# projects

application_id: 10665326
project_number: 1U54DA058256-01
project_title: AppalTRuST Biostatistics and Informatics Core
administering_ic: NIDA
award_notice_date: 2023-09-25
opportunity_number: RFA-OD-22-004
application_type: 1
activity_code: U54
ic: DA
serial_number: 058256
project_start_date: 2023-09-30
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 ICN-R (50)]
subproject_number: 7558
contact_pi_person_id: 8672812
contact_pi: RAYENS, MARY KAY
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:
ABSTRACT  BIOSTATISTICS AND INFORMATICS COREThe Biostatistics and Informatics Core (BIC) will serve as the AppalTRuST hub for study design and all data-related activities including data collection linkage harmonization analysis sharing and security. The core willinclude biostatistics and informatics experts and staff with extensive experience developing surveys managingand analyzing data and ensuring ongoing data security. Leveraging technology resources available throughUK Markey Cancer Center BIC will house all the biostatistical and informatics resources and expertise neededto support AppalTRuST projects and respond to additional needs arising from future TCORS priorities.BIC Aims include: (1) support the statistical planning and analysis data collection and data coordination needsof the AppalTRuST projects and cores; (2) collaborate with the Community Outreach & ParticipantEngagement (COPE) Core to develop data collection instruments harmonized across projects and datacollection timelines; (3) create a secure standardized and integrated AppalTRuST Data Warehouse; and (4)Provide easy-to-use tools to ensure stakeholder access to the AppalTRuST Data Warehouse and other Centerinformation.BIC will oversee and coordinate all aspects of research design as well as data collection harmonization andanalyses for all projects and pilots. Data files including structured semi-structured and unstructured dataalong with data dictionaries and other documentation will be managed centrally for projects pilots and coresin BIC. To facilitate the generalizability of inferential statistical analyses BIC will also develop survey weightsfor all participants recruited to the AppalTRuST cohort. In collaboration with COPE BIC will assist each projectand pilot with coordinated development of data collection instruments to support seamless data sharinglimiting response burden for participants enrolled in more than one project and promoting synergy throughoutthe Center.BIC will also deploy informatics portals and reporting mechanisms to make data widely accessible tostakeholders with users able to access only the data they have been authorized for commensurate with theirneeds. The informatics portal will include dashboards and analytical and query tools which can be customizedto coincide with the level of stakeholder data access needed. State-of-the-art analytical methods andinformation science will support and permeate all projects pilots and cores within AppalTRuST to ensure thatthe TCORS successfully meets its goal of investigating FDA CTP regulatory priorities in Appalachian Kentuckythrough collaboration education and pioneering regulatory science research.

project_terms:
Appalachian Region;Area;Authorization documentation;Biometry;Biostatistics Core;Cancer Center;Characteristics;Cities;Collaborations;Community Outreach;County;Data;Data Collection;Data Files;Data Mart;Data Security;Development;Documentation;Education;Ensure;Future;Goals;Informatics;Information Centers;Information Dissemination;Information Sciences;Kentucky;Measures;Participant;Patient Recruitments;PhenX Toolkit;Pilot Projects;Probability;Probability Samples;Reporting;Research;Research Design;Resource Informatics;Resources;Rural;Rural Community;Sampling;Science;Secure;Security;Staging;Standardization;Statistical Data Interpretation;Structure;Surveys;Technology;Weight;Work;analytical method;analytical tool;authority;career;cohort;dashboard;data access;data dictionary;data format;data infrastructure;data integration;data sharing;data standards;data warehouse;experience;instrument;participant enrollment;patient engagement;peri-urban;query tools;recruit;response;rural counties;socioeconomic disadvantage;structured data;synergism;timeline;tobacco products;tobacco regulatory science;tool;unstructured data;web site


application_id: 10665325
project_number: 1U54DA058256-01
project_title: AppalTRuST Community Outreach and Participant Engagement Core
administering_ic: NIDA
award_notice_date: 2023-09-25
opportunity_number: RFA-OD-22-004
application_type: 1
activity_code: U54
ic: DA
serial_number: 058256
project_start_date: 2023-09-30
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 ICN-R (50)]
subproject_number: 7557
contact_pi_person_id: 8310976
contact_pi: HULL, PAMELA CARMEN
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:
ABSTRACT  COMMUNITY OUTREACH AND PARTICIPANT ENGAGEMENT (COPE) COREThe Community Outreach and Participant Engagement (COPE) Core will recruit and retain the AppalTRuSTCohort of 2000 adults (ages 18+) in Appalachian Kentucky (KY) including a) an address-based probabilitysample (PS) of 1000 participants; and b) a quota-based non-probability sample (NPS) of 1000 participants.The Biostatistics and Informatics Core (BIC) will use statistical methods to combine them. Project 1 will use thefull AppalTRuST Cohort (N=2000) providing an adequate sample to capture estimates of tobacco usebehaviors (e.g. initiation switching transitions) over time among subpopulations of interest (e.g. youngadults tobacco users). Project 2 (n=308 ages 18-24) and Project 3 (n=473 tobacco users ages 21+) will drawfrom the Cohort. All projects pilots and TCORS partners will have access to the Cohort data through ourAppalTRuST Data Warehouse.Using established rural/urban taxonomies we selected heterogeneous counties that make up a ruralcatchment of 5 counties and a peri-urban (i.e. intermediate and smaller cities and towns) catchment of 3counties enabling projects to assess contextual- and individual-level effects of rurality on outcomes enhancinginnovation and our ability to inform more equitable FDA regulations. COPE Aims are to: (1) develop andimplement a culturally tailored community-engaged outreach campaign to promote participation in theAppalTRuST Cohort; (2) implement strategic recruitment and baseline data collection for the AppalTRuSTCohort (Project 1) and recruitment into the other projects and pilot studies; (3) implement strategic retentionstrategies and administer 6-month follow-up surveys; and (4) disseminate AppalTRuST research findings tothe community to sustain support and retention.COPE will co-design a community outreach campaign with two community advisory boards (one percatchment) with promotional materials tailored for Appalachian KY that are strategically disseminated to reachsubpopulations of interest (e.g. tobacco users). COPE will hire train and monitor local field staff to recruit andenroll participants into the AppalTRuST Cohort and manage completion of 6-month follow-up surveys. Cohortparticipants will complete 3 to 8 surveys depending on time of enrollment in Project 1. Multiple strategies willmaximize retention including our community outreach campaign and monthly contact between participantsand field staff. Our community dissemination plan will report back AppalTRuST study findings to sustaincommunity support and Cohort retention. The innovative approaches implemented by COPE will supportAppalTRuST in closing a critical knowledge gap in rural tobacco use behaviors marketing and impact analysisto help shape more equitable FDA regulations.

project_terms:
Address;Adult;Age;Appalachian Region;Back;Behavior;Biometry;Calibration;Cities;Communities;Community Outreach;County;Data;Data Collection;Devices;Electronic Mail;Electronics;Enrollment;Ensure;Equity;Fostering;Future;Goals;Heterogeneity;Home;Individual;Informatics;Interview;Kentucky;Knowledge;Libraries;Longitudinal Studies;Marketing;Mass Media;Monitor;Outcome;Participant;Pattern;Persons;Pilot Projects;Printing;Probability Samples;Regulation;Reporting;Research;Research Project Grants;Rural;Rural Appalachia;Rural Community;Rural Population;Sampling;Services;Shapes;Statistical Methods;Surveys;System;Taxonomy;Telephone;Text;Time;Tobacco use;Training;Trust;Update;Variant;Visit;Work;Writing;cohort;community engaged research;contextual factors;cost efficient;data resource;data warehouse;design;digital;eligible participant;follow-up;innovation;insight;interest;low health literacy;meetings;outreach;participant enrollment;participant retention;patient engagement;peri-urban;recruit;retention rate;rurality;social media;tobacco regulation;tobacco regulatory science;tobacco user;web site;young adult


application_id: 10665323
project_number: 1U54DA058256-01
project_title: AppalTRuST Administrative Core
administering_ic: NIDA
award_notice_date: 2023-09-25
opportunity_number: RFA-OD-22-004
application_type: 1
activity_code: U54
ic: DA
serial_number: 058256
project_start_date: 2023-09-30
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 ICN-R (50)]
subproject_number: 7555
contact_pi_person_id: 7602351
contact_pi: HIMELHOCH, SETH S
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT  ADMINISTRATIVE COREThe Administrative Core (Admin Core) will provide leadership and communications infrastructure strategicplanning and financial management to facilitate the work of all AppalTRuST components as well as advancecollaboration with the wider TCORS community. AppalTRuSTs overarching goal is to investigate the impact ofFederal Drug Administration Center for Tobacco Products regulatory policies in rural communities throughcollaboration education and pioneering tobacco regulatory science (TRS). Specifically the Admin Core willprovide scientific oversight by fostering shared knowledge and maximizing interactions to ensure scientific rigorand transparency. The Admin Core will lead an Executive Committee meeting twice per month with all ProjectPIs and Core Leaders. To ensure representation engagement and input from the study communities inAppalachian KY the Admin Core will collaborate with Community Outreach and Participant Engagement(COPE) Core to ensure our two Community Advisory Boards are fully engaged in Center decision-making. Toadvance educational collaboration and maximize interactions with the wider TCORS community and Federalpartners the Admin Core will work with the Career Enhancement Core (CEC) to sponsor a quarterlyAppalTRuST TRS Seminar Series to engage the TCORS community and share synergistic opportunitiesmethodologic advances and new research findings. The Admin Core will also collaborate with the CEC tosponsor an AppalTRuST Visiting Scholar Program to allow faculty and/or trainees from other TCORS toparticipate in a one-week in-depth learning experience in rural TRS. To provide quality control and evaluationacross projects and cores the Admin Core alongside the Biostatistics and Informatics Core (BIC) and COPEwill oversee a monthly quality control and evaluation meeting to foster seamless tracking and coordinating ofall activities recruitment participant flow data collection and data management. To provide administrativeoversight the Admin Core will guide and coordinate internal and external communications and coordinationfinancial planning and management as well as the research and grants administrative processes. An ExternalAdvisory Board made up of leading scientific experts will meet annually to provide critical counsel and ensurethe Center is meeting its stated goals. An Internal Advisory Board of key University scientific and administrativestakeholders will meet annually to provide counsel and advice and ensure AppalTRuST is able to effectivelyleverage UK and community resources to meet its goals. Impact: The Admin Core will provide the necessaryorganization and leadership to ensure an efficient collaborative infrastructure that will enhance synergiesacross AppalTRuST as well as advance collaboration with the wider TCORS community. Given thatAppalachia is a vulnerable rural region disproportionately impacted by socioeconomic disadvantage andtobacco use the Admin Core will lead AppalTRuST in closing a critical knowledge gap in rural tobacco usebehaviors marketing and impact analysis to help shape more equitable FDA regulations.

project_terms:
Address;Administrator;Appalachian Region;Applications Grants;Behavior;Behavioral;Biometry;Clinical;Collaborations;Communication;Communities;Community Outreach;Coordination and Collaboration;Counseling;Data Collection;Decision Making;Education;Electronic cigarette;Ensure;Environment;Equity;Evaluation;Faculty;Fostering;Funding;Goals;Grant;Informatics;Infrastructure;Kentucky;Knowledge;Lead;Leadership;Learning;Marketing;Medicine;Menthol;Methodology;Nicotine;Nicotine Dependence;Nursing Faculty;Occupational activity of managing finances;Oral;Paper;Participant;Pharmaceutical Preparations;Pilot Projects;Policies;Process;Publishing;Quality Control;Recommendation;Regulation;Reporting;Research;Research Personnel;Resources;Rural;Rural Community;Scholars Program;Science;Series;Shapes;Strategic Planning;Structure;Tobacco;Tobacco use;United States National Institutes of Health;Universities;Variant;Water;Work;Writing;career;cigarette smoking;college;combustible tobacco;data management;design;experience;improved;innovation;low nicotine content cigarette;meetings;novel;operation;patient engagement;polytobacco use;programs;recruit;rural area;rurality;scientific atmosphere;skills;socioeconomic disadvantage;synergism;tobacco products;tobacco regulatory science;visiting scholar


application_id: 10665322
project_number: 1U54DA058256-01
administering_ic: NIDA
award_notice_date: 2023-09-25
opportunity_number: RFA-OD-22-004
application_type: 1
activity_code: U54
ic: DA
serial_number: 058256
project_start_date: 2023-09-30
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 ICN-R (50)]
subproject_number: 7554
contact_pi_person_id: 10316536
contact_pi: KOFFARNUS, MIKHAIL NIKOLAAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-30
project_title:
AppalTRuST Project 3: Impact of proposed tobacco product rules in Appalachia on consumption and product switching with the Experimental Tobacco Marketplace

project_abstract:
ABSTRACT  Project 3Our overall goal reflecting AppalTRuSTs Integrative Theme of investigating the effects of regulatory changeson tobacco product use in Appalachian KY is to assess the impact of proposed tobacco product regulationsusing behavioral economic methods that we have developed and refined in past years to characterize theconsumption of tobacco products within the complex nicotine marketplace of Appalachian KY a diverse andunderserved rural region that would greatly benefit from focused tobacco regulatory science research. Thisproject primarily falls under the Regulatory Scientific Domain of Impact Analysis. In 2009 the Food and DrugAdministration (FDA) was granted authority to regulate tobacco products to benefit public health. In the yearssince the FDA has proposed potential regulatory actions that may benefit public health including regulatingthe maximum nicotine content in combustible cigarettes and restricting flavors of combusted and non-combusted tobacco products. Estimating the impact of any proposed regulatory action is complicated by theexistence of a complex tobacco marketplace containing multiple products that are economic substitutes for oneanother and the frequent introduction of new tobacco products by manufacturers. Furthermore whencompared to more urban non-Appalachian communities rural Appalachian communities often have 1) higherrates of tobacco product use overall 2) different use patterns that include more combusted tobacco productsand 3) different product availability in tobacco stores. It is therefore important to estimate any differential impactof proposed tobacco-product regulations in Appalachia. Using an Experimental Tobacco Marketplace (ETM)model where product availability is manipulated across groups and demand elasticity and substitution ismeasured across tobacco products we will estimate the impact of regulating 1) nicotine content of combustedcigarettes 2) menthol flavor restrictions in combustible cigarettes and 3) flavor additive restrictions in non-combusted nicotine/tobacco products including ENDS. Across two aims we will assess the impact of thesethree regulations within Appalachia (Aim 1) and the effect of rurality on impact of these proposed regulations inAppalachia (Aim 2).

project_terms:
Appalachian Region;Authorization documentation;Behavior;Biometry;Catchment Area;Cigarette;Cities;Communities;Community Outreach;Complex;Consumption;Data;Economics;Elasticity;Environment;Goals;Grant;Informatics;Manufacturer;Measures;Menthol;Methods;Modeling;Nicotine;Participant;Pattern;Policies;Price;Public Health;Randomized;Recommendation;Regulation;Research;Rural;Rural Appalachia;Rural Community;Sampling;Taxation;Tobacco;Tobacco use;United States Food and Drug Administration;Variant;abuse liability;authority;behavioral economics;combustible cigarette;design;falls;low nicotine content cigarette;nicotine user;patient engagement;peri-urban;prospective;recruit;rural area;rural underserved;rurality;tobacco products;tobacco regulation;tobacco regulatory science;urban area


application_id: 10665321
project_number: 1U54DA058256-01
administering_ic: NIDA
award_notice_date: 2023-09-25
opportunity_number: RFA-OD-22-004
application_type: 1
activity_code: U54
ic: DA
serial_number: 058256
project_start_date: 2023-09-30
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZRG1 ICN-R (50)]
subproject_number: 7553
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-30
project_title:
AppalTRuST Project 2: Exposure to tobacco marketing for novel tobacco products and associations with future tobacco use in Appalachian young adults: tobacco regulatory science implications

project_abstract:
ABSTRACT  Project 2Federal tobacco regulatory policies enacted by the US Food and Drug Administration (FDA) are critical to curbthe tobacco epidemic in rural Appalachia and reduce cancer burden. Kentucky (KY) is 50th in the nation foradult smoking rates with 21.4% of KY adults smoking cigarettes a rate not seen nationally in 20 years.Kentucky also has wide geographic disparities between rural and urban residents particularly in AppalachianKY an economically disadvantaged part of the state. In this context Federal policies can be particularlyinfluential in areas with weak tobacco control policies and high rates of tobacco use. In particular (1) theintroduction of novel non-combustible products (2) product standards on flavored cigars/menthol cigarettesand (3) lowering nicotine in cigarettes have great potential to shift the tobacco marketplace moving ruralAppalachian residents to quit smoking switch to potentially less harmful products or never initiate tobacco useat all. Project 2 seeks to expand the evidence base about the extent to which marketing exposure tobacco usebehaviors and attitude towards tobacco products differ across rural communities and the extent to whichregulatory actions by the FDA can potentially reduce use of tobacco among young adults in these areas.Additionally few studies examine how the retail environment novel products and potential policies couldinteract to reduce tobacco-related health disparities among young adult populations by rurality. Tobaccoretailer density is higher in rural areas by population but little is known about how retailers market in stores inthis region. The purpose of the study is to examine how marketing and product availability of such noveltobacco products may change over time and how these patterns may influence tobacco use attitudes andpatterns in rural communities providing guidance on future policy targets. To accomplish the study purposewe will conduct several aims. (1) We will assess marketing trends over time in retail store and digital audits(store websites and social media) in tobacco retailers in 2 rural catchment areas of KY. (2) We will comparemarketing exposure to and appeal and harm perceptions of novel products in young adults through ecologicalmomentary assessment (EMA) evaluating differences by rurality at the individual and census tract level. (3)Finally among EMA participants we will assess the predictive validity of exposure to novel product marketingexposure on use of tobacco at 6-month and 12-month follow-up and evaluate whether these outcomes areassociated with rurality. For all of these activities we will partner closely with the AppalTRUST team coresand local community advisory boards to disseminate lessons learned to communities about industry actionsand potential regulatory policies. Achieving the aims of this Project will expand the evidence base of thepotential impacts of FDA policies on reducing tobacco use and potential geographic equity impact of thesepolicies to reduce tobacco and ultimately cancer disparities.

project_terms:
Adult;Advertising;Affect;Age;Appalachian Region;Area;Attitude;Authorization documentation;Baseline Surveys;Behavior;Cancer Burden;Catchment Area;Censuses;Cigar;Cigarette;Cities;Communities;County;Data;Disparity;Ecological momentary assessment;Electronic cigarette;Environment;Epidemic;Equity;Exposure to;Frequencies;Future;Geography;Goals;Individual;Industry;Influentials;Kentucky;Learning;Link;Marketing;Menthol;Modified Risk Tobacco Product;Nicotine;Outcome;Participant;Patient Self-Report;Pattern;Perception;Persuasive Communication;Policies;Population;Population Density;Predisposition;Prevalence;Price;Regulation;Reporting;Research;Risk;Rural;Rural Appalachia;Rural Community;Rural Population;Sampling;Smokeless Tobacco;Smoking;Source;Time;Time trend;Tobacco;Tobacco use;United States Food and Drug Administration;Work;age group;authority;cancer health disparity;density;digital;economic disparity;electronic liquid;evidence base;experience;federal policy;follow-up;geographic disparity;health disparity;innovation;low nicotine content cigarette;novel;peri-urban;public policy on tobacco;reduce tobacco use;response;rural area;rural counties;rural disparities;rurality;smoking cessation;social media;socioeconomic disadvantage;theories;tobacco advertising;tobacco exposure;tobacco flavor;tobacco products;tobacco regulation;tobacco regulatory science;tobacco user;urban area;web site;young adult


application_id: 10665075
project_number: 5R21CA256385-02
project_title: Investigating the Role of PFKFB4 in the Immune Regulation of Lung Cancer
administering_ic: NCI
award_notice_date: 2023-07-26
opportunity_number: PAR-20-292
application_type: 5
activity_code: R21
ic: CA
serial_number: 256385
program_official: SOMMERS, CONNIE L
project_start_date: 2022-08-01
project_end_date: 2025-07-31
study_section: ZCA1-SRB-A(M1)S
contact_pi_person_id: 9475582
contact_pi: TELANG, SUCHETA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYLung cancer is responsible for the highest number of cancer-related deaths in the world. Non-small cell lungcancers (NSCLC) form the majority of lung tumors. These tumors are often discovered at an advanced stagewhen options are limited and survival is poor. Effective strategies are desperately needed to improve outcomesfrom this devastating cancer.NSCLCs universally exhibit a high rate of glycolysis to support their rapid growth and spread. A key rate-limitingstep in the glycolytic pathway is catalyzed by the enzyme 6-phosphofructo-1-kinase (PFK1). PFK1 is activatedby fructose-26-bisphosphate (F26BP) - produced by the 6-phosphofructo-2-kinase/fructose-26-bisphosphatasefamily of enzymes (PFKFB1-4). In previous studies we found that the PFKFB4 enzyme is highly expressed inNSCLCs and established its requirement in the regulation of glucose metabolism and growth in these tumors.We have developed a potent novel small molecule inhibitor of PFKFB4 MPN-22 that selectively inhibitsPFKFB4 and decreases NSCLC glycolysis and proliferation and tumor growth in vivo. In recent studies we havefound that immunosuppressive Th17 and T17 cells express F26BP and PFKFB4 and that MPN-22administration in lung tumor-bearing mice decreases the frequency and activity of these cells. We hypothesizethat PFKFB4 is required for Th17/T17 activity and that MPN-22 will decrease their activity resulting in anincrease in activated CD4+ and CD8+ T cells. We further postulate that MPN-22 will potentiate the antitumoractivity of immune checkpoint inhibitors (ICIs) to effectively decrease NSCLC growth. We propose to examinethe effects of PFKFB4 inhibition with MPN-22 on Th17/T17 cell development and activity in vitro andadditionally determine the effects of MPN-22 on immune cells and tumor progression and its efficacy incombination with ICIs in relevant oncogene-driven models of lung cancer. We anticipate that MPN-22 willsignificantly decrease the activity of immunosuppressive T cell subsets and increase the efficacy of ICIs inNSCLC. The ultimate goal of our studies is to develop an effective therapeutic strategy to successfullytreat and improve outcomes in advanced NSCLC.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Attenuated;Biological Availability;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Etiology;Cells;Cessation of life;Data;Deoxyglucose;Development;Diagnosis;Disease;Enzymes;Evaluation;Exhibits;Family;Frequencies;Fructose;Fructose-26-bisphosphatase;Genes;Genetic Transcription;Glucose;Glycolysis;Goals;Growth;Hypoxia;IL17 gene;Immune;Immune checkpoint inhibitor;Immunosuppression;Immunotherapeutic agent;In Vitro;Infiltration;KRASG12D;Knockout Mice;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Modeling;Mus;Myeloid-derived suppressor cells;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Oral;Outcome;Pathway interactions;Patients;Phosphotransferases;Play;Positron-Emission Tomography;Production;Proliferating;Pyruvate;Regulation;Resistance;Role;T-Cell Activation;T-Lymphocyte;T-Lymphocyte Subsets;TP53 gene;Therapeutic;Tumor Promotion;United States;advanced disease;analog;anti-PD-1;anti-PD1 antibodies;blood glucose regulation;cell growth;clinically relevant;directed differentiation;effective therapy;effector T cell;efficacy evaluation;fluorodeoxyglucose positron emission tomography;glucose metabolism;growth promoting activity;immunoregulation;improved outcome;in vitro activity;in vivo;inhibitor;lung cancer cell;mortality;neoplastic cell;normoxia;novel;novel therapeutic intervention;phase I trial;rapid growth;response;small molecule;small molecule inhibitor;synergism;systemic toxicity;targeted agent;therapeutically effective;tumor;tumor growth;tumor progression

public_health_relevance:
NARRATIVELung cancer is the most frequent cause of cancer-related death and non-small cell lung cancer (NSCLC) is themost commonly diagnosed lung cancer. Despite therapeutic advancements outcomes from NSCLC remainpoor. We anticipate that our studies will demonstrate the importance of the PFKFB4 enzyme in the activity ofimmunosuppressive T cells and the efficacy of PFKFB4 inhibition in augmenting effects of immune checkpointinhibitors and decreasing tumor progression in NSCLC. Accordingly the proposed studies seek to providerationale to support the targeting of PFKFB4 (in combination with immune checkpoint inhibitors) as a noveltherapeutic strategy to reduce the high mortality associated with NSCLC.


application_id: 10664904
project_number: 5R01CA264652-03
project_title: Plk1 as a prognostic biomarker for prostate cancer
administering_ic: NCI
award_notice_date: 2023-07-19
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 264652
program_official: WEINREICH, MICHAEL DALE
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Plk1 as a prognostic biomarker for prostate cancerAbstractBecause androgen receptor (AR) signaling is essential for development of prostate cancer (PCa)including castration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) arebecoming the first line treatment for CRPC. However the limited clinical success of ASIs makes iturgent to develop new approaches to treat ASI-resistant CRPC. Ionizing radiation is another majorapproach to treat CRPC with limited efficacy. Olaparib a PARP1 inhibitor is recently developed andused to target cancers with a defect in DNA repair such as BRCA mutations. Unfortunately the usageof olaparib in CRPC is profoundly limited by the fact that BRCA mutations only occur in lowpercentages of PCa. Thus identifying additional critical regulators that control DNA damage response(DDR) is of significance as it will identify specific patient populations who will be responsive to olaparib.The objective is to define the role of polo-like kinase 1 (Plk1) in regulating DDR and to exploit its uniqueimpact on the efficacy of olaparib for ASI-resistant CRPC patients. The central hypothesis is that Plk1phosphorylation of Mre11 a component of MRN (Mre11/Rad50/Nbs1) complex and MDC1 (mediatorof DNA damage checkpoint 1) leads to premature termination of DNA damage checkpoint reducedDNA repair thus increased olabparib efficacy based on the concept of synthetic lethality. Our datashow that Plk1 directly phosphorylates Mre11 whose activation is the first step in response to DNAdamage and that Plk1 phosphorylation of Mre11 leads to recovery from DNA damage checkpoint andreduced DNA repair. We also show that MDC1 a protein that further amplifies DDR signals is a Plk1substrate. Our hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1phosphorylation of Mre11 regulates the MRN complex; (2) to test whether Plk1 phosphorylation ofMDC1 contributes to premature termination of checkpoint; and (3) to determine whether Plk1 is aprognostic biomarker for PCa. These complementary aims will be accomplished using biochemicalanalyses of signaling intermediates and employing both cell culture systems and genetic strategieswith inducible mouse models. The rationale for the research is that it will probe the importance of Plk1to DDR and to examine whether Plk1 can be a predictable biomarker for the efficacy of olaparib inCRPC. This contribution is significant because if positive the results of the proposed study will supportan immediate clinical trial to compare the efficacy of olaparib in CRPC patients carrying different levelsof Plk1. The research is innovative as it approaches the disease from a novel Plk1 signaling pathwaychallenging the traditional view that Plk1 functions solely to regulate mitotic events. These studiesprovide a new paradigm for therapies by identifying the key regulator of DDR that is critical for theefficacy of olaparib in CRPC.

project_terms:
ATM activation;Affect;Androgen Receptor;Androgens;BRCA mutations;Biochemical;Biological Markers;Cancer Patient;Castration;Cell Culture System;Cells;Chromatin;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;Creativeness;DNA Damage;DNA Repair;DNA Repair Gene;DNA Repair Inhibition;DNA Repair Pathway;DNA amplification;DNA damage checkpoint;Data;Defect;Development;Disease;Event;Exhibits;Fostering;Frequencies;Genetically Engineered Mouse;Goals;Health;Investigation;Ionizing radiation;Malignant Neoplasms;Malignant neoplasm of prostate;Mediator;Meiotic Recombination;Mission;Mitotic;Mus;Mutation;Outcome;PLK1 gene;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Poly(ADP-ribose) Polymerase Inhibitor;Prognostic Marker;Proteins;Public Health;Receptor Signaling;Recovery;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tumor Subtype;Withdrawal;Work;abiraterone;ataxia telangiectasia mutated protein;brca gene;cancer cell;castration resistant prostate cancer;clinically relevant;comparative efficacy;cytotoxic;design;efficacy evaluation;enzalutamide;genetic approach;improved;inhibitor;innovation;mouse model;novel;novel strategies;overexpression;patient population;premature;prostate cancer cell;prostate cancer progression;response;success;tumor

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


application_id: 10664182
project_number: 1K23HD109471-01A1
project_title: Systemic Mediators and Biomarkers of Injury in Preterm Infants with Intermittent Hypoxemia
administering_ic: NICHD
award_notice_date: 2023-07-11
opportunity_number: PA-20-205
application_type: 1
activity_code: K23
ic: HD
serial_number: 109471
suffix: A1
program_official: KOSO-THOMAS, MARION
project_start_date: 2023-07-12
project_end_date: 2028-06-30
study_section: Pediatrics Study Section[CHHD-A]
contact_pi_person_id: 14544147
contact_pi: ABU JAWDEH, ELIE G
other_pis: Not Applicable
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT This proposal describes a mentored training and research plan that will facilitate the development of ElieAbu Jawdeh M.D. Ph.D. to an independent clinical and translational investigator in neonatal respiratory controland intermittent hypoxemia (IH). Dr. Abu Jawdeh will complement his current background as a neonatologistand a clinical scientist to attain new knowledge in basic science methods and biomarker science. The goal oflearning basic science techniques and methods is imperative for Dr. Abu Jawdeh to make the leap intounderstanding mechanisms of injury from IH and develop treatments in the future. He will achieve these goalsthrough structured mentorship rigorous hands-on laboratory experiences formal classwork and skills training.A team of mentors with an established track record in clinical translational and basic sciences will oversee Dr.Abu Jawdehs development and progress to research independence. Despite significant progress in neonatal intensive care preterm infants continue to suffer from significantmorbidities and neurodevelopmental impairment. The societal cost of prematurity is approximately 26 billiondollars with the cost of care for an extremely preterm infant being 20 times that of a late preterm infant. Majorconsequences of prematurity are apnea and lung disease that lead to repeated occurrences of IH; episodic dropsin blood oxygen saturation. These IH episodes occurring up to hundreds of events/day have a cumulative effecton neonatal outcomes. While the evidence linking IH to impairments is mounting the degree of IH associatedwith injury and pathophysiological mechanisms for IHs contribution to injury remain unclear. This knowledgegap in the mechanistic understanding of IH creates a critical barrier to improving clinical outcomes. Our goal forthis proposal is to better understand mechanisms and biomarkers of injury from IH in order to discover and titratetreatments in the future. Through both a prospective clinical cohort of preterm infants and in vitro cell cultureexperiments we will first test the hypothesis that IH increases systemic circulating ligands (bio-mediators) thatinjure brain cells using in vitro cell culture system of oligodendrocyte progenitor cells (OPC). Identifying bio-mediators and pathways of cell death and injury from IH will help develop treatments that we will also explore invitro. Then we will investigate a promising biomarker Neurofilament-L (NfL) for IH-related brain injury andpredictor of early neurological outcome. Identifying biomarkers of injury will allow prognostication of neonataloutcomes and monitoring of IH treatment effectiveness and titration in the future. We have pilot data to supportboth our Aims and hypotheses. This will be the first time such studies and mechanisms are investigated inpreterm infants with IH.

project_terms:
Adult;Animal Model;Apnea;Axon;Basic Science;Biological Markers;Blood;Blood - brain barrier anatomy;Brain Injuries;Caffeine;Cell Culture System;Cell Culture Techniques;Cell Death;Cells;Central Nervous System;Cessation of life;Clinical;Clinical Investigator;Clinical Sciences;Complement;Data;Development;Development Plans;Disease;Doctor of Medicine;Doctor of Philosophy;Drops;Early identification;Enzyme-Linked Immunosorbent Assay;Event;Exclusion;Frequencies;Future;Generations;Goals;Health Care Costs;Hypoxemia;Impairment;In Vitro;Incubated;Infant;Inflammation;Inflammatory;Injury;Intervention;Knowledge;Lead;Learning;Ligands;Link;Lung diseases;Measures;Mediator;Mentors;Mentorship;Methods;Monitor;Morbidity - disease rate;Neonatal;Neonatal Intensive Care;Neonatal Intensive Care Units;Nervous System Trauma;Neurodevelopmental Impairment;Neurofilament-L;Neurological outcome;Neurological status;Newborn Infant;Nurses;Oligodendroglia;Outcome;Oxygen;Pathway interactions;Patients;Pattern;Plasma;Premature Birth;Premature Infant;Process;Protein Fragment;Proteomics;Published Comment;Quality of life;Research;Risk;Role;Science;Scientist;Severities;Statistical Models;Structure;Supplementation;TLR2 gene;Techniques;Testing;Time;Titrations;Training;Translational Research;Treatment Effectiveness;Urine;Ventilator;Work;biomarker identification;blood-brain barrier crossing;blood-brain barrier function;brain cell;care costs;care outcomes;cell injury;clinical biomarkers;cohort;comparison control;early detection biomarkers;efficacious treatment;experimental study;extreme prematurity;improved;indexing;inhibitor;laboratory experience;neonatal morbidity;neonatal outcome;neurobehavior;oligodendrocyte progenitor;outcome prediction;premature;prognostication;prospective;pulmonary function;receptor;respiratory;skills training;societal costs;stem cells;synergism;systemic inflammatory response;therapy development;tool;translational scientist;treatment strategy;white matter injury

public_health_relevance:
PROJECT NARRATIVEPreterm infants (~0.4 million born in the US yearly) are at risk for frequent blood oxygen drops (IntermittentHypoxemia (IH)) that are linked to multiple short- and long-term neonatal morbidities leading to both lifelongimpairments and increased burden on health care cost. Our study investigates both markers and mechanismsof brain injury from increased intermittent hypoxemia in preterm infants. These data will contribute to ourunderstanding of brain injury from intermittent hypoxemia and identify potential targets for developing treatmentsin the future to improve IH and associated impairments.


application_id: 10663807
project_number: 5F31AA030172-02
project_title: Early environmental risk for the development of urgency and subsequent problem drinking
administering_ic: NIAAA
award_notice_date: 2023-03-28
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: AA
serial_number: 030172
program_official: RUFFIN, BEVERLY
project_start_date: 2022-04-24
project_end_date: 2024-04-23
study_section: ZAA1-GG(32)
contact_pi_person_id: 77814237
contact_pi: ATKINSON, EMILY A.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The proposed study aims to investigate longitudinally childhood maladaptive emotion socialization as a riskfactor for the development of urgency (the tendency to act rashly when experiencing strong emotions) andsubsequent problem drinking in adolescents. Identifying potentially modifiable antecedents of urgency isimportant because a large body of literature has implicated urgency in the risk process for adolescentproblematic drinking (as well as other impulsigenic behaviors such as bulimic behavior risky sex andgambling) (Berg et al. 2016; Coskunpinar et al. 2013; Fischer et al. 2008; Stautz & Cooper 2013).Adolescent drinking is associated with numerous public health harms including physical safety risks increasedrisk for psychiatric disorder increases in maladaptive personality traits and increased risk for premature death(Birkley et al. 2015; De Bellis et al. 2000; Hingson & Zha 2006; Kaminer 2016; Marshall 2014; Guller &Smith 2015). The relationship between urgency and problem drinking reciprocal such that increases in eachfactor precipitate increases in the other (Riley et al 2016). Though the relationship between urgency andproblem drinking has been studied extensively little is known about the etiology of urgency itself. Cyders andSmith (2008) proposed a developmental model of urgency in which childhood temperament and environmentalfactors increase risk for urgency but only temperament has been examined in the literature (Waddell et al.2021). Hersh and Hussong (2009) identified a significant relationship between negative parental emotionsocialization and increased substance use in adolescence and in our own work we found cross-sectionalassociations consistent with the hypothesis that urgency mediates the predictive influence of maladaptiveemotion socialization on adolescent drinking (Atkinson et al. under review). To date no studies haveexamined longitudinally the relationship between childhood maladaptive emotion socialization urgency andsubsequent problem drinking. The research component of this proposal involves a two-wave longitudinaldesign to (a) test whether maladaptive emotion socialization predicts increases in urgency (b) examine thepossibility that maladaptive emotion socialization predicts problem drinking mediated by urgency and (c)examine whether these relationships are invariant by race and gender in a sample of 9th grade students.Identifying environmental risk factors for the development of urgency will provide clear targets for earlyintervention and prevention efforts: interrupting the development of urgency is likely to reduce risk for problemdrinking and related behaviors. The training component of this proposal includes (1) the execution andmanagement of a longitudinal study in a public school setting including data collection liaising with schoolofficials and follow-up; (2) development of complex statistical analytic skills; (3) further advanced training inresearch ethics; (4) preparation of research reports for publication; (5) presenting original research atinternational scientific meetings; and (6) mentoring post-baccalaureate and undergraduate research assistants.

project_terms:
Addictive Behavior;Address;Adolescence;Adolescent;Adolescent and Young Adult;Alcohol abuse;Alcohol consumption;Asian;Award;Behavior;Binge Eating;Bulimia;Caregivers;Cessation of life;Child;Childhood;Clinical;Complex;Data Collection;Development;Dimensions;Disadvantaged;Distress;Early Intervention;Early identification;Educational process of instructing;Emotional;Emotions;Environmental Risk Factor;Ethnic Origin;Etiology;Exanthema;Expressed Emotion;Functional disorder;Future;Gambling;Gender;Goals;Hispanic;Informal Social Control;International;Interruption;K-Series Research Career Programs;Learning;Life;Link;Literature;Longitudinal Studies;Measures;Mediating;Mental Depression;Mental disorders;Mentors;Meta-Analysis;Modeling;Outcome;Parents;Participant;Personality Traits;Play;Postbaccalaureate;Precipitating Factors;Preparation;Prevention;Process;Prospective Studies;Public Health;Publications;Punishment;Race;Regulation;Reporting;Research;Research Assistant;Research Design;Research Ethics;Risk;Risk Behaviors;Risk Factors;Risk Reduction;Role;Safety;Sampling;Schools;Scientist;Smoking;Socialization;Socioeconomic Status;Students;Temperament;Testing;Time;Training;Variant;Work;adolescent alcohol abuse;alcohol use disorder;design;drinking;economic disparity;experience;feature selection;follow-up;high risk sexual behavior;high school;longitudinal design;meetings;multi-racial;ninth grade;premature;prevent;programs;sex;skills;substance use;therapy development;underage drinking;undergraduate research

public_health_relevance:
Urgency consistently predicts problem drinking and many other risky or addictive behaviors; however littleis known about the factors that contribute to the development of urgency. Identifying environmental riskfactors for urgency could inform the development of early intervention and prevention efforts aimed atreducing urgency and subsequent problem drinking. The proposed project is part of a developmentallysensitive program of research designed to examine the effects of environmental factors such asmaladaptive emotion socialization on later problem drinking via emotion-based risk factors.


application_id: 10663664
project_number: 1K99AG078286-01A1
project_title: Early characterization of cognitive status and AD risk in African American men
administering_ic: NIA
award_notice_date: 2023-08-23
opportunity_number: PAR-21-220
application_type: 1
activity_code: K99
ic: AG
serial_number: 078286
suffix: A1
program_official: LUO, YUAN
project_start_date: 2023-09-01
project_end_date: 2024-08-31
study_section: Career Development Facilitating The Transition to Independence Study Section[AGCD-1]
contact_pi_person_id: 78098700
contact_pi: ESIAKA, DARLINGTINA
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY/ABSTRACT Although past studies done primarily on white Americans report that men have a higher risk of mildcognitive impairment (MCI) and more rapid progression from MCI to AD we do not know if this is also the casefor African American men. Early characterization of cognitive status and Alzheimers disease (AD) risk in olderAfrican American men is a critical unmet challenge. There have been notably few dementia studies that includedsubstantial numbers of older African American men. In particular there is a paucity of neuroimaging data onolder African American men in the years prior to and during cognitive decline to AD. We will utilize a cross-sectional study of older urban African American men to characterize genetic social and environmentalinfluences on the brain and neural markers indicative of cognitive status and AD risk. My training application willnot only advance our understanding of neural changes and brain activity in older African American menespecially those exposed to conditions that put them at high risk for AD but how their brain health relates tobehavioral genetic neural lifestyle social and environmental risk factors. Using observational study during theK99 phase I will capture brain and neural pathways to cognitive changes/decline in African Americans whileundergoing extensive training to gain mastery of neuroimaging tools and concepts proficiency in examining brainimage biomarkers neuropsychological assessments and task-based fMRI testing and analyses. In the R00phase we will examine the neural pathways through which social and environmental factors impact cognitionand identify individual variability that moderates their impact. Also we will explore if social and environmentalinfluences are mediated by their effect on the APOE 4 and ABCA7-80 genes to impact cognitive status and ADrisk in older African American men. Understanding the mechanisms involved in brain health and AD risk in olderAfrican American men will improve our knowledge of how AD affects men and which tailored interventions aremost effective for mitigating AD risk and improving cognitive function in African American men. The developmentof tailored interventions is increasingly urgent given the increase in the number of African American older adultsexperiencing AD and the AD-associated burdens to the individuals families and communities. At the end of theK99 I will have obtained intensive training experience in structural and functional neuroimaging analytictechniques and increased my knowledge of cognitive and genetic markers of AD. Further I will have gainedadditional expertise in aging-related chronic illness risk reduction in pre-clinical African American men. Theexpertise would serve as a basis for my R00 and future independent research where I would focus on social andenvironmental determinants of health to observe and document factors that impact brain health and preventAlzheimers disease in urban African American men.

project_terms:
Affect;African American;African American population;Age;Aging;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease related dementia;Alzheimer's disease risk;Behavioral;Biological Markers;Brain;Brain imaging;Brain region;Chronic Disease;Cognition;Cognitive;Communities;Cross-Sectional Studies;Data;Dementia;Development;Diabetes Mellitus;Diagnosis;Diagnostic tests;Diet;Discrimination;Disease Progression;Early Diagnosis;Elderly;Enrollment;Environmental Risk Factor;Exposure to;Family;Functional Magnetic Resonance Imaging;Future;Genes;Genetic;Genetic Markers;Genomics;Health;Hypertension;Impaired cognition;Individual;Intervention;Investigation;Knowledge;Life Style;Low income;Measures;Medial;Mediating;Mediator;Mentors;Moderate Activity;Neighborhoods;Neural Pathways;Neurologic Symptoms;Neuropsychology;Observational Study;Pathway interactions;Patient Self-Report;Phase;Physical activity;Prefrontal Cortex;Reporting;Research;Risk Marker;Risk Reduction;Smoking;Stress;Techniques;Temporal Lobe;Testing;Training;Trauma;biomarker validation;brain health;brain pathway;caucasian American;cognitive change;cognitive function;cognitive neuroscience;cognitive training;comorbidity;coping;diagnostic accuracy;drinking;experience;health determinants;high risk;imaging biomarker;imaging study;improved;individual variation;insight;lifestyle factors;men;mild cognitive impairment;neural;neuroimaging;pre-clinical;prevent;racism;risk variant;sleep quality;social;social factors;tool;urban dwelling;urban setting

public_health_relevance:
PROJECT NARRATIVEWe know little of the pathway to brain health in African American men mainly because therehave been notably few brain imaging studies that included substantial numbers of older AfricanAmerican men. My proposed research will examine cognition and AD risk markers testdiagnostic accuracy and characterize brain health in older cognitively healthy urban AfricanAmerican men. The results will provide insights toward identifying and validating markers ofbrain health and AD risk in African American mena necessary step to understanding how ADaffects men and which tailored interventions are most effective for mitigating AD.


application_id: 10663241
project_number: 5R01CA168658-10
project_title: Cellular Metabolites regulating cancer cell adaptation
administering_ic: NCI
award_notice_date: 2023-07-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 168658
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2013-05-02
project_end_date: 2024-06-30
study_section: Cellular Signaling and Regulatory Systems Study Section[CSRS]
contact_pi_person_id: 8821411
contact_pi: LEE, YOUNG-SAM
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Cellular metabolites regulating cancer cell adaptation SAICAR is a metabolite accumulates in cancer cells upon glucose starvation or EGF stimulation. Uponaccumulation SAICAR promotes cancer cell survival and proliferation by inducing tumor PKM2. However it isnot yet clear how cancer cells but not normal proliferating cells accumulate SAICAR. We hypothesize that transformation-induced alteration of pentose phosphate pathway is responsible forthe accumulation of SAICAR. In this project we will test this hypothesis while evaluating the importance ofSAICAR accumulation for the growth of tumor in vivo. The outcome of this project include a better understanding on metabolic reprogramming contributes tocancer. In addition the outcome of this project will determine whether SAICAR accumulation can be a potentialtherapeutic target.

project_terms:
Affect;Biochemistry;Bypass;Cell Proliferation;Cell Survival;Cells;Complex;Data;EGF gene;Enzymes;Epidermal Growth Factor Receptor;Feedback;Glucose;Glycolysis;Growth Factor;Hela Cells;Human;Lung Adenocarcinoma;Malignant Neoplasms;Measures;Metabolic;Metabolic Pathway;Mitogens;Mus;Normal Cell;Nucleotide Biosynthesis;Nucleotides;Outcome;Pentosephosphate Pathway;Permeability;Phase;Phosphoenolpyruvate;Phosphorylation;Proliferating;Proteins;Receptor Protein-Tyrosine Kinases;Regulation;Science;Small Interfering RNA;Starvation;Testing;Tissues;Tumor Promotion;Tumorigenicity;Tyrosine;Xenograft procedure;cancer cell;cell transformation;dimer;in vitro activity;in vivo;inhibitor;inorganic phosphate;nucleotide metabolism;therapeutic target;tumor;tumor growth

public_health_relevance:
PROJECT NARRATIVE SAICAR is a nucleotide biosynthesis metabolite whose accumulation induces the survival and theproliferation of cultured cancer cells. We will determine the mechanism on how cancer cells but not normallyproliferating cells accumulate SAICAR while testing the relevance to tumor growth in vivo. The outcome willdetermine whether the SAICAR accumulation can be a potential therapeutic target.


application_id: 10663219
project_number: 5R01CA196634-09
project_title: Improving chemotherapy of castration-resistant prostate cancer.
administering_ic: NCI
award_notice_date: 2023-06-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 196634
program_official: FORRY, SUZANNE L
project_start_date: 2016-08-10
project_end_date: 2026-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Improving chemotherapy of castration-resistant prostate cancerAbstractAndrogen receptor (AR) signaling is essential for prostate cancer (PCa) development and growth even incastration-resistant PCa (CRPC) the lethal stage of the disease. Docetaxel is the standard treatment for CRPCpatients due to a combination of mitotic catastrophe and inhibition of AR signaling. Androgen signaling inhibitors(ASI) are also used to treat CRPC post-docetaxel with limited success. Therefore it is urgent to identify newtargets and develop novel approaches to treat CRPC that are resistant to the existing therapies. Brd4 aconserved member of the bromodomain and extraterminal (BET) family of chromatin readers promotes genetranscription via interacting with core positive transcription elongation factor (P-TEFb) consisting of Cdk9 andcyclin T1. Significantly AR signaling-competent CRPC cells are preferentially sensitive to Brd4 inhibitor JQ1 asJQ1 treatment disrupts AR recruitment to target gene loci thus resulting in inhibition of AR signaling directly.Furthermore JQ1 enhances the efficacy of ASI in PCa. Loss-of-function mutations in E3 ubiquitin ligasesubstrate-binding adaptor speckle-type POZ protein (SPOP) cause stabilization of Brd4 and JQ1 resistance.Thus it will be of clinical significance to understand the regulation mechanism of Brd4 regulation and to developa new approach to cause Brd4 degradation even in the presence of SPOP mutations. The long-term goals ofthis study are to identify novel and druggable signaling pathways that offer more effective treatment options forpatients with therapy-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulatingBrd4 degradation and AR signaling and to exploit this unique mechanism to develop a novel approach fortreatment. Our preliminary data show that Plk1 phosphorylation of Brd4 leads to its protein degradation even inthe presence of SPOP mutations. The central hypothesis is that Plk1-associated phosphorylation of Brd4 resultsin its degradation thus docetaxel-associated Plk1 elevation is one approach to overcome resistance to Brd4inhibitors. This hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1 phosphorylationof Brd4 regulates AR signaling; (2) to understand how Brd4 phosphorylation contributes to PCa cell proliferation;and (3) to analyze clinical significance of Plk1-associated Brd4 phosphorylation. These complementary aims willbe accomplished using biochemical analyses of signaling intermediates and employing genetic strategies withPCa mouse models culture systems and PCa xenograft methodologies. The rationale for the research is that itwill be the first to probe the importance of Plk1 to Brd4 and AR signaling and to examine whether a combinationof docetaxel and Brd4 inhibitor ABBV-744 is a novel approach to treat ASI-resistant CRPC. This contribution issignificant because it will (i) define the molecular mechanism by which Plk1 regulates Brd4 degradation andAR signaling; and (ii) validate docetaxel as a therapeutic agent to enhance the efficacy of Brd4 inhibitors.

project_terms:
Ablation;Acetylation;Affect;Androgen Receptor;Androgens;Binding;Biochemical;Bromodomain;Cancer Patient;Castration;Cell Cycle;Cell Cycle Progression;Cell Proliferation;Cells;Chemoresistance;Chromatin;Clinical Research;Creativeness;Data;Development;Disease;Docking;Epigenetic Process;Event;Family;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth and Development function;Health;Investigation;Lysine;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Mitosis;Mitotic;Molecular;Mutation;Operative Surgical Procedures;Outcome;PLK1 gene;Paclitaxel;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphorylation Site;Phosphotransferases;Proteins;Public Health;Reader;Receptor Signaling;Regulation;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;Site;Specimen;System;Testing;Therapeutic;Therapeutic Agents;Transcriptional Elongation Factors;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;castration resistant prostate cancer;chemotherapy;clinically significant;cyclin T1;design;docetaxel;effective therapy;enzalutamide;genetic approach;genomic locus;improved;in vivo;inhibitor;innovation;loss of function mutation;member;mouse model;multicatalytic endopeptidase complex;novel;novel strategies;patient derived xenograft model;prostate cancer cell;prostate cancer progression;protein degradation;recruit;refractory cancer;standard care;success;therapy resistant;ubiquitin-protein ligase

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on discovery of novel signalingpathways that drive castration-resistant prostate cancer. These studies will establish new avenues ofinvestigation to develop improved therapeutics to treat this deadly disease and to greatly improve patientoutcome. Thus the proposed research is relevant to NIH's mission of fostering creative discoveries andinnovative research strategies for protecting and improving health and reducing the burdens associated withcancer.


application_id: 10663193
project_number: 5R01HD080205-09
administering_ic: NICHD
award_notice_date: 2023-07-13
opportunity_number: PA-18-480
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(90)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-08-01
project_title:
Effects of activity dependent plasticity on recovery of bladder and sexual function after human spinal cord injury

project_abstract:
AbstractBladder and bowel complications have consistently been rated as of the upmost importance bythe spinal cord injury (SCI) population. Importantly both bladder and bowel distention havebeen identified as primary triggers of autonomic dysreflexia (AD) in individuals with cervical andupper thoracic level lesions (majority of SCI population) a systolic blood pressure rising oftenmore than 20 mmHg and remaining at these values with intolerable symptoms (poundingheadache and/or chills for example). We have recently documented as part of our current R01this massive unmodulated sympathetic reflex which causes widespread vasoconstriction(presenting as severe hypertension) as a limitation for bladder capacity in numerous researchparticipants. Anecdotally many who use clean intermittent catheterization for bladdermanagement report using AD symptoms daily as a signal of bladder fullness and time foremptying an unsafe practice that needs addressing. Additionally we and others havedocumented in questionnaires regular occurrences of AD symptoms during bowel programs andin ongoing lab-based studies there have been numerous instances of AD upon insertion of arectal probe either for bladder cystometry (for recording abdominal pressure) or during anorectalmanometry. The goals of the current multi-disciplinary study incorporating critical cross viscero-visceral intersystem interactions are 1) to investigate in a controlled laboratory setting and thenwith mobile at-home monitoring the extent severity and frequency of occurrence of AD withrespect to daily bladder and bowel function in conjunction with identifying potential underlyingmechanisms by examining urinary biomarkers for several specific vasoactive hormones and 2)to regulate cardiovascular (CV) function therapeutically as part of bladder and bowelmanagement using spinal cord epidural stimulation which our CV team have shown cannormalize blood pressure.

project_terms:
Address;Anodes;Atrial Natriuretic Factor;Attenuated;Autonomic Dysfunction;Autonomic Dysreflexia;Biological Markers;Bladder;Blood Pressure;Cardiovascular Physiology;Cardiovascular system;Caring;Catheterization;Cathodes;Cervical;Chest;Chills;Data;Electrodes;Event;Feedback;Frequencies;Goals;Guidelines;Headache;Heart Rate;Home;Home environment;Homeostasis;Hormones;Human;Hypertension;Hypotension;Individual;International;Intestines;Laboratories;Lesion;Location;Maintenance;Manometry;Measures;Monitor;Norepinephrine;Outcome;Participant;Persons;Physiological;Piloerection;Population;Quality of life;Questionnaires;Recommendation;Recovery;Rectum;Reflex action;Renin;Reporting;Research;Severities;Sex Functioning;Signal Transduction;Societies;Spinal Cord;Spinal cord injury;Symptoms;System;Tension Headache;Therapeutic;Time;Training;Urodynamics;Vasopressins;Visceral;abdominal pressure;blood pressure elevation;blood pressure regulation;improved;indexing;mobile application;multidisciplinary;pressure;prevent;programs;psychologic;rectal;response;time interval;urinary;vasoconstriction;voltage

public_health_relevance:
NarrativeBoth bladder and bowel distention have been identified as primary triggers of autonomicdysreflexia in individuals with spinal cord injury a sudden sharp rise in blood pressure withintolerable symptoms such as pounding headache and/or chills. We have recently documentedas part of our current R01 this massive unmodulated sympathetic reflex which causeswidespread vasoconstriction (presenting as severe hypertension) as a limitation for bladdercapacity in numerous research participants. The goals of the current multi-disciplinary studyincorporating intersystem interactions are 1) to investigate in a controlled laboratory setting andthen with mobile at-home monitoring the extent severity and frequency of occurrence ofautonomic dysreflexia with respect to daily bladder and bowel function in conjunction withidentifying potential underlying mechanisms by examining urinary biomarkers for severalspecific vasoactive hormones and 2) to regulate cardiovascular function therapeutically as partof bladder and bowel management using spinal cord epidural stimulation.


application_id: 10662957
project_number: 1K01AG070279-01A1
project_title: Cognitive Aging Trajectories in Survivors of Trauma
administering_ic: NIA
award_notice_date: 2023-05-11
opportunity_number: PA-20-190
application_type: 1
activity_code: K01
ic: AG
serial_number: 070279
suffix: A1
program_official: TREVINO, MELISSA
project_start_date: 2023-05-15
project_end_date: 2028-01-31
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 8923142
contact_pi: LAWRENCE, KAREN ANN
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Dementia and the prodromal stages of cognitive decline together affect approximately 25-30% of older adultsacross the United States (U.S.). Posttraumatic Stress Disorder (PTSD) has been linked to a 111% increasedrisk of developing dementia of any type even after controlling for potential confounders such as traumatic braininjury (TBI). Therefore PTSD may be an important target for early prevention of cognitive decline and potentialprogression to dementia. Most studies on PTSD and cognition have used a cross-sectional study design andhave not examined important potential effect modifiers (e.g. sex and APOE4 carrier status) leaving a gap inour fundamental understanding of the effect of PTSD on longitudinal trajectories of cognitive functioning.Further although PTSD is more prevalent in women most research on PTSD and cognition has beenconducted in men. This proposal is of timely public health importance as the pre-pandemic lifetime prevalenceof PTSD in the U.S. was 6% but post-pandemic epidemiological findings have indicated a rise toapproximately 32% among young adults. COVID-19 events have also resulted in PTSD symptoms withoutmeeting Diagnostics and Statistical Manual of Mental Disorders 5th edition (DSM-5) Criterion A. Thereforecritical research gaps in our understanding of the effect of PTSD on cognitive aging include: 1) prospectiveinvestigation wherein temporal sequencing and rate of cognitive decline can be evaluated in the context ofPTSD 2) testing the potential modifying effects of sex and APOE4 carrier status on the relationship betweenPTSD status and cognitive decline and 3) understanding whether Criterion A is necessary when determiningthe relationship between PTSD and cognitive decline. Aims 1 and 2 will leverage existing data from theNational Alzheimer's Coordinating Center (NACC). In adults aged 55+ years multilevel modeling andinteraction analyses will determine the impact of PTSD status on trajectories rate and temporal sequence ofdomain-specific cognitive decline and will test sex and APOE4 carrier status as potential effect modifiers. ForAim 3 men and women participants aged 65+ with and without Criterion A trauma will be recruited andmultiple regression will be used to unambiguously clarify if PTSD severity (Criteria B through E) is associatedwith cognitive functioning without meeting Criterion A. This K01 award will provide training and mentorship inaging health cognitive aging sex-specific health effects of PTSD neuropsychology of PTSD longitudinalstudy design and advanced statistics and propel the PI to become an independent investigator with expertisein the effects of traumatic stress and biopsychosocial factors on cognitive aging with a sex-specific focus andin alignment with Goals B-3 B-4 and F-4 of NIAs Strategic Directions 2020-2025.

project_terms:
Accidents;Address;Adult;Affect;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Anxiety;COVID-19;COVID-19 pandemic;Clinical;Clinical Sciences;Cognition;Cognitive;Cognitive aging;Cross-Sectional Studies;DSM-V;Data;Data Collection;Dementia;Diagnosis;Diagnostic;Diagnostic and Statistical Manual of Mental Disorders;Disasters;Elderly;Epidemiology;Episodic memory;Event;Funding;Goals;Health;Impaired cognition;Incidence;Intervention;Investigation;Kentucky;Link;Longitudinal Studies;Medical;Mental Depression;Mentored Research Scientist Development Award;Mentors;Mentorship;Modeling;Modification;National Center for Advancing Translational Sciences;Neuropsychology;Participant;Pharmaceutical Preparations;Post-Traumatic Stress Disorders;Prevalence;Prevention;Psychologist;Public Health;Recording of previous events;Research;Research Design;Research Personnel;Risk;Risk Factors;Severities;Sex Differences;Short-Term Memory;Survivors;Symptoms;Testing;Training;Translational Research;Trauma;Traumatic Brain Injury;United States;Universities;War;Woman;aged;apolipoprotein E-4;biopsychosocial factor;carrier status;clinical center;cognitive function;cohort;comorbidity;dementia risk;disability;executive function;first responder;functional decline;human old age (65+);meetings;men;mild cognitive impairment;military veteran;multilevel analysis;pandemic disease;post-pandemic;pre-clinical;pre-pandemic;processing speed;prospective;recruit;sex;sexual assault;statistics;traumatic stress;young adult

public_health_relevance:
PROJECT NARRATIVEPTSD prevalence is high and PTSD increases the risk of dementia. The proposed research will: a) investigatethe impact of PTSD on the rate of domain-specific cognitive decline b) test potential effect modifiers includingsex of the relationship between PTSD and rate of cognitive decline and c) determine the association betweencognitive functioning and PTSD severity with and without Criterion A trauma. Successful completion of thisproject has important public health implications including indicating whether PTSD should be considered atarget for the early prevention of cognitive decline that may lead to dementia and increasing understanding ofsex differences in the relationship between PTSD and cognitive decline.


application_id: 10662371
project_number: 5P30AG072946-03
project_title: Core G: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9600
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Research Education ComponentThe Research Education Component (REC) of the UK-ADRC offers a variety of research educational activitiesand comprehensive mentored research skills development programs that will enhance the development of thefuture workforce to meet the nations biomedical behavioral and clinical needs in Alzheimers disease andrelated dementias (ADRD) research. The REC will leverage resources within and outside the UK-ADRC tocreate an outstanding multidisciplinary and collaborative environment for training the next generation ofresearchers in scientific areas that parallel the theme of our ADRC (Transitions from Normal to Late-Life Multi-Etiology Dementias) and with an emphasis on increasing representation of researchers from diversebackgrounds. We will continue to build on a long history of collaborative and dedicated faculty a strongfoundation in multidisciplinary team science and an outstanding track record of success in mentoring andeducation of researchers across the training spectrum. We will also establish a new REC Scholar programaimed at junior investigators (Assistant Professors senior research associates or clinical fellows). Thisprogram will support junior investigators from diverse multidisciplinary fields to pursue mentored basictranslational or clinical research in ADRD and follow a customized training plan to help the scholars movetoward their career development goals. This training will be done in a supportive and collaborative academicenvironment with substantial training resources and an experienced and dedicated training faculty. Scholarswill have the opportunity to learn state-of-the-art research skills in disciplines that have been identified ascritically needed areas for the ADRC workforce of the future. Examples of training areas where the UK-ADRChas strong expertise include analysis of longitudinal clinical outcomes clinical trial design MRI imaging andnovel fluid biomarkers quantitative neuropathology and AD mimics data analysis/ study design in mixeddementias and health literacy and inequities. REC goals will involve interactions with all the UK-ADRC Coresand will be achieved through the following specific aims.Aim 1. Provide education programs and research skills development opportunities for investigators at UK.Aim 2. Identify select support and retain REC scholars from diverse backgrounds and disciplines to engagein ADRD research.Aim 3. Develop an individualized mentoring plan and educational program for each REC scholar to enableadvancement to independent research and funding in ADRD research.Aim 4. Evaluate progress of the REC scholars address barriers towards the goal of independence in ADRDresearch and refine delivery of the programs educational structure and processes.Following completion of the Program participants will have the knowledge expertise and confidence tosuccessfully pursue a long-term career in dementia research.

project_terms:
Acceleration;Achievement;Address;Advisory Committees;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Basic Science;Behavioral;Biological Markers;Clinical;Clinical Research;Clinical Trials Design;Communities;Competence;Data Analyses;Dedications;Dementia;Development;Discipline;Early Diagnosis;Education;Educational Activities;Elderly;Environment;Etiology;Exposure to;Faculty;Foundations;Funding;Future;Goals;Image;Individual;Interdisciplinary Study;Kentucky;Knowledge;Leadership;Learning;Liquid substance;Magnetic Resonance Imaging;Mentors;Monitor;Outcome;Participant;Postdoctoral Fellow;Prevention Research;Process;Program Development;Recording of previous events;Research;Research Design;Research Personnel;Research Project Grants;Resources;Scholars Program;Science;Scientist;Standardization;Structure;System;Teacher Professional Development;Training;Training Programs;Translational Research;Universities;career;career development;collaborative environment;education planning;education research;experience;health inequalities;health literacy;high school;improved;innovation;instrument;investigator training;longitudinal analysis;mixed dementia;multidisciplinary;neuropathology;next generation;novel;prevent;professor;programs;recruit;skill acquisition;skills;success;therapy development;training opportunity;treatment research;undergraduate student


application_id: 10662361
project_number: 5P30AG072946-03
project_title: Core F: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9599
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Biomarker CoreThe theme of our UK-ADRC is Transitions from normal to late-life multi-etiology dementia and the role ofthe Biomarker Core is to provide data and support efforts to develop biomarker profiles for the spectrum ofunderlying pathologies that can contribute to an individuals cognitive decline. The Biomarker core will providecritical characterization of our cohort during their cognitively normal state and through their cognitivetransitions. The utility of biomarkers is expanding rapidly as the dementia field identifies potentially disease-modifying therapies. Rather than focusing on a single biomarker modality (i.e. MRI PET plasma etc.) wehave adopted a multimodal approach to biomarker characterization. Because our center is particularlyinterested in multi-etiology dementia the most common dementia in the normal aging population we believe amultimodal approach to biomarkers will yield novel insights into the progression of such complex dementias.We propose to measure blood- and CSF-based biomarkers for AD cerebral small vessel disease (cSVD)large-vessel ischemic disease and inflammation. In addition we will perform state-of-the-art MRI imagingincorporating biomarkers of AD cSVD and neuroinflammation. We will also explore the utility of wearabledevices to collect digital biomarkers tracking sleep and physical activity especially given that Lewy bodypathology can lead to early sleep disturbances. Finally digital gait assessment will provide physical biomarkersof gait which has been shown to decline early in individuals with cSVD and Lewy body dementia. Importantlythe Biomarker Core has been established for several years and is fully integrated within the UK-ADRCworking closely with the other cores to maximize the utility of the biomarker data collected to date. We willcontinue to support internal and external research projects on biomarkers and will also contribute significantlyto national and international consortium efforts to develop clinic-ready biomarkers for AD VCID and otherunderlying causes of dementia. Our specific aims are:Aim 1: Collect bi-annual blood-based biomarkers of AD cSVD large vessel disease and inflammation.Aim 2: Collect baseline MRI scans and accompanying CSF ATN biomarkers on all cognitively normalparticipants in the longitudinal cohort.Aim 3: Fully characterize biomarkers on all participants at their clinical transition from cognitively normal /preMCI to MCI and from MCI to dementia.Aim 4: Determine the utility of digital biomarkers including activity sleep and gait in predicting cognitivedecline and / or brain pathology.Aim 5: Contribute to national efforts to establish harmonize and standardize biomarkers including NACCADNI and NCRAD.Aim 6: Integrate with the other cores of the UK-ADRC.

project_terms:
Adopted;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimers disease biomarker;Biological Markers;Blood;Brain Pathology;Cerebral small vessel disease;Clinical;Cognitive;Collection;Complex;Consensus;Data;Dementia;Digital biomarker;Disease;Elderly;Etiology;Gait;Goals;Image;Impaired cognition;Individual;Inflammation;International;Ischemia;Kentucky;Lewy Body Dementia;Lewy body pathology;Liquid substance;Longitudinal cohort;MRI Scans;Magnetic Resonance Imaging;Measures;Modality;Participant;Pathologic;Pathology;Physical activity;Plasma;Positron-Emission Tomography;Research;Research Project Grants;Role;Sleep;Sleep disturbances;Standardization;System;Universities;aging population;biomarker development;biomarker identification;biomarker performance;blood-based biomarker;clinic ready;cohort;digital;insight;interest;meetings;multimodality;neuroinflammation;normal aging;novel;novel marker;precision medicine;wearable device


application_id: 10662356
project_number: 5P30AG072946-03
project_title: Core E: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9598
contact_pi_person_id: 9662252
contact_pi: SCHMITT, FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Outreach Recruitment and Engagement CoreThe Outreach Recruitment and Engagement (ORE) Core plays a central role in achieving UK-ADRC goals byfunctioning as a key link between the Center and the local and state communities. ORE Core programs andactivities have created and will maintain an educated local community eager to receive updated information onAD and to participate in our Centers research. Through ORE Core efforts the UK-ADRC will continue to workwith both the Commonwealth of Kentucky and UK partners in directing state and institutional responses tomeeting dementia health care needs and increasing health literacy in the elderly. ORE Core activities includerecruitment and retention of diverse participants into a longitudinal cohort with annual clinical examinations andbrain donation upon death. Other activities involve the development and testing of innovative outreach andengagement activities in the community to increase awareness of AD/ADRD plus the importance of researchand research participation. Over the past five years the ORE Core has taken the lead in developing innovativepartnerships and products to support research participation by African Americans the largest minority group inKentucky. We will continue to emphasize recruitment and retention of research participants at the earlieststages of the cognitive continuum (Cognitively Normal and MCI). These efforts involve engaging theseparticipants in the ADRC longitudinal cohort as well as activities to enhance agreement to brain donationwillingness to engage in affiliated clinical studies and therapeutic trials and donation of antemortembiospecimens. In the next cycle we will maintain and further build on these efforts and partnerships throughthe following specific aims:Aim 1. Recruit and retain participants into our longitudinal cohort affiliated research and NIA initiativesfocusing on improving recruitment and retention of African Americans and other URGs.Aim 2. Increase community awareness of AD and ADRD through the promotion of health literacy that furtherenhances recruitment and retention of minority participants in research.Aim 3. Evaluate the effectiveness of our activities with both qualitative and quantitative metrics.Aim 4. Support the UK-ADRC Cores to maximize national and international collaborations.The ORE Core plays a critical role in the UK-ADRC and works closely with the other Cores to supportrecruitment and retention activities for research protocols clinical trials and national initiatives; increasecommunity awareness of AD and maintain a strong presence in the African-American community; and supportoutreach initiatives for the lay community in collaboration with key partners. These functions are vital to the UK-ADRC mission to catalyze outstanding and innovative research outreach education and clinical programs.

project_terms:
Address;African American;African American population;Aging;Agreement;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Autopsy;Awareness;Biological Markers;Brain;Brothers;Caring;Catchment Area;Censuses;Cessation of life;Church;Clinic;Clinical;Clinical Research;Clinical Trials;Cognitive;Collaborations;Communities;Consent;Data;Databases;Dementia;Development;Disease;Education;Elderly;Elements;Enrollment;Etiology;Event;Extramural Activities;Faith-based organization;Fostering;Foundations;Genetic;Goals;Grant;Health Promotion;Healthcare;Institution;International;Kentucky;Lead;Link;Longitudinal cohort;Measures;Minority;Minority Groups;Mission;Neck;Outcome;Participant;Pathology;Play;Protocols documentation;Reporting;Research;Research Activity;Research Support;Resources;Risk;Risk Assessment;Role;System;Testing;Therapeutic Trials;Time;Underrepresented Populations;Universities;Update;Work;checkup examination;clinical examination;cohort;community engagement;dementia risk;demographics;disparity reduction;effectiveness evaluation;efficacy evaluation;ethnic minority population;ethnoracial;health disparity;health literacy;improved;innovation;meetings;mixed dementia;neuropathology;outreach;outreach program;participant retention;patient engagement;programs;racial minority population;recruit;research study;response;success;volunteer;willingness


application_id: 10662352
project_number: 5P30AG072946-03
project_title: Core D: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9597
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Neuropathology CoreThe overall objective of the Neuropathology Core of the UK-ADRC is to support research on normal brainaging presymptomatic AD MCI early and late AD mixed dementia syndromes and other dementingdisorders. Autopsies will be performed by our Rapid Autopsy Team on longitudinally followed subjects from ourClinical Core. We will perform short post-mortem interval autopsies and we will maintain a high autopsy rate.This Core is optimally tailored to help address important research questions. The Core will provide brain tissueCSF and other biospecimens for investigators at UK other ADRCs and outside investigators. The Core willalso provide consensus conference determined diagnoses quantitation of neurofibrillary tangles neuriticplaques and diffuse plaques from 8 brain regions Ab quantitation Braak staging CERAD and NIA-ReaganInstitute staging on all autopsied cases along with evaluation of alpha-synuclein and TDP-43 proteinopathy.This brain bank has been operating continuously for over three decades with a strong track record so specialcare will be taken to ensure diagnostic excellence consistency and continuity. The Core will maintain a tissuebank of the above specimens and frozen serum plasma buffy coats and CSF from living patients. Specialemphasis will be placed on generating rigorous quantititative pathologic metrics from digital pathology andproviding investigators with specimens from cognitively intact control subjects with no Ab deposition andsparse tau pathology (successful cerebral aging) and many cases with mixed pathologies. Providing thesesamples will contribute to clinical-pathological correlation studies and cutting-edge research that includesponsored studies related to AD genomics oxidative stress hippocampal sclerosis/LATE dementia with Lewybodies Down syndrome and neuroinflammation. Frequent consensus conferences will be held with theClinical Biomarker and Data Management and Statistics Cores to help define clinical-pathological diagnoseson all autopsied subjects. The Neuropathology Core is strongly integrated with other Cores of the UK-ADRCand exploits unique opportunities to conduct clinical-pathological correlative studies on longitudinally followedsubjects. Through these methods we will better understand normal brain aging and the transition to multi-etiology dementia with the goal of contributing to therapeutic or preventive measures. The NeuropathologyCore complements the other Cores of the UK-ADRC to provide extremely essential diagnoses and tissuesamples that are required for many cutting-edge researchers at the University of Kentucky and elsewhere. Wewill build on our track record of excellence using innovative tools related to brain autopsies neuropathologicaldiagnoses tissue banking and clinical-pathological correlation. Our specific aims are:Aim 1: Provide state-of-the-art neuropathological and biospecimen repository servicesAim 2: Leverage neuropathology resources and expertise to contribute to research effortsAim 3: Integrate with other cores to contribute to administrative research and educational missions

project_terms:
Address;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Area;Autopsy;Biological;Biological Markers;Biological Specimen Banks;Biometry;Brain;Brain Diseases;Brain imaging;Brain region;Caring;Catalogs;Cerebrospinal Fluid;Cerebrovascular Disorders;Cerebrum;Clinical;Clinical Trials;Cognitive;Collaborations;Complement;Consensus;Correlation Studies;Correlative Study;DNA;Data;Databases;Dementia;Dementia with Lewy Bodies;Deposition;Diagnosis;Diagnostic;Disease;Down Syndrome;Education;Elderly;Ensure;Etiology;Evaluation;Freezing;Frontotemporal Lobar Degenerations;Genetic;Genetic study;Genomics;Goals;Impaired cognition;Individual;Infrastructure;Investigation;Kentucky;Laboratory Research;Lesion;Memory;Methodology;Methods;Mission;Nerve Degeneration;Neurofibrillary Tangles;Oxidative Stress;Pathologic;Pathology;Patients;Plasma;Preventive measure;Process;Protocols documentation;Publishing;Research;Research Personnel;Research Support;Resources;Running;Sampling;Senile Plaques;Serum;Services;Specimen;Staging;Standardization;Syndrome;System;Tauopathies;Therapeutic;Thinness;Tissue Banks;Tissue Sample;Tissues;Universities;Work;age related;age related neurodegeneration;aging brain;alpha synuclein;blood product;brain tissue;cerebrovascular pathology;clinical center;cohort;data management;demented;digital;digital pathology;experience;genome wide association study;hippocampal sclerosis;innovation;limbic-predominant age-related TDP-43 encephalopathy;meetings;mixed dementia;neuroinflammation;neuropathology;novel;pre-clinical;protein TDP-43;religious order study;statistics;symposium;synucleinopathy;tau Proteins;tool


application_id: 10662348
project_number: 5P30AG072946-03
project_title: Core C: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9596
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advisory Committees;Aging;Alzheimer's Disease;Alzheimer's Disease Core Center;Applications Grants;Attention;Bioinformatics;Biological Markers;Biometry;COVID-19 pandemic;Clinical;Clinical Data;Clinical Trials;Clinical Trials Data Monitoring Committees;Cognitive;Collaborations;Communities;Data;Data Analyses;Data Collection;Dementia;Development;Education;Education and Outreach;Elderly;Elements;Enrollment;Environment;Epidemiology;Etiology;Evaluation;Event;Experimental Designs;Extramural Activities;Faculty;Funding;Generations;Genetic;Gerontology;Information Systems;Interruption;Kentucky;Leadership;Life;Literature;Manuscripts;Methodology;Mission;Neuroepidemiology;Observational Study;Online Systems;Participant;Pathology;Pilot Projects;Procedures;Productivity;Psychology;Public Health;Publications;Reporting;Research;Research Design;Research Methodology;Research Personnel;Resources;Risk Factors;Role;Sampling;Seasons;Services;Statistical Data Interpretation;Study Section;System;Tablets;Time;Training;Universities;Vision;central database;cohort;dashboard;data dictionary;data integration;data management;data warehouse;direct application;doctoral student;education research;electronic data capture system;improved;innovation;interest;meetings;member;mixed dementia;neuropathology;novel;outreach;programs;recruit;statistics;student training;success;user-friendly;web app;web platform;web site


application_id: 10662342
project_number: 5P30AG072946-03
project_title: Core B: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9595
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Clinical CoreThe Clinical Core of the UK-ADRC maintains a well-characterized community-based cohort focused onnormal aging and early transitional disease states and follows individuals longitudinally until brain autopsy.We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority GatewayClinic where autopsy is promoted but not required) allowing major contributions in the area of clinical-pathological correlative studies and definition of early preclinical and pre-dementia disease states. Theseefforts have been a driving force in our recognition of the heterogeneity of community-acquired dementiaincluding major contributions to the field in regard to LATE PART VCID and the role these pathologicstates play in conjunction with traditional AD LBD and FTLD disease states. A major focus of our work hasalso been on defining early clinical transitions involving the interplay of these disease states that has driventhe widespread exploration of late-life multi-etiology dementia syndromes. To further such advances theUK-ADRC Clinical Core emphasizes deep clinical biomarker genetic and post-mortem phenotyping of adiverse cohort of elderly subjects at high risk for multi-etiology dementia. Major initiatives in the area of ADmimics and transitions from normal to late-life multi-etiology dementia are well-poised to continue to move thefield forward in the areas of both diagnosis and translational interventional discoveries. We have introducedexciting new initiatives in our expansion of antemortem biomarker research allowing an even deeper clinicalphenotyping of our participants as we work towards translational discoveries for multi-etiology dementia. TheUK-ADRC will continue to constantly evolve in dynamic ways through our proposed specific aims.Aim 1: Maintain & longitudinally characterize a central longitudinal cohort enrolling cognitively normal subjectsto facilitate our understanding of preclinical disease and early cognitive transitions to multi-etiology MCI &dementia.Aim 2: Maintain and expand our successful Minority Gateway Clinics to maintain and grow our (significantly)above-parity for population minority engagement.Aim 3: Further develop and maintain an infrastructure to support translational therapeutic development throughall clinical trial phases in support of NIH ADCS ACTC initiatives industry-sponsored drug trials andinvestigator-initiated projects.Aim 4: Foster education and support of research participants and families to ensure that our efforts areclinically meaningful both in novel prevention studies as well as treatment in established diseaseOverall the Clinical Core will continue to provide an infrastructure and environment that will continue tocontribute to our success in advancing multidisciplinary innovative AD research supporting our center themeof Transitions from Normal to Late-Life Multi-Etiology Dementia.

project_terms:
Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Area;Automobile Driving;Autopsy;Biological Markers;Brain;Clinic;Clinical;Clinical Trials;Cognitive;Collaborations;Communities;Correlative Study;Dementia;Development;Diagnosis;Disease;Education;Elderly;Enrollment;Environment;Etiology;Family;Fostering;Frontotemporal Lobar Degenerations;Funding;Genetic;Goals;Heterogeneity;Image;Individual;Industry;Infrastructure;Intervention;Kentucky;Link;Liquid substance;Longitudinal cohort;Measures;Minority;Minority Groups;Mission;Participant;Pathologic;Pharmaceutical Preparations;Phase;Phenotype;Play;Prevention;Productivity;Publications;Recommendation;Research;Research Personnel;Research Project Grants;Research Support;Role;Syndrome;System;Trademark;United States National Institutes of Health;Universities;Work;clinical phenotype;cohort;design;driving force;high risk;innovation;minority engagement;multidisciplinary;normal aging;novel;novel therapeutic intervention;parity;pre-clinical;preclinical study;research clinical testing;success;therapeutic development;translational therapeutics


application_id: 10662339
project_number: 5P30AG072946-03
project_title: Core A: University of Kentucky Alzheimer's Disease Core Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G
subproject_number: 9594
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract: Administrative CoreThe ultimate goal of the UK-ADRC is to catalyze innovative and outstanding AD research while ensuring amore rapid rate of progress toward new therapies to delay or prevent AD so that our human volunteerspatients and caregivers become the beneficiaries of our advances in knowledge. The Administrative Coreprovides the foundation infrastructure leadership overall direction strategic planning and integration of allADRC components to more rapidly achieve this goal and advance our overall theme: Transitions from Normalto Late-Life Multi-Etiology Dementia. This theme builds on our traditional strengths in defining mechanismsunderlying the early changes that occur in individuals as they transition through the cognitive continuum riskfactors associated with these cognitive states and how mixed pathology and co-morbidities influence risk andprogression. Two historically outstanding resources of the UK-ADRC that enable research relevant to thistheme are: 1) a strong autopsy program providing clinical-neuropathological correlation and very short (2-4 hrs)postmortem interval (PMI) research material and 2) a unique continuously replenished group of ~500cognitively intact subjects followed longitudinally together with another ~300 initially normal individuals whotransition to pre-MCI MCI or dementia and all committed to brain autopsy upon death. These signatureresources have contributed to our becoming one of the premier centers defining pathogenic mechanismsunderlying the transitions from normal cognitive aging to the earliest stages of cognitive impairment. The UK-ADRC functions in a multidisciplinary integrated collaborative and supportive team science environment thatcatalyzes high-quality AD research within the UK community region nation and beyond. We will continue toprovide the infrastructure resources and intellectual capital to enhance transdisciplinary research and scientificinteractions develop new collaborations and partnerships contribute to national initiatives and offer innovativeeducation and training opportunities in the basic and clinical neurosciences. An effective Administrative Core isessential for transforming our goals into accomplishments. Therefore the Core will continue to support theability of our UK-ADRC to accomplish its goals and to promote the NAPA research implementation milestonesand goals through the following specific aims.Aim 1: Provide leadership administrative structure coordination and financial management to ensure optimalresource utilization to meet the overall goals of the UK-ADRC.Aim 2: Promote and catalyze clinical/translational research activities maximize interactions with otherdepartments and centers and foster new avenues of innovative research.Aim 3: Solicit review select and monitor the Developmental Projects.Aim 4: Contribute to and interact with other ADRCs and other national collaborative activities and increasevisibility in the local and national community.

project_terms:
Administrator;Alzheimer's Disease;Alzheimer's Disease Core Center;Alzheimer's disease related dementia;Autopsy;Biological;Brain;Brain Pathology;Capital;Caregivers;Cessation of life;Clinical;Cognitive;Cognitive aging;Collaborations;Communication;Communities;Decision Making;Dementia;Development;Doctor of Philosophy;Elderly;Ensure;Environment;Etiology;Fostering;Foundations;Goals;Heterogeneity;Human Resources;Human Volunteers;Impaired cognition;Individual;Infrastructure;Kentucky;Knowledge;Leadership;Modality;Monitor;Neurosciences;Occupational activity of managing finances;Pathogenicity;Pathology;Patients;Prevention;Research;Research Activity;Research Personnel;Resources;Risk;Risk Factors;Science;Strategic Planning;Structure;System;Tissues;Training and Education;Translational Research;United States;Universities;accurate diagnostics;beneficiary;cohort;comorbidity;diagnostic strategy;disease heterogeneity;effective therapy;innovation;meetings;multidisciplinary;neuropathology;novel therapeutics;pre-clinical;prevent;programs;success;training opportunity;treatment strategy;volunteer


application_id: 10662314
project_number: 5P30AG072946-03
project_title: University of Kentucky Alzheimer's Disease Research Center
administering_ic: NIA
award_notice_date: 2023-07-03
opportunity_number: RFA-AG-21-019
application_type: 5
activity_code: P30
ic: AG
serial_number: 072946
program_official: ELLIOTT, CERISE
project_start_date: 2021-08-01
project_end_date: 2026-06-30
study_section: ZAG1-ZIJ-G(M1)
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: 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/Abstract: OverallThe University of Kentucky Alzheimers Disease Research Center (UK-ADRC) is an experienced andcollaborative center that has facilitated pioneering research in AD and related dementias (ADRD) since itsinception in 1985. Our principal mission is to serve as the focal point for all AD-related activities at UK and thisregion of the United States by providing an environment and core resources that catalyze innovative researchoutreach education and clinical programs. Our signature resources include: 1) a cognitively normal group of~500 subjects followed longitudinally together with ~300 additional subjects who transitioned to MCI ordementia and all committed to brain autopsy upon death; 2) a strong autopsy program with clinical-neuropathological correlations and short postmortem interval research material; 3) a maturing programstudying the early preclinical biological emergence of mixed pathologies and how they contribute to late lifedementia states with an increasing focus on antemortem biomarker collection; 4) an integrated centralizeddatabase and innovative biostatistical expertise to characterize clinical and biological transitions; 5) asuccessful and close partnership with the African-American community and increased participation ofunderrepresented individuals in our longitudinal cohort and ADRC-affiliated research studies and clinical trials;and 6) a rich interdisciplinary training environment that provides multi-faceted educational opportunities forresearchers healthcare providers and our community partners. The overarching theme of the UK-ADRC is:Transitions 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. The UK-ADRCwill continue to leverage our strengths to enhance our impact and Centerness by our focus on thisoverarching theme and the pursuit of four overall specific aims.Aim 1. Facilitate and enhance basic translational and clinical research in AD and related dementias.Aim 2. Provide the necessary resources and interactive environment to support and create new opportunitiesfor innovative research.Aim 3. Maintain and grow educational opportunities and community partnerships to promote awarenessincrease participation in research and provide an innovative and interdisciplinary training environment.Aim 4. Contribute to the national efforts and collaborative activities with other centers programs and groups toadvance AD/ADRD research education and care.

project_terms:
Address;African American;Aging;Alzheimer's Disease;Area;Autopsy;Awareness;Basic Science;Biological;Biological Markers;Biometry;Brain;Caring;Cessation of life;Clinical;Clinical Research;Clinical Trials;Cognitive;Cognitive aging;Collaborations;Collection;Communities;Community Health Education;Community Outreach;Dedications;Dementia;Development;Disease;Early identification;Education;Elderly;Ensure;Environment;Etiology;Family;Goals;Health Personnel;Heterogeneity;Impaired cognition;Impairment;Individual;Infrastructure;Institution;Kentucky;Knowledge;Longitudinal cohort;Mission;Neurodegenerative Disorders;Outcome;Pathogenicity;Pathology;Recommendation;Research;Research Personnel;Research Project Grants;Resources;Risk;Scholars Program;Training;Translating;Translational Research;United States;United States National Institutes of Health;Universities;aging brain;beneficiary;central database;clinical practice;cohort;collaborative environment;community partnership;comorbidity;data management;driving force;education research;experience;innovation;neuropathology;next generation;normal aging;novel therapeutics;outreach;pre-clinical;programs;recruit;research study;statistics;success;volunteer

public_health_relevance:
NARRATIVE: OVERALLThe University of Kentucky Alzheimers Disease Research Center (UK-ADRC) facilitates and supportsbasic/translational and clinical research efforts to identify the early manifestations of disease and thepathogenic mechanisms underlying the transitions from normal aging to the development of cognitiveimpairment with a special focus on mixed pathology and co-morbidities that influence risk and outcomes inlate-life multi-etiology dementia. We are also dedicated to training the next generation of researchers and togrowing our educational programs and community partnerships to promote awareness of AD and relateddisorders and the importance of research and research participation.


application_id: 10662275
project_number: 5R25GM133328-05
project_title: UofL Bridges to Baccalaureate(ULBB)
administering_ic: NIGMS
award_notice_date: 2023-07-11
opportunity_number: PAR-17-210
application_type: 5
activity_code: R25
ic: GM
serial_number: 133328
program_official: STEPANEK, LAURIE ELIZABETH
project_start_date: 2019-07-15
project_end_date: 2025-06-30
study_section: Training and Workforce Development Study Section - C[TWD-C]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
other_pis: DAVIS, RANDALL
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTFor the last three decades biomedical research has been expanding rapidly and has made a great impact inproducing high quality skilled professionals in the U.S. However minorities and the underprivileged continueto be underrepresented (UR) in this work force. While the Trends in International Mathematics and ScienceStudy (TIMSS) and other reports show that US students are greatly improving their academic preparednesscompared to students from most other nations our country's minorities and underprivileged students remainrelatively poorly prepared to enter high technology careers such as biomedical and behavioral sciences. As aresult minorities who constitute about 29% of the total population represent only about 7% of Ph.D.degrees in biomedical and behavioral sciences and hold only about 4% of the R01 biomedical andbehavioral research grants. Many UR students are deprived of the opportunity to experience earlyengagement in science and math. Therefore because they lack the skills and exposure to move directly into4-year baccalaureate programs they enter into 2-year programs at the community and technical colleges.The UofL Bridges to Baccalaureate (ULBB) program will involve the University of Louisville (UofL) andJefferson Community and Technical College (JCTC) joining forces to develop a sustainable program that willintroduce underrepresented and disadvantaged community college students to the career opportunitiesavailable in biomedical and behavioral research and prepare them for successful transition from a 2-yearprogram at JCTC to a 4-year STEM related baccalaureate program at UofL. The ULBB program will focuson: 1) strengthening the partnership between JCTC and UofL to increase the recruitment ofunderrepresented minority and economically disadvantaged high school students into a pathway tobiomedical research careers increasing the graduation rate in Associate in Science (AS) from 12% in 3years to 50% in 2 years 2) providing a pipeline of support and mentoring personnel and programs includingacademic enrichments career development training and research experience during each 10-week summerprogram (two summers) at UofL under the mentorship of internationally renowned faculty that will enhancetransfer rate from a current 30% to 70% of ULBB-supported students and 3) continued mentoring andcounseling of students transferred from JCTC to UofL in a small group setting promoting their involvement inexisting undergraduate education programs to improve the present graduation rate of 33% to 70% of ourtransferred ULBB students leading to increased recruitment to biomedical research graduate education andcareers. The ULBB program is innovative and will not only impact the underrepresented and underprivilegedstudents themselves but also the broader curricular advising and research programs of both partnerinstitutions and the pool of diverse well-qualified scientists entering biomedical research careers.

project_terms:
Achievement;African American;Area;Bachelor's Degree;Behavioral Research;Behavioral Sciences;Biomedical Research;Budgets;College Preparation;Counseling;Country;Developing Countries;Disabled Persons;Doctor of Philosophy;Dropout;Educational workshop;Enrollment;Exposure to;Face;Faculty;Funding;Goals;Graduate Degree;Graduate Education;Graduation Rates;High School Student;Hispanic;Human Resources;Individual;Institution;International;Internships;Knowledge;Mathematics;Mentors;Mentorship;Minority;Pathway interactions;Population;Preparation;Program Sustainability;Qualifying;Readiness;Reporting;Research;Research Personnel;Research Project Grants;STEM field;STEM program;STEM student;Schools;Science;Science Technology Engineering and Mathematics;Science Technology Engineering and Mathematics Education;Scientist;Secondary Schools;Students;System;Talents;Technology;Training;Underrepresented Minority;Underrepresented Students;Universities;Work;academic preparation;bridge to the baccalaureate;career;career development;college;community college;disadvantaged student;early experience;economic disparity;experience;higher education;improved;innovation;matriculation;neighborhood disadvantage;prevent;programs;recruit;retention rate;skills;student mentoring;summer program;technical college;transfer student;trend;undergraduate education;undergraduate research experience;undergraduate student;underserved students;university student

public_health_relevance:
NARRATIVEThe UofL Bridges to Baccalaureate (ULBB) program will involve the University of Louisville (UofL) and JeffersonCommunity and Technical College (JCTC) joining forces to develop a program that facilitates the transition ofoutstanding students from underrepresented background and enrolled in a two-year program at JCTC toenter into 4-year STEM related baccalaureate programs at UofL. The ULBB program will focus onunderrepresented individuals in the STEM fields especially on African-American Hispanic and economicallydisadvantaged students and will provide paid research internships for the students to participate with fundedresearchers at UofL. The ULBB program will also focus on providing academic preparation combined withextensive pre- and post-transfer mentoring that will facilitate student transfer to 4-year STEM programs andsuccessful completion of the baccalaureate degree with the ultimate goal of increasing recruitment to biomedicalresearch careers.


application_id: 10659462
project_number: 1R01NS127974-01A1
administering_ic: NINDS
award_notice_date: 2023-04-14
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 127974
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2023-04-15
project_end_date: 2028-03-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 15196532
contact_pi: HARP, JORDAN PATRICK
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Predictors and Biomarkers for VCID versus Cognitive Recovery after Stroke Thrombectomy in Rural Appalachia

project_abstract:
Vascular cognitive impairment and dementia (VCID) is present in 25-30% of stroke patients and it is difficult topredict at the time of stroke who those patients will be. The National Plan to Address Alzheimers Disease andthe NHLBI-NINDS VCID Workshop called for increased research on VCID prediction especially in underservedpopulations. The proposed research will identify predictors of cognitive recovery in rural underserved patientsafter mechanical thrombectomy for emergent large vessel occlusion (ELVO) stroke. These predictors will targetpatients that would benefit from intensive rehabilitation. Our novel biologic sample registry was used to identifyproteins in systemic blood samples taken during thrombectomy as independent predictors of cognitiveperformance at post-stroke discharge and 90-day follow-up. The hypothesis is that these proteins will provideincremental predictive validity for cognitive impairment including dementia over and above clinicalcharacteristics social determinants of health and traditional ADRD plasma biomarkers. The proposed study willprospectively enroll 225 patients collecting systemic arterial blood at the time of thrombectomy and analyzeprotein expression. Using a retention strategy tailored to underserved rural participants neurocognitive test dataand venous blood samples for longitudinal protein expression will be collected from 3 months to 2 years post-thrombectomy. The study site located in the US Stroke Belt with some of the most medically underserved ruralcounties in the nation will contribute to the NIH priority focus on health disparities. Specific Aim 1: Test thehypothesis that increased patient home county rurality predicts worse cognitive outcomes post-strokeboth acutely and chronically. Generalized estimating equation models will test the main effect of home countyrurality and other social determinants of health on cognitive status (normal cognitive impairment no dementiadementia) the main effect of time on cognitive performance across time points and the interaction of rurality andtime on cognitive status across time points. Associations among rurality comorbidities and time-of-thrombectomyblood protein expression will be auxiliary analyses. Specific Aim 2: Test the hypothesis that ADRDbiomarkers in systemic blood at time of thrombectomy are biomarkers for acute post-stroke cognitiveimpairment and chronic VCID two years later. Blood samples will be assessed for known proteomicbiomarkers for cognition at the UKY Biomarker Center. Specific Aim 3: Test the hypothesis that novelbiomarkers in systemic blood at time of thrombectomy predict chronic VCID including dementia overand above the effects of ADRD markers. Proteomic analysis will be conducted on time-of-thrombectomy bloodsamples to measure the expression of inflammatory-related proteins. Hierarchical generalized estimatingequation models will assess the incremental improvement in prediction of cognitive status over time added bythese addition markers. Analyses will use LASSO methods and split-sample cross-validation to create apredictive model based on both ADRD and novel biomarkers that predict cognitive outcomes.

project_terms:
Acute;Address;Affect;Alzheimer's Disease;Alzheimer's disease related dementia;Biological;Biological Markers;Blood;Blood Proteins;Blood specimen;Brain;Caregiver Burden;Caring;Catchment Area;Characteristics;Chronic;Clinical;Coagulation Process;Cognition;Cognitive;County;Data;Dementia;Development;Early Diagnosis;Educational workshop;Enrollment;Equation;Excision;Goals;Health Services Accessibility;Home;Home visitation;Impaired cognition;Inflammation;Inflammatory;Joints;Life;Machine Learning;Measures;Mechanics;Medical History;Medical Records;Methods;Modeling;National Heart Lung and Blood Institute;National Institute of Neurological Disorders and Stroke;Outcome;Participant;Patients;Plasma;Positioning Attribute;Procedures;Proteins;Proteomics;Registries;Rehabilitation therapy;Research;Rural;Rural Appalachia;Rural Population;Sampling;Signal Pathway;Site;Statistical Models;Stroke;Stroke Belt;Suburban Population;Testing;Thrombectomy;Time;Travel;Underserved Population;United States National Institutes of Health;Validation;Venous blood sampling;Work;acute stroke;barrier to care;care delivery;cognitive impairment no dementia;cognitive performance;cognitive recovery;comorbidity;disability;follow-up;functional improvement;health care availability;health disparity;improved;medical complication;medically underserved;mortality;neurocognitive test;novel;novel marker;novel therapeutic intervention;novel therapeutics;outcome prediction;patient population;post stroke;post stroke cognitive impairment;precision medicine;predictive marker;predictive modeling;programs;prospective;protein biomarkers;protein expression;retention rate;rural counties;rural underserved;rurality;social health determinants;stroke cognitive outcome;stroke patient;success;underserved area;urban health disparities;vascular cognitive impairment and dementia

public_health_relevance:
Thrombectomy is a life-saving procedure that removes clot from the brain during stroke but it is difficult topredict which patients will recover cognitively and which will have persistent cognitive impairment or decline(VCID: vascular contributions to cognitive impairment and dementia)and it is particularly difficult to predictthese outcomes in rural underserved patients who tend to have more complicated medical histories andbarriers to care. Using a retention strategy tailored to the needs of rural underserved participants theproposed study will test how well certain proteins in blood collected at the time of thrombectomy predict thelong-term cognitive outcomes of stroke patients in one of the most rural and medically underserved regions inthe U.S. Stroke Belt. Study success would address a major rural-urban health disparity and also benefit strokepatients at large by making available the first long-term cognitive profiles of thrombectomy patients byimproving the assignment to proper care using the earliest possible blood markers for VCID versus cognitiverecovery and by opening the door to development of new therapeutics based on blood protein signalingpathways that affect cognitive outcomes.


application_id: 10659303
project_number: 1R21AG082081-01
project_title: Olfactory Epithelium Responses to Human APOE Alleles
administering_ic: NIA
award_notice_date: 2023-03-29
opportunity_number: PAR-22-094
application_type: 1
activity_code: R21
ic: AG
serial_number: 082081
program_official: ST HILLAIRE-CLARKE, CORYSE
project_start_date: 2023-04-01
project_end_date: 2025-03-31
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Deficits in olfaction were recognized decades ago as early symptoms in people with incipient AlzheimersDisease. However these discoveries have had less impact than hoped on the study diagnosis and treatmentof this disease. Though central nervous system olfactory pathways suffer the plaques and/or tangles that arecharacteristic of late-stage disease these symptoms do not set the olfactory system apart from other foci ofresearch into Alzheimers Disease. Perhaps because the regenerative capacity of the olfactory epitheliumobscured the vulnerability of olfactory sensory neurons to Alzheimers Disease especially the early eventsleading to the neurodegeneration characteristic of the disease study of how the olfactory epithelium isimpacted by Alzheimers Disease languished. Clear evidence that the olfactory sensory neurons in theepithelium are susceptible to factors that cause or increase risk of Alzheimers Disease has recently emergedhowever. These findings demonstrate that the olfactory epithelium is a worthy model of how risk factors forAlzheimers Disease affect neurons and their supporting cells. Thus far the data correlate well with effects inthe brain evidence that the olfactory epithelium may be a bellwether for events transpiring in the centralnervous system. The accessibility of the olfactory epithelium for biopsy to assess disease progression inindividuals and to drugs that cannot pass the blood brain barrier further elevates the significance of theolfactory epithelium as a model. This project investigates the effects of a critical risk factor for AlzheimersDisease APOE genotype on the olfactory epithelium and its olfactory sensory neurons. The experimentsfocus on identifying early events and the strength of their effects on phenotype and function. It uses mousemodels of the disease including established genetic models previously used to investigate effects in the brainand a novel model that allows switching at will from a neurodegenerative genotype to a neuroprotectivegenotype. The latter allows testing of whether cellular and molecular events associated with vulnerability toAlzheimers Disease can be prevented or reversed by in vivo genetic manipulation outcomes that would informand inspire further work towards curing this disease.

project_terms:
Adult;Affect;Age;Alleles;Alzheimer associated neurodegeneration;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Apolipoprotein E;Autopsy;Biopsy;Blood - brain barrier anatomy;Brain;Cells;Central Nervous System;Characteristics;Chronic;Complex;Data;Data Correlations;Development;Diagnosis;Disease;Disease Progression;Disease model;Early identification;Epithelium;Event;Foundations;Gene Expression;Genetic;Genetic Models;Genotype;Glucose;Goals;Human;Human Amyloid Precursor Protein;Immune response;Individual;Intervention;Late Onset Alzheimer Disease;Learning;Link;MAPT gene;Measures;Messenger RNA;Metabolic dysfunction;Microglia;Modeling;Molecular;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Neurons;Olfactory Epithelium;Olfactory Pathways;Outcome;Pathologic;Pathway interactions;Persons;Pharmaceutical Preparations;Phenotype;Predisposition;Probability;Proxy;Publishing;Regenerative capacity;Research;Risk Factors;Risk Reduction;Site;Smell Perception;Stress;Supporting Cell;Symptoms;Testing;Tissues;Work;age effect;age related;apolipoprotein E-3;apolipoprotein E-4;cell type;experimental study;gene therapy;genetic manipulation;genetic variant;glucose uptake;improved;in vivo;in vivo Model;lipidome;middle age;mouse model;mutant;neural;neuroinflammation;neuron apoptosis;neuronal survival;neuroprotection;novel;olfactory sensory neurons;prevent;protective effect;response;single-cell RNA sequencing;slow axonal transport;success;sustentacular cell;synergism;therapy design;transcriptome;young adult

public_health_relevance:
Project Narrative:Deficits in olfaction are long-established symptoms of Alzheimers Disease whose potential to revealmechanisms leading to this disease has yet to be realized. Recent evidence that the olfactory epithelium andits olfactory sensory neurons are vulnerable to genetic variants linked to Alzheimers Disease openopportunities to investigate early effects leading to neurodegeneration in a neural tissue that is easilyaccessible including via biopsy in humans. This project investigates the effects of human apoliproprotein Ealleles on the olfactory epithelium and its neurons in mouse models including whether switching expressionfrom a neurodegenerative allele to a neuroprotective allele prevents and reverses effects linked to AlzheimersDisease.


application_id: 10659141
project_number: 5R01CA256893-03
project_title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
administering_ic: NCI
award_notice_date: 2023-06-29
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 256893
program_official: KONDAPAKA, SUDHIR B
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancerAbstractIt has been documented that androgen receptor (AR) signaling remains to play a critical role in castration-resistant prostate cancer (CRPC). Indeed Androgen Signaling Inhibitors (ASI) such as abiraterone aninhibitor of de novo androgen synthesis pathway and enzalutamide a direct AR inhibitor are major drugsused in clinic to manage CRPC now. Unfortunately ASI-based treatment only improves the overallpatient survival by several months. Therefore understanding the underlying mechanisms of ASIresistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgentlyneeded. With the goal to identify new pathways/targets whose inhibition might overcome ASI resistancewe performed extensive bioinformatics analyses of RNA-seq data including those from paired prostatecancer (PCa) cells with different sensitivities to enzalutamide 498 PCa tumors with different responsesto hormone therapy and 52 pairs of PCa specimen (tumors vs adjacent normal). Both the -catenin-dependent canonical Wnt cascade and the -catenin-independent non-canonical Wnt signaling wereidentified as pathways whose elevation might contribute to acquisition of ASI resistance. The objectiveof the proposed research is to define the roles of Wnt signaling in acquisition of ASI resistance in CRPCand to exploit these pathways as novel therapeutic targets for CRPC patients who no longer respond toASIs. The central hypothesis is that Wnt signaling causes constitutive activation of AR signaling thusCRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing threeSpecific Aims - (1) to dissect the role of-catenin signaling in enzalutamide resistance of PCa; (2) toexamine how activation of the non-canonical Wnt signaling contributes to enzalutamide resistance inPCa; and (3) to test whether simultaneous inhibition of canonical and non-canonical Wnt cascades is aneffective approach to treat enzalutamide-resistant PCa and to probe the significance of tumormicroenvironment Wnt in the acquisition of enzalutamide resistance. These complementary aims will beaccomplished using biochemical analyses of signaling intermediates and employing gain-of-function andloss-of-function strategies with inducible PCa mouse models culture systems human PCa xenograftand patient-derived organoid methodologies. The rationale for the research is that it will be the first tocomprenhensively probe the importance of Wnt signaling in acquisition of ASI resistance of CRPC. Thiscontribution is significant because it will (i) define the molecular mechanism by which Wnt signalingactivates AR; (ii) genetically evaluate how these pathways contribute to PCa progression and metastasis;and (iii) demonstrate Wnt cascades as critical therapeutic targets to enhance the efficacy of ASI.

project_terms:
Acetates;Affect;Androgen Antagonists;Androgen Receptor;Androgens;Autocrine Communication;Biochemical;Bioinformatics;Cancer Patient;Castration;Cells;Clinic;Clinical;Coculture Techniques;Creativeness;Cultured Cells;Data;Development;Disease;Drug usage;Event;Fibroblasts;Fostering;Genetically Engineered Mouse;Goals;Health;Human;Investigation;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Modeling;Molecular;Mus;Mutation;Neoplasm Circulating Cells;Neoplasm Metastasis;Organoids;Outcome;Paracrine Communication;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacotherapy;Play;Protein Family;Public Health;RNA analysis;Receptor Activation;Receptor Signaling;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Testing;Therapeutic;Tissue Microarray;United States National Institutes of Health;WNT Signaling Pathway;Withdrawal;Xenograft procedure;abiraterone;castration resistant prostate cancer;clinical translation;clinically relevant;docetaxel;enzalutamide;gain of function;hormone therapy;improved;inhibitor;inhibitor therapy;innovation;loss of function;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;pharmacologic;planar cell polarity;prostate cancer cell;prostate cancer progression;receptor;response;therapeutic target;transcriptome;transcriptome sequencing;tumor;tumor microenvironment


application_id: 10658494
project_number: 1R01AR080708-01A1
project_title: Leveraging Wearables to Transform Patient Recovery after Tibial Fracture Surgery
administering_ic: NIAMS
award_notice_date: 2023-08-10
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AR
serial_number: 080708
suffix: A1
program_official: WASHABAUGH, CHARLES H
project_start_date: 2023-08-10
project_end_date: 2028-06-30
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: ZELIK, KARL E
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Over 490K Americans fracture their tibia (shinbone) yearly and require surgery. However patient recovery 1year following surgery is poor and inconsistent with 2/3 of patients reporting an inability to do pre-injury leisureactivities and 1/2 still not having recovered enough to return to work. A key role of clinicians after tibial shaftfracture surgery is to prescribe a rehabilitation exercise program that exposes each patient's tibia to increasingforces to gradually recover the ability to do pre-injury activities. However major limitations holding backprogress in the field are the lack of knowledge on how much tibial force patients experience during dailyactivities in their rehabilitation program throughout recovery and how tibial force early in recovery affectslonger-term functional recovery. The overarching goal of this work is to generate the knowledgebase and toolsthat will enable us to reimagine and elevate the standard of care for individuals after tibial shaft fracturesurgery by monitoring and managing tibial bone forces in daily life. We propose to accomplish the overarchingobjective through the following aims. Aim 1: Characterize tibial bone force in patients at home over the firstyear following surgery. Aim 2: Create the first clinical reference guide that ranks tibial forces during commonly-prescribed rehabilitation exercises. Aim 3: Assess if higher tibial forces during early recovery correspond withbetter functional outcomes at 6- and 12-month follow up. If our hypothesis is supported then these resultswould inform new clinical guidelines (target bone force thresholds) and biofeedback interventions to monitorand promote healthy bone forces in recovery. This wearable monitoring paradigm has unparalleled potential tobe adapted to elevate care for recovery from numerous musculoskeletal disorders.

project_terms:
Address;Affect;Algorithms;American;Back;Biofeedback;Biological Markers;Caring;Clinic;Clinical;Data;Data Set;Dose;Early Intervention;Ensure;Exercise;Fill-It;Fracture;Future;Goals;Guidelines;Health Care Costs;Home;Hospitals;Individual;Injury;Intervention;Journals;Knowledge;Laws;Leisure Activities;Length of Stay;Life;Limb structure;Link;Longitudinal Studies;Measurement;Measures;Modeling;Monitor;Muscle;Musculoskeletal Diseases;Office Visits;Operative Surgical Procedures;Outcome;Pain;Pathway interactions;Patient-Focused Outcomes;Patients;Physical therapy;Postoperative Period;Publishing;Reaction;Recovery;Recovery of Function;Rehabilitation therapy;Reporting;Risk;Severities;Shoes;System;Techniques;Testing;Tibial Fractures;Time;Training;Walking;Work;bone;demographics;design;empowerment;exercise program;exercise rehabilitation;experience;follow-up;functional outcomes;improved;in vivo;innovation;knowledgebase;light weight;limb injury;mechanotransduction;novel;pressure;programs;remote monitoring;sample fixation;sensor;standard of care;tibia;tool;wearable device;wearable monitor;wearable sensor technology

public_health_relevance:
Project Narrative: Tibial shaft fractures are a common injury resulting in significant problems includinginability to return to work and societal functions. The identification of how individuals load their limb over timeand how physical therapy contributes to tibial loading is unknown. We propose to define how individualsincrease load over time how physical therapy loads the tibia and how recovery is influenced by loading.


application_id: 10658215
project_number: 1RF1AG082339-01
project_title: Genetic Architecture of Aging-Related TDP-43 and Mixed Pathology Dementia
administering_ic: NIA
award_notice_date: 2023-04-13
opportunity_number: PAR-22-093
application_type: 1
activity_code: RF1
ic: AG
serial_number: 082339
program_official: BENNANI-BAITI, MICHAEL
project_start_date: 2023-04-15
project_end_date: 2026-03-31
study_section: Genetics of Health and Disease Study Section[GHD]
contact_pi_person_id: 9594976
contact_pi: FARDO, DAVID WILLIAM
other_pis: NELSON, PETER T.
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Aging-related dementia is highly heritable yet a large proportion of this genetic risk remains unexplained. In>30% of aged individuals with clinical dementia autopsy reveals TDP-43 pathology  an enormous and under-acknowledged public health problem. A term for this prevalent non-Alzheimers amnestic dementia-associatedcondition was recently proposed: limbic predominant age-related TDP-43 encephalopathy (LATE). There isgreat clinical and pathologic heterogeneity among individuals with LATE pathology. Some affected individualshave a rapid and devastating clinical course whereas others have relatively benign symptoms. Both the severityof TDP-43 pathology and the presence of comorbid pathologies appear to be key determinants of clinicaloutcomes in LATE. We have generated exciting preliminary data that indicate distinct (and pleiotropic) geneticrisk factors for LATE and associated pathologies. However there is still an incomplete understanding of thegenetic determinants of these brain diseases. To address this knowledge gap we will develop a robust analysispipeline (leveraging extensive prior work and resources) using data-driven methods to classify pathologyprogression and novel statistical methods to analyze genetic risk/protective factors.AIM 1: Assemble multimodal datasets (including clinical and genetics data) for testing novel hypothesesabout LATE pathogenesis and develop rubrics for pure and mixed subtypes of pathologyWe will leverage extensive data processing resources to derive and test a pathological classification systemoptimal for research at the nexus between genetic risk and neuropathologic endophenotypes. Keyendophenotypes in the dataset will include digital neuropathologic assessment of pathologies. Through thesestudies we will gather and curate clinical genetic and pathological information on diverse populations.AIM 2: Identify genetic regions associated with aging-related TDP-43 brain pathology i.e. LATEWe will employ genome-wide and targeted association testing predicted quantitative trait loci (QTL) detectionand subsequent colocalization. Preliminary results demonstrate that our goals are broadly achievable given ourstudy sample sizes. A set of LATE risk factor genes has been discovered by us and others2-6 including proof-of-concept: a LATE neuropathology gene previously linked to clinical Alzheimers disease (WWOX).7AIM 3: Identify genetic regions and biologic pathways associated with LATE-associated neuropathologicendophenotypes: coexisting hippocampal sclerosis arteriolosclerosis and Alzheimers diseaseWe will test the hypotheses that comorbid LATE-related phenotypes share genetic predisposition and can betreated as subtypes. Further underlying pathways are discoverable with multivariate methodologies. We willexpand our understanding of the genetic risk factors disease-associated pathways and the potential formodifying those pathways. We will develop and employ multivariate clustering and individual-specific networkmethods to infer pathways driving LATE-related pathologic phenotypes.

project_terms:
Address;Affect;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Arterioloscleroses;Automobile Driving;Autopsy;Benign;Bioinformatics;Biological;Biometry;Brain;Brain Diseases;Brain Pathology;Brain region;Classification;Clinical;Collection;Complex;Data;Data Collection;Data Set;Databases;Dementia;Detection;Disease;Genes;Genetic;Genetic Determinism;Genetic Models;Genetic Predisposition to Disease;Genetic Risk;Genomics;Genotype;Goals;Hand;Heritability;Heterogeneity;Human;Individual;Interdisciplinary Study;Knowledge;Link;Maps;Methodology;Methods;Multivariate Analysis;Nerve Degeneration;Outcome;Pathogenesis;Pathologic;Pathology;Pathway interactions;Pattern;Persons;Phenotype;Play;Population;Population Heterogeneity;Prevention;Public Health;Quantitative Trait Loci;Research;Resources;Risk;Risk Factors;Sample Size;Sampling Studies;Severities;Single Nucleotide Polymorphism;Statistical Methods;Symptoms;System;Testing;Variant;Work;age related;aged;analysis pipeline;brain arteriolosclerosis;burden of illness;cerebrovascular pathology;clinical risk;comorbidity;computerized data processing;computing resources;dementia risk;digital;disease phenotype;endophenotype;evidence base;genetic architecture;genetic risk factor;genetic variant;genome wide association study;genome-wide;genomic locus;hippocampal sclerosis;limbic-predominant age-related TDP-43 encephalopathy;member;mixed dementia;multidisciplinary;multimodal data;neuropathology;next generation sequencing;nonalzheimer dementia;novel;protective factors;protein TDP-43;risk variant

public_health_relevance:
PROJECT NARRATIVEAging-related dementia is caused at least in part by a persons genes; exactly which genetic variantsare responsible for this remains largely unknown. This project uses new and existing data to preciselyidentify the genetic causes of a form of non-Alzheimers disease dementia known as limbicpredominant age-related TDP-43 encephalopathy (LATE). Understanding the genetic roots of LATEwill shed considerable light on the mechanisms of the disease which can in turn be leveraged todevelop new modes of prevention and treatment thereby reducing the considerable burden thisdisease has on public health.


application_id: 10658099
project_number: 1R01ES034389-01A1
project_title: Role of Splenic Pro-Resolving Mediators During Exposure to Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2023-04-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: ES
serial_number: 034389
suffix: A1
program_official: NADADUR, SRIKANTH
project_start_date: 2023-05-01
project_end_date: 2028-02-29
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 12651681
contact_pi: SANSBURY, BRIAN EDWARD
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular disease. Although the mechanismsby which PM induces pervasive multi-organ injury are still under investigation evidence strongly implicateschronic inflammation as a primary driver of pathology. Whether exposure to fine PM (PM2.5) specifically impairsthe endogenous pathways that promote the resolution of inflammation is not known. Therefore the long-termgoal of this project is to determine how exposure to PM impacts the resolution of inflammation and whether thiscontributes to PM exposure-exacerbated atherosclerosis. In work in progress we discovered that in miceexposed to concentrated PM (PM2.5) for 30 days circulating erythrocytes expressed markers of premature agingand oxidative damage. In the spleens of these mice there was an expansion of the population of cells responsiblefor erythrocyte disposal red pulp macrophages while pathways related to erythrocyte turnover hememetabolism and iron cycling were upregulated. Additionally we found that several factors related tohematopoiesis were induced in the tissue. These alterations were accompanied by a marked decrease in theabundance of specialized lipid mediators that promote resolution (SPMs) and their receptors. The changes inspleen are particularly critical because the spleen plays a central role in regulating immune response dynamics.It houses an important and distinct reservoir of monocytes which can be rapidly mobilized and deployed inresponse to various insults. In addition to coordinating immune function the spleen acts as a filter to removesenescent and damaged erythrocytes. Though patients survive following splenectomy they are more likely tocontract serious and life-threatening infections and have heightened risk of developing hematologicalmalignancies and coronary artery disease among other disorders. Our preliminary studies suggest that exposureto PM2.5 may disrupt splenic homeostasis with targeted impacts on red pulp macrophages. As macrophages arethe critical facilitators of erythrophagocytosis maintenance of the splenic hematopoietic niche and SPM actionsour central hypothesis is that PM2.5 exposure increases splenic macrophage erythrophagocytosis whichsuppresses SPM production and permits local myelopoiesis thereby enhancing monocyte egress andexacerbating vascular inflammation. To test this hypothesis we will examine the effects of PM2.5 exposure onsplenic macrophages determine the impact of PM2.5 exposure on the splenic hematopoietic niche and delineatethe contribution of splenic myelopoiesis to PM2.5-exacerbated atherosclerosis. This project will elucidate theeffects of PM on the resolution of inflammation and will provide a new mechanism by which exposure to PMestablishes a state of chronic non-resolving inflammation that affects multiple organs and processes.

project_terms:
Acceleration;Address;Adoptive Transfer;Affect;Air Pollution;Apolipoprotein E;Applied Research;Arachidonate 15-Lipoxygenase;Atherosclerosis;Biological;Cardiovascular Diseases;Cells;Chronic;Complex;Contracts;Coronary Arteriosclerosis;Development;Disease;Disease Progression;Engraftment;Enzymes;Erythrocytes;Erythrophagocytosis;Event;Excision;Exposure to;FPR2 gene;Genetic Transcription;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Heme;Homeostasis;Homing;Immune response;Immunity;Impairment;Individual;Infection;Inflammation;Inflammation Process;Inflammatory;Interruption;Investigation;Iron;Knockout Mice;Lead;Leukocytes;Life;Link;Longevity;Macrophage;Maintenance;Maps;Measures;Mediating;Mediator;Metabolism;Mus;Myelogenous;Myelopoiesis;Organ;Particulate;Particulate Matter;Pathology;Pathway interactions;Patients;Phase;Play;Population;Premature aging syndrome;Process;Production;Property;Resolution;Risk;Role;Scheme;Signal Transduction;Site;Spleen;Splenectomy;Splenic Red Pulp;Stimulus;Systemic disease;Testing;Tissues;Up-Regulation;Work;cardiovascular disorder risk;cardiovascular risk factor;cell type;cytokine;exhaustion;fine particles;fundamental research;immune function;immunoregulation;in vivo;interest;lipid mediator;monocyte;multiorgan injury;oxidative damage;prevent;programs;receptor;response;senescence;single-cell RNA sequencing;spleen transplantation;uptake;vascular inflammation

public_health_relevance:
Chronic exposure to ambient particulate matter (PM) leads to systemic inflammation andcardiovascular disease. Promoting the endogenous active mechanisms of resolution mayinterrupt persistent inflammatory inputs induced by PM. Here we will assess the impacts of PMexposure on the cellular facilitators of resolution and determine whether their response to PMgoverns systemic immunity.


application_id: 10657389
project_number: 5R01HD097675-05
project_title: Neurotensin: A Novel Mediator of Ovulation
administering_ic: NICHD
award_notice_date: 2023-06-08
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HD
serial_number: 097675
program_official: TAYMANS, SUSAN
project_start_date: 2019-09-06
project_end_date: 2026-05-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: DUFFY, DIANE M
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
A womans fertility is dependent on the cascade of events leading up to ovulation. Defects in this ovulatoryprocess result in 25% of all female infertility cases supporting the paramount role of ovulation in reproductivesuccess and providing a strong premise to explore mediators of the ovulatory process. We propose thatneurotensin is one of these pivotal regulators of the ovulatory process. Ovulation is set in motion by the preovulatory LH surge which increases ovarian intrafollicular mediatorsthat act to bring about oocyte release. Our novel and exciting preliminary data indicate that neurotensin (NTS)a small neuropeptide is a key intrafollicular mediator of ovulation. This is based upon our findings that NTS isone of the most differentially-expressed genes in the granulosa cells of the human ovulatory follicle up to15000 fold after the ovulatory gonadotropin surge. Likewise LH also rapidly and significantly increases NTSmRNA in granulosa cells from rodent and monkey ovulatory follicles. Importantly injection of a neurotensinantibody into monkey preovulatory follicles blocked oocyte release resulting in luteinized unruptured folliclesconsistent with failure of ovulation. Similarly mice lacking NTS expression form luteinized unruptured folliclesfollowing LH/hCG administration and a NTS receptor antagonist inhibits oocyte release in a novel in vitromodel of mouse ovulation. Yet other than our preliminary data nothing is known regarding the temporalexpression of NTS receptors or the function of NTS in ovulation and female fertility. These questions will beaddressed in this proposal through a collaborative approach utilizing the exceptional backgrounds technicalexpertise and models of the Project Leaders. We will make use of a high-impact translational model wherethe granulosa and theca from human periovulatory follicles will be collected prior to and at three designatedtimes after hCG (early late and postovulatory) to complement in vivo and in vitro studies performed with miceand monkeys. The regulation of NTS and NTS receptor expression in the ovulatory follicle will be illuminatedand compared across women monkeys and mice in Aim 1. The ovulatory functions stimulated by NTS ingranulosa theca cumulus and endothelial cells of the follicle will be elucidated in Aim 2. The actions of NTSon ovulation as well as other key reproductive processes will be revealed in mice and monkeys using micelacking NTS expression NTS receptor antagonists and NTS-neutralizing antibodies in Aim 3. A major strengthof this proposal is the collaborative interactions between Dr. Curry and Dr. Duffy to address the function of NTSand its receptors in periovulatory events across multiple species including exceptional human ovarian tissuesand in vivo studies of non-human primates an animal model with high relevance to human reproductivefunction. Thus there is an exceptional degree of significance in understanding the basic tenets of oocyterelease which provides a fundamental platform to either improve outcomes for infertile women or converselyprovide targets to prevent oocyte release for female contraception.

project_terms:
Address;Agonist;Animal Model;Antibodies;Bioinformatics;Cell physiology;Central Nervous System;Complement;Data;Defect;Development;EGF gene;Endothelial Cells;Evaluation;Event;Failure;Fc Receptor;Female Contraceptive Agents;Female infertility;Fertility;Fertilization;Future;Gene Expression Profiling;Genes;Gonadotropins;Histologic;Human;Human Chorionic Gonadotropin;In Vitro;Infertility;Injections;LH Receptors;Luteinization;Mediating;Mediator;Messenger RNA;Modeling;Monkeys;Motion;Mus;Neuropeptides;Neurotensin;Neurotensin Receptors;New Agents;Oocytes;Ovarian;Ovarian Follicle;Ovarian Tissue;Ovary;Ovulation;Pathway interactions;Play;Pregnancy;Pregnancy Outcome;Process;Progesterone;Prostaglandins;Receptor Signaling;Regulation;Reproductive Process;Reproductive system;Rodent;Role;Rupture;Signal Transduction;System;Technical Expertise;Testing;Time;Vascular Endothelial Cell;Wild Type Mouse;Woman;angiogenesis;antagonist;cell type;collaborative approach;differential expression;experimental study;female fertility;granulosa cell;implantation;improved outcome;in vitro Model;in vivo;mouse model;neutralizing antibody;nonhuman primate;novel;oocyte quality;paracrine;prevent;receptor;receptor expression;reproductive function;reproductive success;response;theca cell;translational model

public_health_relevance:
The present study explores the role of neurotensin in the ovulatory process. Neurotensinincreases prior to ovulation in mice monkeys and women and a loss of neurotensin results inovarian follicles that do not ovulate. The proposed studies will elucidate the role that thisexquisite system plays in the coordinated processes of follicular rupture and oocyte releasewhich will aid in the understanding of the regulation of human fertility.


application_id: 10657188
project_number: 1R01CA272772-01A1
administering_ic: NCI
award_notice_date: 2023-03-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 272772
suffix: A1
program_official: SINGH, ANJU
project_start_date: 2023-04-01
project_end_date: 2028-03-31
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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_title:
Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer

project_abstract:
Lung cancer kills more people than any other type of cancer including more than 130000 people each year inthe United States. Non-small cell lung cancer (NSCLC) is the most common subtype (82% of all lung cancers)and can arise from squamous or non-squamous lung epithelial cells. Combination treatment with immunotherapy(i.e. monoclonal antibodies targeted to PD-1 or PD-L1) plus concurrent chemotherapy (usually including cisplatinor carboplatin) is now part of the standard of care for many patients with NSCLC. Although in lab-based studieschemotherapy has some effects that are expected to enhance the efficacy of immunotherapies whetherchemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is not wellunderstood at present. Based on our preliminary data we propose to investigate how cisplatin a chemotherapycommonly used to treat NSCLC creates an immunosuppressive tumor microenvironment (TME) that limits theanti-tumor activity of anti-PD-1 immunotherapy. Specifically we hypothesize the following steps: (a) cisplatininduces prostaglandin E2 (PGE2) production in tumor cells; (b) PGE2 leads to upregulation of CD73 enzyme onthe surface of monocytic myeloid-derived suppressor cells (M-MDSCs); (c) CD73 catalyzes the production ofextracellular adenosine from AMP (derived from ATP released from dying cells); and (d) adenosine inhibits theactivation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo-immunotherapy. Furthermore we propose a novel therapeutic strategy for overcoming this adenosine-mediatedimmunosuppression and sensitizing tumors to chemo-immunotherapy whereby co-treatment with recombinantpolyethylene glycol-conjugated adenosine deaminase enzyme (PEG-ADA) will convert immunosuppressiveadenosine into immunostimulatory inosine. In Specific Aim 1 of this project we will test our predictions about thekey cellular and molecular players in this pathway including cisplatin-induced PGE2 secretion CD73 expressionon M-MDSC adenosine production and suppression of anti-tumoral T cell activity. We will use a variety of in vivosystems that provide a faithful representation of human NSCLC including an orthotopic murine lung cancermodel and humanized mice with patient-derived xenografts (PDX). In Specific Aim 2 we will test theeffectiveness of selectively deleting CD73 in M-MDSCs or co-treating with PEG-ADA as approaches to increasethe anti-tumor/immunostimulatory activities of chemo-immunotherapy (anti-PD-1 + cisplatin) in transgenic mousemodels of non-squamous and squamous NSCLC. We will also examine tumor samples from NSCLC patientswho have progressed on anti-PD-1/chemotherapy for correlative evidence of this novel mechanism. Completionof these aims will identify novel and actionable immunosuppressive mechanisms that mediate relapse andtherapeutic resistance in metastatic NSCLC patients. Our studies will establish adding PEG-ADA (a drug that isFDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that canbe quickly translated into improved NSCLC treatment regimens.

project_terms:
Address;Adenosine;Attenuated;CD8-Positive T-Lymphocytes;Cancer Model;Cancer Patient;Carboplatin;Cell physiology;Cells;Cisplatin;Clinical;Combination immunotherapy;Combined Modality Therapy;Cytotoxic agent;Data;Dinoprostone;Disease;Effectiveness;Energy-Generating Resources;Enzymes;Epithelial Cells;Eragrostis;FDA approved;Generations;Glucose;Health;Human;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immuno-Chemotherapy;Immunosuppression;Immunotherapeutic agent;Immunotherapy;Inosine;KRASG12D;Life;Lung;Malignant neoplasm of lung;Mediating;Metabolic;Modeling;Molecular;Monoclonal Antibodies;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nucleotidases;Nutrient;Outcome;PTGS2 gene;Paracrine Communication;Pathway interactions;Patients;Persons;Pharmaceutical Preparations;Polyethylene Glycols;Polyunsaturated Fatty Acids;Production;Purine Nucleosides;Recombinants;Relapse;Resistance;Risk;Sampling;Signal Induction;Signal Pathway;Surface;System;T-Lymphocyte;Testing;Therapeutic;Transgenic Mice;Translating;Treatment Failure;Treatment Protocols;Tumor Immunity;United States;Up-Regulation;Xenograft procedure;adenosine deaminase;anti-PD-1;anti-PD1 antibodies;cancer cell;cancer therapy;cancer type;chemotherapy;clinically relevant;effectiveness testing;effector T cell;extracellular;human disease;humanized mouse;immunogenic cell death;improved;in vivo;innovation;monocyte;mortality;mouse model;neoplastic cell;novel;novel therapeutic intervention;patient derived xenograft model;programmed cell death ligand 1;programmed cell death protein 1;randomized clinical trials;response;standard of care;therapy resistant;tumor;tumor ablation;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
Project NarrativeCancer therapy with a combination of cytotoxic drugs and with immune checkpoint inhibitors (ICIs)agentsthat reinvigorate the suppressed immune system to attack cancer cells (e.g. anti-PD-1 antibody)hasrevolutionized the treatment of metastatic lung cancer nevertheless therapeutic resistance is observed in asignificant proportion of patients and a critical determinant of unresponsiveness in these patients is the intra-tumoral accumulation of adenosine a molecule that actively suppresses the effectiveness of immunotherapies.To deplete the intra-tumoral adenosine we have explored the use of an FDA approved drug [PEGylated]-Adenosine Deaminase (PEG-ADA). Our proposed studies will confirm if depletion of adenosine with PEG-ADAcan induce anti-tumor immunity and sensitize lung cancer to chemo-immunotherapy and such a therapeuticstrategy can further extend the life of patient with a disease that is now a major health problem worldwide.


application_id: 10657137
project_number: 1R01HL163712-01A1
project_title: Inflammatory Injury Caused by Silica Exposure
administering_ic: NHLBI
award_notice_date: 2023-04-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 163712
suffix: A1
program_official: VUGA, LOUIS J
project_start_date: 2023-05-01
project_end_date: 2027-04-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryMore than 2 million people in the US are exposed to respirable crystalline silica at work. Inhalationof dust containing respirable crystalline silica causes silicosis which is characterized by chronicinflammation and pulmonary fibrosis. Silica exposure also increases the risk of developingautoimmune diseases and cancer. Silicosis patients have a median survival of 6 years afterdiagnosis. The pathophysiology of silicosis has not been fully understood. Currently there is noeffective treatment against this devastating disease. It has been reported that the dysregulationof alveolar macrophages plays an important role in the pathogenesis of silicosis. The depositionof fine silica particles in alveoli and the ingestion of silica particles by alveolar macrophages triggerpro-inflammatory and pro-fibrotic responses. However molecular mechanisms of thedysregulated alveolar macrophage responses remain elusive. Using a mouse model of silicosisour preliminary studies indicate that myeloid HDAC6 plays an essential role in the pathogenesisof silicosis. In the proposed studies we will test the hypothesis that myeloid HDAC6 is a keymediator of pro-inflammatory and pro-fibrotic responses in silicosis. We will investigate thespecific role of myeloid HDAC6 in silicosis and evaluate the therapeutic potential of HDAC6 as atarget to treat silicosis.

project_terms:
AKT1 gene;Acetylation;Alveolar Macrophages;Alveolus;Autoimmune Diseases;Binding;Cell physiology;Chronic;Clinical Trials;Cytoplasm;Deacetylase;Deacetylation;Deposition;Diagnosis;Disease;Dust;Exposure to;Fibrosis;Functional disorder;Future;Genetic Transcription;HDAC6 gene;Inflammation;Inflammatory;Inflammatory Response;Ingestion;Inhalation;Injury;Leukocytes;Malignant Neoplasms;Mediating;Mediator;Microtubule Stabilization;Microtubules;Molecular;Myelogenous;Nuclear Translocation;Pathogenesis;Patients;Persons;Phenotype;Phosphorylation;Play;Production;Profibrotic signal;Pulmonary Fibrosis;Pulmonary Inflammation;Regulation;Reporting;Risk;Role;Signal Transduction;Silicon Dioxide;Silicosis;TNF gene;Testing;Therapeutic;Transforming Growth Factor beta;Tubulin;Work;alpha Tubulin;effective therapy;mouse model;novel;particle;protective effect;protein function;response;therapeutic target;transcriptomics

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of HDAC6 in the pathogenesisof silicosis. The studies will validate the therapeutic potential of HDAC6 inhibition against silicosis. Theproposed studies will provide important information for future clinical trials.


application_id: 10656916
project_number: 1R01DK133195-01A1
project_title: Targeting urinary tract dysfunctions after spinal cord injury with epidural stimulation
administering_ic: NIDDK
award_notice_date: 2023-09-05
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 133195
suffix: A1
program_official: MULLINS, CHRISTOPHER V
project_start_date: 2023-09-15
project_end_date: 2026-06-30
study_section: Kidney and Urological Systems Function and Dysfunction Study Section[KUFD]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
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
project_abstract:
(PLEASE KEEP IN WORD DO NOT PDF)AbstractSpinal cord epidural stimulation (scES) which creates an electrical field directly over the spinal cord has shown early promise for the restoration of voluntary and reflex control of the lower urinary tract (LUT) among individuals with spinal cord injuries (SCI). A major advantage of the proposed multi-electrode array over the Interstim system and transcutaneous approach is the versatility of the multi-electrode and the ability to activate multiple structures and functions simultaneously with a single electrode placement and device. The goal of this pre-clinical research is to optimize scES for functional benefits and identify mechanism(s) to better facilitate daily management and improve quality of life. It is hypothesized that effective scES for both bladder storage and emptying occurs when initiated chronically post-SCI through activation of spinal bladder circuits including neurons within the dorsal commissure superficial dorsal horn sacral parasympathetic nucleus and Onufs nucleus with the requirement of intact hypogastric/pelvic/pudendal nerves and with greater effectiveness when given in combination with locomotor training. For Aim 1 previously identified optimal parameters will be used to identify neural components of the spinal networks contributing to scES-induced LUT effects with different chronicitys post-SCI in urethane-anesthetized rats using two approaches: a) Fos protein induction (a marker for postsynaptic activation of spinal neurons) and b) select peripheral nerve transections. Examining the contributing spinal central regions activated with scES and key peripheral components for different aspects of LUT function will provide novel targets for further development and refinement of epidural arrays and controllers. For Aim 2 the impact of scES on LUT functions in SCI rats after treatment with differing periodicities of locomotor training will be examined to address the potential added benefit of a combinatory approach (neuromodulation with rehabilitation). A sub-aim examines the underlying Fos induced central neural components as plasticity is likely induced with training. Both aims will also include bladder histology/molecular biology assessments re the effects of chronicity/training. These studies will significantly move the SCI field forward by providing optimal parameters and locations for targeting LUT function that will be key for advancing the existing technology.

project_terms:
Acute;Address;Aftercare;Anesthesia procedures;Ataxia;Bilateral;Biological Markers;Bladder;Bladder Tissue;Cell Nucleus;Cells;Chronic;Clinical Trials;Clinical effectiveness;Commissure;Contusions;Development;Devices;Dorsal;Effectiveness;Electrodes;FOS Protein;Functional disorder;Goals;Health;Health Care Costs;Histology;Hour;Human;Immune;Individual;Location;Locomotor training;Lower urinary tract;Maintenance;Maps;Mediating;Modeling;Molecular Biology;Motor;Nerve;Neurons;Outcome;Pattern;Pelvis;Peripheral;Quality of life;Rattus;Recommendation;Reflex action;Reflex control;Rehabilitation therapy;Source;Sphincter;Spinal;Spinal Cord;Spinal Cord Tract;Spinal cord injury;Structure;Synapses;System;Technology;Training;Urethane;Urinary tract;Vertebral column;chemokine;cholinergic;clinically relevant;design;dorsal horn;electric field;experimental study;functional outcomes;gray matter;improved;multi-electrode arrays;nerve transection;neural;neurological rehabilitation;neuroregulation;novel;peripheral nerve transection;postsynaptic;pre-clinical research;preclinical study;pressure;response;response to injury;restoration;timeline;treadmill;urologic

public_health_relevance:
Spinal cord epidural stimulation which creates an electrical field directly over the spinal cord has shown early promise with clinical effectiveness for restoration of voluntary and reflex control of the lower urinary tract. The goal of this pre-clinical research is to optimize epidural stimulation alone and in combination with neurorehabilitation for functional urological benefits and identify mechanism(s) to better facilitate daily management and improve quality of life for those with spinal cord injuries.


application_id: 10656547
project_number: 5R01NS120882-02
project_title: Neuronal IL-1R1 Signaling in Mild Closed Head Injury
administering_ic: NINDS
award_notice_date: 2023-06-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 120882
program_official: AWWAD, HIBAH OMAR
project_start_date: 2022-07-01
project_end_date: 2027-05-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: NORRIS, CHRISTOPHER MARK
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:
ABSTRACTThe cytokine interleukin-1 (IL-1) is well known to mediate detrimental inflammatory processes in peripheraltissues. IL-1 is elevated in age and in neurodegenerative disease. As a result IL-1 has become a major focusof anti-inflammatory strategies to treat neuroinflammation following acute injury and in chronicneurodegenerative disease. Surprisingly there is scant evidence that neurons are damaged through the directactions of IL-1. To the contrary a neuron-specific non-canonical IL-1 receptor (IL-1R1) pathway thatpromotes rather than erodes neuronal viability has been identified. Despite this paradigm-shifting observationthe non-canonical pathway has received little attention. Much remains unknown about how neuronal IL-1R1signaling contributes to the brain's inflammatory milieu synaptic physiology and cognitive function andrecover from injury and progression of neurodegeneration. This knowledge gap could undermine potentialneuroprotective approaches that target suppression of IL-1 as part of the mechanism-of-action.To address this knowledge gap we will use novel mouse models exhibiting neuron-specific modulation of IL-1signaling (i.e. IL-1R1-floxed mice to look at neuron-specific knockdown and IL-1R1-restore mice to look at theneuron-specific expression of IL-1R1). Our overarching hypothesis is that neuronal IL-1R1 signaling isinherently protective.We will test this hypothesis in the following Specific Aims: SA1 Define the role of the neuronal IL-1R1 pathway in the inflammatory response to a CHI in mice. SA2 Define the neuronal IL-1R1 pathway in homeostatic synaptic plasticity after a CHI in mice. SA3 Determine the temporal role of neuronal IL-1R1 in the cognitive recovery following a CHI.If our hypothesis is affirmed we will provide knowledge of a new neuroprotective approach and enable thedevelopment of new formulations of existing anti-inflammatory interventions that preserve the neuroprotectivefunctions of IL-1. The development of novel IL-1R1 therapies would include agents that only suppress theinflammatory IL-1R1 pathway or only activate the neuroprotective IL-1R1 pathway.

project_terms:
Acute;Address;Age;Animal Disease Models;Anti-Inflammatory Agents;Attention;Autoimmune Diseases;Axon;Behavior;Behavioral Assay;Brain;Cells;Chronic;Closed head injuries;Complex;Data;Development;Electrophysiology (science);Exhibits;FDA approved;Formulation;Functional disorder;Gene Expression Profile;Genes;Goals;Inflammation;Inflammatory;Inflammatory Response;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Intervention;Knockout Mice;Knowledge;LoxP-flanked allele;Maintenance;Mediating;Memory;Modeling;Mus;Nature;Nerve Degeneration;Nervous System Trauma;Neurodegenerative Disorders;Neuroglia;Neurons;Pathway interactions;Peripheral;Phase;Phenotype;Physiology;Process;Receptor Signaling;Recovery;RiboTag;Role;Signal Transduction;Synapses;Synaptic plasticity;System;Testing;Therapeutic;Tissues;Traumatic Brain Injury;cell type;cognitive function;cognitive recovery;cytokine;experimental study;genetic approach;inducible Cre;inflammatory milieu;interleukin-1 receptor accessory protein;knock-down;mouse model;nerve injury;nervous system disorder;neuroinflammation;neuroprotection;neuroregulation;novel;preservation;response;synaptic function

public_health_relevance:
PROJECT NARRATIVEThis study would have critical implications for the pathophysiology of numerous CNS conditions and helpreconcile mixed results with anti-IL-1 therapeutics and inform new IL-1 modulation strategies. Moreoverdefining the role of neuronal IL-1R1 signaling would provide a new neuroprotective approach as well asenable the development of new formulations of existing IL-1 targeted interventions to preserve theneuroprotective functions of IL-1.


application_id: 10655710
project_number: 2R01DE012505-26
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2023-03-02
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: DE
serial_number: 012505
program_official: MCNEALY, TAMARA L
project_start_date: 1998-09-01
project_end_date: 2028-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: POTEMPA, JAN S;URIARTE, SILVIA M
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:
AbstractPolymicrobial infections are inherently more complex than monospecies infections and this complexity hasbeen a significant barrier to both a fuller appreciation of pathogenic mechanisms and to the development ofeffective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases andare among the most common infections of humans. Although certain organisms such as Porphyromonasgingivalis are considered key pathogens it is the polymicrobial community as a whole that initiates anddrives the disease. Interspecies interactions within communities shape overall pathogenic potential andwork supported by this project has uncovered a dynamic and multilevel interaction between P. gingivalisand its community partners. The pathogenicity of P. gingivalis can be constrained by the streptococcaldiffusible metabolite para-amino benzoic acid (pABA) which is as a precursor of de novo folate synthesis inthe physiologically essential one-carbon metabolism (OCM) pathway. However as physically integratedcommunities develop interspecies co-adhesion results in suppression of streptococcal pABA production andadditionally partner organisms such as Streptococcus gordonii and Fusobacterium nucleatum enhanceoverall community pathogenicity. Sensing of both pABA and interspecies physical contact by P.gingivalis is transduced through a protein tyrosine phosphorylation signaling circuit. The tyrosine kinasePtk1 controls flux through OCM as well as the production of virulence factors including the gingipainproteases which can modulate interactions with neutrophils. Indeed Ptk1 is required for pathogenicity inboth murine abscess and alveolar bone loss models of disease. In this proposal we will define the role ofPtk1 as a master regulator which can integrate OCM with pathogenicity. In the first Aim we will examine howPtk1-mediated phosphorylation of gingipains is necessary for their processing and secretion. We willdetermine where non-phosphorylated gingipains remain localized in P. gingivalis and investigate whichcomponents of the type IX secretion system machinery malfunction in the absence of phosphorylation.Additionally we will follow post-translational maturation of non-phosphorylated gingipains to uncover the roleof phosphorylation in catalytic removal of the N-terminal peptide the haemagglutinin domains or the C-terminal domain as is required for the assembly of fully activated proteases. In the second Aim we shallfunctionally dissect the contribution of phosphorylation to the activity of the pABA synthesis enzyme PabC anddecipher a negative feedback loop whereby pABA can inhibit Ptk1. Aim 3 will address the impact of Ptk1 onthe activation state of neutrophils and their potential for tissue destructive responses to P. gingivalis.Completion of this project will provide novel insights into the context-dependent pathophysiology of P.gingivalis which could ultimately be translated into therapeutic strategies designed to target thecommunity-based pathogenesis that underlies periodontal disease.

project_terms:
Abscess;Alveolar Bone Loss;Amino Acids;Bacteria;Benzoic Acids;Binding;C-terminal;Calibration;Carbon;Communication;Communities;Complex;Cues;Data;Development;Dimensions;Disease;Disease model;Environment;Enzymes;Equilibrium;Event;Excision;Feedback;Folic Acid;Functional disorder;Fusobacterium nucleatum;Goals;Human;Immune response;Infection;Inflammatory;Inflammatory Response;Innate Immune Response;Measures;Mediating;Metabolic;Metabolism;Microbe;Modeling;Molecular;Mus;N-terminal;Neutrophil Activation;Neutrophil Infiltration;Organism;Pathogenesis;Pathogenicity;Pathway interactions;Peptide Hydrolases;Peptides;Periodontal Diseases;Phosphorylation;Physiological;Physiology;Polysaccharides;Porphyromonas gingivalis;Process;Production;Property;Protein Tyrosine Kinase;Proteins;Regulation;Role;Shapes;Signal Transduction;Signaling Molecule;Streptococcus;Streptococcus gordonii;System;Testing;Therapeutic;Tissues;Translating;Tyrosine Phosphorylation;Virulence;Virulence Factors;Work;design;dysbiosis;extracellular;gingipain;in vivo;insight;microbial community;neutrophil;novel;oral infection;oral plaque;pathogen;polymicrobial disease;prevent;response

public_health_relevance:
NarrativeDiseases caused by mixtures of bacteria are often more serious and harder to treat that those caused by asingle organism. Periodontal (gum) diseases are caused by mixtures of microbes that communicate with eachother to regulate the level of disease-causing potential of the microbial community. In this proposal we shallstudy the communication mechanisms that allow periodontal bacteria to increase production of toxicproducts become more metabolically active and resist killing by the host.


application_id: 10655683
project_number: 3R35ES032876-02S1
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2022-07-01
opportunity_number: PA-21-071
application_type: 3
activity_code: R35
ic: ES
serial_number: 032876
suffix: S1
program_official: CARLIN, DANIELLE J
project_start_date: 2022-02-09
project_end_date: 2024-06-30
study_section: ZES1-LWJ-D(R3)
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
3-Dimensional;Animals;Attention;Cancer Etiology;Carcinogens;Cell Line;Cells;Cessation of life;Chromosomal Instability;Collection;Colon Carcinoma;Complex;Disease;Environmental Health;Epithelial;Event;Exposure to;Fibroblasts;Funding;Health;Heritability;Human;Individual;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Metal Carcinogenesis;Metal exposure;Metals;Minority;Mutagens;Neoplastic Cell Transformation;Outcome;Persons;Population;Public Health;Risk Assessment;Tobacco;Tobacco use;Translating;United States;carcinogenicity;cell type;chromium hexavalent ion;human subject;improved;induced pluripotent stem cell;insight;interest;malignant breast neoplasm;mixed cell culture;neoplastic;novel;novel strategies;prevent;programs;social stigma;stem cell model;tobacco user;tool


application_id: 10655433
project_number: 5R01CA247365-05
project_title: Chemical Biology of the Control of Neddylation by DCN1
administering_ic: NCI
award_notice_date: 2023-09-08
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 247365
program_official: FU, YALI
project_start_date: 2019-07-01
project_end_date: 2025-06-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 6620313
contact_pi: GUY, RODNEY KIPLIN
other_pis: SCHULMAN, BRENDA A;SINGH, BHUVANESH
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractThe long-term goal is to generate and use complimentary chemical and biological probes to study the cullinRING ubiquitin ligases (CRLs) and understand their activation controlled by the interaction of by the Defectivein Cullin Neddylation 1 (DCN1) and UBE2M proteins. Because the CRLs ultimately control ubiquitination of manydiverse proteins thus regulating their stability intracellular localization and function having spatiotemporalcontrol over DCN-mediated CRL activity has the potential to unravel the mechanism regulating key cellularsignaling networks and driving disease progression. The health relatedness of this project lies in two facts: 1)DCN1 is an oncoprotein amplified in squamous cell carcinomas that drives a highly malignant phenotype and2) CRL driven ubiquitination is a validated target in multiple diseases particularly cancer and immunedysfunction. Therefore inhibitors of the DCN1-UB2M interaction that are potent selective and bioavailable havethe potential to be developed as antitumor drugs and possibly for other diseases. Ubiquitination is regulated bya highly complex dynamic and redundant network. Inhibitors of DCN1-UB2M will allow direct interrogation ofthe function of sub-portions of the network and are likely to unveil fundamental principles of the regulationubiquitination. The generation of complementary cellular and mouse genetic models will enable independentverification of hypotheses. Finally the DCN1-UBE2M interaction requires N-terminal acetylation of UBE2M acommon posttranslational modification controlling protein interactions. Therefore a strategy for targeting N-terminal acetylation dependent protein interactions could be widely applicable. The research design andmethods for achieving these goals involves the integrated and recursive use of structure-driven hypothesis-based medicinal chemistry; in vitro biochemical measures of affinity and inhibitory potency; in vivo measures ofcompound efficacy and pharmacodynamic responses; and in vitro and in vivo measures of compoundbioavailability distribution metabolism excretion and toxicity. The overall goal is to develop new complimentarychemical and biological tools to understand the regulation of the ubiquitin-like protein NEDD8 and uncover thespecific role of DCN-mediated neddylation in Cullin-RING ligase substrate receptor exchange growth factorsignaling and driving tumor progression. Our aims are: Aim 1: Improve the potency and oral exposure of ourcurrent DCN1/2 inhibitors and generate new chemical probes with sufficient potency and selectivity to enableourselves and others to study the consequences of inhibiting this E2-E3 interaction in cells and animals. Aim 2.Investigate how the composition of cellular CUL1 and CUL3 ligases dynamically responds to environmentalperturbations and the importance of DCN1/2 in this process. Aim 3: Use genetic and pharmacologicalapproaches to study the effects of inhibiting DCN1 activity in animal tumor models.

project_terms:
3q26;Acetylation;Affinity;Amines;Amino Acids;Animals;Automobile Driving;Binding;Biochemical;Biological;Biological Availability;Biological Process;Biology;Brain;Bromodomain;C-terminal;CUL1 gene;CUL3 gene;CUL5 gene;Cell Nucleus;Cells;Cervical;Charge;Chemicals;Clinical;Complex;Contact Inhibition;Cullin Proteins;Cytosol;Data;Development;Disease;Disease Progression;Drug Targeting;Enzymes;Excretory function;Family member;Foundations;Generations;Genetic;Genetic Models;Goals;Growth Factor;Health;Homeostasis;Human;Hydrophobicity;Immune System Diseases;In Vitro;Ligase;Ligation;Location;Lysine;Malignant Neoplasms;Mammals;Measures;Mediating;Metabolism;Methionine;Modeling;Molecular;Mus;N-terminal;Names;Nature;Oncogenes;Oncoproteins;Oral;Pathway interactions;Pattern;Pharmaceutical Chemistry;Pharmacodynamics;Phenotype;Post-Translational Protein Processing;Process;Prostate;Proteasome Inhibitor;Protein Dynamics;Protein Isoforms;Proteins;RBX1 gene;Regulation;Reporting;Research Design;Research Methodology;Role;Sequence Homology;Side;Signal Transduction;Squamous cell carcinoma;Structure;Substrate Specificity;System;Testis;Tissues;Toxic effect;Ubiquitin;Ubiquitin Like Proteins;Ubiquitin family;Ubiquitination;antitumor drug;cancer therapy;clinically significant;combinatorial;drug discovery;improved;in vivo;inhibitor;knock-down;malignant phenotype;mouse genetics;novel therapeutics;pharmacologic;pre-clinical;receptor;response;small molecule;spatiotemporal;success;three dimensional cell culture;tool;tumor;tumor progression;ubiquitin ligase;ubiquitin-protein ligase

public_health_relevance:
Project NarrativeDysregulation of the Cullin-RING ubiquitin Ligases (CRLs) which regulate the stability and interactionsof many proteins inside the cell is associated with a growing number of diseases including cancer. Thegoal of this proposal is to develop new complimentary chemical and biological tools to understand theregulation of the CRLs by the ubiquitin-like protein NEDD8. The proposed studies will provide useful toolsfor understanding key biological processes and may also lay the foundation for the development of noveltherapeutics for the treatment of cancer and other diseases.


application_id: 10655402
project_number: 5R01NR019456-04
administering_ic: NINR
award_notice_date: 2023-06-14
opportunity_number: RFA-NR-20-001
application_type: 5
activity_code: R01
ic: NR
serial_number: 019456
program_official: KEHL, KAREN
project_start_date: 2020-09-07
project_end_date: 2025-06-30
study_section: ZNR1-REV-W(23)
contact_pi_person_id: 9701191
contact_pi: MUDD, GIA
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Heart of the Family: A Cardiovascular Disease and Type 2 Diabetes Risk Reduction Intervention in High-Risk Rural Families

project_abstract:
ABSTRACTRural populations in the U.S. have disproportionately higher prevalence of cardiovascular disease (CVD) andtype 2 diabetes (T2D) compared to urban populations. Many rural communities also have greater risk factorburden than urban communities including unhealthier diet higher rates of physical inactivity obesity andsmoking and higher prevalence of hypertension hypercholesterolemia and hyperglycemia. Compoundingthese are poor socioeconomic conditions and limited health resources. Hispanic residents of rural communitiesmay experience worse CVD and T2D disease and risk burden than non-Hispanic residents due to higher ratesof poverty lower educational attainment and greater barriers accessing resources. U.S. Hispanics haveamong the highest rates of T2D of any racial or ethnic group. Culturally responsive lifestyle modificationinterventions are needed to reduce T2D and CVD risk in rural Hispanic and non-Hispanic populations.Modification strategies commonly target individuals and while these may result in behavior change immediatepost-intervention sustained engagement in healthy behaviors is seldom achieved. Family engagement inlifestyle interventions may support sustained engagement in healthy behaviors especially in rural and Hispanicpopulations that often have greater reliance on family members for social support. We will conduct arandomized controlled trial to compare the effects of a dyadic intervention Heart of the Family to an activecontrol intervention. We will compare 3-month (short-term) and 12-month (long-term) impact of the Heart of theFamily intervention on biological and behavioral T2D and CVD risk factors and evaluate whether ethnicitymoderates intervention effects. We will also examine how each active intervention dyad membersengagement in healthy lifestyle behaviors and level of support for their partners engagement in healthylifestyle behaviors affects their own and their partners outcomes. A family focused intervention may bettersupport long-term engagement in healthy lifestyle behaviors to reduce T2D and CVD risk among at-risk ruralHispanics and non-Hispanics. Further this community-based intervention has significant potential for broadimplementation to successfully address T2D and CVD health disparities across U.S. Hispanic communities.

project_terms:
Address;Adult;Affect;Age;Behavior;Behavioral;Biological;Blood Pressure;Body mass index;Cardiovascular Diseases;Cause of Death;Collaborations;Communities;Complement;Controlled Study;Data;Diabetes Mellitus;Disease;Disparity;Economic Conditions;Education;Ethnic Origin;Ethnic Population;Face;Family;Family member;Feedback;Geography;Glycosylated hemoglobin A;Health;Health Resources;Health behavior;Heart;Heart Diseases;Heart Rate;High Prevalence;Hispanic;Hispanic Populations;Hyperglycemia;Hypertension;Individual;Intervention;Kentucky;Life Style Modification;Lipids;Mediating;Modeling;Modification;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Nutritional;Obesity;Outcome;Participant;Pattern;Physical activity;Population;Poverty;Prediabetes syndrome;Prevalence;Public Health;Randomized;Randomized Controlled Trials;Research;Research Design;Resources;Risk;Risk Factors;Risk Management;Risk Reduction;Rural;Rural Community;Rural Population;Self Care;Social support;Testing;Tobacco use;Unhealthy Diet;Urban Community;Urban Population;Weight maintenance regimen;active control;behavior change;behavioral outcome;burden of illness;cardiovascular disorder risk;community based participatory research;comorbidity;comparison control;comparison intervention;diabetes risk;efficacy testing;ethnic disparity;experience;family support;good diet;group intervention;health disparity;health inequalities;healthy lifestyle;high risk;hispanic community;hypercholesterolemia;improved;indexing;intervention effect;lifestyle intervention;lifetime risk;member;mortality;physical inactivity;poor health outcome;post intervention;racial disparity;racial population;rural Hispanic;rural dwellers;rural families;rural residence;smoking prevalence;social;socioeconomics

public_health_relevance:
NARRATIVERural populations in the U.S. are disproportionately burdened by cardiovascular disease and type 2 diabetes.Lifestyle modification interventions are needed that support long-term engagement in risk-reducing healthbehaviors. Our proposal will study the effects of a family focused lifestyle intervention that is culturally tailoredfor use with rural Hispanic and non-Hispanic adults and will have significant potential for broad disseminationto reduce T2D and CVD health disparities in rural U.S. communities.


application_id: 10655174
project_number: 1R01DE031998-01A1
administering_ic: NIDCR
award_notice_date: 2023-07-06
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DE
serial_number: 031998
suffix: A1
program_official: CHEN, ZHONG
project_start_date: 2023-08-01
project_end_date: 2028-07-31
study_section: Imaging Technology Development Study Section[ITD]
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Point-of-care optical spectroscopy platform and novel ratio-metric algorithms for rapid and systematic functional characterization of biological models in vivo

project_abstract:
PROJECT SUMMARYCellular metabolism is highly dynamic and strongly influenced by its local vascular microenvironment gaining asystems-level view of tumor metabolism and vasculature in vivo is essential in understanding many criticalcancer biology questions. However there are surprisingly few techniques available that can quantify the keymetabolic and vascular endpoints together in vivo with easy access. The goal here is to fill this gap bydeveloping a point-of-care optical spectroscopy platform with a tumor-sensitive fiber probe and novel ratio-metric data processing techniques to quantify the major axes of tumor metabolism (glucose uptakemitochondrial membrane potential Bodipy) and the associated vasculature (oxygenation hemoglobin) onbiological models in vivo. For scientific validation and translational purposes we will compare our techniqueswith existing metabolic tools we will also integrate our optical strategies with the state-of-art metabolomicstechnique i.e. Stable Isotope-Resolved Metabolomics (SIRM) to provide a rapid and comprehensiveunderstanding in tumor metabolism. We will then demonstrate our synergistic approach through addressing acontemporary problem in cancer therapy for head and neck squamous cell cancer (HNSCC). Specifically wewill address the critical challenge of radio-resistance (RR) in HNSCC and test the hypothesis that radiotherapy(RT) induced HIF-1 and HIF-2 activation and the following metabolic changes are responsible for HNSCCRR and recurrence the tumor-specific in vivo genetic editing platform targeting on HIF-1 and HIF-2 canimprove RT efficacy. Our point-of-care optical spectroscopy along with novel ratio-metric algorithms make ourtechnologies easy to access easy to use and systematic which are all critical to maximizing its accessibilityfor cancer research. Our spectroscopy techniques and their integration with the SIRM will provide new ways ofstudying cancer biology and diseases and they will also impact the study of a wide array of other biomedicalproblems through the lens of tumor bioenergetics and vasculature. Our study on HNSCC RR mechanisms andthe demonstration of tumor-specific genetic editing platform in orthotropic HNSCC models will offer new waysfor targeted RT to improve HNSCC patient survival rates. The platforms and methodologies developed in thisproject will be applicable to the study of RR and recurrence in other types of human cancers.

project_terms:
Address;Algorithms;Animal Model;Animals;Benchmarking;Bioenergetics;Biological;Biological Assay;Biological Models;Blood Vessels;Cancer Biology;Cancer Model;Cancer Patient;Citric Acid Cycle;Development;Devices;Dimensions;Disease;Fiber;Genes;Genetic;Genus Hippocampus;Geometry;Glycolysis;Goals;Guidelines;Head and Neck Squamous Cell Carcinoma;Hemoglobin;Human;Immunohistochemistry;Lipids;Malignant Neoplasms;Measurement;Measures;Mediating;Membrane Potentials;Metabolic;Metabolic Pathway;Metabolism;Methodology;Modeling;Monitor;Optics;Outcome;Oxygen;Oxygen Consumption;Proteins;Publishing;Radiation Tolerance;Radiation therapy;Recurrence;Risk;Spectrum Analysis;Stains;Survival Rate;System;Targeted Radiotherapy;Techniques;Technology;Testing;Tissues;Treatment Efficacy;Tumor Biology;Validation;Viral;aerobic glycolysis;angiogenesis;anticancer research;cancer therapy;computerized data processing;extracellular;genome editing;glucose uptake;improved;in vivo;in vivo Model;insight;lens;metabolomics;mitochondrial membrane;mitochondrial metabolism;nanoparticle;novel;overexpression;point of care;prevent;radiation resistance;radioresistant;ratiometric;stable isotope;therapy design;tool;trend;tumor;tumor metabolism;vector

public_health_relevance:
PROJECT NARRATIVEThe goal of this project is to establish novel optical strategies for rapid systematic metabolic characterization ofbiological models in vivo to address questions in the field of HNSCC radio-resistance and recurrence usingorthotropic HNSCC models. We will also integrate our optical strategies with the state-of-art Stable Isotope-Resolved Metabolomics (SIRM) to provide rapid and comprehensive understanding in tumor metabolism thatrelates to radio-resistance. Our synergistic approach will provide the metabolic underpinnings of radio-resistance and recurrence and facilitate advances in the understanding of tumor biology assessment ofrecurrence risk and design of therapies that can mitigate radio-resistance and recurrence altogether.


application_id: 10655059
project_number: 1R01AI167953-01A1
project_title: Invasion of the enteric nervous system by neurotropic Listeria monocytogenes
administering_ic: NIAID
award_notice_date: 2023-06-28
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 167953
suffix: A1
program_official: BAQAR, SHAHIDA
project_start_date: 2023-07-01
project_end_date: 2028-06-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 2545336
contact_pi: D'ORAZIO, SARAH E. F.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Listeria monocytogenes (Lm) are Gram-positive facultative intracellular bacteria that cause two types of braininfections in humans: diffuse (meningitis/meningoencephalitis) and focal brainstem (rhombencephalitis).Meningitis occurs in the setting of immune compromise likely due to the failure of the immune system to limitexponential growth of Lm in tissues such as spleen or liver. This leads to high titer bacteremia and either directinvasion of the blood-brain-barrier (BBB) or stealth transport of Lm associated with myeloid-derived cells thatcross the BBB. In contrast rhombencephalitis is an infection of a delayed nature that occurs in young otherwisehealthy immune competent people which suggests that the infection is dependent on bacterially encodedneurovirulence factors. The central hypothesis of this proposal is that the virulence factors which defineneurotropism during rhombencephalitis mediate critical early events in the intestines rather than in the brain.Support for this hypothesis comes from our preliminary data showing that when the neurotropic Lm are injectedintravenously (bypassing the gut phase of the infection) they do not disseminate to the brain. In addition othersshowed that rhombencephalitis isolates did not have an increased ability to survive and replicate in bovineorganotypic brain slices ex vivo relative to other Lm strains. Until recently rhombencephalitis could be studiedonly in cows or sheep due to the lack of a small animal model of Lm brainstem infections. However we recentlyshowed that some clinical isolates of Lm (UKVDL9 and SD4000) could preferentially colonize the brainstems ofmice late in the course of infection without reaching high titer in the blood. Both of the neurotropic strains wereported belong to lineage III the smallest and least characterized group of Lm isolates. The goal of this proposalis to define the factors that promote neurotropism by Lm UKVDL9 and SD4000 during the gut phase of listeriosis.We predict that neurotropic Lm could have an advantage in three different aspects of the intestinal infection;these form the three Specific Aims of the proposal. In Aim 1 we determine if the route used to cross the gutmucosa or inflammatory response induced promotes localization of neurotropic Lm strains in neural bundles inthe intestinal submucosa or within the vagal crypt endings surrounding lymphoid cryptopatches in the gut. InAim 2 we identify the novel Lm surface protein that mediates enhanced invasion of enteric glial cells the celltype that surrounds nerves in the gut. In Aim 3 we test the hypothesis that a truncated actA allele found inneurotropic Lm promotes an altered type of intracellular movement that allows the bacteria to migrate along theentire length of an axon all the way to the brainstem. This work will move the listeriosis field forward by providingthe first real insights into neurotropism during this life-threatening foodborne infection and could also lay thegroundwork for new areas of pathogenesis or microbiome-related research to understand how bacteria interactwith cells of the enteric nervous system.

project_terms:
Actins;Alleles;Animal Model;Area;Axon;Bacteremia;Bacteria;Bacterial Adhesins;Blood;Blood - brain barrier anatomy;Brain;Brain Stem;Bypass;Cattle;Cell Nucleus;Cells;Clinical;Coculture Techniques;Cranial Nerves;Data;Diffuse;Elderly;Endowment;Enteral;Enteric Nervous System;Event;Failure;Follow-Up Studies;Food Contamination;Goals;Growth;Gut Mucosa;Human;Immune;Immune system;Immunocompetent;In Vitro;Individual;Infection;Inflammatory;Inflammatory Response;Ingestion;Intestines;Intravenous;Invaded;Kinetics;Lamina Propria;Length;Life;Listeria;Listeria monocytogenes;Listeriosis;Liver;Lymphoid;Mediating;Membrane Proteins;Meningitis;Meningoencephalitis;Microscopic;Monitor;Movement;Mus;Mutagenesis;Myelogenous;Myenteric Plexus;Nature;Nerve;Nervous System;Neuroglia;Neurons;Neurotropism;Oral;Pathogenesis;Pattern;Persons;Phase;Process;Proline-Rich Domain;Proteins;Reporting;Research;Role;Route;Sheep;Slice;Speed;Spleen;Submucosa;Submucous Plexus;System;Tail;Testing;Time;Tissues;Vagus nerve structure;Variant;Virulence Factors;Work;blood-brain barrier crossing;body system;cell motility;cell type;enteric infection;foodborne;foodborne illness;foodborne infection;in vivo;insight;intestinal epithelium;live cell imaging;microbiome;microbiota;migration;mortality;mouse model;mutant;neonate;nerve supply;neural;neurotropic;neurovirulence;novel;pathogen;transmission process

public_health_relevance:
Ingestion of food contaminated by Listeria monocytogenes bacteria causes two different types of braininfection in humans. One type (meningitis) happens primarily in individuals with compromised immunesystems (for example neonates and the elderly); the other type (rhombencephalitis) occurs in otherwisehealthy people. The goal of this research is to identify the bacterial factors which allow Listeria to invadecranial nerves in the gut and spread directly to the brainstem resulting in rhombencephalitis.


application_id: 10654703
project_number: 5R01CA237643-05
project_title: Targeting epigenetic heterogeneity to improve lung cancer immunotherapy response
administering_ic: NCI
award_notice_date: 2023-06-30
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 237643
program_official: SOMMERS, CONNIE L
project_start_date: 2019-07-01
project_end_date: 2025-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
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:
Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. My central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing the PD-L1 expressing tumorpropagating cells (TPCs) and by depleting immunosuppressive tumor associated neutrophils. Theoverarching goal of the proposed study is to validate combining EZH2 inhibition with PD1/PD-L1 targetedimmunotherapy and learn the molecular mechanisms when the treatment is successful as well as when it is notsuccessful. In Aim 1 I will use both mouse models and human patient derived organoid cultures and serial orthotopictransplantation to examine NGFR and PD-L1 expression and tumor propagation abilities of lung SCC cells afterEZH2 inhibitor treatment. I will also test if non-TPC cells can de-differentiate and continue to fuel tumor growthby sorting for presence or absence of the putative TPC cell surface marker nerve growth factor receptor (NGFR).The epigenetic and transcriptional consequences of EZH2 inhibition on squamous lung tumor cells will beassessed by ChIP-seq and RNA-seq. In Aim 2 I will focus on the tumor associated neutrophils (TANs). I willcompare TANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migrationcapacity and ability to suppress T cells. I will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 I will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. I will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. Completion of these aims will solidify the efficacy of a promising therapeuticcombination and uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2inhibitors in squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibitionwith anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.

project_terms:
Affect;CXCL9 gene;Cancer Etiology;Cancer Patient;Cell surface;Cells;Cessation of life;ChIP-seq;Clinical;Complex;Disease;Drug Combinations;EZH2 gene;Epigenetic Process;Gene Expression;Genes;Genetic Transcription;Goals;Heterogeneity;Human;Immune;Immune Evasion;Immunocompetent;Immunotherapy;In Vitro;Knockout Mice;Learning;Literature;Lung;Lung Neoplasms;Magnetic Resonance Imaging;Malignant neoplasm of lung;Methyltransferase;Molecular;Mus;NGFR Protein;Non-Small-Cell Lung Carcinoma;Organoids;PD-1/PD-L1;Patients;Pharmaceutical Preparations;Phase I/II Clinical Trial;Phase II/III Trial;Phenotype;Placebos;Polycomb;Population;Pre-Clinical Model;Refractory;Resistance;Sorting;Squamous Cell Lung Carcinoma;Squamous cell carcinoma;T-Lymphocyte;Testing;Therapeutic;Transplantation;Tumor stage;anti-PD-1;anti-PD-L1;anti-PD1 antibodies;arm;cancer immunotherapy;cell type;clinically relevant;combinatorial;conditional knockout;effector T cell;improved;in vivo;inhibitor;migration;mouse model;neoplastic cell;neutrophil;programmed cell death ligand 1;programs;recruit;responders and non-responders;response;transcriptome sequencing;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
Lung cancer is the leading cause of cancer-related deaths worldwide and is a very complex disease withdifferent cell types that comprise each tumor. Immunotherapy is ground-breaking because it is able to cure somepatients with late stage tumors but the number of patients that have this great response is still low. In thisproposal we will test the combination of a second drug with immunotherapy to increase the likelihood thatsquamous lung tumors will respond to treatment.


application_id: 10654672
project_number: 5R01GM138882-04
administering_ic: NIGMS
award_notice_date: 2024-07-02
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: GM
serial_number: 138882
program_official: BARSKI, OLEG
project_start_date: 2020-09-01
project_end_date: 2025-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: GLAZER, EDITH C;HEIDARY, DAVID
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
budget_start_date: 2024-07-01
project_title:
Role of small molecule interactions and multiprotein assemblies in CYP1B1 disease-associated function and dysfunction

project_abstract:
AbstractCYP1B1 is absent or expressed at very low levels in the liver and healthy tissues while being overexpressed intumors giving it the title of universal tumor antigen. Evidence from basic science clinical and epidemiologicalstudies demonstrate that CYP1B1 is involved in cancer initiation progression and resistance to a wide range ofchemotherapeutics. In addition several point mutations have been discovered within CYP1B1 that areassociated with other disease states particularly hereditary congenital glaucoma and metabolic disorders.However there is currently no known molecular mechanism that explains how mutations altered protein levelsand environmental conditions impact the function and dysfunction of this enzyme. We hypothesize that CYP1B1subcellular localization oligomerization protein:protein assembly degradation and small molecule binding arealtered in cancer cells as a result of specific single nucleotide polymorphisms or environmental features.Trafficking of CYP1B1 from the ER to the mitochondria association into multimeric states or generation ofabnormal protein:protein assemblies could result in damaging levels of the protein and consequently metabolicproducts including ROS and mutagens that facilitate malignant progression. This work will demonstrate how theprotein:protein interactions of a cytochrome P450 enzyme impacts enzyme activity and protein lifecycle. Singlemolecule microscopy methods and fluorescence lifetime microscopy imaging will be used to gain high resolutioninformation on protein assembly and activity in live cells. Additionally paradigm-shifting inhibitors of this enzymewill be developed that act though two distinct mechanisms: long-residence-time coordinative inhibition andactivation of CYP1B1 degradation. Reduction of CYP1B1 protein levels and activity should suppress its role incancer progression and is anticipated to facilitate restoration of efficacy for a variety of chemotherapeutics.

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

public_health_relevance:
Cytochrome P450-1B1 (CYP1B1) is absent or expressed at very low levels in the liver and healthy tissues whilebeing overexpressed in tumors giving it the title of universal tumor antigen. Evidence from basic scienceclinical and epidemiological studies demonstrate that CYP1B1 is involved in cancer initiation progression andresistance to a wide range of chemotherapeutics. This work will define how CYP1B1 subcellular localizationoligomerization degradation and small molecule binding are altered in cancer cells as a function of specificsingle nucleotide polymorphisms (SNPs) and environmental factors facilitating malignant progression and willprovide a new paradigm for small molecule inhibitors of the enzyme that function by inducing CYP1B1 proteindegradation.


application_id: 10654595
project_number: 5R01CA243529-04
administering_ic: NCI
award_notice_date: 2023-05-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 243529
program_official: CHEN, WEIWEI
project_start_date: 2020-06-01
project_end_date: 2025-05-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 9351620
contact_pi: TSODIKOV, OLEG V
other_pis: LEGGAS, MARKOS ;ROHR, JURGEN T
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-06-01
project_title:
Mechanistic and pharmacologic studies of selective mithramycin analogues targeting EWS-FLI1 in Ewing sarcoma

project_abstract:
Ewing sarcoma family of tumors (ESFT) is a family of resilient devastating cancers of bone and soft tissueaffecting primarily children and young adults. Current highly cytotoxic combination therapy of five drugs providesonly 30% overall survival. The aberrant transcription factor EWS-FLI1 present only in tumor cells is the oncogenicdriver of EWS. However transcription factors were believed to be undruggable until a recent NCI screeningfound mithramycin (MTM) to act as a potent EWS-FLI1 antagonist. MTM has proven to be too toxic with a narrowtherapeutic window and poor pharmacokinetic (PK) properties. Here we propose mechanistic and pharmacologystudies of novel MTM analogues (MTM-SA) with significantly reduced toxicity increased target specificity andgreatly improved PK properties. In contrast to other analogues reported elsewhere which still suffer from poorPK properties the MTM-SA analogs display superior kinetics and reduced toxicity. The goal of this project is togain molecular insights into the mode of action of MTM via structural biochemical and pharmacological studiesto generate a highly efficacious and selective anti-ESFT treatment. To aid synthetic efforts in Aim1 and identifyanalogues with clinical potential we will perform molecular structure-function level studies in Aim 2 to determinehow transcription factor EWS-FLI1 interacts with DNA microsatellite repeats and transcription factor Runx2 (eacha necessary interaction for oncogenesis) and how these oncogenic functions are disrupted by MTM-SA. In Aim3 will assess the in vitro cytotoxicity and target selectivity to identify analogues that will be evaluated inpharmacologic studies that will assess toxicity in humanized liver mice PK and metabolism as well as efficacyin xenograft and PDx models of Ewing Sarcoma. The project will be carried out by a team with an establishedcollaboration who have extensive experience in fragment-based drug design and semi-synthetic routes of naturalproducts X-ray crystallographic biophysical and molecular biology studies and pharmacological evaluations.We expect that these structure-function studies will identify a lead-candidate that could enter a clinical trial forthe treatment of ESFT.

project_terms:
Affect;Animal Model;Antineoplastic Agents;Binding;Biochemical;Biological;Biological Assay;Biophysics;Bone Tissue;Cell model;Cells;Child;Childhood;Clinical;Clinical Treatment;Clinical Trials;Collaborations;Combined Modality Therapy;Complement;Complex;Crystallography;DNA;DNA Binding;DNA Binding Domain;DNA Sequence;Data;Derivation procedure;Development;Drug Design;Drug Kinetics;EWS-FLI1 fusion protein;Elements;Enhancers;Evaluation;Ewings sarcoma;FLI1 gene;Family;Foundations;Genetic Transcription;Goals;Higher Order Chromatin Structure;Human;In Vitro;Investigational Therapies;Kinetics;Liver;Malignant Bone Neoplasm;Metabolism;Microsatellite Repeats;Modeling;Molecular;Molecular Biology;Molecular Structure;Mus;Natural Products;Oncogenic;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacology Study;Phase I/II Clinical Trial;Plasma;Plicamycin;Preclinical Testing;Property;Proteins;Public Health;Reporter;Reporting;Route;Satellite DNA;Shunt Device;Side;Site;Specificity;Structure;Testing;Therapeutic;Toxic effect;Translating;Tube;X-Ray Crystallography;Xenograft Model;analog;antagonist;cancer cell;cancer diagnosis;cytotoxic;cytotoxicity;design;drug candidate;drug clearance;effective therapy;experience;improved;inhibitor;insight;lead candidate;mouse model;neoplastic cell;novel;patient derived xenograft model;pharmacologic;programs;resilience;screening;soft tissue;transcription factor;transcriptional reprogramming;tumor;tumorigenesis;young adult

public_health_relevance:
Ewing sarcoma and other Ewing family tumors are poorly treatable bone and soft tissue cancers diagnosedpredominantly in children and young adults. This project is relevant to public health because it aims to developselective chemotherapeutics to treat Ewing sarcoma through investigating oncogenic mechanisms of thecausative agent of Ewing sarcoma transcription factor EWS-FLI1. This mechanistic inquiry will becomplemented by pharmacological studies and aid the development of selective anti-Ewing sarcomatherapeutics.


application_id: 10654166
project_number: 1R15DK136105-01
administering_ic: NIDDK
award_notice_date: 2023-08-25
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: DK
serial_number: 136105
program_official: SHERKER, AVERELL H
project_start_date: 2023-09-01
project_end_date: 2026-08-31
study_section: Emerging Imaging Technologies and Applications Study Section[EITA]
contact_pi_person_id: 8792882
contact_pi: EL-BAZ, AYMAN S
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-01
project_title:
Generative-AI based system for accurate prediction of deceased donor liver-transplant (DDLT) outcome and viability

project_abstract:
PROJECT SUMMARY There are 4.5 million US patients with chronic liver disease acute liver failures and liver cancer. At endstages patients need to undergo deceased donor liver transplant (DDLT) where the whole liver is explantedfrom clinically dead donors. After liver-explant the tissue is rapidly frozen and a small sample from the donororgan is sliced and processed for rapid histopathological evaluation. Evaluation must be completed during thehighly limited time the organ can remain viable for transplantation. The procedure of histopathologicalevaluation using frozen sections differs from standard paraffin-embedded one which is time-consuming dueto additional steps to extract water and other substances from tissue. Those steps limit how tissue can bestained with dyes to produce special-stains for histopathological evaluation for fibrosis and connective tissue.Massons Trichrome (MT) is not available to pathologists during DDLT. Thus histopathological evaluation offrozen sections is highly challenging which can lead to poor outcomes and rejection of viable marginal liverswhich could be transplanted in patients. To overcome these limitations the objective of this proposal is todevelop and validate a Generative AI-based system that can produce in-silico virtual slides to assistpathologists and surgeons during DDLT. The proposed system will also include a Predictive-AI model forDDLT outcome. The generative module will use a transformation model trained on the texture patterns offibrosis and connective tissue in input hematoxylin and eosin (HE) sections. The predictive module will i)extract features from both generated MT and input HE slides ii) fuse them with recipient clinical data and iii)use deep-learning based model to predict post-transplant outcome. The proposed system can significantly helporgan donor organizations in the process of DDLT recipients selection while enhancing DDLT viability rates.Our preliminary study shows that the proposed system can produce diagnostic-enabled virtual slides thatare validated by experienced pathologists. Also the study shows our predictive model can performautomatic quantification of fibrosis in the virtual slides with accuracy of 86%. In this proposal (1) we willdevelop a deep learning-based software that can produce augmented MT layers on the digital HE slides ofliver allografts frozen sections and (2) we will extend the software to be capable of predicting the outcome ofliver-transplant by learning histopathological and other clinical markers from recipients that predict post-transplant viability.The impacts of our technology are: a) efficient and accurate histopathological evaluation of liver allograft duringDDLT b) improved post-transplant outcome and survival rate c) reduced operational cost in histologylaboratories and d) accelerated pathology workflows and digital pathology transformation.

project_terms:
Acceleration;Acute Liver Failure;Albumins;Blood;Clinical;Clinical Data;Clinical Markers;Collaborations;Computer software;Computer-Assisted Diagnosis;Connective Tissue;Consumption;Data;Diagnostic;Dyes;E-learning;Evaluation;Fibrosis;Freezing;Frozen Sections;Goals;Hematoxylin and Eosin Staining Method;Histology;Human;Implant;Kentucky;Laboratories;Learning;Liver;Malignant neoplasm of liver;Modeling;Organ;Organ Donor;Organ Viability;Outcome;Paraffin Embedding;Pathologist;Pathology;Patient-Focused Outcomes;Patients;Pattern;Phosphoric Monoester Hydrolases;Procedures;Process;Prospective Studies;Protocols documentation;Reporting;Retrospective Studies;Sampling;Slice;Slide;Software Validation;Stains;Surgeon;Survival Rate;System;Technology;Testing;Texture;Time;Tissue Sample;Tissue Stains;Tissues;Training;Transplant Recipients;Transplantation;Trichrome stain;Trichrome stain method;Universities;Validation;Waiting Lists;Water;blind;chronic liver disease;cost;deep learning;deep learning model;digital;digital pathology;experience;improved;in silico;liver allograft;liver transplantation;outcome prediction;post-transplant;predictive modeling;transplant centers;virtual;whole slide imaging

public_health_relevance:
PROJECT NARRATIVE The objective of this proposal is to develop and validate a deep-learning based Computer-Aided Diagnosis(CAD) system for assessing post-transplant viability of livers transplanted from deceased organ donors.. Theproposed system will aid pathologists and surgeons during the highly time-sensitive deceased-donor livertransplant (DDLT) procedure and will help organ donor organizations in nominating the optimum recipient toimprove post-transplant viability rates. In particular the proposed system will use (1) Generative-AIapproaches to generate virtual slides with alternative staining from readily available pathology samples and(2) Predictive-AI approaches to fuse the computed histopathological metrics (from donor) with clinical metrics(from recipients) to accurately predict post-transplant outcome.


application_id: 10654152
project_number: 1R15HL168688-01
project_title: Physiologically relevant cardiac tissue culture model for drug testing and disease modeling
administering_ic: NHLBI
award_notice_date: 2023-05-03
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: HL
serial_number: 168688
program_official: THAKAR, RAHUL GAUTAM
project_start_date: 2023-05-03
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1 CVRS-C (80)]
contact_pi_person_id: 8765816
contact_pi: GIRIDHARAN, GURUPRASAD A
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Human tissue modelling in culture is a major challenge for drug discovery and screening and disease modeling.The ideal cardiac tissue culture model (CTCM) should accurately recreate the critical organ-level structure andfunction. The success of CTCM depends on ability to mimic what occurs in the human body in physiological andpathophysiological conditions. The heart is a unique organ that is subject to continuous cycles of alternatingpressure and stretch due to hemodynamic loading and unloading. These hemodynamic stressors are of criticalimportance to cardiac function and metabolism in health and disease. Changes in stress within physiologic rangeresult in physiological remodeling whereas significant changes (e.g. hypertension ischemia valve disease)result in adverse pathological remodeling leading to cardiovascular dysfunction. We recently developed a systemto culture 300M thick human heart slices that fully maintains their functionality for over 12 days through providingthe precise-cardiac-cycle hemodynamic pressures stresses and electrical stimulation. This technology providesaccess to complete 3D multicellular system that is highly similar to human heart tissue and emulatesphysiological or pathological conditions both functionally and structurally. Within our CTCM we can controlelectrical stimulation (current amplitude and frequency) as well as the critical mechanical parameters includingpreload afterload pressures rate of pressure change and heart rate (HR) to accurately model normal andpathological diseased conditions.We hypothesize that establishment of physiologically relevant Human cardiac Tissue Culture Model needscontinuous functional monitoring of the human heart tissue that undergo a replication of all in vivolike structuraland functional adaptation during health and disease. Through continuous monitoring of any changes on cardiacfunction this system will be able to accurately assess drug toxicity and efficacy in healthy and diseased cardiactissue. We will validate To test this hypothesis we propose the following aims:Specific Aim 1: (a) Incorporation of real-time monitoring of contractile force strain andelectrophysiological properties in culture for 12 days and (b) validate the CTCM with real-timemonitoring to accurately predict drug cardiotoxicity (12 cardiotoxins. Specific Aim 2: Modeling cardiacpathology using CTCM and testing for testing drug efficacy.Successful completion of this project will validate our CTCM system and fulfill a significant need by thepharmaceutical industry and regulatory bodies for a medium throughput tissue culture technology that faithfullyreplicates the human cellular and pathophysiology and is highly sensitive for cardiotoxicity responses to drugsfor drug discovery and screening. Such a system will enable better mechanistic understanding of heart failuretherapies minimize drug related adverse effects in patients and enable faster and more cost-effective drugdevelopment and screening and enhance the confidence in a candidate drug by regulatory bodies (eg. FDA).

project_terms:
3-Dimensional;Address;Adult;Adverse drug effect;Biological Models;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular system;Categories;Cells;Characteristics;Clinical;Consumption;Culture Media;Data;Direct Lytic Factors;Disease;Disease model;Drug Industry;Drug Modelings;Drug Screening;Drug toxicity;Effectiveness;Electric Stimulation;Electrocardiogram;Electrophysiology (science);FDA approved;Frequencies;Functional disorder;Health;Heart;Heart Diseases;Heart Rate;Heart failure;Hip region structure;Human;Human body;Hypertension;Hypertrophy;Ischemia;Measures;Mechanics;Metabolism;Modeling;Monitor;Myocardium;Nutrient;Organ;Pathologic;Pathology;Patients;Pharmaceutical Preparations;Phenotype;Physiological;Physiology;Property;Research;Safety;Slice;Stimulus;Stress;Stretching;Structure;System;Technology;Testing;Therapeutic;Thick;Time;Tissue Model;Tissues;Toxic effect;Treatment Efficacy;Treatment Failure;aorta constriction;cell type;cost;cost effective;drug candidate;drug development;drug discovery;drug efficacy;drug testing;efficacy testing;fetal;first-in-human;functional adaptation;heart function;heart metabolism;hemodynamics;human tissue;imaging system;improved;in vivo;pre-clinical;pressure;real time monitoring;response;sensor;stressor;success;therapeutic evaluation;tissue culture;voltage

public_health_relevance:
Project NarrativeThere is a critical need by the pharmaceutical industry and regulatory bodies for a medium throughput tissueculture technology that faithfully replicates the human cellular and pathophysiology and is highly sensitive forcardiotoxicity and efficacy responses to drugs as this will optimize drug discovery and selection prior toundertaking costly and time consuming first in man trials. To fulfill this need we propose to develop and validatea new human heart slice culture system with continuous monitoring of cardiac function parameters that canaccurately model normal and diseases states and precisely predict drug efficacy and toxicity. Our tissue culturesystem will be the first physiologically relevant medium-throughput cost-effective human heart system in culture.


application_id: 10653980
project_number: 5R01DE030100-03
administering_ic: NIDCR
award_notice_date: 2023-06-09
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 030100
program_official: OKI, NOFFISAT
project_start_date: 2021-07-01
project_end_date: 2025-06-30
study_section: Clinical Data Management and Analysis Study Section[CDMA]
contact_pi_person_id: 10376668
contact_pi: CLARKSON, MELISSA
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Developing standardized graphic libraries for anatomy: A focus on human craniofacial anatomy and phenotypes

project_abstract:
Project summaryCommunicating about anatomical concepts and patient-specific anatomy is fundamental to medicine.Anatomy of the head and face (craniofacial anatomy) is complex and facial morphology varies withinand among populations. Orofacial cleftswhich are among the most common congenital anomaliesdisplay a range of severities and may be preset at more than one site. There is a need to communicate rapidly and accurately about craniofacial anatomy in clinicalpractice medical education and when using clinical data in research. To address this challenge wepropose to create simple standardized graphics of craniofacial anatomy and phenotypes. Our collectionsof graphics or graphic libraries will serve as complements to textual representations and will bedesigned for use within clinical research and educational software applications. Our approach todesigning the graphics is based on four requirements: that the graphics be composable extensibleidentifiable and created using scalable vector graphics (SVGs). We will first develop graphics for adult and developmental anatomy then for phenotype variationsand malformations. We will also develop prototypes for two web-based toolsone that incorporatesgraphics into the Human Phenotype Ontology and the other for documenting craniofacial phenotypesand malformations in clinical settings. By offering a new paradigm for communicating about anatomy ourgraphic libraries will become crucial components of the next generation of software applications forclinical practice research and education.

project_terms:
Address;Adult;Anatomic Models;Anatomy;Clinical;Clinical Data;Clinical Medicine;Collection;Communication;Complement;Complex;Computer software;Computers;Correlation Studies;Data Set;Developmental Anatomy;Documentation;Education;Environment;Evaluation;Face;Future;Genotype;Head;Human;Informatics;Libraries;Maps;Measurement;Medical Education;Medical Illustration;Medical Research;Medicine;Methods;Morphology;Nature;Ontology;Patient Care;Patients;Persons;Phenotype;Physical Anthropology;Play;Population;Positioning Attribute;Production;Research;Role;Severities;Site;Standardization;Terminology;Text;Time;Variant;Visual;Work;clinical application;clinical practice;congenital anomaly;craniofacial;design;malformation;model organism;multidisciplinary;next generation;orofacial cleft;preservation;prototype;real world application;skills;tool;tool development;vector;web app;web-based tool

public_health_relevance:
Project narrativeThis project will produce a large library of graphics depicting craniofacial anatomy. These graphics will bedesigned for use in software applications for clinical practice research and education and will help tofacilitate rapid and accurate communication.


application_id: 10652663
project_number: 5R21ES033334-02
project_title: Benzene Exposure and Heart Failure
administering_ic: NIEHS
award_notice_date: 2023-06-29
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: ES
serial_number: 033334
program_official: SCHUG, THADDEUS
project_start_date: 2022-07-01
project_end_date: 2025-06-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 9705355
contact_pi: ZELKO, IGOR N.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryLong-term exposure air pollutant exposure is recognized as a risk factor for cardiovascular diseases includingmyocardial ischemia and heart failure. Recent epidemiological and experimental data indicate that many volatileorganic compounds including benzene contribute to worsening outcomes in patients with progressive heartdisease. Benzene is the most abundant air pollutant mostly generated from automobile exhaust and tobaccosmoke. Despite high prevalence of benzene in air-pollutants little is known about the direct effects of inhaledbenzene on heart failure morbidity and mortality in well-controlled animal studies. Our recent studies show thatbenzene exposure resembling moderate to high levels of human exposure worsens cardiac function in pressureoverload-induced mice. The benzene-induced worsening of cardiac functions was accompanied by endothelialactivation and infiltration of granulocytes in the heart and upregulation of gene expression for CXCL1 chemokineand alarmin S100A8/A9 complex which promotes neutrophil and monocyte chemotaxis and adhesion throughTLR4 and RAGE signaling. Our new preliminary data show that ambient benzene exposure causes endothelialactivation/injury in humans and chronic low dose exposure stimulates endothelial activation/injury in mice. Usinganimal model of pressure overload-induced cardiac dysfunction we will examine the effects of environmentalbenzene exposure on cardiac dysfunction (echocardiography cardiac hypertrophy analysis of composition andactivation status of infiltrating immune cells) during heart remodeling (Aim 1) and examine the molecularmechanisms by which benzene exacerbate cardiac dysfunction (Aim 2). Successful completion of these studieswill for the first time show how benzene affect cardiac function in patients with progressing heart failure andprovide mechanistic insight into this process.

project_terms:
Adhesions;Affect;Air Pollutants;Animal Model;Animals;Anti-Inflammatory Agents;Automobile Exhaust;Benzene;Benzene Exposure;Bone Marrow;C57BL/6 Mouse;CXCL1 gene;Cardiac;Cardiac Output;Cardiotoxicity;Cardiovascular Diseases;Cell Separation;Cells;Chemicals;Chemotaxis;Cholesterol;Chronic;Clinical Research;Complex;Data;Development;Dichloromethylene Diphosphonate;Dose;Echocardiography;Endothelial Cells;Endothelium;Endotoxins;Environment;Environmental Pollutants;Epidemiology;Exposure to;Flow Cytometry;Functional disorder;Gene Expression Regulation;Genetic Transcription;Goals;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;High Prevalence;Histology;Hospitalization;Human;Hypertrophy;Immune;Immunohistochemistry;Immunologic Stimulation;Infiltration;Inflammation;Inflammatory;Inflammatory Infiltrate;Inhalation;Injury;Insulin Resistance;LCN2 gene;Left;Left ventricular structure;Liposomes;Macrophage;Mediating;MicroRNAs;Molecular;Morbidity - disease rate;Mus;Myocardial Infarction;Myocardial Ischemia;Myocardial dysfunction;Neutrophil Infiltration;Outcome;Pathologic;Patients;Persons;Plasma;Process;Risk;Risk Factors;Role;S100A8 gene;S100A9 gene;Signal Transduction;Site;Source;Styrenes;TLR4 gene;Testing;Time;Tissues;Tobacco smoke;Toluene;United States;Up-Regulation;Ventricular;Ventricular Remodeling;Xylene;acute coronary syndrome;air filter;cardiovascular health;cardiovascular risk factor;chemokine;cigarette smoke;endothelial stem cell;ethylbenzene;exposed human population;granulocyte;heart function;immune cell infiltrate;improved;inhibitor;insight;mimetics;monocyte;mortality;mouse model;myocardial injury;neutrophil;patient prognosis;preclinical study;pressure;recruit;sex;small molecule;small molecule inhibitor;toxicant;transcriptome sequencing;volatile organic compound

public_health_relevance:
Project NarrativeBenzene is the most abundant air pollutant mostly generated from automobile exhaust and tobacco smoke.Despite high prevalence of benzene in air-pollutants direct effects of inhaled benzene on heart failure morbidityand mortality in well-controlled animal studies have not been investigated. The goal of this project is to elucidatethe contribution of benzene on cardiac dysfunction and heart failure.


application_id: 10652484
project_number: 5R25GM132961-05
project_title: STEM Through Authentic Research Training (START) Program for Underrepresented Communities
administering_ic: NIGMS
award_notice_date: 2023-06-14
opportunity_number: PAR-17-339
application_type: 5
activity_code: R25
ic: GM
serial_number: 132961
program_official: FAUPEL-BADGER, JESSICA
project_start_date: 2019-07-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-CB-J(56)R]
contact_pi_person_id: 9077753
contact_pi: BRADLEY, LUKE H
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:
Abstract/ Project SummaryThe increasing importance of technology in contemporary society necessitates a STEM literate population.This represents a challenge for traditionally underrepresented populations (people of color individuals withdisabilities individuals in less affluent communities) impacting upward social mobility. Often members ofthese groups are doubly disadvantaged as the few who become first generation college students often lack aroadmap for success through family near peers and potential mentors. Success for this populationrepresenting a highly motivated group needs to be nurtured to embrace and advance STEM disciplinesbefore they reach their college classrooms. This necessitates the education not only of students but theirteachers providing synergies in teaching and learning to empower students to avail of opportunities perceivedas being beyond their reach. We hypothesize that bridging this expanding gap requires an integrated programbringing together academic social and real-world professional experiences to establish a pipeline linkingsuccess in middle/high school to success for first generation college students and beyond. Such a pipeline willgenerate not only STEM-proficient citizens but also a cadre of near peers to motivate by example. With thiscentral premise we have formed the STEM Through Authentic Research and Training (START) Program totidentify recruit and retaining traditionally underrepresented populations by providing year-round authenticresearch opportunities and professional development for high school students (grades 9-12) and middle andsecondary STEM teachers (grades 5-12). START represents a partnership between the University of Kentuckyproviding opportunities for STEM research The Academies of Lexington a partnership with the FayetteCounty Public Schools- focused on changing the traditional didactic model for STEM instruction the KY-WVLSAMP program an NSF funded consortium led by UK including over 10 diverse academic institutionssupporting undergraduate research aimed at increasing the representation and overall success of traditionallyunderrepresented populations in STEM disciplines. START establishes a natural pipeline to the collegiatelevel by virtue of the alliance with KY-WV LSAMP and its member institutions. Finally we have recruited SpaceTango a Lexington STEM start-up company which builds and integrates systems for scientific and biomedicalresearch under microgravity conditions on the international space station. As such a spectrum of researchopportunities from the molecular and microscopic level in participating UK STEM laboratories to the vastnessof space itself afforded by Space Tango provide an exciting palate of opportunities for traditionallyunderrepresented students and the teachers responsible for their STEM education. We believe that theintegration of real world authentic research opportunities in the context of overall STEM education via a uniquepartnership between academia educational and commercial entities will motivate underrepresented studentpopulations to levels of achievement they often believe are beyond their horizons.

project_terms:
Academia;Academy;Achievement;Address;Adopted;Agreement;Biomedical Research;Collaborations;Communities;County;Critical Thinking;Development;Disabled Persons;Disadvantaged;Education;Educational process of instructing;Educational workshop;Engineering;Family;First Generation College Students;Fostering;Funding;Future;Goals;High School Faculty;High School Student;Individual;Institution;Instruction;International;Kentucky;Laboratories;Leadership;Learning;Life;Link;Mentors;Mentorship;Methods;Microgravity;Microscopic;Middle School Faculty;Modeling;Molecular;Palate;Persons;Population;Positioning Attribute;Research;Research Training;Resources;STEM career;STEM curriculum;STEM field;STEM research;STEM student;Schools;Science;Science Technology Engineering and Mathematics Education;Scientist;Secondary Schools;Social Mobility;Societies;Students;Support System;System;Techniques;Technology;Training;Training Programs;Underrepresented Populations;Underrepresented Students;Underserved Population;Universities;age group;apprenticeship;beneficiary;career;college;design;empowerment;experience;high school;improved;innovation;interdisciplinary collaboration;interest;knowledge integration;literate;member;neglect;novel strategies;peer;peer coaching;people of color;programs;real world application;recruit;role model;skills;social;social integration;space station;student participation;success;synergism;teacher;undergraduate research;undergraduate student

public_health_relevance:
Project NarrativeThe relative shortage of near peers and relatable mentors for first generation college students andunderrepresented student populations inhibits them from reaching their maximal potential. By establishing apipeline to integrate real world research experiences in an academic and/or STEM-intensive commercialsetting for both students (grades 9-12) and STEM teachers (grades 5-12) we expect to deliver opportunities forSTEM education typically neglected for underserved populations. The STEM Through Authentic ResearchTraining (START) program is designed to integrate academia the secondary education system andcommercial interests toward identifying and nurturing STEM proficient students promoting success at thecollege level and beyond.


application_id: 10652467
project_number: 5R01AI139671-05
administering_ic: NIAID
award_notice_date: 2023-06-23
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 139671
program_official: CHUANG, ELEANORE JENNIFER
project_start_date: 2019-07-05
project_end_date: 2025-06-30
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 10797120
contact_pi: FRIEBOES, HERMANN
other_pis: LEWIS, AMANDA L.
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Understanding the Host-Microbiome-Therapeutic Triad: Implications for Designing Alternative Intravaginal Delivery Platforms to Treat Bacterial Vaginosis

project_abstract:
PROJECT SUMMARYBacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome characterized by low levels of lactobacilli whichtypically dominate the vagina in healthy women and overgrowth of diverse anaerobic bacteria most notablyGardnerella vaginalis (G.v.). BV affects ~30% of U.S. women and is associated with increased risk of adversepregnancy outcomes postsurgical infections and sexually transmitted infections (STIs). Current treatmentoptions primarily comprised of orally- or topically-applied antibiotics are initially efficacious; however frequentrelapse is prevalent contributing to recurrent BV infections and adverse side effects. Potential new therapiesincluding prebiotics metabolic products (e.g. lactic acid) and probiotics (lactobacilli) are being studied for theirabilities to re-balance the vaginal microbiome toward normal Lactobacilli and counterbalance G.v. Howeverthese and other methods of BV treatment often require repeated vaginal administrations which can limit theirconvenience and appropriate use. New delivery vehicles that can store and release lactic acid and probioticlactobacilli are needed. However significant gaps remain in our understanding of host microbe and deliveryvehicle interactions contributing to the difficulty in attaining a long-term effective method of protection andtreatment against BV. In this project we seek to develop new therapies to alter BV pathogenesis while advancing theunderstanding of delivery vehicle interactions with the host and vaginal microbes. To achieve these goals wewill optimize the design of a novel delivery platform composed of sequentially-layered or dual-spun polymericelectrospun fibers (EFs) that deliver probiotics test their efficacy in vitro and assess the safety and effectivenessof these fibers in a murine model of BV. These studies will provide the foundation for improved therapeuticoutcomes while providing new insight into the effects of lactic acid-based probiotic fibers on vaginal microbeshost inflammatory response and BV disease markers and progression. While we will initially apply this deliveryapproach to target BV pathogenesis we envision the research outcomes will have a significant impact on thedevelopment of future multipurpose platforms to prevent and treat broader more complex interactions betweenbacterial and viral pathogens in the female reproductive tract.

project_terms:
Acids;Adherence;Affect;Anaerobic Bacteria;Antibiotics;Architecture;Atopobium vaginae;Back;Bacteria;Bacterial Counts;Bacterial Vaginosis;Chronic;Coculture Techniques;Complex;Cream;Data;Development;Disease Marker;Disease Progression;Dosage Forms;Effectiveness;Encapsulated;Enzymes;Epithelium;Equilibrium;Female;Fiber;Formulation;Foundations;Future;Gardnerella vaginalis;Gel;Generations;Goals;Growth;Health;Homeostasis;In Vitro;Infection;Inflammatory Response;Intravaginal Administration;Lactic acid;Lactobacillus;Malignant Neoplasms;Metabolic;Methods;Microbe;Microbial Biofilms;Modeling;Mucous body substance;Oral;Outcome;Outcomes Research;Pathogenesis;Patients;Physiological;Polymers;Pre-Clinical Model;Probiotics;Recurrence;Regimen;Relapse;Risk;Safety;Sexually Transmitted Diseases;System;Tablets;Testing;Therapeutic;Time;Tissue Model;Topical application;Treatment Efficacy;Uterus;Vagina;Viral;Woman;adverse pregnancy outcome;antimicrobial;chemokine;cytokine;delivery vehicle;design;dysbiosis;host microbiome;improved;insight;member;microbiome therapeutics;mouse model;nanoparticle;novel;novel therapeutics;oral biofilm;pathogen;pathogenic bacteria;pathogenic virus;prebiotics;prevent;reproductive tract;residence;response;safety assessment;safety study;scaffold;side effect;success;therapy outcome;treatment strategy;vaginal infection;vaginal microbiome;vaginal microbiota

public_health_relevance:
PROJECT NARRATIVEBacterial vaginosis is a highly recurrent imbalance of the vaginal microbiota that affects 1/3 of U.S. womenand is associated with numerous adverse health outcomes; however antibiotic-sparing treatments such as thedelivery of probiotic bacteria often require daily administration for effectiveness. We will optimize the design ofa novel delivery platform composed of sequentially-layered or dual-spun polymeric electrospun fibers that willdeliver probiotic lactobacilli and lactic acid then test their efficacy in both in vitro and mouse models of BV.This study will provide a foundation for improved therapeutic outcomes while providing new insight into theeffects of probiotic lactic acid-based fibers on BV disease markers and host inflammatory responses.


application_id: 10652078
project_number: 2R15MH121445-02
administering_ic: NIMH
award_notice_date: 2023-05-30
opportunity_number: PAR-21-155
application_type: 2
activity_code: R15
ic: MH
serial_number: 121445
program_official: CHAVEZ, MARK RAY
project_start_date: 2023-06-15
project_end_date: 2026-06-14
study_section: Adult Psychopathology and Disorders of Aging Study Section[APDA]
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: 2023-06-15
project_title:
Personalized Networks and Sensor Technology Algorithms of Eating Disorder Symptoms Predicting Eating Disorder Outcomes

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are severe mental illnesses. Efficacy rates of evidence-based treatmentsare low (<50% response) and relapse rates are high (>35% relapse after treatment). The lowtreatment response and high relapse rates are due in part to the fact that EDs are heterogeneousconditions. As such idiographic (i.e. one person) models are needed that can predict andultimately prevent onset of both problematic ED behaviors (e.g. purging binge eating) andremission/relapse. The current renewal application capitalizes on our existing data collection(N=120 ED) to both increase our sample size (N=140) and extend data collection to two years offollow-up. Our study goals are to: (1) characterize and predict shorter-and-longer-term relapseand remission (2) use real-time physiological data algorithms to predict onset of ED behaviorsrelapse and remission. We will use a multiple units of analysis approach combined with novelcutting-edge advances in idiographic modeling. In our currently funded proposal we collectedintensive real-time data using mobile and sensor-technology from 120 individuals with a diagnosisof anorexia nervosa (AN) atypical AN and bulimia nervosa across 30 days and assessed follow-up at 1-month and 6-months. In this renewal we will collect additional follow-ups at 18-month and2-years and include behavioral assessments of body disturbances and behavioral avoidance. Wewill also collect a new subsample of participants (n=20) and include additional assessment ofglobal positioning system (GPS) the sleep-wake cycle and circadian rhythm disruption (CR).These additional assessments will improve characterization of relapse capture a greaterpercentage of relapse events (~35% across two years) improve accuracy of prediction for EDbehaviors relapse and remission and identify which features (e.g. GPS sleep-wake cycle)contribute to improved accuracy. Specific aims are to: (1) well-characterize longer-term (18 monthand 2 years) relapse/remission in the existing sample of EDs (2) test if both idiographic EMA andphysiological (HR/HRV EDA ACC) features predict longer-term relapse/remission and (3)determine if the addition of GPS and sleep-wake ACC & CR data improve accuracy of ourpredictive algorithms. The proposed research uses highly innovative methods combiningintensive longitudinal data collection methods all remote procedures novel advances inidiographic modeling and sensor-technology and state-of-the-art machine learning techniques.These data will lead directly to novel therapeutics such as just-in-time mobile and sensor alertsystems that can provide guidance to both clinicians and patients on how to prevent problematicED behaviors and ultimately increase remission and decrease relapse rates.

project_terms:
Accelerometer;Adult;Affective;Aftercare;Algorithms;Anorexia Nervosa;Behavior Disorders;Behavior assessment;Behavioral;Binge Eating;Bulimia;Chronic;Circadian Dysregulation;Circadian Rhythms;Cognitive;Data;Data Collection;Diagnosis;Diagnostic;Dimensions;Disease remission;Eating Disorders;Ecological momentary assessment;Event;Evidence based treatment;Feeling;Fright;Funding;Future;Global Positioning System;Goals;Health Personnel;Heart Rate;Hyperphagia;Individual;Lead;Machine Learning;Maintenance;Measures;Methods;Modeling;Outcome;Participant;Patient Self-Report;Patients;Persons;Physiological;Physiology;Precision Medicine Initiative;Procedures;Publishing;Recovery;Relapse;Reporting;Research;Sample Size;Sampling;Severities;Signal Transduction;Sleep;Sleep Wake Cycle;Sleep disturbances;Symptoms;System;Techniques;Testing;Thinking;Thinness;Time;United States National Institutes of Health;Weight Gain;Work;dieting;effective therapy;feature detection;follow up assessment;follow-up;heart rate variability;improved;innovation;mobile computing;novel;novel therapeutics;personalized medicine;prediction algorithm;predictive modeling;prevent;public health relevance;purge;recruit;relapse prevention;response;sensor;sensor technology;severe mental illness;standard care;treatment response

public_health_relevance:
PROJECT NARRATIVEThis project will develop predictive idiographic (e.g. one person) models of eating disorderrelapse. The proposed research has significant public health relevance as it will lead topersonalized novel effective treatments that prevent relapse and decrease the high societalburden associated with eating disorders. The proposed research is relevant to NIHs precisionmedicine initiative as it will identify within-person maintenance symptoms of eating disordersleading to personalized treatments delivered via mobile or sensor technology.


application_id: 10651014
project_number: 1R21CA280453-01
project_title: A lung cancer vaccine based on exosomes of induced pluripotent stem cells
administering_ic: NCI
award_notice_date: 2023-09-20
opportunity_number: PAR-20-292
application_type: 1
activity_code: R21
ic: CA
serial_number: 280453
program_official: CLIFFORD, JOHN LEO
project_start_date: 2023-09-20
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZCA1 SRB-1 (J1)]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: YADDANAPUDI, KAVITHA
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
A lung cancer vaccine based on exosomes of induced pluripotent stem cellsABSTRACTA critical challenge in lung cancer research is to develop innovative vaccines to protect against pulmonarymalignancy. Recent efforts to develop lung cancer vaccines have largely failed probably due to their focus oninducing immune responses against individual lung tumor-associated antigens. If a lung cancer vaccine targetsmultiple antigens present only in lung tumors but not in normal adult tissues the chance of success will begreatly improved. Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells and have thecapacity of self-renewing and developing into all cell types of the adult body. It is known that iPSCs and tumorcells share carcinoembryonic antigens that are absent in normal adult tissues. Lung tumors also contain asubpopulation of tumor-initiating cells (TICs) with high tumorigenicity and self-renewal capability that contributeto the resistance to conventional therapies. Exploiting the antigenic similarity between tumor cells and iPSCswe propose to thoroughly investigate efficacy of a lung cancer vaccine composed of exosomes from murineiPSCs expressing granulocyte-macrophage colony stimulating factor (GM-CSF) as an immunostimulatoryadjuvant (iPSC-exo). We hypothesize that iPSC-exo vaccination prevents lung tumorigenesis by triggeringCD8+ T cell-dependent immune responses and eradicating lung TICs. In this grant we will investigate thishypothesis in two clinically relevant immunocompetent murine lung tumor models. Two specific aims areproposed: 1) Investigate the translational potential of iPSC-exo vaccination against lung cancer; 2) Elucidatethe mechanism by which iPSC-exo vaccination prevents lung cancer. We believe that the success of proposedexperiments will lead to clinical trials of a similar vaccine against human pulmonary malignancy.

project_terms:
Adjuvant;Adult;Allogenic;Antigen Presentation;Autoimmune Responses;Autoimmunity;CD4 Positive T Lymphocytes;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Vaccines;Carcinoembryonic Antigen;Categories;Cells;Chimera organism;Clinical Trials;Coculture Techniques;Enterobacteria phage P1 Cre recombinase;Exclusion;Fibroblasts;Frequencies;Germ Cells;Goals;Grant;Granulocyte-Macrophage Colony-Stimulating Factor;Human;Immune response;Immunity;Immunocompetent;Immunotherapeutic agent;Implant;In Vitro;Individual;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Measures;Mediating;Modeling;Monoclonal Antibodies;Mus;Operative Surgical Procedures;Patients;Pluripotent Stem Cells;Prevention approach;Probability;Property;Recurrence;Residual Neoplasm;Resistance;Serum;Somatic Cell;Source;Splenocyte;Subgroup;T cell response;T-Cell Depletion;TP53 gene;Testing;Tissues;Tumor Antigens;Tumor Immunity;Tumor-Infiltrating Lymphocytes;Tumorigenicity;Vaccinated;Vaccination;Vaccines;anti-cancer;anticancer research;antitumor effect;cell type;clinically relevant;conventional therapy;cytotoxic;cytotoxic CD8 T cells;early embryonic stage;effectiveness evaluation;effector T cell;embryonic stem cell;exosome;experimental study;immunogenic;improved;in vivo;induced pluripotent stem cell;innovation;loss of function;lung development;lung tumorigenesis;mouse model;mutant;neoplastic cell;prevent;response;self-renewal;success;translational potential;tumor;tumor eradication;tumor initiation;tumorigenesis;tumorigenic;vaccination strategy

public_health_relevance:
PROJECT NARRATIVEEmerging evidence supports the hypothesis that vaccination with pluripotent stem cells is efficacious atpreventing lung cancer probably by specifically inducing robust CD8+ cytotoxic T cell responses and immunityagainst tumor-initiating cells (TICs). In this grant we propose to thoroughly explore the efficacy of an anti-lungcancer vaccine  exosomes of allogeneic murine iPSCs expressing granulocyte-macrophage colonystimulating factor (GM-CSF) as an immunostimulatory adjuvant (iPSC-exo vaccine). We will investigate theefficacies of iPSC-exo vaccination against primary as well as recurrent lung malignancy and evaluate whetherTICs are the targets for this vaccination strategy through the induction of robust CD8+ T cell-dependentimmune responses.


application_id: 10650837
project_number: 5R01CA266579-02
project_title: Targeting Polo-Like Kinase 1 in Prostate Cancer to Enhance Therapeutic Efficacy
administering_ic: NCI
award_notice_date: 2023-06-29
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 266579
program_official: XU, WANPING
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: Mechanisms of Cancer Therapeutics - 2 Study Section[MCT2]
contact_pi_person_id: 10992448
contact_pi: LI, ZHIGUO
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:
Title: Targeting Polo-like kinase 1 in prostate cancer to enhance therapeutic efficacyAbstractProstate cancer (PCa) is the second most common cause of cancer death in men in the US. Over the pastseveral decades androgen deprivation therapy has been the primary therapeutic option for patients withadvanced PCa; however the majority of patients developed into a poor prognosis stage of castration-resistantprostate cancer (CRPC) which eventually led to mortality. And the current therapeutic agents for CRPCpatients only extend survival by around 2.5 - 5 months. Therefore novel and effective therapeutic strategies forCRPC patients are urgently needed. The long-term goals of this study are to identify druggable signalingpathways that offer more effective treatment options for patients with CRPC. The objective is to identify the roleof Plk1/p62/Nrf2 signaling pathway in CRPC and to exploit the potentially therapeutic strategies that could bebenefit the CRPC patients. The central hypothesis is that Nrf2 is activated by a noncanonical mechanisminvolving p62 phosphorylation by Plk1 in CRPC. Our hypothesis will be tested by pursuing Three Specific Aims:(1) to determine the novel role of Plk1 as regulator of cellular response to oxidative stress. (2) examine the roleof Plk1/p62/Nrf2 axis in tumor growth in mouse models. And (3) whether inhibition of Plk1/p62/Nrf2 signalingpathway enhance the efficacy of CRPC therapy. The expected results will reveal a novel molecular mechanismto show how Plk1 contributes to PCa progress and will open up new avenues for application of Plk1 inhibitorsas a therapeutic option. The team with expertise in Plk1 in mouse models Plk1 in cancer cell biology PCapathology GU oncology and biostatistics will be able to finish the proposed research in a timely manner.

project_terms:
Alleles;Androgens;Apoptosis;Autophagocytosis;Biometry;Breeding;Cancer Etiology;Cancer Patient;Cell Survival;Cells;Cellular biology;Cessation of life;Clinic;Clinical Research;Creativeness;Data;Disease;Enterobacteria phage P1 Cre recombinase;Fostering;Genetically Engineered Mouse;Goals;Health;Immune checkpoint inhibitor;Immunocompetent;Immunosuppression;Immunotherapy;Infiltration;Investigation;Lymphocyte;Malignant Neoplasms;Malignant neoplasm of prostate;Measurement;Mediating;Membrane;Mission;Molecular;Mus;Myelogenous;Myeloid Cells;Myeloid-derived suppressor cells;Oncology;Outcome;Oxidative Stress;PDL1 inhibitors;PDL1 pathway;PLK1 gene;Pathology;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Play;Prognosis;Proliferating;Prostate Cancer therapy;Public Health;Reactive Oxygen Species;Refractory;Regulation;Research;Residual state;Role;Signal Pathway;Signal Transduction;Survival Rate;Testing;Therapeutic;Therapeutic Agents;Therapeutic Effect;Treatment Efficacy;Tumor Escape;Tumor Immunity;Tumor-infiltrating immune cells;Up-Regulation;Work;advanced prostate cancer;androgen deprivation therapy;anti-PD-L1 therapy;cancer cell;castration resistant prostate cancer;cell growth;comparative efficacy;design;effective therapy;immune cell infiltrate;improved;inhibitor;innovation;men;mortality;mouse model;neoplastic cell;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;pharmacologic;programmed cell death ligand 1;programs;promoter;prostate cancer cell;prostate cancer progression;receptor;response;synergism;targeted treatment;therapeutically effective;tumor;tumor growth;tumor microenvironment;tumor xenograft;tumor-immune system interactions

public_health_relevance:
NarrativeThe proposed research is relevant to public health because it focuses on a novel therapeutic strategy forcastration-resistant prostate cancer. These studies will establish new avenues of investigation to developimproved therapeutics to treat this deadly disease and to greatly improve patient outcome. Thus theproposed research is relevant to NCI's mission of fostering creative discoveries and innovativeresearch strategies for protecting and improving health and reducing the burdens associated with cancer.


application_id: 10650304
project_number: 5R37CA234002-04
project_title: Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors
administering_ic: NCI
award_notice_date: 2023-06-20
opportunity_number: PA-19-056
application_type: 5
activity_code: R37
ic: CA
serial_number: 234002
program_official: FORRY, SUZANNE L
project_start_date: 2020-07-09
project_end_date: 2025-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have recently discovered a novel oncogenic mechanism whereby cyclin D1 bypasses CDK4/6 inhibitionresulting in the stimulation of 6-phosphofructo-2-kinase (PFKFB3) and glucose metabolism. The objective of thisproposal is to characterize the role of PFKFB3 in mediating adaptation or resistance to CDK4/6 inhibition and todefine new approaches to increase the efficacy of CDK4/6 inhibitors in order to enable durable responses instage IV HR+ breast cancer patients. Deregulation of the estrogen receptor (ER)-cyclin D1-CDK4/6 pathway isa hallmark of ER+ breast cancer that has prompted the development of CDK4/6 inhibitors. Althoughadministration of CDK4/6 inhibitors to patients with ER+ advanced breast cancers have resulted in animprovement in progression free survival almost all patients invariable develop resistance and relapse over time.Activation of glucose metabolism upon CDK4/6 inhibition is becoming increasingly evident. A key stimulator ofglycolysis is the PFKFB3 enzyme which synthesizes fructose 26-bisphosphate (F26BP) a potent allostericactivator of the rate-limiting 6-phosphofructo-1-kinase (PFK1). F26BP controls flux throughout the entireglycolytic pathway and as a result is required for the proliferation of cancer cells. In preliminary studies weprovide evidence that PFKFB3 expression and activity is increased in response to CDK4 inhibition in ER+ breastcancer cells and breast cancer patient tumors. Notably we show that a PFKFB3 inhibitor PFK-158 increasesthe anti-tumor activity of anti-CDK4 targeted therapy in vitro and in vivo. We postulate that PFKFB3 is anessential regulatory effector of the cyclin D1-CDK4/6 axis that serves to attenuate CDK4/6 inhibition effects bystimulating glucose metabolism. Furthermore we hypothesize that genetic or pharmacological inhibition ofPFKFB3 will increase the efficacy of CDK4/6 inhibitors by disabling the ability of the cell to sustain sufficientglucose metabolism necessary for survival and growth. Aim 1 will determine the mechanism by which CDK4/6inhibition induces PFKFB3 expression. Aim 2 will determine the effects of combined CDK4/6 and PFKFB3inhibition on glucose metabolism cell cycle growth and survival in vitro. Aim 3 will examine the metabolic andgrowth effects of pharmacological CDK4/6 and PFKFB3 inhibition as monotherapies and in combination inmouse models of breast cancer in vivo. We anticipate that our studies will support the clinical testing of PFKFB3inhibitors in combination with CDK4/6 inhibitors to increase the survival of advanced ER+ breast cancer patients.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Attenuated;Automobile Driving;Binding;Biological Availability;Breast Adenocarcinoma;Breast Cancer Cell;Breast Cancer Model;Breast Cancer Patient;Breast Cancer cell line;Bypass;CDK4 gene;Cell Cycle;Cell Cycle Progression;Cells;Clinical;Clinical Trials;Cyclin D1;Cyclins;Development;ERBB2 gene;Enzymes;Estradiol;Estrogen Receptors;Estrogen receptor positive;FDA approved;Fructose;Genetic;Genetic Transcription;Glucose;Glycolysis;Glycolysis Induction;Growth;In Vitro;Malignant Neoplasms;Mediating;Metabolic;Metastatic breast cancer;Oncogenic;Oral;Pathway interactions;Patients;Phase;Phase I/II Trial;Phosphorylation;Progression-Free Survivals;Proliferating;Relapse;Resistance;Resistance development;Retinoblastoma Protein;Role;Testing;Time;advanced breast cancer;base;blood glucose regulation;cancer cell;combinatorial;cyclin D3;cyclin-dependent kinase 6;design;early phase clinical trial;efficacious treatment;glucose metabolism;hormone receptor-positive;hormone therapy;improved;in vivo;inhibitor;malignant breast neoplasm;mouse model;novel;novel strategies;overexpression;pharmacologic;prevent;rational design;research clinical testing;response;targeted treatment;therapy resistant;treatment response;tumor

public_health_relevance:
While clinical responses to CDK4/6 inhibition have been remarkable metastatic breast cancer remainsincurable. The proposed studies will provide the mechanistic base for the combined targeting of PFKFB3 and CDK4/6. The results should facilitate the rational design of combinatorial phase I/II trials of PFKFB3 inhibitors with CDK4/6 agents for the treatment of stage IV ER+ breast adenocarcinoma patients.


application_id: 10650081
project_number: 3R01EY021769-10S1
project_title: Diversity Supplement -- Vertebrate Photoreceptor Development and Regeneration
administering_ic: NEI
award_notice_date: 2022-09-02
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: EY
serial_number: 021769
suffix: S1
program_official: NEUHOLD, LISA
project_start_date: 2012-08-01
project_end_date: 2024-07-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 10184513
contact_pi: MORRIS, ANN C
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYInherited retinal dystrophies such as retinitis pigmentosa (RP) are a leading cause of blindness forwhich there is currently no cure. One potential treatment for retinal degenerative diseases is cell-based transplantation therapy whereby precursor cells are transplanted into the diseased eye toreplace the lost photoreceptors. While this is an exciting possibility several challenges to theimplementation of transplantation therapies must be overcome including the inefficient integration ofphotoreceptor precursors into the recipient retina and the difficulty of obtaining sufficient numbers ofphotoreceptor precursors for clinical application. To improve protocols for the in vitro culture of suchcells we must have a better understanding of the transcriptional networks that promote specificationof photoreceptor precursors. One of the long-term goals of our laboratory is to contribute to theseefforts by studying photoreceptor development and regeneration in the zebrafish. The zebrafish isespecially useful for studying photoreceptor biology because its retina contains numerous conesubtypes in addition to rods. Furthermore the zebrafish retina is able to regenerate neurons inresponse to experimental damage. The experiments described in this proposal will define the role ofthree transcription factors -- Sox Sox11 and Her9 -- during retinal neurogenesis through theapplication of gene targeting and molecular genetic approaches. Our specific aims are as follows:Specific Aim I: Determine the role of Sox4 and Sox11 in photoreceptor differentiation. Using newlygenerated loss-of-function mutants we will 1) determine whether there is a dosage effect of Sox4/11activity on rod photoreceptor number; 2) use state-of-the-art time-lapse imaging to determine whenand where Sox4 expression is required to achieve proper rod photoreceptor development; 3)determine precisely how Sox4/11 regulate Hh and Bmp signaling; and 4) identify the moleculartargets of Sox4/11. Specific Aim II: Determine the cause and extent of photoreceptor defects in thezebrafish her9 mutant. In this aim we will 1) determine the mechanism for photoreceptor defects inher9 mutants; 2) determine whether loss of Her9 impairs vision; 3) identify the upstream signalingpathway(s) that regulate her9 expression in the retina; and 4) determine whether Her9-mediatedVEGF expression in the avascular zebrafish retina regulates retinal progenitor cell proliferation anddifferentiation. Completion of our proposal will bridge important gaps in our understanding of themolecular mechanisms of vertebrate photoreceptor differentiation and reveal underlying principlesrelevant to the development of approaches for the treatment of human retinal degenerative disease.

project_terms:
Adoption;Animal Model;Biochemical;Biology;Blindness;Cell Differentiation process;Cell Transplantation;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Cone;Data;Defect;Development;Developmental Biology;Disease;Embryo;Event;Evolution;Eye diseases;Family;Gene Targeting;Genetic;Genetic Diseases;Genetic Transcription;Goals;Health;Homologous Gene;Human;Image;In Vitro;Inherited;Injury;Laboratories;Mediating;Microphthalmos;Modeling;Molecular;Molecular Genetics;Molecular Target;Morphogenesis;Morphology;Mutation;Natural regeneration;Nerve Regeneration;Neurons;Optics;Pathway interactions;Photoreceptors;Protocols documentation;Retina;Retinal Cone;Retinal Degeneration;Retinal Dystrophy;Retinitis Pigmentosa;Rod;Role;SOX11 gene;SOX4 gene;Signal Pathway;Signal Transduction;Suggestion;System;Therapeutic;Time;Transcription Repressor;Transgenic Organisms;Transplantation;Vascular Endothelial Growth Factors;Vertebrate Photoreceptors;Visual;Visual impairment;Visual system structure;Work;Zebrafish;base;cellular imaging;clinical application;dosage;experimental study;gene regulatory network;gene therapy;genetic approach;genome editing;imaging modality;improved;in vivo;loss of function;member;mouse genome;mutant;neurogenesis;notch protein;novel;optic cup;parent grant;photoreceptor degeneration;precursor cell;response;retinal neuron;retinal progenitor cell;retinal rods;stem cell differentiation;stem cell proliferation;therapy development;transcription factor;transplantation therapy

public_health_relevance:
PROJECT NARRATIVE/RELEVANCE TO HUMAN HEALTHThe development of therapies to treat visual impairment resulting from photoreceptordegeneration will directly benefit from studies of animal models such as the zebrafish whichdevelops ex utero remains optically transparent throughout development and which displaysthe capacity for injury-induced neural regeneration. The goal of our proposal is to define the roleof the transcription factors Sox4 Sox11 and Her9 in the development of photoreceptor cellsand to identify the pathways that regulate their expression and what they in turn regulate. Thisinformation will facilitate efforts to understand photoreceptor developmental biology and to guidephotoreceptor differentiation from stem cells in vitro and in vivo for therapeutic purposes.


application_id: 10649610
project_number: 5K12DA035150-12
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2023-08-02
opportunity_number: RFA-OD-21-006
application_type: 5
activity_code: K12
ic: DA
serial_number: 035150
program_official: BABECKI, BETH
project_start_date: 2022-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1-PSE-W(50)]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentuckys (UK) BIRCWH program is built around three pillars: mentoringinterdisciplinary research and career development. Given the significant health challenges inKentucky we focus on three areas of important health disparity for Appalachian Kentuckians: 1)substance use 2) violence against women and 3) lifespan changes in health with aging. UKBIRCWH objectives are: 1) to provide the environment mentorship and facilities to enhancethe ability of BIRCWH scholars to compete for NIH research grants in diverse areas of womenshealth research 2) to deepen our understanding of the unique role of sex and gender in themanifestation of health and disease 3) to develop and implement new communication andsocial networking technologies to address sex and gender differences and improve womenshealth 4) to personalize prevention diagnostics and therapeutics to address health disparities5) to stimulate new collaborations in focused interdisciplinary and interactive research areasthat are essential for uncovering sex and gender differences and improving womens health; and6) to use a thematic multidisciplinary focus as a platform for enhancing translational researchbetween basic clinical and public health scientists. Our formal framework for growing the nextgeneration of womens health and sex differences researchers includes a mentoring team foreach Scholar composed of: 1) experienced faculty members (Mentors) and 2) a former BIRCWHscholar (Coach). This mentoring team will collectively provide in-depth research experiencesand didactic training to assistant professor tenure-track faculty. Career development will alsoinclude mechanisms for accountability for manuscript submissions workshops on grantdevelopment and aspects of academic development such as personnel management negotiationskills self-care and promotion. UK BIRCWH Scholar appointments will be 2 years for PhD and3 years for MD scholars. Based on our prior experience we anticipate training 8 scholars over 5years of funding. Outcomes: Since 2000 40 Scholars have completed BIRCWH training (17MDs 23 PhDs) who have produced 1712 peer-reviewed publications secured $41636782 inNIH funding as PI and $239982415 as Co-I or PI from other external sources. UK has retained57% of our BIRCWH graduates who continue active research programs and support BIRCWHas Coaches and Mentors. Given this success why should UKs BIRCWH funding continue?Succinctly Kentuckys need continues. Our rates of substance use violence and chronic disease(3 foci) are among this nations highest. With BIRCWH funding we can support those who willaddress the health inequities Kentuckians and others across the nation still face.

project_terms:
Accountability;Address;Aging;Appalachian Region;Appointment;Area;Chronic Disease;Clinical;Collaborations;Communication;Development;Diagnostic;Disease;Doctor of Philosophy;Educational workshop;Environment;Face;Faculty;Funding;Gender;Grant;Health;Interdisciplinary Study;Kentucky;Longevity;Manuscripts;Mediation;Mentors;Mentorship;Outcome;Peer Review;Personnel Management;Public Health;Publications;Research;Research Personnel;Research Project Grants;Role;Scientist;Secure;Self Care;Sex Differences;Social Network;Source;Technology;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;Violence;Women's Health;career development;experience;gender difference;health difference;health disparity;health inequalities;improved;individualized prevention;member;multidisciplinary;next generation;professor;programs;research and development;sex;skills;substance use;success;tenure track;violence against women

public_health_relevance:
NARRATIVE:Finding and addressing sex and gender differences in effective health care research and treatment are criticalactions toward the goal of improving the health and wellbeing of all Americans. To achieve this goal the UKBIRCWH seeks to continue training and supporting our next generation of academic researchers to recognizesex and gender differences in conditions that disproportionately affect Kentuckians. In this training andmentoring program for emerging researchers we focus on 3 health concerns that disproportionately affectAppalachian Kentuckians: Substance use violence against women and lifespan changes.


application_id: 10649433
project_number: 5R35GM141478-03
project_title: Relative adrenal insufficiency as a risk factor and an endotype for sepsis
administering_ic: NIGMS
award_notice_date: 2023-04-19
opportunity_number: PAR-19-367
application_type: 5
activity_code: R35
ic: GM
serial_number: 141478
program_official: ZHAO, XIAOLI
project_start_date: 2021-05-01
project_end_date: 2026-04-30
study_section: Special Emphasis Panel[ZRG1-CB-T(55)R]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
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:
SummarySepsis is a major health issue with a mortality rate of 30%. Sepsis induces huge stressresponses including a 5-10 fold induction in glucocorticoid (GC) production in adrenalgland however the function of this inducible GC (iGC) remains poorly understood.Importantly 25-60% of septic patients suffer relative adrenal insufficiency  insufficientiGC production in response to stress. Given the potential complications of adrenalinsufficiency GC therapy is often used for septic shock patients. However the truecontribution of adrenal insufficiency to sepsis and the efficacy of GC therapy are highlycontroversial. While a number of factors contribute to the debate a lack of a relativeadrenal insufficiency animal model has limited our capacity to address these issues.Toward a solution scavenger receptor BI (SR-BI) a well-established high densitylipoprotein (HDL) receptor was first identified in our laboratory as a critical protectivefactor in sepsis. A number of laboratories including ours recently reported that SR-BInull mice fail to produce iGC in response to ACTH stimulation establishing SR-BI nullmice as a relative adrenal insufficiency model. Using this unique model wedemonstrated that mice with relative adrenal insufficiency are susceptible to septicdeath and more importantly supplementation of GC rescued mice with relative adrenalinsufficiency but surprisingly caused more death in mice without relative adrenalinsufficiency. Our findings demonstrate that relative adrenal insufficiency is a risk factorand an endotype of sepsis. Our findings also provide a proof of concept to support aprecision medicine approach to guide the use of GC for sepsis therapy specificallyselectively using GC therapy for a subgroup of septic patients with relative adrenalinsufficiency. In this R35/MIRA application we propose to use our newly developedadrenal-specific SR-BI null mice as a unique relative adrenal insufficiency animal modelto understand why relative adrenal insufficiency is a risk factor for sepsis and why GCtherapy benefits mice with relative adrenal insufficiency but harms those without. Thetranslation of this study will improve the overall efficacy of sepsis therapy and savelives.

project_terms:
Address;Adrenal Glands;Adrenal gland hypofunction;Animal Model;Cessation of life;Corticotropin;Glucocorticoids;Goals;Health;Knockout Mice;Laboratories;Modeling;Mus;Patients;Predisposition;Production;Reporting;Risk Factors;SR-BI receptor;Sepsis;Septic Shock;Stress;Subgroup;Supplementation;biological adaptation to stress;high density lipoprotein receptor;improved;mortality;precision medicine;protective factors;response;septic;septic patients;translational study

public_health_relevance:
Project NarrativeThe goal of this application is to investigate the contribution of relative adrenalinsufficiency to sepsis. Accomplishment of this study will improve our understanding ofsepsis and provide a proof of concept to support a precision medicine approach todirect the use of glucocorticoid for sepsis therapy.


application_id: 10647816
project_number: 5R01AG037868-08
project_title: Chronic Stress Glucocorticoids and Progesterone in Brain Aging
administering_ic: NIA
award_notice_date: 2023-05-10
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: GRAY, ERIN EMILY
project_start_date: 2011-03-01
project_end_date: 2026-05-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
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:
Evidence indicates that prolonged/ repeated behavioral stress promotes brain aging. This is thought to be dueat least in part to stress associated glucocorticoid (GC) secretion which in turn binds to glucocorticoid receptorsexerting transcriptional and other effects. A key downstream mediator in this signaling pathway serum-and-glucocorticoid kinase 1 (Sgk1) accelerates and the female sex steroid progesterone (P4) blunts the effects ofGCs. However despite the negative clinical consequences of chronic stress exposure with aging and/or infemale subjects little work has examined how aging may change the stress response the mechanisms throughwhich stress may accelerate brain aging the degree to which stress-accelerated aging is dependent on GC isdriven by Sgk1 or is inhibited by P4. Our preliminary data suggests that hippocampal Sgk1 is upregulated byaging stress and GCs in white matter oligodendrocytes and that the female sex hormone progesterone (P4)blunts the effects of stress/GCs and may serve as an endogenous protectant that is lost with age in females.To address these knowledge gaps we propose 3 aims to investigate: the age-course of the response to chronicstress or chronic GCs in males and females; whether viral overexpression of Sgk1 exacerbates or systemic P4administration ameliorates stress-accelerated aging; and whether the pharmacologic sensitivity of hippocampaltissue to GC and P4 is shifted with age or chronic stress/GC. Cognitive and anxiety-related behavior bloodhormone measures and a novel panel of 205 hippocampal genes that are robustly changed with aging acrossmultiple studies will be used to test for stress/GC-accelerated aging and intervention effects as will downstreamgray and white matter Sgk1 expression and microglial response to microinjury- two processes demonstrated tobe glucocorticoid sensitive and exaggerated in white vs. gray matter in preliminary data. Thus the proposedstudies will yield essentially the first comprehensive test of the hypothesis that chronic stress acceleratestranscriptional brain aging and will illuminate sex differences in stress responsiveness and the potential roles ofGC P4 and Sgk1 in gray and white matter. Even if all of our working hypotheses are rejected by the results theproposed studies should have translational value for geriatric medicine.

project_terms:
Acceleration;Acute;Address;Age;Age Months;Aging;Agonist;Astrocytes;Behavioral;Bilateral;Binding;Biological Assay;Biological Markers;Blood;Cells;Chronic;Chronic stress;Clinical;Cognitive;Corticosterone;Data;Dependence;Dimethyl Sulfoxide;Dose;Female;Gene Expression Profile;Genes;Genetic Transcription;Geriatrics;Glucocorticoid Receptor;Glucocorticoids;Gonadal Steroid Hormones;Health;Hippocampus;Hormone Responsive;Hormones;Hypertrophy;Immunohistochemistry;Injury;Intraperitoneal Injections;Knowledge;Measures;Mediating;Mediator;Microglia;Microinjections;Mifepristone;Modeling;Myelin;Neurons;Oligodendroglia;Oral;Outcome;Outcome Measure;Phosphotransferases;Preparation;Process;Progesterone;Rattus;Research Support;Rodent Model;Role;Serum;Sex Differences;Signal Pathway;Signal Transduction;Slice;Stress;Stress Tests;System;Testing;Therapeutic Uses;Tissues;Up-Regulation;Viral;Work;acute stress;age effect;aged;aging brain;animal age group;antagonist;anxiety-related behavior;biological adaptation to stress;cell type;cytokine;female sex hormone;gray matter;indexing;intervention effect;laser capture microdissection;mRNA Expression;male;morris water maze;nano-string;neuroinflammation;novel;novel strategies;overexpression;pharmacologic;receptor;reproductive hormone;response;sex;stress reduction;transcriptome sequencing;treatment group;uptake;white matter

public_health_relevance:
The proposed studies in rodent models will yield essentially the first comprehensive test of the hypothesis thatchronic stress accelerates transcriptional markers of brain aging. The studies will illuminate sex differences instress and stress hormone responsiveness and the potential protective and mediating roles respectively ofprogesterone and SGK1 (a key effector in glucocorticoid system signaling) in gray and white matter. Even if ourworking hypotheses are rejected the proposed studies should have translational value for geriatric medicine.


application_id: 10646579
project_number: 1R21AG081761-01
administering_ic: NIA
award_notice_date: 2023-03-29
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AG
serial_number: 081761
program_official: ROBERTS, LUCI
project_start_date: 2023-04-01
project_end_date: 2025-03-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
A Refined Murine Model of Post-sepsis Cognitive Impairment for Investigating Mitochondrial Abnormalities and Human ApoE4 Gene Polymorphisms

project_abstract:
ABSTRACTSepsis is an infection-initiated life-threatening medical condition accompanied by severe whole-bodyinflammation. Over 1.7 million sepsis survivors are now discharged from the hospital annually and a majorityof them report reduced quality of life due to considerable long-term dysfunction called chronic critical illnessincluding muscle weakness and cognitive impairment after hospital discharge. We previously developed aclinically relevant murine sepsis-survivor model with an ICU-like resuscitation procedure that enables us toevaluate long-term muscle quality and function after recovery from sepsis. Our studies demonstrated thatsepsis-survivor mice exhibit significant skeletal muscle weakness. Skeletal muscles from these sepsis-survivormice also show profound mitochondrial structural and functional defects. In contrast to muscle dysfunctionlittle is known for cognitive dysfunction in sepsis survivors. Although there are several published studies usinglaboratory animal models for this issue their results remain inconclusive due to several limitations; 1) cognitiveimpairment being assessed by stressful swimming maze tests which sepsis survivors perform poorly due tomuscle weakness; 2) use of surgical sepsis models with artifactual necrosis and resulting systemicinflammation; and 3) the lack of antibiotics treatment and the lack of confirmation of sepsis recovery therebyfocusing on dysfunction during sepsis rather than post-sepsis all limit current research. Importantly allthese limitations are resolved in our above-mentioned sepsis-survivor mouse model that confirms completerecovery from sepsis allows sufficient duration (4 weeks or longer) after sepsis to study long term effects andeliminates surgical procedures to avoid artifactual necrosis and inflammation. Thus our well-refined sepsis-survivor mouse model for muscle weakness can potentially be an appropriate animal model to investigate post-sepsis long-term cognitive impairment. Our major hypothesis is that this sepsis-survivor model will exhibit long-term cognitive impairment. We also hypothesize that ApoE4 gene polymorphism the most common AD-susceptible genotype confers a higher risk of developing cognitive dysfunction after surviving sepsis.Additionally we hypothesize that mitochondrial abnormalities are involved in such post-sepsis cognitiveimpairment. To test these hypotheses two Specific Aims will be pursued. (1) To test whether wild typemice develop long-term cognitive impairment after sepsis; and (2) To test whether mutant micecarrying the human ApoE4 gene polymorphism have a higher risk of developing cognitive impairmentafter sepsis.

project_terms:
Acute;Age;Alzheimer's Disease;Animal Model;Animals;Antibiotic Therapy;Antibiotics;Brain;Cecum;Cells;Chronic;Critical Illness;Defect;Delirium;Dementia;Disease susceptibility;Elderly;Enzymes;Exhibits;Functional disorder;Genes;Genetic Polymorphism;Genotype;Goals;Hospitals;Human;Impaired cognition;Incidence;Infection;Inflammation;Injections;Knock-in;Knock-in Mouse;Laboratory Animal Models;Life;Life Style;Ligation;Liquid substance;Long-Term Effects;Longitudinal Studies;Medical;Memory;Memory impairment;Mitochondria;Modeling;Mus;Muscle;Muscle Weakness;Mutant Strains Mice;Necrosis;Neurons;Operative Surgical Procedures;Pathology;Patients;Persons;Population;Predisposition;Prevention strategy;Procedures;Productivity;Protocols documentation;Public Health;Publishing;Quality of life;Recovery;Reporting;Research;Resuscitation;Risk Factors;Sepsis;Skeletal Muscle;Stains;Survivors;Swimming;Testing;Transmission Electron Microscopy;Wild Type Mouse;aged;apolipoprotein E-3;apolipoprotein E-4;brain tissue;cecal ligation puncture;clinically relevant;cognitive enhancement;cognitive testing;high risk;middle age;mitochondrial dysfunction;mortality;mouse model;novel;object recognition;prevent;skeletal muscle weakness;systemic inflammatory response;transcriptome sequencing;young adult

public_health_relevance:
PROJECT NARRATIVEThis project is relevant to public health because it will enhance our understanding of the mechanisms for long-term cognitive impairment among millions of people who survived sepsis. Obtained information will allow us toelucidate a novel preventive strategy which would help sepsis survivors to return to a more productive andfulfilling lifestyle.


application_id: 10646329
project_number: 5R01DA033862-10
administering_ic: NIDA
award_notice_date: 2023-03-21
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DA
serial_number: 033862
program_official: LYNCH, SEAN EDWARD WINTERS
project_start_date: 2012-09-01
project_end_date: 2027-03-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
Examining the Impact of the Twin Epidemics of Methamphetamine and Opioid Use on Overdose Risky Sex and Treatment Engagement among PWUD in Two Rural Appalachian Cohorts

project_abstract:
ABSTRACTThe goal of this R01 renewal is to examine the impact of methamphetamine (MA) use on fatal and nonfataloverdose engagement in injection- and sex-risk behaviors and treatment for opioid use disorder (OUD) andother substance use disorders (SUD) among people who use drugs (PWUD) from two Appalachian cohorts.MA use among people who use opioids is increasing. Several recent publications have coined this increase inMA/opioid co-usage as the twin epidemics as new onset methamphetamine use has been reported in areasparticularly hard hit by the opioid epidemic. This application builds on work from two established cohort studieslocated in the epicenter of the opioid crisis - the Social Networks Among Appalachian People (SNAP) cohortand GATEWAY2HOPE (G2H). These cohorts will be combined to increase both geographic scope andstatistical power and to examine the following aims: 1) To characterize use of methamphetamine in the contextof continued opioid use (twin epidemics) initiation of meth use and social networks of PWUM. Building on thedata we have gathered for opioid use over time additional prospective data will be collected on initiation anduse patterns for methamphetamine including route of administration; 2) To examine longitudinal changes insex- and injection-risk behaviors as a result of initiation of meth use. Measures specific to this aim include fataland non-fatal overdose sharing of syringe and other injection paraphernalia and unprotected sexualencounters. HIV HCV and STI testing as well as death certificate reviews will be conducted to complementself-reported behavioral data; and 3) determine impact of MA use on SUD/OUD treatment seeking treatmentinitiation and long-term engagement in SUD treatment. While the data collected to date from the SNAP andCARE2HOPE cohorts have been invaluable in informing the opioid epidemic in rural Appalachia it is importantthat this renewal be positioned to fill additional gaps in the literature. Currently there is little information on thetwin epidemic phenomenon and its potential impact on fatal and non-fatal overdoses the SUD treatmentcascade and harm reduction services especially in resource-deprived areas such as rural Appalachia. Theproposed renewal will address these gaps and provide data that are integral to addressing drug-related harmsin the rural U.S.

project_terms:
Address;Appalachian Region;Area;Behavioral;Cohort Studies;Coin;Collection;Complement;Data;Data Collection;Death Certificates;Drug user;Enrollment;Epidemic;Evidence based treatment;Funding;Geography;Goals;HIV;HIV/HCV;Harm Reduction;Health Personnel;Hepatitis C virus;Injections;Intervention;Kentucky;Knowledge;Length of Stay;Literature;Location;Manuscripts;Measures;Methamphetamine;Methamphetamine overdose;Methamphetamine use disorder;Modality;Modeling;National Institute of Drug Abuse;Needle Sharing;Opioid;Outcome;Overdose;Participant;Pathway Analysis;Patient Self-Report;Pattern;Persons;Pharmaceutical Preparations;Policies;Positioning Attribute;Publications;Publishing;Reporting;Resources;Risk;Risk Behaviors;Route;Rural;Rural Appalachia;Rural Community;Rural Population;Sample Size;Sampling;Services;Social Network;Substance Use Disorder;Testing;Time;Twin Multiple Birth;Unsafe Sex;Work;barrier to care;cohort;combat;disease transmission;dosage;follow-up;methamphetamine use;opioid epidemic;opioid injection;opioid use;opioid use disorder;opioid user;overdose death;prescription opioid;programs;prospective;recruit;rural area;sex;sexual encounter;sexual risk behavior;stimulant use;substance use;substance use treatment;therapy development;treatment disparity;treatment program;treatment services

public_health_relevance:
PROJECT NARRATIVERecent studies indicate that use of methamphetamine among those using opioids (coined the twin epidemics)is on the rise. This study seeks to understand the impact of methamphetamine use on drug-related harms(injection overdose HIV/HCV/STI) and SUD treatment enrollment in rural areas that are enmeshed in theopioid epidemic. To this end we will collect prospective data from two extant NIDA-funded cohorts of ruralpeople who use drugs and this proposed renewal will address gaps in our knowledge of the twin epidemics ofmethamphetamine and opioid use and provide data that are integral to addressing drug-related harms in therural U.S.


application_id: 10644996
project_number: 5F31AG076282-02
project_title: Apolipoprotein E and immunometabolism in Alzheimer's disease
administering_ic: NIA
award_notice_date: 2022-12-20
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: AG
serial_number: 076282
program_official: BARRETT, PAUL JOHN
project_start_date: 2022-02-13
project_end_date: 2024-01-15
study_section: Special Emphasis Panel[ZRG1-F03A-T(20)L]
contact_pi_person_id: 16073908
contact_pi: DEVANNEY, NICHOLAS
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:
Summary: Chronic neuroinflammation and metabolic dysfunction characterize neurodegenerative diseasesincluding Alzheimer's disease (AD). One of the earliest known biomarkers of AD is an altered pattern ofregional glucose metabolism in the brain. Carriers of the 4 allele of apolipoprotein E (APOE) exhibit thispattern of altered cerebral glucose metabolism from a young age and suffer from a dramatically increased riskof acquiring AD. Meanwhile 4 individuals are also considered to have a maladaptive and detrimentalneuroinflammatory phenotype with increased pro-inflammatory signaling in 4 microglia. Additionally it is well-established that microglial inflammatory phenotypes are driven by precise metabolic reprogramming with pro-inflammatory cytokine production requiring increased aerobic glycolysis  a phenomenon known as`immunometabolism'. This proposal aims to investigate whether the neuroinflammatory phenotype in 4microglia could be intrinsically driven by 4s effects on glucose metabolism. Aim 1 will investigate thehypothesis that enhanced pro-glycolytic gene expression drives neuroinflammatory 4 transcriptionalphenotypes by leveraging the power of targeted single-cell RNA sequencing to interrogate gene expression ofa panel of pre-selected metabolic neuroinflammatory and disease-associated genes with results validated atthe protein and post-translational level. Aim 2 will address the hypothesis that 4 microglia show an increasedpro-inflammatory phenotype due to underlying impairments in central carbon metabolism. We will use StableIsotope Resolved Metabolomics (SIRM) with a 13C-glucose tracer to measure metabolic flux in 2 3 and 4primary microglia responding to pro- and anti-inflammatory treatments. We will compare oxidativephosphorylation and glycolytic activity in response to these treatments. These metabolic measures will then belinked to readouts of microglial function by assessing cytokine release and phagocytic activity in parallel. Aim 3will evaluate the efficacy of targeting key metabolic nodes to reprogram the 4 inflammatory response. Wehypothesize that pharmacological inhibition or viral overexpression of specific metabolic enzymes identified inour preliminary data as being perturbed by APOE genotype will rebalance cytokine production in 4 microgliaand improve phagocytosis of amyloid beta peptide. Our ultimate goals for this research are to: (1) understandhow APOE genotype influences the metabolic response to inflammatory stimuli in microglia (2) determinewhether altered metabolic gene expression drives a transcriptional profile that favors neuroinflammation andincreased AD risk and (3) identify immunometabolic pathways altered by APOE genotype that could representavenues to target in the treatment of neurodegenerative disease. This proposal integrates innovativetranscriptomic and metabolomic techniques with functional readouts of microglia to unify our understanding oftwo major facets of 4s risk: metabolic dysfunction and chronic neuroinflammation. Targeting both of theseaspects in tandem may hold greater promise in developing successful therapeutics for the treatment of AD.

project_terms:
Age;Alleles;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;Alzheimers disease biomarker;Amyloid beta-Protein;Amyloidosis;Anti-Inflammatory Agents;Apolipoprotein E;Astrocytes;Brain;Carbon;Cells;Cerebrum;Chronic;Citric Acid Cycle;Data;Deposition;Disease;Enzyme Inhibition;Enzymes;Equilibrium;Exhibits;Gene Expression;Gene Expression Profile;Genes;Genetic Transcription;Genotype;Genus Hippocampus;Glucose;Glycolysis;Goals;Homeostasis;Homozygote;Human;Impairment;In Vitro;Individual;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Intrinsic drive;Knowledge;Late Onset Alzheimer Disease;Link;Measures;Metabolic;Metabolic dysfunction;Metabolism;Microglia;Mitochondria;Modeling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Outcomes Research;Oxidative Phosphorylation;Pathway interactions;Pattern;Phagocytes;Phagocytosis;Phenotype;Play;Post-Translational Protein Processing;Production;Protein Isoforms;Proteins;Ramp;Research;Respiration;Risk;Role;Senile Plaques;Series;Signal Transduction;Sorting;Stimulus;Techniques;Testing;Therapeutic;Tracer;Viral;aerobic glycolysis;apolipoprotein E-4;cytokine;efficacy evaluation;efficacy testing;extracellular;genetic risk factor;genome wide association study;glial activation;glucose metabolism;improved;innovation;metabolomics;neuroinflammation;neuropathology;overexpression;pharmacologic;preference;programs;response;single-cell RNA sequencing;small molecule inhibitor;stable isotope;targeted treatment;therapeutic target;transcriptomics;treatment response

public_health_relevance:
Narrative: Neuroinflammation and metabolic dysfunction are prevalent among neurodegenerative diseasesincluding Alzheimer's disease (AD). Outcomes of this research will elucidate how the strongest genetic riskfactor for late-onset AD the 4 allele of apolipoprotein E may predispose microglia to neuroinflammatoryphenotypes by altering central glucose metabolism. Knowledge gained by the completion of this project willidentify immunometabolic nodes that can be targeted therapeutically to improve microglial function anddampen neuroinflammation in AD.


application_id: 10644787
project_number: 3UH3DA044798-05S1
project_title: Kentucky Communities and Researchers Engaging to Halt the Opioid Epidemic (CARE2HOPE)
administering_ic: NIDA
award_notice_date: 2022-07-12
opportunity_number: PA-20-272
application_type: 3
activity_code: UH3
ic: DA
serial_number: 044798
suffix: S1
program_official: LEE-WINN, ANGELA EUNJI
project_start_date: 2017-08-15
project_end_date: 2023-07-31
contact_pi_person_id: 11085214
contact_pi: YOUNG, APRIL MARIE
other_pis: COOPER, HANNAH LF
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:
Abstract: The proposed project will build evidence-based community-rooted public health responses to theepidemics of non-medical prescription opioid (NMPO) and heroin injecting overdoses (ODs) and HCV and toimminent HIV outbreaks in 12 rural Appalachian Kentucky counties at the epicenter of these intertwinednational crises. 10 of these 12 counties rank in the top 5% for HIV/HCV vulnerability. Rates of HCV injectiondrug use (IDU) and ODs are high in these counties and most are in coal country an RFA priority. Unfortunately these counties exemplify an extreme version of the implementation chasm a chasmdividing scientific knowledge from action. Evidence-based public health responses to these epidemics exist(e.g. syringe service programs [SSPs]) and are often deployed in cities. In these 12 rural counties thoughscarcities of resources and of providers conspire with drug-related stigma to constrain public health responses.The counties public health infrastructures are weak their harm reduction infrastructures virtually non-existent. This project will bridge the implementation chasm in these 12 counties and recognizes that bridging thischasm requires more than simply importing SSPs and other evidence-based community response projects(EB-CRPs) from cities. Guided by harm reduction principles the Risk Environment Model and Community/Academic Partnerships (CAPs) in the UG3 we will: (1) Assess and enhance each countys readiness toimprove the local risk environment. (2) Examine the strengths resources needs and gaps of each countysrisk environment. We will conduct a multi-method Community Assessment of the Risk Environment thatintegrates innovative rigorous epidemiology (e.g. modeling); policy assessment; and best practices incommunity-based research (e.g. CAPs). (3) Select an EB-CRP that responds to local needs and strengthsusing elements of Intervention Mapping. Go/no go milestone: Each CAP will have created an EB-CRPpackage that (1) addresses targets common across all counties (e.g. opioid injection OD HCV HIV) and (2)is tailored to local needs resources and readiness. In the UH3 we will: (4) Tailor selected EB-CRP to eachcountys context using ADAPT-ITT. (5) Analyze the effectiveness and cost of each countys EB-CRP packageusing an innovative community randomized trial. We will use continuous quality improvement to enhance eachEB-CRPs fidelity reach immediate effects and outcomes. To inform interventions advanced networkanalyses will overlay risk networks with GHOST phylogenetic transmission data to show where HCV has beenand predict where it is going. We draw strength from our collaborations. CAPs will meld residents localknowledge with researchers scientific expertise. Multi-PIs Young and Cooper have assembled an academicteam with unsurpassed expertise in key substance theories and methods and in multisite studies. Thecombination of a rigorous innovative design strong theories and a stellar team with community roots willensure high impact.

project_terms:
Address;Appalachian Region;Area;Cities;Coal;Collaborations;Communities;Country;County;Disease Outbreaks;Disease Outcome;Drug user;Effectiveness;Elements;Ensure;Environment;Epidemic;Epidemiology;HIV;HIV/HCV;Harm Reduction;Health;Health Services;Health behavior;Hepatitis C Therapy;Hepatitis C virus;Heroin;Infrastructure;Injecting drug user;Intervention;Justice;Kentucky;Knowledge;Laws;Medicaid;Medical;Methods;Modeling;Naloxone;Needle-Exchange Programs;Outcome;Overdose;Pathway Analysis;Pharmaceutical Preparations;Phylogenetic Analysis;Plant Roots;Policies;Prescription opioid overdose;Progress Reports;Provider;Public Health;Readiness;Research;Research Infrastructure;Research Personnel;Resources;Risk;Risk Assessment;Risk Behaviors;Rural;Rural Appalachia;Secure;Site;Unsafe Sex;Work;combat;community based research;cost;data exchange;design;evidence base;heroin use;improved;injection drug use;innovation;intervention mapping;member;opioid epidemic;opioid injection;opioid use disorder;prescription opioid;prescription opioid misuse;programs;randomized trial;response;rural area;rural counties;service utilization;social stigma;theories;treatment program;virtual

public_health_relevance:
Narrative: The proposed project will employ community/academic partnerships to build effective evidence-based community-grounded public health responses to combat the intertwined epidemics of heroin and non-medical prescription opioid injecting overdoses and HCV and imminent HIV outbreaks in 12 of the hardesthit rural counties in the US. Located in Central Appalachian Kentucky 10 of the 12 counties are in the top 5%for HIV/HCV vulnerability in the US. Most counties are in coal country an RFA priority area.


application_id: 10644405
project_number: 1R21NS131903-01
project_title: Mechanism and Therapeutic Potential of CBD to Repair Blood-Brain Barrier Dysfunction in Epilepsy
administering_ic: NINDS
award_notice_date: 2023-03-29
opportunity_number: PA-21-219
application_type: 1
activity_code: R21
ic: NS
serial_number: 131903
program_official: LEENDERS, MIRIAM
project_start_date: 2023-04-01
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1 BN-Z (91)]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Blood-brain barrier dysfunction is both a cause and consequence of seizures in patients with epilepsy yet ther-apeutic options to repair barrier dysfunction do not exist. Key characteristics of barrier dysfunction in epilepsyare neurovascular inflammation and barrier leakage both result from seizure-mediated release of glutamate.Data support that an inflamed and leaky and thus dysfunctional barrier contributes to seizure genesis througha pernicious feedback loop that promotes epilepsy progression. However current therapeutic options to treatepilepsy are largely neuron-centric and do not address barrier dysfunction. In addition existing antiseizure drugs(ASDs) do not reliably control all seizures leaving patients with difficult-to-treat epilepsies prone to uncontrolledseizures. We recently discovered that Cannabidiol (CBD) mitigates barrier dysfunction in epilepsy. We also foundthat CBD blocks glutamate-mediated barrier leakage in isolated capillaries and repairs seizure-induced barrierdysfunction in vivo. These findings suggest that CBD has the potential to block the feedback signaling that drivesbarrier dysfunction and seizure progression in epilepsy. However data that support the use of CBD to repairbarrier dysfunction in epilepsy are not available. This knowledge gap represents a critical unmet need that pre-vents us from achieving therapeutic advances for patients with epilepsy. The overall objective in this applicationis to define the mechanistic link between cannabinoid signaling and barrier dysfunction to explain observed CBDeffects and to evaluate CBD as therapeutic agent to repair barrier dysfunction in epilepsy. Based on preliminarydata the central hypothesis of this project is that CBD repairs barrier dysfunction thereby lowering seizure burdenin epilepsy. The rationale for the proposed research is that its successful completion will provide mechanisticand preclinical data supporting future research for the clinical translation of CBD to treat patients with epilepsy.The hypothesis will be tested by pursuing two specific aims: 1) Describe cannabinoid signaling in glutamate-mediated barrier dysfunction and 2) Evaluate CBD for its potential to repair barrier dysfunction in epilepsy. UnderAim 1 we will describe key mechanistic steps between cannabinoid signaling and glutamate-mediated barrierdysfunction by using brain capillaries isolated from knockout mouse models. We will verify these signaling stepsin isolated human brain capillaries. Under Aim 2 we will evaluate the therapeutic benefit of CBD on seizure-mediated neurovascular inflammation barrier leakage and seizure burden in chronic epileptic rats. The pro-posed research is innovative because it focuses on a thus far unaddressed topic: cannabinoid signaling at theblood-brain barrier and CBD as therapeutic agent to repair barrier dysfunction and reduce seizures in epilepsy.The proposed research is significant because it holds the promise of a novel therapeutic approach to repairbarrier dysfunction that has translational potential to advance treatment of patients with epilepsy and other sei-zure disorders with underlying barrier dysfunction.

project_terms:
2-arachidonylglycerol;Acute;Address;Animal Model;Anticonvulsants;Arachidonate 5-Lipoxygenase;Automobile Driving;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Blood capillaries;CNR1 gene;Cannabidiol;Cannabinoids;Cannabis sativa plant;Characteristics;Childhood;Chronic;Clinical;Data;Endocannabinoids;Endothelium;Enzymes;Epilepsy;Extravasation;Feedback;Functional disorder;Generations;Glutamates;Human;Inflammation;Inflammatory;Knockout Mice;Knowledge;Link;Lipoxygenase;Marketing;Mediating;Medical;Mission;National Institute of Neurological Disorders and Stroke;Neurons;Outcome;Patients;Pharmacology;Policies;Public Health;Rattus;Research;Science;Seizures;Signal Transduction;Testing;Therapeutic;Therapeutic Agents;United States National Institutes of Health;Work;cerebral capillary;clinical translation;cyclooxygenase 2;glutamatergic signaling;improved;in vivo;in vivo Model;innovation;metabotropic glutamate receptor type 1;mouse model;nervous system disorder;neurovascular;novel therapeutic intervention;pre-clinical;prevent;repaired;translational potential

public_health_relevance:
The proposed research is relevant to public health because it is expected to provide mechanistic and preclinicaldata supporting future research for the clinical translation of CBD to treat patients with epilepsy. Thus theproposed research is relevant to the mission of the NINDS that pertains to developing fundamental knowledgethat will help reduce the burden of neurological disease.


application_id: 10642965
project_number: 5R01DK048498-28
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2023-06-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2025-06-30
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The mammalian intestinal mucosa undergoes a process of continual renewal characterized by activeproliferation of stem cells localized near the base of the crypts; progression of these cells up the crypt-villusaxis with cessation of proliferation; and subsequent differentiation into one of the four primary cell types (i.e.enterocytes goblet cells Paneth cells and enteroendocrine cells). An imbalance in this highly-regimented andorderly process within the crypts is associated with a number of common intestinal pathologies (e.g. colorectalcancer and inflammatory bowel disease [IBD]). Delineating the molecular factors regulating intestinalproliferation and differentiation is crucial to our understanding of not only normal gut development andadaptation but also aberrant gut growth. With the support of this grant we have shown the importance of thePI3K/Akt/mTOR and Wnt/-catenin pathways in the regulation of intestinal cell proliferation and differentiation.In addition we showed that enhanced ketogenesis by mTORC1 inhibition contributes to the regulation ofintestinal cell differentiation and that tuberous sclerosis complex 2/mTORC1 signaling contributes to themaintenance of intestinal epithelial homeostasis. Moreover we found that activation of Wnt/-catenin signalingsuppresses the expression of the ketogenic enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) whichinhibits glycolysis in intestinal cells. Recently we have shown that deficiency of SIRT2 a member of the sirtuinfamily of proteins results in the activation of Akt/mTORC1 and Wnt/-catenin increased intestinal cellproliferation and stemness and increased expression of glycolytic hexokinases (HK) 1 and 2. Using single cellsequencing we found that HK1 and HK2 were differentially expressed in various types of intestinal cells;knockdown of HK2 but not HK1 increased Paneth and goblet cell differentiation. Based on our recentlypublished and preliminary findings we have further refined our central hypothesis to state that the glycolyticenzyme HK2 acting downstream of SIRT2 significantly contributes to the maintenance of normal intestinalhomeostasis. To examine our central hypothesis we have planned experiments with the following SpecificAims: 1) to further delineate the cellular mechanisms for SIRT2-mediated alterations of glycolysis andoxidative phosphorylation in intestinal cells; 2) to better define the role of HK2 in mediating the effects of SIRT2in the intestine; and 3) to determine the impact of alterations of SIRT2/HK2 on intestinal homeostasis in vivo.The studies in the current proposal represent direct and novel extensions of our previous findings and aredesigned to define in a systematic fashion the molecular mechanisms and signaling events regulating theprocesses of intestinal proliferation differentiation and adaptation utilizing a number of innovative techniquesincluding murine and human intestinal organoids novel transgenic models single-cell sequencing and stableisotope resolved metabolomics (SIRM).

project_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Biochemical;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell model;Cells;Colorectal Cancer;Data;Development;Differentiation and Growth;Enterocytes;Enteroendocrine Cell;Enzymes;Equilibrium;Event;FRAP1 gene;Glycolysis;Glycolysis Inhibition;Goblet Cells;Grant;Growth;Hexokinase 2;Homeostasis;Human;In Vitro;Inflammation;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Knock-out;Knockout Mice;Maintenance;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Mus;Organoids;Oxidative Phosphorylation;PIK3CG gene;Paneth Cells;Pathology;Pathway interactions;Patients;Play;Process;Proliferating;Protein Family;Proteins;Publishing;Regulation;Role;SIRT1 gene;Seminal;Signal Pathway;Signal Transduction;Sir2-like Deacetylases;Sirtuins;System;Techniques;Testing;Transgenic Model;Tuberous Sclerosis;Villus;base;beta catenin;cell type;clinically relevant;design;differential expression;experimental study;hexokinase;in vivo;innovation;insight;intestinal epithelium;intestinal homeostasis;ketogenesis;ketogentic;knock-down;member;metabolomics;mortality;mouse model;novel;novel therapeutic intervention;single cell sequencing;stable isotope;stem cell function;stem cell proliferation;stemness

public_health_relevance:
NarrativeThe intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to thistightly-controlled and highly-regimented process remain to be completely elucidated. Our recent findings haveidentified the glycolytic enzyme hexokinase 2 (HK2) acting downstream of SIRT2 as a critical factor in themaintenance of normal gut growth and differentiation. Delineating the cellular factors regulating these normalprocesses is crucial to our understanding of normal gut development and maturation and also various intestinalpathologies (e.g. inflammation) that can arise from deregulation of these pathways.


application_id: 10642944
project_number: 5R01DE026963-06
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2023-07-10
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 026963
program_official: MCNEALY, TAMARA L
project_start_date: 2017-09-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Periodontitis is a highly prevalent disease associated with several debilitating systemic conditionsincluding vascular and lung diseases diabetes mellitus and pre-term birth. The most recent epidemiologicalevidence suggests that tobacco smoking accounts for the majority of destructive periodontal disease cases indeveloped nations. Smoking enhances infection rates and enriches numbers of a key periodontal pathogenPorphyromonas gingivalis. However the mechanisms underlying this phenomenon are in need of elucidation. Inthe first iteration of award facilitated by a two year NIGMS-funding mechanism we generated an 80000 colonytransposon sequencing library for P. gingivalis strains ATCC 33277 and exploited this resource to: (i) Successfully identify 256 genes that are putatively essential for surviving tobacco-induced stress; (ii) Delineate a core stress genome commonly required for tobacco-survival epithelial colonization and subcutaneous abscess formation; and (iii) Validated several genes as conditionally essential for P. gingivalis to survival of cigarette smoke- induced stress in vitro by generating single gene deletion mutants that exhibit either reduced absolute fitness in competition assays with the parental P. gingivalis strain in smoked medium; (iv) We have also generated a novel murine model of tobacco-exacerbated periodontitis. We now plan to build on these successes via three specific aims as follow:Aim 1: Further elucidate P. gingival CSE-related survival strategies by generating mutants in single genesthat are both CSE-essential (TnSeq data) ;and tobacco-regulated (RNAseq and qPCR); yet not compromised intheir ability to colonize oral epithelial cells (TIGK model) or immune resistance (murine abscess model).Aim 2: Determine in vivo relevance of putatively CSE-essential genes using a murine smoke-exposurechamber model in a chronic Baker model of P. gingivalis-induced periodontitis.Aim 3: Establish the broad applicability of data gathered in Aims 1 and 2 by confirming biological functionand distribution of CSE essential genes in multiple P. gingivalis strains. Long term advances are likely to include (a) A better understanding of how P. gingivalis thrives in atobacco-toxin rich environment; (b) Future therapeutic targeting of essential genes to control P. gingivalisinfection in smokers (CSE-essentiality data) and in general (multiple disease-relevant conditions core stressgenome data); (c) Alternate treatment regimens for smokers based on mechanistic insight into smoke-inducedand/or exacerbated periodontal diseases;and (d) The establishment of an essential gene database for tobacco-enhanced pathogens that will facilitate the identification of common bacterial strategies for surviving tobaccosmoke exposure thus broadening the significance of the research beyond the oral cavity.

project_terms:
Abscess;Adult;Alveolar Bone Loss;Anaerobic Bacteria;Award;Bacteria;Basic Science;Biological Assay;Biological Process;Blood Vessels;Cells;Chronic;Cigarette;Clinical;Communicable Diseases;Complex;Consumption;Data;Databases;Developed Countries;Diabetes Mellitus;Disease;Dose;Economic Burden;Environment;Epidemiology;Epithelial Cells;Epithelium;Essential Genes;Exhibits;Exposure to;Financial cost;Funding Mechanisms;Future;Gene Deletion;Genes;Genome;Gingiva;Growth;Health;Homologous Gene;Immune;Immune response;In Vitro;Infection;Inflammation;Invaded;Libraries;Lung diseases;Modeling;Mouth Diseases;Mus;National Institute of General Medical Sciences;New Zealand;Nicotine;Oral;Oral cavity;Osteitis;Patients;Peptide Hydrolases;Periodontal Diseases;Periodontitis;Persons;Physiology;Population;Porphyromonas gingivalis;Predisposition;Premature Birth;Prevention;Refractory;Research;Resistance;Resources;Scandinavia;Smoke;Smoker;Smoking;Standardization;Stress;Subcutaneous abscess;System;Testing;Tissues;Tobacco;Tobacco smoke;Tobacco smoking behavior;Tooth structure;Toxin;Treatment Protocols;Variant;Vascular Diseases;Virulence;Work;biological adaptation to stress;cigarette smoke;cigarette smoke-induced;fitness;immune resistance;in vivo;infection rate;insight;mouse model;mutant;non-smoker;novel;novel vaccines;oral cavity epithelium;pathogen;periodontopathogen;success;therapeutic target;tobacco regulation;tobacco smoke exposure;trait;transcriptome;transcriptome sequencing;translational potential;transposon sequencing

public_health_relevance:
PROJECT NARRATIVETobacco smoking is the leading environmental cause of periodontitis (a destructive gum disease).Many periodontal pathogens are highly resistant to the plethora of toxic insults contained in cigarette smokeincluding the representative bacterium Porphyromonas gingivalis.We will identify and characterize those P. gingivalis genes that facilitate this Gram-negative anaerobe not onlyto survive but to thrive in tobacco-rich environments.


application_id: 10642845
project_number: 5R01HL164398-02
project_title: Targeting GLP-1 receptor as a new chronotherapy against nondipping blood pressure in diabetes
administering_ic: NHLBI
award_notice_date: 2023-05-26
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 164398
program_official: OH, YOUNGSUK
project_start_date: 2022-06-15
project_end_date: 2026-05-31
study_section: Integrative Vascular Physiology and Pathology Study Section[IVPP]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYType 2 diabetes is one of the most prevalent and costly chronic diseases worldwide. Hypertension andnondipping blood pressure (BP) are prevalent comorbidities of type 2 diabetes and significant risk factors fordetrimental cardiovascular outcomes. While up to 75% of diabetic patients are nondippers no effective therapytargets nondipping BP in diabetes. Glucagon-like-peptide-1 receptor agonists (GLP-1RA) are a class ofrecently FDA-approved anti-diabetic drugs that provide exciting new means for the critical but challenging taskof managing cardiovascular risk in diabetic patients. The use of GLP-1RAs increased rapidly due to theirrecently recognized cardiovascular benefits including lowering BP in addition to effectively reducing HbA1Cand body weight. However whether GLP-1RA influences nondipping BP in diabetes is scarcely studied andthe mechanisms via which GLP-1RA lowers BP remain to be defined. Our preliminary data demonstrate for thefirst time that a short-acting GLP-1RA exenatide (Ex) when injected i.p. into type 2 diabetic db/db mice at thebeginning of the inactive phase (ZT0 light on time) effectively restored nondipping BP to normal dipping BP.In contrast when administered at the beginning of the active dark phase (ZT12 light off time) Ex worsenednondipping BP to reversed dipping (most harmful disruption). Our preliminary data also show for the first timethat GLP-1 receptor (GLP-1R) mRNA varies with the time of day and is regulated by clock gene BMAL1.Interestingly we also found that Ex administrated at ZT0 or ZT12 restored or inverted food intake rhythm indb/db mice in parallel with its effects on BP. Together with our recent publication that demonstrated time-restricted feeding effectively prevents and treats nondipping BP via the sympathetic nervous system (SNS) indiabetic db/db mice and literature evidence that the vagus nerve links food intake to modulation of BP wehypothesize that GLP-1RA administered at ZT0 inhibits food intake vagus nerve and SNS via the GLP-1receptor and its cross-talk with clock BMAL1 thus protecting BP circadian rhythm in type 2 diabetes. Twospecific aims are Aim 1. Investigate GLP-1RA as a novel chronomedicine to protect BP circadian rhythm viainhibiting food intake in type 2 diabetes. Aim 2. Define the mechanism by which GLP-1RA protects BPcircadian rhythm in type 2 diabetes. To achieve these goals we will determine the effects of short-acting GLP-1RA Ex and long-acting GLP-1RA liraglutide administered at ZT0 or ZT12 on the circadian rhythms ofmetabolism food intake clock genes SNS and BP in diabetic db/db db/db-Per2Luc Bmal1-iKO Glp1r-KObrain-specific Glp1r-KO and vagal neuron-specific Glp1r-KO mice under various feeding regimens. Theproposed studies will provide novel pre-clinical evidence suggesting GLP-1RA serves as a novelchronomedicine targeting the nondipping BP in type 2 diabetes thus improving prognoses and outcomes ofdiabetic patients. Furthermore results from the proposed studies will shed new light on how GLP-1RAs lowerBP thus laying a foundation for optimizing GLP-1RA therapy for diabetic patients.

project_terms:
ARNTL gene;Agonist;Animals;Antidiabetic Drugs;Bilateral;Blood Pressure;Body Weight;Brain;Cardiovascular system;Chronic Disease;Chronotherapy;Circadian Rhythms;Clinical Trials;Darkness;Data;Diabetes Mellitus;Diabetic mouse;Duodenum;Eating;FDA approved;Fatty acid glycerol esters;Female;Foundations;Future;GLP-I receptor;Genes;Glycosylated hemoglobin A;Goals;High Fat Diet;Hippocampus;Hypertension;Hypothalamic structure;Knock-out;Knockout Mice;Knowledge;Light;Link;Literature;Mediating;Messenger RNA;Metabolism;Mus;Neurons;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Phase;Prognosis;Publications;Regimen;Rest;Risk Factors;Role;Scheme;Sympathetic Nervous System;Time;Time-restricted feeding;Type 2 diabetic;Vagotomy;Vagus nerve structure;blood pressure reduction;cardiovascular risk factor;comorbidity;cost;db/db mouse;diabetic;diabetic patient;effective therapy;exenatide;feeding;gut-brain axis;improved;liraglutide;male;novel;pre-clinical;prevent;protective effect;sex;sexual dimorphism;targeted treatment

public_health_relevance:
PROJECT NARRATIVENormal blood pressure has a regular circadian rhythm which is disrupted in up to 75% of diabetic patients andassociates with detrimental cardiovascular outcomes. Using a glucagon-like-peptide-1 receptor agonist (GLP-1RA) an FDA approved anti-diabetic drug we found that it protects blood pressure circadian rhythm in diabeticmice only when administered during their resting time. This proposal will investigate mechanisms of thisprotective effect in diabetic mice for the future potential of GLP-1RA as a chronomedicine that correctsdisrupted blood pressure circadian rhythm in diabetic patients.


application_id: 10641500
project_number: 1R61NS127271-01A1
project_title: Planning Study for the Development of Sigma 2 ligands as Analgesics
administering_ic: NINDS
award_notice_date: 2023-09-11
opportunity_number: RFA-NS-21-029
application_type: 1
activity_code: R61
ic: NS
serial_number: 127271
suffix: A1
program_official: BACHMAN, JULIA LYNN
project_start_date: 2023-09-11
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZNS1 SRB-S (11)]
contact_pi_person_id: 8077002
contact_pi: TIDGEWELL, KEVIN JOSEPH
other_pis: KOLBER, BENEDICT J
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
There is a pressing need to develop novel therapeutic agents against new targets for chronic pain. This proposal will use cyanobacterial-derived natural products as the starting point for chronic neuropathic pain drug development by targeting the sigma 2/transmembrane protein 97 (-2/TMEM97). The -2/TMEM97 receptor has been pharmacologically known for over 40 years but only since 2017 has the molecular identity and its potential role in pain been described. With a new crystal structure -2/TMEM97 and five studies describing the potential of -2/TMEM97 modulators to treat pain in rodents this will be an area of rapid exploration and development in the coming years. Our preliminary data show selectivity of our natural products for -2/TMEM97 as well as early suggestions of potential to modulate human nociceptors in vitro with mechanisms of action identified in primary mouse dorsal root ganglion neurons. We have built and will continue to expand and strengthen complementary biology and chemistry teams in this planning proposal to prepare us for success in transitioning to a U19 phase of the project. These teams consist of an interdisciplinary group of scientists and stakeholders as well as partnerships with an academic drug discovery center and a commercial computational screening group. Our technology offices will ensure strong intellectual property protection throughout the project and business and entrepreneurial consultants will help the teams develop commercial development plans that are feasible and keep key target product profile details as driving forces of the project. Overall this proposal will yield i) a strong integrated and multi-disciplinary research team ii) an in-silico library of potential analogs screened for physicochemical properties and theoretical binding scores resulting in iii) 5-10 synthetic compounds to be evaluated for in vitro efficacy and experimental drug-like properties. These lead compounds and data generated from this team will then form the basis of our U19 proposal to move our top 1-3 candidates towards the clinic.

project_terms:
Affinity;Analgesics;Area;Basic Science;Behavior;Binding;Binding Sites;Biological;Biology;Businesses;C-terminal;Cells;Chemicals;Chemistry;Clinic;Collaborations;Communities;Computational Technique;Data;Development;Development Plans;Docking;Dose;Endoplasmic Reticulum;Ensure;Evaluation;Exhibits;Female;Goals;Grant;Human;Hypersensitivity;In Vitro;Industrialization;Industry;Integral Membrane Protein;Intellectual Property;Interdisciplinary Study;Investigation;Knockout Mice;Lead;Libraries;Ligands;Mechanics;Methodology;Methods;Modeling;Modernization;Modification;Molecular;Molecular Analysis;Molecular Computations;Mus;N-terminal;Natural Products;Neurons;Nociceptors;Pain;Patients;Peptides;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Process;Property;Psychotropic Drugs;Publishing;Research Personnel;Rodent;Role;Scientist;Series;Signal Transduction;Specialist;Specificity;Spinal Ganglia;Structure;Suggestion;Symptoms;Technology;Testing;Therapeutic;Therapeutic Agents;Toxic effect;Work;analog;chemical property;chronic neuropathic pain;chronic pain;clinical practice;cytotoxicity;design;driving force;drug development;drug discovery;drug-like compound;improved;in silico;induced pluripotent stem cell;male;marine;molecular modeling;multi-electrode arrays;nerve injury;neuroinflammation;neuroprotection;non-opioid analgesic;novel;novel strategies;novel therapeutics;pain reduction;pain relief;painful neuropathy;pharmacokinetics and pharmacodynamics;pharmacologic;prospective;receptor;research and development;screening;screening program;sigma-2 receptor;spared nerve;success;therapy outcome

public_health_relevance:
The proposed planning grant is focused on building a team and conducting preliminary investigations into developing of a new series of natural product analogs designed to target a novel target for non-opioid pain relief Sigma2 (-2) a.k.a. Transmembrane Protein 97 (TMEM97). We have brought together an interdisciplinary team of scientists academic drug discovery specialists industry specialists and stakeholders to start our biology and chemistry teams who will work together to progress the development of -2/TMEM97 analogs for the treatment of neuropathic pain.


application_id: 10640822
project_number: 5F31DK130609-02
administering_ic: NIDDK
award_notice_date: 2023-03-27
opportunity_number: PA-21-051
application_type: 5
activity_code: F31
ic: DK
serial_number: 130609
program_official: MARIC-BILKAN, CHRISTINE
project_start_date: 2022-05-01
project_end_date: 2023-05-13
study_section: ZDK1-GRB-G(O1)L
contact_pi_person_id: 16133895
contact_pi: ORWICK, ANDREW
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
The role of PGC-1alpha in repeated low-dose cisplatin-induced kidney injury and the progression to chronic kidney disease

project_abstract:
Project Summary:Cisplatin is a first-line chemotherapeutic for many solid organ cancer types but its usages are limited by itsnephrotoxicity. Thirty percent of patients who receive cisplatin develop acute kidney injury (AKI) which increasesthe risk of chronic kidney disease (CKD) and mortality. There are currently no treatment options to prevent ortreat cisplatin-induced kidney injury (CDDP-KI). Cisplatin-induced kidney injury (CDDP-KI) has been extensivelyinvestigated in the past by our lab and many other labs using a single high-dose model. However patients aretypically treated with periodic low doses of cisplatin not a single high dose. Our lab and others have recentlydeveloped a potentially more clinically relevant model utilizing repeated low-dose cisplatin (RLDC) treatment. Inthis new model mice receive 4 weekly doses of low dose cisplatin and are able to survive more than 6-monthspost-treatment. The RLDC model can be broken up into two phases. The repeated low-level injury phase whichconsists of the four weeks of cisplatin treatment and is characterized by a mild decline in kidney functioninsignificant levels of tubule cell death inflammation and development of fibrosis. After the injury phase thereis a progression phase that is characterized by persistent inflammation exacerbated fibrosis and thedevelopment of CKD. The mechanisms involved in both phases of this model remain largely unknown. Thekidneys have the highest density of mitochondria per organ second only to the heart. The majority of thereabsorption performed occurs in the renal proximal tubule epithelial cells (RPTECs). These cells are highlyenriched in mitochondria and rely on fatty acid oxidation (FAO) as their many energy source. Cisplatin has beenshown to disrupt FAO and defective FAO in RPTEC is seen in other models of fibrosis. Our preliminary datasuggest that the RLDC model causes a decrease in renal function mitochondrial content and PGC-1. PGC-1 is a master transcriptional regulator of mitochondrial biogenesis fatty acid oxidation lipogenesisthermogenesis and glucose metabolism. This research proposal will examine the relationship between PGC-1expression and the development of fibrosis/CKD in both phases of the RLDC model. We hypothesize thatincreasing PGC-1 expression during the injury and/ or progression phases of RLDC will protect againstkidney injury and prevent progression to CKD respectively. This hypothesis will be tested with the followingspecific aims: Aim 1: Determine the role of PGC-1 in the injury phase of the RLDC model. We hypothesize thatPGC-1 protects from RLDC-induced kidney injury and initiation of fibrosis. We will test this hypothesis byoverexpressing and knocking out PGC-1 during the injury phase of the RLDC model. Aim 2: Determine the roleof PGC-1 in the progression phase of the RLDC model. We hypothesize that increased PGC-1 expressionfollowing cisplatin dosing will prevent RLDC-induced fibrosis and progression to CKD. We will overexpress andknockout PGC-1 following RLDC dosing.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Address;Aftercare;Age Months;Automobile Driving;Bioenergetics;Biogenesis;Biopsy;Cancer Patient;Carcinoma;Cell Death;Cells;Cellular biology;Chronic Kidney Failure;Cisplatin;Clinic;Data;Development;Dose;Dose Limiting;Effectiveness;Energy-Generating Resources;Epithelial Cells;Excision;Fibrosis;Generations;Genetic Transcription;Heart;Human;Inflammation;Injury;Injury to Kidney;Kidney;Knock-out;Knowledge;LCN2 gene;Literature;Mediator;Medical;Mitochondria;Modeling;Mus;Organ;Oxygen Consumption;Patients;Periodicals;Pharmaceutical Preparations;Phase;Platinum;Prevention;Process;Proximal Kidney Tubules;Publishing;Renal function;Research Proposals;Risk;Rodent Model;Role;Solid;Solid Neoplasm;Testing;Therapeutic;Therapeutic Uses;Thermogenesis;Tissues;Translations;absorption;cancer type;clinically relevant;density;fatty acid oxidation;glucose metabolism;innovation;kidney cortex;kidney fibrosis;lipid biosynthesis;metabolomics;mortality;mouse model;nephrotoxicity;new therapeutic target;novel;overexpression;prevent;renal damage;therapeutic target

public_health_relevance:
Project NarrativeCisplatin a highly effective chemotherapeutic used for the treatment of many solid tumors; it has a dose-limitingnephrotoxicity and causes acute kidney injury (AKI) in thirty percent of patients increasing the likelihood fordevelopment of chronic kidney disease (CKD). This proposal examines the role of PGC-1 using a clinicallyrelevant model of cisplatin-induced kidney injury. Successful completion of this project will lead to an increasedunderstanding of the mechanisms driving cisplatin-induced kidney injury for the identification of therapeutictargets for the prevention and treatment of cisplatin-induced kidney injury and progression to chronic kidneydisease.


application_id: 10640053
project_number: 5R01AG068331-04
administering_ic: NIA
award_notice_date: 2023-05-29
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AG
serial_number: 068331
program_official: YAO, ALISON Q
project_start_date: 2020-09-15
project_end_date: 2025-05-31
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9202423
contact_pi: EBBERT, MARK T W
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-06-01
project_title:
Using long-range technologies as a multi-omic approach to understand Alzheimers disease in brain tissue

project_abstract:
PROJECT SUMMARY/ABSTRACTOur long-term goal is to help develop a meaningful therapeutic and pre-symptomatic diagnosticfor Alzheimers disease because while a disease-altering therapeutic is essential it will not besufficient without a diagnostic that identifies disease before symptoms onset. We seek tocontribute to these long-term goals by helping identify specific molecular modifications andtherefore specific mechanisms driving disease using long-range optical DNA mapping andsequencing technologies. Unfortunately most Alzheimers disease genes are only implicatedthrough common non-functional variants and it is still unclear how most Alzheimers diseasegenes are involved in disease. Likewise individual RNA isoforms in diseased brains for topAlzheimers disease genes and their involvement in disease are poorly understood. Functionalvariants and RNA sequencing at the isoform level in diseased brain tissue will provide specificmechanisms to target for therapeutics and diagnostics. Large short-read sequencing efforts arealready ongoing to identify small functional variants involved in Alzheimers disease but structuralDNA variantsmany of which directly affect downstream RNA and proteinsalso causeneurodegenerative diseases. We hypothesize that undiscovered SVs and aberrant RNA isoformsplay a direct role in Alzheimers disease. A thorough study in diseased brain using long-rangeDNA and RNA technologies will complement current short-read efforts providing importantdisease insights.

project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease diagnostic;Alzheimer's disease risk;Automobile Driving;Biology;Brain;Brain Diseases;Clinic;Complement;Complex;DNA;DNA mapping;DNA sequencing;Data;Data Set;Detection;Development;Diagnostic;Disease;Genes;Goals;Grant;Individual;Intervention;Maps;Methods;Modification;Molecular;Mutation;Neurodegenerative Disorders;Nucleotides;Optics;Phenotype;Play;Prognosis;Protein Isoforms;Proteins;RNA;RNA Splicing;Research Personnel;Role;Sampling;Symptoms;Technology;Therapeutic;Validation;Variant;Work;advanced disease;brain health;brain tissue;cohort;design;differential expression;disease diagnosis;disease diagnostic;frontal lobe;gain of function;genome-wide;genome-wide analysis;insight;mind control;multiple omics;programs;risk variant;targeted treatment;transcriptome sequencing

public_health_relevance:
PROJECT NARRATIVEOur overarching scientific premise is that Alzheimers disease interventions and pre-symptomatic disease diagnostics remain elusive in part because we still do not understandexactly how top genes are driving disease. Our group seeks to help develop a pre-symptomaticdisease diagnostic and a meaningful therapy by identifying specific molecular modifications andtherefore specific mechanisms driving disease using long-range optical DNA mapping andsequencing technologies.


application_id: 10638507
project_number: 1K18DC020155-01A1
project_title: Perceptual Effects of Odorant Antagonists
administering_ic: NIDCD
award_notice_date: 2023-03-06
opportunity_number: PAR-21-096
application_type: 1
activity_code: K18
ic: DC
serial_number: 020155
suffix: A1
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2023-04-01
project_end_date: 2024-04-30
study_section: Communication Disorders Review Committee[CDRC]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Summary/AbstractDr. McClintocks research on the function of receptors responsive to odors uses a technology thatsimultaneously measures the responses of all 1100 odorant receptors (ORs) and all 14 trace-amineassociated receptors (TAARs) to odors in freely behaving mice capturing the receptor response patterns thatencode odors. These patterns often called combinatorial codes are responsible for odor identification anddiscrimination. This technology quantifies both response and loss of response from ORs and TAARs so amajor theme of these studies is investigating the role of odorant interactions in shaping response patterns.These interactions are common and because odors are nearly always mixtures of many different odorantsthese findings predict that odorant interactions are fundamental to the encoding and perception of odors inmammals. Whether these interactions at receptors correctly predict perceptual effects especially in humans isas yet unknown so studies of perceptual effects represent a way to assess mechanistic commonality withhumans. Investigating how these interactions affect odor perception is generally important for understandingneural coding and antagonist interactions are valuable tools for future studies of odor signal processing in thebrain. In addition odorant interactions also have translational potential. Prime examples are blockingperception of malodors that have negative impacts on human health and quality of life. These translationalopportunities motivate work on the development of pharmacological tools to modify responses from specificORs and TAARs and thereby manipulate the perception of certain odors. Training in human olfactorypsychophysics proposed in this application will put Dr. McClintock in position to leverage his preclinical data onodorant interactions into tests of whether these interactions are mechanisms shared with humans and whethercertain odorant interactions have translational utility in humans.

project_terms:
Affect;Amines;Anterior nares;Binding;Brain;CNS processing;Cigarette;Code;Collaborations;Complex;Data;Detection;Development;Discrimination;Elements;Experimental Designs;Family;Future;Health;Home;Human;Human Biology;Institution;Knowledge;Latrine;Learning;Mammals;Measures;Mentors;Molecular;Mus;Odorant Receptors;Odors;Outcome;Pattern;Perception;Performance;Peripheral;Pharmacology;Physiology;Positioning Attribute;Procedures;Psychophysics;Quality of life;Research;Research Personnel;Research Project Grants;Rodent;Role;Shapes;Signal Transduction;Smell Perception;Smoke;Social Interaction;Technology;Testing;Training;Translational Research;Translations;Visualization;Volatilization;Work;antagonist;behavior test;combinatorial;craving;efficacy testing;experimental study;human subject;improved;in vivo;learning strategy;neural;pharmacologic;pre-clinical;preclinical study;programs;receptor;receptor function;recruit;response;signal processing;stem;tool;translational potential

public_health_relevance:
PROJECT NARRATIVERecent advances in preclinical studies of receptors directly responsive to odors have openedavenues for producing new ways to understand odorant interactions in humans and ways toblock odors that have negative effects on human health and quality of life such as cigaretteodors that increase cravings to smoke fecal odors that decrease use of latrines and bodyodors that affect social interactions. To facilitate translation of his work on volatile molecules thatblock such odors Dr. McClintock will learn methods used in human olfactory psychophysics.This training will allow him to determine which odor blockers act similarly from rodents tohumans and whether they are promising tools for modifying the perception of odors thatnegatively impact human health.


application_id: 10637031
project_number: 1R01DK135885-01
administering_ic: NIDDK
award_notice_date: 2023-03-30
opportunity_number: PAS-20-160
application_type: 1
activity_code: R01
ic: DK
serial_number: 135885
program_official: CENTER, MAUREEN MONAGHAN
project_start_date: 2023-04-01
project_end_date: 2026-03-31
study_section: Health Promotion in Communities Study Section[HPC]
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: KRUSE-DIEHR, AARON
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
Older Adults Using Social Support to Improve Self-Care (OASIS): Adaption Implementation and Feasibility of Peer Support for Older Adults with T2DM in Appalachia

project_terms:
Address;Adult;Age;Appalachian Region;Behavior;Clinical;Clinical Trials;Communities;Community Health;Data;Diagnosis;Dimensions;Disease;Education;Effectiveness;Elderly;Emotional;Ensure;Environmental Risk Factor;Evidence based intervention;Familiarity;Feedback;Frequencies;General Population;Glycosylated hemoglobin A;Goals;Health;Individual;Intervention;Kentucky;Literature;Measures;Mission;Modeling;Monitor;Morbidity - disease rate;National Institute of Diabetes and Digestive and Kidney Diseases;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Overutilization of Health Services;Participant;Practical Robust Implementation and Sustainability Model;Prevalence;Process;Psychosocial Factor;Questionnaires;Randomized;Reach Effectiveness Adoption Implementation and Maintenance;Research;Resources;Rural;Rural Appalachia;Rural Community;Self Care;Social support;Source;Structure;Testing;Vulnerable Populations;acceptability and feasibility;cost;design;diabetes self-management;glycemic control;implementation evaluation;implementation outcomes;implementation strategy;improved;intervention cost;mortality;peer;peer coaching;peer support;post intervention;primary outcome;psychosocial;response;rural dwellers;rural residence;service organization;skills;social;trustworthiness


application_id: 10636872
project_number: 5R01HL147381-04
project_title: Mechanisms regulating the atherogenic activities of serum amyloid A
administering_ic: NHLBI
award_notice_date: 2023-06-20
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 147381
program_official: LIU, LIJUAN
project_start_date: 2020-07-05
project_end_date: 2025-12-31
study_section: Special Emphasis Panel[ZRG1-VH-D(02)M]
contact_pi_person_id: 9353289
contact_pi: SHRIDAS, PREETHA
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:
Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but alsoplays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whoseconcentration in the plasma increases 1000-fold or more during a systemic inflammatory response beforereturning to near undetectable levels. However SAA is also persistently elevated in chronic inflammatoryconditions such as diabetes obesity rheumatoid arthritis etc. While the liver is the major source of SAAduring an acute inflammatory response extra-hepatic expression has also been documented. Most notablyadipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognizedfor decades that plasma levels of SAA predict cardiovascular risk in humans. More recently our groupdetermined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerousreports by multiple laboratories SAA exerts a myriad of effects in vitro that would be expected to exacerbateinflammation and atherosclerosis in vivo. However most of these published studies investigated lipid-free SAAoverlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances plasma SAA isfound associated with the high-density lipoprotein (HDL) fraction and accumulating evidence demonstratesthat HDL inhibits SAAs pro-inflammatory activity. Thus one function of HDL may be to sequester andneutralize SAA and limit the propagation of inflammation in vivo. Notably SAA can also be detected on apoBparticles particularly in human populations with increased risk for cardiovascular disease. Although thepathophysiological significance of the association of SAA with non-HDL lipoproteins is not known we haveshown that SAA on apoB-containing lipoproteins augments their proteoglycan binding which could lead toincreased vascular retention. Taken together these observations lead us to propose that the pro-inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium betweenHDL-SAA very low-density lipoprotein/low-density lipoprotein-SAA and lipid-free SAA. To test this hypothesiswe have developed critical research tools including novel mouse models with inducible tissue-specific SAAexpression to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodelingfactors (e.g. cholesterol ester transfer protein phospholipase A2 and oxidation) leads to the release ofbioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoBlipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA(liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. Theresults of this proposal will validate SAA as a therapeutic target in cardiovascular disease and will developSAA lipoprotein distribution as a potential biomarker of risk.

project_terms:
Acute;Acute-Phase Proteins;Adipose tissue;Age;Anti-Inflammatory Agents;Apolipoprotein E;Apolipoproteins;Apolipoproteins B;Atherosclerosis;Binding;Biological Markers;Biology;Blood Vessels;Cardiovascular Diseases;Cessation of life;Cholesterol Ester Transfer Proteins;Chronic;Circulation;Clinical;Clinical Research;Development;Diabetes Mellitus;Dose;Equilibrium;Event;Extrahepatic;Family;Fatty acid glycerol esters;Generations;Goals;High Density Lipoproteins;Human;Impairment;In Vitro;Individual;Infection;Inflammation;Inflammatory;Inflammatory Response;Interleukin-1 beta;Kidney;Laboratories;Lipids;Lipoprotein (a);Lipoprotein Binding;Lipoproteins;Liver;Low-Density Lipoproteins;Macrophage;Methotrexate;Mus;Natural Immunity;Obesity;Pathologic;Pathway interactions;Persons;Phase;Phospholipase A2;Plasma;Play;Population;Process;Protein Secretion;Proteoglycan;Publishing;Reporting;Research;Rheumatoid Arthritis;Risk;Risk Factors;Role;Series;Serum amyloid A protein;Signal Transduction;Site;Smoking;Source;Techniques;Testing;Tissues;Very low density lipoprotein;burden of illness;cardiovascular disorder risk;cardiovascular risk factor;experimental study;gain of function;high risk;in vivo;insight;loss of function;mouse model;novel;oxidation;particle;potential biomarker;response;systemic inflammatory response;therapeutic target;tissue injury;tool;uptake

public_health_relevance:
Serum Amyloid A (SAA) plays a causal role in atherosclerosis in mice and predictscardiovascular disease (CVD) risk in humans. This proposal will investigate the mechanisms bywhich SAA causes atherosclerosis. Results are expected to validate SAA as a therapeutictarget in CVD and aid in the development of new biomarkers for identifying individuals who areat the highest risk.


application_id: 10635519
project_number: 1R01HL168294-01
administering_ic: NHLBI
award_notice_date: 2023-04-07
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: HL
serial_number: 168294
program_official: BAIZER, LAWRENCE
project_start_date: 2023-04-10
project_end_date: 2028-03-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
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
budget_start_date: 2023-04-10
project_title:
Neuromodulatory rehabilitation for respiratory motor function in individuals with chronic spinal cord injury

project_abstract:
Project Summary/AbstractRespiratory motor control deficit is the leading cause of morbidity and mortality in patients with spinal cordinjury. The long-term goal of this research is to develop a rehabilitation strategy for respiration in patients withspinal cord injury as a standard of care. Our previous findings demonstrate that respiratory function in patientswith chronic spinal cord injury can be improved by using our original inspiratory-expiratory pressure thresholdrespiratory training protocol. However the effectiveness of this intervention is limited to the amount offunctional capacity preserved below the neurological level of injury. Our preliminary data obtained for thisproposal demonstrate that electrical spinal cord stimulation applied non-invasively to target spinal respiratorycircuits in combination with respiratory training can activate and re-organize spinal motor networks forrespiration. We propose to investigate respiratory motor control-related responses to transcutaneous spinalcord stimulation alone and in combination with respiratory training. By characterization of respiratory muscleactivation patterns using surface electromyography in association with pulmonary functional and relatedcardiovascular measures we expect to determine specific stimulation parameters needed to increase spinalexcitability below level of injury to enhance responses to the input from supraspinal centers that remain afterinjury and to promote the neural plasticity driven by the respiratory training. This hypothesis will be tested bypursuing two Specific Aims: 1) Evaluate the acute effects of transcutaneous spinal cord stimulation onrespiratory functional and motor control properties; and 2) Evaluate the effectiveness of transcutaneous spinalcord stimulation combined with respiratory training.

project_terms:
Activities of Daily Living;Acute;Blood Pressure;Breathing;COVID-19;Cardiovascular system;Chronic;Clinical;Complication;Cutaneous;Data;Development;Effectiveness of Interventions;Electromyography;Electrophysiology (science);Evaluation;Goals;Heart Rate;Human;Individual;Injury;Knowledge;Lesion;Lung;Measures;Methods;Modality;Morbidity - disease rate;Motor;Muscle;Neurologic;Neuronal Plasticity;Neurostimulation procedures of spinal cord tissue;Patients;Pattern;Physiological;Population;Property;Protocols documentation;Public Health;Pulmonary function tests;Randomized Controlled Clinical Trials;Rehabilitation therapy;Research;Respiration;Respiration Disorders;Respiratory Muscles;Respiratory physiology;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Surface;Testing;Therapeutic Effect;Time;Training;Vertebral column;Work;comparative;design;disability;effectiveness evaluation;evidence base;fighting;follow-up;functional improvement;functional outcomes;improved;kinematics;mortality;motor control;neural network;neuroregulation;novel therapeutic intervention;preservation;pressure;rehabilitation strategy;respiratory;response;restoration;standard of care;transcutaneous stimulation;voltage

public_health_relevance:
Project NarrativeRespiratory dysfunction after spinal cord injury is the primary public health concern. The proposed study isdesigned to test a novel therapeutic strategy to fight this complication by using respiratory training incombination with electrical spinal cord stimulation applied transcutaneously in patients with chronic spinal cordinjury. This knowledge will help to reduce the burden of human disability.


application_id: 10635511
project_number: 1R01GM149620-01
administering_ic: NIGMS
award_notice_date: 2023-09-21
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: GM
serial_number: 149620
program_official: YUAN, JEAN
project_start_date: 2023-09-25
project_end_date: 2025-08-31
study_section: Clinical Data Management and Analysis Study Section[CDMA]
contact_pi_person_id: 10376668
contact_pi: CLARKSON, MELISSA
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-25
project_title:
Representing Human Anatomy for Computation and Communication: Synergistic Development of an Anatomical Ontology and Semantically-Augmented Anatomical Graphics

project_abstract:
Project summaryOntologies represent a domain of knowledge in a form that can be used by both computers andpeople. Biomedical ontologies provide standardized representations of knowledge that underlie modernbiomedical research and serve as knowledge bases for enabling intelligent software applications. TheFoundational Model of Anatomy (FMA) is an ontology of human anatomy and has a rich history as one ofthe first biomedical ontologies. After 20 years of development two issues that affect the ability of theFMA to continue to serve as a source for standardized computable knowledge of human anatomy havebecome apparent: First variation in modeling schemes and inter-author variation have introducedinconsistencies such that similar structures within the body are represented in slightly different ways.Second ontologies rely on textual and logical representations yet visual representations are often moreeffective for communicating about anatomy. These issues highlight the need for a next-generationresource for human anatomy that is optimized for use by both computers and people. In this project we will undertake synergistic development of an ontology of human anatomy andstandardized visual representations of human anatomy. Aim 1: To develop an ontology of humananatomy suitable for computational reasoning that will serve as a knowledgebase for the next generationof medical information systems we will create the Foundational Model of Human Anatomy (FMHA) as aderivative of the FMA. Aim 2: To provide standardized visual representations of human anatomy for usein information systems we will develop libraries of composable graphics depicting canonical anatomythat will be augmented with computer-readable semantics. Aim 3: To demonstrate use of the FMHA andstandardized graphics to address real-world needs in research education and clinical contexts we willexpand our graphic libraries beyond depictions of canonical anatomy and develop two web applications.Aim 4: To demonstrate how developers can leverage the FMHA and graphics in their own webapplications we will develop a web application for graphically-driven exploration of the DiseaseOntology. By developing the FMHA and anatomical graphics libraries as highly-curated resources they willserve as trustworthy knowledge sources for biomedical applications in data science. By integrating text-based and visual representations of anatomy we will help to ensure that researchers accuratelyannotate the anatomical content of datasets and models using FMHA classes thereby helping topreserve the integrity of integrated datasets and models.1

project_terms:
Address;Affect;Anatomic Models;Anatomy;Biomedical Research;Clinical;Clinical Medicine;Communication;Communities;Computer software;Computers;Data Science;Data Set;Development;Disease;Education;Human;Human Resources;Informatics;Information Resources;Information Systems;Intelligence;Knowledge;Libraries;Medical Illustration;Medicine;Modeling;Modernization;Names;Ontology;Patient Care;Patients;Pattern;Persons;Positioning Attribute;Production;Readability;Recording of previous events;Research;Research Personnel;Resources;Scheme;Semantics;Source;Standardization;Structure;Text;Time;Variant;Visual;Work;biomedical ontology;body system;clinical application;computational anatomy;computational reasoning;data integration;data modeling;design;human model;knowledge base;knowledgebase;medical information system;multidisciplinary;next generation;ontology development;preservation;skills;trustworthiness;web app

public_health_relevance:
Project narrativeThis project will create knowledge resources about human anatomy that will combine textual logical andvisual representations. These are designed to be understood by both computers and people. This workwill enable clinical research and educational software applications to use information about humananatomy.1


application_id: 10634607
project_number: 5R01HL152081-04
administering_ic: NHLBI
award_notice_date: 2023-06-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 152081
program_official: HASAN, AHMED A K
project_start_date: 2020-07-01
project_end_date: 2025-06-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Understanding the role of immune complexes between apolipoprotein A-I and IgG in atherosclerotic cardiovascular disease

project_abstract:
The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediatedpathogenesis of atherosclerotic cardiovascular disease (ASCVD). One target of IgG antibody induction inASCVD patients is apolipoprotein A-I (ApoA-I) the major protein of high density lipoprotein (HDL). Although anti-ApoA-I antibodies have been identified in mice and human subjects their role has not been elucidated. The PIhas identified immune complexes formed between ApoA-I and IgG (ApoA-I/IgG IC) that exhibit anti-inflammatorycharacteristics and associate with decreased CVD risk. Continued evaluation of ApoA-I/IgG ICs will improve ourunderstanding of this component of the immune responses associated with ASCVD. The overall goal of thisproject is to determine the role of ApoA-I/IgG ICs and elucidate their functional impact in ASCVD. To achievethis goal we will characterize the molecular components of ApoA-I/IgG ICs in mouse and patient sera samplesand correlate these factors with cellular interactions functional outcomes and disease progression. Thehypothesis is that ApoA-I/IgG ICs exhibit anti-inflammatory effects mediated through the inhibitory Fc-receptordepending on antibody characteristics (i.e. epitope specificity subclass) and these effects are capable ofsuppressing inflammation and disease. The rationale for this proposed research is that understanding onecomponent of the humoral immune response associated with ASCVD will lead to a better understanding of theunderlying mechanisms and improve patient outcomes. Encouraged by strong preliminary data this hypothesiswill be tested through two specific aims: 1) Elucidate the molecular components and functional implications ofApoA-I/IgG ICs using cultured cells and mouse models of atherosclerosis; and 2) Determine the characteristicsand anti-inflammatory activity of ApoA-I/IgG ICs from human plasma and delineate the association among ApoA-I/IgG ICs and ASCVD in a large community-based cohort. Aim 1 will employ novel immunomodulation strategiesdeveloped in Dr. Venditto's laboratory to achieve epitope-specific immune modulation of antibody responses inmice to elucidate antibody/epitope function and the role in atherosclerosis progression. Aim 2 will employ serafrom human subjects to characterize antibody/epitope function and evaluate the association between ApoA-I/IgGICs and disease progression in the Multi-Ethnic Study of Atherosclerosis (MESA). The approach is innovativedue to the utilization of in vivo immunomodulation approaches to alter ApoA-I/IgG IC profiles and our approachfocused on obtaining detailed ApoA-I/IgG IC profiles in patients for association studies with disease. Theproposed research is significant as the outcomes of this research will improve our understanding of antibody-mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailedcharacterizations of the prefinalantigen epitope specificity antibody subclass and receptor engagement willenhance our understanding of ASCVD to guide therapeutic development and future efforts to improve riskstratification procedures to decrease the burden of ASCVD in patients.

project_terms:
Acceleration;Anti-Inflammatory Agents;Antibodies;Antibody Response;Antigen-Antibody Complex;Antiinflammatory Effect;Apolipoprotein A-I;Arterial Fatty Streak;Atherosclerosis;Autoantibodies;Autoantigens;Autoimmune Diseases;Cardiovascular Diseases;Cell model;Cells;Characteristics;Circulation;Communities;Complex;Cultured Cells;Data;Death Rate;Development;Disease;Disease Progression;Epitopes;Evaluation;Event;Exhibits;Fc Receptor;Future;Goals;High Density Lipoproteins;Homeostasis;Human;IgG4;Immune System Diseases;Immune response;Immunization;Immunoglobulin G;Incidence;Inflammation;Inflammatory;Investigation;Laboratories;Measures;Mediating;Molecular;Multi-Ethnic Study of Atherosclerosis;Multivariate Analysis;Mus;Myocardial Infarction;Outcome;Outcomes Research;Participant;Pathogenesis;Patient-Focused Outcomes;Patients;Phenotype;Plasma;Procedures;Prospective cohort;Proteins;Protocols documentation;Receptor Signaling;Research;Risk;Risk Factors;Role;Sampling;Specificity;Stroke;Testing;adjudication;burden of illness;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;clinical risk;cohort;drug development;follow-up;functional outcomes;human subject;immunoregulation;improved;in vitro activity;in vivo;innovation;male;mouse model;new therapeutic target;novel;novel strategies;novel therapeutics;obese patients;profiles in patients;programs;protocol development;receptor;response;risk stratification;therapeutic development;vaccination strategy;western diet

public_health_relevance:
PROJECT NARRATIVEThis proposal seeks to investigate the antibody response targeting apolipoprotein A-I by implementing novelstrategies to modulate epitope-specific immune responses in mice and characterize the antibody profiles inhumans. These objectives will improve our understanding of the immune response associated withatherosclerosis and promote the identification of novel therapeutic targets. These data will also guide futureclinical risk stratification protocols and drug development studies to reduce the cardiovascular disease burdenin patients.


application_id: 10634551
project_number: 5K01ES033289-02
project_title: Evaluating mechanisms of sex differences in environmentally-induced metabolic diseases
administering_ic: NIEHS
award_notice_date: 2023-05-23
opportunity_number: PAR-21-172
application_type: 5
activity_code: K01
ic: ES
serial_number: 033289
program_official: SCHUG, THADDEUS
project_start_date: 2022-06-03
project_end_date: 2025-05-31
study_section: ZES1-LWJ-S(K1)
contact_pi_person_id: 14294360
contact_pi: WAHLANG, BANRIDA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Mechanistic studies pertaining to sex-based differences in metabolic syndrome (MetS) are currently insufficientto explain and prevent the higher prevalence of certain MetS symptoms in women versus men andhigher prevalence of other symptoms such as hyperlipidemia in men versus women. MetS describes aconstellation of risk factors such as abdominal adiposity hypertension glucose intolerance/hyperglycemiaand dyslipidemia leading to diabetes and cardiovascular morbidity. High-caloric intake and sedentary lifestylehabits are among key players shown to induce symptoms of MetS. However exposures to environmentalchemicals such as persistent organic pollutants (POPs) often dictated by socio-economic status andeducation levels have been increasingly identified as additional key players leading to MetS consequences.Previous studies showed that exposures to POPs such as organochlorine pesticides (OCPs) andpolychlorinated biphenyls (PCBs) in in-vivo models and human studies were associated with diabetes obesityand non-alcoholic fatty liver disease which are hallmarks for MetS development. Furthermore using in-vitro models and diet-induced obesity mouse models we had previously demonstrated that the liver wasthe predominant target organ of toxicity to POPs including PCBs and mechanism(s) of toxicity wereprimarily through activation of hepatic receptors leading to metabolic disruption. The liver has long beenestablished as a sexually dimorphic organ and it is therefore important to address POPs toxicity in term ofbiological differences or sex. Additionally POPs such as OCPs are endocrine disrupting chemicals having theability to interact with androgen or estrogen receptors and potentially promoting variable effects in men andwomen. However most epidemiologic studies demonstrating associations between POPs exposure with livertoxicity/metabolic diseases including diabetes either focused on agricultural workers who were mostly men oradjusted for sex; but POPs exposures occur in both men and women and thus their health risks may vary.POPs exposures today is primarily through ingestion of contaminated food and water and serum levels canvary depending on sex and gender. Hence it is relevant to examine exposures to POPs such as OCPs basedon environment-sex-gene interactions to better address such discrepancies.

project_terms:
Address;Affect;Agricultural Workers;Androgen Receptor;Authorization documentation;Automobile Driving;Award;Binding;Biological;Biological Markers;Body Composition;Cardiovascular system;Chemicals;Chlordan;Development;Diabetes Mellitus;Disease;Dose;Dyslipidemias;Educational Status;Endocrine;Endocrine Disruptors;Endocrine disruption;Energy Intake;Environment;Environmental Epidemiology;Environmental Exposure;Environmental Health;Estrogen Receptors;Ethnic Origin;Exhibits;Exposure to;Female;Food Contamination;Future;Gender;Glucose Intolerance;Goals;Gonadal Steroid Hormones;Grant;Habits;Health;Health Care Costs;Hepatic;Hepatotoxicity;High Fat Diet;High Prevalence;Home;Human;Hyperglycemia;Hyperlipidemia;Hypertension;Incidence;Ingestion;Injury;Investigation;Isoptera;Knowledge;Lipids;Liver;Measures;Metabolic;Metabolic Diseases;Metabolic syndrome;Metabolism;Molecular;Morbidity - disease rate;Mus;Obesity;Organ;Outcome;Pathology;Policy Maker;Polychlorinated Biphenyls;Population;Postmenopause;Predisposition;Prevalence;Process;Proteome;Proteomics;Public Health;Race;Receptor Activation;Receptor Signaling;Reporting;Research;Resistance;Risk;Risk Factors;Serum;Sex Differences;Signal Pathway;Socioeconomic Status;Symptoms;Techniques;Testing;Therapeutic;Toxic effect;Training;Vulnerable Populations;Water;Woman;Work;Xenobiotics;abdominal fat;arm;authority;bioaccumulation;design;diet-induced obesity;effective intervention;environmental chemical;epidemiology study;gene interaction;glucose tolerance;in vitro Model;in vivo Model;male;men;mouse model;non-alcoholic fatty liver disease;nutrition;organochlorine pesticide;organochlorine pesticide exposure;persistent organic pollutants;prevent;receptor;sedentary lifestyle;sex;sex disparity;sexual dimorphism;toxicant

public_health_relevance:
Project NarrativeMechanistic studies pertaining to sex-based differences in the metabolic syndrome are currently insufficient toexplain and prevent the higher prevalence of certain metabolic conditions in women versus men and higherprevalence of other symptoms such as hyperlipidemia in men versus women. In addition epidemiologic studieshave reported that exposure to environmental chemicals such as persistent organic pollutants includingorganochlorine pesticides yield different health outcomes in men and women and therefore the current projectaims to evaluate the underlying cellular mechanisms impacted by sexual dimorphism that potentially drive suchdifferences. The concepts and information that will be gained from this grant will better address sex disparitiesin environmental health as well as provide health authorities with further knowledge to identify metabolicsyndrome-related factors in susceptible populations and design sex-specific therapeutic strategies to bettercontrol future health care costs.


application_id: 10634416
project_number: 7R01DK118082-04
project_title: Pharmacological Approach to the Restoration of Hypoglycemia Awareness
administering_ic: NIDDK
award_notice_date: 2022-08-31
opportunity_number: PA-21-268
application_type: 7
activity_code: R01
ic: DK
serial_number: 118082
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 7926891
contact_pi: FISHER, SIMON J
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:
Abstract: Hypoglycemia is the most prevalent clinical complication in the daily management of diabetes and is themajor obstacle to normalizing blood sugar. For people with Type 1 diabetes (T1DM) hypoglycemia associatedautonomic failure (HAAF) increases the risk for severe hypoglycemia by a factor of 25 or more. A major componentof HAAF is hypoglycemia unawareness which involves in the loss/diminution of warning symptoms tohypoglycemia that would normally prompt a corrective behavioral response (e.g. eating food). With a goal ofidentifying existing biological compounds that could restore hypoglycemia awareness (ie repurpose existing FDA-approved drugs) our laboratory recently completed a drug screen using a novel animal model of hypoglycemiaunawareness in which preconditioned rats failed to increase food consumption in response to an episode of insulininduced hypoglycemia. Of all drugs tested the dopamine antagonist metoclopramide consistently restoredhypoglycemia awareness in several of our animal models tested. The goal of Aim 1 in the proposed grant is tovalidate in T1DM animal models of HAAF whether leading drugs identified in our recent drug screen restore both1) hypoglycemia awareness and 2) the impaired sympathoadrenal response to hypoglycemia. Utilizing the goldstandard hyperinsulinemic hypoglycemic clamp technique drug validation studies are proposed in twoindependent T1DM rodent models of HAAF (both hypoglycemia unaware rats as well rats with recurrenthypoglycemia-induced sympathoadrenal deficiency) to determine if treatment with our leading drugs reverse thesetwo principal pathologic components of HAAF. In Aim 2 a clinical trial is proposed to test whether the leadcompound identified in our drug screen can restore both hypoglycemia awareness and the counterregulatoryresponse to hypoglycemia in subjects with T1DM and HAAF. A placebo controlled randomized trial will testwhether four weeks of treatment with metoclopramide (our lead drug noted to particularly efficacious in severalpreclinical models) will 1) reduce the incidence of hypoglycemia 2) improve hypoglycemia symptom recognitionand 3) improve the sympathoadrenal response to hypoglycemia. Indices of improvement will be assessed 1) inthe outpatient setting with hypoglycemia event diaries hypoglycemia awareness questionnaires and continuousglucose monitors and 2) in the laboratory setting with stepped hypoglycemic clamps which quantifiesmeasurements of symptomatic awareness and counterregulatory hormone responses. By proceeding forward withthe novel results from our recent drug screen the proposed studies are the logical next step in seeking torepurpose existing FDA approved drugs to treat hypoglycemia associated autonomic failure in people with Type 1diabetes.

project_terms:
Animal Model;Awareness;Biochemical;Biological;Blood Glucose;Clinical;Clinical Trials;Closure by clamp;Complication;Defect;Diabetes Mellitus;Dopamine Antagonists;Drug Screening;Eating;Event;FDA approved;Failure;Food;Goals;Gold;Grant;Hormones;Hypoglycemia;Impairment;Incidence;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Laboratories;Lead;Life;Measurement;Metoclopramide;Outpatients;Pathologic;Patients;Persons;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Placebo Control;Pre-Clinical Model;Preclinical Testing;Questionnaires;Rattus;Recurrence;Reporting;Risk;Rodent Model;Savings;Symptoms;Techniques;Testing;Therapeutic Agents;behavioral response;counterregulation;diabetes management;diabetic;diaries;drug testing;drug use screening;experimental study;food consumption;glucose monitor;hypoglycemia unawareness;improved;indexing;novel;pre-clinical;preconditioning;randomized trial;response;restoration;validation studies

public_health_relevance:
Project Narrative: Hypoglycemia unawareness and impaired counterregulation are pathological defects that markedlyincrease the risk for life-threatening severe hypoglycemia in people with Type 1 diabetes (T1DM). With a goal ofidentifying and repurposing existing FDA-approved drugs to treat these conditions our laboratory recentlycompleted a drug screen that identified a metoclopramide as a drug that consistently restored hypoglycemiaawareness in several different animal models tested. It is now proposed to perform definitive testing in preclinicalT1DM animal models and proceed with a clinical trial to determine if metoclopramide treatment restores bothhypoglycemia awareness and the sympathoadrenal response to hypoglycemia in subjects with T1DM.


