# projects

application_id: 10604325
project_number: 5R35HL150818-04
project_title: Platelet Exocytosis and Endocytosis in Thrombosis and Immunity
administering_ic: NHLBI
award_notice_date: 2023-03-27
opportunity_number: RFA-HL-20-011
application_type: 5
activity_code: R35
ic: HL
serial_number: 150818
program_official: KINDZELSKI, ANDREI L
project_start_date: 2020-04-01
project_end_date: 2027-03-31
study_section: ZHL1-CSR-R(O1)
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractSurprisingly platelets are capable of bidirectional interactions with their microenvironmentthrough basic cellular processes that are largely unexplored. In this R35 proposal we expand onour active research themes: one unraveling the mechanistic role of exocytosis in hemostasis andthe other investigating endocytosis as an entry pathway to define the role of platelets in innateimmunity. By linking these two areas we can gain deeper insights into how platelet interact withtheir microenvironments. Despite advances in understanding signaling from vascular damagedetection our view of how activated platelets execute the steps needed for clot formation islimited. We have probed the mechanisms of platelet secretion and how it affects hemostasisusing genetically altered models and determined that modulating secretion controls thrombusgrowth without compromising hemostasis. To build on that advance a better understanding ofplatelet exocytosis is clearly needed so logical therapeutic strategies can be developed. Our workon platelet endocytosis endo-lysosomal trafficking and processing of endocytosed cargo led tothe discovery that platelets take up pathogens e.g. viruses and are activated. Increasinglyplatelets are being associated with immune responses yet the mechanisms underlying thesenon-hemostatic functions are largely unknown. Very little is known about platelet endocytosisand next to nothing is known about how platelets traffic and process endocytosed material. OurR35 research program seeks to fill these gaps in knowledge by taking a holistic approach to thestudy of platelet cell biology. Building on our innovative past work (>50 publications) we willfurther define platelet membrane trafficking (endocytosis exocytosis cargo sorting/processingetc.). We hypothesize that bidirectional trafficking processes endo- and exocytosis are essentialfor platelet-specific functions specifically thrombosis and innate immune responses. To addressthis hypothesis we will examine platelet exocytosis and endocytosis at mechanistic andphysiological levels using an extensive suite of reagents transgenic mouse strains andtechnologies. Going forward we will use these powerful tools and approaches to define howplatelet membrane trafficking (both exo- and endocytosis) affects hemostasis/thrombosis andimmune responses at molecular and organismal levels. The data generated are directlyapplicable to the understanding and treatment of human disease especially thrombotic diseaseswhich accounts for 1 in 4 deaths world-wide and chronic viremia e.g. AIDS/HIV1 whichincreases CVD risk.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;Area;Blood Platelets;Blood Vessels;Cell physiology;Cellular biology;Cessation of life;Chronic;Coagulation Process;Cytoplasmic Granules;Data;Detection;Endocytosis;Exocytosis;Growth;HIV-1;Hemostatic function;Immune response;Immune system;Immunity;Innate Immune Response;Knowledge;Link;Membrane;Modeling;Molecular;Mouse Strains;Natural Immunity;Pathogen detection;Pathway interactions;Physiological;Process;Publications;Reagent;Research;Risk;Role;Signal Transduction;Sorting;Technology;Therapeutic;Thrombosis;Thrombus;Transgenic Mice;Viremia;Virus;Work;holistic approach;human disease;innovation;insight;pathogen;programs;tool;trafficking

public_health_relevance:
Platelets detect vessel damage and secrete granule cargo to form clots. They also detectpathogens via endocytosis and process them to alert the immune system. Understanding howplatelets do these things will lead to a better understanding of thrombotic disease.


application_id: 10604311
project_number: 5R01NS116058-04
administering_ic: NINDS
award_notice_date: 2023-03-31
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 116058
program_official: CORRIVEAU, RODERICK A
project_start_date: 2020-04-01
project_end_date: 2025-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)

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

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

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


application_id: 10603701
project_number: 1R43TR004327-01
administering_ic: NCATS
award_notice_date: 2023-01-16
opportunity_number: PA-21-259
application_type: 1
activity_code: R43
ic: TR
serial_number: 004327
program_official: HAPPEL, CHRISTINE MARIE
project_start_date: 2023-02-01
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 BST-F (10)]
contact_pi_person_id: 78270408
contact_pi: JANIS, BRETT R
other_pis: Not Applicable
congressional_district: 04
department: Unavailable
primary_duns: 117049277
primary_uei: KNA4L6N847S3
duns_number: 117049277
uei: KNA4L6N847S3
fips: US
organization_id: 10065978
organization_name: DESICORP, INC.
organization_city: LA GRANGE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400319132
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-02-01
project_title:
Developing a High-Flow Acoustofluidic Loading Platform for Research Cell Stabilization in the Anhydrous State

project_abstract:
Project SummaryModel cells for cancer research and drug discovery are currently stored using cryogenic methods thatnecessitate powerful freezers and liquid nitrogen. Frozen cells require regular upkeep have high energy coststake up a lot of space and rapidly degrade if cooling devices fail. Efforts to develop a lyophilization protocol formodel cell lines have been ongoing for decades however loading protective agents into nucleated cells hasproven challenging. DesiCorp has developed a novel and innovative cell loading device termed the high flowacoustofluidic loading (HFAL) that can deliver protective osmolytes proteins and nucleotides into eukaryoticcells. Unlike microfluidic loading techniques HFAL uses large channel dimensions that allow substantiallylarger volumes of cell suspension to flow through it at once. The cells are mixed with cationic lipid-coatedmicrobubbles that resonate with ultrasound waves inducing cavitation. These cavitation-induced microjetsphysically inject compounds from the surrounding media into the cells in suspension which then repair anymembrane damage and seal membrane-impermeant compounds inside of the cell. This technology haspreviously been utilized to load human erythrocytes with protective compounds allowing them to belyophilized stored at ambient temperatures then rehydrated with over 90% cell recovery. A notable innovationof the HFAL platform is the ability to load cells at high rates exceeding 500 billion erythrocytes per minute.However the unique challenges of protecting organelles requires additional work to design and validate theHFAL platform for eukaryotic cell stabilization during lyophilization. The specific aims for this proposal are 1) todevelop a complete sterile acoustofluidic loading system that loads HepG2 and HEK 293 cells with over 60%cell recovery which will be measured using trypan-blue exclusion; 2) to achieve compound loading into HepG2and HEK293 that is sufficient for their stabilization in the desiccated state which will be measured usingenzymatic and colorimetric assays; and 3) to lyophilize HepG2 and HEK293 cells store them at ambienttemperature and rehydrate them with high enough recovery for culturing and their organelle structure shouldresemble that of frozen and thawed model cells which will be measured using fluorescence microscopy. Themain criterion for success of this phase I proposal is the fabrication of a fully integrated acoustofluidic loadingplatform that successfully loads eukaryotic cells with protective agents that allow them to be lyophilized storedrehydrated and cultured. Lyophilized cell stocks have several advantages over cryogenically preserved cellssuch as the lack of ongoing maintenance and energy costs. Large storage devices such as freezers or liquidnitrogen dewars are unnecessary for lyophilized products because they are thermally stable. If this proposedwork is successful then cell stocks could be stored in drawers binders or even with the notebooks detailingtheir creation modification and data associated with grants or publications.

project_terms:
3D Print;Address;Animals;Antineoplastic Agents;Area;Asphyxia;Biological Assay;Cancer Model;Cell Count;Cell Culture Techniques;Cell Line;Cell Nucleus;Cell Survival;Cell Volumes;Cell model;Cells;Cellular Structures;Complex;Cryoprotective Agents;Culture Media;Dangerousness;Data;Desiccation;Devices;Dimensions;Dryness;Effectiveness;Equipment;Erythrocytes;Eukaryotic Cell;Exclusion;Exposure to;Failure;Fluorescence Microscopy;Freeze Drying;Freezing;Future;Gases;Goals;Grant;Hazardous Substances;HepG2;Hour;Human;Hydration status;Induction of Apoptosis;Lipids;Liquid substance;Longevity;Maintenance;Measures;Medical;Medical Research;Membrane;Methods;Microbubbles;Microfluidics;Microscopic;Mitochondria;Modification;Mothers;Nitrogen;Nucleotides;Organelles;Phase;Plants;Process;Protective Agents;Proteins;Protocols documentation;Publications;Qualifying;Records;Recovery;Reproducibility;Research;Research Personnel;Risk;Sampling;Sterility;Structure;Suspensions;System;Techniques;Technology;Temperature;Toxic effect;Treatment Efficacy;Trehalose;Trypan Blue;Ultrasonic wave;Vendor;Water;Work;anticancer research;cancer cell;cancer therapy;cold temperature;cost;cryogenics;daughter cell;design;drug discovery;drug efficacy;efficacy study;evaporation;experience;experimental study;fabrication;innovation;novel;novel therapeutics;preservation;pressure;prototype;repaired;safety study;seal;sonoporation;success;tool;ultrasound

public_health_relevance:
Project NarrativeExperiments using model cancer cells are a critical step for researchers developing novel drugs and cancertreatments. These cells are very valuable and must be kept for years in order to replicate experiments butstoring them is expensive and uses a lot of space. If these cells can instead be loaded with preservatives usingour ultrasound technique then they could be freeze-dried and stored without expensive equipment or powerrequirements which would help make cell research more accessible affordable and reproducible.


application_id: 10603559
project_number: 1F31MH132194-01
administering_ic: NIMH
award_notice_date: 2022-09-16
opportunity_number: PA-21-051
application_type: 1
activity_code: F31
ic: MH
serial_number: 132194
program_official: CORNELL, ASHLEY ROSE
project_start_date: 2022-12-18
project_end_date: 2023-12-17
study_section: Special Emphasis Panel[ZRG1 F16-L (20)]
contact_pi_person_id: 78504634
contact_pi: TIPSWORD, JORDYN M
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-12-18
project_title:
The Experience and Regulation of Posttraumatic Shame among Women with Histories of Interpersonal Trauma

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

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

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


application_id: 10602993
project_number: 1R43OD034180-01
project_title: Dye-loaded Nanoparticle Platform for Rapid and Sensitive Vivarium Pathogen Detection
administering_ic: OD
award_notice_date: 2023-08-16
opportunity_number: PAR-21-225
application_type: 1
activity_code: R43
ic: OD
serial_number: 034180
program_official: CONTRERAS, MIGUEL A
project_start_date: 2023-08-15
project_end_date: 2025-05-14
study_section: Special Emphasis Panel[ZRG1 IMST-J (10)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryThis proposal develops key aspects of an ultrasensitive pathogen detection system for rodent animal healthsurveillance and is in response to the NIH FOA PAR-21-225 to develop novel tools and devices for animalresearch facilities and to support the care of animal models. The goal of the project is to develop a microfluidicdevice for rapid and inexpensive pathogen detection directly from an animal or from soiled bedding. The devicewill be used cage-side and will complement current rodent health monitoring programs which are designed tomonitor rooms or cage racks quarterly. Use of the device will encourage rapid outbreak mitigation and resolutionas well as confirm health status for animal importation. The advantages of the platform will be specificitysimplicity speed and sensitivity in a 3Rs consistent approach.The specificity of the detection system relies on DNA hybridization of a synthetic oligonucleotide designedspecifically for the pathogen of interest with DNA captured from infectious agents directly from the rodent or frombedding samples. The detection step will be rapid since the DNA hybridization will not rely on cyclic amplificationof the DNA but instead will shift the sensitivity requirements to release of dye from mesoporous silicananoparticles using pH-dependent dye release. In this Phase I proposal the key aspects of the platform will beoptimized and tested for feasibility in 4 Aims. First the pathogen DNA preparation protocol will be establishedusing a bacterial and viral DNA source and the limit of pathogen detection quantified for DNA collection. Secondthe synthetic oligonucleotide that serves in pathogen detection will be optimized and bound to magneticnanoparticles. Third internal pores and external surfaces of mesoporous silica nanoparticles (mSNPs) will bedifferentially labelled so that the internal surfaces are saturated with reversibly bound dye molecules while theexternal surfaces are coated with DNA that will hybridize with the pathogen specific detection oligonucleotide.Lastly proof of feasibility of the platform will be tested by combining the pathogen detection and ultrasensitivepH-responsive dye release aspects. The innovation of this platform is in the use of DNA secondary structure toprovide pathogen specificity the use of mSNPs designed specifically for saturated dye loading with pH-sensitivedye release and the use of DNA hybridization to physically bind the specificity and sensitivity features togetherallowing enrichment of the detection complexes with the use of magnetic nanoparticles.

project_terms:
Affect;Animal Model;Animal Welfare;Animals;Bacterial DNA;Beds;Binding;Biological Assay;Biomedical Research;Clinical;Collaborations;Collection;Complement;Complex;DNA;DNA amplification;Detection;Development;Device Designs;Device or Instrument Development;Devices;Disease;Disease Outbreaks;Dyes;Fluorescent Dyes;Funding;Funding Opportunities;Goals;Health;Health Status;Infectious Agent;Label;Laboratories;Laboratory Animal Production and Facilities;Letters;Linker DNA;Magnetic nanoparticles;Methods;Microfluidic Microchips;Microfluidics;Monitor;Oligonucleotides;Outcome;Pathogen detection;Periodicity;Personal Satisfaction;Phase;Physiology;Preparation;Protocols documentation;Research;Resolution;Rodent;Rodent Model;Sampling;Sensitivity and Specificity;Sentinel;Side;Silicon Dioxide;Site;Soil;Source;Specificity;Speed;Structure;Surface;System;Technology;Testing;Therapeutic;United States National Institutes of Health;Validation;animal care;design;detection platform;feasibility testing;improved;innovation;interest;magnetic beads;manufacture;nanoparticle;novel;outbreak control;pathogen;programs;response;skills;surface coating;tool;viral DNA

public_health_relevance:
Project NarrativeRodents are used extensively for biomedical research and are essential for study of physiology disease andtherapeutics. The basic health and wellbeing of rodent models used in research is of the utmost concern becauseanimals infected with pathogens will not have the same clinical or experimental outcomes as healthy animalsaffecting the rigor of scientific outcomes. This proposal develops an ultrasensitive pathogen detection platformfor cage-side health surveillance to encourage rapid outbreak mitigation and resolution as well as health statusconfirmation.


application_id: 10602757
project_number: 1R43AG080890-01
project_title: Inhibition of Complement Pathways with VCP As A Treatment For Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2023-02-13
opportunity_number: PAS-19-316
application_type: 1
activity_code: R43
ic: AG
serial_number: 080890
program_official: MARTIN, ZANE
project_start_date: 2023-02-15
project_end_date: 2024-09-30
study_section: Special Emphasis Panel[ZRG1 ETTN-A (11)]
contact_pi_person_id: 1971555
contact_pi: ZHOU, JIANHUA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 801721601
primary_uei: G942LFRXSK87
duns_number: 801721601
uei: G942LFRXSK87
fips: US
organization_id: 10017951
organization_name: INFLAMED, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402411864
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractVaccinia virus complement control protein (VCP) has been shown to have structural and functional similarityto human complement control proteins. VCP modulates the human and rodent complement system. Duringthe past two decades we have studied VCP extensively in a number of preclinical inflammatory diseasemodels including Alzheimers disease (AD) and spinal cord injury (SCI) and demonstrated that controllingcomplement mediated inflammation by VCP has significantly improved outcomes leading to our hypothesisthat VCP can be potentially used for therapeutic treatments of these diseases. AD is one of the mostdevastating diseases amongst the aging population in the world and the 6th leading cause of death in theUS. It is well known that amyloid proteins and plaques are associated with activation of severalproinflammatory mediators especially complement components. Interestingly ApoE genotypes thatsignificantly facilitate A- deposit are strongly involved in regulation of classical complement cascade.These pro-inflammatory mediators can cause damage on their own as well as working in synergy with eachother ultimately leading to neurodegeneration. Over time the damaging role of complement componentsoverpowers their beneficial effects as the disease progresses. As a result complement pathways havebecome potential targets for developing treatments of diseases such as AD. To provide a proof of conceptwe investigated the role of complement pathways regulated by VCP in AD mice model. In this model VCPwas shown to be effective in preventing memory loss. To further develop VCP as a potential treatment forAD in this SBIR phase I study we will aim at characterizing high qualify humanized recombinant VCP(hrVCP) and at the assessment of candidate hrVCP in animal models in a more clinical relevant manner byan independent CRO company with two specific aims: 1) To subject hrVCP to a full battery of in-houseanalytical characterization and stability profiling; ; Specific Aim 2: To validate our previous findings bytesting efficacy of hrVCP in APP/PS1 AD models with collaboration of an independent CRO laboratory. Ourmilestone goals include development of active and stable hrVCP pre-formulation in Saline production ofmore hrVCP if resources allow and validation of efficacy data in AD models from a laboratory other thanour own. If we are successful PK/safety assessments and other preclinical studies of purified hrVCPprotein will be the goal of Phase II studies along with even more rigorous safety studies including in vitrocardiotoxicity hepatotoxicity and bone marrow toxicity studies in stem cells derived tissue cells. We expectthat the SBIR phase1 studies will lead to development of hrVCP for a commercial scale therapeuticapproach to target the progression of neuroinflammation and neurodegeneration anticipated in AD patients.

project_terms:
APP-PS1;Achievement;Aducanumab;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid Proteins;Amyloid beta-Protein;Amyloid deposition;Animal Disease Models;Animal Model;Animals;Apolipoprotein E;Award;Binding;Bone Marrow;Brain;Carcinogens;Cardiotoxicity;Cause of Death;Cells;Characteristics;Clinical Research;Clinical Trials;Collaborations;Complement;Complement Activation;Contractor;Data;Dementia;Deposition;Development;Disease;Disease Progression;Disease model;Effectiveness;Endotoxins;Event;FDA approved;Formulation;Funding;Genotype;Goals;Government;Grant;Heavy Metals;Hepatotoxicity;Human;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Injections;Insurance;Intervention;Laboratories;Legal patent;Mediating;Memory Loss;Modeling;Mus;Mutagens;Nerve Degeneration;Nose;Outcome;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physicians;Population;Poxviridae;Privatization;Production;Proteins;Publishing;Qualifying;Regulation;Resources;Rodent;Role;Safety;Saline;Senile Plaques;Small Business Innovation Research Grant;Social Impacts;Spinal cord injury;Sterility;Testing;Therapeutic;Therapeutic Uses;Time;Tissues;Toxic effect;Toxin;Traumatic Brain Injury;Vaccinia Virus Study;Vaccinia virus;Vaccinia virus complement-control protein;Validation;aging population;clinically relevant;complement C3 precursor;complement pathway;complement system;cost;economic impact;efficacy evaluation;efficacy testing;efficacy validation;extracellular;genetic regulatory protein;improved;improved outcome;manufacture;mouse model;neuroinflammation;phase 1 study;phase 2 study;pre-clinical;preclinical study;prevent;safety assessment;safety study;stem cell derived tissues;synergism

public_health_relevance:
Narrative:In our preliminary studies we have shown promising results to treat Alzheimers disease(AD) in animal models by inhibiting complement pathways with humanized recombinantVaccinia Virus Complement Control Protein (hrVCP). This project will carry outcharacterizing a large scale of high quality hrVCP in pre-formulation saline solution thatwill be then tested in AD animal models for validation of our earlier results by anindependent CRO laboratory so that we will be able to seek additional funds fromgovernments and private investors pre-clinical and then clinical studies in animals andhumans. If successful it will contribute to an intervention for AD.


application_id: 10601816
project_number: 1R43AG078020-01A1
project_title: Wicked Smart Pad: Washable Sensorized Bedding for the Prevention and Detection of Moisture Events
administering_ic: NIA
award_notice_date: 2023-01-30
opportunity_number: PAS-19-316
application_type: 1
activity_code: R43
ic: AG
serial_number: 078020
suffix: A1
program_official: BAKOS, ALEXIS DIANE
project_start_date: 2023-02-01
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1 BBBP-D (12)]
contact_pi_person_id: 78348749
contact_pi: TRUTTMANN, ALLISON
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 017805579
primary_uei: XG5NUX82V251
duns_number: 017805579
uei: XG5NUX82V251
fips: US
organization_id: 10065690
organization_name: WICKED SHEETS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402183064
organization_country: UNITED STATES
project_abstract:
Project Summary/Abstract:Due to decreased mobility deterioration in activities of daily living and neurological decline that contributes toloss of bladder control incontinence is a leading comorbidity for those individuals suffering from Alzheimersdisease and related dementias (ADRD). Further individuals with incontinence are susceptible to thedevelopment of pressure ulcers (PUs) with nearly 40% of advanced dementia patients developing PUs.Rightly there is heighten concern that increasing rates of dementia will lead to higher rates of PUs resulting inincreased suffering and mortality in the ADRD population. While the impact of PUs in the acute setting is wellunderstood there is a range of potential iatrogenic skin injuries regarded as an inevitable part of aging thatremain underappreciated and under-investigated in ambulatory memory care units and assisted living (AL)facilities. Maintaining skin integrity in ADRD patients is an ever-present challenge for healthcare providers andcaregivers as well as a significant financial burden. Early detection of moisture events mitigates thecomplications associated with incontinence improving the quality-of-care patients receive. While efforts havebeen made to address incontinence through product innovation none have utilized a fully integrated systemsapproach that incorporates unobtrusive sensor technology early detection and has a positive environmentalimpact. Wicked Sheets a Kentucky-based woman-owned business has developed the Wicked Smart Pad awashable and reusable sensorized bedding pad system. It alerts caregivers when a moisture event occurs viawireless communication collecting vital information to support the care team. In Phase I the PI and thecollaborating site Atria Park of Great Neck New York will determine the feasibility and usability of thesensorized bedding pad system evaluate its acceptability by care staff and residents alike. Aims: 1: Evaluatethe feasibility usability and durability of the Wicked Smart Pad for individuals with ADRD in an assisted livinghome. 2: Evaluate usage and acceptability of care staff interaction with the Wicked Smart pad. 3: Engineerpower-efficient firmware that collects and transmits moisture event data through a HIPAA compliant wirelessnetwork which integrates within the test sites network on a user-friendly dashboard. At the end of Phase 1Wicked Sheets will have implemented the Wicked Smart Pad to patients with ADRD in an assisted livingcommunity received feedback on the bedding hardware and software from the end-users and assessed theability to collect moisture samples. Phase II efforts will include device and firmware enhancements. This noveltechnology serves as a prevention and intervention tool for care staff ADRD family members and thehealthcare community at large to reduce the burdens of the workforce and financial strain enhancing thequality of life and care of those individuals living with ADRD.

project_terms:
Activities of Daily Living;Acute;Address;Adult;Aging;Agitation;Alzheimer's disease patient;Alzheimer's disease related dementia;Assisted Living Facilities;Beds;Behavior;Bladder Control;Blood Circulation;Businesses;COVID-19 pandemic;Caregivers;Caring;Cellular Phone;Collaborations;Collection;Communication;Computer software;Confusion;Data;Dementia;Dementia caregivers;Detection;Deterioration;Development;Devices;Distress;Dryness;Early Diagnosis;Engineering;Enrollment;Ensure;Environmental Impact;Event;Family member;Feedback;Financial Hardship;Goals;Health;Health Insurance Portability and Accountability Act;Health Personnel;Health care facility;Healthcare Systems;Heart Atrium;Home;Iatrogenesis;Incontinence;Individual;Infection;Intervention;Interview;Kentucky;Kidney;Laundering;Life;Long-Term Care;Marketing;Measures;Methods;Monitor;Neck;Neurologic;New York;Nursing Homes;Organ;Pain;Panic;Patient Care;Patients;Phase;Population;Predisposition;Prevention;Pus;Quality of Care;Quality of life;Reporting;Risk Factors;Sampling;Sensory;Signal Transduction;Site;Skin;Skin injury;Surveys;System;Testing;Time;Update;Urinary tract infection;Urine;Withdrawal;Woman;advanced dementia;aged;community living;comorbidity;dashboard;data exchange;decubitus ulcer;dementia care;design;healthcare community;high risk;improved;innovation;innovative technologies;memory care;mortality;new technology;patient home care;phase 1 study;predictive tools;preference;satisfaction;sensor;sensor technology;supply chain;tool;transmission process;usability;user-friendly;wireless communication;wireless network;wireless sensor;wireless transmission

public_health_relevance:
Project Narrative:Patients suffering from Alzheimers disease and related dementias (ADRD) are at a significantlyhigher risk of developing pressure ulcers (PUs) and skin breakdown particularly whenincontinence is present. Incontinence and PU contribute to declining quality of life for ADRDpatients and increased caregiver distress causing strain on the healthcare system. WickedSheets has developed the Wicked Smart Pad: a washable and reusable sensorized technologythat provides ADRD caregivers with early detection of moisture events mitigating thecomplications associated with incontinence improving the quality-of-care patients receive.


application_id: 10601677
project_number: 3R35ES032876-02S2
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2022-08-22
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: ES
serial_number: 032876
suffix: S2
program_official: CARLIN, DANIELLE J
project_start_date: 2022-08-23
project_end_date: 2023-06-30
study_section: ZES1(R3)
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY OF THE FUNDED PARENT GRANTLung cancer is the leading cause of cancer death with little improvement in survivability over many decades.Understanding and support for lung cancer have suffered from the stigma that the disease is merely aconsequence of tobacco use when in fact other agents are a major factor in the disease. Many people with lungcancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However whilelung cancer kills more people than colon breast and prostate cancer combined it receives less federal fundingthan each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All establishedlung carcinogens cause CIN yet the mechanisms for how they do have received little attention. Metal exposureis a worldwide health concern. Metals cause lung cancer and carcinogenic metals are a component in tobacco.Metals are poor mutagens but potently induce CIN yet how metals cause lung cancer and CIN is poorlyunderstood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induceCIN in lung cancer. We use hexavalent chromium [Cr(VI)] a human lung carcinogen of major public healthconcern as our primary metal of interest although we will compare Cr(VI) outcomes with other metal lungcarcinogens. We will study how Cr(VI) induces structural and numerical CIN considering human lung fibroblastepithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types tomore complex three-dimensional mixed cell culture studies. We enhance and deepen our understanding ofthese mechanisms with a One Environmental Health approach which leverages the ability of wildlife to resistCr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover we maximize theimpact of these findings by translating our outcomes into animals and into a powerful and unique collection ofhuman subjects and populations ranging from workers with primarily Cr(VI) exposure to workers with a mixedmetal exposure including Cr. This combined approach of humans animals and cell lines with One EnvironmentalHealth tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particularwe will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable atthe cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus ourproposed R35 program will revolutionize our understanding of Cr(VI) CIN metal carcinogenesis and lungcancer while also providing important insights for other cancers that involve CIN. Outcomes will include majorscientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic;2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells thathave transformed and 4) how to prevent neoplastic change from occurring leading to improved risk assessmenttreatments and health outcomes for people exposed to metals.

project_terms:
3-Dimensional;Address;Animals;Apoptosis;Attention;Biological Markers;Cancer Etiology;Carcinogens;Cell Line;Cells;Cessation of life;Chromosomal Instability;Clone Cells;Collection;Colon Carcinoma;Complex;DNA Repair;DNA Repair Pathway;DNA Sequence;Data;Disease;Environment;Environmental Health;Epithelial;Epithelial Cells;Event;Exposure to;Fibroblasts;Funding;Genes;Genome;Genomics;Grant;Hazardous Substances;Health;Heritability;Human;Human Cloning;Individual;Knowledge;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Measures;Metal Carcinogenesis;Metal exposure;Metals;Microsatellite Instability;Microsatellite Repeats;Minority;Mismatch Repair;Mutagens;National Institute of Environmental Health Sciences;Neoplastic Cell Transformation;Outcome;Parents;Particulate;Pathway interactions;Persons;Population;Public Health;Risk Assessment;Risk Management;Role;Route;Structure;Structure of parenchyma of lung;Tissues;Tobacco;Tobacco use;Translating;United States;Work;Workplace;cancer stem cell;carcinogenesis;carcinogenicity;cell type;chromium hexavalent ion;environment related cancer;gene repair;genome sequencing;human subject;improved;in vivo;induced pluripotent stem cell;innovation;insight;interest;malignant breast neoplasm;mixed cell culture;neoplastic;next generation;novel;novel strategies;parent grant;prevent;programs;repaired;social stigma;stem cell model;targeted biomarker;therapeutic target;tobacco user;tool;tumor progression;whole genome

public_health_relevance:
PROJECT NARRATIVE OF THE FUNDED PARENT GRANTLung cancer is the number one cause of cancer death in the United States and metals are a major cause of thedisease. Our study focuses on how hexavalent chromium a metal with widespread exposure known to causelung cancer causes chromosome instability a hallmark event in lung cancer. Our findings will transform ourunderstanding of how metals cause chromosome instability and lung cancer which may spur new potentialtreatment targets new approaches to reduce and prevent metal-induced lung cancer and new insights to betterdetermine and manage safer exposure levels for this major public health concern.


application_id: 10600871
project_number: 5R01CA251663-03
project_title: Targeting Mitochondrial Redox Capacity to Overcome Cancer Subtype that Regrowth After Radiation
administering_ic: NCI
award_notice_date: 2023-03-25
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 251663
program_official: PRASANNA, PAT G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 11588541
contact_pi: CHAISWING, LUKSANA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animal Model;Antibiotics;Azithromycin;Biochemical;Biogenesis;Cell Death;Cell Survival;Cells;Cellular Metabolic Process;Cessation of life;Clinical Treatment;Computer software;Coupled;Cytoplasm;Data;Dose;Electron Transport;Enzymes;Event;Exhibits;External Beam Radiation Therapy;FDA approved;Failure;Growth;Homeostasis;Hydrogen Peroxide;Image;Impairment;In Vitro;Macrolides;Magnetic Resonance Imaging;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mitochondrial Proteins;Molecular;Mus;Normal Cell;Oxidation-Reduction;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;Property;Prostate;Protein Array;Proteins;Radiation;Radiation Tolerance;Radiation therapy;Reactive Oxygen Species;Recurrence;Recurrent Malignant Neoplasm;Regulation;Research Design;Resistance;Resistance development;Resolution;Site;Testing;Therapeutic;Time;Translating;Translational Repression;Translations;Treatment Efficacy;Visualization;Xenograft Model;bioluminescence imaging;cancer cell;cancer heterogeneity;cancer recurrence;cancer subtypes;cancer survival;catalase;fractionated radiation;high risk;improved;in vivo;inhibitor;insight;knock-down;metabolomics;mitochondrial dysfunction;mitochondrial metabolism;mortality;mtTF1 transcription factor;novel;novel therapeutics;overexpression;patient derived xenograft model;prevent;prostate cancer cell;prostate cancer model;prototype;radiation delivery;radiation resistance;radioresistant;response;stable isotope;success;superresolution microscopy;tempol;tumor;tumor growth;tumor heterogeneity


application_id: 10600145
project_number: 5P30ES030283-04
project_title: PILOT PROJECT
administering_ic: NIEHS
award_notice_date: 2023-03-30
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6994
contact_pi_person_id: 8957618
contact_pi: LEBLANC, AMANDA JO
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Louisville Center for Integrated Environmental Health Science (CIEHS) will promote research toward understanding how lifestyle factors interact with exposure to environmental toxicants in human health and disease. The CIEHS Pilot Project Program will further this overall goal by providing support for short-term projects leading to data collection enabling new external grant applications. In this way the Pilot Project Program will enhance capacity for novel research in environmental health science at the University of Louisville. The Program will publicize the availability of pilot project funds solicit and coordinate the review of pilot project applications make funding recommendations monitor the progress of research projects assess usage of center cores by pilot projects and track deliverables. A mix of investigators will be targeted including new early stage investigators community partners and established researchers who can apply their expertise in novel ways relevant to environmental health. Results obtained through pilot projects will be disseminated via the annual Research!Louisville event that showcases research to the university local and regional communities. Because the ultimate goal is to develop new self-sustaining research projects an emphasis will be placed on facilitating and improving the quality of new grant applications pertaining to environmental exposures/lifestyle factors. Strategies for this include obtaining feedback from CIEHS members regarding pilot project findings and experimental design as well as performing rigorous internal review of grant proposals. Thus the Program will assist investigators throughout the pilot project life cycle from initial idea to extramurally funded project and is expected to generate significant new research funding and enhance the capacity for research in the environmental health sciences at the University of Louisville.

project_terms:
Accountability;Applications Grants;Area;Award;Benchmarking;Categories;Collaborations;Communication;Communities;Data Collection;Disease;Eligibility Determination;Environmental Exposure;Environmental Health;Event;Experimental Designs;Exposure to;Extramural Activities;Feedback;Fostering;Funding;General Population;Goals;Grant;Grant Review;Health;Human;Individual;Life Cycle Stages;Malignant Neoplasms;Mentors;Monitor;National Institute of Environmental Health Sciences;Organ;Pilot Projects;Publications;Recommendation;Reporting;Research;Research Peer Review;Research Personnel;Research Project Grants;Research Support;Technology;Toxic Environmental Substances;Toxicology;Translational Research;Universities;Work;career;career development;citizen science;community engagement;design;improved;lifestyle factors;meetings;member;novel;programs;stem;success;symposium


application_id: 10600117
project_number: 5P30ES030283-04
project_title: COMMUNITY ENGAGEMENT
administering_ic: NIEHS
award_notice_date: 2023-03-30
opportunity_number: RFA-ES-18-003
application_type: 5
activity_code: P30
ic: ES
serial_number: 030283
project_start_date: 2020-07-15
project_end_date: 2025-03-31
study_section: Environmental Health Sciences Review Committee[EHS]
subproject_number: 6990
contact_pi_person_id: 12053538
contact_pi: HUNTINGTON-MOSKOS, LUZ G
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The Center for Integrative Environmental Health Sciences (CIEHS) will promote the translation of research onpollution and lifestyle factors to understand their role in human health and diseases. The CIEHS CommunityEngagement Core (CEC) vision is to develop and sustain community-academic partnerships that enhance thehealth of south-central and western Kentucky residents by empirically addressing pollution and lifestyle factorsinfluencing chronic diseases. The aims of the CEC are to: (1) facilitate and support multi-directionalinteractions among residents community agencies and the CIEHS to assess community needs and priorities;(2) facilitate and support multi-directional interactions to increase community awareness and understanding ofCIEHS research and resources; 3) cultivate environmental literacy among identified audiences; and (4) buildcapacity for community-led and community-engaged environmental health research. The approach to engagethe identified audiences has three tiers: (1) engage community residents via housing agencies to assessenvironmental health needs and community priorities; (2) involve healthcare providers to impact the healthcaresystem as it relates to environmental health needs; (3) share environmental health knowledge with communityyouth as a catalyst to promote environmental health literacy within families. In Aim 1 the CEC will work directlywith residents and community partners across south-central and western Kentucky to assess their uniquecommunity needs and priorities. Based upon the needs identified the CEC will translate and disseminateenvironmental health information to our targeted audience including CIEHS research findings (Aim 2). We willcommunicate with communities using multiple traditional (e.g. newspapers factsheets) and non-traditionalformats (e.g. social media platforms). With Aim 3 the CEC will leverage its community engagement efforts toincrease environmental health literacy in a three-tiered staggered approach in the four University of LouisvilleArea Health Education Center (AHEC) regions of south-central and western Kentucky. Outreach andengagement efforts will involve community members healthcare providers and community youth. Establishedresources from the EPA and NIEHS will be accessed including the Partnerships for Environmental PublicHealth. In Aim 4 the CEC will collaborate with the Pilot Projects Program the Stakeholders Advisory Boardand other community organizations to develop and implement through the Integrated Health Sciences FacilityCore (IHSFC ) community-led environmental health research. Aim 4 will also include working closely with theIHSFC to facilitate investigator-initiated community-engaged environmental health studies. The four targetedUofL AHEC areas include smaller urban areas multiple townships and rural areas. Residents in these ruralareas are exposed to diverse environmental exposures from industry (e.g. rural distilleries; urban/smalltown/rural manufacturing) 12 superfund sites and urban and rural agriculture. The CEC is an integral corewithin the CIEHS structure with direct impact on CIEHS research direction and decision-making.

project_terms:
Address;Agriculture;Area;Area Health Education Centers;Awareness;Chronic Disease;Collaborations;Communication;Communities;Core Facility;Decision Making;Diabetes Mellitus;Disease;Ensure;Environmental Exposure;Environmental Hazards;Environmental Health;Exposure to;Family;Gender;Goals;Health;Health Personnel;Health Resources;Health Sciences;Healthcare Systems;Housing;Human;Huntington Disease;Hypertension;Industry;Kentucky;Knowledge;Leadership;Life;Malignant Neoplasms;National Institute of Environmental Health Sciences;Newspapers;Obesity;Pilot Projects;Pollution;Public Health;Research;Research Personnel;Resources;Role;Rural;Structure;Toxic Environmental Substances;Translating;Translational Research;Translations;Universities;Vision;Work;Youth;burden of illness;catalyst;community engaged research;community engagement;community involvement;community organizations;experience;health assessment;health knowledge;health literacy;health science research;household environmental exposure;lifestyle factors;literacy;manufacture;member;outreach;programs;research faculty;rural area;social media;superfund site;urban area


application_id: 10600021
project_number: 5R01DC017770-05
project_title: Communities Helping the Hearing of Infants by Reaching Parents: The CHHIRP Navigator Trial
administering_ic: NIDCD
award_notice_date: 2023-03-23
opportunity_number: PA-18-385
application_type: 5
activity_code: R01
ic: DC
serial_number: 017770
program_official: KING, KELLY ANNE
project_start_date: 2019-04-01
project_end_date: 2026-09-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 11512687
contact_pi: BUSH, MATTHEW LEE
other_pis: Not Applicable
congressional_district: 06
department: OTOLARYNGOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYAs the most common neonatal sensory disorder in the United States infant hearing loss has an incidence of1.7 per 1000 births. The consequences of delayed diagnosis and failure to obtain timely intervention includesignificant communication impairment and negative socioeconomic effects. The overall lifetime medicaleducational and occupational costs due to deafness is estimated to be over $2.1 billion. Early detection ofhearing may prevent language development and learning disorders. National standards dictate that all infantsshould be screened by 1 month of age diagnosed by 3 months of age and initiate treatment by 6 months ofage (1-3-6 rule) and no more than 10% of infants should be non-adherent to diagnosis within 3 months afterbirth. In 2015 59.4% of U.S. infants failed to obtain a diagnosis within 3 months after abnormal screening.There is a need for the development and implementation of interventions that promote adherence to timelydiagnosis and treatment standards. Early infant hearing detection and intervention (EHDI) programs arecoordinated on a state level and the diagnostic process is complex and difficult for parents to navigate.Families of children with hearing loss report that they lack confidence and support in obtaining care for theirchild. Patient navigator (PN) programs have improved adherence to recommended diagnostic testing in cancercare after the detection of a screening abnormality resulting in substantial healthcare system cost savings.PNs are trained individuals who mitigate barriers to promote healthcare adherence by educating patients andimproving self-efficacy. We have recently demonstrated the PN efficacy to decrease non-adherence with infanthearing diagnostic care; however PN has yet to be tested in diverse communities or implemented into EHDIprograms and there is a gap in this field regarding effectiveness and implementation research on interventionsto reduce non-adherence. The proposed research is a community-engaged type 1 hybrid effectiveness-implementation trial of a PN intervention aimed at decreasing infant hearing diagnosis non-adherence afterfailed newborn hearing screening delivered in state-funded EHDI clinics. Guided by our community advisoryboard and partners we aim to 1) to test the effectiveness of PN to decrease non-adherence to receipt of infanthearing diagnosis within 3 months after birth using a stepped-wedge trial design 2) investigate implementationoutcomes and factors influencing implementation and 3) determine the cost-effectiveness of PN from theperspective of third party payers. This study is significant because it aims to reduce non-adherence to timelyinfant diagnostic hearing testing to prevent life-long negative consequences. This research is innovative intesting an intervention not previously assessed in hearing healthcare within a state-funded EHDI program andin integrating implementation research and cost-effectiveness methods with our effectiveness aim. Our resultswill impact the field by partnering with communities to inform the scale-up of this and other innovative patientsupportive interventions to create efficient and effective EHDI programs and maximize public health impact.

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

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


application_id: 10598722
project_number: 3R01CA258421-02S1
project_title: Gold-derived Therapeutic Compounds for Disease Application
administering_ic: NCI
award_notice_date: 2022-08-29
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: CA
serial_number: 258421
suffix: S1
program_official: FU, YALI
project_start_date: 2021-08-04
project_end_date: 2026-07-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 11956743
contact_pi: AWUAH, SAMUEL GORMAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Mitochondrial metabolism is crucial for physiological processes spanning cell signaling & growth geneexpression and immune response. At the same time mitochondrial dysfunction contributes toneurodegenerative cardiovascular ageing and cancer progression. Current strategies with metal agents ororganic small-molecule probes that target mitochondria have either poor target potency (e.g metformin) unclearmechanisms or their toxicity (e.g rotenone) precludes in vivo application. Thus potent selective and in vivotolerable chemical reagents are urgently needed. The major objective of our research program is to developnovel gold-based compounds as agents that selectively alter and probe distinct mitochondrialfunctions. The significance of this proposal is the development of new chemical modulators for the often-intractable mitochondrial pathways including OXPHOS. Our research program has made significantcontributions already by developing biologically active gold compounds that either inhibit OXPHOS (AuDTC)increase OXPHOS and mitochondrial biogenesis or modify mitochondrial structure in vitro and in vivo. We havemade foundational discoveries regarding mitochondrial metabolism in triple negative breast cancer (TNBC)defined how complex I impact cellular processes developed cutting-edge tools to determine the underlyingcellular mechanisms and established therapeutic platforms to inhibit mitochondrial complex I. We hypothesizethat mitochondrial metabolism are a driving force for disease progression in TNBC. Defining themechanisms of mitochondrial metabolism in TNBC provides insights into the dependence of aggressive tumorson mitochondria for growth. This supplement will allow Mr. Omar Bojang to further hone his skills in translationaltherapeutics. His results will assist in determining the role of mitochondrial complex I inhibition in TNBC. He willlook at modifications of lead AuDTC compound in perturbing the mitochondrial mechanisms at the molecularlevel and establish novel therapeutic modalities at the organismal level.

project_terms:
Adopted;Aging;Antineoplastic Agents;Apoptosis;Autophagocytosis;Biogenesis;Bioinformatics;Biometry;Breast Cancer Cell;Cancer Biology;Cancer Model;Cardiovascular system;Cell physiology;Cellular Metabolic Process;Cessation of life;Chemicals;Complex;Comprehension;Data;Dependence;Development;Disease;Disease Progression;Drug Kinetics;Electron Transport;Environment;Event;FRAP1 gene;Fostering;Foundations;Gene Expression;Goals;Gold;Gold Compounds;Growth;Immune response;Impairment;In Vitro;Knowledge;Lead;Ligands;Malignant Neoplasms;Maximum Tolerated Dose;Medical;Metabolic;Metals;Metformin;Mitochondria;Modality;Modeling;Modification;Molecular;Morphology;Neoplasm Metastasis;Nerve Degeneration;Normal Cell;Oxidative Phosphorylation;Pathway interactions;Patients;Pharmacodynamics;Physiological Processes;Process;Prognostic Marker;Proteins;Proteomics;Reagent;Research;Respiration;Respiratory Chain;Role;Rotenone;Signal Transduction;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Therapeutic Index;Time;Toxic effect;Translating;Work;analog;anti-cancer;antitumor agent;antitumor effect;base;cancer cell;cell growth;clinical efficacy;driving force;drug development;drug discovery;improved;in vitro Assay;in vivo;innovation;insight;mitochondrial dysfunction;mitochondrial metabolism;mouse model;novel;novel strategies;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;programs;rational design;response;scaffold;skills;small molecule;targeted agent;therapeutic target;tool;translational therapeutics;triple-negative invasive breast carcinoma;tumor;tumor growth;tumor metabolism;tumor progression;tumor xenograft;uptake

public_health_relevance:
PROJECT NARRATIVE. The focus of our work is to define the mechanism by which a novel and highly potentclass of gold-based agents (AuDTC) inhibit mitochondria complex I to achieve anticancer action in vivo. Ourproposal is built on our recent and past discoveries and uses complementary approaches to advance ourunderstanding of the intertwined events of cell metabolism and cancer. Completion of this work will yield a bettercomprehension of these complex events and will allow us to translate our insights into disease mechanismsTNBC vulnerabilities and treatments.


application_id: 10598622
project_number: 5R01DE022597-10
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2023-02-15
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DE
serial_number: 022597
program_official: MCNEALY, TAMARA L
project_start_date: 2013-02-01
project_end_date: 2025-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SummaryPorphyromonas gingivalis a keystone pathogen in chronic periodontitis secretes a large variety of virulencefactors including an enzyme peptidylarginine deiminase (PAD) unique for pathogenic species of thePorphyromonas genus. Alike human endogenous PADs the bacterial enzyme converts arginine residues inproteins to citrulline but it has a strong preference for C-terminal Arg. We postulated that P. gingivalis PAD(PPAD) activity not only contributes to pathogenesis of periodontitis but also it may be involved in thebreakdown of immunotolerance and the development of rheumatoid arthritis (RA) a diseases driven byautoantibodies targeting citrullinated epitopes. This contention is supported by findings that PPAD inconjunction with Arg-specific gingipain proteases (Rgps) can generate a large spectrum of citrullinatedpeptides derived from bacterial and host proteins including fibrinogen and enolase  both acceptedautoantigens in RA. Also citrullinated proteins of P. gingivalis stimulate human gingival fibroblasts (HGF) toproduce prostaglandin E2 (PGE2) one of the most potent mediators of bone resorption implicated in thepathogenesis of PD and RA. Moreover our unpublished data show that both resting and P. gingivaliscitrullinome-stimulated HGFs derived from periodontitis patients produce significantly more PGE2 than cellsfrom healthy donors. Finally we discovered two allelic forms of the ppad gene among P. gingivalis clinicalisolates one encoding a superactive isoform of the enzyme which crystal structure suggests that it bindssubstrates with higher affinity than the other form of PPAD. The tighter substrate binding may contribute toproposed second important function of PPAD as the carrier protein of haptens (bacteria and/or host protein-derived citrullinated peptides) presented to B cell followed by T cell activation and the breakdown ofimmunotolerance in a hapten/carrier mechanism. Based on these findings we postulate that PPAD is directlyresponsible for the breakdown of immunotolerance and subsequent anti-citrullinated protein antibody (ACPA)production - key pathological events preceding clinical onset of RA; and the severity of PD and its link to RA isassociated with the occurrence of a superactive variant of PPAD expressed by subset of P. gingivalis strains.To experimentally verify these hypotheses we propose the following specific aims: (i) investigate the functionalrelevance of citrullinated bacterial proteins in pathological interactions between P. gingivalis and fibroblasts; (ii)determine if PPAD targeting by T cells provides help for the production of ACPA through a hapten/carriermechanism; and (iii) analyse the prevalence of P. gingivalis strains carrying the superactive PPAD gene in thecontext of the severity of PD and relation to associated RA.Successful completion of this project will drive the field forward by providing a novel perspective to theunderstanding the pathogenesis of PD-RA associations thus offering venues to develop novel strategies totreat these debilitating diseases.

project_terms:
Affinity;Alleles;Alveolar Bone Loss;Animal Model;Antibodies;Antibody Formation;Arginine deiminase;Autoantibodies;Autoantigens;Autoimmune;B-Lymphocytes;Bacteria;Bacterial Proteins;Binding;Bone Resorption;Bone Resorption Stimulation;C-terminal;Carrier Proteins;Cells;Characteristics;Chronic;Citrulline;Clinical;Collaborations;Collagen Arthritis;Communities;Complex;Data;Development;Diagnosis;Dinoprostone;Disease;Enzymes;Epitopes;Etiology;Event;Fibrinogen;Fibroblasts;Genes;Gingiva;Gingival Crevicular Fluid;Grant;HLA-DR4 Antigen;Haptens;Human;Immune response;Immunize;Inbred C3H Mice;Individual;Inflammation;Inflammatory Arthritis;Inflammatory Response;Link;Mammals;Mediator;Mucous Membrane;Norway;Pathogenesis;Pathogenicity;Pathologic;Patients;Peptide Hydrolases;Peptides;Periodontal Ligament;Periodontitis;Periodontium;Play;Porphyromonas;Porphyromonas gingivalis;Predisposition;Prevalence;Process;Production;Protein Isoforms;Protein-arginine deiminase;Proteins;Research;Rest;Rheumatoid Arthritis;Role;Saliva;Self Tolerance;Serum;Severities;Site;Solid;Specimen;Structure;Surface;Symptoms;T-Cell Activation;T-Lymphocyte;Testing;Tissues;Universities;Variant;Virulence;Virulence Factors;arthropathies;biobank;citrullinated protein;cohort;comparison control;dysbiosis;enolase;gingipain;joint destruction;mouse model;novel;novel strategies;oral bacteria;pathogen;periodontopathogen;preference;response

public_health_relevance:
NarrativePorphyromonas gingivalis an established periodontal pathogen is able to produce citrullinated proteinsthrough the action of an enzyme (PPAD) unique to this bacterium. Citrullinated bacterial proteins are able toinduce human fibroblasts to produce prostaglandin E2 (PGE2) which can stimulate the bone resorption processimplicated in the pathogenesis in periodontitis and rheumatoid arthritis (RA). PPAD may also directly promotebreakdown of self-tolerance in susceptible individuals to generate autoantibodies against citrullinated self-proteins in the development of RA.


application_id: 10598572
project_number: 5R01GM070559-16
project_title: Epigenetic regulation of hormone action in Tribolium and Aedes
administering_ic: NIGMS
award_notice_date: 2023-03-30
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: GM
serial_number: 070559
program_official: PHILLIPS, ANDRE W
project_start_date: 2005-02-01
project_end_date: 2025-03-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 7355989
contact_pi: PALLI, SUBBA R
other_pis: Not Applicable
congressional_district: 06
department: ZOOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThere has been a continuous demand for development of insect control methods that are target-specific.Juvenile hormone (JH) and ecdysteroids (20-hydroxyecdysone 20E is the most active form) are the majorhormones that regulate many physiological and developmental processes in insects. Since these hormonesare not present in vertebrates they represent attractive targets for development of insect control methods.Hindering this effort is the lack of understanding on the molecular basis of action of these hormones. There hasbeen excellent recent progress in understanding the molecular basis of 20E and JH action. Key playersincluding receptors co-activators response elements and target genes involved in the action of thesehormones have been identified. Non-steroidal ecdysone agonists and JH analogs have been discovered andcommercialized for the control of pests and disease vectors. Research supported by this program showed thatepigenetic modifications especially acetylation levels of histones regulated by histone acetyltransferases(HAT) and histone deacetylases (HDAC) modulate JH and 20E action. Hormone action requires multiple layersof regulation because the same circulating levels of hormones exert diverse functions in different tissues andunder different physiological conditions. Based on the published literature and preliminary data included in thisapplication we hypothesize that epigenetic regulators HDACs HATs histone lysine methyltransferases(HKMT) and histone demethylases (HDM) modulate JH and 20E action in the regulation of postembryonicdevelopment and reproduction. The main goal of this proposal to test this hypothesis by studying themechanisms of action of epigenetic modifiers in JH and 20E action using T. castaneum TcA cells Ae. aegyptiand Aag2 cells as model systems. The two Specific Aims of the proposal are 1. To identify and characterizeepigenetic modifiers required for 20E and JH regulation of postembryonic development and femalereproduction and 2. To study mechanisms of action of epigenetic modifiers required for 20E and JH regulationof postembryonic development and female reproduction. In the first Specific Aim RNAi CRISPR/Cas9genome editing methods RNA sequencing bioinformatics RT-qPCR enzyme assays and cell cultureapproaches will be used to identify and characterize HATs HDACs HKMTs and HDMs required forpostembryonic development and female reproduction in T. castaneum and Ae. aegypti. In the second SpecificAim the mechanisms of action of 10-12 epigenetic modifiers will be studied using western blots and ChIPreporter Two-hybrid and pull-down assays and mass spectrometry approaches. Results from the proposedresearch will impact medicine by providing information for the development of vector control methods. Thisinformation could help in understanding epigenetics of human diseases such as cancer. The results from theproposed research may help to transform our understanding of endocrinology of disease vectors.

project_terms:
Acetylation;Adult;Aedes;Agonist;Animals;Antibodies;Binding;Bioinformatics;Biological Assay;Biological Metamorphosis;Biological Models;CRISPR/Cas technology;Cell Culture Techniques;Cells;Complex;Culicidae;Data;Deacetylation;Development;Developmental Process;Disease;Disease Vectors;Ecdysone;Ecdysteroids;Ecdysterone;Embryonic Development;Endocrinology;Ensure;Environment;Enzymes;Epigenetic Process;Female;Food;Friends;Genes;Goals;Growth;Histone Deacetylase;Histone-Lysine N-Methyltransferase;Histones;Homologous Gene;Hormone Receptor;Hormones;Human;Insect Control;Insect Hormones;Insecta;Insecticides;Juvenile Hormones;Knowledge;Laboratories;Life;Ligands;Literature;Livestock;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Medicine;Methods;Methoprene;Methylation;Modeling;Modification;Molecular;Pathway interactions;Pest Control;Physiological;Physiological Processes;Plants;Play;Postembryonic;Principal Investigator;Process;Proteins;Publishing;RNA Interference;Regulation;Reporter;Reproduction;Reproductive Process;Research;Research Support;Response Elements;Role;Steroid Receptors;Testing;Tissues;Tribolium;Vertebrates;Western Blotting;chromatin immunoprecipitation;commercialization;demethylation;ecdysone receptor;enzyme activity;epigenetic regulation;experimental study;gene product;genome annotation;genome editing;histone acetyltransferase;histone demethylase;histone modification;hormone analog;hormone regulation;hormone response element;human disease;insect disease vector;mass spectrometer;programs;promoter;receptor;receptor binding;response;success;transcription factor;transcriptome sequencing;transmission process;vector control;yeast two hybrid system

public_health_relevance:
Project Narrative Mosquitoes transmit deadly diseases. The research proposed in this application will provideinformation of potential importance for development of insecticides for vector control. The proposed studieswill reveal functions and mechanisms of action of epigenetic marks which will help in understandingepigenetics of human diseases such as cancer.


application_id: 10598530
project_number: 5R01NS121193-03
project_title: Functional Diversity of Reactive Astrocytes in Spinal Cord Repair
administering_ic: NINDS
award_notice_date: 2023-04-19
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: NS
serial_number: 121193
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 9380335
contact_pi: CHEN, MEIFAN
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY / ABSTRACTAs key modifiers of injury outcome following CNS insults reactive astrocytes represent a rational cellular targetfor neural repair. CNS injury results in scar-forming astrogliosis at the primary lesion and diffuse astrogliosis inareas of distal axon degeneration the latter of which is poorly characterized. Without a complete understandingof how reactive astrocyte subtypes impact the CNS injury response harnessing the full therapeutic potentials ofreactive astrocytes will remain unlikely. The long-term goal is to translate knowledge of the diverse functions ofreactive astrocytes to treat CNS trauma. Towards this goal the objective of this proposal is to identify themolecular and cellular mechanisms that determine location-specific functions of scar-forming and diffuseastrogliosis in the injured spinal cord. The hypothesis is that scar-forming astrogliosis supports pathologicalmacrophage retention within the chronic scar at the lesion whereas diffuse astrogliosis induces axon growthdistal to the lesion after spinal cord injury (SCI). The rationale for this proposal is that defining the cell-intrinsicand environmental contributions to the diverse functions of reactive astrocytes will inform on how to targetreactive astrocytes efficaciously for CNS repair. Based on strong supporting data this hypothesis will be testedby pursuing three specific aims: 1) determine the role of scar-forming astrocytes in macrophage maintenance atthe chronic SCI scar; 2) examine the role of diffuse astrogliosis in promoting axon growth distal to the lesion; and3) assess the effects of locally modifying either scar-forming or diffuse astrogliosis by an AAV-mediated approachon SCI recovery. These studies will significantly advance understanding of reactive astrocytes and the ability todevelop novel astrocyte-targeted therapeutic approaches to attenuate chronic scarring and promote axon growthafter SCI.

project_terms:
Abbreviations;Area;Astrocytes;Attenuated;Axon;Cells;Chest;Chronic;Cicatrix;Corticospinal Tracts;Data;Diffuse;Distal;Functional disorder;Genetic;Glial Fibrillary Acidic Protein;Goals;Hindlimb;Human;Injury;Knock-out;Knowledge;Lateral;Lesion;Leucine Zippers;Location;Macrophage;Macrophage Colony-Stimulating Factor;Maintenance;Mediating;Microglia;Microinjections;Modeling;Molecular;Motor;Mus;Outcome;Paralysed;Pathologic;Pathology;Pathway interactions;Phenotype;Phosphotransferases;Primary Lesion;Proliferating;Reaction;Recovery;Regulation;Repression;Research;Role;Sensory;Site;Spinal;Spinal Cord;Spinal cord injury;Tamoxifen;Testing;Therapeutic;Tissues;Translating;Traumatic CNS injury;United States;Vertebral column;Work;astrogliosis;axon growth;axonal degeneration;axonal sprouting;cellular targeting;central nervous system injury;disability;genetic manipulation;in vivo;injury and repair;injury recovery;insight;monocyte;neural;neural repair;novel;overexpression;promoter;repair strategy;repaired;response to injury;restoration;spinal cord repair;targeted treatment;tool;translational approach

public_health_relevance:
PROJECT NARRATIVESpinal cord injury is a leading cause of paralysis in the United States with limited treatment options. Astrocytesinfluence injury outcome after spinal cord injury and therefore present an attractive cellular target for repairstrategies. This proposed research will determine location specific functions of reactive astrocytes in the injuredspinal cord to provide the basis for an astrocyte-targeted approach to promote neural recovery and reducehuman disability.


application_id: 10598337
project_number: 3P30ES026529-05S1
administering_ic: NIEHS
award_notice_date: 2022-08-10
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: ES
serial_number: 026529
suffix: S1
program_official: THOMPSON, CLAUDIA L
project_start_date: 2022-04-01
project_end_date: 2023-05-31
contact_pi_person_id: 1906116
contact_pi: HAHN, ELLEN J
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-04-01
project_title:
Center for Appalachian Research in Environmental Sciences Administrative Supplement for Cost Extension

project_abstract:
PROJECT SUMMARY  OverallThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) willestablish an Environmental Health Sciences Core Center to enhance research capacity focused on majorenvironmental health impacts to air and water quality that have been implicated in environmentally induceddisease. This Center will provide advanced infrastructure and leading expertise dedicated career developmentand mentorship and community-engaged interactions to facilitate innovative discovery and new understandingsof environmental factors in disease initiation progression and outcomes and their community impacts. Thecentral hypothesis is that toxic environmental agents are contributors to the disproportionately high incidence ofchronic diseases e.g. cancers cardiopulmonary disease and metabolic disorders in Appalachian Kentuckyand that the impacts of early exposure are especially harmful. UK-CARES draws on a strong and diverse baseof environmental health science and community-engaged research to build environmental health researchcapacity to meet the needs of communities in three Area Development Districts in southeastern Kentucky: BigSandy Kentucky River and Cumberland Valley. Center members bring notable strengths in environmentalhealth across four Research Interest Groups: Cardiopulmonary Diseases Metabolic Disorders Cancer andChild Health and Early Life Exposures. To achieve the Centers goal UK-CARES will: 1) establish a richresearch environment and a framework for transdisciplinary leadership and integrated infrastructure to facilitatecollaboration and efficient use of resources for research expansion and development of new scientific directions;2) build research capacity in environmental health sciences by providing an outstanding intellectual environmentand advanced infrastructure to support innovation and community engagement; 3) recruit new talent andfacilitate career development of investigators whose research addresses critical issues in environmentallyinduced disease through mentorship and structured career training activities; 4) develop multi-directional andmutually beneficial communications and interactions with community residents policymakers and publichealth/healthcare professionals to identify environmental concerns of target communities as a stimulus to newresearch; and 5) bridge the gap between discovery of novel research findings and population-level awarenessand practice via community-focused science communication training. An Integrative Health Sciences FacilityCore Analytical Core and Community Outreach and Engagement Core are integral to this effort and willcatalyze multi-directional translation across the whole spectrum of research; provide advanced analyticalsupport in metabolomics computational biology analytical chemistry biospecimen management andbioinformatics; and bridge Center and community priorities. Complementary activities in career development ofscientists who are interested in tackling challenging environmental health questions and pilot project funding willsupport developing research and evolving scientific directions.

project_terms:
Address;Administrative Supplement;Air;Analytical Chemistry;Appalachian Region;Area;Arsenic;Asthma;Atherosclerosis;Awareness;Bioinformatics;Chemicals;Child Health;Chromium;Chronic Disease;Chronic Obstructive Pulmonary Disease;Clinical;Collaborations;Colorectal Cancer;Communication;Communities;Community Outreach;Complex;Computational Biology;Core Facility;Development;Diabetes Mellitus;Disease;Environment;Environmental Health;Environmental Risk Factor;Environmental Science;Exposure to;Fostering;Foundations;Funding;Genetic Predisposition to Disease;Goals;Health;Health Professional;Health Sciences;Healthcare;Heart;Heart Diseases;Heavy Metals;Human;Incidence;Individual;Infrastructure;Integrative Medicine;Interest Group;Kentucky;Leadership;Longevity;Malignant Neoplasms;Malignant neoplasm of lung;Medical;Medical center;Mentorship;Metabolic Diseases;Mining;National Institute of Environmental Health Sciences;Nickel;Obesity;Outcome;Particulate;Pilot Projects;Population;Positioning Attribute;Public Health;Pulmonary Heart Disease;Radon;Research;Research Personnel;Resources;Rivers;Rural;Science;Scientist;Stimulus;Strategic vision;Structure;Talents;Toxic Environmental Substances;Toxicology;Training;Training Activity;Translations;Universities;Water;advanced analytics;base;career;career development;community engaged research;community engagement;cost;early life exposure;health science research;hydraulic fracturing;innovation;interest;member;metabolomics;neonate;novel;population health;programs;recruit;socioeconomic disadvantage;water quality

public_health_relevance:
PROJECT NARRATIVE  OverallThe University of Kentucky Center for Appalachian Research in Environmental Sciences (UK-CARES) willenhance programmatic and scientific capacity toward the goal of facilitating innovative discovery and newunderstandings of environmental factors in disease initiation progression and outcomes and their communityimpacts. Further the Center will foster career development of environmental scientists interested in tacklingchallenging environmental health questions facing the southeastern Kentucky region. UK-CARES will achievethis goal by providing advanced infrastructure and expertise training and mentorship and community-engagedinteractions.Project Narrative Page 136


application_id: 10598309
project_number: 3P40OD019794-08S2
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2022-07-29
opportunity_number: PA-20-272
application_type: 3
activity_code: P40
ic: OD
serial_number: 019794
suffix: S2
program_official: CONTRERAS, MIGUEL A
project_start_date: 2022-07-01
project_end_date: 2023-02-28
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Ambystoma Genetic Stock Center (AGSC) is a P40 Research Resource that distributeslaboratory axolotls (Ambystoma mexicanum) to researchers and educators nationally andinternationally. The AGSC houses approximately 880 adults in aquatic recirculating systemsand static bowls to sustain a captive wildtype breeding population and a small number ofmutant and transgenic lines. Several dozen axolotl transgenic and knock-out axolotl lines havebeen created by the axolotl community in the past couple of years and more lines areanticipated in the future. The AGSC does not have enough tanks or infrastructure to house alladult breeders or newly created lines as living stocks. An effort is underway to develop a spermcryopreservation protocol so that axolotl lines can be managed as both living stocks andcryopreserved stocks. Until the sperm cryopreservation protocol is developed and shown toreproducibly allow for the re-derivation of axolotl lines from frozen sperm there is critical need toincrease the number of tanks in the AGSC. This Administrative Supplement will be used topurchase two recirculating systems that will add 240 tanks to the AGSC. The addition of thesenew tanks to the AGSC will provide infrastructure that is critically needed to sustain lines for theaxolotl community.

project_terms:
Administrative Supplement;Adult;Ambystoma;Ambystoma mexicanum;Award;Biological;Biomedical Research;Breeding;CRISPR/Cas technology;Communities;Cryopreservation;Derivation procedure;Development;Disease;Embryonic Development;Future;Genetic;Goals;Health;Housing;Human;Infrastructure;International;Knock-out;Laboratories;Methods;Modeling;Organ Model;Parents;Population;Protocols documentation;Research;Research Personnel;Resources;System;Transgenic Organisms;Translating;equipment acquisition;genome editing;mutant;organ regeneration;sperm cryopreservation;tissue repair;tool


application_id: 10598223
project_number: 1R21AI169231-01A1
project_title: Function of the type 7 secretion system in Group B Streptococcus
administering_ic: NIAID
award_notice_date: 2022-11-07
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 169231
suffix: A1
program_official: GU, XIN-XING
project_start_date: 2022-11-07
project_end_date: 2024-10-31
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
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;Female;Firmicutes;Foundations;Future;Gastrointestinal tract structure;Gene Cluster;Genome;Goals;Gram-Positive Bacteria;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;antitoxin;clinically relevant;cytotoxicity;experimental study;genetic approach;genomic locus;gut microbiome;human microbiota;in vivo;member;microbiome components;microbiota;microorganism;mouse model;neonatal infection;neonate;pathobiont;pathogen;prevent;reproductive tract;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: 10598172
project_number: 3R01ES029846-05S1
project_title: Diversity Supplement to Urban Greenness and Cardiovascular Health
administering_ic: NIEHS
award_notice_date: 2022-03-30
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: ES
serial_number: 029846
suffix: S1
program_official: SCHUG, THADDEUS
project_start_date: 2018-07-01
project_end_date: 2024-03-31
study_section: Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
AbstractExtensive research suggests that components of the natural environment have profound effectson human health. In particular individuals living in areas of low pollution and high levels ofvegetation have been reported to have a lower burden of cardiovascular disease (CVD). Althoughmany studies have shown that exposure to air pollution increases CVD risk and mortality theimpact of greenspaces and vegetation on CVD has not been directly studied. Hence to assessthe impact of greenery on cardiovascular health and disease risk we will conduct a pragmaticinterventional trial designed to test the hypothesis that exposure to neighborhood greenspacesdiminishes CVD risk by decreasing the levels of local air pollution. To test this hypothesis we willfirst evaluate baseline cardiovascular health in 16 residential neighborhood clusters with sparsegreenspaces (Aim 1). In these areas we will measure the levels of greenery air pollution noiseand traffic and determine how these neighborhood characteristics are associated with hospitaladmissions as well as cardiovascular and all-cause mortality. To acquire individual level datawe will recruit 700 area residents and assess their cardiovascular health as well as psychosocialstress. Then in 8 target clusters we will plant nearly 8000 established trees (Aim 2). There willbe no deliberate change in greenspace in the 8 control clusters. Following the greeningintervention we will determine how an increase in greenspaces within the target clusters affectsair pollution levels hospital admissions and mortality and how the greening intervention affectsCVD risk and psychosocial stress within this community in comparison with the control area (Aim3). Completion of this project would provide a new understanding of the link between urbangreenspaces and cardiovascular health and might lead to the development of new strategies toprevent CVD and to decrease the levels of urban air pollution. Importantly the results of theproject will lead to the development of a comprehensive model that could be readily adopted bycities throughout the world to create urban environments that are more conducive to humanhealth.

project_terms:
Adopted;Affect;Air;Air Pollutants;Air Pollution;Area;Biochemical;Biological Markers;Blood;Carbon Black;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Characteristics;Chronic Disease;Cities;Communities;Data;Developed Countries;Developing Countries;Development;Ecosystem;Environment;Evaluation;Exposure to;Formulation;Grasslands;Green space;Hair;Health;Health Policy;Heart;Hospital Mortality;Hospitalization;Human;Individual;Intervention;Intervention Trial;Kentucky;Lead;Life Expectancy;Link;Location;Maintenance;Measurement;Measures;Mediating;Modeling;Neighborhoods;Noise;Outcome;Ozone;Particulate;Perception;Physiological;Plants;Poaceae;Pollution;Population;Prevalence;Prevention strategy;Psychosocial Stress;Public Health;Questionnaires;Reporting;Research;Risk;Risk Factors;Sampling;Severities;Stress;Sulfate;Sunlight;Surface;Surveys;Testing;Trees;Ultrafine;Urban Community;Urine;Vascular Plant;Wood material;Work;air filtration;built environment;cardiovascular disorder prevention;cardiovascular disorder risk;cardiovascular health;cohort;demographics;design;fine particles;foot;insight;land use;mortality;pollutant;premature;prevent;psychologic;recruit;residence;social;social cohesion;trial design;urban area;urban setting;urinary;volatile organic compound

public_health_relevance:
LAY SUMMARYThis project is to determine how an increase in urban greenspaces affects cardiovascular disease riskseverity and mortality. To assess the impact of greenspaces we will examine how an increase inneighborhood greenspaces affects the levels of air pollution and cardiovascular health in an urbancommunity.


application_id: 10597648
project_number: 5R01NS116990-04
project_title: Elucidating the role of placental growth factor in diffuse white matter disease
administering_ic: NINDS
award_notice_date: 2023-05-15
opportunity_number: RFA-NS-19-039
application_type: 5
activity_code: R01
ic: NS
serial_number: 116990
program_official: CORRIVEAU, RODERICK A
project_start_date: 2020-04-01
project_end_date: 2023-07-15
study_section: ZNS1-SRB-O(04)
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractDiffuse white matter disease (DWD) is a common manifestation of small-vessel cerebrovascular pathology anda key subtype of vascular contributions to cognitive impairment and dementia (VCID). However themechanistic underpinnings of DWD remain incompletely characterized. Based on assessment of extensivedata in humans and animal models we have identified angiogenic mediators in particular placentalgrowth factor (PlGF) as being strongly associated with diffuse white matter disease. Much like the pathologic angiogenesis that occurs in retinopathies pathologic angiogenesis in the brainresults in blood-brain barrier leakage and counterintuitively tissue ischemia. We have exciting preliminarydata indicating robust relationships between PlGF and human DWD. We have also identified PlGF as beingincreased in association with blood-brain barrier leakage. We hypothesize that PlGF and relatedangiogenic mediators result in pathologic angiogenesis with leaky tortuous vessels and surroundinginflammation leading to diffuse white matter disease. Importantly these pathologic changes alsorepresent a potentially targetable mechanism to improve cognition in aging. To test these hypotheseswe propose focused studies in an extensively characterized human cohort and a mouse model of small vesseldisease. We answer the what where why questions surrounding PlGF. What cell type is responsible forPlGF; where is PlGF being expressed; why is PlGF upregulated and can it be modulated. To test thesehypotheses we propose focused studies in an extensively characterized human autopsy cohort and a mousemodel of small vessel disease:Specific Aim 1: Determine contributions to plasma PLGF and related angiogenic proteins using cell-specific exosomes and their association with periventricular and deep white matter pathologies.Specific Aim 2: Ascertain the regional expression of PLGF and related angiogenic proteins withinadjacent to and distant from periventricular and DWD and the association with aberrant angiogenesis.Specific Aim 3: Test the potential to manipulate PLGF related small vessel pathology in response tohyperhomocysteinemia (HHcy)-induced small vessel disease.

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

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


application_id: 10597629
project_number: 5R01AI144126-04
project_title: SpoVG and PlzA Regulation of Lyme Disease Spirochete Infection Processes
administering_ic: NIAID
award_notice_date: 2023-03-22
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 144126
program_official: BOWDEN, NADINE
project_start_date: 2020-04-01
project_end_date: 2026-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
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:
v ABSTRACTBacterial infections require that the pathogen accurately produce essential factors at appropriate levels duringeach stage of infection processes. Understanding how bacteria control levels of their proteins in response tocues from their hosts provides important insights on microbial infectious properties. Such knowledge can alsoreveal new targets for improved preventative and curative therapies.The Lyme disease spirochete Borrelia burgdorferi survives in nature through cycles of infecting vertebratesand ticks. The CDC calculates that there are approximately 300000 new cases of human Lyme disease in theUSA each year. B. burgdorferi can persistently infect immunocompetent humans and other mammals for manyyears. Failure to treat Lyme disease promptly and adequately can result in persistent debilitating effects orsometimes death. Long-term infections may require extensive periods of antibiotic treatment. In order to bettertreat Lyme disease it is critical to develop a more thorough understanding of B. burgdorferi biology includingthe mechanisms by which the spirochete controls production of virulence factors.We discovered that a borrelial protein SpoVG binds with specificity and high affinity to DNA and RNA.Deletion of spoVG significantly impaired B. burgdorferi's ability to colonize ticks and be transmitted from ticksto mammals. Dysregulation of spoVG transcription caused significant changes in bacterial physiology. Wefurther found that SpoVG directly interacts with another B. burgdorferi protein PlzA the Lyme spirochete'scyclic-di-GMP-binding protein. Our studies revealed that PlzA is also a site-specific nucleic acid-bindingprotein and plzA mutants are defective in their infectivity. Among the many regulated targets we identified forSpoVG and PlzA is the antigenically-variable VlsE surface protein which is essential for persistent B.burgdorferi infection.The planned studies will simultaneously investigate SpoVG and PlzA as well as the effects of c-di-GMP ontheir functions. These preliminary data stemmed from long-standing collaborations between the P.I. and co-investigators of this proposal. Our combined efforts will yield a comprehensive view of the mechanisms throughwhich B. burgdorferi controls production of these critical regulatory factors and deep insights on how SpoVGPlzA and c-di-GMP regulate VlsE and other virulence-associated proteins.In addition many other pathogenic bacteria produce homologs of SpoVG and our observations on B.burgdorferi SpoVG bear similarities with the protein's known effects in other bacterial pathogens. To date littleis known about how SpoVG affects virulence and physiology in any bacterial species. The interactions wediscovered between SpoVG and PlzA raise the possibilities that other bacteria also control SpoVG functionthrough c-di-GMP-binding proteins. Results of the planned investigations will provide useful insights on theregulatory mechanisms and infectious properties of numerous important human pathogens.

project_terms:
Affect;Affinity;Anti-Bacterial Agents;Antibiotic Therapy;Antibiotics;Antigenic Variation;Back;Bacteria;Bacterial Infections;Bacterial Physiology;Binding;Binding Proteins;Binding Sites;Biology;Borrelia;Borrelia burgdorferi;Cessation of life;ChIP-seq;Collaborations;Cues;DNA;DNA Binding;Data;Development;Environment;Failure;Gene Expression;Genes;Genetic Transcription;Genome;Homologous Gene;Human;Immunocompetent;Impairment;Infection;Infection Control;Infectious Agent;Invaded;Investigation;Joints;Knowledge;Laboratory Finding;Lyme Disease;Mammals;Maps;Mechanics;Membrane Proteins;Mus;Nature;North America;Order Spirochaetales;Organism;Pathogenesis;Pathogenicity;Patients;Periodicity;Physiology;Preventive therapy;Process;Production;Property;Proteins;Proteomics;RNA;RNA Sequences;RNA immunoprecipitation sequencing;RNA-Binding Proteins;Recording of previous events;Regulation;Regulatory Pathway;Regulon;Repression;Research Personnel;Role;Site;Specificity;Spirochaetales Infections;Ticks;Vertebrates;Virulence;Virulence Factors;Work;arthropod-borne;curative treatments;genetic regulatory protein;human disease;human pathogen;improved;insight;member;microbial;mutant;novel therapeutics;nucleic acid binding protein;pathogen;pathogenic bacteria;posttranscriptional;protein expression;response;stem;tick feeding;tick transmission;transcriptome;transcriptomics;transmission process;vector-borne pathogen

public_health_relevance:
v NARRATIVEThe SpoVG and PlzA proteins of the Lyme disease bacterium Borrelia burgdorferi operate in conjunction tocontrol infection-associated functions. Elucidating their regulatory networks will provide substantial insight oninfectious properties of B. burgdorferi and will identify key checkpoints that can be exploited for developmentof improved antibacterial therapies.


application_id: 10597307
project_number: 1U01DK135111-01
project_title: Restoration of Impaired Awareness of Hypoglycemia U01 Consortium: University of Kentucky
administering_ic: NIDDK
award_notice_date: 2022-09-21
opportunity_number: RFA-DK-21-020
application_type: 1
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: Special Emphasis Panel[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;Coupled;Development;Diabetes Mellitus;Education;Event;Failure;Frequencies;Glucose;Glycosylated hemoglobin A;Goals;Heterogeneity;Hormones;Hybrids;Hypoglycemia;Impairment;Individual;Infrastructure;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;base;burden of illness;clinical research site;counterregulation;experience;follow-up;glucose monitor;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: 10596986
project_number: 5R01CA251478-03
project_title: Local Flavor Policies to Enhance Equity in Tobacco
administering_ic: NCI
award_notice_date: 2023-03-16
opportunity_number: PAR-18-675
application_type: 5
activity_code: R01
ic: CA
serial_number: 251478
program_official: RODITIS, MARIA LEIA
project_start_date: 2021-04-08
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-RPHB-N(56)R]
contact_pi_person_id: 11156218
contact_pi: ROSE, SHYANIKA W
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Advertising;Affect;Area;California;Cigarette;Code;Communities;County;Data;Data Collection;Data Set;Databases;Disparity;Ecological momentary assessment;Education;Electronic cigarette;Ensure;Equity;Ethnic Origin;Exposure to;Goals;Home;Income;Individual;Kentucky;Laws;Learning;Link;Longitudinal cohort;Longitudinal trends;Low income;Malignant Neoplasms;Malignant neoplasm of lung;Marketing;Menthol;Modeling;Neighborhoods;Outcome;Participant;Persuasive Communication;Policies;Population;Protocols documentation;Public Policy;Race;Reduce health disparities;Research;Resources;Respondent;Risk;Sales;Smokeless Tobacco;Socioeconomic Status;Statistical Data Interpretation;Structure;Testing;Time;Tobacco;Tobacco use;United States Food and Drug Administration;Universities;Variant;Vulnerable Populations;Youth;attributable mortality;cancer health disparity;cancer risk;cigarette smoking;cigarillos;cohort;cost;demographics;disparity reduction;emerging adult;evidence base;follow-up;health disparity;health equity;implementation framework;innovation;low socioeconomic status;neighborhood disadvantage;people of color;public policy on tobacco;racial difference;reduce tobacco use;theories;tobacco advertising;tobacco exposure;tobacco flavor;tobacco products;tobacco user;trend;vulnerable community;young adult


application_id: 10596495
project_number: 5R01DK123712-04
administering_ic: NIDDK
award_notice_date: 2023-03-29
opportunity_number: PAR-19-294
application_type: 5
activity_code: R01
ic: DK
serial_number: 123712
program_official: NGUYEN, KHOA DINH DANG
project_start_date: 2020-06-20
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-F(50)R]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
Preclinical validation of oral therapeutic lead proteins targeting epithelial GM1 ganglioside for ulcerative colitis therapy

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

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

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


application_id: 10596287
project_number: 5P42ES007380-25
project_title: Postnatal Complications and Interventions against Halogenated Organics during Pregnancy
administering_ic: NIEHS
award_notice_date: 2023-01-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5741
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYChildhood obesity rates have more than tripled over the last 40 years with 18.5% of children and adolescentswho are now obese. Endocrine-disrupting chemicals particularly obesogens such as polychlorinated biphenyls(PCBs) and per- and polyfluoroalkyl substances (PFAS) are contributing to the rapid increases in obesity.Recent studies indicate that prenatal exposures to PCBs and PFAS contribute to gender-specific obesitydevelopment in children. Both groups of contaminants share a common underlying mechanistic pathway thatof oxidative stress and their actions arise from the considerable crosstalk between transcription factorsincluding nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the aryl hydrocarbon receptor. Others havefound that treating cells in culture directly with PCBs or PFAS [perfluorooctanesulfonic acid (PFOS) andperfluorooctanoic acid (PFOA)] influences adipogenesis using human and mouse cells. Importantly PFOSinduced adipogenesis and glucose uptake by acting through Nrf2. Using a mouse model as part of theprevious round of funding similar observations were made in that offspring exposed perinatally to PCBs hadsignificantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Furthermature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring fromvehicle-treated dams. Importantly a healthy behavioral intervention maternal voluntary exercise duringpregnancy improved offspring disease risk associated with in utero PCB exposure. The proposed project willcontinue to use an in vivo mouse model as well as transition to human samples in order to examine themolecular impact of environmental contaminant toxicity during a narrow window of susceptibility. Aim 1 will testwhether voluntary exercise during pregnancy or in the offspring themselves can be used as an interventionstrategy to protect against the long-term metabolic detriments associated with in utero PCB exposure. Aim 2will elucidate the mechanism of impaired glucose tolerance and altered body composition in offspring born toPCB-exposed dams (including the use of Nrf2 knockout mice) and will determine how maternal exercise isprotecting offspring from these impairments. Aim 3 will use human cells to identify biomarkers of the specificharm associated with in utero halogenated organic pollutant exposures and to elucidate the potentialmechanisms that contribute to increased obesity and diabetes risk in exposed infants. Our work will measureactual contaminant exposure levels in maternal and cord serum and quantify adipocyte differentiation directlyin cells isolated from the same neonates. Anticipated results are particularly significant in that they highlightearly developmental stages as potential periods of particular vulnerability to program lasting obesity anddiabetes effects of toxic environmental insults.

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

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


application_id: 10596286
project_number: 5P42ES007380-25
project_title: Superfund Chemicals Nutrition and Multi-Organ Cardiovascular Risk
administering_ic: NIEHS
award_notice_date: 2023-01-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5740
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe overall goal of Project 1 is to understand the signaling pathways and metabolic or biological changes bywhich bioactive nutrients modulate impacts of acute or chronic exposure to persistent organic pollutants suchas polychlorinated biphenyls (PCBs) and long-chain per- and polyfluoroalkyl substances (PFAS). Suchpersistent pollutants express significant chemical stability in the environment and toxic insults from POPs areknown to correlate with a range of post-exposure human health impacts including vascular inflammation.Atherosclerosis a chronic inflammatory disease remains the leading cause of death in the United States.Biological events associated with inflammation and atherosclerosis can be modified by circulating toxicantsand bioactive nutrients and their metabolites which dictate final redox changes and inflammatory outcomes byaltering NF-kB and Nrf2 signaling. For example preliminary data demonstrate down-regulation of PCB 126-mediated toxicity and inflammation by plant-derived bioactive nutrients e.g. polyphenols and fiber (e.g.inulin). Importantly it is known that the pathology of atherosclerosis is dependent on the health and cross-talkof multiple tertiary organ systems including the liver and gut as exemplified by recent findings linking PCBexposure with increased plasma levels of trimethylamine N-oxide (TMAO) a diet-derived metabolite formedthrough cross-talk between gut microbiota and hepatic oxidation and associated with risk of atherosclerosis.Preliminary findings indicate that persistent organic pollutants and especially PCBs caused liver dysfunctionand alterations of gut microbiota and that prior liver injury exacerbated PCB-mediated systemic inflammation.Metabolomic profiling further suggested that increased formation of pro-atherogenic metabolites (e.g.ceramides) may drive multi-organ inflammation and increased cardiovascular risk. Based on these findingsthree specific aims test the hypotheses that 1) administration of PCB 126 and/or PFAS to mice increasescardiometabolic disease risk by increasing ceramide production via modulation of hepatic gene expressionand/or the gut microbiota; 2) administration of green tea catechins and/or soluble inulin fiber in vivo decreasesceramides and thereby stabilizes cellular redox status modulating NF-kB and Nrf2 signaling and pro-atherosclerotic pathologies as determined by en face and lipid staining in atherogenic LDL receptor-deficientmice; and 3) exposure to PCBs and/or PFAS increases pro-atherogenic metabolites (e.g. ceramides) throughincreased de novo synthesis in preclinical models. Transcriptomic and metabolomic technologies will be usedto explore the mechanistic interactions between pollutant exposure nutritional intervention and cardiovasculardisease (CVD) risks. These data will be confirmed in biobanked samples of humans with CVD. Results willsupport the paradigm that healthful nutrition interventions offer a powerful strategy to reduce disease risksassociated with environmental toxic insults and to prevent inflammatory diseases such as atherosclerosis thathave been linked to exposure to Superfund pollutants.

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

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


application_id: 10596284
project_number: 5P42ES007380-25
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2023-01-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5738
contact_pi_person_id: 12559398
contact_pi: BREWER, DAWN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY The research proposed by the University of Kentucky Superfund Research Center (UK-SRC) uses basic biological chemical and physical methods through nutrition and physical activity to reduce the amount and toxicity of hazardous substances (Superfund Research P Mandate #4). Incorporating good nutrition and physical activity strategies in conjunction with increasing environmental health literacy focused on nutrition and contaminant exposures aligns with the central theme of the UK-SRC  reducing risk posed by environmental contaminants in vulnerable communities  and with the prevention/intervention activities implemented by CEC. The CEC will continue to engage in bi-directional communication with its longest standing community partner of 12 years the Harlan community located in southeastern Kentucky near the National Priorities List (NPL) site in Dayhoit Kentucky. At this NPL site disposal of chlorinated solvents affected plant workers and neighbors living in a nearby mobile home park and surrounding area. New partnerships have been formed in eastern Kentucky Letcher County which has concerns related to the negative health consequences associated with air and water pollution derived from coal mining. The CEC also brought environmental pollutant and healthy lifestyle-focused interventions to older adults in central Kentucky. Although not exposed to a particular environmental contaminant the older adult population is an important one to include in its engagement activities due to the rapid growth of this population sector. By virtue of being an older adult these individuals have been exposed to more environmental contaminants and with age the detoxification capacity of the liver and kidneys has declined putting older adults at greater risk of experiencing more pronounced negative health effects of environmental contaminants. The innovation of the CEC to engage communities is apparent in the six prevention/intervention activities outlined in this proposal. The six programs are grounded in evidence-based approaches by intervening at multiple levels of the social ecological model of health behavior change including the individual community and organizational levels which allows the CEC to implement healthy lifestyle and environmental pollution education into existing community programs that reach populations across the lifespan. Major community partners include county Cooperative Extension Service Family and Consumer Science (FCS) and Horticulture Agents county senior centers community centers and farmers markets. The CEC plans to incorporate the science of the UK-SRC into existing community programs including walking programs FCS Extension health programs gardening programs senior center health programs and youth day camp programs. The gardening program will not only foster collaboration with community entities but also with the Duke SRC as it combines the expertise of both. Overall collaboration with community partners will benefit residents by providing opportunities to improve health and receive new knowledge pertaining to using healthy lifestyles to reduce exposure to environmental contaminants.

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

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


application_id: 10596283
project_number: 5P42ES007380-25
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2023-01-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5737
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) Data Management and Analysis Core(DMAC) has a goal to provide an overarching technology and research support infrastructure for themanagement and integration of data and information assets. Given that interdisciplinary research requiresresearchers to use methods and data from a range of disciplines this goal addresses a critical need forinterdisciplinary research to overcome hurdles posed by discipline-specific methods that impede progresswhen many disciplines attempt to share data. The DMAC is designed in alignment with FAIR (FindableAssessable Interoperable and Reusable) data principles to encourage interaction of data users and sharing ofdata. The specific aims are: 1) coordination of projects and cores; 2) foster data integration sharing andinteroperability; 3) ensure data quality assurance and quality control (QA/QC). The datasets to be managedand curated within the DMAC encompass the full range of basic research to translational work from animal-based studies to chemical analysis from experimental studies evaluating remediation of hazardoussubstances to community engagement activities. The DMAC will engage regularly with project/core leaders toprioritize data sets. It will streamline analytic resources data management data quality validation and dataintegration across projects and cores to improve efficiencies and reproducibility enhance project coordinationand promote resource sharing. The DMAC will promote interoperability by incorporating FAIR guidingprinciples in its data dashboards data archives and its query exploration interface to permit projects and coresto better integrate. By developing common terminologies data dictionaries training etc. the DMAC willfacilitate a common data resource to foster sharing within and beyond the UK-SRC. To facilitate interactionwith investigators and trainees there will be (on-site and electronic) opportunities for regular interaction withbiostatisticians data scientists and informaticians where formal and informal training can occur. Theseactivities will be coordinated and advertised closely with the Research Experience Training Coordination Core(RETCC). The DMAC will create a new WHY ENVIRONMENT module to enable projects and cores to engagein investigator-initiated research translation activities to allow them to form new questions and hypotheses thatcan be tested in projects and cores and shared beyond the confines of UK-SRC. Lastly the DMAC willincorporate best practices outlined by Data Observation Network for Earth (DataONE.org). It will establish aplan for data QA/QC so that UK-SRC research will not be subjected to pitfalls associated with poor qualitydata.

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

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


application_id: 10596280
project_number: 5P42ES007380-25
project_title: Administration Core
administering_ic: NIEHS
award_notice_date: 2023-01-23
opportunity_number: RFA-ES-18-002
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
project_start_date: 1997-04-07
project_end_date: 2025-01-31
study_section: ZES1-JAB-D
subproject_number: 5735
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe University of Kentucky Superfund Research Center (UK-SRC) will focus on a prevention and interventionparadigm with an overarching goal to promote healthy lifestyles (i.e. healthful nutrition and increased physicalactivity) to reduce disease risks associated with exposure to a subclass of persistent halogenated chemicals(e.g. PCBs TCE and PFAS). Our biomedical research will be coupled with environmental science/engineeringresearch that uses novel sensing remediation and fate and transport science to prevent or reduce exposurerisks in the environment. Our biomedical research is integrated around a full life-span perspective and aparadigm that uses animal studies to identify possible hypotheses that can be tested against existing humandatabases to further identify potential intervention strategies. Our environmental science research is integratedaround a project cross-talk that uses fate and transport science to help inform technology development usingnovel material science designed to reduce exposure to organic pollutants and that can then be deployed infield applications. Both biomedical and environmental science projects are crosslinked around a common set ofpollutants and the use of animal models to test the toxicity of these pollutants and different remediation by-products. To provide an optimal support environment and the requisite infrastructure to accomplish theCenters goal we propose four specific aims for our Administrative Core (ADMC): 1) activities managementand integration 2) bi-directional communication strategies 3) partnerships and technology transfer and 4)evaluation and management processes. Management and integration functions are facilitated by monthlyCenter meetings and ADMC leadership and trainee interns are drawn from the individual research projects. Bi-directional communication with other SRP centers and agency scientists and research translation to otherstakeholders are now fully integrated within the ADMC and overseen by a dedicated research translationcoordinator with support from a communications director. The ADMC effectively facilities investigator-initiatedresearch translation and technology transfer functions by leveraging a new integrated Data Management andAnalysis Core along with multidirectional internal (e.g. NIH funded UK Center for Clinical and TranslationalScience (CCTS) WHY program UK P30 pilot grants Kentucky Water Institute) and external (e.g. EPAADSTR Kentucky Cabinet for Energy and the Environment (KYEEC) ARCADIS Consultants individual waterutilities) partnerships. Evaluation and management processes are overseen by the ADMC director as assistedby the program administer. The focus of the ADMC on the establishment and maintenance of a continuousimprovement development processes along with internal and external relationships positions the UK-SRC tocontribute not only important scientific findings but also to the collaborative processes and innovativeendeavors associated with the national Superfund Research Program.

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

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


application_id: 10596083
project_number: 5K08DK123381-03
administering_ic: NIDDK
award_notice_date: 2023-03-23
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: DK
serial_number: 123381
program_official: LOH, KATRINA SHUEH WEN
project_start_date: 2021-04-01
project_end_date: 2024-07-10
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 9291843
contact_pi: JOPHLIN, LORETTA L.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
Interaction of the Microtubule Cytoskeleton and Perilipin-2 Regulates Hepatic Lipid Droplets - a Potential Therapeutic Target for Fatty Liver Disease

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

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

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


application_id: 10595227
project_number: 3P20GM135004-03S1
administering_ic: NIGMS
award_notice_date: 2022-06-14
opportunity_number: PA-18-935
application_type: 3
activity_code: P20
ic: GM
serial_number: 135004
suffix: S1
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2025-01-31
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-06-15
project_title:
Surveillance and identification of variants of concern within circulating SARS-CoV-2 across Kentucky

project_abstract:
PROJECT SUMMARYThe emergence and circulation of SARS-CoV-2 the virus that causes COVID-19 disease has led to >464 millioninfections and more than 6 million deaths worldwide in just over 2 years. Global sequencing efforts have identifiedseveral viral variants of concern (VOC) and interest (VOI) that result in increased transmission virulence vaccineescape and/or increased mortality for those infected. Ongoing viral genomic surveillance is necessary to identifyand characterize viral variants to inform both ongoing public health efforts and future vaccine/treatment designstrategies. This is a particularly urgent need for Institutional Development Award (IDeA) states for whichknowledge of circulating SARS-CoV-2 variants is relatively limited. The mechanistic forces driving SARS-CoV-2diversification and variant emergence are certainly multifactorial. Recent reports suggest that biological sex andage may impact immunopathogenesis and individual resilience and that geographically restricted circulation andtransmission of variants along with pre-existing social vulnerabilities may also impact SARS-CoV-2 variantdynamics. It is well documented that COVID-19 disproportionately impacts underrepresented populationsincluding Black Indigenous and people of color (BIPOC) and Latinx peoples. Data regarding SARS-CoV-2circulation and variant profiling in these populations continues to be underreported. Evaluating how viral VOCand VOI are impacted by differential genetic biological and social backgrounds will be critical for providingequitable representation of the frequency and characteristics of SARS-CoV-2. Environmental surveillance effortshave also been developed to track SARS-CoV-2 spread at the population/community-level providing minimallyinvasive unbiased VOC detection at low cost. Integration of clinical surveillance data with wastewater (WW)monitoring programs will enrich both datasets laying the groundwork for modeling how WW data may best beutilized as an early warning system for public health authorities. Despite the development of multiple robust andeffective vaccines ongoing viral evolution has resulted in resistance to current (and waning) levels of vaccine-mediated protection and this pattern will likely continue with emerging VOCs. Using a robust high throughputand cost-effective single molecule real-time sequencing approach we propose to perform large scale SARS-CoV-2 genomic surveillance from ~6000 samples sourced across Kentucky (KY) to (1) substantially improvedata availability regarding SARS-CoV-2 dynamics and variant circulation investigating biological andgeographical association with VOC dynamics (2) integrate wastewater and clinical SARS-CoV-2 surveillancedata and (3) identify mutational signatures associated with clinically relevant SARS-CoV-2 infections.. Toachieve this we have built a multi-institutional collaborative effort developing key partnerships among a deepnetwork of academic healthcare private and public health stakeholders positioning this team as a pathogensurveillance center for ongoing and future efforts.

project_terms:
2019-nCoV;Address;Age;Award;Biological;Black Indigenous People of Color;Blood Circulation;COVID-19;COVID-19 monitoring;COVID-19 severity;COVID-19 surveillance;Cessation of life;Characteristics;Clinical;Clinical Data;Clinical Pathology;Color;Communities;County;Custom;Data;Data Set;Databases;Deposition;Detection;Development;Diagnostic;Disease;Environmental Monitoring;Ethnic Origin;Etiology;Evolution;Female;Frequencies;Future;Genbank;Genetic;Genomics;Geography;Goals;Health Care Research;Healthcare;Hospitalization;Immune;Immunity;In Vitro;Individual;Infection;Infection Control;Kentucky;Knowledge;Laboratories;Latinx population;Length;Location;Long COVID;Mediating;Methods;Modeling;Monitor;Mutation;Outcome Study;Pathogenicity;Pathology;Pattern;Population;Positioning Attribute;Predisposition;Privatization;Public Health;RNA;Race;Reporting;Research Proposals;Resistance;Resolution;SARS-CoV-2 genome;SARS-CoV-2 immunity;SARS-CoV-2 infection;SARS-CoV-2 transmission;SARS-CoV-2 variant;Sampling;Secure;Severity of illness;Source;Specimen;Surveillance Program;Syndrome;System;Underrepresented Populations;Universities;Vaccination;Vaccines;Variant;Viral;Viral Genome;Viral Pathogenesis;Virulence;Virus;authority;base;biological sex;clinical phenotype;clinically relevant;comparative;cost;cost effective;data sharing;driving force;genomic variation;health inequalities;improved;infection rate;informatics tool;interest;male;minimally invasive;molecular sequence database;mortality;novel;pandemic disease;pathogen;programs;prospective;public database;racial disparity;resilience;sex;single molecule real time sequencing;social;social vulnerability;surveillance data;therapy design;transmission process;vaccine response;validation studies;variants of concern;viral genomics;viral transmission;wastewater monitoring

public_health_relevance:
PROJECT NARRATIVESARS-CoV-2 infection the etiologic agent of COVID-19 has resulted in a global pandemic resulting >6 milliondeaths which continues due to the emergence of viral variants of concern that demonstrate increased viraltransmission virulence and resistance to vaccine-mediated immunity. Continued expansion of surveillanceefforts is urgently needed particularly in Institutional Development Award (IDeA) states that are vastlyunderrepresented in public SARS-CoV-2 databases. We are proposing to extend our SARS-CoV-2 genomicsurveillance program including samples (n=6000) sourced from across Kentucky (KY) to substantially improvepublicly available KY-based data integrate with ongoing environmental SARS-CoV-2 monitoring and definemutational signatures associated with vaccine breakthrough.


application_id: 10594448
project_number: 5R01CA249734-03
project_title: Targeting Lipid Metabolism in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2023-02-28
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 249734
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated and activated in CRC and its activity is associated with poor prognosis higher risk of disease recurrence and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis palmitate is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipid implicated in metastasis. Therefore in Aim 1 we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore our preliminary studies show a correlation between expression of FASN and CD36 a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore in Aim 2 we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3 we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients human primary CRC cells tumor organoids established from genetically modified mice and CRC metastasis models which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches including targeted and stable isotope-resolved metabolomics (SIRM) to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN SphKs and CD36 as therapeutic targets in CRC the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.

project_terms:
Biological;Biological Assay;Biological Sciences;CD36 gene;Cancer Etiology;Cancer Patient;Cause of Death;Cecum;Cell Survival;Cessation of life;Clinical;Clinical Trials;Collaborations;Colorectal Cancer;Compensation;Data;Development;Disease;Drug Evaluation;Drug Targeting;Environment;Enzymes;Fatty Acids;Fatty-acid synthase;Goals;Growth;Human;In Vitro;Incidence;Injections;Knowledge;Lipids;Literature;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Microarray Analysis;Modeling;Molecular;Morbidity - disease rate;Mus;Neoplasm Metastasis;Oncology;Organ;Organoids;Outcome;Palmitates;Pathway interactions;Patients;Phase;Phase I/II Clinical Trial;Phase II Clinical Trials;Pre-Clinical Model;Prognosis;Public Health;Recurrent disease;Regulation;Research;Role;Sampling;Signal Pathway;Solid;Solid Neoplasm;Specimen;Sphingolipids;Sphingosine;Testing;Therapeutic;Tissue Microarray;Tumor Angiogenesis;United States;Up-Regulation;Validation;Woman;analog;cancer cell;colorectal cancer metastasis;colorectal cancer progression;fatty acid metabolism;genetic approach;high risk;in vivo;in vivo Model;inhibitor;lipid biosynthesis;lipid metabolism;men;metabolomics;mortality;mouse model;neutralizing antibody;new therapeutic target;novel;novel therapeutic intervention;overexpression;patient derived xenograft model;pharmacologic;preclinical study;prevent;resistance mechanism;response;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;therapeutic target;transcriptome sequencing;translational impact;translocase;tumor;tumor metabolism;uptake

public_health_relevance:
PROJECT NARRATIVEColorectal cancer is the 2nd most common cause of cancer death among men and women in the Unites States with a majority of the mortality associated with metastasis that has spread to other organs. We have proposed to investigate the mechanisms of how lipid metabolism promotes CRC metastasis. The completion of this study will help to advance our knowledge of the contribution of lipid metabolism to CRC metastasis and to further guide the development of novel therapeutic strategies to treat CRC and potentially other solid cancers.


application_id: 10594065
project_number: 2R25ES027684-06
project_title: Summer Research in Environmental Health Sciences
administering_ic: NIEHS
award_notice_date: 2022-12-13
opportunity_number: PAR-21-168
application_type: 2
activity_code: R25
ic: ES
serial_number: 027684
program_official: HUMBLE, MICHAEL C
project_start_date: 2017-05-01
project_end_date: 2027-10-31
study_section: Special Emphasis Panel[ZES1 LKB-S (SR)]
contact_pi_person_id: 1883439
contact_pi: SWANSON, HOLLIE ISABEL
other_pis: PEARSON, KEVIN JOSEPH
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Summer Undergraduate Research in Environmental Health Sciences (SURES) program at the University ofKentucky is designed to introduce students to the highly interdisciplinary and collaborative nature ofenvironmental health science (EHS) research that is focused on solving key global health problems. Anadditional focus is to prepare underprivileged and under-represented students for successful careers in relevantfields. This is a competitive renewal application seeks support to continue our 10-week summer program andsupport fellowships for 10 students. The SURES program leverages the substantial and ongoing efforts at theUniversity of Kentucky driven to enhance the undergraduate research experience with the robust environmentalhealth science research programs of involved faculty mentors. The specific aims are to 1) enhance studentunderstanding and interest in EHS and 2) improve student scientific and career skills. Towards this end studentswill be recruited from the Commonwealth of Kentucky with an emphasis on those from the Appalachian regionas well as from a variety of undergraduate institutions in order to create a cohort of participants representingdiverse populations. The SURES program will commence with a week-long session that introduces students toresearch laboratory safety and scientific ethics. The students will then experience hands-on research byperforming experiments in the laboratories of their chosen mentors. Professional development and a sense ofbelonging to the EHS community will be built via student participation in weekly lunches with EHS researchersand professionals net-working opportunities and tours of research facilities. In addition students will be pairedwith a near-peer mentor and engage in weekly activities that include a citizen science lead collection groupexercise a theatre improvisation workshop community-building circle on mentoring painting their projects andviewing a discussing a film on climate change. Each participant will create an EHS-relevant podcast. TheSURES program will culminate in a campus-wide poster session attended by the faculty staff students andstudent family members. Success of the program is indicated by the engagement of prior participants in careersin university research (13%) industry (16%) government/nonprofits (11%) and pursuing graduate (16%)/professional (37%) education. Dissemination of the approaches used in this program and their outcomes willbuild upon the expansion of the traditional environmental health sciences research training from the graduateand post-doctoral level to the undergraduates at a national level.

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

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


application_id: 10594046
project_number: 5R01HL147921-04
administering_ic: NHLBI
award_notice_date: 2023-01-30
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 147921
program_official: TJURMINA, OLGA A
project_start_date: 2020-04-22
project_end_date: 2023-09-22
study_section: Cardiac Contractility, Hypertrophy, and Failure Study Section[CCHF]
contact_pi_person_id: 15587997
contact_pi: MOHAMED, TAMER M A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
Induction of Cardiomyocyte Proliferation via Transient Expression of Cell Cycle Factors as a Promising Therapy for Heart Failure

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

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

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


application_id: 10593895
project_number: 5R01HL141191-05
project_title: The role of bioactive lipids in CMC-induced myocardial repair.
administering_ic: NHLBI
award_notice_date: 2023-03-31
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141191
program_official: WONG, RENEE P
project_start_date: 2019-04-01
project_end_date: 2024-03-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 11176762
contact_pi: WYSOCZYNSKI, MARCIN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
A variety of sterile diseases including myocardial infarction (MI) and subsequent repair involve theimmune system. Although unresolved inflammation exacerbates heart failure depletion of macrophages in theinfarcted myocardium leads to left ventricular (LV) rupture and death. Thus indiscriminate immunosuppressionis not a viable approach. Nevertheless persistent inflammation in the failing heart must be addressed.Unfortunately significant barriers to progress remain because we do not know how immune cells regulatemyocardial repair and what determines their harmful versus salutary actions. Cell therapy provides a uniqueopportunity for understanding how immune cells contribute to myocardial repair and recent findings implicatemacrophages as direct contributors to cell therapy-mediated myocardial repair. Although few injected cellssurvive long-term in the recipient common benefits include reduction of fibrosis enhanced angiogenesis andimprovement in LV function. These improvements occur independently of differentiation of the injected cellsinto cardiomyocytes suggesting that cell therapy must recruit endogenous repair mechanisms; however thesemechanisms remain unidentified. Our preliminary data show that injection of cardiac mesenchymal cells(CMCs) into the infarcted heart promotes accumulation of reparative macrophages decreases fibrosis andimproves LV function. Co-culture of CMCs with macrophages favors a reparative macrophage program and itmay be due to CMC-derived bioactive lipidssuch as prostaglandins leukotrienes and resolvins which offertestable explanations of the `paracrine hypothesis' of cell-mediated repair. Thus we propose that CMCs recruitmonocytes and activate reparative macrophages which promote favorable anti-fibrotic cardiac remodeling andimprove cardiac function in the infarcted heart. In the current project we will determine the capacity for thebioactive lipid synthesis and secretion in CMCs. Mass spectrometry will be performed to explore the role ofCox and Lox pathways in bioactive lipid synthesis in CMCs. Moving forward we will ascertain the role bioactivelipids in macrophage recruitment and their reparative function with the particular focus on macrophage BLT-1receptor and its CMC-derived ligands. Finally we will determine the reparative effect of CMCs with enhancedbioactive lipid synthesis in mouse model of HF. This project will be the first systematic analysis of bioactivelipid synthesis profile in reparative CMCs. This project will provide novel insights into not only pathways ofbioactive lipid synthesis in CMC but also the mechanisms regulating cell therapy-mediated myocardial repair.

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

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


application_id: 10592661
project_number: 1R21DA055879-01A1
administering_ic: NIDA
award_notice_date: 2022-09-26
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: DA
serial_number: 055879
suffix: A1
program_official: NAIR, SUNILA GOPI
project_start_date: 2022-09-30
project_end_date: 2024-08-31
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
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;Brain region;Caring;Cells;Chronic;Contraceptive Agents;Contraceptive Usage;Data;Electrophysiology (science);Estradiol;Estrogens;Ethinyl Estradiol;Ethinyl Estradiol/Levonorgestrel;Exposure to;Female;Formulation;Foundations;Future;Glutamates;Goals;Hormone use;Hormones;Intravenous;Levonorgestrel;Measures;Methods;Motivation;N-Methylaspartate;Neurobiology;Neurons;Nicotine;Nicotine Dependence;Norethisterone Acetate;Nucleus Accumbens;Oral;Oral Contraceptives;Outcome;Ovarian;Ovarian hormone;Ovariectomy;Ovary;Pathway interactions;Periodicity;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;base;behavioral economics;birth control;cigarette craving;craving;critical period;drug reward;insight;men;neural circuit;neurobehavioral;nicotine reward;nicotine use;novel;patch clamp;prevent;protective effect;receptor;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: 10592400
project_number: 5R24OD010435-21
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2023-02-15
opportunity_number: RFA-OD-19-027
application_type: 5
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-G(55)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: SMITH, JERAMIAH JAMES
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:
This application proposes to develop fundamental genomic and bioinformatic resources that will better enablestudies of the axolotl (Ambystoma mexicanum). The axolotl provides the best model for identifying mechanismsof regeneration that can translate to humans. This is because it can regenerate multiple damaged body partsincluding whole limbs spinal cord and brain and because it shares tetrapod biology with human. Understandinghow axolotls regenerate complex tissues may reveal mechanisms to activate stem cells within human tissues toorganize and reform damaged tissues. Beyond regeneration the axolotl presents many untapped diseasemodels that were identified and rigorously examined with traditional developmental approaches before thegenetics/genomics era. With our recent development of the first chromosome-scale assembly of the axolotlgenome these and new models that will be created in coming years through genome editing can be advancedfor the first time to significantly impact biomedical research. However to advance these models improvementsof the genome assembly are needed along with new datasets to enable genome-wide studies of the large axolotlgenome. To accomplish these objectives we propose three specific aims. In Aim 1 we will resolve inter- andintra-specific variation within the current assembly and resolve complex repetitive regions that have hamperedthe placement of ~6 Gb of the 32 Gb genome. Specifically we will employ a powerful trio binning strategy thattakes advantage of long read sequencing of DNA from axolotl x tiger salamander (A. tigrinum) hybrids. Thisapproach leverages decades of experience in generating interspecific hybrids to resolve assembly gaps/errorsand accurately place gene models within their non-coding regulatory environments. Additionally we will analyzesequence data from 10 AGSC axolotls from branches of the pedigree that optimally sample laboratory geneticdiversity. In Aim 2 we will perform Chip-Seq to identify changes in histone post-translational modifications duringtail and limb regeneration. Characterization of epigenetic marks for embryo larval and adult models ofregeneration will provide new resources for regeneration research and advance community efforts in performinggenome wide studies. Aim 3 will address significant community needs user-friendly access to large scalegenomic datasets and improvement of genomic and bioinformatic capabilities of investigators in the axolotlcommunity. Accomplishment of these aims will significantly advance axolotl as an animal model for biomedicalresearch.

project_terms:
Achievement;Adult;Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Area;Base Sequence;Bioinformatics;Biology;Biomedical Research;Body part;Brain;ChIP-seq;Chromatin;Chromosomes;Communities;Complex;DNA Binding;DNA sequencing;Data;Data Set;Development;Disease model;Embryo;Enhancers;Ensure;Environment;Epigenetic Process;Funding;Gene Expression;Generations;Genes;Genetic;Genetic Transcription;Genetic Variation;Genome;Genomics;Growth;Haploidy;Histones;Human;Hybrids;Laboratories;Limb structure;Methods;Modeling;Molecular;Natural regeneration;Phase;Positioning Attribute;Post-Translational Protein Processing;Protocols documentation;Publishing;Reagent;Recommendation;Regenerative research;Repetitive Sequence;Research;Research Personnel;Resources;Salamander;Sampling;Site;Spinal Cord;System;Tail;Tetrapoda;Tigers;Time;Tissues;Translating;Untranslated RNA;Variant;bioinformatics resource;cell type;data dissemination;data integration;data sharing networks;design;empowerment;experience;genetic pedigree;genome browser;genome editing;genome resource;genome-wide analysis;genomic data;histone-binding proteins;human tissue;improved;innovation;knowledgebase;limb regeneration;promoter;regeneration model;stem cells;tissue regeneration;user-friendly;web portal

public_health_relevance:
The project will develop critical resources to enhance research efforts using the laboratory axolotl(Ambystoma mexicanum). Improvements to the axolotl genome assembly will be made epigenetic datawill be generated for limb and tail regeneration and all data from the project will be made publiclyavailable. Studies using the axolotl may reveal strategies to achieve endogenous tissue regeneration inhumans.


application_id: 10591498
project_number: 5F31CA260840-03
project_title: Exploring the Role of Drp1 in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2023-02-08
opportunity_number: PA-20-246
application_type: 5
activity_code: F31
ic: CA
serial_number: 260840
program_official: SCHMIDT, MICHAEL K
project_start_date: 2021-04-01
project_end_date: 2023-07-25
study_section: Special Emphasis Panel[ZRG1-F09A-R(20)L]
contact_pi_person_id: 16493761
contact_pi: HASANI, SUMATI RAJ
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract - Exploring the Role of Drp1 in Colorectal Cancer. Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately150000 new cases and 50000 deaths are predicted for the year 2020. Emerging research suggests that thedysregulation of mitochondrial fitness due to an imbalance in mitochondrial dynamics can lead to metabolicreprogramming in various cancer types. A number of epidemiological studies indicate that obesity is as a majorrisk factor for several types of cancer including colorectal cancer. Our group and others have shown thatincreased uptake of fatty acids promotes the development and progression of difference cancers by alteringmetabolic pathways to favor mitochondrial fatty acid oxidation. However the molecular mechanisms by whichfatty acid consumption influences mitochondrial fitness to promote tumor cell survival and progression is poorlyunderstood. In this proposed study I plan to investigate the signaling crosstalk between mitochondrial dynamicsand fatty acid metabolism in colorectal cancer. In my preliminary experiments I discovered that fatty acid uptakepromotes mitochondrial fragmentation by activating Drp1 a small GTPase required for mitochondrial fission byincreasing the phosphorylation at the S616 site and its interaction with mitochondria. Importantly silencing Drp1inhibits cancer stem cell functions by attenuating Wnt signaling in colon cancer cells. The central hypothesis isthat Drp1-dependent mitochondrial fission is required for fatty acids to promote tumor progression in coloncancer. Specifically I will determine how fatty acid uptake alters Drp1 activity and how mitochondrial dynamicsaugments cancer stem cell functions to drive tumorigenesis in vivo. The following specific aims are proposed:1) to delineate the molecular mechanism by which fatty acid uptake enhances Drp1 activity; 2) to determine thefunctional importance of Drp1 in promoting CSC functions in colorectal cancer; and 3) to define the role of Drp1in regulating tumorigenesis using in vivo colon cancer models. Results from this study will provide novel insightsinto the role of mitochondrial dynamics in connecting cellular metabolic pathways with cancer stem cell signaling.Dr. Gao has extensive experience in studying the regulation of signaling pathways and mitochondrial metabolismin colorectal cancer. I will also benefit from additional expertise provided by my committee members and state-of-the-art facilities of the Markey Cancer Center at the University of Kentucky. A comprehensive training planhas been developed to fit my research background and career goals. Based on my strong preliminary data withmy mentors knowledge and training and the excellent research environment at the Department of Molecularand Cellular Biochemistry and the Markey Cancer Center I am confident that this project will be successful.Ultimately this study will help develop personalized treatment options by targeting mitochondrial dynamics toeradicate cancer stem cells.

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

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


application_id: 10591411
project_number: 5R01AI152258-05
administering_ic: NIAID
award_notice_date: 2023-03-06
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 152258
program_official: ROBINSON, RICHARD THOMAS
project_start_date: 2020-04-16
project_end_date: 2025-03-31
study_section: Special Emphasis Panel[ZRG1-CVRS-R(03)]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-04-01
project_title:
Mechanisms of increased susceptibility to pulmonary Nontuberculous Mycobacterial disease in the elderly

project_abstract:
SUMMARYMycobacterium avium (MAC) and other non-tuberculous mycobacteria (NTM) can cause chronic insidious andoften debilitating lung disease necessitating complicated and extensive multi-drug antibiotic therapy that can belife-long. Additionally 50% of treated patients who have culture conversion to negative will suffer a relapse ofeither their existing infection or a new infection. While NTM are ubiquitous in the environment and humanexposure throughout life is frequent pulmonary disease is found almost exclusively among the elderly. It istherefore not surprising that pulmonary NTM disease is increasing in incidence and prevalence mirroringchanges in the overall age structure of the U.S. Mechanisms underlying the increased susceptibility to NTMdisease with age are not well understood. Consequently there is an unmet need in virtually all aspects of thisdisease and its management including an understanding of disease pathogenesis. Adding urgency to thisresearch area is the fact that the U.S. Census Bureau estimates that by 2030 more than 20% of the US residentsare projected to be at least 65 years old and over. In this application we propose to test the central hypothesisthat aged individuals are more susceptible to NTM disease due to defects in Th1 T cell immunity coupledwith dysregulation in lung microbiome that favor the acquisition of pathogenic bacteria. To that end wewill leverage the highly translational rhesus macaque model to first identify age-associated changes inimmunological parameters inflammatory markers and microbial community. Then we will leverage a novelrhesus macaque model established by our group that recapitulates the hallmarks of pulmonary MAC disease tocarry out experimental prospective studies to uncover age-mediated alterations in immune responses and lungmicrobial communities that are associated with susceptibility to and development of chronic NTM pulmonarydisease. These studies will lead to novel insight into the pathogenesis of this chronic lung disease that causessignificant morbidity in the elderly and continues to increase in incidence and prevalence as the Americanpopulation ages. Identification of immune or microbiome correlates of protection or risk of disease could leaddirectly to improvements in the clinical care of these patients and the prevention of this disease in the elderly.

project_terms:
Acute Disease;Affect;Age;Age Years;Aged 80 and over;Aging;American;Animal Diseases;Antibiotic Therapy;Antibiotics;Antibodies;Area;Biological Assay;Biology;Cells;Censuses;Chronic;Chronic Disease;Chronic lung disease;Communities;Coupled;Cytokine Gene;Defect;Development;Disease;Elderly;Environment;Female;Genetic Transcription;Genomics;Genus Mycobacterium;Health;Immune;Immune response;Immunity;Immunologics;Immunology;Immunology procedure;Incidence;Individual;Infection;Interferon Type II;Interleukin-12 Gene;Kinetics;Lead;Life;Lower respiratory tract structure;Lung;Lung diseases;Lung infections;Macaca mulatta;Mediating;Modeling;Morbidity - disease rate;Mucociliary Clearance;Mutation;Mycobacterium Infections;Mycobacterium avium;Mycobacterium avium Complex;Mycobacterium avium-intracellulare Infection;Mycobacterium tuberculosis;Oral;Pathogenesis;Patient Care;Patients;Peripheral Blood Mononuclear Cell;Physiological;Play;Population;Predisposition;Prevalence;Prospective Studies;Pulmonology;Relapse;Research;Risk;Role;Severities;Severity of illness;Statistical Models;Structure;T-Lymphocyte;TNF gene;Testing;Tuberculosis;United States;Upper respiratory tract;age effect;age related;aged;aging population;clinical care;cytokine;disorder prevention;disorder risk;exposed human population;genome wide association study;human old age (65+);immune activation;improved;inflammatory marker;inhibitor;insight;juvenile animal;lung microbiome;lung microbiota;mathematical model;microbial community;microbiome;next generation sequencing;non-tuberculosis mycobacteria;nonhuman primate;novel;pathogen;pathogenic bacteria;probiotic therapy;pulmonary function;respiratory microbiome;response;virtual

public_health_relevance:
NARRATIVEPulmonary nontuberculous mycobacterial disease is increasing in incidence and disproportionately affects theelderly. However the mechanisms underlying increased vulnerability and disease severity in the elderly areunknown. Therefore in this proposal we will identify these mechanisms by investigating age related changes inimmunity and microbial communities in the lung using a translational nonhuman primate model.


application_id: 10590375
project_number: 1K23DE031807-01A1
administering_ic: NIDCR
award_notice_date: 2023-07-21
opportunity_number: PA-20-206
application_type: 1
activity_code: K23
ic: DE
serial_number: 031807
suffix: A1
program_official: THIRUMANGALATHU, SHOBA
project_start_date: 2023-09-01
project_end_date: 2028-08-31
study_section: Special Emphasis Panel[ZDE1 AC (04)]
contact_pi_person_id: 11936065
contact_pi: BOGGERO, IAN ANDRES
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_title:
Initial Evidence for a Brief Psychological Telehealth Intervention for Patients with Chronic Masticatory Muscle Pain

project_abstract:
Chronic masticatory muscle pain disorders (MMPD) affect between 5-12% of the population are the secondmost common musculoskeletal pain conditions after chronic low back pain and are associated withmanagement costs of over $4 billion per year presenting a serious public health issue. Multidisciplinary carecombining dental care with psychological interventions appears to offer the best prognosis. Physical self-regulation (PSR) is a brief two-session psychological intervention that has been shown to lead to long-termreductions in pain intensity over standard dental care alone in patients with chronic MMPD. Unfortunatelytreatment utilization for PSR is low when it is offered in-person with fewer than 50% of eligible patientschoosing to begin treatment. Offering PSR over telehealth (PSR-TH) may help address this issue withpreliminary data demonstrating >80% treatment utilization for PSR-TH. A full-scale trial is needed to test theefficacy of PSR-TH and 1) determine if PSR-TH effects are due to the intervention itself or to nonspecifictreatment effects and 2) determine moderators and mediators of treatment effects. However additional dataare needed before such a trial can be conducted. The goal of this proposal is to obtain data to support a futurefull-scale Phase II efficacy trial by achieving the following specific aims. First PSR-TH and a controlintervention need to be formally piloted in patients with MMPD to determine recruitment and retention ratesinterventionist fidelity and patient-reported acceptability credibility and burden of the interventions (Aim 1).Second we need to identify potential moderators and mediators of PSR-TH so that we can focus onthoroughly assessing those specific variables in the future trial (Aim 2). Treatment-seeking females withchronic MMPD will be randomly assigned to two 50-min telehealth sessions of PSR-TH or a controlintervention (N=52/group) and will provide biopsychosocial moderator data (week 0) treatment feasibility dataimmediately following the intervention (week 3) mediation data two weeks following the intervention (week 5)and outcome data (pain intensity pain interference and quality of life) two weeks and three months followingthe intervention (weeks 5 and 15). We hypothesize that both PSR-TH and the control intervention willdemonstrate strong feasibility (i.e. recruitment of at least 1 participant per week >75% retention >95%interventionist fidelity and adequate acceptability credibility and burden). We also hypothesize that specificbiopsychosocial variables will moderate PSR-related changes in outcomes and that PSR-TH-related changesin perceived control over pain self-efficacy coping parafunctional habits and relaxation will mediate treatmenteffects. In addition to supporting a future efficacy trial of PSR-TH the proposed project will leverage myprevious training a collaborative environment at the University of Kentucky and the expertise of world-renownmentors to provide me training in clinical research assessment of moderators and mediators in orofacial painand leadership of research teams giving me the skills for a successful independent clinical research career.

project_terms:
Address;Adult;Affect;Age;Awareness;COVID-19 pandemic;Caring;Chronic;Chronic low back pain;Clinical;Clinical Research;Continuity of Patient Care;Data;Dental;Dental Care;Disease;Educational process of instructing;Eligibility Determination;Exercise;Fatigue;Female;Financial Hardship;Future;Goals;Habits;Individual;Informal Social Control;Intervention;Kentucky;Knowledge;Leadership;Literature;Loneliness;Manuals;Masticatory muscles;Mediating;Mediation;Mediator;Medical;Mental Health;Mentors;Muscle relaxation phase;Musculoskeletal Pain;Myalgia;Orofacial Pain;Outcome;Pain;Pain Disorder;Pain intensity;Pain interference;Pain management;Participant;Patients;Persistent pain;Persons;Phase;Population;Prognosis;Public Health;Publishing;Quality of life;Randomized;Readiness;Relaxation;Reporting;Research;Research Personnel;Self Efficacy;Social support;Standardization;Stress;Symptoms;Testing;Training;Universities;active control;anxiety symptoms;biopsychosocial;biopsychosocial factor;career;career development;chronic pain;chronic painful condition;collaborative environment;comorbidity;coping;cost;depressive symptoms;design;efficacy testing;efficacy trial;improved;intervention effect;multidisciplinary;pain catastrophizing;pain outcome;pain reduction;post intervention;psychologic;recruit;research and development;research study;retention rate;satisfaction;skills;sleep quality;social;telehealth;treatment effect

public_health_relevance:
PROJECT NARRATIVEChronic masticatory muscle pain disorders (MMPD) affect between 5-12% of the adult population and are themost common cause of chronic non-odontogenic orofacial pain. Combining standard dental care with brieftelehealth psychological interventions offers hope for reducing negative pain outcomes and improving quality oflife in this population but few such interventions exist. The proposed submission will generate data to supporta future full-scale Phase II efficacy trial of a brief telehealth psychological intervention for MMPD potentiallyleading to an efficacious widely implementable and disseminatable treatment option for patients with chronicMMPD.


application_id: 10590132
project_number: 1R21AG077495-01A1
project_title: Drug repurposing for Alzheimers disease-related inflammation caused by a TBI
administering_ic: NIA
award_notice_date: 2023-02-08
opportunity_number: PAR-22-094
application_type: 1
activity_code: R21
ic: AG
serial_number: 077495
suffix: A1
program_official: ARUNKUMAR, NANDINI
project_start_date: 2023-02-15
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1 BDCN-A (55)]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: GENSEL, JOHN C
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 SUMMARY/ABSTRACTThe CDC estimates that at least 200000 older Americans (> 65 years) will have a traumatic brain injury (TBI)each year primarily caused by a closed head injury (CHI) from a fall. The aged brain with Alzheimers diseaseneuropathological changes has significant reactive microglia and astrocytes and other markers ofneuroinflammation. An acquired brain injury can further exacerbate this state of reactive gliosis andneuroinflammation. Alzheimers disease poses a significant therapeutic challenge given that pathology candevelop over decades. However we believe that it is an obtainable therapeutic goal to prevent the worseningof neuroinflammation caused by an acquired brain injury in those at risk for developing Alzheimers disease .Control of neuroinflammation following the TBI in older adults is a promising avenue for improving patientoutcomes. However no drug has earned FDA approval for specific use in mild TBI. There is also limitedevidence to guide the repurposing of FDA-approved drugs that target neuroinflammation for this uniquepopulation. Broad-spectrum immunosuppressants are not advisable and while selective biologics (such asanti-TNF) are promising they also come with the risk of increasing infection which is problematic in an olderadult population at risk for infections. Our goal is to identify targeted immunomodulatory (notimmunosuppressants) with a high benefit-to-risk ratio. We recently identified the commonly prescribedantibiotic Azithromycin (AZM) as an immunomodulatory agent with neuroprotective effects in spinal cordinjury. Because of its safety profile AZM is frequently prescribed as a prophylactic treatment in severalconditions and broadly administered in at-risk disease populations. This proposal aims to provide proof-of-principal data for AZM as a safe and effective neuroinflammatory modulatory drug. We will test the centralhypothesis that AZM can alter neuroinflammation and improve cognitive outcomes following a CHI in anAPP/PS1 KI mouse model of Alzheimers disease-related pathology in the following two specific aims (SA). SA1: Define the immunomodulatory dose-dependent effect of AZM in 8-month-old APP/PS1 KI mouse model following a CHI. SA2: Evaluate the effects of AZM on CHI-induced behavioral and Alzheimers disease-related neuropathology in 8-month-old APP/PS1 KI mice.This proof-of-concept study could establish AZM as a safe and well-tolerated FDA-approved drug to reducedamage and speed recovery in the fragile older brain following a CHI. Once the feasibility of AZM treatmenthas been established new areas of drug development and clinical research with the potential to more quicklydevelop a new drug to slow the devastating effects of Alzheimers disease can be created.

project_terms:
APP-PS1;Acceleration;Acute;Age;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease risk;American;Antibiotics;Area;Astrocytes;Azithromycin;Behavioral;Behavioral Assay;Biological Products;Brain;Brain Injuries;Clinical Research;Closed head injuries;Cognitive;Cognitive deficits;Data;Dementia;Dose;Drug Targeting;Drug usage;Elderly;Environmental Risk Factor;Evaluation;Evaluation Research;Exploratory/Developmental Grant;FDA approved;Failure;Gliosis;Goals;Histopathology;Immunosuppressive Agents;Incidence;Infection;Inflammation;Inflammatory;Injury;Kentucky;Knock-in Mouse;Microglia;Modeling;Nervous System Trauma;Odds Ratio;Outcome;Pathology;Patient-Focused Outcomes;Pharmaceutical Preparations;Phase;Phenotype;Population;Populations at Risk;Positioning Attribute;Pre-Clinical Model;Predisposition;Property;Prophylactic treatment;Radial;Recovery;Research;Resolution;Risk;Safety;Speed;Spinal cord injury;Synapses;TBI treatment;TNF gene;Testing;Therapeutic;Therapeutic Agents;Time;Traumatic Brain Injury;Universities;Wild Type Mouse;Work;aging brain;amyloid pathology;arm;blood-brain barrier crossing;cost;disorder risk;drug development;drug discovery;drug efficacy;drug repurposing;experience;falls;human old age (65+);immune modulating agents;immunomodulatory therapies;immunoregulation;improved;infection risk;medical attention;mild traumatic brain injury;mouse model;neuroinflammation;neuropathology;neuroprotection;novel therapeutics;pharmacokinetics and pharmacodynamics;pre-clinical;prevent;primary endpoint;research and development;response;tau Proteins;therapeutic development;therapeutic evaluation;treatment duration;water maze

public_health_relevance:
PROJECT NARRATIVEThis project will investigate the potential of the commonly prescribed antibiotic Azithromycin as animmunomodulatory agent to speed recovery and reduce injury-exacerbated Alzheimers diseaseneuropathological changes following an acquired brain injury. Hypothesis-based drug repurposing ofazithromycin will provide a novel therapeutic agent for use in Alzheimers disease with a reduced time framefor the drug development.


application_id: 10590000
project_number: 1R01DA057686-01
project_title: Fast and fine: NLP methods for near real-time and fine-grained overdose surveillance
administering_ic: NIDA
award_notice_date: 2022-09-16
opportunity_number: RFA-DA-22-044
application_type: 1
activity_code: R01
ic: DA
serial_number: 057686
program_official: KURAMOTO-CRAWFORD, SATOKO JANET
project_start_date: 2022-09-30
project_end_date: 2025-09-29
study_section: Special Emphasis Panel[ZDA1 JRB-A (12)]
contact_pi_person_id: 11081240
contact_pi: KAVULURU, VENKATA NAGA RAMAKANTH
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This study is part of the NIHs Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction. Timely and accurate estimation of overdose (OD) event rates is an indispensable surveillance component to mit-igate the toll of the ongoing OD epidemic. Getting fast updates for nonfatal ODs is crucial in decreasing further escalations in OD deaths. Traditional approaches to OD surveillance currently rely on CDC's syndromic surveil-lance system and aggregated emergency department (ED) billing data. However national level estimates are plagued by substantial delays. Hence there is an increasing push to monitor (sub)state level datasets including ED and emergency medical service (EMS) records. Meanwhile the role of narrative data in these records is being recognized to offer complementary signal for ODs and drugs leading to them because existing diagnosis code based OD denitions are shown to have lower recall (sensitivity). Even rule-based denitions that search for terms in narratives are missing the sequential semantic context in narrative data. To address these shortcom-ings we propose to design and implement state-of-the-art natural language processing (NLP) models using deep neural networks (DNNs) for OD classication and ne-grained recognition of drug terms leading to ODs. To this end we will rst create and disseminate the rst of their kind public gold standard hand-labeled datasets for these tasks using ED and EMS narratives. Our de-identied notes will be used to build DNN models that will also beshared publicly to the wider OD surveillance community. Our models are expected to improve recall substantially and lead to better nonfatal OD surveillance in a timely manner. We will also develop domain adaption methods to enhance the application of models developed with data from a site to datasets from a different site. Overallour project will create novel public resources (data code models) for the OD surveillance community to leverage latest advances in NLP methods.

project_terms:
Accident and Emergency department;Address;Benchmarking;COVID-19 pandemic;Centers for Disease Control and Prevention (U.S.);Classification;Clinical;Code;Collaborations;Communities;Computer software;County;Data;Data Set;Death Certificates;Diagnosis;Docking;Drug usage;Emergency department visit;Emergency medical service;Epidemic;Evaluation;Event;Goals;Gold;Grain;Hand;Health;Helping to End Addiction Long-term;Human;Information Retrieval;International Statistical Classification of Diseases and Related Health Problems Tenth Revision (ICD-10);Kentucky;Label;Lead;Learning;Letters;Life;Linear Models;Logistic Regressions;Machine Learning;Manuscripts;Methods;Modeling;Monitor;Naloxone;Names;Natural Language Processing;Neural Network Simulation;Non-linear Models;Opiate Addiction;Opioid;Overdose;Performance;Pharmaceutical Preparations;Prevention Research;Public Health;Records;Recurrence;Reporting;Research;Research Personnel;Resource Allocation;Resource-limited setting;Resources;Role;Semantics;Service delivery model;Signal Transduction;Site;Source;Speed;Spottings;Structure;Substance abuse problem;Supervision;System;Time;Training;Triage;United States National Institutes of Health;Universities;Update;Work;base;billing data;care delivery;dashboard;data modeling;data reuse;deep neural network;design;disability;experimental study;improved;injury prevention;insight;learning strategy;machine learning method;neural model;novel;open source;opioid misuse;opioid use disorder;overdose death;random forest;relating to nervous system;stem;supervised learning;syndromic surveillance;tool;transfer learning

public_health_relevance:
NARRATIVEAs the overdose epidemic continues to ravage the nation high quality surveillance efforts to generate timelyand actionable insights are needed. In this project we aim to increase the quality and timeliness of overdoseestimates by leveraging textual narratives authored by emergency department (ED) clinicians and emergencymedical services (EMS) staff. We will produce reusable de-identied ED/EMS textual datasets and machinelearned models to extract overdose information from textual notes.


application_id: 10589257
project_number: 1R01AG080589-01
project_title: APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2022-11-23
opportunity_number: PAR-22-093
application_type: 1
activity_code: R01
ic: AG
serial_number: 080589
program_official: DIBATTISTA, AMANDA
project_start_date: 2022-12-01
project_end_date: 2027-11-30
study_section: Special Emphasis Panel[ZRG1 BDCN-A (55)]
contact_pi_person_id: 11146000
contact_pi: JOHNSON, LANCE ALLEN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractIn comparison to the highly protective E2 allele of Apolipoprotein E (APOE) the E4 allele hasbeen associated with a host of detrimental effects including but not limited to increasedamyloid deposition more severe tau pathology heightened neuroinflammation cerebrovasculardysfunction and various metabolic deficits. With its strong risk profile and varied biologicalmechanisms APOE itself has emerged as an attractive candidate for gene therapy. In additionto providing a much-needed preclinical model for ongoing and future trials exploration of E4 toE2 allele switching has the potential to help answer several fundamental and longstandingbiological questions in the field. For example which ApoE-synthesizing cell-type(s) drive ADpathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associateddeficits set in stone at birth (developmentally) or is later-life APOE editing a feasible approachto mitigate AD neuropathology and cognitive dysfunction? To this end we have generated aseries of novel APOE switch (4s2) mouse models that allow for temporal and cell-specific alleleswitching from E4 to E2. Our preliminary data confirms that these 4s2 mice synthesize a full-length human ApoE4 at baseline and importantly when crossed to various inducible CreERT2strains the switch successfully leads to efficient recombination and expression of human ApoE2in cell types of interest. Given the remarkable protective effects of E2 carriage and the variousroles of ApoE at differing steps of AD pathogenesis we hypothesize that astrocyte-specificallelic switching to E2 will simultaneously rescue multiple metabolic immune andneuropathological deficits associated with E4. We propose to leverage these unique mousemodels to determine the therapeutic window for CNS-specific E4 to E2 allele switching tosimultaneously mitigate metabolic deficits neuroinflammation cerebrovascular dysfunctionamyloid pathology and cognitive dysfunction. If successful this proposal will provide anessential preclinical model for ongoing and future clinical trials and will provide critical newinformation regarding ideal cell- region- and temporally-specific opportunities for therapeuticApoE modulation.

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

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


application_id: 10588669
project_number: 1R01DA057605-01
project_title: Rapid Actionable Data for Opioid Response in Kentucky (RADOR-KY)
administering_ic: NIDA
award_notice_date: 2022-09-21
opportunity_number: RFA-DA-22-044
application_type: 1
activity_code: R01
ic: DA
serial_number: 057605
program_official: KURAMOTO-CRAWFORD, SATOKO JANET
project_start_date: 2022-09-30
project_end_date: 2025-09-29
study_section: Special Emphasis Panel[ZDA1 JRB-A (12)]
contact_pi_person_id: 12111311
contact_pi: SLAVOVA, SVETLA STEFANOVA
other_pis: TALBERT, JEFFERY C
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractOpioid use disorder (OUD) remains a persistent public health crisis and epidemic. In spite of robust nationalstate and local public health responses to the epidemic opioid overdose deaths continue to increase; of the91799 drug overdose deaths in 2020 reported by the Centers for Disease Control and Prevention (CDC) themajority 68630 (75%) involved opioids a 38% increase from 2019. The opioid overdose death burden inKentucky is even higher with a 63% increase from 2019 (n=1036) to 2020 (n=1688). In the context of thedynamically changing opioid epidemic complicated by the challenges presented by the COVID-19 pandemicagencies and organizations responsible for monitoring and improving the health of the population need timelystate and local data to make critical decisions on resource allocation and targeted responses. Such decisionsare typically related to a set of evidence-based practices (EBPs) aimed at preventing opioid overdose mortality.We will harness the infrastructure and methodological expertise at the University of Kentucky (UK) researchcenters (incl. the Kentucky Injury Prevention and Research Center the Center on Drug and Alcohol Researchand the Institute for Biomedical Informatics) along with the experience gained from our work on the HEALingCommunities Study supported by the National Institute on Drug Abuse and the Overdose Data to Actionproject sponsored by the CDC. The specific aims of this project are to establish the Rapid Actionable Data forOpioid Response in Kentucky (RADOR-KY) an integrated population-based near-real time statewidesurveillance system that will ingest data from multiple state agencies and implement advanced informaticsalgorithms for fast data processing data linkage machine learning and predictive analytics to shorten the timebetween data capture and when analytical results are available to support opioid overdose prevention andcontrol. RADOR-KY will have mobile and web-based applications to provide immediate dissemination andaccess to near-real time community or state level data reports and visual analytics to share with agencies andcommunity end-users. RADOR-KY End-user Advisory Group including partners in state government and localcommunities will guide the development of the RADOR-KY reporting and visualization functionality. RADOR-KY will establish a longitudinal dataset accessible thru the RADOR-KY portal and also shared within the HEALData Ecosystem. Programming code for implemented algorithms and web-based dashboards will be shared ina public repository to advance the efforts to mitigate the opioid epidemic across the U.S.

project_terms:
Agreement;Algorithms;Area;COVID-19 pandemic;Centers for Disease Control and Prevention (U.S.);Code;Communities;County;Data;Data Linkages;Data Reporting;Development;Environment;Epidemic;Evidence based practice;Evidence based treatment;Goals;Harm Reduction;Health;Heterogeneity;Informatics;Information Systems;Infrastructure;Intervention;Kentucky;Link;Machine Learning;Measures;Methodology;Monitor;Morbidity - disease rate;National Institute of Drug Abuse;Online Systems;Opioid;Outcome;Overdose;Persons;Pharmaceutical Preparations;Policy Maker;Population Surveillance;Predictive Analytics;Prevention;Prevention Research;Public Health;Randomized Clinical Trials;Recovery;Reporting;Research;Research Institute;Resource Allocation;Risk;State Government;Statistical Models;Stimulant;System;Thinness;Time;Universities;Visual;Visualization;Visualization software;Waiting Lists;Work;addiction;alcohol research;base;biomedical informatics;computerized data processing;dashboard;data ecosystem;data ingestion;data quality;experience;healing;improved;informatics infrastructure;injury prevention;longitudinal dataset;mortality;multiple datasets;next generation;opioid epidemic;opioid exposure;opioid mortality;opioid overdose;opioid use disorder;overdose death;overdose prevention;population based;population health;prevent;public repository;response;trend

public_health_relevance:
Project NarrativeThis project will establish the Rapid Actionable Data for Opioid Response in Kentucky (RADOR-KY) anintegrated population-based near-real time statewide surveillance system that will ingest data from multiplestate agencies and implement advanced informatics algorithms for fast data processing data linkagemachine learning and predictive analytics to shorten the time between data capture and when analyticalresults are available to support opioid overdose prevention and control. RADOR-KY End-User AdvisoryGroup including partners in state government and local communities will guide the development of thereporting and visualization functionality. RADOR-KY will establish a longitudinal dataset accessible thru theRADOR-KY portal and shared within the HEAL Data Ecosystem.


application_id: 10587797
project_number: 1R01EY032645-01A1
administering_ic: NEI
award_notice_date: 2023-02-28
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: EY
serial_number: 032645
suffix: A1
program_official: SHEN, GRACE L
project_start_date: 2023-03-01
project_end_date: 2028-02-29
study_section: Pathophysiology of Eye Disease - 1 Study Section[PED1]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: GREGG, RONALD G
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Preclinical evaluation of a homing endonuclease gene therapy for adRP in models of P23H retinopathy.

project_abstract:
Autosomal dominant Retinitis pigmentosa (adRP) is a blinding eye disease that results in loss of rods andeventually cone photoreceptors. A large fraction of adRP is caused by mutations in the rhodopsin (Rho) geneand the most common mutation in North America causes a P23H mutation in rhodopsin. Patients typicallypresent with mid- to late-stage disease when many rod photoreceptors already have degenerated.We will evaluate genome editing using a meganuclease genome editing tool (Rho1-2) that is specific for thesequence causing the P23H mutation in several preclinical animal models of P23H adRP. We will deliver AAV5-GRK1-Rho1-2 via subretinal injection to infect photoreceptors. We will measure efficacy the ability of Rho1-2 toalter rod degeneration and functional decline. We will quantitatively determine Rho1-2 efficiency the proportionof P23H alleles with insertions/delections (indels) specificity the proportion of P23H to WT alleles with indelsand its safety the absence of indels in other genes throughout the human genome (off target editing).In Pig P23H adRP models we will evaluate Rho1-2 editing efficacy because of the similarities between pigs andhumans in eye size and retinal structure and because the pig has a cone rich visual streak. We will use the samenon-invasive tools used in the clinic to measure retinal function (full field electroretinograms) and structure(spectral domain OCT). We will use two existing transgenic pig lines that harbor the entire P23H hRHO genebut differ in their time course resulting in a fast or slow loss of rods and rod function. We will match treatmenttime with the natural history of rod structural and functional decline compare Rho1-2 editing efficacy in early-mid- and late-stage P23H adRP and define its temporal treatment window. In Humanized adRP mouse modelswe will evaluate Rho1-2 editing efficiency and specificity because they contain WT and P23H human alleles inthe appropriate genomic context. In human retinal organoids we will evaluate Rho1-2 editing safety (off-targetcutting throughout the genome) because they contain human photoreceptors as well as the rest of the humangenome in a relevant context..Taken together the results of our experiments will determine if Rho1-2 should move forward for eventual use inhuman clinical trials and will define endpoints for those trials.

project_terms:
Accounting;Affect;Alleles;Animal Euthanasia;Animal Model;Animals;Behavior;Biological Models;Blindness;Canis familiaris;Cells;Clinic;Clinical;Clinical Trials;Clustered Regularly Interspaced Short Palindromic Repeats;Cone;Development;Disease;Double Strand Break Repair;Electroretinography;Engineering;Eye;Eye diseases;Family suidae;Frequencies;GRK1 gene;Gene Expression;Gene Mutation;Genes;Genome;Genomics;Goals;Homing;Human;Human Genome;Intervention;Measures;Methodology;Modality;Modeling;Morphology;Mus;Mutate;Mutation;Natural History;Night Blindness;Nonhomologous DNA End Joining;North America;Organoids;Outcome;Patient Selection;Patients;Photoreceptors;Pre-Clinical Model;Proteins;Rare Diseases;Research Personnel;Rest;Retina;Retinal Cone;Retinal Degeneration;Retinal Diseases;Retinitis Pigmentosa;Rhodopsin;Rod;Safety;Selection Criteria;Site;Specificity;Structure;Technology;Therapeutic;Time;Transgenic Organisms;Vertebrate Photoreceptors;Viral Packaging;Visual;alternative treatment;autosome;deep sequencing;efficacy evaluation;efficacy testing;endonuclease;experimental study;functional decline;gene therapy;genome editing;human model;humanized mouse;in silico;individualized medicine;insertion/deletion mutation;interest;mouse model;mutant;neglect;nonhuman primate;nuclease;off-target site;optimal treatments;porcine model;pre-clinical;preclinical evaluation;retinal rods;safety assessment;subretinal injection;timeline;tool;zinc finger nuclease

public_health_relevance:
In retinitis pigmentosa (RP) rod photoreceptors die leading to blindness. Patients typically come to the clinicwith mid/late-stage disease after many rods have died. We will test the efficacy efficiency specificity andsafety a gene therapy for this autosomal dominant orphan disease caused the P23H mutation in rhodopsin.


application_id: 10587418
project_number: 1R01HL163003-01A1
project_title: Mechanisms Contributing to Pregnancy-induced Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2022-12-15
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 163003
suffix: A1
program_official: POIZAT, CORALIE ISABELLE
project_start_date: 2022-12-15
project_end_date: 2027-11-30
study_section: Basic Biology of Blood, Heart and Vasculature Study Section [BBHV]
contact_pi_person_id: 11677367
contact_pi: COLLINS, HELEN E
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Maternal healthcare in the US continues to rank poorly in comparison to other developed countries. Maternalmortality rates in US have been increasing yearly accounting for 23.8 deaths per 100000 live births in 2020.Cardiovascular complications are the leading cause of death in pregnant and postpartum women; however littleis known regarding the underlying factors leading to this increase which has been hindered by the lack ofknowledge of how the heart responds to normal pregnancy. Despite this it is known that during pregnancy theheart adapts to meet the increased metabolic demands of maternal organs and the growing fetus. Thisadaptation is characterized by reversible cardiac growth and ventricular remodeling which sustain high cardiacoutput during the final trimester of pregnancy. Yet the molecular programs that support the coordinatedremodeling of the maternal heart during and after pregnancy remain unknown. Coordinated changes inmetabolism could be critical to pregnancy-induced cardiac remodeling as suggested by their importance in othercontexts. For example increased cardiac ketone body (KB) metabolism prevents cardiac dysfunction andremodeling in heart failure and changes in glucose metabolism regulate exercise-induced cardiac growth.Nevertheless surprisingly little is known in the context of pregnancy. This knowledge is important because itcould be leveraged to support maternal cardiac health. There is rationale to expect a link between KB metabolismand cardiac remodeling. To wit circulating fatty acids and triglycerides are higher during pregnancy; they supplyenergy to highly metabolic tissues and they are used for liver ketogenesis. Indeed circulating KBs increaseduring late pregnancy in humans and are thought to provide alternative fuel sources for the heart. Furthermoreour data indicate that the KB metabolism enzyme -hydroxybutyrate dehydrogenase 1 (Bdh1) is upregulatedin the heart early in pregnancy followed in late pregnancy by higher levels of circulating KBs and reduced cardiacglucose catabolism. These findings suggest that KB availability and the capacity of the maternal heart to oxidizeKBs are increased during pregnancy. We hypothesize that higher cardiac KB oxidation during pregnancy mayspare glucose-derived carbon for anabolic pathways to increase the abundance of glucose-derived metabolitesthat facilitate cardiac growth. In support of this idea our preliminary studies show increased glucose-derivedcarbon allocation to nucleotides glycerophospholipids and amino acids during pregnancy. In this study we willtest three aims: in Aim 1 we will determine the extent to which KB availability influences cardiac structure andfunction during pregnancy; in Aim 2 we will evaluate the impact of cardiac KB utilization on structural andmetabolic remodeling in the maternal heart; and in Aim 3 we will delineate the influence of KB metabolism onthe reversal of pregnancy-induced cardiac remodeling. Knowledge of how cardiac metabolism contributes topregnancy-induced cardiac growth will provide a framework for developing interventions to support maternalcardiac health.

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

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


application_id: 10585936
project_number: 5U01DP006632-03
administering_ic: NCCDPHP
award_notice_date: 2023-03-09
opportunity_number: RFA-DP-21-001
application_type: 5
activity_code: U01
ic: DP
serial_number: 006632
project_start_date: 2021-05-01
project_end_date: 2026-04-30
study_section: ZDP1-KVA(02)
contact_pi_person_id: 10799084
contact_pi: JEWELL, TRACEY DANIELLE
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
budget_end_date: 2024-04-30
project_title:
RFA-DP-21-001 DP006632 Kentucky Pregnancy Risk Assessment Monitoring SystemApplication for Core PRAMS funding RFA-DP-21-001


application_id: 10584131
project_number: 1R01DC020303-01A1
project_title: Perception of speech in context by listeners with healthy and impaired hearing
administering_ic: NIDCD
award_notice_date: 2022-09-21
opportunity_number: PAR-21-063
application_type: 1
activity_code: R01
ic: DC
serial_number: 020303
suffix: A1
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
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 Threshold;Auditory system;Behavioral;Bypass;Cochlear Implants;Code;Communication;Computer Models;Cues;Environment;Event;Foundations;Frequencies;Goals;Grain;Hearing Aids;Hearing problem;Impairment;Individual;Individual Differences;Intervention;Investigation;Knowledge;Lead;Link;Masks;Measures;Methods;Modeling;Nerve;Noise;Operating System;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;base;contrast enhanced;experimental study;hearing impairment;improved;insight;model design;neural model;neuroadaptation;neuromechanism;normal hearing;relating to nervous system;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: 10584022
project_number: 1R01AR081002-01A1
project_title: Muscle and physical function recovery after acute critical illness
administering_ic: NIAMS
award_notice_date: 2023-09-18
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AR
serial_number: 081002
suffix: A1
program_official: LINDHURST, MARJORIE JEAN
project_start_date: 2023-09-18
project_end_date: 2028-08-31
study_section: Musculoskeletal Rehabilitation Sciences Study Section[MRS]
contact_pi_person_id: 1884084
contact_pi: DUPONT-VERSTEEGDEN, ESTHER E
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:
Many patients who survive critical illness including sepsis and acute respiratory failure have arduousrecoveries plagued by an inability to recover muscle and physical function after hospital discharge resulting inlower quality of life inability to return to work and disability. The number of patients surviving critical illnesses inthe United States continues to rise each year and therefore it is critically important to develop interventions thatwill support their recovery. Clinical and muscle cellular factors driving skeletal muscle dysfunction are relativelyunknown after an acute critical illness but are necessary to inform intervention development. We will addressthis knowledge gap by studying myofibrillar and collagen protein turnover cellular signaling pathways andmarkers of damage inflammation and immune response in the first year of recovery. The unique aspect of thisproposal is the serial intra-patient muscle tissue sampling paired with simultaneously obtained clinicalfunctional parameters over the first year of recovery post hospital discharge. Physical function and quality oflife outcomes will be assessed to understand why some patients recover muscle function yet others developsevere disability. The overall goal of this clinical observational study is to elucidate the cellular environmentand the patients clinical characteristics contributing to failed muscle recovery and physical disability insurvivors of critical illness. Our central hypothesis is that alterations in myofibrillar mitochondrial and collagenprotein homeostasis are underlying muscle and physical dysfunction in patients surviving critical illness. In Aim1 we will identify trajectory of recovery for muscle strength and power as well as physical function in patientssurviving ICU-related critical illness including pneumonia sepsis and COVID-19 etiologies. We hypothesizethat patients with a higher initial severity of illness will show poor recovery of muscle strength and physicalfunction during the first year of recovery. In Aim 2 we will determine mechanisms of skeletal muscledeficiencies contributing to disparate recovery in patients surviving ICU-related COVID-19 or other acute lunginjury etiologies. We hypothesize that patients with longer ICU durations will show poor recovery of muscle sizeand increased collagen deposition during the first year of recovery. In addition we hypothesize that patientswith persistent weakness and fatigue have prolonged impairments in mitochondrial function compared topatients who recover their muscle function. Finally we hypothesize that patients with long-term disability havean inability to recover muscle function due to a cellular environment of that is not permissive to a positiveprotein balance. We will use stable isotope mass spectroscopy measurements of muscle biopsies to determinesynthesis of myofibrillar mitochondrial and collagen protein. Findings from this study will inform why somepatients develop persistent disability and others gradually improve. The results from this research will guidefuture development of therapeutic interventions that are specific to skeletal muscle deficits with considerationfor patient related factors such as age and co-morbid burden.

project_terms:
Acceleration;Acute;Acute Lung Injury;Acute Respiratory Distress Syndrome;Acute respiratory failure;Adult;Age;Area;Attention;Automobile Driving;Awareness;Biopsy;COVID-19;Cells;Characteristics;Clinical;Collagen;Communities;Critical Illness;Data;Deposition;Deuterium Oxide;Development;Disabled Persons;Disparate;Environment;Equilibrium;Etiology;Extracellular Matrix;Fatigue;Fibrosis;Functional disorder;Future;Goals;Growth;Hospitalization;Hospitals;Immune;Immune response;Impairment;Inflammation;Inflammatory;Influenza;Intensive Care Units;Intervention;Knowledge;Label;Mass Spectrum Analysis;Measurement;Measures;Metabolic;Mission;Mitochondria;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Muscle satellite cell;National Institute of Arthritis and Musculoskeletal and Skin Diseases;Observational Study;Outcome;Patients;Pattern;Pharmacological Treatment;Phenotype;Physical Function;Pneumonia;Proteins;Quality of life;Recovery;Recovery of Function;Rehabilitation therapy;Research;Research Project Grants;Respiration;Sepsis;Severity of illness;Signal Pathway;Skeletal Muscle;Survivors;Therapeutic Intervention;Time;Tissue Sample;Tissues;United States;Work;comorbidity;disability;evidence base;improved;interest;muscle strength;nutrition;participant enrollment;patient subsets;pharmacologic;physically handicapped;predictive modeling;protein biomarkers;protein degradation;proteostasis;response;sepsis induced ARDS;skeletal muscle wasting;stable isotope;therapeutic development;therapy development

public_health_relevance:
Patients who survive an acute critical illness including sepsis COVID-19 influenza and acute respiratorydistress syndrome often develop physical disability that can persist for years after hospital discharge. Theplanned proposal will determine cellular and clinical parameters responsible for the reduced or inability torecover muscle and physical function after critical illness. The findings of this study will inform the developmentof future therapeutic interventions that mitigate long-term impairments and stimulate muscle and physicalrecovery after critical illness.


application_id: 10583861
project_number: 1R01MH129357-01A1
project_title: Anxiety and Interoception Risk for Eating Disorders in Childhood
administering_ic: NIMH
award_notice_date: 2023-09-04
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: MH
serial_number: 129357
suffix: A1
program_official: THOMAS, LAURA ANDERSON
project_start_date: 2023-09-15
project_end_date: 2028-08-31
study_section: Child Psychopathology and Developmental Disabilities Study Section[CPDD]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: BUFFERD, SARA J
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
project_terms:
12 year old;Adolescence;Adolescent;Age;Age of Onset;Anxiety;Anxiety Disorders;Behavior;Behavioral;Body Size;Brain;Cessation of life;Characteristics;Child;Childhood;Chronic;Clinical;Cognition;Cognition Disorders;Cognitive;Control Groups;Data;Development;Diagnosis;Diagnostic;Down Syndrome;Early Diagnosis;Early Intervention;Early identification;Eating;Eating Behavior;Eating Disorders;Esthesia;Etiology;Exhibits;Extinction;Family;Fasting;Female;Fright;Goals;Health;High Prevalence;Hyperphagia;Hypersensitivity;Impairment;Individual;Interoception;Knowledge;Lead;Learning;Link;Literature;Malignant Neoplasms;Mental Depression;Mental disorders;National Institute of Mental Health;Non-Insulin-Dependent Diabetes Mellitus;Occupations;Onset of illness;Parents;Pathology;Physiological;Population;Predisposing Factor;Prevention;Prevention program;Recording of previous events;Reporting;Research;Risk;Risk Factors;Sampling;Societies;Sudden infant death syndrome;Symptoms;Testing;Time;Traction;United States;Work;Youth;bodily sensation;body dissatisfaction;childhood anxiety;cohort;cost;design;dieting;early adolescence;early childhood;early onset;experience;follow-up;gastrointestinal system;girls;high risk;improved;innovation;insight;maternal anxiety;mortality;multimodality;negative affect;novel;opioid use;prospective;public health relevance;recruit;restraint;social anxiety;societal costs;standard care;theories;tool


application_id: 10583576
project_number: 5R01HL150581-03
project_title: Epidural spinal cord stimulation and respiratory motor function after injury
administering_ic: NHLBI
award_notice_date: 2023-05-10
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: HL
serial_number: 150581
program_official: NATARAJAN, ARUNA R
project_start_date: 2021-05-01
project_end_date: 2026-02-28
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9348839
contact_pi: OVECHKIN, ALEXANDER VLADIMIROVICH
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractRespiratory motor control deficit is the leading cause of morbidity and mortality in patients with spinal cordinjury. The long-term goal of this research is to develop a rehabilitation strategy for respiration in patients withspinal cord injury as a standard of care. Our previous findings demonstrate that respiratory function in patientswith chronic spinal cord injury can be improved by using our original inspiratory-expiratory pressure thresholdrespiratory training protocol. However the effectiveness of this intervention is limited by the levels of functionalcapacity preserved below the neurological level of injury. Our preliminary data obtained for this proposaldemonstrate that electrical spinal cord stimulation applied epidurally at the lumbar level in combination withrespiratory can activate and re-organize spinal motor networks for respiration. We propose to investigaterespiratory motor control-related responses to epidural spinal cord stimulation alone and in combination withrespiratory training. By characterization of respiratory muscle activation patterns using surfaceelectromyography in association with pulmonary functional and related cardiovascular measures we expect todetermine specific stimulation parameters needed to increase spinal excitability below level of injury toenhance responses to the input from supraspinal centers that remain after injury and to promote the neuralplasticity driven by the respiratory training. This hypothesis will be tested by pursuing two specific aims: 1)Evaluate the acute effects of epidural spinal cord stimulation on respiratory functional and motor controlproperties; and 2) Evaluate the effectiveness of epidural spinal cord stimulation combined with respiratorytraining.

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

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


application_id: 10583442
project_number: 261201800013I-P00006-26100001-2
project_title: SEER CORE INFRASTRUCTURE SUPPORT
administering_ic: NCI
project_start_date: 2018-05-01
project_end_date: 2022-04-30
contact_pi_person_id: 78147083
contact_pi: DURBIN, ERIC
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
funding_mechanism: R and D Contracts
project_terms:
Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Pattern;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;trend


application_id: 10582198
project_number: 3P20GM113226-07S1
project_title: Freezer Supplement to Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2022-08-10
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 113226
suffix: S1
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1(C2)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Alcoholic Liver Diseases;Area;Basic Science;Biomedical Research;Centers of Research Excellence;Cirrhosis;Collaborations;Development;Ensure;Freezing;Funding;Grant;Hepatitis B;Hepatitis C;Injury;Laboratories;Link;Liver;Liver Failure;Liver diseases;Mentors;Metabolic syndrome;Molecular Target;Pharmaceutical Preparations;Phase;Prevention;Primary carcinoma of the liver cells;Program Sustainability;Publications;Research;Research Infrastructure;Research Personnel;Resources;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translational Research;Universities;career development;clinical practice;drug induced liver injury;education research;experience;liver injury;member;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;personalized medicine;prevent;programs;success


application_id: 10582129
project_number: 3P30GM127607-05S1
administering_ic: NIGMS
award_notice_date: 2022-08-03
opportunity_number: PA-20-272
application_type: 3
activity_code: P30
ic: GM
serial_number: 127607
suffix: S1
program_official: ZHOU, YANG
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1(C3)
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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_title:
Supplement to Center for Excellence in Diabetes and Obesity Research: Implementing Biomechanics Instrumentation in the Diabetes and Obesity Center

project_abstract:
AbstractThe parent COBRE award (P30 GM127607) focuses on the metabolic mechanisms of cardiovascular disease.The current objectives of the Center are to support molecular cellular and translational investigations into thecardiovascular causes and consequences of derangements in metabolismnotably those associated withdiabetes and obesity. This thematic focus facilitates the sharing of both resources and expertise and promotesthe development of multi-disciplinary research projects that have contributed to the long-term stability of theCenter. To support the research activities of its investigators particularly our ESI members the Center hascreated and sustained (for nearly 15 years) key core facilities which include flow cytometry imaging andpathology surgical models cardiovascular function and immunometabolic-focused mass spectrometry. Hencethe Center is uniquely positioned to establish new paradigms in cardiometabolic health while nurturing thedevelopment of ESI/NI faculty. Heart failure and ventricular remodeling are the most used models in the Center.These models involve significant biomechanical changes to the myocardium; however there is no suitablesystem on the Health Sciences Center Campus to interrogate such changes in biomechanics. The requestedinstrument is relevant and allocable to this parent COBRE award. This supplement request outlines the Centersneed for a Bruker JPK NanoWizard 4 XP AFM (atomic force microscope). This state-of-the-art system features30 pm noise resolution in the z-axis and 90 pm in the xy-axes simultaneous fluorescence/diascopic lightmicroscopy with image overlay high speed signal capture user programmable software (ideal for imagingfacilities with multiple users) and compatibility with the Centers existing Nikon A1 confocal microscope. Thesefeatures and many others will serve well the users in the COBRE-funded Center but also in other Centers andDepartments across campuswhere currently no atomic force microscopy system exists. The requested systemwill address significant unmet needs of investigators within the Center and elsewhere on campus. The Centerwill leverage existing infrastructure and install the new system in dedicated space. The system will be managedby an experienced team. Robust institutional support will be provided to assure effective and efficient operationof this system in the Center. Given the nearly nonexistent costs of operation the lifetime support for softwareupgrades and the relative simplicity of the system this instrument will be self-sustainable after installation.Hence the Bruker JPK NanoWizard 4 XP AFM will create both immediate and sustained impacts on the scienceperformed both within the Center and in other laboratories across the Health Sciences Center Campus. Thissystem will also be available for other qualified users particularly those within the larger IDeA-funded KY-INBREnetwork in the Commonwealth of Kentucky.

project_terms:
10 year old;Address;Administrative Supplement;Area;Atomic Force Microscopy;Award;Biocompatible Materials;Biomechanics;Biomedical Research;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cells;Centers of Research Excellence;Cicatrix;Computer software;Core Facility;Data;Deposition;Development;Diabetes Mellitus;Elasticity;Environment;Faculty;Fees;Fibroblasts;Flow Cytometry;Fluorescence;Fresh Tissue;Funding;Future;Goals;Grant;Growth;Health;Health Sciences;Heart;Heart failure;Image;Individual;Infrastructure;Interdisciplinary Study;Investigation;Kentucky;Laboratories;Mass Spectrum Analysis;Metabolic;Metabolism;Microscope;Modeling;Modernization;Molecular;Myocardium;Noise;Obesity;Parents;Pathology;Positioning Attribute;Process;Research;Research Activity;Research Personnel;Research Project Grants;Research Support;Resolution;Resources;Scanning Probe Microscopes;Science;Services;Signal Transduction;Speed;Surgical Models;Surveys;System;Technology;Training;United States National Institutes of Health;Vendor;Ventricular Remodeling;base;cardiometabolism;cardiovascular health;cost;experience;flexibility;imaging facilities;instrument;instrumentation;interest;light microscopy;materials science;member;operation;programs;ranpirnase;success;sustainable resource;time use;user-friendly;wound healing

public_health_relevance:
NarrativeThis supplement supports the purchase installation and training for an atomic force microscopy system. Thissystem enables users to interrogate biomechanics of biologic materials including hearts vasculature cells andrelated biomaterials. Because this will be the only atomic force microscope on campus the impact will spanmulti-COBRE/INBRE awards.


application_id: 10582060
project_number: 3P20GM130456-03S1
project_title: Administrative Supplement: COBRE in Pharmaceutical Research and Innovation
administering_ic: NIGMS
award_notice_date: 2022-06-20
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 130456
suffix: S1
program_official: FRINCU, CRINA
project_start_date: 2020-03-01
project_end_date: 2025-01-31
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY/ABSTRACT OF FUNDED PARENT AWARD (P20 GM130456)The Center of Biomedical Research Excellence in Pharmaceutical Research and Innovation (CPRI) at theUniversity of Kentucky (UK) is a comprehensive multidisciplinary center focused on translational chemicalbiology [the nexus of chemical biology (the application of chemical biology principles to develop validatedprobe/models to advance our understanding of biology) and pharmaceutical science (the application ofpharmaceutical principles to advance leads/materials/devices that address unmet clinical needs)]. This Phase ICOBRE leverages and develops unique translational chemical biology research support infrastructure/expertiseto facilitate junior faculty mentorship and career development innovative biomedical researchprobe/tool/model/materials development and validation and the early advancement of potential translatableassets. Key COBRE infrastructure to be developed and implemented in Phase I includes the CPRI AdministrativeCore and two research support cores (the Translational Core and the Computational Core) and the COBRE willalso further develop and leverage the COBRE for Molecular Medicines Organic Synthesis Core to support CPRIjunior faculty projects/pilots. CPRI currently supports four outstanding junior investigators working in threetherapeutic areas (cancer infectious disease and tissue/bone regeneration). Our overarching hypothesis is that CPRIs translational chemical biology focus presents a distinctly uniqueUK platform to: i) engage integrate and mentor junior faculty from a broad range of fundamental applied andclinical disciplines; ii) facilitate the development of new impactful probes/tools/models and advance innovativetransdisciplinary research; and iii) bridge the gap between basic academic research discoveries andcommercial/clinical application via education mentorship and key support infrastructure. CPRIs distinct focuson translational chemical biology and early translation fills a notable preclinical research gap for many of UKsexceptional research centers strategically focused on understanding treating and preventing the major diseasesthat contribute to Kentuckys disproportionate health challenges. Anticipated COBRE outcomes include anincrease in the number and diversity of UK junior faculty engaged in translational chemical biology research andbetter-prepared to develop and employ innovative biomedical probes/tools/models/materials new sustainableUK translational chemical biology research support infrastructure and capabilities an increase in the number ofUK junior faculty with independent research funding and a boost in the number potentially translatable UKpreclinical assets.

project_terms:
Address;Administrative Supplement;Area;Award;Biology;Biomedical Research;Bone Regeneration;Bone Tissue;Cardiovascular Diseases;Centers of Research Excellence;Chemicals;Clinical;Collaborations;Communicable Diseases;Communication;Core Facility;Development;Devices;Discipline;Disease;Education;Environment;Faculty;Fostering;Funding;Goals;Health;Infrastructure;Kentucky;Malignant Neoplasms;Mentors;Mentorship;Modeling;Molecular Medicine;Organic Synthesis;Outcome;Parents;Pharmacologic Substance;Pharmacy facility;Phase;Pilot Projects;Research;Research Personnel;Research Project Grants;Research Support;Science;Scientist;Testing;Therapeutic;Translational Research;Translations;Universities;Validation;career development;clinical application;college;experience;faculty research;innovation;interdisciplinary collaboration;interest;multidisciplinary;pre-clinical;pre-clinical research;prevent;tool

public_health_relevance:
PROJECT NARRATIVE OF FUNDED PARENT AWARD (P20 GM130456)The University of Kentucky (UK) Center of Biomedical Research Excellence (COBRE) in PharmaceuticalResearch and Innovation (CPRI) will serve as a unique comprehensive translational chemical biology center.The center will support junior faculty career development advance impactful chemical biology andpharmaceutical science research/tools and stimulate transdisciplinary collaboration research innovation andearly preclinical translational research.


application_id: 10582037
project_number: 3R35GM131807-03S1
project_title: Hedgehog Signaling in Development and Metabolism
administering_ic: NIGMS
award_notice_date: 2022-06-29
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: 2024-08-31
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
arra_indicator: N
project_abstract:
Abstract:The existing MIRA R35 is supporting the research in our laboratory. We focus on the Hedgehog (Hh) signalingpathway that plays critical roles in pattern formation and cell growth control and is also involved in metaboliccontrol. While many components in the Hh pathway have been identified how the Hh signal is transducedthrough the 12-span transmembrane protein Patched (Ptc) to the 7-span transmembrane protein Smoothenedis still unclear. The overarching goal of our research program is to understand how Hh signals are sensed andtransmitted to control downstream biological events that ultimately govern cell growth and patterning. Drosophilafat body and oenocyte have emerged as attractive models to study lipid metabolism and circulation. Publishedand preliminary findings in these models have indicated that lipid accumulation is regulated by highly conservedsignaling pathways and that Hh signaling controls not only lipogenesis but also lipolysis by regulating specificgenes. These studies provide new tools and hypotheses for investigating the mechanisms of Smo signaling andthe role of Hh/Smo signaling in regulating lipid metabolism which relevance to such cancers as basal cellcarcinoma and medulloblastoma. This administrative supplemental application to acquire a higher qualityconfocal system as an add-on to the existing microscope platform will foster the ongoing experiments in thisresearch program. The advanced scanning capacities in addition to the higher resolution the new confocalsystem will significantly improve the quality of the imaging analysis to examine Hh signaling in lipid metabolicregulation in the fat body and dramatically enhance our ability to examine how localization of lipids and/orcholesterol regulates Smo abundance in metabolic tissues such as the fat body.

project_terms:
Administrative Supplement;Area;Basal cell carcinoma;Biological;Blood Circulation;Cholesterol;Development;Drosophila genus;Embryonic Development;Erinaceidae;Event;Fat Body;Fostering;G-Protein-Coupled Receptors;Genes;Genetic Transcription;Goals;Image;Insecta;Integral Membrane Protein;Investigation;Laboratories;Lipids;Lipolysis;Malignant Neoplasms;Mammals;Metabolic;Metabolic Control;Metabolic Diseases;Metabolism;Microscope;Modeling;Mutation;Na(+)-K(+)-Exchanging ATPase;Obesity;Pathway interactions;Pattern;Pattern Formation;Play;Process;Protein Family;Proteins;Publishing;Regulation;Research;Research Support;Resolution;Role;Scanning;Signal Pathway;Signal Transduction;System;Tissues;cancer type;cell growth;experimental study;hedgehog signal transduction;human disease;improved;insight;lipid biosynthesis;lipid metabolism;medulloblastoma;novel;patched protein;programs;public health relevance;smoothened signaling pathway;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCEHedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation anddifferentiation during embryogenesis. Mutations in Smoothened (Smo) a critical protein in the signal receptionsystem results in human diseases such as basal cell carcinoma and medulloblastoma. Investigation of how Hhand Smo signaling regulates lipid metabolism and how Smo is regulated by cholesterol will provide insights intodevelopmental problems and create novel concepts of Hh signaling in cancer obesity and metabolic diseases.


application_id: 10580946
project_number: 3P42ES007380-24S1
project_title: KC Donnelly Externship Admin Supplement for Francisco Leniz P42ES007380 UKSRC
administering_ic: NIEHS
award_notice_date: 2022-08-09
opportunity_number: PA-20-272
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S1
program_official: HENRY, HEATHER F
project_start_date: 1997-04-07
project_end_date: 2023-01-31
study_section: ZES1(SF)
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
KC Donnelly Abstract for Francisco Leniz PD/PI: Kelly PennellAbstractThe challenge of providing drinkable water to the world population and its close relation to the need ofpurifying natural water from contaminants has been present throughout the history of the humankind. Aspart of the Project 3 at the UKSRC Responsive Membranes and Advanced Materials for Sensing andRemediation of Halo-organics we have been working on the development of multifunctional materialstoward the increase of separation rates more energy efficient and portable technologies. Per- andpolyfluoroalkyl substances (PFAS) were our case of study in our previous manuscript. Bringing togetherProject 3 at the UKSRC and Project 4 from MEMCARE at Yale University Designing the nextgeneration of highly selective sorbents for water remediation means merging teams' efforts with acommon goal the remediation of water for the society. Recently Project 4 from MEMCARE has focusedon developing selective adsorbents for the separation of Arsenic in water from non-contaminantcompetitors. Our knowledge on synthesis of multifunctional platform can provide intriguing opportunitiesfor the integration of these adsorbents. Overall this experience will expand my understanding ofseparation technologies and the transport mechanisms of solutes through these for the application of abroader range of contaminants in water from organic to inorganic anions. The pore-functionalizedadsorptive nanofiltration membranes with the integration of highly selective adsorbents is hypothesizedto bring new high separation rates in a more compact fashion which can benefit people and communitiesby easing the portability of this technology.

project_terms:
Anions;Arsenic;Case Study;Characteristics;Communities;Development;Excision;Goals;Ions;Knowledge;Lanthanoid Series Elements;Lead;Learning;Manuscripts;Membrane;Persons;Poly-fluoroalkyl substances;Polymers;Population;Process;Property;Recording of previous events;Research;Research Project Grants;Selenium;Societies;Technology;Testing;Universities;Water;Water Pollutants;Work;contaminated water;design;experience;externship;improved;innovative technologies;inorganic phosphate;next generation;portability;remediation;solute;water treatment

public_health_relevance:
KC Donnelly for Francisco Leniz PD/PI: Kelly PennellProject DescriptionThe research project I would be performing during the KC Donnelly externship would be focusing on thedevelopment of a selective and compact polymeric platform for the use in separation of arsenic and otherinorganic pollutants from water. This platform is meant to be both an extension and an improved versionof my previous work that was about the synthesis of dual-functional adsorptive nanofiltration (NF)membranes as an innovative technology for the separation of per- and polyfluoroalkyl substances(PFAS) from water. This last work was performed within the Project 3 of the UKSRC. Dr. Zimmerman'sgroup from Project 4 from MEMCARE at Yale University has recently studied selective platforms toseparate arsenic and selenium from water avoiding non-contaminant adsorbing competitors such asphosphate. Combining both groups' efforts for the remediation of contaminated water using selective andmultifunctional separation platforms has the potential of creating a breakthrough in terms of separationtechnologies for the treatment of water contaminated with ionic species. Specifically I will be learningabout the separation technologies and the current challenges for separating arsenic from water as wellas learning from the technological advancements from Dr. Zimmerman's group. These last would leadme to the synthesis of a properly designed selective and compact separation platform for the removal ofarsenic from water. The benefits of this platform will be further investigated as well as the potential ofthis technology to be functionalized with different properties to expand its application to the removal ofother ionic pollutants from water.


application_id: 10580596
project_number: 5F31DK131920-02
project_title: High fat diet-induced adrenergic dysfunction and resolution of adipose inflammation
administering_ic: NIDDK
award_notice_date: 2023-03-21
opportunity_number: PA-21-052
application_type: 5
activity_code: F31
ic: DK
serial_number: 131920
program_official: BODDIE, THOMAS ARTIS
project_start_date: 2022-04-01
project_end_date: 2024-08-31
study_section: ZDK1-GRB-2(J1)L
contact_pi_person_id: 14522014
contact_pi: PENA CALDERIN, ERNESTO HECTOR
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Excess nutrient consumption promotes systemic and tissue-specific inflammatory responses inhibiting insulinreceptor signaling pathways and prevents glucose uptake. Although specific molecular and cellular mechanismsthat lead to the development of insulin resistance remain unclear chronic inflammation is central to obesity-induced T2D. Diet-induced adipose tissue (AT) expansion with infiltration of classically activated macrophagesand production of pro-inflammatory cytokines perpetuates chronic inflammation and insulin resistance.Therapeutic approaches that directly interrupt innate immune responses are problematic however as they couldlead to immunosuppression and thus have limited therapeutic applicability. We have shown that persistentinflammation in diabetes and obesity is due to a deficiency in the processes that normally resolve inflammation.Nonetheless mechanisms by which obesity induces perturbations in pro-resolving pathways and promote thedevelopment of unmitigated chronic inflammation remains undefined. Physical inactivity contributes to increasedadiposity markers of inflammation chronic disease and premature death while physical activity protects againstthe development of obesity and chronic inflammation independent of reductions in weight. Cellular mechanismsby which physical activity protects against chronic inflammation however remain largely unknown. Recent workhas shown that resolution of inflammation is mediated in part by enzymatic (15-12- 5-lipoxygenase andcyclooxygenases) conversion of polyunsaturated fatty acids into specialized proresolving lipid mediators (SPMs;e.g. resolvins lipoxins maresins and protectins) that act to quell inflammatory signaling. Importantly our laband others have also shown that obese-diabetic mice treated with SPMs display elevated alternatively activatedmacrophages with reduced AT inflammation improved insulin sensitivity and enhanced wound healing capacity.Additionally our lab has shown that high fat diet-induced insulin resistance develops due to elevated pro-inflammatory lipid mediator leukotriene B4 (LTB4) production and that BLT-1 (LTB4 receptor) deficient mice areprotected against diet-induced insulin resistance a paradigm that also persists in atherosclerotic lesions. Thesefindings suggest that imbalanced production of pro-inflammatory and proresolving lipid mediators contribute toobesity-induced insulin resistance. Our preliminary data show that exercise increases AT SPM biosynthesis andis inhibited by short duration high fat diet (HFD) feeding. We also find that HFD inhibits exercise-inducedalternatively activated adipose tissue macrophages (ATM) levels. Interestingly adrenal gland expression ofbiosynthetic enzymes and catecholamine levelswhich our lab has previously shown to stimulate SPMbiosynthesis in macrophagesare reduced following HFD feeding. Thus we hypothesize that HFD-inducedadrenergic dysfunction inhibits the proresolving response to exercise in AT. In pursuit of the scientific questionsherein I will hone my basic laboratory skills learn advanced techniques develop professional skills and networkall of which will propel me towards achieving my goal of becoming an independent investigator in academia.

project_terms:
Academia;Adipocytes;Adipose tissue;Adrenal Glands;Adrenergic Agents;Adrenergic Receptor;Anabolism;Animals;Arachidonate 5-Lipoxygenase;Arterial Fatty Streak;CD59 Antigen;Catecholamines;Cells;Cessation of life;Chronic;Chronic Disease;Consumption;Crowns;Data;Development;Diabetes Mellitus;Diabetic mouse;Diet;Enzymes;Exercise;Functional disorder;Glucose;Goals;High Fat Diet;Immune;Immunohistochemistry;Immunosuppression;Individual;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Insulin Receptor;Insulin Resistance;Interruption;Knowledge;LTB4R gene;Laboratories;Learning;Leukotriene B4;Lipoxins;Macrophage;Macrophage Activation;Measures;Mediating;Metabolism;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Pathway interactions;Phenotype;Physical activity;Polyunsaturated Fatty Acids;Process;Production;Prostaglandin-Endoperoxide Synthase;RNA Interference;Research Personnel;Resistance development;Resolution;Signal Pathway;Signal Transduction;Sorting;Structure;Techniques;Testing;Therapeutic;Tissue Expansion;Tissues;Weight;Work;cardiorespiratory fitness;cytokine;diet and exercise;feeding;glucose uptake;improved;inflammatory marker;insight;insulin sensitivity;lipid mediator;lipidomics;magnetic beads;obesity development;physical inactivity;premature;prevent;receptor expression;response;sedentary;skills;systemic inflammatory response;wound healing

public_health_relevance:
PROJECT NARRATIVEChronic inflammation is a central feature in the development of obesity-induced insulin resistance and type 2diabetes. Although physical activity protects against adiposity and chronic inflammation the cellular mechanismsremain undefined. We will assess how exercise and diet contribute to the development of adipose tissueinflammation and diet-induced insulin resistance.


application_id: 10580145
project_number: 1R15AI174177-01
project_title: Genetic Analyses of bacteremia non-typhoidal Salmonella
administering_ic: NIAID
award_notice_date: 2022-11-29
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: AI
serial_number: 174177
program_official: ALEXANDER, WILLIAM A
project_start_date: 2022-12-01
project_end_date: 2025-11-30
study_section: Special Emphasis Panel[ZRG1 AIDC-D (80)]
contact_pi_person_id: 2147829
contact_pi: WORLEY, MICAH
other_pis: Not Applicable
congressional_district: 03
department: BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary There are at least 3.4 million cases of bacteremia with invasive non-typhoidal Salmonellaper year that result in 680000 deaths1. Despite its significant cost on human health with a 20%fatality rate bacteremia caused by this pathogen is poorly understood. One important class ofvirulence factors is ones that are anti-inflammatory. Traditionally such genes were thought topromote virulence by attenuating anti-microbial mechanisms such as intracellular killing and theinduction of apoptosis. My undergraduates surprisingly discovered that one of dozens of sucheffectors SpvC is instead required for extraintestinal dissemination by interdicting the host'sability to control the movement of infected phagocytes. They developed an in vitro cell c0-cultureassay that models the traversal of the blood vascular endothelium by phagocytes in the basal toapical direction that before their work had only been observed with uninfected cells a processthat immunologists refer to as reverse transmigration. The long-term goal of this work is todevelop new therapeutic intervention strategies for compartmentalizing infections therebygreatly reducing their chance of lethality. The short-term objective of this work is to characterizehow microbial and host factors regulate the extraintestinal dissemination of invasive non-typhoidal Salmonella. In the first aim with two in vitro models we will test a detailed molecularmechanism that accounts for the ability of SpvC to promote movement. In the second aim wequantify how much each of the known pathways of extraintestinal dissemination contribute tosystemic disease and assess the role of SpvC in each. We hypothesize that the phosphothreoninelyase activity of SpvC deactivates three MAPK kinases to down regulate the host cytokine MIFwhich normally potently inhibits phagocyte movement. We will test if this prevents Salmonellafrom disseminating through both the lymphatic system and the reverse transmigration pathways.

project_terms:
Anti-Inflammatory Agents;Antibiotics;Apical;Attenuated;Bacteremia;Biological Assay;Blood;Blood Circulation;Cells;Cessation of life;Chemotaxis;Circulation;Clinical;Dendritic Cells;Disease;Effectiveness;Endothelium;Fatality rate;Gastrointestinal tract structure;Genes;Goals;Health;Homologous Gene;Human;Immunologist;In Vitro;Induction of Apoptosis;Infection;Inflammation;Inflammatory;Inflammatory Response;Inhibition of Apoptosis;Innate Immune System;Integration Host Factors;Intervention;Intestines;Invaded;Lethal Genes;Life;Link;Lyase;Lymphatic Endothelium;Lymphatic System;MAPK8 gene;Mentors;Microbe;Migration Assay;Migration Inhibitory Factor;Mitogen-Activated Protein Kinase Kinases;Modeling;Molecular;Movement;Multi-Drug Resistance;Mus;Operon;Pathway interactions;Persons;Phagocytes;Phosphothreonine;Physiological;Process;Property;Publications;Reporting;Role;Route;Salmonella;Sepsis;Signal Pathway;Signal Transduction;Site;Students;Systemic disease;Talents;Testing;Vascular Endothelium;Virulence;Virulence Factors;Work;antimicrobial;cost;cytokine;enteric pathogen;experimental study;genetic analysis;in vitro Assay;in vitro Model;in vivo;lymphatic vessel;member;microbial;microbicide;migration;monolayer;non-typhoidal Salmonella;novel therapeutic intervention;p38 Mitogen Activated Protein Kinase;pathogen;prevent;resistant strain;undergraduate student

public_health_relevance:
Narrative It is unfortunate that the routes of extraintestinal dissemination available toenteropathogens are not clear as bloodstream infections with such microbes are responsible formillions of deaths per year. Here we will dissect what the various pathways including the newestmember reverse transmigration contribute to bloodstream infections with non-typhoidalSalmonella which kills 680000 people per year. Specifically we will clarify the role of an anti-inflammatory effector that may attenuate virulence by manipulating the movement of infectedhost cells rather than their microbicidal activities.


application_id: 10580042
project_number: 5R01AI168475-02
administering_ic: NIAID
award_notice_date: 2023-01-18
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AI
serial_number: 168475
program_official: CONNOLLY, KRISTIE LEE
project_start_date: 2022-02-25
project_end_date: 2027-01-31
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 10797120
contact_pi: FRIEBOES, HERMANN
other_pis: LEWIS, AMANDA L.
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-02-01
project_title:
3D-bioprinting  of sustained- and phased-release antibiotic and probiotic scaffolds to treat bacterial vaginosis

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

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

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


application_id: 10579909
project_number: 5R01AG068055-03
project_title: Identifying Associations between Brain Iron Neurocognitive Networks and Protective Factors
administering_ic: NIA
award_notice_date: 2023-03-09
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AG
serial_number: 068055
program_official: WAGSTER, MOLLY V
project_start_date: 2021-05-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1-BDCN-L(02)M]
contact_pi_person_id: 7993908
contact_pi: GOLD, BRIAN TIMOTHY
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Identifying Associations between Brain Iron Neurocognitive Networks andProtective FactorsAlzheimers disease (AD) involves accumulation of pathological levels of amyloid-beta (A)and phospho-tau proteins. However a significant proportion of individuals with AD pathologydo not have clinical AD indicating contributions of other factors. Novel in-vivo measures arerequired to track other factors contributing to AD-related cognitive declines. Increasingevidence suggests that age-related accumulation of brain iron and its correlates contribute tothe manifestation of memory declines. Our recent neuroimaging results suggest that highbrain iron concentration measured with in vivo quantitative susceptibility mapping (QSM) isassociated poor connectivity within brain memory networks. This proposal seeks to identifyassociations between QSM-based iron concentration and neurocognitive changes toward agoal of improving AD biomarkers. We will also define the interplay between QSM-based ironsignal AD pathology inflammatory markers on cognitive declines. Finally we will test thepossibility that brain iron accumulation may be slowed by an antioxidant rich diet. Wepropose to study 140 healthy older adults using neuroimaging measures including fMRI andQSM measures of CSF and plasma A p-tau and t-tau and inflammatory markers.Additional structural neuroimaging measures will include regional volumes FLAIR imagingfor quantification of WMH volumes and diffusion tensor imaging for quantification ofregionally distributed white matter connectivity. A subset of participants will be complete thesame CSF and imaging measures approximately 3 years later. We aim to identify (1) effectsof QSM-based iron signal on functional and structural brain networks supporting cognition;(2) associations between brain iron inflammatory markers AD pathology and cognitivedeclines and; (3) modifiers of brain iron or its effects on cognition. We will test hypothesesthat high QSM-based brain iron is associated with low connectivity in memory circuitsindependently of AD pathology but may and synergistically interacts with AD over time. Wewill also test the hypothesis that reserve factors will offset the effects of brain iron oncognitive functions via mechanisms of brain maintenance or plastic functional brainreorganization of large-scale brain functional networks in some older adults.

project_terms:
Affect;Alzheimer's Disease;Alzheimer's disease pathology;Alzheimer's disease risk;Alzheimers disease biomarker;American;Amyloid beta-Protein;Antioxidants;Attenuated;Biological Markers;Brain;Cerebrospinal Fluid;Cerebrum;Clinical;Cognition;Cognitive;Cognitive aging;Compensation;Diet;Diffusion Magnetic Resonance Imaging;Disease Progression;Early Diagnosis;Early Intervention;Early identification;Elderly;Episodic memory;Functional Magnetic Resonance Imaging;Goals;Health;Image;Impaired cognition;Individual;Intake;Iron;Linear Regressions;Liquid substance;MRI Scans;Magnetic Resonance Imaging;Maintenance;Maps;Measures;Mediating;Memory;Memory Loss;Modeling;Neurocognitive;Neurocognitive Deficit;Neuropsychology;Participant;Pathologic;Pathology;Pattern;Performance;Plasma;Positron-Emission Tomography;Predisposition;Regression Analysis;Sampling;Scanning;Short-Term Memory;Signal Transduction;System;Testing;Time;age related;base;behavior measurement;blood-brain barrier crossing;brain based;cognitive function;cognitive process;cognitive reserve;functional plasticity;good diet;improved;in vivo;indexing;inflammatory marker;lifestyle factors;neural;neuroimaging;neuroimaging marker;novel;novel marker;pre-clinical;protective factors;support network;tau Proteins;tau-1;white matter

public_health_relevance:
Project NarrativeNovel biomarkers of Alzheimers disease (AD) are needed to aid early identification ofindividuals at high AD-risk. This study will test the accuracy of brain iron neuroimaging as apredictor AD-related neurocognitive declines. It is anticipated that findings from this study willimprove the ability to detect early AD and track changes in cognitive status during diseaseprogression.


application_id: 10579874
project_number: 5R34MH124799-03
administering_ic: NIMH
award_notice_date: 2023-02-17
opportunity_number: RFA-MH-18-706
application_type: 5
activity_code: R34
ic: MH
serial_number: 124799
program_official: BURSTEIN, MARCY ELLEN
project_start_date: 2021-03-15
project_end_date: 2025-02-28
study_section: ZMH1-ERB-K(09)
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-03-01
project_title:
A Pilot Randomized Control Trial of a Relapse Prevention Online Exposure Protocol for Eating Disorders and Mechanisms of Change

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

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

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


application_id: 10579521
project_number: 1R15MH132060-01
administering_ic: NIMH
award_notice_date: 2022-09-20
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: MH
serial_number: 132060
program_official: TONELLI, LEONARDO HERALDO
project_start_date: 2022-09-20
project_end_date: 2026-08-31
study_section: Special Emphasis Panel[ZRG1 MDCN-R (86)]
contact_pi_person_id: 15786531
contact_pi: WILLIAMSON, LAUREN L
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
budget_start_date: 2022-09-20
project_title:
A role for maternal helminth treatment to alter central inflammation and to reduce lifelong offspring inflammation

project_abstract:
PROJECT SUMMARYNeuroinflammation is correlated with a broad spectrum of disorders including cognitive and mentalhealth disorders. Treating and reducing neuroinflammation remains a medical challenge. Thepurpose of this research is to determine the effects of maternal helminth colonization on her neonataland adult offspring specifically focused on the effects on microglia function and inflammation acrossthe lifespan as well as hippocampal-dependent behavior in adulthood. As previous work has shownneonatal infection alters neuroinflammation via changes in microglial function and has an enduringnegative effect on adult learning and memory. Current work in patient populations suffering from non-communicable inflammatory disorders such as multiple sclerosis shows that treatment withcommensalist parasites may be a new form of intervention beyond pharmaceutical treatments.Commensalist organisms emit anti-inflammatory signals in order to survive and these signals mayhave potential benefits by reducing inflammation within their hosts. Previous work has shown thatmaternal helminth colonization attenuates neuroinflammation in the offspring following a neonatalinfection with Escherichia coli. The same work showed that the combination of maternal and weanlingoffspring helminth colonization rescues learning deficits on a hippocampal-dependent contextual fearconditioning task. Further research is needed to understand the effects on the offspring of maternalhelminth colonization alone as well as to define the duration and time course of the effects ofmaternal helminth colonization in our neonatal infection model. This proposal will test the hypothesisthat maternal helminth colonization alone is sufficient to protect offspring from the lifelong effects ofneonatal infection by reducing inflammation within the hippocampus throughout the lifespan. It willalso characterize the effects of maternal helminth colonization on the offspring to explore possiblemechanisms including mRNA-sequencing of isolated cell populations (microglia astrocytes andneurons) from the central nervous system. Importantly this project proposes to engage and trainapproximately 8 undergraduates working in the lab each year with rodents on behavioral taskanalysis as well as cellular and molecular analysis techniques such as immunohistochemistry andreal-time quantitative PCR as well as bioinformatics projects with NextGen RNAsequencing. Thesestudies will elucidate potential mechanisms for the effects of maternal helminths that can be furtherexplored as interventions for populations susceptible to immune-mediated inflammatory diseases.

project_terms:
ARHGEF5 gene;Academic Research Enhancement Awards;Acute;Adolescence;Adult;Adult Children;Adverse event;Affect;Animal Model;Anti-Inflammatory Agents;Antiinflammatory Effect;Anxiety;Astrocytes;Attenuated;Autoimmune Diseases;Bacterial Infections;Behavior;Behavioral;Behavioral Paradigm;Bioinformatics;Biological Models;Blood Circulation;Brain;Cell Communication;Cell Separation;Cells;Chronic;Cognition;Cognition Disorders;Cognitive;Cognitive deficits;Conceptions;Disease;Elderly;Encephalitis;Escherichia coli;Escherichia coli Infections;Female;Gene Expression;Genes;Genetic;Goals;Health;Helminths;Hippocampus (Brain);Hour;Human;Immune;Immune response;Immunohistochemistry;Impaired cognition;Infant;Infection;Inflammation;Inflammatory;Intervention;Laboratories;Learning;Life;Longevity;Measures;Mediating;Medical;Memory;Memory impairment;Mental Depression;Mental disorders;Microglia;Microspheres;Modeling;Molecular;Molecular Analysis;Mothers;Multiple Sclerosis;Neonatal;Neuraxis;Neuroimmune;Neurons;Newborn Infant;Organism;Outcome;Parasites;Pathway interactions;Peripheral;Pharmacologic Substance;Physiological;Population;Population Intervention;Psychoneuroimmunology;RNA;Rattus;Research;Rodent;Role;Signal Transduction;Symptoms;Techniques;Testing;Time;Tissues;Training;Work;autism spectrum disorder;cell type;cognitive performance;conditioned fear;cytokine;fascinate;mRNA sequencing;neonatal infection;neonatal period;neuroinflammation;neuroprotection;offspring;patient population;postnatal;prenatal intervention;prevent;protective effect;protein expression;pup;relating to nervous system;task analysis;transcriptome sequencing;undergraduate student

public_health_relevance:
PROJECT NARRATIVEThis proposal will characterize the effects of an anti-inflammatory treatment in mothers that will reduceinflammation in their babies. It will identify target pathways for early-life inflammation that can be the focus ofprenatal interventions to reduce the burden of inflammation and the lifelong effects of early-life adverse events.


application_id: 10579417
project_number: 1K99CA277245-01
project_title: Reducing Lung Cancer Risk among Appalachian Women Using CommunityEngaged Intervention Research
administering_ic: NCI
award_notice_date: 2023-01-12
opportunity_number: RFA-CA-21-061
application_type: 1
activity_code: K99
ic: CA
serial_number: 277245
program_official: RADAEV, SERGEY
project_start_date: 2023-02-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZCA1 RTRB-U (O1)]
contact_pi_person_id: 15107621
contact_pi: THOMPSON, JESSICA RUTH
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYAppalachian women are at high risk for lung cancer. Lung cancer is the leading cause of cancer-related deathfor women in the US including the Appalachian region. Although lung cancer rates have declined steadily amongmen since the 1990s such decreases have not been seen among women including alarming mortality rates inCentral Appalachia. Interventions to reduce lung cancer risk among Appalachian women need to consider socialand environmental contexts. Research: This project titled Reducing Lung Cancer Risk among AppalachianWomen Using Community-Engaged Intervention Research relies on community perspectives to guide theselection adaptation and pilot testing of a culturally-targeted intervention to reduce lung cancer risk amongAppalachian women. We will employ the NIH model for creating behavioral intervention trials to inform therefinement of an intervention through direct community input (Phase 1a; Aim 1; K99) and to pilot test the selectedand adapted intervention protocol using a 2-armed randomized controlled trial (Phase 1b; Aim 2; R00). In thepilot with Central Appalachian KY women we will demonstrate the feasibility of the adapted intervention protocolincluding demand acceptability and implementation. The selected intervention will seek to increase knowledgeself-efficacy and targeted behaviors among Appalachian women thereby reducing their future lung cancer riskand ultimately lung cancer disparities among women in the Appalachian region. Candidate: Dr. JessicaThompson is a postdoctoral scholar in an NCI-designated cancer center at the University of Kentucky (UK) withextensive previous training in community-engaged mixed methods research and chronic disease preventionamong Appalachian women. Three training goals will enhance her trajectory toward becoming an independentinvestigator including developing expertise in: 1) the use of participatory systems science and community-engaged approaches to select and adapt an intervention; 2) lung cancer prevention and risk reductioninterventions; and 3) intervention development and implementation science. Mentors/Environment: Dr.Thompsons career development plan includes substantial mentorship didactic training and experientiallearning at the UK Markey Cancer Center (MCC) with additional support from the UK Center for Health EquityTransformation (CHET) and the UK Center for Clinical and Translational Science (CCTS). She will receive directmentorship from MCC Community Impact Office director Dr. Pamela Hull (Primary Mentor) and CHET directorDr. Nancy Schoenberg (Co-Primary Mentor) with additional mentorship from Dr. Ellen Hahn (Mentor) in lungcancer prevention and risk reduction Dr. Teresa Waters (Mentor) in assessments of intervention effectivenessand health economics and Dr. Jessica Burke (Mentor; University of Pittsburgh) in systems science andparticipatory methods. Overall the objectives of this K99/R00 application will advance lung cancer interventionresearch for Appalachian women by providing evidence for a future R01 submission and support Dr. Thompsonstraining as an independent scientist in implementing interventions to improve the health of Appalachian women.

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

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


application_id: 10579030
project_number: 1R15AG074538-01A1
project_title: Genetic Mechanisms of Circadian Clock-Mediated Dietary Restriction in Drosophila
administering_ic: NIA
award_notice_date: 2023-01-30
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: AG
serial_number: 074538
suffix: A1
program_official: FU, YI-PING
project_start_date: 2023-02-01
project_end_date: 2027-01-31
study_section: Special Emphasis Panel[ZRG1 CB-H (80)]
contact_pi_person_id: 11550061
contact_pi: HWANGBO, DAE-SUNG
other_pis: Not Applicable
congressional_district: 03
department: BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractDietary Restriction (DR) where caloric or diet intake is reduced but not to the point of malnutrition extendslifespan and healthspan in model organisms from single cellular yeast to non-human primates. However themolecular mechanisms by which DR delays aging and promotes health are not fully understood. Due to theirshort lifespan versatile genetic tools and high conservation of molecular pathways for metabolism behaviorand aging the fruit fly Drosophila melanogaster has been widely used as a model organism for DR-relatedresearch. Using Drosophila our long-term goal is to understand how the circadian clock (genetic pathway)interacts with diets and light:dark cycles (environmental factors) to optimize organismal metabolism physiologyand behavior that ultimately promotes health and longevity. PIs preliminary data obtained through systemiclifespan/behavior assays and tissue- and diet-dependent transcriptomic analysis suggests a critical role of thecircadian clock in the peripheral fat body (functionally homologues to the liver) for the beneficial effects of DR.The overall objective of this proposal is to understand genetic mechanisms by which circadian clocks in fatbody mediate DR-dependent lifespan extension and physiological changes. For this objective we propose toleverage versatile Drosophila genetics to test our central hypothesis formulated based on the preliminary dataand literature survey that clock-controlled genes (CCGs) in fat body promote health and longevity bycoordinating time-dependent metabolic physiological and behavioral homeostasis. To test this hypothesis wepropose to perform three independent yet interconnected specific aims: First by completing a large-scale tissuespecific in vivo functional screening we will determine key CCGs and molecular pathways in fat body that areimportant for DR response (Aim 1). Second by employing a genomic and metabolomic profiling we will identifymolecular and metabolic signatures responsible for DR-mediated lifespan extension through clock-controlledproteasome in fat body. Third by applying a forced circadian misalignment (similar to jet-lag) we will determinethe impact of desynchrony between the external environmental time and the internal molecular clock on DR andCCGs (Aim 3). This study is meritorious because it will generate outcomes that provide insight into how thecircadian clock orchestrates environmental cues to promote health and longevity. This study also strengthensthe research environment of undergraduate students at the University of Louisville because it is designed tobe completed by a research team primarily composed of undergraduate students at the University.

project_terms:
Aging;Behavior;Behavioral;Biological Assay;Circadian Dysregulation;Circadian desynchrony;Complex;Cues;Darkness;Data;Diet;Disease;Drosophila genus;Drosophila melanogaster;Environment;Environmental Risk Factor;Enzymes;Fat Body;Fertility;Functional disorder;Gene Silencing;Genes;Genetic;Genetic Screening;Genomics;Goals;Health;Health Promotion;Homeostasis;Homologous Gene;Individual;Intake;Intervention;Jet Lag Syndrome;Light;Link;Liver;Longevity;Maintenance;Malnutrition;Mammals;Mediating;Metabolic;Metabolism;Modeling;Molecular;Mus;Organism;Outcome;Output;Pathway interactions;Peripheral;Physiological;Physiology;Play;Public Health;RNA Interference;Recycling;Research;Resistance;Role;Sleep;Starvation;Stress;System;Testing;Time;Tissues;Universities;Yeasts;abdominal fat;circadian;circadian pacemaker;design;dietary restriction;environmental change;feeding;fitness;fly;genetic analysis;genetic testing;genome-wide;healthspan;in vivo;insight;knock-down;literature survey;metabolomics;model organism;molecular clock;multicatalytic endopeptidase complex;mutant;nonhuman primate;proteostasis;reduced food intake;response;screening;shift work;social;tool;trait;transcription factor;transcriptome;transcriptome sequencing;transcriptomics;undergraduate student

public_health_relevance:
Relevance to Public HealthCircadian clocks are instrumental in organisms health and survival by orchestrating physiology and behavior inresponse to daily environmental changes such as feeding and light exposure. While circadian clock disruptionssuch as jet lag and shift work are linked to many diseases reducing food intake without malnutrition (dietaryrestriction: DR) promotes health and delays aging. What are the relationships between circadian clocks and DR?Using Drosophila as a model organism this study investigates the roles of circadian clocks for the beneficialeffects of DR.


application_id: 10577893
project_number: 5R01DC007176-18
project_title: Regulation of taste neuron morphology and function
administering_ic: NIDCD
award_notice_date: 2023-03-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2027-02-28
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Anatomy;Axon;Brain;Brain-Derived Neurotrophic Factor;Calcium;Characteristics;Chemicals;Citric Acid;Communication;Development;Disease;Epithelium;Food;Functional Imaging;Ganglia;Gene Expression;Genetic;Goals;Health;Hour;Image;Individual;Intrinsic factor;Label;Link;Longevity;Measurement;Measures;Methods;Morphology;Mus;Nerve Fibers;Neurons;Pattern;Peripheral;Persons;Population;Process;Quality of life;Receptor Cell;Regulation;Role;Stimulus;Structure;Taste Bud Cell;Taste Buds;Taste Disorders;Taste Perception;Temperature;Time;Variant;Wild Type Mouse;cell type;cellular transduction;experimental study;functional plasticity;in vivo;insight;intravital imaging;neurotrophic factor;overexpression;preproenkephalin;proenkephalin;reconstruction;sensory system;taste stimuli;taste system;taste transduction;two photon microscopy


application_id: 10577784
project_number: 5P20GM135004-04
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NIGMS
award_notice_date: 2023-01-30
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2023-05-01
study_section: ZGM1-RCB-4
subproject_number: 8112
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Lung cancer is a prevalent disease and consumes many lives every year. Cancer immunotherapy using immune checkpoint inhibitors (ICIs; e.g. anti-PD-1 anti-CTLA-4 antibodies) has revolutionized the treatment of metastatic lung cancer resulting in long-term complete responses for many patients. Nevertheless there remains an urgent need for new strategies because not all patients respond to ICIs; moreover resistance can occur in those that do. Myeloid-derived suppressor cells (MDSCs) in particular monocytic MDSCs (MMDSCs) are potent immunosuppressive innate immune cells that actively inhibit CD8+ T cell tumor homing and activation. Since M-MDSC levels are elevated in multiple human cancers and correlate with decreased patient survival we postulate that these cells contribute to anti-PD-1 resistance. The purine nucleoside adenosine is produced in copious amounts within the tumor microenvironment (TME) where it serves to suppress the immune system and promote tumor growth. There is evidence to suggest that overproduction of adenosine can mediate resistance to ICIs. Immune suppressive adenosine is produced via the enzymatic conversion of extracellular AMP by the cell surface enzyme CD73 (ecto-5-nucleotidase; AMP  adenosine). Our preliminary studies demonstrate that tumor cell-derived prostaglandin E2 (PGE2) maintains M-MDSC suppressive activity in large part by directly inducing cell surface CD73 expression via a novel PGE2cAMPCREB/STAT3 pathway leading to increased immune suppressive adenosine within the TME. The overall hypothesis of this proposal is that tumor cell-derived PGE2 dictates CD73 expression in M-MDSCs leading to substantial increases in adenosine-dependent inhibition of anti-tumor CD8+ T cell activation resulting ultimately in anti-PD-1 immunotherapeutic resistance A major goal of this proposal is to test the antitumor efficacy of a novel cancer immunotherapy involving systemic administration of adenosine deaminase (ADA)an enzyme that irreversibly converts adenosine into inosine a non-immunosuppresive nucleoside. A pegylated version of bovine ADA (PEG-ADA) is already FDA-approved for use as an enzyme replacement therapy in children with ADA-associated severe combined immunodeficiency (ADA-SCID). We hypothesize that depletion of adenosine-mediated T cell immune suppression by PEG-ADA sensitizes tumors to PD-1 inhibitor therapy and improves clinical outcomes for NSCLC patients. To fulfill the stated objectives the following aims are proposed: 1) Delineate the signaling pathway and molecular mechanisms by which PGE2 induces CD73 expression in M-MDSCs; 2) Determine whether inhibition of the PGE2cAMPCREB/STAT3CD73adenosine pathway attenuates anti-PD-1 resistance in a mouse model of lung cancer; and 3) Validate PGE2  CD73+ M-MDSC  adenosine mediated anti-PD-1 resistance pathway in lung cancer patients receiving pembrolizumab therapy. Our proposed study will provide important insights towards developing a safe and novel immunotherapy to attenuate ICI resistance in lung cancer patients.

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


application_id: 10577776
project_number: 5P20GM135004-04
project_title: Mechanisms of resistance to immune therapy in NSCLC
administering_ic: NIGMS
award_notice_date: 2023-01-30
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2023-06-30
study_section: ZGM1-RCB-4
subproject_number: 8110
contact_pi_person_id: 14384874
contact_pi: LI, QINGSHENG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Despite having been approved as first and second line therapy for non-small cell lung cancer (NSCLC) anti-PD- 1 antibodies still fail in a substantial proportion of lung cancer patients. The mechanism that underlies the failure of anti-PD-1 therapy in the majority of NSCLC patients is not yet fully understood. We have discovered that in the anti-PD-1-resistant LSL-KrasG12D murine lung adenocarcinoma mouse model treatment induces a T-cell activation profile that favors Th17/T17 reinvigoration over CD8+ T cell activation. In contrast when administered in conjunction with an anti-IL-17 neutralizing antibody anti-PD-1 treatment results in a dramatic enhancement of CD8+ T-cell cytotoxicity with near-complete eradication of established disease. These findings provide the premise for our central hypothesis that in NSCLC the failure of anti-PD-1 is at least in part due to reinvigoration of PD-1+ type 17 T cells (Th17/T17) which actively undermine anti-PD-1-mediated restoration of cytotoxic function in CD8+ T-cells. Based on additional murine data we are also advancing the extended hypothesis that the severity of pre-existing T17 activity in the neoplastic lung is determined by commensal bacteria and that the lung microbiota signature can ultimately predict responsiveness to anti-PD-1 therapy. The goal of this proposal is to demonstrate the relevance of these findings to human prior to initiating an R01 application. Specifically in Aim 1 we will establish whether intrinsic lung T17/CTL ratio is predictive of anti-PD- 1 responsiveness in NSCLC patients independent of neoantigen burden. In Aim 2 we will determine whether specific human lung microbiota individually or in defined combinations drive the ontogeny of intrinsic T17 immunity and ultimately resistance to ICI therapy. The proposed study is conceptually impactful as it addresses an important clinical conundrum; is mechanistically novel; and has translational relevance since it introduces therapeutic/prognostic approaches that can rapidly move to the clinic.

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


application_id: 10577764
project_number: 5P20GM135004-04
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2023-01-30
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: ZGM1-RCB-4
subproject_number: 8107
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The goal of the CCII COBRE is to establish a thematic multidisciplinary research center of excellence at the University of Louisville that focuses on improving our understanding of cancer immunology and developing novel immunotherapeutic approaches. Importantly with the recent clinical successes of immune checkpoint inhibitors and oncolytic viruses there is great interest and momentum in understanding the interaction between the host immune system and neoplastic cells. Our projects proposing basic immunology research coupled with translational and human specimen studies are expected to ultimately lead to entirely new immunotherapeutic approaches as well as strategies for overcoming resistance to existing agents. The Administrative Core (AC) will coordinate the professional activities of the more than 40 individuals who will constitute the new Center for Cancer Immunology and Immunotherapy (CCII). The AC will provide administrative fiscal and scientific oversight and planning for junior investigators mentors projects the research core a pilot program and advisory committees. In addition to governance functions the AC will provide key research and mentoring support. This will include the awarding of project grants assignment of mentors provision of a grant writing mentorship program biostatistics and bioinformatics support compliance and regulatory oversight mentoring of pilot projects and encouragement of diversity and inclusion. Internal advisors and an External Advisory Committee (EAC) that consists of five leading scientists in the CCII thematic area will guide the AC. The EAC will provide scientific guidance and constructive feedback regarding center/project progress and be involved in CCII strategic planning and in the selection of replacement and pilot projects. The two PIs of the overall CCII program will direct the AC with key support from two co-Is who have extensive experience administering multi- component grant programs and from two additional co-Is who are well qualified to oversee the essential biostatistics and bioinformatics support. Their efforts will supplement a mentoring program that is anchored by eight senior investigators who are experienced mentors and have been highly productive and well funded in the thematic area. The three specific aims of this Administrative Core that encompass all of these functions are to: (1) Establish procedures for CCII administration planning and decision-making; (2) Provide a mentorship program to accelerate the careers of the CCII junior investigators; and (3) Create a CCII pilot grant program that will stimulate new projects and collaborations. Innovative features of the AC are built on lessons learned from establishing other multidisciplinary thematic centers and include a shared governance approach that aims to ensure engagement of all participants and a holistic mentoring strategy that provides comprehensive guidance for our CCII junior investigators. By the end of the 5-year funding program we expect that 4-6 CCII junior investigators will have been awarded R01 grants and that many of these graduates will remain key members of this new COBRE focused on cancer immunology and immunotherapy.

project_terms:
Acceleration;Adoptive Cell Transfers;Advisory Committees;Applications Grants;Area;Award;Bacterial Infections;Basic Science;Bioinformatics;Biometry;Cancer Biology;Cancer Center;Cancer Patient;Centers of Research Excellence;Clinical;Clinical Research;Collaborations;Coupled;Credentialing;Decision Making;Education;Ensure;Evaluation;Feasibility Studies;Feedback;Feeling hopeless;Funding;Goals;Grant;Human;Human Resources;Immune checkpoint inhibitor;Immune mediated destruction;Immune response;Immune system;Immunology;Immunotherapeutic agent;Individual;Interdisciplinary Study;International;Leadership;Learning;Malignant Neoplasms;Mentors;Mentorship;Molecular;Molecular Profiling;Nobel Prize;Oncolytic viruses;Participant;Patients;Physicians;Pilot Projects;Prediction of Response to Therapy;Procedures;Productivity;Qualifying;Research;Research Personnel;Resistance;Role;Scientist;Specimen;Strategic Planning;Study Section;Testing;Training Programs;Translational Research;Treatment outcome;Tumor Escape;United States National Institutes of Health;Universities;Writing;cancer immunotherapeutics;cancer immunotherapy;career;diversity and inclusion;experience;improved;innovation;interest;meetings;member;multidisciplinary;neoplastic cell;next generation;novel;operation;programs;response;senior faculty;success;translational study;tumor;tumor immunology


application_id: 10577271
project_number: 1R21CA277314-01
project_title: A Stem Cell Based Exosomal Vaccine for the Prevention of Cancer
administering_ic: NCI
award_notice_date: 2023-02-17
opportunity_number: PAR-20-292
application_type: 1
activity_code: R21
ic: CA
serial_number: 277314
program_official: MALONE, WINFRED F
project_start_date: 2023-02-17
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZCA1 TCRB-Q (O1)]
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: LI, CHI
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Lung cancer is a prevalent disease and consume many lives every year. Disease relapse invasion andmetastases are the main causes of death. Recent discoveries provide compelling evidence that at least sometypes of cancer are initiated and maintained by a small population of malignant cells called cancer-initiatingstem cells (CICs). Relapse invasion and metastases are explained by the fact that CICs have a differentbiology than all the other tumor cells and importantly are resistant to chemotherapies and radiation. LungCICs have been shown to represent about 115% of all tumor cells and can form tumors with injections as lowas 100 cells. Evidence from published studies have demonstrated that human as well as rodent cancerscontain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteinsalso express markers used to identify lung CICs; therefore we hypothesized that ES cells and CICs shareseveral common molecular traits. To test this hypothesis we vaccinated mice with exosomes derived from EScells expressing GM-CSF and investigated whether an anti-tumor immune response was elicited. Wediscovered that ES cell-derived exosome-based vaccination strategy (ES-exo vaccine) is very effective inpreventing both implantable and carcinogen-induced lung adenocarcinoma development without anydetectable toxicity or signs of autoimmunity. Recently published results from our laboratory reveal thatsplenocytes from ES cell-immunized mice are preferentially cytotoxic to lung CICs. Experiments proposed inthis application seek to expand these novel findings to convincingly demonstrate that ES-exo vaccineimmunize against lung cancer-associated CICs and that anti-CIC immunity is responsible for preventing lungadenocarcinoma development. The anti-tumor activities of ES-exo vaccine as well as their immunostimulatoryproperties will be investigated in in vitro and in vivo lung cancer mouse models. Experiments proposed in thisstudy will address the translational potential of our novel ES-exo vaccine as a cell-free prophylactic vaccinemodality in implantable transgenic and xenograft mouse models of lung cancer. One of the major goals of thisapplication is to identify tumor antigens important for anti-lung cancer efficacy of ES-exo vaccine using aproteomics-based screening methodology. To fulfill the stated objectives the following aims are proposed: 1)Investigate whether lung cancer-initiating cells are targets of ES cell-derived exosomes (ES-exo) vaccination-induced anti-tumor immunity and 2) Evaluate the translational potential of ES cell-derived exosomes (ES-exo)as a novel cell-free vaccine for lung cancer. Our proposed study will provide important insights towardsdeveloping a safe prophylactic vaccine for lung cancer onset and/or recurrence.

project_terms:
Address;Adenocarcinoma;Adjuvant;Adult;Age Months;Allogenic;Antigens;Autoimmunity;Binding;Biology;CD34 gene;CD8B1 gene;Cancer Biology;Cancer Etiology;Cancer Patient;Cancer Vaccines;Carcinogens;Cause of Death;Cell Proliferation;Cells;Cessation of life;Chemotherapy and/or radiation;Consumption;Data;Daughter;Development;Disease;Embryo;Fibroblasts;Goals;Grant;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;Health;Health Care Costs;Human;Immune;Immune response;Immunity;Immunization;Immunize;Immunophenotyping;Implant;In Vitro;Injections;Invaded;KRASG12D;Laboratories;Lewis Lung Carcinoma;Life;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Messenger RNA;Methodology;MicroRNAs;Modality;Molecular;Mus;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Population;Preventive vaccine;Proliferating;Property;Proteins;Proteomics;Publishing;Recurrence;Recurrent disease;Relapse;Reporting;Resistance;Risk;Rodent;Solid Neoplasm;Source;Specificity;Splenocyte;Teratoma;Testing;Tissues;Toxic effect;Transgenic Organisms;Tumor Antigens;Tumor Immunity;Tumor Stem Cells;Tumor-infiltrating immune cells;Vaccinated;Vaccination;Vaccines;Validation;Vesicle;Work;Xenograft procedure;anti-cancer;anti-tumor immune response;antitumor effect;cancer cell;cancer initiation;cancer prevention;cancer therapy;cancer type;cell type;conventional therapy;cross reactivity;cytotoxic;efficacy testing;embryonic antigen;embryonic stem cell;exosome;experimental study;human embryonic stem cell;humanized mouse;in vivo;insight;intercellular communication;lung cancer prevention;lung development;lung tumorigenesis;mouse model;neoplastic cell;novel;oncofetal antigen;patient derived xenograft model;prevent;prophylactic;relapse risk;response;screening;self-renewal;stem cell biomarkers;stem cell exosomes;stem cells;trait;translational potential;tumor;tumor progression;vaccination strategy;vaccine development;vaccine efficacy

public_health_relevance:
Project NarrativeLung cancer patients remain at elevated risk for relapse following conventional treatment and recent studies oflung cancer biology provide compelling evidence that lung cancer is initiated by a small population of malignantcells called cancer-initiating cells (CICs); currently available cancer treatments may be ineffective against lungCICs. Our preliminary work using a vaccine consisting of exosomes derived from mouse embryonic stem cells(ES-exo vaccine) has provided validation that immunization with ES-exo vaccine prevents lung cancers in miceand our goal in this proposal is to investigate whether our novel cell-free ES-exo vaccine is effective indepleting lung CICs and preventing lung cancer onset and recurrence. Such a cancer vaccine will reducehealth care costs and loss of life from a disease that is now a major health problem worldwide.


application_id: 10576387
project_number: 5R01DE028916-04
project_title: Biosynthesis structure and function of cell wall in Streptococcus mutans
administering_ic: NIDCR
award_notice_date: 2023-03-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 028916
program_official: MCNEALY, TAMARA L
project_start_date: 2020-04-08
project_end_date: 2025-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The cell wall of many species of Lactobacillales consists of multiple peptidoglycan layersdecorated with serotype-specific polysaccharides that are characterized by the presence ofrhamnose. Streptococcus mutans is a key etiological agent of human dental caries and hasalso been implicated in bacteremia and infective endocarditis. Based on the chemical structuresof serotype-specific carbohydrates S. mutans is classified into serotypes c e f and k withapproximately 70-80% of strains found in the oral cavity classified as serotype c. The serotypec-specific carbohydrate (SCC) of S. mutans is composed of a polyrhamnose backbone with -linked glucose side-chains. Although carbohydrate structures have been reported for allS. mutans serotypes our recent insights into the structure of these glycopolymers indicate thatthe functionally important modification glycerol phosphate was overlooked possibly due to itsloss during the purification steps. This new finding justifies a re-examination of the chemicalstructures of serotype-specific carbohydrates. One of the goals of the proposed study is todetermine the molecular structure of SCC isolated from S. mutans using mild non-destructivemethods. Moreover little is known about the multienzyme processes involved in attachment ofthe glucose side-chains to the polyrhamnose backbone of SCC and the function of the glycerolphosphate modification in S. mutans. Our preliminary findings revealed that the glycerolphosphate modification plays important roles in S. mutans morphology autolysis resistance toantimicrobials and biofilm formation. We propose to identify and functionally characterize theenzymes involved in glucose side-chain attachment to polyrhamnose and investigate themolecular mechanisms underlying the functions of glycerol phosphate modification inmorphology autolysis and biofilm formation. To accomplish our goals we will employstreptococcal genetics in vitro enzymology NMR spectroscopy of polysaccharides analyticalchemistry mass spectrometric analysis of phospholipids and various methods of microscopyincluding AFM-based nanomechanics. The cell wall biosynthetic machinery is an historicallypreferred target for the development of novel antimicrobials. In order to validate the pathway ofSCC decoration with glycerol phosphate as a potential drug target we will determine the role ofthis modification in a rat caries model. Successful outcomes will guide future studies of cell wallbiogenesis in other important Gram-positive bacteria and the development of novel strategies totreat S. mutans infections.

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

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


application_id: 10574516
project_number: 5R01AG038651-10
project_title: Role of impaired cognitive states & risk factors in conversion to mixed dementias
administering_ic: NIA
award_notice_date: 2023-01-31
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AG
serial_number: 038651
program_official: ANDERSON, DALLAS
project_start_date: 2011-09-01
project_end_date: 2025-01-31
study_section: Neurological, Aging and Musculoskeletal Epidemiology Study Section[NAME]
contact_pi_person_id: 1874302
contact_pi: KRYSCIO, RICHARD J.
other_pis: ABNER, ERIN ;YU, LEI
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 ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractPopulation demographic trends suggest an expected dramatic increase in age-associateddementias and a looming public health crisis. Current emphasis is on disease prevention with afocus on older adults who express early cognitive impairment. The SMART (Statistical Modelingof Aging and Risk of Transitions) has successfully harmonized data from nine differentlongitudinal studies on aging involving records on 5032 subjects with 1657 having autopsyinformation. We propose to identify authoritatively the roles of diabetes and hypertension on theoccurrence and duration of pre-dementia states as well as mixed pathology. The project hasshown that self-reported diabetes is not a risk for Alzheimer pathology but is a risk forcerebrovascular pathology that subjective memory complaints are a risk for a future cognitiveimpairment and that transitioning to a subjective complaint or even to mild cognitive impairmentis no guarantee of future dementia. The SMART renewal proposes to obtain Medicare claimsdata on its participants to determine the severity of diabetes hypertension and othercomorbidities that have not been investigated such as renal disease with a focus on improvingthe prediction of who is at risk for a transition to an impaired cognitive state and mixed dementiapathology. This will be accomplished through the following specific aims:Aim 1. Update and extensively revise the existing SMART project database with additionalparticipant data; obtain and integrate linked Medicare claims data; assess agreement betweenself-reported medical history and claims data. Aim 2. Investigate the relationship of HTN T2DMand multimorbidity in advanced old age with AD and non-AD neuropathologies. Aim 3. Investigatethe relationship of HTN T2DM and multimorbidity in advanced old age with cognitive statesincluding subjective memory complaints mild cognitive impairment and dementia.

project_terms:
Academic Medical Centers;Adult;Affect;Age;Age of Onset;Aging;Agreement;Alzheimer's Disease;Alzheimer's disease diagnosis;Alzheimer's disease pathology;Alzheimer's disease risk;Area;Autoimmune Diseases;Autopsy;Brain;Cerebrovascular Disorders;Cessation of life;Chronic Disease;Clinical;Cognitive;Data;Databases;Dementia;Diabetes Mellitus;Diagnosis;Elderly;Factor Analysis;Female;Funding;Future;Genetic;Goals;Grant;Health;Hypertension;Impaired cognition;Impairment;Individual;Infarction;Investments;Kentucky;Kidney Diseases;Knowledge;Life;Link;Longitudinal Studies;Medical History;Medicare;Medicare claim;Memory;Microvascular Dysfunction;National Institute on Aging;Non-Insulin-Dependent Diabetes Mellitus;Oregon;Paper;Participant;Pathology;Patient Self-Report;Population;Primary Prevention;Probability;Public Health;Records;Research;Research Personnel;Respiratory Disease;Risk;Risk Factors;Role;Sample Size;Science;Secondary Prevention;Severities;Statistical Models;Universities;Update;Washington;Writing;age related;care costs;cerebrovascular pathology;clinical diagnosis;cognitive testing;comorbidity;data harmonization;data integration;dementia risk;disorder prevention;follow-up;human old age (65+);improved;mild cognitive impairment;mixed dementia;multiple chronic conditions;neuropathology;sex;trend

public_health_relevance:
Project NarrativeWith the graying of America the cost of caring for older adults with dementia will risesubstantially over the next few decades. Current emphasis in the field is on primary andsecondary prevention. This project will study diabetes and hypertension as risk factors forvarious forms of dementia inducing pathology as well as the impaired clinical states thatprecede diagnosed dementia.


application_id: 10574163
project_number: 1R21AA030638-01
project_title: Role of urolithin A in progression of alcohol-associated liver disease
administering_ic: NIAAA
award_notice_date: 2023-03-15
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AA
serial_number: 030638
program_official: WANG, JOE
project_start_date: 2023-03-15
project_end_date: 2025-02-28
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
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:
AbstractExcessive consumption of alcohol is a global problem and is the worlds third largest risk factor for diseases anddisabilities and accounting for 5.9% of all deaths worldwide. Alcohol-associated liver disease (ALD) is aspectrum of disease that starts with steatosis progressing to fibrosis and finally cirrhosis in ~20 to 30% patientsof in chronic excessive alcohol drinkers. However rest of the 70-80% with alcohol use disorders (AUD) patientsmay not progress into severe ALD. Therefore we asked what are factors that potentially prevent AUD patientsto progress in to ALD. The composition of gut microbiota and their metabolites are significantly vary in ALDpatients compared to AUD and healthy subjects and play a critical role in manifesting ALD pathogenesis. Ourpilot studies in mouse of ALD showed that treatment with gut microbial metabolite Urolithin A (UroA) significantlyreduced ALD pathogenesis. UroA treatment decreased EtOH-induced gut permeability hepatic steatosis andhepatitis in chronic chronic+binge ALD mouse models. UroA is a dietary microbial metabolite produced fromellagitannin/ellagic acid-rich diets such as pomegranate walnuts and berries. We postulate that harboring UroA-producing bacteria in healthy or AUD subjects may prevent from developing severe ALD. In this exploratoryproject we will test the hypothesize that microbiota and their metabolites (urolithins) in healthy and AUD withoutALD differ from AUD patients with ALD and presence of UroA-producing bacteria when combined with diets richin EA/ET or with direct supplementation of UroA will protect from ALD progression. To test this hypothesis weproposed two specific aims. In aim 1 we will collect stool samples from healthy AUD and severe ALD patientsand determine their ability to produce UroA in vitro cultures. Next we will generate humanized microbiota mice(HMM) by fecal microbiota transplantation (FMT) of UroA-producing or non-producing stool samples (collectedfrom healthy/AUD/ALD subjects) in to germ free mice. In aim 2 these humanized microbiota mice (UroAproducers vs non-producers) will subjected to chronic+binge (10+1) ALD model and determine extent of ALDdevelopment in these mice upon supplementing with EA. Further we will test whether direct supplementation ofUroA mitigate severe ALD in these humanized microbiota mice. Upon successful completion of these studieswe will determine whether UroA-producing microbiota and/or direct supplementation of UroA provides protectionagainst ALD in humanized microbiota mice. These studies would unravel potential of microbiota dependentpersonalized dietary patterns to control ALD.

project_terms:
Accounting;Alcoholic Liver Diseases;Alcohols;Attenuated;Bacteria;Berry;Cessation of life;Chronic;Cirrhosis;Colitis;Collaborations;Consumption;Development;Diet;Diet Habits;Dietary Practices;Disease;Disease Progression;Disease model;Ellagi-Tannins;Ellagic Acid;Endotoxins;Exhibits;Fatty Liver;Fibrosis;Genetic;Germ-Free;Goals;Health;Heavy Drinking;Hepatitis;Human;In Vitro;Inflammation;Intestinal permeability;Juglans;Laboratories;Liver diseases;Mediating;Modeling;Molecular;Mus;Obesity;Pathogenesis;Patients;Pilot Projects;Play;Pomegranate;Pre-Clinical Model;Preventive;Primary carcinoma of the liver cells;Production;Regulation;Rest;Risk Factors;Role;Sampling;Supplementation;Testing;Therapeutic;Treatment Efficacy;alcohol research;alcohol use disorder;cigarette smoking;clinically significant;deter alcohol use;dietary;disability;dysbiosis;epidemiologic data;experience;experimental study;fecal transplantation;gut microbiota;high reward;high risk;human subject;liver inflammation;liver injury;microbial;microbiome;microbiota;mouse model;prevent;problem drinker;stool sample

public_health_relevance:
Project NarrativeAbout 70% of alcohol use disorder patients do not develop severe alcohol-associated liver disease. The currentproject explores whether gut microbiota and their metabolites are key players determining transition from alcoholuse disorders to severe alcohol-associated liver disease. Finally therapeutic efficacies of microbial metaboliteurolithin A against alcoholic liver diseases progression will be examined in humanized microbiota mice.


application_id: 10573422
project_number: 1R21HD110951-01
project_title: Delineating impacts of gestational opioid exposure on central swallow networks.
administering_ic: NICHD
award_notice_date: 2022-12-28
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: HD
serial_number: 110951
program_official: CHAKHTOURA, NAHIDA ABDO
project_start_date: 2023-01-01
project_end_date: 2023-04-26
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 10816268
contact_pi: PITTS, TERESA G
other_pis: MELLEN, NICHOLAS M
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The ability coordinate breathing suckling and swallow is required for survival at birth. Infants with prenatalexposure to opioids can have abnormalities in swallow efficiency and swallow-breathing coordination sensory-motor responses to pharyngeal stimulus and esophageal motility reflexes which often results in persistentfeeding difficulties. The swallow pattern generator is located within the brainstem but it has been difficult tostudy due to its location and widely dispersed neural circuits. Our preliminary studies describe a novel methodthat allows for the visualization and recording of a vast number of neurons along the intermediate zone of themedial reticular formation and Nucleus Ambiguus (NA) while preserving the Nucleus Tractus Solitarius. Wedemonstrate reliable central stimulation of swallow with simultaneous optical recording of neurons in thesemicompact and compact regions of the NA along with nerve root recordings. Activation of NA neuronsduring swallow is affected by prenatal opioid exposure. Our methods also allow superimposition of opticalrecordings onto subsequent immunohistochemical images to identify regional cellular phenotypes and toconfirm recording locations. Our working hypothesis is that the brainstem swallow network spans the medullaand is vulnerable to opioids. The current application has evolved from collaborative work from two establishedinvestigators bringing together expertise in central neural circuitry optical/ histological techniques andregulation of swallow. The proposed studies are designed to describe location and type of neurons activeduring swallow alterations when swallow is stimulated across the respiratory cycle and the impact of neonatalopioid withdrawal syndrome. The combined state-of-the-art techniques will provide much-needed mechanisticinsight into swallow and clinical observation of infants with neonatal opioid withdrawal syndrome (NOWS).

project_terms:
Acute;Affect;Algorithms;Anatomy;Animals;Area;Birth;Brain Stem;Breathing;Breeding;Calcium;Cell Nucleus;Cells;Cervical;Child;Classification;Clinical;Color;Confocal Microscopy;Core Facility;Data;Data Collection;Deglutition;Deglutition Disorders;Development;Diagnosis;Dissection;Dorsal;Eating;Ensure;Esophagus motility;Exposure to;Female;Goals;Histologic;Histological Techniques;Human Milk;Hypoglossal nerve structure;Image;Immunohistochemistry;Infant;Injections;Label;Laboratories;Length of Stay;Location;Maps;Medial;Mediating;Methadone;Methods;Modeling;Motor;Motor Neurons;Motor output;Mus;Neonatal Abstinence Syndrome;Nerve;Neuromodulator;Neurons;Nucleus solitarius;Opioid;Optics;Patient Care;Pattern;Pharyngeal structure;Phenotype;Population;Preparation;Process;Reflex action;Regulation;Research Personnel;Reticular Formation;Rodent;Saline;Sensory;Somatostatin;Stimulus;Structure of phrenic nerve;Techniques;Technology;Testing;Tissues;Translations;Ventral Roots;Visualization;Withdrawal;Work;brain pathway;central pattern generator;cohort;design;experience;experimental study;feeding;fetal opioid exposure;hindbrain;histological image;indexing;insight;interest;machine vision;mouse model;neonate;neural circuit;neural patterning;new therapeutic target;novel;novel therapeutics;nucleus ambiguus;opioid exposure;opioid use in pregnancy;opioid withdrawal;postnatal period;prenatal exposure;preservation;public health relevance;pup;respiratory;response;screening;subcutaneous;suckling;tissue fixing

public_health_relevance:
Public Health Relevance StatementUse of opioids during pregnancy can result in a diagnosis of neonatal opioid withdrawal syndrome. Thesechildren can experience long hospital stays and have difficulty eating. Our fundamental goal is to understandhow opioids affects the brain pathways essential to swallow and to develop a platform in which new therapiescan be tested.


application_id: 10573177
project_number: 5P20GM121327-07
administering_ic: NIGMS
award_notice_date: 2022-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2026-12-31
study_section: ZGM1-RCB-3
subproject_number: 6478
contact_pi_person_id: 11597020
contact_pi: FONG, KA-WING
other_pis: ST CLAIR, DARET K
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-01
project_title:
TRIM28 fuels prostate cancer growth through SETDB1-mediated epigenetic silencing of androgen metabolic genes UGT2B15 and UGT2B17

project_abstract:
Prostate cancer (PCa) is the second-leading cause of cancer-related death in men. The mainstay treatment for metastatic PCa is androgen deprivation therapy (ADT). However the disease will inevitably return in an incurable form termed castration-resistant prostate cancer (CRPC). Importantly aberrant androgen receptor (AR) activation in the milieu of low androgen is the main driver of CRPC. Molecular characterization of CRPC paves the way for discovery of novel therapeutic targets and my previous studies showed that TRIM28 is aberrantly upregulated in advanced PCa. High TRIM28 levels are associated with worse clinical outcomes which suggests that TRIM28 could serve as a promising target for PCa therapy. It is known that TRIM28 in a complex with trimethyl-histone H3 lysine 9 (H3K9me3)-specific methyltransferase (SETDB1) possesses transcriptional co-repressor activity but its genomic targets remain largely unexplored in PCa. Moreover the TRIM28 downstream oncogenic pathway has not been comprehensively investigated in PCa. By molecular gene signature analysis I found that the steroid hormone metabolic pathway is regulated by TRIM28. In particular I found that the androgen eliminating enzymes UGT2B15 and UGT2B17 are the key TRIM28-repressed genes. It is known that genomic targeting of the TRIM28 complex is facilitated by transcription factors that bind to specific DNA recognition motifs. My data revealed that TRIM28 interacts with AR. In addition my preliminary results indicated there is co-occupancy of TRIM28 AR and H3K9me3 deposition at UGT2B15 and UGT2B17 gene loci. Based on these findings I hypothesize that TRIM28 acts together with AR to epigenetically silence the expression of androgen metabolic enzymes through SETDB1-mediated H3K9me3. I propose to test this hypothesis in Aim1. UGT2B15 and UGT2B17 are known to inactivate androgen through glucuronidation using UDPGlucA as the sugar-donor. Given that the overexpression of UGT2B15 and UGT2B17 correlate to more UDP-GlucA consumption I hypothesize that levels of UDP-GlucA will decrease in TRIM28 knockdown cells or with treatment of the SETDB1 inhibitor Mit in CRPC cells. I propose to test this hypothesis in Aim2. The results from this proposal will not only reveal a novel epigenetic mechanism for regulating androgen glucuronidation but also have significant implications for the development of SETDB1-targeted therapy for CRPC treatment.

project_terms:
Androgen Receptor;Androgens;Binding;Cancer Center;Cancer Etiology;Cells;Cessation of life;Clinical;Complex;Consumption;DNA;Data;Deposition;Development;Disease;Enzymes;Epigenetic Process;Genes;Genetic Transcription;Genomics;Growth;Histone H3;Kentucky;Lysine;Malignant neoplasm of prostate;Mediating;Metabolic;Metabolic Pathway;Metastatic Prostate Cancer;Methyltransferase;Molecular;Oncogenic;Outcome;Pathway interactions;Prostate Cancer therapy;Receptor Activation;SETDB1 gene;Testing;Universities;advanced prostate cancer;androgen deprivation therapy;castration resistant prostate cancer;epigenetic silencing;gene repression;genetic corepressor;genetic signature;genomic locus;inhibitor;knock-down;men;new therapeutic target;novel;overexpression;prostate cancer cell;steroid hormone;sugar;targeted treatment;transcription factor;tumor metabolism


application_id: 10573171
project_number: 5P20GM121327-07
administering_ic: NIGMS
award_notice_date: 2022-12-23
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2017-03-01
project_end_date: 2023-01-01
study_section: ZGM1-RCB-3
subproject_number: 6637
contact_pi_person_id: 14584136
contact_pi: ZHU, CAIGANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-01-01
project_title:
An intra-vital metabolic microscope to reveal the mechanisms of radiation resistance in  head and neck carcinomas

project_abstract:
PROJECT SUMMARY Given the clinical importance of radio-resistance in head and neck squamous cell cancer (HNSCC) understanding how radio-resistant tumors rewire their metabolic pathways and vascular network to escape radiotherapy (RT) is critical towards developing strategies to eliminate residual tumor cells and/or prevent subsequent recurrence. Currently no techniques are available to provide a systems level approach to image the major axes of metabolism and the associated vasculature at a spatial resolution that can elucidate the modulation of cancer cell metabolism or vascular reprogramming in vivo. Our technological goal is to create innovative solutions in microscopy automated algorithms and experimental strategies to image tumor metabolism vascular function and architecture at a spatial resolution that allows for visualization of primary tumors residual disease and recurrence following RT to facilitate the understanding of tumor biology and function assessment of recurrence risk and design of therapies to mitigate residual disease and/or recurrence altogether in pre-clinical models. Our technological approach fills an important gap that exists between in vitro cell studies and whole- body imaging and is complementary to metabolomics and immunohistochemistry. The Specific Aims of this proposal are to develop a portable multi-parametric microscope that combines structured illumination microscopy and dark field microscopy in a re-emission geometry to image key metabolic and vascular endpoints simultaneously (Specific Aim 1); and use the technology with in vivo HNSCC orthotropic models to test the novel hypothesis that RT-induced hypoxia-inducible factors (HIF-1 and HIF-2) expression and subsequent changes in metabolism/vasculature underlie HNSCC radio-resistance (Specific Aim 2). This proposal will set the foundation for translating our technology to patient-derived xenograft models that have been shown to faithfully recapitulate many of the micro-environmental features of patient tumors allowing us to move our technique forward towards translational pharmaceutical research.

project_terms:
Algorithms;Animal Model;Architecture;Bioenergetics;Biological;Biomedical Research;Blood Vessels;Cancer Biology;Cancer Center;Cancer Model;Cancer Patient;Cells;Characteristics;Citric Acid Cycle;Clinical;Complement;Dark-Field Microscope;Darkness;Development;Esters;Foundations;Geometry;Glycolysis;Goals;Head and Neck Squamous Cell Carcinoma;Hypoxia;Hypoxia Inducible Factor;Image;Immunohistochemistry;In Vitro;Kentucky;Label;Lighting;Lipids;Measures;Membrane Potentials;Metabolic;Metabolic Pathway;Metabolism;Microscope;Microscopy;Modeling;Monitor;Optics;Outcome;Patients;Pharmacologic Substance;Pre-Clinical Model;Primary Neoplasm;Process;Proliferating;Radiation Tolerance;Radiation therapy;Radiobiology;Reactive Oxygen Species;Recurrence;Research;Residual Neoplasm;Resolution;Risk;Role;SLC2A1 gene;Structure;System;Targeted Radiotherapy;Techniques;Technology;Testing;Time;Tissues;Translating;Tumor Angiogenesis;Tumor Biology;Tumor Volume;Universities;Visualization;Warburg Effect;angiogenesis;automated algorithm;cancer cell;cancer imaging;cancer stem cell;design;glucose uptake;high resolution imaging;image processing;imaging capabilities;improved outcome;in vivo;in vivo imaging;innovation;insight;lens;metabolic imaging;metabolic phenotype;metabolomics;mitochondrial membrane;mitochondrial metabolism;neoplastic cell;new technology;novel;novel strategies;optical imaging;overexpression;patient derived xenograft model;portability;pre-clinical;prevent;radiation resistance;radioresistant;stable isotope;stem-like cell;targeted treatment;tetramethylrhodamine;therapy design;therapy resistant;tissue oxygenation;tool;translational cancer research;trend;tumor;tumor metabolism;whole body imaging


