# projects

application_id: 10735953
project_number: 1R21AG080859-01A1
project_title: 4D Flow MRI in Assessment of True Severe Low-Gradient Aortic Stenosis
administering_ic: NIA
award_notice_date: 2023-08-22
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AG
serial_number: 080859
suffix: A1
program_official: TSAP, LEONID V
project_start_date: 2023-09-01
project_end_date: 2025-05-31
study_section: Clinical Translational Imaging Science Study Section[CTIS]
contact_pi_person_id: 1880208
contact_pi: AMINI, AMIR 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
project_abstract:
Degenerative aortic stenosis is a progressive valvular heart disease affecting the aging population and whenhemodynamically significant is associated with serious adverse outcomes such as heart failure syncope anddeath. Although symptomatic classical severe aortic stenosis (AS) wherein aortic valve anatomical or effectivearea is  1.0 2 and mean gradient  40 mmHg raises no diagnostic dilemma patients with low gradient aorticstenosis (i.e. mean gradient < 40 mmHg) that may be severe (i.e. aortic valve area  1.0 2) remain achallenge for determining the true severity of aortic stenosis and present a significant unmet clinical need. Thediscordance between aortic valve area of  1.0 2 and mean gradient < 40 mmHg is encountered in as manyas 30 to 40% of patients with aortic valve area  1.0 2 by transthoracic echocardiography (TTE). In patientswith these discordant findings the true severity is uncertain and have led to the use of dobutamine stressechocardiography (DSE). Based on DSE one can classify the potentially severe low-gradient subjects into 4distinct subgroups a) Low gradient severe aortic stenosis (LGS): aortic valve area of  1.0 2 and a meangradient of  40 mmHg with DSE. b) Low gradient pseudo-severe aortic stenosis (LGPS): aortic valve area of >1.0 2 and a mean gradient of < 40 mmHg with DSE. c) Low gradient indeterminate aortic stenosis severity(LGI): aortic valve area of  1.0 2 and a mean gradient of < 40 mmHg with DSE. d) Finally aortic valve areaof > 1.0 2 and a mean gradient of  40 mmHg with DSE are classified as moderate or less severe aorticstenosis (LSA). Nearly one-third of patients classified as LGS are classified as LGPS with DSE (6). Furthercompounding the concern in patients classified as LGPS LGI LSA is that they often manifest with symptomspotentially attributable to severe AS suggesting an initial misclassification perhaps due to measurement errors.Compared to echo with MRI the velocities can be measured in all 3D directions and due to its tomographicnature no geometric assumptions are required. The hypothesis of the study is that our planned CMR methodswhich we will develop based on previous work will be able to better stratify these AS subjects. Our specific aimsare: 1) We will develop efficient rest and dobutamine stress 4D Spiral flow imaging protocols based on k-spacedependent respiratory gating. 2) We have recently developed a Deep Learning framework which based onComputational Fluid Dynamics (CFD) simulations of training data learns to directly map velocities to pressures.This will be adapted to measure the transvalvular pressure gradients (TVPG) in human subjects and validated.3) In 40 subjects with potentially severe low gradient AS (10 in each of the LGS LGPS LGI LSA) a TTE studyand a CMR study will be performed both at rest and under dobutamine stress. To validate TVPG will bemeasured with cath in a group with n=10 of moderate AS (MAS) subjects undergoing cath for other purposes.This group will also undergo TTE and CMR studies. Subjects with severe AS were not selected for cath for safetyreasons. Classification across modalities flow velocity pressure and orifice area will be statistically correlated.

project_terms:
3-Dimensional;4D MRI;Adopted;Affect;Anatomy;Aortic Diseases;Aortic Valve Stenosis;Area;Breathing;Catheterization;Cessation of life;Chest;Chronic;Classification;Clinical;Correlation Studies;Data;Diagnostic;Diagnostic Procedure;Dobutamine;Dobutamine Stress Echocardiography;Doppler Echocardiography;Drops;Echocardiography;Enrollment;Equation;Goals;Heart;Heart Valve Diseases;Heart failure;Image;Learning;Left Ventricular Ejection Fraction;Liquid substance;Magnetic Resonance Imaging;Maps;Measurement;Measures;Methods;Modality;Morphologic artifacts;Nature;Noise;Operative Surgical Procedures;Patients;Protocols documentation;Rest;Risk;Safety;Scanning;Severities;Severity of illness;Stratification;Stress;Subgroup;Survival Rate;Symptoms;Syncope;Therapeutic Embolization;Training;Work;adverse outcome;aging population;anatomic imaging;aortic valve;aortic valve disorder;aortic valve replacement;data space;deep learning;hemodynamics;human subject;imaging modality;improved;pressure;respiratory;simulation;tomography;ultrasound

public_health_relevance:
Aortic Stenosis (AS) is a significant disease of the aortic valve of the heart which is chronicprogressive and has a 2-year survival rate of 50% in symptomatic patients who are untreated. Inas many as 30-40% of subjects with low gradient but potentially severe AS current diagnosticmethods are discordant and inconclusive. The proposal will develop new MRI methods forimproved stratification of these subjects.


application_id: 10735898
project_number: 5R21AI169231-02
project_title: Function of the type 7 secretion system in Group B Streptococcus
administering_ic: NIAID
award_notice_date: 2023-10-24
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 169231
program_official: GU, XIN-XING
project_start_date: 2022-11-07
project_end_date: 2025-10-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
other_pis: PATRAS, KATY
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Streptococcus agalactiae commonly known as Group B Streptococcus (GBS) is a member ofthe vaginal and gut microbiome of up to 30% of healthy individuals. GBS can cause pneumoniameningitis and sepsis in neonates when transmitted from mother to child. In addition GBS cancause a range of diseases in immunocompromised adults and the elderly including urinary tractinfections pneumonia and meningitis. GBS has to compete with other microbiome members indifferent niches of the human host. Other Firmicutes Staphylococcus aureus Streptococcusintermedius and Enterococcus faecalis employ the Type VII Secretion Systems (T7SS) forintrabacterial or interbacterial antagonism. Analyses of GBS genomes revealed the presence ofputative T7SS loci. These gene clusters encode the core components of T7SS machinery aswell as putative secreted effectors/toxins. The goals of this application are to define the functionof GBS T7SS in vaginal colonization and to characterize the role of GBS T7SS in interbacterialantagonism. We propose to assess the contribution of the GBS T7SS to GBS adherenceinvasion and host responses of the vaginal epithelium using in vitro human vaginal cell linesand mouse models of GBS vaginal colonization. We will also study the contribution of the GBST7SS to GBS competition with other microbes in vitro and in humanized microbiota mousemodels. The results of our study will significantly advance the understanding of the contributionof GBS T7SS to interbacterial interactions that shape the outcome of the host infection.

project_terms:
Abscess;Adherence;Adult;Antibiotic Prophylaxis;Antibiotic Resistance;Bacteria;Bacterial Infections;Biochemical;Bioreactors;Blood - brain barrier anatomy;Cell Line;Cells;Communities;Complex;Core Protein;Cytolysis;Development;Disease;Ecosystem;Elderly;Enterococcus faecalis;Epithelium;Family;Firmicutes;Foundations;Future;Gastrointestinal tract structure;Gene Cluster;Genome;Goals;Gram-Positive Bacteria;Group B Streptococcus colonization;Hand;Human;Immune response;Immunocompromised Host;In Vitro;Individual;Infection;Invaded;Life;Measures;Mediating;Meningitis;Microbe;Molecular;Mothers;Mucous Membrane;Mus;Newborn Infant;Nutrient;Organism;Outcome;Pathway interactions;Pelvis;Play;Pneumonia;Pregnant Women;Preventive measure;Process;Proteins;Research Design;Role;Route;Sepsis;Shapes;Solid;Staphylococcus aureus;Streptococcal Infections;Streptococcus;Streptococcus Group B;Streptococcus intermedius;Surface;System;Testing;Time;Toxic effect;Toxin;Urinary tract;Urinary tract infection;Vagina;Vertical Disease Transmission;Virulence;antagonist;anti-toxin;clinically relevant;cytotoxicity;experimental study;female reproductive tract;genetic approach;genomic locus;gut microbiome;human microbiota;in vivo;member;microbiome components;microbiota;microorganism;mouse model;neonatal infection;neonate;pathobiont;pathogen;prevent;translational model;transmission process;uptake;vaginal microbiome;vaginal microbiota

public_health_relevance:
Group B Streptococcus is an important pathobiont that causes life-threatening infections inneonates the elderly and the immunocompromised adults. The proposed studies will determinehow the Type VII Secretion System contributes to the interbacterial antagonism and how itcontributes to the colonization and infection processes.


application_id: 10735893
project_number: 5R13AI129382-06
project_title: Autumn Immunology Conference
administering_ic: NIAID
award_notice_date: 2023-10-20
opportunity_number: PA-21-151
application_type: 5
activity_code: R13
ic: AI
serial_number: 129382
program_official: BARTELS, ADELINA EWURA-ABENA
project_start_date: 2016-11-01
project_end_date: 2024-10-31
study_section: ZAI1-MFH-D(S1)
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
arra_indicator: N
project_abstract:
This proposal requests 2 years of support for the Autumn Immunology Conference (AIC) an annual gatheringof immunologists at the Marriott Downtown Magnificent Mile hotel in Chicago IL. Year 1 will support the 50thannual AIC on November 18-21 2022 and Year 2 will support the 51st annual meeting to be held November 17-20 2023. The purpose of AIC is to foster communication and collaboration among immunologists particularlythose located in the upper Midwest region of the US. Chicago is an exciting destination and within drivingdistance for many midwestern academic institutions that are home to numerous NIAID-funded investigators.Since its inception in 1972 AIC continues to be very highly regarded and has a fiercely loyal group of regularattendees from the Midwest but it also attracts immunologists from around the US each year. The Specific Aimsof AIC are to: 1) disseminate new immunological research findings from top labs in the field 2) provide a forumfor trainees to hone their presentation skills and 3) increase interactions between a diverse group of scientistsinterested in immunology research. The meeting starts with a Meet the Speakers event for trainees a Keynotespeaker and a welcome reception on Friday. Saturday & Sunday have similar structures: morning symposiathen smaller themed workshops followed by poster sessions. The meeting ends on Monday with just a morningplenary session. Each year three different topic areas are chosen for the morning symposia. For 2022 6 female& 6 male invited speakers will present talks on Transplantation T Cell Development & Autoimmunity; the 2023topics will be chosen by the AIC Chair in consultation with the Executive Council (EC) at the spring planningmeeting. All accepted abstracts (typically ~250 from postdocs/grad students/undergrads) are invited to give a10 min. talk during the afternoon workshops followed by a 1 h poster presentation. AIC is organized by adedicated all-volunteer group of faculty that serve multi-year terms including the leadership track that consistsof a 4 year commitment to serve as the Workshop Coordinator the Secretary the Chair and then the PastChair/Councilor. Since 1992 the EC has strived to maintain a gender balance amongst its members; we typicallyrotate males and females to enter the leadership track such that the 2022 meeting will be chaired by Dr. RichardDiPaolo (St. Louis Univ) and the 2023 meeting will be led by Dr. Kerry Empey (U. Pitt). Another unique featureof AIC is the Undergraduate Workshop with a Careers in Immunology panel discussion and a table fair of PhDprograms in Immunology. AIC is truly a formative experience for trainees and this remains one of the mostpositively evaluated aspects of the meeting. The volunteer EC works hard to solicit academic and corporatedonations so that we can keep the registration fee low allowing as many trainees as possible to attend thismeeting. In fact the registration fee is waived for any undergrad who presents an abstract. The 50th annual AICis significant because it also marks the 30th anniversary of the inception of our Wallace Diversity Fellows programwhich provides travel awards and networking opportunities to underrepresented minorities.

project_terms:
Address;Anniversary;Area;Autoimmune Diseases;Autoimmunity;Automobile Driving;Award;Beer;COVID-19 pandemic;Cheese;Chicago;Coffee;Collaborations;Communicable Diseases;Communication;Consultations;Data;Dedications;Destinations;Development;Doctor of Philosophy;Education;Educational workshop;Equilibrium;Event;Faculty;Fees;Female;Fostering;Funding;Gender;Home;Hypersensitivity;Immunologics;Immunologist;Immunology;Institution;International;Laboratories;Leadership;Learning;Malignant Neoplasms;Midwestern United States;Mission;National Institute of Allergy and Infectious Disease;Nature;Positioning Attribute;Postdoctoral Fellow;Process;Public Health;Regimen;Request for Applications;Request for Proposals;Research;Research Personnel;Role;Rotation;Scientist;Services;Structure;Students;T-Cell Development;Therapeutic;Transplantation;Travel;Underrepresented Minority;United States National Institutes of Health;Vaccines;Visit;Volunteer Group;Wine;Work;cancer immunotherapy;career;career development;design;equity diversity and inclusion;experience;graduate student;improved;interest;male;meetings;member;new technology;posters;prevent;programs;recruit;skills;symposium;undergraduate student;volunteer

public_health_relevance:
This application requests funding to support the Autumn Immunology Conference an annual gathering ofscientists (primarily from the midwestern US) that is designed to facilitate the dissemination of new researchresults to establish or strengthen collaborations between laboratories and to serve as a platform for thedevelopment of young trainees in the field of immunology. Research in immunology is important for the publichealth mission of NIH and greatly impacts our ability to understand autoimmunity and allergy to design effectivevaccines to prevent infectious diseases and to improve cancer immunotherapy regimens.


application_id: 10735892
project_number: 5R21AI173735-02
project_title: Addressing genetic tractability and species-specific infection biology in Chlamydia pneumoniae
administering_ic: NIAID
award_notice_date: 2023-10-23
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 173735
program_official: UPADHYAY, MEENU MISHRA
project_start_date: 2022-11-07
project_end_date: 2025-06-30
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Chlamydia species represent a paradigm for understanding successful obligate intracellularparasitism. While C. trachomatis and C. pneumoniae are both prevalent human pathogens C.pneumoniae respiratory infections are likely most common. Acute C. pneumoniae infectionsmanifest as community acquired pneumonia bronchitis and sinusitis while additionalinflammatory sequelae are associated with chronic infection. Advances in genetic tractabilityhave facilitated considerable progress in characterizing C. trachomatis pathogenesis.Unfortunately similar progress has lagged for C. pneumoniae leading to a paucity in detailsregarding molecular mechanisms of infection and precluding informative approaches leveragingcomparative studies. To overcome this barrier we will engineer plasmid systems enabling allelicreplacement and ectopic gene expression for C. pneumoniae. These new technologies will beapplied in proof-of-principle studies to address functional aspects manifested by a pair ofdivergent type III secreted effectors employed by C. pneumoniae to manipulate host cellbiology. At the end of these studies we will have established new approaches that will benefitthe entire Chlamydia research community and advance the understanding of how chlamydialspecies have evolved to accomplish common developmental requirements.

project_terms:
Acceleration;Acute;Address;Alleles;Biology;Bronchitis;Cell Separation;Cells;Cellular biology;Chlamydia;Chlamydia trachomatis;Chlamydial pneumonia;Chlamydophila pneumoniae;Communities;Comparative Study;Complement;Data;Development;Disease;Ectopic Expression;Endocytosis;Engineering;Epithelial Cells;Epitopes;Exhibits;Filopodia;Foundations;Future;Gene Deletion;Gene Duplication;Gene Expression;Genes;Genetic;Genetic Techniques;Genitalia;High Prevalence;Human;Infection;Inflammatory;Invaded;Light;Maintenance;Mediating;Molecular;Mucous Membrane;Mutagenesis;Pathogenesis;Pathogenicity;Phagocytes;Phenotype;Plasmids;Prevalence;Probability;Process;Proteins;Recruitment Activity;Research;Respiratory Disease;Respiratory Tract Infections;Reverse engineering;Role;Sinusitis;System;Techniques;Technology;Work;cell type;chronic infection;community acquired pneumonia;constitutive expression;design;efficacy testing;expression vector;gene product;genetic manipulation;human pathogen;inducible gene expression;intracellular parasitism;member;mutant;new technology;novel strategies;obligate intracellular parasite;pathogen;protein function;receptor mediated endocytosis;recruit;respiratory pathogen;seropositive;sorting nexins;tissue tropism;trafficking;vector

public_health_relevance:
Chlamydia pneumoniae an agent of human respiratory disease relies on specializedmechanisms that exert anti-host activities essential to pathogenesis. Understanding thosemechanisms requires a tractable means of genetic manipulation. This proposal contains workdesigned to develop mutagenesis and expression techniques for C. pneumoniae that will beimportant for the study of disease.


application_id: 10735077
project_number: 1R01NS129668-01A1
project_title: Regulation of synapse development by small GTPase cascades in Caenorhabditis elegans
administering_ic: NINDS
award_notice_date: 2023-06-02
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 129668
suffix: A1
program_official: LEENDERS, MIRIAM
project_start_date: 2023-08-01
project_end_date: 2028-07-31
study_section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR]
contact_pi_person_id: 9428270
contact_pi: CHERRA, SALVATORE JAMES
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
project_abstract:
Project SummarySynaptic development is a highly conserved process that underlies the functional connectivity of the nervoussystem. Deficits in synaptic development are associated with multiple neurological disorders like autismspectrum disorders intellectual disabilities epilepsy and schizophrenia. Therefore restoration of healthysynapse development in cases of neurodevelopmental disorders represents one goal for developing bettertreatments. However the lack of molecular targets to achieve this goal presents a significant barrier to thedevelopment of new therapies. Identifying the signaling pathways that promote or restore synapse developmentwill reveal new mechanisms for modulating neuronal circuit development and function. The overall goal for theproposed research is to uncover how a series of small GTPases coordinate synapse development at theCaenorhabditis elegans neuromuscular junction. The central hypothesis is that PXF-1 a Rap guanine nucleotideexchange factor promotes synapse development through the sequential activation of Rap Ras and RacGTPases to sustain perisynaptic actin filaments during neuromuscular development. To identify the molecularmechanisms that govern the putative GTPase signaling cascade we will use genetics and cell biology to identifythe guanine nucleotide exchange factors and GTPase activating proteins that modulate each GTPase in thepathway. We will use fluorescent biosensors and genetic engineering to elucidate the molecular mechanismsthrough which Rap Ras and Rac signaling pathways interact with one another. The proposed research isinnovative because it uses the powerful model system of Caenorhabditis elegans to study how GTPase networksfunction as molecular switches to control synapse development and motor circuit function. The development anduse of new molecular tools to observe and modulate signal transduction in vivo will provide additional innovationsfor cellular and molecular neuroscience. The studies proposed in this application are significant because theywill reveal how small G protein signaling networks promote synapse development and how modulation of theseGTPase signaling modules can mitigate neuronal circuit dysfunctions.

project_terms:
Actins;Affect;Alzheimer's Disease;Animals;Binding;Biochemistry;Biological Assay;Biological Models;Biophysics;Biosensor;Brain;Caenorhabditis elegans;Cellular biology;Complex;Data;Development;Dominant-Negative Mutation;Electron Microscopy;Electrons;Ensure;Epilepsy;F-Actin;Fluorescence Microscopy;Foundations;Functional disorder;Future;GTPase-Activating Proteins;Genetic;Genetic Engineering;Goals;Guanine Nucleotide Exchange Factors;Guanosine Triphosphate Phosphohydrolases;Impairment;In Vitro;Intellectual functioning disability;Knowledge;Light;Maintenance;Measures;Microfilaments;Microscopic;Mission;Modeling;Molecular;Molecular Target;Monomeric GTP-Binding Proteins;Motor;Motor Neurons;Mutation;Nervous System;Nervous System Physiology;Neurodegenerative Disorders;Neurodevelopmental Disorder;Neuromuscular Junction;Neurons;Neurophysiology - biologic function;Neurosciences;Organism;Pathway interactions;Pervasive Development Disorder;Polymers;Presynaptic Terminals;Process;Proteins;Public Health;Regulation;Research;Schizophrenia;Series;Signal Pathway;Signal Transduction;Signaling Protein;Synapses;Synaptic Vesicles;United States National Institutes of Health;autism spectrum disorder;cholinergic;cholinergic neuron;cholinergic synapse;disability;improved;in vitro Assay;in vivo;innovation;insight;light microscopy;motor neuron development;mutant;nervous system development;nervous system disorder;neural circuit;neuromuscular;neuronal circuitry;new therapeutic target;novel therapeutics;polymerization;presynaptic;prevent;protein degradation;protein protein interaction;ras GTPase-Activating Proteins;restoration;synaptic function;therapeutic development;tool

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because it focuses on identifying new therapeutic targets forneurological disorders such as epilepsy autism spectrum or other pervasive developmental disorders.Determining how small G protein networks coordinate nervous system development and function will providesignificant advances in the understanding of brain function and nervous system disorders at a fundamental level.Therefore the proposed research is relevant to NIHs mission to seek fundamental knowledge about livingsystems and to reduce illness and disability.


application_id: 10734939
project_number: 1U24NS133945-01
project_title: Federated digital pathology platform for AD/ADRD research and diagnostics
administering_ic: NINDS
award_notice_date: 2023-09-21
opportunity_number: RFA-NS-22-062
application_type: 1
activity_code: U24
ic: NS
serial_number: 133945
program_official: UMOH, NSINI ALEASE
project_start_date: 2023-09-20
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZNS1 SRB-O (23)]
contact_pi_person_id: 1911366
contact_pi: NELSON, PETER T.
other_pis: BUMGARDNER, CODY ;FLANAGAN, MARGARET E
congressional_district: 06
department: PATHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract We will connect multiple Alzheimers disease and related dementias (AD/ADRD) research centers for optimized and standardized whole slide image (WSI) advanced analytics. We propose these Specific Aims:  Specific Aim 1: Generate a federated platform for data sharing and analysis of human digital neuropathological (DNP) slides. Specific Aim 1a: Develop an open-source platform to aggregate data distributed across multiple repositories into a central registry portal. This subaim will follow federated data curation harmonization annotation and standardization employing FAIR (findable accessible interoperable and reusable) principles. Specific Aim 1b: Develop a federated data curation and management system. This subaim provides methods to curate physical data such as digital images across federated sites. WSI data and metadata will be shared with private repositories and high-performance clusters.  Specific Aim 2: Develop and demonstrate a platform for federated machine learning/artificial intelligence (ML/AI) result evaluation and central project information constituting a management hub for AD/ADRD studies. Specific Aim 2a: Develop a federated data annotation and automated AI/ML processing system. This subaim provides methods for users to prepare AI-ready multimodal (WSIs metadata demographics etc.) datasets from distributed sources and conduct multi-site data transfer and federated training. Services and tools developed in Aim 1 will be used to programmatically generate and populate user-defined AI/ML pipelines. Specific Aim 2b: Develop an open-source platform for the generation and review of datasets and associated models. This subaim will provide a project evaluation portal integrating cohort dataset and model training results in a unified interface. A public-facing model hub will provide project data specifications and model data to support data sharing and analysis requirements. To optimize and demonstrate the strengths of the novel federated network five integrated projects are proposed. These will span a diverse sampling of human populations and diseases to leverage the unique strengths of DNP.  The following sites will contribute resources expertise experimental study design data and analyses: University of Kentucky (PIs Nelson and Bumgardner Co-Is Cheung and Fardo). Generate standardized SOPs useful for DNP diagnoses and research along with ML/AI expertise for a federated network. Northwestern/Nun Study and UTSA Universities (PI Flanagan). A focus on TDP-43 proteinopathy in community-based cohorts and ethno-racially diverse populations. Universityof So Paulo and UCSF (Co-I Suemoto and OSC Grinberg). Evaluate ADNC from the brains of individuals with African and non-African ancestries. University of Toronto (Co-I Kovacs): Use ML to study white matter tau pathologic changes for novel insights into multiple tauopathies. University of Washington (Co-I Keene): Study tau pathologies across ages and environmental exposures with a focus on traumatic brain injuries.

project_terms:
African;African ancestry;Age;Alzheimer's disease related dementia;Area;Artificial Intelligence;Autopsy;Benchmarking;Brain;Classification;Clinical;Collection;Communities;Computer software;Correlation Studies;Data;Data Aggregation;Data Analyses;Data Element;Data Management Resources;Data Set;Diagnosis;Diagnostic;Disease;Environmental Exposure;Evaluation;FAIR principles;Generations;Hand;Human;Image;Image Analysis;Individual;Institution;Kentucky;Machine Learning;Metadata;Methods;Modeling;Pathologic;Pathology;Performance;Population;Population Heterogeneity;Privatization;Procedures;Process;Recording of previous events;Registries;Reproducibility;Research;Research Design;Research Personnel;Resources;Sampling;Scanning;Secure;Services;Site;Slide;Source;Specific qualifier value;Standardization;System;Tauopathies;Training;Traumatic Brain Injury;Universities;Washington;Work;Workload;advanced analytics;annotation  system;cohort;data curation;data exchange;data harmonization;data modeling;data sharing;demographics;digital;digital imaging;digital pathology;distributed data;experimental study;federated data;imaging Segmentation;insight;machine learning pipeline;multimodal data;multimodality;neuropathology;novel;open source;protein TDP-43;racial diversity;repository;tau Proteins;tau mutation;tool;white matter;whole slide imaging

public_health_relevance:
Project NarrativeTo optimize and standardize procedures for digital neuropathology studies in Alzheimers disease and related dementia (AD/ADRD) we will connect multiple research centers for integrated whole slide image (WSI) advanced analytics. Using thousands of WSIs from diverse subjects and methods cross-validated with benchmark standards we will develop a novel platform that can be meaningfully expanded for research diagnostic and didactic applications. A key strength of this proposal is clinical-pathological correlation studies from content experts to be used as models for leveraging WSI analyses in AD/ADRD research.


application_id: 10734172
project_number: 1R24OD035430-01
project_title: Acquisition of Shared Thermoneutral Rodent Housing Resources
administering_ic: OD
award_notice_date: 2023-07-06
opportunity_number: PAR-22-190
application_type: 1
activity_code: R24
ic: OD
serial_number: 035430
program_official: LI, XIANG-NING
project_start_date: 2023-07-15
project_end_date: 2024-07-14
study_section: Special Emphasis Panel[ZRG1 KUDS-Y (90)]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMARY/ABSTRACTThe need to house and maintain laboratory rodents under conditions of thermoneutrality i.e. at the ambienttemperature at which energy expenditure is limited to that required to maintain basal metabolic rate isincreasingly recognized as critical to achieving rigorous research outcomes. Evidence of temperature effectson a vast array of physiological functions and pathologies spanning energy expenditure immune function andresponse blood pressure heart rate sleep food intake tumor growth and resistance and more have raisedawareness of the need to factor thermoneutrality into research designs to enhance the validity of researchfindings and their translation to understand and enhance human health. To accommodate recent and ongoingcampus expansion of research capabilities for conducting biomedical studies in mice under thermoneutralitythe University of Kentucky (UK) proposes to establish a Thermoneutrality Suite in its newest vivarium in therecently constructed Healthy Kentucky Research Building (HKRB). The 3000 sq. ft. HKRB vivarium supports a265000 sq. ft. six-floor state-of-the-art biomedical research facility that opened in 2018 and is contiguous toanimal facilities in two adjacent modern research buildings. The long-term goal of this equipment application isto enhance and modernize animal research support operations managed by the UK Division of LaboratoryAnimal Resources (DLAR) by equipping a three-room Thermoneutrality Suite (970 sq. ft. of space) withdedicated advanced thermoneutrality caging. The proposed suite to be operated by DLAR and overseen bythe Associate Vice President for Research Core Facilities will achieve the specific aim to permit both thebreeding and housing of mouse colonies at thermoneutrality by acquiring six mobile Solace Zone IVC cagingsystems to be installed in a 385 sq. ft. space adjoining two rooms equipped for experimentation underthermoneutral study conditions. This request to the NIH will complement acquisition of separately acquiredthermoneutral experimental equipment to be consolidated in two adjacent rooms but not part of this fundingrequest. The completed suite will elevate DLARs research-supporting operations for NIH-funded investigatorswho studies require access to three Power Scientific Inc. model RIS70SD rodent experimental chambers tosupport behavioral studies and four Actimetrics Clocklab Chambers suitable for performing circadian studiesone of which is already in place. The HKRB vivarium is a modern high-end facility. This facilities upgrade willenable new research efficiencies and provide enhanced rigor to researchers whose study objectives requirecarefully calibrated environmental conditions through an integrated research support operation. Addressing thisneed for cutting-edge mobile animal housing units will impact diverse NIH-funded studies spanning cardiacarrythmias vascular dementia and neurodegeneration skeletal muscle hypertrophy metabolic disease fetalprogramming and more to produce more rigorous study outcomes. These areas represent some of UKs mostprominent areas of research activity conducted by a highly productive and collaborative faculty.

project_terms:
Address;Affect;Animal Experimentation;Animal Housing;Animals;Area;Awareness;Basal metabolic rate;Behavioral;Biomedical Research;Blood Pressure;Breeding;Calibration;Cardiac;Chronic;Complement;Core Facility;Data;Dedications;Disease;Disease Outcome;Eating;Energy Metabolism;Environmental Impact;Equipment;Faculty;Floor;Funding;Goals;Health;Heart Rate;House mice;Housing;Human;Immune response;Individual;Intervention;Kentucky;Laboratories;Laboratory Animals;Laboratory mice;Literature;Maintenance;Metabolic Diseases;Modeling;Modernization;Mus;Nerve Degeneration;Outcome Study;Outcomes Research;Pathologic;Pathology;Physiological;Plants;Procedures;Process;Productivity;Publications;Research;Research Activity;Research Design;Research Personnel;Research Support;Resistance;Resources;Rodent;Services;Skeletal Muscle;Sleep;Stress;System;Temperature;Translations;United States National Institutes of Health;Universities;Vascular Dementia;animal facility;animal resource;behavioral study;circadian;cold stress;cost;design;experimental study;fetal programming;genetic manipulation;human disease;immune function;muscle hypertrophy;operation;research facility;response;square foot;tumor growth;ventilation

public_health_relevance:
PROJECT NARRATIVEA growing body of literature supports the breeding and rearing of and experimentation with mice atthermoneutral temperatures to better mimic a human-relevant response to the experimental condition. Mostlaboratory mice are housed at temperatures that are much lower than the environmental temperature at whichmice do not have to generate heat creating conditions of chronic cold stress that can change the outcomes ofdisease states. This request for six mobile individually ventilated caging systems that can house mice atthermoneutral temperatures which are much warmer than standard room temperature for humans willproduce more reliable research findings that are more relevant to human disease.


application_id: 10734121
project_number: 1R01HL166280-01A1
project_title: Mechanisms of L-type Calcium Channel Regulation in Heart Health and Disease
administering_ic: NHLBI
award_notice_date: 2023-07-31
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 166280
suffix: A1
program_official: BALIJEPALLI, RAVI C
project_start_date: 2023-07-31
project_end_date: 2027-05-31
study_section: Integrative Myocardial Physiology/Pathophysiology A Study Section [MPPA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
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:
Inotropic support for hearts progressing towards failure represents an unmet need. Direct attempts to improvesystolic function by activating -adrenergic receptor (-AR) signaling increases associated risk of heart failureand death. Calcitropes (agents influencing Ca2+ handling) that bypass -AR signaling are not necessarilyproarrhythmic. Our working global hypothesis based on our recent and ongoing work studying RAD regulationof the L-type Ca2+ channel (LTCC) is that bypassing -AR signaling to increase Ca2+-induced Ca2+ release (CICR)provides safe stable gain of function to counter heart failure progression. In this application we focus on themechanisms of Rad  LTCC interactions as a novel means to instill inotropic support to the heart. The LTCC isa macromolecular hub that integrates multiple signaling pathways including protein kinase A (PKA) and Ca2+-calmodulin kinase II (CaMKII). RAD is a member of the RGK family of monomeric G-proteins. RAD binds toauxiliary CaV2 and CaV1.2 the pore-forming subunit of the LTCC. Deletion or phosphorylation of RAD causesLTCC current (ICaL) modulation and facilitation. Modulation of ICaL is commonly observed after -AR signaling toactivate PKA; facilitation is caused by CaMKII activation. In Specific Aim 1 we will dissect how RAD integrateseach of these signaling pathways using a combination of pharmacological and genetic approaches. In SpecificAim 2 we will explore RAD  CaV1.2 structure-function using knock-in models of genetically modified mice thatallow us to explore RAD  LTCC effects retaining native stoichiometry of the LTCC heteromultimeric proteincomplex. Specific Aim 3 explores RAD  LTCC interplay as an approach to attenuate progression of heart failure.To achieve these goals we will integrate findings among Aims using in vivo ex vivo and cellular/molecularapproaches in animal models. Ex vivo human heart slices will be tested to evaluate the translational potential ofRAD  LTCC regulation in heart health and disease.

project_terms:
Acceleration;Address;Adrenergic Receptor;Agonist;Angiotensins;Animal Model;Attenuated;Binding;Biophysics;Bypass;C-terminal;Ca(2+)-Calmodulin Dependent Protein Kinase;Calcium Channel;Cardiac health;Cessation of life;Clinical Trials;Cyclic AMP-Dependent Protein Kinases;Data;Disease model;Diuretics;Down-Regulation;EFRAC;Failure;Family;Family suidae;Goals;Health;Heart;Heart Diseases;Heart failure;Human;Hydrophobicity;Inotropism;Kinetics;Knock-in;Knock-in Mouse;Knock-out;L-Type Calcium Channels;Macromolecular Complexes;Measures;Mediating;Modeling;Modification;Molecular;Monomeric GTP-Binding Proteins;Mouse Strains;Mus;Myocardial Contraction;Pathologic;Patients;Phosphatidylinositol 45-Diphosphate;Phosphorylation;Pilot Projects;Preparation;Receptor Signaling;Regulation;Risk;Risk Reduction;Safety;Sarcomeres;Signal Pathway;Signal Transduction;Slice;Structural Models;Structure;Sympathomimetics;Testing;Therapeutic;Therapeutic Uses;United States;Work;antagonist;early phase clinical trial;follow-up;gain of function;genetic approach;improved;in vivo;loss of function;member;novel;novel therapeutics;pharmacologic;phosphoric diester hydrolase;protein complex;response;sensor;stoichiometry;success;translational potential;voltage

public_health_relevance:
Heart failure is a major health problem in the United States. By definition heart failure involves the inability ofthe heart to generate sufficiently forceful contractions - defined as an insufficient inotropic response. Thisproposal tests foundational molecular interactions that regulate force of heart contractions.


application_id: 10733855
project_number: 1R01DK133076-01A1
project_title: Origins of Skeletal Fragility in Type 1 Diabetes
administering_ic: NIDDK
award_notice_date: 2023-07-24
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DK
serial_number: 133076
suffix: A1
program_official: MALOZOWSKI, SAUL N
project_start_date: 2023-07-25
project_end_date: 2027-04-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 6741266
contact_pi: FOWLKES, JOHN L
other_pis: NYMAN, JEFFRY STEPHEN
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:
Humans with type 1 diabetes mellitus (T1D) experience several disorders of skeletal health includingdecreased bone mineral density (BMD) and increased risk for fragility fractures (i.e. osteoporosis). Thesefeatures are the primary clinical characteristics of diabetic bone disease (DBD). Evidence suggests that DBDoccurs early in the progression of T1D; involves impaired bone formation; results in micro-architecturalabnormalities and poor bone matrix quality; and coincides with hyperglycemia and a decline in endogenousinsulin and insulin-like growth factor-1 production. While many have postulated that skeletal deficits in diabetesoccur as a direct result of glucose dysregulation our pre-clinical studies in mouse models supported byobservational studies in humans show that impairment in the production and action of insulin and insulin-likegrowth factor-1 (IGF-1) may be root causes of DBD. Specifically our laboratory and others have demonstratedthat in rodent models of T1D: 1) deficits in bone formation occur in the context of insulin-deficiency; 2) near-normalization of serum glucose alone is not sufficient to prevent DBD; 3) insulin and IGF-1 therapy improvefracture resistance and new bone formation; and 4) both insulin and IGF-1 utilize similar down-streampathways to promote osteoblastogenesis and bone formation. To clarify the mechanisms and signalingpathways by which insulin and/or IGF-1 modulate osteogenesis; to understand how deficiencies or impairedsignaling of each may contribute to DBD; and to delineate how each may contribute to therapeutic approachesto prevent or treat DBD we propose to 1) determine how insulin and IGF-1 deficiencies contribute to DBD atthe tissue cellular and molecular level and 2) how each hormone may perform overlapping and independenteffects through specific downstream signaling pathways that may ultimately become therapeutic targets forpreventing and/or reversing DBD.

project_terms:
Ablation;Affect;Architecture;Bone Density;Bone Matrix;Characteristics;Clinical;Critical Pathways;Development;Diabetes Mellitus;Effectiveness;Event;Evolution;Exposure to;FOXO1A gene;Fracture;Glucose;Health;Homologous Gene;Hormones;Human;Hyperglycemia;Impairment;Insulin;Insulin Signaling Pathway;Insulin deficiency;Insulin-Dependent Diabetes Mellitus;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;Intervention;Knockout Mice;Laboratories;Ligands;Maps;Molecular;Mus;Observational Study;Osteoblasts;Osteogenesis;Osteoporosis;PI3 gene;Pathway interactions;Personal Satisfaction;Persons;Predisposition;Prevention;Production;Proto-Oncogene Proteins c-akt;Resistance;Risk;Rodent Model;Serum;Signal Pathway;Signal Transduction;Therapeutic;Tissues;bone;bone health;bone strength;diabetic;diabetic bone disease;experience;fragility fracture;improved;inhibitor;mechanical properties;mouse model;osteoprogenitor cell;pharmacologic;preclinical study;prevent;receptor;response;skeletal;skeletal disorder;therapeutic target;transcriptomics

public_health_relevance:
Humans with Type 1 diabetes (T1D) are susceptible to diabetic bone disease and are more likely to suffer afragility fracture than humans without T1D. Despite this now well-recognized increased risk of osteoporosis andfracture in persons with T1D it is still not well understood how insulin or its homolog insulin-like growth factor1 (IGF-1) directly affects skeletal well-being in this condition. The studies described in this project will define therelative contributions of insulin and IGF-1 to the molecular cellular and tissue-level events involved in thedevelopment of diabetic bone disease as well as explore the therapeutic potential of insulin and IGF-1 inpreventing and treating diabetic bone disease.


application_id: 10733214
project_number: 3UL1TR001998-07S1
project_title: Kentucky Center for Clinical and Translational Science
administering_ic: NCATS
award_notice_date: 2023-07-07
opportunity_number: PA-21-071
application_type: 3
activity_code: UL1
ic: TR
serial_number: 001998
suffix: S1
program_official: DOYLE, JAMIE MIHOKO
project_start_date: 2016-08-15
project_end_date: 2026-06-30
study_section: ZTR1(99)
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
PARENT GRANT PROJECT SUMMARY - OVERALL The University of Kentucky (UK) Center for Clinical and Translational Science (CCTS) has created anintegrated home for clinical and translational research which promotes scientific progress and discoveries atevery phase of the translational continuum. The CCTS has partnered with communities in Central Appalachiato address multiple generations of recalcitrant health inequities related in part to the economic distress of ruralcommunities. The CCTS has fundamentally transformed UK and Central Appalachia through the developmentof strong academic-community research networks and collaborations within the CTSA consortium.Appalachian health disparities are further magnified by the opioid and substance abuse epidemic which hasgreatly impacted eastern Kentucky and West Virginia. The strong UK research portfolio puts the UK CCTS inan optimal position to lead local regional and national research efforts focused on rural health inequities. The aligned missions of UK UK HealthCare and the CCTS focus on achieving health equity by engaging inhighly innovative collaborative and dynamic translational research to address rural health needs. The CCTSwill continue to educate the translational workforce of the future engage rural communities in translational andbi-directional team science and work with the national network to advance transdisciplinary research andclinical trials through the following Specific Aims: 1) develop innovate and transform our research environmentto promote impactful science and discovery within our integrated health care system to meet the unique healthneeds of Central Appalachian residents; 2) lead institutional innovation in the delivery of impactful clinical andtranslational research that covers the lifespan fully engages the community and embraces team science; 3)catalyze an efficient university-wide clinical trials organization which adds value to the CTSA consortium byengaging participants from rural Central Appalachia; and 4) foster and enhance a workforce characterized bydiversity and inclusivity across all translational science disciplines and populations. The UK CTSA hub isuniquely positioned in the National CTSA Consortium to foster novel technologies team science clinical trialstart-up and cutting-edge translational research across the lifespan with a focus on rural communities. Wehave a particular focus on the Central Appalachian community a rural area with many of the highest levels ofhealth disparities in the nation. This focus will ultimately elevate the health and quality of life of ruralcommunities throughout the United States.

project_terms:
Address;Adolescence;Adult;Age;Air Pollution;Appalachian Region;Automobile Driving;Award;Back;Body mass index;Cardiovascular system;Child;Childhood;Clinic Visits;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Collection;Communication;Communities;Community Healthcare;Development;Diabetes Mellitus;Diagnosis;Discipline;Disparity;Distress;Drowsiness;Economics;Elderly;Environment;Environmental Exposure;Environmental Pollutants;Environmental Risk Factor;Epidemic;Epidemiology;Exposure to;Fostering;Frequencies;Future;Generations;Glycosylated hemoglobin A;Goals;Hair;Health;Health Disparities Research;Health Status;Healthcare;Heavy Metals;Home;Individual;Institution;Integrated Health Care Systems;Joints;Kentucky;Lead;Leg Cramp;Letters;Life Cycle Stages;Link;Literature;Longevity;Malignant Neoplasms;Measurement;Measures;Metal exposure;Metals;Mission;Modeling;Neurosciences;Obesity;Occupational;Outcome;Outcome Study;Parasomnias;Participant;Patient Self-Report;Pediatric cohort;Persons;Phase;Population;Positioning Attribute;Prevalence;Process;Quality of life;Questionnaires;Recommendation;Recording of previous events;Reporting;Research;Role;Rural;Rural Appalachia;Rural Community;Rural Health;School-Age Population;Science;Serum;Sleep;Sleep Apnea Syndromes;Sleep Deprivation;Sleep Disorders;Sleep disturbances;Smoke;Smoking;Snoring;Statistical Methods;Structure of nail of toe;Substance abuse problem;Symptoms;Syndrome;Translational Research;Underserved Population;United States;Universities;Update;West Virginia;Whole Blood;Work;cardiometabolism;clinical center;cohort;community based participatory research;community engagement;deciduous tooth;diversity and inclusion;early life exposure;environmental tobacco smoke;environmental tobacco smoke exposure;health disparity;health equity;health inequalities;improved;innovation;new technology;obesity in children;obesity risk;opioid abuse;parent grant;patient engagement;poor sleep;preadolescence;programs;rural area;rural dwellers;sleep behavior;sleep health;sleep onset;social factors;urinary;web site

public_health_relevance:
PARENT GRANT PROJECT NARRATIVE - OVERALLThe UK CTSA program hub is uniquely positioned in the National CTSA Consortium to foster noveltechnologies team science clinical trial start-up and cutting-edge translational research across the lifespan.Our UK CTSA hub has a significant presence on the national stage and our focus on the Central Appalachiancommunity a rural region with many of the highest priorities (i.e. cardiovascular neuroscience cancerobesity/diabetes) of health disparities in the nation and an epicenter for the opioid and substance abuseepidemic distinguishes our mission and activities. The programs in this proposal will ultimately elevate thehealth and quality of life for people of this region and provide a national model for rural underservedpopulations.


application_id: 10732764
project_number: 5R01ES033767-03
project_title: Phthalate-Induced Dysregulation of Prostaglandin and Angiogenic Function During Ovulation in Women
administering_ic: NIEHS
award_notice_date: 2023-10-23
opportunity_number: RFA-ES-21-001
application_type: 5
activity_code: R01
ic: ES
serial_number: 033767
program_official: SCHUG, THADDEUS
project_start_date: 2022-01-01
project_end_date: 2026-10-31
study_section: ZES1-LAT-S(R1)
contact_pi_person_id: 12252020
contact_pi: HANNON, PATRICK RYAN
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThis ONES award will elucidate the mechanisms by which phthalates a class of endocrine-disrupting chemicalsdisrupt prostaglandin and angiogenic function during the critical period of ovulation. Further rescue approacheswill be investigated to alleviate phthalate-induced inhibition of ovulation and fertility which is crucial forenvironmental and reproductive health as exposure to phthalates is unavoidable. Phthalates are incorporated inseveral common consumer medical housing and personal care products leading to daily human exposure.However little is known about the effects of environmentally relevant levels and mixtures of phthalates onovulation especially in women. This is alarming because defects in ovulation are the leading cause of femaleinfertility. The abundant increase of prostaglandins in the ovary and the surge of new vasculature formation viaangiogenesis are vital for ovulation and fertility. Preliminary data for this proposal are the first to show that anenvironmentally relevant phthalate mixture decreases the levels of prostaglandins and factors that driveangiogenesis in human and mouse ovarian samples. Further the phthalate mixture decreased ovulation ratesby 96% in mouse samples. These findings suggest that environmentally relevant phthalate exposure targetsovulatory prostaglandin and angiogenic action which may cause infertility. Our compelling preliminary data alsosuggest that supplementation with cyclic adenosine monophosphate a common cell signaling molecule tohuman ovarian cells may rescue the phthalate-induced decreases in ovulatory prostaglandin and angiogenicfactor levels. A major strength of this proposal is our ability to mimic human exposure to phthalates by the useof environmentally relevant phthalate mixtures and human ovarian models. These models as well as in vivo andin vitro mouse models will be used to test the hypothesis that phthalates inhibit ovulatory prostaglandinproduction and function leading to impaired angiogenesis and ovulatory failure/infertility. Specific Aim 1 willelucidate the mechanism by which phthalates decrease ovulatory prostaglandin levels. Specific Aim 2 willdetermine the deficiencies in angiogenesis ovulation and fertility caused by phthalates. Specific Aim 3 will defineapproaches to alleviate phthalate toxicity. These findings will advance environmental health sciences byproviding mechanistic data establishing the impact of environmentally relevant phthalate mixture exposure onprostaglandin and angiogenic function which are essential mediators for fertility. Thus these findings will revealnovel actions of phthalates on infertility and reproductive dysfunction. Additionally the use of human samplesand the establishment of rescue approaches provide a translational approach to understanding and mitigatingphthalate toxicities. Infertility in women seeking to conceive leads to a decreased quality of life includingincreased levels of stress diminished social functioning and mental and physical health issues. By delineatingthe detrimental impacts of phthalate exposure on ovulation and fertility the overarching goal of this proposal isto provide a foundation to benefit womens reproductive and general healthcare.

project_terms:
Agonist;Angiogenesis Inhibition;Angiogenic Factor;Animal Model;Award;Biological Assay;Blood capillaries;Cell Proliferation;Cell model;Cells;Chemicals;Couples;Cyclic AMP;Cyclooxygenase Inhibitors;Data;Defect;Dose;Endocrine Disruptors;Endothelial Cells;Ensure;Environment;Environmental Health;Exhibits;Exposure to;FGF2 gene;Failure;Female infertility;Fertility;Fertility Rates;Foundations;Functional disorder;Goals;Healthcare;Housing;Human;Impairment;In Vitro;Infertility;Link;Literature;Mediator;Medical;Mental Health;Metabolism;Modeling;Mus;Nature;Non-Steroidal Anti-Inflammatory Agents;Oocytes;Outcome;Ovarian;Ovarian Follicle;Ovarian Granulosa Cell;Ovary;Ovulation;Ovulation Inhibition;PTGS2 gene;Parents;Pathway interactions;Pregnant Women;Prevalence;Process;Production;Proliferating;Prostaglandin Inhibition;Prostaglandin Production;Prostaglandin-Endoperoxide Synthase;Prostaglandins;Public Health;Quality of life;Reproductive Health;Research;Rodent Model;Sampling;Signal Transduction;Signaling Molecule;Social Functioning;Societies;Stress;Supplementation;Testing;Time;Toxic effect;VEGFA gene;Woman;Women's Health;Women's prevalence;Work;angiogenesis;cost;critical period;exposed human population;granulosa cell;human model;in vivo;migration;mouse model;novel;personal care products;phthalates;physical conditioning;prevent;receptor;reproductive;translational approach;urinary

public_health_relevance:
PROJECT NARRATIVEExposure to phthalates a class of chemicals that humans are unavoidably exposed to on a daily basis isincreasingly being recognized as contributing to the prevalence of infertility in which defects in ovulation are theleading cause of infertility in women. The proposed research will address this public health concern by providinga more complete understanding of how phthalates inhibit prostaglandins and angiogenesis which are essentialfor ovulation and fertility in women. Because infertility in women seeking to conceive leads to impairments intheir physical and mental health the overarching goal of this proposal is to establish novel rescue approachesto alleviate phthalate-induced reproductive dysfunction and infertility.


application_id: 10732755
project_number: 5R01ES032396-04
project_title: A university-community partnership to reduce exposure to disinfection byproducts in Appalachia
administering_ic: NIEHS
award_notice_date: 2023-11-03
opportunity_number: RFA-ES-20-002
application_type: 5
activity_code: R01
ic: ES
serial_number: 032396
program_official: O'FALLON, LIAM
project_start_date: 2021-01-01
project_end_date: 2025-10-31
study_section: ZES1-ARL-K(R)
contact_pi_person_id: 14229942
contact_pi: UNRINE, JASON
other_pis: HOOVER, ANNA GOODMAN
congressional_district: 06
department: OTHER BASIC SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acids;Address;Appalachian Region;Businesses;Cardiovascular system;Characteristics;Chemicals;Chemistry;Chloramines;Chlorates;Chlorine;Coal;Collaborations;Communication;Communities;Congenital Abnormality;Consultations;County;Data;Disinfectants;Disinfection;Economics;Environmental Health;Exposure to;Funding;Goals;Grant;Halogens;Health;Home;Human;Infrastructure;Intervention;Kentucky;Knowledge;Laws;Location;Malignant neoplasm of urinary bladder;Methods;Modeling;National Institute of Environmental Health Sciences;Ozone;Participant;Persons;Pilot Projects;Population;Process;Public Health;Reaction;Regulation;Research;Research Personnel;Resources;Risk;Risk Reduction;Route;Rural Community;Sampling;Scientist;Source;Surface;System;Testing;Training and Infrastructure;Trihalomethanes;Trust;Ultraviolet Rays;United States;United States Environmental Protection Agency;Universities;Variant;Virginia;Water;West Virginia;citizen science;community academic partnership;community partners;drinking water;exposure route;ground water;health communication;health literacy;improved;indoor air;predictive modeling;public drinking;rural America;rural dwellers;social;water quality

public_health_relevance:
PROJECT NARRATIVEAppalachian Kentuckians in Martin and Letcher Counties are grappling with a health-threateningdrinking water crisis arising from exposures to disinfection by-products (DBPs). DBPs includecompounds that have been associated with a variety of adverse health effects includingincreased risk of bladder cancer and cardiovascular birth defects. This study which builds onfindings from two community-engaged NIEHS P30-funded pilot studies and one P30-fundedcommunity grant uses a multi-method approach stakeholder-engaged approach to reduce DBPexposures and improve public health in target counties.


application_id: 10732131
project_number: 3R34MH128213-02S1
administering_ic: NIMH
award_notice_date: 2022-11-10
opportunity_number: RFA-MH-18-706
application_type: 3
activity_code: R34
ic: MH
serial_number: 128213
suffix: S1
program_official: SWEENEY, MARY MARGARET
project_start_date: 2021-12-17
project_end_date: 2024-11-30
study_section: ZMH1-ERB-N(08)
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
project_title:
A Pilot Investigation of Network-Informed Personalized Treatment for Eating Disorders versus Enhanced Cognitive Behavioral Therapy and Dynamic Mechanisms of Change

project_abstract:
PROJECT SUMMARY/ABSTRACTEating disorders (EDs) are serious mental illness with the second highest mortality rate of anypsychiatric disorder and carry high societal personal and economic costs. Treatment responsefor EDs are suboptimal with only 50% of adults responding to evidence based treatments andno evidence-based treatment for anorexia nervosa (AN) or Other Specified Feeding or EatingDisorder (OSFED) in existence. Part of the reason EDs are so difficult to treat is the highheterogeneity in symptom presentation making it difficult to identify what to target in treatmentas two individuals even with the same diagnosis substantially vary. Personalized treatments forEDs are urgently needed that can improve treatment response and minimize the sufferingassociated with these illnesses. Our scientific premise developed from our past work is thattreatment personalized based on idiographic models (termed Network Informed PersonalizedTreatment; NA-PT) will outperform the current gold-standard treatment (Enhanced CognitiveBehavioral Therapy: CBT-E). Our study goals are to (1) develop and test the acceptabilityfeasibility and preliminary efficacy of a randomization of NA-PT versus CBT-E and (2) to test ifnetwork-identified precision targets are the mechanism of change. These goals will ultimatelylead to the very first personalized treatment for ED and can be extended to additionalpsychiatric illnesses. The proposed research uses highly innovative methods; intensivelongitudinal data collected with mobile technology is combined with state-of-the art idiographicmodeling methods to deliver a virtual personalized treatment. Specific aims are (1) To collectpreliminary data on the feasibility and acceptability of the randomization of NA-PT (n=40) forEDs versus CBT-E (n=40) (2) To test the initial clinical efficacy of NA-PT versus CBT-E onclinical outcomes (e.g. ED symptoms body mass index quality of life) and (3) To examine ifchanges in NA-identified precision targets as well as in dynamic network structure areassociated with change in clinical outcomes. The proposed research has clinical impact.Ultimately this proposal will lead directly to the creation and dissemination of an evidence-based personalized treatment for EDs as well as will serve as an exemplar for personalizedtreatment development across the entire field of psychiatry.

project_terms:
Address;Adult;Aftercare;Anorexia Nervosa;Behavior Disorders;Binge Eating;Binge eating disorder;Body mass index;Bulimia;Caring;Cellular Phone;Cessation of life;Clinical;Cognitive Therapy;Complex;Data;Development;Diagnosis;Diagnostic;Dropout;Eating Disorders;Evidence based treatment;Fright;Goals;Heterogeneity;Impairment;Individual;Intervention;Investigation;Judgment;Lead;Left;Mental disorders;Methodology;Methods;Modeling;Outcome;Participant;Pathology;Pathway Analysis;Pattern;Population;Precision therapeutics;Prediction of Response to Therapy;Psychiatry;Psychotherapy;Quality of life;Randomized;Research;Specific qualifier value;Structure;Symptoms;Testing;Time;Translating;Treatment outcome;United States National Institutes of Health;Visualization;Weight Gain;Work;acceptability and feasibility;clinical efficacy;cognitive enhancement;comorbidity;economic cost;evidence base;feeding;follow-up;improved;individualized medicine;innovation;long term recovery;mobile computing;mortality;novel;personalized medicine;prevent;public health relevance;response;severe mental illness;smartphone based assessment;societal costs;standard care;theories;therapy development;treatment optimization;treatment planning;treatment response;user friendly software;virtual

public_health_relevance:
PROJECT NARRATIVEThis project will collect data on the feasibility acceptability efficacy and target engagement of apersonalized treatment for eating disorders. The proposed research has significant public healthrelevance as it will directly lead to a highly accessible and deployable personalized treatmentthat can improve treatment response rates and decrease the high societal burden associatedwith eating disorders. The proposed research is relevant to NIHs strategic aim 3.3b as it willlead to the creation of a personalized treatment consistent with NIHs precision treatmentinitiative.


application_id: 10731943
project_number: 1R01CA272483-01A1
project_title: Targeting the Plk1/Pdcd4/mTORC2 Signaling to Treat Castration-Resistant Prostate Cancer
administering_ic: NCI
award_notice_date: 2023-06-05
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 272483
suffix: A1
program_official: GREENBERG, WILLIAM A
project_start_date: 2023-07-01
project_end_date: 2028-06-30
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: YANG, HSIN-SHENG
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:
Title: Targeting the Plk1/Pdcd4/mTORC2 signaling to treat castration-resistant prostate cancerAbstractAndrogen receptor (AR) signaling is essential for development of prostate cancer (PCa) including castration-resistant prostate cancer (CRPC). Consequently androgen signaling inhibitors (ASIs) such as abiraterone andenzalutamide are becoming the first line treatment for CRPC. However the limited success of ASIs makes iturgent to develop approaches to treat CRPC patients who are no longer responsive to ASIs. Programmed celldeath 4 (Pdcd4) is a tumor suppressor which has been demonstrated to inhibit tumor progression andchemoresistance. Furthermore Pdcd4 is an androgen-repressed protein that regulates PCa growth andcastration resistance. As such it will be of clinical significance to understand the regulation mechanism of Pdcd4as it will reveal novel approaches to overcome ASI resistance. Polo-like kinase 1 (Plk1) a critical regulator ofcell cycle-related events is a documented target for PCa treatment. Of note we previously demonstrated thatinhibition of Plk1 enhances the efficacy of ASIs. The long-term goals of this study are to identify druggablesignaling pathways that offer effective treatment options for patients with CPRC who are no longer responsiveto ASIs. The objective is to define the role of Plk1 in regulating Pdcd4 and to exploit these pathways as a noveltherapeutic target for CRPC. Our data show that 1) Pdcd4 enhances the sensitivity to enzalutamide due toinhibition of mTORC2 (the mammalian target of rapamycin complex 2) and AR expression; 2) Plk1phosphorylation of Pdcd4 results in its protein degradation; and 3) the dominant negative Pdcd4 peptide (TAT-RBD) overcomes ASI resistance in PCa. Based on these observations we aim to test the central hypothesis thatPlk1-associated phosphorylation of Pdcd4 results its degradation which causes subsequent activation of themTORC2 eventually contributing to activation of AR signaling and ASI resistance. Our hypothesis will be testedby pursuing three Specific Aims - (1) to demonstrate that loss of Pdcd4 to activate mTORC2 contributes to ASIresistance; (2) to dissect how Plk1 phosphorylation of Pdcd4 regulates its function as a tumor suppressor; and(3) to analyze clinical significance of Plk1 phosphorylation of Pdcd4. These complementary aims will beaccomplished using biochemical analyses of signaling intermediates and employing genetic strategies withculture systems inducible PCa mouse models patient-derived xenograft (PDX) and human PCa samples. Therationale for the research is that it will probe the importance of Plk1-associated activity to Pdcd4 and to examinewhether TAT-RBD peptide is a novel approach to treat ASI-resistant CRPC. This contribution is significantbecause if positive the results of the proposed study will support an immediate clinical trial for TAT-RBD peptideto treat CRPC that not respond to ASIs. The multiple-PI team consisted of complementary expertise on Plk1 (X.Liu) and Pdcd4 (Yang) as well as prostate cancer pathology (Allison) and biostatistics (Chen) will be able tofinish the proposed research in a timely manner.

project_terms:
Ablation;Agreement;Androgen Receptor;Androgens;Apoptosis;Binding;Biochemical;Biometry;Cancer Patient;Castration;Cell Cycle;Cells;Chemoresistance;Clinical Research;Clinical Trials;Complex;Creativeness;Data;Development;Disease;Dominant-Negative Mutation;Down-Regulation;Drug resistance;Event;FRAP1 gene;Fostering;Genetically Engineered Mouse;Goals;Growth;Health;Human;Investigation;Knock-out;Laboratories;Malignant Neoplasms;Malignant neoplasm of prostate;Mission;Operative Surgical Procedures;Outcome;PLK1 gene;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Peptides;Pharmaceutical Preparations;Phosphorylation;Play;Prostate Cancer therapy;Proteins;Public Health;Receptor Signaling;Regulation;Reporting;Repression;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Tertiary Protein Structure;Testing;Therapeutic;Tumor Suppression;Tumor Suppressor Proteins;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;castration resistant prostate cancer;clinically significant;design;docetaxel;effective therapy;enzalutamide;genetic approach;improved;in vivo;inhibitor;innovation;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;programmed cell death protein 1;prostate cancer cell;prostate cancer progression;protein degradation;receptor expression;success;tumor growth;tumor initiation;tumor progression


application_id: 10731597
project_number: 1R01MH131633-01A1
administering_ic: NIMH
award_notice_date: 2023-08-31
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: MH
serial_number: 131633
suffix: A1
program_official: CHAVEZ, MARK RAY
project_start_date: 2023-09-01
project_end_date: 2028-06-30
study_section: Adult Psychopathology and Disorders of Aging Study Section[APDA]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: SMITH, APRIL ROSE
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
project_abstract:
PROJECT SUMMARY/ABSTRACTAnorexia nervosa (AN) is a severe mental illness with the highest mortality rate of any psychiatric disorder withsuicide as the second leading cause of death. Despite extremely high rates of suicide risk factors for suicidalideation (SI) and behaviors/attempts (SA) in this high-risk population are not well understood. While there isevidence that threat reactivity stress-response over-arousal emotion dysregulation and agitation contributeto suicide risk the dynamic relations among these processes have not been characterized on acomprehensive momentary basis. Our scientific premise developed from our past work is that the applicationof ideation-to-action and network theories will enable the identification of dynamic longitudinal interactionsamong core dimensions (e.g. arousal threat) AN symptoms and SI/SA both between and within individuals.Our study goals are to (1) identify symptom and dimension risk interactions of co-occurring AN and SI/SAbetween and within persons (2) differentiate which risk factors predict SI vs SA and (3) test if these risk factorspredict onset of SI/SA. These goals will ultimately identify which factors should be targeted in novel preventionand treatment efforts. We will use a multiple units of analysis approach combined with novel cutting-edgeadvances in suicide and network science. We will collect intensive real-time data on AN and suicide behaviorsanxiety over-arousal emotion regulation and agitation using mobile technology as well aspsychophysiological assessment of emotion regulation (via heart-rate variability) and arousal (viaelectrodermal activity characterizing over-arousal and acceleration characterizing the sleep-wake cycle) from230 individuals with a diagnosis of AN/Atypical AN (AAN). At 1-month 6-month and one year follow-up we willtest if individual risk factors predict SI/SA. We expect 35-58 participants will have SA across our study period.Specific aims are to (1) test which symptoms and dimensions across time and between-persons maintaincomorbid SI/SA and AN symptoms (2) develop personalized network models to identify which suicide and ANfeatures predict SI/SA within individuals and an exploratory aim (3) to test if there are differences between ANand AAN. The proposed research uses highly innovative methods combining intensive longitudinal datacollection methods measurement of physiological data via wearable sensor technology and novel advances innetwork science to answer previously unresolvable questions pinpointing which individual risk factorscontribute to suicide outcomes. The proposed research has clinical impact. If we identify patterns thatcontribute to suicide risk these data will provide a model of personalized medicine for the entire field ofpsychiatry as well as providing novel intervention targets to prevent and treat AN spectrum illnesses.Additionally the algorithms we develop can be used in both (a) clinician friendly software to identify treatmenttargets to prevent SI/SA and (b) in wearable alert devices that can disrupt SA before it occurs.

project_terms:
Acceleration;Accelerometer;Adult;Affect;Agitation;Algorithms;Anorexia Nervosa;Anxiety;Arousal;Behavioral;Cause of Death;Clinical;Computer software;Data;Data Collection;Devices;Diagnosis;Diagnostic;Dimensions;Distal;Eating Disorders;Ecological momentary assessment;Feeling suicidal;Female;Friends;General Population;Goals;Hour;Individual;Intervention;Interview;Life;Link;Measurement;Mediator;Mental Health;Mental disorders;Methodology;Methods;Modeling;Movement;Negative Valence;Outcome;Participant;Pathology;Pathway Analysis;Pathway interactions;Pattern;Persons;Physiological;Physiology;Population;Precision Medicine Initiative;Precision therapeutics;Predictive Factor;Prevention;Prevention program;Process;Psychiatry;Psychophysiology;Reporting;Research;Resistance;Risk;Risk Factors;Science;Shapes;Skin;Sleep Wake Cycle;Sleep disturbances;Suicide;Suicide attempt;Suicide prevention;Symptoms;Testing;Thinking;Time;United States National Institutes of Health;Variant;Weight;Work;biological adaptation to stress;comorbidity;dynamic system;emotion dysregulation;emotion regulation;follow-up;handheld mobile device;heart rate variability;high risk;high risk population;ideation;improved;indexing;individualized prevention;innovation;mobile computing;mobile sensing;mortality;network models;novel;personalized medicine;prediction algorithm;prevent;psychologic;public health relevance;restrictive eating;severe mental illness;suicidal;suicidal behavior;suicidal morbidity;suicidal risk;suicide rate;theories;user-friendly;wearable device;wearable sensor technology

public_health_relevance:
PROJECT NARRATIVEThis project will identify dynamic risk factors for suicidal ideation and behaviors withinindividuals with anorexia nervosa. The proposed research has significant public healthrelevance as it will lead to personalized novel preventative efforts that disrupt suicidalbehaviors before they occur in an extremely high-risk population. The proposed research isrelevant to NIHs precision medicine initiative as it will identify within-person risk factors acrossmultiple levels of analysis leading to user-friendly personalized prevention programs andtreatments which incorporate dynamic interactions among core dimensions symptoms andphysiology of individuals.


application_id: 10731405
project_number: 1R21AI178652-01
administering_ic: NIAID
award_notice_date: 2023-05-19
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 178652
program_official: GU, XIN-XING
project_start_date: 2023-05-19
project_end_date: 2025-04-30
study_section: Prokaryotic Cell and Molecular Biology Study Section[PCMB]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-19
project_title:
Genetic screen to define the regulation of beta-hemolysin toxin expression in Streptococcus agalactiae

project_abstract:
Group B Streptococcus (GBS) is a normal constituent of the intestinal and vaginal florain 1530% of healthy adults. The bacterium can however cause infections in elderly andimmunocompromised patients and pregnant women and is the main cause of fatal invasivedisease in newborns. GBS translocation through epithelial endothelial and placental barriers isfacilitated by a pore-forming toxin -hemolysin also known as the -hemolytic pigmented lipidor granadaene. To identify factors involved in the regulation of -hemolysin expression wedeveloped new peptide-free culture media for screening of a transposon mutant library of GBSCJB111. The pilot screens identified nine novel genetic loci associated with positive andnegative modulation of -hemolysin expression. Based on preliminary findings we hypothesizethat GBS possesses a regulatory mechanism that tailors -hemolysin expression to theenvironment. To unravel the mechanism we will employ transposon mutant library screeningRNA-seq and metabolomics analyses isolation and de novo sequence determination ofsecreted peptide-based repressors. The results of this exploratory work have the potential tolead to the development of a novel inhibitor of the invasion state of GBS.

project_terms:
Abbreviations;Adult;Agar;Antibiotic Prophylaxis;Antibiotic Resistance;Bacteria;Binding;Blood;Blood - brain barrier anatomy;Blood Circulation;Cell Separation;Central Nervous System;Chemicals;Colon;Culture Media;Cytolysins;Detection;Development;Disease;Endothelium;Environment;Epithelium;Family;Folic Acid;Gene Expression;Genes;Genetic Screening;Genetic Transcription;Goals;Gram-Positive Bacteria;Hemolysin;Human;Immune;Immune Evasion;Immunocompromised Host;Induction of Apoptosis;Infection;Invaded;Libraries;Lipids;Meningitis;Mothers;Neonatal meningitis;Newborn Infant;Niacinamide;Nutrient;Oligopeptides;Pathway interactions;Peptide Sequence Determination;Peptides;Phagocytes;Phagocytosis Induction;Pigments;Pregnant Women;Preventive measure;Production;Proteins;Regulation;Repression;Research;Sepsis;Sequence Determination;Serum;Signal Transduction;Small Intestines;Starch;Streptococcal Infections;Streptococcus Group B;System;Testing;Therapeutic;Toxin;Vaccines;Virulence;Virulence Factors;Water;Work;blood-brain barrier disruption;clinically relevant;gastrointestinal;genomic locus;gut microbiota;in vivo;inhibitor;inorganic phosphate;intestinal epithelium;metabolomics;microbiome;microbiota;microorganism;mutant;neonatal sepsis;novel;novel therapeutics;older patient;pathogen;placental membrane;prevent;quorum sensing;screening;small molecule;transcriptome sequencing;transmission process;treatment group;vaginal microbiota

public_health_relevance:
Streptococcus agalactiae is the leading cause of neonatal sepsis and meningitis and animportant pathogen in pregnant women and elderly patients. The proposed research has apotential to lead to the development of a novel drug selectively repressing the invasion state ofStreptococcus agalactiae.


application_id: 10730699
project_number: 2R15ES030541-02A1
project_title: Genetic Susceptibility to Developmental Benzo[a]pyrene Neurotoxicity
administering_ic: NIEHS
award_notice_date: 2023-08-15
opportunity_number: PAR-21-155
application_type: 2
activity_code: R15
ic: ES
serial_number: 030541
suffix: A1
program_official: HOLLANDER, JONATHAN
project_start_date: 2019-05-16
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1 KUDS-A (04)]
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
Project Summary. This is a renewal application of an initial award to explore genetic susceptibility tobenzo[a]pyrene (BaP)-induced developmental neurotoxicity. BaP is a model polycyclic aromatic hydrocarbonfound in traffic-related air pollution (TRAP) wildfire and cigarette smoke and grilled foods. Human studies havelinked prenatal and early life exposure to PAHs with adverse effects on cognition and behavior persisting fromearly childhood to adolescence. Extensive animal studies have strongly implicated aryl hydrocarbon receptor(AHR) agonists including PAHs in developmental neurotoxicity. Our initial studies used mice with geneticdifferences in the AHR and two metabolic enzymes regulated by the AHR: CYP1A1 and CYP1A2. All threegenes of interest vary in the human population and have been linked to adverse effects following exposure toTRAP. Data from our initial studies strongly supported our hypothesis that the AHR pathway plays a key role inmediating BaP developmental neurotoxicity. Both Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice had greaterimpairments in tests of learning and memory compared with wild type mice exposed to the same dose of BaPduring gestation and lactation. Interestingly we also found differences in behavior based on genotype alone inthe knockout lines. This novel finding suggests both genes have a normal role in brain development or function.Both humans and mice have three members of the CYP1 family so our future work will probe the significanceof CYP1B1 and further explore mechanisms of neurotoxicity in the Cyp1a1 and Cyp1a2 knockouts. Aim 1:Determine the role of CYP1B1 in BaP neurotoxicity by comparing Cyp1b1(+/+) wild type and Cyp1b1(-/-)knockout mice using validated tests of learning & memory behavior and motor function quantification ofneurotransmitters and gene expression in brain regions governing those functions. Our initial studies uncoveredincreased susceptibility to developmental BaP exposure in mice lacking CYP1A1 and CYP1A2. These studieswill allow us to complete the characterization of the entire CYP1 family in our mouse model. Aim 2: Identifychanges in the gut microbiome and downstream metabolites associated with neuroprotection vneuroinflammation. During our initial studies we were able to do an exploratory analysis of the gut microbiomein BaP-treated and control Cyp1a1(+/+) wild type and Cyp1a1(-/-) knockout dams and pups. We found significantdifferences in beta diversity in BaP-exposed knockouts. Using a targeted metabolomics approach we also foundstriking differences in the tryptophan-kynurenine pathway in BaP treated Cyp1a2(-/-) knockout mice. These dataand recent studies identifying links between AHR activation and dysregulation of the TRP-KYN pathway suggesta potential mechanism of neurotoxicity. As an AREA-R15 application this will strengthen the researchenvironment at Northern Kentucky University a predominantly undergraduate institution in the Greater Cincinnatiarea serving a large percentage of diverse and disadvantaged students and support an Early Stage Investigatorwho can train these students in the use of bioinformatics techniques.

project_terms:
Acids;Adolescence;Adverse effects;Agonist;Animals;Area;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Award;Bacteria;Behavior;Benzo(a)pyrene;Bioinformatics;Brain;Brain region;CYP1A1 gene;CYP1A2 gene;CYP1B1 gene;Chemicals;Cigarette;Circulation;Cognition;Data;Development;Dose;Environment;Enzymes;Excretory function;Exposure to;Family;Food;Funding;Future;Gene Expression;Gene Expression Profiling;Genes;Genetic;Genetic Predisposition to Disease;Genotype;Goals;Hippocampus;Human;Human Activities;Impairment;Individual;Indoles;Institution;Kentucky;Knock-out;Knockout Mice;Kynurenine;Lactation;Learning;Life;Link;Mediating;Memory;Metabolic;Metabolism;Modeling;Motor;Mus;Neurotransmitters;Pathway interactions;Play;Population;Predisposition;Pregnancy;Problem behavior;Receptor Activation;Research;Research Personnel;Resistance;Risk;Risk Reduction;Role;Serotonin;Shotgun Sequencing;Signal Transduction;Smoke;Techniques;Testing;Tissues;Tryptophan;Universities;Wild Type Mouse;Wildfire;Work;adult neurogenesis;aryl hydrocarbon receptor ligand;behavior test;beta diversity;cigarette smoke;developmental neurotoxicity;disadvantaged student;early childhood;early life exposure;gut microbes;gut microbiome;gut-brain axis;high risk;interest;member;metabolomics;mouse model;nervous system disorder;neuroinflammation;neuroprotection;neurotoxic;neurotoxicity;novel;prenatal;pup;student training;traffic-related air pollution;undergraduate student

public_health_relevance:
Project Narrative. Traffic-related air pollution wildfire smoke cigarettes and grilled food allcontain a significant concentration of polycyclic aromatic hydrocarbons (PAHs). Exposure toPAHs during early brain development is associated with lower IQ and behavioral problems andthese chemicals are also associated with changes in the gut microbiome that can impair normalbrain development and function. We will use mice with genetic differences to identify individualsat highest risk prenatal following early life PAH exposure with an over-arching goal of protectingthe most vulnerable human populations.


application_id: 10730480
project_number: 2R15MH113045-02
project_title: Cognitive and Contextual Factors in Suicide Ideation Persistence in Adolescents
administering_ic: NIMH
award_notice_date: 2023-07-21
opportunity_number: PAR-21-155
application_type: 2
activity_code: R15
ic: MH
serial_number: 113045
program_official: MURPHY, ERIC ROUSSEAU
project_start_date: 2018-08-01
project_end_date: 2026-07-31
study_section: Special Emphasis Panel[ZRG1 BP-P (02)]
contact_pi_person_id: 12499648
contact_pi: BRAUSCH, AMY MARIE
other_pis: Not Applicable
congressional_district: 02
department: PSYCHOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Cognitive and Contextual Factors in Suicide Ideation Persistence in Adolescents. Deaths from suicide continueto be a major public health concern particularly among youth for whom suicide ranks as the second leadingcause of death. Recent suicide ideation is reported by almost 20% of high school students and the majority ofthose report persistent ideation of more than one year. If the factors that associate with persistent and remittingsuicide ideation can be identified then resources can be directed to those most at risk with a likely impact onrates of suicide. Depression hopelessness and psychiatric diagnoses have been studied as risk factors forover 50 years yet they are neither sufficient nor effective for understanding suicide risk. It is important toevaluate cognitive and contextual factors for suicide ideation which are understudied particularly for ruralyouth. Cognitive factors that may relate to suicide ideation are defeat entrapment grit and self-efficacy.Contextual factors with potential to make an impact on suicide ideation are socio-economic status access tolethal means social support food and housing security and access to health care. The proposed study aimsto fill these knowledge gaps through a 12-month longitudinal study of 225 non-clinical rural adolescentsbetween the ages of 14 and 18 who report a history of suicide ideation. The current study proposes thatcognitive and contextual factors will differentiate adolescents with and without suicide ideation history in thebaseline sample. It is further expected that the cognitive factors defeat and entrapment will associate withpersisting suicide ideation and self-efficacy and grit will associate with remitting suicide ideation at follow-ups.Lastly it is expected that contextual factors will associate with persisting (low SES and access to lethal means)vs. remitting (social support food and housing security access to health care) suicide ideation at follow-ups.Adolescents in 9th-11th grades will be recruited to complete a research protocol of self-report and behavioralmeasures at their home schools at baseline (n=700); adolescents with suicide ideation history (est. n=225) willbe recruited into follow-up assessments at 6- and 12-months post baseline. Teacher reports for the 225adolescents with suicide ideation history will also be collected. Binominal linear regression will be used toexamine which factors differentiate adolescents with and without suicide ideation history at baseline. To testhypotheses about cognitive and contextual factors associating with suicide ideation persistence andremittance change groups will be scored (persistent and remitting ideation across time points). Repeatedmeasures ANOVA will be conducted to test group by time interactions to determine if adolescents withpersistent ideation show differential change in cognitive and contextual factors compared to adolescents withremitting ideation. The findings will inform youth suicide research which will significantly impact upstreamprevention and early intervention by identifying new factors that increase protect and moderate risk.

project_terms:
Address;Adolescent;Age;Analysis of Variance;Anxiety;Award;Awareness;Behavioral;Cause of Death;Cessation of life;Cognitive;Common Data Element;Data;Data Collection;Development;Disease remission;Early Intervention;Feeling hopeless;Feeling suicidal;Food;Funding;Future;Goals;High School Student;Home;Housing;Knowledge;Learning;Linear Regressions;Longitudinal Studies;Measures;Mental Depression;National Institute of Mental Health;Patient Self-Report;PhenX Toolkit;Prevention program;Prospective Studies;Protocols documentation;Psychiatric Diagnosis;Public Health;Publications;Recording of previous events;Remittance;Reporting;Research;Research Priority;Resources;Risk;Risk Factors;Risk Reduction;Rural;Rural Community;Sampling;Schools;Security;Self Efficacy;Self-Injurious Behavior;Social support;Socioeconomic Status;Suicide;Suicide attempt;Suicide prevention;Symptoms;Testing;Thinking;Time;Youth;behavior measurement;contextual factors;design;eleventh grade;emotion regulation;experience;follow up assessment;health care availability;ideation;innovation;intervention program;low socioeconomic status;morphogens;prevent;preventive intervention;promote resilience;prospective;recruit;showing emotion;sleep quality;substance use;suicidal behavior;suicidal morbidity;suicidal risk;suicide rate;symposium;teacher;undergraduate student

public_health_relevance:
Adolescents with persistent suicidal thoughts are at greater risk for future suicide attempts.Identifying factors that relate to diminishing these thoughts will aid in the development ofprevention and early intervention programs for youth.


application_id: 10730229
project_number: 2R15DA047610-02A1
project_title: Contribution of BLA-mPFC pathway to risky choice and compulsive cocaine seeking
administering_ic: NIDA
award_notice_date: 2023-05-17
opportunity_number: PAR-21-155
application_type: 2
activity_code: R15
ic: DA
serial_number: 047610
suffix: A1
program_official: MOORE, HOLLY MARIE
project_start_date: 2019-06-01
project_end_date: 2026-06-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 11434612
contact_pi: YATES, JUSTIN RYAN
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractThis is a resubmission of a renewal application for an AREA R15 grant to continue research funded inDA047610 (Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine now titledContribution of BLA-mPFC pathway to risky choice and compulsive cocaine seeking). The purpose of theR15 grant is to stimulate research at primarily educational institutions like Northern Kentucky University (NKU)that support baccalaureate training but are not recipients of major NIH support. Risky choice is characteristic ofseveral psychiatric conditions including substance use disorders (SUDs). Substance misuse can beconsidered a risky behavior as individuals can become incarcerated for their drug use or can ultimately diefrom overdose. Understanding the neurobiology of risky choice is important for designing effective treatmentinterventions for individuals that are at risk for developing SUDs. During our current funding period we haveshown that the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor mediates risky choiceas assessed in the risky decision task (RDT) and it mediates addiction-like behaviors as measured in cocaineself-administration and in methamphetamine conditioned place preference. Because the RDT uses foot shockas punishment determining if a rat displays increased risky choice or insensitivity to shock is difficult. Thus thefirst goal of the current proposal is to use a novel task to measure risky choice. To this end rats will be testedin an equivalent expected value (EEV) task in which reinforcer magnitude and reinforcement probability will beadjusted across concurrently available reinforcers such that the expected utility (value) of each alternative isequivalent. Because the expected value is equivalent across reinforcer alternatives there is no suboptimalchoice. However risky choice can be measured by the percentage of responses for the lower probability/largerreward alternative. To further elucidate the neurocircuitry of risky choice we will determine if chemogeneticinhibition of medial prefrontal cortex (mPFC)-projecting basolateral amygdala (BLA) neurons and/or BLA-projecting mPFC neurons decreases risky choice in the EEV task (Specific Aim 1). Specific Aims 2 and 3 willutilize the same chemogenetic approach from Specific Aim 1 to determine if the reciprocal connectionsbetween the BLA and the mPFC mediate compulsive cocaine seeking and resurgence of cocaine seeking(model of relapse-like behavior). Renewed funding will allow us to answer these critical questions and will allowundergraduate students to continue gaining research experience in behavioral neuroscience research at NKU.

project_terms:
3-Dimensional;Address;Amygdaloid structure;Animal Model;Behavior;Behavioral;Catheters;Characteristics;Cocaine;Decision Making;Disease;Dose;Drug usage;Economics;Education;Extinction;Female;Food;Funding;Genetic;Glutamates;Goals;Grant;Implant;Imprisonment;Individual;Infusion procedures;Injections;Institution;Intervention;Kentucky;Measures;Medial;Mediating;Methamphetamine;Modeling;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Neural Pathways;Neurobiology;Neurons;Neurosciences Research;Overdose;Pathway interactions;Pharmaceutical Preparations;Pharmacology;Prefrontal Cortex;Probability;Psychological reinforcement;Punishment;Rattus;Recovery;Relapse;Research;Rewards;Risk;Risk Behaviors;Role;Shock;Substance Use Disorder;Testing;Training;United States National Institutes of Health;Universities;Viral Vector;Withdrawal;addiction;antagonist;behavioral construct;cocaine seeking;cocaine self-administration;conditioned place preference;design;designer receptors exclusively activated by designer drugs;effective therapy;efficacious treatment;enhanced green fluorescent protein;experience;experimental study;flexibility;foot;genetic approach;male;meetings;neural circuit;neuromechanism;novel;pain sensitivity;receptor;reinforcer;response;stimulant use disorder;substance misuse;substance use;undergraduate student;vector control

public_health_relevance:
Project NarrativeCurrently there are few treatments that are efficacious in treating individuals with disorders characterized bymaladaptive risky decision making including psychostimulant use disorders. The purpose of the proposedresearch is to determine how chemogenetic inhibition of medial prefrontal cortex (mPFC)-projecting basolateralamygdala (BLA) neurons and BLA-projecting mPFC neurons alter risky decision making and cocaine-seekingbehavior. The results of the current proposal will be important because novel interventions that target specificneural circuits (e.g. BLA-mPFC pathway) can be used to better treat those that engage in risky behaviorsincluding compulsive substance use.


application_id: 10728339
project_number: 5R01AI143690-05
project_title: Biogenesis and Function of Streptococcus Pyogenes Cell Wall
administering_ic: NIAID
award_notice_date: 2023-10-26
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 143690
program_official: GU, XIN-XING
project_start_date: 2019-11-25
project_end_date: 2025-10-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Group A streptococcus (GAS Streptococcus pyogenes) is a leading bacterial pathogen of thehuman pharynx and skin. In recent years a striking resurgence in severe invasive GASinfections has been observed worldwide. GAS infections account for more than 650000 casesof severe invasive disease annually. The invasive GAS infections necrotizing fasciitis cellulitisand erysipelas with concomitant scarlet fever and streptococcal toxic syndrome are difficult totreat with antibiotics and a GAS vaccine is urgently needed to combat this neglected disease. Amajor component of the GAS cell wall is the Group A Carbohydrate (GAC) covalently linked topeptidoglycan consisting of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc)side-chains. GAC is an attractive vaccine candidate due to its conserved expression in all GASserotypes and the absence of its constitutive component rhamnose in humans. Our geneticbiochemical and structural studies identified two novel modifications of GAC glycans: glycerolphosphate modification of GAC and de-N-acetylation of the GAC linkage unit. The goal of thisproposal is to characterize the mechanisms of GAC biosynthesis and modification andelucidate the roles of cell wall modifications in antimicrobial resistance mechanisms and GASpathogenesis. To help answer these questions we will employ a variety of genetic biochemicalanalytical and structural approaches. The function of cell wall modifications in GASpathogenesis will be studied in ex vivo and in vivo models of GAS infection. The proposedstudies provide a platform for design of a safe and effective vaccine against this importanthuman pathogen and should have broad application to other streptococci which express similarcell wall polysaccharides. Since the enzymes of the GAC biosynthesis pathway are attractivedrug targets the proposed studies will have important implications for drug design.

project_terms:
Acetylation;Anabolism;Analytical Chemistry;Antibiotic Therapy;Antibiotics;Antimicrobial Cationic Peptides;Antimicrobial Resistance;Bacterial Physiology;Binding;Biochemical;Biogenesis;Biological;Biological Assay;Carbohydrates;Cations;Cell Physiology;Cell Wall;Cell membrane;Cells;Cellulitis;Charge;Chemicals;Communicable Diseases;Control Groups;Data;Deacetylase;Dental;Development;Diagnostic;Disease;Drug Design;Drug Targeting;Electrostatics;Enzymatic Biochemistry;Enzymes;Epitopes;Erysipelas;Freeze Substitution;Gene Cluster;Genetic;Glycerol;Goals;Histones;Homologous Gene;Human;Infection;Knowledge;Link;Mass Spectrum Analysis;Methods;Modeling;Modification;Molecular;Molecular Genetics;Molecular Structure;Muramidase;Necrotizing fasciitis;Outcome;Outcome Study;Outcomes Research;Pathogenesis;Pathway interactions;Peptidoglycan;Permeability;Pharyngeal structure;Phospholipase A2;Polymers;Polysaccharides;Predisposition;Proteins;Publishing;Rhamnose;Role;Scarlet Fever;Serotyping;Serum;Skin;Streptococcal Infections;Streptococcal Vaccines;Streptococcus;Streptococcus mutans;Streptococcus pyogenes;Structure;Surface;Syndrome;Techniques;Testing;Therapeutic Intervention;Thick;Vaccine Antigen;Vaccine Design;Vaccines;Vertebral column;Work;analog;anti-microbial peptide;antimicrobial;carbohydrate biosynthesis;cell envelope;combat;density;design;drug development;extracellular;human pathogen;improved;in vivo;in vivo Model;inorganic phosphate;insight;molecular size;mortality;mouse model;mutant;neglect;neutrophil;novel;pathogen;pathogenic bacteria;resistance mechanism;targeted treatment;vaccine candidate

public_health_relevance:
The proposed studies investigate structure biosynthesis pathway and function of cellwall in the important human pathogen Streptococcus pyogenes. The outcomes of this researchare expected to have a positive impact on the development of highly targeted therapeutics tocontrol S. pyogenes infections.!


application_id: 10725969
project_number: 1R03ES035480-01
project_title: Mitigating Developmental Neurotoxicity Through Maternal and Offspring Exercise
administering_ic: NIEHS
award_notice_date: 2023-09-04
opportunity_number: PA-20-200
application_type: 1
activity_code: R03
ic: ES
serial_number: 035480
program_official: HOLLANDER, JONATHAN
project_start_date: 2023-09-07
project_end_date: 2025-08-31
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 8110072
contact_pi: CURRAN, CHRISTINE PERDAN
other_pis: Not Applicable
congressional_district: 04
department: BIOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Benzo[a]pyrene (BaP) is a known carcinogen and ranked 8th on the U.S. governments PriorityPollutants List while the entire class of compounds (polycyclic aromatic hydrocarbons or PAHs) ranks 9th.Human exposures are widespread from traffic-related air pollution wildfires cigarette smoke and grilled foodsand nearly impossible to avoid. Recent human studies found strong correlations between prenatal PAHexposure and persistent cognitive and behavioral deficits in exposed children. We recently reported resultsfrom a mouse study demonstrating that genetic differences in the aryl hydrocarbon receptor (AHR) andCYP1A2 increase risk following developmental exposure to BaP. AhrbCyp1a2(-/-) mice with the high-affinityAHR and AhrdCyp1a2(-/-) mice with the poor-affinity receptor both had impaired performance in the Morriswater maze test of spatial learning and memory. High-affinity Ahr knockouts also had motor deficits in Rotarodand poor-affinity knockouts exhibited higher levels of anxiety-like behavior. The benefits of regular exercise onbrain health are well established but considerably less is known about the effects of exercise duringpregnancy on the health of the mother and brain function in her offspring. The neurological benefits of exerciseinclude increased levels of brain-derived neurotrophic factor (BDNF) and beneficial modifications ofneurosignaling by serotonin dopamine and noradrenaline. The mechanism of action for aerobic exercisebenefits on hippocampal dependent learning and memory were directly tied to BDNF signaling. Both maternaland offspring exercise have been successful in reversing spatial learning and memory deficits induced byprenatal stress. Exercise during early life has additional benefits on improving mood and reducing levels ofstress hormones whereas anxiety-like behavior is increased in mice with a knockdown of the BDNF receptorTrkB. We conducted pilot studies in C57BL/6J mice and found that both maternal and offspring voluntary wheelrunning increased circulating BDNF levels. Our proposed studies will use aerobic exercise to increaseBDNF levels in offspring exposed to BaP during early brain development with the goal of rescuing theneurological deficits observed in our previous studies. First we will compare the relative effectiveness offour different exercise treatments and ensure they do not cause harm to the dam or pups. Next we will use theexercise regimen determined to be safe and most effective in an attempt to rescue learning and memory andmotor deficits and to reduce anxiety-like behavior in our most susceptible mouse lines.The translational valueof these studies is high because we seek to identify the minimum level of exercise necessary to producebeneficial effects. This greatly increases the feasibility of compliance in the human population.

project_terms:
Adverse effects;Aerobic Exercise;Affinity;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Behavior;Behavioral;Benzo(a)pyrene;Biochemical;Brain;Brain-Derived Neurotrophic Factor;CYP1A2 gene;Carcinogens;Chemicals;Child;Cognitive;Data;Development;Dopamine;Ensure;Exercise;Exhibits;Exposure to;Food;Gene Expression;General Population;Genetic;Genetic Predisposition to Disease;Genetic study;Goals;Government;Health;Hippocampus;Hormones;Human;Impairment;Intervention;Knock-out;Lead;Learning;Life;Literature;Memory;Memory impairment;Methods;Modification;Molecular;Moods;Mothers;Motor;Mus;Neurologic;Neurologic Deficit;Neurological outcome;Neurotransmitters;Neurotrophic Tyrosine Kinase Receptor Type 2;Norepinephrine;Performance;Pilot Projects;Plasma;Population;Predisposition;Pregnancy;Regimen;Reporting;Risk;Running;Serotonin;Signal Transduction;Stress;Testing;Wildfire;anxiety reduction;anxiety-like behavior;brain health;cigarette smoke;developmental neurotoxicity;early life exposure;exercise intensity;exercise regimen;exposed human population;health of the mother;improved;knock-down;morris water maze;motor deficit;mouse model;offspring;pollutant;prenatal;prenatal stress;pup;receptor;relative effectiveness;traffic-related air pollution

public_health_relevance:
Project NarrativeAlthough we know that prenatal and early life exposure to chemicals found in traffic-related airpollution (TRAP) grilled food wildfire and cigarette smoke leads to adverse effects of learningmemory and behavior it is extremely difficult to reduce these exposures in the generalpopulation. This study will use a mouse model to develop and validate a simple intervention tomitigate the adverse effects by incorporating exercise for both the mother and her offspring. Acritical aspect of this study will be determining the duration and intensity of exercise that is bothsafe and effective.


application_id: 10725358
project_number: 1R03TR004310-01A1
administering_ic: NCATS
award_notice_date: 2023-08-30
opportunity_number: PAR-21-121
application_type: 1
activity_code: R03
ic: TR
serial_number: 004310
suffix: A1
program_official: BROWN, PATRICK
project_start_date: 2023-09-01
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZTR1 CI-1 (02)]
contact_pi_person_id: 11256608
contact_pi: ROBERTS, JILL MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: 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:
Contribution of Vitamin D Deficiency to Pathological Progression in Models of Cerebral Hypoperfusion

project_abstract:
ABSTRACT Vitamin D deficiency (VDD) is linked to a number of non-skeletal chronic conditions includingcardiovascular disease stroke autoimmune disease and dementia which are leading causes of disability anddeath worldwide. VDD increases the risk and severity of stroke likely because vitamin D regulates endothelialcell function vascular response and the innate and adaptive immune system. Numerous preclinical studieshave focused on the role of vitamin D in acute stroke but what is not known are the effects of VDD on thepathological progression of chronic cerebral hypoperfusion. Chronic cerebral hypoperfusion is a pervasivestate of long-term cerebral blood flow insufficiency that can lead to white matter damage neuroinflammationstroke and cognitive impairment. Here we propose to utilize two animal models of chronic cerebralhypoperfusion in combination with a vitamin D modified diet to delineate the role of vitamin D in pathologiesassociated with reduced cerebral blood flow. Bilateral Carotid Artery Stenosis (BCAS) is a model of vasculardementia which is associated with small vessel disease blood-brain barrier (BBB) dysfunction micro-infarctsand cognitive impairment. The Internal Carotid Artery Stenosis (ICAS) mouse model was developed as part ofmy KL2 project focused on moyamoya syndrome a cerebrovascular condition that leads to stroke andcompensatory angiogenesis at the base of the brain. The ICAS model is associated with decreased vesseldiameter increased vascular endothelial growth factor (VEGF) BBB dysfunction and inflammation. Ourcentral hypothesis is that VDD increases the pathological severity of chronic cerebral hypoperfusion throughincreased vascular dysfunction and chronic inflammation and that vitamin D supplementation will attenuatethese effects. To test these hypotheses we propose two specific aims. Aim 1 will focus on hypoxia-inducedangiogenesis and vessel wall pathology via quantification of angiogenic markers signaling pathways vascularnetwork density and assessment of the various components of the vessel wall. Aim 2 will focus on identifyinginflammatory T cell subtypes (e.g. Th17 cells) and quantification of associated cytokines and signalingpathways in the blood and brain tissue. All animals will be subjected to cognitive testing to measure the effectsof vitamin D modification on functional outcome following chronic cerebral hypoperfusion. Collectively webelieve the studies pursued in this proposal will address several critical knowledge gaps utilizing a collectiveapproach to define the role of vitamin D in the pathological progression of chronic cerebral hypoperfusion.Results from this study will be broadly applicable to patients suffering from reduced cerebral blood flow suchas atherosclerosis moyamoya syndrome and vascular dementia. Future expanded studies utilizing vitamin Dintervention represent a potentially novel therapeutic for these patients worldwide.

project_terms:
25-hydroxyvitamin D;Adaptive Immune System;Affect;Age;Alzheimer's Disease;Animal Model;Animals;Atherosclerosis;Attenuated;Autoimmune Diseases;Awareness;Bilateral;Blood;Blood - brain barrier anatomy;Blood Vessels;Blood brain barrier dysfunction;Blood flow;Cardiovascular Diseases;Carotid Stenosis;Cell physiology;Cells;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrum;Cessation of life;Chronic;Clinical;Communities;Data;Dementia;Development;Diameter;Diet;Disease;Endothelial Cells;Exposure to;External carotid artery structure;Fat-Soluble Vitamin;Female;Food;Future;Hypoxia;Impaired cognition;Incidence;Infarction;Inflammation;Inflammatory;Ingestion;Innate Immune System;Internal Carotid Artery Stenosis;Intervention;Investigation;Ischemia;Ischemic Stroke;Knowledge;Link;Maintenance;Measures;Microvascular Dysfunction;Modeling;Modification;Moyamoya Disease;Mus;Neurodegenerative Disorders;Pathologic;Pathology;Patients;Production;Public Health;Regulation;Research;Research Design;Risk;Risk Factors;Role;Serum;Severities;Signal Pathway;Signal Transduction;Skin;Stroke;Stromal Cell-Derived Factor 1;Sunlight;T-Lymphocyte;Testing;Therapeutic;Vascular Dementia;Vascular Diseases;Vascular Endothelial Growth Factors;Vasodilator Agents;Vitamin D;Vitamin D Deficiency;Vitamin D supplementation;absorption;acute stroke;angiogenesis;attenuation;brain based;brain tissue;cerebral hypoperfusion;cerebrovascular;cognitive testing;cost;cytokine;density;disability;functional improvement;functional outcomes;male;modifiable risk;mouse model;neuroinflammation;novel therapeutic intervention;novel therapeutics;preclinical study;response;steroid hormone;white matter;white matter damage

public_health_relevance:
NARRATIVE The proposed research is relevant to public health because vitamin D deficiency is a worldwide problemthat may contribute to the severity of chronic cerebral hypoperfusion which leads to blood vesselabnormalities ischemic stroke vascular dementia and other debilitating and costly complications for whichthere are few treatment options. Data that result from these studies will determine the angiogenic andinflammatory mechanisms regulated by vitamin D that contribute to cerebral pathology and cognitiveimpairment using two mouse models of cerebral hypoperfusion. This knowledge could lead to new treatmentoptions for cerebrovascular-related conditions.


application_id: 10724670
project_number: 3P20GM103436-23S1
administering_ic: NIGMS
award_notice_date: 2023-08-10
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 103436
suffix: S1
program_official: ZHOU, YANG
project_start_date: 2001-09-30
project_end_date: 2024-04-30
study_section: ZGM1(IN)
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
KY INBRE NOSI Supplement: Personalizing Disordered Eating Treatment Using Mobile Technology: Self-Guided Personalized Treatment for Women

project_abstract:
PROJECT SUMMARY/ABSTRACTThree out of four (75%) women in the United States endorse problematic disordered eatingbehaviors and cognitions such as binge eating purging restriction and/or body dissatisfaction.Disordered eating is associated with a huge host of poor physical and mental health outcomesincluding heightened risk for cardiovascular disease obesity depression anxiety death bysuicide poor quality of life and can develop into clinical threshold eating disorders which carryone of the highest mortality rates of all psychiatric illnesses. Disordered eating disproportionallyimpacts women with prevalence rates growing in the past two years. Despite the commonality ofdisordered eating there are few evidence-based treatments and prevention efforts that exist.The treatments that do exist were developed and implemented in a standardized and onaverage manner. Despite the fact that there is extremely high heterogeneity in disorderedeating both in terms of how disordered eating presents and in underlying causes there are nopersonalized treatments for disordered eating. Thus it is unsurprising that treatments only workfor about 50% of women. The overarching goal of the current supplement is to refine andimplement a personalized self-guided digital intervention for women to address disorderedeating and promote overall health and well-being. The proposed research uses highly innovativemethods; data collected directly on the users smartphone is combined with state-of-the-artidiographic modeling to deliver a digital personalized and self-guided intervention in womenseveryday life. The specific aims of the current supplement are to (1) collect preliminary data onthe feasibility acceptability and user uptake of a personalized self-guided mobile interventionfor disordered eating in women (N=50) and (2) test the initial clinical efficacy of a personalizedself-guided disordered eating digital intervention. The proposed research has clinical impact.Ultimately these data will lead directly to the creation and dissemination of an evidence-basedpersonalized self-guided treatment for disordered eating. As digital interventions overcometraditional barriers to accessing care this research will create an easy-to-access deliverable thatcan reach women who would traditionally be unable to access needed treatment. Additionallythis research will provide training and educational experiences consistent with the parentproposal for undergraduates graduate students post-doctoral fellows and will help propel theearly career investigators toward additional independent funding. This proposal has highpotential to decrease a common and impairing problem for women and provide additionaltraining and resources to advance women in science.

project_terms:
Address;Affect;Algorithms;Anorexia Nervosa;Anxiety;Behavior;Binge Eating;Caring;Cellular Phone;Chronic;Clinical;Cognition;Communities;Complex;Computer software;Data;Development;Diagnosis;Early Intervention;Eating Behavior;Eating Disorders;Evidence based treatment;Fasting;Feeling;Focus Groups;Fright;Funding;Goals;Health;Health Services Accessibility;Heterogeneity;High Prevalence;Impairment;Improve Access;Individual;Insurance;Intervention;Lead;Life;Mental Depression;Mental Health;Mental disorders;Methodology;Methods;Modeling;Monitor;Obesity;Outcome;Parents;Pathology;Patients;Personal Satisfaction;Persons;Postdoctoral Fellow;Precision therapeutics;Prediction of Response to Therapy;Prevalence;Prevention;Provider;Psyche structure;Quality of life;Recommendation;Reporting;Research;Research Personnel;Resources;Science;Standardization;Symptoms;Testing;Time;Training;Training and Education;Treatment Efficacy;Treatment outcome;United States;United States National Institutes of Health;Visualization;Weight Gain;Woman;Work;acceptability and feasibility;body dissatisfaction;cardiovascular disorder risk;career;clinical efficacy;digital;digital intervention;eating pathology;evidence base;experience;graduate student;improved;innovation;mobile application;mobile computing;mortality;network models;personalized intervention;personalized medicine;physical conditioning;programs;public health relevance;purge;reduce symptoms;response;severe mental illness;smartphone based assessment;societal costs;suicidal morbidity;theories;undergraduate student;uptake;user friendly software

public_health_relevance:
PROJECT NARRATIVEThis project will collect data on the feasibility acceptability user uptake and initial clinicalefficacy of a personalized digital and self-guided intervention for disordered eating in women.The proposed research has significant public health relevance as it will directly lead to a highlyaccessible and deployable personalized intervention that can be easily accessed and decreasethe high societal burden and physical and mental impairment associated with disorderedeating which affects 3 in 4 women. The proposed research is relevant to NIHs strategic aim3.3b as it will lead to the creation of a personalized intervention consistent with NIHs precisiontreatment initiative.


application_id: 10722648
project_number: 1R01AI178106-01
project_title: Impact of inflammatory lipids on Yersinia pestis infection
administering_ic: NIAID
award_notice_date: 2023-07-14
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AI
serial_number: 178106
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2023-07-14
project_end_date: 2027-06-30
study_section: Bacterial-Host Interactions Study Section [BHI]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Yersinia pestis causes the acute human disease commonly referred to as plague. A hallmark manifestation ofthis disease is delayed inflammation despite active bacterial replication. Y. pestis modulates inflammation byactively inhibiting the expression of pro-inflammatory cytokines via the action of a group of proteins called Yopeffectors that are directly injected into host cells by a bacterial type three secretion system (T3SS). Becauseestablishment of this non-inflammatory environment is key for Y. pestis to colonize the host understanding howY. pestis modulates the host inflammatory response during early stages of infection will provide crucial insightsinto both the pathogenesis of the bacterium and potential strategies to improve therapy. Lipid mediators suchas members of the eicosanoid family are essential to initiate the cascade of signaling events that regulatesinflammation. Therefore disruption of the synthesis of pro-inflammatory eicosanoids can effectively stifle a rapidimmune response. Despite their importance in initiating inflammation the role of lipid mediators in the context ofplague has not been previously investigated. Recently we discovered a dysregulation in eicosanoid synthesisduring pneumonic plague highlighted by the inhibition in the synthesis of the pro-inflammatory lipid leukotrieneB4 (LTB4). Furthermore using Y. pestis mutants we uncovered a novel mechanism for the recognition of theT3SS by neutrophils that triggers LTB4 synthesis which is normally inhibited by the Yop effectors. Togetherthese discoveries support a conceptually innovative hypothesis that Y. pestis actively manipulates the synthesisof lipid mediators to disrupt the proper inflammatory cascade that would normally recruit circulating leukocytesto control infection. In Aim 1 we will test this hypothesis using animal models to define the contribution ofeicosanoids to the host response during plague and determine how disruption of LTB4 synthesis benefits Y.pestis. In Aim 2 we will use Y. pestis as a tool to define the molecular mechanisms responsible for T3SS-dependent LTB4 synthesis by neutrophils. Because lipid mediators of inflammation have been overlooked in thecontext of Y. pestis immune evasion completion of these studies will significantly transform our conceptualunderstanding of the early immune events during pneumonic plague.

project_terms:
Acute;Animal Model;Bacteria;Bacterial Infections;Biology;Cells;Chemotactic Factors;Data;Disease;Eicosanoids;Environment;Event;Family;Goals;Immune;Immune Evasion;Immune response;Infection;Infection Control;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Innate Immune System;Kinetics;Leukocytes;Leukotriene B4;Lipids;Lipoxygenase;Lung;Macrophage;Mediating;Molecular;Mus;Neutrophil Infiltration;Pathogenesis;Pathway interactions;Plague;Pneumonic Plague;Predisposition;Production;Proliferating;Prostaglandin-Endoperoxide Synthase;Proteins;Role;Signal Transduction;Site;System;Testing;Therapeutic Intervention;Time;Tissues;Type III Secretion System Pathway;Virulence;Virulence Factors;Yersinia pestis;chemokine;cytokine;defined contribution;host colonization;human disease;immunoregulation;improved;in vivo;innovation;insight;leukocyte mediator;lipid mediator;mast cell;member;mutant;neutrophil;novel;pathogen;recruit;response;tool

public_health_relevance:
PROJECT NARRATIVEInflammation is controlled by a cascade of signaling events which are initiated by the secretion of lipid mediatorsby leukocytes to recruit and activate additional immune cells to sites of infection. Our goal is to define how Y.pestis dysregulation of host lipid mediator synthesis contributes to the establishment of plague. Because theinhibition of inflammation is key to Y. pestis virulence defining the role of host lipid mediators during plague isessential for us to understand the pathogenesis of this bacterium and provide new insights to improve currentplague therapy.


application_id: 10721139
project_number: 7K08AI151100-04
project_title: Defining the impact of zinc on Streptococcus agalactiae biofilm and colonization
administering_ic: NIAID
award_notice_date: 2022-11-11
opportunity_number: PA-19-117
application_type: 7
activity_code: K08
ic: AI
serial_number: 151100
program_official: GU, XIN-XING
project_start_date: 2020-03-09
project_end_date: 2025-02-28
study_section: Microbiology and Infectious Diseases B Research Study Section[MID-B]
contact_pi_person_id: 12264080
contact_pi: DOSTER, RYAN S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryDuring pregnancy zinc deficiency is associated with an increased risk of infection. Streptococcus agalactiaealso known as Group B Streptococcus (GBS) colonizes 20-30% of pregnant women. GBS vaginal colonizationincreases the risk for stillbirth preterm labor and neonatal sepsis. One strategy that GBS may use to stablycolonize the reproductive tract is to produce biofilm and we have found that GBS biofilm production issuppressed in the presence of zinc. This proposal tests the hypothesis that GBS biofilm production isnegatively regulated by zinc and this biofilm contributes to stable colonization of host tissues by limiting innateimmune responses against GBS. To test this hypothesis Aim 1 will use mutagenesis and transcriptomicapproaches to identify genetic pathways regulating GBS biofilm. Aim 2 will define the impact of zinc-regulatedbiofilm at the host-microbial interface by evaluating GBS mutants lacking cadD a zinc efflux transporter whichresults in impaired biofilm production. We will examine these interactions using in vitro models of humanvaginal epithelial cells explanted human fetal membranes and an Instrumented Fetal Membrane Organ on aChip (IFMOC) model under conditions that modify zinc availability. Aim 3 will use a mouse vaginal colonizationmodel to define how the zinc transporter cadD impacts vaginal colonization in settings of zinc deficiency orsupplementation. Completion of these Aims will shed new light on how zinc impacts GBS-host interactions thatculminate in colonization (and infection) of the reproductive tract.Dr. Ryan Doster is an Instructor in the Division of Infectious Diseases at Vanderbilt University Medical Center.His past work investigated gestational tissue innate immune responses to infection. This project will expand hisresearch focus to mechanisms of GBS colonization. This project complements Dr. Dosters clinical training inpediatrics and adult infectious diseases medicine. Under the mentorship of Dr. David Aronoff Dr. JenniferGaddy and a multidisciplinary Scholarship Oversight Committee Dr. Doster will master techniques includingbacterial mutagenesis transcriptomics and modeling infection within the reproductive tract to determine howzinc alters bacterial physiology and pathogenesis. Vanderbilt offers cutting-edge technology and expertise inthese areas through Vanderbilt Technologies for Advanced Genomics and other shared research corefacilities. These studies and a strong career development program will prepare Dr. Doster for transition to anindependent researcher investigating the pathogenesis of bacterial infections during pregnancy.

project_terms:
Academic Medical Centers;Adult;Area;Bacterial Infections;Bacterial Physiology;Cells;Clinical;Communicable Diseases;Complement;Core Facility;Data;Development;Epithelial;Epithelial Cells;Event;Female;Fetal Membranes;Future;Genetic;Genetic Transcription;Genomics;Glucose;Goals;Human;Immune response;Impairment;In Vitro;Infection;Inflammatory Response;Innate Immune Response;Light;Link;Medicine;Mentors;Mentorship;Microbial Biofilms;Microscopy;Modeling;Morbidity - disease rate;Mus;Mutagenesis;Newborn Infant;Nutrient;Pathogenesis;Pathway interactions;Pediatrics;Perinatal;Perinatal Infection;Physicians;Pregnancy;Pregnant Women;Premature Birth;Premature Labor;Production;Program Development;Regulator Genes;Regulatory Pathway;Research;Research Personnel;Resolution;Risk;Risk Factors;Role;Scholarship;Scientist;Stimulus;Streptococcal Infections;Streptococcus Group B;Supplementation;Techniques;Technology;Testing;Tissue membrane;Tissues;Training;United States;Vagina;Woman;Work;Zinc;Zinc deficiency;Zinc supplementation;career;career development;dietary;early onset;host colonization;human model;in vitro Model;in vivo;infection risk;innovation;instructor;instrument;intraamniotic infection;intrauterine infection;microbial host;mortality;mouse model;multidisciplinary;mutant;neonatal infection;neonatal sepsis;novel strategies;organ on a chip;pathogen;premature;prevent;reproductive tract;response;stillbirth;transcriptome;transcriptomics;zinc-binding protein

public_health_relevance:
Project NarrativeZinc deficiency increases the risk for infections during pregnancy. Perinatal bacterial infections often originatein the vagina where asymptomatic bacterial colonization leads to ascending intrauterine infection followed bypreterm labor stillbirth or neonatal infection. As part of a long-term goal to identify novel approaches toprevent and treat of perinatal infections this proposal will investigate how zinc alters the ability of a commonperinatal pathogen Group B Streptococcus to colonize and infect the female reproductive tract.


application_id: 10717195
project_number: 1R21CA282484-01
project_title: Antitumor potential of AvFc lectibody in non-small cell lung cancer
administering_ic: NCI
award_notice_date: 2023-09-19
opportunity_number: PAR-22-216
application_type: 1
activity_code: R21
ic: CA
serial_number: 282484
program_official: HARRIS, RAYMOND D
project_start_date: 2023-09-19
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZCA1 SRB-P (M2)]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: GUO, HAIXUN ;TELANG, SUCHETA
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTThe goal of this project is to develop a novel tumor glycobiomarker-targeting agent against non-small cell lungcancer (NSCLC). NSCLC accounts for the majority of all lung tumors and is frequently diagnosed at an advancedstage with poor prognosis. Current therapies including novel targeted drugs and immunotherapies have led toimproved outcomes but have had less efficacy in advanced disease and several of these agents result inresistance. Given that a combination of multiple therapeutic strategies may be necessary to produce an optimaltherapeutic outcome development of novel therapeutic agents targeting a unique biomarker of NSCLC iswarranted. Particularly tumor-targeted immunotherapy that can boost an antitumor immune response mightenhance the efficacy of immune checkpoint inhibitors. There is growing evidence for an aberrant increase ofhigh-mannose glycans in the glycome of cancer cells including those of NSCLC. To target this glycobiomarkerthe applicants lab has developed Avaren-Fc (AvFc) a recombinant antibody-like molecule lectibody efficientlyrecognizing high-mannose glycans on the surface of malignant cells. The antitumor potential and safety of AvFchas been demonstrated in human A549 and H460 NSCLC xenograft challenge models using immunodeficientmice as well as in syngeneic B16F10 melanoma challenge models using immunocompetent C57bl/6 mice. Inthe latter model AvFc treatment increased the infiltration of non-classical monocytes and other myeloid cells aswell as CD4/CD8 T lymphocytes. Furthermore immunohistochemical analysis revealed that AvFc can selectivelyrecognize primary human NSCLC tumors over adjacent non-tumor lung tissues. Based on these findings wehypothesize that AvFc may serve as a novel immunotherapeutic agent targeting tumor-associated high-mannoseglycans in NSCLC. To substantiate the possibility in a more clinically relevant NSCLC model the goal of thisR21 project is to reveal the immunotherapeutic efficacy and tumor-targeting profile of AvFc in a conditionalKras/p53 mutation-driven NSCLC mouse model. In Specific Aim 1 we will determine and characterize thetherapeutic effects of AvFc based on overall survival immunohistochemistry of lung tumors andimmunophenotyping of lung-infiltrated immune cells. Additionally we will assess the efficacy of AvFc incombination with the immune checkpoint blocker anti-PD-1 antibody. In Specific Aim 2 we will analyzebiodistribution and tumor detection profiles of AvFc in the NSCLC mice using a radiolabeled AvFc derivative ina microPET/CT imaging analysis. Building on our preliminary data we will design and optimize radiolabeledAvFc derivatives to have an optimal pharmacokinetic profile and tumor-detection sensitivity. In particular we willassess the capability of radiolabeled AvFc to detect tumor progression and metastasis. Collectively theproposed research will provide critical information addressing the question of whether AvFc could be a viableimmunotherapeutic and/or diagnostic agent against NSCLC. Should the answer be positive the results willsignificantly facilitate further preclinical development of AvFc towards a Phase I clinical trial.

project_terms:
A549;Address;Affect;Antibodies;Apoptosis;Binding;Biodistribution;Biological Markers;C57BL/6 Mouse;CD8-Positive T-Lymphocytes;Cancer Model;Cancer cell line;Cell surface;Cells;Chimeric Proteins;Collaborations;Cytometry;Data;Detection;Development;Diagnosis;Diagnostic;Drug Kinetics;Drug Targeting;E-Cadherin;Endoplasmic Reticulum;Flow Cytometry;Glycocalyx;Glycoconjugates;Goals;Histopathology;Human;IgG1;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunodeficient Mouse;Immunohistochemistry;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;In Vitro;Infiltration;Investigational Drugs;Lectin;Link;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mannose;Melanoma Cell;Modeling;Monitor;Mus;Mutate;Mutation;Myeloid Cells;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Normal Cell;Oligosaccharides;Pharmaceutical Preparations;Phase I Clinical Trials;Polysaccharides;Population;Prognosis;Proteins;Radiolabeled;Recombinant Antibody;Recombinant Fusion Proteins;Research;Resistance;SCID Mice;Safety;Structure of parenchyma of lung;Surface;TP53 gene;Therapeutic;Therapeutic Effect;Time;Treatment Efficacy;Tumor Markers;Variant;Vascularization;Visualization;X-Ray Computed Tomography;Xenograft procedure;advanced disease;anti-PD-1;anti-PD1 antibodies;anti-tumor immune response;antibody mimetics;antibody-dependent cell cytotoxicity;antitumor effect;cancer cell;cancer diagnosis;cancer immunotherapeutics;cancer immunotherapy;cancer therapy;clinically relevant;design;detection sensitivity;efficacy evaluation;immune cell infiltrate;immune checkpoint;immune checkpoint blockers;improved outcome;lung cancer cell;melanoma;microPET/CT;monocyte;mouse model;mutant;new therapeutic target;novel;novel therapeutics;preclinical development;response;targeted agent;targeted treatment;therapy outcome;tool;tumor;tumor growth;tumor progression;tumor xenograft

public_health_relevance:
NARRATIVEThis project will evaluate the immunotherapeutic and tumor-targeting effects of Avaren-Fc in a Kras/p53mutation-driven non-small cell lung cancer mouse model. Avaren-Fc is a lectin-Fc fusion protein targeting tumor-associated high-mannose glycans. Successful completion of the proposed studies will establish an importantproof-of-concept data package justifying further preclinical development of the glycobiomarker-specificimmunotherapeutic and diagnostic candidate.


application_id: 10713025
project_number: 1R01NS133250-01
project_title: Bisphenol-Induced Blood-Brain Barrier Dysfunction in Alzheimers Disease
administering_ic: NINDS
award_notice_date: 2023-09-14
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: NS
serial_number: 133250
program_official: YIN, XILING
project_start_date: 2023-09-15
project_end_date: 2028-07-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 9238548
contact_pi: HARTZ, ANIKA M.S.
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:
Identifying environmental risk factors for Alzheimers Disease (AD) is critical to mitigate cognitive decline inhumans. We provide first evidence showing that endocrine disrupting bisphenols (BP) are clinically relevantenvironmental risk factors for AD. Human exposure to BPA and the bisphenol analogs BPF and BPS is inevitabledue to their ubiquitous presence in the environment. Our data show that BPA triggers blood-brain barrierdysfunction and cognitive impairment both hallmarks of AD indicating that environmental BPs are a critical yetunderrecognized AD risk factor. Key characteristics of BP-induced barrier dysfunction include: 1) loss of theamyloid-beta (Ab) clearance transporter P-glycoprotein (P-gp) and 2) development of barrier leakage. Both thesefactors contribute to a pathological cascade that leads to cognitive decline in AD. While there is evidence thatBP exposure results in a dysfunctional barrier the mechanism underlying this phenomenon is unknown and keymechanistic data linking BPs and AD are not available which hinders our understanding of environmental riskfactors for AD. In this application we address this critical unmet need and propose to define the relevance ofBPs as risk factors for AD. Our objective in this proposal is to define signaling steps through which BPs inducebarrier dysfunction and contribute to cognitive decline in AD. Based on preliminary data our central hypothesisis that BPs induce barrier dysfunction increase Ab levels and enhance cognitive decline in an AD model. Ourrationale for this research is that identifying the mechanism through which BPs induce barrier dysfunction andexacerbate cognitive impairment will provide proof-of-concept that endocrine disruptors are an environmentalrisk factor for AD. The hypothesis will be tested by pursuing three specific aims: 1) Identify the mechanismresponsible for BP-induced barrier dysfunction. 2) Determine BP levels barrier dysfunction and cognition in ADpatients compared to CNI. 3) Develop a strategy to repair BP-induced barrier dysfunction and slow cognitivedecline in vivo. In Aim 1 we will identify signaling steps that lead to BP-induced P-gp loss and barrier leakage inisolated mouse brain capillaries and we will verify these findings in capillaries from KO mice and in isolatedhuman brain capillaries. In Aim 2 we will determine BP levels and the degree of barrier dysfunction BP levels inhuman tissue samples from cognitive normal individuals preclinical AD MCI and AD patients. In Aim 3 we willblock BP signaling to mitigate barrier dysfunction and evaluate the benefit of this strategy on slowing cognitivedecline in vivo in a mouse AD model. The proposed research is innovative because it represents a substantivedeparture from the status quo by shifting to a mechanism-driven approach focused on the impact endocrinedisruptors have on barrier function and cognition in AD. The proposed research is significant because it isexpected to create a paradigm shift in our understanding of the importance of environmental risk factors for AD.

project_terms:
ABCB1 gene;Abeta clearance;Address;Aging;Air;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid beta-Protein;Beverages;Blood brain barrier dysfunction;Blood capillaries;Brain;Characteristics;Cognition;Cognitive;Cognitive deficits;Data;Development;Dust;Endocrine Disruptors;Endocrine disruption;Environment;Environmental Impact;Environmental Risk Factor;Estrogen Receptor beta;Exposure to;Extravasation;FDA approved;Food;Fulvestrant;Functional disorder;Health;Human;Impaired cognition;Impairment;Individual;Knockout Mice;Knowledge;Link;Medical Device;Mission;Monkeys;Mus;National Institute of Environmental Health Sciences;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Outcome;Oxidative Stress;PIK3CG gene;Paper;Pathologic;Pharmaceutical Preparations;Plastics;Public Health;Research;Risk Factors;Rodent;Sampling;Signal Transduction;Soil;Testing;Time;Tissue Sample;Work;analog;bisphenol A;burden of illness;cerebral capillary;clinically relevant;cognitive enhancement;drinking water;exposed human population;human tissue;in vivo;in vivo Model;innovation;neuron development;pre-clinical;repaired

public_health_relevance:
The proposed research is relevant to public health because it is expected to identify bisphenols as environmentalrisk factors for blood-brain barrier dysfunction and provide a mechanistic link between bisphenols barrierdysfunction and cognition in Alzheimers disease. Thus the proposed research is relevant to the missions ofthe NINDS the NIA and the NIEHS that pertain to developing fundamental knowledge of environmental impactson human health that will help promote healthier lives and reduce the burden of diseases and conditions relatedto aging.


application_id: 10712126
project_number: 2P30CA177558-11
project_title: Shared Resource Management
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5472
contact_pi_person_id: 7719959
contact_pi: WEISS, HEIDI L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Management of Shared Resource Facilities (SRF) fosters the execution of strategic science goals of theMarkey Cancer Center (MCC). Since their inception MCC SRFs have benefitted from strong and experiencedleadership significant investment and support from MCC and the University of Kentucky utilization of uniqueprocesses to facilitate effective delivery and coordination of services and governance by evaluation andoversight from advisory committees and the MCC Directors Council. The aims of SRF Management are to: 1)Promote state-of-the-art technology methodologic and content expertise to foster MCC scientific strategiesacross three Research Programs; 2) Conduct rigorous monitoring and evaluation processes and supportfinancial health for stability of SRF infrastructure and 3) Facilitate robust and stable access to MCC sharedresources through innovative initiatives. The SRFs received improved ratings from NCIs 2018 site visit andhave exhibited continued growth in breadth of services depth of skills and service provision aligned with theresearch direction of MCCs programs. In addition SRF management was guided by a culture of integratedand collaborative relationships with MCC researchers with formalized processes for hand-offs among SRFsfacilitating enhanced support and the bi-directional continuum of MCC research from basic science to clinicand into the community. MCC is supported by seven established SRFs: Biospecimen Procurement andTranslational Pathology (BPTP) Biostatistics and Bioinformatics (BB) Cancer Research Informatics (CRI)Flow Cytometry and Immune Monitoring (FCIM) Redox Metabolism (RM) with Oncogenomics (OG) andPatient-Oriented and Population Sciences (POP) as new fully operational facilities in this application resultingfrom rigorous SRF management evaluation processes and advisory committee recommendations andapproval. SRFs are led by Dr. Heidi Weiss (TO) Associate Director for Shared Resources; she is assisted byDr. Thrse Bocklage (MCO) Assistant Director for Shared Resources the SRF Management Office and MCCAdministration. MCC has invested $8.3M in SRF enhancements since 2018. SRF usage is robust evident byhigh numbers of users; SRFs also appropriately prioritize their services evident by the percent of users from2018-2022 who are MCC members: BB (156 users 79%) BPTP (150 users 61%) CRI (161 users 65%)FCIM (87 users 61%) OG (61 users 69%) POP (34 users 71%) and RM (72 users 68%). MCC ResearchProgram members heavily utilize SRFs as follows: 84% of Molecular and Cellular Oncology 85% ofTranslational Oncology and 82% of Cancer Prevention and Control. The total number of MCC members usingall SRFs remains consistently high (151 and 171 over MCCs first two CCSG cycles respectively). Fiscalmanagement and business planning from MCC Administration ensure SRF income mechanisms and financialprocesses are robust and appropriate. These management strategies and consequent value-added metricsdemonstrate the critical role of SRFs and their direct contributions to MCCs mission.

project_terms:
Advisory Committees;Affect;Applications Grants;Assessment tool;Basic Science;Bioinformatics;Biometry;Budgets;Businesses;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Prevention Intervention;Cancer Therapy Evaluation Program;Clinic;Clinical Research;Clinical Trials;Communication;Communities;Comprehensive Cancer Center;Decision Making;Dedications;Dissemination and Implementation;Documentation;Electronics;Ensure;Evaluation;Evidence based intervention;Exhibits;Financial Support;Flow Cytometry;Fostering;Funding;Genomics;Goals;Growth;Health;Health Insurance Portability and Accountability Act;Human Resources;Immunologic Monitoring;Improve Access;Income;Informatics;Infrastructure;Institution;Investigation;Investments;Kentucky;Laboratories;Lead;Leadership;Marketing;Measurement;Metabolism;Methodology;Mission;Modeling;Modification;Molecular;Monitor;NCI Center for Cancer Research;Office Management;Oncology;Outcome;Oxidation-Reduction;Pathology;Peer Review Grants;Performance;Population Intervention;Population Sciences;Population Study;Process;Productivity;Recommendation;Reporting;Research;Research Personnel;Resource Sharing;Resources;Role;Science;Screening for cancer;Secure;Service provision;Services;Site Visit;Strategic Planning;System;Technical Expertise;Technology;Therapeutic Trials;Tobacco;Training;Training and Education;Universities;Work;anticancer research;biomarker driven;cancer genomics;cancer prevention;cancer research center director;cellular oncology;community based research;cost;cost effective;cost effectiveness;data sharing;epidemiology study;experience;implementation facilitation;improved;innovation;instrumentation;member;molecular oncology;oncology program;operation;patient oriented;programs;service coordination;skills;survivorship;targeted treatment;tool;translational oncology;translational study;treatment program


application_id: 10712125
project_number: 2P30CA177558-11
project_title: Protocol Review and Monitoring System
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5471
contact_pi_person_id: 1926108
contact_pi: ANTHONY, LOWELL B.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT In accordance with CCSG guidelines the Markey Cancer Center (MCC) has established appropriatemechanisms for ensuring rigorous scientific oversight of cancer clinical trials through the Protocol Review andMonitoring System (PRMS). Protocols undergo initial scientific review by Clinical Care and Research Teams(CCARTs) including assessment of relevance to the patient population fit within the portfolio and interest ofinvestigators. In 2019 the MCC formalized first-stage review by CCARTs expanding structure and functionand enhancing communication with the Protocol Review and Monitoring Committee (PRMC). FollowingCCART approval review for operational feasibility is completed by the Feasibility Review Committee. The goalof these reviews is to ensure that only the highest quality trials are submitted to the PRMC. The MCC PRMC isresponsible for independent peer-review of scientific merit feasibility and prioritization of new protocols.Following activation PRMC monitors protocols for ongoing scientific progress and has ultimate authority tosuspend or close protocols that do not meet MCC scientific standards. The Specific Aims of the PRMS are: 1)Optimize the PRMS structure and process for sufficient size and breadth of expertise to conduct a criticalrigorous and fair scientific review of all institutional cancer-related research protocols involving human subjects;2) Ensure that clinical trials conducted at MCC support and enable the scientific mission of the center arerelevant to patients in the catchment area including those from underserved groups and enhance theinclusion of diverse populations; 3) Safeguard the scientific integrity feasibility and prioritization of all cancer-related interventional clinical research of the MCC and apply rigorous scientific review criteria in a consistentand objective manner; 4) Oversee the progress and performance of all interventional cancer clinical trials toensure their continued scientific merit and accomplishment of the scientific goals of the protocol and the MCC.Highlights during the funding period include incorporation of first-stage reviews into PRMS frameworkenhanced member education expanded representation in key scientific areas and strengthened quorumexpectations. From 2019 to 2021 the CCARTs reviewed 409 clinical trials for potential opening approved 294(72%) and declined 115 (28%); the Feasibility Review Committee declined 20 (4%) due to lack of feasibility.From 2019 to 2021 the PRMC reviewed and/or prioritized 239 new protocols of which 230 were approved and9 were disapproved. In the past three years the PRMC reviewed 552 active protocols for scientific progressclosing 29 protocols due to low accrual or a change in scientific merit. The PRMC continuously assesses itsown performance. In 2021 median time from PRMC submission to approval was 8 days overall (7 national 8industry 24 institutional). As the MCC has matured the PRMS has continued to optimize the first- and second-stage review and to increase scientific rigor objectivity and scrutiny of each trials relevance to our diversepopulation in order to ensure MCC brings the highest quality clinical research to Kentuckians.

project_terms:
Area;Authorization documentation;Basic Science;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Intervention;Catchment Area;Charge;Clinical Cancer Center;Clinical Oncology;Clinical Protocols;Clinical Research;Clinical Trials;Committee Members;Communication;Conduct Clinical Trials;Data;Discipline;Disease;Education;Electronics;Ensure;Evaluation;Faculty;Funding;Goals;Guidelines;Individual;Industry;Institution;Institutional Review Boards;Intervention;Intervention Studies;Kentucky;Laboratory Research;Malignant Neoplasms;Mission;Modification;Monitor;Observational Study;Outcome;Pathology;Patients;Peer Review;Performance;Pharmacology;Policies;Population Heterogeneity;Prevention;Process;Protocols documentation;Radiology Specialty;Recommendation;Reporting;Research;Research Personnel;Resources;Review Committee;Safety;Scientific Advances and Accomplishments;Structure;System;Time;Underserved Population;Universities;Vulnerable Populations;authority;cancer clinical trial;cancer prevention;cancer research center director;clinical care;clinical translation;clinically relevant;community engagement;expectation;human subject;innovation;interest;member;mid-career faculty;patient population;professor;success;trial enrollment


application_id: 10712124
project_number: 2P30CA177558-11
project_title: Community Outreach and Engagement
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5470
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:
PROJECT SUMMARY/ABSTRACT The University of Kentucky (UK) Markey Cancer Center (MCC) embraces the entire Commonwealth ofKentucky as its catchment area. Despite notable recent advances Kentucky has the highest all-site cancerincidence and mortality in the U.S. driven largely by socioeconomic geographic and racial/ethnic inequities.With a 47-year history the goal of MCC Community Outreach and Engagement (COE) is to engagecommunities practitioners and researchers in mutually beneficial collaborations to accelerate health equity andreduce the burden of cancer. MCCs long-standing COE programs include regionally-based communityoutreach management of the states cancer coalition and policy efforts and the MCC Affiliate Network(MCCAN) MCCs innovative clinical outreach program with 19 community-based (non-UK) hospitals acrossthe state. Since 2018 MCC made strategic investments to enhance COE strengths and further integrateresearch and cancer control. COEs previous needs assessment shaped the FY19-23 MCC ResearchPriorities. Key accomplishments include conducting the 2021 Kentucky Cancer Needs Assessment (KY CNA)launching new research engagement initiatives (e.g. Community Impact Ambassadors as Research Programliaisons Research Advocacy Program Clinical Trial Referral Ambassadors internal COE funding) and cancercontrol activities with extensive reach (e.g. training/technical assistance policy changes individual educationfacilitating access to services). Building on existing efforts and FY24-28 MCC Research Priorities COESpecific Aims are to: 1) Monitor cancer burden and disparities in Kentucky and identify community-drivenpriorities. In addition to monitoring cancer burden and disparities and conducting the next KY CNA in 2026each year COE will carry out a focused needs assessment on a specific population to address data gaps anddisparities identified in the 2021 KY CNA. 2) Foster impactful research that responds to community needs andpromotes equity. COE will expand the Research Advocacy Program with a training module for basic andclinical researchers and Rapid Feedback Sessions. COE will add two new strategies to facilitate clinical trialparticipation: providing culturally appropriate patient and community education including testimonial videosand assisting studies prioritized for underrepresented minority accruals through consultations and diverseresearch advocate feedback. 3) Disseminate and implement sustainable evidence-based guidelines practicesand policies. COE is currently using the 2021 KY CNA to guide development of the states new five-yearCancer Action Plan. Next COE will assess its portfolio of community cancer control programs to strategicallyrealign them with the new state plan to address gaps leverage partnership opportunities and maximize impact.IMPACT: COE has made important advances in synergizing MCC research and cancer control efforts withstatewide partners and significant contributions to population-level improvements in colon and lung cancerscreening and outcomes smoking and HPV vaccination. COE is poised to further accelerate MCC impact.

project_terms:
Acceleration;Address;Advocacy;Advocate;Appalachian Region;Award;Back;Black Populations;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Cervical;Clinical;Clinical Trials;Collaborations;Colon Carcinoma;Colorectal;Communities;Community Health Education;Community Outreach;Consultations;Data;Data Sources;Development;Disparity;Dissemination and Implementation;Education;Education and Outreach;Electronics;Environmental Exposure;Equity;Evidence based practice;Feedback;Fostering;Funding;Geography;Goals;Grant;Head and neck structure;Health Services Accessibility;Hepatitis C virus;Hispanic Populations;Hospitals;Human Papilloma Virus Vaccination;Human Papillomavirus;Incidence;Individual;Investments;Kentucky;Leadership;Lung;Malignant Neoplasms;Monitor;NCI Center for Cancer Research;Needs Assessment;Obesity;Outcome;Patient Education;Patients;Persons;Policies;Population;Poverty;Preventive service;Printing;Process;Professional Practice;Quality Indicator;Race;Recording of previous events;Reporting;Research;Research Personnel;Research Priority;Risk Factors;Rural;Screening for cancer;Shapes;Smoking;Therapeutic Trials;Tobacco;Training;Training Activity;Underrepresented Minority;Universities;Virus;Visit;cancer care;cancer health disparity;cancer site;colon cancer screening;community engagement;ethnic disparity;evidence based guidelines;geographic disparity;health equity;improved;innovation;lung cancer screening;meetings;melanoma;member;mortality;outreach program;programs;racial disparity;screening program;social media;socioeconomics;volunteer


application_id: 10712123
project_number: 2P30CA177558-11
project_title: Clinical Protocol and Data Management
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5469
contact_pi_person_id: 6772940
contact_pi: ARNOLD, SUSANNE 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 The Markey Cancer Center (MCC) Clinical Protocol and Data Management (CPDM) facilitates all clinicalcancer research at the University of Kentucky. CPDMs Specific Aims are: 1) To provide comprehensivecentralized support for MCC clinical research activities; 2) To ensure the safety compliance and quality of allclinical cancer research performed at the center and MCCs Research Network (MCCRN) in accordance withthe Data Safety and Monitoring Plan and NCI requirements; 3) To integrate all efforts of the Cancer Center toprovide clinical trial access to MCCs patients including women minorities underserved populations andindividuals across the lifespan; and 4) To provide ongoing education and training services for CPDM andMCCRN staff and faculty that enhance quality diversity consistency and efficiency of teams and lead toincreased engagement with MCCs catchment population. The CPDM facilitates clinical research through theClinical Research Offices four units (72 FTEs) Protocol Development Teams (10 FTE) a Quality AssuranceProgram (5 FTE) and MCCRN (11 FTE) which provide centralized expertise for development coordinationand execution of trials. In 2022 the Clinical Research Office managed 369 active trials211 cooperativegroup 113 industry sponsored and 45 investigator-initiated (12 investigational new drug-enabling). MCCsstatewide infrastructure supports research referral and accrual within the catchment area. As the CPDM hasmatured the center increased clinical research engagement to 98 of Kentuckys 120 counties with 18753 totalaccruals (8857 interventional; 9896 non-interventional 2018-2022). The Quality Assurance Program andAudit Committee function independently from other CPDM components to support education safety andquality of trial conduct. All cancer trials are guided by MCCs Data and Safety Monitoring Plan which providesoversight in accordance with NCI CCSG requirements. The Data and Safety Monitoring Committee ensurespatient safety and protocol compliance by staff and investigators. MCC leaders investigators and staff promotethe inclusion of women minorities and Kentuckys special population of Appalachia in clinical cancer researchwith impactful engagement of females (77% of all interventional accrual 2018-2022) and AppalachianKentuckians (61%). Enhanced efforts have increased minority trial participation to reflect this patientpopulation focusing on important cancer disparities such as lung and prostate cancers. In support of NIHpolicies MCC strives for inclusion of individuals across the lifespan in clinical research. In 2021 40% oftherapeutic trial accruals were adults 65 or older surpassing national averages. Cancer care for children isprovided by one of two comprehensive pediatric oncology programs in the state. MCC is the first center in theregion to offer germline testing to all pediatric oncology patients supported by the Molecular Tumor Boardinterpretation of results.

project_terms:
Adherence;Adult;Age;Appalachian Region;Awareness;Biometry;COVID-19 pandemic;Cancer Center;Cancer Center Support Grant;Catchment Area;Child Care;Clinical;Clinical Cancer Center;Clinical Data;Clinical Management;Clinical Protocols;Clinical Research;Clinical Research Associate;Clinical Trials;Clinical Trials Network;Collaborations;Communities;Community Outreach;County;Data;Data Collection;Data Management Resources;Dedications;Development;Devices;Disease;Education;Electronics;Ensure;Ethnic Origin;Faculty;Female;Gender;Goals;Improve Access;Individual;Industry;Infrastructure;Institution;Institutional Review Boards;Intervention;Investigational Drugs;Investigational Therapies;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Minority;Mission;Molecular;Monitor;NCI Center for Cancer Research;National Cancer Institute;National Clinical Trials Network;Needs Assessment;Nurses;Office Management;Patients;Pediatric Oncology;Performance;Policies;Population;Procedures;Process;Protocol Compliance;Protocols documentation;Race;Reporting;Research;Research Activity;Research Design;Research Personnel;Research Priority;Research Support;Resource Allocation;Resource Sharing;Risk;Safety;Services;Site;Special Population;Specialist;System;Testing;Therapeutic Trials;Time;Toxic effect;Training;Training and Education;Translational Research;Underserved Population;United States National Institutes of Health;Universities;Vision;Woman;anticancer research;cancer care;cancer health disparity;clinical care;community engagement;data management;design;experience;improved;industry partner;investigator-initiated trial;oncology program;operation;patient engagement;patient oriented;patient population;patient safety;programs;protocol development;quality assurance;response;success;tool;tumor


application_id: 10712122
project_number: 2P30CA177558-11
project_title: Developmental Funds
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5468
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT CCSG Developmental Funds are a vital mechanism for furthering the strategic mission and vision of theMarkey Cancer Center (MCC) through pilot funding to MCC members and support of emerging SharedResource Facilities. During the current funding period Developmental Funds helped support 17 basic clinicalpopulation and translational cancer research pilot projects from MCCs Molecular and Cellular OncologyCancer Prevention and Control and Translational Oncology Research Programs stimulating a high return oninvestment of $15.16 per CCSG dollar. These projects have fostered five new extramurally funded grants andhave opened clinical trials that accrued 241 new participants. In close alignment with MCCs scientific direction14 of the 17 projects are on topics that correspond to the centers FY19-23 Research Priorities for the currentfunding period including those involving clinical and health disparity issues within the MCC catchment area.Outside of the routine CCSG pilot award process MCC also elected to use Developmental Funds to supporttwo interdisciplinary teams of researchers who ultimately successfully applied for a CCSG Supplementdesigned to foster the development of multiproject research programs. Developmental Funds were alsoinvested in two developing Shared Resource Facilities (Oncogenomics and Patient-Oriented and PopulationSciences) which have supported research projects from all three MCC programs and after careful annualevaluation have been approved by the MCC Directors Council as fully functioning resources presented assuch in this CCSG application. Leveraged with philanthropic investment and institutional supportDevelopmental Funds will also be strategically allocated during the upcoming funding period to address twoSpecific Aims: 1) Cultivate innovative and collaborative science through the use of pilot grants in areas thatalign with MCCs FY24-28 Strategic Plan and Research Priorities and reflect the scientific aims of MCCs threeResearch Programs; and 2) Foster deeper collaboration across the UK campus through strategic partnershipsto fund innovative pilot awards and ensuring the continuation of community input through the CCSG pilotreview process. To achieve these aims MCC requests $150000 per year in Developmental Funds allowingthe center to achieve several key objectives outlined in the Strategic Plan including fostering research thataligns with its research priorities expanding transdisciplinary opportunities for research teams and increasingclinical studies that are informed by MCC basic research. MCC will also continue partnerships with other majorresearch centers across campus allowing cancer research to have an impact far beyond what MCC alone canachieve and will foster the maturity of a new process by which Community Advisory Board members directlycontribute to the CCSG pilot reviews allowing community input to inform and influence funding decisions.

project_terms:
Address;Area;Award;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Research Project;Catchment Area;Clinical;Clinical Cancer Center;Clinical Research;Clinical Sciences;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Community Participation;Comprehensive Cancer Center;Data;Dedications;Development;Ecosystem;Education;Electronics;Ensure;Evaluation;Extramural Activities;Fostering;Funding;Funding Agency;Future;Goals;Grant;Guidelines;Institution;Investments;Kentucky;Leadership;Link;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Obesity;Participant;Philanthropic Fund;Pilot Projects;Population;Population Sciences;Prevention;Process;Program Description;Program Research Project Grants;Racial Equity;Recurrence;Research;Research Personnel;Research Priority;Research Project Grants;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Secure;Strategic Planning;Translational Research;Universities;Vision;Vulnerable Populations;Work;anticancer research;cancer genomics;cancer prevention;cancer research center director;cellular oncology;clinical center;clinically relevant;community engagement;design;evidence base;flexibility;health disparity;innovation;interest;member;molecular oncology;novel;patient oriented;programs;recruit;screening;translational cancer research;translational oncology


application_id: 10712121
project_number: 2P30CA177558-11
project_title: Leadership Planning and Evaluation
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5467
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT B. Mark Evers MD (TO) Director of the Markey Cancer Center (MCC) is assisted by eight Senior Leaderswho support activities in cancer research outreach education and training diversity and inclusion clinical careand administration. With the exception of some notable additions during this reporting period that haveexpanded the effectiveness and expertise of the Senior Leadership team this highly experienced group ofleaders has worked together since 2009 overseeing MCCs initial NCI designation in 2013 a successfulrenewal application in 2018 the preparations for this renewal and quest for Comprehensive Cancer Centerstatus as well as a future five-year outlook in the form of MCCs FY24-28 Strategic Plan. MCCs SeniorLeaders leverage all available resources at the University of Kentucky state and national levels to further theircohesive plan to fulfill MCCs mission to reduce the cancer burden with a focus on Kentucky and its mostvulnerable populations through research prevention treatment education and community engagement. Tothat end MCCs Leadership Planning and Evaluation efforts are centered around the following Specific Aims:1) Implement and execute MCCs FY24-28 Strategic Plan and lead MCC based on the opportunities andneeds of the statewide catchment area and in tandem with institutional and NCI priorities; 2) Lead the ongoingplanning and evaluation of the center coordinating and responding to internal and external reviews; and 3)Ensure the appropriate resources and infrastructure to foster success across all areas of MCCs StrategicPlan including the success of MCCs Research Programs Shared Resources clinical and translationalscientific endeavors and outreach mentoring and diversity-focused initiatives. MCCs planning and evaluationefforts sustaining its substantial growth since 2018 are accomplished through External and Internal AdvisoryBoards that meet regularly the Directors Council and committees that provide both the Director and SeniorLeadership ongoing guidance and support. Future directions for the center are guided by plans outlined inMCCs FY24-28 Strategic Plan which was constructed through an extensive review and vetting process withinput from key internal and external stakeholders. The plan is a living document and roadmap to guide the nextfive years of excellence in key pillars of activity across the center: 1) basic research 2) clinical translation 3)cancer prevention and control 4) cancer education and mentoring 5) community outreach and engagement6) diversity equity and inclusion and 7) clinical care. These pillars are reinforced by strong institutionalsupport philanthropy Shared Resource Facilities and administration all of which work in tandem to support acancer center poised to continue its trajectory of increasing contributions to cancer research trainingeducation equity and outreach.

project_terms:
Address;Area;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Catchment Area;Clinical;Clinical Research;Communities;Community Outreach;Comprehensive Cancer Center;Consultations;Development;Education;Effectiveness;Electronics;Ensure;Epidemiologist;Equity;Evaluation;Fostering;Funding;Future;Goals;Growth;Healthcare;Infrastructure;Institution;Intervention Trial;Investments;Kentucky;Lead;Leadership;Legal patent;Malignant Neoplasms;Mentors;Mission;Molecular;NCI Center for Cancer Research;Names;Needs Assessment;Patients;Population Sciences;Positioning Attribute;Preparation;Prevention;Process;Recording of previous events;Reporting;Research;Research Personnel;Resource Sharing;Resources;Scientist;Secure;Source;Strategic Planning;Time;Training;Training and Education;Universities;University resources;Vision;Vulnerable Populations;Work;anticancer research;cancer education;cancer genomics;cancer prevention;cancer research center director;clinical care;clinical translation;community engagement;community organizations;diversity and inclusion;equity diversity and inclusion;experience;functional status;improved;meetings;novel therapeutics;outreach;patient oriented;programs;recruit;success;translational pipeline;translational scientist;tumor metabolism


application_id: 10712120
project_number: 2P30CA177558-11
project_title: Translational Oncology Research Program
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5466
contact_pi_person_id: 2020455
contact_pi: KOLESAR, JILL MARIE
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 The Markey Cancer Centers (MCC) Translational Oncology (TO) Research Program is scientificallyfocused on identifying novel targets discovering new anticancer agents and devices and leading catchment-relevant clinical trials to decrease cancer burden in Kentucky and the nation. The overarching theme of the TOProgram is to use precision medicine to enhance patient outcomes through three Specific Aims: 1) Identify andvalidate mechanistic targets of cancer 2) Discover re-design and develop new anticancer agents and devicesand 3) Develop and lead biomarker directed catchment-relevant clinical trials. Currently 33 ongoingtranslational studies are evaluating molecular targets and mediators of cancer. Since 2018 38 new drugsnovel combinations and repurposed anticancer agents and devices have been developed with a focus onidentified mutations and phenotypes as informed by COE catchment area data. TO is a cross-disciplinaryprogram with 67 investigators from four colleges and 16 departments producing research awards ofapproximately $10M in annual direct costs a 68% increase from 2017 including $1.8M from the NCI and$3.4M from other NIH agencies. Members have published 613 manuscripts (2018 to 2022) of which 148(24%) are inter-programmatic 169 (28%) are intra-programmatic 344 (56%) are inter-institutional and 13% ofwhich have an impact factor >10. TO members lead 26 new therapeutic interventional investigator-initiatedtrials (IITs) a 53% increase since the previous funding period (17 IITs 2013-2017). These IITs have enrolled870 patients (2018-2022) a 111% increase in IIT accruals (413 patients 2013-2017) with 52% of participantsfrom Appalachia. In addition TO investigators enrolled 12689 individuals to the programs interventional andnon-interventional trials compared to 8571 from 2013-2017 a 48% increase. TO Program members areinternational leaders in target discovery and validation have national and international collaborations and holdleadership roles in the National Cancer Institutes Experimental Therapeutics Clinical Trials Network theOncology Research Information Exchange Network and Onco-Array Networks and the MCC-led GlobalCancer Consortium. The TO Program fosters continuous collaboration among MCC program members toinform and advance MCC basic science into the clinic. Examples include translating early identification of thebiomarker FASN to an ongoing colorectal cancer trial and demonstrating the upregulation of tumor suppressorPAR-4 by hydroxychloroquine in three trials. The TO Program has a cohesive and collaborative team focusedon translating MCC scientific discoveries into safe and effective anticancer treatments with a demonstrateddepth and breadth of impact in MCCs catchment area nationally and internationally.

project_terms:
Address;Antineoplastic Agents;Appalachian Region;Area;Award;Basic Science;Biological Markers;Biological Models;Breast;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Clinic;Clinical;Clinical Oncology;Clinical Trials;Clinical Trials Network;Collaborations;Colorectal Cancer;Communities;Community Outreach;Data;Development;Devices;Diet;Direct Costs;Disparity;EIF4EBP1 gene;Early Therapeutic-Clinical Trials Network;Early identification;Electronics;Enrollment;FASN gene;Fostering;Funding;Future;Genomics;Goals;Gold Compounds;Hydroxychloroquine;Incidence;Individual;Infrastructure;Institution;Interdisciplinary Study;International;Intestinal Hormones;Investigational Drugs;Investigational Therapies;Kentucky;Lead;Leadership;Malignant Neoplasms;Manuscripts;Mediator;Mission;Molecular;Molecular Target;Multi-Institutional Clinical Trial;Mutation;NCI Center for Cancer Research;National Cancer Institute;Natural Products;Nursing Faculty;Obesity;Oncology;Participant;Patient-Focused Outcomes;Patients;Peer Review;Pharmaceutical Preparations;Phase;Phenotype;Population;Prostate;Public Policy;Publications;Publishing;Radiopharmaceuticals;Research;Research Personnel;Research Priority;Resources;Role;Ruthenium Compounds;Science;Strategic Planning;Structure;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Translating;Translations;Tumor Suppressor Proteins;United States National Institutes of Health;Universities;Up-Regulation;Validation;anticancer treatment;cancer care;cancer prevention;cancer therapy;cellular oncology;clinical development;clinical translation;clinical trial enrollment;clinically relevant;college;community engagement;cross disciplinary program;design;drug repurposing;early phase clinical trial;ethnic disparity;genome resource;inhibitor;insight;inter-institutional;intervention program;investigator-initiated trial;member;molecular oncology;mortality;next generation sequencing;novel;novel anticancer drug;novel therapeutic intervention;novel therapeutics;oncology program;phase 1 study;pre-clinical;precision medicine;preclinical development;programs;racial disparity;recruit;repository;translational goal;translational oncology;translational pipeline;translational study;treatment trial;tumor;working group


application_id: 10712119
project_number: 2P30CA177558-11
project_title: Molecular and Cellular Oncology Research Program
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5465
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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 The goal of the Molecular and Cellular Oncology (MCO) Research Program is to gain a comprehensiveunderstanding of basic mechanisms driving cancer initiation progression metastasis and therapeuticresistance to facilitate development of novel and rational approaches for cancer prevention and therapy. MCOresearch efforts are central to the overall Markey Cancer Center (MCC) mission to reduce the cancer burdenwith a focus on Kentucky and its most vulnerable populations through research prevention treatmenteducation and community engagement. MCO investigators determine signaling genetic epigenetic andmetabolic mechanisms that promote cancer development fuel tumor progression and contribute to therapeuticresistance. To achieve its goal MCO proposes three inter-related aims: 1) Identify aberrant signaling networksand critical interactions of tumor cells with their microenvironment to delineate molecular mechanisms thatdrive tumor initiation progression and metastasis and resistance; 2) Determine the contribution of metabolicreprogramming and epigenetic dysregulation to define novel pathways promoting cancer cell survival andadaptation; 3) Delineate the mechanisms by which dysregulation of redox signaling promotes genomicinstability therapeutic resistance and normal tissue toxicity. The 54 members of the MCO Program are expertsin cancer cell signaling tumor microenvironment cancer metabolism epigenetic regulation and redox biologywho hail from 16 departments in the Colleges of Medicine; Engineering; Arts and Sciences; and AgricultureFood and Environment reflecting diverse disciplinary perspectives. Cancer-related MCO funding is nearly$10.3M in annual direct costs and 53% of MCO peer-reviewed funding is from the NCI. Members havepublished 320 manuscripts (July 2018June 2022) of which 106 (33%) are inter-programmatic 81 (25%) areintra-programmatic and 195 (61%) are inter-institutional. The program is co-led by three researchers withexpertise in each of the three programmatic areas. Dr. Rina Plattner (an expert in oncogenic kinase signalingand tumor metastasis) Dr. Binhua Peter Zhou (a specialist in epigenetic and metabolic reprogramming ofepithelial-mesenchymal transition) and Dr. Tianyan Gao (an expert in protein phosphatases and mitochondrialregulation of cancer stem cells) bring together expertise in cancer signaling (Plattner Aim 1) epigenetics andmetabolism (Zhou Aim 2) and redox biology and mitochondrial bioenergetics (Gao Aim 3). In addition to theirscientific leadership each offers significant strengths in clinical translation junior faculty mentoringcommunications among MCC Research Programs and expertise on populations within the MCC catchmentarea. By leveraging comprehensive program strengths the MCO Program collectively provides a richenvironment to facilitate multidisciplinary collaboration and builds a productive pipeline for translation of MCOscience into the clinic.

project_terms:
Address;Adhesions;Agriculture;Area;Arts;Automobile Driving;Bioenergetics;Biogenesis;Biology;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Caregivers;Catchment Area;Cell Proliferation;Cell Survival;Chromatin;Clinic;Clinical Trials;Collaborations;Colorectal Cancer;Communication;Community Outreach;DNA Repair;Development;Direct Costs;Disparity;Education;Electronics;Engineering;Ensure;Environment;Enzymes;Epigenetic Process;Epithelium;Extracellular Matrix Proteins;FASN gene;FDA approved;Food;Funding;Future;Genetic;Genomic Instability;Goals;Heart Injuries;Incidence;Interdisciplinary Study;Intervention;Invaded;Joints;Kentucky;Leadership;Maintenance;Malignant - descriptor;Malignant Neoplasms;Manuscripts;Medicine;Mesenchymal;Metabolic;Metabolism;Mission;Mitochondria;Modeling;Molecular;NCI Center for Cancer Research;Neoplasm Metastasis;Normal tissue morphology;Oncogenic;Oxidation-Reduction;Pathway interactions;Patients;Peer Review;Phosphoric Monoester Hydrolases;Phosphotransferases;Population;Prevention;Production;Productivity;Protein Kinase;Protein phosphatase;Publications;Publishing;Reactive Oxygen Species;Recurrence;Regulation;Research;Research Personnel;Research Priority;Resistance;Science;Signal Transduction;Signaling Molecule;Specialist;Stress;Survivors;Tissues;Toxic effect;Translating;Treatment Efficacy;Universities;Vulnerable Populations;base;cancer cell;cancer health disparity;cancer initiation;cancer prevention;cancer stem cell;cancer therapy;cellular oncology;clinical translation;college;community engagement;diagnostic biomarker;epigenetic regulation;extracellular vesicles;faculty mentor;immune checkpoint blockade;inter-institutional;melanoma;member;microbiome;molecular oncology;mortality;multidisciplinary;neoplastic cell;novel;novel therapeutic intervention;oncology program;programs;recruit;stem cell biology;therapeutic target;therapy resistant;tissue injury;translational oncology;translational pipeline;tumor;tumor immunology;tumor initiation;tumor metabolism;tumor microenvironment;tumor progression


application_id: 10712118
project_number: 2P30CA177558-11
project_title: Cancer Prevention and Control Research Program
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5464
contact_pi_person_id: 10885868
contact_pi: STAPLETON, JEROD L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Markey Cancer Centers (MCC) Cancer Prevention and Control (CP) Research Program fosters high-impact population-based and community-engaged research with the overarching goal of reducing cancerdisparities in Kentucky. CP research spans the population science translation pipeline from advancingunderstanding of risk factors and intervention targets to developing and testing new interventions to studyingthe process of dissemination and implementation of evidence-based interventions into practice. Impactfulscientific contributions include genetic associations of human papillomavirus and patient survival inoropharyngeal cancer timely regulatory and policy research on novel smokeless tobacco products trials ofinnovative interventions to reduce carcinogenic environmental exposures trials of interventions to promotequality of life outcomes among rural cancer survivors and community implementation trials to prevent hepatitisC transmission and implement cancer prevention and screening guidelines in communities throughoutKentucky and Appalachia. CP impact also extends to public health policy within Kentucky and nationally andin advancing standards of care related to tobacco cessation and lung cancer screening. The CP Programcombines these strengths to address three Aims: Advance the understanding of risk factors and interventiontargets for cancer prevention and control (Aim 1); Develop and test the efficacy of interventions across thecancer control continuum (Aim 2); Study the dissemination and implementation of evidence-basedinterventions (Aim 3). The CP Program has been transformed by substantial strategic investments that haveled to new leadership and by the infusion of multiple recruitments that have expanded the breadth and depth ofprogram research combined with the continued success of long-standing program members. The programspeer-reviewed funding has increased by 50% and NCI funding has grown dramatically by 567% to nowcomprise 33% of peer-reviewed funding compared to 7% in 2017. The maturation of the program is evident ina 24% increase in clinical trial accrual and by the awarding of NCI P01 and UH3 multi-investigator inter-institutional grants and the only NCI T32 focused on rural cancer disparities. CP investigators are highlyengaged with and responsive to the needs of MCCs catchment area residents and are engaged in inter-programmatic research that addresses MCCs catchment research priorities in collaboration with CommunityOutreach and Engagement. Thus the CP Program is integral to achieving the overall MCC mission to reducethe cancer burden with a focus on Kentucky and its most vulnerable populations through research preventiontreatment education and community engagement.

project_terms:
Address;Adoption;Affect;Appalachian Region;Area;Award;Behavioral;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;Cancer Control Research Program;Cancer Survivor;Cancer Survivorship;Caring;Catchment Area;Clinic;Clinical Trials;Collaborations;Communities;Community Outreach;County;Disclosure;Dissemination and Implementation;Early Diagnosis;Education;Electronics;Ensure;Environmental Exposure;Evidence based intervention;Financial Hardship;Fostering;Funding;Future;Genetic Markers;Goals;Grant;Growth;Health Policy;Healthcare;Hepatitis C Transmission;Hospitals;Human Genetics;Human Papillomavirus;Infusion procedures;Intervention;Intervention Studies;Intervention Trial;Investments;Kentucky;Knowledge;Leadership;Malignant Neoplasms;Mission;Modeling;Molecular;NCI Center for Cancer Research;Obesity;Oncology;Outcome;Patient-Focused Outcomes;Patients;Peer Review;Pilot Projects;Policies;Policy Research;Population Sciences;Population Study;Prevention;Prevention Guidelines;Prevention program;Process;Public Health;Quality of life;Radon;Regulation;Research;Research Personnel;Research Priority;Resources;Risk;Risk Factors;Rural;Science;Science Policy;Screening for cancer;Smokeless Tobacco;Survivors;Technology;Testing;Tobacco;Tobacco Use Cessation;Translating;Treatment Efficacy;Universities;Vulnerable Populations;Work;Youth;cancer care;cancer health disparity;cancer prevention;cancer risk;carcinogenicity;cellular oncology;college;community engaged research;community engagement;design;efficacy testing;ethnic minority population;genetic association;genetic epidemiology;implementation intervention;implementation research;implementation science;implementation trial;improved;innovation;inter-institutional;lung cancer screening;malignant oropharynx neoplasm;member;molecular marker;molecular oncology;novel;oncology program;population based;prevent;programs;racial minority population;recruit;risk stratification;routine care;screening guidelines;screening program;smoke-free policy;success;survivorship;tobacco control;tobacco flavor;tobacco products;tobacco regulation;translational oncology;translational pipeline;treatment risk


application_id: 10712117
project_number: 2P30CA177558-11
project_title: Plan to Enhance Diversity
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5463
contact_pi_person_id: 10552456
contact_pi: WILLIAMS, LOVORIA B
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The proposed Plan to Enhance Diversity (PED) at the University of Kentucky (UK) Markey Cancer Center(MCC) under the leadership of Dr. Lovoria Williams (CP) applies an equity lens to MCCs comprehensivemission to reduce the cancer burden with a focus on Kentucky and its most vulnerable populations throughresearch prevention treatment education and community engagement. As the MCC inaugural AssociateDirector (AD) for Equity Diversity and Inclusion Dr. Williams (CP) has a prominent role with direct reporting toMCC Director Dr. B. Mark Evers (TO) as part of MCCs priority on diversity equity and inclusion (DEI) within ahighly collaborative senior leadership team. DEI efforts are fully integrated into MCCs FY24-28 Strategic Planwith a dedicated pillar of activity. PED is supported by DEI Coordinator Ms. Tianna Acree and operatescollaboratively with Cancer Research Training and Education Coordination (CRTEC) and MCC Administration.PED builds on early DEI successes that established a DEI Committee leveraged campus-wide trainee andfaculty career-enhancing programs (such as NIH-funded T32s) and applied a highly successful model of rural-focused cancer research education to the development of new dynamic DEI-focused pathway programs led byCRTEC. Moreover MCCs Leadership and members are participating in training in foundational DEI and healthequity education that will prepare them to cultivate diverse inclusive environments. The overall objectives ofPED are to integrate DEI throughout the fabric of the MCC and to promote a climate that advances inclusiveexcellence in cancer research education and community outreach. Three Specific Aims of the proposed PEDare to: 1) Enhance participation of underrepresented minority (URM) and women trainees staff and faculty inthe cancer center. To achieve this Aim we plan on developing equitable processes to bolster implement andsustain efforts to recruit retain and develop diverse talent; 2) Accelerate the career and leadershipdevelopment of women and URM early career faculty. This Aim will be accomplished by leveraging internaland national research and leadership development programs to support career and research agendasincreasing engagement in MCC decision-making processes and developing a new leadership academy; 3)Establish a sustainable infrastructure to advance DEI throughout the MCC and criteria for monitoring progresstoward achievement of diversity goals. This Aim will be achieved by maintaining the MCC DEI Committeecoalescing DEI resources providing DEI training and developing appropriate methods and timepoints toevaluate fidelity to the methods proposed under each Specific Aim and track DEI progress. Baselinedemographic data of MCC members trainees and staff will allow the examination of data gaps. With continuedCCSG support MCC will build on early successes and MCCs strong infrastructure and will leverageinstitutional commitment to advance workforce diversity of trainees research staff faculty and leadersreflective of the statewide Kentucky catchment area and eventually the nation.

project_terms:
Academy;Acceleration;Achievement;Address;Appalachian Region;Appointment;Area;Black race;Cancer Burden;Cancer Center;Cancer Center Support Grant;Career Choice;Career Mobility;Catchment Area;Climate;Clinical Sciences;Community Outreach;Comprehensive Cancer Center;Data;Decision Making;Dedications;Development;Disparity;Education;Education and Outreach;Electronics;Environment;Equity;Faculty;Funding;Goals;Growth;Hispanic Populations;Infrastructure;Institution;Kentucky;Leadership;Malignant Neoplasms;Methods;Minority;Minority Access;Mission;Modeling;Monitor;NCI-Designated Cancer Center;Not Hispanic or Latino;Oncology;Pathway interactions;Population;Prevention;Process;Program Development;Racial Equity;Recommendation;Reporting;Research;Research Personnel;Research Priority;Resources;Role;Rural;Rural Appalachia;Scholars Program;Science;Strategic Planning;Talents;Textiles;Training;Training and Education;Translational Research;Underrepresented Minority;United States National Institutes of Health;Universities;Vulnerable Populations;Woman;Workforce Development;anticancer research;cancer health disparity;cancer research center director;career;career development;clinical center;clinical encounter;community engagement;demographics;early-career faculty;education research;equity diversity and inclusion;experience;health equity;high school;improved;leadership development;lens;male;member;minority trainee;multidisciplinary;oncology program;programs;recruit;research and development;success;undergraduate student


application_id: 10712116
project_number: 2P30CA177558-11
project_title: Cancer Research Training and Education Coordination
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5462
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) at the University of Kentucky collectively delivers highly successfultraining programs spanning from K-12 to faculty level through the Cancer Research Training and EducationCoordination (CRTEC) component. MCCs CRTEC programs and activities are structured around specific aimsto: 1) Generate early interest in cancer-related careers emphasizing those underrepresented in science; 2)Promote education and career development of a diverse cadre of graduate and postdoctoral cancerresearchers; and 3) Foster research faculty career development in basic population and clinical/translationalsciences. Key education activities address the academic challenges across medically and educationallyunderserved rural Appalachian Kentucky and for underrepresented minorities through support from five grantsthat include an NCI Youth Enjoy Science R25 program. These efforts complement impactful structuredacademic and research training at the graduate postdoctoral and medical residency levels including threeNCI-funded T32 training grants. Through new initiatives such as the recently funded NCI T32 focused onhealth equities and undergraduate research programs targeting underrepresented and underservedpopulations MCCs CRTEC component expands its comprehensive training reach to implement bold diversityinitiatives that complement well-established and emerging state-of-the-art cancer curricula and enrich MCCResearch Programs. The establishment of sustainable NIH-funded Centers of Biomedical ResearchExcellence awards with dedicated cancer themes and associated junior faculty mentorship augment MCCslong-standing American Cancer Society Institutional Research Grant support for early-stage faculty andeffective team-based faculty mentorship mechanisms across basic population and clinical research levels thatare significantly expanding MCCs extramural funding base. Further targeted mentorship of early career clinicalinvestigators through mechanisms such as the Clinical Trials Boot Camp fosters the development ofinvestigator-initiated trials that translate MCC science to the clinic. The MCC Affiliate Network provides aneffective conduit for multi-faceted statewide training of health care professionals in state-of-the-art cancer carewhich is needed to address the tremendous cancer burden within Kentucky and the region. A rich cadre ofseminars symposia meetings and career enrichment activities facilitate successful career development for allindividuals engaged in cancer research and clinical practice. The MCCs collective efforts draw on vitalinstitutional training resources to achieve the overarching goals of this program which are to guide cohesivegrowth and coordinate transdisciplinary education and mentoring endeavors across the MCC and integratethem with efforts campus-wide and nationally. Through coordination supported by MCCs Cancer CenterSupport Grant this comprehensive program will continue to evolve innovative curricula and strategically linkedinitiatives to prepare trainees and faculty for evolving cancer career opportunities.

project_terms:
Academic Training;Address;American Cancer Society;Award;Basic Science;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Career Choice;Catchment Area;Centers of Research Excellence;Clinic;Clinical;Clinical Investigator;Clinical Research;Clinical Trials;Community Outreach;Complement;Data;Dedications;Development;Education;Education Projects;Educational Activities;Educational Curriculum;Educational Status;Electronics;Evolution;Extramural Activities;Faculty;Fostering;Foundations;Funding;Goals;Grant;Growth;Health Professional;High School Student;Individual;Institution;Investments;Kentucky;Link;Malignant Neoplasms;Medical;Medical Residency;Mentors;Mentorship;Middle School Student;Mission;Modernization;NCI Center for Cancer Research;Oncology;Physicians;Population;Population Research;Postdoctoral Fellow;Prevention;Research;Research Personnel;Research Project Grants;Research Training;Resources;Rural Appalachia;Rural Population;Science;Scientist;Structure;Time;Training;Training Programs;Training and Education;Translating;Translational Research;Underrepresented Minority;Underrepresented Populations;Underserved Population;United States National Institutes of Health;Universities;Urban Population;Vulnerable Populations;Youth;anticancer research;base;cancer care;cancer education;cancer prevention;career;career development;cellular oncology;clinical practice;community engagement;design;diversity and inclusion;education research;educational atmosphere;health equity;health training;high school;improved;innovation;interest;investigator-initiated trial;meetings;molecular oncology;next generation;programs;research faculty;rural underserved;symposium;training opportunity;translational oncology;undergraduate research experience;undergraduate student


application_id: 10712115
project_number: 2P30CA177558-11
project_title: Cancer Center Administration
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
subproject_number: 5461
contact_pi_person_id: 78871078
contact_pi: ROGERS, JENNIFER F
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 Markey Cancer Center (MCC) Administration provides efficient administrative support to MCCs DirectorSenior Leadership Research Program leaders Shared Resource Facility (SRF) directors and MCC members.Administration fosters exceptional science and impact through the following Specific Aims: 1) Lead MCCsplanning and evaluation efforts; 2) Foster collaboration through inter- and intra-programmatic activities andinvesting in and leveraging resources and infrastructure; 3) Support MCCs comprehensive researcheducation community outreach and diversity equity and inclusion activities; and 4) Support sustainability andbusiness planning. During the current reporting period Administration has facilitated member science through:1) creating a new FY24-28 MCC Strategic Plan which is coupled with a $64.4M financial commitment andinvestment from UK Leadership in the cancer center; 2) assisting in the restructuring of MCCs ResearchPrograms; 3) expanding MCCs Research Communications Office in key areas to continue robust support ofCCSG-related activity; 4) driving a 128% expansion of MCCs Clinical Protocol and Data Management teamswhich paved the way for a 56% increase in accruals to interventional treatment trials; 5) overseeing a 78%expansion of MCCs physical space which has grown from 128587 sq. ft. to 228237 sq. ft. since 2009; 6)facilitating all MCCs pilot and seed award programs which have awarded $2.2M to investigators since 2018;7) streamlining the membership application and review process; and 8) improving MCCs internal and externalcommunication channels ranging from upgrades to MCCs public-facing website to establishing new channelsfor internal communication among staff leaders. To enhance cancer focus Administration created andimplemented a center-wide policy on determining cancer-relatedness of all grants and contracts listed on DataTable 2. Together these efforts supported an increase in peer-reviewed funding of $11.1M since 2017 and theaddition of 66 new cancer center members. Over the coming five years Administration will work closely withthe MCC Director and Senior Leaders to: 1) implement and evaluate the centers FY24-28 Strategic Plan; 2)implement the planned expansion of MCCs capabilities to lead multi-site clinical trials which represents a$2.2M commitment from the center to build out this new competency; 3) expand diversity equity and inclusionefforts through improvements to MCCs faculty and staff recruitment and retention practices and evaluatingsuccess; 4) expand reporting and analysis capabilities and achieve greater efficiency through theimplementation of CCSG data and electronic regulatory systems; and 5) facilitate planning efforts for anadvanced ambulatory building site work for which is slated to begin in late fall 2022. Through robust planningand evaluation efforts Administration will lead the alignment of MCC functions in support of the centers goal ofachieving Comprehensive Cancer Center status.

project_terms:
Administrative Efficiency;Area;Automobile Driving;Award;Businesses;Cancer Center;Cancer Center Support Grant;Characteristics;Clinical Cancer Center;Clinical Data;Clinical Protocols;Clinical Research;Clinical Treatment;Clinical Trials;Collaborations;Communication;Community Health Education;Community Outreach;Competence;Comprehensive Cancer Center;Contracts;Coupled;Data;Decision Making;Education;Electronics;Ensure;Evaluation;Faculty;Fostering;Funding;Future;Goals;Grant;Growth;Healthcare;Infrastructure;Intervention;Investments;Kentucky;Lead;Leadership;Malignant Neoplasms;Mentors;Mission;Monitor;Multi-Institutional Clinical Trial;NCI Center for Cancer Research;Organization and Administration;Output;Patients;Peer Review;Play;Policies;Process;Reporting;Research;Research Activity;Research Personnel;Resource Sharing;Resources;Role;Science;Site;Strategic Planning;Structure;System;Technology;Training and Education;Universities;Vision;Work;anticancer research;cancer research center director;data management;diversity and inclusion;equity diversity and inclusion;experience;falls;improved;innovation;meetings;member;outreach;programs;recruit;square foot;success;treatment trial;web site


application_id: 10712114
project_number: 2P30CA177558-11
project_title: University of Kentucky Markey Cancer Center Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2023-09-05
opportunity_number: PAR-21-321
application_type: 2
activity_code: P30
ic: CA
serial_number: 177558
program_official: ROBERSON, SONYA
project_start_date: 2013-07-08
project_end_date: 2028-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-F (M1)]
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:
PROJECT SUMMARY/ABSTRACT The Markey Cancer Center (MCC) is a university-based matrix cancer center at the University of Kentucky(UK) with a mission to reduce the cancer burden with a focus on Kentucky and its most vulnerable populationsthrough research prevention treatment education and community engagement. As the only National CancerInstitute (NCI)-designated Cancer Center in the state the MCC is vital to Kentucky the U.S. leader for highestall-site cancer incidence and mortality. Notably recognition of the extraordinary disease burden in Kentuckysvulnerable populations as a significant underpinning of that national ranking shapes the MCC vision and goalsand drives its unique focus on prevalent cancers and cancer risk factors in the catchment population. Over$569M in state institutional and philanthropic investment since 2009 has supported significant research andresource expansion propelling new faculty recruitment program development clinical and shared resourcespace renovations new state-of-the art instrumentation and statewide education and community outreach.MCCs 159 members align with one of three MCC Research Programs: Cancer Prevention and ControlMolecular and Cellular Oncology and Translational Oncology and are supported by seven Shared ResourceFacilities that facilitate cutting-edge research via robust infrastructure specialized expertise and advancedmethods: Biospecimen Procurement and Translational Pathology Biostatistics and Bioinformatics CancerResearch Informatics Flow Cytometry and Immune Monitoring Oncogenomics Patient-Oriented andPopulation Sciences and Redox Metabolism. Significant achievements in this funding period include anincreased research depth and breadth as indicated by increased total cancer-relevant funding (41%) peer-reviewed funding (35%) and NCI funding (55%). Expanded transdisciplinary collaborations driven in partthrough a strategic focus on precision medicine and a more streamlined translational pipeline resulted in 26new therapeutic trials 8 concepts or devices in Phase I or II clinical trials 10 agents or devices undergoing invivo validation 43 patent applications and 17 patents during the current funding periodall based on MCCscience. In collaboration with other U.S. and international cancer centers the number of U- and P-series grantsawarded to the MCC increased by 80%. The number of member publications increased by 28% (total of 1093)with 62% of the publications with cancer investigators at other institutions. Expanded education and traininginitiatives include a new NCI T32 focused on rural cancer health disparities a new NCI R25 Youth EnjoyScience award to engage Appalachian students in cancer research and two new training programsemphasizing diversity equity and inclusion. With unique research strengths and integrated statewidecommunity outreach and engagement MCCs programs provide robust capacity to deliver transformativeinterventional research to Kentuckys underserved populations thereby contributing to national efforts toconquer cancer through discovery and clinical translation cancer prevention and community outreach.

project_terms:
Acceleration;Achievement;Address;Appalachian Region;Award;Basic Science;Behavioral;Bioinformatics;Biometry;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Patient;Catchment Area;Centers of Research Excellence;Climate;Clinical;Clinical Research;Clinical Trials;Clinical Trials Network;Collaborations;Community Outreach;Comprehensive Cancer Center;Development;Devices;Education;Education and Outreach;Epigenetic Process;Faculty Recruitment;Flow Cytometry;Foundations;Funding;Genetic;Geography;Goals;Grant;Immunologic Monitoring;Incidence;Informatics;Infrastructure;Institution;International;Intervention;Intervention Studies;Intervention Trial;Investigational Therapies;Investments;Kentucky;Leadership;Legal patent;Link;Malignant Neoplasms;Mediator;Mentors;Metabolic;Metabolism;Methods;Mission;Molecular;NCI Center for Cancer Research;National Cancer Institute;Needs Assessment;Oncology;Outcome;Oxidation-Reduction;Paper;Participant;Pathology;Patients;Peer Review;Phase;Policies;Population;Population Sciences;Positioning Attribute;Preclinical Testing;Prevalence;Prevention;Program Development;Publications;Publishing;Quality of life;Research;Research Personnel;Resource Sharing;Resources;Risk Factors;Rural;Rural Appalachia;SEER Program;Science;Scientist;Series;Services;Shapes;Signal Transduction;Strategic Planning;Students;Textiles;Therapeutic Clinical Trial;Therapeutic Trials;Training;Training Programs;Training and Education;Translating;Translational Research;Underserved Population;Universities;Validation;Vision;Vulnerable Populations;Work;Workforce Development;Youth;acronyms;anticancer research;burden of illness;cancer care;cancer education;cancer genomics;cancer health disparity;cancer prevention;cancer risk;cancer site;cancer survival;career;cellular oncology;clinical practice;clinical translation;community engagement;community organizations;equity diversity and inclusion;expectation;health disparity;health equity;improved;in vivo;innovation;instrumentation;interdisciplinary collaboration;investigator-initiated trial;member;molecular oncology;mortality;neoplasm registry;next generation;novel therapeutics;patient oriented;personalized diagnostics;personalized therapeutic;precision medicine;programs;recruit;social;translational impact;translational oncology;translational pipeline;treatment response;tumor

public_health_relevance:
PROJECT NARRATIVE As the only NCI-designated Cancer Center in Kentucky the University of Kentucky Markey Cancer Centerserves a statewide catchment area with a population of 4.4 million residents and extraordinary cancerprevalence. In its mission to reduce the cancer burden with a focus on Kentucky and its most vulnerablepopulations through research prevention treatment education and community engagement the center hasmade and will continue to make significant strides in advancing access to quality cancer care; implementingbold transformational research spanning basic translational and population science including clinical trials toaddress Kentuckys unique cancer burden; and introducing innovative population-level interventions toaccelerate translational impact in reducing challenging health disparities and significantly impact patients in thestate and the nation.


application_id: 10711172
project_number: 3R01DK124774-03S1
project_title: Feasibility of implementing time-restricted eating in women with mild cognitive impairment
administering_ic: NIDDK
award_notice_date: 2023-04-27
opportunity_number: RFA-AG-22-025
application_type: 3
activity_code: R01
ic: DK
serial_number: 124774
suffix: S1
program_official: SILVA, CORINNE M
project_start_date: 2021-04-01
project_end_date: 2026-01-31
study_section: Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section[NNRS]
contact_pi_person_id: 7003021
contact_pi: PENDERGAST, JULIE S
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryAlzheimers disease (AD) is an incurable neurodegenerative disease affecting 6.5 million Americans above theage of 65. Currently no pharmacological therapy prevents AD or markedly slows the progression to severedementia. Women have twice the lifetime risk of developing AD compared to men so it is critical to studydisease progression and develop interventions in women. Clinical studies show that circadian rhythm andsleep disruption are associated with cognitive impairment and preclinical markers of AD. Thus therapeuticsthat improve circadian rhythms and sleep may prevent AD development and progression. Numerous preclinicaland clinical studies have shown that time-restricted eating (TRE) a circadian behavioral intervention that alignsfood intake to the active phase improves cardiometabolic health outcomes. Recent studies have shown thatTRE can also improve cognition. Thus TRE is a promising intervention strategy for AD but no study hasinvestigated its efficacy at improving cognition in cognitively impaired individuals. A first step toward our long-term goal of studying TRE efficacy for cognition is to determine whether TRE is feasible in a population withcognitive impairment. This feasibility study will examine the implementation of an 8-week 10-h TREintervention in postmenopausal women with mild cognitive impairment (MCI). We will recruit 15 women withMCI from an ongoing longitudinal study of cognitive aging at the University of Kentucky. Cognitive impairmentsleep and activity rhythms diet composition metabolic assessment body composition and anthropometricmeasures will be assessed at baseline and after the 8-week TRE intervention. For the duration of the studythe times of first and last meals will be collected from participants with an SMS texting system that wedeveloped. Participants will be instructed to eat during a 10-h eating window and fast at night. The primaryoutcome of this study will be adherence to the TRE protocol regimen. This pilot study will also providepreliminary data about the effects of TRE on cognition which are essential for powering a future randomizedclinical efficacy trial.

project_terms:
Adherence;Administrative Supplement;Affect;Age;Alzheimer's Disease;Alzheimer's disease related dementia;American;Award;Behavior Therapy;Body Composition;Brain;Circadian Rhythms;Clinical Research;Cognition;Cognitive aging;Consumption;Data;Dementia;Development;Diet;Disease Progression;Dyslipidemias;Eating;Energy-Generating Resources;Fasting;Feasibility Studies;Future;Goals;Health;Human;Hypertension;Impaired cognition;Impairment;Individual;Intervention;Kentucky;Ketones;Knowledge;Learning;Letters;Longitudinal Studies;Measures;Memory;Metabolic;Metabolic dysfunction;Mus;Neurodegenerative Disorders;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Outcome;Outcome Study;Participant;Persons;Phase;Pilot Projects;Population;Postmenopause;Protocols documentation;Randomized;Regimen;Research;Risk;Role;Sleep;Sleep disturbances;System;Testing;Text Messaging;Therapeutic;Time;Time Study;Time-restricted feeding;Universities;Woman;Work;cardiometabolism;circadian;cohort;design;efficacy clinical trial;efficacy study;efficacy testing;improved;lifetime risk;men;mild cognitive impairment;pharmacologic;pre-clinical;preclinical study;prevent;primary outcome;randomized clinical trials;recruit

public_health_relevance:
Project NarrativeTargeted interventions that improve cognitive impairment and delay onset of Alzheimers disease areparticularly important for women who have twice the lifetime risk of developing Alzheimers disease comparedto men. This project will investigate the feasibility of implementing a time-restricted eating behavioralintervention in postmenopausal women with mild cognitive impairment which is a first step in developingcircadian-based eating interventions for women with cognitive impairment.


application_id: 10710219
project_number: 5R21DA055879-02
administering_ic: NIDA
award_notice_date: 2023-08-07
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: DA
serial_number: 055879
program_official: NAIR, SUNILA GOPI
project_start_date: 2022-09-30
project_end_date: 2025-08-31
study_section: Neurobiology of Motivated Behavior Study Section[NMB]
contact_pi_person_id: 9706320
contact_pi: GIPSON-REICHARDT, CASSANDRA D
other_pis: Not Applicable
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: 2023-09-01
project_title:
Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use

project_abstract:
PROJECT SUMMARY/ABSTRACTLong-term smoking cessation is more difficult to achieve in women than men and more than 170000 womendie of complications related to smoking in the United States each year. Cyclical variations in hormone levels aredifferentially associated with craving and relapse to smoking in women with increases in 17-estradiol (E2) andprogesterone being associated with addiction vulnerability and resilience respectively. Further women can bechronically maintained on synthetic hormones contained in oral contraceptives which contain ethinyl estradiol(EE) a synthetic orally bio-available estrogen and a synthetic progesterone termed progestins. EE is morepotent and bioavailable than the endogenous E2 and women are prescribed EE during critical periods ofreproductive development in adolescence and young adulthood. Further progestins such as levonorgestrel(LEVO) or norethisterone acetate (NETA) can have either beneficial or potentially deleterious effects on women.Despite this there are no studies to date that have examined the impact of these synthetic hormones on nicotineneurobehavioral outcomes in females. Nicotine produces cellular adaptations such as changes in synapticplasticity in brain regions associated with drug reward especially within the nucleus accumbens core (NAcore).Mechanistically the E2 receptors (ERs) are located on medium spiny neurons (MSNs) within the NAcore whichwe show undergo hormone-dependent changes in synaptic plasticity (measured via the ratio of AMPA to NMDAcurrents) following nicotine self-administration (SA). Further we show that EE alone partially rescuesovariectomy-induced decreases in nicotine consumption and demand and LEVO decreases nicotineconsumption during SA as compared to EE+LEVO treatment in ovary-intact females. Here we will systematicallyevaluate the contributions of two different progestins LEVO or NETA to nicotine demand and NAcore glutamateplasticity either independently or interactively with EE in ovary-intact females. Specifically Aims 1a and 1b willfocus on LEVO whereas Aims 2a and 2b will focus on NETA. We hypothesize that these two progestins willdifferentially impact nicotine demand and glutamate plasticity such that LEVO alone will reduce nicotine demandand increase AMPA/NMDA ratios and NETA alone will increase nicotine demand and decrease AMPA/NMDAratios. We hypothesize that when combined with EE the protective effects of LEVO will be occluded. Furtherwe hypothesize that EE+NETA will enhance nicotine demand and further decrease AMPA/NMDA ratios thusexacerbating the neurobehavioral outcomes associated with nicotine use. These studies will systematicallyevaluate the contributions of exogenous synthetic hormones contained in oral contraceptives to nicotine use andwill uncover unknown consequences on neural circuitry. Findings from this R21 will lay a foundation for a futureR01 application to further delve into examination of progestins contained in various other contraceptiveformulations. Together these studies may provide insight into conditions that impact reproductive cycles whichwill allow a mechanistic understanding of nicotine use motivation in women.

project_terms:
Acids;Adolescence;Affect;Animals;Area;Automobile Driving;Behavioral;Biological Availability;Brain region;Caring;Cells;Chronic;Contraceptive Agents;Contraceptive Usage;Data;Electrophysiology (science);Estradiol;Estradiol Receptors;Estrogens;Ethinyl Estradiol;Ethinyl Estradiol/Levonorgestrel;Exposure to;Female;Formulation;Foundations;Future;Glutamates;Goals;Hormone use;Hormones;In Vitro;Intravenous;Levonorgestrel;Measures;Methods;Motivation;N-Methylaspartate;Neurobiology;Neuronal Plasticity;Neurons;Nicotine;Nicotine Dependence;Norethisterone Acetate;Nucleus Accumbens;Oral;Oral Contraceptives;Outcome;Ovarian hormone;Ovariectomy;Ovary;Pathway interactions;Play;Procedures;Progesterone;Progestins;Public Health;Publishing;Rattus;Relapse;Research;Rewards;Role;Saline;Self Administration;Smoke;Smoking;Substance Use Disorder;Synaptic plasticity;System;Time;Toxic effect;Translations;United States;Variant;Woman;addiction;behavioral economics;birth control;cigarette craving;craving;critical period;drug reward;insight;men;neural circuit;neurobehavioral;nicotine reward;nicotine self-administration;nicotine use;novel;patch clamp;prevent;protective effect;reproductive;reproductive development;resilience;reward circuitry;smoking cessation;xenoestrogen;young adult

public_health_relevance:
PROJECT NARRATIVE Women are typically more vulnerable to substance use disorders (SUDs) and long-term smokingcessation is more difficult to achieve in women than men. As well ovarian hormones in women can affectcigarette craving and relapse and synthetic hormones contained in oral contraceptives may impact nicotine useand neurobiology. The proposed research has the potential to uncover novel mechanisms by which syntheticestrogen and various progestins modulate nicotine reward circuitry.


application_id: 10708981
project_number: 5R01DC020303-02
project_title: Perception of speech in context by listeners with healthy and impaired hearing
administering_ic: NIDCD
award_notice_date: 2023-07-26
opportunity_number: PAR-21-063
application_type: 5
activity_code: R01
ic: DC
serial_number: 020303
program_official: KING, KELLY ANNE
project_start_date: 2022-09-22
project_end_date: 2027-07-31
study_section: Auditory System Study Section[AUD]
contact_pi_person_id: 11529504
contact_pi: STILP, CHRISTIAN EDMUND
other_pis: WINN, MATTHEW BRANDON
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
project_abstract:
Project Summary / AbstractPerceptual systems operate in context: perception of a given object/event is influenced by the objects/eventsthat surround it. Speech perception operates in the same way where perception of speech sounds is heavilyinfluenced by the acoustic properties of contextual sounds that surround them. These acoustic context effectsare critically important to perception because they help maintain perceptual constancy in the face ofconsiderable variability in speech acoustics and listening environments. Despite this importance there is apoor understanding of how acoustic context shapes speech perception. The well-established ways ofmeasuring speech perception routinely present stimuli without any context or when they do it is to study asingle context effect in quiet for listeners with normal hearing (NH). These approaches severely impedeunderstanding of speech perception in everyday listening conditions (in context amidst background noise) andfor listeners with hearing difficulties. The long-term goal of this project is to improve our understanding of themechanisms underlying these acoustic context effects in speech perception in normal and impaired auditorysystems. This goal is addressed through three specific aims. The first aim is to define the unifying relationshipsbetween different context effects in speech perception by NH and hearing-impaired (HI) populations.Experiments in the first aim utilize an individual differences approach to explore auditory context effects as aunified system rather than individual isolated effects. The second aim is to study the impact of backgroundnoise on these context effects for NH and HI populations. Experiments in the second aim will test competingpredictions regarding whether noise diminishes the influence of context via masking or enhances the influenceof context via streaming. The third aim is to investigate context effects in speech perception by cochlearimplant (CI) users. Experiments in the third aim with real- and simulated-CI listening will elucidate mechanismsunderlying context effects and the impacts of different aspects of CI processing. These aims are supplementedby computational modeling of neural responses to the speech stimuli in order to clarify peripheral versuscentral mechanisms underlying these context effects. Overall the results will provide new insights into howNH HI and CI populations perceive sounds in the context of other sounds and in background noise. Theseefforts will produce better understanding of auditory perception with the realistic and prominent constraint ofcontextual influence and will help to provide a neural and behavioral framework for translational applications.

project_terms:
Acoustics;Address;Affect;Auditory;Auditory Perception;Auditory system;Behavioral;Bypass;Cochlear Implants;Code;Communication;Computer Models;Cues;Environment;Event;Experimental Models;Foundations;Frequencies;Goals;Grain;Hearing Aids;Hearing problem;Impairment;Individual;Individual Differences;Intervention;Investigation;Knowledge;Link;Measures;Methods;Modeling;Nerve;Noise;Pattern;Perception;Peripheral;Play;Population;Process;Property;Psychoacoustics;Reporting;Role;Sensorineural Hearing Loss;Shapes;Speech;Speech Acoustics;Speech Perception;Speech Sound;Stimulus;Stream;System;Testing;Time;Work;auditory pathway;auditory processing;contrast enhanced;experimental study;hearing impairment;improved;insight;model design;neural;neural model;neuroadaptation;neuromechanism;normal hearing;response;sensory system;sound;spectral energy;translational applications;translational framework

public_health_relevance:
This project investigates the perception of speech in the context of surrounding sounds for the normal auditorysystem and the effects of background noise hearing loss and cochlear implant processing on speechperception. These context effects play a critically important in perception allowing us to maintain stableperception despite considerable variability in sounds and in listening environments. An improvedunderstanding of context effects should lead to improvements in hearing aids and cochlear implants which willhelp individuals with hearing difficulties communicate more effectively.


application_id: 10708858
project_number: 5U01DE031223-02
project_title: Susceptibility Patterns for Grade C Periodontitis in Young Individuals
administering_ic: NIDCR
award_notice_date: 2023-08-29
opportunity_number: PAR-20-060
application_type: 5
activity_code: U01
ic: DE
serial_number: 031223
program_official: CHOU, ALICIA YESIU
project_start_date: 2022-09-22
project_end_date: 2027-08-31
study_section: ZDE1-YM(12)
contact_pi_person_id: 8964577
contact_pi: SHADDOX, LUCIANA MACCHION
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: 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 DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Academy;Actinobacillus actinomycetemcomitans;Adopted;Affect;African ancestry;Age;American;Bacteria;Characteristics;Clinical;Communities;Complex;DNA;DNA sequencing;Development;Diagnosis;Dideoxy Chain Termination DNA Sequencing;Disease;Disease Progression;Economics;Elderly;Environment;Environmental Exposure;Epithelial Cells;Esthetics;Etiology;European;Exhibits;Family;Genes;Genetic;Genetic Predisposition to Disease;Genotype;Geographic Locations;Gingival Crevicular Fluid;Goals;Immune response;Incisor;Individual;Inflammation Mediators;Inflammatory;Inflammatory Response;Link;Metagenomics;Molecular;Multicenter Studies;Names;Oral;Pathogenesis;Pathway Analysis;Pathway interactions;Pattern;Periodontitis;Phenotype;Population;Predisposition;Property;Public Health;Rehabilitation therapy;Saliva;Sampling;Series;Shotguns;Siblings;Site;Susceptibility Gene;Taxonomy;Terminology;Testing;Tooth structure;Variant;Virulence;Virulent;Work;candidate identification;case control;cohort;data integration;disease diagnosis;early onset;exome sequencing;gene interaction;genetic association;genetic variant;genome-wide analysis;high risk;individualized medicine;metagenome;microbial;microbial colonization;microbial community;microbiome;neutrophil;oral cavity epithelium;oral microbiome;peripheral blood;social;targeted treatment;transcriptome;transcriptome sequencing


application_id: 10708156
project_number: 5U01DK135111-02
project_title: Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of Kentucky
administering_ic: NIDDK
award_notice_date: 2024-04-18
opportunity_number: RFA-DK-21-020
application_type: 5
activity_code: U01
ic: DK
serial_number: 135111
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2022-09-25
project_end_date: 2027-12-31
study_section: ZDK1-GRB-9(O1)
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:
Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of KentuckyAbstractFor insulin-treated people with Type 1 Diabetes (T1D) hypoglycemia is the rate limiting step in their goals toappropriately control their blood sugar and avoid long-term diabetes complications. Unfortunately repeatedepisodes of hypoglycemia have been shown to induce a pathological process leading to impaired awarenessof hypoglycemia (IAH) and an impaired counterregulatory response hypoglycemia that increases the risk forlife-threatening hypoglycemia. This grant application (in response to RFA-DK-21-020) seeks to establish a 10-site clinical consortium to determine the factors that contribute to the heterogeneity in the restoration of IAHand improved counterregulatory responses in adult individuals with T1D. It is proposed to test the hypothesisthat a combination of 1) advanced diabetes care technology comprised of a hybrid closed loop insulin pumpwith continuous glucose monitor (CGM) coupled with 2) intensive hypoglycemia avoidance education will leadto a decrease in the frequency/severity of hypoglycemia and thereby improve the awareness of hypoglycemiaand improve the counterregulatory response. The specific aims of this proposal as outlined in the RFA are; 1)determine if diabetes care with use of the most up-to-date management strategies (i.e. a hybrid closed loopsystem and hypoglycemia avoidance education) which optimizes HbA1c while minimizing hypoglycemia canrestore awareness of hypoglycemia in individuals with T1D and IAH 2) determine the physiological factors thatare associated with restoration of hypoglycemia awareness and counterregulatory response including but notlimited to age duration of diabetes and metrics of glycemia (eg time in range time spent in hypoglycemia orother CGM metrics) and 3) determine the association of the current self-report questionnaires (or develop newmetrics) for identification of IAH with measurement of CRR using "state of the art" metabolic assessments i.e.hypoglycemic hyperinsulinemic clamps. The University of Kentucky is well-poised to contribute to this valuableconsortium effort because 1) the University has the requisite institutional infrastructure to support all aspects ofthis research 2) this proposal outlines several novel approaches to measure and analyze hypoglycemiaawareness 3) the PI has assembled an experienced leadership team has the requisite expertise in T1Dsubject recruitment and conducting hypoglycemia awareness studies and importantly 4) this site will providethe NIDDK with access to unique pool of US-based often understudied rural study subjects with T1D.

project_terms:
Adult;Age;Applications Grants;Awareness;Blood Glucose;Caring;Clinical Research;Closure by clamp;Complications of Diabetes Mellitus;Continuous Glucose Monitor;Coupled;Development;Diabetes Mellitus;Education;Event;Failure;Frequencies;Glucose;Glycosylated hemoglobin A;Goals;Heterogeneity;Hormones;Hybrids;Hyperinsulinism;Hypoglycemia;Impairment;Individual;Infrastructure;Institution;Insulin;Insulin Infusion Systems;Insulin-Dependent Diabetes Mellitus;Intervention;Kentucky;Leadership;Life;Measurement;Measures;Metabolic;Methodology;National Institute of Diabetes and Digestive and Kidney Diseases;Pathologic Processes;Patient Self-Report;Patients;Persons;Physiological;Play;Questionnaires;Recurrence;Research;Research Project Grants;Risk;Role;Rural;Severities;Site;Study Subject;Symptoms;System;Technology;Testing;Time;U-Series Cooperative Agreements;Universities;burden of illness;clinical research site;counterregulation;experience;follow-up;improved;novel;novel strategies;recruit;response;restoration

public_health_relevance:
Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of KentuckyNarrativeFor people with Type 1 Diabetes (T1D) who must use insulin daily to stay alive hypoglycemia (low blood sugar)is the rate limiting step in their goals to appropriately control their blood sugar and avoid long-term diabetescomplications. People with T1D often develop an inability to sense when their blood sugar is low (known asimpaired awareness of hypoglycemia) that increases their risk for life-threatening episodes of severehypoglycemia. This grant application seeks to establish a 10-site clinical consortium to determine if advanceddiabetes care technology coupled with intensive hypoglycemia avoidance education will improve their awarenessof hypoglycemia and thus decrease their risk for life-threatening low blood sugar events.


application_id: 10708057
project_number: 5K99AA030627-02
project_title: Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH
administering_ic: NIAAA
award_notice_date: 2023-08-02
opportunity_number: PAR-21-271
application_type: 5
activity_code: K99
ic: AA
serial_number: 030627
program_official: LIN, LI
project_start_date: 2022-09-21
project_end_date: 2023-09-30
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 14169641
contact_pi: HARDESTY, JOSIAH E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract:Alcohol-associated hepatitis (AH) is a clinical manifestation of alcohol-associated liver disease (ALD) that has avery poor prognosis. Current treatments are ineffective and liver transplantation is the only long-term solution.The liver has the unique ability to regenerate post-injury but in ALD/AH this process becomes compromised.Mitochondria dysfunction is a hallmark of ALD and AH that can contribute to compromised liver regeneration.Mitochondria enriched with cardiolipin maintain the energy requirements (e.g. ATP) necessary for hepatocyteproliferation and liver regeneration. Preliminary data demonstrate that hepatic cardiolipin synthesis iscompromised in clinical AH and experimental AH. Cardiolipin is required to maintain mitochondrial bioenergeticsand undergoes oxidation and depletion in ALD compromising liver regeneration. However treatment withcardiolipin or elamipretide (drug that prevents cardiolipin oxidation) can restore hepatocyte mitochondrial functionand proliferation. The aim of this study is to determine if cardiolipin supplementation and preservation willpromote liver regeneration via maintenance of ATP synthesis and prevention of hepatocyte apoptosis alleviatinghepatic insufficiency in AH. This study uses pre-clinical animal models and human in vitro models of AH toassess the treatment efficacy of cardiolipin supplementation and preservation. Aim 1 will determine if mice withcardiolipin deficient hepatocytes have compromised liver regeneration due to loss of mitochondrial ATPsynthesis in a model of AH. Aim 2 will test whether treatment with cardiolipin and elamipretide will enhancehepatic mitochondrial function liver regeneration and proliferating hepatocyte populations in an experimentalanimal model of AH. Aim 3 will identify cardiolipin species in human AH liver and plasma and assess their effecton hepatocyte proliferation and inflammatory responses in immune cells. The K99-phase (Aim 1) will providetraining in assaying liver regeneration and mitochondrial function sc-RNASeq analysis and use of a mousedeficient in hepatocyte cardiolipin. This MOSAIC K99/R00 proposal will provide the training necessary (K99) tobuild a solid research foundation providing a pathway to independence as an independent researcher in the fieldof ALD and liver regeneration (R00). Findings from this study will identify a therapeutic strategy to treat AH viaenhanced liver regeneration which could replace the only long-term treatment alternative liver transplantation.

project_terms:
ATP Synthesis Pathway;Affect;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic liver damage;Alcohols;Animal Model;Animals;Apoptosis;Binding;Bioenergetics;Biogenesis;Biological Assay;Biological Markers;Cardiolipins;Cells;Cessation of life;Clinical;Clinical Trials;Culture Media;Data;Dextrins;Dose;Enzymes;Ethanol;Euthanasia;Evaluation;Experimental Animal Model;Foundations;Galactosamine;Genes;Genus Hippocampus;Hepatic;Hepatic Insufficiency;Hepatitis;Hepatocyte;Human;Immune;Impairment;In Vitro;Inflammation;Inflammatory Response;Injections;Injury;Lead;Lipids;Liver;Liver Mitochondria;Liver Regeneration;Liver diseases;LoxP-flanked allele;Maintenance;Maltose;Measurement;Mediating;Mitochondria;Mitochondrial Myopathies;Modeling;Mus;Natural regeneration;Oxidative Phosphorylation;Partial Hepatectomy;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phase;Phospholipids;Plasma;Population;Prevention;Process;Prognosis;Proliferating;Proliferation Marker;Proteins;Regimen;Research;Research Personnel;Respiratory Chain;Rodent;Role;Safety;Sampling;Solid;Sorting;Structure;Supplementation;TNF gene;Tail;Testing;Therapeutic;Training;Translations;Treatment Efficacy;Veins;Vesicle;Viral;Viral Genome;alternative treatment;chronic liver disease;cytochrome c;cytokine;disorder control;feeding;hepatocyte injury;improved;in vitro Model;ineffective therapies;lipidomics;liver cell proliferation;liver function;liver transplantation;male;mitochondrial dysfunction;mitochondrial membrane;mortality;novel;oxidation;particle;patient prognosis;pharmacologic;pre-clinical;preclinical study;preservation;prevent;problem drinker;response;restoration;single-cell RNA sequencing;therapeutically effective;treatment arm;treatment strategy

public_health_relevance:
Project Narrative:This study will aim to exploit the livers ability to regenerate in order to reverse alcohol-induced liver damagecommon in alcoholic-associated liver disease (ALD) and alcohol-associated hepatitis (AH). Specifically the studywill determine whether preservation and/or supplementation of hepatic cardiolipin promotes liver regeneration inALD/AH via multiple models (animal in vitro and human samples). Findings from this pre-clinical study will leadto the evaluation of the safety dose tolerance and efficacy of cardiolipin lipid vesicles and elamipretide as atreatment strategy for ALD/AH in clinical trials.


application_id: 10706936
project_number: 2R25CA221765-06
project_title: Appalachian Career Training in Oncology (ACTION) Program
administering_ic: NCI
award_notice_date: 2023-09-20
opportunity_number: RFA-CA-21-020
application_type: 2
activity_code: R25
ic: CA
serial_number: 221765
program_official: GHOSH, SANGEETA AHUJA
project_start_date: 2018-09-18
project_end_date: 2028-08-31
study_section: Institutional Training and Education Study Section (F)[NCI-F]
contact_pi_person_id: 11045331
contact_pi: VANDERFORD, NATHAN LANE
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:
PROJECT SUMMARY/ABSTRACT The rural Appalachian Kentucky region has the highest cancer incidence and mortality rates in the UnitedStates and it is also one of the most economically disadvantaged medically underserved and poorly educatedregions of the country. These disparities reveal a critical need for educational and scientific workforcepreparedness intervention strategies targeted to this population. Through a Continuing Umbrella of ResearchExperiences (CURE) supplement in 2016 the research clinical care educational and outreach strengths of theUniversity of Kentuckys Markey Cancer Center were leveraged to create the Appalachian Career Training InONcology (ACTION) Program which has been funded as a Youth Enjoy Science education intervention since2018. In this renewal each year the ACTION Program will immerse 20 underrepresented high school and 20undergraduate students from Appalachian Kentucky in mentored cancer research cancer care observationexperiences cancer education and career development activities as well as hands-on community outreachactivities. The goal of the program is to enhance the diversity of the biomedical workforce by preparingunderrepresented Appalachian Kentucky high school and undergraduate students for biomedical careers whilealso increasing the communitys understanding of cancer thereby addressing the cancer and educationdisparities in Appalachian Kentucky and beyond. Impacts of the program will include: 1) supporting studentsmatriculation into post-secondary professional and/or graduate biomedical degree programs; 2) instilling instudents a lifelong commitment to research education/outreach and/or health care careers focused on thecancer burden and unique challenges in Appalachian Kentucky and beyond; and 3) enhancing the AppalachianKentucky communitys understanding of cancer cancer research and clinical care and linking these facets tothe benefits of science education. The overarching goal and the program impacts will be accomplished throughthree Specific Aims: 1) to develop students cancer research knowledge and skills through cross-disciplinaryfaculty- and peer-mentored research training experiences; 2) to enhance students career preparation byproviding cancer education and career development curriculum through faculty- and peer-led coursesworkshops seminars and career coaching and mentoring; and 3) to increase the understanding of the researchand clinical aspects of cancer and the importance of science education among students and teachersparents/caregivers and families of ACTION students and general community members through impactfuloutreach activities in students communities. New features of the program will include virtual research educationexperiences that complement hands-on research and education activities a multi-institutional virtual outreachprogram and a cancer curriculum outreach program for middle and high school students and teachers. Withsignificant momentum achieved since its creation the ACTION Program will continue having a transformationalimpact on Appalachian Kentucky students their families and their communities.

project_terms:
Academic achievement;Achievement;Address;Appalachian Region;Area;Bachelor's Degree;COVID-19 pandemic;Cancer Burden;Cancer Center;Cancer Research Project;Caregivers;Clinical;Communities;Community Outreach;Complement;Country;County;Degree Completion;Degree program;Disparity;Doctor's Degree;Early Intervention;Education;Education and Outreach;Educational Activities;Educational Curriculum;Educational Intervention;Educational workshop;Faculty;Family;Female;Funding;Goals;Health;Health behavior;Healthcare;High School Student;Home;Incidence;Income;Individual;Institution;Intervention;Kentucky;Knowledge;Link;Malignant Neoplasms;Mentors;Mentorship;Middle School Student;National Cancer Institute;Oncology;Parents;Population;Poverty Areas;Preparation;Readiness;Research;Research Activity;Research Training;Rest;Rural;Rural Appalachia;Science;Students;Target Populations;Training;Training and Education;Underrepresented Populations;Underrepresented Students;United States;Universities;Youth;anticancer research;burden of illness;cancer care;cancer education;cancer health disparity;career;career development;career preparation;clinical care;curriculum development;economic disparity;economic indicator;education research;experience;faculty mentor;hands on research;health inequalities;high school;higher education;matriculation;medically underserved;member;mortality;oncology program;outreach;outreach program;peer;peer coaching;peer networks;programs;science education;skills;social;social health determinants;socioeconomics;teacher;training opportunity;undergraduate student;virtual

public_health_relevance:
PROJECT NARRATIVEThe renewal of the University of Kentucky Markey Cancer Centers Appalachian Career Training In ONcology(ACTION) Program will continue a culturally centered cancer education and training opportunity for studentsfrom rural disease-burdened low socioeconomic and low education-attainment Appalachian Kentuckycommunities. The program will enhance the diversity of the biomedical workforce by preparing underrepresentedAppalachian Kentucky high school and undergraduate students for biomedical careers. ACTION will alsoincrease the communitys understanding of cancer thereby addressing the cancer and education disparities inAppalachian Kentucky and beyond.


application_id: 10706662
project_number: 3R35GM131807-05S1
project_title: Hedgehog Signaling in the Brain Contributes to Alzheimers Disease in a Drosophila Model
administering_ic: NIGMS
award_notice_date: 2023-07-20
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: GM
serial_number: 131807
suffix: S1
program_official: CHOW, CHI-WING
project_start_date: 2019-09-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZRG1(55)-R]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Abstract:Hedgehog (Hh) signaling plays critical roles in pattern formation embryonic development and cell growthcontrol; however its function(s) in adulthood remain largely unknown although the mylfunction of Hh signalingcauses several types of cancer. Hh signaling has also been shown to be involved in neurodegenerative diseaseand shown to regulate the proliferation of neuroal stem cells. It is unknown whether Hh signaling is involved inAlzheimers disease. Transduction of the Hh signal requires the G protein-coupled receptor (GPCR) familyprotein Smoothened (Smo) in both insects and mammals. Recent studies have demonstrated that cholesterolactivates Smo through direct interaction and possibly covalent attachment. Whether and how cholesterolbiosynthesis pathway regulates Smo are unclear. We recently discovered that Hh signaling activity maintainsthe viability of dopaminergic neurons in Drosophila adult brain. Inactivation of Hh signaling significantlydecreased the lifespan of adult flies. In addition we identified a non-canonical cholesterol biosynthesis pathwaythat critically regulates Smo. We have established a Alzhermers disease model by expressing human amyloidbeta (A) in adult flies. We hypothesize that the non-canonical cholesterol biosynthesis pathway plays a role incompromising the defects caused by A expression. We will determine whether cholesterol biosynthesis protectsdopaminergic neurons in the adult brain and modulates Drosophila lifespan (Aim 1). We will determine whethercholesterol biosynthesis provide a protective effect in A-induced neurodegeneration of the Alzheimers diseasemodel (Aim 2). Proposed studies use a combination of genetic and biochemical approaches to build on priorcontributions and to transition to newly emergent avenues of inquiry. The knowledge gained from this study willprovide novel insights into mechanisms of Hh signaling in the protection of neurodegeneration and Alzheimersdisease.

project_terms:
Adipose tissue;Adult;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Amyotrophic Lateral Sclerosis;Applications Grants;Binding;Biochemical;Brain;Cell surface;Cholesterol;Critical Pathways;Defect;Development;Dimerization;Disease;Disease model;Drosophila genus;Embryo;Embryonic Development;Endocytosis;Enzymes;Erinaceidae;Exhibits;Family;Foundations;Future;G-Protein-Coupled Receptors;Genetic;Genetic Transcription;Goals;Health;Human;Hydroxymethylglutaryl-CoA reductase;Insecta;Investigation;Knowledge;Laboratories;Lipase;Lipolysis;Locomotion;Longevity;Mammals;Mediating;Metabolic;Modeling;Molecular;Nerve Degeneration;Neurodegenerative Disorders;Neuroglia;Neurotensin;Obesity;Optic Lobe;Pathway interactions;Pattern;Pattern Formation;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Process;Production;Proliferating;Protein Family;Regulation;Research;Role;Signal Transduction;Solid;Sumoylation Pathway;Testing;Ubiquitination;cancer type;cell growth;cholesterol biosynthesis;diagnostic tool;dopaminergic neuron;fly;fused in sarcoma;gain of function;hedgehog signal transduction;human disease;in vivo;insight;interest;lamin B receptor;loss of function;member;morphogens;novel;novel therapeutic intervention;overexpression;phosphatidylinositol 4-phosphate;protective effect;smoothened signaling pathway;stem cells;transcription factor

public_health_relevance:
PROJECT NARRATIVEHedgehog (Hh) signaling is known for its roles in directing processes such as cell growth and patterning.Investigation of how Hh signaling protects the neurodegeneration defects in a Drosophila Alzheimers diseasemodel will provide insights into how Hh signaling is involved in neurodegenerative diseases and create novelconcepts of Alzheimers disease treatment.


application_id: 10706464
project_number: 5R01AA029488-02
administering_ic: NIAAA
award_notice_date: 2023-07-12
opportunity_number: PA-20-184
application_type: 5
activity_code: R01
ic: AA
serial_number: 029488
program_official: ZHA, WENXING
project_start_date: 2022-09-20
project_end_date: 2023-08-31
study_section: Special Emphasis Panel[ZRG1-RPHB-M(02)M]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: LEEMAN, ROBERT F.
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Linking Impulsivity Domains and Subjective Response to Alcohol in Young Adults Using Lab and Daily Assessment Methods

project_abstract:
PROJECT SUMMARY/ABSTRACTYoung adult alcohol misuse is an urgent growing public health crisis as young adults have the highest alcoholuse disorder rates of any age group with rates increasing in young women. Interventions for this population arehampered by small effects few options and lack of tailoring to salient risk factors. A recent review in Addictionargued that research informing interventions fails to account for the complexity of relationships among factorscontributing to young adult alcohol misuse. We will address these needs by examining relationships betweentwo cardinal etiologic risk factors: impulsivity and subjective response to alcohol (SR). Despite theoretical andbiological links between them little is known about relations between the two risk factors or how associationsbetween them may promote young adult alcohol misuse longitudinally and on a momentary or daily basis. Priortheory and evidence linking impulsivity and positive rewarding alcohol effects have been primarily learning andexpectancy based. Here based on exciting preliminary results we posit an inherent biological link betweenimpulsivity and high-risk SR (elevated stimulation and dampened sedation). This research is nascent withmultiple gaps in knowledge. We will address these gaps by examining impulsivity pre-drinking SR and alcoholuse in a lab setting and via seven 10-day daily assessment periods over 2 years using ecological momentaryassessment (EMA) (N=250 50% female). Using self-report and both lab and mobile tasks we will characterize3 unique established impulsivity domains: poor inhibitory control delay discounting and negative urgency. SRwill be assessed at successive breath alcohol levels using precision intravenous (IV) methods in the labfollowed by opportunity to self-administer more IV alcohol. We will also measure SR at roughly comparableestimated blood alcohol levels via daily EMA methods. This design enables testing of SR early in a drinkingevent as a predictor of in-lab and daily alcohol use along with alcohol use and consequences over time plusSRs potential role as a mediator of impulsivity/alcohol relations. Recent findings indicate daily changes inimpulsivity predict subsequent drinking and consequences. These types of changes are challenging to capturewith lab methods only. Daily measures also enable modeling of both person-level individual differences anddaily within-subject effects. However there are no published studies relating daily impulsivity and SRmeasures. In this study we will: 1) determine relations between lab-based impulsivity and SR; 2) determinerelations between daily impulsivity and SR; and 3) relate impulsivity and SR to alcohol misuse longitudinally.We hypothesize impulsivity will relate to heightened stimulation and less sedation following alcohol and that SRwill partially mediate relations between impulsivity and alcohol misuse. Evidence of links between specificimpulsivity domains and SR longitudinally and on a momentary/daily basis will point to specific interventiontargets to ameliorate two critical vulnerability factors for young adult alcohol misuse. Thus we will: 1) identifymechanisms of alcohol action and 2) facilitate prevention and treatment research: two NIAAA priority areas.

project_terms:
Accounting;Alcohol consumption;Alcohols;Area;Biological;Biological Markers;Biosensor;Blood alcohol level measurement;Data;Ecological momentary assessment;Etiology;Event;Exanthema;Expectancy;Failure;Female;Impulsivity;Individual Differences;Intervention;Intravenous;Knowledge;Learning;Life;Link;Measures;Mediating;Mediator;Methods;Mission;Modeling;National Institute on Alcohol Abuse and Alcoholism;Outcome;Participant;Patient Self-Report;Persons;Population Intervention;Prevention;Prevention Research;Public Health;Publishing;Research;Rewards;Risk;Risk Factors;Role;Sedation procedure;Self Administration;Sex Differences;Testing;Time;Woman;Wrist;addiction;adolescent alcohol misuse;age group;alcohol consequences;alcohol effect;alcohol intervention;alcohol measurement;alcohol misuse;alcohol response;alcohol reward;alcohol sensitivity;alcohol use disorder;design;discounting;drinking;examination questions;high risk;innovation;lectures;men;negative affect;novel;pharmacologic;preference;protective factors;response;theories;trait;treatment research;young adult;young woman

public_health_relevance:
Findings from this project will determine the relationship between two vulnerability factors for Alcohol UseDisorder (AUD) in young adults: impulsivity and subjective response to alcohol. The results will identify badlyneeded novel targets for prevention and treatment efforts to simultaneously reduce impulsivity and subjectiveresponses in at-risk young adults. As such the project is directly relevant to NIAAAs mission to identifymechanisms of alcohol action and facilitate prevention and treatment research.


application_id: 10705023
project_number: 5R01HL160910-02
project_title: Platelet Metabolism in Diabetes Mellitus
administering_ic: NHLBI
award_notice_date: 2023-07-07
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 160910
program_official: GOLDBERG, ILANA GRACE
project_start_date: 2022-09-20
project_end_date: 2026-06-30
study_section: Hemostasis, Thrombosis, Blood Cells and Transfusion Study Section[HTBT]
contact_pi_person_id: 8688832
contact_pi: WANG, QINGJUN
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: 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 Heart disease and stroke are the No. 1 and 5 causes of deaths in the US. Type 1 diabetes mellitus (T1DM)significantly increases the risk for heart attacks and strokes. Intense glycemic control has been reported toreduce major cardiovascular events by >30% suggesting that hyperglycemia is one of the major contributors toT1DM-associated heart attack and stroke risk escalation. However how T1DM and hyperglycemia exacerbatesuch risk is unclear. Platelets are vascular first-responders that activate for hemostasis upon blood vesseldamage; whereas pathogenic platelet activation leads to spurious thrombosis and acute vascular obstruction.T1DM and hyperglycemia lead to platelet hyperactivity and increased propensity to form thrombi. This proposalsaims to understand how hyperglycemia causes platelet hyperactivity and thrombosis in T1DM and to developnew therapeutic strategies to mitigate T1DM-associated heart attacks and strokes. Utilizing an integratedmetabolism toolkit including state-of-the-art Stable Isotope Resolved Metabolomics (SIRM) we demonstratedcritical role of altered platelet metabolism in thrombin-induced platelet activation. Specifically thrombinstimulation alters platelet metabolism that is centered on glycogen metabolism pentose phosphate pathway(PPP) and fructose 16-bisphosphate (F16BP) namely the glycogen-PPP-F16BP axis modulating energyredox and calcium homeostasis in platelets and leading to their activation. Literature and our compellingpreliminary data further reveal that hyperglycemia increases glycogen storage and its mobilization that generatesATP PPP inhibition reactive oxygen species and intracellular calcium all of which are in line with increasedpropensity for platelets to activate. Therefore our overarching hypothesis is that hyperglycemia changes theglycogen-PPP-F16BP axis in platelets to drive platelet hyperactivity and thus thrombotic risk in T1DM. In Aim 1we will delineate these hyperglycemia-induced changes in the glycogen-PPP-F16BP axis in platelets isolatedfrom T1DM patients and normal healthy platelets subject to acute hyperglycemia in vitro. In Aim 2 we willdetermine how modulation of the glycogen-PPP-F16BP axis by pharmacological and genetic means suppresseshyperglycemia-induced platelet hyperactivity in vitro. In Aim 3 we will determine how modulation of the glycogen-PPP-F16BP axis by pharmacological and genetic means reduces hyperglycemia-exacerbated thrombosis andstroke in animal models. Our team is in a unique position to address our hypothesis as we possess recognizedexpertise in metabolism and metabolomics (Qingjun Wang PhD and Matthew Gentry PhD) platelet biology(Sidney Whiteheart PhD) T1DM (Lisa Tannock MD) and stroke (Justin Fraser MD and Jill Roberts PhD) andwe have strong partnership with the University of Kentucky Metabolomics Redox Metabolism and RodentSurgery Cores. Upon completion of the proposed project we will have presented a novel mechanism formetabolic dysregulation in platelets to mediate hyperglycemia-induced platelet hyperactivity and thrombosis inT1DM and will have identified new therapeutic targets for mitigating T1DM-associated heart attacks and strokes.

project_terms:
Acute;Address;Affect;Animal Model;Arterial Injury;Binding;Biological Assay;Biology;Blood Glucose;Blood Platelets;Blood Vessels;Blood coagulation;Buffers;Calcium;Carbon;Cardiovascular system;Cause of Death;Chelating Agents;Citric Acid Cycle;Clot retraction;Coagulation Process;Consumption;Data;Development;Diabetes Mellitus;Doctor of Philosophy;Enzymes;Event;Fibrin;Fructose;Genetic;Gluconeogenesis;Glucose;Glucose Transporter;Glucosephosphate Dehydrogenase;Glycogen;Glycogen Phosphorylase;Glycolysis;Heart Diseases;Hemostatic function;Homeostasis;Human;Hyperactivity;Hyperglycemia;Impairment;In Vitro;Incidence;Insulin-Dependent Diabetes Mellitus;Kentucky;Kinetics;Knowledge;Lead;Learning;Literature;Mediating;Metabolic;Metabolic Pathway;Metabolism;Middle Cerebral Artery Occlusion;Modeling;Morbidity - disease rate;Mus;Myocardial Infarction;NADP;Obstruction;Operative Surgical Procedures;Outcome;Oxidation-Reduction;Pathogenicity;Patients;Pentose Phosphate Cycle Pathway;Pentosephosphate Pathway;Phosphoric Monoester Hydrolases;Phosphorylases;Platelet Activation;Positioning Attribute;Production;Protein Dephosphorylation;Pulmonary Embolism;Reactive Oxygen Species;Reduced Glutathione;Regulation;Reporting;Rest;Risk;Risk Reduction;Rodent;Role;Source;Streptozocin;Stroke;Testing;Thrombin;Thrombosis;Thrombus;Traction;Universities;chelation;diabetic patient;first responder;glucose metabolism;glucose uptake;glycemic control;glycogen metabolism;in vivo;inhibitor;metabolomics;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;pharmacologic;platelet function;stable isotope;stroke risk;thrombotic;tool

public_health_relevance:
Project Narrative Type 1 diabetes mellitus (T1DM) a condition of high blood glucose greatly increases the risk of heartattacks and strokes; yet how T1DM exacerbates heart attacks and strokes is unclear. This proposal looks intohow high blood glucose alters glucose-related metabolic pathways in platelets making them more prone toactivation and blood clot formation. The knowledge gained from our studies will facilitate development of newtherapeutic strategies to reduce the risk of heart attacks and strokes in diabetic patients.


application_id: 10704036
project_number: 5F30EY031545-04
project_title: Ocular complications of CHARGE Syndrome: The role of Sox11
administering_ic: NEI
award_notice_date: 2023-08-31
opportunity_number: PA-19-192
application_type: 5
activity_code: F30
ic: EY
serial_number: 031545
program_official: AGARWAL, NEERAJ
project_start_date: 2020-09-01
project_end_date: 2024-08-02
study_section: Special Emphasis Panel[ZRG1-F03A-N(20)L]
contact_pi_person_id: 15716225
contact_pi: KRUEGER, LAURA
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Disruptions in eye development are associated with structural birth defects such as microphthalmiaanophthalmia and coloboma (collectively referred to as MAC) and are a significant cause of pediatricblindness. Ocular abnormalities often occur alongside those of brain and craniofacial defects highlighting thesignificant signaling interactions between the developing structures of the head; indeed MAC is a commonfeature of systemic congenital malformation syndromes. One example is CHARGE syndrome a genetic neuralcristopathy characterized by coloboma heart defects choanal atresia growth retardation genitalabnormalities and ear abnormalities. Mutations in chromodomain helicase binding protein 7 (CHD7) anddefects in neural crest cell development and migration have been implicated in the pathogenesis of CHARGEsyndrome however the mechanisms underlying the ocular birth defects observed in CHARGE patients havenot been identified. Our laboratory studies the development of the vertebrate visual system using zebrafish (Danio rerio).Previous work from our lab has shown that knockdown of Sox11 a member of the SoxC family of transcriptionfactors in zebrafish results in microphthalmia coloboma brain trunk and heart defects all phenotypesobserved in CHARGE syndrome. Furthermore we found that Sox11 is required for the expression of Bonemorphogenic proteins (BMPs) during ocular development. In humans a duplication of Sox11 has beenidentified in a patient clinically diagnosed with CHARGE syndrome and CHD7 has been shown to directlyinteract with Sox11 and Sox4 in neural stem cells. Based on these data my central hypothesis is that the lossof Sox 11 expression leads to disruptions in neural crest cell dynamics as well as alterations in BMP signalingduring development. This hypothesis will be tested in the following aims 1) Determine the role that Sox11 andChd7 play in the specification proliferation survival and migration of cranial neural crest cells and 2)Determine whether Sox11 and Chd7 deficiency alters cranial BMP signaling. This proposal will employinnovative and cutting edge live imaging techniques as well as advanced biochemical and molecular biologyapproaches and will leverage the power of the zebrafish model to tackle an important problem in ocularpediatric genetics. Successful completion of this project will define the role of Sox11 in the pathogenesis of the oculardefects such as those observed in CHARGE syndrome and make progress towards improving theidentification management and treatment of congenital eye malformations. Additionally this predoctoralproposal allows the candidate to develop unique technical critical thinking and effective communication skillscrucial to a physician-scientist specializing in ophthalmic pediatric genetics.!

project_terms:
Anophthalmos;Binding Proteins;Biochemical;Biological Models;Blindness;Bone Morphogenetic Proteins;Brain;CHARGE syndrome;CHD7 gene;Cephalic;Childhood;Choanal Atresia;Chromatin;Chromosomal Duplication;Code;Coloboma;Communication;Confocal Microscopy;Congenital Abnormality;Craniofacial Abnormalities;Critical Thinking;DNA Binding Domain;Data;Defect;Development;Disease;Ear;Eye;Eye Development;Eye diseases;Family;Fetal Development;Fluorescence-Activated Cell Sorting;Future;Genes;Genetic;Genetic Research;Genital;Genitalia;Goals;Growth;Head;Heart Abnormalities;Human;Image;Imaging Techniques;Immunoprecipitation;Inherited;Label;Laboratories;Laboratory Study;Light;Microphthalmos;Microscopy;Modeling;Molecular Biology;Morphogenesis;Mutation;Names;Neural Crest Cell;Pathogenesis;Pathway interactions;Patients;Phenotype;Physicians;Play;Process;Proliferating;Proteins;Regulation;Reporter;Reporter Genes;Research;Research Ethics;Role;SOX11 gene;SOX4 gene;Scientist;Signal Pathway;Signal Transduction;Signaling Protein;Specific qualifier value;Structural Congenital Anomalies;Structure;Syndrome;Systems Development;Testing;Training;Transcription Coactivator;Transgenic Organisms;Visual System;Visual impairment;Work;Zebrafish;clinical diagnosis;clinical phenotype;developmental genetics;eye formation;helicase;improved;innovation;knock-down;malformation;member;migration;mutant;nerve stem cell;neural;novel therapeutics;pre-doctoral;preservation;sex;sight restoration;skills;sry Genes;transcription factor;vision development

public_health_relevance:
Microphthalmia anophthalmia and coloboma (collectively referred to as MAC) are congenital ocular disordersthat are a significant cause of visual impairment. The proposed research will define the role of protein codinggene Sox11 in development of the eye and will determine if defects in Sox11 cause inherited eye diseases.Findings from this project will further our understanding of eye formation during fetal development and provideavenues for future treatments of inherited eye diseases.!


application_id: 10704004
project_number: 5R01CA230758-05
project_title: Characterize the role of EBF1 in breast cancer progression
administering_ic: NCI
award_notice_date: 2023-08-10
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 230758
program_official: CERO, CHERYL
project_start_date: 2018-09-01
project_end_date: 2025-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 11716117
contact_pi: WU, YADI
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:
Basal-like breast cancer (BLBC) is a devastating form with limited therapeutic options. Duringtumor progression and metastasis tumor cells rewire their metabolism which results in anenhanced nutrient uptake to supply the energetic and biosynthetic pathway under the hypoxiccondition. It is important for tumor cells to activate mitochondrial selective autophagy (mitophagy)to avoid metabolic crisis and maintain the mitochondrial homeostasis. The means by which BLBCcells fine-tune mitochondrial biogenesis and mitophagy to maintain metabolic and mitochondrialhomeostasis in order to adapt the hypoxic microenvironment remain elusive. We found that EBF1is highly expressed in BLBC. Knockdown of EBF1 induced extensive mitophagy and eventualcell death. Interestingly silencing HIF1 blocked the EBF1 deficiency-induced mitophagy and celldeath in BLBC. In addition we found that HIF1 induced EBF1 expression and that EBF1interacted with HIF1 and inhibited HIF1 activity. Based on these preliminary data we speculatethat EBF1 functions as a safeguard to ensure metabolic homeostasis through a regulation ofHIF1 activity which when compromised can contribute to imbalanced mitochondria andmassive mitophagy in BLBC. Our strategy will be to first delineate the role of EBF1 in BLBC (Aim1); then determine the molecular interplay between EBF1 and HIF1 (Aim 2); and to characterizethe role of EBF1 in vivo in human samples as well as in several mouse models (Aim 3). Theknowledge gained from these studies will increase our fundamental understanding about biologicrelationship between metabolic reprogramming and mitochondrial homeostasis particular duringhypoxia. Our work also reveals a pivotal function for the EBF1 in BLBC and suggests that targetingthis pathway may offer alternative treatment strategies for this aggressive subtype of breastcancer.

project_terms:
Address;Affect;Autophagocytosis;B-Lymphocytes;Biogenesis;Bioinformatics;Biological;Brain;Breast Cancer Cell;Breast Cancer cell line;Cell Death;Cessation of life;Clinical;Data;Disease;EP300 gene;Early identification;Ensure;Environment;Event;Feedback;Genes;Genetic Transcription;Goals;Growth;HIF1A gene;Homeostasis;Human;Hypoxia;Hypoxia Inducible Factor;Immunocompetent;Interruption;Intrinsic factor;Knockout Mice;Knowledge;Luciferases;Lung;Malignant Neoplasms;Mammary gland;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;NCI-Designated Cancer Center;Neoplasm Metastasis;Nutrient;Oxygen;Pathogenesis;Pathologist;Pathway interactions;Patients;Play;Process;Prognosis;Property;Reaction;Reagent;Regulation;Repression;Research;Response Elements;Role;Sampling;Signal Transduction;Specimen;Stress;System;Talents;Testing;Therapeutic;Tumorigenicity;Work;alternative treatment;breast cancer progression;cancer initiation;conditional knockout;druggable target;in vivo;inhibitor;innovation;insight;interest;knock-down;malignant breast neoplasm;mouse model;multidisciplinary;neoplastic cell;novel;overexpression;prevent;programs;response;targeted treatment;transcription factor;treatment strategy;tumor;tumor growth;tumor metabolism;tumor microenvironment;tumor progression;uptake

public_health_relevance:
Despite immense interest in metabolic reprogramming related to tumor progression we still havelittle knowledge about how this process is balanced to maintain catabolic homeostasis particularlyduring conditions of stress. By defining the role of EBF1 in regulation of HIF1 activity this projectwill provide unique and new insight into how HIF1-mediated metabolic reprogramming isregulated through EBF1.


application_id: 10701814
project_number: 5R01CA207772-07
project_title: Roles of Hsp47 in Breast Cancer Progression
administering_ic: NCI
award_notice_date: 2023-05-09
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 207772
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2017-03-03
project_end_date: 2027-05-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and poor survivaloutcomes. One feature of obese adipose tissue is the excess extracellular matrix (ECM)deposition/remodeling in the form of fibrosis. However function and regulation of obesity-related ECMdeposition/remodeling in cancer progression largely remain to be determined. We recently identifiedHsp47 a chaperone protein facilitating collagen secretion as a hub of the ECM transcription network.Our new data showed that Hsp47 was highly expressed in adipose tissue. Importantly increased Hsp47expression in human and mouse adipose tissues was significantly associated with obesitydevelopment. We found that adipocyte-specific deletion of Hsp47 was sufficient to suppress high fatdiet (HFD)-induced obese and mammary tumor growth which is accompanied by reduced collagendeposition/alignment and macrophage infiltration in adipose tissue. The overall objective of thisproposal is to define the mechanism by which adipocyte Hsp47 promotes obese-related fibrosis andbreast cancer progression and to explore the value of Hsp47 as a potential target to suppress obesity-associated cancer progression. Using unbiased proteomics analysis we identified asporin as a newtarget of Hsp47 in adipocytes. Based on these data the central hypothesis of this proposal is thatHsp47 induces obesity-related fibrosis by facilitating asporin secretion in adipocytes and subsequentlyenhances adipocyte plasticity and breast cancer progression. Following aims are proposed to test ourhypothesis: Aim 1. Elucidate the molecular mechanism by which adipocyte Hsp47 induces obesity- andcancer-associated ECM remodeling; Aim 2. Determine how Hsp47 regulates obesity-associated andcancer-induced adipocyte plasticity; Aim 3. Define the potential of targeting Hsp47 to suppress obesity-associate fibrosis inflammation and breast cancer progression/metastasis.

project_terms:
3-Dimensional;Adipocytes;Adipose tissue;Binding;Bioinformatics;Biological Assay;Blood Platelets;Breast;Breast Cancer Risk Factor;Breast cancer metastasis;Cardiovascular Diseases;Co-Immunoprecipitations;Coculture Techniques;Collagen;Data;Deposition;Diabetes Mellitus;Epithelium;Extracellular Matrix;Fibrosis;Funding;Genetic Transcription;High Fat Diet;Human;Infiltration;Inflammation;Knockout Mice;Knowledge;Link;Macrophage;Malignant Neoplasms;Mammary Neoplasms;Mesenchymal;Modeling;Molecular;Molecular Chaperones;Mus;Nature;Neoplasm Metastasis;Non obese;Obesity;Obesity associated cancer;Pathologist;Pathway interactions;Patients;Play;Positioning Attribute;Proteins;Proteomics;Recurrent Malignant Neoplasm;Regulation;Repression;Research;Role;Scheme;Signal Transduction;Surface Plasmon Resonance;Testing;Tissue Sample;Tissues;Transgenic Organisms;Tumor Tissue;adipocyte differentiation;asporin;breast cancer progression;cancer cell;cancer recurrence;carcinogenesis;diet-induced obesity;digital;experimental study;immune cell infiltrate;in vivo;inhibitor;insight;malignant breast neoplasm;mammary gland development;mouse model;multidisciplinary;nano-string;novel;obesity development;recruit;second harmonic generation imaging;single-cell RNA sequencing;stemness;survival outcome;tissue culture;tumor growth;tumor progression

public_health_relevance:
Defining roles of adipocyte Hsp47 in obesity- and cancer-associated fibrosis and adipocyte plasticity will fillcritical gaps in our knowledge of the remodeling of tissue microenvironment during cancer progression. Thestudy of Hsp47 in regulating asporin in adipocytes will reveal a novel pathway in regulating collagen depositionand alignment; and further defining roles of the Hsp47/asporin axis in cancer metastasis will identify a potentialtarget to halt obesity-associated breast cancer progression.


application_id: 10700452
project_number: 1R21AI177008-01
administering_ic: NIAID
award_notice_date: 2023-03-16
opportunity_number: PAR-22-109
application_type: 1
activity_code: R21
ic: AI
serial_number: 177008
program_official: GEZMU, MISRAK
project_start_date: 2023-03-16
project_end_date: 2025-02-28
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 14497209
contact_pi: ZHANG, HONGBIN
other_pis: NASH, DENIS
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-03-16
project_title:
Developing Statistical Methods on Event History Data Subject to Data Complexities for HIV Disease Progression and Policy Evaluation

project_abstract:
PROJECT SUMMARY/ABSTRACTIn 2015 the World Health Organization (WHO) introduced Treat-All guidelines for people living with HIV whichrecommend immediate initiation of antiretroviral therapy (ART) treatment upon diagnosis regardless of diseaseseverity. Since then most countries worldwide have adopted the policy. However the understanding of the impact ofsuch policy is quite limited especially regarding HIV disease progression. Focused on event history outcome(represented by WHO clinical stages and death) we recently conducted a preliminary analysis. We used data fromthe Central Africa region of the International epidemiology Database to Evaluate AIDS (CA-IeDEA) for a multistatemodel based on a target trial design (where two cohorts were constructed one before and one after the policyadoption). This work illuminated several limitations. For example the assumption of non-informative censoring wasunlikely to hold for all censored individuals due to loss of follow-up or transfer out. Also the relatively small samplesize of the CA-IeDEA hindered our capacities to 1) explore more clinically relevant and biologically plausible modelsfor HIV disease progression and 2) explore population heterogeneities regarding the impact of the Treat-All on theoutcome. In the proposed study we plan to address these limitations by developing new statistical methods andleveraging the multi-regional i.e. the global-IeDEA data which will provide a substantially larger sample. We willdevelop procedures to address informative (dependent) censoring for the multistate models under the target trialdesign to allow for sensitivity analysis. For example we propose parametric nonparametric and semi-parametricapproaches to handle censoring at random. In addition we offer a controlled multiple imputation method to handlecensoring not at random. We will compare and validate those methods using both internal and external data. Finallywe will comprehensively analyze the global-IeDEA data where the sensitivity analysis will ensure the robustness ofour findings. The proposed work will advance research in HIV care by providing more detailed information on possibleevolutionary courses of HIV disease progression and factors that modify the effectiveness of Treat-All. Our analysisis a first step towards developing more precise patient treatment options and resource allocation thereby improvingpatient outcomes. The proposed statistical methods may also have applications to model other diseases that evolvethrough predefined clinical states with intermittent data collection schema subject to similar data complexities.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Adopted;Adoption;African;Binding;CD4 Lymphocyte Count;Caring;Cells;Central Africa;Cessation of life;Characteristics;Clinic;Clinical;Country;Data;Data Collection;Databases;Development;Diagnosis;Disease;Disease Progression;Disease model;Effectiveness;Eligibility Determination;Enrollment;Ensure;Epidemic;Epidemiology;Evaluation;Event;Evolution;Future;Guidelines;HIV;HIV/AIDS;Individual;International;Intervention;Investigation;Laboratories;Methods;Modeling;Outcome;Patient Care;Patient-Focused Outcomes;Patients;Performance;Persons;Pharmaceutical Preparations;Policies;Policy Analysis;Policy Developments;Population Heterogeneity;Probability;Procedures;Prognostic Factor;Randomized Controlled Trials;Recommendation;Recording of previous events;Research;Research Personnel;Resource Allocation;Sample Size;Sampling;Selection Bias;Severity of illness;Statistical Methods;Structure;Testing;Time;Validation;Withdrawing Care;Work;World Health Organization;antiretroviral therapy;clinically relevant;cohort;data complexity;demographics;design;follow-up;hazard;improved;mortality;outreach;semiparametric;trial design

public_health_relevance:
PROJECT NARRATIVEThis project will develop statistical methods and use multi-regional International epidemiology Databases to EvaluateAIDS (IeDEA) data to support a worldwide evaluation of the Treat-All policy regarding the global HIV/AIDS epidemic.The methods will bring robustness in understanding HIV disease evolution subjected to data complexities theeffectiveness of WHO's Treat-All policy and the patient clinic and country characteristics that modify the policy'simpact. In addition the findings from this project may lead to the development of more precise intervention andresource-allocation options that take these factors into account and ultimately improve overall outcomes for peopleliving with HIV.


application_id: 10699790
project_number: 1R43HL169071-01
administering_ic: NHLBI
award_notice_date: 2023-05-11
opportunity_number: PA-22-176
application_type: 1
activity_code: R43
ic: HL
serial_number: 169071
program_official: THAKAR, RAHUL GAUTAM
project_start_date: 2023-06-01
project_end_date: 2025-08-31
study_section: Special Emphasis Panel[ZRG1 ISB-W (12)]
contact_pi_person_id: 11058700
contact_pi: TOPAZ, STEPHEN R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 832402486
primary_uei: RK1ZDCXE3LJ7
duns_number: 832402486
uei: RK1ZDCXE3LJ7
fips: US
organization_id: 10024870
organization_name: W-Z BIOTECH, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-06-01
project_title:
Pediatric Transapical Double Lumen Cannula with Integrated Compliance Chambers Doubles Flow of Paracorporeal Pulsatile VAD

project_abstract:
Pediatric patients with severe heart failure require a ventricular assist device (VAD). The paracorporealBerlin Heart EXCOR is still the only FDA-approved VAD for pediatric patients. This diaphragm displacementpump is small/light weight to facilitate ambulation. However EXCOR withdraws and pumps blood at differenttimes for interrupted pulsatile blood flow with its drainage and infusion cannulas functioning only half the time(50% efficiency). EXCOR also generates a high peak blood flow rate which may cause blood damage. Aparacorporeal continuous flow (PediMag/CentriMag) VAD has also been used with Berlin Heart cannulas insmaller children but its bulky/heavy motor hinders ambulation. Pediatric paracorporeal VADs require twoseparate cannulas for withdrawal and infusion and their installation requires an invasive median sternotomywhich complicates later surgery for heart transplant or repair. Our ultimate goal is to develop a minimallyinvasive high efficiency paracorporeal pulsatile diaphragm displacement VAD system for pediatric patents.The enabling technology is a transapical double lumen cannula (DLC) with integrated compliance chambersthat features: 1) Single transapical cannulation via less invasive small left thoracotomy; 2) Two integratedcompliance chambers that: a) Continuously withdraw/infuse blood to increase efficiency for higher blood flowrates; b) Adjust continuous flow fluctuation for desired pulsatility; c) Reduce peak blood flow rate to mitigateblood trauma; d) Reduce infusion lumen peak pressure decreasing pump afterload to enhance pump output;e) Allow smooth withdrawal to infusion transition for high frequency pumping. Bench testing of an initialtransapical DLC with integrated compliance chambers prototype with EXCOR showed double pumping flowwith decreased peak pump flow. The Phase I SBIR objective: We will redesign a transapical DLC with optimalminimal compliance chambers and conduct performance testing in lambs. Specific Aim 1: To designfabricate and bench test the high efficiency transapical DLC with integrated compliance chambers.The transapical DLC compliance chambers will be integrated into the drainage and infusion outlets. The 24 Frmain DLC body will be one-piece reinforced polyurethane. The super-elastic silicone compliance chambers willbe very small with 50% stroke volume. The final prototype will be tested for 1 week in an EXCOR mock loopwith 37% glycerin for performance/reliability/durability. Specific Aim 2: To test the new 24 Fr transapicalDLC with compliance chambers in an EXCOR VAD circuit in lambs (n=8). These lamb (10-15 kg) studieswill investigate ease of transapical deployment 6 hr in vivo performance/reliability and initial biocompatibility.Prototype design/fabrication/bench testing will be done at W-Z Biotech and the animal studies will be done atthe University of Kentucky. Upon completion the commercialized transapical DLC with integrated compliancechambers will provide a less invasive paracorporeal pulsatile VAD with doubled efficiency. This technology canalso be used in adults and may significantly impact cardiogenic shock/bridge to heart transplant management.

project_terms:
Adult;Animals;Apical;Berlin;Biotechnology;Blood;Blood flow;Cannulas;Cannulations;Cardiac;Cardiac Surgery procedures;Cardiogenic Shock;Cardiomyopathies;Child;Childhood;Complex;Coupled;Dedications;Devices;Drainage procedure;Engineering;FDA approved;Frequencies;Glycerol;Goals;Head;Heart;Heart Transplantation;Heart failure;Implant;Infusion procedures;Interruption;Kentucky;Laboratory Animal Production and Facilities;Left;Legal patent;Letters;Motor;Myocarditis;North America;Output;Patients;Performance;Phase;Polyurethanes;Publications;Pump;Research Support;Respiratory Diaphragm;Scientist;Silicones;Small Business Innovation Research Grant;Sternotomy;Stroke Volume;Surgeon;System;Technology;Testing;Thoracotomy;Time;Trauma;Universities;Withdrawal;biomaterial compatibility;blood damage;blood pump;cardiac repair;commercialization;congenital heart disorder;design;experience;fabrication;improved;improved outcome;in vivo;interest;light weight;minimally invasive;multidisciplinary;pediatric heart failure;pediatric patients;performance tests;pressure;prototype;research and development;respiratory;shear stress;ventricular assist device

public_health_relevance:
We are proposing to develop a minimally invasive high efficiency paracorporeal pulsatile diaphragmdisplacement ventricular assist device (VAD) system for pediatric heart failure patients. The enablingtechnology is a transapical double lumen cannula (DLC) with integrated compliance chambers. When coupledwith a paracorporeal pulsatile blood pump (Berlin Heart EXCOR) this transapical DLC with integratedcompliance chambers will enable continuous blood flow with pulsatility to improve VAD system efficiency via aless invasive small left thoracotomy potentially improving outcomes.


application_id: 10698532
project_number: 1R41AG082600-01
project_title: Noninvasive sleep enhancement and behavior monitoring technologies for Alzheimer's model mice
administering_ic: NIA
award_notice_date: 2023-06-09
opportunity_number: PAS-19-317
application_type: 1
activity_code: R41
ic: AG
serial_number: 082600
program_official: MACKIEWICZ, MIROSLAW
project_start_date: 2023-07-01
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1 NV-G (13)]
contact_pi_person_id: 1883852
contact_pi: O'HARA, BRUCE FREDERICK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The aims of this project are to develop new technologies to identify and track sleep and wakeabnormalities present in mouse models of Alzheimers disease (AD) as well as to test a sleep enhancementtechnology for applications in AD animal research. Signal Solutions LLC has previously developed andcommercialized a piezoelectric based system for noninvasive high-throughput sleep and wake monitoring ofrodents. Automated scoring of sleep and wake allows for simultaneous recordings of many animals over longerperiods with little burden on the researcher rivalling EEG/EMG methods that are more complicated andexpensive to perform. Behavioral changes in sleep and wake can precede memory loss in the progression of Alzheimersdisease (AD). Clinical studies suggest sleep disturbances are exhibited in a high percentage of AD patients.Animal models of AD also display sleep disturbances and some models show changes in wake behaviorsbefore the molecular hallmarks and memory problems appear as clearly occurs in human AD. In the treatmentof AD a potential therapeutic target is preventing the aggregation of pathogenic forms of amyloid-beta (A-beta)and tau. Waste clearance in the brain has been shown to be increased with increased sleep includingclearance of A-beta. Recently non-pharmacological approaches using mechanical devices for rocking haveshown promise for sleep enhancement which could be applied to AD research. The specific aims of this project are to 1) Develop advanced sleep/wake tracking technology: Add anew multipoint touch sensor to our current piezoelectric technology that together will identify specific behaviorsassociated with AD progression tested with AD mouse model 3xTg. 2) Develop Sleep EnhancementTechnology: Modify our current MouseQwake sleep-disruption system for mechanical sleep-enhancementwith companion sleep and wake tracking capabilities.Anticipated Outcomes: The envisioned product is a home cage sensor and software that will allowresearchers to accurately measure changes in sleep and wake during long-term AD disease progression aswell as track subtle changes in behavior in AD model mice. This system will minimize the amount of work timetesting behaviors and time for analyzing the videos or electrophysiology that is currently a major bottleneck.An expanded MouseQwake system will provide a tool for sleep manipulation of both sleep enhancement anddisruption as well as simultaneous sleep/wake and behavioral recording. If successful a Phase II investigationwill involve large scale studies of multiple AD rodent models and continue iterative improvements to bothhardware and software developed in phase I.

project_terms:
3xTg-AD mouse;Abeta clearance;Acceleration;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Amyloid beta-Protein;Animal Disease Models;Animal Experimentation;Animal Model;Animals;Behavior;Behavior monitoring;Behavioral;Brain;Classification;Clinical Research;Collaborations;Communities;Companions;Computer software;Consumption;Detection;Development;Devices;Discrimination;Disease;Disease Progression;Disease model;Early Intervention;Early identification;Electroencephalography;Electrophysiology (science);Enhancement Technology;Exhibits;Floor;Funding;Future;Goals;Home;Human;Industrialization;Intervention;Investigation;Letters;Longitudinal Studies;Measures;Mechanical Stimulation;Mechanics;Memory;Memory Loss;Methods;Modeling;Modification;Molecular;Monitor;Mus;Neurodegenerative Disorders;Operative Surgical Procedures;Outcome;Pathogenicity;Pathology;Phase;Physiology;Pre-Clinical Model;Rattus;Recording of previous events;Research;Research Personnel;Resources;Rodent;Rodent Model;Running;Signal Transduction;Sleep;Sleep Disorders;Sleep disturbances;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Symptoms;System;Technology;Testing;Time;Touch sensation;Wakefulness;Work;Workload;behavior test;commercialization;comorbidity;feasibility testing;glymphatic flow;improved;improvement on sleep;mechanical device;mouse model;new technology;non rapid eye movement;non-invasive system;pharmacologic;preclinical study;pressure;prevent;prototype;sensor;sensor technology;side effect;sleep quality;software development;tau Proteins;therapeutic target;tool;wasting

public_health_relevance:
Sleep disruption is now recognized not only as an early symptom of Alzheimers Disease (AD)but also a contributor to its ongoing development and thus sleep enhancement is a promisingapproach to slow the disease. This proposal intends to provide new technology to facilitatepreclinical studies in AD model mice including long term monitoring of behaviors associatedwith disease progression and a new method to manipulate and enhance sleep in mice toassess effects on disease and interventions.


application_id: 10698251
project_number: 1R43AG079739-01A1
administering_ic: NIA
award_notice_date: 2023-09-19
opportunity_number: PAS-19-316
application_type: 1
activity_code: R43
ic: AG
serial_number: 079739
suffix: A1
program_official: HARRELL, ERIN
project_start_date: 2023-09-20
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1 BP-C (10)]
contact_pi_person_id: 78083865
contact_pi: HOAGLAND, RICHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 080967428
primary_uei: WWN3NEW2K2Z7
duns_number: 080967428
uei: WWN3NEW2K2Z7
fips: US
organization_id: 10064272
organization_name: RALPHVR INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40507
organization_country: UNITED STATES
arra_indicator: N
project_title:
VRSingTogether: Digital therapeutic virtual reality tool to mitigate the effects of Alzheimer's Disease (AD) and Alzheimer's-Disease-Related Dementias (ADRD)

project_abstract:
Project SummaryOne in three seniors die with Alzheimers Disease (AD) or Alzheimers Disease related dementias (ADRD). Morethan six million Americans are living with AD and by 2050 this number is projected to rise to nearly 13 million.The economic costs of AD are significant with 355 billion in national costs for caring for people with AD andADRD. Disconcertingly there is also an estimated 256 billion in care provided by family members and otherunpaid caregivers. These statistics illustrate the necessity for scalable strategies and interventions to delay theonset of and halt the progression of AD and ADRD. Indeed a 2020 report by the Lancet indicated that 40% ofdementia cases could be prevented by modifying lifestyle factors; with a recommendation for individuals tomaintain cognitive physical and social activity through midlife and beyond. Crucially interventions should beinitiated as early in the disease process as possiblein those with normal cognition or only mild cognitiveimpairment (MCI)as the effects of lifestyle factors on dementia onset are cumulative. In fact the MCIdesignation itself was developed to signal that a patient is at higher risk for AD/ADRD prompting enhanced care.Importantly existing solutions leveraging technology lack the ability to combine physical cognitive and socialmodalities together due to the inability to foster meaningful social connection and co-presence. In-personprograms can foster meaningful social connections and co-presence. Unfortunately these solutions are onlyaccessible to those with the time money and geography to have access and furthermore these solutionscannot scale effectively. To address the significant unmet need for a multi-modal intervention to delay the onsetof and halt the progression of AD and ADRD RalphVR is developing VRSingTogether a scalable digitaltherapeutic that fosters social engagement mental activity and physical activity with music singing andlight physical activity through rhythmic elements in a collaborative and shared virtual space. VRSingTogether isa networked (multi-user) VR application to be offered on low-cost commercially available VR headsets. RalphVRis applying for this NIA Phase I SBIR to achieve three Specific Aims. Aim 1: Employ a focus group of experts togenerate critical insights for RalphVR to develop a design document. Aim 2: Develop the VRSingTogetherprototype. Aim 3: Investigate the feasibility and usability of VRSingTogether in patients with age-related MCI(65 years of age) and the individuals who care for them (18 years of age). Three long-term objectives must bemet to bring VRTogether to market: 1) determine the feasibility of VRSingTogether to mitigate the effects of ADand ADRD 2) determine VRSingTogethers efficacy to promote light physical cognitive and social activity and3) determine the efficacy of VRSingTogether as an intervention to slow or halt the onset of AD and ADRD.Successfully completing the long-term goals and aims will result in a clinically validated scalable and low-costintervention to mitigate the effects of AD and ADRD.

project_terms:
18 year old;Acclimatization;Address;Adult;Age;Age Years;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimer's disease risk;American;Area;Behavior;Cardiac;Caregivers;Caring;Cause of Death;Cerebrum;Clinical;Cognition;Cognitive;Collaborations;Data Analytics;Dementia;Development;Disease;Elderly;Elements;Emotional;Experimental Designs;Faculty;Family member;Feedback;Focus Groups;Fostering;Geography;Gerontology;Goals;Health care facility;Individual;Intervention;Interview;Kentucky;Letters;Light;Location;Loneliness;Longevity;Marketing;Measures;Modality;Movement;Music;Music Therapy;Participant;Patients;Performance;Periodicity;Persons;Phase;Physical activity;Population;Prevalence;Preventive treatment;Process;Psyche structure;Quality of life;Questionnaires;Recommendation;Reporting;Research;Risk Reduction;Signal Transduction;Small Business Innovation Research Grant;Social Distance;Social isolation;Structure;Technology;Testing;Time;Universities;age related;care costs;cognitive function;cognitive performance;cognitive rehabilitation;cost;design;digital;digital health;digital treatment;economic cost;efficacy evaluation;enhanced care;experience;health application;high risk;improved;innovation;insight;instructor;intervention cost;lifestyle factors;middle age;mild cognitive impairment;multi-component intervention;multimodality;new technology;prevent;programs;prototype;psychologic;psychosocial;risk mitigation;satisfaction;social;social engagement;statistics;success;tool;treatment guidelines;treatment strategy;usability;virtual;virtual environment;virtual reality;virtual reality headset

public_health_relevance:
Project Narrative A multi-modal digital therapeutic that fosters social engagement mental activity and light physical activitythrough singing music therapy and gaming to provide a low-cost and scalable strategy to delay or halt theonset of Alzheimers Disease (AD) and Alzheimers Disease Related Dementias (ADRD). Current digital healthapplications are unable to foster meaningful social connection and co-presence severely limiting their efficacyrelative to in-person strategies while in-person strategies are costly and hard to scale. This project intends todevelop a cheaper more effective and more scalable digital therapeutic impacting research in areas of digitalhealth digital therapeutics virtual reality virtual co-presence and psychosocial interventions for AD and ADRD.


application_id: 10697442
project_number: 1R43HL169129-01
project_title: Development of a Neutrophil Degranulation Inhibitor to Treat ARDS
administering_ic: NHLBI
award_notice_date: 2023-03-22
opportunity_number: PA-22-176
application_type: 1
activity_code: R43
ic: HL
serial_number: 169129
program_official: SHENOY, SIDDHARTH KAUP
project_start_date: 2023-04-01
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1 CVRS-B (11)]
contact_pi_person_id: 1886516
contact_pi: MCLEISH, KENNETH R
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 101792061
primary_uei: VL8XANRYGA41
duns_number: 101792061
uei: VL8XANRYGA41
fips: US
organization_id: 10066155
organization_name: DEGRANIN THERAPEUTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402051712
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Acute respiratory distress syndrome (ARDS) is a critical problem in pulmonary medicine accounting for10% of intensive care unit (ICU) admissions and totaling over 200000 patients/year in the U.S. Currenttreatment cost typically exceeds $70000 per patient. Decades of clinical trials failed to identify effectivepharmacologic therapy for ARDS while mortality remains above 30%. Thus there is a critical unmet clinicalneed for successful pharmacologic strategies to treat ARDS. Neutrophils play an essential role in the lunginjury leading to ARDS including that due to COVID-19 through extracellular release of reactive oxygenspecies (ROS) granule constituents and neutrophil extracellular traps (NETs). The scientific foundationunderlying our innovative therapy is that inhibition of neutrophil degranulation also prevents release of ROSand NETs making degranulation a therapeutic target. We generated a recombinant protein degranin-23(degranulation inhibitor of SNAP-23 DGN-23) containing a SNARE motif from SNAP-23 and a cellpermeability peptide. DGN-23 rapidly enters human neutrophils in vitro and in vivo inhibits degranulation by50% to 80% prevents priming of ROS release and reduces NET formation. Importantly in vitro studies showDGN-23 does not impair neutrophil phagocytosis granule fusion with phagosomes or bacterial killing withinphagosomes and in vivo studies show that DGN-23 administration at the initiation of lung injury inhibits acutelung injury in 3 rodent models without obvious toxicity. Thus in vitro and in vivo data provide strong support forour novel therapeutic strategy that inhibition of neutrophil exocytosis attenuates lung injury leading to ARDS.The next steps are development of manufacturing capability and quality control to move from a laboratorygrade recombinant protein to a pharmaceutical grade drug and validation of therapeutic effect without toxicityunder clinically relevant conditions. This transition will be accomplished by two Aims. Aim 1: Characterizeproduction characteristics and off-target/side effects of DGN-23. This aim will determine purity presenceof bacterial contaminants yield reproducibility of potency and stability in multiple production runs of DGN-23.Cell toxicity and off target effects on circulating immune cells will be determined. Organ and cell localization ofDGN-23 will be determined in all major organs from animals undergoing experiments described in Aim 2. Aim2: Determine therapeutic efficacy of DGN-23 under clinically relevant conditions. The ability of DGN-23to prevent acute lung injury and improve mortality when administered at various times after the initiating injurywill be determined in a mouse model of H1N1 influenza virus-induced acute lung injury. Improved survival andimproved blood oxygenation will serve as outcomes to proceed with development. At the conclusion of thiswork this Phase 1 project will have identified a drug candidate with an optimal combination of efficacy yieldstability and potency to advance to advanced pre-clinical studies in a Phase 2 project.

project_terms:
Accounting;Acute Lung Injury;Acute Respiratory Distress Syndrome;Admission activity;Animal Model;Animal Organ;Animals;Anti-Bacterial Agents;Attenuated;Bacteria;Binding;Biodistribution;Biological;Blood;COVID-19;COVID-19 pandemic;Cells;Characteristics;Clinical;Clinical Trials;Complication;Critical Illness;Cytoplasmic Granules;Data;Development;Discipline of Nursing;Disease;Endotoxins;Event;Exocytosis;Exocytosis Inhibition;Extravasation;Failure;Family suidae;Foundations;Healthcare Systems;Histopathologic Grade;Host Defense;Human;Immune;Immunohistochemistry;In Vitro;Inflammatory;Influenza A Virus H1N1 Subtype;Inhalation;Injury;Innovative Therapy;Intensive Care Units;Laboratories;Legal patent;Life;Limulus;Lung;Lung infections;Maintenance;Mass Spectrum Analysis;Measures;Modeling;Molecular Target;Mus;Neutrophil Activation;Neutrophil Infiltration;Organ;Oryctolagus cuniculus;Outcome;Pathogenesis;Patients;Peptides;Permeability;Phagocytes;Phagocytosis;Phagosomes;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacological Treatment;Pharmacotherapy;Phase;Physicians;Physiological;Plasma;Play;Positron-Emission Tomography;Production;Proteins;Protocols documentation;Pulmonology;Quality Control;Radiolabeled;Reactive Oxygen Species;Recombinant Proteins;Reproducibility;Respiratory Failure;Respiratory physiology;Rodent Model;Role;SARS-CoV-2 infection;SNAP receptor;SNAP23 gene;Scientist;Sheep;Small Business Innovation Research Grant;Supportive care;Syndrome;Technology;Therapeutic;Therapeutic Effect;Time;Toxic Neutrophil;Toxic effect;Transmembrane Transport;Treatment Cost;Treatment Efficacy;Validation;Vascular Endothelial Cell;Virus;Work;alveolar epithelium;aptamer;cecal ligation puncture;cell injury;clinically relevant;commercialization;cost;drug candidate;experimental study;extracellular;immunogenicity;improved;in vivo;influenzavirus;inhibitor;innovation;lung injury;manufacturing capabilities;manufacturing quality;manufacturing run;mortality;mouse model;neutrophil;novel therapeutic intervention;pharmacokinetics and pharmacodynamics;pharmacologic;phase 2 study;pneumonia model;preclinical study;prevent;recruit;screening;sepsis induced ARDS;side effect;therapeutic candidate;therapeutic target

public_health_relevance:
NarrativeAcute respiratory distress syndrome (ARDS) is a common life-threatening complication in ICU patients with noeffective drug therapy. Successful completion of the proposed pre-clinical studies will lead to development ofan effective non-viral biologic that treats the acute lung injury responsible for ARDS.


application_id: 10697009
project_number: 2R42CA243600-02
administering_ic: NCI
award_notice_date: 2023-09-22
opportunity_number: PA-22-178
application_type: 2
activity_code: R42
ic: CA
serial_number: 243600
program_official: EVANS, GREGORY
project_start_date: 2023-09-25
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 ISB-Z (10)]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078515036
primary_uei: HSZNRZ4JS954
duns_number: 078515036
uei: HSZNRZ4JS954
fips: US
organization_id: 10032228
organization_name: BIOPTICSTECHNOLOGY, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405131245
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-09-25
project_title:
Development of a Wearable Fluorescence Imaging Device for IntraoperativeIdentification of Brain Tumors

project_abstract:
ABSTRACTApproximately 700000 people in the United States are diagnosed with a primary brain tumor. Of these malignantgliomas (MGs) account for approximately 40% of all intracranial tumors with an overall survival rate of only~34%. Surgical resection remains the cornerstone of therapy and the extent of resection correlates with survival.Fluorescence imaging has emerged as an adjunctive technique allowing for real-time cancer-specific detection.Surgeries guided by fluorescence imaging achieve gross-total-resection (GTR) rates of 75-100% which aresignificantly higher than conventional surgeries with GTR rates of 30-55%. However most clinical-grade imagingsystems are hampered by high costs limited portability and lack of operation flexibility. Some neurosurgicalfluorescence microscopes cost upwards of ~$500K and weigh ~800 pounds (PENTERO 900 with fluorescencekits Carl Zeiss). Many surgeons prefer and continue to use wearable surgical eye loupes which allow forconvenient and fast operation but are not capable of fluorescence visualization. Supported by the STTR Phase1 Award (R41CA243600) and Kentucky State Matching Fund Bioptics Technology (BOT) has developed a low-cost wearable FLoupe device (US Patent Application #62/530613 2017) attached to surgical eye loupes forintraoperative identification of fluorescent MGs. We have tested FLoupe prototypes to image fluorescent MGsduring surgery in a small group of patients. Comparable results are observed against the PENTERO 900system. Based on neurosurgeons feedback in Phase 1 this Phase 2 project will further optimize the headlights(LEDs) video camera emission filters electrical control system and mechanical design of the FLoupe devicein terms of weight size imaging quality and ease to wear/operate (Aim 1). The optimized FLoupe device willbe calibrated and validated against the PENTERO 900 system for equivalence to image fluorescent MGs in alarge group of patients (Aim 2). We expect that fluorescence images taken at the surgical site and from biopsiedsamples by both devices will be equivalent and agree with the blinded histopathological analyses (the goldstandard). Resulting data will be used for FDA clearance via the pre-market notification 510(k) submission withthe PENTERO 900 system as the primary predicate. Compared to the PENTERO 900 system the FLoupedevice is significantly less expensive (<$10K unit sale price) more compact (wearable) and easier to operate(hand free with wireless control). This affordable and wearable device will significantly increase the ability ofneurosurgeons to conduct fast and thorough operations thus improving patient safety and outcomes. At the endof this Phase 2 a clinical-grade FLoupe device will be generated as a pre-manufactured product forintraoperative identification of MGs. Moreover the FLoupe device with a modular design is easily modifiedwith optimized excitation lights and emission filters to image a variety of visible dyes (e.g. fluorescein 5-ALAmethylene blue). Thus our product has the potential to be incorporated in other surgical settings beyond braintumor resection based on the fluorescence characteristics of cancers thereby expanding its market share.

project_terms:
Agreement;Aminolevulinic Acid;Award;Biopsy Specimen;Blinded;Bluetooth;Brain Neoplasms;Calibration;Characteristics;Clinical;Clinical assessments;Color;Conventional Surgery;Data;Detection;Development;Devices;Diagnosis;Diffuse;Dyes;Ensure;Equilibrium;Equipment;Excision;Eye;Feedback;Fluorescein;Fluorescence;Fluorescent Dyes;Funding;Hand;Hospitals;Image;Imaging Device;Intracranial Neoplasms;Kentucky;Legal patent;Malignant Glioma;Malignant Neoplasms;Marketing;Mechanics;Methylene blue;Microscope;Movement;Neurosurgeon;Normal tissue morphology;Notification;Obstruction;Operative Surgical Procedures;Ophthalmologic Surgical Procedures;Outcome;Patient-Focused Outcomes;Patients;Performance;Persons;Phase;Price;Primary Brain Neoplasms;Raspberry Pi;Resected;Sales;Side;Site;Small Business Technology Transfer Research;Surgeon;Survival Rate;System;Techniques;Technology;Testing;Time;Tissues;Touch sensation;Tracer;United States;Visualization;Weight;brain tumor resection;cancer imaging;commercialization;cost;design;flexibility;fluorescence imaging;fluorescence microscope;fluorescence-guided surgery;imaging system;improved;innovation;manufacture;miniaturize;neoplastic cell;neurosurgery;operation;patient safety;portability;prototype;tumor;wearable device;wireless;wireless fidelity

public_health_relevance:
PROJECT NARRATIVEFluorescent imaging of cancers during surgery allows real-time cancer-specific detection for guiding tumorremoval often resulting in significant improvements in patient survival; however it is hampered by largeexpensive equipment. Bioptics Technology (BOT) is developing an innovative low-cost wearable fluorescenceimaging device (FLoupe BOT brand) that attaches to standard surgical eye loupes to help neurosurgeonseasily and accurately identify brain tumors for safe and maximal removal. This affordable and wearable devicewill significantly increase the ability of more surgeons to conduct fast and thorough operations and thusimproving patient safety and outcomes.


application_id: 10694295
project_number: 1R21ES035322-01
administering_ic: NIEHS
award_notice_date: 2023-06-08
opportunity_number: RFA-ES-19-011
application_type: 1
activity_code: R21
ic: ES
serial_number: 035322
program_official: HENRY, HEATHER F
project_start_date: 2023-06-08
project_end_date: 2026-05-31
study_section: Special Emphasis Panel[ZES1 LWJ-W (R2)]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-06-08
project_title:
Extent of PFAS Contamination Resulting from a Fire at a Hazardous Waste Incinerator in East Liverpool Ohio

project_abstract:
Abstract On June 27 2022 a hazardous waste incinerator in East Liverpool Ohio an environmental justicecommunity caught fire. The incinerator is one of only eight receiving per- and polyfluoroalkyl substances(PFAS) for incineration and received the most shipments in the past year. PFAS referred to as foreverchemicals represent a large group of synthetic chemicals including PFOA PFOS GenX and encompassapproximately 5000 different compounds. PFAS exposure has been linked with toxic health effects and theconsequences of PFAS incineration including the potential of incomplete combustion are currently unknown.Due to a longstanding over 10-year community-academic partnership with the community our team hadrecently characterized PFAS in soil surrounding the incinerator thereby providing our team with a uniqueopportunity to determine the impact of the fire on PFAS contamination and the extent of this contaminationthroughout the community. Through our ongoing research partnerships we have immediate access torecruiting families in the community to participate in successfully accomplish the following time-sensitivespecific aims: Aim 1: Characterize post-fire PFAS soil concentrations at the same locations as previouslycollected and identify geospatial patterns in concentrations to discern differences pre- and post-fire. Aim 2:Determine the extent of PFAS exposure in the community by measuring PFAS in residential soil drinkingwater household dust and blood samples from individuals who live in close proximity to the incinerator tobegin to identify the route of exposure to PFAS exposure in the community. Aim 3: Engage the communitythroughout the process. We will work through our existing partnerships to inform residents of the study hostcommunity meetings and provide report-back materials to both community and individuals. We will alsodevelop a website to keep the community informed about the process. This study will provide key informationfor community members regulators and scientists about community PFAS exposure following a fire disaster ata hazardous waste incinerator.

project_terms:
Animals;Area;Back;Biological;Birth Weight;Blood;Blood specimen;Chemicals;Cholesterol;Coal;Collection;Communities;Disasters;Dust;Engineering;Environmental Health;Environmental Impact;Epidemiology;Exposure to;Family;Fertility;Film;Fire - disasters;Focus Groups;Hazardous Waste;Health;House Dust;Household;Human;Immune response;Impairment;Incineration;Individual;Link;Location;Malignant Neoplasms;Measurable;Measures;Medicine;Metadata;Methods;Ohio;Participant;Pattern;Plasma;Poly-fluoroalkyl substances;Process;Public Health;Publishing;Recommendation;Reporting;Research;Scientist;Serum;Smoke;Soil;Source;Testing;Time;United States National Academy of Sciences;Work;aqueous;clinical care;cohort;community engaged research;community engagement;drinking water;environmental justice;epidemiology study;exposed human population;exposure route;innovation;meetings;member;recruit;research clinical testing;research study;soil sampling;web site

public_health_relevance:
Project NarrativeThis study explores community exposure to per- and polyfluoroalkyl substances (PFAS) following a fire at anearby hazardous waste incinerator. Community exposure will be determined by analyses of pre- and post-firesoil sampling and engagement of residents in a study to determine their household exposure. This study willprovide valuable information for community members decision-makers and scientists about community PFASexposure from incinerators particularly following a fire disaster.


application_id: 10694218
project_number: 5P01AG078116-02
project_title: Project 4 - Astrocytic KATP channels in LATE+HS
administering_ic: NIA
award_notice_date: 2023-08-01
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7475
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 4 SUMMARY/ABSTRACTAn astrocyte mechanism will be targeted with the goal of preventing a common subtype of dementia. Limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (HS) pathology arepresent at autopsy in approximately 25% of Alzheimers-type dementia cases. Notably a specific ABCC9gene variant is associated with increased risk of developing LATE+HS. ABCC9 encodes a protein that servesas a metabolic sensor linking brain hypoxia and stress to changes in intracellular calcium and blood flow.We hypothesize that dysregulation of ABCC9 in astrocytes causes or exacerbates LATE+HS via impairedcerebrovascular function hypometabolism (with ionic dyshomeostasis) and neuronal hyperexcitabilityaligning perfectly with themes of this P01. These astrocyte mechanisms can be targeted by a well-tolerateddrug (nicorandil) that has been shown to be clinically safe and effective with high potential public healthimpact. The research will be conducted with the following Specific Aims: Aim 1: Characterize ABCC9/SUR2transcripts and proteins in human astrocytes. We will test the hypothesis that the ABCC9 genetic variantassociated with LATE+HS risk is also associated with decreased ABCC9 expression in astrocytes. AstrocyteABCC9 transcripts are mostly unknown. In human samples we will evaluate the repertoire of mRNAtranscripts and splicing in astrocytes. We will characterize ABCC9 gene expression with RNA-Seq dataacross cell types. In genotyped human brains from Core C (LATE+HS and controls) we will evaluate ABCC9proteins immunohistochemically and we will explore Sur2 expression in mouse models. Aim 2: Test thehypothesis that modulation of astrocytic ABCC9//KATP leads to improved neurovascular and metabolicfunction in LATE+HS model mice. The novel (TetR-TDP) mouse an excellent animal model that has provenhippocampal cell loss astrocytosis TDP-43 proteinopathy and memory impairment will be used to test theimpact of astrocyte specific ABCC9 upregulation on neurovascular function (multiphoton to look atneurovascular coupling and vessel leakiness; MRI to look at cerebral blood flow and other endpoints). Theimpact of astrocyte specific upregulation of SUR2B on brain metabolism will also be tested (glutamate uptakein astrocytes; Ca2+ dynamics [GCaMP]; and MRS to characterize brain metabolites). Aim 3: Test thehypothesis that pharmacological modulation with nicorandil (a KATP channel agonist well-tolerated in oralpreparations) leads to improved neuronal and astrocyte function and neurobehavioral assessment outcomesin TetR-TDP mice. These outcomes will include readouts of neurobehavioral parameters (RAWM and Y-maze) and other endpoints including electrophysiological assessments in astrocytes. Follow-up assessmentswill include detailed neuropathology (astrocytosis HS TDP-43 proteinopathy and small vessel morphology).In summary while studying the mechanisms of astrocyte metabolic and neurovascular pathophysiology inLATE+HS we hope to test a novel therapeutic strategy.

project_terms:
Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Animal Model;Animals;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Binding;Blood Vessels;Blood flow;Brain;Brain Hypoxia;CRSP3 gene;Calcium;Cerebrovascular Circulation;Cerebrum;Clinical;Collaborations;Data;Dementia;Disease;Dose;EEF1A2 gene;Elderly;Electrophysiology (science);Evaluation;Functional disorder;Gene Expression;Genes;Genetic Variation;Genotype;Glutamates;Goals;Human;Image;Immunohistochemistry;Impairment;Ischemic Preconditioning;Knowledge;Link;Magnetic Resonance Imaging;Measures;Memory impairment;Messenger RNA;Metabolic;Methods;Microscopy;Modeling;Morphology;Mus;Nerve Degeneration;Neurons;Nicorandil;Oral;Outcome;Outcome Assessment;Pathologic;Pathology;Persons;Pharmaceutical Preparations;Physiology;Play;Potassium Channel;Preparation;Proteins;Public Health;RNA Splicing;Reporting;Research;Resources;Risk;Role;Sampling;Signal Transduction;Slice;Stress;Testing;Transcript;Up-Regulation;Western Blotting;biological adaptation to stress;brain metabolism;cell type;cerebrovascular;data management;disorder control;drinking water;follow up assessment;genetic variant;hippocampal cell loss;hippocampal sclerosis;improved;in vivo;limbic-predominant age-related TDP-43 encephalopathy;member;mouse model;multi-photon;multidisciplinary;neurobehavioral;neurobehavioral test;neuropathology;neurovascular;neurovascular coupling;novel;novel therapeutic intervention;pharmacologic;prevent;protein TDP-43;sensor;single-cell RNA sequencing;skills;sulfonylurea receptor;transcriptome sequencing;two-photon;uptake


application_id: 10694215
project_number: 5P01AG078116-02
project_title: Project 3 - Astrocytic glutamate dysregulation in AD and VCID
administering_ic: NIA
award_notice_date: 2023-08-01
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7473
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT 3  ABSTRACT SUMMARYIn alignment with the overall P01Strategies for targeting Astrocyte Reactivity in AD and ADRD Project 3 willtarget the astrocyte glutamate transporter EAAT2/Glt-1 (gene name SLC1A2) and assess the impact oncerebrovascular function metabolism and neural network activity in Alzheimers disease (AD) and relateddementias (ADRD). We and other groups have shown that SLC1A2 levels are reduced in AD and ADRD achange that is recapitulated in many AD and ADRD mouse models. SLC1A2 is well known to guard againstexcitotoxic damage to synapses by minimizing synaptic glutamate spillover. This mechanism has been studiedin many different disease models. However much less is known about whether SLC1A2 similarly preventsglutamate from adversely affecting astrocyte endfeet and cerebrovessels which are widely known to undergodysfunction in AD and ADRD. SLC1A2 is also well known to drive the production of lactate a key componentof the astrocyte-neuron lactate shuttle. Nonetheless few studies have investigated the possibility that loss ofSLC1A2 in reactive astrocytes impairs lactate shuttling leading to hypometabolism (another well-characterizedpathology in AD and ADRD). We hypothesize that the loss of SLC1A2 is a key loss of function phenotypeof reactive astrocytes that underlies impaired cerebro-vascular function/integrity hypometabolism and disruptedneural network activity in AD and ADRD. We will test this hypothesis across three Aims using two astrocyte-targeting approaches: a restoration approach where we use AAV-Gfa2 to overexpress SLC1A2 in astrocytesof a comorbid A/vascular model (5xFAD mice with hyperhomocystenemia) and a knockdown approach wherewe will use AAV-GfaP-Cre to knock-down astrocytic SLC1A2 in FLOX-SLC1A2 mice. Aim 1 will determine theimpact of SLC1A2 modulation on astrocyte Ca2+ signaling endfeet and BBB integrity cerebral blood flow andneurovascular coupling using two photon (2P) imaging in awake mice and MRI (in anesthetized mice). Aim 2will determine the impact of SLC1A2 modulation on lactate and glucose signaling in awake mice usingmicroelectrode arrays. And Aim 3 will test the effects of SLC1A2 modulation on neuronal network fidelity andsynaptic function and plasticity using either 2P imaging of awake mice or electrophysiology on in situ brain slices.Points of interaction: All functional outcomes are assessed in our Animal Vascular-Metabolic-Neural Networkcore (Core B). Interrelationships between different astrocyte pathways (MMP9 modulation /Project 1 Insulinreceptor modulation/Project 2 and KATP modulation/Project 4) will be assessed as a function of AD and ADRDcomorbidities through the shared use of postmortem tissue across projects (cerebrovascular pathology/Project1 amyloid pathology/Project 2 amyloid+vascular pathology/Project 3 LATE + hippocampal sclerosispathology/Project 4). Similar interrelationships will be assessed across comorbidities in shared postmortemhuman biospecimens (Core C Human Consultation-Biosamples-Biomarkers). All data will flow into our DataManagement and Biostatistics Core (Core D) for analysis of endpoint measures both within and across projects.

project_terms:
Address;Affect;Alzheimer's Disease;Alzheimer's disease related dementia;Amyloid;Amyloid beta-Protein;Anesthesia procedures;Animals;Astrocytes;Attention;Autopsy;Biochemical;Biological Markers;Biostatistics Core;Blood Vessels;Blood flow;Brain;Cerebrovascular Circulation;Cerebrovascular Disorders;Collaborations;Consultations;Data;Dementia;Disease model;Electrophysiology (science);Endothelial Cells;Enterobacteria phage P1 Cre recombinase;Enzymes;Functional disorder;Genes;Glucose;Glucose Transporter;Glutamate Transporter;Glutamates;Human;Hyperhomocysteinemia;Image;Impairment;In Situ;Individual;Insulin Receptor;Intervention;Knowledge;Lactate Transporter;MMP9 gene;Magnetic Resonance Imaging;Measures;Metabolic;Metabolic dysfunction;Metabolism;Microelectrodes;Microvascular Dysfunction;Modeling;Mus;Names;Neurons;Outcome Assessment;Pathology;Pathway interactions;Phenotype;Production;Property;Proteins;Receptor Signaling;Rest;Role;Signal Transduction;Slice;Synapses;Synaptic plasticity;Testing;Tissues;Vibrissae;Work;amyloid pathology;awake;barrel cortex;calmodulin-dependent protein kinase II;cerebrovascular;cerebrovascular pathology;comorbidity;data management;excitotoxicity;extracellular;functional outcomes;hippocampal sclerosis;human tissue;knock-down;loss of function;mouse model;network dysfunction;neural network;neuroinflammation;neurotoxicity;neurovascular coupling;neurovascular unit;novel therapeutic intervention;overexpression;prevent;restoration;synaptic function;two-photon;vascular cognitive impairment and dementia;vector


application_id: 10694202
project_number: 5R01DK118082-05
project_title: Pharmacological Approach to the Restoration of Hypoglycemia Awareness
administering_ic: NIDDK
award_notice_date: 2023-03-29
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 118082
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2019-04-01
project_end_date: 2025-03-31
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;Continuous Glucose Monitor;Defect;Diabetes Mellitus;Dopamine Antagonists;Drug Screening;Eating;Event;FDA approved;Failure;Food;Goals;Grant;Hormones;Hyperinsulinism;Hypoglycemia;Impairment;Incidence;Individual;Insulin;Insulin-Dependent Diabetes Mellitus;Laboratories;Lead;Life;Measurement;Metoclopramide;Outpatients;Pathologic;Patients;Persons;Pharmaceutical Preparations;Pharmacotherapy;Pre-Clinical Model;Preclinical Testing;Questionnaires;Rattus;Recurrence;Reporting;Risk;Rodent Model;Symptoms;Techniques;Testing;Therapeutic Agents;behavioral response;counterregulation;diabetes management;diabetic;diaries;drug testing;drug use screening;experimental study;food consumption;hypoglycemia unawareness;improved;indexing;novel;pharmacologic;pre-clinical;randomized placebo controlled 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.


application_id: 10694201
project_number: 5P01AG078116-02
project_title: Project 1 - Astrocytic end-feet and VCID
administering_ic: NIA
award_notice_date: 2023-08-01
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7469
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 1 ABSTRACT/SUMMARYVascular contributions to cognitive impairment and dementia (VCID) are a major cause of dementia both aloneand co-morbid with Alzheimers disease (AD) and AD Related Dementias (ADRD). Astrocytic end-feet arephysically anchored to the vascular basement membranes via dystroglycan complexes. At the end-feet arepotassium and water channels Kir4.1 and aquaporin 4 (AQP4) as well as monocarboxylic acid transporters(MCTs). AQP4 and Kir4.1 channels are polarized at the end-foot and are co-anchored via a -syntrophin-dystrophin 1 complex. We have found that cerebral small vessel disease (cSVD) induced byhyperhomocysteinemia (HHcy) resulted in degeneration and dissociation of the astrocytic end-feet and anassociated loss of AQP4 and Kir4.1 from the end-feet. This suggests that the end-feet are particularlysusceptible to vascular injury and as such may mediate neuronal dysfunction and neurodegenerationassociated with dementia. We have observed increased activity of matrix metalloproteinases (MMPs) inparticular MMP9 coincident with astrocytic end-foot degeneration. We therefore hypothesize that MMP9 isnecessary and sufficient for astrocytic end-foot degeneration and associated neurovascular couplingand metabolic and ionic dyshomeostasis.We will test our hypothesis in mice by manipulating MMP9 in our well-characterized HHcy mouse model of VCIDand our multi-modal multi-faceted outcome measures leverage the specific expertise of our Cores includingintravital MRI/MRS and electrophysiological measures provided by Core B and human tissue images andbiospecimens from Core C. We collaborate extensively with Projects 2-4 to determine relationships betweenend-foot disruption and glutamate transporters K+ATP channels and insulin transporters. All data will flowthrough Core D to quantitatively assess relationships between MMP9 and astrocytic and neuronal function withinthis Project and across all Projects in our P01Strategies for Targeting Astrocyte Reactivity in ADRD P01.To test our hypothesis we propose three distinct aims. Specific Aim 1: MMP9 mediated astrocytic end-foot degeneration will result in cerebrovascular dysfunction impaired neurovascular coupling. Specific Aim 2: MMP9 mediated astrocytic end-foot degeneration will result in metabolic and ionicdyshomeostasis. Specific Aim 3: Astrocytic end-foot degeneration results in profound changes in gene and protein expression and end-foot proteins can be used as biomarkers of end-foot degeneration.

project_terms:
Alzheimer's Disease;Alzheimer's disease related dementia;Astrocytes;Autopsy;Basement membrane;Biochemical;Biological Markers;Blood Vessels;Brain;Brain region;Cerebral small vessel disease;Cerebrovascular Disorders;Collaborations;Complex;Data;Dementia;Dissociation;Dystroglycan;Dystrophin;Electrophysiology (science);Euthanasia;Gene Expression;Gene Expression Profile;Glutamate Transporter;Harvest;Hemorrhage;Histologic;Human;Hyperhomocysteinemia;Image;Impaired cognition;Impairment;Inflammatory;Insulin;Lasers;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinases;Measurement;Measures;Mediating;Metabolic;Microelectrodes;Microscopy;Monocarboxylic Acid Transporters;Mus;Nerve Degeneration;Neuronal Dysfunction;Neurons;Outcome Measure;Pathology;Perfusion;Plasma;Potassium Channel;Predisposition;Proteins;Radial;Regulation;Slice;Testing;Time;Water;Wild Type Mouse;Work;aquaporin 4;arm;awake;candidate identification;candidate marker;cerebrovascular;comorbidity;cytokine;digital;human tissue;in vivo;mouse model;multimodality;neurovascular coupling;novel;object recognition;overexpression;protein expression;syntrophin;two-photon;vascular cognitive impairment and dementia;vascular injury;water channel;water maze


application_id: 10694194
project_number: 5P01AG078116-02
project_title: Core C - Human Consultation-Biosamples-Biomarkers Core
administering_ic: NIA
award_notice_date: 2023-08-01
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7464
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:
CORE C: HUMAN CONSULTATION BIOSAMPLES BIOMARKERS (CBB)ABSTRACTThe Human Consultation Biosamples Biomarkers (CBB) Core (Core C) will complement and integrate theProjects of the P01 Strategies for Targeting Reactive Astrocytes in AD and ADRD. It is critical to validatethe translational relevance of mechanistic mouse models and to extend those results toward further clinicalstudies. Yet there are challenges when it comes to addressing the complex pathobiology of the dementia clinicalsyndrome. Core C will bridge those critical gaps through the following Specific Aims: Aim 1: Optimizeclinically-relevant study design and manage ongoing data streams incorporating human biomarker andautopsy data. This Aim will foster integration organization coherence and documentation for Core C. Themultimodal data include molecular metabolic and network-wide domains in human endophenotypes andhuman preclinical and clinical endpoints. Aim 2: From existing autopsy material and data generate a setof human cases from the UK-ADRC that encompasses the AD/ADRD phenotypes studied in all 4Projects (AD VCID LATE+HS and controls) and provides a common basis for downstream biochemicaland neuropathological endpoint assessments relevant to the Projects. We will analyze a panel of 100cases for this Aim. Aim 2a: Biochemistry. We will perform multi-level protein extracts and run immunoblotswith quantitative measurements on each sample with astrocytic proteins (e.g. AQP4 Kir4.1 GFAP SLC1A2ABCC9/SUR2 Insulin receptor) being studied in the Projects. We will separately assess snap-frozenhippocampal samples as well as frontal cortex (Brodmann Area 9) white matter and gray matter seperately.Aim 2b: Neuropathology. Neuropathologic endpoints will be characterized in a quantitative manner in thesame panel of 100 cases: Astrocytosis (GFAP+) A plaques TDP-43 proteinopathy and Tau tangles. Wealso will perform highly quantitative assessments of blood vessel morphology using CD34 (capillaries) and ?-SMA (arteriole) markers. Double-label IFC will characterize IR and SUR2 proteins cellular distributions.Samples will also be genotyped for ABCC9 risk alleles. Aim 3: From existing clinical outcome measuresgenerate a set of biomarker (in vivo) data from human participants that represents a common basis fordownstream biofluids and neuroimaging endpoint assessments relevant to the projects. Aim 3A:Neuroimaging. A 3D anatomical magnetization-prepared rapid acquisition with gradient echo (MPRAGE)cerebrovascular reactivity (CVR) from existing human imaging on a 3T MRI scanner will be generated andprovided to Projects and Core D. Drs. Powell and Bahrani in Core C are also performing parallel neuroimagingexperiments in mice (Core B). Aim 3B: Fluid Biomarkers. Cerebrospinal fluid (CSF) and plasma that arebanked from UK-ADRC and UK-MarkVCID participants will be assayed for MMP9 and GFAP using QuanterixSimoa assays and AQP4 Kir4.1 and Dp71 will be assayed using a standard colorimetric ELISA method.

project_terms:
3-Dimensional;ABCC9 gene;Address;Alzheimer's disease related dementia;Amyloid beta-Protein;Anatomy;Astrocytes;Astrocytosis;Automobile Driving;Autopsy;Biochemical;Biochemistry;Biological Assay;Biological Markers;Blood Vessels;Blood capillaries;Brain;Brodmann's area;CD34 gene;CRSP3 gene;Cerebrospinal Fluid;Clinical;Clinical Research;Complement;Complex;Consultations;Data;Data Management Resources;Dementia;Diagnosis;Documentation;Enzyme-Linked Immunosorbent Assay;Experimental Models;Fostering;Freezing;Funding;Genotype;Glial Fibrillary Acidic Protein;Hippocampus;Human;Image;Immunofluorescence Immunologic;Infrastructure;Insulin Receptor;Label;Liquid substance;Longitudinal cohort;MMP9 gene;Magnetic Resonance Imaging;Measurement;Measures;Metabolic;Methods;Molecular;Morphology;Mus;Neocortex;Neurofibrillary Tangles;Neuropsychology;Participant;Phenotype;Plasma;Proteins;Research;Research Design;Resources;Running;Sampling;Senile Plaques;Structure;Syndrome;Testing;Therapeutic Intervention;Tissues;Translating;Translational Research;Translations;Triton X100;United States National Institutes of Health;Urea;Western Blotting;Work;alpha synuclein;arteriole;biobank;biomarker identification;blood oxygen level dependent;cerebrovascular;clinical diagnosis;clinical material;clinical outcome measures;clinically relevant;data modeling;data streams;endophenotype;experimental study;frontal lobe;gray matter;human data;human imaging;human subject;in vivo;meetings;mouse model;multimodal data;neocortical;neuroimaging;neuropathology;pre-clinical;protein TDP-43;risk variant;sarkosyl;specific biomarkers;synergism;tau Proteins;white matter


application_id: 10694188
project_number: 5P01AG078116-02
project_title: Core B - Animal Vascular-Metabolic-Neural Network Core
administering_ic: NIA
award_notice_date: 2023-08-01
opportunity_number: PAR-19-314
application_type: 5
activity_code: P01
ic: AG
serial_number: 078116
project_start_date: 2022-09-01
project_end_date: 2027-06-30
study_section: ZAG1-ZIJ-8
subproject_number: 7461
contact_pi_person_id: 10287198
contact_pi: SOMPOL, PRADOLDEJ
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:
CORE B - ABSTRACTThe goals of the Mouse VMN (vascular metabolism network) Core B are to serve the P01 Projects with cutting-edge methods specifically tailored to the P01 themes: Strategies for Targeting Astrocyte Reactivity in AD andADRD (STAR-AD-ADRD). Astrocytes support brain function by integrating their roles with several cell types.They support neurons and regulate blood flow to supply and preserve active brain regions. Astrocytes becomereactive in Alzheimers disease (AD) and Alzheimers disease related dementias (ADRD) and their functions arenot fully understood. Our group at the Sanders-Brown Center on Aging including Drs. Wilcock Thibault Norrisand Nelson investigate roles of astrocytes neurons and vascular pathology in aging and AD/ADRD brain. Theseresearch topics are inter-connected and the success of this P01 will move our understanding of reactiveastrocytes beyond neuroinflammation constraints. Our VMN Core will provide multiple approaches tocharacterize the roles of reactive astrocytes on cerebrovascular function brain metabolism and neuronal networkactivity. Moreover results uniformly generated from our core will permit useful comparisons across projects. TheSpecific aims are to: (1) Coordinate for small animal surgeries and intravital imaging techniques includingtraining and oversight. (2) Coordinate all brain slice electrophysiology experiments. (3) Coordinate and provideservice for microelectrode array experiments. (4) Coordinate and provide service for Magnetic ResonanceImaging experiments. Furthermore our Core will work with the DMB (Data Management and Biostatistics)Core D where the results will be stored processed and easily accessed from our collaborative groups both inUK and beyond.

project_terms:
Acute;Aging;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease related dementia;Animals;Astrocytes;Biological Assay;Biological Markers;Biometry;Biostatistics Core;Blood Vessels;Blood flow;Brain;Brain region;Cells;Cephalic;Cerebrovascular Disorders;Cerebrovascular system;Chronic;Consultations;Craniotomy;Data;Data Analyses;Data Collection;Dementia;Electrophysiology (science);Ensure;Faculty;Gene Delivery;Goals;Human;Human Pathology;Human Resources;Image;Image-Guided Surgery;Imaging Techniques;Impairment;Injections;Kentucky;Laser Speckle Imaging;Magnetic Resonance Imaging;Metabolic;Metabolism;Methods;Microelectrodes;Microscopy;Monitor;Mus;Neurons;Operative Surgical Procedures;Pathology;Phenotype;Physiological;Physiology;Postdoctoral Fellow;Preparation;Procedures;Process;Property;Protocols documentation;Research;Resources;Role;Services;Signal Pathway;Signal Transduction;Slice;Students;Synaptic Transmission;Synaptic plasticity;Techniques;Testing;Thinness;Training;Universities;Vibrissae;Work;brain cell;brain metabolism;cell type;cerebrovascular;cohesion;cranium;data management;experience;experimental study;imaging facilities;implantation;in vivo;intravital imaging;knock-down;molecular pathology;mouse model;neural network;neurochemistry;neuroinflammation;novel;patch clamp;preservation;success;two-photon


application_id: 10694071
project_number: 5R01NR020478-02
administering_ic: NINR
award_notice_date: 2023-06-07
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: NR
serial_number: 020478
program_official: HUSS, KAREN
project_start_date: 2022-08-31
project_end_date: 2026-06-30
study_section: Clinical Management in General Care Settings Study Section[CMGC]
contact_pi_person_id: 11595895
contact_pi: WU, JIA-RONG
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:
Improving medication adherence using family-focused and literacy-sensitive strategies in patients with heart failure

project_abstract:
Project SummaryMedication adherence is thought by many providers and researchers to be the most important self-carebehavior yet it is also the most problematic. Poor medication adherence can cause poor quality of life (QoL)hospitalization and death. In the United States approximately 125000 deaths per year are due to poormedication adherence and up to 50% of heart failure (HF) patients are re-hospitalized within 6 months of aprevious HF exacerbation and one of the most common causes is poor medication adherence. Lifelong andusually complex medication regimens are needed for patients with HF yet 40-60% of HF patients havesuboptimal medication adherence. Health literacy plays a significant role in suboptimal medication adherence.Support by a care partner (CP; usually a family member) can improve adherence and reduce hospitalizations.Although some interventions have improved HF patients adherence improvements were small and effectswere not sustained. To enhance and sustain intervention effects we will use an approach that is literacy-sensitive and incorporates social support. Using easy-to-understand language for patients and CPs we willtest an interactive behavioral family-focused and literacy-sensitive (FamLit) intervention delivered by nursesincorporating evidence-based multi-components (e.g. teach-back coaching role-playing goal setting) toengage both patients and CPs in improving and sustaining medication adherence and health outcomes. Wewill conduct a randomized controlled trial to evaluate the efficacy of FamLit intervention on medicationadherence hospitalization death and QoL. We will randomly assign 164 dyads of patients and their primaryCPs (patients-CPs) to either the FamLit intervention or an attention-control group. Both groups will have an in-person session (delivered on the day of a clinic appointment for regular follow-up) one month after baselineand phone boosters every other week for up to 3 months. FamLit group sessions will focus on improvingmedication adherence and control group sessions will focus on general health issues. Our aims are to: 1) testthe efficacy of the FamLit intervention compared to an attention control group on outcomes (i.e. primary:medication adherence and secondary: a) HF hospitalization or all-cause death b) QoL c) social support andd) communication) over 12 months; 2) determine if TPB-related intermediate outcomes (attitudes subjectivenorms perceived behavioral control) mediate the effects of the intervention on medication adherence; 3)examine whether each dyad members a) health literacy b) social support and c) communication moderatethe effect of the FamLit intervention on medication adherence; and 4) determine how each dyad membersattitudes subjective norms perceived behavioral control social support and communication affect their ownand their partners QoL over 12 months using the innovative Actor-Partner Interdependence Model. TheFamLit intervention if efficacious holds potential to improve/sustain medication adherence and reducehospitalizations and death. We will follow up with an effectiveness-implementation hybrid trial as our next step.

project_terms:
Address;Adherence;Adverse effects;Affect;Agreement;Appointment;Attitude;Back;Behavior;Behavior Control;Behavioral;Caring;Cause of Death;Cessation of life;Chronic;Clinic;Communication;Complex;Control Groups;Educational Materials;Educational process of instructing;Event;Family;Family member;Friends;Goals;Happiness;Health;Health Promotion;Heart failure;Hospitalization;Individual;Instruction;Intervention;Language;Learning;Link;Mediating;Medical;Modeling;Morbidity - disease rate;Motivation;Nurses;Outcome;Partner Communications;Patient Care;Patients;Persons;Pharmaceutical Preparations;Planning Theory;Play;Prevention;Primary Care;Printing;Provider;Quality of life;Randomized;Randomized Controlled Trials;Reading;Regimen;Research;Research Personnel;Role;Role playing therapy;Self Care;Social support;Spouses;Symptoms;Telephone;Testing;Time;Treatment Efficacy;United States;Work;Writing;attentional control;comparison control;comparison intervention;compliance behavior;effectiveness/implementation trial;efficacy evaluation;efficacy testing;empowerment;evidence base;family support;follow-up;fourth grade;group intervention;health literacy;high risk;hospital readmission;improved;innovation;interest;intervention effect;literacy;low health literacy;medication compliance;member;mortality;multi-component intervention;older patient;optimism;pilot test;post intervention;primary outcome;secondary outcome;skills

public_health_relevance:
Project NarrativePeople with heart failure who do not take their medications as prescribed are at high risk of complicationsleading to hospitalization death and poor quality of life. In the proposed intervention nurses will use easy-to-understand language to coach patients and their care partners to help them work together and build skills toovercome their individual barriers to adherence in order to improve and sustain patient medication adherence.If effective this intervention will support long-term medication adherence thus reducing hospitalizations anddeaths related to heart failure.


application_id: 10693826
project_number: 5P42ES023716-07
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7386
contact_pi_person_id: 11775218
contact_pi: HEBERLE, LAUREN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Air;Area;Awareness;Cardiometabolic Disease;Chronic;Chronic Disease;Communication;Communities;Development;Diabetes Mellitus;Elements;Ensure;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Science;Equipment and supply inventories;Ethnic Origin;Exposure to;Face;Farm;Geographic Locations;Goals;Green space;Hazardous Substances;Hazardous Waste;Health;Health Food;Health Sciences;Heart Diseases;Home;Housing;Hypertension;Industry;Institution;Intervention;Kentucky;Knowledge;Natural Sciences;Neighborhoods;Obesity;Outcome;Patient Recruitments;Persons;Play;Policy Maker;Population;Populations at Risk;Poverty;Prevention;Productivity;Race;Research;Research Personnel;Research Project Grants;Resources;Risk;Role;Science;Site;Social Sciences;Source;Structural Racism;Superfund;Syndrome;Toxic effect;Toxin;Training;Transcend;Transportation;biological systems;cardiometabolic risk;cardiometabolism;community center;community engagement;community involvement;empowerment;fatty liver disease;health disparity;interest;landfill;meetings;member;pollutant;risk mitigation;social;superfund site;therapy design

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


application_id: 10693816
project_number: 5P42ES023716-07
project_title: Research Experience and Training Coordination Core
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7384
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary. The RETCC has played a coordinating role in the success of ULSRC since its inception inSeptember 2017. By working closely with other NIEHS-supported training programs at the UofL (T32ES011564;T35ES014559) the RETCC has developed a rich diverse and comprehensive training program that is bothmultidisciplinary and inclusive. In addition to the course work and on the bench training activities RETCCroutinely organizes participatory field trips to the Lees Lane Superfund site to better understand and appreciatehealth concerns of residents in the adjacent community of Riverside Gardens; facilitates the meeting of traineeswith regional Superfund site coordinators and officials and the Metro Louisville Public Health and WellnessDepartment. Our training core in collaboration with Superfund Research Centers at Duke University Universityof Kentucky and University of Pennsylvania organized a trip to Washington D.C. so trainees could attend aScience and Policy Institute meeting that included interactions with congressional leaders and their staff. Suchactivities have been instrumental in the well-rounded growth of our trainees. Moreover these trainees not onlyprovide the force that turns the wheel but also are the focus and hub of intellectual crosstalk and fertilizationacross projects cores other SRCs and the National SRP. To date ULSRC success is the product of our traineessuccesses through their many accomplishments including publications presentations awards degreesfellowships interactions with community partners and environmental health sciences-related careeropportunities. Thus although we are proud of our current success via integration of trainee activities across theULSRC we continue to strive to build on these successes by implementing innovative and unifying features intoRETCC-directed activities that focus on fulfilling the goals and furthering the success of our trainees.

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

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


application_id: 10693813
project_number: 5P42ES023716-07
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7383
contact_pi_person_id: 9753394
contact_pi: RAI, SHESH N.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe primary objective of the Sample and Data Management Core (DMAC) is to provide statistical support anddata management and storage capabilities to all components of the University of Louisville Superfund ResearchCenter (ULSRC). The functions of the Core are matched to the needs of each project and cover a full range ofservices from collaboration and routine service to protocol preparation to procedural review and oversight. TheCore will provide two main services: it will establish a repository for the long-term storage and archiving of data;and it will assist Center investigators in the statistical analysis of their results. The core will assure the authenticityand quality of these specimens and it will prepare these samples for long-term storage or dispense samples asneeded. The Core will also provide scientifically valid and rigorous statistical analysis of data and support thedevelopment of innovative methods to enhance the basic and translational research efforts of Centerinvestigators. It will provide state-of-the-art biostatistics and bioinformatics expertise and analytical support. Corebiostatisticians will also develop new statistical methods such as quantitative risk assessment modelsmultipollutant exposure analysis and land-use regression models for estimating cardiometabolic disease risk inexposed populations and for the analysis and evaluation of exposures and health effects. In collaboration withother projects and cores DMAC statisticians will harmonize the data by defining standards (e.g. creatingsearchable data dictionaries and defining variables relevant for each project. In the next funding cycle we willcontinue to use these procedures. The core will serve as a unique educational resource for training graduatestudents post-doctoral fellows residents and junior faculty and in collaboration with the Training andAdministration Cores. This Core will allow Center investigators easy access to high quality centralized datamanagement and statistical services and thereby will strengthen the organizational cohesion of the Center. Thiscomprehensive and integrated service permits one or more biostatisticians to be involved from the initial planningstage of a project (when statistical consultation is most beneficial) throughout its implementation analysis andcompletion. The Core will provide a stable and collegial environment that fosters long-term working relationshipsbetween biostatisticians and investigators and continues to promote sophisticated approaches to experimentaldesign and analysis. The biostatisticians of this Core are knowledgeable about clinical research and have broadexpertise in statistical applications for epidemiological investigations clinical trials pre-clinical studies andprevention and control research. Their interdisciplinary interactions with basic scientists and clinical investigatorswill add a new dimension to the interpretation of experimental results one that is only possible when collaboratorsshare a mutual appreciation of problems and issues.

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

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


application_id: 10693807
project_number: 5P42ES023716-07
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7380
contact_pi_person_id: 9972311
contact_pi: NANTZ, MICHAEL H
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-07-01
project_title:
Project 3 - Development and Field Application of Novel Ultrasensitive Devices for the Measurement of Airborne VOCs

project_abstract:
PROJECT SUMMARY (Project 3)This proposed work is to advance airborne volatile organic compound (VOC) detection and quantificationtechnologies and to robustly characterize indoor/outdoor contrast and in-home determinants for exposures totarget Superfund-relevant VOCs. This research will continue to grow and expand two VOC real-time in situmeasurement platforms developed by the University of Louisville Superfund Research Center established in2017. One platform comprises small low-cost sensors that can be deployed alone or in networks. Novel gassensors and sensor arrays are being developed to measure target Superfund-relevant VOCs including acroleintrichloroethene (TCE) benzene toluene ethylbenzene and xylene (BTEX). The devices use novel surfacechemistries to address the common challenges of selectivity and sensitivity and are fabricated usingmicroelectromechanical systems (MEMS) technology. Another platform addresses the need for flexiblydesigned field-deployable instruments that can measure with high sensitivity a large range of compounds tointerrogate microenvironments with complex VOC mixtures. The Multichannel Organics In-situ enviRonmentalAnalyzer (MOIRA) instrument developed in the first cycle of Center funding for mobile monitoring will beexpanded and optimized for indoor/outdoor VOC monitoring studies. MOIRA is a gas chromatographymassspectrometry (GC-MS) instrument with high time resolution (e.g. ten minutes). Its capabilities will be expandedto measure both higher and lower volatility compounds than can be achieved with the current design. Theseinnovative high time resolution in situ measurements will be coupled with conventional time-integrated VOCpassive sampling to measure target Superfund-relevant VOCs at homes of some participants in the allied clinicalstudy. These data will be used to build spatiotemporal models to estimate ambient VOCs at the homes of allclinical study participants and to gain new insights into VOC levels and their determinants in the homemicroenvironment. In addition to exposure assessment the two measurement platforms are responsive toongoing Superfund program advancements; these innovative developments will expand future capacities tomonitor VOC indoor vapor intrusion monitor outdoor VOC levels during site remediation and monitor bothindoors and outdoors during post-remediation surveillance.

project_terms:
Acrolein;Address;Air;Ally;Automobile Driving;Benzene;Cardiometabolic Disease;Chemistry;Clinical Research;Collection;Complex;County;Coupled;Custom;Data;Detection;Development;Devices;Electrodes;Environmental Exposure;Exhibits;Exposure to;Funding;Future;Gases;Goals;Gold;Home;Hour;In Situ;Indoor environment;Industrialization;Infiltration;Investigation;Mass Fragmentography;Measurement;Measures;Modeling;Modification;Monitor;Participant;Pattern;Process;Protons;Reaction;Research;Residual state;Resolution;Sampling;Signal Transduction;Site;Small-Area Variations;Source;Sulfhydryl Compounds;Superfund;Surface;System;Technology;Temperature;Testing;Time;Toluene;Trichloroethylene;Universities;Work;Xylene;cost;design;ethylbenzene;exposed human population;flexibility;gas analyzer;innovation;insight;instrument;mass spectrometer;metal oxide;miniaturize;nanoGold;new technology;novel;programs;remediation;residence;sensor;spatiotemporal;superfund chemical;superfund site;technology platform;time use;tool;urban setting;vapor intrusion;volatile organic compound

public_health_relevance:
RELEVANCEThis proposed work is to support continued research within the University of Louisville Superfund ResearchCenter on novel technologies to detect and quantify Superfund-relevant volatile organic compounds (VOCs) inair. These technology platforms will be used to better understand VOC sources and human exposures.


application_id: 10693804
project_number: 5P42ES023716-07
project_title: Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 7379
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARYExposure to toxicants has been linked to the development or exacerbation of chronic disease. However little isknown about how volatile organic chemicals (VOC)a class of toxicants associated with higher prevalence oftype 2 diabetes (T2D) and strokepromote the development of cardiometabolic disease (CMD). Accordinglythe overarching goals of this Superfund project are to determine the mechanisms by which VOCs negativelyimpact cardiovascular health and metabolism identify biomarkers for VOC exposure and vascular injury andtest therapeutic strategies to minimize VOC-induced CMD. Our studies in the current funding cycle andpreliminary data suggest that VOC such as benzene vinyl chloride and crotonaldehyde promote endoplasmicreticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells. Specifically wehypothesize that aldehyde metabolites of VOC which are generally more toxic than their parent compounddiminish endothelial toxicity by inducing ER stress which triggers metabolic changes that accelerate ectopic lipiddeposition and promote cardiometabolic dysfunction. To test this hypothesis we will: (1) examine the effects ofVOC exposure on endothelial function and insulin resistance; (2) delineate the contribution of protein misfoldingto the cardiometabolic toxicity of VOC. The design of these studies includes molecular and pharmacologicalinterventions designed to detoxify or quench the reactive intermediates evoked by VOC exposure as well asstudies that could lead to the identification of novel sensitive and robust biomarkers of both VOC exposure andvascular injury. These studies were designed to synergize with and provide biological plausibility for theassociations identified in Project 1. Successful completion of this project will lead to identification of theunderlying cellular and molecular mechanisms by which VOC affect cardiometabolic function and provideinsights into how VOC toxicity could be prevented or therapeutically minimized by targeting aldehydes or protein-folding pathways.

project_terms:
13-Butadiene;2-butenal;ATF6 gene;Acceleration;Acrolein;Adipose tissue;Adult;Affect;Aldehydes;Animal Model;Apoptosis;Apoptotic;Atherosclerosis;Benzene;Biological;Biological Markers;Blood Vessels;Body Burden;Butadiene;Cardiometabolic Disease;Cardiovascular Physiology;Cardiovascular system;Carnosine;Cell physiology;Chemical Exposure;Chemical-Induced Change;Chemicals;Chronic Disease;Data;Deposition;Development;Diabetes Mellitus;Disease Resistance;Dose;Drug Metabolic Detoxication;Endoplasmic Reticulum;Endothelial Cells;Endothelium;Environmental Exposure;Environmental Impact;Exposure to;Fatty acid glycerol esters;Formaldehyde;Functional disorder;Funding;Glutathione;Goals;Hazardous Chemicals;Hazardous Substances;Health;Heart Diseases;Heart failure;Heat shock proteins;Hepatic;High Prevalence;Human;Hypertension;Individual;Inflammatory;Inhalation;Injury;Insulin Resistance;Investigation;Link;Lipid Peroxidation;Lipids;Measures;Mediating;Mediator;Metabolic;Metabolism;Molecular;Molecular Chaperones;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Obesity;Oxidative Stress;Oxidative Stress Induction;Parents;Pathway interactions;Plasma;Platelet Activation;Poison;Process;Production;Property;Proteins;Protocols documentation;Reporting;Risk;Role;Signal Recognition Particle;Signal Transduction;Source;Stroke;Structure;Superfund;Surveys;Testing;Therapeutic;Tobacco smoke;Toxic effect;Trichloroethylene;Vinyl Chloride;Work;ambient air pollution;biomarker identification;cardiometabolic risk;cardiometabolism;cardiovascular health;cardiovascular injury;design;diet-induced obesity;disorder risk;endoplasmic reticulum stress;endothelial dysfunction;fatty liver disease;heart function;indexing;insight;insulin sensitivity;metabolomics;mouse model;novel;overexpression;pharmacologic;preclinical study;prevent;protein folding;protein misfolding;response;superfund site;synergism;systemic inflammatory response;therapeutic evaluation;therapy design;toxicant;urinary;vascular inflammation;vascular injury;volatile organic compound;western diet

public_health_relevance:
PROJECT NARRATIVEExposure to hazardous substances has been linked to the development or worsening of chronic disease. Thepurposes of this Superfund project are to understand how a particular class of compounds i.e. volatile organiccompounds affect cardiovascular health and the onset or progression of diabetes heart disease and fatty liverdisease as well as to develop therapeutic strategies to minimize these affect after exposure to toxic compounds.


application_id: 10693801
project_number: 5P42ES023716-07
project_title: Project 1 - Cardiometabolic Injury due to VOCs
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S
subproject_number: 5053
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe overall goal of this project is to assess the impact of exposure to Superfund-relevant volatileorganic compounds (VOCs) on cardiometabolic disease the underlying conditions thatcontributes to diabetes cardiovascular and liver diseases. VOCs such as trichloroethylenebenzene acrolein formaldehyde xylene and butadiene are major chemicals of concern at mostSuperfund sites and extensive previous work suggests the exposure to VOC could have a varietyof adverse health effects. Nevertheless whether exposure to VOCs at levels relevant toneighborhood adjacent to Superfund sites could adversely affect cardiometabolic health remainsunknown. Our extensive studies with animal exposed to different VOCs suggest that chronicexposure to low dose VOCs could increase blood pressure inflict vascular injury accelerateatherosclerosis and induce liver disease. Nevertheless the cardiometabolic risk of VOCs hasnot been evaluated and longitudinal data to interrogate exposure-response relationships aremissing. Hence to assess CMD risk imposed by VOCs we will test the hypothesis that exposureto VOCs exacerbates/induces vascular and hepatic dysfunction leading to a cascade of eventsthat increase CMD risk. To assess the impact of VOC exposures we will examine 1200 residentsof Jefferson County including those who live in areas adjacent to Superfund sites such as LeesLane and Distiller Farm as well as high VOC emission such as the Rubbertown neighborhood.In each participant we will assess CMD risk by measuring arterial stiffness marker of hepatocytedeath as well as suite of biomarkers indicative of risk for diabetes cardiovascular and liverdiseases. To determine population-level VOC exposure and its relationship with CMD-relatedhospital admissions and mortality we will establish a network of VOC monitors to measure VOClevels throughout Jefferson County and monitor domestic wastewater for urinary VOCmetabolites. We will monitor wastewater every other month for 3 years and assess the extent towhich population-level exposure estimates reflect ambient air VOC levels and individual-levelexposure (Aim 1) and how these estimates relate to population-level and individual-level CMDrisk. To obtain longitudinal data we will examine CMD progression and determine theassociation between individual-level and community-level VOC exposures with vascular andhepatic function and other indices of cardiometabolic risk. This will help us in assessing how VOCexposure and/or residential proximity to Superfund sites affects the risk of CMD and thisexcessive risk differs from that imposed by background VOC exposures in urban neighborhood.We expect that completion of this project will lead to the development of quantitative risk modelsand rigorous estimates of the additional CMD risk attributable to residential VOC exposures.

project_terms:
Acceleration;Acrolein;Affect;Air;Animals;Area;Atherosclerosis;Benzene;Bile Acids;Biological Markers;Blood Platelets;Blood Pressure;Blood Vessels;Butadiene;Carcinogens;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Chronic;Collaborations;Communities;County;Data;Data Analyses;Development;Diabetes Mellitus;Disease Progression;Dose;Environmental Exposure;Enzymes;Event;Exposure to;Farm;Formaldehyde;Functional disorder;Goals;Hazardous Chemicals;Health;Hepatic;Hepatocyte;Hepatotoxicity;Hospital Mortality;Hospitalization;Human;Individual;Injury;Insulin Resistance;Kentucky;Keratin;Lipids;Liquid substance;Liver;Liver diseases;Location;Measurement;Measures;Metabolic Diseases;Metabolism;MicroRNAs;Modeling;Monitor;Neighborhoods;Participant;Plasma;Population;Process;Risk;Serology;Serum;Steatohepatitis;Superfund;Target Populations;Testing;Toluene;Trichloroethylene;Variant;Vascular Diseases;Water;Work;Xylene;arterial stiffness;blood glucose regulation;blood pressure elevation;carcinogenicity;cardiometabolic risk;cardiometabolism;cardiovascular disorder risk;circulating biomarkers;cohort;data management;diabetes risk;disorder risk;exposed human population;fatty liver disease;indexing;land use;landfill;liver biopsy;monocyte;mortality;particle;primary endpoint;response;stem cells;superfund site;toxicant;urinary;vascular injury;volatile organic compound;wastewater monitoring

public_health_relevance:
NARRATIVEThis project is to identify assess and evaluate the potential health effects due to exposure to hazardouschemicals prevalent in urban neighborhoods and areas around Superfund sites.


application_id: 10693800
project_number: 5P42ES023716-07
project_title: Environmental Exposure and Cardiometabolic Disease
administering_ic: NIEHS
award_notice_date: 2023-08-25
opportunity_number: RFA-ES-20-014
application_type: 5
activity_code: P42
ic: ES
serial_number: 023716
program_official: CARLIN, DANIELLE J
project_start_date: 2017-09-01
project_end_date: 2027-06-30
study_section: ZES1-LAT-S(SF)
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY (Overall)This proposal is to continue to grow and expand the University of Louisville Superfund Center established in2017. Currently the Center supports research on the cardiometabolic effects of volatile organic chemicals(VOCs) that are of high relevance to the Superfund Program. Center investigators conduct mode-of-actionresearch to unravel critical pathways of toxicity and to identify toxicological end-points (cardiometabolic changes)of chemicals (VOCs) found at Superfund and related sites. Using high throughput mass spectrometry and aninnovative suite of mechanism-based biomarkers animal experiments and human population studies Centerinvestigations have contributed to the discovery and validation of novel biomarkers of both exposure andcardiometabolic injury that would lay the foundation for future remediation strategies. These studies employstate-of-the-art tools to develop pollutant atmospheres for animal exposure and to measure unique and sensitivebiological endpoints reflective of cardiometabolic injury. In addition work supported by the Center is leading tothe development of new methods and devices for quantifying atmospheric levels of VOCs that employ advancedtechnologies and offer precise but low-cost measurements of hazardous waste sites. As before the majorobjectives of the Center are to conduct state-of-the-art research on the cardiometabolic toxicity of VOCs and todetermine how they affect cardiometabolic disease (CMD) prevalence and severity in exposed populations.These studies will be complemented by mode-of-action mechanistic studies in animals to identify the molecularand cellular mechanisms that contribute to VOC toxicity. The findings of these studies will continue to contributeto both the discovery and the validation of sensitive and robust biomarkers that could be used to assess theextent of exposure metabolism and toxicity. Center investigators are creating new technologies for detectingVOCs at low environmental levels to enable future exposure assessment activities. Senior Center memberseducate and train junior investigators graduate students and post-doctoral Fellows in the field of environmentalscience and promote relevant community awareness and participation to enhance mutual bidirectionalunderstanding of exposure risk and the health effects of exposure. The findings and discoveries of the Centerwill be transferred to affected communities end users in public and private sectors and other stakeholders. Forfuture use and analysis all samples of human and animal tissues and all data collected during Centerinvestigations will be stored in a computer-coded biorepository. Collectively expansion and growth of the Centeractivities will enhance its contribution and lead to rigorous evaluation and better understanding of the effects ofthese hazardous chemicals on obesity diabetes and cardiovascular disease.

project_terms:
Action Research;Advanced Development;Affect;Animal Experiments;Animal Model;Animals;Area;Atmosphere;Awareness;Biological;Biological Markers;COVID-19;Cardiology;Cardiometabolic Disease;Cardiovascular Diseases;Chemical Exposure;Chemicals;Chemistry;Communities;Community Outreach;Complement;Cost Measures;Critical Pathways;Data;Data Analyses;Data Storage and Retrieval;Decision Making;Development;Devices;Diabetes Mellitus;Disease Pathway;Education and Outreach;Ensure;Environment;Environmental Exposure;Environmental Science;Epidemiology;Etiology;Evaluation;Exposure to;Foundations;Funding;Future;Generations;Goals;Growth;Hazardous Chemicals;Hazardous Substances;Hazardous Waste Sites;Health;Heart Diseases;Hepatology;Human;Incidence;Industrialization;Injury;Investigation;Knowledge;Mass Spectrum Analysis;Measures;Membrane;Metabolism;Methods;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Population;Postdoctoral Fellow;Predisposition;Prevalence;Private Sector;Procedures;Process;Public Health;Public Sector;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Risk;Sampling;Science;Severities;Site;Superfund;Technology;Tissue Sample;Toxic effect;Toxicology;Training;Training Programs;Universities;Validation;Work;animal tissue;biobank;cardiometabolism;community engagement;computer code;data archive;data management;data sharing;detection method;education research;education resources;experience;exposed human population;fatty liver disease;graduate student;human population study;human tissue;innovation;interest;member;new epidemic;new technology;novel;novel marker;obesity development;outreach program;pollutant;programs;remediation;repository;resilience;response;self assembly;superfund chemical;superfund site;tool;translational medicine;volatile organic compound

public_health_relevance:
RELEVANCEThis proposal is to support research within the University of Louisville Superfund Center on the health effect ofhazardous Superfund chemicals. Continued work in this Center will help in further evaluating the health impactof several hazardous chemicals that are present in the environment and in understanding how exposure tochemicals could contribute to the risk and development of obesity diabetes and heart disease.


