advisory Committees. A Functional Immunomics Core will provide important newinfrastructure and leverage existing resources (including other IDeA programs) to provide outstanding supportto the four promising junior investigators who have been selected as the first cohort of CCII Project PIs. Thefour overall specific aims of the CCII are to: (1) Establish the administrative and mentoring infrastructure for theCCII; (2) Create a research core that provides new capabilities while leveraging existing facilities; (3) Supportthe research and career development of junior PIs in the thematic area; and (4) Develop and initiate a plan forlong-term sustainability and growth of the CCII. We are confident that this new COBRE center will lead to theawarding of innovative R01 grants for 4-6 CCII junior investigators in the first five years and that many of thesegraduates will remain key members of this new COBRE to further build the center in the future. Mostimportantly our combination of rigorous basic science with highly translational animal and human specimenstudies should ultimately contribute to the development of new treatment strategies that will help to improve theoutlook for the more than 17 million people worldwide who are diagnosed with cancer each year.

project_terms:
Adoptive Cell Transfers;Advanced Malignant Neoplasm;Advisory Committees;Animals;Antibodies;Area;Award;Basic Science;Bioinformatics;Biological Markers;Biomedical Research;Biometry;Bladder;CAR T cell therapy;CTLA4 gene;Cancer Center;Cancer Death Rates;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Conduct Clinical Trials;Country;Cytometry;Development;Diagnosis;Discipline;Disease remission;Disseminated Malignant Neoplasm;Early Diagnosis;Financial Support;Flow Cytometry;Funding;Future;Genomics;Goals;Grant;Growth;Head and neck structure;Home;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Surveillance;Immunologist;Immunotherapeutic agent;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;International;Investments;Kidney;Lung;Malignant Neoplasms;Mediating;Melanoma;Mentors;Mission;Molecular;Mus;Names;Oncolytic viruses;Outcome;Paper;Patients;Personnel Selection;Persons;Phase;Pilot Projects;Proteins;Publications;Qualifying;Recording of previous events;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Sampling;Seminal;Services;Specimen;Study Section;T cell therapy;Talents;Testing;Training;Translating;Translational Research;Tumor Immunity;Universities;Vaccines;Work;anti-cancer;cancer cell;cancer clinical trial;cancer immunotherapy;cancer therapy;cancer type;career development;checkpoint therapy;chimeric antigen receptor T cells;cohort;equipment acquisition;immune checkpoint;improved;innovation;interest;member;microbiome research;new therapeutic target;novel strategies;novel therapeutic intervention;optimism;programmed cell death ligand 1;programmed cell death protein 1;programs;recruit;research and development;response;senior faculty;side effect;statistics;success;systemic toxicity;treatment strategy;tumor;tumor immunology

public_health_relevance:
Decades of research have demonstrated that the immune system can eradicate cancer cells but only if immuneevasion mechanisms such as immune checkpoint proteins can be overcome. Multiple new immunotherapeuticapproaches have recently been developed that can induce durable remissions in patients with advanced cancers unfortunately the majority of patients still succumb to their cancers. The goal of this COBRE application is toestablish a new Center for Cancer Immunology and Immunotherapy that will focus on understanding immuneescape mechanisms developing new approaches to activate/reinvigorate anticancer immunity trainingpromising young cancer immunologists and improving the research infrastructure of the University of Louisville.


application_id: 10771165
project_number: 5R01EY030933-05
project_title: Blood outer retina barrier regulation
administering_ic: NEI
award_notice_date: 2024-01-29
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EY
serial_number: 030933
program_official: COOK, TIFFANY
project_start_date: 2020-02-01
project_end_date: 2025-05-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 1877760
contact_pi: DEAN, DOUGLAS CHASE
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractMutations in rod photoreceptor-specific genes in retinitis pigmentosa (RP) cause diminishedperipherial and night-time vision. But it is secondary loss of cone function leading todiminished high-resolution daylight vision utilized for reading facial recognition and other dailytasks that is most debilitating. Events leading to loss of cone function in RP are still beingunraveled. Like other neurons photoreceptors depend upon glucose which they use forenergy as well as ongoing synthesis to replace visual pigment-rich membraneous outersegments (OS) as they undergo daily light-induced phagocytosis. The RPE serves as ablood-outer retinal barrier transporting glucose and nutrients from the choroid circulationto adjacent photoreceptors. We provide evidence that glucose transport from the RPE tophotoreceptors for new OS synthesis is linked to OS phagocytosis. As abundant mutantrod OS are lost and phagocytosis diminishes in RP glucose transport becomes short-circuited leading to cone starvation. We will examine the signaling pathway regulatingglucose transport from the RPE and linked metabolome/epigenome changes in thesecells during RP progression in both mice and pigs a large animal model of RP wherecones are concentrated into a visual streak.

project_terms:
AKT inhibition;Adaptor Signaling Protein;Age;Animal Model;Apical;Arrestins;Automobile Driving;Back;Binding;Birth;Blood;Catheters;Cell Death;Cells;Choroid;Circulation;Clathrin;Complex;Cone;Cytoplasm;Cytoskeletal Modeling;DNA;Dark Adaptation;Development;Disease;Disease Progression;Down-Regulation;Endocytosis;Environment;Epigenetic Process;Epithelial Cells;Event;Face;Family;Family suidae;Feedback;Feeds;GLUT 4 protein;GLUT-1 protein;Gene Expression;Genes;Glucose;Glucose Transport Induction;Glucose Transporter;Hypoglycemia;Injections;Insulin;Integrins;Investigation;Label;Light;Link;Lipids;Macrophage;Malignant Neoplasms;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Modeling;Mus;Mutation;Neurons;Nutrient;Pathway interactions;Peripheral;Phagocytosis;Phagocytosis Induction;Phosphatidylserines;Phosphorylation;Photoreceptors;Proteins;Reading;Regulation;Resolution;Retina;Retinal Pigments;Retinitis Pigmentosa;Rod;Rod Outer Segments;Signal Pathway;Signal Transduction;Starvation;Structure of retinal pigment epithelium;Surface;Transplantation;Vision;Visual;Work;alpha ketoglutarate;blood glucose regulation;coated pit;cofactor;enhancing factor;epigenome;experimental study;functional loss;glucose metabolism;glucose transport;glucose uptake;histone demethylase;inhibitor;loss of function;metabolome;mutant;overexpression;prevent;receptor;recruit;response;restoration;retinal rods;scaffold;subretinal injection;uptake

public_health_relevance:
Project NarrativeAlthough many mutations in retinitis pigmentosa (RP) arise in rod-specific genes it issecondary loss of cone function leading to diminished high-resolution daylight vision that ismost debilitating. We provide evidence glucose transport from RPE to photoreceptors isdiminished in RP causing their starvation and loss of function. A pathway regulatingglucose transport is identified and we link its deregulation to RPE metabolome changesin RP.


application_id: 10769718
project_number: 5K23MH126211-03
project_title: A Precision Medicine Approach to Target Engagement for Emotion Regulation
administering_ic: NIMH
award_notice_date: 2024-01-19
opportunity_number: PA-20-206
application_type: 5
activity_code: K23
ic: MH
serial_number: 126211
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
arra_indicator: N
project_abstract:
Emotion dysregulation is a transdiagnostic maintenance factor involved in a wide array of costly anddebilitating psychiatric disorders. Although numerous full-model behavioral health treatments have beendesigned to improve patients emotion regulation capacities these treatments consist of multiple componentsmaking it difficult to discern which are active mechanisms leading to reductions in negative emotion intensity.Further it is unclear whether the delivery of these evidence-based components can be tailored to the individualpatient. The proposed Mentored Patient-Oriented Research Career Development Award (K23) is a four-yearplan to support the applicants long-term career goal of becoming a clinical scientist with expertise in (1)identifying active mechanisms of emotion regulation interventions for psychopathology (2) tailoring theseinterventions to individual patients and (3) developing scalable interventions for wide dissemination. Theapplicants training and career thus far are aligned with these long-term goals. Throughout his graduate workhe conducted studies testing emotion regulation mechanisms in transdiagnostic samples and used thisinformation to explore for whom these mechanisms were most impactful. The immediate goals of the K23award are for the applicant to become skilled at intensive longitudinal experimental designs to disaggregatebetween- from within-person mechanisms of change and enhance his proficiency in conducting and analyzingmultimethod assessments of emotion regulation. This proposal uses a two-phase approach to address thesegoals. In line with an experimental therapeutics approach the goal of Phase 1 is to compare the effects ofteaching one or three emotion regulation skills on daily changes in negative emotion intensity amongparticipants with elevated emotion dysregulation. The first goal of Phase 2 is to apply a personalizationalgorithm based on Phase 1 data to an independent sample to determine which baseline participantcharacteristics predict greater reductions in negative emotion intensity in each experimental condition. Thesecond goal of Phase 2 is to compare the effects of teaching participants emotion regulation skill(s) accordingto their optimal or non-optimal delivery condition based on the personalization algorithm. The training planclosely matches the proposed research and long-term goals including (a) developing advanced understandingin statistical methods to test between- and within-person mechanisms of emotion regulation interventions (b)gaining proficiency in applying novel personalization algorithms and (c) enhancing expertise in theimplementation and analysis of multimethod assessments of emotion regulation skills. The broader aim of thisresearch and training is to address the need for more efficient personalized and scalable interventions fortransdiagnostic psychiatric conditions in line with the NIMH strategic plan. This study will answer importanttheoretical and practical questions about the efficacy of different emotion regulation mechanisms on clinicaloutcomes that may promote the development of more targeted and disseminable interventions.

project_terms:
Address;Aftercare;Algorithms;Anger;Anxiety;Articulation;Behavioral;Behavioral Model;Borderline Personality Disorder;Characteristics;Clinical;Consensus;Data;Dedications;Development;Diagnostic;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;Methods;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;Role;Sampling;Scientist;Signal Transduction;Statistical Methods;Strategic Planning;Symptoms;Techniques;Testing;Therapeutic;Time;Training;Trauma;Work;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;prospective;response;skills

public_health_relevance:
The proposed study is designed to first test whether teaching people with emotion dysregulation asingle emotion regulation skill in depth or multiple emotion regulation skills in less depth leads to greaterdecreases in daily negative emotion intensity. Second using data from an initial sample we will prospectivelyassign an independent sample of participants to receive their predicted optimal or non-optimal skill condition todetermine if it is feasible and efficacious to match the participants to a single- or multiple-skill condition. Resultsof these studies may identify the mechanisms by which emotion regulation interventions impact emotionalfunctioning and allow for the development of personalized evidence-based and scalable emotion regulationinterventions.


application_id: 10768786
project_number: 5R01CE003360-03
project_title: STIMuLINK
administering_ic: NCIPC
award_notice_date: 2023-05-02
opportunity_number: RFA-CE-21-002
application_type: 5
activity_code: R01
ic: CE
serial_number: 003360
project_start_date: 2021-09-30
project_end_date: 2024-09-29
study_section: ZCE1-MLW(04)R
contact_pi_person_id: 11262879
contact_pi: DELCHER, CHRIS
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: 2023-09-30
project_abstract:
Project AbstractSTIMuLINK will address Objective 2 of RFA-CE-21-002 by identifying risk/protective factors forstimulant-involved deaths that are actionable for the development or adaptation of current preventionand intervention efforts. For the period 2017-2024 STIMuLINK will link records from stimulant-involved fataloverdoses found in Kentuckys drug overdose fatality surveillance system (DOFSS) to electronic medicalrecords (EMR) available from the states largest primary and safety net healthcare system UK Healthcare(UKHC). This innovative data linkage reduces the surveillance bias associated with medical informationobtained only from coroner reports makes EMR gold standard medical information available for researchimproves data completeness needed for risk/protective factor ascertainment using the concept of computablephenotypes and enables a comparative cohort of patients found in the EMR (i.e those with evidence ofharmful stimulant use). Using traditional and novel (the Feasible Solution Algorithm) statistical approaches toanalyze these cohorts STIMuLINK will examine risk/protective factors predictive of fatal stimulant overdosesusing the social ecological model as the principal framework. In parallel with these Aims STIMuLINK tests theuse of existing biomedical natural language processing (NLP) tools to extract additional factors from the literaltext notes found in DOFSS (added back as structured variables to the risk/protective models when possible)and compares findings from notes written by coroners to notes written by medical examiners in a neighboringstate. The guidance and open-source software developed from this Aim will advance the science of NLP forautomating the workflow for injury surveillance. STIMuLINKs diverse multidisciplinary and accomplished teamincludes epidemiologists computer scientists lawyers statisticians and behavioral scientists with experienceworking directly with communities impacted by the current polydrug overdose epidemic. The project specificallyincludes on-going communication points with vulnerable communities and clinical populations to increase thetranslational impact of the research.

public_health_relevance:
Project NarrativeSTIMuLINK provides insight on the risk and protective factors predictive of stimulant-involved deaths byunlocking the information available in the electronic medical records from prior healthcare visits and the literaltext written by coroners during an overdose investigation.


application_id: 10767347
project_number: 5P42ES007380-26
project_title: Fate and Transport of Contaminants in Aging Piping Systems
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6738
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYMillions of miles of water and sewer piping systems are currently buried across the United States. Near sitescontaminated with hazardous wastes pipe deterioration provides pathways for contaminant entry and transportto surrounding communities. One challenge of leaking sewer pipes near Superfund sites involves volatilizationof contaminants that enter subsurface pipes posing indoor inhalation exposure risks. In drinking water pipingsystems pipe fractures coupled with pressure transients within the piping system allow subsurfacecontaminants to enter the systemespecially at contaminated sites where such breaks become conduitsimpacting water quality. This project provides strategies to reduce and prevent exposure risks to environmentalcontaminants especially chlorinated ethenes and per- and polyfluoroalkyl substances (PFAS) that result fromleaking and damaged subsurface piping networks. The overarching project goal is to combine pipinginfrastructure science with fate and transport science to identify and reduce exposure risks associated withtrichloroethene (TCE) tetrachloroethene (PCE) and PFAS. To achieve this goal we propose three specificaims: 1) To measure mass flux of contaminants at field sites where TCE and PCE exposure risks are impactedby piping networks; evaluate flow and pressure field data from drinking water systems; and determine theeffect of broken or failed piping components and joints in lab settings 2) To develop models that: a) predictmass flux of contaminants to indoor air and evaluate exposure risks; b) predict mass flux of contaminantsthrough piping networks; and 3) To use stakeholder input and stochastic analyses to characterize modeluncertainty and sensitivity in an effort to develop stakeholder-relevant solutions that reduce and preventexposure risks. The specific aims integrate advanced computational modeling approaches with fieldmeasurements collected from piping systems in Eastern Kentucky and at a start-of-the-art vapor intrusionresearch facility near a Superfund site. Comparing data from different measurement techniques including anovel sensor technology provides information about temporal variability of sewer gas mass flux which iscritical due to the high level of uncertainty that surrounds environmental exposure risks. The research teamaims to bolster a paradigm shift in the way uncertain exposure risks are managed and develop solutions toreduce exposure risks in ways that are acceptable to communities. Risk communication science will informstrategies to evaluate uncertainty using stakeholder perspectives and evidence-based practices as aframework to promote solution-oriented research and environmental health literacy.

project_terms:
Address;Aging;Air;Analytical Chemistry;Biological Monitoring;Biomedical Research;Calibration;California;Communication;Communities;Computer Models;Coupled;Data;Data Analyses;Deterioration;Ensure;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Hazards;Environmental Health;Environmental Pollutants;Environmental Science;Equation;Ethylenes;Evidence based practice;Foundations;Fracture;Gases;Goals;Hazardous Waste;Health;Human;Individual;Indoor Air Quality;Industry;Infrastructure;Inhalation Exposure;Interview;Joints;Kentucky;Knowledge;Measurement;Measures;Membrane;Modeling;North Carolina;Outcome;Outcome Study;Pathway interactions;Policies;Poly-fluoroalkyl substances;Polymers;Public Health;Regulation;Reporting;Research;Research Project Grants;Risk;Risk Management;Risk Reduction;Route;Sampling;Science;Services;Site;Superfund;Surveys;System;Techniques;Temperature;Testing;Tetrachloroethylene;Time;Toxic effect;Transcend;Translational Research;Transport Process;Trichloroethylene;Uncertainty;United States;Volatilization;Water;Water Supply;aged;base;community engagement;contaminant transport;data interoperability;data management;data modeling;drinking;drinking water;engineering design;epidemiology study;field study;ground water;health literacy;hookah;indoor air;informant;mass flux;novel;nutrition;predictive modeling;pressure;prevent;research facility;sensor;sensor technology;stakeholder perspectives;superfund chemical;superfund site;tool;vapor intrusion;ventilation;water quality

public_health_relevance:
PROJECT NARRATIVEThe overarching goal of this project is to advance fate and transport research to identify and reduce exposurerisks associated with trichloroethene (TCE) tetrachloroethene (PCE) and PFAS. Field study results verify andcalibrate new models that predict contaminant mass flux associated with damaged subsurface piping networkswhich serve as preferential pathways for contaminants to be transported throughout communities. Evidence-based practices serve as a framework to promote environmental health literacy so that communitystakeholders representatives from regulatory agencies and industry groups can provide information todevelop solutions that will ensure Superfund mandates are addressed and public health is protected.


application_id: 10767345
project_number: 5P42ES007380-26
project_title: Responsive Membranes and Advanced Materials for Sensing and Remediation of Halo-organics
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6737
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYChlorinated organic compounds such as polychlorinated biphenyls (PCBs) and trichloroethylene (TCE PCE)and polyfluoroalkyl substances (PFAS) continue to pose both remediation challenges and human health risks.Despite decades of remediation effort chloro- and perfluoro-organic compounds remain Superfund pollutantsof national health concern due to their high toxicity persistence and varied sources of distribution in theenvironment. Many current treatments (microbial transformation carbon adsorption etc.) for the reclamation ofcontaminated water sources are chemical-intensive energy-intensive and/or require post-treatment due tounwanted by-product formation. Project 3 proposes trans-disciplinary integration of the materials surfacescience and engineering concepts including responsive polymer and reduced graphene oxide 2D membranescience nanostructured metals and nutrition and food science using approaches common in the biomedicalresearch field to develop more efficient methods of organic detoxification. The development of nanosized iron-based materials has brought important and promising techniques into the field of environmental remediation. Inrecent years zero-valent nanoscale metal (especially bimetallic) particles have attracted growing attention ingroundwater remediation of chlorinated solvents. Our overarching goals are to create catalytic domains inrobust polymer hollow fibers and in 2D graphene-based membranes for both reductive and oxidativedegradation and temperature-responsive polymers for PFAS and PCB sorption/ desorption. Two specific aimsare to: 1) to create robust polymeric/gel and 2-D material-based (reduced graphene oxide and composites)metal catalyzed functionalized membranes and materials to enhance TCE PCE PCB degradation efficiencyand reduce material usage and demonstration of the use of catalytic membrane filters for two site-basedapplications (2) to concentrate and regenerate PFAS and PCB individual compounds using ultra high sorptioncapacity temperature responsive hydrogel/membranes or localized heating through AMF (alternating magneticfield) using magnetite nanoparticles and to create functionalized smart adsorptive filters and sensors for PFASdetoxification applications with real-world water samples. Each of these objectives represent highly significantmaterial science advancement in terms of confined reactive nanosized metals in robust membrane domainand novel temperature swing adsorption/desorption through creation of responsive materials. The applicationsof our technologies will include collaborations with Rockwell International Site in Russellville Kentucky forPCBs and the ATKEMIX TEN Site in Louisville Kentucky for TCE PCE chloroform and carbon tetrachloridemixture identified water utilities in Eastern Kentucky for PFAS sorption application and Arcadis Corporationinvolved with remediation activities.

project_terms:
Adsorption;Advanced Development;Aftercare;Area;Attention;Biomedical Research;Carbon;Carbon Tetrachloride;Catalysis;Catalytic Domain;Chemicals;Chloroform;Collaborations;Detection;Development;Drug Metabolic Detoxication;Energy consumption;Engineering;Environment;Environmental Health;Fiber;Funding;Gel;Goals;Hazardous Waste Sites;Health;Heating;Human;Hydrogels;Individual;Industrialization;International;Iron;Kentucky;Magnetism;Membrane;Metals;Methods;Nanostructures;Natural regeneration;Nutritional Science;Oxidants;Oxides;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Polymers;Property;Public Health;Research;Risk;Risk Reduction;Science;Site;Soil;Solvents;Source;Sulfate;Superfund;Surface;System;Techniques;Technology;Temperature;Tetrachloroethylene;Toxic effect;Toxicant exposure;Trichloroethylene;Water;contaminated water;cost;cost effective;design;drinking water;food science;global environment;graphene;ground water;halogenation;magnetic field;magnetite ferrosoferric oxide;materials science;metallicity;microbial;nanocomposite;nanoparticle;nanoscale;nanosized;novel;nutrition;particle;pollutant;prevent;reaction rate;remediation;sensor;superfund chemical;superfund site;water sampling

public_health_relevance:
PROJECT NARRATIVEThe persistence of toxic pollutants at Superfund sites poses a major environmental public health problem anda serious need for environmental solutions to reduce risk. Our research is expected to lead to cost-effectivetechnologies for remediation of chemicals such as TCE PCE and PCBs to nontoxic and biodegradableintermediates and for superfast sorption of PFAS compounds with responsive polymer materials. Ourapproaches to develop new polymer membrane and 2D-based materials to detoxify water and low energyconsuming adsorption/desorption technologies should lead to an advanced technology solution in the field ofremediation science and engineering from Superfund sites to water utility companies.


application_id: 10767343
project_number: 5P42ES007380-26
project_title: Postnatal Complications and Interventions against Halogenated Organics during Pregnancy
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6736
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYChildhood obesity rates have more than tripled over the last 40 years with 18.5% of children and adolescentswho are now obese. Endocrine-disrupting chemicals particularly obesogens such as polychlorinated biphenyls(PCBs) and per- and polyfluoroalkyl substances (PFAS) are contributing to the rapid increases in obesity.Recent studies indicate that prenatal exposures to PCBs and PFAS contribute to gender-specific obesitydevelopment in children. Both groups of contaminants share a common underlying mechanistic pathway thatof oxidative stress and their actions arise from the considerable crosstalk between transcription factorsincluding nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the aryl hydrocarbon receptor. Others havefound that treating cells in culture directly with PCBs or PFAS [perfluorooctanesulfonic acid (PFOS) andperfluorooctanoic acid (PFOA)] influences adipogenesis using human and mouse cells. Importantly PFOSinduced adipogenesis and glucose uptake by acting through Nrf2. Using a mouse model as part of theprevious round of funding similar observations were made in that offspring exposed perinatally to PCBs hadsignificantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Furthermature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring fromvehicle-treated dams. Importantly a healthy behavioral intervention maternal voluntary exercise duringpregnancy improved offspring disease risk associated with in utero PCB exposure. The proposed project willcontinue to use an in vivo mouse model as well as transition to human samples in order to examine themolecular impact of environmental contaminant toxicity during a narrow window of susceptibility. Aim 1 will testwhether voluntary exercise during pregnancy or in the offspring themselves can be used as an interventionstrategy to protect against the long-term metabolic detriments associated with in utero PCB exposure. Aim 2will elucidate the mechanism of impaired glucose tolerance and altered body composition in offspring born toPCB-exposed dams (including the use of Nrf2 knockout mice) and will determine how maternal exercise isprotecting offspring from these impairments. Aim 3 will use human cells to identify biomarkers of the specificharm associated with in utero halogenated organic pollutant exposures and to elucidate the potentialmechanisms that contribute to increased obesity and diabetes risk in exposed infants. Our work will measureactual contaminant exposure levels in maternal and cord serum and quantify adipocyte differentiation directlyin cells isolated from the same neonates. Anticipated results are particularly significant in that they highlightearly developmental stages as potential periods of particular vulnerability to program lasting obesity anddiabetes effects of toxic environmental insults.

project_terms:
Address;Adipocytes;Adolescent;Adult;Agonist;Aryl Hydrocarbon Receptor;Behavior Therapy;Biochemical;Body Composition;Cell Separation;Cells;Child;Collaborations;Development;Diabetes Mellitus;Discipline of Nursing;Endocrine Disruptors;Environmental Exposure;Environmental Impact;Environmental Pollutants;Epidemic;Erythroid;Evaluation;Exercise;Exposure to;Fatty acid glycerol esters;Female;Funding;Future;Gender;Glucose Clamp;Glucose Intolerance;Goals;Hazardous Substances;Health;Home;Human;Human Development;Human Milk;Hyperinsulinism;Impairment;Infant;Insulin Resistance;Intervention;Kentucky;Knockout Mice;Life Style;Liver;Measures;Mesenchymal Stem Cells;Metabolic;Methods;Modeling;Molecular;Mus;Muscle Cells;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Oxidative Stress Induction;Pathway interactions;Perinatal;Perinatal Exposure;Phenotype;Placenta;Play;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Predisposition;Pregnancy;Process;Research;Risk Assessment;Role;Running;Sampling;Serum;Superfund;Testing;Thinness;Time;Tissues;Toxic effect;Umbilical cord structure;Universities;Work;adipocyte differentiation;biological adaptation to stress;biomarker identification;blood glucose regulation;cohort;cost effective;dechlorination;detection method;diabetes risk;diphenyl;disorder risk;exercise intervention;fetal;glucose uptake;halogenation;impaired glucose tolerance;improved;in utero;in vivo;innovation;insight;insulin sensitivity;insulin signaling;lipid biosynthesis;male;mouse model;neonate;nutrition;obesity development;obesity in children;obesity risk;obesogen;offspring;offspring obesity;perfluorooctane sulfonate;perfluorooctanoic acid;perinatal development;pollutant;postnatal;prenatal exposure;programs;sedentary;specific biomarkers;superfund chemical;transcription factor;trend

public_health_relevance:
PROJECT NARRATIVEObesity and diabetes are at epidemic levels and the toxicity of environmental contaminants during perinataldevelopment could be a significant contributor to these trends. The proposed studies will offer innovative newinsights to understanding the role of exercise in mitigating the health impacts of in utero contaminantexposures. Project 2 clearly addresses three of the Superfund Research Program primary objectives: Mandate1 advanced techniques for detection assessment and evaluation of the effect of hazardous substances onhuman health Mandate 2 methods to assess the risks to human health presented by hazardoussubstances and Mandate 4 methods to reduce the amount and toxicity of hazardous substances.


application_id: 10767340
project_number: 5P42ES007380-26
project_title: Superfund Chemicals Nutrition and Multi-Organ Cardiovascular Risk
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6735
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe overall goal of Project 1 is to understand the signaling pathways and metabolic or biological changes bywhich bioactive nutrients modulate impacts of acute or chronic exposure to persistent organic pollutants suchas polychlorinated biphenyls (PCBs) and long-chain per- and polyfluoroalkyl substances (PFAS). Suchpersistent pollutants express significant chemical stability in the environment and toxic insults from POPs areknown to correlate with a range of post-exposure human health impacts including vascular inflammation.Atherosclerosis a chronic inflammatory disease remains the leading cause of death in the United States.Biological events associated with inflammation and atherosclerosis can be modified by circulating toxicantsand bioactive nutrients and their metabolites which dictate final redox changes and inflammatory outcomes byaltering NF-kB and Nrf2 signaling. For example preliminary data demonstrate down-regulation of PCB 126-mediated toxicity and inflammation by plant-derived bioactive nutrients e.g. polyphenols and fiber (e.g.inulin). Importantly it is known that the pathology of atherosclerosis is dependent on the health and cross-talkof multiple tertiary organ systems including the liver and gut as exemplified by recent findings linking PCBexposure with increased plasma levels of trimethylamine N-oxide (TMAO) a diet-derived metabolite formedthrough cross-talk between gut microbiota and hepatic oxidation and associated with risk of atherosclerosis.Preliminary findings indicate that persistent organic pollutants and especially PCBs caused liver dysfunctionand alterations of gut microbiota and that prior liver injury exacerbated PCB-mediated systemic inflammation.Metabolomic profiling further suggested that increased formation of pro-atherogenic metabolites (e.g.ceramides) may drive multi-organ inflammation and increased cardiovascular risk. Based on these findingsthree specific aims test the hypotheses that 1) administration of PCB 126 and/or PFAS to mice increasescardiometabolic disease risk by increasing ceramide production via modulation of hepatic gene expressionand/or the gut microbiota; 2) administration of green tea catechins and/or soluble inulin fiber in vivo decreasesceramides and thereby stabilizes cellular redox status modulating NF-kB and Nrf2 signaling and pro-atherosclerotic pathologies as determined by en face and lipid staining in atherogenic LDL receptor-deficientmice; and 3) exposure to PCBs and/or PFAS increases pro-atherogenic metabolites (e.g. ceramides) throughincreased de novo synthesis in preclinical models. Transcriptomic and metabolomic technologies will be usedto explore the mechanistic interactions between pollutant exposure nutritional intervention and cardiovasculardisease (CVD) risks. These data will be confirmed in biobanked samples of humans with CVD. Results willsupport the paradigm that healthful nutrition interventions offer a powerful strategy to reduce disease risksassociated with environmental toxic insults and to prevent inflammatory diseases such as atherosclerosis thathave been linked to exposure to Superfund pollutants.

project_terms:
Acceleration;Acute;Address;Amines;Animal Model;Antibiotics;Atherosclerosis;Binding;Biological;Biological Markers;Blood Vessels;Body System;Cardiometabolic Disease;Cardiovascular Diseases;Cause of Death;Ceramides;Chemicals;Chronic;Data;Data Set;Development;Diet;Dietary Fiber;Dietary Intervention;Dioxins;Disease;Down-Regulation;Endothelium;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Science;Enzymes;Epigallocatechin Gallate;Event;Exposure to;Fiber;Functional disorder;Future;Gene Expression;Genes;Goals;Green tea;Hazardous Waste Sites;Health;Hepatic;Hepatocyte;Human;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Inulin;Life Cycle Stages;Link;Lipids;Liver;Liver Dysfunction;Low Density Lipoprotein Receptor;Macrophage;Mediating;Metabolic;Metabolic dysfunction;Metabolism;Methionine;Modeling;Molecular;Mus;NF-kappa B;Nutrient;Organ;Outcome;Oxidation-Reduction;Oxides;Pathology;Peripheral;Permeability;Persons;Plants;Plasma;Poison;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Population;Pre-Clinical Model;Process;Production;Public Health;Reporting;Research;Risk;Sampling;Signal Pathway;Signal Transduction;Sphingolipids;Stains;Superfund;Technology;Testing;Toxic effect;United States;Vascular Endothelial Cell;Volatile Fatty Acids;animal data;atherosclerosis risk;biobank;cardiovascular disorder risk;cardiovascular risk factor;chemical stability;choline deficient diet;chronic inflammatory disease;disorder risk;experimental study;exposed human population;gut bacteria;gut microbiota;halogenation;in vivo;lipid metabolism;liver injury;metabolic profile;metabolomics;nutrition;oxidation;persistent organic pollutants;pollutant;polyphenol;prebiotics;prevent;programs;response;stable isotope;superfund chemical;systemic inflammatory response;toxicant;transcriptomics;vascular inflammation

public_health_relevance:
PROJECT NARRATIVEThis project explores connections between two major public health concerns that are highly relevant toSuperfund Research Program (SRP) stakeholders and the SRP: widespread contamination of the environmentby a class of long-lasting toxic chemical contaminants known as PCBs and PFAS. These contaminants havebeen linked to a leading U.S. health challenge cardiovascular diseases and also linked to the liver and gut.The project addresses specifically SRP Mandate 4 by testing dietary interventions that may disrupt diseaseprocesses by stabilizing the gut bacteria and liver and reducing cardiovascular risks initiated by exposure topollutants particularly in people who reside near Superfund or other hazardous waste sites where PCBs andother pollutants are prevalent.


application_id: 10767338
project_number: 5P42ES007380-26
project_title: Research Experience and Training Coordination Core
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6734
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) e addresses a major environmental issuefocusing on halogenated organics occurring at Superfund sites and that persist in the ground and watersources in many other locations nationwide. The Research Experience and Training Coordination Core(RETCC) aims to train students to investigate these issues via exposing trainees to interdisciplinaryapproaches to training providing opportunities to enhance their professional career development and throughextensive outside laboratory experiences program that coordinates opportunities for participation in theCommunity Engagement Core and the Administrative Cores research translational function and engagingthem with the Data Management and Analysis Core (DMAC). These diverse activities will give the traineesbroad exposure to environmental issues that affect their surroundings and equip them with a unique toolset tomake disruptive impacts to the field. Addressing environmental challenges requires an integrative approachthat leverages knowledge from disparate disciplines and perspectives. A combination of knowledge andscientific methods from biomedical and environmental science and engineering-based disciplines are requiredwhile also considering the social impact of these issues on the surrounding communities. While the RETCCpromotes strong cross-disciplinary training it also encourages the interdisciplinary thinking needed to developproblem-solving skills and to become effective environmental communicators. The specific aims are: 1) tointroduce innovative training components designed to spur disruptive impacts and spark creative solutions tocomplex environmental problems. The RETCC will fund trainee-developed pilot grants that necessitate cross-disciplinary collaborations (e.g. data science/bioinformatics) among the projects and cores; 2) to integratecareer development training activities critical for academic and nonacademic interests developed throughinteractions with the Kentucky Center for Clinical and Translational Science and newly developed DMAC andoffer specific skills training (responsible conduct of research and grantsmanship) that prepare students forsuccess in academic governmental and industrial research careers; and 3) to increase integration of thetrainees throughout all aspects of the Center to enhance overall productivity and to expand trainingopportunities from recruitment of the next generation of trainees to reporting the Centers activities and traineeoutcomes to the SRP.

project_terms:
Address;Affect;Bioinformatics;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Complex;Creativeness;Data Analyses;Data Collection;Data Science;Development;Discipline;Disparate;Doctor of Philosophy;Education;Educational workshop;Environmental Engineering technology;Environmental Health;Environmental Science;Exposure to;Funding;Goals;Government;Grant;Health;Individual;Industrialization;Industry;Interdisciplinary Study;Kentucky;Knowledge;Laboratory Research;Leadership;Life Style;Location;Medical Ethics;Mentors;Methods;Mind;Modeling;Modernization;Outcome;Policies;Positioning Attribute;Postdoctoral Fellow;Problem Solving;Productivity;Public Health;Recording of previous events;Reporting;Research;Research Project Grants;Resources;STEM field;Science Technology Engineering and Mathematics;Scientist;Series;Signal Recognition Particle;Social Impacts;Source;Students;Superfund;Technology;Thinking;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Training and Education;Translational Research;Universities;Water;Writing;career;career development;clinical center;community engagement;data management;data sharing;design;empowerment;experience;flexibility;halogenation;innovation;interdisciplinary approach;interest;laboratory experience;meetings;multidisciplinary;next generation;novel;nutrition;outreach;pollutant;programs;recruit;remediation;responsible research conduct;skills;skills training;student training;success;superfund chemical;superfund site;training opportunity;webinar

public_health_relevance:
PROJECT NARRATIVEThe focus of University of Kentucky Superfund Research Center (UK-SRC) is committed to developing an in-depth understanding of environmental health associated with exposure to organic pollutants as well as thedevelopment of protective technologies to aid in reduction of such exposure incidents. The proposedinterdisiplinary training activites of the UK-SRC will be led and coordinated by the Research Experience andTraining Coordination Core to successfully train skilled individuals who will positively impact our environmentalhealth and the overall health of our nation.


application_id: 10767337
project_number: 5P42ES007380-26
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6733
contact_pi_person_id: 12559398
contact_pi: BREWER, DAWN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY The research proposed by the University of Kentucky Superfund Research Center (UK-SRC) uses basic biological chemical and physical methods through nutrition and physical activity to reduce the amount and toxicity of hazardous substances (Superfund Research P Mandate #4). Incorporating good nutrition and physical activity strategies in conjunction with increasing environmental health literacy focused on nutrition and contaminant exposures aligns with the central theme of the UK-SRC  reducing risk posed by environmental contaminants in vulnerable communities  and with the prevention/intervention activities implemented by CEC. The CEC will continue to engage in bi-directional communication with its longest standing community partner of 12 years the Harlan community located in southeastern Kentucky near the National Priorities List (NPL) site in Dayhoit Kentucky. At this NPL site disposal of chlorinated solvents affected plant workers and neighbors living in a nearby mobile home park and surrounding area. New partnerships have been formed in eastern Kentucky Letcher County which has concerns related to the negative health consequences associated with air and water pollution derived from coal mining. The CEC also brought environmental pollutant and healthy lifestyle-focused interventions to older adults in central Kentucky. Although not exposed to a particular environmental contaminant the older adult population is an important one to include in its engagement activities due to the rapid growth of this population sector. By virtue of being an older adult these individuals have been exposed to more environmental contaminants and with age the detoxification capacity of the liver and kidneys has declined putting older adults at greater risk of experiencing more pronounced negative health effects of environmental contaminants. The innovation of the CEC to engage communities is apparent in the six prevention/intervention activities outlined in this proposal. The six programs are grounded in evidence-based approaches by intervening at multiple levels of the social ecological model of health behavior change including the individual community and organizational levels which allows the CEC to implement healthy lifestyle and environmental pollution education into existing community programs that reach populations across the lifespan. Major community partners include county Cooperative Extension Service Family and Consumer Science (FCS) and Horticulture Agents county senior centers community centers and farmers markets. The CEC plans to incorporate the science of the UK-SRC into existing community programs including walking programs FCS Extension health programs gardening programs senior center health programs and youth day camp programs. The gardening program will not only foster collaboration with community entities but also with the Duke SRC as it combines the expertise of both. Overall collaboration with community partners will benefit residents by providing opportunities to improve health and receive new knowledge pertaining to using healthy lifestyles to reduce exposure to environmental contaminants.

project_terms:
Address;Adopted;Affect;Age;Air Pollution;Area;Back;Behavior;Biological;Chemicals;Chronic Disease;Coal Mining;Communication;Communities;Consumption;Country;County;Development;Drug Metabolic Detoxication;Education;Environmental Hazards;Environmental Health;Environmental Pollutants;Environmental Pollution;Evaluation;Exposure to;Family;Focus Groups;Fostering;Goals;Hazardous Substances;Health;Health Benefit;Health behavior;Health behavior change;Home;Individual;Intervention;Interview;Journals;Kentucky;Kidney;Knowledge;Lead;Life Style;Liver;Methods;Modeling;Needs Assessment;Outcome;Peer Review;Physical activity;Physiological;Plants;Policies;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Population;Population Growth;Populations at Risk;Predisposition;Prevention;Prevention strategy;Public Health;Recommendation;Reporting;Research;Research Activity;Research Project Summaries;Resources;Risk;Risk Reduction;Science;Scientist;Services;Site;Solvents;Superfund;Surveys;System;Toxic effect;Translating;United States;Universities;Water Pollution;Work;Youth;behavior change;community center;community collaboration;community engagement;community led intervention;community partners;design;environmental change;evidence base;experience;farmers markets;good diet;health knowledge;health literacy;healthy lifestyle;improved;innovation;life span;meetings;novel;nutrition;older adult;pollutant;prevent;programs;rapid growth;social;superfund chemical;superfund site;symposium;tool;tool development;vulnerable community;walking program

public_health_relevance:
PROJECT NARRATIVE The Community Engagement Core (CEC) works to achieve public health benefits within communities and supports the UK-SRC by encouraging Superfund Research Program (SRP) stakeholders to protect their health from exposure to environmental contaminants by consuming a healthy diet and increasing physical activity to reduce the bodily amount and toxicity of hazardous substances (mandate #4). The proposed CEC prevention/ intervention activities are community-driven solution-oriented programs that translate the science of the UK- SRC and addresses the needs of SRP stakeholders with concerns regarding exposure to hazardous substances. The CEC programs achieve this by providing community residents with the opportunity to improve nutrition increase physical activity and enhance environmental health literacy among community residents.


application_id: 10767335
project_number: 5P42ES007380-26
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6732
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) Data Management and Analysis Core(DMAC) has a goal to provide an overarching technology and research support infrastructure for themanagement and integration of data and information assets. Given that interdisciplinary research requiresresearchers to use methods and data from a range of disciplines this goal addresses a critical need forinterdisciplinary research to overcome hurdles posed by discipline-specific methods that impede progresswhen many disciplines attempt to share data. The DMAC is designed in alignment with FAIR (FindableAssessable Interoperable and Reusable) data principles to encourage interaction of data users and sharing ofdata. The specific aims are: 1) coordination of projects and cores; 2) foster data integration sharing andinteroperability; 3) ensure data quality assurance and quality control (QA/QC). The datasets to be managedand curated within the DMAC encompass the full range of basic research to translational work from animal-based studies to chemical analysis from experimental studies evaluating remediation of hazardoussubstances to community engagement activities. The DMAC will engage regularly with project/core leaders toprioritize data sets. It will streamline analytic resources data management data quality validation and dataintegration across projects and cores to improve efficiencies and reproducibility enhance project coordinationand promote resource sharing. The DMAC will promote interoperability by incorporating FAIR guidingprinciples in its data dashboards data archives and its query exploration interface to permit projects and coresto better integrate. By developing common terminologies data dictionaries training etc. the DMAC willfacilitate a common data resource to foster sharing within and beyond the UK-SRC. To facilitate interactionwith investigators and trainees there will be (on-site and electronic) opportunities for regular interaction withbiostatisticians data scientists and informaticians where formal and informal training can occur. Theseactivities will be coordinated and advertised closely with the Research Experience Training Coordination Core(RETCC). The DMAC will create a new WHY ENVIRONMENT module to enable projects and cores to engagein investigator-initiated research translation activities to allow them to form new questions and hypotheses thatcan be tested in projects and cores and shared beyond the confines of UK-SRC. Lastly the DMAC willincorporate best practices outlined by Data Observation Network for Earth (DataONE.org). It will establish aplan for data QA/QC so that UK-SRC research will not be subjected to pitfalls associated with poor qualitydata.

project_terms:
Academy;Acceleration;Address;Adverse effects;Animals;Awareness;Basic Science;Biometry;Chemicals;Collaborations;Common Data Element;Communities;Complex;Computational Science;Consensus;Data;Data Analyses;Data Coordinating Center;Data Science;Data Scientist;Data Set;Deposition;Development;Discipline;Documentation;E-learning;Educational workshop;Electronics;Ensure;Environment;Environmental Health;Environmental Science;Formulation;Fostering;Goals;Grant;Hazardous Chemicals;Hazardous Substances;Information Resources;Infrastructure;Interdisciplinary Study;Kentucky;Knowledge;Knowledge Discovery;Life Cycle Stages;Metadata;Methods;National Institute of Environmental Health Sciences;Online Systems;Ontology;Outcome;Planet Earth;Population;Problem Solving;Process;Protocols documentation;Public Health;Quality Control;Registries;Reproducibility;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Risk;Science;Scientist;Secure;Series;Site;Superfund;Technology;Terminology;Testing;Toxic effect;Training;Translational Research;Universities;Validation;Work;application programming interface;biomedical informatics;community engagement;data archive;data dashboard;data dictionary;data ecosystem;data integration;data management;data quality;data resource;data sharing;data standards;data tools;design;experience;experimental study;improved;innovation;interoperability;investigator-initiated translational research;meetings;member;nutrition;programs;quality assurance;remediation;repository;superfund chemical;symposium;tool;training data;training opportunity;training project;webinar

public_health_relevance:
PROJECT NARRATIVEThe Data Management and Analysis Core (DMAC) of the University of Kentucky Superfund Research Center(UK-SRC) provides an integral new resource by functioning as a nexus for interactions across projects andcores. It systematically integrates data assets through the entire lifecycle of the grant and facilitates interactionof investigators and trainees to assist them in conducting research that addresses Superfund mandates. TheDMAC will foster data sharing within and beyond UK-SRC including researchers as well as communitystakeholders and governmental agencies committed to protecting public health from the adverse effects ofhazardous chemicals.


application_id: 10767332
project_number: 5P42ES007380-26
project_title: Biomonitoring and Environmental Analytical Chemistry Core
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6731
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis core provides analytical services to UK-SRC investigators who are engaged in studies of the sensingdistribution and remediation of environmental toxicants and who are investigating their mechanisms of toxicityapproaches to mitigate these toxic effects. This research is important because exposure to these kinds ofenvironmental chemicals contributes to risk of non-communicable diseases such as cancer and cardiovasculardisease in humans. The core provides access to state-of-the-art gas and liquid chromatography coupled massspectrometer systems that are used for measurements of environmental chemicals their metabolites anddegradation products and other biomolecules of interest including biomarkers of diet nutrition and disease risk.Core services encompass targeted and untargeted analytical methods using liquid chromatography and gaschromatography coupled multistage/high resolution mass spectrometry. The core provides established/routineservices and can develop new services or adapt services from literature methods. The core is managed by theDirector who works with the Administrative Core to oversee the business operation scheduling andprioritization of services which are provided by experienced PhD level staff. A Laboratory InformationManagement System is used for sample tracking enforcement of standard operating procedures qualitymanagement and data reporting to project leaders and the Data Management and Analysis Core (DMAC).Services are further validated by participation in external proficiency testing programs. The goals of the corewill be accomplished by addressing the following specific aims: 1. To provide analytical chemistry servicesto UK SRC investigators. The core provides services to all the component projects. These includemeasurements of chemical pollutants in environmental matrices including water and soil for studies of theirtransport distribution sensing and remediation conducted by projects 1 and 2. Services provided to thebiomedical projects 1 and 2 include measurements of environmental pollutants in studies using in vitro systemsand preclinical models. Untargeted analytical methods using high resolution mass spectrometry will supportsystems level studies of the effects of diet nutrition and exercise on biological processes that are proposed tomitigate the deleterious health effects of exposure to environmental pollutants. 2. To conduct biomonitoringmeasurements for population health studies. The core will enable interactions between UK-SRCinvestigators and collaborators who have completed or ongoing clinical/population health studies that providean opportunity to investigate relationships between environmental exposures and health outcomes as aconduit for clinical translation of advances made by the biomedical projects. In coordination with DMAC thecore will conduct large scale measurements of environmental chemicals their metabolites and degradationproducts and biomarkers of exposure or lifestyle associated stressors using both targeted and untargetedapproaches to examine association of environmental exposures and interventions with clinical outcomes.

project_terms:
Address;Amendment;Analytical Chemistry;Basic Science;Biological;Biological Markers;Biological Monitoring;Biological Process;Businesses;Cardiovascular Diseases;Chemicals;Clinical;Clinical Management;Cohort Studies;Collaborations;Communities;Consent;Coupled;Data Analyses;Data Analytics;Data Reporting;Data Science;Data Storage and Retrieval;Detection;Development;Diet;Diet and Nutrition;Disease;Doctor of Philosophy;Ensure;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Pollutants;Environmental Science;Equipment;Evaluation;Exercise;Exposure to;Funding;Gas Chromatography;Goals;Grant;Health;High Pressure Liquid Chromatography;Human;Human Resources;In Vitro;Institutional Review Boards;Intervention;Investigation;Laboratories;Lead;Life Style;Link;Liquid Chromatography;Literature;Malignant Neoplasms;Management Information Systems;Mass Spectrum Analysis;Measurement;Medical center;Methods;National Institute of Environmental Health Sciences;Outcome;Pre-Clinical Model;Preparation;Procedures;Protocols documentation;Publications;Quality Control;Reaction;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resolution;Risk;Role;Sampling;Schedule;Service provision;Services;Soil;Source;Superfund;Support System;System;Technology;Testing;Toxic Environmental Substances;Toxic effect;United States Department of Veterans Affairs;United States National Institutes of Health;Veterans Health Administration;Vulnerable Populations;Water;Work;analytical method;cardiovascular disorder risk;clinical translation;computerized data processing;data management;disorder risk;environmental chemical;environmental chemical exposure;environmental intervention;experience;human disease;improved;instrument;instrumentation;interest;laboratory facility;lipidomics;mass spectrometer;metabolomics;nutrition;offspring;operation;pollutant;population health;preclinical study;programs;quality assurance;remediation;risk mitigation;stressor;superfund chemical;water sampling

public_health_relevance:
PROJECT NARRATIVEExposure to environmental chemicals increases the risk of many non-communicable human diseases. The UK-SRC serves our stakeholders and the broader objectives of the Superfund Research Program by conductingstudies to understand mechanisms linking exposure to environmental chemicals with human disease risklifestyle based approaches to mitigate these risks and strategies for improved sensing and remediation of toxicenvironmental chemicals. This core component provides UK-SRC investigators with measurements of theseenvironmental chemicals their metabolites and degradation products and other biological molecules ofrelevance to human health.


application_id: 10767331
project_number: 5P42ES007380-26
project_title: Administration Core
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D
subproject_number: 6730
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) will focus on a prevention and interventionparadigm with an overarching goal to promote healthy lifestyles (i.e. healthful nutrition and increased physicalactivity) to reduce disease risks associated with exposure to a subclass of persistent halogenated chemicals(e.g. PCBs TCE and PFAS). Our biomedical research will be coupled with environmental science/engineeringresearch that uses novel sensing remediation and fate and transport science to prevent or reduce exposurerisks in the environment. Our biomedical research is integrated around a full life-span perspective and aparadigm that uses animal studies to identify possible hypotheses that can be tested against existing humandatabases to further identify potential intervention strategies. Our environmental science research is integratedaround a project cross-talk that uses fate and transport science to help inform technology development usingnovel material science designed to reduce exposure to organic pollutants and that can then be deployed infield applications. Both biomedical and environmental science projects are crosslinked around a common set ofpollutants and the use of animal models to test the toxicity of these pollutants and different remediation by-products. To provide an optimal support environment and the requisite infrastructure to accomplish theCenters goal we propose four specific aims for our Administrative Core (ADMC): 1) activities managementand integration 2) bi-directional communication strategies 3) partnerships and technology transfer and 4)evaluation and management processes. Management and integration functions are facilitated by monthlyCenter meetings and ADMC leadership and trainee interns are drawn from the individual research projects. Bi-directional communication with other SRP centers and agency scientists and research translation to otherstakeholders are now fully integrated within the ADMC and overseen by a dedicated research translationcoordinator with support from a communications director. The ADMC effectively facilities investigator-initiatedresearch translation and technology transfer functions by leveraging a new integrated Data Management andAnalysis Core along with multidirectional internal (e.g. NIH funded UK Center for Clinical and TranslationalScience (CCTS) WHY program UK P30 pilot grants Kentucky Water Institute) and external (e.g. EPAADSTR Kentucky Cabinet for Energy and the Environment (KYEEC) ARCADIS Consultants individual waterutilities) partnerships. Evaluation and management processes are overseen by the ADMC director as assistedby the program administer. The focus of the ADMC on the establishment and maintenance of a continuousimprovement development processes along with internal and external relationships positions the UK-SRC tocontribute not only important scientific findings but also to the collaborative processes and innovativeendeavors associated with the national Superfund Research Program.

project_terms:
Academia;Address;Advisory Committees;Analytical Chemistry;Animal Model;Animals;Appalachian Region;Biological Monitoring;Biomedical Research;Chemicals;Clinical Sciences;Communication;Communities;Community of Practice;Complex;Coupled;Data;Data Analyses;Databases;Dedications;Detection;Development;Educational workshop;Engineering;Ensure;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Science;Evaluation;Event;Exercise;Exposure to;Funding;General Population;Goals;Government Agencies;Grant;Health;Human;Human Resources;Individual;Industry;Information Dissemination;Infrastructure;Internships;Intervention;Kentucky;Leadership;Life Style;Link;Maintenance;Mentorship;National Institute of Environmental Health Sciences;Physical activity;Poly-fluoroalkyl substances;Polychlorinated Biphenyls;Positioning Attribute;Prevention;Process;Productivity;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Risk;Role;Science;Scientist;Structure;Superfund;Targeted Research;Technology;Technology Transfer;Testing;Toxic effect;Toxicity Tests;Training;Training Activity;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Water;arm;clinical center;community engagement;crosslink;data integration;data management;design;disorder risk;experience;halogenation;healthy lifestyle;improved;innovation;investigator-initiated translational research;life span;materials science;meetings;member;multidisciplinary;novel;nutrition;pollutant;prevent;process improvement;programs;remediation;superfund chemical;technology development;webinar

public_health_relevance:
PROJECT NARRATIVEThe Administrative Core of the UK-SRC will continue to promote problem-based solution-oriented research toreduce exposure and/or negative health impacts associated with exposure to a subclass of persistenthalogenated chemicals (e.g. PCBs TCE and PFAS). This will be accomplished by using an innovativetransdisciplinary research approach that brings together biomedical and environmental scientists engineersand trainees using an integrative administrative structure that links together individual projects and cores. TheAdministrative Core will ensure the continued relevance of the proposed research through bi-directionalcommunication with the SRP and SRP staff academia the general public and relevant federal and statecommunities of practice (e.g. EPA ATSDR KYDEP) as well as communities of impact in Appalachia.


application_id: 10767330
project_number: 5P42ES007380-26
project_title: Nutrition and Superfund Chemical Toxicity
administering_ic: NIEHS
award_notice_date: 2024-01-25
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2027-01-31
study_section: ZES1-JAB-D(SF)
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:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) provides a focused cross-disciplinaryresearch and training environment to address critical human health challenges associated with halogenatedorganic substance exposures. Four center projects and five cores make up the proposed UK-SRC to furtherdevelop research on lifestyle changes (e.g. nutrition and exercise) in addition to two environmental scienceprojects that will focus on the remediation and engineering solutions to this set of problems. Due to theirrelative chemical stability and ubiquity in the environment chlorinated organic contaminants such aspolychlorinated biphenyls (PCBs) and trichloroethylene (TCE) pose significant health risks and enduringremediation challenges including sites such as the Paducah Gaseous Diffusion Plant the largest Superfundsite in Kentucky. The UK-SRCs overall focus for this next cycle is the human health impacts of persistenthalogenated organics (e.g. PCBs TCE and tetrachloroethene (PCE) and in this new cycle of fundingadditional questions about per- and polyfluoralkyl substances (PFAS) will be incorporated. Projects coveringbiomedical research hypothesize that healthy nutrition and exercise components provide a platform to developprimary prevention strategies for diseases associated with environmental toxic insults while also providing thebasis for new risk assessment paradigms. Further novel iron-based nano-structured sensing capture andremediation systems based on biomimetic binding domains and functionalized membrane platforms offerpotential for sustainable advances in technical capability for site remediation. The UK-SRC proposes thefollowing goals: 1) to expedite data-driven discovery as facilitated by the Data Management and Analysis Corethat will provide insight about biomarkers of exposures to generate new information about the relationshipbetween pollutant exposure nutrient intake physical activity and disease risk; 2) to better understand thebiochemical molecular and cellular mechanisms underlying the toxicity of halogenated organic compounds(i.e. PCBs and PFAS) with a specific focus on chronic inflammatory diseases and windows of susceptibility; 3)to foster informed decisions that expedite clean-up of halogenated organic compounds through advancedmaterial-based technologies smart filters and fate and transport science to reduce exposure risks; 4) topromote and interdisciplinary approaches to environmental health science training that accelerate the impact ofcomplex solution-oriented stakeholder-engaged research aimed at reducing exposures and improving humanhealth; and 5) to engage bi-directionally and provide environmental health programmatic activities tovulnerable socially-isolated under-resourced communities in Kentucky especially Eastern Kentucky (i.e.Central Appalachia) where chronic inflammatory diseases exceed national averages and exposure risks toenvironmental pollutants are prevalent. Activities will involve community engaged research and an innovativemeans of integrating projects through the WHY-ENVIRONMENT initiative.

project_terms:
Acceleration;Address;Aging;Appalachian Region;Awareness;Binding;Biochemical;Biological;Biological Markers;Biological Models;Biological Monitoring;Biomedical Research;Biomimetics;Chemicals;Communication;Communities;Complex;Consumption;Data;Data Analyses;Diet;Diffusion;Disease;Disease Outcome;Economically Deprived Population;Engineering;Environment;Environmental Engineering technology;Environmental Health;Environmental Pollutants;Environmental Science;Evaluation;Exercise;Exposure to;Fiber;Fostering;Funding;Future;Goals;Hazardous Substances;Health;Human;Industry;Intake;Interdisciplinary Study;Intervention;Iron;Kentucky;Life;Life Style;Link;Membrane;Metabolic;Metals;Methods;Molecular;Nanostructures;National Institute of Environmental Health Sciences;Nutrient;Outcome;Oxides;Pathway interactions;Physical activity;Physiological;Plants;Policy Maker;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevention;Prevention strategy;Primary Prevention;Problem Sets;Recommendation;Research;Research Project Grants;Resources;Risk;Risk Assessment;Risk Management;Science;Scientist;Services;Site;Social isolation;Superfund;System;Techniques;Technology;Tetrachloroethylene;Toxic effect;Toxicant exposure;Training;Translational Research;Trichloroethylene;Universities;Vulnerable Populations;chemical stability;chronic inflammatory disease;community engaged research;community engagement;community intervention;community involvement;data management;detection method;dietary;disorder prevention;disorder risk;environmental chemical;environmental chemistry;experience;exposure pathway;graphene;halogenation;healthy lifestyle;human old age (65+);improved;innovation;insight;interdisciplinary approach;lifestyle intervention;lipidomics;metabolomics;next generation;novel;nutrition;organic contaminant;policy recommendation;pollutant;polyphenol;prevent;programs;remediation;superfund chemical;superfund site;tool;vulnerable community

public_health_relevance:
PROJECT NARRATIVEOutcomes and results from the proposed activities and research of the UK-SRC will provide importanttechnology tools and insights for primary stakeholders for improving Superfund site risk assessment andmanagement specifically related to the class of compounds known as halogenated organics. In addition theproposed research has implications for novel dietary and exercise recommendations and policyrecommendations for the economically disadvantaged populations of Kentucky.


application_id: 10766987
project_number: 1R21CA285253-01
project_title: Novel Strategy to Augmenting Immunotherapy against Melanoma
administering_ic: NCI
award_notice_date: 2024-02-29
opportunity_number: PAR-22-216
application_type: 1
activity_code: R21
ic: CA
serial_number: 285253
program_official: HU, ZHANG-ZHI
project_start_date: 2024-03-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZCA1 SRB-P (O2)]
contact_pi_person_id: 7598539
contact_pi: YANG, JIN-MING
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe overarching goal of this R21 proposal is to explore the potential of nelfinavir a widely used antiviral agentas a modulator to significantly augment the efficacy of adoptive cell transfer (ACT) therapy against melanoma.Melanoma one of the most aggressive and fatal neoplasms is responsible for over 80% of skin cancer-relateddeaths. Despite recent advances in treatment for this devastating disease including surgical resectiontargeted therapy and chemotherapy the prognosis of patients with melanoma remains dismal. Cellular therapyusing ACT approach represents a particularly promising strategy to treatment of this malignancy; yet thetherapeutic outcomes remain elusive due to a variety of factors that limits the anti-tumor immunity. We recentlyrevealed the critical roles of eukaryotic elongation factor-2 kinase (eEF-2K) in promoting the survival andcytocidal activity of CD8+ T cells and in augmenting the antitumor activity of CAR-T therapy suggesting thepotential of manipulating this kinase in boosting immunotherapy against melanoma. eEF-2K belongs to thefamily of atypical -kinases and is an evolutionarily conserved regulator of protein synthesis. This kinasephosphorylates eEF-2 a 100 kDa protein that promotes ribosomal translocation from the A to the P-site thereaction that induces movement of mRNA along the ribosome during translation. Phosphorylated eEF2 isunable to catalyze ribosomal translocation thereby inhibiting peptide elongation. Notably studies showed thateEF-2K can be activated by nelfinavir an orally bioavailable antiviral agent that have been widely used inclinical treatment of human immunodeficiency virus infection such as HIV and AIDS and that activation of eEF-2K in tumor cells promotes tumor cell death and suppresses tumor progression. Thus based on ourobservation of the role of eEF-2K in reinvigoration of cytotoxic CD8+ T cells as well as the above studies wehypothesize that pharmacologic activation of eEF-2K by nelfinavir can be exploited as a novel and effectivetherapeutic approach to substantially augment the efficacy of ACT against melanoma. Addressing thishypothesis would provide a proof of concept and rationale for improving the efficacy of current anti-melanomatherapies through targeting eEF-2K by use of nelfinavir. To test this hypothesis we will characterize the effectsof nelfinavir on cytotoxic T lymphocytes including T cell functions persistence and stability and evaluate theimpact of nelfinavir on reinforcing the efficacy of ACT against melanoma through use of in vitro and in vivomelanoma models. Successful completion of this study may provide a rapid path to enter clinical trials ofnelfinavir in treatment of patients with immune poor-responsive melanoma yielding new therapeuticopportunities to significantly improve current melanoma treatment through use of nelfinavir.

project_terms:
Address;Adoptive Cell Transfers;Affect;Anti-viral Agents;Antibodies;Biological Availability;CAR T cell therapy;CD8-Positive T-Lymphocytes;Cell Death;Cell Line;Cell Physiology;Cell Therapy;Cell-Mediated Cytolysis;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Clinical Trials;Coculture Techniques;Cytotoxic T-Lymphocytes;Disease;EEF2 gene;Effectiveness;Excision;FDA approved;Family;Glycolysis;Goals;HIV;HIV/AIDS;HLA-A2 Antigen;Human;Immune;Immunologics;Immunotherapy;In Vitro;Malignant Neoplasms;Measures;Mediating;Melanoma;Melanoma Cell;Messenger RNA;Metastatic Melanoma;Modeling;Monitor;Movement;Mus;Mutation;Nelfinavir;Neoplasms;Operative Surgical Procedures;Oral;PDL1 inhibitors;Patients;Peptides;Phosphorylation;Phosphotransferases;Pluripotent Stem Cells;Protein Biosynthesis;Proteins;Reaction;Retroviral Vector;Ribosomes;Role;Site;Skin Cancer;T-Lymphocyte;Testing;Therapeutic;Translations;Tumor Immunity;Tumor Promotion;Virus;Virus Diseases;calmodulin-dependent protein kinase III;chemotherapy;cytotoxic CD8 T cells;cytotoxicity;fatty acid oxidation;feasibility testing;improved;in vivo;neoplastic cell;novel;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;patient prognosis;pharmacologic;programmed cell death protein 1;response;targeted treatment;therapeutically effective;therapy outcome;treatment strategy;tumor;tumor progression

public_health_relevance:
Project NarrativeThis proposal is aimed at evaluating and defining nelfinavir an FDA-approved and commonly usedantiviral agent as an immune-sensitizer for enhancing cell-based therapy against melanoma. Thisstudy may lay groundwork and provide rapid path to enter clinical trials of nelfinavir for treatment ofpatients with immune poor-responsive melanoma an aberrantly aggressive and fatal disease.


application_id: 10766824
project_number: 5R21AI176298-02
administering_ic: NIAID
award_notice_date: 2023-12-07
opportunity_number: PA-20-194
application_type: 5
activity_code: R21
ic: AI
serial_number: 176298
program_official: HUNTLEY, CLAYTON C
project_start_date: 2023-01-20
project_end_date: 2025-12-31
study_section: Interdisciplinary Clinical Care in Specialty Care Settings Study Section[ICSC]
contact_pi_person_id: 16276827
contact_pi: COOK, AARON M
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: 2024-01-01
project_title:
A Randomized Clinical Trial of Continuous vs. Intermittent Infusion Vancomycin: Effects on Measured GFR and Kidney Injury Biomarkers

project_abstract:
PROJECT SUMMARY/ABSTRACTVancomycin is the most commonly administered antibiotic in hospitalized patients and a mainstay treatmentoption for empiric and definitive therapy of gram-positive infections particularly methicillin-resistantStaphylococcus aureus (MRSA). Patients receiving vancomycin are at risk of drug-associated acute kidneyinjury (DA-AKI) which occurs in 5-43% of patients. Experimental preclinical data and observational clinicaldata from our group indicate that the administration of vancomycin via continuous as opposed to intermittentinfusion (the standard of care in most institutions) reduces urinary markers of kidney injury and leads to lessDA-AKI. In order to translate these findings from the rat model this application proposes a randomized open-label clinical trial of continuous versus intermittent infusion vancomycin in hospitalized patients alreadyprescribed vancomycin by their treating physician in order to evaluate the change in kidney function and injurybetween the two infusion strategies. Given the known limitations of serum creatinine in assessing DA-AKI thisproposal includes measured glomerular filtration rate (mGFR) using iohexol the gold-standard index of kidneyfunction and other biomarkers of kidney injury and function to work toward the overall objective of testing theimpact of infusion strategy (continuous versus intermittent) on kidney function. Our central hypothesis is thatvancomycin administered as a continuous versus intermittent infusion results in less DA-AKI as assessed bymGFR and kidney injury biomarkers. To test this hypothesis the following specific aims are proposed: (1)Determine if patients randomized to receive vancomycin administered via intermittent infusion experiencegreater reductions in mGFR assessed using the gold standard plasma iohexol clearance in the 72 hours aftertherapy initiation compared to continuous infusion (2) Determine if patients randomized to receive vancomycinadministered via intermittent infusion demonstrate greater elevations in plasma (cystatin C) and urinary (kidneyinjury molecule-1 clusterin and osteopontin) kidney biomarkers of injury and function in the 72 hours aftertherapy initiation compared to continuous infusion and (3) Compare the pharmacokinetic target attainmentclinical safety and tolerability of infusion strategy in patients randomized to receive vancomycin via continuousvs. intermittent infusion. Given the millions of patients that receive vancomycin annually in the United States forthe treatment of MRSA or other gram-positive infections the proposal aligns with NIAIDs mission of bettertreating infectious diseases by optimizing the risk-benefit profile of this antibiotic. Testing this hypothesis iscrucial to translate the preclinical findings to patients as well as determine if larger definitive trials are neededto test if infusion strategy improves outcomes including safety with vancomycin therapy.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Antibiotics;Benefits and Risks;Biological Markers;Clinical;Clinical Data;Clinical Research;Clinical Trials;Communicable Diseases;Continuous Infusion;Creatinine;Data;Dose;Drug Kinetics;Eligibility Determination;Glomerular Filtration Rate;Histology;Hospitalization;Hour;Infection;Infusion procedures;Injury;Injury to Kidney;Institution;Iohexol;Kidney;Measurement;Measures;Mission;Modeling;National Institute of Allergy and Infectious Disease;Patients;Pattern;Pharmaceutical Preparations;Physicians;Plasma;Randomized;Rattus;Renal function;Research;Risk;Safety;Scheme;Serum;Techniques;Testing;Time;Toxic effect;Translating;United States;Vancomycin;Work;antimicrobial;experience;improved outcome;indexing;methicillin resistant Staphylococcus aureus;nephrotoxicity;novel strategies;novel therapeutics;open label;osteopontin;pathogen;post gamma-globulins;pre-clinical;prospective;randomized clinical trials;rat KIM-1 protein;standard of care;sulfated glycoprotein 2;tool;urinary

public_health_relevance:
PROJECT NARRATIVEAlthough vancomycin is the most commonly prescribed antibiotic to hospitalized patients in the United Statesit unfortunately carries a well-known risk of kidney injury. The proposed research will test whetheradministration of vancomycin via a continuous infusion as opposed to more traditional intermittent infusion isless harmful to the kidneys based on specific measurements of kidney function and injury. If the infusionstrategy influences toxicity as we hypothesize it could mean safer use of this antibiotic for the millions ofpatients that receive this medication annually.


application_id: 10766706
project_number: 5F31MH132194-02
administering_ic: NIMH
award_notice_date: 2023-11-15
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: MH
serial_number: 132194
program_official: AVENILLA, FRANK R
project_start_date: 2022-12-18
project_end_date: 2024-12-17
study_section: Special Emphasis Panel[ZRG1-F16-L(20)L]
contact_pi_person_id: 78504634
contact_pi: TIPSWORD, JORDYN M
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-12-18
project_title:
The Experience and Regulation of Posttraumatic Shame among Women with Histories of Interpersonal Trauma

project_abstract:
Project Summary/Abstract. Approximately 14 million women in the United States will develop posttraumaticstress disorder (PTSD) during their lifetime following physical or sexual assault or abuse (interpersonal trauma[IPT]). Posttraumatic shame  an emotion stemming from harsh attitudes about the self after trauma  iscentral to PTSD for many women post-IPT. Yet knowledge of the frequency intensity stability and triggers ofshame in the daily lives of women with IPT histories is lacking. Further though shame and guilt (an emotiondefined by negative feelings about ones actions) are studied separately by researchers no work has assessedwhether women with IPT histories make similar distinctions and see shame and guilt as differentiallyinfluencing their recovery from IPT. While some work has begun to explore shame-specific emotion regulation(ER) or processes aimed at changing emotional responses to meet specific goals it remains unclear which  ifany  ER strategies are effective in reducing the frequency or intensity of shame. Other factors likely to shapeposttraumatic shame regulation  including perceived effectiveness of ER strategies goals of ER and PTSDseverity  also have yet to be explored. Addressing these gaps could strengthen treatments for shame andPTSD. This project will use a sequential mixed methods design to explore 1) daily experiences ofposttraumatic shame (including triggers; frequency intensity and stability; relations to PTSD symptoms;changes over time; and factors distinguishing shame from guilt) and 2) regulation of posttraumatic shame(including use perceived effectiveness and adaptiveness of ER strategies and roles of PTSD symptoms andER goals in shame regulation). Both aims will be assessed quantitatively (Study 1) and qualitatively (Study 2).Study 1 will involve secondary analysis of ecological momentary assessment data on shame and ER obtained5 times per day for 14 days from 60 women with IPT histories and varying levels of PTSD symptoms. Study 2will involve qualitative interviews on the experience and regulation of posttraumatic shame with 20-35 womenwith IPT histories. It is expected that higher PTSD symptoms will predict higher subsequent shame and thatshame will predict more frequent rumination emotion suppression and distraction and less frequent emotionsharing emotional reflection and reappraisal within persons and across days. Relations between shame andER strategies are expected to be stronger among women with more severe PTSD symptoms and reversemodels (ER predicting shame) will be tested. Themes regarding triggers distinctions between shame and guiltconsequences of shame and the role of PTSD symptoms are expected and new themes may emerge. Greaterunderstanding of the experience and regulation of posttraumatic shame could improve treatments for shameand PTSD among women with IPT histories and will be key to advancing the PIs research. This training grantwill facilitate the PIs progression toward an independent grant-funded research career examining the role ofemotional vulnerabilities in PTSD among women with IPT histories.

project_terms:
Address;Attitude;Data;Data Collection;Development;Ecological momentary assessment;Effectiveness;Emotional;Emotions;Extramural Activities;Feeling;Frequencies;Funding;Goals;Grant;Guilt;Individual;Intervention Studies;Interview;Knowledge;Life;Literature;Lived experience;Maintenance;Memory;Methods;Modeling;Morals;Participant;Persons;Physiological;Post-Traumatic Stress Disorders;Process;Qualitative Methods;Recording of previous events;Recovery;Regulation;Research;Research Personnel;Risk;Risk Factors;Role;Secondary to;Severities;Shame;Shapes;Symptoms;Testing;Time;Training;Trauma;United States;Withdrawal;Woman;Work;career;design;distraction;emotion regulation;experience;improved;insight;interpersonal trauma;novel;physical assault;prospective;response;rumination;secondary analysis;sexual assault;stem;trait;traumatic event;women's treatment

public_health_relevance:
The proposed project will address critical gaps in current knowledge regarding the experience andmanagement of posttraumatic shame  an emotion consistently implicated in the development maintenanceand/or worsening of PTSD symptoms among women with a history of sexual or physical assault or abuse (i.e.interpersonal trauma). Existing treatments for PTSD often fail to fully address posttraumatic shame anduntreated shame represents an ongoing risk factor for the development or worsening of PTSD symptoms.Findings from this study hold promise for improving treatment efforts for shame and PTSD by clarifying aspectsof how women experience and manage shame after interpersonal trauma.


application_id: 10766127
project_number: 5R01AG066724-04
administering_ic: NIA
award_notice_date: 2023-11-16
opportunity_number: PA-17-088
application_type: 5
activity_code: R01
ic: AG
serial_number: 066724
program_official: GAO, HONGWEI
project_start_date: 2021-01-01
project_end_date: 2025-11-30
study_section: Aging Systems and Geriatrics Study Section[ASG]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
other_pis: KOSMAC, KATE
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-12-01
project_title:
Novel gastrocnemius muscle characteristics in peripheral artery disease patients associated with impaired functional performance

project_abstract:
Lower extremity peripheral artery disease (PAD) significantly affects aging populations and results in functionalimpairment. Although the clinical importance of finding efficacious interventions for PAD is well-recognized fewmedical therapies are currently available. PAD is diagnosed using the ankle brachial index (ABI) a measure ofblood flow to the lower extremities. Lower ABI is associated with worse function; however low ABI alonecannot fully explain functional impairments in PAD. Small studies have reported oxidative stress mitochondrialdysfunction and/or fiber damage in gastrocnemius muscle biopsies from PAD patients suggesting skeletalmuscle perturbations may contribute to functional decline. We reported highly variable fiber type compositionand fiber type grouping in a small cohort of PAD patients and observed lack of intermyofibrillar mitochondria(IMFM-) in oxidative myosin heavy chain (MyHC) type I fibers. We have provocative new preliminary datasuggesting variability in response to ongoing denervation and in fiber type and mitochondrial adaptations withPAD. The purpose of this study is to define specific characteristics of muscle in PAD associated with impairedwalking performance through detailed immunohistochemical analyses of 400 baseline gastrocnemius musclebiopsies stored in the Northwestern biorepository collected from 9 different clinical trials. This biorepository ofmuscle from PAD patients is one-of-a-kind and is associated with detailed clinical and functional characteristicsof the donors. We hypothesize that variability in fiber size fiber type and mitochondrial adaptations in responseto ischemia-reperfusion damage and denervation in individuals with PAD will have value in predicting walkingimpairment. In Aim 1 we will quantify the proportion of IMFM- areas in type I fibers with normal type I MyHCabundance or accumulation of type IIX MyHC and/or LC3 a marker of autophagy and determine associationswith fiber type composition and fiber size as well as relationships of muscle features to walking performance inPAD. We hypothesize that LC3 will co-localize with IIX MyHC in IMFM- areas suggesting both incompleteautophagic clearance of IIX MyHC and mitochondrial biogenesis during fiber transition from type IIX to type Ias a result of denervation and reinnervation. In Aim 2 we will quantify denervated NCAM+ fibers and fiberswith elevated oxidative damage markers by fiber type. We hypothesize that denervation in PAD willpreferentially affect fibers expressing IIX MyHC and that only IMFM- areas that accumulate IIX MyHC will beNCAM+. In Aim 3 we will perform predictive modeling of PAD disease severity and functional impairment usingmorphological characteristics of muscle quantified in Aims 1 and 2 as biomarkers in conjunction withsupervised classification approaches. In Aim 4 we will test the hypothesis that baseline muscle characteristicswill predict longitudinal functional outcomes at 6-month follow up. This model will provide a powerful tool toaide in identifying biologic processes for targeted interventions and to assess the mechanism of action andeffectiveness of current pharmacological and exercise interventions in ongoing PAD clinical trials.

project_terms:
Affect;Aging;Ankle;Area;Atrophic;Autophagocytosis;Biogenesis;Biological Markers;Biological Process;Biological Specimen Banks;Biopsy;Blood flow;Characteristics;Classification;Clinical;Clinical Trials;Data;Defect;Denervation;Development;Diagnosis;Diagnostic;Disability prevention;Disease;Disease Progression;Effectiveness;Fiber;Foundations;Functional impairment;Future;Gait abnormality;Gastrocnemius Muscle;Goals;Grouping;Individual;Injury;Intervention;Ischemia;Lower Extremity;Measures;Medical;Mitochondria;Modeling;Morphology;Motor Neurons;Muscle;Muscle Fibers;Myopathy;Myosin Heavy Chains;Myosin Type I;NCAM1 gene;Outcome;Oxidative Stress;Participant;Pathology;Patients;Performance;Perfusion;Peripheral arterial disease;Persons;Phase;Population;Property;Proteins;Recycling;Reperfusion Injury;Reperfusion Therapy;Reporting;Sampling;Severity of illness;Skeletal Muscle;Testing;Theoretical model;Training;Walking;biobank;cohort;coping;efficacious intervention;exercise intervention;follow-up;functional decline;functional improvement;functional outcomes;improved;indexing;mitochondrial autophagy;mitochondrial dysfunction;novel;oxidative damage;pharmacologic;predictive modeling;preservation;reinnervation;response;tool;walking performance

public_health_relevance:
Peripheral artery disease (PAD) significantly affects aging populations and results in functional impairment andmobility loss. Few medical therapies are currently available to treat PAD because the underlying pathology incalf muscle is not understood. The goal of this study is identify aberrant properties of muscle to aide in thedevelopment of new targeted interventions to improve walking ability in individuals with PAD.


application_id: 10766126
project_number: 5R01AR073906-06
project_title: Epigenetic control of muscle stem cell function by PASK-Wdr5 signaling
administering_ic: NIAMS
award_notice_date: 2023-12-04
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AR
serial_number: 073906
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2020-02-25
project_end_date: 2026-11-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 10909082
contact_pi: KIKANI, CHINTAN K
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryMuscle trauma is one of the most common and repetitive types of injury in humans. Owing to theregenerative functions of Muscle Stem Cells (MuSCs) the injured myotome can fully regain its structural andfunctional integrity within just a few days. In addition to this remarkable regenerative function MuSCs also playa significant role in the maintenance of muscle homeostasis under the normal condition. On the other hand thedecline in MuSCs function is implicated in muscle wasting diseases and several forms of musculardystrophy. The functions of MuSCs are influenced by the niche it occupies. For example the niche emitssignals to regulate MuSCs quiescence in the uninjured state or activation when regeneration is required.Understanding how these signaling pathways control quiescence and activation of MuSCs is essential to devisethe next generation of therapeutic approaches for diseases of MuSCs dysfunction. We recently described anovel signaling pathway in MuSCs that stimulates regenerative myogenesis by epigenetically activating thetranscription of the Myog promoter. In this pathway Per-Arnt-Sim domain Kinase (PASK) phosphorylatesWD40-domain repeat 5 (Wdr5) at the onset of the myogenesis program. Phosphorylated Wdr5 stimulatesthe Myog transcription by inducing histone H3 trimethylation at lysine 4 (H3K4me3) and the recruitmentof the MyoD transcription factor at the Myog promoter. We present evidence that PASK expression and activityis induced in regenerating myoblasts by signaling cues such as insulin and nutrients in mTOR complex 1dependent manner. Functionally loss of Pask in mice retards regenerative myogenesis and over-expressionof PASK depletes the stem cells. Thus we hypothesize that PASK plays a role balancing self-renewal vsdifferentiation during regeneration. Building upon these data in this proposal we will investigate howPASK expression and activity is regulated in the regenerating myoblast (Specific Aim 1). In activatedMuSCs PASK phosphorylated Wdr5 induces H3K4me3 modification MyoD recruitment and nucleosomalremodeling on the Myog promoter yet the mechanism is not clear. In Specific Aim 2 we will extensivelystudy two interacting partners of Wdr5 which could remodel the Myog promoter for its activation. Uponinduction of Myogenin Pax7 expression is down-regulated and terminal differentiation is established. SincePASK is an upstream regulator of the Myog expression we are interested determining how loss or gainof PASK affects the self-renewing population during regeneration and normal aging process which we willstudy in Specific Aim 3. Ultimately these aims will allow us to understand how niche signaling cues controlthe balance between self-renewal and differentiation and how it can be exploited for improvement ofphysiological conditions such as sarcopenia.

project_terms:
Acetylation;Acute;Adult;Affect;Aging;Binding;Cell Count;Cell Physiology;Cells;Collaborations;Complex;Cues;Data;Disease;Epigenetic Process;Equilibrium;FRAP1 gene;Functional disorder;Genetic Transcription;Goals;Histone H3;Histones;Homeostasis;Human;Injury;Insulin;Legal patent;Lysine;Maintenance;Messenger RNA;Metabolism;Methylation;Modeling;Modification;Molecular;Mus;Muscle;Muscle Cells;Muscle function;Muscular Atrophy;Muscular Dystrophies;Myoblasts;Myogenin;Myopathy;Natural regeneration;Nucleosomes;Nutrient;Pathway interactions;Phosphorylation;Phosphotransferases;Physiological;Play;Population;Process;Proliferating;Property;Protein Kinase;Proteins;Publishing;Reagent;Repression;Research;Research Proposals;Role;Signal Pathway;Signal Transduction;Testing;Therapeutic;Transcription Process;Transferase;Trauma;WD Repeat;Wasting Syndrome;age-related muscle loss;aging process;hormonal signals;human disease;improved;in vivo;inhibitor;injured;interest;member;mouse model;muscle aging;muscle progenitor cell;myogenesis;normal aging;novel;novel therapeutics;overexpression;programs;promoter;recruit;regeneration function;regeneration potential;regenerative;response;sarcopenia;self-renewal;stem cell differentiation;stem cell exhaustion;stem cell fate specification;stem cell function;stem cells;transcription factor

public_health_relevance:
Project NarrativeDysregulation of Muscle Stem Cell (MuSC) function contributes to many human diseases. Here we describea novel signaling pathway that stimulates MuSC differentiation while suppressing selfrenewal. Wepropose that this pathway can be therapeutically exploited for the treatment of ageassociated musclewasting.


application_id: 10765729
project_number: 5R01AG064234-05
project_title: Regulation of Microglial Activation State by a Lipid Transporter
administering_ic: NIA
award_notice_date: 2023-12-15
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 064234
program_official: OPANASHUK, LISA A
project_start_date: 2020-03-01
project_end_date: 2025-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 2275110
contact_pi: BIEBERICH, ERHARD
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractFunctional genome wide association studies have indicated that dysregulated microglia activationis a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease(AD). Thus regulating the microglia activation state could have profound therapeutic potential forAD. However the underlying mechanisms by which microglia transition between different statesduring normal and disease conditions are largely unknown. S1P-signaling has been implicated toplay important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports.On one hand the level of S1P is reduced in postmortem AD patient brains suggesting aprotective role of S1P. On the other hand there are also reports indicating that S1P might playthe opposite. Although has been tested in A-related AD mouse models the role of FTY720 intau pathology is elusive. Further FTY720 can have different function depending on the cellularcontext and treatment procedure which makes interpretation of S1P's role challenging. Thus thefunction of S1P-signaling in AD is more complex than assumed and demands further investigationOur preliminary studies suggest that Spinster homolog 2 (Spns2) an S1P transporter criticallymodulates microglial transition from inflammatory to anti-inflammatory states when treated withA peptide. This data is interesting in that it reveals microglia states could be regulated throughSpns2 and/or S1P. Since microglia form the first and major line of immune defense in the centralnervous system we will mainly investigate the function of Spns2 on microglia activation in thisapplication. The role of astrocytes the other major glial cell type and other S1P transporters suchas ABCA1 will also be evaluated. Our goal is to define the function and underlying mechanismof Spns2 in microglial responses in AD. Our goal is to define the function and underlyingmechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced byAD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microgliainduced by AD-related stimuli (2) Spns2/S1P promotes NFB and p38 MAPK pro-inflammatorysignaling induced by A and tau in microglia and (3) Spns2 deficiency ameliorates AD-relatedphenotypes in murine AD models. By focusing on the S1P transporter Spns2 this proposal holdsa unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.

project_terms:
ATP binding cassette transporter 1;Affect;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Autopsy;Brain;Central Nervous System;Ceramides;Chronic;Clinical;Complex;Data;Disease;Drug Kinetics;Exposure to;Extracellular Space;Goals;Homologous Gene;Immune;Impaired cognition;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Inorganic Phosphate Transporter;Investigation;Knockout Mice;Lipids;MAPT gene;Mediating;Microglia;Mus;NF-kappa B;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neuroglia;Onset of illness;Pathogenesis;Pathology;Pathway interactions;Peptides;Phagocytosis;Phagocytosis Induction;Phenotype;Play;Procedures;Process;Proteins;Public Health;Regulation;Reporting;Repression;Research;Role;Senile Plaques;Signal Induction;Signal Pathway;Signal Transduction;Sphingosine-1-Phosphate Receptor;Stimulus;Testing;Therapeutic;amyloid pathology;antagonist;astrogliosis;cell type;cognitive function;extracellular;genome wide association study;glial activation;improved;mouse model;neuroinflammation;neuroprotection;novel;novel therapeutic intervention;p38 Mitogen Activated Protein Kinase;pre-clinical;response;sphingosine 1-phosphate;sphingosine kinase;tau Proteins

public_health_relevance:
The function of S1P-signaling in AD is more complex than assumed and demands furtherinvestigation. Our research will test a novel hypothesis that the S1P transporter Spns2 contributesto AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-relatedstimuli. By focusing on Spns2 this proposal holds a unique premise to reveal novel aspects ofS1P-signaling in AD


application_id: 10765687
project_number: 5R01AI168475-03
administering_ic: NIAID
award_notice_date: 2024-01-22
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 168475
program_official: CONNOLLY, KRISTIE LEE
project_start_date: 2022-02-25
project_end_date: 2027-01-31
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 10797120
contact_pi: FRIEBOES, HERMANN
other_pis: LEWIS, AMANDA L.
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
budget_start_date: 2024-02-01
project_title:
3D-bioprinting  of sustained- and phased-release antibiotic and probiotic scaffolds to treat bacterial vaginosis

project_abstract:
PROJECT SUMMARYBacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that affects ~29% of reproductive age womenand is linked with higher risks of adverse pregnancy outcomes postsurgical infections and sexually transmittedinfections. While lactobacilli typically dominate the healthy vagina BV is characterized by low lactobacilli levelsand an overgrowth of diverse anaerobic bacteria most often including Gardnerella and Prevotella. Current oralor topical antibiotic treatments alleviate symptoms in 80% of women at least temporarily. However most womenwill experience a recurrence of BV within one-year post-treatment. A recent clinical study showed that a vaginalprobiotic treatment regimen (with Lactobacillus crispatus) used following a vaginal course of antibiotics(metronidazole) significantly improved long-term treatment efficacy. Unfortunately current topically-appliedformulations require repeated administrations (once to twice daily) which can hinder female convenience andadherence to treatment particularly when undergoing multiple weeks of treatment (required to administer bothantibiotic and probiotics).In this project we will use 3D printing and computational modeling iteratively enabled by functional investigationof prototype scaffolds in vitro and in vivo to design long-acting products that sustain therapeutic delivery whileenabling phased-delivery of antibiotics and probiotics to the female reproductive tract. Our team brings togetherfemale reproductive tract-specific expertise in delivery vehicle design computational modeling and preclinicalBV models. The ultimate goal is to use 3D-bioprinting to incorporate different device compartments whichsequentially release antibiotics that target anaerobic overgrowth followed by live probiotics that restore balanceback in favor of vaginal lactobacilli. In Aim 1 we will design and characterize 3D-printed silicone scaffolds thatsustain antibiotic-only delivery. Aim 2 will design and evaluate 3D-printed silicone and gelatin alginatecomposites that sequentially release antibiotics followed by probiotics providing a 1-2 punch strategy to kill BVbacteria and provide a healthy Lactobacillus alternative. Each aim will focus first on a materials-basedcharacterization of Met-containing silicone (1A) or Met-silicone probiotic-gelatin alginate composites (2A).Measurements from in vitro release experiments will be used to develop and test computational models thatpredict the delivery of antibiotic (1B) or dual agents (2B) in a virtual female reproductive tract and ultimately ina mouse co-infection model. We will evaluate Met-silicone (1C) and Met-silicone probiotic-gelatin alginatecomposites (2C) for cytotoxicity to the vaginal epithelium and ability to stimulate soluble proinflammatorymediators and downstream histopathology. In our mouse model we will measure levels of viable Gardnerellaand Prevotella recovered from vaginal and uterine tissues following treatment with blank or active agent-containing 3D-printed scaffolds. If successful this project will support the development of multipurpose platformsto prevent and treat BV as well as other female reproductive tract applications.

project_terms:
3-Dimensional;3D Print;Adherence;Adverse event;Affect;Aftercare;Age;Alginates;Anaerobic Bacteria;Antibiotic Therapy;Antibiotics;Appearance;Atopobium vaginae;Back;Bacteria;Bacterial Vaginosis;Biological Assay;Biomedical Engineering;Calibration;Cell Line;Cells;Clinical;Clinical Research;Clinical Trials;Complex;Computer Models;Data;Development;Devices;Epithelial Cells;Epithelium;Equilibrium;Experimental Models;Female;Formulation;Gardnerella;Gardnerella vaginalis;Gelatin;Goals;Growth;HIV;Health;Histopathology;Human;In Vitro;Infection;Infertility;Inflammation Mediators;Investigation;Kinetics;Lactobacillus;Link;Measurement;Measures;Medicine;Metronidazole;Microbe;Modeling;Mucous body substance;Mus;Oral;Outcome;Pelvic Inflammatory Disease;Phase;Pre-Clinical Model;Prevotella;Printing;Probiotics;Process;Proliferating;Property;Reapplication;Records;Recurrence;Regimen;Retreatment;Serum;Sexually Transmitted Diseases;Silicones;Symptoms;Syndrome;Testing;Therapeutic;Therapeutic Agents;Tissues;Topical Antibiotic;Topical application;Treatment Efficacy;Treatment Protocols;Treatment outcome;Uterus;Vagina;Woman;Work;adverse pregnancy outcome;aged;anti-fungal agents;bioprinting;co-infection;cytotoxicity;delivery vehicle;design;dysbiosis;engineering design;experience;experimental study;fabrication;female reproductive tract;gut health;high risk;improved;improved outcome;in vitro Model;in vitro testing;in vivo;mathematical model;microbial;microbicide;mouse model;multidisciplinary;novel;pathogen;pre-clinical;predictive modeling;prevent;probiotic therapy;prototype;reduce symptoms;reproductive;scaffold;vaginal lactobacilli;vaginal microbiome;virtual

public_health_relevance:
NARRATIVEBacterial vaginosis (BV) is a dysbiotic condition of the vaginal microbiome that affects ~29% of reproductive agewomen and is linked with higher risks of adverse pregnancy outcomes postsurgical infections and sexuallytransmitted infections. Current topically-applied medicines require frequent repeated administrations which canhinder convenience and adherence to treatment particularly when undergoing multiple weeks of treatment. Inthis project we will use 3D-printing and computational modeling iteratively enabled by functional investigation ofprototype scaffolds to design long-acting products that sustain phased-delivery of antibiotics and probiotics torestore and maintain vaginal health.


application_id: 10765652
project_number: 5R01AG070830-04
project_title: Contributions of astrocyte RelA signaling in aging-related neurodegenerative sequelae following TBI
administering_ic: NIA
award_notice_date: 2023-12-14
opportunity_number: PAR-19-070
application_type: 5
activity_code: R01
ic: AG
serial_number: 070830
program_official: OPANASHUK, LISA A
project_start_date: 2021-01-15
project_end_date: 2025-12-31
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG-R]
contact_pi_person_id: 10594155
contact_pi: MORGANTI, JOSH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTTraumatic brain injury (TBI) is significantly correlated with increased risk for developing severalneurodegenerative disorders including Alzheimers Disease (AD) and AD-related dementia (ADRD)representing one of the most powerful environmental risk factors for AD/ADRD. Compounding these correlatesis that aging is a substantial factor in the incidence and vulnerability to TBI. Owing to the complexities surroundingTBI as a progressive neurodegenerative disorder leading to AD/ADRD the cellular mechanisms potentiallyunderlying the aging brains susceptibility to acquire degenerative responses remains elusive. To date the bulkof published findings related to TBI-related Alzheimers-like impairments have been examined using young adultand predominantly male rodents which does not accurately model the greatest at-risk population in humans.However our aging TBI model recapitulates several correlates of Alzheimers like impairments including chronicmemory impairment exacerbated neuroinflammation gliosis phosphorylated tau as well as microglialphenotypes previously documented in both humans and mouse models of Alzheimers disease. Guided bypreliminary findings our overarching hypothesis is that in the aging brain following TBI RelA drives exacerbatedastrocyte responses underlying the aging brains susceptibility for persistent decremental outcomes related tohomeostatic astrocyte susceptibility neuroinflammation and neural network dysfunction. We believe thesealtered responses initiated by TBI in the aging brain ultimately manifest in correlates characteristic of progressiveneurodegeneration associated with AD/ADRD. We will pursue three aims to test this hypothesis using novelgenetic models for targeting astrocytes in young and aged mice to determine 1.) The susceptibility of agedastrocytes to lose critical homeostatic features following TBI 2.) The ability of astrocytes to regulate theconversion of microglia towards decremental AD-associated inflammatory phenotypes following TBI and 3.) Therole of astrocytes in the vulnerability of synaptic circuitry and impaired memory a critical hallmark associatedwith TBI/ADRD. Cumulatively these studies will help to elucidate both the cellular and molecular substratesthrough which the aging brains response to TBI facilitates progressive neurodegenerative sequelae that caneventually lead to AD/ADRD. Our salient findings will ultimately determine the extent to which RelA is a criticalmediator in these AD-associated sequelae with the potential to elucidate new therapeutic targets toward theirprevention.

project_terms:
Acute;Affect;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Alzheimer's disease risk;Animal Model;Astrocytes;Automobile Driving;Behavioral;Brain;Calcium;Cells;Characteristics;Chronic;Complement;Complex;Data;Development;Disease;Environmental Risk Factor;Excision;Feedback;Functional disorder;Genetic Models;Gliosis;Heterogeneity;Human;Impaired cognition;Impairment;Incidence;Inflammation;Inflammatory;Inflammatory Response;Ischemia;Knockout Mice;Lead;Link;Mediator;Memory impairment;Methods;Microglia;Modality;Modeling;Molecular;Multiple Sclerosis;NF-kappa B;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurons;Neurophysiology - biologic function;Outcome;Pathway interactions;Persons;Phenotype;Physiology;Populations at Risk;Predisposition;Prevention;Publishing;Risk;Rodent;Role;Signal Pathway;Signal Transduction;Slice;Spinal cord injury;Synapses;Synaptic plasticity;Testing;Time;Tissues;Transcriptional Activation;Trauma;Traumatic Brain Injury;age related;aged;aging brain;aging population;aging related;astrogliosis;cerebrovascular;conditional knockout;knockout animal;knowledgebase;loss of function;male;mouse model;network dysfunction;neural;neural circuit;neural network;neuroinflammation;new therapeutic target;novel;old mice;progressive neurodegeneration;protein profiling;response;response to injury;restoration;single-cell RNA sequencing;tau-1;transcription factor;transcriptome sequencing;transcriptomics;young adult

public_health_relevance:
Project NarrativeTraumatic brain injury (TBI) is a complex and progressive neurodegenerative disorder affectingmillions of people each year in the US as well as being a known environmental risk factor forthe development of Alzheimers disease-related dementia. However the mechanisms underlyingthe increased risk to develop Alzheimers disease-related dementia following TBI remainunclear. The salient findings from this project will significantly contribute to fundamentalknowledge-base of the role of inflammatory response of astrocytes in the aging brain asdeterminants of outcome following TBI.


application_id: 10764134
project_number: 1R35GM152104-01
project_title: Obesity-mediated protection in sepsis
administering_ic: NIGMS
award_notice_date: 2024-06-20
opportunity_number: PAR-22-180
application_type: 1
activity_code: R35
ic: GM
serial_number: 152104
program_official: ZHAO, XIAOLI
project_start_date: 2024-07-01
project_end_date: 2029-04-30
study_section: Maximizing Investigators' Research Award - D Study Section[MRAD]
contact_pi_person_id: 10399494
contact_pi: STARR, MARLENE ELENA
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSepsis is a major burden to the healthcare system being the most common cause for admission to the intensivecare unit and the most expensive condition treated in US hospitals. It is a complex physiologic condition involvinga heterogenous patient population with high morbidity and mortality and no specific therapies aside fromsupportive measures. Clinical studies indicate that obesity is paradoxically associated with improved survival insepsis; however the mechanisms behind this obesity-mediated protection are not known. Capitalizing on theunique resistance in this patient population may allow for the development of novel therapies to prevent themorbidity and mortality associated with sepsis. The primary goals of my research program are to 1) investigatedifferences in sepsis pathophysiology in patients stratified by obesity status with a major focus on immunealterations and 2) define shifts in immune cell function and metabolism in obesity and determine their roles inconferring protection during sepsis utilizing a validated murine model and patient samples. The gainedinformation will aid in the development strategies to reduce morbidity and mortality in sepsis.

project_terms:
Admission activity;Cell Physiology;Cells;Cellular Metabolic Process;Clinical Research;Complex;Development;Functional disorder;Goals;Healthcare Systems;Hospitals;Immune;Intensive Care Units;Measures;Mediating;Metabolism;Morbidity - disease rate;Obesity;Patients;Phenotype;Physiological;Research;Resistance;Rodent;Role;Sampling;Sepsis;improved;mortality;mouse model;novel therapeutics;patient population;patient stratification;prevent;programs

public_health_relevance:
PROJECT NARRATIVEObesity is paradoxically associated with improved survival during sepsis; however the mechanistic basis for thisprotection is not understood. This project will investigate alterations in immune cell phenotype function andmetabolism during sepsis in patients and rodents with underlying obesity.


application_id: 10763893
project_number: 5K99CA277245-02
project_title: Reducing Lung Cancer Risk among Appalachian Women Using CommunityEngaged Intervention Research
administering_ic: NCI
award_notice_date: 2024-02-05
opportunity_number: RFA-CA-21-061
application_type: 5
activity_code: K99
ic: CA
serial_number: 277245
program_official: RADAEV, SERGEY
project_start_date: 2023-02-01
project_end_date: 2024-04-30
study_section: ZCA1-RTRB-U(O1)
contact_pi_person_id: 15107621
contact_pi: THOMPSON, JESSICA RUTH
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 SUMMARYAppalachian women are at high risk for lung cancer. Lung cancer is the leading cause of cancer-related deathfor women in the US including the Appalachian region. Although lung cancer rates have declined steadily amongmen since the 1990s such decreases have not been seen among women including alarming mortality rates inCentral Appalachia. Interventions to reduce lung cancer risk among Appalachian women need to consider socialand environmental contexts. Research: This project titled Reducing Lung Cancer Risk among AppalachianWomen Using Community-Engaged Intervention Research relies on community perspectives to guide theselection adaptation and pilot testing of a culturally-targeted intervention to reduce lung cancer risk amongAppalachian women. We will employ the NIH model for creating behavioral intervention trials to inform therefinement of an intervention through direct community input (Phase 1a; Aim 1; K99) and to pilot test the selectedand adapted intervention protocol using a 2-armed randomized controlled trial (Phase 1b; Aim 2; R00). In thepilot with Central Appalachian KY women we will demonstrate the feasibility of the adapted intervention protocolincluding demand acceptability and implementation. The selected intervention will seek to increase knowledgeself-efficacy and targeted behaviors among Appalachian women thereby reducing their future lung cancer riskand ultimately lung cancer disparities among women in the Appalachian region. Candidate: Dr. JessicaThompson is a postdoctoral scholar in an NCI-designated cancer center at the University of Kentucky (UK) withextensive previous training in community-engaged mixed methods research and chronic disease preventionamong Appalachian women. Three training goals will enhance her trajectory toward becoming an independentinvestigator including developing expertise in: 1) the use of participatory systems science and community-engaged approaches to select and adapt an intervention; 2) lung cancer prevention and risk reductioninterventions; and 3) intervention development and implementation science. Mentors/Environment: Dr.Thompsons career development plan includes substantial mentorship didactic training and experientiallearning at the UK Markey Cancer Center (MCC) with additional support from the UK Center for Health EquityTransformation (CHET) and the UK Center for Clinical and Translational Science (CCTS). She will receive directmentorship from MCC Community Impact Office director Dr. Pamela Hull (Primary Mentor) and CHET directorDr. Nancy Schoenberg (Co-Primary Mentor) with additional mentorship from Dr. Ellen Hahn (Mentor) in lungcancer prevention and risk reduction Dr. Teresa Waters (Mentor) in assessments of intervention effectivenessand health economics and Dr. Jessica Burke (Mentor; University of Pittsburgh) in systems science andparticipatory methods. Overall the objectives of this K99/R00 application will advance lung cancer interventionresearch for Appalachian women by providing evidence for a future R01 submission and support Dr. Thompsonstraining as an independent scientist in implementing interventions to improve the health of Appalachian women.

project_terms:
18 year old;Active Learning;Address;Appalachian Region;Area;Attitude;Awareness;Behavior;Behavior Therapy;Behavioral;Cancer Center;Cancer Etiology;Cancer Intervention;Chronic Disease;Chronic stress;Clinical Sciences;Communities;Coping Behavior;Country;County;Death Rate;Development;Development Plans;Disproportionately impacts women;Economically Deprived Population;Effectiveness of Interventions;Enrollment;Environment;Environmental Exposure;Environmental Risk Factor;Equity;Evidence based intervention;Farm;Funding;Future;Gender;Goals;Health;Health Technology;High Risk Woman;Incidence;Individual;Insurance;Intervention;Intervention Studies;Intervention Trial;Kentucky;Knowledge;Literature;Malignant Neoplasms;Malignant neoplasm of lung;Mentors;Mentorship;Methods;Mining;Modeling;NCI-Designated Cancer Center;Needs Assessment;Participant;Passive Smoking;Perception;Persons;Phase;Population;Postdoctoral Fellow;Poverty;Preventive;Preventive screening;Preventive service;Process;Protocols documentation;Psychosocial Factor;Quality of life;Radon;Randomized Controlled Trials;Research;Research Methodology;Research Personnel;Risk;Risk Factors;Risk Reduction;Rural;Rural Appalachia;Sample Size;Science;Scientist;Self Efficacy;Series;Smoking;Source;Specificity;Surveys;System;Targeted Research;Training;Translational Research;Trust;United States National Institutes of Health;Universities;Water;Woman;Women's mortality;cancer health disparity;cancer risk;care giving burden;career development;clinical center;community center;community collaboration;community engaged approach;community engaged intervention;community engagement process;community partners;community-level factor;disorder prevention;disparities in women;experience;falls;geographic disparity;health care availability;health disparity;health disparity populations;health economics;health equity;human centered design;implementation cost;implementation science;improved;intervention mapping;intervention refinement;lung cancer prevention;men;model building;mortality;non-smoker;pilot test;primary care provider;public policy on tobacco;satisfaction;service providers;sex;skills;social;socioeconomic disadvantage;socioeconomic disparity;therapy development;training opportunity;women's diagnosis

public_health_relevance:
PROJECT NARRATIVEThe short-term goal of this K99/R00 application is the development of the PI as an independent investigatorskilled in the use of participatory systems science and community-engaged approaches to select and adapt anintervention lung cancer prevention and risk reduction interventions and intervention development andimplementation science. The proposed research will select and adapt an intervention protocol to reduce lungcancer risk among Central Appalachian Kentucky women through a community-engaged process and will pilottest the selected intervention using a two-armed randomized controlled trial. The long-term goal is to reduce lungcancer disparities among Appalachian women and for the PI to become an independent researcher and expertin community-engaged intervention development for cancer risk reduction among Appalachian women.


application_id: 10763798
project_number: 5R00HL145117-05
project_title: Macrophage Pyroptosis in Abdominal Aortic Aneurysm
administering_ic: NHLBI
award_notice_date: 2023-11-14
opportunity_number: PA-18-398
application_type: 5
activity_code: R00
ic: HL
serial_number: 145117
program_official: CHARETTE, MARC F
project_start_date: 2021-12-01
project_end_date: 2024-11-30
study_section: NSS
contact_pi_person_id: 14992976
contact_pi: WU, CONGQING
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The purpose of this K99/R00 application is to (1) provide me with necessary training in research andcareer development for my transition to a successful independent researcher; (2) study the role ofpyroptosis a novel form of programmed cell death in the rupture of Abdominal Aortic Aneurysm (AAA).AAA is a progressive pathological dilation and weakening of the aorta. AAA is associated with extremerates of death (up to 80%) in the event of aortic rupture. There has no medical therapy to prevent or treataortic rupture which is largely attributed to that mechanisms underlying AAA rupture have not beendefined. AAA is characterized by inflammation and frequent presence of thrombus. Inflammatory lesionsoften contain dead cells. Until recently programmed cell death was thought to occur only in one formcalled apoptosis. In 2015 and 2016 four Nature publications from three groups revealed gasdermin D(GSDMD)-dependent mechanisms of pyroptosis. GSDMD forms pores on cell surface and ruptures cellmembrane. In ruptured cell membrane phosphatidylserine which is exclusively located in the innermonolayer in living cells freely flip into outer monolayer and forms a procoagulant surface for tissuefactor by facilitating the assembly of proteins of clotting cascade. We recently discovered thatmacrophage pyroptosis caused septic death through tissue factor release which triggered disseminatedintravascular coagulation in mice. My preliminary data show that genetic deficiency of GSDMD protectsagainst AAA rupture in angiotensin II-infused mice. In this proposal I will test the hypothesis thatmacrophage pyroptosis promotes AAA rupture through tissue factor-dependent thrombus propagation.Two aims will be addressed to test this hypothesis. In Aim 1 I will profile macrophage pyroptosis inangiotensin II-induced AAA rupture using caspase-1 and Caspase-11 deficient mice (K99 PHASE). InAim 2 I will determine how macrophage pyroptosis through tissue factor-mediated mechanismscontributes to AAA rupture (R00 PHASE). Together I will examine the causal relationship betweenthrombus and AAA rupture and test the concept of a feedforward loop between macrophage pyroptosisand tissue factor/thrombus until AAA rupture. This project is important because GSDMD and pyroptosismay represent a therapeutic target. This project is innovative because it defines a novel procoagulantmechanism in AAA. I will also examine macrophage biology and pyroptosis in human aortic aneurysmtissues available in Dr. LeMaires Aortic Disease Biobank at Baylor College of Medicine to enhance thetranslational aspects of my proposed research.

project_terms:
Abdominal Aortic Aneurysm;Address;Angiotensin II;Aorta;Aortic Aneurysm;Aortic Diseases;Aortic Rupture;Apoptosis;Biology;CASP1 gene;Caspase;Cell membrane;Cell surface;Cells;Cessation of life;Coagulation Process;Data;Death Rate;Disseminated Intravascular Coagulation;Event;Genetic;Human;Inflammation;Inflammatory;Lesion;Macrophage;Mediating;Medical;Medicine;Mus;Nature;Pathologic;Phosphatidylserines;Proteins;Publications;Research;Research Personnel;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Surface;Testing;Thromboplastin;Thrombus;Tissues;Training;biobank;career development;college;innovation;monolayer;novel;prevent;release factor;research and development;septic;therapeutic target


application_id: 10763473
project_number: 3R01DK121797-05S1
project_title: Novel Liver Signaling Pathways Controlling Adiposity
administering_ic: NIDDK
award_notice_date: 2023-03-21
opportunity_number: PA-19-056
application_type: 3
activity_code: R01
ic: DK
serial_number: 121797
suffix: S1
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
project_abstract:
There is little doubt that we are in the midst of a worldwide epidemic of obesity. Almost two-thirds of adults in theUnited States are obese or overweight. Whether if obesity arises from genetic factors or high caloric intake itstill may lead to insulin resistance and type II diabetes. Our recent data show that bilirubin (BR) which has beentypically considered as an antioxidant may function as a metabolic ligand that signals to the nuclear receptortranscription factor PPAR to reduce lipid accumulation. We also found that BR induces the hepatic fibroblastgrowth factor 21 (FGF21) hormone via PPAR which is known to have systemic effects on insulin sensitivity.Hepatic lipid accumulation and insulin resistance are interlocking pathophysiologic events but the mechanismsof these abnormalities and how these distinct processes interact are inadequately understood. For unknownreasons BR plasma levels are lower in the obese and several obese patients progress to nonalcoholic fattyliver disease (NAFLD) which is likely due to obesity-induced insulin resistance. However in patients withpathological liver disease such as Crigler-Najjar syndrome the BR plasma levels are very high. This paradoxmay be explained by the hepatic UDP-glucuronosyltransferase 1-1 (UGT1A1) enzyme that conjugates BR tomake it soluble and for deposition into bile and eventually into the intestine which lowers unconjugated BR fromthe blood. In humans a polymorphism in the UGT1A1 gene (UGT1A1*28) known as Gilberts syndrome (GS)reduces expression resulting in increased plasma BR levels but not in liver disease. We have shown thathumanized mice with the Gilberts polymorphism (UGT1A1*28) on a high-fat diet have significantly higher plasmaBR levels reduced adiposity and insulin intolerance and are resistant to fatty liver disease. Agents that regulateUgt1a1 during weight gain or loss are unknown. In the preliminary data we show exciting data that microRNA-365 (miR365) suppresses Ugt1a1 expression and increases plasma BR levels. We also found that Ugt1a1expression is higher in the livers of obese mice while miR365 and plasma BR levels are lower which indicatesthat miR365 targeting Ugt1a1 may be beneficial in increasing plasma BR to regulate adiposity. Our centralhypothesis is that BR functions as a metabolic ligand that activates the liver PPAR-FGF21 pathway to reduceadiposity and insulin resistance. We will pursue this plan with three primary scientific aims: 1) Determine theselectivity of BR on PPAR isoforms; 2) Determine the systemic effects of BR mediated by hepatic FGF21; and3) Determine if miR365 elevation of BR reduces adiposity and insulin resistance via PPAR. Collectively thisproject is the first systematic investigation of the BR-PPAR-FGF21 module and its control of insulin resistanceassociated with obesity. The proposal provides advances to new strategies (miR365) of targeting this module tocontrol adiposity which offers therapeutic benefits.

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;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;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;Shapes;Signal Pathway;Signal Transduction;Signaling Molecule;Testing;Therapeutic;Tissue Expansion;Tissues;Transactivation;UDP-Glucuronosyltransferase 1A1;Uncertainty;United States;Visceral fat;Weight Gain;carbohydrate metabolism;clinically relevant;comparison control;cost;cytokine;fatty liver disease;fibroblast growth factor 21;hormonal signals;humanized mouse;improved;insulin sensitivity;lipid metabolism;microRNA delivery;mouse model;non-alcoholic fatty liver disease;novel;novel therapeutics;obese patients;oxidation;preference;promoter;recruit;transcription factor

public_health_relevance:
During obesity visceral fat tissue expands causing oxidative stress and the release of pro-inflammatorycytokines that can cause insulin resistance and cardiovascular complications. This project explores theantioxidant bilirubin in molecular detail as a signaling molecule to reduce adiposity and insulin resistance andimprove metabolic health. A comprehensive investigation of the signaling preferences for bilirubin may open newavenues for potential new therapeutics for obesity and insulin resistant diabetes and for cardiovascular diseasesin humans.


application_id: 10761399
project_number: 1R43HL170888-01
administering_ic: NHLBI
award_notice_date: 2023-08-10
opportunity_number: PA-22-176
application_type: 1
activity_code: R43
ic: HL
serial_number: 170888
program_official: FENTON, KATHLEEN NELLE
project_start_date: 2023-08-10
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZRG1 ISB-W (12)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-10
project_title:
Integration of Compliance Chambers into Diaphragm Displacement Pump to Double the Pumping Flow of Pediatric Paracorporeal Pulsatile Ventricular Assist Device

project_abstract:
The paracorporeal Berlin Heart EXCOR is the only FDA-approved ventricular assist device (VAD) forpediatric patients. This pulsatile diaphragm displacement pump (DDP) is small/light weight to facilitate pediatricpatient ambulation. However EXCOR efficiency is only 50% since it withdraws and pumps blood at differenttimes (interrupted pulsatile flow). This generates a high peak blood flow rate which may cause blood damage.A paracorporeal continuous flow PediMag VAD has also been used in smaller children. This centrifugal pumpis highly efficient due to the constant flow through the drainage/infusion cannulas but the PediMag pump headmust be attached to a bulky/heavy motor which hinders ambulation. We previously developed a transapical toaorta (TAA) double lumen cannula (DLC) for a minimally invasive ambulatory LVAD which showed excellent96 hr performance/hemocompatibility in neonate lambs. Our ultimate goal is to develop an efficient minimallyinvasive paracorporeal LVAD system for pediatric patients which combines the small size/weight (ambulationpotential) of current interrupted pulsatile flow pump (e.g EXCOR) and the current high efficiency of acontinuous flow pump (e.g PediMag). The enabling technology is a compliant diaphragm displacement pump(cDDP) which has compliance chambers integrated into the drainage and infusion outlets to double blood flow.The cDDP will be high performing due to: 1) noninterrupted/continuous blood flow; 2) infusion/drainagecompliance chambers that decrease cDDP afterload/increase cDDP preload. The lower peak drainage/infusionflow of the cDDP will also reduce blood trauma. Preliminary data showed that adding compliance chambersincreased pumping flow from 1.1 to 2.6 L/min and decreased peak flow rate. The Phase I SBIR objective is todesign and fabricate a cDDP working prototype with optimal compliance chambers size. This cDDP will betested in lambs with our previously developed TAA DLC. Specific Aim 1: To design fabricate and benchtest a cDDP. Compliance chambers will be integrated into the cDDP drainage and infusion outlets. The cDDPwill be made of polycarbonate housing with a polyurethane diaphragm in the middle. A tricuspid valve willconnect the cDDP housing to the two small silicone compliance chambers. The final prototype will be tested for1 week in a 37% glycerin mock loop for performance/reliability/durability. Specific Aim 2: To test the cDDPworking prototype in lambs. The cDDP will be combined with the TAA DLC to form a less invasiveambulatory LVAD which will be tested in 10-15 kg lambs (n=9) to evaluate 6 hr performance/reliability andinitial biocompatibility. Prototype design/fabrication/bench testing will be done at W-Z Biotech and the lambstudies will be done at the University of Kentucky. Rather than fine-tuning existing technology our cDDP is anovel invention which will enable a pulsatile paracorporeal VAD with doubled efficiency. This technology canalso be used in adults and may significantly impact cardiogenic shock/bridge to heart transplant management.

project_terms:
Adult;Aorta;Apical;Berlin;Biotechnology;Blood;Blood flow;Cannulas;Cardiac;Cardiogenic Shock;Cardiomyopathies;Child;Childhood;Complex;Coupled;Data;Devices;Diastole;Drainage procedure;Engineering;FDA approved;Frequencies;Glycerol;Goals;Head;Heart;Heart Transplantation;Heart failure;Housing;Implant;Infusion procedures;Interruption;Kentucky;Laboratory Animal Production and Facilities;Lung;Membrane;Molds;Motor;Movement;Myocarditis;Patients;Performance;Phase;Polyurethanes;Publications;Pulsatile Flow;Pump;Research Support;Respiratory Diaphragm;Scientist;Silicones;Small Business Innovation Research Grant;Stress;Surgeon;System;Systole;Technology;Testing;Thrombosis;Time;Trauma;Tricuspid valve structure;Universities;Vacuum;Weight;Withdrawal;biomaterial compatibility;blood damage;blood pump;commercialization;congenital heart disorder;design;experience;fabrication;flexibility;hemocompatibility;improved;improved outcome;in vivo;innovation;invention;left ventricular assist device;light weight;minimally invasive;multidisciplinary;neonate;novel;pediatric heart failure;pediatric patients;polycarbonate;pressure;prototype;research and development;shear stress;ventricular assist device

public_health_relevance:
We are proposing to develop an efficient minimally invasive paracorporeal left ventricular assist device(LVAD) system for pediatric heart failure patients which combines the small size/weight of interrupted pulsatileflow pump and the high efficiency of continuous flow pump. The enabling technology is a compliant diaphragmdisplacement pump (cDDP) with integrated drainage and infusion compliance chambers. When coupled withour previously developed minimally invasive transapical to aorta double lumen cannula this cDDP will enablecontinuous blood flow with pulsatility to improve VAD system efficiency potentially improving outcomes.


application_id: 10760409
project_number: 1R43HL169087-01A1
project_title: A breakthrough mobile phone technology that aids in early detection of COPD
administering_ic: NHLBI
award_notice_date: 2023-09-11
opportunity_number: PA-22-176
application_type: 1
activity_code: R43
ic: HL
serial_number: 169087
suffix: A1
program_official: SHENOY, SIDDHARTH KAUP
project_start_date: 2023-09-15
project_end_date: 2025-01-10
study_section: Special Emphasis Panel[ZRG1 HSS-J (10)]
contact_pi_person_id: 78826114
contact_pi: WOLFSON, DAVID
other_pis: HUECKER, MARTIN RICHARD
congressional_district: 03
department: Unavailable
primary_uei: CHJ8YC513988
uei: CHJ8YC513988
fips: US
organization_id: 10072316
organization_name: TELE-STETHOSCOPE INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40207
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-15
project_abstract:
Project Summary / AbstractCOPD is the fourth leading global killer in part because of the failure of frontline medicine todetect the disease. Poor early detection leads to unfavorable outcomes and high healthcarecosts. Tele-stethoscope* or TS is novel technology that allows acoustic data captured fromordinary mobile phones to perform robust analysis of hemodynamics and pneumodynamics.TS is intended to be used in primary care particularly in Tele-health and before scheduledphysical examination. Its purpose is to alert primary care physicians to the need for physicalexamination and possibly referral. In these situations there are no other comparable testingoptions.TS has three important innovations. First is a clinical use innovation which brings remoteimpromptu patient evaluation to anyone with a smartphone. Customer discovery has validatedboth a workflow and reimbursement strategy consistent with commercial success. FurtherFDA guidance suggests viability of agency clearance. Second is TSs novel approach tomaking AI algorithms. TS uses acoustic data captured by OEM phone microphones intorigorous physics-based features that describe organ hemodynamics and pneumodynamics.The features or independent variables are then used to create binary classification modelswith logistic regression. By relying on physics TS never has to use neural networks oroverfitting strategies that have raised concerns about data intensity model stability regulatorytransparency and unknown reliability. The third innovation is that by relying on passiveacoustic data TS classifies organ function by observing organ dynamics directly rather thanfrom forced air capacity. TS uses many ideas from physics that were not available until fairlyrecently. By relying on dynamics TS offers a novel approach to forced air that may eventuallybe additive to our understanding of respiratory conditions even in PFT labs.This will be the third large scale human study that demonstrates classification of cardio -pulmonary functionality. It follows a published study on COVID detection as well as soon tobe published study on the ability of TS to reproduce echocardiogram estimates of ejectionfraction. Analysis of stethoscope recordings suggests that the COPD diagnostic will rely ona combination of right heart side hemodynamics and low frequency lung pneumodynamics. Asignificant body of research is presented which validates the use of mobile phones as anauscultation device with the ability to detect and diagnosis COPD.The Aim of this study is to develop evaluate and test an algorithm that allows ordinary mobilephones to detect COPD. Our hypothesis is that TS technology can detect COPD by matchingphone acoustic recordings to diagnosis. Diagnosis will be determined by a physician afterconsidering gold standard testing. Performance of the models will be evaluated by usingcommon statistical approaches such as area under the receiver operating curve AUCsensitivity specificity accuracy. The research will have 3 milestones based on recruitment of30 60 and 100 patients respectively.Our approach is based on recruitment from patients assigned to a hospital PFT lab so thatrecordings and gold standard testing are done concurrently. Our team consists of a broadrange of talent including the inventor of TS pulmonology expertise the research director ofemergency medicine for the hospital running the tests statistical expertise and projectmanagement.* Tele-stethoscope or "TS" is patent pending technology developed by Fleming Scientific.

project_terms:
Acoustics;Address;Air;Algorithms;Area;Auscultation;Blood;COVID detection;COVID-19 detection;Cardiopulmonary;Cells;Cellular Phone;Chronic Obstructive Pulmonary Disease;Classification;Clinical;Code;Data;Development;Devices;Diagnosis;Diagnostic;Disease;EFRAC;Early Diagnosis;Echocardiography;Economics;Emergency Medicine;Evaluation;Failure;Frequencies;Funding;Future;Geography;Goals;Grant;Health Care Costs;Heart;Hospitals;Human;Image;Institutional Review Boards;International;Legal;Legal patent;Logistic Regressions;Lung;Lung Capacity;Machine Learning;Maps;Medicine;Modeling;Observational Study;Office Visits;Organ;Outcome;Patient Recruitments;Patients;Performance;Phase;Physical Examination;Physicians;Physics;Population;Primary Care;Primary Care Physician;Process;Protocols documentation;Provider;Publishing;Pulmonary Function Test/Forced Expiratory Volume 1;Pulmonology;Race;Research;Research Support;Running;Schedule;Sensitivity and Specificity;Series;Shapes;Side;Site;Specificity;Spirometry;Stethoscopes;Talents;Technology;Telephone;Testing;Universities;accurate diagnosis;accurate diagnostics;artificial intelligence algorithm;clinical practice;commercial launch;cost;demographics;diagnostic platform;diagnostic strategy;hemodynamics;human error;human study;improved;improved outcome;infrastructure development;innovation;interest;member;microphone;neural network;new technology;novel;novel strategies;power analysis;recruit;remote grading;respiratory;screening;success;technology development;telehealth;text searching

public_health_relevance:
The research supports development of technology that allows ordinary mobile phones to be usedto detect COPD in patients remotely. The intent is to improve early detection of the disease infrontline medicine thereby improving outcomes and lowering healthcare costs. The technology isscientifically important in that it relies on dynamics modeling rather than lung capacity evaluationor imaging and employs a novel rigorous approach to AI.


application_id: 10760193
project_number: 1R42MH135825-01
administering_ic: NIMH
award_notice_date: 2023-07-26
opportunity_number: PA-22-178
application_type: 1
activity_code: R42
ic: MH
serial_number: 135825
program_official: GRABB, MARGARET CHRISTINE
project_start_date: 2023-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1 ISB-Z (10)]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078515036
primary_uei: HSZNRZ4JS954
duns_number: 078515036
uei: HSZNRZ4JS954
fips: US
organization_id: 10032228
organization_name: BIOPTICSTECHNOLOGY, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405131245
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-01
project_title:
Time-resolved laser speckle contrast imaging of resting-state functional connectivity in neonatal brain

project_abstract:
ABSTRACTContinuous monitoring of neonatal brain development is crucial for effective management of brain injury andassociated complications thus reducing healthcare burden and costs. One rapidly developing method for earlycharacterization of abnormal brain development is to map resting-state functional connectivity (rs-FC) acrossdistinct regions of the brain. However currently available neuroimaging technologies are either expensive anddifficult to use continuously (fMRI and PET) or lack the combination of temporal-spatial resolution and large field-of-view (FOV) to image distributed rs-FC (EEG and near-infrared spectroscopy and tomography). In collaborationwith University of Kentucky inventors Bioptics Technology is developing validating and commercializing arevolutionary time-resolved laser speckle contrast imaging (TR-LSCI) technology that enables noncontact fasthigh-resolution imaging of cerebral blood flow (CBF) over a large FOV. TR-LSCI illuminates picosecond-pulsedwidefield coherent near-infrared light onto the brain and synchronizes a newly developed picosecond-gatedhigh-resolution single-photon avalanche diode (SPAD) camera for 2D mapping of cerebral blood flow (CBF) atdifferent depths into the head. By applying the time-gated strategy TR-LSCI differentiates short and long photonpaths through the layered head tissues at different depths thus eliminating the need for time-consuming complex3D reconstruction in near-infrared diffuse optical tomography technologies. In preliminary studies continuousmapping of CBF at different depths has been demonstrated by a lab-made benchtop TR-LSCI prototype in flow-simulating phantoms and in vivo rodents. In this Fast Track STTR proposal through two phases we will developoptimize validate and commercialize a user-friendly portable TR-LSCI device for fast high-solution andmultiscale imaging of CBF and rs-FC in neonatal rodents (Phase 1) and neonatal piglets (Phase 2). SpecificallyPhase 1 will optimize and assess the benchtop TR-LSCI prototype for imaging CBF and extracting rs-FC (derivedfrom time-course CBF images) in neonatal rodents with perinatal hypoxic-ischemic encephalopathy (HIE).Neonatal rats are used in this Phase 1 feasibility test to de-risk the TR-LSCI before its full-scale development inneonatal piglets during Phase 2. HIE is selected to study as it affects 2-9 babies per 1000 term births and isassociated with severe neurodevelopmental problems and mortality. Phase 2 will develop optimize and assessa user-friendly portable TR-LSCI device for continuous imaging of CBF and rs-FC in neonatal piglets with HIE.Neonatal piglets are selected to study as their head size and post-HIE pathology are analogous to humanneonates. TR-LSCI results will be correlated with MRI results and clinical outcomes to identify biomarkers forassessing neonatal brain injury after HIE. While this proposal tests it on HIE models of neonatal rats and pigletsas the first step for preclinical commercialization the TR-LSCI device is broadly applicable to investigate manyneurovascular diseases beyond HIE occurring in human neonates thereby providing a significant opportunityfor future clinical development and commercialization.

project_terms:
3-Dimensional;Affect;Algorithms;Animal Model;Biological Markers;Brain;Brain Injuries;Brain imaging;Brain region;Calibration;Cerebrovascular Circulation;Clinical;Collaborations;Complex;Consumption;Development;Diffuse;Diffusion;Disease;Early Diagnosis;Electroencephalography;Functional Magnetic Resonance Imaging;Future;Head;Health;Healthcare;Human;Image;Imaging Device;Imaging technology;Infant;Investigation;Kentucky;Laboratories;Laser Speckle Imaging;Light;Magnetic Resonance Imaging;Maps;Methods;Modality;Modeling;Monitor;Near-Infrared Spectroscopy;Neonatal;Neonatal Brain Injury;Neonatal Intensive Care Units;Neurodevelopmental Problem;Neurosciences Research;Noise;Operating System;Outcome;Pathology;Perinatal anoxic ischemic brain injury;Phase;Photons;Physiologic pulse;Positron-Emission Tomography;Property;Rattus;Resolution;Rest;Risk;Rodent;Scalp structure;Signal Transduction;Small Business Technology Transfer Research;Statistical Models;System;Technology;Term Birth;Testing;Time;Tissues;Universities;Variant;biomarker identification;brain abnormalities;care burden;care costs;cerebral hemodynamics;clinical application;clinical development;commercialization;cost;cranium;denoising;design;diffuse optical tomography;experimental study;feasibility testing;high resolution imaging;imager;improved;in vivo;lens;mortality;neonatal brain;neonatal brain development;neonatal hypoxic-ischemic brain injury;neonate;neuroimaging;neurovascular;operation;porcine model;portability;pre-clinical;prevent;prototype;reconstruction;tomography;user-friendly

public_health_relevance:
PROJECT NARRATIVEContinuous monitoring of neonatal brain development is crucial for effective management of brain injury andassociated complications thus reducing healthcare burden and costs. Bioptics Technology is developingvalidating and commercializing a revolutionary time-resolved laser speckle contrast imaging (TR-LSCI)technology that enables noncontact fast high-resolution imaging of cerebral blood flow and resting-statefunctional connectivity across distinct regions of the brain for noninvasive and continuous assessment ofneonatal brain development to prevent brain injury. While the proposal tests this imaging technology in perinatalhypoxic-ischemic encephalopathy models of neonatal rats and piglets as the first step for preclinicalcommercialization the TR-LSCI device is broadly applicable to investigate many neurovascular diseases beyondHIE occurring in human neonates thereby providing a significant opportunity for future clinical development andcommercialization.


application_id: 10759365
project_number: 5F30NS124136-02
administering_ic: NINDS
award_notice_date: 2023-04-20
opportunity_number: PA-21-050
application_type: 5
activity_code: F30
ic: NS
serial_number: 124136
program_official: CORRIVEAU, RODERICK A
project_start_date: 2022-05-08
project_end_date: 2025-07-07
study_section: Special Emphasis Panel[ZRG1-F03A-T(20)L]
contact_pi_person_id: 15915830
contact_pi: SHADE, LINCOLN
other_pis: Not Applicable
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-08
project_title:
Elucidating Shared Risk of Brain Arteriolosclerosis and Related Pathologies with Multiple 'omics Modalities

project_abstract:
Abstract Brain arteriolosclerosis (B-ASC) is a cerebrovascular disease characterized by pathological thickening ofthe arterioles in the brain. Non-Alzheimers disease brain pathologies including B-ASC are increasinglyrecognized as important contributors to cognitive decline in aged individuals. In autopsy cohorts B-ASC isfound in over 50% of participants aged eighty years or older at death. B-ASC is associated with multiple otherneuropathologies including hippocampal sclerosis. Despite its clinical importance the pathophysiology of brainarteriolosclerosis and its mechanistic relationship to other pathologies are not well understood. We haveaggregated and harmonized genotype and autopsy data between four high-quality neuropathology cohorts: theNational Alzheimers Coordinating Center (NACC) the Religious Orders Study and the Memory and AgingProject (ROSMAP) the Adult Changes in Thought Study (ACT) and the Alzheimers Disease NeuroimagingInitiative Neuropathology Cohort (ADNI). In preliminary genetic association and functional genomic studiesusing NACC participants we identified multiple B-ASC risk loci that replicated in at least one independentcohort and established a framework for genetic studies of neuropathological endophenotypes (NPE). In Aim 1we hypothesize that analyses employing gene expression and DNA methylation will further characterizegenomic risk factors for B-ASC pathology. We will investigate the relationship between B-ASC geneexpression and DNA methylation in the dorsolateral prefrontal cortex using ROSMAP. These analyses will befollowed by computational approaches that will estimate the contribution of different cell types and predict geneexpression from genotype data in other cohorts. In Aim 2 we hypothesize that B-ASC shares genomic risk withassociated NPE. We will first use our established analytic pipeline to perform genetic association studies ofNPE comorbid with B-ASC. We will then use statistical methods to quantify and localize shared genetic riskbetween B-ASC and other NPE. Findings from these studies will provide a rigorous characterization of B-ASCrisk factors and relevant biological pathways. Our cross-trait analyses will help clarify B-ASCs place in thecomplex web of mixed brain pathologies common in aged individuals. The mentors and collaborators I haverecruited comprise an experienced and multidisciplinary team that includes two biostatisticians a geneticepidemiologist and an experimental neuropathologist. This NIH F30 fellowship will provide the requisiteexperience knowledge and skills necessary as preparation to the next stage in my career as a clinicalresearcher.

project_terms:
Adult;Age;Aging;Alzheimer's Disease;Architecture;Autopsy;Bioinformatics;Biological;Biological Assay;Brain;Brain Pathology;Cells;Cerebrovascular Disorders;Cerebrovascular system;Cessation of life;Chromosomes;Clinical;Clinical Research;Cognitive;Complex;DNA Methylation;Data;Data Set;Dementia;Development;Diabetes Mellitus;Disease;Epidemiologist;Fellowship;Functional disorder;Gene Expression;Generations;Genetic;Genetic Risk;Genetic study;Genomics;Genotype;Hypertension;Impaired cognition;Individual;Internet;Knowledge;Memory;Mentors;Methods;Methylation;Modality;Molecular;Multiomic Data;Outcome;Participant;Pathologic;Pathology;Pathway interactions;Phenotype;Pilot Projects;Prefrontal Cortex;Preparation;Process;Research;Research Personnel;Resources;Risk;Risk Factors;Sampling;Source;Statistical Methods;Testing;Training Programs;Translating;United States National Institutes of Health;Update;aged;arteriole;brain arteriolosclerosis;career;case control;cell type;clinical risk;cohort;comorbidity;design;endophenotype;experience;functional genomics;genetic association;genetic risk factor;genome wide association study;genome-wide;hippocampal sclerosis;human old age (65+);insight;molecular phenotype;multidisciplinary;multiple omics;neuroimaging;neuropathology;new therapeutic target;recruit;religious order study;risk sharing;risk variant;skills;therapeutic target;trait;translational genomics

public_health_relevance:
Project Narrative Brain arteriolosclerosis (B-ASC) the pathologic thickening of small blood vessels in the brain is a commoncontributor of cognitive decline in aged individuals but the genetic risk factors are poorly understood. Thisproject will identify multi-omic risk factors of B-ASC and identify the shared genetic risk between B-ASC andassociated neuropathologies. Findings will provide mechanistic insight into B-ASC and identify potentialtherapeutic targets.


application_id: 10757437
project_number: 5P20GM121327-08
project_title: Targeting Glutamine Uptake via ASCT2 Inhibition in MYCN-amplified Neuroblastomas
administering_ic: NIGMS
award_notice_date: 2023-12-20
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6479
contact_pi_person_id: 12051773
contact_pi: RELLINGER, ERIC JAMES
other_pis: ST CLAIR, DARET K
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Neuroblastoma (NB) is the most common extracranial solid tumor in children. MYCN-amplification is present in ~25% of NBs and nearly half of all high-risk NBs. N-MYC is a proto-oncogene that drives cancer cell growth angiogenesis and metabolism. Aberrant glutamine metabolism is a hallmark of MYC-driven cancers. N-MYC enhances expression of the glutamine transporter ASCT2. ASCT2 has been shown to be critical for MYCN-amplified NB cell survival in vitro and in subcutaneous xenograft formation in vivo. Our central hypothesis is that aberrant glutamine uptake via ASCT2 is critical for MYCN-amplified NB primary tumor growth and metastasis. We will define the critical role of ASCT2 in NB utilizing CRISPR-Cas9 knockout and V-9302 a small molecule ASCT2 inhibitor in 3-D organoid and patient-derived orthotopic xenograft (PDOX) models of MYCN-amplified NB. Stable-isotope resolved metabolomics will be used to define aberrant metabolic pathways activated to sustain NB survival in the presence of ASCT2 blockade. We will also seek to define metabolic vulnerabilities uncovered by ASCT2 inhibition utilizing an unbiased CRISPR-Cas9 lineage dropout screen to assess for dual synthetic lethality in MYCN-amplified NB cells.

project_terms:
3-Dimensional;CRISPR/Cas technology;Cancer Cell Growth;Cancer Center;Cell Survival;Cephalic;Dropout;Glutamine;In Vitro;Kentucky;Knock-out;MYCN gene;Malignant Neoplasms;Metabolic;Metabolic Pathway;Metabolism;Neoplasm Metastasis;Neuroblastoma;Organoids;Patients;Pediatric Neoplasm;Primary Neoplasm;Proto-Oncogenes;Role;Solid Neoplasm;Universities;Xenograft Model;Xenograft procedure;angiogenesis;high risk;in vivo;inhibitor;metabolomics;neuroblastoma cell;small molecule;stable isotope;subcutaneous;tumor growth;tumor metabolism;uptake


application_id: 10756950
project_number: 5R01DA053070-04
project_title: Functional and Genomic Signatures of Escalated Fentanyl Use
administering_ic: NIDA
award_notice_date: 2023-12-14
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_abstract:
Project Summary/AbstractMisuse of opioids represents a substantial public and economic burden in the US and worldwide. The existingpharmacological approaches to treatment of opioid use disorder (OUD) are most efficacious when coupled withbehavioral therapies that target individual triggers to reduce or eliminate excessive drug consumption. Whileindividual variability in opioid use have been acknowledged repeatedly in animal behavioral models thegenomic markers linked to neurobiological adaptations underlying such variability are not well understood. Weargue that understanding the molecular background of individual differences in behavioral vulnerability toopioid use is critical for development of personalized pharmacogenomic approaches for OUD that mayreplicate clinical success of personalized cancer treatments. In line with this argument we hypothesize thatindividual behavioral variability in escalation of fentanyl use is linked to systems level variability ofgenomic and functional networks within in the nucleus accumbens and prefrontal cortex. Escalation ofdrug intake is a central component of OUD diagnosis that can be modeled in animals trained to self-administeropioids under extended access conditions. Based on the published literature and preliminary data we proposethree complementary Aims to monitor development of escalated intake at behavioral functionalcellular/network and genomic levels of analysis. Our Aim 1 hypothesizes that escalation of fentanyl intakeemerges on the background of individual differences in sensitivity to non-drug (sucrose) reward. Findingevidence to support this aim has the potential to identify vulnerable individuals prior to initiation of opioid use.Aim 2 examines neuronal outcomes associated with escalated fentanyl intake. Specifically we will evaluatewhether individual profiles of escalated intake reflect altered regulation of cell excitability by four potassiumchannel families and the impact on neuronal output at single cell and network levels. The data collected as partof this aim will establish functional neuronal drivers of vulnerability to escalated intake. Finally Aim 3compares the genomic landscape underlying variable fentanyl escalation in laboratory animals (rats) to humanopioid use databases. In this aim we take advantage of cell-type specific RNA sequencing to evaluate bothneuronal and non-neuronal mechanisms of escalated intake in the nucleus accumbens and prefrontal cortex.This aim is expected to identify novel molecular pathways linked to fentanyl escalation and test thetranslational relevance of our preclinical findings to a human sample. To characterize interactions at thebehavioral functional and genomic levels of analysis a unifying statistical framework is developed based onlinear mixed models to examine the strength of bi-directional relationships between behavioral escalation ofintake and molecular outcomes.

project_terms:
Acceleration;Animal Behavior;Animal Model;Animals;Astrocytes;Awareness;Behavior;Behavior Therapy;Behavioral;Behavioral Model;Biology;Biometry;Brain;Calcium;Calcium Signaling;Cells;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;Opioid Receptor;Outcome;Output;Patch-Clamp Techniques;Pathway interactions;Pattern;Permeability;Persons;Pharmaceutical Preparations;Pharmacogenomics;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;Vulnerable Populations;antagonist;behavioral pharmacology;behavioral phenotyping;big-data science;cancer therapy;cell type;drug abstinence;fentanyl abuse;fentanyl seeking;fentanyl self-administration;fentanyl use;gene product;genomic biomarker;genomic profiles;genomic signature;imaging approach;individual variation;interdisciplinary approach;medication-assisted treatment;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;pharmacologic;pre-clinical;reinforcer;success;synthetic opioid;targeted treatment;transcriptome sequencing;transcriptomics;whole genome

public_health_relevance:
PROJECT NARRATIVEAccording to 2018 data collected by the CDC 128 people die per day from opioid overdose (CDC/NCHS). Thisnumber represents the culmination of a 40% increase in deaths attributed to opioid overdose since 2015despite aggressive public messaging campaigns policies to curb availability of non-prescription opioids andwide-spread awareness of the dangers associated with opioid misuse. This proposal aims to understand howindividual variability for non-drug rewards relates to escalation of fentanyl-seeking and define the neurocircuitryand genomic contributors to these relationships.


application_id: 10756130
project_number: 5R21HL166178-02
project_title: Precise in vivo gene editing of HSPC for the treatment of genetic hematologic diseases
administering_ic: NHLBI
award_notice_date: 2023-12-13
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: HL
serial_number: 166178
program_official: QASBA, PANKAJ
project_start_date: 2023-01-01
project_end_date: 2025-12-31
study_section: Gene and Drug Delivery Systems Study Section[GDD]
contact_pi_person_id: 14341515
contact_pi: TONG, SHENG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryCRISPR/cas9 gene editing has shown great promise for the treatment of genetic hematologicdisorders including sickle cell disease and -thalassemia. Current therapeutic strategies areprimarily focused on ex vivo gene editing of autologous patient-derived hematopoieticstem/progenitor cells (HSPCs) which require isolation of patients HSPCs ex vivo gene editingselection and expansion of corrected HSPCs and transplantation back into the patients.Despite its initial success the clinical translation of this technique is hampered by the difficultiesin ex vivo processing of HSPCs the risks associated with myeloablation the low engraftmentefficiency and the prohibitively high cost of individualized cell therapy. Recent studies haveshown that HSPCs are sustained in specialized niches in the adult bone marrow. HSPC nichesare located near the sinusoidal blood vessels where the fenestrated endothelium is highlypermeable to nanoparticles and viral vectors. To this end we propose that the HSPCs in thebone marrow can be gene-edited by CRISPR/cas9 in situ. However in vivo CRISPR/cas9 geneediting can have substantial off-target effects due to the systemic dissemination of the deliveryvehicles and the non-specific activities of the cas9 nuclease. Recently we developed a novelgene-editing platform that combines the baculoviral vector with magnetic nanoparticles (MNP-BV). Compared with conventional viral vectors the baculoviral vector can transduce a broadrange of mammalian cells without replication. MNP-BV uses an external magnetic field and theintrinsic complement system as the on- and off-switch for site-specific transgene delivery. In thisproject we will develop an MNP-BV-based gene-editing technique for precise gene editing ofHSPCs in the bone marrow. MNP-BV will be administrated via intraosseous infusion. We willdesign a magnetic targeting method to enhance the retention of MNP-BV in the bone marrowand the extravasation of MNP-BV to the perisinusoidal niches. Furthermore the baculoviralvector has a large DNA loading capacity (>38 kb) and thus can deliver inducible cas9 or gRNAexpression cassettes targeting specific cell populations. We will design gRNAs that can only beactivated by microRNAs (miRNAs) highly expressed in HSPCs. The central hypothesis is thatby combining intraosseous infusion magnetic targeting and miRNA-mediated posttranslationalregulation the MNP-BV system can efficiently and precisely transduce HSPCs in the bonemarrow and correct hematological diseases-associated gene mutations. The success of thisproject will pave the way for developing an effective and low-cost cure for a range ofhematological diseases.

project_terms:
Adult;Allogenic;Autologous;Autologous Transplantation;Back;Basic Science;Binding Sites;Blood Vessels;Bone Marrow;Bone Marrow Cells;Bone Marrow Purging;CRISPR/Cas technology;Cell Therapy;Cells;Chromosome Mapping;Clinical Treatment;Clustered Regularly Interspaced Short Palindromic Repeats;DNA;DNA Sequence;DNA Sequence Alteration;DNA cassette;Disease;Endothelium;Engraftment;Extravasation;Face;Femur;Future;Gene Delivery;Gene Mutation;Genes;Genetic;Guide RNA;Hematological Disease;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Hemoglobinopathies;Human;Immunologics;In Situ;Infusion procedures;Insect Viruses;Magnetic nanoparticles;Magnetism;Mammalian Cell;Mediating;Messenger RNA;Methods;MicroRNAs;Mus;Mutation;Myelogenous;Nanotechnology;Patients;Permeability;Population;Post-Translational Regulation;Regulatory Element;Risk;Sickle Cell Anemia;Site;Specificity;System;Techniques;Therapeutic;Toxic effect;Transfection;Translation Initiation;Transplantation;Untranslated RNA;Viral Vector;adaptive immunity;beta Globin;beta Thalassemia;clinical application;clinical translation;complement system;cost;curative treatments;delivery vehicle;design;gene correction;gene editing technology;gene-editing approach;genotoxicity;in vivo;intravenous injection;lipid nanoparticle;mRNA Translation;magnetic field;mouse model;multidisciplinary;nanomedicine;nanoparticle;novel;nuclease;preclinical study;self-renewal;stem cell biology;stem cells;success;synthetic biology;targeted delivery;therapeutic target;tool;transgene delivery;translational potential;vector

public_health_relevance:
Project NarrativeCRISPR/cas9 gene editing has shown great promise for the treatment of genetic hematological diseases. Herewe propose to develop a novel gene editing platform that combines nanotechnology and synthetic biologyapproaches for precise in vivo gene editing of HSPCs in the bone marrow. The success of this project has thepotential to provide an effective and low-cost therapy for hematological diseases.


application_id: 10755288
project_number: 5K23DK128562-03
administering_ic: NIDDK
award_notice_date: 2023-11-21
opportunity_number: PA-20-205
application_type: 5
activity_code: K23
ic: DK
serial_number: 128562
program_official: GREER, RAQUEL CHARLES
project_start_date: 2022-01-01
project_end_date: 2024-08-16
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
budget_start_date: 2023-12-01
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;Chronic;Chronic Disease;Classification;Clinical;Clinical Research;Critical Illness;Data;Death Rate;Development;End stage renal failure;Etiology;Event;Evolution;Frequencies;Functional disorder;Future;Health;Hospitalization;Infection;Inflammatory;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;Tubular formation;Universities;Up-Regulation;Urine;bench to bedside;biobank;career development;clinical care;clinical translation;cohort;college;complex biological systems;improved;metabolome;metabolomics;molecular marker;mouse model;patient oriented research;patient subsets;professor;receptor;receptor expression;regenerative;renal damage;response;skills;translational approach;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: 10754940
project_number: 5R01HL163003-02
project_title: Mechanisms Contributing to Pregnancy-induced Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2023-11-17
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163003
program_official: POIZAT, CORALIE ISABELLE
project_start_date: 2022-12-15
project_end_date: 2027-11-30
study_section: Basic Biology of Blood, Heart and Vasculature Study Section [BBHV]
contact_pi_person_id: 11677367
contact_pi: COLLINS, HELEN 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:
Maternal healthcare in the US continues to rank poorly in comparison to other developed countries. Maternalmortality rates in US have been increasing yearly accounting for 23.8 deaths per 100000 live births in 2020.Cardiovascular complications are the leading cause of death in pregnant and postpartum women; however littleis known regarding the underlying factors leading to this increase which has been hindered by the lack ofknowledge of how the heart responds to normal pregnancy. Despite this it is known that during pregnancy theheart adapts to meet the increased metabolic demands of maternal organs and the growing fetus. Thisadaptation is characterized by reversible cardiac growth and ventricular remodeling which sustain high cardiacoutput during the final trimester of pregnancy. Yet the molecular programs that support the coordinatedremodeling of the maternal heart during and after pregnancy remain unknown. Coordinated changes inmetabolism could be critical to pregnancy-induced cardiac remodeling as suggested by their importance in othercontexts. For example increased cardiac ketone body (KB) metabolism prevents cardiac dysfunction andremodeling in heart failure and changes in glucose metabolism regulate exercise-induced cardiac growth.Nevertheless surprisingly little is known in the context of pregnancy. This knowledge is important because itcould be leveraged to support maternal cardiac health. There is rationale to expect a link between KB metabolismand cardiac remodeling. To wit circulating fatty acids and triglycerides are higher during pregnancy; they supplyenergy to highly metabolic tissues and they are used for liver ketogenesis. Indeed circulating KBs increaseduring late pregnancy in humans and are thought to provide alternative fuel sources for the heart. Furthermoreour data indicate that the KB metabolism enzyme -hydroxybutyrate dehydrogenase 1 (Bdh1) is upregulatedin the heart early in pregnancy followed in late pregnancy by higher levels of circulating KBs and reduced cardiacglucose catabolism. These findings suggest that KB availability and the capacity of the maternal heart to oxidizeKBs are increased during pregnancy. We hypothesize that higher cardiac KB oxidation during pregnancy mayspare glucose-derived carbon for anabolic pathways to increase the abundance of glucose-derived metabolitesthat facilitate cardiac growth. In support of this idea our preliminary studies show increased glucose-derivedcarbon allocation to nucleotides glycerophospholipids and amino acids during pregnancy. In this study we willtest three aims: in Aim 1 we will determine the extent to which KB availability influences cardiac structure andfunction during pregnancy; in Aim 2 we will evaluate the impact of cardiac KB utilization on structural andmetabolic remodeling in the maternal heart; and in Aim 3 we will delineate the influence of KB metabolism onthe reversal of pregnancy-induced cardiac remodeling. Knowledge of how cardiac metabolism contributes topregnancy-induced cardiac growth will provide a framework for developing interventions to support maternalcardiac health.

project_terms:
Accounting;Affect;Amino Acids;Biochemical;Birth;Carbon;Cardiac;Cardiac Myocytes;Cardiac health;Cardiovascular system;Catabolism;Cause of Death;Cessation of life;Contrast Echocardiography;Data;Death Rate;Developed Countries;Echocardiography;Energy Supply;Ensure;Enzymes;Exercise;Extracellular Matrix;Fatty Acids;Fetus;Genetic Transcription;Glucose;Glycerophospholipids;Goals;Growth;Heart;Heart failure;High Cardiac Output;Histologic;Histological Techniques;Human;Hypertrophy;Intervention;Ketone Bodies;Knowledge;Lactation;Late pregnancy;Link;Literature;Live Birth;Liver;Maternal Health Services;Maternal Mortality;Measures;Mechanics;Metabolic;Metabolism;Molecular;Mus;Myocardial;Myocardial dysfunction;Nucleotides;Nutrient;Organ;Oxidoreductase;Oxygen;Pathology;Pathway interactions;Perfusion;Physiological;Physiology;Postpartum Period;Postpartum Women;Pregnancy;Pregnancy Trimesters;Pregnant Women;Radiolabeled;Signal Transduction;Source;Structure;Testing;Tissues;Tracer;Triglycerides;Ventricular;Ventricular Remodeling;Western Blotting;Wit;angiogenesis;beta-Hydroxybutyrate;glucose metabolism;heart dimension/size;heart function;heart metabolism;hemodynamics;in vivo;indexing;ketogenesis;metabolic phenotype;osmotic minipump;overexpression;oxidation;post pregnancy;prevent;programs;stable isotope;transcriptome sequencing

public_health_relevance:
Project NarrativePregnancy promotes remarkable changes in maternal metabolism and physiology. To ensure appropriatedelivery of oxygen and nutrients to the fetus and maternal organs the maternal heart undergoes a physiologicalform of hypertrophy; however the mechanisms that contribute to this adaptive remodeling are unknown. Thisproject will examine how the maternal heart adapts to the demands of pregnancy with the goal of understandinghow changes in cardiac metabolism influence pregnancy-induced cardiac growth as well as reversal of cardiacgrowth following pregnancy.


application_id: 10754284
project_number: 5R25ES027684-07
project_title: Summer Research in Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2023-10-23
opportunity_number: PAR-21-168
application_type: 5
activity_code: R25
ic: ES
serial_number: 027684
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-05-01
project_end_date: 2027-10-31
study_section: ZES1-LKB-S(SR)1
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: PEARSON, KEVIN JOSEPH
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Summer Undergraduate Research in Environmental Health Sciences (SURES) program at the University ofKentucky is designed to introduce students to the highly interdisciplinary and collaborative nature ofenvironmental health science (EHS) research that is focused on solving key global health problems. Anadditional focus is to prepare underprivileged and under-represented students for successful careers in relevantfields. This is a competitive renewal application seeks support to continue our 10-week summer program andsupport fellowships for 10 students. The SURES program leverages the substantial and ongoing efforts at theUniversity of Kentucky driven to enhance the undergraduate research experience with the robust environmentalhealth science research programs of involved faculty mentors. The specific aims are to 1) enhance studentunderstanding and interest in EHS and 2) improve student scientific and career skills. Towards this end studentswill be recruited from the Commonwealth of Kentucky with an emphasis on those from the Appalachian regionas well as from a variety of undergraduate institutions in order to create a cohort of participants representingdiverse populations. The SURES program will commence with a week-long session that introduces students toresearch laboratory safety and scientific ethics. The students will then experience hands-on research byperforming experiments in the laboratories of their chosen mentors. Professional development and a sense ofbelonging to the EHS community will be built via student participation in weekly lunches with EHS researchersand professionals net-working opportunities and tours of research facilities. In addition students will be pairedwith a near-peer mentor and engage in weekly activities that include a citizen science lead collection groupexercise a theatre improvisation workshop community-building circle on mentoring painting their projects andviewing a discussing a film on climate change. Each participant will create an EHS-relevant podcast. TheSURES program will culminate in a campus-wide poster session attended by the faculty staff students andstudent family members. Success of the program is indicated by the engagement of prior participants in careersin university research (13%) industry (16%) government/nonprofits (11%) and pursuing graduate (16%)/professional (37%) education. Dissemination of the approaches used in this program and their outcomes willbuild upon the expansion of the traditional environmental health sciences research training from the graduateand post-doctoral level to the undergraduates at a national level.

project_terms:
Address;Affect;Appalachian Region;Area;Collection;Communities;Critical Thinking;Development;Doctor's Degree;Economics;Education;Educational workshop;Elevator;Engineering;Environment;Environmental Exposure;Environmental Health;Environmental Science;Ethics;Evaluation;Exercise;Faculty;Family member;Fellowship;Film;Funding;Future;Goals;Government;Health Professional;Individual;Industry;Institution;Interview;Kentucky;Laboratories;Lead;Life;Measures;Mentors;Mission;National Institute of Environmental Health Sciences;Nature;Oral;Outcome;Paint;Participant;Personal Satisfaction;Persons;Play;Population Heterogeneity;Positioning Attribute;Postdoctoral Fellow;Poverty Areas;Professional Competence;Publications;Questionnaires;Reporting;Research;Research Personnel;Research Project Grants;Research Training;Role;STEM field;Safety;Science;Scientist;Speech;Students;Surveys;Technology;Training;Training Programs;Underrepresented Students;United States;Universities;Work;career;citizen science;climate change;cohort;college;community building;design;experience;experimental study;faculty mentor;global health;hands on research;health science research;improved;interest;member;multidisciplinary;novel;outreach;patient engagement;peer;peer coaching;podcast;posters;programs;recruit;research facility;skills;social;student mentoring;student participation;student retention;success;summer program;summer research;supportive environment;undergraduate education;undergraduate research;undergraduate research experience;undergraduate student

public_health_relevance:
NARRATIVEThe overall objective of the Summer Undergraduate Research Experience in EnvironmentalHealth Sciences (SURES) program is to use a research-intensive approach for introducingstudents from the impoverished region of Appalachia to the multidisciplinary nature ofenvironmental sciences and opportunities for pursuing relevant careers. Exceptional training ina wide variety of research areas working with interdisciplinary collaborative research groupswho are housed in multiple departments and colleges is provided. In addition seminarsoutreach opportunities and interactive workshops are designed to prepare students forsuccessful environmental health related careers.


application_id: 10754268
project_number: 5R01HL166225-02
project_title: Targeting smooth muscle cell BMAL1 as a new therapeutic strategy against restenosis
administering_ic: NHLBI
award_notice_date: 2023-12-14
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 166225
program_official: FLEG, JEROME L
project_start_date: 2023-01-01
project_end_date: 2026-12-31
study_section: Integrative Vascular Physiology and Pathology Study Section[IVPP]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: GONG, MING C
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractCoronary heart disease (CHD) is the single leading cause of death in the United States. Coronaryrevascularization including coronary artery bypass graft and percutaneous coronary intervention is the mostcommon modality in patients with CHD. However it is often associated with a high incidence of restenosis.Although the rate of restenosis is reduced significantly by using bare-metal stent (BMS) and particularly withdrug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stentthrombosis with DES has been encountered as a major significant gap in the field. The current applicationproposes to bridge this gap and specifically investigates the role of the smooth muscle cell (SMC) BMAL1 inneointimal hyperplasia in mouse models of arterial injury. BMAL1 is a core molecular component of thecircadian clock. It has long been believed that loss of function of BMAL1 is detrimental to well-being. Howeverthis dogma was challenged by our recent report that genetic deletion of Bmal1 in SMCs (SM-Bmal1-KO)protects mice from aldosterone or angiotensin II-induced abdominal aortic aneurysm. Consistent with thisfinding our preliminary demonstrate that SMC-specific Bmal1 deletion also protects mice femoral artery wireinjury- or carotid artery ligation-induced neointimal hyperplasia. While the underlying mechanism remainselusive our preliminary data reveal arachidonic acid metabolism is most significantly affected by SMC-specificBmal1 deletion. Interestingly among enzymes implicated in arachidonic acid metabolism cytosolicphospholipase A2 alpha (cPLA2) is most downregulated by SMC-specific Bmal1 deletion. Mechanistically ourpreliminary data illustrate that BMAL1 binds to the mouse cPLA2 promoter and SMC BMAL1 is required forvascular injury-induced cPLA2 upregulation in neointima. Given the potential role of cPLA2 in VSMCproliferation and neointimal hyperplasia we hypothesize that upregulation of BMAL1 in SMCs by vascularinjury promotes cPLA2 expression thus mediating the initiation and progression of neointimal hyperplasia andsignificantly contributing to the development of restenosis after coronary revascularization. Aim 1 will test thehypothesis that upregulation of SMC BMAL1 by vascular injury is critical for the onset and progression ofneointimal hyperplasia. Aim 2 will define the mechanism by which SMC BMAL1 regulates cPLA2 and therebymediates vascular injury-induced neointimal hyperplasia. To achieve the goals SM-Bmal1-KO SM-cPLA2-KO and SM-Bmal1/cPLA2-KO mice will be subjected to femoral artery wire injury or carotid artery ligation toinduce neointimal hyperplasia and to determine the mechanism by which SMC BMAL1 and cPLA2 mediatevascular injury-induced neointimal hyperplasia. Results from the proposed studies will provide new mechanisticinsight on how SMC BMAL1 mediates vascular injury-induced neointimal hyperplasia via cPLA2. Moreoverresults from the proposed studies will provide preclinical evidence that inhibiting the BMAL1/cPLA2 signalingat the lesion site is a new therapeutic strategy against restenosis after coronary revascularization.

project_terms:
ARNTL gene;Abdominal Aortic Aneurysm;Adopted;Affect;Aging;Aldosterone;Alzheimer's Disease;American;Angiotensin II;Arachidonic Acids;Arterial Injury;Atherosclerosis;Binding;Biological Assay;Carotid Arteries;Cause of Death;Cell Proliferation;Cells;Clinical Research;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Cytosolic Phospholipase A2;Data;Development;Diabetes Mellitus;Endothelial Cells;Enzymes;Female;Genetic;Genetic Transcription;Goals;Hyperplasia;Hypertension;Immune response;Incidence;Injury;Knockout Mice;Lesion;Ligation;Malignant Neoplasms;Mediating;Messenger RNA;Metabolism;Metals;Modality;Molecular;Mus;Pathway Analysis;Patients;Personal Satisfaction;Pharmaceutical Preparations;Platelet-Derived Growth Factor;Proliferating;Reporting;Risk;Role;Scheme;Signal Transduction;Site;Sleep;Smooth Muscle Myocytes;Stents;Testing;Thrombosis;Time;United States;Up-Regulation;Vascular Smooth Muscle;Vascular remodeling;Woman;chromatin immunoprecipitation;circadian pacemaker;cost;femoral artery;insight;loss of function;male;men;mouse model;new therapeutic target;novel therapeutic intervention;novel therapeutics;overexpression;percutaneous coronary intervention;pleiotropism;pre-clinical;promoter;restenosis;revascularization;stent thrombosis;transcription factor;transcriptome sequencing;vascular inflammation;vascular injury

public_health_relevance:
Project narrativeCoronary revascularization (i.e. stent placement) has been adopted worldwide and is the most commonmodality in patients with coronary heart diseases in the United States. However it is also among the mostcostly and is often associated with a high incidence of restenosis (repeat narrowing of a coronary artery). Thisapplication aims to elucidate the mechanisms responsible for restenosis and thus identify new therapeutictargets to develop new drugs to treat restenosis after coronary revascularization.


application_id: 10754252
project_number: 5K08DK124566-04
project_title: Muscle bone interaction and its role in diabetic bone disease of Type I diabetes
administering_ic: NIDDK
award_notice_date: 2023-12-19
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_abstract:
Summary Bone fracture incidence observed in individuals with Type 1 diabetes (T1D) is much higher compared tothe general population. The burden of diabetic bone disease is partially due to lack of evidence to supporttargeted prevention and interventions to reduce fractures in this population. Furthermore those with T1Dexhibit skeletal muscle dysfunction associated with decreased muscle strength and muscle mass. Skeletalmuscle and bone communication is a potential modifiable factor that may contribute to development of diabeticmusculoskeletal disease. More specifically the candidate proposes that a myokine called myostatin is directlyinvolved in development of diabetic bone disease and may associate with skeletal muscle dysfunction. Therole of myostatin in T1D and how it affects the musculoskeletal system in this disease are gaps in knowledgethat will be addressed with this proposal. Specifically the three aims of this proposal are: 1. Quantify therelationship between myostatin levels in serum and skeletal muscle and bone parameters of humans with andwithout T1D; 2. Quantify the relationship between myostatin levels in serum and muscle and the bonephenotype of mice with insulin-deficient diabetes; 3. Evaluate whether inhibition of myostatin is beneficial forprevention of DBD in insulin-deficient diabetes; and lastly 4: Determine the mechanism of action of myostatinon osteoblastic bone cells under normoglycemic and hyperglycemic conditions. Myostatin which is thought tonegatively affect both bone and skeletal muscle may serve both as a marker of musculoskeletal function andsurrogate for risk for fracture in those with T1D. Additionally it may offer an opportunity for targetedintervention to prevent or improve musculoskeletal dysfunction associated with T1D. The knowledge gainedfrom these studies will set the ground for future studies in musculoskeletal health in diabetes and will offer thecandidate an opportunity to transition towards an independent career in the abovementioned field. This proposal presents a five-year research career development program focused on the study ofmuscle and bone interactions in Type 1 diabetes; and specifically how muscle derived molecules calledmyokines contribute to diabetic bone disease a serious and emerging complication of Type 1 diabetes. Thecandidate currently holds a position as an Assistant Professor of Pediatrics in the Division of PediatricEndocrinology at the University of Kentucky. She has 75% protected time for research independent officespace laboratory space and access to all equipment and resources offered by the Barnstable Brown DiabetesCenter. The candidate is strongly committed to an academic career in the field of musculoskeletal research indiabetes and is supported by her mentors and her department. The proposed study and the complementarydidactic work will provide the candidate with research skills in basic translational and clinical research therebyenabling to transition to an independent clinician scientist.

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;Incidental Findings;Individual;Insulin deficiency;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Knowledge;Laboratories;Life;MAP Kinase Gene;Measures;Mechanics;Mediating;Mediator;Mentors;Mus;Muscle;Muscle function;Musculoskeletal;Musculoskeletal Diseases;Musculoskeletal System;Nurses' Health Study;Osteoblasts;Osteocalcin;Osteocytes;Osteogenesis;Outcome;Pathway interactions;Pediatrics;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;novel;osteoblast differentiation;paracrine;pharmacologic;prevent;professor;prospective;receptor;reduced muscle mass;reduced muscle strength;skills;young adult

public_health_relevance:
Project NarrativeIndividuals with Type 1 diabetes have higher fracture rates and smaller and weaker muscles compared tothose without diabetes even in young ages. With this project we will try to identify whether a molecule thatcomes from skeletal muscle called myostatin is involved in the increased risk of fractures and the poor qualityof skeletal muscle in young individuals with Type 1 diabetes.


application_id: 10753949
project_number: 3P20GM135004-04S1
project_title: Center for Cancer Immunology and Immunotherapy (CCII)
administering_ic: NIGMS
award_notice_date: 2023-01-31
opportunity_number: PAR-18-266
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
study_section: ZGM1-RCB-4(C1)
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
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:
The objective of this program is to establish a thematic multidisciplinary research center of excellence at theUniversity of Louisville (UofL) named the Center for Cancer Immunology and Immunotherapy (CCII). Themission of the CCII is to conduct outstanding biomedical research that works towards harnessing the power ofthe immune system to eradicate cancer. There is currently a great deal of optimism about the prospects forcancer immunotherapies given the recent clinical successes of immune checkpoint inhibitors oncolytic virusesand adoptive cell transfer therapies. Immunotherapies have the potential to be used to treat all types of cancerand to induce long-lasting remissions or cures. However more research and development is needed forcancer immunotherapy to reach its full potential. The University of Louisville is exceptionally qualified to be thehome of the CCII for many reasons including our 10-year track record of conducting clinical trials ofimmunotherapeutic agents unique resources that include access to human specimens from these trials oursenior investigators expertise in cancer immunology our focus on translational research and the impact thatthis COBRE would have in a state with the highest cancer death rates in the nation. Importantly the Universityof Louisville is highly invested in making this proposed center a success as best evidenced by more than$16.8M in institutional commitments over five years. The two PIs of the CCII program are highly regardedexperts in the field who have made seminal contributions spanning from basic cancer immunology to pivotalclinical trials of cancer immunotherapies. Senior mentors with expertise in the thematic area and a stronghistory of funding publications mentoring and study section service will support the CCIIs mentoring missionas will a team of co-investigators with essential expertise (in administration biostatistics and bioinformatics)and Internal and External Advisory Committees. A Functional Immunomics Core will provide important newinfrastructure and leverage existing resources (including other IDeA programs) to provide outstanding supportto the four promising junior investigators who have been selected as the first cohort of CCII Project PIs. Thefour overall specific aims of the CCII are to: (1) Establish the administrative and mentoring infrastructure for theCCII; (2) Create a research core that provides new capabilities while leveraging existing facilities; (3) Supportthe research and career development of junior PIs in the thematic area; and (4) Develop and initiate a plan forlong-term sustainability and growth of the CCII. We are confident that this new COBRE center will lead to theawarding of innovative R01 grants for 4-6 CCII junior investigators in the first five years and that many of thesegraduates will remain key members of this new COBRE to further build the center in the future. Mostimportantly our combination of rigorous basic science with highly translational animal and human specimenstudies should ultimately contribute to the development of new treatment strategies that will help to improve theoutlook for the more than 17 million people worldwide who are diagnosed with cancer each year.

project_terms:
Adoptive Cell Transfers;Advanced Malignant Neoplasm;Advisory Committees;Animals;Antibodies;Area;Award;Basic Science;Bioinformatics;Biological Markers;Biomedical Research;Biometry;Bladder;CAR T cell therapy;CTLA4 gene;Cancer Center;Cancer Death Rates;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Conduct Clinical Trials;Country;Cytometry;Development;Diagnosis;Discipline;Disease remission;Disseminated Malignant Neoplasm;Early Diagnosis;Financial Support;Flow Cytometry;Funding;Future;Genomics;Goals;Grant;Growth;Head and neck structure;Home;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunologic Surveillance;Immunologist;Immunotherapeutic agent;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;International;Investments;Kidney;Lung;Malignant Neoplasms;Mediating;Mentors;Mission;Molecular;Mus;Names;Oncolytic viruses;Outcome;Paper;Patients;Personnel Selection;Persons;Phase;Pilot Projects;Proteins;Publications;Qualifying;Recording of previous events;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Sampling;Seminal;Services;Specimen;Study Section;T cell therapy;Talents;Testing;Training;Translating;Translational Research;Tumor Immunity;Universities;Vaccines;Work;anti-cancer;cancer cell;cancer clinical trial;cancer immunotherapy;cancer therapy;cancer type;career development;checkpoint therapy;chimeric antigen receptor T cells;cohort;equipment acquisition;immune checkpoint;improved;innovation;interest;melanoma;member;microbiome research;new therapeutic target;novel strategies;novel therapeutic intervention;optimism;programmed cell death ligand 1;programmed cell death protein 1;programs;recruit;research and development;response;senior faculty;side effect;statistics;success;systemic toxicity;treatment strategy;tumor;tumor immunology

public_health_relevance:
Decades of research have demonstrated that the immune system can eradicate cancer cells but only if immuneevasion mechanisms such as immune checkpoint proteins can be overcome. Multiple new immunotherapeuticapproaches have recently been developed that can induce durable remissions in patients with advanced cancers unfortunately the majority of patients still succumb to their cancers. The goal of this COBRE application is toestablish a new Center for Cancer Immunology and Immunotherapy that will focus on understanding immuneescape mechanisms developing new approaches to activate/reinvigorate anticancer immunity trainingpromising young cancer immunologists and improving the research infrastructure of the University of Louisville.


application_id: 10753729
project_number: 1R21AA031172-01
project_title: Cannabidiol as a treatment for alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2023-08-25
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AA
serial_number: 031172
program_official: WANG, JOE
project_start_date: 2023-09-01
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZAA1 GG (01)]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: FENG, WENKE
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:
ANSTRACT Cannabidiol (CBD) is the major non-psychoactive cannabinoid in cannabis. Recently US FDA hasapproved Epidiolex an oral CBD formulation for the treatment of two forms of pediatric epileptic syndromes. Inaddition CBD is currently in clinical trials for a variety of diseases. Two recent studies have demonstrated thatintraperitoneal injection of CBD to mice in a binge-on-chronic alcoholic liver disease (ALD) model alleviatedliver steatosis metabolic dysregulation oxidative stress inflammation and neutrophil-mediated injuryindicating CBD has protective potentials against ALD. However it is unknown if CBD can be administeredorally to achieve its protective effects against ALD and if CBD has therapeutic in addition to its preventivepotentials against ALD. Furthermore intestinal mechanisms underlying the protective effects of CBD againstALD is unknown. GPR3 is an orphan G protein-coupled receptor (GPCR) recently identified by us to be a novel CBDreceptor. In preliminary studies we found that GPR3 is upregulated in the ileum of mice fed with alcohol.Furthermore our preliminary data demonstrated that CBD enhanced the level of claudin-1 and significantlyinhibited alcohol-induced barrier dysfunction in intestinal epithelial Caco-2 cells. These preliminary datasuggest that by acting on GPR3 CBD may restore the intestinal barrier function disrupted in ALD. Arylhydrocarbon receptor (AhR) is a ligand-activated nuclear receptor expressed in intestinal type 3 innatelymphoid cells (ILC3). Recent studies by us and others have demonstrated that AhR ligands such astryptophan metabolites from beneficial bacteria protect against ALD in mouse models through the intestinalAhR-IL22-Reg3 pathway. Interestingly recent reports have identified CBD as a ligand for AhR with therapeuticpotentials. These previous studies imply that CBD may exert its protective effects against ALD throughintestine AhR to ameliorate intestinal barrier dysfunction and gut dysbiosis. Previous literature and our preliminary studies provide the foundation for our central hypothesis for thisR21 project: oral CBD treatment has preventive and therapeutic potential against ALD through intestinalGPR3- and/or AhR-mediated restoration of gut barrier function and eubiosis. Two aims are designed to test ourhypothesis: (1) To investigate the potential therapeutic effects of oral CBD against alcohol-induced gutmicrobiota dysbiosis intestinal barrier dysfunction and liver injury. We will use a chronic alcohol feedingmouse model in this aim. (2) To explore the potential GPR3- and AhR-mediated mechanisms underlying theeffects of oral CBD against alcohol-induced intestine and liver injury. We will use both GPR3 knockout miceand intestinal ILC3 specific AhR knockout mice to test our hypothesis. Completion of this study is expected tosignificantly impact the development of oral CBD in the treatment of alcohol-associated liver diseases.

project_terms:
Acute;Address;Agonist;Alcoholic Liver Diseases;Alcohols;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Caco-2 Cells;Cannabidiol;Cannabinoids;Cannabis;Cells;Childhood;Chronic;Clinical Trials;Data;Development;Disease;Disease model;Dose;Endotoxemia;Epidiolex;Epilepsy;Epithelial Attachment;Fatty Liver;Formulation;Foundations;Functional disorder;G-Protein-Coupled Receptors;GPR3 gene;Hepatic;Immune;Immunologic Surveillance;Inflammation;Injury;Intestines;Intraperitoneal Injections;Knockout Mice;Kupffer Cells;Ligands;Literature;Lymphoid Cell;Mediating;Metabolic;Modeling;Mucous Membrane;Mus;Nuclear Receptors;Oils;Oral;Oral Administration;Orphan;Outcome Study;Oxidative Stress;Pathway interactions;Patients;Preventive;Proteins;Refractory;Reporting;Research;Route;Syndrome;Testing;Therapeutic;Therapeutic Effect;Tight Junctions;Tryptophan;United States;United States Food and Drug Administration;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;beta-arrestin;chronic liver disease;claudin-1 protein;design;dysbiosis;feeding;gut dysbiosis;gut microbiota;ileum;interleukin-22;intestinal barrier;intestinal epithelium;intestinal injury;liver injury;mouse model;neutrophil;novel;oral supplementation;pre-clinical;protective effect;receptor;recruit;restoration

public_health_relevance:
NARRATIVE Cannabidiol (CBD) is the major non-psychoactive cannabinoid in cannabis. We will study the potentials andmechanisms of oral CBD in treating alcoholic liver disease (ALD). Completion of this study will help to developa new treatment of ALD using CBD which is generally safe to use and has already been approved by US FDAfor other indications.


application_id: 10752509
project_number: 1R13HL170691-01
project_title: Don S. Fredrickson Lipid Research Conference
administering_ic: NHLBI
award_notice_date: 2023-08-01
opportunity_number: PA-21-151
application_type: 1
activity_code: R13
ic: HL
serial_number: 170691
program_official: LIU, LIJUAN
project_start_date: 2023-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZHL1 CSR-B (M2)]
contact_pi_person_id: 8553632
contact_pi: GRAF, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe Don S. Fredrickson Lipid Research Conference (FLRC) brings together scientists andtrainees investigating the impact of lipid and lipoprotein metabolism on the development andtreatment of Cardiometabolic Disease. The FLRC is named after the late Don S. Fredricks whoas the director of the National Heart Institute (now the NHLBI) from 1966  1974 and later theNIH developed the clinical classification for dyslipidemias (Type I-V) described Tangier'sDisease and made seminal discoveries in lipoprotein metabolism. Most importantly he trainedboth basic and clinical scientists and practitioners who have had a tremendous impact on thefield of lipoprotein metabolism.Since 2016 the FLRC has employed a rotating institutional host model and has been hosted bythe University of Kentucky ('16 `17 '21) Vanderbilt University ('18 `23) the University ofCincinnati ('19) Duke University and the University of North Carolina ('22). The FLRC will behosted by the Medical College of Wisconsin in 2024 and return to UK in 2025.Keynote Lectures at the 2023 Fredrickson conference include Barbara Kahn Harvard Universityand Alan Remaley National Heart Lung and Blood Institute. The thematic scientific sessionsinclude: Intestinal Microbiome Control of Lipid Metabolism Stable Isotope Studies in LipidMetabolism Atherosclerosis Regression and Efferocytosis Modulators of TriglycerideMetabolism & Lipoprotein Lipase. The FLRC places a strong emphasis students and fellowsearly career faculty and underrepresented groups. In accordance with that mission the agendaalso includes additional scientific sessions dedicated for trainees a Poster Pitch session (5-790-second presentations) and a judged poster session. By design the agenda affords everytrainee in attendance the opportunity to present their research on stage network with leaders inthe field and broaden their scope and understanding of research in lipid metabolism andCardiometabolic Diseases.Our format encourages informal interactions between scientists at all levels providing aninnovative approach to the exchange of ideas and synthesis that will move the field of lipidresearch forward. The conference will have high impact as the program spans basic sciencediscovery to clinical significance. It is therefore expected that the meeting will provide newinsights not only into basic aspects of lipid metabolism but also how to treat and ultimatelycure a wide variety of Cardiometabolic Disease states.

project_terms:
Address;Adipose tissue;Atherosclerosis;Award;Basic Science;Cardiometabolic Disease;Cardiovascular Diseases;Classification;Clinical;Clinical Investigator;Collaborations;Dedications;Development;Diabetes Mellitus;Doctor of Philosophy;Dyslipidemias;Ensure;Esters;Faculty;Fatty Acids;Fostering;Goals;Heart;Hypertension;Hypertriglyceridemia;Institution;Insulin Resistance;Kentucky;Lipase;Lipids;Lipoproteins;Metabolic Diseases;Metabolic syndrome;Metabolism;Midwestern United States;Mission;Modeling;Names;National Heart Lung and Blood Institute;North Carolina;Obesity;Oral;Participant;Regulation;Research;Research Activity;Research Personnel;Research Project Grants;Role;Rotation;Science;Scientist;Seminal;Senior Scientist;Students;Talents;Tangier Disease;Technology;Thinking;Training;Triglyceride Metabolism;Underrepresented Populations;United States National Institutes of Health;Universities;Wisconsin;cardiovascular risk factor;career;career development;clinically significant;design;early-career faculty;experience;gut microbiome;hydroxy fatty acid;innovation;insight;lectures;lipid metabolism;lipoprotein lipase;medical schools;meetings;new technology;novel strategies;posters;programs;relative cost;social;social engagement;stable isotope;symposium;translational scientist

public_health_relevance:
Project NarrativeThe Don S. Fredrickson Lipid Research Conference is an annual meeting held since 1992 that bringstogether scientists in the field of lipid and lipoprotein metabolism and their impact on cardiovascularand metabolic disease. Its goal is to provide a venue for senior scientists early career investigatorsand trainees to share cutting-edge science; encourage new lines of thinking experimentation andcollaboration; and the opportunity for host institutions to showcase their research activity to have agreater impact in the advancement of our understanding and treatment of cardiometabolic disease.


application_id: 10750181
project_number: 1F31AI178999-01
project_title: Defining the impact of Extracellular Vesicles on inflammation during pneumonic plague
administering_ic: NIAID
award_notice_date: 2023-07-07
opportunity_number: PA-21-052
application_type: 1
activity_code: F31
ic: AI
serial_number: 178999
program_official: ADGER-JOHNSON, DIANE S
project_start_date: 2023-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1 F07A-B (20)]
contact_pi_person_id: 77802022
contact_pi: SHENEMAN, KATELYN RENEE
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTDuring infection immune cells rely on communication to productively target and eliminate invading pathogens.Extracellular vesicles (EVs) are one key mediator of intercellular communication between immune cells. Thesemembrane-bound vesicles contain proteins lipids and nucleic acids that represent the inflammatory state of agiven cell. Upon release these EVs can fuse with other immune cells establishing biochemical communicationbetween cells and amplifying the inflammatory response to augment pathogen clearance. Yersinia pestis is theetiologic agent of the human disease known as plague. A hallmark of this disease is the sophisticatedsuppression of the host immune system in a biphasic manner. During acute infection Y. pestis utilizes its type 3secretion system (T3SS) to inject effector proteins into host cells which disrupt signaling pathways essential forbacterial clearance. Thus acute infection is hallmarked by the maintenance of a non-inflammatory environmentin which the bacteria can proliferate without host intervention. The second stage of infection the pro-inflammatory phase begins 36-48 hours post-infection in which the host begins to successfully mount animmune response against the pathogen. However the bacterial load ultimately overwhelms the host delayedresponses at which point the host may succumb to infection. Previous work has demonstrated that thegeneration of this non-inflammatory environment during acute infection is essential for Y. pestis virulence. Whilenumerous studies have highlighted the importance of suppressing phagocytosis exocytosis and otherantibacterial responses there is a gap in knowledge of how Y. pestis manipulates the EV response and how thisimpacts intercellular communication. Preliminary studies suggest that Y. pestis can manipulate the proteinspackaged into EVs by neutrophils in vitro. These data support the hypothesis that Y. pestis disrupts EVsproduction during infection to alter inflammation. The studies presented here will expand on our preliminary databy delineating the in vivo EV response during pneumonic plague (Aim 1) and defining the impact of EVs onimmune modulation (Aim 2). These studies will be the first to investigate the role of EV-mediated intracellularcommunication during plague. Therefore completion of these aims will significantly improve our understandingof how. Y. pestis exploits EV trafficking to manipulate the host immune response.

project_terms:
Antibacterial Response;Bacteria;Bacterial Infections;Binding;Biochemical;Cells;Communication;Data;Dependence;Development;Disease;Disease Progression;Endocytosis Inhibition;Environment;Etiology;Exocytosis;Generations;Goals;Hour;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Intervention;Invaded;Knowledge;Lipids;Lung;Lung infections;Maintenance;Mediating;Mediator;Membrane;Neutrophil Infiltration;Nucleic Acids;Organism;Outcome;Pathogenesis;Pathway interactions;Phagocytes;Phagocytosis;Phase;Plague;Play;Pneumonic Plague;Population;Production;Productivity;Proliferating;Protein Secretion;Proteins;Pulmonary Inflammation;Role;Signal Pathway;Testing;Time;Tissues;Type III Secretion System Pathway;Vesicle;Virulence;Work;Yersinia pestis;acute infection;antimicrobial;cell type;cytokine;extracellular vesicles;human disease;immunoregulation;improved;in vivo;intercellular communication;mutant;neutrophil;new therapeutic target;pathogen;response;tool;trafficking

public_health_relevance:
PROJECT NARRATIVEYersinia pestis the etiologic agent of the plague has refined mechanisms to manipulate the host immuneresponse and suppress inflammation. This project will define the impact of disrupting extracellular vesicletrafficking and illustrate how this manipulation contributes to disease pathogenesis. Understanding thesemechanisms of immune subversion is essential for the development of novel targeted therapeutics.


application_id: 10750132
project_number: 1F31HL170972-01
administering_ic: NHLBI
award_notice_date: 2023-08-18
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: HL
serial_number: 170972
program_official: HUANG, LI-SHIN
project_start_date: 2024-01-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZDK1 GRB-2 (M1)]
contact_pi_person_id: 78710593
contact_pi: KIPP, ZACHARY A
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-01-01
project_title:
Bilirubin Catabolism induces Plasminogen-Activator Inhibitor 1 (PAI-1) worsening Metabolic Dysfunction

project_abstract:
Summary:Urobilin is formed in the intestine as a biproduct of conjugated bilirubin catabolism. Currently the physiologicalfunction of urobilin is unknown. Human association studies have indicated a positive correlation to obesity andcardiovascular diseases (CVD). Since obesity is a major risk factor for the development of CVD we hypothesizedthat urobilin levels might change with the altered metabolic state and induce adiposity. To determine the role ofurobilin in lean mice we treated C57/bl6 mice on a normal-chow diet with urobilin for 4 weeks. We found thaturobilin had no effect on body weight but significantly increased adiposity in the inguinal white adipose tissue(iWAT) depot compared to the vehicle-treated mice. To determine how urobilin changes the transcriptome profilein the iWAT we preformed RNA-sequencing which showed that urobilin increases the expression of Serpine1mRNA. Serpine1 is translated into the protein plasminogen activator inhibitor-1 (PAI-1). PAI-1 is secreted intocirculation promoting a prothrombotic environment and is thought to increase the risk of CVD. The goal of thisresearch proposal is to determine whether urobilin induces CVD via PAI-1 and if this mechanism is a link betweenCVD and obesity. We will investigate if lowering plasma urobilin is a possible therapeutic for the treatment andprevention of CVD. To study this in Aim 1 we will use PAI-1 knockout (KO) mice and littermate controls treatedwith urobilin or vehicle while on a high-fat or calorie-match low-fat diets. We expect the PAI-1KO mice will beprotected from urobilin induced CVD. In Aim 2 we will use diet-induced obese (DIO) mice treated with a liver-specific GalNac-Ugt1a1-RNAi or GalNac-scramble control to suppress hepatic Ugt1a1 which is responsible forinitiating the conjugation of bilirubin that leads to elevated urobilin production. We show preliminary data that theRNAi technology suppresses Ugt1a1 94.7% and that this leads to a significant (p<0.01) decrease in plasmaurobilin and an increase in plasma unconjugated bilirubin. We expect that the suppression of Ugt1a1 will protectthe mice from the development of CVD by lowering urobilin levels increasing unconjugated bilirubin preventingadiposity and high PAI-1 plasma levels. This is the first proposed mechanism of urobilin in promoting thedevelopment of CVD which we will extensively study to better understand how to reverse its deleterious effects.This fellowship will provided critical training in research techniques scientific training and professionaldevelopment to give me the tools to become a successful independent scientist.

project_terms:
Adipose tissue;Affect;Antioxidants;Arterial Fatty Streak;Bilirubin;Binding;Blood Pressure;Blood Vessels;Body Weight;Calories;Cardiovascular Diseases;Cardiovascular system;Catabolism;Cause of Death;Cessation of life;Cholesterol;Circulation;Coagulation Process;Data;Development;Diet;Environment;Enzymes;Excretory function;Fat-Restricted Diet;Fatty acid glycerol esters;Fellowship;Fibrosis;Financial Hardship;Foundations;Future;Generations;Genetic Polymorphism;Gilbert Disease;Glucuronic Acids;Goals;Healthcare Systems;Heart;Heart Diseases;Heart failure;Heme;Hepatic;High Fat Diet;Hormonal;Human;Intestines;Knock-out;Knockout Mice;Lead;Link;Liver;Measures;Mediator;Messenger RNA;Metabolic;Metabolic Diseases;Metabolic dysfunction;Mus;Nuclear Receptors;Obese Mice;Obesity;PPAR alpha;Pathway interactions;Patients;Physiological;Plasma;Plasminogen Activator Inhibitor 1;Portal System;Prevention;Production;Proteins;RNA Interference;Research;Research Proposals;Research Technics;Risk;Risk Factors;Role;Scientist;Serum;Structure;Technology;Testing;Therapeutic;Thinness;Training;Translating;Travel;UGT1A1 gene;United States;Water;Woman;Work;absorption;bile duct;cardioprotection;cardiovascular disorder prevention;cardiovascular disorder risk;career;comorbidity;diet-induced obesity;feeding;glucose tolerance;gut microbiota;improved;men;mouse development;new therapeutic target;novel marker;novel therapeutics;obese patients;prevent;promoter;therapeutic target;tool;transcriptome;transcriptome sequencing

public_health_relevance:
Project Narrative:The work proposed in this fellowship has the potential to uncover a possible link between obesityand the development of cardiovascular disease. This research could lead to the discovery of anovel biomarker and a possible therapeutic target for the prevention and treatment ofcardiovascular disease.


application_id: 10749910
project_number: 5R13AG081016-02
project_title: Dysphagia: In Search of a Unified Definition for the Aging Population
administering_ic: NIA
award_notice_date: 2023-11-16
opportunity_number: PA-21-151
application_type: 5
activity_code: R13
ic: AG
serial_number: 081016
program_official: SALIVE, MARCEL
project_start_date: 2022-12-15
project_end_date: 2024-11-30
study_section: Career Development for Established Investigators and Conference Grants Study Section[AGCD-4]
contact_pi_person_id: 9259461
contact_pi: SUITER, DEBRA M
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract. Dysphagia is a significant health problem associated with aging contributing to hospitalization formalnutrition dehydration frailty falls and pneumonia. By 2030 the US elderly population is anticipated toexceed 72 million with over 12 million of these individuals considered to be experiencing swallowing difficulties.Despite the high incidence and prevalence of dysphagia particularly in the adult aging population there is nouniform definition of adult dysphagia. Instead heterogenous definitions in the extant literature pave the way forambiguity and philosophical differences among dysphagia experts and other key stakeholders. Establishing anaccepted and cogent definition for dysphagia is a critical step in quantifying the exact magnitude of disease ina specific population and assuring accuracy and consistency across healthcare settings researchers thirdparty payers and other key stakeholders. The goal of this proposal is to convene two multidisciplinaryconferences to develop and derive a cohesive definition for dysphagia in the aged population. This applicationis to request support for the Dysphagia: In Search of a Unified Definition for the Aging Population conference.This unique multidisciplinary endeavor will leverage experts from numerous specialty areas includinggerontology critical care otolaryngology gastroenterology pulmonology bioengineering nursing nutritionand speech-language pathology to converge and through evidence-based synthesis and discussion agreeupon an accepted definition for dysphagia across the domains of screening diagnosis treatmentmanagement and ongoing care. The specific aims of this conference are to engage experts and keystakeholders who work with older adults with dysphagia and to collaborate and develop a consensus validationfor a unified definition of dysphagia and guidelines that can be applied for use in clinical patient populationspublic health and policy. This work is imperative and long overdue given the continued greying of Americaand that the majority of the literature in swallowing and swallowing disorders is <40 years old. The culminationof this project will result in data driven consensus statement for evaluation replication and/or endorsement byinternational institutions. The resulting definition and guideline will also be employed to develop a multi-siteclinical study (R01) incorporating this new definition to promote best care and test adherence and codingaccuracy within the medical record. This work will provide uniformity in the literature and throughout thehealthcare landscape driving informed decision making diagnostic accuracy targeted treatment andearly prevention of dysphagia in aged persons to reduce the burden of complications and in turnhealth care cost.

project_terms:
Address;Adherence;Adult;Advocacy;Affect;Aging;Agreement;American;Area;Automobile Driving;Award;Biomedical Engineering;Caregivers;Caring;Childhood;Clinical;Code;Collaborations;Communication;Communities;Consensus;Critical Care;Data;Decision Making;Dedications;Deglutition;Deglutition Disorders;Dehydration;Diagnosis;Discipline;Discipline of Nursing;Disease;Elderly;Etiology;Evaluation;Family;Fostering;Funding;Gastroenterology;Gerontology;Goals;Government Officials;Guidelines;Health;Health Care Costs;Healthcare;Hospitalization;Incidence;Individual;Infrastructure;Institution;International;Intervention;Journals;Knowledge;Letters;Link;Literature;Lobbying;Malnutrition;Medical;Medical Records;Methods;Minority Groups;Modeling;Multi-site clinical study;Names;National Institute on Aging;Oral;Otolaryngology;Outcome Measure;Patients;Peer Review;Philosophy;Physiological;Pneumonia;Policies;Policy Maker;Population;Prevalence;Prevention;Public Health;Public Policy;Publications;Pulmonology;Quality of life;Research;Research Personnel;Resources;Science;Scientist;Services;Speech-Language Pathology;Testing;Third-Party Payer;Underrepresented Minority;United States National Institutes of Health;Validation;Work;aging population;career;cost;diagnostic accuracy;evidence base;experience;falls;frailty;health care settings;improved;interest;lectures;medical specialties;member;minority scientist;multidisciplinary;nutrition;older adult;patient population;posters;psychosocial;screening;symposium;systematic review;targeted treatment

public_health_relevance:
PROJECT NARRATIVESwallowing disorders are directly linked to aging and contribute to multiple other health care problems potentiallyaffecting more than 70 million aging Americans. The proposed Dysphagia: In Search of a Unified Definition forthe Aging Population conference will bring together expert scientists researchers and stakeholders in the arenaof dysphagia and aging to formally synthesize discuss and agree upon an accepted definition for dysphagiaacross the domains of screening diagnosis treatment management and ongoing care. Requested funding fromthis R13 award will support attendance of discussants in aging and dysphagia stakeholders under-representedjunior and minority scientists and support associated conference service costs leading to uniformity in thedefinition of dysphagia for academics research public policy and health care landscape to improve the care ofthe aging population.


application_id: 10749897
project_number: 5R01CA175105-10
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2023-11-21
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 175105
program_official: AULT, GRACE S
project_start_date: 2013-04-01
project_end_date: 2025-11-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYMetastatic colorectal cancer (CRC) is an aggressive disease impacting about 50000 deaths annually in theUSA. Patients with metastatic CRC are predominantly unresponsive to existing therapies. The metastaticprocess is mediated in part by dysregulated translation of oncogenic mRNAs leading to overproduction of theirencoded proteins. Previous findings established dysregulation of cap-dependent mRNA translation downstreamof mTOR at the level of 4E-BP1/eIF4E as a key to tumor formation and metastatic progression in CRC. Whiletargeting mTOR is thought to be a promising strategy for CRC therapy limited therapeutic efficacy of mTORinhibitor drugs correlates largely with loss of the translation repressive function of 4E-BP1. More recent findingsindicate that Snail acts as a strong repressor of 4E-BP1 transcription and cooperates with mTOR-mediatedphosphorylation (inactivation) of 4E-BP1 to significantly increase eIF4E-initiated cap-dependent mRNAtranslation. These processes support tumor growth and decrease the efficacy of the mTOR kinase (ATP-competitive) inhibitors (mTORkis) in CRC therapy. Although mTORkis effectively inhibit phosphorylation of 4E-BP1 and restore its repressive effects on cap-dependent translation and tumor growth treatment with mTORkisin CRC cells can promote the active translation and expression of the immunosuppressive protein PD-L1 viainitiation at an internal ribosome entry site (IRES) in a cap-independent manner. In addition the RNA helicaseeIF4A is a key PD-L1 IRES binding protein that regulates its translation and expression. Importantly elevatedPD-L1 levels induced by mTORkis result in evasion of anti-CRC immunity. Further targeted inhibition of PD-L1can restore T-cell immunity and enhance the efficacy of mTORkis. Based on these findings the centralhypothesis of the proposed study is that CRC cells usurp the regulatory mechanisms underlying both cap-dependent translation through co-activation of Snail and mTOR and IRES-mediated translation of PD-L1 toescape immune surveillance in mTOR kinase-targeted therapy thereby causing CRC resistance to mTORkisand promoting CRC progression. To test this hypothesis the following specific aims are proposed: 1) to identifyhow Snail cooperates with mTOR in translational control of CRC progression and modulation of mTOR kinase-targeted therapy; 2) to determine the cap-independent mechanism of PD-L1 mRNA translation upon mTORkinase inhibition; and 3) to define the in vivo utility of co-targeting PD-L1 and mTOR to enhance CRC therapy.The focus of this study is the innovative concept that both Snail and PD-L1 promote CRC progression bycooperating with mTOR to modulate therapeutic response to mTORkis through dysregulation of 4E-BP1-mediated translation initiation processes. This research will not only define the novel mechanistic roles of bothSnail and PD-L1 in the modulation of mTOR/4E-BP1-mediated translational control of CRC progression andresistance to mTORkis but also facilitate rational approaches for the development of new translatabletherapeutic strategies for patients with advanced CRC.

project_terms:
Binding Proteins;Biological Markers;Biology;Cancer Etiology;Cell Line;Cessation of life;Clinical;Colorectal Cancer;Dependence;Development;Disease;Down-Regulation;EIF4EBP1 gene;Environment;Epigenetic Process;FRAP1 gene;Fostering;Foundations;Funding;Genes;Genetic Transcription;Goals;Immune Evasion;Immunity;Immunologic Surveillance;Immunologist;Immunotherapy;Internal Ribosome Entry Site;Knowledge;Left;Malignant Neoplasms;Mediating;Messenger RNA;Molecular;Monoclonal Antibodies;Neoplasm Metastasis;Oncogenic;Oncologist;Outcome Study;Pathogenesis;Pathologist;Patients;Phosphorylation;Phosphorylation Inhibition;Phosphotransferases;Polyribosomes;Positioning Attribute;Process;Production;Property;Protein Biosynthesis;Proteins;Public Health;RNA;RNA Helicase;Reporting;Research;Resistance;Role;Signal Pathway;Signal Transduction;Snails;T-Lymphocyte;Testing;Therapeutic;Transact;Translating;Translation Initiation;Translational Regulation;Translations;Treatment Efficacy;Tumor Immunity;Tumor-Infiltrating Lymphocytes;United States;Woman;Work;anti-PD-1;cancer cell;clinically relevant;colon cancer patients;colorectal cancer progression;colorectal cancer treatment;effective therapy;effectiveness evaluation;experience;genetic corepressor;improved;in vivo;in vivo evaluation;inhibitor;inhibitor therapy;innovation;insight;kinase inhibitor;mRNA Translation;mTOR Inhibitor;men;metastatic colorectal;metastatic process;mouse model;novel;novel strategies;novel therapeutics;patient derived xenograft model;polysome profiling;programmed cell death ligand 1;protein complex;recruit;response;silvestrol;targeted treatment;therapeutic target;treatment response;tumor;tumor growth

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the second most common cause of cancer deaths in the United States for men and womencombined and approximately 40% of patients with this disease will eventually die of tumor metastasis. Thisproposal aims to deepen our understanding of signaling pathways and immune evasion mechanisms inmetastatic colorectal cancer by taking a novel approach for investigating mTOR signaling biology and itsderegulation in the molecular pathogenesis of this invasive disease with the goal of identifying selectivetranslational regulators as novel cancer therapeutic targets. This knowledge is expected to lay a foundation forthe development of novel therapies for metastatic colorectal cancer a goal with clear and significant implicationsfor public health.


application_id: 10749885
project_number: 5R01GM144349-03
administering_ic: NIGMS
award_notice_date: 2023-12-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 144349
program_official: CHO, THOMAS Y
project_start_date: 2022-01-01
project_end_date: 2026-12-31
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 15235905
contact_pi: SABO, THOMAS MICHAEL
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: 2024-01-01
project_title:
Linking the conformational landscape to enzymatic function through functional site distant mutations

project_abstract:
An ongoing debate concerns the role conformational motions often termed dynamics play in biomolceularfuntion. For enzymes it so happens that the timescales for large-scale domain motions are similar to theapparent "$$). catalytic rate (!"# This observation is where the major point of contention has developed: do "$$. In this context the proposed studiesconformational motions directly impact the true rate of catalysis (!"#) or !"#will further explore how the modulation of the conformational landscape can indeed fine-tune "$$ without!"#impacting !"# and the ground state structure. The genesis of this proposal arises from our work with humanguanylate kinase (hGMPK) a potential therapeutic target for treating cancer and perhaps even SARS-CoV-2which motivated us to solve the first structure of hGMPK with nuclear magnetic resonance (NMR) spectroscopy(PDB: 6NUI). While solving the hGMPK structure we expressed a series of seven functional site distant (FSD) "$$ when compared to the wild-non-synonymous single nucleotide variants (nsSNVs) of hGMPK that enhance !"#type (wt). Intriguingly the 2D [1H15N]-HSQC NMR spectra of the wt hGMPK and its nsSNVs suggest that the ) for GMP binding toFSD mutations minimally impact hGMPKs backbone fold yet the apparent off-rates (wt and the FSD mutant V91M differ by ~3000 s-1. We hypothesize that hGMPKs activity can be modulated withFSD mutants by reshaping the conformational landscape. Utilizing NMR spectroscopy and isothermalcalorimetry we will test this hypothesis in the following two Specific Aims. In Aim 1 we will quantify the impactof the FSD mutations on the conformational landscape from kinetic and thermodynamic perspectives. The resultsfrom this Aim will provide a comprehensive picture as to where within the hGMPK catalytic and binding schemesthe FSD mutations have the largest impact on function. For Aim 2 we will deconvolute the contribution transientstructures within the conformational landscape play in enzymatic catalysis through experimentally drivenensemble generation. Our protocol will select hGMPK structures from unbiased molecular dynamics (MD)simulations based on residual dipolar couplings and cross-correlated relaxation rates measured with NMR. Theensembles will aid in the identification of the functionally important transient conformations and an assessmentof the impact the FSD mutations have on backbone dihedral correlated motions. To our knowledge this proposalprovides the first examples 1.) of experimentally driven ensemble generation for an enzyme spanningphysiologically relevant timescales and 2.) of determining thermodynamic and kinetic parameters with ligandbinding to the same exact site on a series of enzyme variants. The impact of this proposal is the direct linkageof the conformational landscape to enzymatic function. Immediate applications for these results include drugdiscovery where targeting structures within the conformational landscape rather than the ground state structurewill lead to better outcomes and biomolecular design where FSD mutations can be implemented to adjustfunction through manipulation of the conformational landscape.

project_terms:
2019-nCoV;Active Sites;Affect;Antineoplastic Agents;Architecture;Binding;Calorimetry;Catalysis;Cyclic GMP;DNA;Data;Development;Dissociation;Distant;Enzymes;Equilibrium;Future;Generations;Grant;Guanosine Triphosphate;Guanylate kinase;Human;Kinetics;Laboratories;Ligand Binding;Ligands;Link;Malignant Neoplasms;Measurable;Measures;Methods;Molecular Conformation;Motion;Muramidase;Mutation;NMR Spectroscopy;Nuclear Magnetic Resonance;Nucleosides;Nucleotides;Outcome;Phosphorylation;Phosphotransferases;Physiological;Play;Probability;Prodrugs;Production;Proteins;Protocols documentation;RNA;Rationalization;Regulation;Relaxation;Research Personnel;Residual state;Role;SARS coronavirus;Sampling;Scheme;Series;Shapes;Single Nucleotide Polymorphism;Site;Structural Biologist;Structure;Testing;Therapeutic;Thermodynamics;Titrations;Ubiquitin;Variant;Vertebral column;Viral;Work;cancer cell;conformational conversion;design;drug discovery;enthalpy;inhibitor;molecular dynamics;mutant;small molecule inhibitor;therapeutic target;tool

public_health_relevance:
Human guanylate kinase (hGMPK) is an essential enzyme in the production of DNA and RNA making it apotential therapeutic target for cancer and SARS-CoV-2. We have shown that active site distant mutations arisingfrom non-synonymous single nucleotide variants of hGMPK enhance enzymatic catalysis without a perceptiblechange in the kinases backbone structure an apparent contradiction to the structure-function paradigm. Thisproposal investigates what is responsible for this catalytic enhancement from a rigorous kinetic andthermodynamic perspective the results of which will impact future approaches toward drug discovery andbiomolecular regulation through the direct linkage of enzymatic function to the conformational landscape.


application_id: 10749033
project_number: 5R01ES030380-05
project_title: Radon on the RADAR
administering_ic: NIEHS
award_notice_date: 2023-12-05
opportunity_number: PA-18-260
application_type: 5
activity_code: R01
ic: ES
serial_number: 030380
program_official: O'FALLON, LIAM
project_start_date: 2020-02-20
project_end_date: 2024-08-14
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Kentucky's high radon potential and high smoking rates create the perfect storm for theoverrepresentation of lung cancer cases. Our transdisciplinary community-academic team-led projectRadon on the RADAR (Residents Acting to Detect and Alleviate Radon) will address community concernsabout lung cancer by identifying geological and atmospheric conditions that increase radon intrusion intohomes translating this knowledge into greater residential awareness of risk enabling home radon testingand report back and growing access to affordable and adequate radon mitigation. We will team geologistswith citizen scientists to determine how new radon detection technology (i.e. Airthings) compares totraditional charcoal kits and outdoor soil radon measurements over a range of atmospheric and geologicalconditions to close a critical knowledge gap in our understanding of radon risk. The study will buildcapacity in environmental health by: (a) training citizens in rigorous data collection and interpretation offindings; (b) engaging these citizen scientists in creating and promoting library loan programs to increaseradon testing; and (c) creating sustainable environmental health action plans to alleviate radon exposurein rural communities. Our overall hypothesis is that by increasing knowledge on how geological andatmospheric conditions can impact radon partnering with citizen scientists to use new radon detectiontechnology and translate the data and by growing access to low-cost radon mitigation we will reduceradon risk. Aim 1 will use a citizen science approach to identify and train 60 community residents in fourKY counties to test for radon and evaluate change in environmental health literacy (EHL) and self-efficacy.Aim 2 will compare indoor home radon values and soil radon values over time controlling for atmosphericconditions seasonality geology topography and smoking in the home. Aim 3 will create and evaluate apilot radon detector library loan program with 400 homeowners in the four counties. Aim 4 will launch theradon detector loan program and examine changes in home testing and accessing geologically basedradon potential maps. Aim 5 will examine the impact of citizen scientist-led radon coalitions on reacheffectiveness adoption implementation maintenance and environmental health literacy. The RADARstudy challenges and expands the current environmental health science paradigm by collaborating withgeologists and integrating their scientific approach. We will impact community concerns about high lungcancer rates by: 1) transforming radon detection and report back using geoscience and new radon gasdetection technology; 2) developing a library-lending approach to increase radon testing; and 3) supportingenvironmental action by creating and sustaining citizen science-led radon coalitions that share newknowledge and engage health advocates radon mitigation professionals policymakers builders anddevelopers to promote improved radon management in rural Kentucky.

project_terms:
Address;Advocate;Atmosphere;Awareness;Back;Certification;Charcoal;Collaborations;Communities;County;Data;Data Analyses;Data Collection;Detection;Diagnostic Reagent Kits;Disease;Environment;Environmental Exposure;Environmental Health;Environmental Risk Factor;Equipment;Feedback;Gases;Geological Survey;Geology;Geoscience;Health;Home;Information Dissemination;Kentucky;Knowledge;Libraries;Low income;Malignant neoplasm of lung;Maps;Marketing;Measurement;Monitor;Outcome;Policy Maker;Precipitation;Procedures;Property;Provider;Radon;Reach Effectiveness Adoption Implementation and Maintenance;Reporting;Risk;Rural;Rural Community;Sampling;Seasons;Self Efficacy;Smoking;Soil;Technology;Temperature;Testing;Time;Tobacco smoke;Training;Translating;atmospheric conditions;cancer risk;citizen science;cost;design;detector;digital;environmental tobacco smoke exposure;health literacy;home test;improved;information seeking behavior;interest;knowledge integration;member;novel;programs;remediation;time use;usability;web site

public_health_relevance:
PROJECT NARRATIVEThe public is concerned about the high rates of lung cancer from environmental exposure to tobacco smokeand radon. We will identify geological and atmospheric conditions that increase radon intrusion into homestranslate this knowledge into increased residential awareness of lung cancer risk facilitate home radon testingand report back and increase access to affordable and adequate radon mitigation. By bringing residents andtraditional (e.g. public libraries) and non-traditional (e.g. low interest loan providers) organizations to the tableto reduce radon exposure the way communities address environmental health issues will be transformed.


application_id: 10748535
project_number: 1R01CA277946-01A1
project_title: Roles of mRNA Transfer in Cancer Cell-Platelet Communication
administering_ic: NCI
award_notice_date: 2023-06-28
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 277946
suffix: A1
program_official: WATSON, JOANNA M
project_start_date: 2023-07-01
project_end_date: 2028-06-30
study_section: Tumor Evolution, Heterogeneity and Metastasis Study Section[TEHM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The interaction between cancer cells and platelets plays important roles in regulating cancer cell function.Understanding how platelets communicate with cancer cells to modulate cancer cell colonization at distantorgans may identify novel strategies to halt cancer spreading. We recently showed that recruitment of platelet tocancer cells is essential for the colonization of circulating tumor cells (CTCs) at the secondary organs. Howeverthe molecular mechanism by which platelets modulate cancer cell function to promote cancer cell colonizationremains to be determined. By analyzing RNA-seq data from CTCs and primary tumors we found that platelet-specific mRNA was significantly enriched in CTCs. RNAscope and Translating Ribosome Affinity Purification(TRAP) analyses showed the delivery of platelet mRNA and translation of platelet-derived mRNA in cancer cells.In vivo functional screening identified multiple platelet-derived mRNAs contribute to colonization of breast cancercell at distant organs. These results reveal the new role of platelet mRNA in mediating intercellularcommunication and in promoting cancer cell spreading. The overall objective of this proposal is to define themolecular mechanism by which platelet mRNA is delivered into breast cancer cells and determine roles of plateletmRNA as the signaling molecular in promoting cancer cell colonization at distant organs. We showed that CD9expression in CTCs correlated with the accumulation of platelet-specific mRNA. Silencing CD9 in breast cancercells significantly reduced platelet mRNA transferring and colonization of cancer cells. Platelet factor 4 (PF4) isa small cytokine belonging to the CXC chemokine family that is highly expressed in platelets. We showed thatthe transfer of PF4 mRNA from platelets to breast cancer cells enhanced stemness and colonization of cancercells. Based on these results the central hypothesis of this proposal is that the CD9-dependent mRNA transfermediates the platelet-cancer cell communication and promotes cancer cell stemness. We propose the followingtwo aims to test this hypothesis and achieve our objective. Aim 1. Elucidate the mechanism by which plateletmRNA is transferred into cancer cells. Aim 2. Determine how the transfer of platelet PF4 mRNA in cancer cellspromotes cancer metastasis.

project_terms:
Affinity Chromatography;Binding Proteins;Biological Assay;Biology;Blood Platelets;Breast Cancer Cell;CXC Chemokines;CXCR4 Receptors;CXCR4 gene;Cancer Patient;Cell Communication;Cell fusion;Cell physiology;Cells;Co-Immunoprecipitations;Communication;Complex;Cytokine Activation;Data;Distant;Family;Galectin 3;Genes;Genetic Engineering;Hematogenous;Incidence;Knockout Mice;Knowledge;Malignant Neoplasms;Mediating;Membrane Fusion;Membrane Proteins;Messenger RNA;MicroRNAs;Microfluidic Microchips;Molecular;Neoplasm Circulating Cells;Neoplasm Metastasis;Organ;PF4 Gene;Pathway Analysis;Pathway interactions;Play;Population;Positioning Attribute;Primary Neoplasm;Proteins;Recurrence;Regulation;Research;Ribosomes;Role;Signal Transduction;Small RNA;Stromal Cell-Derived Factor 1;Testing;Tissues;Translating;Translations;breast cancer progression;cancer cell;cancer genetics;carcinogenesis;chemokine;confocal imaging;cytokine;extracellular vesicles;gain of function;genetic signature;human data;in vivo;inhibitor;insight;intercellular communication;loss of function;mRNA delivery;malignant breast neoplasm;mouse model;multidisciplinary;neoplastic cell;novel;novel strategies;protein complex;recruit;screening;small molecule;stemness;therapeutic target;tissue culture;transcriptome sequencing;tumor progression

public_health_relevance:
Defining how mRNA transferring mediates the platelet-cancer cell interaction will fill a critical gap in ourknowledge about the intercellular communication during cancer progression. Elucidating the mechanism bywhich CD9 regulates platelet mRNA transferring will significantly expand our understanding about cell fusion inthe platelet-cancer cell interaction and help to identify a potential therapeutic target to suppress the platelet-induced cancer progression and metastasis. The study of platelet PF4 mRNA in regulating cancer cell stemnesswill reveal a chemokine regulation pathway and new roles of PF4 in cancer cell colonization.


application_id: 10748428
project_number: 1R01DA059152-01
project_title: POPI: Placenta Opioids and Perinatal Implications
administering_ic: NIDA
award_notice_date: 2023-07-31
opportunity_number: RFA-HD-23-030
application_type: 1
activity_code: R01
ic: DA
serial_number: 059152
program_official: WU, DA-YU
project_start_date: 2023-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1 EMS-S (50)]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: O'BRIEN, JOHN M
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYMaternal opioid use which dramatically increased in recent years exerts severe adverse consequences for theoffsprings health. Data from animal models and clinical studies demonstrated that prenatal opioid exposure issignificantly associated with preterm birth fetal growth restriction low birth weights neonatal opioid withdrawalsyndrome smaller brain sizes and impaired neurobehavioral outcomes. However the mechanisticunderpinnings of these adverse outcomes remain poorly understood. Available published data and ourpreliminary studies strongly suggest that maternal opioid use disorder (OUD) perturbs the placenta-brainaxis. One potential mechanism is that OUD disrupts placental development and function impairing nutrient andgas exchange between mother and fetus. Another mechanism is that opioids accumulate in placental tissuesthereby directly disrupting normal fetal development. However the molecular underpinnings and the contributionof each pathway remain poorly understood. Therefore this application will test the central hypothesis thatmaternal OUD driven inflammation and dysregulation of the placental landscape are linked to adverseneurocognitive outcomes in the offspring. The novelty of this application lies in the systems biology approachthat integrates phenotypic functional and genomic readouts at the maternal-fetal interface umbilical cord bloodat delivery and neonatal blood with neurobehavioral and motor skill assessments throughout the first year oflife. Completion of the proposed experiments will result in novel insights into the dysregulations of the placenta-brain axis elicited by maternal OUD and will pave the way to building a comprehensive construct and inform thedevelopment of early interventions during opioid-exposed pregnancies.

project_terms:
Abstinence;Address;Admission activity;Animal Model;Appalachian Region;Biochemical Markers;Biological Markers;Biometry;Biophysics;Birth;Blood;Blood specimen;Brain;Caring;Cells;Circulation;Clinic;Clinical;Clinical Research;Cognitive deficits;Data;Decidua;Dedications;Development;Diagnosis;Doppler Ultrasound;Early Intervention;Encephalitis;Epigenetic Process;Exposure to;Fetal Development;Fetal Growth;Fetal Growth Retardation;Fetal Reduction;Fetus;Gases;Genetic Transcription;Genomics;Growth;Head circumference;Health;Histologic;Home;Homeostasis;Hospitalization;Hour;Human;Image;Immunology;Impairment;Incidence;Infant;Inflammation;Inflammation Mediators;Inflammatory;Intervention;Investigation;Kentucky;Knowledge;Life;Link;Longitudinal Studies;Low Birth Weight Infant;Macrophage;Maintenance;Maternal-Fetal Exchange;Maternal-fetal medicine;Measurement;Measures;Mediating;Microglia;Modeling;Molecular;Mothers;Motor Skills;Neonatal;Neonatal Abstinence Syndrome;Neonatology;Neurocognitive;Neurocognitive Deficit;Newborn Infant;Nutrient;Opioid;Organoids;Outcome;PGF gene;Pathology;Pathway interactions;Perinatal;Phenotype;Placenta;Placentation;Plasma;Play;Positioning Attribute;Pregnancy;Pregnant Women;Premature Birth;Production;Publishing;Reporting;Research;Research Design;Risk;Rodent Model;Role;Sampling;Spontaneous abortion;Substance Use Disorder;Systems Biology;Testing;Tissues;Umbilical Cord Blood;United States;Universities;Variant;Villous;Withdrawal;adverse outcome;animal data;brain health;brain size;brain tissue;early childhood;early pregnancy;exosome;experience;experimental study;fetal;fetal opioid exposure;indexing;innovation;insight;maternal opioid use;mental development;monocyte;multidisciplinary;multimodality;myelination;neonate;neurobehavioral;neurodevelopment;neuroinflammation;neuroprotection;neurotrophic factor;novel;offspring;opioid epidemic;opioid exposure;opioid use disorder;perinatal outcomes;predictive modeling;pregnant;prenatal exposure;programs;transcriptomics;trophoblast;vascular factor

public_health_relevance:
NARRATIVEMaternal opioid use is increasing in the United States and is associated with significant adverse health outcomesfor the offspring including preterm birth neonatal opioid withdrawal syndrome and impaired neurocognitiveoutcomes suggestive of a dysregulated placenta-brain axis. This application will carry out an in-depthinvestigation of maternal opioid use-changes to placental health and neonatal inflammation as well asneurobehavioral and neuromotor outcomes during the first year of life. This research will contribute to thefundamental knowledge of the placenta-brain axis and identify potential interventions to address opioid-induceddysregulations.


application_id: 10748106
project_number: 1R01DC021325-01
project_title: ACTIVITY-DRIVEN PLASTICITY OF THE HAIR CELL CYTOSKELETON
administering_ic: NIDCD
award_notice_date: 2023-06-06
opportunity_number: RFA-DC-23-001
application_type: 1
activity_code: R01
ic: DC
serial_number: 021325
program_official: FREEMAN, NANCY
project_start_date: 2023-06-07
project_end_date: 2028-05-31
study_section: Special Emphasis Panel[ZDC1 SRB-Z (41)]
contact_pi_person_id: 12084410
contact_pi: VELEZ ORTEGA, ALEJANDRA CATALINA
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The mechanosensitivity of the inner ear hair cells depends on cellular projections known asstereocilia organized in rows of increasing height with mechano-electrical transduction (MET) channelslocated at the tips of shorter row stereocilia. The core of stereocilia consists of a highly crosslinkedparacrystalline array of actin filaments. While crosslinker proteins are constantly renewed the renewal ofactin is limited to the stereocilia tips. We previously reported that the stereocilia actin core exhibits activity-dependent plasticity (Velez-Ortega et al. eLife 2017). We showed that the blockage of MET channelsor the breakage of the tip links that gate these channels lead to the selective shortening of transducingstereocilia (i.e. the stereocilia that harbor MET channels) while the non-transducing tallest row stereociliaremain unaffected. Once the MET blockage is removed or the tip links regenerate the stereocilia regrow.Our preliminary data also show that this MET-dependent stereocilia remodeling can affect the restingtension within the MET machinery in seconds. Thus this process may dynamically regulate the sensitivityof hair cells to sound-induced vibrations and hence the sensitivity of our hearing. Yet the exactmechanisms of MET-dependent stereocilia remodeling are still obscure. It is unknown even whether theactivity-dependent plasticity of the stereocilia cytoskeleton is limited to the regions of active actin renewalor can expand beyond this region into the stable part of the stereocilia shaft. Here we hypothesize thatthe MET activity regulates the extent of the stereocilia cytoskeleton undergoing active actin remodeling.To test this Aim 1 will evaluate MET-dependent changes in actin dynamics within the stereocilia and thecuticular plate an actin-rich structure supporting the stereocilia bundle. Aim 2 will evaluate MET-drivenchanges in the ultrastructural organization of stereocilia actin with transmission electron microscopytomography. Since the MET-dependent stereocilia remodeling was studied so far only in young postnatalhair cells Aim 3 will assess whether this phenomenon is present also in the mature adult auditory haircells. In Aim 4 we begin to explore the molecular players involved in the MET-driven stereociliaremodeling by evaluating the expression of so-called stereocilia row identity proteins in a mutant mousemodel that exhibits MET-dependent actin remodeling not only in transducing stereocilia but alsounexpectedly in non-transducing stereocilia. The study is significant because it may clarify how exactlya hair cell performs fine adjustments of the architecture of the stereocilia bundle thereby maintaining thesensitivity of our hearing throughout a lifetime. In addition stereocilia shorteningand perhaps theireventual disappearancecould occur after noise exposure (when the MET current is reduced due to tiplink breakage) or in certain cases of congenital deafness (due to impaired MET current). Therefore thisstudy will expand our knowledge of the molecular mechanisms of various types of hearing loss.

project_terms:
Actins;Adult;Affect;Architecture;Auditory;Cells;Cochlea;Crosslinker;Cytoskeleton;Data;Development;Exhibits;F-Actin;Filament;Fluorescence Recovery After Photobleaching;Freeze Substitution;Freezing;Hair;Hair Cells;Hearing;Height;Impairment;In Situ;Ions;Knowledge;Label;Labyrinth;Lead;Length;Link;Maintenance;Measures;Mediating;Microfilaments;Molecular;Morphology;Mus;Myosin ATPase;Natural regeneration;Noise-Induced Hearing Loss;Organelles;Organism;Pattern;Physiological;Polymers;Process;Protein Isoforms;Proteins;Rattus;Reporting;Rest;Sampling;Scanning Electron Microscopy;Sensory;Shapes;Stereocilium;Structure;Supporting Cell;Testing;Transmission Electron Microscopy;beta Actin;cellular microvillus;congenital deafness;crosslink;depolymerization;experimental study;gamma Actin;hearing impairment;mutant mouse model;new therapeutic target;noise exposure;polymerization;postnatal;sound;tomography;vibration

public_health_relevance:
PROJECT NARRATIVE Our sense of hearing relies on the survival of a limited number of inner ear sensory cells throughoutour entire lifetime. This project will provide clues about the molecular machinery regulating the stabilityand shape of the inner ear sensory organelles known as stereocilia. The identification of these molecularplayers might uncover novel therapeutic targets to maintain the integrity of stereocilia in some types ofcongenital or noise-induced hearing loss.


application_id: 10747173
project_number: 3R15ES028440-02A1S1
project_title: Prenatal Cigarette Smoke Exposure: Impact on Offspring Gut Bacterial Microbiome
administering_ic: NIEHS
award_notice_date: 2023-03-02
opportunity_number: PA-21-071
application_type: 3
activity_code: R15
ic: ES
serial_number: 028440
suffix: A1S1
program_official: DZIERLENGA, ANIKA LIN
project_start_date: 2023-03-01
project_end_date: 2025-05-31
contact_pi_person_id: 2095188
contact_pi: CORBITT, CYNTHIA
other_pis: Not Applicable
congressional_district: 03
department: 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 ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThis Research Supplement to Promote Diversity in Health-Related Research is to support a graduate studentto perform research funded by R15 award 2R15ES028440-02A1 Prenatal Cigarette Smoke Exposure: Impacton Offspring Gut Bacterial Microbiome. Mr. Isaiah Burciaga is eligible for this award on multiple fronts: he is anunderrepresented minoritized (Afro-Latino) student in science from a rural economically disadvantagedbackground who is a first-generation college student. He has demonstrated interest in a biomedical researchcareer and has exhibited ability both academically and technically to fulfill that career goal. The studiesproposed within the parent award use a well-developed murine model of developmental exposure to tobaccosmoke. We have shown effects of prenatal cigarette smoke exposure (CSE) on birth weight catch-up growthand gut bacterial microbiome in mouse dams and their offspring as well as effects on offspring phenotype.However we do not know if the observed changes in microbiome and offspring phenotype are linked. We willmeasure the effect of cecal transfer of microbiomes or dietary resistant starch on those same measures in thismodel. Our central hypothesis that CSE-induced gut microbiome alterations are linked to offspring phenotypewill be tested within 2 aims:Aim 1: use cecal transfer in weanlings to separate effects of CSE-induced microbiome from CSE itselfAim 2: use dietary resistant starch to increase short-chain fatty acids before vs after pubertyIf our central hypothesis is supported additional studies will delve into gut-liver-brain axis consequences ofintestinal dysbiosis as well as investigate potential interventions. Mr. Burciagas research training will focusprimarily on Aim 2 and will include participation in professional development activities through the UofL GraduateSchool participation in scientific conferences grant writing and publication.

project_terms:
Acetates;Age;Age Months;Air;Attenuated;Award;Behavior Disorders;Behavioral;Biological Assay;Biomedical Research;Birth Weight;Birth length;Blood Glucose;Brain;Calorimetry;Carbohydrates;Cecum;Characteristics;Chemicals;Child;Coupled;Data;Development;Dual-Energy X-Ray Absorptiometry;Dyslipidemias;Eating;Eligibility Determination;Euthanasia;Exhibits;Family;Fasting;Feces;Female;Fermentation;Firmicutes;First Generation College Students;Funding;Gene Expression;Genes;Glucose;Glucose Intolerance;Glucose tolerance test;Goals;Grant;Growth;Health;Hepatic;High Fat Diet;Hormones;Hour;Immune system;Immunologist;Inflammation;Inhalation;Insulin;Intervention;Intestines;Kentucky;Latino;Link;Lipids;Liver;Low Birth Weight Infant;Lupus;Measures;Mediating;Metabolic;Metabolic syndrome;Modeling;Mus;Nutritional;Organ;Overweight;Pancreas;Parents;Phenotype;Plasma;Pregnancy;Production;Proteobacteria;Protocols documentation;Puberty;Publications;Reporting;Research;Research Training;Resistance;Rural;Same-sex;Scanning;Science;Serum;Signal Transduction;Smoke;Starch;Structure;Students;Supplementation;Testing;Transplantation;Underrepresented Minority;Variant;Volatile Fatty Acids;Weaning;Woman;Work;Writing;absorption;bacterial community;bacteriome;beta diversity;career;cigarette smoking;dietary;disadvantaged background;dysbiosis;economic disparity;environmental tobacco smoke exposure;exposure to cigarette smoke;fetal tobacco exposure;functional disability;glucagon-like peptide 1;graduate school;graduate student;gut dysbiosis;gut microbiome;gut microbiota;impaired glucose tolerance;in utero;insulin sensitivity;interest;male;metabolic phenotype;metabolomics;microbial;microbial composition;microbiome;microbiome alteration;microbiome composition;microbiota;mouse model;obesity risk;offspring;outcome disparities;postnatal;pregnant;prenatal;pup;sex;smoking during pregnancy;symposium;transcriptome sequencing;transcriptomics

public_health_relevance:
NARRATIVEThe studies proposed within this application use a well-developed murine model of developmental exposure totobacco smoke. We have shown effects of prenatal cigarette smoke exposure (CSE) on birth weight catch-upgrowth and gut bacterial microbiome in mouse dams and their offspring as well as effects on offspringphenotype (preliminary data). We will measure the effect of cecal transfer of microbiomes post-weaning (Aim 1)or addition of dietary resistant starch (Aim 2) on those same measures in this model.


application_id: 10747004
project_number: 1R21EY034634-01A1
project_title: Endocannabinoid system as a therapeutic target for PVR
administering_ic: NEI
award_notice_date: 2023-09-15
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: EY
serial_number: 034634
suffix: A1
program_official: COOK, TIFFANY
project_start_date: 2023-09-30
project_end_date: 2026-07-31
study_section: Pathophysiology of Eye Disease - 1 Study Section[PED1]
contact_pi_person_id: 2093529
contact_pi: SONG, ZHAO-HUI
other_pis: TAMIYA, SHIGEO
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
project_abstract:
ABSTRACTTwo ocular cell types retinal pigment epithelium (RPE) and Mller glia (MG) have been implicated to playimportant roles in the development and final outcome of proliferative vitreoretinopathy (PVR) by undergoingTrans differentiation to myofibroblasts. The endocannabinoid system including endocannabinoid ligands andtheir receptors including CB1 CB2 and non-CB1/CB2 cannabinoid receptors play essential roles in health anddisease and are promising therapeutic targets. Previously it has been shown that blockade of CB1 andactivation of CB2 inhibit fibrosis. Our preliminary results demonstrate that myofibroblast trans differentiation ofboth RPE and MG cells can be inhibited by N-oleoyl dopamine (OLDA) an endogenous inverse agonist forGPR6 a non-CB1/CB2 cannabinoid receptor. In addition CB1 selective inverse agonist/antagonist SR141716Ainhibited myofibroblast trans differentiation of MG cells. Based on the literature and our preliminary data wehypothesize that CB1 and GPR6 inverse agonists/antagonists and CB2 agonists inhibit myofibroblastic changesby working via CB1 GPR6 CB2 receptors respectively and modifying downstream signaling pathways crucialfor myofibroblast trans differentiation. To test our hypothesis CB1 CB2 and GPR6 will either be activated byselective agonists or inhibited by inverse agonists or shRNA knockdown to examine their role on myofibroblasttrans differentiation assessed by mesenchymal and myofibroblast marker protein expression and matrixcontraction a key function of myofibroblasts. In addition effects of CB1 CB2 and GPR6 ligands on signalingpathways activated by profibrotic cytokine TGF2 will be examined by assessing activation status of keysignaling molecules as well as nuclear localization of fibrotic transcription factors. Finally the expression of CB1CB2 and GPR6 receptors will be investigated in human retinal scar tissues from PVR patients. The main goal ofthis project is to test the potential of CB1 CB2 and GPR6 ligands as preventative treatments of PVR.Furthermore this project will identify fibrotic signaling pathways targeted by the endocannabinoid system andshould contribute to the development of specific and effective therapeutic agents for PVR.

project_terms:
Agonist;Blindness;CNR1 gene;CNR2 gene;Cannabinoids;Cannabis;Categories;Cells;Chemicals;Cicatrix;Complication;Data;Development;Disease;Dopamine;Endocannabinoids;Extracellular Matrix;Eye Injuries;Failure;Family suidae;Fibrosis;Future;G-Protein-Coupled Receptors;GPR6 gene;Goals;Health;Human;Immunohistochemistry;Inflammation;Investigation;Legal Status;Ligands;Literature;Mediating;Medical Marijuana;Medicine;Mesenchymal;Modeling;Modification;Molecular;Muller's cell;Myofibroblast;Nuclear;Operative Surgical Procedures;Outcome;Pathology;Patients;Pharmaceutical Preparations;Play;Prevention;Preventive treatment;Proliferative Vitreoretinopathy;Reporting;Research;Retina;Retinal Detachment;Role;SR 141716A;Signal Pathway;Signaling Molecule;Structure of retinal pigment epithelium;Surface;Testing;Therapeutic Agents;Therapeutic Effect;Tissues;Traction;Visual;Visual Acuity;antagonist;antiproliferative drugs;cannabinoid receptor;cell type;design;endogenous cannabinoid system;improved;in vivo;interest;knock-down;mouse model;phytocannabinoid;prevent;profibrotic cytokine;protein biomarkers;protein expression;receptor;response;small hairpin RNA;synthetic cannabinoid;therapeutic target;therapeutically effective;transcription factor;transdifferentiation

public_health_relevance:
NARRATIVEThe main goal of this project is to test the potential of cannabinoids as preventative treatments of proliferativevitreoretinopathy (PVR) a complication in which a fibrotic scar develops on the surface of the retina causingretinal folds and/or traction retinal detachment.


application_id: 10746884
project_number: 4R00CA249048-03
project_title: A pro-metastatic secretory program activated by epithelial-to-mesenchymal transition
administering_ic: NCI
award_notice_date: 2024-03-12
opportunity_number: PA-20-188
application_type: 4
activity_code: R00
ic: CA
serial_number: 249048
program_official: BENAVIDEZ, JUSTIN MICHAEL
project_start_date: 2024-03-12
project_end_date: 2027-02-28
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 15823901
contact_pi: XIAO, GUAN-YU
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ProjectSummary/AbstractCandidate:Dr.XiaohasreceivedbroadtrainingincellandcancerbiologyincludingpostdoctoraltrainingatUT-SouthwesternMedicalCenter(UTSW)andMDAndersonCancerCenter(MDACC).Heseekstounderstandhowepithelial-to-mesenchymaltransition(EMT)drivesmalignantsecretiontopromotelungcancermetastasis.Dr.Xiaoisahighlyproductiveinvestigatorwith4first-authoredpeer-reviewedpapers.Asrecognitionofhisachievementshereceivednumerousawardsduringhisdoctoralandpostdoctoraltraining.Career Development/Training: Dr. Xiaos primary mentor is Dr. Jonathan Kurie a physician-scientist withexpertise in cancer biology and mouse modeling of human lung adenocarcinoma (LUAD). His co-mentor is Dr.SandraSchmidwhowashismentoratUTSWandisaleaderinthefieldofendocyticvesicletrafficking.Additionalinput will come from Dr. Angela Wandinger-Ness (University of New Mexico) who identified Rab GTPases asregulatorsofendosomaltraffickingandisdevelopingGTPase-targetedtherapiesforcancer.TheseinvestigatorshavedesignedatrainingprogramcenteredontheirkeyscientificdisciplinesthatwillstrengthenDr.Xiaosabilitiesintheirrespectivefieldsandprovidetheskillsneededforasmoothtransitiontoindependence.Research:EMTinductionincancercellsinitiatesthemetastaticcascadebypromotingmotilityandinvasivenessthrough cell-autonomous mechanisms. Our group has shown thatEMT also increases the secretion of proteinsthat maintain LUAD cell viability and create an immunosuppressive and fibrotic tumor microenvironment (TME)that facilitates LUAD metastasis. These findings are the basis for our hypothesis that EMT promotes LUADmetastasisthroughdualcell-autonomousandnon-autonomousmechanisms.TheobjectiveofmyproposalistoelucidatethemolecularunderpinningsofEMT-dependentsecretioninLUAD.InmypreliminaryresultsIshowthatthe EMT-activating transcription factor ZEB1 upregulates the expression of Rab6A and Rab8A by silencingmicroRNAsthattargettheseeffectors.IshowthatZEB1requiresRab6AandRab8AtodrivepolarizedtraffickingofsecretoryvesiclestowardtheleadingedgeofmigratingLUADcellstoincreasecytokinesecretiontogenerateanimmunosuppressiveTMEandtopromoteLUADcellmigrationinvasionandmetastasis.Becausesecretoryvesicle exocytosis occurs at hot spots juxtaposed to focal adhesions I hypothesize that ZEB1 coordinatelyregulates anterograde trafficking of secretory vesicles and remodeling of actin-based cytoskeletal structures toinitiate polarized secretion of pro-tumorigenic effector proteins that drive LUAD progression. I will test thishypothesis by determining how ZEB1 coordinately regulates anterograde vesicle trafficking and cytoskeletalremodelingtodrivepolarizedsecretionofpro-tumorigeniceffectorproteinsandLUADprogression.InsummyproposalwilladdresstheclinicalproblemofLUADmetastasis.Thenoveltyrestsinpreliminaryresultsthat demonstrate a transcriptional governance of polarized vesicular transport providing the potential to targetZEB1-drivensecretorypathwaysforthepurposeofblockingmetastasisinLUAD.

project_terms:
Achievement;Actins;Adenocarcinoma Cell;Aerosols;Alleles;Apical;Award;Belief;Biogenesis;Biological;Cancer Biology;Cancer Center;Cancer Etiology;Cell Line;Cell Survival;Cell membrane;Cells;Cellular biology;Clinical;Cytoskeleton;Data;Discipline;Endocytic Vesicle;Endosomes;Exocytosis;Focal Adhesions;Genetic Transcription;Growth;Guanosine Triphosphate Phosphohydrolases;Hot Spot;Human;Immunocompetent;Invaded;KRASG12D;Kinetics;Knowledge;Laboratories;Lentivirus;Lung Adenocarcinoma;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Medical center;Mentors;MicroRNAs;Microtubules;Molds;Molecular;Monomeric GTP-Binding Proteins;Motility;Mus;Neoplasm Metastasis;New Mexico;Organelles;Paper;Pathway interactions;Peer Review;Physicians;Positioning Attribute;Process;Productivity;Property;Protein Secretion;Proteins;Proxy;Receptor Protein-Tyrosine Kinases;Research;Research Personnel;Rest;Scientist;Secretory Vesicles;Signal Transduction;Site;Source;Stains;Structure;Survival Rate;Testing;The Cancer Genome Atlas;Tissues;Training;Training Programs;Translating;Tumor Promotion;Universities;Vesicle;Vimentin;Work;actionable mutation;activating transcription factor;anti-cancer research;cancer cell;career development;cell fixing;cell motility;cohort;congenic;cytokine;design;epithelial to mesenchymal transition;human model;imaging study;inhibitor;loss of function;migration;mouse model;paxillin;post-doctoral training;programs;rab GTP-Binding Proteins;skills;small hairpin RNA;targeted cancer therapy;therapeutically effective;trafficking;transcriptome;tumor;tumor microenvironment;tumor-immune system interactions;tumorigenic;vesicle transport

public_health_relevance:
ProjectNarrativeTherearefeweffectivetherapeuticoptionsformetastaticlungadenocarcinomas(LUADs)thatlackactionablemutations in receptor tyrosine kinases and there is an urgent need to develop a better understanding of thebiological basis of LUAD growth and metastasis. On the basis of the preliminary results presented here Ipostulate that LUAD growth and metastasis is driven by a secretory program activated by epithelial-to-mesenchymaltransition(EMT).IfproventruethesefindingswouldshowthatEMTpromotesmetastasisthroughacellnon-autonomousmechanismwhichwouldadvanceourunderstandingofthemolecularunderpinningsofLUAD progression and would provide a rationale to identify actionable targets in the EMT-activated secretoryprogram.


application_id: 10746813
project_number: 5R01DK128033-03
project_title: Mirabegron and tadalafil effectiveness for treatment of prediabetes
administering_ic: NIDDK
award_notice_date: 2023-12-15
opportunity_number: PAS-20-160
application_type: 5
activity_code: R01
ic: DK
serial_number: 128033
program_official: GOROSPE, RAFAEL
project_start_date: 2021-12-01
project_end_date: 2026-11-30
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
arra_indicator: N
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 Agonists;Adrenergic beta-Agonists;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;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;Recommendation;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: 10746442
project_number: 5R01EB028792-04
administering_ic: NIBIB
award_notice_date: 2023-11-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EB
serial_number: 028792
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2020-03-15
project_end_date: 2025-11-30
study_section: Imaging Guided Interventions and Surgery Study Section[IGIS]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-12-01
project_title:
Perioperative Diffuse Optical Imaging of Tissue Blood Flow and Oxygenation for Optimization of Mastectomy Skin Flap Viability

project_abstract:
ABSTRACTMastectomy is performed on approximately half of women with breast cancer. Postmastectomy breastreconstruction has benefits for body image sexuality self-esteem and quality of life. Poor clinical prognosesafter breast reconstruction often involve mastectomy skin flap necrosis (MSFN) or other complicationsassociated with the lack of blood flow and oxygenation to wound tissue volumes. MSFN and wound dehiscenceleads to a number of challenges including wound management problems delays to adjuvant therapy estheticcompromise implant extrusion patient distress and financial loss. A technology that allows surgeons toperioperatively assess and optimize preservation of skin flaps while avoiding complications is essential to ensuresuccessful clinical outcomes. Although alternative techniques have been explored to identify ischemic-hypoxictissues at risk of necrosis none have achieved universal acceptance as each technique has a few challengingissues that decrease its clinical usefulness. Moreover no single technique provides both blood flow andoxygenation information which are essential for precise assessment of skin flap viability. Our recent innovativedevelopment of near-infrared speckle contrast diffuse correlation tomography (scDCT) technique provides anoninvasive (dye-free) and noncontact means for continuous 2D/3D imaging of blood flow distributionsthroughout large/thick tissue volumes such as mastectomy skin flaps. We propose to extend this scDCTprototype to a next generation multi-wavelength scDCT (MW-scDCT) device for perioperative imaging of bothblood flow and oxygenation distributions in mastectomy skin flaps. New high-speed algorithms for 2D mappingand 3D image reconstruction will be developed to accommodate rapid online assessment of skin flaphemodynamics. This MW-scDCT system will be tested/optimized using standard tissue-simulating phantoms(Aim 1) and calibrated/validated against a commercial dye-based fluorescence angiography device (SPY Elite)in swine (Aim 2) and patients (Aim 3) undergoing mastectomy with expander-implant based breastreconstruction. The in vivo studies will determine the capability of our MW-scDCT for intraoperative prediction ofMSFN regions/volumes and postoperative optimization of incremental expander volumes to reduce risks ofMSFN and other complications. We expect that combined measurements of preoperative baseline andintraoperative alteration in skin flap flow and oxygenation will provide a more accurate assessment of skin flapviability than a one-time single-parameter measurement (i.e. blood flow blood oxygenation or fluorescenceperfusion). Study outcomes will provide the rationale for designing MW-scDCT guided clinical trials ofmastectomy with breast reconstruction to reduce postoperative complications and healthcare costs. Moreoverthis noninvasive (dye-free) noncontact continuous and cost-efficient imaging system has the potential forperioperative use in many other clinical settings especially where contact measurements may not be possiblesuch as for continual and longitudinal monitoring of burns wounds and other types of tissue flaps.

project_terms:
Adjuvant Therapy;Algorithms;Area;Blood;Blood capillaries;Blood flow;Body Image;Brain;Brain Hypoxia-Ischemia;Breast;Burn injury;Calibration;Clinical;Clinical Trials;Color;Dermal;Development;Devices;Diffuse;Distress;Dyes;Ensure;Esthetics;Excision;Family suidae;Fluorescence;Fluorescence Angiography;Health Care Costs;Hemorrhage;Heterogeneity;Human;Image;Imaging Techniques;Implant;Incidence;Indocyanine Green;Interruption;Judgment;Laboratories;Lateral;Malignant Breast Neoplasm;Mammaplasty;Maps;Mastectomy;Measurement;Measures;Metabolic;Monitor;Necrosis;Operative Surgical Procedures;Optics;Outcome;Outcome Study;Oxygen;Patients;Pattern;Perfusion;Perioperative;Postoperative Complications;Postoperative Period;Quality of life;Risk;Risk Reduction;Rodent;Sexuality;Skin;Speed;Surface;Surgeon;System;Techniques;Technology;Temperature;Testing;Thick;Three-Dimensional Image;Three-Dimensional Imaging;Tissue imaging;Tissues;Woman;breast surgery;clinical prognosis;cost efficient;design;diffuse optical spectroscopy and imaging;hemodynamics;image reconstruction;imager;imaging system;in vivo;innovation;multimodality;next generation;non-invasive optical imaging;novel;operation;preclinical study;preservation;prevent;prototype;self esteem;surgery outcome;tomography;translational study;women's diagnosis;wound;wound treatment

public_health_relevance:
PROJECT NARRATIVEClinical prognoses after surgical breast reconstruction often involve mastectomy skin flap necrosis or othercomplications associated with lack of blood flow and oxygenation to wound tissue volumes. The objective of thisproject is to design and optimize a novel noninvasive optical imaging technique which will enable rapid online3D imaging of both blood flow and oxygenation distributions throughout the entire volume of mastectomy skinflaps to perioperatively assess ischemic-hypoxic tissue regions/volumes. Outcomes from this translational studyin swine and patients undergoing mastectomy with expander-implant based breast reconstruction will provideessential information for intraoperative guidance of compromised tissue excision and postoperative optimizationof incremental expander fill volumes to reduce postmastectomy complications and healthcare costs.


application_id: 10746421
project_number: 5R01DK124626-04
project_title: Mechanisms for activation of beige adipose tissue in humans
administering_ic: NIDDK
award_notice_date: 2023-12-15
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 124626
program_official: GOROSPE, RAFAEL
project_start_date: 2020-12-01
project_end_date: 2026-11-30
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have been studying subcutaneous white adipose tissue (SC WAT) beiging in response to mirabegronwhich is a 3 adrenergic receptor (3AR) agonist. 3ARs are found in adipocytes and smooth muscle andmirabegron is an FDA approved drug for overactive bladder. Treatment of obese insulin resistant humans fortwelve weeks with mirabegron consistently induced SC WAT beiging and this led to improved oral glucosetolerance and a lower HbA1c. The mechanism for improved glucose homeostasis involved both a smallimprovement in insulin sensitivity and a significant improvement in -cell function (insulin secretion) along withan increase in muscle oxidative type 1 fibers; however there was no weight loss or induction of brown fat.Since pancreatic -cells and muscle do not express the 3AR the beneficial effects of mirabegron in thesecells likely occurred by an indirect mechanism. The physiological effects of mirabegron are likely mediated in part by the induction of beige adipose whichrepresents a metabolic sink for glucose and lipids and which may alter adipose remodeling. In addition thechanges in adipose tissue and other organs may result in secondary effects that target other tissues. Specific Aim 1. To examine the effects of the 3 agonist mirabegron on glucose metabolism we willcomprehensively analyze glucose tolerance insulin sensitivity and -cell function in prediabetic subjects in a4-month placebo-controlled randomized trial. We will assess changes in adipose tissue including beiginginflammation fibrosis and insulin-stimulated glucose uptake by adipocytes. We will also fully characterizegene expression in SC WAT by RNA-seq to identify potential mechanisms such as altered adipokine profiles. Specific Aim 2. We hypothesize that mirabegron causes cells that express the 3AR to change the levelsof secreted factors that affect peripheral cell types such as -cells and muscle. We will use biochemical andpharmacological approaches to identify the mechanism by which conditioned medium from mirabegron-treatedadipocytes increases PGC1 expression in muscle in vitro. We will utilize unbiased approaches to identifychanges in lipids metabolites and exosome miRNA composition in the adipocyte conditioned media. We willuse these approaches to identify molecules altered in plasma by mirabegron treatment that are responsible forthe improvement in -cell and muscle function. Clinical relevance: Mirabegron treatment has positive effects on glucose tolerance due to improvementsin insulin sensitivity and -cell function. This may be exploited to prevent conversion of prediabetes todiabetes or used as a therapeutic in diabetics. This application will also increase our understanding of themechanism(s) by which mirabegron acts which may reveal new therapeutic targets

project_terms:
Adipocytes;Adipose tissue;Adrenergic Agonists;Adrenergic Receptor;Affect;Agonist;Anti-diabetic Drugs;Beta Cell;Biochemical;Body Weight decreased;Brown Fat;Cell Physiology;Cells;Chronic;Conditioned Culture Media;Consumption;Development;Diabetes Mellitus;Epidemic;FDA approved;Fatty acid glycerol esters;Fiber;Fibrosis;Gene Expression;Glucose;Glycosylated hemoglobin A;Health;Homeostasis;Human;In Vitro;Inflammation;Insulin;Insulin Resistance;Lipids;Lipolysis;Mammals;Measures;Mediating;Metabolic;Metabolic syndrome;Methods;MicroRNAs;Mus;Muscle;Muscle Cells;Muscle function;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Overactive Bladder;Participant;Peripheral;Pharmaceutical Preparations;Physiological;Plasma;Play;Prediabetes syndrome;Property;Proteins;Research;Research Project Grants;Rodent;Role;Skeletal Muscle;Smooth Muscle;Structure of beta Cell of islet;Therapeutic;Thinness;Tissues;Volatile Fatty Acids;adipokines;adult obesity;bile acid metabolism;blood glucose regulation;cell type;clinically relevant;combat;design;diabetic;exosome;fighting;functional improvement;glucose metabolism;glucose tolerance;glucose uptake;human study;improved;insulin secretion;insulin sensitivity;interest;mRNA Expression;new therapeutic target;novel strategies;obesity treatment;older adult;oral glucose tolerance;pharmacologic;prevent;randomized placebo controlled trial;response;subcutaneous;transcriptome sequencing;uncoupling protein 1

public_health_relevance:
This research grant is designed to determine whether chronic treatment with mirabegron a 3adrenergic receptor agonist approved for treatment of over active bladder improves metabolichomeostasis in prediabetic obese research participants. We will also investigate theunderlying mechanisms for improved -cell function and insulin sensitivity by mirabegrontreatment which we recently demonstrated. There is a tremendous need for new approachesto fight the obesity and type 2 diabetes epidemic and this research is thus highly relevant tohuman health.


application_id: 10746197
project_number: 1RF1AG084134-01
administering_ic: NIA
award_notice_date: 2023-08-22
opportunity_number: PAR-22-093
application_type: 1
activity_code: RF1
ic: AG
serial_number: 084134
program_official: ROVESCALLI, ALESSANDRA C
project_start_date: 2023-09-01
project_end_date: 2026-08-31
study_section: Clinical Neuroscience and Neurodegeneration Study Section[CNN]
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: GERMAN, DWIGHT C.;ZHANG, RONG ;ZHU, DAVID C
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-01
project_title:
Biomarkers to Track Effective Interventions that Delay Dementia Onset in Participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" Trial

project_abstract:
Project SummaryIt is often hard to distinguish between Alzheimers disease (AD) and AD-related dementias (ADRDs) includingVascular contributions to Cognitive Impairment and Dementia (VCID) due to a similar clinical presentation ofmemory loss and the presence of cardiovascular (CV) risk factors (e.g. hypertension dyslipidemia). While CVrisk factors have available drug therapies increased physical activity also significantly lowers these co-morbidities. Unfortunately evidence linking CV and exercise interventions to the prevention of cognitive declineis inconclusive nor are biomarkers available to determine the efficacy of pre-dementia lifestyle interventions.This ancillary R01 will use plasma-based biomarkers and neuroimaging from subjects enrolled in our NIH-funded trial Risk Reduction for Alzheimers Disease (rrAD; NCT02913664). This phase II randomizedcontrolled trial will determine the independent and combined effects of Intensive pharmacological Reduction ofVascular Risk factors (IRVR; i.e. blood pressure lipids) and aerobic exercise (Ex) on cognitive function.Participants were randomized into 2-year interventions (IRVR Ex IRVR+Ex and a control arm of standardcare (SC)) with plasma and neuroimaging collected at baseline and yearly. Of the 513 initial rrAD subjects(63% females; 34% aged 71-85; 13% African-American; 4% LatinX) 89% (458 subjects) have longitudinalserum and neuroimaging biomarkers available for linear mixed-models analyses. Banked longitudinal rrADplasma samples will be used to test the hypothesis that 1) benchmark AD 2) benchmark VCID and/or 3) novelcirculating brain-derived biomarkers can be modulated by positive lifestyle interventions. Aim 1 will test if thebenchmark AD biomarkers A42/A40 ratio will increase while pTau181 and pTAu 231 will decrease thegreatest with IRVR+Ex. Higher ratios and lower tau will be associated with our secondary outcome measuresof preserved hippocampal volume (T1-weighted MRI). Aim 2 will test if primary benchmark VCID biomarkerswill reveal effects of vascular and exercise interventions on cerebrovascular health. We will test if lowerpathologic pro-angiogenic proteins (i.e. VEGF-D PlGF bFGF) measured longitudinally decrease withintervention. Lower expression will coincide with secondary outcome measures of increased regional cerebralblood flow (i.e. arterial spin labeling MRI) and fewer white matter hyperintensities (i.e. T2 FLAIR MRI). Aim 3will test if vascular and exercise interventions alter the neurotrophic cargo of circulating neuronal-enrichedextracellular vesicles (EVs). We will test IRVR+Ex lowers pro- (i.e. uncleaved) brain-derived neurotrophicfactor (BDNF) and increases mature BDNF in neuronal-enriched EVs. Higher BDNF will coincide with thesecondary outcome of preserved default-mode network (DMN) connectivity measured by resting-statefunctional (rs-f)MRI. We hypothesize that AD VCID and EV biomarkers not only identify individuals with highrisk for AD/ADRDs but can also track efficacy of independent and combined lifestyle interventions that improvecerebrovascular health and delay dementia onset in sedentary adults.

project_terms:
3-Dimensional;Address;Adult;Aerobic Exercise;African American;Age;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease related dementia;Alzheimer's disease risk;Alzheimers disease biomarker;Amyloid beta-42;Amyloid beta-Protein;Angiogenic Proteins;Benchmarking;Biological Assay;Biological Markers;Biological Specimen Banks;Blood;Blood Pressure;Blood Vessels;Blood specimen;Brain;Brain Ischemia;Brain-Derived Neurotrophic Factor;Cardiovascular Diseases;Cardiovascular system;Cell Communication;Cell surface;Cells;Cerebral small vessel disease;Cerebrovascular Circulation;Clinical;Clinical Trials;Cognitive;Data;Dementia;Dyslipidemias;Endothelium;Enrollment;Exercise;FGF2 gene;Family history of;Female;Functional Magnetic Resonance Imaging;Funding;High Prevalence;Hippocampus;Hypertension;Impaired cognition;Individual;Intervention;Knowledge;Latinx;Link;Lipid Binding;Lipids;Magnetic Resonance Imaging;Measurable;Measures;Memory;Memory Loss;Modeling;National Institute of Neurological Disorders and Stroke;Neurocognitive;Neurons;Outcome Measure;PGF gene;Participant;Pathologic;Pharmacotherapy;Phase;Physical activity;Plasma;Prevention;Randomized;Randomized Controlled Trials;Rest;Risk Reduction;Sampling;Serum;Site;Structure;Testing;United States National Institutes of Health;Validation;Vascular Endothelial Growth Factor D;White Matter Hyperintensity;abeta deposition;aged;arm;arterial spin labeling;biomarker identification;blood lipid;blood-brain barrier disruption;brain health;brain-derived neurotrophic factor precursor;cardiovascular disorder risk;cardiovascular risk factor;cerebrovascular health;cognitive function;comorbidity;effective intervention;efficacy evaluation;exercise intervention;extracellular vesicles;follow-up;high risk;high risk population;improved;lifestyle intervention;nervous system disorder;neural network;neurobiological mechanism;neuroimaging;neuroimaging marker;neuroprotection;novel;novel marker;particle;pharmacologic;preservation;primary outcome;prodromal Alzheimer's disease;secondary outcome;sedentary;specific biomarkers;standard care;tau Proteins;theranostics;trial enrollment;vascular cognitive impairment and dementia;vascular risk factor

public_health_relevance:
Project NarrativeAlzheimers disease (AD) is a devastating neurologic disorder that will impact millions in the U.S. withinthe next decades. This ancillary R01 will use blood specimens and neuroimaging from our NIH-fundedtrial Risk Reduction for Alzheimers Disease (rrAD) to identify biomarkers that track effective lifestyleinterventions to delay dementia in individuals with cardiovascular disease and at a high-risk for AD. Wewill utilize current benchmark biomarkers for 1) AD and 2) vascular contributions to cognitiveimpairment and dementia (VCID) along with 3) novel circulating brain-derived extracellular vesicles toidentify mechanisms for the independent and combined neuroprotective effects of exercise andintensive cardiovascular disease risk reduction over the 2 years of trial enrollment.


application_id: 10745738
project_number: 5R01AG080589-02
project_title: APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2023-11-29
opportunity_number: PAR-22-093
application_type: 5
activity_code: R01
ic: AG
serial_number: 080589
program_official: DIBATTISTA, AMANDA
project_start_date: 2022-12-01
project_end_date: 2027-11-30
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
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:
AbstractIn comparison to the highly protective E2 allele of Apolipoprotein E (APOE) the E4 allele hasbeen associated with a host of detrimental effects including but not limited to increasedamyloid deposition more severe tau pathology heightened neuroinflammation cerebrovasculardysfunction and various metabolic deficits. With its strong risk profile and varied biologicalmechanisms APOE itself has emerged as an attractive candidate for gene therapy. In additionto providing a much-needed preclinical model for ongoing and future trials exploration of E4 toE2 allele switching has the potential to help answer several fundamental and longstandingbiological questions in the field. For example which ApoE-synthesizing cell-type(s) drive ADpathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associateddeficits set in stone at birth (developmentally) or is later-life APOE editing a feasible approachto mitigate AD neuropathology and cognitive dysfunction? To this end we have generated aseries of novel APOE switch (4s2) mouse models that allow for temporal and cell-specific alleleswitching from E4 to E2. Our preliminary data confirms that these 4s2 mice synthesize a full-length human ApoE4 at baseline and importantly when crossed to various inducible CreERT2strains the switch successfully leads to efficient recombination and expression of human ApoE2in cell types of interest. Given the remarkable protective effects of E2 carriage and the variousroles of ApoE at differing steps of AD pathogenesis we hypothesize that astrocyte-specificallelic switching to E2 will simultaneously rescue multiple metabolic immune andneuropathological deficits associated with E4. We propose to leverage these unique mousemodels to determine the therapeutic window for CNS-specific E4 to E2 allele switching tosimultaneously mitigate metabolic deficits neuroinflammation cerebrovascular dysfunctionamyloid pathology and cognitive dysfunction. If successful this proposal will provide anessential preclinical model for ongoing and future clinical trials and will provide critical newinformation regarding ideal cell- region- and temporally-specific opportunities for therapeuticApoE modulation.

project_terms:
Affect;Alleles;Alzheimer's Disease;Alzheimer's disease pathology;Amyloid;Amyloid beta-Protein;Amyloid deposition;Amyloidosis;Apolipoprotein E;Astrocytes;Automobile Driving;Biological;Birth;Brain;Candidate Disease Gene;Cells;Cerebrovascular Disorders;Cerebrum;Clinical Trials;Cognitive deficits;Cre lox recombination system;Data;Development;Functional disorder;Future;Gene Expression Profile;Genes;Genetic;Genetic Recombination;Genotype;Homozygote;Human;Hyperlipidemia;Image;Immune;Impaired cognition;Individual;Inflammation;Knockout Mice;Late Onset Alzheimer Disease;Length;Link;Measures;Metabolic;Metabolism;Modeling;Mouse Strains;Mus;Myelin;Nature;Nerve Degeneration;Neurons;Odds Ratio;Outcome;Pathogenesis;Pathologic;Pathology;Pathway interactions;Peripheral;Phagocytosis;Physiological;Play;Pre-Clinical Model;Risk;Role;Series;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Supplementation;Synapses;Testing;Therapeutic;amyloid pathology;apolipoprotein E-4;brain dysfunction;cell type;cerebrovascular;efficacy testing;gene therapy;genetic risk factor;in vivo;induced pluripotent stem cell;interest;late life;life span;lipidomics;loss of function;metabolomics;mouse model;neuroinflammation;neuropathology;novel;overexpression;protective effect;single-cell RNA sequencing;stable isotope;tau Proteins;transcriptomics

public_health_relevance:
PROJECT NARRATIVEThe strongest genetic risk factor for developing late-onset Alzheimers disease is the gene Apolipoprotein E(APOE) where the E4 allele dramatically increases risk while the E2 allele is strongly protective. In thisproject we will determine whether allelic switching from E4 to E2 will simultaneously rescue multipleneuropathological deficits associated with E4. If successful this proposal will provide an essential preclinicalmodel for ongoing and future clinical trials and will provide critical new information regarding opportunitiesfor therapeutic ApoE modulation.


application_id: 10745654
project_number: 5R01HL160927-03
project_title: Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2023-11-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 160927
program_official: LIU, LIJUAN
project_start_date: 2021-12-01
project_end_date: 2026-11-30
study_section: Special Emphasis Panel[ZRG1-TDPS-R(01)]
contact_pi_person_id: 12101586
contact_pi: TAN, YI
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Atherosclerosis is a narrowing of arteries caused by plaque buildup. Dyslipidemia especially elevated low-density lipoprotein cholesterol is a major risk factor for atherosclerotic plaque formation. Current therapies foratherosclerosis focus on lowering cholesterol. However conventional lipid lowering therapies (such as statins)are associated with obvious side effects. Developing more specific and efficient treatments are needed.Fibroblast growth factor 1 (FGF1) has been widely studied for its therapeutic benefits in cardiovascular disordersprimary utilization of its mitogenic functions. Recently FGF1 was shown to exert an unexpected metabolic activityby regulating adipose remodeling and glucose homeostasis demonstrating a potential for treatment of metabolicsyndrome. However wild-type FGF1 (FGF1WT) induced hyperproliferation can lead to increased tumorigenic risk;this becomes the primary obstacle for its widespread application. To reduce this risk we recently engineered apartial FGF1 agonist carrying triple mutations of the heparin-binding sites (FGF1HBS) which abolishedproliferative potential but maintains full FGF1WT metabolic activity. Notably chronic treatment of db/db mice withFGF1HBS almost completely reversed diabetes-associated NAFLD. These findings suggest that FGF1HBS is apotentially safe and efficient therapeutic approach for treatment of metabolic syndrome.Although characterization of the metabolic functions of FGF1 is ongoing little is known about its roles inatherosclerosis. A small case observation found an increased FGF1 expression in neovascularized andmacrophage-rich regions of plaque implying a potential pathological role of FGF1 in human atherogenesis.However whether and how FGF1 plays beneficial or detrimental roles in atherogenesis remain unexplored. Werecently examined the impact of FGF1 administration on the pathogenesis of atherosclerosis in ApoE-KO miceand found that FGF1HBS markedly ameliorated atherosclerotic phenotypes without significant proliferativepotential in liver. Furthermore FGF1 treatment reduced cholesterol levels in the blood liver and intestine butincreased cholesterol contents in feces. These preliminary data indicate that FGF1 regulation of cholesterolhomeostasis in both liver and intestine is responsible for its protection from atherosclerosis. The liver is a majorsite for cholesterol biosynthesis while the intestine maintains cholesterol homeostasis by mediating intestinalabsorption of dietary and biliary cholesterol. Therefore we hypothesize that non-mitogenic variant FGF1HBSprevents atherosclerosis by inhibiting hepatic cholesterol synthesis and suppressing intestinalcholesterol absorption without risks of hyperproliferation. We will test the hypothesis in three specific aims:1) Determine the roles of FGF1 in the development of atherosclerosis; 2) Determine the effects and mechanismof FGF1 on hepatic cholesterol biosynthesis; 3) Determine the effects and mechanism of FGF1 on intestinalcholesterol absorption. This project will provide fundamental evidence for FGF1HBS acting at the hepatocytesand intestinal enterocytes as a novel approach for the prevention of atherosclerosis in future clinical studies.

project_terms:
Adipose tissue;Agonist;Animal Model;Apolipoprotein E;Arterial Fatty Streak;Arteries;Atherosclerosis;Attenuated;Biliary;Binding Sites;Blood;Breeding;Cardiovascular Diseases;Cell Proliferation;Cells;Cholesterol;Cholesterol Homeostasis;Chronic;Clinical Research;Coagulation Process;Data;Development;Diabetes Mellitus;Dose;Dyslipidemias;Engineering;Enterocytes;FGF1 gene;Feces;Fluorescein;Future;Genetic Transcription;Heparin Binding;Hepatic;Hepatocyte;Human;Hyperlipidemia;Intestinal Absorption;Intestines;Knockout Mice;LDL Cholesterol Lipoproteins;Label;Life Style;Lipids;Liver;Macrophage;Mediating;Mediator;Metabolic;Metabolic syndrome;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Nuclear Translocation;Operative Surgical Procedures;Organ;Organoids;Pathogenesis;Pathologic;Patients;Phenotype;Play;Prevention approach;Radioisotopes;Recombinants;Regulation;Risk;Risk Factors;Role;Site;Testing;Therapeutic;Up-Regulation;Variant;angiogenesis;atherogenesis;blood glucose regulation;cholesterol absorption;cholesterol biosynthesis;clinical practice;clinical translation;db/db mouse;dietary;insight;neovascularization;non-alcoholic fatty liver disease;novel;novel strategies;novel therapeutic intervention;overexpression;prevent;side effect;transcription factor;translational potential;tumorigenic

public_health_relevance:
The objective of this study is to define how FGF1 protects against atherosclerosis and whether there is aclinical translational potential of the novel non-mitogenic variant FGF1HBS for preventing atherosclerosis byinhibiting hepatic cholesterol biosynthesis and suppressing intestinal cholesterol absorption without risk ofhyperproliferation. We will first optimize the doses of FGF1 protection against atherosclerosis in two distinctatherogenic animal models and determine the roles of endogenous FGF1 in the development ofatherosclerosis. Next we will determine the effects and mechanism of FGF1 on hepatic cholesterolbiosynthesis and intestinal cholesterol absorption. This project will reveal new insight into the underlyingmechanism behind FGF1 protection against atherosclerosis as well as provide fundamental evidencesupporting the non-mitogenic variant FGF1HBS as a novel therapeutic approach for prevention ofatherosclerosis in future clinical practice.


application_id: 10740150
project_number: 1U24DA058961-01
project_title: The University of Kentucky Racial Equity Initiative Coordinating Center
administering_ic: NIDA
award_notice_date: 2023-08-10
opportunity_number: RFA-DA-23-025
application_type: 1
activity_code: U24
ic: DA
serial_number: 058961
program_official: ROMBERG, ALEXA RUTH
project_start_date: 2023-08-15
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZDA1 TXT-E (M1)]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
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 EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY The overarching goal of the University of Kentucky Racial Equity Initiative CoordinatingCenter (UK-REI-CC) is to focus on collectivism and elevate the resilience of People of Color andIndigenous (POCI) communities through supporting REI grantees to conduct culturally relevantbest practice community engaged substance use research. UK-REI-CC will draw from theRadical Healing in Communities of Color6 a strength-based framework to coordinate projectsfrom both Highly Resourced Institutions (HRIs) and Limited Resourced Institutions (LRIs). TheUK-REI-CC is led by a PI and faculty with established collaborations and extensive experiencefocused on community-engagement drug treatment HIV randomized controlled trialsimplementation science pharmacology and justice-involvement. In collaboration with the NIDASteering Committee and expert panel UK-REI-CC will complete the following aims: 1) Todevelop and support a learning community through networking & training among REI grantees.UK REI-CC will organize and convene a kick-off annual meetings and monthly meetings of REIgrantees. Using Pure network mapping system7 REI grantees and community partners willaccess investigators and their worldwide networks. UK-REI-CC will conduct a bi-annual needsassessment convene workgroups devise quarterly trainings develop a speaker series andhost networking events encouraging collectivism and highlighting assets among the REIinstitutions. 2) To enhance REI projects by providing research resources focused on communityengagement. UK REI-CC will provide technical assistance and consultations focused onelevating the voices of marginalized communities. The center will provide quarterly trainings toREI project sites and resources focused on building and strengthening academic-communitypartnerships. 3) To optimize data collection and analyses by the REI community. UsingTableau UK-REI-CC will host an interactive dashboard illustrating progress for REI projects.The center will provide consultation on devising research questions culturally appropriatemeasures recruitment and retention strategies qualitative and quantitative data analyses andincorporating community partners in data analyses. 4) To facilitate broad and accessiblecommunication and dissemination of REI project findings for end users. UK REI-CC will developonline resources to share press releases publications and research presentations. In additionthe UK-REI-CC will leverage our expertise in culturally tailoring messaging to ensureaccessibility for all communities participating in the research. Taken together these activitieswill enhance the capacity for REI projects to conduct impactful substance use research.

project_terms:
Acceleration;Affect;Black American;Collaborations;Color;Communication;Communities;Community Participation;Consultations;Data;Data Analyses;Data Collection;Ensure;Ethnic Origin;Event;Faculty;Goals;HIV;Hospitals;Indigenous;Indigenous American;Inequity;Institution;Intervention;Justice;Kentucky;Limited English Proficiency;Maps;Measures;Modeling;National Institute of Drug Abuse;Needs Assessment;Pharmacology;Pharmacotherapy;Positioning Attribute;Press Releases;Publications;Qualifying;Race;Racial Equity;Randomized Controlled Trials;Research;Research Personnel;Research Project Grants;Resource Sharing;Resources;Science;Series;Site;Substance Use Disorder;System;Testing;Training;Trauma;Universities;Voice;Work;community engaged research;community engagement;community partnership;dashboard;diversity and inclusion;experience;forgetting;healing;implementation science;indigenous community;innovation;learning community;marginalized community;meetings;member;novel;online resource;overdose death;people of color;recruit;resilience;retention rate;rural setting;social media;structural determinants;substance use;synergism;tailored messaging;urban setting;webinar

public_health_relevance:
Project Title: The University of Kentucky Racial Equity Initiative Coordinating Center (UK-REI-CC)Project Narrative: The UK-REI-CC is an innovative coordinating center model centering collectivism andemphasizing the resilience of racial and ethnic marginalized communities. The UK-REI-CC will enhance andsupport the NIDA REI projects by providing resources for networking and training conducting community-engaged research data collection and analyses and communication and dissemination. Completing theobjectives of the UK-REI-CC will result in accelerating the high impact work of the NIDA Racial Equity Initiative.


application_id: 10739409
project_number: 3RF1NS088555-07A1S1
administering_ic: NINDS
award_notice_date: 2023-09-21
opportunity_number: PA-21-071
application_type: 3
activity_code: RF1
ic: NS
serial_number: 088555
suffix: A1S1
program_official: BOSETTI, FRANCESCA
project_start_date: 2015-02-01
project_end_date: 2024-06-30
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-16
project_title:
Diversity Supplement: B Cells Directly Alter Adaptive Plasticity to Support Functional Recovery After Stroke

project_abstract:
Our novel data from the past New Investigator R01 award period show post-stroke B cells diapedese intoremote regions (e.g. dentate gyrus) that support motor and cognitive recovery after transient middle cerebralartery occlusion (tMCAo). B cells can provide neurotrophic support through secretion of both interleukin (IL)-10and additional neurotrophin(s) to support post-stroke plasticity. The central hypothesis of this R01 renewal isthat a subset of B cells diapedese into brain regions remote from the infarct to provide long-term neurotrophicsupport for functional recovery. Brain-derived neurotrophic factor (BDNF) mediates synaptic transmission andmemory formation during health and protects neurons from glutamate-induced excitotoxicity after stroke. BDNFalso mediates B cell egress from bone marrow and can be produced by B cells in response to glutamatestimulation through the NMDAR subunit GluN2A. Based on our pilot data we will test: if a subset of post-strokeB cells referred to as B cellsBDNF+ upregulate BDNF after encountering glutamate; if B cellsBDNF+ support motorand cognitive recovery; and if B cell-derived BDNF is impaired in aged females. We will use 4 mos. (young)and 16 mos. (aged) female and male mice to test if B cellsBDNF+ support neuronal function plasticity motorand multi-domain cognitive recovery post-stroke. Aim 1 will test if (1A) post-tMCAo glutamate binds to B cellGluN2A to increase BDNF production and drive recovery-linked intracellular Ca2+ signaling that is sex- andage-dependent. We will (1B) use B cellsNtrk2tm1Ddg/J in vitro to test if the BDNF receptor TrkB is required forBDNF production and in vitro neuroprotection. Aim 2 will test if B cellsBDNF+ support remote plasticity motor andcognitive recovery in a primary motor cortex photothrombosis stroke model. Inducible depletion of (2A) all Bcells or (2B) specific B cell-derived BDNF in young and aged female hCD20TamCre/ BDNFfl/fl mice and littermatecontrols will occur either acute (at D0) or delayed (beginning D7 post-stroke). Primary outcomes will include 1)peri-infarct and contralesional M1 plasticity 2) improved forelimb precision reaching and 3) preservation ofPavlovian stimulus-reinforcer learning on an automated touchscreen task. Aim 3 will test if B cell-derived BDNFaugments long-term motor and cognitive recovery. Aged C57BL/6J female mice will receive tMCAo or shamsurgery and adoptive transfer of B cells that (3A) overexpress BDNF or (3B) lack BDNF the latter derived fromhCD20TamCre/BDNFfl/fl donor mice beginning D7 post-stroke. Primary outcomes will include 1) improvedprecision skilled reaching 2) ameliorated hippocampal-specific cognitive deficits tested via touchscreen patternseparation and 3) regional ipsi- and contralesional diapedesis of B cells as determined via whole brain serialtwo-photon tomography that correlates to within-animal magnitude of brain circuit-specific cognitive functionand motor recovery. These studies will confirm an age-dependent loss of a novel subset of B cells BcellsBDNF+ in females. They will also confirm that therapeutically targeting B cells can improve motor andcognitive deficits  a potential treatment supporting plasticity-based recovery after any CNS injury or disease.

project_terms:
Acute;Adult;Affect;Age;Anatomy;Animals;Anxiety;Area;Automobile Driving;Award;B-Cell Acute Lymphoblastic Leukemia;B-Cell Development;B-Lymphocyte Subsets;B-Lymphocytes;Binding;Bone Marrow;Brain;Brain region;Brain-Derived Neurotrophic Factor;Cell Survival;Cell secretion;Cell surface;Cells;Central Nervous System Diseases;Cognitive deficits;Data;Elderly woman;FDA approved;Female;Forelimb;Genetic Polymorphism;Genetic Transcription;Glutamates;Growth Factor;Health;Hippocampus;Immune;Immune system;Impaired cognition;Impairment;In Vitro;Individual;Infarction;Infiltration;Interleukin-10;Ischemia;Learning;Leukocytes;Link;Mediating;Memory;Middle Cerebral Artery Occlusion;Modeling;Motor;Motor Activity;Motor Cortex;Mus;N-Methyl-D-Aspartate Receptors;Neuronal Plasticity;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Pattern;Population;Production;Publishing;Recovery;Recovery Support;Recovery of Function;Research;Research Personnel;Role;Signal Transduction;Stimulus;Stroke;Support System;Synaptic Transmission;Tamoxifen;Techniques;Testing;Therapeutic;Up-Regulation;adoptive B cell transfer;age related;aged;central nervous system injury;cognitive function;cognitive recovery;dentate gyrus;disability;excitotoxicity;extracellular;functional plasticity;improved;in vitro testing;learning strategy;long term recovery;male;migration;motor deficit;motor recovery;neuroinflammation;neuronal survival;neuroprotection;neurotrophic factor;novel;overexpression;post stroke;preservation;primary outcome;reinforcer;response;rituximab;sex;sham surgery;skills;stroke model;stroke recovery;stroke risk;synaptogenesis;therapeutic target;tomography;touchscreen;two-photon

public_health_relevance:
PROJECT NARRATIVEStroke the leading cause of long-term adult disability has no FDA-approved therapeutic treatments to boostlong-term recovery in part because we do not understand long-term mechanisms that influence recovery. Thisresearch proposes to identify mechanisms of neurotrophin support by B cells an immune cell subset thatmoves into uninjured areas of the post-stroke brain to support recovery. These studies will be critical inunderstanding how the immune system supports neuronal plasticity to improve long-term motor and cognitiverecovery after stroke with critical consideration of age and sex in the response of B cells to stroke.


application_id: 10738817
project_number: 5R00DA049908-04
project_title: Executive function in opioid-exposed offspring and subsequent molecular signatures
administering_ic: NIDA
award_notice_date: 2023-11-09
opportunity_number: PA-19-130
application_type: 5
activity_code: R00
ic: DA
serial_number: 049908
program_official: LIN, YU
project_start_date: 2020-05-01
project_end_date: 2025-11-30
study_section: ZDA1-SXM-M(02)S
contact_pi_person_id: 11000796
contact_pi: SMITH, BRITTANY L
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary My long-term career goal is to become a translational researcher who uses rodent models and humansamples to facilitate innovative interventions that readily adapt to the clinic. The current proposal represents animportant step in my transition to scientific independence and will significantly extend my training in behavioraland developmental neuroscience as well as provide new training in bioinformatics and translational research.These training activities will occur within the context of a timely public health crisis seen with the opioidepidemic. Children born to opioid-abusing mothers including mothers stabilized on medication-assistedtreatment (MAT) are at an increased risk for cognitive deficits that frequently display as problems withexecutive function (e.g. inattention impulsivity). Work in an animal model is necessary to 1) identify themechanisms underlying executive function deficits in order to develop treatment strategies and 2) control forunavoidable confounds seen in the clinic (e.g. polysubstance use). Currently there are no animal studies ofexecutive function after maternal opioid use and the present proposal seeks to fill this gap. Further tounderstand potential biological mechanisms we will use an unbiased hypothesis-driving bioinformaticsapproach to discover offspring molecular signatures of maternal opioid use. Overall the current proposal willtest the hypothesis that maternal opioid exposure including MAT causes executive function deficits inadulthood that are associated with transcriptional changes within the prefrontal cortex an area of the brainvulnerable to environmental exposures and important for executive function. Specific Aim 1 (mentored phase) will examine executive function in opioid-exposed offspring includingMAT using the 5 choice serial reaction time task. This training will extend my expertise in developmental andbehavioral neuroscience. Specific Aim 2 will test the hypothesis that maternal opioid exposure includingMAT creates gene expression signatures in the prefrontal cortex that relate to executive function deficits andwill include training (mentored phase; certificate program in Bioinformatics) and experiments (independentphase; RNA-seq of brains from Aim 1). I will use bioinformatics strategies to integrate RNA sequencing dataand complex executive function behavioral data. Specific Aim 3 (mentored phase) will test the hypothesis thatin humans maternal opioid exposure produces distinct epigenomic signatures that are detectable in humanDNA samples. This will take advantage of unique access to human samples from both opioid-exposed andnon-exposed children as well as access to their paired electronic health records. This will provide criticaltraining in working with clinical samples and is a key aspect of my training in translational research. My trainingwill be further supported by regular meetings with an expert Advisory Committee and completion of graduatecertificates in both Biomedical Informatics and Clinical & Translational Research.

project_terms:
Address;Adolescence;Adult;Advisory Committees;Affect;Animal Model;Animals;Area;Attention;Attention deficit hyperactivity disorder;Automobile Driving;Behavior;Behavior assessment;Behavioral;Bioinformatics;Biological;Blood;Blood specimen;Brain;Brain region;Buprenorphine;Child;Clinic;Clinical;Clinical Research;Cognition;Cognitive deficits;Complex;Complex Variables;DNA;Data;Development;Diagnosis;Electronic Health Record;Environment;Environmental Exposure;Epidemic;Epigenetic Process;Executive Dysfunction;Exposure to;Fetal Development;Foundations;Future;Future Generations;Gene Expression;Gene Expression Profile;Genetic Transcription;Goals;Government-Sponsored Programs;Healthcare;Hospital Charges;Hospitalization;Human;Impulsivity;Incidence;Infant;Intervention;Investigation;Life;Mentors;Methadone;Methylation;Molecular;Molecular Profiling;Mothers;Mus;Neonatal Abstinence Syndrome;Neurosciences;Newborn Infant;Opiate Addiction;Opioid;Outcome;Pattern;Peripheral;Pharmaceutical Preparations;Phase;Placenta;Population;Prefrontal Cortex;Pregnancy;Pregnant Women;Problem behavior;Prognosis;Public Health;Reaction Time;Recording of previous events;Reporting;Research;Resources;Risk;Rodent;Rodent Model;Sampling;Self-control as a personality trait;Severities;Short-Term Memory;Survival Rate;Swab;Testing;Therapeutic Intervention;Time;Training;Training Activity;Translational Research;Whole Blood;Woman;Work;biomedical informatics;career;certificate program;epigenomics;executive function;experimental study;genome-wide;help-seeking behavior;human DNA;human data;improved;improved outcome;in utero;inattention;innovation;maternal opioid use;medication-assisted treatment;meetings;mouse model;neonate;offspring;opioid abuse;opioid epidemic;opioid exposure;opioid use;polysubstance use;pre-clinical;prenatal;programs;response;standard of care;therapeutically effective;transcriptome sequencing;translational scientist;translational study;treatment strategy

public_health_relevance:
Project Narrative Children exposed to opioids in utero either through the mothers opioid use/abuse or via medication-assisted treatment for opioid addiction (MAT methadone or buprenorphine) are at an increased risk forcognitive deficits particularly those related to attention and impulse control. No study has addressed this in ananimal model so the goal of this proposal is to test how maternal opioid use including MAT affects offspringbrain development and behavior in a mouse model. These studies will establish a foundation for futureinvestigations into potential interventions to improve outcomes in opioid-exposed children.


application_id: 10738641
project_number: 3R01AA029798-02S1
project_title: Phosphodiesterase 4 mediated pathogenic mechanisms in alcohol associated liver disease
administering_ic: NIAAA
award_notice_date: 2023-03-30
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: AA
serial_number: 029798
suffix: S1
program_official: RADAEVA, SVETLANA
project_start_date: 2021-09-22
project_end_date: 2026-06-30
contact_pi_person_id: 11058066
contact_pi: GOBEJISHVILI, LEILA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThis is a proposal for a Diversity Supplement for an assistant professor in University ofLouisville School of Medicine to enhance research training and career development in a newfield of alcohol associated liver disease (ALD). The parent grant for this proposed supplementexamines phosphodiesterase 4 mediated pathogenic mechanisms contributing to thedevelopment of alcohol induced hepatic steatosis and injury. The proposed supplement projectexamines the cross talk between hepatocytes and hepatic stellate cells (HSC) via exosomes inthe development of ALD fibrosis. Dr. Gobejishvili (PI of the parent grant) Dr. McClain (mentorDirector of Alcohol Research Center at UofL) and Dr. Montoya-Durango developed new specificaims which are related to Aim 2 of the parent grant. Dr. Montoya-Durango will share hisexpertise in exosome research and epigenetics with our research team. This diversitysupplement will allow Dr. Montoya-Durango to enhance his skills and knowledge in a new fieldof study. During the Diversity Supplement period he will: (1) actively participate in experimentsoutlined in the proposal (2) publish at least 3 lead papers (3) present at the RSA and AASLDmeetings (4) receive regular individual mentoring on training progress and career goals and (5)submit grant applications.

project_terms:
ADD-1 protein;Accounting;Affect;Alcoholic Liver Diseases;Alcohols;Applications Grants;Architecture;Autocrine Communication;CYP2E1 gene;Cells;Cessation of life;Cholestasis;Cirrhosis;Development;Disease;Epigenetic Process;Ethanol Metabolism;Extracellular Matrix Proteins;FDA approved;Faculty;Fatty Liver;Fibrosis;Funding;Goals;Grant;H19 gene;Hepatic;Hepatic Stellate Cell;Hepatocyte;In Vitro;Individual;Knock-out;Knockout Mice;Knowledge;Lead;Life;Liver;Liver Cirrhosis;Liver Failure;Liver Fibrosis;Liver Regeneration;Liver diseases;Mediating;Mentors;Messenger RNA;Mus;Myofibroblast;Nutritional Support;Organ;Paper;Paracrine Communication;Pathogenicity;Patients;Physiology;Population;Process;Publishing;Regulation;Research;Research Training;Role;Steatohepatitis;Time;Training;United States;Universities;Untranslated RNA;Wild Type Mouse;alcohol exposure;alcohol research;career;career development;cell type;chronic liver injury;exosome;experimental study;field study;healing;hepatocyte injury;in vivo;lipid biosynthesis;lipid metabolism;liver injury;liver transplantation;medical schools;meetings;mortality;mouse model;parent grant;pharmacologic;phosphodiesterase IV;professor;public health relevance;skills

public_health_relevance:
Public Health Relevance StatementProject Narrative This diversity supplement to R01AA029798-02 will provide funding forUniversity of Louisville School of Medicine faculty Diego Montoya-Durango to conduct researchthat will substantially add to the parent grant. It also provides funding for his training in a newfield of study alcohol associated liver disease and his career development.


application_id: 10736668
project_number: 1R01CA283929-01
administering_ic: NCI
award_notice_date: 2023-07-25
opportunity_number: RFA-CA-22-050
application_type: 1
activity_code: R01
ic: CA
serial_number: 283929
program_official: STRECK, BRENNAN PARMELEE
project_start_date: 2023-07-25
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RPRB-6 (M2)]
contact_pi_person_id: 11642450
contact_pi: MCLOUTH, LAURIE
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
budget_start_date: 2023-07-25
project_title:
Pathways a Hope-Based Intervention to Support Personal Goal Pursuit Mental Health and Quality of Life during Advanced Lung Cancer Treatment

project_abstract:
ABSTRACTThe psychosocial care of patients with advanced lung cancer (ALC) has not kept pace with current medicaltreatments creating significant gaps in care. Treatments like immunotherapy have radically changed ALC careyielding less toxicity and unprecedented increases in 5-year survival. However mental health and quality of lifeconcerns persist which must be addressed to fully realize the survival benefits of these medicaladvancements. To meet the needs of patients in this new treatment context psychosocial and palliative carefor ALC must shift from a predominant end-of-life framework to one of survivorship. A hope-based interventionto support patients goal pursuits in their family social work and leisure lives is a promising approach tosupport mental health and quality of life in this current context. The long-term goal of this research is toimprove ALC patient mental health and quality of life during cancer treatment. The overall objective in thisapplication is to test the efficacy of a novel psychosocial intervention called Pathways to support personalgoal pursuit during ALC treatment. The central hypothesis is that Pathways will reduce goal disruption andthereby improve mental health and quality of life during ALC treatment. The rationale for this project is thatPathways a brief hope-based intervention delivered primarily at the point of ALC patient care by a range ofhealthcare providers (e.g. nurse occupational therapist social worker) has demonstrated feasibility andacceptability to ALC patients with encouraging preliminary effects on goal disruption mental health andquality of life outcomes. The central hypothesis will be tested through two specific aims: 1) Test the efficacy ofPathways against enhanced usual care; and 2) Evaluate goal interference and goal adjustment as mediators ofintervention effects. Because ALC disproportionately affects rural older underserved populations who havebeen underrepresented in psychosocial intervention trials Aim 3 will use mixed-methods to evaluate the reachand effectiveness of the Pathways intervention among these subgroups. To accomplish these aims 234patients undergoing treatment for ALC at the University of Kentucky Markey Cancer Center will be randomizedto Pathways or enhanced usual care with outcomes collected pre post and at follow-up. The researchproposed in this application is innovative because it is testing a novel intervention with respect to interventionfocus and intervention delivery at the point of ALC care. The proposed research is significant because it willdetermine the efficacy of an intervention that is responsive to patients needs in the current medical landscapefor ALC and has high potential for broad dissemination into routine ALC care in both high- and low-resourcedsettings. Once efficacy is demonstrated the effectiveness of the intervention will be tested in both academicand community oncology practices with other advanced cancer patient populations significantly advancingpsychosocial and palliative care in this new treatment era and ultimately having a large impact on the over600000 people living with advanced cancer in the U.S.

project_terms:
Address;Adult;Advanced Malignant Neoplasm;Affect;Age;Anxiety;Attention;Behavioral Sciences;Cancer Burden;Cancer Center;Cancer Patient;Cancer Survivorship;Caregivers;Caring;Clinical;Clinical Trials;Community Clinical Oncology Program;Data;Diagnosis;Distress;Effectiveness;Effectiveness of Interventions;Family;Feedback;Friends;Future;Goals;Health Care Costs;Health Personnel;Immunotherapy;Impairment;Incidence;Infusion procedures;Intervention;Intervention Trial;Kentucky;Leisures;Life;Malignant neoplasm of lung;Mediating;Mediator;Medical;Medical Oncology;Mental Health;Methods;Mind;Mission;National Cancer Institute;Normalcy;Nurses;Occupational Therapist;Outcome;Palliative Care;Pathway interactions;Patient Care;Patients;Performance Status;Persons;Population;Poverty;Premature Mortality;Psychology;Psychosocial Assessment and Care;Public Health;Quality of life;Randomized;Reporting;Research;Resource-limited setting;Role;Rural;Social Functioning;Social Workers;Subgroup;Telephone;Testing;Thinking;Toxic effect;Treatment Efficacy;Underserved Population;Universities;Update;Work;acceptability and feasibility;anxiety symptoms;cancer care;cancer therapy;care delivery;clinical practice;community setting;depressive symptoms;design;effectiveness trial;efficacy evaluation;efficacy testing;efficacy trial;end of life;evidence base;follow-up;health related quality of life;improved;innovation;intervention delivery;intervention effect;male;novel;palliative;patient population;primary outcome;psychological distress;psychosocial;randomized trial;reduce symptoms;residence;response;routine care;satisfaction;sex;skills;social;socioeconomic disadvantage;survivorship;theories;therapy design;treatment as usual;treatment response

public_health_relevance:
PROJECT NARRATIVEThe proposed research is relevant to public health because it proposes to test a new psychosocial interventionthat addresses a critical intervention gap in current psychosocial care for patients living with advanced lungcancer the most common advanced cancer associated with high rates of psychological distress and poorquality of life and which disproportionately affects rural socioeconomically disadvantaged adults. Because theintervention was designed with patient needs and clinical practice in mind it could easily be implemented inroutine advanced cancer care in both academic and community oncology settings and could be exported foruse among the over 600000 people living with advanced cancer in the U.S. Thus the proposed research willsupport the National Cancer Institutes mission of reducing the burden of cancer through high quality cancercare.


application_id: 10736321
project_number: 1R24OD035462-01
project_title: University of Louisville Cagewash Modernization
administering_ic: OD
award_notice_date: 2023-06-26
opportunity_number: PAR-22-190
application_type: 1
activity_code: R24
ic: OD
serial_number: 035462
program_official: LI, XIANG-NING
project_start_date: 2023-07-01
project_end_date: 2024-06-30
study_section: Special Emphasis Panel[ZRG1 KUDS-Y (90)]
contact_pi_person_id: 8666997
contact_pi: SHERWOOD, LESLIE C.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe University of Louisville (UofL) is an Institution of Emerging Excellence (IEE) and one of 23states designated by the National Institutes of Health (NIH) as an Institutional DevelopmentAward (IDeA) state serving the research needs of medically underserved communities. As partof the IDeA state program UofL is the recipient of four NIH funded Centers of BiomedicalResearch Excellence (COBRE) projects to target local and regional health crises in Kentuckyand Appalachia. These include centers in 1) Center for Cardiometabolic Science 2)Microbiomics and Inflammation 3) Hepatobiology and Toxicology and 4) Cancer Immunologyand Immunotherapy. UofL is also the recipient of NIH funding for the Alcohol Center and theEnvirome Institute Superfund Research Center which studies the effects of cigarette smoke e-cigarettes and other inhaled toxins on the cardiovascular system. UofL is requesting$306360.00 for a modern innovative eco-friendly tunnel washer in the centrally located A-Tower Research Building Cagewash Facility. The A-Tower is adjacent to six research buildingsthat comprise the nucleus of the Health Sciences Campus (HSC) and serves as the primarycage wash facility for all rodent species on the HSC and the undergraduate Belknap campus. Italso provides essential support for large animal cage washing. The current tunnel washer isover 20 years old and is not ergonomically or eco-friendly. Routine maintenance and repair arefrequent and costly. The Better Built Tunnel Washer Model T236 represents a major innovativeupgrade in cage wash equipment that is eco-friendly integrative and utilizes microcomputertechnology. The new tunnel washer will increase our current cage wash throughput capacity by25% for rodent caging and large animal caging accessories to accommodate our growingrodent and large animal populations. The new cage washer will provide essential support for thefour NIH funded COBRE grants the Envirome Institute Superfund and 64 investigators in 24departments across the HSC and Belknap campus. A broad diverse range of investigators andtheir research efforts in both biomedical and basic sciences will benefit from this equipment inthis shared-use facility. This aligns with the principal missions of the NIH-NIGMS. UofL echoesthese missions with the establishment of the Diversity Equity and Inclusion Strategic Plan in2017 and the HSC Office of Diversity and Inclusion which is committed to expanding fundingand employment of ethnic minorities.

project_terms:
20 year old;Alcohols;Allergens;Animal Experimentation;Animals;Appalachian Region;Area;Award;Basic Science;Cardiovascular system;Cell Nucleus;Censuses;Centers of Research Excellence;Development;Electronic cigarette;Employment;Equipment;Friends;Funding;Grant;Growth;Health;Health Sciences;Inflammation;Inhalation;Institution;Kentucky;Maintenance;Microcomputers;Mission;Modeling;Modernization;National Institute of General Medical Sciences;Occupational Health;Phase;Population;Research;Research Personnel;Rodent;Science;Strategic Planning;Superfund;Technology;Toxicology;Toxin;United States National Institutes of Health;Universities;animal facility;cancer immunotherapy;cardiometabolism;cigarette smoke;cost;diversity and inclusion;equity diversity and inclusion;ergonomics;ethnic minority;hazard;improved;innovation;medically underserved;microbiome research;programs;repaired;tumor immunology;undergraduate student;underserved community

public_health_relevance:
NarrativeThe University of Louisville (UofL) an Institution of Emerging Excellence (IEE) located in anInstitutional Development Award (IDeA) program state requests funds ($306360.00) tomodernize our shared-use A-Tower Cagewash Facility which provides primary support forrodent and large animal facilities utilized by NIH funded investigators from seven departmentson the Health Sciences Campus. The first phase in modernizing this facility is to replace thecurrent Scientek tunnel washer (installed in 1999) with a modern eco-friendly integrative tunnelwasher that will also improve ergonomics and reduce allergen exposure for our staff. Ourcurrent tunnel washer is dated energy inefficient and unable to meet our current cage washingdemands as our animal census increases in our existing facilities and will balloon once our A-Tower vivarium construction project is complete in 2023 which will add 2112 rodent cages.


