# projects

application_id: 10633912
project_number: 1R01CA279748-01
project_title: Immunotherapeutic targeting of MIF-dependent chaperone activity
administering_ic: NCI
award_notice_date: 2023-03-31
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 279748
program_official: FORRY, SUZANNE L
project_start_date: 2023-04-01
project_end_date: 2028-03-31
study_section: Special Emphasis Panel[ZRG1 TIO-D (01)]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Immunotherapeutic targeting of MIF-dependent chaperone activity Metabolic reprogramming that favors mitochondrial respiration plays an important role in controllingdifferential gene expression patterns in myeloid lineage cells. Our recent findings have identified a novel proteinchaperone-dependent pathway that indirectly controls mitochondrial homeostasis and metabolic programmingthat are needed to drive maximal intratumoral myeloid cell immune suppressive phenotypes. Our hypothesispredicts that small molecule inhibition of this chaperone activity carried out by the multifunctional cytokine MIFinduces spontaneous Cu/Zn superoxide dismutase (SOD1) misfolding and aberrant mitochondrial bindingleading to metabolic reprogramming and subsequent phenotypic reversion of intratumoral myeloid cell immunesuppressive phenotypes into immune stimulatory phenotypes. Studies proposed in this application will: 1)Delineate the mechanisms of action of 4-IPP-based MIF chaperone inhibitors in the context of MIF/SOD1-dependent TAM/MDSC polarization; 2) Determine the relative contribution of hypoxia as a physiologic ERstressor that exacerbates myeloid wt SOD1 misfolding in the context of MIF and 4-IPP and 3) Evaluate thetherapeutic potential of lead MIF chaperone antagonists as individual and combinatorial modalities againstestablished metastatic melanoma.

project_terms:
ALS patients;Acute;Antibody Therapy;Binding;Biological Assay;Biological Availability;CTLA4 gene;Cell Lineage;Cell surface;Cells;Clinic;Clinical;Communities;Cuprozinc Superoxide Dismutase;Data;Disease Progression;Disease Resistance;Drug Targeting;Effector Cell;Functional disorder;Future;Gene Expression Profile;Genetic Transcription;Homeostasis;Human;Hypoxia;Immune;Immune checkpoint inhibitor;Immunosuppression;Immunotherapeutic agent;Immunotherapy;In complete remission;Individual;Innate Immune Response;Laboratories;Lead;Lesion;Macrophage;Malignant - descriptor;Malignant Neoplasms;Metabolic;Metastatic Melanoma;Migration Inhibitory Factor;Mitochondria;Modality;Molecular Chaperones;Monoclonal Antibodies;Myelogenous;Myeloid Cell Activation;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Oral;Pathway interactions;Patients;Phenocopy;Phenotype;Physiological;Play;Proteins;Respiration;Role;Solid;Solid Neoplasm;Stromal Cells;Structure-Activity Relationship;Suicide;Superoxide Dismutase;T-Lymphocyte;Testing;Therapeutic;Tissue-Specific Gene Expression;Transgenic Organisms;Tumor-associated macrophages;analog;angiogenesis;antagonist;anti-CTLA4;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;cancer immunotherapeutics;cancer therapy;combinatorial;cytokine;endoplasmic reticulum stress;immune checkpoint blockade;immunogenic;immunoregulation;improved;inhibitor;melanoma;mitochondrial dysfunction;monocyte;mouse model;mutant;neovascularization;neurotoxicity;novel;overexpression;partial response;polarized cell;prevent;programmed cell death protein 1;protein folding;receptor;response;small molecule;small molecule inhibitor;stressor;tumor;tumor microenvironment;tumor progression;tumorigenic

public_health_relevance:
NARRATIVE Immunotherapeutic targeting of MIF-dependent chaperone activity Despite some very encouraging improvements in response rates and overall survival in late-stagemelanoma patients receiving anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB) immunotherapies anunacceptably high percentage of treated patients remain unresponsive to these therapies. Studies proposed inthis project application will investigate a unique metabolic transcriptional programming pathway that is governedby MIF-dependent chaperone activity. When therapeutically inhibited with a suicide antagonist discovered by ourlaboratory highly immune suppressive myeloid lineage cells are converted to highly immune stimulatory myeloidcells in the tumor microenvironment which is sufficient to induce tumor rejection and increased survival.


application_id: 10633074
project_number: 5R01DE011111-30
project_title: P. gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2023-06-06
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DE
serial_number: 011111
program_official: MCNEALY, TAMARA L
project_start_date: 1995-04-01
project_end_date: 2025-04-16
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The epithelial layer of host mucosal surfaces presents an initial interface for colonizing microorganisms. Inaddition to constituting a physical barrier to the ingress of organisms epithelial cells can sense and respond tothe presence of bacteria through an elaborate signaling network that can also communicate information to theunderlying immune effector cells in the mucosa. Bacteria that colonize the epithelial surface often engageepithelial cells in a complex molecular dialog which results in significant changes to the host cell transcriptionalprogram and can fundamentally alter epithelial properties. Moreover in vivo bacteria on epithelial surfaces tendto accumulate into polymicrobial communities and communities of organisms can exhibit properties distinct fromindividual constituent species in isolation. Ultimately it is the collective action of the community organisms thatdetermines the impact of the microbial challenge on the host.Our ongoing studies of gingival epithelial cells (GECs) show that the periodontal pathogen Porphyromonasgingivalis can regulate the activity of a number of transcription factors and co-factors which control inflammationcell viability and proliferation. These include -catenin which is proteolytically activated by P. gingivalis andFOXO1 which is activated by site specific dephosphorylation. Activation of -catenin and FOXO1 by P. gingivalisleads to the regulation of ZEB2 a transcription factor pivotal for governing essential epithelial properties andtissue integrity. Moreover ZEB2 can control the maturation of immune cells and the production of inflammatorymediators such as IL-6. We also found that manipulation of the -catenin-FOXO1 axis by P. gingivalis can beantagonized by Streptococcus gordonii and S. oralis but remains unaffected by other common oral streptococci.Hence our hypotheses are that i) the interplay between -catenin and FOXO1 controls ZEB2 expression inresponse to P. gingivalis and impacts epithelial cell characteristics with relevance to the maintenance of tissuehomeostasis; and ii) specific oral community profiles can modulate the influence of P. gingivalis on epithelialsignaling pathways that regulate -catenin and FOXO1 function. The Aims of the project are thus: 1. Tocharacterize the functional integration of -catenin and FOXO1 in the control of ZEB2 by P. gingivalis. 2. Todetermine the functional relevance of site-specific dephosphorylation of FOXO1 by P. gingivalis for the FOXO1transcriptional program and ZEB2 regulation. 3. To characterize the mechanisms by which S. gordonii cansubvert P. gingivalis-induced activation of the -catenin-FOXO1-ZEB2 axis. Successful completion of thisproject will define novel mechanisms for the integration and control of epithelial cell transcription factors andcharacterize modulation of these pathways by P. gingivalis both as a single species infection and in the contextof a community. These studies will increase our understanding of oral diseases that arise from dysbiotic hostresponses such as periodontitis and potentially oral squamous cell carcinoma.

project_terms:
Apoptosis;Bacteria;Binding;Biological;Cell Proliferation;Cell Survival;Cells;Characteristics;Communication;Communities;Community Actions;Complex;Disease;Effector Cell;Epithelial Cells;Epithelium;Exhibits;FOXO1A gene;Fusobacterium nucleatum;Genetic Transcription;Gingiva;Grant;Homeostasis;Human;Immune;Immune response;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-1 beta;Interleukin-6;Maintenance;Modeling;Molecular;Mouth Diseases;Mucous Membrane;Oral;Organism;Outcome;Pathologic;Pathway interactions;Periodontitis;Physiological;Porphyromonas gingivalis;Post-Translational Protein Processing;Process;Production;Property;Protein Dephosphorylation;Regulation;Role;Serine;Signal Pathway;Signal Transduction;Site;Specificity;Streptococcus;Streptococcus gordonii;Streptococcus oralis;Surface;Tissues;alveolar bone;beta catenin;bone metabolism;cofactor;dysbiosis;immunological status;in vivo;microbial;microorganism;mouth squamous cell carcinoma;novel;oral bacteria;oral streptococci;periodontopathogen;programs;promoter;recruit;response;therapy design;transcription factor;transcriptional reprogramming

public_health_relevance:
Project NarrativeSevere periodontal (gum) diseases occur when there is an imbalance in the interaction between colonizingbacteria and the host response. We will characterize the interface between oral bacteria and human epithelialcells which leads to a disruption in the integrity of periodontal tissue. An understanding of this process couldultimately form the basis of treatments designed to maintain host tissue in a healthy state even in the presenceof disease-causing bacteria.


application_id: 10632935
project_number: 1R01AI175220-01
project_title: Chlamydia type III effectors affecting the host actin-based cytoskeleton
administering_ic: NIAID
award_notice_date: 2023-02-06
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 175220
program_official: VINCENT, LEAH REBECCA
project_start_date: 2023-02-06
project_end_date: 2028-01-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Grant title: Chlamydia type III effectors affecting the host actin-based cytoskeletonAbstract:Chlamydia trachomatis is a significant concern for human health world-wide due to its prevalence andthe combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligateintracellular pathogens that possess the ability to modulate host-cell biology while sequestered within amembrane-bound parasitophorous vacuole. Accumulating evidence indicates that a type III secretionsystem (T3SS) represents a significant mechanism employed by chlamydiae to manipulate thesecritical host cell functions. The host actin cytoskeleton and vesicular transport machinery representmajor targets for Chlamydia-mediated alterations. We have identified a novel pathway by whichintracellular chlamydiae redirect host cell vesicular trafficking. This mechanism requires the branchedactin network and at least two type III secretion effectors designated TmeA and TmeB. We propose toaddress the hypothesis that these effectors differentially modulate branched actin networks toaccomplish trafficking of host-cell resources to the mature inclusion by imposing an axis of host Arp2/3activation. We propose to elucidate molecular details by which the combined activities of C. trachomatisTmeA and TmeB affect host cells to promote intracellular development and evasion of cell-intrinsic hostdefenses. Corresponding C. muridarum mutant strains will be employed to elucidate the contributionsof these effectors to pathogenesis in an animal model. A balanced combination of genetic biochemicalcell-biology and animal-based studies are proposed that will define the overall role of these effectors inestablishing and maintaining infectivity that culminates in Chlamydia-mediated disease. Completion ofthis work will lead to an enhanced understanding of the molecular mechanisms employed by Chlamydiato impact host-pathogen interactions governing disease.

project_terms:
Actins;Acute Disease;Address;Affect;Animal Model;Animals;Binding;Biochemical;Biological;Biology;Cell membrane;Cell physiology;Cells;Cellular biology;Chlamydia;Chlamydia Infections;Chlamydia muridarum;Chlamydia trachomatis;Chronic Disease;Communities;Cytoskeleton;Data;Detection;Development;Disease;Disease Progression;Epithelial Cells;Event;Genetic;Grant;Growth;Health;Host Defense;Human;Immune;In Vitro;Infection;Invaded;Link;Lipids;Mediating;Membrane;Microbiology;Modeling;Modification;Molecular;Mus;Mutation;Organelles;Outcome;Pathogenesis;Pathology;Pathway interactions;Polymers;Prevalence;Process;Proteins;Resources;Role;Science;Sexually Transmitted Agents;Sexually Transmitted Diseases;Source;Testing;Time;Type III Secretion System Pathway;Vacuole;Virulence;Work;comparative;design;economic impact;health economics;human pathogen;immunopathology;in vivo;member;mutant;novel;obligate intracellular parasite;parasitism;pathogen;polymerization;reproductive tract;socioeconomics;trafficking;vesicle transport

public_health_relevance:
Chlamydia trachomatis an agent of sexually transmitted disease relies on a specializedsecretion mechanism to deploy proteins exerting anti-host activities essential to pathogenesis.This proposal contains work designed to determine their specific contributions to chlamydialdisease.


application_id: 10632815
project_number: 1S10OD034432-01
administering_ic: OD
award_notice_date: 2023-04-21
opportunity_number: PAR-22-080
application_type: 1
activity_code: S10
ic: OD
serial_number: 034432
program_official: LI, XIANG-NING
project_start_date: 2023-05-01
project_end_date: 2024-04-30
study_section: Special Emphasis Panel[ZRG1 IMST-D (30)]
contact_pi_person_id: 11573326
contact_pi: SMITH, MELISSA LAIRD
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Expanding regional capacity for single molecule sequencing through the purchase of the Sequel IIe sequencing system

project_abstract:
PROJECT SUMMARYThe University of Louisvilles Sequencing Technology Center (STC) is requesting support to acquire a PacificBiosciences Sequel IIe sequencing system. The requested system would be the second Sequel IIe system inthe Center as demand from the diverse STC user base comprised of regional national and internationalextramurally funded investigators has far exceeded the capacity of our initial single instrument. Since launchingin 2021 the STC has assisted in the planning preparation and execution of many projects leveraging the powerof long read single molecule real-time (SMRT) sequencing for projects that use both standard high fidelity (HiFi)workflows and those that involve development of custom innovative targeted methods to elucidate complexgenomic loci or communities with phased highly accurate long reads. Unlike other sequencing systems on themarket the Sequel IIe system has the combination of long read capabilities (150 bp  100 kb) and the highestaccuracy available from any NGS- and single molecule-sequencing instrument (ranging from Q30 99.9% - toQ60 99.9999% across our projects) both of which are critical for meeting the needs of our Major Minor andservice users. The STC is well established and already has the infrastructure and operational capabilities toimplement this requested second Sequel IIe system which is absolutely necessary for meeting the needs of ourgrowing user base Major User research projects and further genomics methods development using the powerof SMRT sequencing technology. The University of Louisville particularly the Office of Research and Innovationis dedicated to supporting the requested system through financial and infrastructure investment into the STC.From the generation of new reference genomes to targeted characterization of viral reservoirs and immune lociand critically important SARS-CoV-2 pathogen surveillance across the Commonwealth of Kentucky the STCfacility has and will use its expertise with SMRT sequencing and the proposed new Sequel IIe system to workclosely with local and national experts to facilitate cutting-edge genomics projects across a wide variety ofresearch areas with the major goal of promoting and inspiring research and innovation in support of the growthof the research enterprise at the University of Louisville.

project_terms:
2019-nCoV;Area;Biological Sciences;Communities;Complex;Custom;Dedications;Development;Extramural Activities;Funding;Generations;Genomics;Goals;Growth;Immune;Infrastructure;International;Investments;Kentucky;Marketing;Methods;Minor;Phase;Preparation;Research;Research Personnel;Research Project Grants;Services;System;Technology;Universities;Viral reservoir;Work;base;genomic locus;high standard;innovation;instrument;meetings;method development;pathogen;reference genome;single molecule;single molecule real time sequencing

public_health_relevance:
PROJECT NARRATIVEHigh fidelity (HiFi) reads generated with single molecule real time (SMRT) sequencing are the foundational datatype needed to generate highly accurate contiguous whole genome de novo assemblies and are incrediblypowerful when used in a targeted fashion to unambiguously resolve haplotype-phased complex genomic loci.As nucleic acid sequencing technologies continue to develop and improve we have the responsibility and needto provide investigators with the state-of-the-art tools required to perform cutting-edge genomics research in atimely and cost-effective manner. The goal of this proposal is to obtain support for the purchase of a secondPacific Biosciences Sequel IIe sequencing system for our Sequencing Technology Center which will providemuch needed additional bandwidth and throughput for funded NIH projects significantly enhancing thebiomedical research programs at University of Louisville and our regional and national collaborative partners.


application_id: 10632714
project_number: 1R01AA030756-01
administering_ic: NIAAA
award_notice_date: 2023-08-15
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AA
serial_number: 030756
program_official: WANG, JOE
project_start_date: 2023-08-15
project_end_date: 2028-05-31
study_section: Xenobiotic and Nutrient Disposition and Action Study Section[XNDA]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-15
project_title:
Characterization of the role of neuropeptide VIP-mediated fucosylation in alcohol associated liver disease

project_abstract:
Alcohol-induced changes in gut flora and intestinal metabolites increase portal endotoxin level which is directlyassociated with intestinal barrier dysfunction and is one of the well-recognized contributing factors to thepathogenesis of ALD. Gut fucosylation is a key force in maintaining a homeostatic relationship between the gutand its microbiota. Nevertheless it is unclear how host fucosylation machinery contributes to alcohol-associatedbarrier function and microbial translocation. It is shown that epithelial 12-fucosylation regulates the colonizationof E. faecalis which causes more severe alcoholic hepatitis. Our initial studies found that alcohol consumptionreduces the levels of neurons-derived peptide VIP in the gut. Neuropeptide VIP has previously been implicatedin circadian regulation food consumption and goblet cell mucus secretion. Our preliminary data further foundthat neuropeptide VIP administration or deletion of VIP receptor (VIPR1) can regulate intestinal fucosylation.Membrane-bound fucosylated glycoproteins on mucosal ECs function as important communication toolsbetween the host and luminal microbes. Many intestinal Bifidobacteria use 12-L-fucosidases to ferment theglycans of host glycoconjugates to produce fucose for its colonization. We found that fucose-derived propionatecould contribute to the induction of IL-22 producing group 3 innate lymphoid cells (ILC3s) which can regulateepithelial integrity in ALD. Therefore we hypothesize that a high amount of alcohol consumption isassociated with disturbances in gut VIP secretion reductions in IECs fucosylation and beneficialsymbionts and subsequently overgrowth of cytolysin-positive E. faecalis all of which lead to intestinalbarrier dysfunction and contribute to the development of ALD. We postulate that prebiotic and probioticsupplementation will attenuate alcohol-induced intestine and liver injury in part by inhibiting of E.faecalis colonization and increasing IL-22+ ILC3 in the intestine. Following specific aims will be carried out:Aim 1: Determine the impact of VIP signaling on the gut fucosylation and the effects of this impact on intestinalbarrier integrity in ALD. We will document the impact of VIP/VIPR1 signaling changes on intestinal fucosylationand integrity in ALD; We will explore the mechanisms by which fucosylation is enhanced by VIP. Aim 2:Investigate whether probiotic fucosidase-producing Bifidobacterium attenuates ALD via inhibition of E. faecaliscolonization and activation of IL-22+ILC3. We will examine the effect of fucosidase-producing Bifidobacteriumand fucose-derived propionate on E. faecalis colonization; We will investigate whether fucosidase-producingBifidobacterium attenuates ALD via the activation of gut ILC3 and IL-22/ IL-22RA signaling. Aim 3: Evaluate theefficacy of VIP-fucosylation-based therapeutic interventions in ALD. We will first evaluate and compare theefficacy of dietary prebiotic 2'-FL with VIP supplementation in the treatment of experimental ALD. We will alsodetermine the effect of metabolite propionate treatment with/without dietary 2'-FL supplementation on ALD inWT mice or ILC3-deficient mice. We propose that exploiting this mechanism will allow the design of novelstrategies to manipulate these forces to increase barrier function and/or prevent/delay the development of ALD.

project_terms:
Alcohol abuse;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Anti-Inflammatory Agents;Attenuated;Bacteria;Bifidobacterium;Binding;Communication Tools;Cytolysins;Data;Development;Endotoxins;Enterococcus faecalis;Epithelial Cells;Epithelium;Fatty Liver;Fermentation;Fucose;Fucosidase;Fucosyltransferase;Functional disorder;Glycoconjugates;Glycopeptides;Glycoproteins;Goblet Cells;Growth;Immune Tolerance;Immune system;Inflammation;Intestines;Knockout Mice;Ligands;Liver diseases;Lymphoid Cell;Mediating;Membrane;Microbe;Mucous Membrane;Mucous body substance;Mucus-Secreting Cell;Mus;Neurons;Neuropeptides;Oral;Pathogenesis;Pathologic;Penetration;Peptides;Play;Polysaccharides;Probiotics;Production;Propionates;Propylene Glycols;Receptor Signaling;Recombinants;Role;Sampling;Secretor blood group alpha-2-fucosyltransferase;Shapes;Signal Transduction;Stress;Supplementation;Symbiosis;Therapeutic Intervention;Tight Junctions;Toll-like receptors;Vasoactive Intestinal Peptide Receptors;Volatile Fatty Acids;Work;adherent junction;alcohol abuse therapy;alcohol prevention;alcohol response;antimicrobial;circadian regulation;commensal bacteria;comparative efficacy;cytokine;design;dietary;efficacy evaluation;food consumption;gastrointestinal epithelium;glycosylation;gut inflammation;gut microbiota;interleukin-22;intestinal barrier;intestinal epithelium;intestinal injury;liver injury;loss of function;metabolomics;microbial;microbial host;microbiome;microbiota;new therapeutic target;novel strategies;pathogenic bacteria;prebiotics;prevent;probiotic supplementation;response;symbiont

public_health_relevance:
Project NarrativeThis proposal provides the basis for a better understanding of the mechanisms for alcohol-induced intestinalfucosylation and barrier function in the development of ALD and may lead to the identification of novel therapeutictargets.


application_id: 10632084
project_number: 5R01DK131442-02
project_title: The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation
administering_ic: NIDDK
award_notice_date: 2023-03-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 131442
program_official: GARCIA, MARTHA
project_start_date: 2022-06-01
project_end_date: 2028-03-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: 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:
There is an increasing evidence that demonstrates a critical pathogenic role for the gut-liver axis in thedevelopment of nonalcoholic fatty liver diseases (NAFLD). Gut-derived endotoxin leakiness is increased underpathological conditions including high fat diet (HFD) consumption. Gut fucosylation is a key force in maintaininga homeostatic relationship between the gut and its microbiota. Nevertheless it is unclear how host fucosylationmachinery contributes to obesity-associated intestinal barrier function microbial translocation and inflammation.Glycosphingolipids (GSLs) are major constituents of enterocytes and consist of glycans conjugated to a lipid(ceramide) core. Ceramide is at the center of sphingolipid metabolism and is hydrolyzed to generate sphingosineand fatty acid by ceramidases including neutral ceramidase (NcDase). However whether gut NcDasecontributes to intestinal fucosylation in NAFLD is unclear. We found that deletion of intestinal epithelial cells(IECs) NcDase induced marked upregulation of intestinal fucosylation in response to HFD exposure. Ourpreliminary studies further demonstrated that HFD-fed NcDase-/- mice have increases in intestinal AhR activityIL-22 secretion and the production of fucosylated gangliosides (fucosyl-GM1). We also found that fucosyl-GM1can bind to DC-SIGN a C-type lectin expressed in hepatic macrophages and can induce anti-inflammatory M2macrophage. This has led to the central hypothesis that gut NcDase regulates the intestinal fucosylationand subsequent barrier function via IEC AhR signal; and that IECs NcDase-derived fucosylatedglycosphingolipids induce hepatic macrophage polarization via fucosyl-GM1/DC-SIGN pathway andprevent the development of NAFLD. Importantly the proposal also pursues translational studies that examinethe efficacy of prebiotic 2-FL feeding and fucosyl-GM1 treatment targeted at intestinal fucosylation and hepaticinflammatory macrophages in mitigating gut-liver axis changes. Following specific aims will be carried out: Aim1: Determine the impact of NcDase on the gut fucosylation and the effects of this impact on intestinal barrierintegrity. We will determine the impact of NcDase-related gut microbiota on the gut fucosylaton and barrierfunction. Aim 2: Determine whether NcDase regulation of IEC AhR contributes to gut fucosylation via microbialmetabolite in response to HFD exposure. Aim3: Determine whether IEC NcDase-derived fucosylatedgangliosides contribute to the induction of liver tolerogenic macrophages and evaluate the efficacy offucosylation-based therapeutic interventions in NAFLD. Our studies on the NcDase-mediated gut fucosylationand prebiotic intervention will likely bring new mechanistic understanding and identify new therapeutic targetsfor the prevention and treatment of NAFLD.

project_terms:
Alcohols;Anti-Inflammatory Agents;Apical;Aryl Hydrocarbon Receptor;Bacteria;Binding;Butyrates;C-Type Lectins;CD209 gene;Cells;Ceramidase;Ceramides;Chronic;Complex;Consumption;Data;Development;Endotoxemia;Endotoxins;Enterocytes;Epithelial Cells;Epithelium;Farber's lipogranulomatosis;Fatty Acids;Fatty Liver;Functional disorder;Gangliosides;Glycolipids;Glycosphingolipids;Hepatic;High Fat Diet;Immune;Immune system;Inflammation;Inflammatory;Intervention;Intestines;Ligands;Lipids;Liver;Macrophage;Mediating;Metabolism;Mucins;Mucous body substance;Mus;Obesity;Pathogenicity;Pathologic;Pathway interactions;Penetration;Phosphorylation;Polysaccharides;Prevention;Production;Receptor Activation;Receptor Signaling;Regulation;Role;Sampling;Secretor blood group alpha-2-fucosyltransferase;Sphingolipids;Sphingosine;Stimulus;Stress;Symbiosis;Therapeutic Effect;Therapeutic Intervention;Tight Junctions;Toll-like receptors;Up-Regulation;Xenobiotics;adherent junction;efficacy evaluation;feeding;galactosylgalactosylglucosylceramidase;gastrointestinal epithelium;gene product;glycosylation;gut inflammation;gut microbiota;gut-liver axis;interleukin-22;intestinal barrier;intestinal epithelium;liver inflammation;liver injury;microbial;microbial host;microbiota;new therapeutic target;non-alcoholic fatty liver disease;pathogenic bacteria;prebiotics;prevent;response;sphingosine kinase;symbiont;translational study

public_health_relevance:
Project NarrativeThis proposal provides the basis for a better understanding of the mechanisms for NcDase-induced gutfucosylation and glycosphingolipid-regulated macrophages in the development of NAFLD and may lead to theidentification of novel therapeutic targets.


application_id: 10631427
project_number: 3P20GM113226-07S2
administering_ic: NIGMS
award_notice_date: 2022-08-25
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 113226
suffix: S2
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2026-03-31
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-09-01
project_title:
COVID Effects on Experimental Alcohol-Associated Liver Disease and the Impact of Novel Nutritional Interventions

project_terms:
2019-nCoV;Address;Adult;Affect;Alcoholic Liver Diseases;Alcohols;American;Animal Model;Area;Attenuated;Basic Science;Biochemical;Biomedical Research;Butyrates;COVID-19;COVID-19 impact;COVID-19 patient;Centers of Research Excellence;Child;Cirrhosis;Clinical;Collaborations;Complex;Development;Dietary Intervention;Drug Interactions;Drug abuse;Ensure;Environment;Enzymes;Epigenetic Process;Equipment;Ethanol;FDA approved;Functional disorder;Funding;Goals;Grant;Health;Hepatic Tissue;Hepatitis;Hepatitis A;Hepatitis B;Hepatitis C;Hepatotoxicity;Histone Deacetylase;Homelessness;Hypoalbuminemia;Industrialization;Infection;Injury;Laboratories;Laboratory Research;Lactobacillus;Link;Liver;Liver Failure;Liver diseases;Mediator of activation protein;Mentors;Metabolic syndrome;Metabolism;Modeling;Molecular Target;Natural regeneration;Neutrophilia;Nutritional Support;Omega-3 Fatty Acids;Organ;Outcome;Parents;Pathogenicity;Patients;Pharmaceutical Preparations;Phase;Prevention;Primary carcinoma of the liver cells;Probiotics;Prodrugs;Program Sustainability;Protocols documentation;Publications;Regimen;Reporting;Research;Research Infrastructure;Research Personnel;Resources;SARS-CoV-2 infection;Scientist;Signal Pathway;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translational Research;Treatment Efficacy;Universities;alcohol effect;career development;clinical practice;coronavirus disease;cytokine;dietary;drug induced liver injury;education research;experience;gut inflammation;intestinal barrier;liver inflammation;liver injury;member;molecular targeted therapies;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;nutrition;personalized medicine;prevent;programs;research facility;success;targeted treatment;tissue repair;toxicant;tributyrin;viral liver disease;virtual


application_id: 10631406
project_number: 3G20AI167407-01S1
project_title: Upgrading infectious disease research facilities at University of Louisville RBL
administering_ic: NIAID
award_notice_date: 2022-08-19
opportunity_number: AI22-049
application_type: 3
activity_code: G20
ic: AI
serial_number: 167407
suffix: S1
program_official: DIAZ SAN SEGUNDO, FAYNA C
project_start_date: 2022-08-22
project_end_date: 2025-02-28
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Louisville Regional Biocontainment Laboratory (RBL) is an operational unit of the UniversitysCenter for Predictive Medicine for Biodefense and Emerging Infectious Diseases (CPM). The CPM operates theonly Biosafety Level 3 laboratories and animal research facilities available to researchers in the Commonwealthof Kentucky. We request support from NIAID through this proposal for additional facility related upgrades andmodernization of research equipment. In this administrative supplement we are not proposing any new specificaims. First we shall repair renovate and modernize specific RBL building systems to enhance functions of theresearch facilities. In this administrative supplement we shall replace the end of life Continuum building accesscontrols system with a Lenel system that meets our layered security access controls requirements. The buildingchillers necessary for maintaining appropriately conditioned air to the laboratories and vivaria will have criticalcomponents that are near end of life replaced. The building air compressors are critical to the facilitys HVACcontrols systems and must be replaced. Secondly we propose to enhance and modernize the CPM in vivoresearch facilities. In this administrative supplement we shall achieve our second aim by augmenting our in vivoresearch capabilities with new CT/PET imaging equipment that will allow fine granularity of data acquisitionimproving our understanding of infectious disease and assisting in discovery of vaccines and therapeuticsagainst biothreats and emerging infectious diseases. This equipment achieves major goals of humane in vivoresearch: more comprehensive and detailed information about the infectious disease model and effect oftherapy closely linked with reduction in the number of research subjects necessary for comprehensiveassessment of the treatment efficacy. The facility and equipment upgrades will modernize our researchinfrastructure enhancing the CPM RBL capabilities to rapidly develop and assist in deployment ofcountermeasures to mitigate the effects of biothreats and emerging infectious diseases.

project_terms:
Administrative Supplement;Air;Communicable Diseases;Emerging Communicable Diseases;Equipment;Goals;Infectious Diseases Research;Kentucky;Laboratories;Laboratory Animal Production and Facilities;Laboratory Research;Link;Medicine;Modernization;National Institute of Allergy and Infectious Disease;PET/CT scan;Positron-Emission Tomography;Research;Research Infrastructure;Research Personnel;Research Subjects;Security;System;Therapeutic;Treatment Efficacy;Universities;biodefense;biothreat;data acquisition;end of life;improved;in vivo;infectious disease model;repaired;research facility;vaccine discovery

public_health_relevance:
PROJECT NARRATIVEThe University of Louisville Regional Biocontainment Laboratory (RBL) operates the only BSL-3and ABSL-3 research facilities in the Commonwealth of Kentucky. The requested facilityupgrades and research instruments should ensure that the RBL remains operational to supportpreparedness for future pandemics and other infectious threats.


application_id: 10630755
project_number: 3R34DK132548-01S1
project_title: COVID-19 Infection and Diabetes Incidence in Native Americans
administering_ic: NIDDK
award_notice_date: 2022-08-22
opportunity_number: PA-18-935
application_type: 3
activity_code: R34
ic: DK
serial_number: 132548
suffix: S1
program_official: BURCH, HENRY B
project_start_date: 2022-08-01
project_end_date: 2025-01-31
contact_pi_person_id: 12349240
contact_pi: LACY, MARY E.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT ABSTRACTAmerican Indians and Alaska Natives (Native Americans) have suffered disproportionately during the COVID-19 pandemic with higher rates of infection hospitalization and mortality from COVID-19 compared to Non-Hispanic Whites. Native Americans also suffer disproportionately from diabetes with nearly 3 times theprevalence and 2.3 times the diabetes-related death rate of Non-Hispanic Whites. Growing evidence suggeststhat COVID-19 infection increases the risk of developing diabetes. Large cohort studies have reported a ~50%increased risk of developing diabetes following COVID-19 infection compared to matched or historic controlswithout known COVID-19 infection. While these studies offer important insight into the magnitude of risk of newonset diabetes following COVID-19 infection existing studies were not inclusive of some of the highest riskpopulations because they studied US veterans commercially insured patients enrolled in large US healthinsurance plans and communities outside the US. Little is known how this risk varies across diversepopulations within the US. Understanding the epidemiologic links between COVID-19 infection and diabetes inNative Americans is critical to address health disparities in a population that faces a disproportionate burden ofboth COVID-19 and diabetes. To measure the association between COVID-19 infection and diabetes risk inNative Americans we will conduct a series of analyses using two distinct data sources: 1) a large nationallyrepresentative clinical database available through Indian Health Service and 2) the Alaska Diabetes Registrywith linked electronic health record data from the Alaska Tribal Health System. Aim 1 will measure theassociation between COVID-19 infection and risk of incident diabetes in Native Americans via a matchedretrospective cohort study using national data from the Indian Health Service. Aim 2 will compare the clinicalpresentation of incident diabetes cases at diabetes onset and compare clinical progression over the 6 monthsfollowing diagnosis by antecedent COVID-19 infection status in a retrospective cohort of individuals usingnationwide data from Indian Health Service as well as the comprehensive Alaska Diabetes Registry maintainedby the Alaska Native Tribal Health Consortium. The proposed studies will provide a comprehensiveepidemiologic assessment of the COVID-19-diabetes association in Native Americans including a nationwidedescription of COVID-19 infection-related diabetes risk and a deep dive into the clinical presentation of incidentdiabetes cases. This knowledge will support the continued efforts of Tribal Federal State and communityentities to mitigate the impacts of the COVID-19 pandemic in Native Americans and further efforts to addressthe COVID-19 and diabetes health disparities faced by this population.

project_terms:
Address;Age;Alaska;Alaska Native;American Indians;Body mass index;COVID-19;COVID-19 mortality;COVID-19 pandemic;COVID-19 pandemic effects;COVID-19 patient;Clinical;Clinical Data;Code;Cohort Studies;Communities;Comprehensive Health Care;Data;Data Set;Data Sources;Database Management Systems;Databases;Death Rate;Diabetes Mellitus;Diagnosis;Electronic Health Record;Enrollment;Epidemiology;Ethnic group;Face;Glycosylated hemoglobin A;Health Insurance;Health system;Healthcare Systems;Hospitalization;Incidence;Individual;Infection;Insulin;Knowledge;Laboratories;Link;Matched Group;Measures;Medical;Morbidity - disease rate;Native Americans;Native-Born;Not Hispanic or Latino;Patients;Persons;Population;Population Heterogeneity;Prevalence;Race;Registries;Reporting;Retrospective cohort;Retrospective cohort study;Risk;SARS-CoV-2 infection;Series;Severities;Severity of illness;Site;System;Time;United States Indian Health Service;Vaccination;Variant;Veterans;Virus;clinical database;clinical diagnostics;cohort;comorbidity;coronavirus disease;diabetes risk;hazard;health disparity;health organization;high risk population;hospitalization rates;infection rate;infection risk;insight;mortality;pandemic disease;post SARS-CoV-2 infection;secondary analysis;trend;tribal health

public_health_relevance:
PROJECT NARRATIVEGrowing evidence suggests that COVID-19 infection increases the risk of developing diabetes. AmericanIndians and Alaska Natives (Native Americans) have suffered disproportionate morbidity and mortality fromdiabetes and COVID-19 compared to Non-Hispanic Whites. We will study the relationship between COVID-19infection and diabetes in Native Americans to support the continued efforts of Tribal Federal State andcommunity entities to address the COVID-19 and diabetes health disparities facing this population.


application_id: 10630687
project_number: 3R01DK124626-02S1
project_title: Mechanisms for Activation of Beige Adipose Tissue in Humans; Supplement
administering_ic: NIDDK
award_notice_date: 2022-08-10
opportunity_number: PA-18-935
application_type: 3
activity_code: R01
ic: DK
serial_number: 124626
suffix: S1
program_official: LAUGHLIN, MAREN R
project_start_date: 2020-12-01
project_end_date: 2025-11-30
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:
AbstractThis proposal is a supplement to Mechanisms for Activation of Beige Adipose Tissue in Humans R01DK124626 in response to NOT-DK-22-017. The supplement is titled: Impact of COVID-19 on diabetesincidence and severity in the United States and Kentucky.There is mounting evidence that COVID-19 is associated with increased risk of incident diabetes. Thissupplement assembles a team of Endocrinologists Pulmonary intensivists Informaticians Epidemiologists andStatisticians who will perform a detailed analysis of linked comprehensive data sets to identify key factors (andputative mechanisms) that relate COVID-19 infection to incident diabetes. In the proposed project the teamwill explore the COVID and incident diabetes relationship among adults and children using three distinct datasources: 1) a large nationwide database of commercially insured individuals (MarketScan) 2) Kentucky stateMedicaid claims data and 3) detailed clinical data from the University of Kentucky HealthCare (UKHC)electronic health record (EHR). Our overall hypothesis is that new onset diabetes is greater in subjects with themost severe COVID infections and in areas of Kentucky with the health disparities. To address thesehypotheses we propose the following Specific Aims 1) to compare population-level trends in the incidenceand severity of new onset diabetes during the COVID-19 pandemic (2020-2021) to historical data (2018-2019)in three distinct study populations and 2) to examine the association between COVID infection and incidentdiabetes at the individual level using a matched retrospective cohort design. We will also examine factors thatmodify this association including severity of diabetes diabetes type sociodemographics (age race/ethnicityregion) BMI severity of COVID infection vaccination status timing of diabetes onset following COVID-19 andoverall health from diagnosis codes lab values medications and clinical notes. In summary this study willexamine the relationship between COVID-19 and incident diabetes in very different populations including ruralKentucky which has high health disparities. In addition we will examine the effects of prior vaccination whichmay lessen the severity of disease and decrease diabetes incidence.

project_terms:
Academic Medical Centers;Address;Adipose tissue;Adult;Americas;Area;Autoantibodies;Autoimmunity;Beta Cell;Body mass index;C-Peptide;COVID-19;COVID-19 impact;COVID-19 pandemic;COVID-19 severity;Caring;Child;Childhood;Clinical;Clinical Data;Code;Communities;Data;Data Analyses;Data Set;Data Sources;Databases;Development;Diabetes Mellitus;Diabetic Ketoacidosis;Diagnosis;Electronic Health Record;Endocrinologist;Epidemiologist;Epidemiology;Ethnic Origin;Glucocorticoids;Glycosylated hemoglobin A;Health;Healthcare;High Prevalence;Human;Incidence;Individual;Infection;Inflammation;Inflammatory;Inpatients;Insulin Resistance;Insulin-Dependent Diabetes Mellitus;Kentucky;Laboratories;Link;Lung;Medicaid;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outpatients;Patients;Persons;Pharmaceutical Preparations;Population;Process;Race;Registries;Reporting;Resources;Retrospective cohort;Risk;Rural;SARS-CoV-2 infection;Severities;Severity of illness;Test Result;United States;Universities;Vaccination;Vaccines;Vital Statistics;autoimmune pathogenesis;beneficiary;clinically relevant;coronavirus disease;design;diabetogenic;health disparity;high risk;improved;marginalized population;post SARS-CoV-2 infection;response;severe COVID-19;sociodemographics;socioeconomic disadvantage;study population;trend;vaccine acceptance

public_health_relevance:
NarrativeAlthough there is mounting evidence that COVID-19 is associated with increased risk of incidentdiabetes the key factors (and putative mechanisms) that relate COVID-19 infection to incidentdiabetes remain largely unknown. In the proposed project the team of EndocrinologistsPulmonary intensivists Informaticians Epidemiologists and Statisticians will explore therelationship between COVID and incident diabetes among adults and children by analyzing datafrom three distinct data sources: 1) a large nationwide database of commercially insuredindividuals (MarketScan) 2) Kentucky state Medicaid claims data and 3) detailed clinical datafrom the University of Kentucky HealthCare electronic health record. Our overall hypothesis isthat new onset diabetes is greater in subjects with the most severe COVID infections and inareas of Kentucky with the greatest health disparities and lowest vaccination rates.


application_id: 10630158
project_number: 5R21DK127295-03
administering_ic: NIDDK
award_notice_date: 2023-05-18
opportunity_number: PAR-19-222
application_type: 5
activity_code: R21
ic: DK
serial_number: 127295
program_official: SERRANO, KATRINA JANE
project_start_date: 2021-06-23
project_end_date: 2025-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-H(54)]
contact_pi_person_id: 10299348
contact_pi: RASHID, CETEWAYO SAIF
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: 2023-06-01
project_title:
Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes

project_abstract:
PROJECT SUMMARYType 2 diabetes (T2D) burden rests disproportionately on ethnic minorities and economically distressedAppalachian communities. These populations also have high rates of low birth weight (LBW) which itself is anindependent risk factor for T2D. One major cause of LBW is uteroplacental insufficiency and subsequentintrauterine growth restriction (IUGR). We model uteroplacental insufficiency in late gestation pregnant rats byligating the uterine arteries. The growth-restricted offspring display diminished glucose-stimulated insulinsecretion (GSIS) reduced islet capillary density and decreased -cell proliferation. We recently sequenced theIUGR islet transcriptome at 2 weeks of age revealing increased expression of Hyaluronan Synthase 2 (Has2)which makes the extracellular matrix glycosaminoglycan hyaluronan (HA) and Cd44 the principal HA receptor.HA has size-dependent opposing effects on angiogenesis and inflammation with native high molecular weight(HMW) HA being inhibitory and its enzymatic or oxidative fragmentation to LMW-HA being activating. Previousstudies show increased HA in serum and adipose tissue of humans with T2D and attenuating HA levels or CD44activity improves insulin sensitivity. Studies have yet to quantify islet HA in T2D despite evidence that HA andHA-binding proteins are normal islet components and HA levels are altered in T2D. To determine whether HAcontributes to IUGR-mediated islet dysfunction we will determine HA abundance size and cell type-specificinteractions. There is a paucity of research regarding effects of HA on -cell function. However HA modulatesactin cytoskeleton dynamics via regulation of monomeric G-proteins in a variety of cell types which if occurringin -cells can have profound effects on GSIS. Taken together I hypothesize that HA abundance and sizedistribution are altered in IUGR islets and HA size-specifically modulates GSIS in vitro. The goal ofSpecific Aim 1 is to determine whether IUGR alters abundance size distribution and cell type-specific bindingof HA in islets. The goal of Specific Aim 2 is to determine whether HA size-specifically alters GSIS in vitro viamodulation of monomeric G-proteins and associated actin dynamics. In a move toward an interventionalapproach we will examine whether pharmacological modulation of HA content normalizes GSIS in IUGR isletsex vivo. Successful completion of the proposed studies will fill a key knowledge gap regarding changes in islet-associated HA in T2D and provide strong evidence that HA negatively impacts -cell function. These data willprovide rationale and demonstrate feasibility for my future R01 grant application investigating an etiological rolefor HA in IUGR-mediated T2D.

project_terms:
Accounting;Actins;Address;Adipose tissue;Adult;Affect;Age;Age Months;American;Animal Model;Appalachian Region;Applications Grants;Arteries;Beta Cell;Binding;Blood capillaries;CD44 Antigens;CD44 gene;Cell Culture Techniques;Cell Proliferation;Cell physiology;Cells;Clinical Research;Communities;Cytoskeleton;Data;Disparity;Distress;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Etiology;Extracellular Matrix;F-Actin;Family;Fetal Growth Retardation;Fetus;Flow Cytometry;Functional disorder;Future;GTP-Binding Proteins;Genes;Glucose;Glycosaminoglycans;Goals;Growth;HAS2 gene;HMMR gene;Human;Hyaluronan;Hyaluronidase;Immunohistochemistry;Impairment;In Vitro;Incidence;Individual;Inflammation;Insulin Resistance;Intervention;Islet Cell;Knowledge;Leukocytes;Ligation;Low Birth Weight Infant;Mediating;Mediator;Modeling;Molecular;Molecular Weight;Monomeric GTP-Binding Proteins;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;PTPRC gene;Peripheral;Population;Potassium;Prediabetes syndrome;Pregnancy;Primary Cell Cultures;Rattus;Regulation;Reporting;Research;Rest;Risk;Risk Factors;Role;Serum;Signal Pathway;Testing;Tissues;Uterus;Vulnerable Populations;Weaning;angiogenesis;cell type;density;epidemiology study;ethnic minority;gel electrophoresis;human tissue;improved;insulin secretion;insulin sensitivity;islet;offspring;pharmacologic;pregnant;protein activation;response;rho;transcriptome

public_health_relevance:
PROJECT NARRATIVELow birth weight is an independent risk factor for type 2 diabetes in adulthood. Populations that have high ratesof low birth weight are the same populations with disproportionate incidence of type 2 diabetes. Using a well-characterized animal model and cell cultures studies the proposed research shows that fetal growth restrictiondysregulates an extracellular matrix molecular hyaluronan in islets which disrupts insulin secretion.


application_id: 10629613
project_number: 1R16GM149498-01
project_title: Brain Development after Early-Life Antipsychotic Treatment
administering_ic: NIGMS
award_notice_date: 2023-05-30
opportunity_number: PAR-21-169
application_type: 1
activity_code: R16
ic: GM
serial_number: 149498
program_official: CUPIT, PAULINE
project_start_date: 2023-06-01
project_end_date: 2027-04-30
study_section: Special Emphasis Panel[ZGM1 RCB-A (SU)]
contact_pi_person_id: 1893500
contact_pi: BARDGETT, MARK EDWARD
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:
7. Project Summary/Abstract This is an application for a Support of Research Enhancement (SuRE) R16 award. These grants areintended to support small scale research projects at institutions like Northern Kentucky University that do notreceive substantial NIH funding with an additional emphasis on providing biomedical research experiences tostudents from groups traditionally underrepresented in biomedical and health science and enhancing theresearch environment at the university. Antipsychotic drugs (APDs) are widely used in children mainly as off-label treatments for a multitude ofpediatric psychiatric disorders despite the lack of basic research documenting their effects on later brain andbehavioral function. One concern is that APD exposure during early brain development alters later sensitivity todrugs of abuse. Our previous NIH-funded research showed that adult rats administered the APD risperidoneearly in life are hyperactive exhibit enhanced locomotor and rewarding responses to the psychostimulant D-amphetamine and display alterations in forebrain dopamine transporters and receptors. These data weregenerated by undergraduate students at NKU many of whom served as first- or co- authors on publishedpapers and some of whom went on to pursue graduate study in psychology. Having ascertained that early-life risperidone modifies responses to psychostimulant drugs that directlytarget dopamine synapses we now seek to determine if behavioral and neural sensitivity to other classes ofdrugs such as opioids that indirectly work though dopamine pathways is enhanced by early-life risperidone.The proposed work will ascertain whether behavioral neural and genetic responses to the opioid drugoxycodone are altered in adult rats administered risperidone early in life (daily injections from postnatal day14-42). This issue is especially germane to NKU students since our geographic area is marked by relativelyhigh rates of opioid use and overdose. Overall the proposed research will address the following questions: 1)Does early-life APD administration enhance the rewarding effects of oxycodone during adulthood? 2)Does early-life APD administration increase neural sensitivity to oxycodone in the forebrain duringadulthood? and 3) Does early-life APD administration modify patterns of forebrain gene transcriptioninduced by oxycodone during adulthood? The last aim will be achieved by collaborating with the nearbyUniversity of Louisville to quantify mRNA expression in tissue samples using next-generation RNA-Seqtechnology. A concomitant goal of this work will be to continue engaging NKU undergraduate students in theexecution analysis and reporting of research. The proposed work will take advantage of training andpedagogical resources offered by NKU and the KY-INBRE program to enhance these experiences and in turncontribute to the overall research environment at NKU.

project_terms:
Adult;Affect;Age;Amphetamines;Antipsychotic Agents;Attention deficit hyperactivity disorder;Award;Basic Science;Behavioral;Bioinformatics;Biomedical Research;Brain;Brain region;Child;Childhood;Collaborations;Control Groups;Core Facility;Data;Development;Dextroamphetamine;Disease;Disruptive Behavior Disorder;Dopamine;Dopamine Agonists;Dopamine Receptor;Dose;Drug Exposure;Elderly;Environment;Exhibits;Extinction;FOS gene;Funding;Genetic;Genetic Transcription;Geographic Locations;Goals;Grant;Health Sciences;Hyperactivity;Immediate-Early Genes;Injections;Institution;Kentucky;Label;Laboratory Rat;Life;Long-Term Effects;Mental disorders;Mentors;Messenger RNA;Metabolic;Modification;Neurons;Neurosciences;Neurotransmitter Receptor;Nucleus Accumbens;Opioid;Outcome;Oxycodone;Paper;Pathway interactions;Pattern;Pharmaceutical Preparations;Pharmacotherapy;Policy Maker;Population;Prosencephalon;Psychology;Publishing;Rattus;Reporting;Research;Research Project Grants;Research Support;Resources;Rewards;Risk;Risperidone;Science;Scientist;Series;Short-Term Memory;Students;Substance abuse problem;Synapses;Techniques;Technology;Time;Tissue Sample;Training;Transcript;Underrepresented Populations;United States;United States National Institutes of Health;Universities;Work;boys;college;conditioned place preference;conditioning;dopamine transporter;drug of abuse;experience;girls;high risk;mRNA Expression;member;model organism;neural;next generation;opioid overdose;opioid use;postnatal;programs;psychostimulant;response;transcriptome sequencing;undergraduate student

public_health_relevance:
8. Project NarrativeThe use of antipsychotic drugs in pediatric populations has increased dramatically over the past 30 yearsdespite a lack of basic research documenting the effects of these drugs on brain and behavioral development.This research will use laboratory rats to ascertain whether early-life antipsychotic drug administration leads togreater behavioral and neural sensitivity to opioid drugs in adulthood. This research will provide scientistspolicy-makers and practitioners with critical information regarding the impact of prolonged antipsychotic drugtreatment during development on the risk of substance abuse in later life as well as offer transformativeresearch experiences in neuroscience to college undergraduates in Kentucky hailing from groupsunderrepresented in biomedical science.


application_id: 10628058
project_number: 3R01AG019223-16S1
project_title: Ceramide and acute phase proteins elevation during aging
administering_ic: NIA
award_notice_date: 2022-06-08
opportunity_number: PA-20-222
application_type: 3
activity_code: R01
ic: AG
serial_number: 019223
suffix: S1
program_official: OROSZ, ANDRAS
project_start_date: 2002-08-01
project_end_date: 2024-05-31
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 6730250
contact_pi: NIKOLOVA-KARAKASHIAN, MARIANA N
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract(Some of the leading causes of death among the elderly are a number of chronic conditions associated withpersistent low-grade inflammation in which IL-1 has a central role. One of the paths by which low-gradeinflammation contributes to aging-associated diseases is by interfering with the ability of the host to maintainhomeostasis. The experiments from the previous funding period provided evidence for a novel pathway bywhich inflammation may deteriorate a major regulatory mechanism. Specifically we found that IL-1 increasesthe levels of glucocorticoid receptor an effect especially potent in aged animals leading to an augmentedresponse to glucocorticoids. This proposal investigates the mechanisms and impact of IL-1 control ofglucocorticoid -dependent functions in the elderly. The proposed studies will do that in the context of fatty livera condition of paramount health importance for public health which is frequent in the elderly and in somecases may progress to non-alcoholic fatty liver disease. In aim 1 a series of in vitro studies will identify themechanisms for IL-1-induced increases in GR levels and delineate some of the functional consequences inhepatocytes. A candidate approach paralleled by an unbiased genome wide analyses using ChipSeq andmRNA arrays will determine the degree of IL-1 impact on GR-dependent transcriptional regulation of geneexpression in the liver. Specific aim 2 is dedicated to investigating the impact IL-1 has on GR responses invivo using a diet-induced mouse model of steatosis and metabolic syndrome. The magnitude of IL-1 responsein hepatocytes will be modulated in vivo or in vitro by targeting a key component of its signaling cascadenSMase2. The consequences on lipogenesis gluconeogenesis and insulin sensitivity will be main readouts.Glucocorticoid hypersensitivity underlies many aging-associated disease. The chronic used of glucocorticoidsfor the treatment of inflammation is associated with significant side effects particularly in the elderly. Thereforeby uncovering the mechanisms that regulate glucocorticoid response in the liver during aging the proposedstudies have the potential to discover both basic mechanisms of aging as well as novel approaches tomanage unwanted side effects of chronic use of glucocorticoids.

project_terms:
Acute-Phase Proteins;Affinity;Aging;Agonist;Alzheimer's Disease;Animals;Cause of Death;Cell Aging;Cell physiology;Cells;Ceramides;ChIP-seq;Chronic;Clinical;Complex;Diet;Disease;Dose;Drug Prescriptions;Elderly;Enzymes;FOXO1A gene;Fatty Liver;Funding;Gene Delivery;Gene Expression Regulation;Genes;Genetic;Glucocorticoid Receptor;Glucocorticoids;Gluconeogenesis;Goals;Grant;Health;Hepatic;Hepatocyte;Histologic;Homeostasis;Hypersensitivity;IGFBP1 gene;IRAK1 gene;In Vitro;Incidence;Infection;Inflammation;Inflammation Mediators;Inflammatory;Insulin Signaling Pathway;Interleukin-1 beta;Lead;Link;Liver;MAPK8 gene;Medical;Messenger RNA;Metabolic syndrome;Minor;Morbidity - disease rate;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Organ;Organism;Oxidation-Reduction;Pain;Pathway interactions;Pattern;Persons;Pharmacology;Phosphorylation;Play;Population;Process;Progress Reports;Protein Phosphatase 2A Regulatory Subunit PR53;Public Health;Rattus;Receptor Signaling;Regulation;Research;Role;Series;Signal Transduction;Sphingomyelinase;Stress;Testing;Transcriptional Regulation;Trauma;Ubiquitination;Work;adenoviral-mediated;aged;antagonist;experimental study;genome-wide;genome-wide analysis;in vivo;in vivo evaluation;insulin sensitivity;lipid biosynthesis;mouse model;non-alcoholic fatty liver disease;novel;novel strategies;response;senescence;side effect;stressor;transcription factor;transcriptome sequencing

public_health_relevance:
Project narrativeSome of the leading causes of death among the elderly are a number of chronic conditions associated withpersistent low-grade inflammation. Uncovering new aging-specific factors that influence the onset ofinflammation is of uttermost significance for the over health and medical treatment of the elderly. The proposedstudies are concentrated on steatosis the hepatic manifestation of metabolic syndrome which is a commondisease of the aged.


application_id: 10626881
project_number: 5R01AI095032-10
project_title: Cooperation of CD8+ T cells and phagocytes to eliminate Toxoplasma cysts
administering_ic: NIAID
award_notice_date: 2023-05-15
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 095032
program_official: PESCE, JOHN T
project_start_date: 2012-01-01
project_end_date: 2025-05-31
study_section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Chronic infection with Toxoplasma gondii can reactivate and cause life-threatening toxoplasmic encephalitis inAIDS patients and other immunocompromised individuals. The basis of persistence of this chronic infection isthe tissue cyst. Thus eliminating T. gondii cysts from chronically infected individuals before they becomeseverely immunosuppressed will be able to prevent this serious disease. However there are currently nodrugs effective against the cysts. Our recent studies using a murine model uncovered that CD8+ immune Tcells have a potent activity to directly penetrate into the cysts and induce their elimination through perforin-mediated mechanisms. We also identified that the N-terminal region (amino acids 41-152) of dense granuleprotein (GRA) 6 (GRA6Nt) of the parasite presented by the H-2Ld molecule is a key antigen to activate the anti-cyst CD8+ T cells. Our studies also identified that Iba1+ microglia and Ly6C+ macrophages accumulate to thecysts during the T cell-initiated immune process and that these phagocytes kill T. gondii bradyzoites within thecysts at least in part by phagolysosome acidification. Based on these observations the proposed studies aredesigned to obtain the information required for proceeding towards development of a vaccine to activate CD8+T cells capable of targeting T. gondii cysts and eradicate chronic infection with this parasite in humans. Forthis purpose we need to determine whether GRA6Nt activates anti-cyst CD8+ T cells through human MHCclass I molecules since the MHC class I molecules present antigens to activate CD8+ T cells. Aim 1 willaddress this point by employing three transgenic mouse strains expressing either of the three major MHC classI supermotifs that cover 90% of human population. Once the anti-cyst T cells are primed these T cells need tobe recruited to cyst-containing cells and activated not only by recognizing T. gondii antigens but also byappropriate costimulatory molecules expressed on the cyst-containing cells. Our recent studies suggested aninvolvement of CXCL10 chemokine and inducible constimulator ligand (ICOSL) in these processes. Thus Aim2 will determine the roles of CXCL10 and ICOSL in recruitment and activation of anti-cyst CD8+ T cellsrespectively. Another critical but unsolved issue is that small numbers of cysts persist in the brains of infectedmice even in the presence of anti-cyst CD8+ T cells. Our recent study revealed that these persisting cystsexpress significantly greater levels of mRNA for selected GRA and rhoptry (ROP) proteins when compared tothe overall cyst population that exists in the absence of the T cells. Since GRAs and ROPs are secreted fromthe parasite into infected cells upregulated secretion of these selected GRAs and ROPs could play crucialroles in manipulating the functions of cyst-containing cells to prevent the attack by CD8+ T cells. Thus Aim 3focuses to determine whether these GRAs and ROPs play key roles in the evasion of the cysts from the T cellattack. We will also address the molecular mechanisms underlying this evasion process. The information fromthese studies will establish the basis for developing a novel method to eradicate chronic T. gondii infection.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Amino Acids;Antigen Presentation;Antigens;Brain;CD28 gene;CD8 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;CXCL10 gene;CXCR3 gene;Cell surface;Cells;Chronic;Combined Vaccines;Cyst;Cytoplasmic Granules;Disease;Epitopes;Excision;Funding;HLA-A2 Antigen;Histocompatibility Antigens Class I;Human;Immune;Immune Evasion;Immunity;Immunize;Immunocompromised Host;Immunologics;Individual;Interleukin-2;Knockout Mice;Life;Ligands;MHC Class I Genes;Macrophage;Mediating;Messenger RNA;Methods;Microglia;Molecular;Mouse Strains;Mus;N-terminal;Parasites;Patients;Penetration;Phagocytes;Phagocytosis;Phagolysosome;Pharmaceutical Preparations;Play;Population;Process;Protein Secretion;Proteins;Rag1 Mouse;Role;System;T-Cell Activation;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Transgenic Mice;Vaccines;chemokine;chronic infection;design;immunological intervention;immunosuppressed;improved;inducible gene expression;mouse model;novel;pathogen;perforin;prevent;rab GTP-Binding Proteins;recruit;rhoptry;toxoplasmic encephalitis;vaccine development

public_health_relevance:
Toxoplasma gondii establishes a chronic infection by forming tissue cysts preferentiallyin the brain and reactivation of this chronic infection causes life-threatening toxoplasmicencephalitis in immunocompromised individuals such as those with AIDS. The proposedstudies aim to identify T. gondii antigen applicable to a vaccine for activating theprotective immunity capable of eliminating the cysts in humans and to uncover themechanisms that T. gondii employs to escape from the protective immunity. Thecombination of the vaccine and a treatment to block the escape mechanism of thepathogen will allow us to develop a novel method to eradicate this widespread chronicinfection in humans.


application_id: 10626681
project_number: 1R56NS124707-01A1
project_title: G Protein Signaling in Brain Injury
administering_ic: NINDS
award_notice_date: 2022-06-30
opportunity_number: PA-20-185
application_type: 1
activity_code: R56
ic: NS
serial_number: 124707
suffix: A1
program_official: AWWAD, HIBAH OMAR
project_start_date: 2022-07-01
project_end_date: 2025-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Traumatic brain injury (TBI) is a major cause of morbidity and mortality and affects >1.7 million people annuallyin the United States. Long-term TBI-related disability results in reduced quality of life for the patient and prolongedmedical social and economic effects on society. TBI is a heterogeneous disease encompassing both localizedregions of necrotic neuron death driven by oxidative damage and excitotoxicity persistent tissue inflammationand both progressive axonal injury and cerebral glucose hypometabolism. However the mechanism(s) thatinitiate these diverse injury programs remains a critical knowledge gap and a barrier to the development ofeffective TBI treatments. Remarkably work in our lab now identifies the neuron-specific G-protein RIT2(Rin) as a regulator of neurodegeneration following brain injury. Exciting preliminary data demonstratesthat RIT2 GTPase silencing significantly blunts in vivo hippocampal neuron death attenuates behavioraldysfunction and regulates the expression of the injury-activated SARM1 NADase following TBI. In keeping witha role for RIT2 in promoting neurodegeneration expression of constitutively active RIT2 promotes energycollapse and neuronal death. Moreover innovative metabolic studies identify a role for RIT2 in the regulation ofcerebral glucose metabolism suggesting that RIT2 contributes to the metabolic dysfunction seen following CCI.These data motivate the central hypotheses that: (1) RIT2 regulated signaling cascades contribute to theneuronal loss metabolic and neurobehavioral dysfunction seen following brain trauma and (2) thatinhibition of RIT2 signaling will therefore have broad therapeutic potential in the setting of TBI. Threecomplementary aims guide our studies. Aim1 will evaluate the extent to which RIT2 signaling controls neuronalloss and behavorial dysfunction following contusive brain injury. Aim 2 will employee innovative transcriptomicapproaches to explore RIT2- and TBI-dependent alterations in neuronal gene expression define the molecularbasis of RIT2-SARM1 signaling and explore the role for RIT2 in traumatic axonal injury. Finally studies in Aim3 will leverage state-of-the-art metabolic approaches to define the role for RIT2 in the regulation of neuronalmetabolism following TBI. Together this innovative multi-system approach will generate insights into themolecular mechanisms that orchestrate neuronal dysfunction following brain contusion and test the therapeuticpotential of targeting RIT2 and its signaling partners for the treatment of TBI.

project_terms:
Acute;Affect;Alternative Splicing;Attenuated;Axon;Behavioral;Biochemical Pathway;Bioenergetics;Biotin;Brain;Brain Contusions;Brain Injuries;Cause of Death;Cerebrum;Clinical;Closed head injuries;Data;Development;Disease;Economics;Employee;Event;Functional disorder;GTP-Binding Proteins;Gene Expression;Genetic Transcription;Glucose;Goals;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);In Vitro;Inflammation;Injury;Knock-out;Knowledge;Link;Medical;Mental Depression;Metabolic;Metabolic dysfunction;Mitochondria;Modeling;Molecular;Morbidity - disease rate;Morphology;Mus;NAD+ Nucleosidase;Necrosis;Nerve Degeneration;Nervous System Physiology;Neurologic;Neurologic Dysfunctions;Neuronal Dysfunction;Neuronal Injury;Neurons;Pathology;Pathway interactions;Patients;Persons;Positioning Attribute;Proteins;Public Health;Quality of life;RNA Splicing;Regulation;Research;RiboTag;Role;Signal Pathway;Signal Transduction;Signaling Protein;Societies;TBI treatment;Testing;Therapeutic;Time;Tissues;Transgenic Mice;Traumatic Brain Injury;United States;Up-Regulation;Work;axon injury;controlled cortical impact;disability;economic cost;excitotoxicity;glucose metabolism;in vivo;innovation;insight;metabolic abnormality assessment;mortality;motor disorder;mouse model;neurobehavioral;neuron loss;neuronal metabolism;neuronal survival;neurotransmission;novel;novel therapeutics;oxidative damage;preservation;programs;sensor;social;stable isotope;therapeutic candidate;therapeutic evaluation;transcription factor;transcriptomics

public_health_relevance:
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States with enormousclinical social and economic costs. This project will investigate the RIT2 protein as a key injury sensorresponsible for neuron loss following TBI. This research is relevant to public health because it will define anovel mechanism controlling neuron death and identify novel therapeutic candidates for treating thedevastating neurological consequences of brain injury.


application_id: 10626076
project_number: 5R01CA258751-02
project_title: Combating melanoma resistance by targeting ABL1/2
administering_ic: NCI
award_notice_date: 2023-04-24
opportunity_number: PAR-21-033
application_type: 5
activity_code: R01
ic: CA
serial_number: 258751
program_official: SONG, MIN-KYUNG H
project_start_date: 2022-05-23
project_end_date: 2027-04-30
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: KOLESAR, JILL MARIE;WILSON, MELISSA A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYDespite treatment advances over the past decade five-year survival rates for metastatic melanoma remain low(23%). BRAF mutations occur in 50-75% of melanoma and a combination of BRAF and MEK inhibitors (BRAFiMEKi) are effective therapies; however acquired resistance rapidly develops for most patients. Research overthe past decade has identified mechanisms by which melanoma cells develop resistance to BRAF/MEKinhibitors but thus far there are no FDA-approved regimens that reverse BRAFi/MEKi resistance and increasethe 5-year survival rate. Here we demonstrate that the activities of the ABL family of non-receptor tyrosinekinases are potentiated following BRAFi or BRAFi/MEKi resistance and ABL1/2 drive resistance. Moreovertargeting ABL1/2 with an FDA-approved anti-leukemia drug nilotinib dramatically reverses BRAFi/MEKi(dabrafenib/trametinib) resistance in vivo inducing prolonged tumor regression. Based on these excitingfindings the central hypothesis of our proposal is that ABL1/2 are key nodes that activate ERK-dependent or-independent pathways to drive BRAFi/MEKi resistance; thus targeting ABL1/2 may be effective for overcomingresistance and ultimately extending survival for patients with treatment-refractory melanomas. Our long-termtranslational goal is to develop a novel regimen to improve the 5-year survival rate for patients with metastaticmelanoma. We propose a comprehensive hypothesis-driven experimental design and multi-disciplinaryapproach. Aim 1 will define mechanisms by which ABL1/2 drive resistance. To achieve our objectivebiochemical molecular biological and cell biological approaches using parental/resistant melanoma cell linespharmacological inhibitors/RNAi mass spectrometry xenograft GEM PDX and syngeneic in vivo approachesas well as human tissue collected from the clinical trial (Aim 3) will be used to test the hypothesis that ABL1/2drive MAP3K activation of MEK/ERK/MYC (ERK-dependent resistance); induce ERBB2/ERBB3 activation ofPI3K/AKT (ERK-independent resistance); and alter immune cell infiltration. In Aim 2 conditioned medium fromparental/resistant cell lines co-culture experiments using in vitro and in vivo models and serum collected fromanimals and patients will be used to test the prediction that the ABL1/2-driven secretome contributes toBRAFi/MEKi resistance. Finally Aim 3 is a multi-site seamless Phase I/II clinical trial that tests the safety ofcombining nilotinib with dabrafenib+trametinib (BRAFi/MEKi) for treatment-refractory patients. Additionalendpoints include identifying the recommended Phase II dose initial efficacy (PFS) based on Phase II dataPK/PD studies and initial exploratory biomarker development. Results from these studies not only will increaseour understanding for how melanomas resist the effects of BRAFi/MEKi but also will lay the groundwork for alarge multi-center randomized clinical trial.

project_terms:
ABL1 gene;Animal Model;Animals;BRAF gene;Basic Science;Biochemical;Biological;Cell Line;Cells;Cessation of life;Clinical;Clinical Trials;Coculture Techniques;Collaborations;Conditioned Culture Media;Coupling;Data;Dose;Dose Limiting;Drug Kinetics;Drug resistance;ERBB2 gene;ERBB3 gene;Experimental Designs;FDA approved;Family;Flow Cytometry;Genetically Engineered Mouse;Goals;Growth Factor;Hematologic Neoplasms;Immune;Immunotherapeutic agent;Immunotherapy;In Vitro;Incidence;Intervention;Invaded;Kentucky;Link;MAP3K1 gene;MEKs;Maintenance;Malignant Neoplasms;Manuscripts;Mass Spectrum Analysis;Mediating;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Monitor;Mutation;Neoplasm Metastasis;Oncologist;PI3K/AKT;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase I/II Clinical Trial;Phase I/II Trial;Phosphotransferases;Protein Family;Protein Secretion;Protein Tyrosine Kinase;Proteomics;Proto-Oncogene Proteins c-akt;Publishing;Qualifying;RELA gene;RNA Interference;Recommendation;Records;Refractory;Regimen;Relapse;Research;Research Personnel;Resistance;Resistance development;Role;Safety;Sampling;Series;Serum;Serum Proteins;Site;Survival Rate;Testing;Toxic effect;Translational Research;Treatment Protocols;Tumor Burden;Xenograft procedure;advanced disease;antileukemic agent;arm;biomarker development;chemokine;cytokine;drug-sensitive;early phase clinical trial;effective therapy;experimental study;gain of function;human tissue;immune cell infiltrate;immunoregulation;improved;in vivo;in vivo Model;inhibitor;innovation;interdisciplinary approach;loss of function;melanoma;mutant;next generation sequencing;novel;open label;patient subsets;pharmacokinetics and pharmacodynamics;pharmacologic;phase 2 study;prevent;primary endpoint;randomized clinical trials;resistance mechanism;response;safety testing;secondary endpoint;single-cell RNA sequencing;targeted agent;therapy resistant;transcriptome sequencing;translational goal;tumor;tumor-immune system interactions

public_health_relevance:
PROJECT NARRATIVEMetastatic melanoma is one of the deadliest cancers and although immunotherapy and targeted agents extendsurvival some melanomas do not respond to the treatments or develop resistance; thus the 5-year survival rateremains dismal. This proposal examines the mechanism by which ABL family proteins contribute to BRAF/MEKinhibitor resistance and includes a clinical trial to test the safety and initial efficacy of an ABL1/2 inhibitor incombination with BRAF/MEK inhibitors for treating refractory melanomas.


application_id: 10625858
project_number: 5P50AA024337-08
project_title: Probiotic-derived nano-particles in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2023-04-27
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8880
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
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:
Probiotics have been used to prevent/treat alcoholic liver disease (ALD). Live probiotics need to colonize the gutto exert their function. Unfortunately underlying disease states provide an unfavorable environment for probioticbacterial gut colonization which diminishes probiotics function. In the last few years we showed that LGGculture supernatant (LGGs without live bacteria) was effective in the prevention of ALD in experimental modelsof acute and chronic alcohol exposure in mice. However how LGG supernatant exerts its therapeutic effects isnot fully understood. Exosomes are nanoparticles (NPs) derived from cell endocytosis which act as transmittersbetween cells. Recent studies show that bacteria both Gram-negative and Gram-positive produce NPs. TheNPs derived from bad bacteria have been demonstrated to be pathogenic. However good bacteria-probiotics-derived NPs have not been studied. Our preliminary study showed that administration of LGG-derivedexosome-like NPs (LDNPs) effectively reversed ALD in the binge-on-chronic alcohol exposure mouse modelsuggesting that probiotic LGGs may exert its function through LDNPs in ALD. Administration of LDNPs markedlyincreased intestinal AhR activity IL-22 and regenerating islet-derived 3 (Reg3)  and  expression which playa key role in maintaining gut microbiota homeostasis and preventing bacterial intestinal transcytosis. In additionLDNPs administration significantly increased intestinal epithelial cell (IEC) tight junctions and decreasedcirculating LPS concentration associated with upregulation of intestinal Nrf2 signaling which is known forprotecting intestinal barrier junctions against oxidative stress-induced damage by alcohol. Metabolomic analysisrevealed that LDNPs contain high levels of microbial metabolites of tryptophan which are AhR ligands indicatingLDNPs may activate intestinal AhR signaling. Furthermore we demonstrated that ginger exosome-likenanoparticles (GDNPs) are preferentially taken up by LGG suggesting that GDNP may serve as a prebiotic toenhance the effects of LGG. These preliminary studies provide the groundwork for our central hypothesis thatby activating intestinal AhR-Nrf2 signaling LDNPs increase intestinal expression of Il-22 Reg3 and tightjunctions and modulate gut microbiota homeostasis and enhance intestinal barrier function leading to thesuppression of ALD. We will test our hypothesis in following four specific aims: (1) Determine the role of bacteria-derived NPs in ALD; (2) Define the mechanisms of the beneficial effects of LDNPs in ALD; (3) Determine whetherGDNPs treatment enhances LDNP production and AhR agonist enrichment that lead to improved effects ofLDNPs against ALD; and (4) Evaluate the intestinal AhR-Nrf2 signaling in alcoholic hepatitis patients treated withLGG. Completion of this study is expected to significantly impact the development of LGG-based probiotictherapeutics in the treatment of alcohol-associated liver diseases.

project_terms:
Acute;Agonist;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Bilophila wadsworthia;Biological Markers;Cells;Chronic;Clinical;Development;Digestive System Disorders;Disease;Endocytosis;Environment;Epithelial Cells;Epithelium;Evaluation;Experimental Models;Functional disorder;Future;Ginger;Growth;Homeostasis;Intestines;Mediating;Mus;National Institute on Alcohol Abuse and Alcoholism;Natural regeneration;Outcome;Oxidative Stress Induction;Pathogenicity;Pathway interactions;Patients;Play;Prevention;Probiotics;Production;Receptor Signaling;Regenerating islet derived protein 3-Gamma;Role;Sampling;Signal Transduction;Testing;Therapeutic Effect;Tight Junctions;Tryptophan;Up-Regulation;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;clinical application;disorder prevention;dysbiosis;exosome;gut colonization;gut inflammation;gut microbes;gut microbiota;improved;interleukin-22;intestinal barrier;intestinal epithelium;islet;metabolomics;microbial;mouse model;nanoparticle;nutrition;organ injury;pathogenic bacteria;prebiotics;prevent;probiotic therapy;programs;protective effect;transcytosis


application_id: 10625855
project_number: 5P50AA024337-08
administering_ic: NIAAA
award_notice_date: 2023-04-27
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8879
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Enhancer-mediated transcriptional dysregulation in neural crest cells and ethanol-induced teratogenesis

project_abstract:
Fetal Alcohol Spectrum Disorders (FASD) is among the most devastating consequences of the widespread useand abuse of alcohol. Growing evidence suggests that impairment of the differentiation migration and survivalof neural crest cells (NCCs) is a major component of the pathogenesis of FASD. However there is a fundamentalgap in understanding how ethanol leads to the dysregulation of gene expression and subsequently impairs NCCdevelopment in embryos. Enhancers are DNA elements that govern spatial and temporal regulation of geneexpression through its function as integrated transcriptional factor binding platforms. We have recentlydemonstrated that ethanol exposure resulted in a locus-specific reduction in enhancer activity across the genomein zebrafish embryos as indicated by lower levels of H3K27ac mark in ethanol-exposed embryos relative tocontrol. We termed these sites as the Ethanol-induced Variant Enhancer Loci (E-VELs). In addition ethanoltreatment reduced the activity of the selected enhancers in human NCCs (hNCCs). The objective of this proposalis to elucidate the mechanisms by which enhancers mediate ethanol-induced impairment of NCC developmentand teratogenesis and to establish epigenetic modulation of enhancer activity as a feasible approach forpreventing FASD. The central hypothesis of this project is that ethanol epigenetically modulates the activity ofthe selected enhancers and subsequently disrupts the expression of their cognate genes in NCCs leading tothe impairment of the differentiation migration and survival of NCCs and teratogenesis and that epigeneticmodulation of the activity of the selected enhancers and the expression of their cognate genes by sulforaphane(SFN) or broccoli-derived exosome-like nanoparticles (BELNs) can prevent ethanol-induced teratogenesis. Totest our hypothesis the following specific aims will be addressed: Aim 1: To identify the E-VELs that areassociated with aberrant expression of their cognate genes involved in NCC and craniofacial development inhNCCs and zebrafish embryos. Aim 2: To functionally validate the role of the selected E-VELs in ethanol-induceddysregulation of gene expression impairment of the differentiation migration and survival of NCCs and ethanol-induced teratogenesis. Aim 3: To elucidate the mechanisms by which ethanol epigenetically modulates theactivity of the selected E-VELs that modulate the expression of genes involved in the differentiation migrationand survival of NCCs. Aim 4: To test the hypothesis that epigenetic modulation of the activity of the selected E-VELs by SFN or BELNs represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis.The proposed work is innovative because this is the first study attempting to prevent FASD through the newlyrecognized role of enhancers in regulating gene expression and NCC development. It also represents the firstattempt to prevent FASD using edible plant-derived exosome-like nanoparticles. This study is also significantbecause the results from this study are expected to provide insights into the mechanisms by which enhancersmediate ethanol-induced teratogenesis and to yield enhancer-based strategies for the prevention of FASD.

project_terms:
Address;Alcohol abuse;Alcohols;Behavioral;Binding;Broccoli - dietary;Cell physiology;Congenital Abnormality;DNA;Defect;Development;Disease;Edible Plants;Elements;Embryo;Embryonic Development;Enhancers;Epigenetic Process;Ethanol;Event;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Human;Impairment;Learning Disabilities;Mediating;Neural Crest Cell;Neuronal Dysfunction;Pathogenesis;Prevalence;Prevention;Prevention approach;Prevention strategy;Psyche structure;Regulation;Role;Site;Sulforaphane;Testing;Therapeutic;Variant;Work;Zebrafish;alcohol consumption during pregnancy;alcohol exposure;cell type;craniofacial development;embryonic alcohol exposure;exosome;innovation;insight;maternal alcohol use;migration;nanoparticle;novel therapeutic intervention;nutrition;organ injury;prevent;programs;teratogenesis;transcription factor


application_id: 10625506
project_number: 5R01NS114404-04
project_title: BMAL1/ARNTL plays a critical non-circadian role in secondary tissue damage after contusive SCI
administering_ic: NINDS
award_notice_date: 2023-06-23
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 114404
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-08-15
project_end_date: 2025-05-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: SARASWAT, SUJATA OHRI
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Circadian rhythms regulate a wide spectrum of biological processes of critical importance for organismalhealth. Perturbations of those rhythms underlie many pathologies including systemic inflammation depressionand neurodegeneration. Mechanistically circadian rhythms are driven by intrinsic oscillatory changes in geneexpression that are orchestrated by several regulators of gene transcription and mRNA translation forming thecore oscillator circuitry. Those key regulators most importantly the non-redundant transcription/translationfactor BMAL1/ARNTL are active in most cells throughout the body and undergo circadian entrainment byexternal time cues such as light or feeding. At the organismal level the pro-rhythmic role of the oscillator iswidely recognized as a critical contributor to homeostasis. BMAL1 effects that are independent of the centralrhythm include anti-oxidant protection in the brain life span regulation contributions to atherosclerosis andendoplasmic reticulum (ER) stress-sensitization of cancer cells. Those or similar tissue-specific functions ofBMAL1 may affect the outcome after SCI. However clock function at the molecular level has never beeninvestigated in the context of SCI. Unexpectedly we found that: (i) moderate contusive thoracic SCIupregulates BMAL1 in penumbral oligodendrocytes (OLs) coinciding with induction of the ER stress response(ERSR)-activated pro-apoptotic transcription factor CHOP and ER stress-mediated apoptosis of OLs (ii) afterSCI Bmal1-/- mice show improved locomotor recovery and white matter sparing (WMS) as well as selectivedownregulation of Chop and its pro-apoptotic target gene death receptor 5 (Dr5) and reduced bloodextravasation and inflammation with extensive changes in microglia/macrophage (MM) and endothelial (EC)-specific gene expression. Also pharmacological enhancement of the negative feedback inhibition of BMAL1reduces ER stress toxicity in OPC cultures. These exciting findings suggest a novel role of BMAL1 in thepathogenesis of SCI which may include OL-cell autonomous regulation of CHOP-mediated OL apoptosisand/or EC/MM-cell autonomous modulation of post-SCI hemorrhage/vascular dysfunction/cytotoxic neuro-inflammation. Therefore we will test the hypothesis that BMAL1 regulates OL EC and/or MM gene expressionthat contributes to SCI-associated white matter loss and impaired locomotor recovery. To test this hypothesiswe will: (i) determine the cell autonomous roles of OL- MM- and EC-BMAL1 in SCI-associated white matterdamage and locomotor recovery (ii) identify mechanism(s) that underlie BMAL1-mediated enhancement ofSCI-driven white matter loss and (iii) evaluate mediators of the negative feedback inhibition of BMAL1 aspharmacological targets for interventions to reduce SCI-associated white matter loss and locomotorimpairment. We will use a moderate T9 SCI contusion model in wild type or cell type-selective Bmal1-/- miceand non-toxic CNS-permeable drugs targeting the feedback regulation of BMAL1. This research may uncovernovel previously unrecognized contributions of BMAL1 to `secondary tissue injury after SCI.

project_terms:
ARNTL gene;Acute;Affect;Agonist;Antioxidants;Apoptosis;Apoptotic;Arrhythmia;Atherosclerosis;Biological Process;Blood;Blood coagulation;Brain;Cardiovascular Diseases;Cell Count;Cell Proliferation;Cells;Cervical spinal cord injury;Cessation of life;Circadian Dysregulation;Circadian Rhythms;Clinical;Complex;Contusions;Cues;Down-Regulation;Drug Targeting;Endothelial Cells;Endothelium;Enhancers;Extravasation;Feedback;Functional disorder;Gene Expression;Genes;Genetic Transcription;Health;Hemoglobin;Hemorrhage;Homeostasis;Human;Impairment;Inflammation;Injury;Intervention;Intrinsic drive;Knock-out;Light;Locomotor Recovery;Longevity;Macrophage;Malignant Neoplasms;Mediating;Mediator;Mental Depression;Metabolic syndrome;Microglia;Modeling;Molecular;Mus;Mutant Strains Mice;Natural Immunity;Nerve Degeneration;Oligodendroglia;Organ;Outcome;Pathogenesis;Pathology;Periodicity;Permeability;Phosphorylation;Play;Protein Kinase;Proteins;Proteolipids;Recovery;Recovery of Function;Regulation;Regulator Genes;Reporting;Repression;Research;RiboTag;Role;Secondary to;Signal Transduction;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;TNFRSF10B gene;Technology;Testing;Thoracic spinal cord structure;Time;Tissues;Toxic effect;Transcription Repressor;Vascular Diseases;adaptive immunity;angiogenesis;biological adaptation to stress;cadherin 5;cancer cell;cell type;circadian;cytotoxic;effective therapy;endoplasmic reticulum stress;experimental study;feeding;gain of function;improved;improved outcome;inhibitor;insight;loss of function;mRNA Translation;neuroinflammation;new therapeutic target;novel;pharmacologic;selective expression;systemic inflammatory response;tissue injury;transcription factor;transcription factor CHOP;transcriptome sequencing;translation factor;white matter;white matter damage

public_health_relevance:
Project narrativeCurrently there are no clinically effective treatments to improve outcome after traumatic spinal cord injury(SCI). This proposal will examine the role of novel candidate mediators of secondary tissue damage followingSCI. Hence new therapeutic targets may be identified to enhance functional recovery after SCI.


application_id: 10625496
project_number: 5R21AI166233-02
project_title: Functional Role of the Enterococcal Polysaccharide Antigen
administering_ic: NIAID
award_notice_date: 2023-04-12
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 166233
program_official: HUNTLEY, CLAYTON C
project_start_date: 2022-05-20
project_end_date: 2025-04-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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:
Enterococci represent one of the leading causes of infections among hospitalized patients andresidents of long-term care facilities. In the USA there were over 50000 cases of enterococcalinfections in 2017 with ~10% fatality rate. The majority of infections are caused byEnterococcus faecalis and E. faecium which include bacteremia urinary tract and surgical sitesinfections and endocarditis. E. faecalis and E. faecium display high levels of natural andacquired antibiotic resistance that severely limits the treatment options. The major component ofstreptococcal cell wall is the Enterococcal Polysaccharide Antigen (EPA). The recently solvedstructure of EPA consists of a polyrhamnose backbone decorated with a polyribitol phosphate-containing teichoic acid. While a hypothetical mechanism of EPA biosynthesis has beenproposed studies are required to test it. The goal of this application is to decipher the criticalsteps of EPA polyrhamnose and teichoic acid assembly. In addition we will examine the role ofEPA in binding to the enterococcal autolysins and the resistance mechanism to hostantimicrobial protein expressed in the intestinal epithelial cells ReGIII. We will utilize acombination of genetic analytical and biochemical methods to answer these questions. Theenzymes of EPA biosynthetic pathway constitute promising targets for the development of novelantimicrobials to combat enterococcal infections. Thus the proposed experiments will provide abetter understanding of cell wall biogenesis in enterococci to enable the development ofalternative approaches to treat drug-resistant infections. Furthermore the proposed studies willenhance our understanding of the functions of EPA in antimicrobial resistance and persistenceof enterococci in gut microbiota.

project_terms:
Acetylgalactosamine;Adherence;Anabolism;Antibiotic Resistance;Antibiotics;Antigens;Antimicrobial Resistance;Autolysin;Autolysis;Automobile Driving;Bacteremia;Bacteriophages;Binding;Biochemical;Biogenesis;Biological Assay;Biological Process;Cell Wall;Cell membrane;Cells;Cellular Morphology;Complement;Daptomycin;Data;Development;Drug Controls;Drug resistance;Endocarditis;Enterococcus;Enterococcus faecalis;Enterococcus faecium;Enzymatic Biochemistry;Enzymes;Epithelial Cells;Essential Genes;Evolution;Exhibits;Fatality rate;Future;Genes;Genetic;Genome;Glycobiology;Goals;Gram-Positive Bacteria;Health care facility;Hospitalization;Hospitals;Host Defense;Human;In Vitro;Infection;Intestines;Ions;Life;Lipids;Long-Term Care;Mediating;Methods;Microbial Biofilms;Microscopy;Modeling;Molecular;Molecular Genetics;Mucous body substance;Multi-Drug Resistance;Muramidase;New Agents;Outcome;Pathway interactions;Patients;Peptidoglycan;Permeability;Phagocytes;Phospholipase A2;Physiology;Play;Polysaccharides;Proteins;Resistance;Role;Site;Streptococcus;Structure;Surface;Surgical Wound Infection;Teichoic Acids;Testing;Thick;Urinary tract;Vancomycin Resistance;Vertebral column;Virulence;antimicrobial;antimicrobial peptide;beta-Lactams;combat;experimental study;gut microbiota;inorganic phosphate;intestinal epithelium;novel;novel therapeutics;pathogen;polyribitol phosphate;resistance mechanism;therapeutic target;trait

public_health_relevance:
Enterococcus faecalis and Enterococcus faecium are important nosocomial pathogens thatcause life-threatening infections. The goal of the proposed studies is to determine themechanism and the function of the Enterococcal Polysaccharide Antigen to enable thedevelopment of alternative approaches to treat these drug-resistant infections.


application_id: 10625330
project_number: 5R01DA048876-05
administering_ic: NIDA
award_notice_date: 2024-05-01
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DA
serial_number: 048876
program_official: LYNCH, SEAN EDWARD WINTERS
project_start_date: 2019-08-01
project_end_date: 2026-05-31
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6264981
contact_pi: OSER, CARRIE BETH
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-06-01
project_title:
DAT18-08 Geographic variation in Opioid Addiction Treatment (GATE) study: Multi-Level Factors Influencing MAT Use Other Treatment & Adverse Outcomes among Re-entering Rural and Urban Prisoners

project_abstract:
ABSTRACT: As outlined in DAT18-08 NIDA has a strong interest in understanding treatment utilization amongpersons with opioid use disorders (POUDs) as they transition from prison to the community because treatingindividuals with opioid use disorder (OUD) simultaneously improves public health and public safety. Kentuckyis in the midst of an opioid crisis with many POUDs cycling through the criminal justice system each year. Whileevidenced-based medications for addiction treatment (MAT) exist for treating OUD MAT is underutilized withinprisons which elevates the risk of relapse and overdose when POUDs are released and re-enter theircommunities. Research is scant regarding the multi-level factors associated with offenders willingness to initiateMAT while in prison and their continued engagement in treatment after release. Furthermore rural and urbanpopulations have not been compared. In response to NIDA DAT18-08 we propose to conduct the high-impactGeographic variation in Addiction Treatment (GATE) study which will address the knowledge gap on multi-levelfactors influencing prison-based extended-release injectable naltrexone (XR-NTX) initiation as well as examinepredictors of post-release MAT use and adverse outcomes (i.e. relapse overdose recidivism) among both ruraland urban POUDs. This mixed methods study employs a social ecological framework to understand individualcharacteristics that influence MAT initiation and adverse outcomes as well as contexts more distal to theindividual including social networks and structural factors. The specific aims of the GATE study are: 1) toidentify the individual personal network and structural factors associated with XR-NTX initiation inprison among rural as compared to urban POUDs and 2) to examine the individual personal networkand structural factors predicting MAT use treatment use and adverse outcomes in the communityamong re-entering rural as compared to urban POUDs over time. A prospective observational longitudinalcohort study will be conducted with 500 POUDs using survey and social network data collected in prison andat 6- and 12-months post-release to explore multi-level rural-urban variation in key outcomes. In-depth guidedqualitative interviews will be conducted with POUDs prison-based treatment staff and social service clinicians.To maximize rigor and reproducibility we will employ a concurrent triangulation strategy whereby qualitativeand quantitative data contribute equally to the analysis and are used for cross-validation. This study is led by aqualified interdisciplinary team and is the first mixed methods study examining the processes of social influencesthat occur in rural and urban social networks as POUDs transition from prison back to geographically diversecounties. The GATE study will enhance our ability to address the opioid epidemic within the correctional contextsof prisons and community supervision by informing process improvement efforts for prison-based MAT initiationand post-release retention in care applying network science findings to improve the re-entry planning processand establishing the foundation for future R-level intervention applications.

project_terms:
Address;Back;Caring;Characteristics;Communities;Continuity of Patient Care;County;Crime;Criminal Justice;Data;Distal;Drug Screening;Drug usage;Education;Elements;Eligibility Determination;Enrollment;Equipment and supply inventories;Foundations;Future;Geographic Locations;Geography;Goals;Health;Health Services Accessibility;Healthcare;Imprisonment;Individual;Injectable;Intervention;Interview;Kentucky;Knowledge;Literature;Longitudinal cohort study;Measures;Mediating;Medicaid;Mentors;Methods;Naltrexone;National Institute of Drug Abuse;Opiate Addiction;Outcome;Outpatients;Overdose;Persons;Pharmaceutical Preparations;Pilot Projects;Predictive Factor;Prisoner;Prisons;Process;Public Health;Qualifying;Recovery;Relapse;Reproducibility;Research;Resources;Rural;Rural Appalachia;Rural Population;Safety;Sampling;Science;Social Network;Social Work;Structure;Substance abuse problem;Supervision;Support Groups;Surveys;System;Time;Treatment outcome;United States National Institutes of Health;Urban Population;Validation;Variant;Woman;addiction;adverse outcome;economic disparity;effective therapy;evidence base;experience;follow-up;geographic difference;improved;interest;medication for opioid use disorder;offender;opioid epidemic;opioid misuse;opioid use disorder;primary outcome;process improvement;programs;prospective;recidivism;recruit;relapse risk;response;social;social influence;social structure;structural determinants;uptake;willingness

public_health_relevance:
PROJECT NARRATIVE To improve future treatment interventions for persons with opioid use disorders (POUDs) who areincarcerated this study compares the multi-level factors influencing prison- and community-based initiation ofmedications for addiction treatment (MAT) and associated post-release outcomes under real-world conditionsin rural Appalachian Kentucky an economically-deprived region with limited service availability and moreresource-rich urban counties. This study will make significant contributions to public health and public safetyby examining how rural-urban variation in personal social network characteristics support or impede the effortsof POUDs to access continuing treatment post-release achieve stable recovery and desist from crime duringthe vulnerable re-entry period.


application_id: 10624991
project_number: 4R44DA053848-02
project_title: Digital Therapeutic Development of Virtual Cognitive-Affective Training for Opioid Use Disorder
administering_ic: NIDA
award_notice_date: 2022-08-03
opportunity_number: RFA-DA-19-019
application_type: 4
activity_code: R44
ic: DA
serial_number: 053848
program_official: ANGELONE, LEONARDO MARIA
project_start_date: 2021-05-15
project_end_date: 2025-07-31
study_section: ZDA1-GXM-A(03)R
contact_pi_person_id: 7594377
contact_pi: WEISBERG, RISA B
other_pis: Not Applicable
congressional_district: 02
department: Unavailable
primary_duns: 080772307
primary_uei: PYRCCX2DHMJ7
duns_number: 080772307
uei: PYRCCX2DHMJ7
fips: US
organization_id: 10047086
organization_name: BEHAVR, LLC
organization_city: ELIZABETHTOWN
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 427014430
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary: The US is experiencing an opioid crisis with an estimated 2.5 million Americans meetingfull criteria for opioid use disorder (OUD). Medications for opioid use disorder (MOUD) like buprenorphine arecurrently the most effective form of intervention for OUD. In spite of the proven efficacy of MOUD nearly half ofpeople who begin a MOUD relapse within six months. As such novel and efficacious behavioral adjuncts toMOUD are needed to improve treatment outcomes. Mindfulness-Oriented Recovery Enhancement (MORE) acognitive-affective training intervention generated through a NIDA-funded treatment development process hasshown significant promise demonstrating therapeutic effects in four randomized controlled trials (RCTs) byreducing opioid use and misuse and modulating neurophysiological responses during drug cue-reactivity andnatural reward processing. However the MORE intervention requires significant human interaction and istherefore resource intensive. Further in light of the COVID-19 pandemic people with OUD may be reticent toengage in face-to-face interventions due to the risk of viral spread. To overcome these implementation barriersand increase access to treatment the proposed project will develop and test a virtual reality version of theMORE intervention (MORE-VR) built on BehaVR LLC's VR existing commercially available platform theDynamic eXperience Engine (DXE). The DXE uses machine learning to integrate biometrics into the VRexperience to personalize addictions treatment boosting patient engagement and optimizing the efficacy ofclinical intervention. In Phase I we will develop and test the MORE-VR prototype in a single arm clinical studyof OUD patients receiving buprenorphine in an opioid treatment program (OTP) focusing on patient safety andengagement. If the prototype is perceived to have adequate usability and Net Promoter Scores as well as toproduce improvements in proximal measures of craving and affective state the project will progress to PhaseII. In Phase II we will first develop the MORE-VR Minimal Viable Program using feedback from our Phase Istudy to optimize the intervention and then conduct a RCT of MORE-VR vs. MOUD treatment as usual. Ourrobust and unbiased research design will triangulate clinical outcome measurement with biochemicalverification of abstinence ecological momentary assessments (EMA) and neurophysiological assessment ofcue-reactivity. Further we will integrate the MORE-VR Program into the OTP operational environment buildingFast Healthcare Interoperability Resources interfaces to ingest patient data from electronic medical records(EMRs) and to export patient utilization assessment and biometric data back to EMRs to create patientrecords and inform clinicians of patient progress. Activities in Phase I and Phase II will help define theregulatory pathway and establish regulatory feasibility to precede Food and Drug Administration (FDA)approval of the MORE-VR system as a Class II medical device. In sum this project will translate an evidence-based biobehavioral treatment approach into an innovative digital therapeutic for OUD.

project_terms:
Abstinence;Adherence;Affect;Affective;American;Area Under Curve;Back;Behavior Therapy;Behavioral;Biochemical;Biometry;Brain;Buprenorphine;COVID-19 pandemic;Clinic;Clinical;Clinical Research;Cloud Computing;Cognitive;Computerized Medical Record;Custom;Data;Development;Dropout;Ecological momentary assessment;Educational Intervention;Electronic Health Record;Environment;Epidemic;Fast Healthcare Interoperability Resources;Feedback;Funding;Goals;Health Services Accessibility;Human;Human Resources;Individual;Ingestion;Intervention;Light;Link;Machine Learning;Measurement;Measures;Medical Device;National Institute of Drug Abuse;Opioid;Outcome;Participant;Patients;Persons;Pharmaceutical Preparations;Phase;Plant Roots;Process;Protocols documentation;Psychophysiology;Randomized Controlled Trials;Records;Recovery;Regulatory Pathway;Relapse;Research Design;Resources;Rewards;Risk;Safety;Self Efficacy;Services;Signal Transduction;Small Business Innovation Research Grant;Specific qualifier value;Sum;System;Techniques;Teleconferences;Testing;Therapeutic Effect;Training;Translating;Treatment outcome;United States;United States Food and Drug Administration;Viral;addiction;affective neuroscience;arm;barrier to care;biobehavior;chronic pain;clinical efficacy;commercialization;craving;cue reactivity;design;digital treatment;effective intervention;efficacy study;electronic data;evidence base;experience;implementation barriers;improved;innovation;meetings;mindfulness;neurophysiology;novel;opioid epidemic;opioid misuse;opioid treatment program;opioid use;opioid use disorder;patient engagement;patient safety;phase 1 study;pilot test;prevent;programs;promoter;prototype;response;reward processing;satisfaction;skills;success;therapeutic development;therapy development;treatment as usual;treatment program;treatment risk;treatment strategy;usability;virtual;virtual machine;virtual reality;virtual reality system

public_health_relevance:
Project NarrativeMedications for opioid use disorder (MOUD) like buprenorphine are currently the mosteffective form of intervention for opioid use disorder (OUD); however novel behavioraladjuncts are needed to remediate dysregulation in brain reward systems enhance MOUDadherence and prevent relapse. BehaVR LLC will meet this need by translating anevidence-based biobehavioral treatment approach into an innovative digital therapeuticfor OUD that will increase accessibility to services to improve the patient's chances oflong-term treatment success.


application_id: 10624964
project_number: 5R01DC019054-04
project_title: GIPC3 multifunctional myosin adaptor in mammalian auditory hair cells
administering_ic: NIDCD
award_notice_date: 2023-05-23
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DC
serial_number: 019054
program_official: FREEMAN, NANCY
project_start_date: 2020-06-10
project_end_date: 2025-05-31
study_section: Special Emphasis Panel[ZRG1-IFCN-E(02)M]
contact_pi_person_id: 8360158
contact_pi: FROLENKOV, GREGORY I
other_pis: VANDER KOOI, CRAIG
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:
GIPC3 a member of G-Interacting Protein C-terminus (GIPC) family is known to be essential forhearing. Eleven mutations in GIPC3 spread throughout its three structural domains cause inheritedautosomal recessive hearing loss. However the molecular basis for GIPC3 function in the auditorysystem and the mechanisms by which these human mutations result in hearing loss are unknown. Wehave recently determined the structure of GIPC3 bound to a prototypical receptor and determined themolecular mechanism of GIPC3 activation and its subsequent binding to MYO6 the unconventionalmyosin that is expressed in the auditory hair cells and is essential for hearing. These biochemical andstructural studies allowed us to predict the effects of known deafness-related mutations in GIPC3 on itsactivation and MYO6 binding. We have generated two new mouse models one that is lacking functionalGIPC3 and another one with a W301X point mutation in Gipc3 that corresponds to a mutation with themost severe auditory phenotype in humans. This study will explore the central hypothesis that GIPC3 hasa dual role in the auditory hair cells. We hypothesize that in stereocilia GIPC3 is involved in shapingmechanotransduction and hair bundle structure through its interactions with CDH23/myosin-VIIa andmyosin-XVa respectively. In the cell body GIPC3 is essential for apical endocytosis at the pericuticularneckless region due to its interaction with myosin-VI. All these functions are crucial for normal hearing.However the exact molecular mechanisms that determine the resting tension in the mechanotransduc-tion machinery as well as gradation of stereocilia heights and diameters in the auditory hair cell bundlesare still enigmatic. Likewise very little is known about molecular mechanisms and even the role ofpericuticular neckless endocytosis in the hair cell function. The expected outcomes of this study are touncover (a) the precise mechanism of deafness associated with GIPC3 deficiency and (b) thephysiological role of GIPC3 in hair cell functions especially in mechanotransduction formation of the hairbundle architecture and endocytosis at the pericuticular neckless. Deciphering the function of GIPC3protein and its known mutations is a critical step towards the development of therapies for the treatmentand/or prevention of GIPC3-dependent deafness and hearing loss.

project_terms:
Actins;Adopted;Affect;Age;Age Months;Ankle;Apical;Architecture;Auditory;Auditory system;Belief;Binding;Biochemical;Biochemistry;C-terminal;CDH23 gene;Cadherin Domain;Cell physiology;Cells;Cellular Structures;Complex;Consensus;Coupling;Custom;DLG4 gene;Data;Development;Diameter;Dimerization;Endocytosis;Epidermal Growth Factor Receptor Pathway Substrate 8;Family;Family member;Hair;Hair Cells;Hearing;Height;Human;Inherited;Inner Hair Cells;Knowledge;Label;Labyrinth;Link;MYO7A gene;Mechanics;Mediating;Molecular;Motor;Mouse Strains;Mus;Mutation;Myosin ATPase;N-terminal;Outcome Study;Patients;Phenotype;Physiological;Point Mutation;Positioning Attribute;Prevention;Protein Family;Proteins;Receptor Activation;Reporting;Rest;Role;Shapes;Site;Structure;Surface;Synaptic Transmission;Therapeutic;Time;Ubiquitin;Vesicle;WHRN gene;autosome;cell type;deaf;deafness;dimer;hearing impairment;in vivo;insight;live cell imaging;mechanotransduction;member;mouse model;mutant;myosin VI;myosin XVA;nanobodies;normal hearing;novel;prevent;receptor;receptor binding;response;structural biology;therapy development;trafficking;two-photon;uptake

public_health_relevance:
Advancement in our understanding of molecular mechanisms of key molecules in the inner ear isa prerequisite to developing therapeutic strategies for hearing loss. The studies outlined in thisproposal explore structural and functional effects of all eleven reported patient mutations in GIPC3protein that have been identified to date as a cause of non-syndromic autosomal recessive deafnessDFNB72. In addition since GIPC3 is a previously unexplored molecular partner of other deafnessproteins our study will provide fundamental knowledge into the pathophysiological mechanisms of otherforms of deafness that will help to reduce the burden of human hearing loss.


application_id: 10624963
project_number: 5R01GM138837-03
project_title: Ex vivo single molecule tools to analyze membrane receptor dynamics
administering_ic: NIGMS
award_notice_date: 2023-05-16
opportunity_number: PAR-19-253
application_type: 5
activity_code: R01
ic: GM
serial_number: 138837
program_official: YEH, ALVIN TIEN-WEI
project_start_date: 2021-06-03
project_end_date: 2025-05-31
study_section: Enabling Bioanalytical and Imaging Technologies Study Section[EBIT]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Membrane receptors play a crucial role in many physiological processes throughout the body bymediating communication between cells. Single molecule imaging has been used extensively tostudy membrane receptor assembly and stoichiometry in vitro using isolated protein and to alesser extent cell culture. While studies in isolated cellular systems provide insight into manyprocesses they lack the context of the complex environment present in an animal wherecommunication between cell types residing in tissue is critical for receptor activity. Single-molecule imaging of native proteins synthesized in vivo would provide a direct approach tomeasure processes such as receptor dimerization that regulate physiological activity. Howevercurrent methods are not capable of applying single molecule techniques to study the regulationof protein dynamics taking place within the complex environment of an animal. We have maderecent advances in the development of ex vivo single molecule techniques to monitor changes inprotein assembly that occur within specific organs. The goal of this proposal is to develop andvalidate ex vivo single molecule tools that provide new capabilities to monitor the properties ofoligomeric membrane receptor assembly resolve cell type and subcellular region specific singlemembrane receptors and automate single molecule data analysis using a machine learningplatform. This novel ex vivo technology will enable researchers to take a snap shot in time of themembrane receptor dynamics that took place in the mouse and monitor changes in membranereceptor assembly in response to changes in the animal's physiological environment such asdisease and exposure to therapeutics.

project_terms:
Address;Animal Communication;Animal Disease Models;Animal Model;Animals;Biological;Biological Models;Brain;Brain region;Cardiac;Cell Culture Techniques;Cells;Chemicals;Classification;Communication;Complex;Consumption;Data;Data Analyses;Data Set;Development;Dimerization;Disease;Encapsulated;Environment;Exposure to;Future;Genes;Goals;Heart;High Performance Computing;Image;In Vitro;Knock-in;Knock-in Mouse;Machine Learning;Manuals;Measurement;Mediating;Membrane;Membrane Proteins;Methodology;Methods;Monitor;Mus;Organ;Pharmaceutical Preparations;Pharmacotherapy;Physiological;Physiological Processes;Play;Population;Preparation;Process;Process Measure;Property;Protein Biosynthesis;Protein Dynamics;Proteins;Regulation;Research;Research Methodology;Research Personnel;Role;RyR2;Ryanodine Receptor Calcium Release Channel;Sampling;Signal Transduction;System;Techniques;Technology;Testing;Therapeutic;Time;Tissues;Training;Vesicle;animal tissue;cell type;cluster computing;convolutional neural network;design;imaging capabilities;in vivo;insight;large datasets;molecular imaging;nanoscale;nanovesicle;novel;open source;postsynaptic neurons;presynaptic;protein purification;prototype;receptor;response;sex;single molecule;stoichiometry;technique development;therapeutic target;tissue preparation;tool;trafficking

public_health_relevance:
Membrane receptors are important therapeutic targets for many diseases and are expressed throughout thebody. Understanding the role of receptor assembly in the complex environment of a live animal is an importantstep in understanding their mechanism of activation and regulation. We will develop ex vivo single-moleculemethods that for the first time will enable quantitative studies of stoichiometry for receptors extracted frommice.


application_id: 10624899
project_number: 5SB1ES028171-06
project_title: Electrochemical POU Water Purification System
administering_ic: NIEHS
award_notice_date: 2023-04-28
opportunity_number: PAR-20-128
application_type: 5
activity_code: SB1
ic: ES
serial_number: 028171
program_official: HENRY, HEATHER F
project_start_date: 2017-09-15
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-IMST-K(19)B]
contact_pi_person_id: 14657253
contact_pi: BOEHME, LINDSAY
other_pis: RASSOOLKHANI, ALAN
congressional_district: 06
department: Unavailable
primary_duns: 079388085
primary_uei: JD9MTUKKNG13
duns_number: 079388085
uei: JD9MTUKKNG13
fips: US
organization_id: 10036767
organization_name: POWERTECH WATER, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40508
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYLead contamination in drinking water is a pervasive health problem across the US.1 Children are especiallyvulnerable to lead poisoning which can have permanent detrimental effects on brain development.23 Despitecorrosion prevention measures taken by public water authorities lead concentrations in drinking water areroutinely elevated nationwide and an estimated 12 million lead services lines are in need of replacement.4 TheEnvironmental Protection Agency (EPA) established The Lead and Copper Rule in 1991 to limit exposure ofthese elements and set the action level to 15 ppb; however there is no safe level of lead consumption andmore stringent regulations are starting to be adopted around the world.5-8 The crisis observed in Flint Michiganin 2014 put lead exposure into the public spotlight increasing consumer awareness. Seven years later leadcontamination of drinking water supplies remains a national issue.Lead filters currently on the market lack specificity with limited device lifetime dictated by the total amount ofwater volume filtered regardless of lead concentration. Incumbent solutions for home water purification arearchaic and outdated. ElectraMetTM from PowerTech Water (PTW) is an electrochemical filter that can targetthe removal of lead. The device uses activated carbon electrodes and a small applied voltage (< 2.0 V) toinduce Faradaic reactions at both the carbon-based anodes and cathodes within the cell. By tuning the deviceconfiguration and operating parameters lead will precipitate out of solution and be permanently removed whileother dissolved minerals are left unaffected.In this CRP project PTW's goal is to design a POU device that meets target end-use product specificationsand certification standards. At the completion of this work we anticipate a consumer-focused device thatexceeds the performance of current off-the-shelf solutions. The device will be reliable and specific for leadhave a multi-year system lifetime and will not be consumed by abundant water constituents. Theseperformance targets will be achieved through the following Specific Aims:1. Product form factor design for a POU solution. Expected outcome: A design that fits under the sink and meets product specifications for the overall device size pressure tolerance price point and lead removalperformance.2. Replication of testing standards to obtain drinking water filtration certifications. Expected Outcome: ElectraMetTM performance to meet NSF/ANSI 53 and 61 certification standards for lead removal and structural integrity.3. Testing of a POU installation to simulate a real-world scenario. Expected Outcomes: Operating parameters required for lead removal under different water usage scenarios and a method to track device lifetime to predict filter replacement.

project_terms:
Adopted;Anodes;Authorization documentation;Awareness;Brain;Carbon;Cathodes;Cells;Certification;Child;Consumption;Copper;Correlation Studies;Corrosion;Development;Devices;Drops;Electrodes;Elements;Engineering;Ensure;Excision;Filtration;Foundations;Funding;Goals;Guidelines;Health;Home;Infrastructure;Institution;Knowledge;Lead;Lead Poisoning;Lead levels;Left;Maintenance;Marketing;Measurement;Metal exposure;Metals;Methods;Michigan;Minerals;Outcome;Performance;Phase;Prevention Measures;Price;Process;Reaction;Regulation;Resources;Sampling;Sanitation;Science;Services;Signal Transduction;Source;Specific qualifier value;Specificity;System;Technology;Testing;Time;Trust;United States;United States Environmental Protection Agency;Update;Water;Water Purification;Water Supply;Work;authority;contaminated drinking water;cost;cost effective;design;drinking water;economic evaluation;lead concentration;lead contamination;lead exposure;manufacture;pressure;response;success;voltage;water treatment

public_health_relevance:
PROJECT NARRATIVELead contamination of drinking water continues to be one of the greatest health threats in theUnited States due to outdated infrastructure and the Environmental Protection Agency (EPA)emphasizes that there is no safe level of lead exposure. PowerTech Water's goal is to design apoint-of-use (POU) drinking water purification device for installation under a sink that is highlyspecific for lead as well as more reliable efficient and longer-lasting than state-of-the-artsolutions. If successful this technology will deliver safe drinking water at the source in a low-cost low-complexity and low-maintenance format.


application_id: 10623283
project_number: 5R44DK133065-02
project_title: Developing a new DFU dressing
administering_ic: NIDDK
award_notice_date: 2023-05-31
opportunity_number: PA-21-259
application_type: 5
activity_code: R44
ic: DK
serial_number: 133065
program_official: LI, YAN
project_start_date: 2022-05-17
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZRG1-SBIB-K(11)B]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Diabetic foot ulcers (DFUs) are the leading cause of nontraumatic lower extremityamputations in the United States and are responsible for more hospitalizations than anyother complication of diabetes. Despite thousands of dressings developed in the pastcentury none have shown any specific effectiveness as DFU treatments. Currentlyeven the best available treatments achieve only a 50% healing rate for thesewoundsand this healing is often temporary with a 66% chance of recurrence. For the first time in history we have found an approach that may change the currentdogma. We have developed a technique for intracellular ATP delivery (ATP-vesicles orVitaSol). When we use VitaSol for wound healing granulation tissue starts toappear within 24 hours. This new tissue keeps growing and fills the wound cavitywithin a few days a phenomenon never seen or reported before by any othertechniques. Control dressings including normal saline free Mg-ATP empty lipidvesicles and the only FDA-approved prescription growth factor Regranex have nosuch effects. The final healing time is much shorter than the controls in long-timediabetic plus ischemic wounds. A preliminary mechanistic study has shown that theextremely rapid tissue regeneration is the result of very early (5 hours after surgery)rapid and massive macrophage accumulation in situ proliferation M2 polarization anddirect collagen production long before traditional fibroblasts come into play. This type ofhealing is totally different from the conventional process known to the wound carecommunity where fibrin platelets and red blood cells are the main components of theearly provisional matrix which is gradually replaced by granulation tissue during theproliferation phase after 36 days of lag time. Although the growth seen with VitaSolis extremely rapid it does not display any unusual growth or hypertrophic scar formationafter 2 years in animals and after more than 9 years in limited human volunteers. If thiscan be duplicated in humans it will be a major breakthrough in medicine. Our central hypothesis is that intracellular ATP delivery provides critical energy atvery early time activates various transcription mechanisms resulting in extremely earlyand rapid tissue regeneration that fills the wound cavity quickly. In this proposal we will perform a preclinical toxicity study aimed at IND applicationand test the effectiveness of VitaSolTM in a new animal model with long-term diabetesischemia and neuropathy. Our product for intracellular energy delivery has consistently been viewed asinnovative. The outcome of this project will be the clinical introduction of a highlyeffective inexpensive and easy-to-use new dressing for DFU treatment. The potentialimpact is very high.

project_terms:
Amputation;Animal Model;Animals;Becaplermin;Blood Platelets;Clinical;Clinical Trials;Collagen;Community Healthcare;Complications of Diabetes Mellitus;Cyclic GMP;Diabetes Mellitus;Diabetic Foot Ulcer;Effectiveness;Erythrocytes;FDA approved;Fibrin;Fibroblasts;Genetic Transcription;Granulation Tissue;Growth;Growth Factor;Hospitalization;Hour;Human;Human Volunteers;Hypertrophic Cicatrix;In Situ;Ischemia;Lipids;Lower Extremity;Macrophage;Medicine;MgATP;Neuropathy;Normal saline;Operative Surgical Procedures;Outcome;Phase;Play;Preparation;Process;Production;Proliferating;Recording of previous events;Recurrence;Reporting;Sterile coverings;Techniques;Testing;Time;Tissues;Toxic effect;United States;Vesicle;Wound models;commercialization;diabetic;effective therapy;effectiveness testing;healing;innovation;phenome;preclinical toxicity;success;tissue regeneration;wound;wound care;wound healing

public_health_relevance:
NARRATIVE Diabetic foot ulcers (DFUs) are the leading cause of nontraumatic lower extremityamputations but effective treatment is still lacking. In this proposal we will use ournewly developed intracellular ATP delivery for wound care in a newly developed long-term diabetes plus ischemia and neuropathy and to test its toxicity in preparation forFDA approval. The success of the project will have a major contribution to medicine.


application_id: 10622520
project_number: 5R01EY029719-05
project_title: Glycine subunit specific inhibition and ganglion cell visual responses
administering_ic: NEI
award_notice_date: 2023-04-06
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: EY
serial_number: 029719
program_official: WRIGHT, CHARLES BAKER
project_start_date: 2019-03-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1-MDCN-V(04)S]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: GREGG, RONALD G
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Retinal ganglion cells (GCs) integrate excitatory and inhibitory inputs and perform computations that encodediverse features of the visual scene. The output of these functionally and morphologically diverse GCs establishvisual signaling streams maintained throughout the visual pathway. Ultimately they create our perception of thesize shape and color of objects and their relationships in space. They establish relationships of objects in time sothat we know when it is stationary or moving and when moving its direction and velocity. To this end there is ageneral division of labor between the retina's inhibitory neurotransmitter systems. GABA and its receptorsmodulate spatial vision whereas glycine and its receptors modulate temporal vision. There are five glycinereceptor subunits (one  and 4s). The GlyR subunits combine with a single  subunit to make functionalreceptors with diverse biophysical properties. Our work shows that all GCs expresses one or more GlyRs and thecomposition differs across GC type. We hypothesize that variety enhances the diversity of inhibitory functions acrossand within GC types and are used to encode the visual scene. However the specific function of GlyR subunits isalmost completely unknown.We know that the responses (and transmitter release) of the GABA and glycinergic amacrine cells presynapticto GCs are modulated by other glycinergic amacrine cell input. This means that until GlyRs can be selectivelyeliminated in GCs or ACs we cannot disambiguate the role of direct GlyR inhibition to GCs from GlyR modulationin the upstream circuit that provides input to the GCs. We developed a novel AAV-shRNA knockdown (KD)approach that eliminates expression of individual G lyR subunits in GCs while leaving their upstream expressionintact. We propose to use this approach to define the role of GlyR direct inhibition in 7 identified GC types and byextension the role of isolated GABA inputs in those same GCs. In Aim 1 we ask if a single GlyR GlyR1 expressed by the 4 functionally diverse GCs modulates the same or different aspects of their visual responses. In aim 2 we ask iftwo different GlyR subunits expressed in the same GC increase the diversity of inhibition to modulate differentaspects of the visual response in a single GC type. We use electrophysiological assays to characterize the spikingresponses of the GCs underlying currents and the relationships between the kinetics of excitatory and inhibitoryinput with the postsynaptic response.This proposal addresses the novel concept: that diverse glycine subunit specific inhibition interacts withpresynaptic inputs to controls visual computation.

project_terms:
Address;Amacrine Cells;Biological Assay;Brain Stem;Categories;Cells;Central Nervous System;Color;Cre driver;Data;Electrophysiology (science);Feedback;Glycine;Glycine Receptors;Goals;Individual;Injections;Interneurons;Kinetics;Knock-out;Knockout Mice;Light;Location;Masks;Mediating;Morphology;Mus;Neurotransmitters;Object Attachment;Output;Pharmacology;Process;Property;Publishing;Reaction Time;Reporter;Rest;Retina;Retinal Ganglion Cells;Role;Shapes;Signal Transduction;Size Perception;Spinal Cord;Stimulus;Stream;Structure;Strychnine;Synapses;System;Time;Vision;Visual;Visual Pathways;Work;biophysical properties;cell type;gamma-Aminobutyric Acid;ganglion cell;knock-down;novel;object motion;parallel processing;pharmacologic;postsynaptic;presynaptic;receptor;response;retrograde transport;small hairpin RNA;spatial vision;spatiotemporal;superior colliculus Corpora quadrigemina;synaptic inhibition;vector;visual control

public_health_relevance:
The visual scene contains multiple streams of information that are efficiently processed and categorized by theretina. The spatio-temporal responses of GCs require the correct integration of bipolar cell excitatory andamacrine cell inhibitory inputs to GC. This project will define how diverse inhibitory inputs are shaped and howthey are matched with excitation which results in the accurate representation of the visual scene that is provedby the retina to the rest of the central nervous system.


application_id: 10621715
project_number: 5R24ES030904-04
administering_ic: NIEHS
award_notice_date: 2023-04-28
opportunity_number: RFA-ES-18-009
application_type: 5
activity_code: R24
ic: ES
serial_number: 030904
program_official: GRAY, KIMBERLY A
project_start_date: 2020-05-06
project_end_date: 2025-04-30
study_section: ZES1-VSM-K(R)
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Retention Maintenance and Enhancement of the Communities Actively Researching Exposure Study (CARES)

project_abstract:
PROJECT SUMMARYManganese (Mn) plays an essential role in normal growth and development The Communities ActivelyResearching Exposure Study (CARES) was built upon community-engaged research practices. Participantsreside in three communities with the nation's highest levels of ambient Mn: Marietta and East Liverpool Ohioand Southeast Side Chicago Illinois. The CARES cohort consists of over 600 children and their primarycaregiver with two time-points (ages 7-9 years and ages 13-17 years) of extensive neurodevelopmentaloutcomes biomarkers of exposure and home environmental measures. The CARES has been supported bymultiple NIEHS-funded grants and has been instrumental in the training of next generation community-engaged environmental health scientists for over a decade. The cohort has been instrumental in thedevelopment of a lab-on-a-chip sensor for blood metals assessment and is currently exploring the impact ofMn on neuroanatomy function chemistry and physiology through magnetic resonance imaging. Through thisproject the CARES research team will be able to conduct the following: Aim 1) Maintain the integrity of theCARES cohort by implementing community-engaged research strategies to improve participant retention; Aim2) Expand CARES to enhance characterization of critical windows of exposure across the lifespan and assessthe role of caregiver child and community-level psychosocial factors on the etiology of toxicant-inducedneurodevelopmental deficits; and Aim 3) Maintain and enhance biorepository and data managementinfrastructure and develop methods to implement data sharing. The CARES is the only cohort poised toinvestigate ambient exposure to Mn and its relationship to brain function in both a pediatric and adolescentpopulation. The proposed cohort retention enhancement and maintenance plans will accelerate and sustainthe ability of the CARES cohort to investigate the impact of ambient Mn on neurodevelopmental outcomesinform federal polices related to ambient exposure to Mn and serve as a valuable resource for environmentalhealth science trainees and scientists across the globe.

project_terms:
Acceleration;Adolescent;Adult;Age;Air;Anatomy;Applications Grants;Biological;Biological Markers;Blood;Brain;Caregivers;Chemistry;Chicago;Child;Childhood;Cohort Studies;Collaborations;Communities;Community Developments;Data;Data Management Resources;Data Set;Development;Dust;Environmental Epidemiology;Environmental Exposure;Environmental Health;Environmental Impact;Equipment and supply inventories;Etiology;Evaluation;Exposure to;Funding;Grant;Growth and Development function;Hair;Home;Illinois;Infrastructure;Knowledge;Lab On A Chip;Laboratories;Longevity;Magnetic Resonance Imaging;Maintenance;Manganese;Measurement;Measures;Metals;Methods;Motor;National Institute of Environmental Health Sciences;Neuroanatomy;Neurodevelopmental Deficit;Neuropsychology;Ohio;Outcome;Parents;Participant;Pediatric cohort;Pediatric epidemiology;Physiology;Play;Police;Population;Psychosocial Factor;Reporting;Resources;Role;Saliva;Sampling;Scientific Advances and Accomplishments;Scientist;Serum;Side;Soil;Structure of nail of toe;Time;Training;United States;Urine;Water;Whole Blood;biobank;cohort;community engaged research;data management;data sharing;deciduous tooth;early childhood;improved;innovation;neurodevelopment;next generation;novel;participant retention;patient engagement;point of care;preservation;primary caregiver;research study;sensor;toxicant

public_health_relevance:
PROJECT NARRATIVEThe Communities Actively Researching Exposure Study (CARES) is a successful and well-establishedenvironmental pediatric epidemiology cohort study that has reported the impact of environmental manganeseexposure on pediatric brain function. This proposal will retain the over 600 child-parent pairs enhance therobust dataset with ambient and internal exposure characterization during early childhood development andbuild the infrastructure needed to share the unique data within the cohort.


application_id: 10621175
project_number: 5R01EY031322-04
project_title: Parallel Pulvinar Pathways
administering_ic: NEI
award_notice_date: 2023-05-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: EY
serial_number: 031322
program_official: FLANDERS, MARTHA C
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTThe concept of parallel pathways that code different aspects of the visual scene has led to many key insightsregarding the functional organization of the visual system. Inspired by this concept the proposed studies focuson parallel visual pathways from the retina to the superior colliculus (SC) through the pulvinar nucleus (PUL).Projections from the SC to the PUL originate from motion-detecting widefield vertical (WFV) cells and theirsynaptic organization defines two distinct PUL subdivisions: one that receives ipsilateral topographic WFVprojections (specific) and one that is innervated by bilateral convergent WFV projections (diffuse). These twoWFV innervation patterns are correlated with distinct cortical and subcortical connections as well a variety ofhistochemical criteria suggesting that the tectorecipient PUL may be organized into separate visual movementprocessing streams. However we currently lack a functional framework that allows us to test this hypothesis anddecipher the modular organization of the PUL. We plan to address this gap in knowledge by defining PUL celltypes and synaptic inputs in the context of their functional properties. Our guiding hypothesis is that the PUL iscomposed of two distinct modules that coordinate visual perception with body movements or motivational stateto initiate appropriate motor commands. To begin to test this theory with mice as our animal model we will useanatomical intersectional viral vector approaches and in vitro whole cell recordings coupled with dual optogeneticactivation of cortical and WFV synaptic inputs to define circuit mechanisms that can alter firing properties withineach PUL module (Aim 1). We will use in vivo extracellular recordings coupled with optogenetic activation andsilencing of synaptic inputs to determine how circuit interactions within each PUL module adjusts receptive fieldproperties (Aim 2). A key innovation of our experiments is the ability to identify PUL neuron subtypes by theirunique frequency-dependent responses to optogenetic activation of WFV inputs (neuron identification via singleinput dynamics). This new method will allow us to link detailed in vitro circuit dissection techniques with in vivorecording of visual response properties providing a framework of PUL function that has thus far been elusive.By comparing two parallel PUL modules our goal is to understand how visual motion signals are parsed toinitiate appropriate behavioral responses.

project_terms:
Address;Anatomy;Animal Model;Bilateral;Cell Nucleus;Cells;Code;Contralateral;Coupled;Depressed mood;Diffuse;Disease;Dissection;Dorsal;Dyslexia;Environment;Frequencies;Goals;Head;In Vitro;Injections;Ipsilateral;Knowledge;Label;Laboratories;Lateral Geniculate Body;Light;Link;Location;Methods;Motion;Motion Perception;Motivation;Motor;Movement;Mus;Neurons;Opsin;Pathway interactions;Pattern;Property;Pulvinar structure;Retina;Retinal Ganglion Cells;Rewards;Running;Schizophrenia;Sensory;Signal Transduction;Stream;Structure/Function Nuclei;Synapses;Techniques;Testing;Time;Viral;Viral Vector;Visual;Visual Motion;Visual Pathways;Visual Perception;Visual System;Visual attention;Whole-Cell Recordings;Work;area striata;autism spectrum disorder;behavioral response;brain circuitry;cell cortex;cell type;experimental study;extracellular;in vivo;innovation;insight;nerve supply;neural circuit;novel;optogenetics;parallel processing;receptive field;response;segregation;success;superior colliculus Corpora quadrigemina;theories;visual stimulus

public_health_relevance:
PROJECT NARRATIVEThe results of these experiments will significantly enhance our understanding of the brain circuitry underlyingvisual motion perception thus providing information relevant to the treatment of disorders in which visual motionprocessing is compromised such as dyslexia and schizophrenia. In addition the results of these experimentswill enhance our understanding of subcortical visual pathways which may be altered in autism spectrumdisorder.


application_id: 10619566
project_number: 5P20GM103436-23
project_title: Developmental Research Project Program
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7347
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Developmental Research Program (DRPP) - Project Summary The Development Research Project Program provides an array of support programs to develop competitive biomedical research faculty in Kentuckys colleges and universities. The primary assumption underlying this program is that each Kentucky institution needs a critical mass of independent biomedical research faculty in order to provide the highest quality biomedical research training to undergraduate students. Furthermore Kentucky research faculty must be provided with the infrastructure to succeed in their research careers in order to provide first-rate research experiences to undergraduate students which will inspire them to join the biomedical workforce. With the overarching goal of increasing biomedical research capacity in Kentucky the Developmental Research Project Program aims to address the existing low numbers of independent research faculty and existing deficits in infrastructure by enhancing faculty recruitment promoting the research and career development of junior faculty and building a sustainable research network. Based upon our past successes we will focus our efforts on institutions eligible for NIH R15 funding. These institutions are primarily undergraduate institutions (PUIs) so this concentration provides the greatest benefit to undergraduate students. At these institutions we focus our efforts on developing faculty to increase success rates in obtaining R15 funding. In this way we have been successful in increasing the numbers of independent research faculty and building a sustainable research network.

project_terms:
Address;Applications Grants;Award;Biomedical Research;Career Mobility;Core Facility;Data;Development;Discipline;Educational workshop;Eligibility Determination;Faculty;Faculty Recruitment;Funding;Goals;Grant;Howard Temin Award;Infrastructure;Institution;Kentucky;Mentors;Pilot Projects;Postdoctoral Fellow;Process;Productivity;Program Research Project Grants;Research;Research Personnel;Research Support;Research Training;Services;Training;United States National Institutes of Health;Universities;Work;Writing;career;career development;college;experience;postdoctoral investigator;programs;recruit;research and development;research faculty;success;undergraduate research experience;undergraduate student


application_id: 10619564
project_number: 5P20GM103436-23
project_title: Electron Microscopy Core
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7346
contact_pi_person_id: 8537263
contact_pi: AEBERSOLD, JULIA WEYER
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:
Electron Microscopy Core Summary  While methods to image fluorescent molecules have advanced dramatically in recent years the resolution of electron microscopy remains unsurpassed. In the state of Kentucky there are numerous research programs that require the resolution that can only be achieved by the interaction of a beam of electrons with a specimen to distinguish ultrastructural features of tissues cell components viruses or bacteria. However due to declining institutional support for electron microscopy facilities many established Kentucky investigators have utilized facilities and expertise outside the state for their electron microscopic analyses. Furthermore new Kentucky investigators are hesitant to add electron microscopy to their research programs without accessible training and technical support. We propose to address these gaps in infrastructure and education by establishing a statewide electron microscopy core to facilitate equipment sharing provide technical support and offer training.

project_terms:
Address;Adopted;Applications Grants;Bacteria;Biomedical Research;Businesses;Cellular Structures;Collaborations;Cost Sharing;Education;Education and Outreach;Educational workshop;Electron Beam;Electron Microscope;Electron Microscopy;Electron Microscopy Facility;Electrons;Ensure;Equipment;Faculty;Fee-for-Service Plans;Fostering;Funding;Health;Infrastructure;Institution;Kentucky;Methods;Microscopic;Pilot Projects;Postdoctoral Fellow;Research;Research Personnel;Research Project Grants;Research Training;Resolution;Resources;Site;Specimen;Students;Techniques;Tissues;Training;Universities;Virus;cost;fluorescence imaging;graduate student;outreach;programs;technology training;undergraduate student


application_id: 10619563
project_number: 5P20GM103436-23
project_title: Statistics Core
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7345
contact_pi_person_id: 8252047
contact_pi: STROMBERG, ARNOLD JAMES
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:
RESEARCH CORES - STATISTICSProject Summary/Abstract:The primary goal of the Statistics Core located at the University of Kentucky is to provide accessto statistics support for experimental design preparation of manuscripts and grant applications. Thecore will also provide statistical training and professional development opportunities for KBRINinvestigators and trainees at UK through regional conferences workshops and seminars and ateach regional university during site visits. We will continue to utilize unique strategies via theApplied Statistics Lab (ASL) to bring in new regional investigators into the KBRIN network andprovide statistical expertise for their research. Some of these endeavors include providing easieraccess to statistical services through video conferences on-site visits and educatinginvestigators about KBRIN statistical resources. ASL faculty students and staff have workedand will work remotely and in person with the regional investigators to supply expertise inexperimental design statistical analysis and data management. Finally with an emphasis onmentorship and training ASL graduate students are partnered with an experienced faculty/staffmember who mentors the graduate student through all stages of a project. Training will be in theareas of data security data management data analysis using SAS and R automatic tablecreation post-hoc analysis and statistical consultation. In summary the Statistics Core willprovide the statistical support to develop a highly skilled workforce in the Commonwealth ofKentucky.

project_terms:
Applications Grants;Appointment;Area;Biological;Biomedical Research;Centers of Research Excellence;Consultations;Data Analyses;Data Security;Department chair;Development;Doctor of Philosophy;Educational workshop;Ensure;Experimental Designs;Faculty;Goals;Grant;Infrastructure;Institution;Kentucky;Laboratories;Lead;Manuscripts;Mentors;Mentorship;Methodology;Methods;Persons;Preparation;Reporting;Research;Research Assistant;Research Personnel;Resources;Site Visit;Statistical Data Interpretation;Students;Training;United States National Institutes of Health;Universities;Visit;Work;college;data management;experience;experimental study;graduate student;improved;member;professor;skills;statistical service;statistics;symposium


application_id: 10619560
project_number: 5P20GM103436-23
project_title: Genomics Core
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7344
contact_pi_person_id: 1969307
contact_pi: ZACHARIAS, WOLFGANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
GENOMICS CORE Summary: The thematic research focus of the KBRIN program is functional genomics. This field ofstudy is relevant to all aspects of life health and behavior of humans based on their genetic make-up andinteractions with their individual environment. The study of genes their gene products and their mutualinteractions has become crucial for the development of therapies to combat human diseases to understandthe etiology of such diseases and to narrow in on personalized individual treatment options based ongenetic and genomic information of the patient. Thus functional genomics technologies like thoseimplemented in the UofL Genomics Core will be increasingly essential for the health care of current andfuture populations. Innovative technologies like whole genome DNA and transcriptome RNA sequencing and massivelyparallel gene expression profiling have become technically and economically feasible. However theinfrastructure is best placed in centralized facilities because it is cost-prohibitive for individual researchlaboratories. Thus the instrumental and intellectual research infrastructure provided by the Core representsa critical component for the future overall strategic purpose for biomedical research community in Kentuckywith the potential for a positive state-wide impact for the development of competitive research. This core itsequipment and its staff will serve the UofL and its research base and will also serve the investigators in thenetwork-affiliated institutions in the KBRIN.

project_terms:
Applications Grants;Award;Behavior;Bioinformatics;Biomedical Research;Cancer Center;Centers of Research Excellence;Collaborations;Communities;Core Facility;DNA;Data Analyses;Development;Disease;Environment;Equipment;Etiology;Experimental Designs;Floor;Future;Gene Expression Profiling;Genes;Genetic;Genetic Medicine;Genomics;Genotype;Grant;Health;Health Sciences;Healthcare;Human;Human Resources;Individual;Infrastructure;Institution;Kentucky;Laboratory Research;Life;Logistics;Manuscripts;Methods;MicroRNAs;Molecular;Molecular Medicine;Molecular Target;Nucleic Acids;Patients;Pilot Projects;Population;Preparation;RNA;Research;Research Infrastructure;Research Personnel;Sampling;Services;Technology;Training;Translational Research;Universities;Visualization;base;clinical translation;combat;cost;data acquisition;equipment acquisition;field study;functional genomics;gene product;genetic makeup;genomic data;human disease;innovative technologies;programs;student training;therapy development;transcriptome;transcriptome sequencing;whole genome


application_id: 10619559
project_number: 5P20GM103436-23
project_title: Bioinformatics Core
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7343
contact_pi_person_id: 7948398
contact_pi: ROUCHKA, ERIC C
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Bioinformatics CoreThe Bioinformatics Core based at the University of Louisville Health Science Campus is designed to serve thebioinformatics needs of faculty and students within KBRIN-affiliated institutions. A specific focus is placed onDNA and RNA sequence analysis (i.e. Genomics and Transcriptomics) with an expertise in the field of high-throughput genomic and transcriptomic data resulting from array-based and high-throughput sequencingtechnologies. We have developed the core through recruitment of expert faculty and postdoctoral level researchassociates so as to quickly build a capacity for bioinformatics research as well as to provide service andcollaboration with biomedical research scientists. In addition the core provides multiple levels of student trainingactivities. We will continue to pursue those activities that lead to excellence in this rapidly evolving scientificarena.

project_terms:
Algorithms;Area;Bioinformatics;Biomedical Research;ChIP-seq;Cloud Computing;Collaborations;Computational Biology;Computers;DNA Sequence;Data;Engineering;Faculty;Funding;Genetic Transcription;Genomics;Health Sciences;High-Throughput Nucleotide Sequencing;Institution;Kentucky;Modeling;Network Infrastructure;Postdoctoral Fellow;RNA Sequence Analysis;Reporting;Research;Research Personnel;Resources;Scientist;Sequence Analysis;Services;Students;Technology;Training;Training Activity;Training and Education;Universities;bioinformatics network;circular RNA;computer science;design;experience;member;metagenomic sequencing;novel;recruit;ribosome profiling;student training;transcriptome sequencing;transcriptomics


application_id: 10619557
project_number: 5P20GM103436-23
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9
subproject_number: 7342
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Administrative Core Summary The primary purpose of the administrative core is to provide sound management of the INBRE-award on behalf of the network. In addition this core will provide leadership and direction to enable the network to grow in a purposeful and managed way. The administrative core will provide leadership and oversight of the bioinformatics and research cores as well as all other activities adjusting and balancing the commitments and needs of each such that the overall network is productive and impactful. The core will be responsible for tracking and evaluation of all network activities including mentoring and training.

project_terms:
Advisory Committees;Applications Grants;Award;Bioinformatics;Biomedical Research;Budgets;Businesses;Educational workshop;Evaluation;Goals;Institution;Kentucky;Leadership;Logistics;Mentors;Output;Process;Productivity;Research;Research Personnel;Services;Site Visit;Structure;Students;Training;Travel;Work;investigator training;meetings;programs;sound;symposium;undergraduate research experience;undergraduate student


application_id: 10619556
project_number: 5P20GM103436-23
project_title: IDeA Networks of Biomedical Research Excellence in Kentucky
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-18-262
application_type: 5
activity_code: P20
ic: GM
serial_number: 103436
program_official: ZHOU, YANG
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1-RCB-9(IN)
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Overall SummaryThe overarching goal of the Kentucky Institutional Development Award (IDeA) Network ofBiomedical Research Excellence (KY-INBRE) is to build capacity for health-related andbiomedical research in the Commonwealth of Kentucky. We will build a collaborative researchand research-training community throughout the state. Our primary collaborative network isrepresented by 2 research intensive universities 5 state-supported and one independentprimarily undergraduate institutions (PUIs). We provide outreach activities in support of manyother of our smaller state supported and independent institutions including community technicalcolleges. Overall our activities are designed to build on our established multi-disciplinary researchnetwork with a focus on functional genomics as a means to strengthen research infrastructureof the lead and partner institutions. One aim is to support the development of young researchfaculty investigators to help them become independently competitive for federal research grants.Another aim of our network is to provide a variety of research training opportunities for ourundergraduate and graduate students. These students represent the next generation of the healthcare and/or biomedical research industries and they need to be mentored to develop appropriatescientific research skills..

project_terms:
Award;Biomedical Research;Communities;Development;Educational workshop;Faculty;Goals;Health;Healthcare;Industry;Infrastructure;Institution;Interdisciplinary Study;Kentucky;Knowledge;Lead;Location;Mentors;Network Infrastructure;Osteopathic Medicine;Poa plant;Postdoctoral Fellow;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Schools;Science;Students;Technology;Training;Universities;base;career;college;community college;design;experience;functional genomics;graduate student;hazard;higher education;next generation;outreach;performance site;programs;research faculty;skills;summer research;technical college;training opportunity;undergraduate student

public_health_relevance:
OVERALLProject Narrative:The health relatedness of this project lies with its goal to build capacity for health andbiomedical research throughout the Commonwealth of Kentucky. Moreover one of its primaryconcerns is to train the next generation of workers in the health care and biomedical researchindustries in Kentucky


application_id: 10618978
project_number: 5F30NS118777-03
administering_ic: NINDS
award_notice_date: 2023-04-20
opportunity_number: PA-20-245
application_type: 5
activity_code: F30
ic: NS
serial_number: 118777
program_official: CORRIVEAU, RODERICK A
project_start_date: 2021-05-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 15841458
contact_pi: WINDER, ZACHARY
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
budget_start_date: 2023-05-01
project_title:
Investigating Angiogenic Mediators as Biomarkers and Targets for Rescuing Small Vessel Disease in a Model of VCID

project_abstract:
Project Summary Dementia is a disorder characterized by a significant decline from baseline in one or more cognitivedomains that interferes with independence. Prevalence of dementia worldwide is estimated at 50 million withthat number expected to triple by 2030 coming with a cost of roughly $2 trillion. Vascular Contributions toCognitive Impairment and Dementia (VCID) is the second leading cause of dementia and is the umbrella termused to characterize patients with cognitive dysfunction as a result of cerebrovascular pathology. Small vesseldisease (SVD) is one type of cerebrovascular pathology that is found in roughly 50% of patients with VCID.Common neuropathological findings associated with SVD include microinfarctions microhemorrhages andarteriolosclerosis. While MRI identifies larger infarctions and microbleeds it is limited by resolution of the scan.Therefore identification of these pathologies has proven difficult outside of post-mortem evaluation. White matterhyperintensities (WMH) on MRI have become the standard used to evaluate SVD; but are limited by their costand lack of targetable mechanisms for preventing progression of the disease. In this proposal we explore therole of angiogenic mediators as modifiable fluid biomarkers which can be used to evaluate SVD and potentiallyaltered to decrease progression of SVD. We focus on placental growth factor (PLGF) due to its upregulation inhypoxic environments which is found in arteriolosclerosis. Our preliminary data suggests that patients with VCIDhave increased PLGF concentrations compared to controls. Additionally previous studies have shown that PLGFinduces degradation of the extracellular matrix and the blood brain barrier which are initiating steps in formationof microhemorrhages. This proposal first seeks to evaluate whether plasma PLGF is upregulated in patients withincreased levels of SVD pathology as measured in post-mortem neuropathological evaluation (Aim 1a) andwhether PLGF has a tight spatial co-localization with SVD pathology in human tissue (Aim 1b). This willdemonstrate the viability of PLGF as a fluid biomarker for SVD pathology. Secondly we will use a diet to inducea well-established model of VCID in PLGF-KO transgenic mice to evaluate the role of PLGF on development ofmicrohemorrhages (Aim 2). This aim will help support our hypothesis that reducing availability of PLGF willreduce the burden of microhemorrhages in patients with SVD. This mechanism can then be used to developnovel therapeutics in order to halt the progression of VCID. Through this proposal and under the mentorship ofDr. Wilcock and Dr. Jicha at the Sanders-Brown Center on Aging the applicant will investigate the utility of PLGFas a modifiable fluid biomarker for SVD. In doing so the applicant will be trained in immunoassay-basedbiomarker discovery statistical linear modeling clinical patient evaluation immunohistochemistry pathologicalhistology evaluation and oral and written scientific communications for a future career as an independentphysician-scientist.

project_terms:
Aging;Alzheimer's Disease;Analysis of Covariance;Animal Model;Arterioloscleroses;Autopsy;Biological Markers;Blood - brain barrier anatomy;Blood Vessels;Brain;Cells;Cerebrovascular Disorders;Clinical;Cognitive;Communication;Data;Dementia;Development;Diagnosis;Diet;Disease;Disease Progression;Environment;Evaluation;Extracellular Matrix;Extracellular Matrix Degradation;Future;Genotype;Hematoxylin and Eosin Staining Method;Hemorrhage;Histology;Human;Hyperhomocysteinemia;Hypoxia;Immunoassay;Immunohistochemistry;Impaired cognition;Infarction;Linear Models;Link;Liquid substance;Magnetic Resonance Imaging;Measures;Mediation;Mediator;Mentorship;Microvascular Dysfunction;Modeling;Monitor;Mus;Neurocognitive;Neurosciences;Oral;Outcome;PGF gene;Pathologic;Pathology;Patients;Physicians;Plasma;Play;Pre-Clinical Model;Prevalence;Recording of previous events;Resolution;Role;Scanning;Scientist;Sensitivity and Specificity;Statistical Models;Technology;Testing;Tissue Sample;Tissues;Training;Transgenic Mice;Up-Regulation;White Matter Hyperintensity;Work;Writing;angiogenesis;biomarker discovery;brain tissue;burden of illness;candidate marker;career;cerebrovascular pathology;cohort;comparison control;cost;cost effective;digital;histological stains;human tissue;imaging modality;in vivo;magnetic resonance imaging biomarker;mouse model;nano-string;neuroimaging;neuropathology;novel therapeutics;prevent;protein expression;response;targeted treatment;therapeutic target;tool;vascular cognitive impairment and dementia

public_health_relevance:
Project Narrative Current imaging methods using MRI for evaluating small vessel disease (SVD) in patients with vascularcontributions to cognitive impairment and dementia (VCID) lack appropriate resolution to identify much of theneuropathology associated with the disease. Fluid biomarkers that correlate to SVD pathology may be usefulas a lower cost alternative to MRI for monitoring its progression and act as a therapeutic target for delayingthe progression of SVD. This project investigates the role of placental growth factor (PLGF) as a biomarker forSVD using human tissue samples and as a target for rescuing SVD in a mouse model of VCID.


application_id: 10618207
project_number: 5R01AG062550-05
administering_ic: NIA
award_notice_date: 2023-06-01
opportunity_number: PAR-16-370
application_type: 5
activity_code: R01
ic: AG
serial_number: 062550
program_official: BARRETT, PAUL JOHN
project_start_date: 2019-04-01
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-E(56)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
budget_start_date: 2023-04-01
project_title:
Changing the energy substrate balance:  Does APOE2 promote glucose usage to protect from Alzheimer's Disease?

project_abstract:
Metabolic dysfunction as in the case of obesity contributes to the development of several age-relateddiseases including Alzheimers disease (AD). Apolipoprotein E (apoE) is a critical component of circulatinglipoproteins found both in the periphery and brain and the APOE gene encodes three major isoforms in thehuman population: E2 E3 and E4. E4 is the most significant genetic risk factor for sporadic AD while E2 isprotective. Like obesity the E4 isoform is also associated with an increased risk of AD. Paradoxically miceand humans with E4 have an increased risk of AD despite having reduced adiposity while those with E2 areprotected from AD despite increased adiposity. Our preliminary findings in mice suggest that these two factors obesity and apoE  may be linked by a unifying biological mechanism related to energy substrate preferenceand have broad implications for the prevention and personalized (genetic) treatment of AD. Our centralhypothesis is that the apoE isoforms differentially shift the Randle cycle balance: E2 in favor of glucose E4 infavor of FA. Specifically we hypothesize that E2 exerts its neuroprotective effects through a metabolicpreference for glucose utilization at the expense of fatty acid oxidation. To test the hypothesis that E2 affordsneuroprotection by decreasing fatty acid oxidation and increasing glucose utilization we will quantitatively tracksubstrate entry and metabolism through the unique precursor-product tracing afforded by Stable IsotopeResolved Metabolomics (SIRM). We will then use a multi-omics approach to integrate SIRM results withtranscriptomic profiling of human apoE expressing mice and cells in order to identify the specific metabolicpathways altered by E2 expression in both the brain and periphery. Finally we will translate our findings bymeasuring basal metabolic rates in E2- E3- and E4-expressing individuals at rest and during a cognitivechallenge. Using O2 and CO2 recordings we will calculate the respiratory exchange ratio (RER) which reflectsthe ratio of carbohydrate/lipid oxidation across each trial. Analyzing these data based on APOE status willprovide a new understanding of substrate utilization in E2+ individuals and offer insight into potential apoEeffects on peripheral and neural energy responses. If successful this proposal will provide novel targets bycharacterizing the neuroprotective metabolic profile of E2 individuals and designing future therapies to mimicthese effects. Enhancing cerebral metabolism by making E2-like changes to energy balance could have greatimpact in preventing or delaying the onset of AD.

project_terms:
Affect;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Animals;Apolipoprotein E;Astrocytes;Basal metabolic rate;Biochemical;Biochemical Pathway;Biological;Biological Markers;Brain;Carbohydrates;Carbon Dioxide;Cell Line;Cells;Cerebrum;Clinical;Coculture Techniques;Cognitive;Data;Dementia;Development;Dimensions;Disease;Equilibrium;Fatty Acids;Future;Gene Expression Profiling;Genes;Genetic;Genotype;Glucose;Human;Impaired cognition;In Vitro;Individual;Intervention;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipids;Lipoproteins;Measures;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mus;Neuronal Dysfunction;Neurons;Obesity;Pathway interactions;Pattern;Peripheral;Population;Prevention;Protein Isoforms;Reporting;Rest;Severities;Symptoms;System;Testing;Tissues;Tracer;Translating;age related;apolipoprotein E-4;brain tissue;design;energy balance;experimental study;fatty acid oxidation;fluorodeoxyglucose positron emission tomography;genetic risk factor;genome-wide;glucose metabolism;glucose transport;glucose uptake;high risk population;in vivo;innovation;insight;metabolic profile;metabolomics;mouse model;multiple omics;neural;neuronal survival;neuropathology;neuroprotection;novel;oxidation;pharmacologic;preference;prevent;respiratory;response;stable isotope;therapeutic target;transcriptomic profiling;translational study;uptake

public_health_relevance:
While the E4 allele of APOE is the strongest genetic risk factor for late-onset Alzheimers disease (AD) theunderstudied E2 allele is protective. This translational study aims to establish how E2 exerts its neuroprotectiveeffects by studying cerebral energy substrate balance. If successful this will provide new biomarkers andtherapeutic targets to normalize metabolism and potentially prevent or delay the onset of AD.


application_id: 10618205
project_number: 5R01HL152714-04
administering_ic: NHLBI
award_notice_date: 2023-04-27
opportunity_number: PAR-19-274
application_type: 5
activity_code: R01
ic: HL
serial_number: 152714
program_official: BROWN, ALISON GWENDOLYN MARY
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Dissemination and Implementation Research in Health Study Section[DIRH]
contact_pi_person_id: 8535975
contact_pi: SCHOENBERG, NANCY E.
other_pis: SPRING, BONNIE
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Implementing an evidence-based mHealth diet and activity intervention: Make Better Choices 2 for rural Appalachians

project_abstract:
ABSTRACT We propose a type 1 hybrid effectiveness-implementation study to test an adapted evidence-basedintervention and explore critical implementation issues including feasibility acceptability and costs thatinfluence scale-up and sustainment. We focus this adaptation effectiveness and implementation study onunderserved rural residents a population that maintains extremely high rates of suboptimal diet and sedentarybehaviors placing them at elevated risk for cardiovascular disease obesity diabetes cancer and otherchronic conditions. Within the vulnerable low socioeconomic status population of rural residents AppalachianKentuckians experience even worse health outcomes including among the highest rates of morbidity andmortality in the nation. Such adversity is exacerbated by and associated with inadequate community resources.Increasingly however Appalachian residents and other vulnerable populations are gaining access tomodalities that may be useful in addressing these health challenges including internet connectivity and nearlyubiquitous cell phone use. Despite this accelerating technology use the evidence base on personaltechnology-associated interventions (mHealth) in a rural high need population remains sparse. We proposefinalizing adaptation and testing an evidence-based multicomponent mHealth intervention Make BetterChoices 2 (MBC2) a behavioral program consisting of personalized health coaching an app accelerometerand financial incentives. In a recent randomized controlled trial among urban adults MBC2 produced largesustained diet and physical activity improvements by leveraging effective behavior change techniquesincluding goal-setting self-monitoring accountability and support. To prepare for the implementation of thissuccessful intervention with a new population marked by extreme health inequities and sparse resources ourteam has engaged in extensive foundational efforts based on the Dynamic Adaptation Process framework.These include: (1) completing focus groups and key informant interviews to assess the feasibility andacceptability for rural Appalachian residents to use the MBC2 program; (2) undertaking a comprehensivecommunity inventory to reveal existing and needed resources; (3) engaging stakeholders in community andacademic team meetings including community forums and CAB meetings; and (4) identifying MBC2programmatic and structural elements in need of adaptation. With this extensive preliminary activity we nowpropose a type 1 hybrid effectiveness-implementation trial in which we: (1) finalize adaptation by wireframe andusability testing MBC2 with local Appalachian residents; (2) conduct a RCT to test the effectiveness of theadapted MBC2 compared to an active control arm; and (3) explore implementation outcomes and contextualfactors with a focus on sustainment. This project aspires to demonstrate that systematic adaptation andimplementation of an evidence-based intervention can lead to meaningful and sustained behavioral changesand to prepare for potential scale-up and sustainment of the intervention to maximize its public health impact.

project_terms:
Acceleration;Accelerometer;Accountability;Address;Adult;Appalachian Region;Behavior;Behavioral;Blood Pressure;Body mass index;Budgets;Cardiovascular Diseases;Cellular Phone;Characteristics;Chronic;Chronic Disease;Clinical;Communities;Consolidated Framework for Implementation Research;Consumption;Data;Devices;Diabetes Mellitus;Diet;Effectiveness;Elements;Equipment and supply inventories;Evidence based intervention;Fatty acid glycerol esters;Focus Groups;Future;Goals;Health;Influentials;Intake;Internet;Intervention;Interview;Leisures;Life Style;Lipids;Malignant Neoplasms;Methods;Modality;Monitor;Morbidity - disease rate;Obesity;Outcome;Participant;Physical activity;Population;Process;Public Health;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research Activity;Resources;Rural;Rural Appalachia;Rural Population;Shapes;Techniques;Technology;Testing;Time;Training Support;Underserved Population;Unhealthy Diet;Vulnerable Populations;acceptability and feasibility;active control;active lifestyle;arm;attentional control;behavior change;cardiovascular disorder risk;contextual factors;cost;design;effectiveness evaluation;effectiveness research;effectiveness study;effectiveness testing;effectiveness trial;effectiveness/implementation study;effectiveness/implementation trial;evidence base;experience;financial incentive;fruits and vegetables;good diet;health equity;health inequalities;hybrid type 1 design;implementation context;implementation evaluation;implementation outcomes;implementation research;implementation science;implementation study;improved;informant;information gathering;insight;intervention cost;intervention delivery;intervention program;iterative design;knowledge base;low socioeconomic status;mHealth;meetings;mortality;physical inactivity;poor health outcome;prevent;primary outcome;programs;rural dwellers;rural underserved;scale up;secondary outcome;sedentary;sedentary lifestyle;smartphone application;smartphone based device;stress management;successful intervention;tool;tv watching;usability;virtual;waist circumference

public_health_relevance:
PROJECT NARRATIVE Rural residents especially Appalachians have among the nations highest rates of cardiovasculardisease (CVD) diabetes and obesity all associated with unhealthy diet and lack of physical activity. Newtools including personal technology offers an opportunity to make long lasting behavioral changes andimprove health. We will test a culturally adapted evidence-based multicomponent mHealth intervention MakeBetter Choices 2 (MBC2) a behavioral program consisting of personalized health coaching an appaccelerometer and financial incentives and explore optimal implementation and sustainment approaches.


application_id: 10618144
project_number: 5R35HL155649-03
project_title: Determinants of Aorta Heterogeneity
administering_ic: NHLBI
award_notice_date: 2023-05-26
opportunity_number: RFA-HL-20-011
application_type: 5
activity_code: R35
ic: HL
serial_number: 155649
program_official: CHARETTE, MARC F
project_start_date: 2021-06-01
project_end_date: 2028-05-31
study_section: ZHL1-CSR-I(O2)
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
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_terms:
Affect;Aneurysm;Aorta;Aortic Diseases;Atherosclerosis;Basic Science;Biological;Biology;Brain;Cell physiology;Cells;Characteristics;Clinical;Data;Disease;Dissection;Embryo;Extracellular Matrix;Funding;Heterogeneity;Inflammation;Kidney;Length;Life;Lipoproteins;Lung;Magnetic Resonance Imaging;Medical;Metabolism;Molecular;Operative Surgical Procedures;Organ;Pathogenesis;Patient observation;Pharmaceutical Preparations;Proteomics;Reagent;Research;Rupture;Scientist;Signal Pathway;Skin;Specificity;Syndrome;Techniques;Therapeutic;Tissues;Training;Translational Research;Ultrasonography;bone;extracellular;flexibility;insight;intravital microscopy;mouse model;next generation;novel;programs;single-cell RNA sequencing;tool;transcriptomics


application_id: 10617504
project_number: 3R01AG062550-04S1
administering_ic: NIA
award_notice_date: 2022-05-06
opportunity_number: PAR-16-370
application_type: 3
activity_code: R01
ic: AG
serial_number: 062550
suffix: S1
program_official: BARRETT, PAUL JOHN
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-E(56)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_title:
Changing the energy substrate balance:  Does APOE2 promote glucose usage to protect from Alzheimer's Disease?

project_abstract:
Metabolic dysfunction as in the case of obesity contributes to the development of several age-relateddiseases including Alzheimers disease (AD). Apolipoprotein E (apoE) is a critical component of circulatinglipoproteins found both in the periphery and brain and the APOE gene encodes three major isoforms in thehuman population: E2 E3 and E4. E4 is the most significant genetic risk factor for sporadic AD while E2 isprotective. Like obesity the E4 isoform is also associated with an increased risk of AD. Paradoxically miceand humans with E4 have an increased risk of AD despite having reduced adiposity while those with E2 areprotected from AD despite increased adiposity. Our preliminary findings in mice suggest that these two factors obesity and apoE  may be linked by a unifying biological mechanism related to energy substrate preferenceand have broad implications for the prevention and personalized (genetic) treatment of AD. Our centralhypothesis is that the apoE isoforms differentially shift the Randle cycle balance: E2 in favor of glucose E4 infavor of FA. Specifically we hypothesize that E2 exerts its neuroprotective effects through a metabolicpreference for glucose utilization at the expense of fatty acid oxidation. To test the hypothesis that E2 affordsneuroprotection by decreasing fatty acid oxidation and increasing glucose utilization we will quantitatively tracksubstrate entry and metabolism through the unique precursor-product tracing afforded by Stable IsotopeResolved Metabolomics (SIRM). We will then use a multi-omics approach to integrate SIRM results withtranscriptomic profiling of human apoE expressing mice and cells in order to identify the specific metabolicpathways altered by E2 expression in both the brain and periphery. Finally we will translate our findings bymeasuring basal metabolic rates in E2- E3- and E4-expressing individuals at rest and during a cognitivechallenge. Using O2 and CO2 recordings we will calculate the respiratory exchange ratio (RER) which reflectsthe ratio of carbohydrate/lipid oxidation across each trial. Analyzing these data based on APOE status willprovide a new understanding of substrate utilization in E2+ individuals and offer insight into potential apoEeffects on peripheral and neural energy responses. If successful this proposal will provide novel targets bycharacterizing the neuroprotective metabolic profile of E2 individuals and designing future therapies to mimicthese effects. Enhancing cerebral metabolism by making E2-like changes to energy balance could have greatimpact in preventing or delaying the onset of AD.

project_terms:
Affect;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Animals;Apolipoprotein E;Astrocytes;Basal metabolic rate;Biochemical;Biochemical Pathway;Biological;Biological Markers;Brain;Carbohydrates;Carbon Dioxide;Cell Line;Cells;Cerebrum;Clinical;Coculture Techniques;Cognitive;Data;Data Analyses;Dementia;Development;Disease;Equilibrium;Fatty Acids;Future;Gene Expression Profiling;Genes;Genetic;Genotype;Glucose;Human;Impaired cognition;In Vitro;Individual;Intervention;Knowledge;Late Onset Alzheimer Disease;Lead;Link;Lipids;Lipoproteins;Measures;Metabolic;Metabolic Pathway;Metabolic dysfunction;Metabolism;Mus;Neuronal Dysfunction;Neurons;Obesity;Oxides;Pathway interactions;Pattern;Peripheral;Pharmacology;Population;Prevention;Protein Isoforms;Reporting;Rest;Severities;Symptoms;System;Testing;Tissues;Tracer;Translating;age related;apolipoprotein E-4;base;brain tissue;design;energy balance;experimental study;fatty acid oxidation;fluorodeoxyglucose positron emission tomography;genetic risk factor;genome-wide;glucose metabolism;glucose transport;glucose uptake;high risk;in vivo;innovation;insight;metabolic profile;metabolomics;mouse model;multiple omics;neuronal survival;neuroprotection;novel;oxidation;precision genetics;preference;prevent;relating to nervous system;respiratory;response;stable isotope;therapeutic target;transcriptomics;translational study;uptake

public_health_relevance:
While the E4 allele of APOE is the strongest genetic risk factor for late-onset Alzheimers disease (AD) theunderstudied E2 allele is protective. This translational study aims to establish how E2 exerts its neuroprotectiveeffects by studying cerebral energy substrate balance. If successful this will provide new biomarkers andtherapeutic targets to normalize metabolism and potentially prevent or delay the onset of AD.


application_id: 10616854
project_number: 3R01AA028735-04S2
administering_ic: NIAAA
award_notice_date: 2022-08-31
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: AA
serial_number: 028735
suffix: S2
program_official: LIN, LI
project_start_date: 2021-11-01
project_end_date: 2025-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYChronic heavy drinking (CHD) is associated with multiple adverse health outcomes including increasedincidence of liver disease cardiovascular disease cancer and/or infectious disease. Given the increasedincidence of viral bacterial and/or fungal infections often seen in patients with CHD this suggests that alcoholcan have a significant impact on the host immune response and host defense. Several studies have shownthat the most dramatic and consistent changes induced by CHD are evident in the innate immune arm. Using anon-human primate (NHP) model of voluntary ethanol self-administration we have reported significant defectsin monocytes/macrophages. CHD is also associated with increased risk for respiratory infection and diseasenotably acute respiratory distress disease syndrome (ARDS). Alveolar macrophages play a critical role in theinflammatory process associated with ARDS. More recently we have reported that alveolar macrophagesfrom CHD macaques exhibit signs of increased oxidative damage generate an exaggerated inflammatoryresponse and dampened anti-bacterial and anti-viral immune responses; thereby providing a link betweenCHD and increased incidence of ARDS. However exact mechanisms remain poorly understood. The purposeof this diversity supplement is to support Dr. Jamie Sturgill to test the hypothesis that dysregulation ofceramide levels and signaling in alveolar macrophage with CHD leads to exacerbated inflammatoryresponses. Previous work by the Sturgill lab has shown that ceramide is a critical sphingolipid in the lung andthat alterations of ceramide signaling lead to increased reactive oxygen production macrophage inflammatoryresponses apoptosis and pulmonary dysfunction. Moreover ceramide levels are increased in patients withalcoholic liver disease. Thus ceramide is a logical target to investigate. This supplement is in line with theparent R01 that is investigating mechanisms of aberrant inflammation by circulating monocytes. Thissupplement will allow Dr. Sturgill to address a critical gap in our knowledge in a focused and mentored projectwhile honing technical skills and gaining expertise in the field of alcohol and immunity in order to facilitate herability to submit an R01 proposal to further interrogate the effects of CHD on pulmonary disease.

project_terms:
Acute Respiratory Distress Syndrome;Address;Alcoholic Liver Diseases;Alcohols;Alveolar Macrophages;Anti-Bacterial Agents;Apoptosis;Bacterial Infections;Blood;Cardiovascular Diseases;Ceramides;Chronic;Communicable Diseases;Defect;Disease;Epigenetic Process;Ethanol;Exhibits;Functional disorder;Health;Heavy Drinking;Host Defense;Immune;Immune response;Immunity;Incidence;Inflammation;Inflammatory;Inflammatory Response;Knowledge;Lead;Life;Link;Lipids;Liver diseases;Lung;Lung diseases;Macaca;Malignant Neoplasms;Mentors;Modeling;Mycoses;Outcome;Oxygen;Parents;Patients;Play;Predisposition;Process;Production;Reporting;Respiratory Disease;Respiratory Tract Infections;Risk;Role;Self Administration;Signal Transduction;Sphingolipids;Syndrome;Technical Expertise;Testing;Viral;Virus Diseases;Work;arm;chronic alcohol ingestion;drinking;lung injury;macrophage;monocyte;nonhuman primate;oxidative damage;progenitor

public_health_relevance:
NARRATIVEChronic heavy drinking can lead to serious health issues including lung injury and increased risk for acuterespiratory distress syndrome (ARDS) is a serious disease that leads to low oxygen levels in the blood andcan be life-threatening. The reasons behind this increased susceptibility are not well understood. We proposeto investigate the role of a class of lipids called sphingolipids as the potential link between chronic drinking andARDS.


application_id: 10616742
project_number: 5T32AA027488-05
project_title: Interdisciplinary Training in Alcohol Research
project_terms: Training;alcohol research
administering_ic: NIAAA
award_notice_date: 2023-05-03
opportunity_number: PA-18-403
application_type: 5
activity_code: T32
ic: AA
serial_number: 027488
program_official: GRAKALIC, IVANA
project_start_date: 2019-05-01
project_end_date: 2024-04-30
study_section: ZAA1-GG(35)
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: PRENDERGAST, MARK A
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT/SUMMARY The aim of this training program is to provide graduate students with the research skills to identifyalcohol-related risk factors by investigating their expression in response to acute and chronic exposure toalcohol at the cellular level behaving laboratory animal and the human subject. The training program willemphasize training in cellular and behavioral pharmacology of alcohol with the broad objective to understandhow such acute and chronic reactions combine or interact with personal and environmental factors to conferrisk for alcohol use disorders. The training is designed to achieve three objectives: 1) deliver intensive trainingin alcohol research; 2) foster interdisciplinary and translational perspectives on alcohol research; and 3)develop professional skills to support career development in alcohol research fields. The proposal requestssupport for five pre-doctoral appointments. The appointments will be for a two-year period. Training will beprimarily delivered within the research programs of the faculty and the core facilities at UK. This includes atraining faculty team of 20 researchers drawn from six academic and research units of the University ofKentucky. The rich environment provides opportunities for translational and multidisciplinary bio-behavioralresearch training in facilities such as the: 1) Center on Drug and Alcohol Research; 2) Center for Clinical andTranslational Science; and 3) The Substance-abuse Prevention in Emerging Adults Research Center(SPEAR). The alcohol-specific expertise and broad research foci of our faculty coupled with theirinterdisciplinary research provides a solid foundation by which implementation of the proposed T32 trainingprogram will bolster the research skills of our students for the ultimate goal of producing bright productivescientists capable of significant developments and discovery in the etiology prevention and treatment ofalcohol use disorders.

public_health_relevance:
The purpose of this application is to initiate a translational and interdisciplinary training program in alcoholresearch. This multidisciplinary program will provide training in bio-behavioral factors associated with inalcohol-use disorders at the pre-doctoral level; graduates of this program w i l l b e actively involvedin research teaching publishing articles and becoming independent researchers in the alcohol field. Weaim to establish a program of excellence in translational or interdisciplinary research training because theneed for a translational or interdisciplinary program is greater today than ever before and the proposedtraining program fills a unique niche in alcohol research.


application_id: 10616702
project_number: 5UG1DA050069-05
project_title: Kentucky Women's Justice Community Opioid Innovation Network (WJCOIN)
administering_ic: NIDA
award_notice_date: 2023-04-28
opportunity_number: RFA-DA-19-025
application_type: 5
activity_code: UG1
ic: DA
serial_number: 050069
program_official: HIGHSMITH, KEISHER S
project_start_date: 2019-07-15
project_end_date: 2026-04-30
study_section: ZDA1-HXO-H(05)R
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe opioid crisis continues to ravage US communities with overdose deaths at an all-time high. Women aredisproportionately affected by the opioid crisis due to increased pain sensitivity physician prescribing practicesand self-medication as well as a faster trajectory from opioid exposure to the development of opioid use disorder(OUD). The opioid overdose death rate among women has risen 492% since 1999 a higher rate than men(404%). However research on approaches to increase initiation of life-saving medications for opioid use disorder(MOUD) among women is limited. The University of Kentucky proposes to establish the Womens ClinicalResearch Center as part of the NIDA Justice Community Opioid Innovation Network (W-JCOIN). The overallgoal of the W-JCOIN is to increase initiation and maintenance of MOUD among high-risk justice-involved womenin the transition from jail to the community to reduce opioid relapse and overdose. As part of this NIH collaborativenetwork the W-JCOIN will lead a type 1 hybrid effectiveness and implementation trial to examine an innovativeMOUD pre-treatment model using telehealth (alone and in combination with peer navigators) for justice-involvedwomen in transition from jail to the community in 6 experimental and 3 comparison (Services as Usual-SAU)sites. The following aims guide the study: (1) Compare the effectiveness of MOUD Pre-Treatment Telehealth(alone versus in combination with Peer Navigators) to increase MOUD initiation and maintenance among high-risk justice-involved women in the community after release relative to services as usual (SAU). (2) Estimate theincremental cost and cost effectiveness of MOUD Pre-Treatment Telehealth (alone and in combination with PeerNavigators) relative to SAU for high-risk justice involved women with OUD in achieving desired changes inclinical public health and public safety outcomes over one-year post-release. (3) Examine temporal changes inkey implementation constructs hypothesized by the EPIS framework to influence successful innovationimplementation. This application is supported by an experienced team of NIH funded investigators with a trackrecord of engaging in NIH justice research cooperative. The research team is well-positioned to be active membersof the JCOIN network to rapidly conduct studies on quality care for OUD with special focus on underserved andunderstudied justice-involved women. The KY W-JCOIN has the potential for significant impact on the OUDtreatment field by contributing empirical evidence on the effectiveness and implementation of innovativetechnologies to increase initiation and maintenance of life-saving medications during a critical high-risk time ofcommunity re-entry among vulnerable justice-involved women in both urban and non-urban communities. Thelong-term goal of this research is to increase the capacity for the justice system to respond to the opioid crisisthrough increased access to treatment to reduce opioid relapse and overdose.

project_terms:
Affect;Benefits and Risks;Climate;Clinical;Clinical Research;Communities;Community Healthcare;Cost Analysis;Criminal Justice;Death Rate;Development;Drug abuse;Drug usage;Effectiveness;Eligibility Determination;Exposure to;Funding;Goals;Health Services Accessibility;High Risk Woman;Imprisonment;Intervention;Jail;Justice;Kentucky;Lead;Leadership;Life;Link;Maintenance;Methods;Modeling;National Institute of Drug Abuse;Opioid;Outcome;Overdose;Perception;Persons;Pharmaceutical Preparations;Physicians;Positioning Attribute;Public Health;Quality of Care;Randomized;Recording of previous events;Recovery;Relapse;Reporting;Research;Research Personnel;Rewards;Safety;Self Medication;Services;Site;System;Time;Treatment Cost;United States National Institutes of Health;Universities;Woman;arm;community reentry;compare effectiveness;comparison group;cost;cost effectiveness;cost-effectiveness ratio;effectiveness/implementation trial;experience;follow-up;high risk;improved;incremental cost;incremental cost-effectiveness;innovation;innovative technologies;intervention cost;medication for opioid use disorder;member;men;opioid epidemic;opioid exposure;opioid injection;opioid mortality;opioid use disorder;organizational readiness;overdose death;pain sensitivity;peer;programs;recidivism;safety outcomes;services as usual;telehealth;treatment as usual

public_health_relevance:
PROJECT NARRATIVEThe University of Kentucky proposes to establish the Womens Clinical Research Center as part of the NIDAJustice Community Opioid Innovation Network (W-JCOIN) with the overall goal of increasing initiation andmaintenance of MOUD among high-risk justice-involved women in the transition from jail to the community toreduce opioid relapse and overdose. The KY W-JCOIN has the potential for significant impact on the OUDtreatment field by contributing empirical evidence on the effectiveness and implementation of innovativetechnologies to increase initiation and maintenance of life-saving medications during a critical high-risk time ofcommunity re-entry among vulnerable justice-involved women in both urban and non-urban communities. Thisresearch will impact the field by increasing the capacity of the justice system to respond to the opioid crisisthrough increased access to MOUD treatment to reduce opioid relapse and overdose.


application_id: 10616562
project_number: 5R01DE029650-05
project_title: HPV16 E6 Antibody Detection as an Early Marker for Oropharyngeal Cancer Among Men Living with HIV
administering_ic: NIDCR
award_notice_date: 2023-05-03
opportunity_number: RFA-DE-20-001
application_type: 5
activity_code: R01
ic: DE
serial_number: 029650
program_official: BACCAGLINI, LORENA
project_start_date: 2021-02-05
project_end_date: 2026-04-30
study_section: ZDE1-GZ(13)
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE 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:
People living with HIV (PLWH) have an increased life expectancy due to effective therapies. This has resulted in anincreased incidence of non-AIDS defining cancers (NADCs) in particular cancers caused by human papillomavirus (HPV).The most rapidly increasing HPV-related malignancy in the general US population is HPV-driven oropharyngeal cancer(HPV-OPC) a type of head and neck that has increased in incidence by more than 200% over the past few decades.1 2PLWH are 1.5 to 4 times more likely to develop HPV-OPC than the general population.3 They are also more likely todevelop HPV-OPC at younger ages (51 versus 60)4 and have a less favorable cancer prognoses.5 Unlike cervical cancerwhere the introduction of highly effective screening has significantly reduced the incidence and mortality of cervicalcancer there are no methods for early detection of HPV-OPC. A major barrier for early detection has been the inabilityto identify PLWH at highest risk for HPV-OPC given that a precancerous precursor lesion for OPC has yet to be identified.Recently HPV16 E6 antibody positivity has been identified as a promising early biomarker. Previous work from ourgroup showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients6 and appear more than 10 yearsprior to diagnosis.7-9 Additionally we have shown that HPV16 E6 antibodies are highly specific for HPV-OPC10 and are notstrongly associated with the 5 other cancers caused by HPV.11 The objective of this study is to evaluate the ability of theHPV16 E6 marker to identify a sub-population of PLWH at highest risk for developing HPV-OPC and for which head andneck cancer screening would be most effective. To accomplish this we will conduct a natural history study of the HPV16E6 antibody marker. This study will focus on men aged 40+ living with HIV given that ~85% of HPV-OPC cases occur inmiddle aged men and HIV infection additionally elevates risk by up to 4-fold. Using the Tennessee Center for AIDSResearch (TN-CFAR) Biorepository banked blood samples from men aged 40+ living with HIV (N=3261) will be tested forHPV16 E6 antibodies. All HPV16 E6 seropositives and a subset of HPV16 E6 seronegatives (1:2 ratio) will be invited toparticipate in yearly (4 total) comprehensive head and neck cancer screening exams performed by a Vanderbilt IngramCancer Center (VICC) head and neck surgeon. Cancer screening visits will include: visual inspection of the mouth andpalpation of tonsils ultrasound imaging laryngoscope exam a detailed questionnaire and biospecimen collection. E6seropositive men will be compared to E6 seronegative men in terms of: a) markers of elevated HPV-OPC risk and b)development of HPV-OPC. The specific aims are: (1) Estimate the prevalence of HPV16 E6 antibodies among men aged40+ living with HIV; (2) Determine the association between HPV16 E6 seropositivity and markers of HPV-OPC risk; (3)Estimate the risk of developing: a) precancerous markers of HPV-OPC and/or; b) HPV-OPC by HPV16 E6 serostatus. Wehypothesize that men with HPV16 E6 antibodies will be more likely to have known risk factors associated with HPV-OPCdevelopment [sexual behavior persistent oral HPV infection] and will be more likely to develop HPV-OPC than menwithout HPV16 E6 antibodies. These efforts could help to generate evidence for oral health screening guidelines tailoredto PLWH. This work is particularly impactful given that HPV-OPC disproportionately affects PLWH.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;Age;Antibodies;Behavioral;Biological Markers;Blood;Blood Banks;Blood specimen;Cancer Center;Cancer Etiology;Cancer Patient;Cancer Prognosis;Clinic;Collection;Comprehensive Health Care;Development;Diagnosis;Early Diagnosis;Eligibility Determination;General Population;HIV;HIV Infections;HIV Seronegativity;HPV oropharyngeal cancer;HPV-High Risk;Head and Neck Cancer;Head and Neck Surgeon;Head and neck structure;High Prevalence;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Incidence;Individual;Laryngoscopes;Lesion;Life Expectancy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Natural History;Oncoproteins;Oral cavity;Oral health;Palpation;Patients;Persons;Population;Positioning Attribute;Prevalence;Quality of life;Questionnaires;Research;Resources;Risk;Risk Estimate;Risk Factors;Screening for cancer;Screening procedure;Seroprevalences;Sex Behavior;Surrogate Markers;Tennessee;Testing;Tonsil;Ultrasonography;Visit;Visual;Work;aged;antibody detection;biobank;cancer risk;chemoradiation;clinical examination;cohort;early detection biomarkers;effective therapy;high risk;improved;malignant oropharynx neoplasm;men;middle age;mortality;novel;oral HPV;oral HPV infection;premalignant;rapid detection;screening;screening guidelines;seropositive

public_health_relevance:
NARRATIVECases of human papillomavirusdriven oropharyngeal cancer (HPVOPC) now outnumber cervical cancer cases in the US men and people living with HIV (PLWH) are at highest risk. Unlike cervical cancer where the introduction of highlyeffective screening protocols significantly reduced the incidence and mortality due to cervical cancer there are nomethods for early detection of HPVOPC. We are proposing to use HPV16 E6 seropositivity an early biomarker of HPVOPC to develop a cohort of men living with HIV who are at highest risk for OPC to better understand HPV16 E6antibodies as an early marker of HPVOPC and b) to develop new methods of early detection for this rapidly increasingcancer.


application_id: 10615876
project_number: 5R01DE029498-03
project_title: Role of Notch-1/PLA2-IIA in oral dysbiosis inflammation and periodontal disease
administering_ic: NIDCR
award_notice_date: 2023-04-24
opportunity_number: PAR-19-172
application_type: 5
activity_code: R01
ic: DE
serial_number: 029498
program_official: CHANDER, PREETHI
project_start_date: 2021-08-01
project_end_date: 2026-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
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:
The mechanisms by which mucosal responses to the microbiota in the presence of specific pathogenic bacterialspecies (e.g. P. gingivalis-Pg) could abrogate the host-microbe symbiotic relationship leading to dysbiosis andinflammatory disease remain not fully understood. Our pioneering R21 studies demonstrated that Pg-inducedphospholipase A2 group IIA (PLA2-IIA) in a mechanism that involves activation of Notch-1 receptor (N1R) byPg gingipains modulates the antimicrobial properties of oral epithelial cells (OECs). This is consistent with invivo and clinical evidence supporting the potent (ng/mL) antimicrobial effects of PLA2-IIA. Noteworthy oralbacterial species exhibited differential antimicrobial susceptibility to PLA2-IIA. Moreover gingival PLA2-IIAexpression and N1R activation were elevated during initiation and progression of periodontal disease which wasconcurrent with oral dysbiosis in non-human primates. In agreement with these observations new preliminarystudies using mice models demonstrated increased gingival PLA2-IIA expression and N1R activation early afterPg infection. Remarkably the oral microbiome of transgenic mice overexpressing PLA2-IIA (PLA2-IIA-Tg)exhibited significant differences in the abundance of bacterial species (decreased Firmicutes and increasedProteobacteria) compared to their wild type co-caged littermates. Oral dysbiosis in PLA2-IIA-Tg mice wasassociated with changes in the gingival expression of genes involved in intracellular sensing (NOD2) classicalantimicrobial factors (S100a8/S100a9 hBD1) and M1/M2 macrophage chemokines. N1R is a critical modulatorof mucosal immunity; therefore the ability of Pg to activate N1R in OECs is an exciting and innovativeobservation. Preliminary data suggested that other OEC functions/responses (bacterial sensing apoptosis andautophagy) could involve Pg-induced N1R activation. Based on this evidence we hypothesize that activation ofNotch-1/PLA2-IIA pathway in gingival epithelial surfaces would be an innovative and plausible mechanism bywhich pathogens such as Pg could specifically enhance oral dysbiosis inflammation and periodontal disease. Totest this hypothesis we propose three specific aims: (i) To determine the role of PLA2-IIA in Pg-inducedoral dysbiosis inflammation and periodontal disease (ii) To determine the role of epithelialNotch-1 in Pg-induced PLA2-IIA and periodontitis and (iii) To identify and validate oralepithelial innate responses modulated by Pg through Notch-1 activation. To address theseknowledge gaps we will use the Pg-induced periodontitis oral gavage model in mouse strains with or without anatural PLA2-IIA mutation PLA2-IIA-Tg mice with their WT littermates epithelial-specific N1R deficient miceas well as OEC cultures to validate the role of this pathway in Pg-induced oral dysbiosis and periodontal disease.These findings will enable a better understanding of the cellular and molecular mechanisms that are specificallymodulated by pathogens to alter microbial communities at mucosal surfaces as well as contribute to the evidencefor future research designed to determine the role of N1R in oral health and other diseases (e.g. oral cancer).

project_terms:
Address;Adverse effects;Agreement;Animal Model;Antimicrobial Effect;Antimicrobial susceptibility;Apoptosis;Autophagocytosis;Bacteria;Cell Proliferation;Cell physiology;Cells;Clinical;Complex;Data;Development;Disease;Eating;Ecology;Enzymes;Epithelial Cells;Epithelium;Event;Exhibits;Firmicutes;Gene Expression;Gingiva;Health;Human;Immune;In Vitro;Inbred BALB C Mice;Infection;Inflammation;Inflammatory;Knowledge;Lesion;Macrophage;Mediating;Microbe;Modeling;Molecular;Mouse Strains;Mucosal Immunity;Mucous Membrane;Mus;Mutation;Natural Immunity;Oral;Oral health;PLA2G2A gene;Pathogenicity;Pathway interactions;Periodontal Diseases;Periodontitis;Phospholipase A2;Play;Porphyromonas gingivalis;Property;Proteobacteria;Public Health;Receptor Activation;Reporting;Research;Research Design;Resistance;Role;Surface;Testing;Time;Transgenic Mice;Variant;adaptive immunity;antimicrobial;bone loss;chemokine;chronic infection;chronic inflammatory disease;dysbiosis;gingipain;in vivo;innovation;malignant mouth neoplasm;microbial;microbial community;microbiota;mouse model;nonhuman primate;notch protein;oral cavity epithelium;oral microbiome;oral pathogen;overexpression;pathogen;prevent;receptor;recruit;response

public_health_relevance:
This research is relevant to public health because it will identify a potential new molecular mechanism throughwhich pathogens like P. gingivalis could be specifically manipulating epithelial innate responses to alter normalhost-bacteria interactions at mucosal surfaces that will evolve to dysbiosis persistent infection and inflammatorydisease. Positive findings of these studies will provide new opportunities for the development of innovativeapproaches to prevent/treat periodontal disease and its potential adverse effects in systemic health.


application_id: 10615695
project_number: 5R01LM013240-04
project_title: Advanced End-to-End Relation Extraction with Deep Neural Networks
administering_ic: NLM
award_notice_date: 2023-03-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: LM
serial_number: 013240
program_official: WANG, YANLI
project_start_date: 2020-07-01
project_end_date: 2026-03-31
study_section: Biomedical Computing and Health Informatics Study Section[BCHI]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
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:
ABSTRACTRelations linking various biomedical entities constitute a crucial resource that enables biomedical data scienceapplications and knowledge discovery. Relational information spans the translational science spectrum goingfrom biology (e.g. proteinprotein interactions) to translational bioinformatics (e.g. genedisease associations)and eventually to clinical care (e.g. drugdrug interactions). Scientists report newly discovered relations in nat-ural language through peer-reviewed literature and physicians may communicate them in clinical notes. Morerecently patients are also reporting side-effects and adverse events on social media. With exponential growth intextual data advances in biomedical natural language processing (BioNLP) methods are gaining prominence forbiomedical relation extraction (BRE) from text. Most current efforts in BRE follow a pipeline approach containingnamed entity recognition (NER) entity normalization (EN) and relation classication (RC) as subtasks. Theytypically suffer from error snowballing  errors in a component of the pipeline leading to more downstream errors resulting in lower performance of the overall BRE system. This situation has lead to evaluation of differentBRE substaks conducted in isolation. In this proposal we make a strong case for strictly end-to-end evaluationswhere relations are to be produced from raw text. We propose novel deep neural network architectures thatmodel BRE in an end-to-end fashion and directly identify relations and corresponding entity spans in a singlepass. We also extend our architectures to n-ary and cross-sentence settings where more than two entities mayneed to be linked even as the relation is expressed across multiple sentences. We also propose to create twonew gold standard BRE datasets one for drugdisease treatment relations and another rst of a kind datasetfor combination drug therapies. Our main hypothesis is that our end-to-end extraction models will yield supe-rior performance when compared with traditional pipelines. We test this through (1). intrinsic evaluations basedon standard performance measures with several gold standard datasets and (2). extrinsic application orientedassessments of relations extracted with use-cases in information retrieval question answering and knowledgebase completion. All software and data developed as part of this project will be made available for public use andwe hope this will foster rigorous end-to-end benchmarking of BRE systems.

project_terms:
Adverse event;Architecture;Area;Benchmarking;Bioinformatics;Biology;Biomedical Research;Black race;Classification;Clinical;Code;Collaborations;Combination Drug Therapy;Communication;Communities;Complex;Computer software;Data;Data Set;Dependence;Disease;Distant;Drug Interactions;Encapsulated;Etiology;Evaluation;Fostering;Funding;Future;Generations;Genes;Growth;Hand;Heart;Information Retrieval;Information Sciences;Intramural Research;Joints;Knowledge Discovery;Label;Language;Lead;Link;Literature;Manuals;Maps;Measures;Methodology;Methods;Modeling;Molecular;Names;Natural Language Processing;Patients;Peer Review;Performance;Periodicals;Pharmaceutical Preparations;Physicians;Positioning Attribute;Process;Reporting;Research;Research Personnel;Resources;Review Literature;Scientist;Semantics;Software Tools;Source;Standardization;Structure;Supervision;System;Terminology;Testing;Text;Training;Translational Research;Trees;United States National Library of Medicine;biomedical data science;clinical care;deep neural network;improved;insight;interest;knowledge base;knowledgebase;machine learning method;natural language;neural;neural network;neural network architecture;new therapeutic target;novel;off-label use;protein protein interaction;side effect;social media;supervised learning;syntax;transfer learning

public_health_relevance:
NARRATIVERelations connecting biomedical entities are at the heart of biomedical research given they encapsulate mech-anisms of disease etiology progression and treatment. As most such relations are rst disclosed in textualnarratives (scientic literature or clinical notes) methods to extract and represent them in a structured format areessential to facilitate applications such as hypotheses generation question answering and information retrieval.The high level objective of this project is to develop and evaluate novel end-to-end supervised machine learningmethods for biomedical relation extraction using latest advances in deep neural networks.


application_id: 10615143
project_number: 5R01HL163977-02
project_title: Data-driven optimization of therapy for heart failure
administering_ic: NHLBI
award_notice_date: 2023-04-20
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 163977
program_official: SHANBHAG, SUJATA MADHUKAR
project_start_date: 2022-05-01
project_end_date: 2026-04-30
study_section: Modeling and Analysis of Biological Systems Study Section[MABS]
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: LEE, LIK CHUAN ;WENK, JONATHAN F
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThis collaborative project integrates concepts from engineering artificial intelligence computer modelingphysiology and clinical cardiology to explore new therapeutic strategies for patients who have heart failure. Themoonshot goal is a simulation framework that can predict how a patient's heart will grow and remodel during apotential therapeutic intervention. Once the framework has been validated with patient data it could be deployedto compare the outcomes predicted for different treatments. A clinician could then use the predictions to guidetheir choice of therapy.This project seeks to advance computational cardiology and move the field closer to a randomized clinical trialthat tests whether patients treated with model-optimized therapies have better outcomes than patients whoreceived standard clinical care.The multidisciplinary research team consists of 3 scientists (Ken Campbell PhD; Jonathan Wenk PhD; Lik-Chuan Lee PhD) and 2 cardiologists (Emma Birks MD/PhD; Gaurang Vaidya MD). Together their skillsetsrange from molecular biophysics through computer modeling and engineering to clinical care and VentricularAssist Devices.The plan has 3 Aims: 1) Develop PyMyoVent as a testbed for implementing baroreflex control and myocardial growth. 2) Use MyoFE to create and validate patient-specific biventricular finite element models that incorporate growth and functional remodeling. 3) Deploy personalized MyoFE models to predict optimal therapies for patients who have heart failure.The plan is highly innovative reward and makes intelligent use of clinical data collected as part of normal carefrom 100 patients who are enrolled in a research registry at the University of Kentucky. These data will includepressure signals transmitted wirelessly from patients who have had a CardioMEMS device inserted around theirpulmonary artery. Fundamental contributions include the creation of finite element models that are controlled bya baroreflex and grow and adapt in response to physiological signals including myofilament stress and cellularenergy use.

project_terms:
Algorithm Design;Algorithms;Area;Artificial Intelligence;Atrial Fibrillation;Baroreflex;Biophysics;Cardiac;Cardiology;Cardiovascular system;Caring;Circulation;Clinical;Clinical Data;Computer Models;Computer software;Data;Development;Devices;Dimensions;Doctor of Philosophy;EFRAC;Echocardiography;Elements;Engineering;Enrollment;Foundations;Future;Geometry;Goals;Growth;Heart;Heart failure;Intelligence;Interdisciplinary Study;Intervention;Kentucky;Left ventricular structure;Machine Learning;Magnetic Resonance Imaging;Manuscripts;Microfilaments;Modeling;Molecular;Myocardial;Myosin ATPase;Paper;Patient-Focused Outcomes;Patients;Physiological;Physiology;Positioning Attribute;Pulmonary artery structure;Recommendation;Reflex action;Registries;Research;Research Personnel;Rewards;Running;Science;Scientist;Signal Transduction;Stress;Structure;Swarm intelligence;System;Techniques;Testing;Therapeutic;Therapeutic Intervention;Thick;Time;Universities;Ventricular;algorithm development;algorithm training;blood pressure control;blood pump;clinical care;computer program;constriction;gradient boosting;improved;innovation;laptop;novel therapeutic intervention;optimal treatments;outcome prediction;pressure;random forest;randomized clinical trials;research vision;response;simulation;skills;standard care;success;therapeutic evaluation;treatment optimization;ventricular assist device;wireless transmission

public_health_relevance:
NARRATIVEThis project develops computer programs that can predict how different potential therapies change the waythat a patient's heart will grow and adapt. The long-term goal is to create software that cardiologists can use tooptimize therapies for patients who have heart failure.


application_id: 10614659
project_number: 5R01HL151419-04
project_title: Biophysical Mechanisms of Hyperoxia-Induced Lung Injury
administering_ic: NHLBI
award_notice_date: 2023-05-04
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 151419
program_official: ZHOU, GUOFEI
project_start_date: 2020-04-15
project_end_date: 2024-10-31
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Acute lung injury and its more severe form acute respiratory distress syndrome(ARDS) are devastating illnesses with high rates of incidence and mortality. Patientswith acute lung injury are typically provided supplemental oxygen using positivepressure mechanical ventilation but this can lead to additional injury termed ventilator-induced lung injury (VILI). The long term objective of this proposal is to improveunderstanding of the mechanisms by which the combination of exposure to high levelsof oxygen (hyperoxia) and overdistention (or stretch) of lung cells contributes toventilator-induced lung injury. The central hypothesis of this application is thathyperoxia induces structural changes in alveolar epithelial and endothelial cells as wellas macrophages that alter their mechanical properties making them more susceptibleto injury caused by mechanical stretch. Mechanisms of the initiation of cell injury will beinvestigated using primary cultures of mouse alveolar type II (AT2) epithelial cellsprimary human lung endothelial cells mouse alveolar and bone marrow-derivedmacrophages cultures of mouse lung slices and a mouse model of combinedhyperoxia and VILI. In Aim 1 we will test the hypothesis that exposure of cells or lungslices causes changes in cell structural elements that increase the elastic modulus ofthe cells through activation of RhoA. We will measure the Youngs modulus anindication of an objects ability to deform using atomic force microscopy in theindentation mode and we will determine how hyperoxia changes cytoskeletal structuresincluding f-actin microtubules and focal adhesions. In Aim 2 we will investigate howhyperoxia increases stretch-induced cell detachment and injury. In Aim 3 we will testthe hypothesis that RhoA-mediated changes in structure and mechanical propertiesincreases lung injury in mice in a combined model of hyperoxia and VILI. The proposedstudies will investigate the biophysical mechanisms that contribute to lung injury duringmechanical ventilation and provide new insights into mechanotransduction the processof converting mechanical signals to biological signals.

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

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


application_id: 10614378
project_number: 5F31MH127892-02
administering_ic: NIMH
award_notice_date: 2022-12-20
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: MH
serial_number: 127892
program_official: CHAVEZ, MARK RAY
project_start_date: 2022-01-01
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-F16-L(20)L]
contact_pi_person_id: 15681647
contact_pi: CHRISTIAN, CAROLINE
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-01
project_title:
Behavioral and Momentary Assessment of Fear-based Mechanisms underlying Remission in Weight-restored Anorexia Nervosa

project_abstract:
Project Summary/Abstract Anorexia nervosa (AN) is a psychiatric illness characterized by low weight extreme food restrictionintense fear of weight gain and disturbance in body self-evaluation. AN is markedly persistent and there areno empirically supported treatments for adults with this deadly illness. Indeed over half of individuals withAN do not reach full remission during treatment and approximately one third of individuals experienceat least one relapse after discharge. There is great need for identifying remission-promoting targets to adaptand create optimized interventions for this population. The period of partial remission in AN (i.e. weight-restored individuals who continue to endorse significant cognitive-affective AN pathology) represents a criticaltime for identifying mechanisms underlying remission. Specifically unaddressed cognitive-affective ANsymptoms (e.g. extreme fear of weight gain) at this stage represent the greatest barrier to achieving lasting fullremission and thus mechanisms underlying the persistence vs. reduction of these symptoms are critical tostudy at this stage. AN is highly comorbid with anxiety disorders and shares several maintenance factorsincluding high levels of fear anxiety and harm avoidance. Despite considerable overlap with anxietydisorders fear and avoidance have not been tested as mechanisms inhibiting remission in weight-restored AN. The proposed study will test how fear-based learning (e.g. fear extinction fear renewal fearapproach fear avoidance) relates to AN pathology in the naturalistic environment in a sample of 45 individualsmeeting criteria for AN in partial remission. This study will use both behavioral assessment (i.e. Approach-Avoidance Task Behavioral Approach Task associative fear-learning paradigm) and momentary assessment(i.e. smartphone-based intensive longitudinal data collection) of fear avoidance and approach behaviors toconceptualize how these mechanisms of interest operate in the real world. First we will test whetherbehavioral approach avoidance fear extinction and fear renewal are correlated with real-time approachavoidance fear and AN symptoms (Aim 1). Second vector autoregressive models using the intensive time-series data will elucidate prospective associations across fear-based processes and AN symptoms betweensubjects (Aim 2) and within individuals (Aim 3) to identify group-level and intraindividual targets for care duringthis critical stage in recovery. In the between-subjects models we will test behavioral fear extinction andrenewal as moderators (Aim 2). The opportunities resources and expert consultation afforded by this awardwould support my training goals to collect and analyze behavioral data learn new analytic approaches withintensive longitudinal data and gain experience working with clinical AN participants. Overall this proposedstudy will implement advanced statistics and multimethod research design conducted fully remotelyat an important stage of AN. These results will inform precision relapse prevention interventions andstep-down care improving outcomes for this impairing persistent and costly disorder.

project_terms:
Address;Adult;Affective;Anorexia Nervosa;Anxiety;Anxiety Disorders;Award;Behavior;Behavior assessment;Behavioral;Behavioral Paradigm;Caring;Cellular Phone;Cessation of life;Clinical;Cognitive;Cognitive Therapy;Computers;Consultations;Dangerousness;Data;Data Collection;Development;Diagnostic;Disease;Disease remission;Eating Disorders;Empirical Research;Environment;Exposure to;Extinction;Food;Fright;Future;Goals;Impairment;Individual;Intake;Intervention;Investigation;Lead;Learning;Literature;Maintenance;Mental disorders;Modeling;Nutritional;Partial Remission;Participant;Pathology;Persons;Play;Population;Population Intervention;Prevalence;Procedures;Process;Recovery;Relapse;Research;Research Design;Research Methodology;Resources;Role;Sampling;Self-Examination;Series;Stimulus;Symptoms;Testing;Time;Training;Treatment outcome;United States;Weight;Weight Gain;approach behavior;avoidance behavior;behavior test;career;cognitive enhancement;comorbidity;conditioned fear;cost;critical period;experience;food restriction;healthy weight;improved outcome;interest;meetings;mortality;personalized approach;personalized intervention;prevent;preventive intervention;prospective;reduce symptoms;relapse prevention;relapse risk;response;standard care;statistics;theories;treatment optimization;trend;vector;weight restoration

public_health_relevance:
Project Narrative Anorexia nervosa is a costly impairing and persistent psychiatric disorder associated with poortreatment outcomes and high rates of relapse. A large body of evidence suggests anorexia nervosa often co-occurs with anxiety disorders and is characterized by fear and avoidance yet research on these maintainingprocesses in anorexia nervosa are critically lacking. The current study will test the associations across fearextinction renewal approach avoidance and eating disorder symptoms during the critical period of partialremission in anorexia nervosa to identify precision relapse prevention targets that can optimize treatments forthis serious psychiatric disorder.


application_id: 10613906
project_number: 5R01AG075583-02
project_title: Blood-Brain Barrier Repair in Alzheimers Disease with Epilepsy
administering_ic: NIA
award_notice_date: 2023-05-04
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 075583
program_official: NEWMAN, ELIZABETH
project_start_date: 2022-05-01
project_end_date: 2027-04-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
other_pis: BAUER, BJOERN
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:
More than 25% of patients with Alzheimers disease (AD) develop epilepsy as co-morbidity. In AD with epilepsy(ADxEpi) seizures accelerate cognitive decline and further reduce life expectancy compared to AD alone. Onehallmark of both AD and epilepsy is blood-brain barrier dysfunction. We discovered that barrier dysfunction ismore severe in ADxEpi patients compared to seizure-free AD patients. Collectively our data suggest that acombination of Ab and seizure-released glutamate (A/Glu) triggers a dual positive feedback loop which exac-erbates barrier dysfunction seizures and cognitive decline in ADxEpi. However the detailed mechanism(s) thatleads to barrier dysfunction in ADxEpi is/are unknown and treatment options for ADxEpi patients are limited toanti-seizure drugs that by themselves accelerate cognitive decline. This knowledge gap represents a critical andunmet need which will prevent us from achieving therapeutic advances for ADxEpi patients. Our overall objectivein this application is to define the mechanism that underlies barrier dysfunction in ADxEpi and to develop atherapeutic intervention. Based on preliminary data the central hypothesis is that blocking A/glutamate signal-ing repairs barrier dysfunction reduces seizure burden and slows cognitive decline in AD with epilepsy. Therationale for the proposed research is that its completion will provide the basis for a novel therapeutic interventionto successfully treat ADxEpi patients. The hypothesis will be tested by pursuing three specific aims: 1) Identifythe mechanism responsible for A/glutamate-mediated barrier dysfunction. 2) Define the relation between barrierdysfunction cognition and seizures in AD patients with epilepsy. 3) Develop a therapeutic intervention that re-pairs barrier dysfunction in AD with epilepsy. In Aim 1 we will determine signaling steps that lead to A/Glu-mediated neurovascular inflammation and barrier leakage in isolated mouse brain capillaries and verify thesefindings in vivo. In Aim 2 we will determine barrier dysfunction in brain tissue from ADxEpi patients and correlatethe degree of barrier dysfunction with seizure burden and patient cognition scores. In Aim 3 we will develop anintervention therapy designed to repair barrier dysfunction and we will evaluate the benefit of this interventionin two rodent ADxEpi models. The proposed research is innovative because it represents a substantive departurefrom the status quo by shifting the focus from traditional anti-seizure drugs to targeting molecular pathways torepair barrier dysfunction thereby improving seizure burden and slowing cognitive decline in ADxEpi. The pro-posed research is significant because it holds the promise of a new therapeutic approach that has translationalpotential for clinical use to advance the treatment of ADxEpi patients.

project_terms:
Acceleration;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid beta-Protein;Anticonvulsants;Attenuated;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Brain;Characteristics;Clinical;Cognition;Cyclooxygenase Inhibitors;Data;Disease Progression;Epilepsy;Extravasation;Feedback;Functional disorder;Glutamates;Health;Impaired cognition;Inflammation;Intervention;Knowledge;LOX gene;Life Expectancy;Link;Matrix Metalloproteinases;Mediating;Mission;Modeling;Molecular Target;Mus;National Institute of Neurological Disorders and Stroke;Outcome;Oxidative Stress;Oxidative Stress Induction;Pathway interactions;Patients;Personal Satisfaction;Process;Public Health;Research;Rodent;Seizures;Signal Transduction;Testing;Therapeutic;Therapeutic Intervention;Tight Junctions;United States National Institutes of Health;Work;brain tissue;cerebral capillary;comorbidity;design;glutamatergic signaling;improved;in vivo;innovation;nervous system disorder;neurovascular;novel therapeutic intervention;pre-clinical;prevent;repaired;therapy design;translational potential

public_health_relevance:
The proposed research is relevant to public health because it is expected to advance understanding of themechanisms underlying blood-brain barrier dysfunction in Alzheimers disease with epilepsy as comorbidity. Theresearch is designed to provide a novel therapeutic intervention that repairs blood-brain barrier dysfunction toimprove seizure control and reduce cognitive decline in patients that have Alzheimers disease with epilepsy.Thus the proposed research is relevant to the missions of the NIH/NINDS and the NIH/NIA that pertain todeveloping fundamental knowledge that will help reduce the burden of neurological disease and improve thehealth and well-being in aging.


application_id: 10613880
project_number: 5R35GM136295-04
project_title: Mechanisms and functions of Shoc2-transduced cellular signals
administering_ic: NIGMS
award_notice_date: 2023-04-24
opportunity_number: PAR-17-094
application_type: 5
activity_code: R35
ic: GM
serial_number: 136295
program_official: LEWIS, MECHELLE MAYLEBEN
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1-CB-J(55)R]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The overall vision of our NIGMS-supported program is to address the molecular mechanisms of theextracellular signal-regulated kinases 1 and 2 (ERK1/2) signal transmission as guided by scaffold proteins.Essential for the normal functioning of the cell the ERK1/2 ability to rewire signaling pathways is a majorproblem for clinical intervention. The rationale for the proposed studies is that a thorough understanding of themechanism by which key regulators such as scaffold protein Shoc2 modify ERK1/2 signaling is essential forunderstanding dysregulated mechanisms in ERK1/2-related diseases and for identifying new drug targets. Ourstudies have raised many exciting questions and the most transformative research will be pursued in the nextfive-year period. Our efforts during the first cycle of NIGMS funding led to the discovery that the ubiquitin machineryregulates the signal transmission of ERK1/2 signals through the Shoc2 scaffolding module and controlsassembly of the proteins in the complex. We identified key enzymes modulating the ability of Shoc2 to transmitERK1/2 signals. We then discovered that organized spatial distribution of the Shoc2 complexes is critical forthe proper transmission of ERK1/2 signals. Our work further revealed a distinct function of the signalstransduced by the Shoc2 scaffold in ERK1/2 in mediating cell adhesion and motility. We also established thatloss of Shoc2 in zebrafish has a systemic effect of on early development recapitulating congenitalmalformations observed in patients with Shoc2 mutations. For MIRA application we propose to define the mechanisms by which endosomal sorting regulates theubiquitin-driven remodeling of the Shoc2 complexes and signaling. The key steps that segregate Shoc2 intothe distinct intracellular sorting pathways will be delineated. The molecular details of how Shoc2-activatedERK1/2 signals promote early developmental stages will be determined. We will use an innovativecomprehensive approach encompassing genetic state-of-the-art microscopy as well as cell-based andbiophysical methodologies. Of note we will use zebrafish as a vertebrate model to investigate the in vivo effectof Shoc2 gene editing on the early stages of development since they offer distinct advantages for studies ofdevelopment including their transparency as well as external and rapid development. The proposed researchis expected to produce an ambitious and comprehensive mechanistic understanding of how Shoc2 is involvedin determining the specificity of ERK1/2 signaling outcomes and has the potential for high impact by laying thegroundwork for future studies on developmental disorders and contributing to the advancement of noveltherapeutic strategies and biomarkers.

project_terms:
Address;Biological Markers;Cell Adhesion;Cell physiology;Cells;Clinical;Complex;Congenital Abnormality;Development;Disease;Endosomes;Enzymes;Funding;Future;Genes;Genetic;Intervention;MAPK3 gene;Malignant Neoplasms;Mediating;Microscopy;Modeling;Molecular;Mutation;National Institute of General Medical Sciences;Outcome;Pathway interactions;Patients;Proteins;Research;Scaffolding Protein;Signal Pathway;Signal Transduction;Sorting;Spatial Distribution;Specificity;Syndrome;Ubiquitin;Vision;Work;Zebrafish;biophysical techniques;cell motility;cellular transduction;developmental disease;in vivo;innovation;new therapeutic target;novel diagnostics;novel therapeutic intervention;programs;public health relevance;scaffold;segregation;targeted treatment;therapeutic development;transmission process;tumor;virtual

public_health_relevance:
Public Health Relevance Statement Deregulation of the ERK1/2 signaling cascade is found in 30% of all tumors and multipledevelopmental abnormalities. While virtually every component of the cascade is target fortherapeutic development the effective targeting of this pathway in disease relies upon a clearunderstanding of all the intricacies in modulating numerous signaling components. The resultsof this study focused on the non-canonical regulators of the ERK1/2 pathway may lead to thediscovery of new diagnostics as well as new treatments for diseases including Noonan-likeSyndrome and some cancers.


application_id: 10612833
project_number: 5K01MH119942-04
project_title: Examining HIV-related Stigma and HIV Testing Among Formerly Incarcerated African American Youth
administering_ic: NIMH
award_notice_date: 2023-05-18
opportunity_number: PA-19-126
application_type: 5
activity_code: K01
ic: MH
serial_number: 119942
program_official: GREENWOOD, GREGORY LOUIS
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 12373928
contact_pi: KERR, JELANI
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractPersistent HIV health disparities impacts African Americans and are a public health priority. Despite decliningHIV rates nationally African American communities continue to experience disproportionate HIV burden andincreasingly account for the largest share of HIV-related morbidity and mortality in the United States. Theseconcerning disparities necessitate research to inform robust responses that target priority subgroups within thispopulation. High rates of incarceration in many African American communities contribute to high HIV riskenvironments where the risks persist after release from the criminal justice system. Formerly incarceratedAfrican American youth (FIAAY ages 18-24 years) in particular are at heightened risk in terms of sexualbehavior illicit drug use and challenged rates of HIV testing behavior after release. A prominent barrier to HIVtesting and timely diagnosis in this and other vulnerable populations is HIV-related stigma. Thus moreresearch needs to not only examine stigma-related factors that reduce HIV testing behavior but also create abasis for interventions that can reduce stigma and increase HIV testing and HIV preventive behaviors in prioritypopulations such as FIAAY. Towards these goals my proposed study focusing on FIAAY in LouisvilleKentucky will allow me to: 1) develop a risk profile of HIV-negative or HIV status unknown FIAAY at greaterlikelihood of having stigmatizing beliefs related to HIV infection and longitudinally examine the likelihood of HIVtesting based on this profile and 2) delineate mediating and moderating mechanisms by which stigma reducesHIV testing in this population. These actions will help generate knowledge for the development of a multilevelintervention targeting individual and structural factors to reduce HIV-related stigma and increase HIV testingand prevention among this population of vulnerable youth. This Career Development Award will provide thenecessary knowledge and skills to conduct this and future research with criminal justice-involved populations.This entails enhancing my skills in advanced statistical methods such as survival analysis and structuralequation modeling. In addition it will foster content expertise in decision science and the criminal justicesystem which will help inform intervention development. Study methods will include longitudinal survey datacollection (baseline 12-months 24-months) from 274 FIAAY in Louisville KY. This research will inform thedevelopment of stigma-related HIV-risk profiles for FIAAY who are less likely to test and delineate mediatorsand moderators of the stigma-HIV testing relationship. If a relationship between stigma and testing is notdetected other psychosocial factors will be examined to determine mediators and moderators of HIV testing.This study has important downstream benefits for HIV prevention and treatment in this highly vulnerablepopulation.

project_terms:
AIDS prevention;Address;Affect;African American;African American population;Age;Behavior;Behavior Therapy;Behavioral;Belief;Caring;Characteristics;Communities;Criminal Justice;Data;Data Collection;Demographic Factors;Development;Diagnosis;Disparity;Drug usage;Early Diagnosis;Environment;Equation;Exhibits;Fostering;Fright;Gender;Gender Identity;General Population;Goals;HIV;HIV Infections;HIV Seronegativity;HIV diagnosis;HIV disparities;HIV risk;Health;Health behavior;Homophobia;Human immunodeficiency virus test;Imprisonment;Individual;Intervention;K-Series Research Career Programs;Kentucky;Knowledge;Longitudinal Surveys;Mediating;Mediator;Methods;Modeling;Morbidity - disease rate;Neighborhoods;Participant;Pathway interactions;Persons;Population;Poverty;Predisposition;Prevention;Prevention strategy;Preventive;Psychosocial Factor;Public Health;Recording of previous events;Religiosity;Research;Research Personnel;Research Project Grants;Risk;Risk Behaviors;Science;Sex Behavior;Sex Orientation;Statistical Methods;Stereotyping;Stigmatization;Subgroup;Survival Analysis;System;Testing;Translational Research;Unemployment;United States;Vulnerable Populations;Work;Youth;aged;behavior test;care systems;career development;condoms;ethnic disparity;experience;health disparity;illicit drug use;improved;male;mortality;outcome disparities;pre-exposure prophylaxis;prediction algorithm;prevent;prevention service;psychologic;public health priorities;racial disparity;response;sexual risk behavior;skills;social stigma;structural determinants;substance use;testing uptake;therapy development;treatment disparity;uptake

public_health_relevance:
Project NarrativeAfrican American youth with a history of incarceration are at heightened HIV risk thus early detection amongthis group is critical for linkage to prevention and care services improving survival prospects and reducingracial disparities in HIV. Despite the benefits of testing HIV-related stigma remains a significant barrier totimely HIV diagnosis however little research examines the mechanisms by which HIV-related stigma inhibitstesting behavior. This study will delineate the relationships between stigma stigma-related factors and HIVtesting and the information will be used to help generate knowledge for intervention development to improveHIV testing and stigma-reduction for formerly incarcerated African American youth.


application_id: 10612256
project_number: 3R34MH128213-01S1
administering_ic: NIMH
award_notice_date: 2022-06-13
opportunity_number: PA-21-071
application_type: 3
activity_code: R34
ic: MH
serial_number: 128213
suffix: S1
program_official: VILLATTE, JENNIFER L
project_start_date: 2022-08-01
project_end_date: 2024-11-30
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-01
project_abstract:
PROJECT SUMMARY/ABSTRACTDespite eating disorders (EDs) carrying one of the highest mortality rates among all psychiatricdisorders there is no evidence-based treatment for anorexia nervosa and only 50% of individualsrespond to the gold standard treatment for bulimia nervosa and binge eating disorder (cognitive-behavioral therapy enhanced: CBT-E). These low response rates are likely partially due to thelarge variations in symptom presentations. One major factor contributing to the high rates ofheterogeneity across EDs is the wide variety of cognitive-affective factors which maintain activeillness states. CBT-E is based on the idea that overvaluation of weight and shape is the primarycognitive-affective mechanism responsible for maintaining EDs on average (i.e. for mostindividuals) and is delivered in a standardized format. However there is a well-documentedrelationship between non-traditional cognitive-affective mechanisms such as perfectionismworry and shame and EDS. Therefore a method is needed that can provide a morepersonalized approach to ED treatment by addressing the high heterogeneity and specificallytargeting non-traditional cognitive-affective mechanisms. The specific aims of the proposedproject are to: (1) develop a coding system to identify the traditional and non-traditionalcognitive-affective targets that are addressed in both a personalized and standardized (CBT-E)treatment (2) use personalized networks to examine if coded treatment targets correspond withdata-identified and manualized (i.e. CBT-E) treatment targets (3) identify coded profiles ofparticipants with non-traditional cognitive-affective profiles versus ED-traditional cognitive-affective profiles and (4) test if participants with non-traditional cognitive-affective profilesversus ED-traditional cognitive-affective profiles from idiographic networks differ in treatmentoutcomes via condition. This project will be an important initial step towards identifying therelations between eating disorders cognitive-affective factors and outcomes in eating disordersto use in personalized treatments. Importantly the career development and mentorship planoutlined in this diversity supplement application will promote Ms. Ortizs success as a minorityresearcher and contribute to the initiative of building a scientific workforce.

project_terms:
Address;Affective;Anorexia Nervosa;Award;Binge eating disorder;Bulimia;Code;Cognitive;Cognitive Therapy;Data;Doctor of Philosophy;Eating Disorders;Evidence based treatment;Gold;Heterogeneity;Individual;Investigation;K-Series Research Career Programs;Mental disorders;Mentorship;Methods;Minority;Outcome;Participant;Research Personnel;Series;Shame;Shapes;Standardization;Symptoms;Testing;Treatment outcome;United States National Institutes of Health;Variant;Weight;base;career development;cognitive enhancement;mortality;personalized approach;personalized medicine;response;standard care;success

public_health_relevance:
PROJECT NARRATIVEThis project is a diversity supplement to support PhD candidate Anna Marie Ortiz. The careerdevelopment and mentorship plan outlined in this diversity supplement application will promoteMs. Ortizs success as a minority researcher and contribute to the initiative of building ascientific workforce. Further it will prepare Ms. Ortiz to submit a NIH K-series careerdevelopment award at the end of the award period.


application_id: 10611958
project_number: 5R01AG068215-04
project_title: Sleep Fragmentation and Alzheimers Disease
administering_ic: NIA
award_notice_date: 2023-04-12
opportunity_number: PAR-18-497
application_type: 5
activity_code: R01
ic: AG
serial_number: 068215
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2020-08-01
project_end_date: 2025-04-30
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8535896
contact_pi: MURPHY, MICHAEL PAUL
other_pis: BACHSTETTER, ADAM D;DUNCAN, MARILYN J.;O'HARA, BRUCE FREDERICK;SUNDERAM, SRIDHAR
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Chronic sleep disruption resulting from work schedules noise exposure family obligations sleep disorders orlifestyle choices is a pervasive feature of contemporary life. Sleep problems affect up to 40% of AD patientsmay precede cognitive impairments by more than a decade and worsen as the disease progresses. As well asaffecting mood and well-being sleep disruption may drive the development of AD neuropathology for instanceby reducing clearance of amyloid- (A) and by promoting a neurotoxic proinflammatory state involvingastrocytes and microglia. Sleep disruption can include reduced total sleep (sleep restriction [SR]) loss of deepsleep (also known as slow-wave sleep [SWS] marked by large amplitude low frequency electrical activity)and fragmentation of sleep (SF) into shorter bouts. Fragmentation of the daily sleep-wake rhythm is associatedwith greater risk of incident AD and earlier cognitive decline in older humans. In spite of these correlativestudies whether or how chronic SF impacts the progression of AD has not been experimentally investigated.SF may be a better model of the sleep disruption associated with AD than the traditional approach of SR. Ourstudies of AD mouse models show that spontaneously occurring SF is associated with more severe Aaccumulation and that experimentally-induced SF leads to A accumulation and neuroinflammation. BesidesSF loss of SWS may exacerbate AD and improving SWS may be beneficial in mild cognitive impairment(MCI) or even in AD. Since sleep disruption adversely affects the development of AD-related neuropathology itis surprising that sleep enhancement (SE) strategies to consolidate sleep and increase SWS have not beenadequately explored to slow or reverse these effects. Our overall working hypothesis is that a change in thequality of sleep especially sleep fragmentation and loss of SWS is more important than the quantity of sleep.Further we hypothesize that the mechanism underlying these effects is primarily neuroinflammation at least inpart mediated by A peptide deposition. We will use a unique well-characterized mouse model that exhibitsAD-related A pathology neuroinflammation and cognitive deficits. This project has three specific aims: (1)that SF will accelerate (and SE decelerate) AD progression; (2) that increases in A accumulation mediatesSF-induced neuroinflammation neuropathology and cognitive decline; and (3) that increases inneuroinflammation mediate SF-induced neuropathology and cognitive decline. We will use multiple novelapproaches including thermoneutral temperature manipulation and a unique anti-inflammatory compound thathas recently entered early stage clinical trials. Thus these studies will elucidate the underlying mechanisms bywhich sleep disruption is linked to AD and will lay the groundwork for new therapeutic strategies.

project_terms:
Abeta clearance;Acceleration;Address;Affect;Aging;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Anti-Inflammatory Agents;Astrocytes;Attenuated;Biological;Brain;Chronic;Cognition;Cognitive deficits;Correlative Study;Deceleration;Dementia;Demographic Factors;Deposition;Development;Disease Progression;Exhibits;Family;Frequencies;Human;Impaired cognition;Impairment;Inflammation;Inflammatory;Knock-in Mouse;Life;Life Style;Light;Link;Mediating;Mediator;Medical History;Microglia;Modeling;Moods;Mus;Nerve Degeneration;Noise;Pathology;Personal Satisfaction;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Process;Rest;Risk;Role;Schedule;Sleep;Sleep Deprivation;Sleep Disorders;Sleep Fragmentations;Sleep disturbances;Slow-Wave Sleep;Societies;Synapses;System;Temperature;Testing;Time;Work;abeta accumulation;age related;beta amyloid pathology;circadian;circadian pacemaker;design;improved;improvement on sleep;middle age;mild cognitive impairment;mouse model;neuroinflammation;neuropathology;neurotoxic;noise exposure;novel;novel strategies;novel therapeutic intervention;pharmacologic;pre-clinical;prevent;response;sleep quality;sleep quantity

public_health_relevance:
Age-related dementia is a significant and growing burden on our society  the most well known of which isAlzheimer's disease (AD)  and chronic sleep disruption is a pervasive feature of contemporary life that isassociated with and exacerbated in AD. This project will examine the idea that sleep quality is more importantthan sleep quantity and will investigate the underlying biological mechanisms of this process as well asexplore novel strategies for improving sleep and treating deleterious inflammation in the brain.


application_id: 10611830
project_number: 4UF1NS125488-02
administering_ic: NINDS
award_notice_date: 2023-08-24
opportunity_number: RFA-NS-21-005
application_type: 4
activity_code: UF1
ic: NS
serial_number: 125488
program_official: MCGAVERN, LINDA
project_start_date: 2021-09-29
project_end_date: 2026-07-31
study_section: ZNS1-SRB-O(15)
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: WILCOCK, DONNA M
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-01
project_title:
The University of Kentucky MarkVCID Biomarker Validation Cohort: Development of a Toolbox to Advance VCID Interventional Studies

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

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

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


application_id: 10611819
project_number: 4R01NS122028-02
project_title: Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel Disease
administering_ic: NINDS
award_notice_date: 2025-06-03
opportunity_number: PAR-19-070
application_type: 4
activity_code: R01
ic: NS
serial_number: 122028
program_official: YIN, XILING
project_start_date: 2022-02-01
project_end_date: 2027-01-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)R]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: WANG, DANNY JJ
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Reduced BBB Water Exchange as a Preclinical Biomarker of Small Vessel DiseaseVascular cognitive impairment and dementia (VCID) is common in older adults and is a majorpublic health risk. VCID affects the network of small blood vessels that supply all parts of thebrain resulting in cognitive decline. Clinical trials have been hampered by the lack of non-invasive tools to detect early stages of VCID. Consequently innovative tools for theidentification of early-stage VCID have become a major research priority. The blood-brainbarrier (BBB) may be a key system affected early in the course of VCID. Recent advances inthe development of a novel diffusion-weighted ASL (DW-ASL) sequence and post-processinganalyses have made it possible to quantify water exchange rate across the BBB a metric ofBBB functioning. Our preliminary results using this novel sequence suggest that low waterexchange across the BBB (low kw) is associated with high concentrations of plasma vascularinflammatory markers and poor cognitive performance suggesting that it may represent anearly marker of VCID. Longitudinal research is required to test this possibility. This proposalseeks to assess the accuracy of low kw as a predictor of subsequent neurocognitive declines.We will also test the possibility that low kw is associated with oxidative stress assessed viacerebrospinal fluid (CSF) isoprostane levels. We propose to study 140 healthy older adults atbaseline using DW-ASL plasma inflammatory markers and CSF measures of isoprostanes Ap-tau and t-tau. In addition structural neuroimaging measures will be obtained and quantifiedincluding regional volumes white matter hyperintensity (WMH) volumes diffusion tensorimaging for quantification of regionally distributed white matter abnormalities and susceptibilityweighted imaging for quantification of cerebral microbleeds. A subset of participants willcomplete the same neuroimaging and biofluid measures approximately 3 years later. We aim toidentify the relationship between baseline BBB water exchange and subsequent WMH growth(Aim 1); cognitive declines (Aim 2) and biofluid indices of oxidative stress (Aim 3). The overallhypothesis we will test is that that low water exchange rate assessed with a novel DW-ASLsequence represents an early marker BBB dysfunction associated with later WMH growthcognitive declines and oxidative stress.

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

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


application_id: 10611448
project_number: 5R34MH126965-02
administering_ic: NIMH
award_notice_date: 2023-04-24
opportunity_number: RFA-MH-20-500
application_type: 5
activity_code: R34
ic: MH
serial_number: 126965
program_official: BURSTEIN, MARCY ELLEN
project_start_date: 2022-05-01
project_end_date: 2025-04-30
study_section: ZMH1-ERB-N(03)
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Facing Eating Disorder Fears for Anorexia Nervosa: A Virtual Relapse Prevention Program Targeted at Approach and Avoidance Behaviors

project_abstract:
PROJECT SUMMARY/ABSTRACTAnorexia nervosa (AN) is chronic and disabling; most individuals never achieve full remissioneven after acute treatment and 50% of those who access acute treatment will relapse within 6-months of discharge. AN relapse-prevention treatments are urgently needed that can disrupt thepersistent cycle of admission and discharge from acute treatment. Importantly existingtreatments do not differ from control treatments in the ability to alter cognitive-behavioral ANpathology which is the primary remaining symptomatology at discharge from acute care. Theinability to alter cognitive-behavioral pathology is a function of the limited availability oftreatments that include skills training to promote behavior change in a real-world contextoutside of treatment facilities. As such relapse-prevention treatments should explicitly targetcore cognitive-behavioral pathology to facilitate approach behaviors (e.g. facing fear foods) inthe real-world. Our scientific premise developed from our past work is that the application of avirtual format of Facing Eating Disorder Fears (FED-F) for AN will facilitate engagement inapproach behaviors and minimize avoidance behaviors - improving outcomes enhancing fullrecovery and decreasing the likelihood of relapse. FED-F is a modular treatment that enhancesexposure therapy with psychoeducation and cognitive skills teaching how to face fears of (a)food (b) weight gain (c) interoception/body and (d) social situations. Our study goals are to (1)refine and test the acceptability and feasibility of FED-F delivered post-acute treatment asadjunctive to step-down specialty care (2) test if this treatment outperforms treatment as usual(TAU) and (3) to examine if treatment targets our hypothesized mechanism of action: approachbehaviors. These goals will lead to a highly deployable and accessible virtual treatment targetedat core AN mechanisms that predict relapse. The proposed research uses highly innovativemethods; we will use an all-remote technology-based approach combining a virtual non-therapist assisted treatment with remote behavioral and momentary assessment ofapproach/avoidance behaviors. Specific aims are to (1) refine FED-F into a fully virtual formatwith input from patients and stakeholders and collect preliminary data (N=10) on its feasibilityand acceptability (2) conduct a small pilot RCT of FED-F (n=30) as compared to TAU (n=30)and (3) examine if FED-F targets approach/avoidance behaviors and test if this mechanism isassociated with clinical outcomes. Ultimately this proposal will lead to the creation anddissemination of a highly user-friendly easily accessible and deployable intervention deliveredduring a critical period of care that can prevent AN relapse which will decrease mortalitymorbidity and the high costs associated with chronic treatment.

project_terms:
Acute;Admission activity;Aftercare;Anorexia Nervosa;Anxiety;Behavior;Behavior assessment;Behavioral;Caring;Cessation of life;Chronic;Clinical;Cognitive;Cognitive Therapy;Communities;Data;Disease remission;Eating Disorders;Educational process of instructing;Ensure;Environment;Extinction;Face;Feedback;Focus Groups;Food;Fright;Goals;Hospitalization;Hospitals;Individual;Inpatients;Interoception;Intervention;Lead;Literature;Medical;Methods;Morbidity - disease rate;Neurobehavioral Manifestations;Outcome;Outpatients;Pathology;Patient Discharge;Patient Self-Report;Patients;Play;Preparation;Prevention program;Provider;Randomized Controlled Trials;Recovery;Relapse;Research;Role;Service delivery model;Services;Stimulus;Symptoms;System;Technology;Testing;Time;Translating;Translations;United States National Institutes of Health;Weight;Weight Gain;Work;acceptability and feasibility;acute care;approach behavior;avoidance behavior;behavior change;care systems;clinical efficacy;cognitive benefits;cognitive function;cognitive skill;cost;cost outcomes;critical period;evidence base;experience;feasibility testing;habituation;hospital readmission;improved outcome;innovation;medical specialties;mortality;outpatient facility;prevent;psychoeducation;psychoeducational;public health relevance;relapse prediction;relapse prevention;skills training;social;social situation;symptomatology;therapy design;treatment as usual;treatment center;user-friendly;virtual;virtual delivery;virtual platform;virtual therapy;weight restoration

public_health_relevance:
PROJECT NARRATIVEThis project will refine the Facing Eating Disorder Fears (FED-F) for anorexia nervosa (AN)relapse-prevention treatment designed to prevent relapse after discharge from acute treatment.We will assess the feasibility acceptability clinical efficacy and target engagement of thistreatment versus treatment as usual. The proposed research has significant public healthrelevance as it will directly lead to a highly accessible and deployable treatment that candecrease AN relapse and the high societal burden associated with AN. The proposed researchis relevant to NIHs strategic aim 4.3 as it will lead to the creation of an innovative evidence-based service delivery model using technology that can be easily disseminated to communitiesin need during a critical period of transition of care.


application_id: 10610933
project_number: 5R01HL148443-04
project_title: Mechanisms of cardiac remodeling triggered by gestational diabetes
administering_ic: NHLBI
award_notice_date: 2023-03-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 148443
program_official: TJURMINA, OLGA A
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTGestational diabetes mellitus (GDM) heightens the risk of developing cardiovascular disease in both motherand offspring. A recent large population-based prospective study (CARDIA) found that GDM is independentlyassociated with cardiac hypertrophy and impaired heart function later in life. In agreement with this finding ourpreliminary data show cardiac hypertrophy and activation of Ca2+-dependent transcriptional signaling twomonths after a GDM-complicated pregnancy in female rats. Although hyperglycemia is generally consideredthe critical mediator numerous studies reported that GDM has negative long term consequences even withgood glycemic control in the mother. Thus additional mechanisms promote metabolic and cardiovasculardysfunction in GDM. We previously demonstrated an essential role for amylin a pancreatic hormone withamyloidogenic properties and whose secretion increases in parallel with that of insulin in the cardiacremodeling and dysfunction induced by type-2 diabetes. Moreover we found that amylin activates Ca2+-dependent transcriptional signaling in cardiac myocytes. Our preliminary studies show higher amylin levels inblood from female rats with GDM and their offspring. Based on these findings we hypothesize that GDMpromotes pathological remodeling of maternal and offspring heart through activation of Ca2+-dependenthypertrophy signaling that is triggered by systemic amylin dyshomeostasis. To test this overall hypothesis wewill i) determine the molecular mechanisms underlying the GDM-induced pathological remodeling of the heartii) probe the amylin-cardiac myocyte interaction in GDM and iii) assess the effect of hyperamylinemia onpregnancy-induced cardiac remodeling in the absence of other metabolic alterations associated with GDM.Experiments will combine in vivo assessment of heart structure and function and pharmacological treatmentwith measurements in explanted hearts and isolated cardiac myocytes in female rats with normal and GDM-complicated pregnancies and their offspring as well as in pregnant amylin-KO females injected withrecombinant amylin. Thus the project will provide unique insights into the complex mechanisms through whichGDM programs cardiac remodeling in mother and offspring. The study may be paradigm shifting by assertingamylin dyshomeostasis as a key player in this pathology which will help design new therapeutic strategies forreducing the postpartum risk of heart disease in mothers with GDM and their offspring.

project_terms:
Acids;Age Months;Agreement;Beta Cell;Blood;Calcineurin;Cardiac;Cardiac Myocytes;Cardiovascular Diseases;Cardiovascular system;Complex;Complications of Diabetes Mellitus;Data;Deposition;Development;Female;Functional disorder;Genetic Transcription;Gestational Diabetes;Heart;Heart Diseases;Heart Hypertrophy;Histone Deacetylase;Hormones;Human;Hyperglycemia;Hypertrophy;Impairment;Incubated;Individual;Injections;Insulin;Insulin Resistance;Life;Measurement;Mediating;Mediator;Membrane;Metabolic;Modeling;Molecular;Mothers;Muscle Cells;Myocardial dysfunction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pancreas;Pancreatic Hormones;Participant;Pathologic;Pathology;Pathway interactions;Pharmacological Treatment;Poloxamer 188;Postpartum Period;Prediabetes syndrome;Pregnancy;Pregnancy Complications;Property;Prospective Studies;Rat Transgene;Rattus;Recombinants;Reporting;Risk;Risk Reduction;Role;Signal Transduction;Structure;Structure of beta Cell of islet;Testing;Woman;Work;calmodulin-dependent protein kinase II;design;diabetic;experimental study;glycemic control;heart dimension/size;heart disease risk;heart function;in vivo;insight;insulin secretion;islet amyloid polypeptide;male;neonate;novel therapeutic intervention;nuclear factors of activated T-cells;offspring;pharmacologic;population based;pregnant;programs;pup

public_health_relevance:
NARRATIVEBoth women with gestational diabetes mellitus and their offspring are at increased risk of developingcardiovascular disease including cardiac hypertrophy and dysfunction later in life. Proposed work seeks totest the hypothesis that gestational diabetes promotes pathological hypertrophy of maternal and offspring heartthrough Ca2+-dependent hypertrophy signaling triggered by dyshomeostasis of the pro-hypertrophic pancreatichormone amylin. By providing insights into the underlying mechanisms this study will help design noveltherapeutic strategies during and after GDM-complicated pregnancies to reduce the risk of heart disease inmother and offspring.


application_id: 10610825
project_number: 5R01NS115895-04
project_title: Long-term effects of wildtype huntingtin lowering in the primate corticostriatal tract and thalamus
administering_ic: NINDS
award_notice_date: 2023-04-11
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 115895
program_official: MILLER, DANIEL L
project_start_date: 2020-04-01
project_end_date: 2026-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8559816
contact_pi: GRONDIN, RICHARD C.
other_pis: KAEMMERER, WILLIAM F
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:
PROJECT SUMMARY / ABSTRACTMost huntingtin-lowering treatments in development or clinical trials are not selective for the mutant allele butalso lower wildtype huntingtin expression. The purpose of this project is to fill critical gaps in our knowledgeabout the effects of wildtype huntingtin lowering in the primate brain over an extended period of time in brainregions relevant to Huntingtons disease (HD) and to the functions of wildtype huntingtin. Data from mousemodels of HD indicate that lowering huntingtin in cortical neurons that are part of the corticostriatal system maybe necessary for optimal therapeutic efficacy.1-3 Although prior research has established that lowering wildtypehuntingtin by 45% in the primate striatum is well-tolerated for six months4 this and other research5 has notlowered wildtype huntingtin in primate corticostriatal neurons whose axons comprise the corticostriatal tract.Huntingtin is involved in the rate of production6 and transport7 of BDNF (brain-derived neurotrophic factor) fromcortical neurons to the striatum on which striatal neurons depend.8 It is unknown whether reduction of wildtypehuntingtin in corticostriatal neurons/tract of the primate brain will adversely affect the survival and functioning ofstriatal neurons. AIM 1 will assess the long-term tolerability of wildtype huntingtin lowering in the corticostriataltract over 9 months by quantitatively measuring the effects of this lowering on locomotor activity BDNF levelsand neurotransmitter systems. As research tools the project uses an shRNA already known to lower huntingtinin the primate4 and a serotype of AAV already known to retrogradely transduce cortical neurons from a striatalpoint of infusion.9 Treatment of the thalamus has been proposed as a means of enhancing vector distribution inthe brain16. However pathologic calcification of the thalamus has been reported in mice 9 months after partialconditional knockout of wildtype huntingtin.10 AIM 2 will determine if reduction of wildtype huntingtin in theprimate thalamus will result in an increased thalamic calcium accumulation whether occurring incidentally fromstriatal infusion of vectors or directly by vector infusion targeting the thalamus. In the proposed studies thirty-two (32) adult rhesus monkeys will be equally divided into four experimental groups (N= 8 animals/group) andrandomly assigned to receive MRI-guided injections of AAV6 encoding a huntingtin-lowering shRNA or acontrol shRNA directly into either the striatum (AIM 1) or thalamus (AIM 2). Monkeys will be assessed byperiodic behavioral and neurological exams. In vivo glutamate signaling in the cortex striatum and thalamuswill be assessed 9 months after AAV administration. Post-mortem analysis will include assessments ofdopamine turnover and BDNF levels in striatal tissue as well as calcium in the thalamus and neuropathologicalevaluations of coronal brain sections including cortex striatum and thalamus. The data obtained by thisproject in the nonhuman primate will provide information that cannot be readily obtained from human clinicaltrials of huntingtin-lowering treatments. This information will be pertinent to any current and future therapies forHD that use non-allele-specific means to lower huntingtin irrespective of the agent or route of delivery.

project_terms:
Adult;Affect;Age;Alleles;Animals;Autopsy;Axon;Behavior;Behavioral;Biosensor;Blinded;Brain;Brain region;Brain-Derived Neurotrophic Factor;Calcinosis;Calcium;Clinical Treatment;Clinical Trials;Collection;Corpus striatum structure;Data;Deposition;Development;Disease;Disease Progression;Dopamine;Evaluation;Future;Future Generations;Genes;Glutamates;Health;Health Status;Histology;Human;Huntington Disease;Huntington gene;Infusion procedures;Injections;Intervention;Knowledge;Long-Term Effects;Macaca mulatta;Magnetic Resonance Imaging;Measurement;Measures;Methods;Molecular;Monitor;Monkeys;Motor Activity;Mus;Nature;Neurodegenerative Disorders;Neurologic;Neurological status;Neurons;Neurotransmitters;Participant;Pathology;Patients;Periodicals;Primates;Production;Randomized;Reporting;Research;Resolution;Route;Serotyping;Structure;System;Thalamic structure;Time;Tissues;Treatment Efficacy;brain tissue;calcification;clinically significant;conditional knockout;end stage disease;experimental group;glutamatergic signaling;in vivo;mouse model;mutant;neuropathology;nonhuman primate;protein expression;putamen;retrograde transport;small hairpin RNA;therapeutic target;therapy adverse effect;tool;uptake;vector

public_health_relevance:
PROJECT NARRATIVETreatment of the cortex as well as the striatum may be desirable for optimal efficacy of a huntingtin-loweringtreatment for Huntingtons disease but lowering huntingtin in the cortex may affect underlying neurotransmittersystems and/or reduce the transport of trophic factors from the cortex to the striatum that are necessary for thesurvival and function of striatal neurons. The thalamus is also a potential therapeutic target but reduction ofhuntingtin in the thalamus causes pathologic calcification in mice and it is unknown whether this might alsooccur in the primate brain. The purpose of this project is to fill critical gaps in our scientific knowledgeabout the effects of lowering huntingtin protein expression in the corticostriatal connections and thethalamus of the primate brain to provide useful information for current and future generations of huntingtin-lowering therapies for Huntingtons disease.


application_id: 10610572
project_number: 3R35NS116824-03S1
project_title: Brain Glycogen - Metabolism Mechanisms and Therapeutic Potential
administering_ic: NINDS
award_notice_date: 2022-04-20
opportunity_number: PA-21-071
application_type: 3
activity_code: R35
ic: NS
serial_number: 116824
suffix: S1
program_official: LEENDERS, MIRIAM
project_start_date: 2020-05-15
project_end_date: 2022-08-12
study_section: ZNS1-SRB-M(12)
contact_pi_person_id: 7923267
contact_pi: GENTRY, MATTHEW S.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Brain metabolism is a fundamental aspect of biology and human disease. The brain critically depends onglucose consuming large quantities as the biochemical fuel for cognition memory and behavior. Fundamentalaspects of brain metabolism have been extensively studied but recent evidence regarding the key role ofglucose and glycogen metabolism in neurological diseases has recently opened up new avenues of research.The neurological disease where aberrant glucose metabolism has been investigated in-depth is Lafora disease(LD). LD is an autosomal recessive fatal glycogen storage disease (GSD) that equally affects both sexes.Symptoms emerge in adolescence with drug-resistant epilepsy ataxia neurodegeneration and a rapid declineinto a vegetative state before death. Results from several labs using multiple models have demonstrated thataberrant intracellular glycogen-like aggregates known as polyglucosan bodies (PGBs) are the cause of LD.Strikingly we and others have identified PGBs in multiple neurological diseases and we hypothesize thatPGBs are a driving force in disease progression for brain-impacted GSDs and that PGBs also play acritical role in Alzheimers disease (AD). We have made foundational discoveries regarding glucose hypometabolism in LD defined how PGBsimpact cellular processes developed cutting-edge tools to determine the underlying cellular mechanisms andestablished therapeutic platforms to inhibit and/or eliminate PGBs. Defining the mechanisms of glycogenmetabolism in LD provides insights into how PGBs form and impact brain homeostasis. Thus LD offers aunique window into both normal brain glucose metabolism and broader disease implications when thismetabolism is perturbed. This R35 will combine our NINDS-funded LD-centric R01 and P01 and extend our expertise to brain-impacted GSDs and determining the role of PGBs in AD. Moving forward we will further define LD-drivenperturbations in signaling at the molecular level elucidate changes in cellular physiology and establish noveltherapeutic modalities at the organismal level. Excitingly the work on LD serves as a model for how tointerrogate brain metabolic perturbations in other neurological diseases involving PGBs. We will apply thesepowerful LD-developed tools and insights to define how PGBs impact multiple neurological diseasesdetermine the glycogen-centric molecular mechanisms impacting disease progression and define how PGBremoval affects brain metabolism as a pre-clinical therapeutic. Importantly we have key pieces of preliminarydata for LD brain-impacted GSDs and AD from both mouse models and patient tissue. The increasedstability freedom and flexibility provided by the R35 would allow us to make seminal discoveries in brainmetabolism and define the role of PGBs in multiple diseases while carrying out key steps in the development oftherapies and biomarker development.!

project_terms:
Adolescence;Affect;Alzheimer's Disease;Ataxia;Behavior;Biochemical;Biology;Brain;Carbohydrates;Cell physiology;Cellular Metabolic Process;Cessation of life;Cognition;Complex;Comprehension;Consumption;Data;Diagnosis;Disease;Disease Progression;Event;Excision;Foundations;Freedom;Funding;Glucose;Glycogen;Glycogen Storage Disease;Homeostasis;Intractable Epilepsy;Knowledge;Lafora Disease;Memory;Metabolic;Metabolism;Modality;Modeling;Molecular;Mutation;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Patients;Play;Research;Role;Seminal;Signal Transduction;Symptoms;Therapeutic;Tissues;Translating;Vegetative States;Work;biomarker development;brain metabolism;driving force;flexibility;glucose metabolism;glycogen metabolism;human disease;insight;mouse model;nervous system disorder;novel therapeutics;polyglucosan;pre-clinical;sex;therapy development;tool

public_health_relevance:
The focus of our work is to determine how mutations carbohydrate aggregates impact multiple neurologicaldiseases and to translate this knowledge into therapies. Our proposal is built on our past discoveries and usescomplementary approaches to advance our understanding of the intertwined events of cell metabolismneurodegeneration and neurological disease. Completion of this work will yield a better comprehension ofthese complex events and will allow us to translate our insights into disease mechanisms diagnoses andtreatments.


application_id: 10610330
project_number: 5R01AI153275-04
administering_ic: NIAID
award_notice_date: 2023-04-13
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 153275
program_official: DUPUY, LESLEY CONRAD
project_start_date: 2020-05-21
project_end_date: 2025-04-30
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 10849785
contact_pi: SOKOLOSKI, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Comprehensive Definition of the Critical Role(s) of the Alphaviral Noncapped Genomic RNAs to Infection and Pathogenesis

project_abstract:
Alphaviruses are vector-borne pathogens that have proven capable of causing significant outbreaks of clinical disease. Currently there is an absolute lack of safe and approved antiviral therapies / vaccines. Thus research which defines the molecular basis of infection is essential and critically important to not only understanding alphaviral pathogenesis but to the development of innovative antiviral strategies. The overarching research objective of this proposal is to define the mechanism by which a novel alphavirus RNA species impacts infection and pathogenesis. The scientific premise and rationale supporting this objective are based upon a wealth of preliminary evidence which indicates that the production of noncapped genomic RNAs (ncgRNAs) is essential for alphaviral infection as evidenced by studies involving Sindbis virus (SINV) and Ross River virus. Nonetheless the extent to which the ncgRNAs impact viral infection is unknown and represents a critical gap in the knowledge base. Thus we propose the following specific aims- i) To determine the mechanism with which the noncapped genomic vRNAs impact infection and ii) To define the impact of the noncapped genomic vRNAs on viral pathogenesis. To accomplish the first aim we will undertake an exhaustive molecular analysis of SINV infection to determine the mechanism by which the ncgRNAs effect viral infection. Specifically we will determine whether or not ncgRNA function is linked to its translatability via a novel IRES-based approach. In addition we will determine which viral process is negatively affected by ncgRNA reduction; and determine the molecular interactions required for ncgRNA function. The second aim uses a combinatorial approach of in vivo studies and IFN-competent tissue culture models to comprehensively define the contribution of the ncgRNAs to SINV pathogenesis. Briefly the contribution of the ncgRNAs to the induction of a detrimental neuroinflammatory response will be evaluated in depth histologically and at the transcriptomic and proteomic levels. Moreover the consequences of increasing and decreasing alphaviral capping efficiency on the host innate immune response will also be defined in highly tractable tissue culture models of infection. The proposed work is highly significant in that it seeks to characterize and define the molecular importance of a novel viral RNA species. Moreover the proposed research is conceptually and technically innovative as state-of-the-art techniques approaches and models of infection are used to delineate the contributions of the novel ncgRNA species to molecular infection and pathogenesis. The successful completion of this work will fundamentally expand the knowledgebase by eliminating the critical gap in understanding described above; in addition the proposed research has a high likelihood of leading to the identification of novel antiviral strategies.

project_terms:
Address;Affect;Alphavirus;Alphavirus Infections;Antiviral Agents;Antiviral Therapy;Arthritis;Attenuated;Binding;Biology;Brain;Cell Line;Cessation of life;Chikungunya virus;Clinical;Cytoplasm;Defect;Development;Disease;Disease Outbreaks;Environment;Event;Failure;Gene Expression;Genomics;Growth;Histologic;Immune response;Impairment;In Vitro;Individual;Infection;Innate Immune Response;Integration Host Factors;Interferons;Internal Ribosome Entry Site;Invertebrates;Joints;Kinetics;Link;Modeling;Molecular;Molecular Analysis;Morbidity - disease rate;Nature;Nucleocapsid;Pathogenesis;Pathologic;Process;Production;Proteins;Proteomics;Public Health;RNA;RNA chemical synthesis;Reporting;Research;Role;Ross river virus;Sindbis Virus;Structure;Techniques;Testing;Therapeutic;Vaccines;Venezuelan Equine Encephalitis Virus;Viral;Viral Encephalitis;Viral Genes;Viral Pathogenesis;Virion;Virulence;Virus Diseases;Virus Replication;Wild Type Mouse;Work;combinatorial;defined contribution;effective therapy;expectation;genomic RNA;improved;in vivo;innovation;knowledge base;knowledgebase;mortality;mutant;negative affect;neuroinflammation;novel;particle;pathogen;response;tissue culture;tissue/cell culture;transcriptomics;vaccine strategy;vector-borne pathogen;viral RNA

public_health_relevance:
Alphaviruses such as Sindbis virus Chikungunya virus and Venezuelan Equine Encephalitis virus are significant threats to public health. Alphaviral infection in otherwise healthy individuals may result in severe disease- including persistent severe multi-joint arthritis viral encephalitis and death. This proposal seeks to characterize the importance of a novel noncapped viral RNA in regards to the establishment of viral infection and pathogenesis for the purpose of improving the understanding of alphaviral biology to identify innovative therapeutic strategies.


application_id: 10610036
project_number: 2P30ES026529-06A1
project_title: Center for Appalachian Research in Environmental Sciences-Pilot Project Program (PPP)
administering_ic: NIEHS
award_notice_date: 2023-06-02
opportunity_number: RFA-ES-20-006
application_type: 2
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 8173
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY  Pilot Project ProgramThe University of Kentucky Center for Appalachian Research and Environmental Science (UK-CARES) PilotProject Program (PPP) aims to support highly innovative and collaborative research studies that will enhancethe ability to identify and capitalize on the Centers science themes and build community-academicpartnerships across the translational spectrum. This goal will be accomplished by providing pilot funds alongwith guidance and support for innovative time-sensitive preliminary studies and community projects thatimprove our understanding of environmental exposures human biology and disease. Specifically the aims ofthe PPP are to 1) support new opportunities for innovative collaborative environmental health research; 2)enhance interactions and expand the critical mass of investigators with expertise and experience in multi-disciplinary translational environmental health research at UK and in Appalachian communities; 3) provideguidance and support to ensure the success of UK-CARES Pilot Projects; and 4) evaluate utilizationefficiency quality and impact of the PPP. Strong institutional support of the PPP from UK is a hallmark of ourproposal. In fact UK entities will provide matching funds representing 37% of the total funds allocated for pilotprojects. The PPP will provide three general categories of pilot research funding opportunities consistent withthe science themes and strategic vision of UK-CARES. First Pilot grants will generate new preliminary dataand support (a) established Center members to catalyze new research opportunities consistent with Centerscience themes; (b) non-member scientists to expand collaborations and bring new dimensions to the Center;and (c) creative early-stage investigators to establish competitive research programs. Second Communitygrants will provide direct support to community organizations with a UK faculty collaborator to address a priorityscience theme. Third Mini grants will foster rapid time-sensitive development of or access to new and noveltechnologies as well as community-engaged research. The PPP will communicate collaborate coordinateand create synergy across Center cores and programs to ensure that pilot-funded investigators receive theassistance they need to develop and carry out their pilot projects. The PPP will engage investigators andcommunity stakeholders both within UK-CARES and outside the Center as reviewers and grantees toaddress questions related to environmental pathways (e.g. water air) to exposures human biology and newcontaminants and emerging threats. The overall progress of the PPP and how effectively it has promotedenvironmental health research will be monitored through the existing tracking and evaluation component ofUKs Center for Clinical and Translational Science in coordination with the Administrative Core. Incorporatingpilot-funded faculty into the Center will have a major impact on expanding the ability of our Center to examineimportant questions related to emerging environmental health issues and novel technologies and to bolster thedevelopment of the next generation of environmental health scientists.

project_terms:
Address;Air;Appalachian Region;Award;Categories;Clinical;Clinical Sciences;Collaborations;Communication;Communities;Core Facility;Creativeness;Data;Development;Dimensions;Discipline;Disease;Emerging Technologies;Ensure;Environmental Exposure;Environmental Health;Environmental Science;Evaluation;Exposure to;Faculty;Fostering;Funding;Funding Opportunities;Goals;Grant;Health Sciences;Human Biology;IACUC;Institution;Institutional Review Boards;Investigation;Kentucky;Lead;Leadership;Legal patent;Manuscripts;Monitor;Pathway interactions;Pilot Projects;Publishing;Research;Research Personnel;Resources;Rural Appalachia;Science;Scientist;Strategic vision;Time;Translational Research;United States National Institutes of Health;Universities;Water;Work;clinical center;community building;community engaged research;community organizations;design;electronic data;experience;high risk;improved;innovation;meetings;member;multidisciplinary;new technology;next generation;novel;population based;pre-clinical;programs;research study;success;synergism;translational pipeline


application_id: 10610035
project_number: 2P30ES026529-06A1
project_title: Center for Appalachian Research in Environmental Sciences-Community Engagement Core (CEC)
administering_ic: NIEHS
award_notice_date: 2023-06-02
opportunity_number: RFA-ES-20-006
application_type: 2
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 8172
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY- Community Engagement Core (CEC)The University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES)Community Engagement Core (CEC) will grow maintain and enhance strong sustained multidirectionalcommunity-academic partnerships that 1) support meaningful community engagement; 2) build environmentalhealth literacy; 3) reduce environmental health risks; and 4) decrease health disparities in rural Appalachia.Decades of legacy mining and fracking operations as well as an aging water infrastructure have resulted inexposure to water and air contaminants which have led to community concerns about water and air quality aswell as emerging environmental health threats. The CEC will build on a strong foundation of successfulcommunity engagement and support environmental health science (EHS) by connecting investigators withcommunity partners to promote projects consistent with the three science themes of the Center(a) HealthImpacts of Waterborne Contaminants; (b) Health Impacts of Indoor & Outdoor Airborne Contaminants; and (c)Emerging Environmental Health Threats. The CEC will use an iterative multidirectional process that bringslocal knowledge into the Center leverages UK-CARES investigator strengths and institutional support reportsback research findings with at-risk communities and encourages solution-focused communication amongcommunity and organizational stakeholders. Specifically the aims of the CEC are to: 1) foster and cultivatemultidirectional community-academic partnerships engaged in UK-CARES research that is responsive toregional environmental health issues needs and concerns; 2) translate and disseminate EHS findings throughscience communication and advocacy training to foster clinical decision making and policy formation; and 3)strengthen partnerships with community and healthcare stakeholders in UK-CARES environmental healthresearch across the translational spectrum. First we will engage our Stakeholder Advisory Board members tooffer culturally appropriate insight that will inform and assist Center investigators in their research. The CECwill use formal (e.g. focus groups) and informal (e.g. listening sessions) means to engage in multi-directionaldialogue with community stakeholders to assess environmental health concerns. In turn the CEC will serve asa bridge to and from the community to facilitate community engagement in EHS that leverages the strengths ofUK-CARES and is responsive to community concerns. Second will provide training in effective sciencecommunication and advocacy with healthcare providers faculty and community stakeholders. We will build onour impactful science communication training curriculum to prepare scientists for effective multi-modaldissemination of findings including use of evidence-based advocacy skills with policymakers. Lastly we willcollaborate with the Integrated Health Sciences Facility Core to create tailored multi-modal report backapproaches to reach healthcare providers to promote clinical decision making related to how the environmentaffects health in the region and policymakers to promote policy formation that fosters environmental justice.

project_terms:
Address;Advocacy;Affect;Aging;Air;Analytical Chemistry;Appalachian Region;Attention;Back;Bacteria;Catchment Area;Chemicals;Chronic Disease;Chronic Obstructive Pulmonary Disease;Chronically Ill;Coal;Collaborations;Colorectal Cancer;Communication;Communication Programs;Communities;Community Healthcare;Core Facility;County;Diabetes Mellitus;Disease;Disinfection;Educational Curriculum;Ensure;Environment;Environmental Exposure;Environmental Health;Environmental Risk Factor;Environmental Science;Exposure to;Faculty;Floods;Focus Groups;Fostering;Foundations;Funding;Grant;Health;Health Personnel;Health Sciences;Healthcare;Infrastructure;Institution;Kentucky;Knowledge;Link;Malignant Neoplasms;Malignant neoplasm of lung;Metabolic Diseases;Mining;Names;Natural Disasters;Obesity;Particulate Matter;Pilot Projects;Policies;Policy Maker;Process;Public Health;Reduce health disparities;Reporting;Research;Research Methodology;Research Personnel;Resources;Risk;Rural Appalachia;Science;Scientist;System;Training;Translating;Trust;Universities;Water;Water Pollutants;Work;air contaminant;citizen science;clinical decision-making;community engaged research;community engagement;community organizations;environmental justice;evidence base;health assessment;health communication;health literacy;health science research;hydraulic fracturing;insight;investigator training;malignant breast neoplasm;member;multimodality;novel;operation;people of color;programs;skills;socioeconomic disadvantage;toxicant;translational pipeline;waterborne


application_id: 10610034
project_number: 2P30ES026529-06A1
administering_ic: NIEHS
award_notice_date: 2023-06-02
opportunity_number: RFA-ES-20-006
application_type: 2
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 8171
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
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_title:
Center for Appalachian Research in Environmental Sciences - Analytical Chemistry Core for Environmental Sciences (ACCESS)

project_abstract:
PROJECT SUMMARY- Analytical Chemistry Core for Environmental Sciences (ACCESS)The University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES)ACCESS will provide Center investigators with priority access to biological and environmental sample analysisusing state-of-the-science technologies services and instrumentation for studies related to the UK-CARESthree science themes: Health Impacts of Waterborne Contaminants (WATER); Health Impacts of Indoor andOutdoor Airborne Contaminants (AIR); and Emerging Environmental Health Threats (EMERGING THREATS).To optimize efficiency ACCESS uses the following two existing laboratory facilities to leverage resourcesavailable to these facilities and extend the capabilities ACCESS: the Environmental Chemistry and ToxicologyLaboratory (College of Agriculture Food and Environment) and the Small Molecule Mass Spectrometry Facility(College of Medicine) to measure organic chemical environmental pollutants trace-elements theirmetabolites and related molecules of interest to UK-CARES investigators. Effective use of these facilities byUK-CARES investigators will require both routine analysis and new method development and validation.Specifically Aim 1 of ACCESS is to provide measurements of panels of environmental chemicals. We willprovide technically robust methods for detection and quantification of a range of halogenated organics:polychlorinated biphenyls dioxins trihalomethanes and haloacetonitriles per- and poly- fluorinated alkylsubstances non-halogenated organics including flame-retardants environmental phenols and trace-elementsto support EHS research across the translational spectrum. Aim 2 is to develop or adapt novel methods tosupport ongoing needs of UK-CARES investigators. Methods will be developed de novo or adapted from theliterature. We will use our Thermo TSQ Altis Plus triple stage quadrupole mass spectrometer to develop andvalidate survey methods that can profile environmental chemicals in multiple classes using a single analyticalworkflow and use high-resolution MS methods employing our Thermo Exploris 240 orbitrap mass spectrometerfor untargeted profiling of environmental chemicals in relevant matrices. Techniques for spatial analysismicroanalysis and speciation analysis of trace-elements are refined for environmental health studies using ourAgilent 7900 ICP-MS and associated peripherals. Aim 3 is to work with administrative and data managementfunctions of the Center to enable robust fiscal oversight project management sample tracking and datareporting. We will work in tandem with the Integrated Health Sciences Facility Core and the AdministrativeCore to ensure that Center members receive priority access that the activities of ACCESS are aligned with theUK-CARES strategic vision of the three science themes and that services and outcomes are tracked throughthe online IHSFC Research Support Portal. ACCESS will provide reliable technically robust methods andservices while pursuing opportunities for innovation. Services provided by the core will support UK-CARESmembers efforts to make innovative contributions to environmental health science.

project_terms:
Address;Agriculture;Analytical Chemistry;Appalachian Region;Biological;Biological Monitoring;Chemicals;Clinical;Coal;Communities;Core Facility;County;Coupled;Data;Data Reporting;Dioxins;Disease;Disinfection;Ensure;Environment;Environmental Health;Environmental Pollutants;Environmental Science;Exposure to;Flame Retardants;Food;Funding;Gas Chromatography;Grant;Health;Health Sciences;High Pressure Liquid Chromatography;Individual;Inductively Coupled Plasma Mass Spectrometry;Industrialization;Infrastructure;Institution;Kentucky;Laboratories;Liquid Chromatography;Literature;Mass Spectrum Analysis;Measurement;Measures;Medicine;Methods;Monitor;Office of Administrative Management;Organic Chemicals;Outcome;Particulate Matter;Peripheral;Phenols;Polychlorinated Biphenyls;Process;Recovery;Research;Research Personnel;Research Project Grants;Research Support;Resolution;Resources;Rural Appalachia;Sampling;Science;Services;Strategic vision;Superfund;Survey Methodology;Technical Expertise;Techniques;Technology;Trace Elements;Translational Research;Trihalomethanes;Universities;Validation;Water Pollutants;Work;air contaminant;analytical method;base;college;community engaged research;community engagement;cost;cost effective;data management;detection method;drinking;environmental chemical;environmental chemistry;environmental toxicology;faculty support;halogenation;health science research;innovation;instrument;instrumentation;interest;laboratory facility;mass spectrometer;member;method development;novel;operation;small molecule;toxicant;translational pipeline;waterborne


application_id: 10610033
project_number: 2P30ES026529-06A1
administering_ic: NIEHS
award_notice_date: 2023-06-02
opportunity_number: RFA-ES-20-006
application_type: 2
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 8170
contact_pi_person_id: 6457660
contact_pi: BAUER, JOHN ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Center for Appalachian Research in Environmental Sciences-Integrated Health Sciences Facility Core (IHSFC)

project_abstract:
PROJECT SUMMARY  Integrative Health Sciences Facility CoreThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES)Integrated Health Sciences Facility Core (IHSFC) will facilitate translational research in environmental healthscience (EHS) ranging from basic clinical exposure assessment and communication research to supportand sustain collaborative multidisciplinary connections and academic-community partnerships. A key elementof the IHSFC is the formation of four EHS translational research hubs: 1-Molecular Toxicology; 2-ClinicalResearch and Data Sciences; 3-Community Exposure Assessment; and 4-Environmental HealthCommunication. Each hub will provide content expertise support and access to EHS methodologies andservices and facilitate project development across the translational research spectrum. The hub structure willenhance disciplinary diversity within the IHSFC and support campus-wide integration and cross-Centercommunication. The IHSFC will build on our record of early success refining our operational model andtargeting new partnerships among Center members while providing expert consultation translational researchsupport and team building strategies across the Centers re-aligned science themes: (a) Health Impacts ofWaterborne Contaminants (WATER); (b) Health Impacts of Indoor and Outdoor Airborne Contaminants (AIR);and (c) Emerging Environmental Health Threats (EMERGING THREATS). Specifically the IHSFC aims to 1)provide access to EHS research services 2) deliver EHS project support and 3) enhance translationalresearch partnerships. First the IHSFC Research Support Portal will direct the flow of investigator requests toIHSFC staff and relevant hub leaders who will link Center members to the appropriate cores (e.g. AnalyticalChemistry Core for Environmental Sciences and Community Engagement Core) and resources (e.g. datamanagement and statistical analysis) for project facilitation. The Portal will facilitate coordination prioritizationtracking and use of facility core services Center-wide. Second IHSFC hub leaders will provide EHS bestpractices workshops and training sessions in collaboration with the Career Development Program. Third wewill establish Rapid Response Teams comprised of the hub leaders and other Center members to promoteresearch translation and partnerships enabling prompt responses to community identified EHS threats andnew exposures. The IHSFC will fulfill the need for a centralized and accessible core that supportsmultidirectional EHS research activities within the Center across UK campus with community investigatorsand with other EHS Core Centers providing timely consultation and support for an impactful portfolio of EHSresearch projects while fostering a highly collaborative institutional EHS culture. The IHSFC will expandexpertise and services enhancing the cores central role in daily UK-CARES operations and provide theinfrastructure to facilitate the progression and expansion of EHS from fundamental questions into testingclinical practice and public health impact to improve public health and clinical practice in environmental health.

project_terms:
Address;Analytical Chemistry;Appalachian Region;Area;Back;Categories;Clinical;Clinical Data;Clinical Research;Clinical Sciences;Collaborations;Communication;Communication Research;Communities;Consultations;Core Facility;Data;Data Analyses;Data Science;Development;Dimensions;Disasters;Educational workshop;Elements;Environmental Exposure;Environmental Health;Environmental Science;Evaluation;Fostering;Funding;Goals;Growth;Health;Health Sciences;Human;Infrastructure;Institution;Institutional Review Boards;Integrative Medicine;Kentucky;Laboratories;Leadership;Link;Methodology;Methods;Modeling;Molecular Toxicology;National Institute of Environmental Health Sciences;Output;Patients;Peer Review;Pilot Projects;Policy Maker;Process;Program Development;Public Health;Public Health Practice;Publishing;Reporting;Research;Research Activity;Research Methodology;Research Personnel;Research Project Grants;Research Support;Resources;Review Literature;Role;Sampling;Science;Scientist;Services;Statistical Data Interpretation;Strategic Planning;Structure;Testing;Toxicology;Training;Translational Research;Universities;Water;Work;biobank;career development;clinical practice;cohort;community building;community engagement;community partnership;data management;health assessment;health communication;health science research;health training;high risk;improved;innovation;meetings;member;multidisciplinary;novel;novel strategies;operation;prevent;repository;response;service coordination;success;translational health science;translational impact;translational pipeline;waterborne


application_id: 10610032
project_number: 2P30ES026529-06A1
project_title: Center for Appalachian Research in Environmental Sciences-Administrative Core
administering_ic: NIEHS
award_notice_date: 2023-06-02
opportunity_number: RFA-ES-20-006
application_type: 2
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS (P)]
subproject_number: 8169
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY  Administrative CoreThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES)Administrative Core will coordinate oversee and evaluate all programmatic and scientific activities and leadcross-disciplinary career development initiatives while providing and receiving support from the IntegratedHealth Sciences Facility Core the Analytical Chemistry Core for Environmental Sciences the CommunityEngagement Core the Pilot Project Program and our community partners. The Administrative Core leadershipis comprised of highly regarded senior scientists and research mentors who are well qualified to operate anEnvironmental Health Sciences Core Center (EHS CC) that is responsive to the concerns of people in ruralAppalachia and to advance EHS across the translational spectrum. The Administrative Core will activelycollaborate with all Center members community and academic promoting their research and involving them inCenter decision-making and strategic programmatic activities as well as engaging with other UK Centers andEHS CCs. The organizational structure of UK-CARES will allow for optimal multidirectional Center-Community-University communications and institutional support. Three Advisory Boards will inform our research provideadvice and support help us form and maintain robust community-academic partnerships and evaluateprogram progress: 1) a 12-member Stakeholder Advisory Board representing higher education environmentaljustice groups healthcare and public health in rural Appalachia; 2) an Internal Advisory Board comprised of 10high-level campus and community decision makers; and 3) a 4-member External Advisory Board of prominentnational leaders in EHS. The Administrative Core has four Aims to: 1) coordinate monitor and evaluate theCenters scientific and programmatic activities; financial oversight and regulatory compliance; productivity; andeffectiveness as intellectual needs change; 2) facilitate internal multidirectional communication and responsibleconduct of research; 3) facilitate external multidirectional communication; and 4) cultivate careers in EHS witha focus on underrepresented minority faculty. The Core will ensure effective internal and externalcommunications by directing monthly Executive Committee meetings; coordinating an Annual ScientificRetreat monthly scientific work groups with Center members and a seminar series; and partnering with keycommunity and state partners via social media our website and other scientific and professional venues. TheCores Career Development Program will recruit and support early-stage investigators (ESIs) to becomeindependent EHS researchers and facilitate established investigators to transition to an EHS research focusthrough maximizing the use of Center services cross-disciplinary activities and mentorship. CareerDevelopment Program funding will support independent investigators newly recruited to UK from outside UK-CARES or Center member ESIs with partial salary support. In the first cycle the Administrative Core hasgrown the Center as a recognizable entity in EHS and public health in rural Appalachia.

project_terms:
Administrator;Affect;Analytical Chemistry;Appalachian Region;Chronically Ill;Clinical;Collaborations;Communication;Communities;Community Outreach;Core Facility;Decision Making;Dedications;Discipline;Discipline of Nursing;Disparity;Educational workshop;Effectiveness;Ensure;Environment;Environmental Exposure;Environmental Health;Environmental Science;Evaluation;Event;Faculty;Funding;Goals;Grant;Health;Health Sciences;Healthcare;Institution;Kentucky;Lead;Leadership;Learning;Letters;Manuscripts;Mentors;Mentorship;Mission;Monitor;National Institute of Environmental Health Sciences;Outcome;Persons;Pilot Projects;Population;Procedures;Process;Productivity;Professional Organizations;Program Development;Public Health;Public Relations;Publishing;Qualifying;Reporting;Research;Research Personnel;Resource Sharing;Risk;Rural Appalachia;Science;Scientist;Senior Scientist;Series;Services;Strategic Planning;Superfund;Trace Elements;Training;Translating;Translational Research;Underrepresented Minority;Universities;Wages;career;career development;college;community center;community engagement;design;effectiveness evaluation;environmental justice;health science research;higher education;improved;meetings;member;operation;organic contaminant;organizational structure;programs;recruit;responsible research conduct;social media;socioeconomic disadvantage;success;translational pipeline;waterborne;web site;working group


application_id: 10610031
project_number: 2P30ES026529-06A1
project_title: Center for Appalachian Research in Environmental Sciences
administering_ic: NIEHS
award_notice_date: 2023-06-02
opportunity_number: RFA-ES-20-006
application_type: 2
activity_code: P30
ic: ES
serial_number: 026529
suffix: A1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2017-05-01
project_end_date: 2028-04-30
study_section: Environmental Health Sciences Review Committee[EHS (P)]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
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:
PROJECT SUMMARY  OverallThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) willbuild on our early successes capitalize on lessons learned and enhance our mission through a dual focus onbetter understanding exposure pathways and emerging environmental health threats and optimizing researchtranslation. Our Mission is to focus on exposure pathways to better match with community concerns and toemphasize research translation. Our Values reflect strong multidirectional community-academic partnershipswith a renewed commitment to meaningful processes procedures and policies that respect and promotediversity equity and inclusivity. Responsible conduct of research is at the foundation of our Centerappreciating the essential value of rigorous and reproducible multidisciplinary team science. Our goals are to(a) advance multidisciplinary environmental health science (EHS); (b) analyze organic contaminants and trace-elements; (c) cultivate early-stage stage and established investigators; (d) learn with and from the communityhelping to inform and translate our research; and (e) build science communication skills with investigators andcommunity partners to boost research translation. We will advance EHS across the translational spectrumaround three highly integrated science themes informed by residents of rural Appalachia: 1) Health Impacts ofWaterborne Contaminants (WATER); 2) Health Impacts of Indoor and Outdoor Airborne Contaminants (AIR);and 3) Emerging Environmental Health Threats (EMERGING THREATS). The central hypothesis is thatexposure to established contaminants via environmental exposure pathways (e.g. water air) and emergingenvironmental health threats combined with lifestyle and societal risk factors contributes to thedisproportionately high incidence of chronic diseases and health disparities in rural Appalachia. UK-CARESdraws on a strong and diverse base of EHS and community-engaged research to meet the needs ofcommunities in rural Appalachia. We will support and mentor investigators so they can reach the translationalmilestones in research: (1) asking fundamental questions; (2) applying and synthesizing; (3) implementing andadjusting; (4) moving ideas to practice; and (5) creating impact. In short UK-CARES will leverage its resourcesto enhance EHS at UK while also reducing health risks and disparities in rural Appalachia. An IntegratedHealth Sciences Facility Core Analytical Chemistry Core for Environmental Sciences and CommunityEngagement Core are integral to this effort as these cores will provide dedicated support in analyticalchemistry trace-elements analysis biospecimen management and bioinformatics and bridge Center andcommunity priorities. The Pilot Project Program supports developing research and new scientific directionsadvancing the careers of scientists interested in tackling challenging environmental health questions. UK-CARES will positively impact rural Appalachia through collaborative EHS designed to generate anddisseminate new knowledge and translate research to inform clinical decision making and policy development.

project_terms:
Acceleration;Address;Affect;Air;Air Pollution;Analytical Chemistry;Appalachian Region;Arsenic;Asthma;Bioinformatics;COVID-19 surveillance;Career Mobility;Chemicals;Chromium;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical Data;Clinical Research;Coal Mining;Colorectal Cancer;Communication;Communities;Community Outreach;Complex;Core Facility;Data Science;Dedications;Diabetes Mellitus;Discipline;Disparity;Dissemination and Implementation;Environmental Exposure;Environmental Health;Environmental Impact;Environmental Pollutants;Environmental Science;Exposure to;Faculty;Fostering;Foundations;Funding;Geology;Goals;Grant;Health;Health Promotion;Health Sciences;Heart;Heart Diseases;Incidence;Infrastructure;Joints;Kentucky;Knowledge;Lead;Learning;Life Style;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Medically Underserved Area;Mentors;Mentorship;Mission;Molecular Toxicology;Natural Gas;Nickel;Obesity;Oils;Particulate;Pilot Projects;Policies;Policy Developments;Population;Procedures;Process;Public Health;Radon;Reproducibility;Research;Research Personnel;Research Project Grants;Resources;Risk;Risk Factors;Rural Appalachia;Science;Scientist;Services;Superfund;Trace Elements;Training;Translating;Translational Research;Universities;Water;Water Pollutants;air contaminant;base;career;career development;citizen science;clinical decision-making;community engaged research;community engagement;design;disease disparity;environmental justice;equity diversity and inclusion;experience;exposure pathway;health assessment;health communication;health disparity;health equity;health science research;improved;innovation;interest;member;multidisciplinary;novel;organic contaminant;outreach;population health;programs;research facility;research study;responsible research conduct;rural dwellers;skills;socioeconomic disadvantage;success;synergism;tobacco smoke exposure;translational pipeline;wastewater surveillance;water quality;waterborne

public_health_relevance:
PROJECT NARRATIVE  OverallThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) willenhance programmatic and scientific capacity to facilitate innovative discovery and new understandings ofenvironmental exposure pathways of concern to our community (e.g. water air emerging threats). Furtherthe Center will foster career development of environmental health scientists interested in tackling challengingenvironmental health questions facing rural Appalachia. UK-CARES will achieve these goals by providingadvanced infrastructure and expertise cross-disciplinary training and mentorship and multidirectionalcommunity-academic partnerships to reduce health risks and health disparities in rural Appalachia.


application_id: 10609965
project_number: 4R01NS118558-02
project_title: Inflammatory contributions of astrocytic RelA in comorbid VCID/AD
administering_ic: NINDS
award_notice_date: 2024-09-11
opportunity_number: PAR-19-070
application_type: 4
activity_code: R01
ic: NS
serial_number: 118558
program_official: YIN, XILING
project_start_date: 2020-09-15
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1-BDCN-W(91)S]
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:
PROJECT SUMMARY/ABSTRACTMultiple lines of evidence in both humans and animal models suggest that neuroinflammation mediated viareactive gliosis plays a critical role associated with the initiation and progression of vascular contributions tocognitive impairment and dementia (VCID) and Alzheimers disease (AD) potentially suggesting convergentpathophysiological mechanisms. In particular several of these neuroinflammatory hallmarks in comorbidVCID/AD animal models have been linked with the dysfunctional responses of reactive astrocytes. In thehealthy brain it is well known that astrocytes play a critical role in maintaining a variety of homeostaticmechanisms. However as a response to injury or disease astrocytes are able to rapidly respond in ageneralized description referred as astrogliosis with a variety of neuroinflammatory modalities which recentevidence suggests may cause dysfunctional responses of neurons. Contemporary work has demonstrated acritical component to these dystrophic neuroinflammatory response of astrocytes is their utilization of canonicalNFkB (RelA) signaling pathway. However relatively little is known regarding the role of RelA in astrocytesexposed to the co-morbid degenerative milieu in VCID/AD representing a critical knowledge gap for the field.Our overarching hypothesis for this proposal is that astrocytic RelA represents a convergentinflammatory mechanism driving dysfunctional sequelae in the comorbid VCID/AD milieu. This proposalwill examine three specific aims to determine how RelA utilization by astrocytes shapes both intrinsic and non-cell autonomous dysfunctional responses to the comorbid VCID/AD degenerative environment: 1. Determine the capacity of astrocytic-RelA in propagating inflammatory phenotypes of microglia and astrocytes in comorbid VCID/AD. 2. Determine the role of astrocytic-RelA in driving cerebrovascular dysfunction in comorbid VCID/AD. 3. Determine if synaptic and cognitive dysfunction in VCID/AD is linked with RelA expression in astrocytes.

project_terms:
Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid beta-Protein;Animal Disease Models;Animal Model;Astrocytes;Automobile Driving;Blood Vessels;Brain;Cells;Cerebrovascular Circulation;Cerebrovascular Disorders;Coupling;Data;Degenerative Disorder;Dementia;Deposition;Development;Disease;Environment;Excision;Exposure to;FDA approved;Functional disorder;Future;Gliosis;Healthcare;Human;Impaired cognition;Individual;Inflammatory;Inflammatory Response;Ischemia;Knowledge;Label;Lead;Link;Mediating;Medical;Microglia;Modality;Modeling;Multiple Sclerosis;NF-kappa B;Neuroglia;Neurological outcome;Neuronal Dysfunction;Neurons;Pathologic;Pathology;Pathway interactions;Phenotype;Play;Population;Publishing;Recording of previous events;Recovery of Function;Research;Risk;Role;Senile Plaques;Shapes;Signal Pathway;Signal Transduction;Spinal cord injury;Synapses;Testing;Tissues;Work;abeta deposition;aging population;astrogliosis;blood-brain barrier permeabilization;cerebrovascular;comorbidity;conditional knockout;disease model;human model;innovation;neuroinflammation;new therapeutic target;novel;response;response to injury;restraint;therapeutic target;vascular cognitive impairment and dementia;vascular contributions;vascular injury;vascular risk factor

public_health_relevance:
PROJECT NARRATIVEGrowing evidence suggests that pure Alzheimers disease is rare among the human population butstrikingly a significant proportion of individuals with Alzheimers present with vascular comorbidities intandem with plaque deposition. Both Alzheimers and VCID are a major unment medical need withno FDA approved therapy. Defining the role of abberant astrocyte inflammatory response in theseconditions and whether RelA is a factor in these responses will enable new lines of development forfuture therapeutic targeting of these pathways to either restrain or enhance critical facets of astrocyteresponse to the comorbid disease milieu.


application_id: 10609292
project_number: 3P40OD019794-08S3
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2022-07-30
opportunity_number: PA-20-272
application_type: 3
activity_code: P40
ic: OD
serial_number: 019794
suffix: S3
program_official: CONTRERAS, MIGUEL A
project_start_date: 2022-07-01
project_end_date: 2023-02-28
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Ambystoma Genetic Stock Center (AGSC) is a P40 Research Resource that distributeslaboratory axolotls (Ambystoma mexicanum) to researchers and educators nationally andinternationally. The AGSC is currently working on a project to develop a reproducible protocolfor cryopreserving axolotl sperm which is needed to efficiently manage axolotl stocks within theAGSC and the broader axolotl community. Early results from this project found that axolotlspermatids are viable for only a short time after they are packaged into structures calledspermatophores. This presents a challenge to develop a sperm cryopreservation protocolbecause there is a narrow window of time within which spermatophores can be harvested toobtain viable sperm. Additionally spermatophores were found to be laid by males at varioustimes of the day more often at night and not during the workday. Temporal parameters forcollecting spermatophores with viable sperm have not been defined because the matingprocess has never been rigorously monitored to know when spermatophores are deposited.Until these parameters are defined it will not be possible to collect large numbers of viablespermatophores from which to develop and optimize methods for cryopreservation. There iscritical need to develop a standard protocol for collecting spermatophores with viable sperm.There is also critical need to optimize and gain capacity for sperm freezing and thawing at theAGSC and to integrate in vitro fertilization into the workflow. To address these needs theAGSC will hire a full-time employee with previous experience in cryopreservation and axolotlbiology. The new employee will work with undergraduate student workers to monitor axolotlcourtship during the day and night for the purpose of recording behavioral data and collectingspermatophores. Spermatophores will be frozen and thawed using reagents and conditionsrecommended by the Aquatic Germplasm and Genetic Resources Center (AGGRC) at theLouisiana State University Agricultural Center and experiments will be performed to assaysperm viability and in vitro fertilization success. Protocols arising from the proposed work will bemade publicly available. This administrative supplement will accelerate progress in developingan axolotl sperm cryopreservation protocol and building AGSC capacity to manage germplasmfor the axolotl community..

project_terms:
Address;Administrative Supplement;Ambystoma;Ambystoma mexicanum;Behavioral;Biological;Biological Assay;Biology;Collection;Communities;Courtship;Cryopreservation;Culture Media;Data;Deposition;Derivation procedure;Disease;Embryonic Development;Employee;Female;Fertilization;Fertilization in Vitro;Freezing;Genetic;Harvest;Health;Human;Human Resources;Ice;International;Laboratories;Louisiana;Methods;Modeling;Monitor;Organ Model;Partner in relationship;Process;Protocols documentation;Reagent;Reproducibility;Research;Research Personnel;Resources;Sampling;Spermatids;Spermatogonia;Structure;Time;Training;Translating;Universities;Vas deferens structure;Work;agricultural center;experience;experimental study;genetic resource;male;organ regeneration;repository;sperm cell;sperm cryopreservation;sperm quality;sperm viability;success;tissue repair;undergraduate student


application_id: 10609225
project_number: 1R13AG081016-01
project_title: Dysphagia: In Search of a Unified Definition for the Aging Population
administering_ic: NIA
award_notice_date: 2022-12-07
opportunity_number: PA-21-151
application_type: 1
activity_code: R13
ic: AG
serial_number: 081016
program_official: ELDADAH, BASIL A
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;Persons;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;aged;aging population;career;cost;diagnostic accuracy;evidence base;experience;falls;frailty;health care settings;improved;interest;lectures;medical specialties;member;minority scientist;multidisciplinary;nutrition;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: 10608931
project_number: 5K22CA258678-02
project_title: Admixture mapping of mosaic copy number alterations for identification of cancer drivers
administering_ic: NCI
award_notice_date: 2023-04-13
opportunity_number: PAR-18-467
application_type: 5
activity_code: K22
ic: CA
serial_number: 258678
program_official: JAKOWLEW, SONIA B
project_start_date: 2022-04-15
project_end_date: 2025-03-31
study_section: ZCA1-RTRB-R(J1)
contact_pi_person_id: 12387511
contact_pi: JAKUBEK SWARTZLANDER, YASMINKA ALEKSANDRA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTBackground: Somatic mosaicism arises due to the clonal expansion of a cell with an acquired mutation whichleads to genetically distinct sub-populations of cells in an organism derived from a single zygote. As a cloneproliferates its subclones can accumulate further molecular changes that seed cancer. A better understandingof acquired point mutations and copy number changes in these clonal expansions can help elucidate theearliest stages of cancer development. Studies of tissues from healthy individuals have found that those withclonal mosaicism in blood specifically copy number alterations (CNAs) have a ~10-fold higher risk ofdeveloping hematological malignancies thus underscoring the translational potential of mosaicism studies forthe development of improved risk assessment and cancer prevention strategies. Research up to now hasmainly focused on persons of European ancestry. My own preliminary results show differences in the genomiclandscape of CNAs between individuals of African American or Latino ancestry when compared withEuropeans. Understanding these differences and the underlying molecular mechanisms is critical in order toinclude these still under-researched populations in translational mosaicism studies for early detection andprevention of hematological and potentially other cancers. Proposed Research: Aim 1 is to address the greatneed for comprehensive studies of mosaicism in American minority populations through a large-scale analysesof CNAs in African American and Latino whole genome sequencing (WGS) data sets. This approach willenable a robust comparison of mosaicism profiles across populations; WGS will allow for joint analysis ofCNAs and somatic point mutations to gain insights into mechanisms that underlie different rates and subtypesof hematological malignancies across populations. Aim 2 is to develop novel methods to combine CNA andhaplotype level ancestry data for detection of variants associated with increased mosaicism rates. I will usethese methods to identify genetic variants that are associated with mosaicism and with increased cancer risk inLatinos and African Americans. Candidate: I have led projects to discover and analyze acquired CNAs inthousands of non-malignant tissues  first of their kind studies for pathologically normal and premalignanttissues  as well as in cancer tissues that complement these. This expertise and my established track record inthe development of computational methods for human/cancer genomics will ensure the successful completionof these aims. As larger volumes of normal tissues are molecularly profiled I will be able to extend methodsdeveloped in Aim 2 to additional normal tissue types and conduct integrative omics analyses. I will follow upthis work and the associated publications with an R01 proposal focused on translational applications of mosaicmutations in normal tissues as markers for cancer risk assessment early detection and prognosis. The K22award will be fundamental as I launch my independent investigator career offering management and grantwriting training helping to hone my skills as a mentor/PI and establish a long-term funded research program.

project_terms:
Address;Admixture;African;African American;African American population;African ancestry;American;Blood;Cell Fraction;Cells;Cessation of life;Clonal Expansion;Complement;Computing Methodologies;DNA Sequence Alteration;Data;Data Set;Development;Disease;Early Diagnosis;Ensure;European;European ancestry;Frequencies;Funding;Genes;Genetic;Genetic Population Study;Genetic Variation;Genetic study;Genomic Segment;Genomics;Goals;Grant;Haplotypes;Hematologic Neoplasms;Hematology;Human;Incidence;Individual;Inherited;Japanese;Japanese Population;Joints;K22 Award;Latino;Latino Population;Link;Loss of Heterozygosity;Malignant Neoplasms;Maps;Mentors;Methodology;Methods;Minority Groups;Modeling;Molecular;Molecular Profiling;Mosaicism;Mutation;Non-Malignant;Normal tissue morphology;Organism;Paint;Pathologic;Pattern;Persons;Point Mutation;Population;Population Genetics;Prevention;Prevention strategy;Prognosis;Proliferating;Publications;Recurrence;Reporting;Research;Research Personnel;Risk Assessment;Sampling;Screening for cancer;Single Nucleotide Polymorphism;Statistical Methods;Testing;Tissues;Training;Translations;Underrepresented Populations;Variant;Work;Writing;admixture mapping;ancestry analysis;cancer biomarkers;cancer genomics;cancer prevention;cancer risk;cancer seeding;career;detection method;follow-up;genetic variant;genome sequencing;genome wide association study;genomic variation;high risk;improved;innovation;insight;leukemia;method development;mosaic;mosaic analysis;mosaic variant;multi-ethnic;novel;premalignant;programs;skills;translational applications;translational potential;variant detection;whole genome;zygote

public_health_relevance:
PROJECT NARRATIVEClonal mosaicism in the blood has not been comprehensively investigated in African American and Latinopopulations. We will assess this biomarker of cancer risk in these populations through the development ofnovel methodology that will enhance integrative analysis of mosaic mutations germline variation and ancestry.A better understanding of mosaicism in these under-studied populations will allow for more targeted cancer riskassessment and early detection.


application_id: 10608722
project_number: 3P30AG072946-02S1
administering_ic: NIA
award_notice_date: 2022-08-24
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: AG
serial_number: 072946
suffix: S1
program_official: ELLIOTT, CERISE
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
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_title:
Portable and modular UDS Data Collection software to increase collaboration and engagement of Alzheimers Disease Research Center research software engineers

project_abstract:
PROJECT SUMMARYThis is an administrative supplement application to the University of Kentucky Alzheimers Disease ResearchCenter (UK-ADRC) submitted in response to NOT-OD-22-068 Administrative Supplements to SupportEnhancement of Software Tools for Open Science. We are requesting funds to support the Data Managementand Statistics (DMS) Core for data management activities relevant to NOT-OD-22-068. The UK-ADRC is anexperienced and collaborative Center whose principal mission is to provide an environment and core resourcesthat catalyze innovative research outreach education and clinical programs. Our overarching theme isTransitions from Normal to Late-Life Multi-Etiology Dementia. Our well-characterized longitudinal cohortand historically strong neuropathology program focused on normal aging preclinical disease states and earlycognitive transitions have been central to our success in defining early pathogenic mechanisms underlying thetransitions from normal cognitive aging to impairment. In addition these efforts have been a driving force in ourrecognition of the heterogeneity and multiple pathologies that characterize late-life dementia. Our strong andactive DMS Core is critical for integration of the ADRC Cores and is vital to the success of the UK-ADRC. Overthe years ADRC data collection has grown in scope scale and complexity to include not just collection ofUDS data but a multitude of parallel data collections covering clinical imaging biospecimens biomarker andbiometric data across the ADRC longitudinal cohort as well as other related research studies. The DMS Corehas developed a cloud-based .NET Core MVC web application to collect UDS data in a way that works withinan existing enterprise ecosystem with varied interconnected data sources and stores. We propose hereenhancements to the codebase that include refactoring the codebase for interoperability adding automatedtesting tools for sustainable community engagement and implementing containerization to facilitate a widerange of deployment environments.The specific aims of the supplement are:AIM 1: Increase software interoperability by refactoring current codebase to decouple the data access layerfrom the presentation layer.AIM 2: Promote ADRC developer community engagement by adding automated testing tools to preparecodebase for external contributions.AIM 3: Increase portability and ADRC adoption of software through containerization.These software tools will be extremely useful not just to the UK-ADRC but to the national ADRC community byenhancing the ability to integrate data within a robust large-scale research environment.

project_terms:
Administrative Supplement;Adoption;Alzheimer's Disease;Alzheimer's disease model;Biological Markers;Biometry;Clinical;Code;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Developments;Computer software;Data;Data Collection;Data Sources;Data Store;Database Management Systems;Decision Making;Dementia;Development;Disease;Ecosystem;Education;Elderly;Environment;Etiology;Funding;Genetic;Goals;Growth;Heterogeneity;Human Resources;Hybrids;Image;Impairment;Individual;Infrastructure;Investments;Kentucky;Libraries;Longitudinal Studies;Longitudinal cohort;Maintenance;Mission;Modeling;Modernization;Pathogenicity;Pathology;Research;Resources;Secure;Software Engineering;Software Tools;Technology;Testing;Universities;Work;cloud based;community center;community engagement;data access;data management;driving force;experience;flexibility;improved;infancy;innovation;interoperability;neuroimaging;neuropathology;normal aging;open data;open source;operation;outreach;portability;pre-clinical;programs;recruit;research study;response;software development;statistics;success;tool;web app

public_health_relevance:
NARRATIVEAs our understanding of Alzheimers disease and related disorders has grown so too has the need forpowerful flexible and shareable research software to support data collection and management in longitudinalstudies. The expertise of research software engineers is needed to create these tools and moreover to createthem in such a way that they are readily usable and shareable to other research teams. The tools developed inthis project will not only improve operations at the University of Kentucky Alzheimers Disease ResearchCenter (ADRC) but also will be a resource to the national ADRC community.


application_id: 10608185
project_number: 5P20GM113226-08
project_title: Project 3 - Ming Song
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2024-03-31
study_section: ZGM1-RCB-3
subproject_number: 6813
contact_pi_person_id: 10972280
contact_pi: SONG, MING
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Title: Metabolic effect of fructose in intestine induces gut microbiota dysbiosis Abstract. Emerging evidence has demonstrated that gut microbiota dysbiosis plays a causative role in the development of obesity type 2 diabetes and NAFLD. Gut physiologic hypoxia is key to maintaining a balanced gut microbiota and gut barrier function. Disturbance of gut physiologic hypoxia namely oxygenation results in gut microbiota dysbiosis. Our preliminary studies have shown that chronic feeding with either fructose or glucose induces gut microbiota dysbiosis in a similar manner in rats and mice. Moreover both daily gavage and chronic feeding with fructose or glucose results in intestinal oxygenation as shown by HIF-1 alpha reporter (ODD-luc) mice and this effect is more robust with glucose. Given that fructose is preferentially metabolized under hypoxia and glucose can be rapidly converted to fructose via the polyol pathway the proposed studies will test the hypothesis that fructose metabolism in the intestine results in metabolic reprogramming which switches the host metabolic pathway from mitochondrial -oxidation to glycolysis and consumes less oxygen. This in turn leads to intestinal oxygenation subsequent inhibiting the growth of obligate anaerobic bacteria and facilitating the expansion of pathogenic bacteria. The hypothesis will be tested in three specific aims: Aim 1. Determine whether fructose induces metabolic reprogramming in intestinal epithelial cells and determine if this results in gut microbiota dysbiosis. We will test the hypothesis that fructose metabolism in the intestine results in metabolic reprogramming and leads to intestinal oxygenation which in turn results in gut microbiota dysbiosis. Aim 2. Determine whether modulation of glycolytic activity in intestinal epithelial cells alters gut microbiota composition. We hypothesize that genetic modulation of glycolytic activity via 6-phosphofructo-2-kinase/fructose-26- bisphosphatase (PFK2) in intestinal epithelial cells results in altered oxygen consumption rate which in turn leads to the alteration of gut microbiota. Aim 3. Determine whether the metabolic effect of fructose in intestine contributes to the development of NAFLD. We will test the hypothesis that the metabolic effects of fructose in intestine on the development of NAFLD is mediated by gut microbiota dysbiosis.

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


application_id: 10608183
project_number: 5P20GM113226-08
project_title: Project 2 - Joshua Hood PhD
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1-RCB-3
subproject_number: 6812
contact_pi_person_id: 7170643
contact_pi: HOOD, JOSHUA L.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related mortality. It is inherentlydifficult to treat given the often-times co-occurrence of underlying cirrhosis which exacerbatesconventional chemotherapeutic toxicity. A sizeable number of patients remain non-responsive oruntreatable to cutting edge immune checkpoint inhibitor therapy necessitating the development of newor augmentative therapies. Given their role in removing foreign nanomaterials as participants of themononuclear phagocyte system coupled to their role in mediating HCC Kupffer cells (KCs) are an idealimmunotherapeutic target for small extracellular vesicles (sEVs). Small EVs are enriched in exosomenanovesicles. Our previous studies demonstrate that melanoma and lung cancer sEVs can directly inducea pro-tumor M2-like M phenotype or be modified with melittin peptide to induce anti-tumor M1-like Ms.Theoretically HCC sEVs might also be modified with melittin to induce anti-tumor M1 KC Ms. The bee venom peptide melittin is a powerful adjuvant for activating M1 immunity. The FDAapproves the use of bee venom injections for bee sting immunotherapy. In this proposal we hypothesizethat (i.) HCC sEVs can be converted into stable melittin adjuvant nanocarriers and (ii.) melittin-modifiedHCC sEVs associate with and induce KCs toward an anti-tumor M1-like phenotype in vivo. In aim 1 HCC sEVs will be converted into stable melittin nanocarriers. A fluorescent redbioluminescent 3D HepG2-Red-Fluc spheroid sEV source model will be developed. We will compare 2Dversus 3D HepG2-Red-Fluc sourced natural and melittinized sEVs for their ability to influence primary KCpolarization in vitro and determine differences in M1/M2 polarizing miRNA content using qRT-pcr. In aim 2 an orthotopic syngeneic model using bioluminescent Hepa1-6-Fluc-Neo cells inimmunocompetent C57L/6 mice will be used. Natural vs. melittinized Hepa1-6-Fluc-Neo sEVs will becompared to determine whether they influence KC M1/M2 polarization. We will also assess whether pre-treatment with melittinized Hepa1-6-Fluc-Neo sEVs inhibits subsequent orthotopic HCC growth. Studieswill be accomplished via utilization of all U of L Hepatobiology & Toxicology COBRE cores. The results of these studies will further our understanding of the relationship between natural HCCsEVs and KC tumor supportive functions and a therapeutic means to antagonize this pathogenicrelationship using melittin-modified KC sEVs will also be evaluated. Translationally sEV populationsmight be harvested from the blood of HCC patients modified into personalized immunotolerantnanomedicines using melittin or other agents and re-administered. The proposed studies also serve as aplatform to pursue pathologic and therapeutic sEV investigations concerning other M driven liverdiseases including hepatitis alcoholic and non-alcoholic-SH and liver fibrosis.

project_terms:
3-Dimensional;Adjuvant;Alcoholic steatohepatitis;Antigen Presentation;Attenuated;Autologous;BAY 54-9085;Bee Venoms;Bees;Biological Assay;Blood;Cancer Etiology;Cancer Vaccines;Cell Line;Cells;Centers of Research Excellence;Cirrhosis;Coupled;Development;Doctor of Philosophy;Effector Cell;Enzyme-Linked Immunosorbent Assay;FDA approved;Growth;Harvest;HepG2;Hepatitis;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune response;Immunity;Immunocompetent;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Impairment;In Vitro;Inflammatory;Injections;Investigation;Kupffer Cells;Liver;Liver Fibrosis;Liver diseases;Macrophage;Malignant Epithelial Cell;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;MicroRNAs;Modeling;Modernization;Mononuclear;Mus;Myeloid-derived suppressor cells;Natural Source;Neoplasm Metastasis;Nivolumab;Participant;Pathogenicity;Pathologic;Patients;Peptides;Phagocytes;Phenotype;Plasma;Population;Primary carcinoma of the liver cells;Process;Proteins;Quantitative Reverse Transcriptase PCR;Reporting;Research;Role;Source;Sting Injury;System;Testing;Therapeutic;Toxicology;Treatment Efficacy;Treatment-related toxicity;Tyrosine Kinase Inhibitor;Vaccine Adjuvant;arginase;cancer therapy;checkpoint therapy;exosome;extracellular vesicles;hepatocellular carcinoma cell line;in vivo;light scattering;melanoma;mortality;nanocarrier;nanomaterials;nanomedicine;nanovesicle;neoplastic cell;non-alcoholic;nonalcoholic steatohepatitis;polarized cell;problem drinker;recruit;response;tumor;tumor growth;zeta potential


application_id: 10608181
project_number: 5P20GM113226-08
project_title: Project 1 - Yan Li PhD
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 113226
project_start_date: 2016-06-10
project_end_date: 2024-03-31
study_section: ZGM1-RCB-3
subproject_number: 6811
contact_pi_person_id: 9527186
contact_pi: LI, YAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Non-alcoholic steatohepatitis (NASH) a potential precursor of hepatocellular carcinoma (HCC) currently has no FDA-approved treatment. Recent studies of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggest that endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic condi- tions including NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studied in clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities pro- gression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithe- lial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosis- cirrhosis-HCC sequence in patients. Recent studies indicated that FGF21 down-regulates the Th17-IL-17 axis suppresses NF-B but activates p53 pathways which are the critical anti-cancer mechanism(s). However there is no evidence demonstrating the specific anticancer effect of FGF21 on the NASH associated HCC. It is also unknown whether FGF21 could negatively affect the Th17-IL-17 axis and the carcinogenetic signaling to abolish the carcinogenetic transformation from NASH to HCC. Our central hypothesis is that FGF21 and FGF15/19 prevent NASH-HCC through in turn controlling lipolysis clearing excessive FFAs and inhibiting the IL- 17A signaling mediated inflammation and carcinogenesis. The hypothesis will be tested in the following Specific Aims. Aim 1: Investigate lipid metabolic disorder and IL-17A mediated inflammation during NASH-HCC transition. Establishing NASH-HCC mice to 1) determine FFA pools (plasma adipose liver and feces) and FA metabolites by metabolomics; 2) determine metabolic enzymes and components of IL-17A signaling by targeting proteomics. Aim 2: Evaluate the efficacy of FGF21 (LY2405319) and FGF19 (NGM282) against NASH-HCC transition. Administrating LY2405319/NGM282 in NASH-HCC mice to 1) evaluate NASH score HCC incidence hepatic injury and HCC lesion; 3) determine IL-17A-mediated inflammation/carcinogenesis and tumor-initiating cells. Aim 3: Explore the preventive mechanism(s) of FGF21/FGF15/19 against NASH-HCC transition. Repro- ducing NASH-HCC in FGF21 knockout (KO) FGF15KO and IL-17A mutation mice to investigate the feedback loop of FGF21/FGF15/19-IL-17A on molecular target(s) linking to carcinogenetic pathways. The importance of this proposal is: 1) to explore pharmacological use of FGF21/FGF15/19 against the NASH-HCC transition; and 2) to reveal therapeutic targets and mechanism(s) especially the IL-17 signaling linked carcinogenetic pathways during NASH-HCC transition.

project_terms:
Acceleration;Adipose tissue;Agonist;Attention;Biological Process;Cell Adhesion Molecules;Cells;Centers of Research Excellence;Chimeric Proteins;Cirrhosis;Development;Diabetes Mellitus;Disease Progression;Doctor of Philosophy;Early treatment;Endocrine;Enzymes;Epithelial Cells;FDA approved;FGF19 gene;FGF21 gene;Fatty Liver;Feces;Feedback;Fibroblast Growth Factor;Goals;Hepatocyte;Hormones;Human;IL17 gene;Incidence;Inflammation;Inflammatory Infiltrate;Insulin Resistance;Interleukins;Investigation;Knock-out;Knowledge;Lesion;Link;Lipids;Lipolysis;Liver;Malignant neoplasm of liver;Mediating;Metabolic;Metabolic Diseases;Metabolism;Molecular Target;Mus;Mutation;Neurons;Nonesterified Fatty Acids;Obesity;Orthologous Gene;Pathway interactions;Patients;Phase;Phase II Clinical Trials;Plasma;Population;Preventive;Primary carcinoma of the liver cells;Production;Prognosis;Proteomics;Publishing;Research;Risk Factors;Signal Transduction;TLR4 gene;TP53 gene;Testing;Toxicology;Variant;anti-cancer;blood glucose regulation;cancer stem cell;carcinogenesis;clinical application;efficacy evaluation;fatty acid metabolism;fibroblast growth factor 21;fibroblast growth factor receptor 4;glucose metabolism;high risk;ileum;insight;lipid metabolism;liver cancer model;liver injury;markov model;metabolomics;negative affect;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel strategies;novel therapeutic intervention;novel therapeutics;overexpression;pharmacologic;polypeptide;prevent;therapeutic target;therapeutically effective;tumor initiation;uptake


application_id: 10607620
project_number: 1RF1NS130834-01
project_title: Establishing the role of MMP9 in amyloid-immunotherapy-induced ARIA
administering_ic: NINDS
award_notice_date: 2022-09-14
opportunity_number: PA-20-185
application_type: 1
activity_code: RF1
ic: NS
serial_number: 130834
program_official: CORRIVEAU, RODERICK A
project_start_date: 2022-09-15
project_end_date: 2023-07-15
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAnti-Ab immunotherapies such as aducanamab donanemab and lecanemab are either approved or awaitingapproval for the treatment of Alzheimers disease (AD). While these agents hold great promise for the future ofdementia treatment their broad acceptance and use is hindered by significant concerns regarding safety. Almosttwo decades ago our group and others first described microhemorrhages in the brains of transgenic miceresulting from anti-Ab immunotherapy. Since then a substantial number of anti-Ab clinical trial subjects werealso affected by vasogenic edema. Re-defined as amyloid-related imaging abnormalities (ARIA) of the edema-(ARIA-E) or hemorrhagic- (ARIA-H) types ARIA events occurred in a third of aducanamab trial participants andremain a major concern surrounding the use of anti-Ab immunotherapy. We will test the novel hypothesis thatanti-Ab immunotherapy triggers ARIA through inflammatory sequelae involving activation of the matrixmetalloproteinase MMP9 degrading tight junction/basement membranes of vasculature inducing ARIA.Equipped with new technologies not available to us two decades ago (i.e. 7T MRI intravital two-photonimaging and single cell transcriptomics) we are poised to reveal mechanistic cause-and-effect relationshipsbetween A-immunotherapy MMP9 and ARIA-H using novel humanized A mouse models (i.e. hA andhASAA mice). We propose using these novel mouse models to evaluate cellular molecular and functionalchanges resulting from immunotherapy using the antibody 3D6; a murine monoclonal antibody with an epitopelike that of aducanamab. We propose three specific aims to test out hypothesis:Specific Aim 1: Define neurovascular and neuroimmune responses to Ab immunotherapy in the humanized-Abmouse model.Specific Aim 2: Determine the role of MMP9 in ARIA development resulting from Ab immunotherapy.Specific Aim 3: Evaluate the potential of MMP9 inhibition to eliminate ARIA.

project_terms:
Adverse event;Affect;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animals;Antibodies;Arctic Regions;Basement membrane;Biochemical;Blood Vessels;Brain;Cells;Cerebral Amyloid Angiopathy;Clinical Trials;Cognitive;Data;Dementia;Development;Edema;Epitopes;Event;Future;Gelatinase A;Hemorrhage;Histologic;Human;Image;Immunotherapy;Incidence;Inflammation;Inflammatory;Inflammatory Response;Laboratories;MMP2 gene;MMP9 gene;Magnetic Resonance Imaging;Marimastat;Matrix Metalloproteinases;Mediating;Microglia;Modeling;Molecular;Mus;Mutation;Neuroimmune;Participant;Pathologic;Play;Point Mutation;Role;Safety;Testing;Tight Junctions;Time;Transgenic Mice;Transgenic Model;cerebrovascular;cytokine;digital;in vivo imaging;inhibitor;mouse model;murine monoclonal antibody;neurovascular;neurovascular unit;new technology;novel;prevent;response;sex;tool;transcriptomics;two-photon;vascular cognitive impairment and dementia;vasogenic edema

public_health_relevance:
PROPOSAL NARRATIVEAnti-Ab immunotherapies such as aducanamab donanemab and lecanemab are either approved or awaitingapproval for the treatment of Alzheimers disease (AD). Despite lowering brain amyloid very effectively thesetherapies cause concerning adverse events called ARIA-E and ARIA-H which are changes associated with theblood vessels in the brain. The proposed studies examine a potential mechanism of ARIA and try to administeran adjunct therapy to prevent ARIA.


application_id: 10606561
project_number: 5R01CA259580-03
project_title: Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis
administering_ic: NCI
award_notice_date: 2023-03-31
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 259580
program_official: WATSON, JOANNA M
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
N-methyltransferase (NNMT) a key enzyme in the NAD+ salvage pathway with unclear functions isexpressed highly and specifically in basal-like breast cancer (BLBC). We found that NNMT is robustlyelevated when BLBC cells detach from a matrix and grow in suspension. Knockout (KO) of NNMT not onlyinhibits anchorage-independent growth in vitro but also suppresses tumor growth and metastasis in animalmodels. Using an unbiased CRISPR-Cas9 library screening we identified the FOXC1-CARM1 complex asbeing responsible for NNMT upregulation in BLBC. Importantly inhibition of NNMT by either KO or use of aninhibitor increases the proapoptotic effects mediated by chemo-drugs. We thus hypothesize that NNMT is acritical gatekeeper that maintains NAD+ homeostasis for BLBC progression and metastasis; this homeostasisboosts the cellular antioxidative defense machinery and prevents surges of ROS that BLBC cells encounterduring metastasis. The objective of this proposal is to (1) characterize NNMT function in regulating NAD+homeostasis in tumor progression and metastasis; (2) delineate the transcriptional regulation of NNMT bythe FOXC1-CARM1 complex; and (3) explore the clinical value of NNMT as a prognostic biomarker and adruggable target for BLBC. Guided by strong preliminary data we will test this hypothesis by pursuing threespecific aims: (1) to determine the critical roles of NNMT in BLBC; (2) to delineate NNMT transcription by theFOXC1-CARM1 complex; and (3) to define the roles of NNMT in the development of mammary gland andbreast cancer metastasis. Our proposal is innovative and significant because NNMT represents the achillesheel of BLBC; targeting this metabolic vulnerability offers an effective therapeutic option against metastaticBLBC.

project_terms:
Acetylation;Aging;Anchorage-Independent Growth;Animal Model;Apoptotic;Brain;Breast Cancer Cell;Breast cancer metastasis;CRISPR library;Cancer Biology;Cancer Cell Growth;Cell Nucleus;Cell model;Clinical;Code;Complex;Cytoplasm;Data;Development;Diabetes Mellitus;Diagnosis;Disease;Drug resistance;Endowment;Environment;Enzymes;Event;Exhibits;Extravasation;FOXC1 gene;Family;Gatekeeping;Genetic Transcription;Goals;Homeostasis;Human;In Vitro;Knock-out;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolic Pathway;Metabolism;Methyltransferase;Mitochondria;NADH;NADP;Neoplasm Metastasis;Niacinamide;Nicotinamide N-Methyltransferase;Nicotinamide adenine dinucleotide;Oncogenic;Oxidation-Reduction;Oxidative Stress;Pathologist;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;Prognosis;Prognostic Marker;Proliferating;Property;Reactive Oxygen Species;Regimen;Regulation;Rejuvenation;Research;Respiration;Rodent;Role;Shapes;Signal Pathway;Site;Specimen;Suspensions;Talents;Testing;Therapeutic;Transcriptional Regulation;Tumor Promotion;Up-Regulation;Vertebral column;Xenograft Model;arginine methyltransferase;breast cancer progression;coactivator-associated arginine methyltransferase 1;druggable target;experimental study;extracellular;in vivo;inhibitor;innovation;knock-down;malignant breast neoplasm;mammary gland development;metabolomics;mouse model;multidisciplinary;novel therapeutic intervention;oxidative damage;patient derived xenograft model;prevent;screening;stem-like cell;success;synergism;therapeutically effective;therapy resistant;transcription factor;tumor growth;tumor progression;uptake

public_health_relevance:
Nicotinamide N-methyltransferase (NNMT) a key enzyme in the NAD+ salvage pathway with unclear functionsis expressed highly and specifically in basal-like breast cancer (BLBC). We propose that NNMT which isregulated by the FOXC1-CARM1 complex is a critical gatekeeper to promote tumor progression metastasisand drug-resistance in BLBC. Our systematic and complementary analyses will lead to a major advance in theunderstanding of breast cancer biology and the development of novel therapeutic strategies for metastaticBLBC.


