# projects

application_id: 10454933
project_number: 5R01HL147844-04
project_title: Biosynthetic Pathways in Cardiac Remodeling
administering_ic: NHLBI
award_notice_date: 2022-07-28
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 147844
program_official: SCHWARTZ, LISA
project_start_date: 2019-08-01
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-CVRS-L(02)]
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: JONES, STEVEN P
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:
The ability of the heart to use multiple substrates provides the flexibility needed to balance catabolic demandswith anabolic requirements; however the failing heart shifts its energetic reliance toward glucose and hasdiminished fuel flexibility. This switch in fuel use is associated with pathological remodeling but it remainsunclear how increased reliance on glucose catabolism affects cardiac health. We propose the generalhypothesis that the inability of the failing heart to spare glucose-derived carbon for biosynthetic reactionscauses pathological remodeling. We find that several collateral biosynthetic pathway metabolites are higher inthe compensatory phase of hypertrophy and that reductions in their abundance coincide with the early stagesof heart failure. Nevertheless how cardiac metabolic pathways are inter-regulated remains unclear and howchanges in metabolism elicit myocardial responses to stress remains unanswered. To span such gaps inknowledge we will examine how collateral biosynthetic pathways change with cardiac remodeling in vivo byusing deep network stable isotope tracing after pressure overload. We will also examine how physiologicstimuli for cardiac growth regulate cardiac biosynthetic pathway activity. We will correlate the changes inbiosynthetic pathways with catabolic pathway activity. In Aim 2 we will determine how changes in the cardiaccatabolism modulate collateral biosynthetic pathway activity in the heart. For this we will force glucose fat orketone oxidation using pharmacological and genetic approaches and measure glucose carbon fate in anabolicpathways using deep network stable isotope tracing. Under controlled metabolic conditions we will constructan atlas demonstrating how glycolysis mitochondrial activity and substrate availability affect glucose carbonfate and anabolic pathway activity in cardiomyocytes. In Aim 3 we will augment biosynthetic pathway activityby genetically or allosterically regulating key metabolic steps in the heart or by introducing enzymes to activatemetabolic pathways that are not typically operational in the mammalian heart. We will determine how theseinterventions regulate cardiac metabolism and affect myocardial structure and function during pressureoverload-induced heart failure. We will delineate how these interventions affect the metabolism-guideddecisions in cell signaling and gene expression that modulate cardiac hypertrophy and heart failure. Thus thisproject will provide fresh perspectives about how metabolism regulates cardiac health and could identifyinnovative metabolic approaches to control cardiac remodeling. In particular these studies will integrate ourcurrent understanding of cardiac catabolism with new knowledge of how cardiac anabolism is regulated in theheart. Such insights are conceptually novel and will contribute to understanding how metabolism regulatescardiac hypertrophy. Thus these studies will identify: the metabolic pathway flux configurations that occurduring different forms of ventricular remodeling; how fuel selection in the cardiomyocyte regulates anabolicmetabolism; and new metabolic approaches to prevent deleterious remodeling.

project_terms:
Affect;Anabolism;Atlases;Carbon;Cardiac;Cardiac Myocytes;Cardiac health;Catabolism;Cues;Data;Deterioration;Dilated Cardiomyopathy;Enzymes;Equilibrium;Exercise;Face;Fat Body;Fatty acid glycerol esters;Functional disorder;Gene Expression;Genes;Glucose;Glycolysis;Goals;Growth;Heart;Heart Diseases;Heart Hypertrophy;Heart failure;Hexosamines;Hypertrophy;Intervention;Ketone Bodies;Ketones;Knowledge;Measures;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Myocardial;Myocardial Infarction;Nucleic Acids;Organ;Pathologic;Pathway interactions;Pentosephosphate Pathway;Pharmacology;Phase;Phosphoenolpyruvate Carboxylase;Physiological;Pregnancy;Proteins;Reaction;Serine;Signal Transduction;Stimulus;Stress;Structure;Testing;Ventricular Remodeling;flexibility;genetic approach;glucose metabolism;heart function;heart metabolism;improved;in vivo;innovation;insight;membrane synthesis;novel;oxidation;polyol;preference;pressure;prevent;programs;response;stable isotope

public_health_relevance:
The high metabolic demands of the healthy heart are normally satisfied by its intrinsic metabolic flexibility. Duringheart failure however metabolic inflexibility emerges and may underlie the deterioration of cardiac function. Inthis project we will test how metabolic pathways are coordinated in healthy and diseased hearts with the goalof creating new understanding of cardiac pathophysiology.


application_id: 10453771
project_number: 5R01HD080205-08
administering_ic: NICHD
award_notice_date: 2022-07-11
opportunity_number: PA-18-480
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2025-07-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(90)]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-01
project_title:
Effects of activity dependent plasticity on recovery of bladder and sexual function after human spinal cord injury

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

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

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


application_id: 10453700
project_number: 5R01GM130954-04
project_title: Insulin Degrading Enzyme: Physiological Function and its Spatial and Activity Modulation
administering_ic: NIGMS
award_notice_date: 2022-07-18
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: GM
serial_number: 130954
program_official: BARSKI, OLEG
project_start_date: 2019-09-01
project_end_date: 2024-07-31
study_section: Molecular and Cellular Endocrinology Study Section[MCE]
contact_pi_person_id: 7875201
contact_pi: LOUIS HERSH, LOUIS HERSH LOUIS HERSH
other_pis: RODGERS, DAVID W
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:
Insulin-degrading enzyme (IDE insulysin) is a primarily cytosolic peptidase shown to beimportant in the catabolism of insulin the amyloid beta peptide and likely other signaling andintracellular peptides. Its cellular physiology is therefore of considerable interest in the treatmentof disorders such as diabetes and Alzheimer's disease. However the site of IDE action on thesepeptides which are internalized into or otherwise present in the endosomal system is yet to befully understood. We propose to address the question of how this cytosolic enzyme encounterssubstrate peptides like insulin in the endosomal system exploring a novel mechanism for IDEsubcellular localization to this compartment. In particular we propose that IDE is trafficked toendosomes by binding to membrane anionic lipids particularly phosphoinositides through apolyanion-binding site. In the first aim we will test this hypothesis by using IDE polyanion sitemutants by altering levels of a key phosphoinositide and by expressing a phosphoinositidebinding competitor. We further propose to study in the second aim the participation ofendosomal IDE in insulin and amyloid(beta(peptide(catabolism. We will manipulate endosomalIDE levels using mutant forms of the enzyme with reduced endosome localization bydecreasing PtdIns(3)P levels and by increasing endosomal IDE by fusing it with a PtdIns(3)P-targeting domain. In the third aim we will study the polyanion-dependent activation of IDE andits role in affecting its catabolism of cytosolic peptides. We will use IDE mutants to test the effectof activation on hydrolysis of peptide substrates identified using a ligand trapping technique andpeptidomic analyses. We will also test for activation of cellular IDE by inositol phosphates andother potential endogenous activators. We will use our trapping technique to identify otherendogenous effectors. These studies will develop a clearer picture of how IDE carries out itsphysiological functions and greatly benefit efforts to treat IDE related pathophysiological states.(

project_terms:
Address;Affect;Affinity;Alzheimer's Disease;Amyloid beta-Protein;Binding;Binding Sites;Biological Assay;Catabolism;Cell Fractionation;Cell physiology;Cells;Cultured Cells;Development;Diabetes Mellitus;Disease;Endosomes;Enzyme Activation;Enzymes;Genetic study;Goals;Human Genetics;Hydrolysis;Inositol Phosphates;Insulin;Insulinase;Knowledge;Ligands;Link;Lipids;Membrane;Microscopy;Monitor;Peptide Hydrolases;Peptides;Phosphatidylinositols;Physiological;Play;Regulation;Role;Signal Transduction;Site;System;Techniques;Testing;Yeasts;base;endosome membrane;enzyme activity;enzyme substrate;inhibitor;innovation;interest;mutant;novel;phosphatidylinositol 3-phosphate;polyanion;receptor internalization;receptor mediated endocytosis

public_health_relevance:
Numerous studies including human genetic studies link Insulin Degrading Enzyme (IDE) toboth diabetes and Alzheimer's disease likely through its role as a key regulator of insulininvolved in diabetes and amyloid beta peptide involved in Alzheimer's disease. This projectwill focus on how the physiological functions of Insulin Degrading Enzyme are affected by itsintracellular localization and by its regulation by polyanions.


application_id: 10453698
project_number: 5R25GM133328-04
project_title: UofL Bridges to Baccalaureate(ULBB)
administering_ic: NIGMS
award_notice_date: 2022-07-08
opportunity_number: PAR-17-210
application_type: 5
activity_code: R25
ic: GM
serial_number: 133328
program_official: STEPANEK, LAURIE ELIZABETH
project_start_date: 2019-07-15
project_end_date: 2024-06-30
study_section: Training and Workforce Development Study Section - C[TWD-C]
contact_pi_person_id: 1858952
contact_pi: KAKAR, SHAM S.
other_pis: DAVIS, RANDALL
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTFor the last three decades biomedical research has been expanding rapidly and has made a great impact inproducing high quality skilled professionals in the U.S. However minorities and the underprivileged continueto be underrepresented (UR) in this work force. While the Trends in International Mathematics and ScienceStudy (TIMSS) and other reports show that US students are greatly improving their academic preparednesscompared to students from most other nations our country's minorities and underprivileged students remainrelatively poorly prepared to enter high technology careers such as biomedical and behavioral sciences. As aresult minorities who constitute about 29% of the total population represent only about 7% of Ph.D.degrees in biomedical and behavioral sciences and hold only about 4% of the R01 biomedical andbehavioral research grants. Many UR students are deprived of the opportunity to experience earlyengagement in science and math. Therefore because they lack the skills and exposure to move directly into4-year baccalaureate programs they enter into 2-year programs at the community and technical colleges.The UofL Bridges to Baccalaureate (ULBB) program will involve the University of Louisville (UofL) andJefferson Community and Technical College (JCTC) joining forces to develop a sustainable program that willintroduce underrepresented and disadvantaged community college students to the career opportunitiesavailable in biomedical and behavioral research and prepare them for successful transition from a 2-yearprogram at JCTC to a 4-year STEM related baccalaureate program at UofL. The ULBB program will focuson: 1) strengthening the partnership between JCTC and UofL to increase the recruitment ofunderrepresented minority and economically disadvantaged high school students into a pathway tobiomedical research careers increasing the graduation rate in Associate in Science (AS) from 12% in 3years to 50% in 2 years 2) providing a pipeline of support and mentoring personnel and programs includingacademic enrichments career development training and research experience during each 10-week summerprogram (two summers) at UofL under the mentorship of internationally renowned faculty that will enhancetransfer rate from a current 30% to 70% of ULBB-supported students and 3) continued mentoring andcounseling of students transferred from JCTC to UofL in a small group setting promoting their involvement inexisting undergraduate education programs to improve the present graduation rate of 33% to 70% of ourtransferred ULBB students leading to increased recruitment to biomedical research graduate education andcareers. The ULBB program is innovative and will not only impact the underrepresented and underprivilegedstudents themselves but also the broader curricular advising and research programs of both partnerinstitutions and the pool of diverse well-qualified scientists entering biomedical research careers.

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

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


application_id: 10453125
project_number: 1R01AA029488-01A1
administering_ic: NIAAA
award_notice_date: 2022-09-19
opportunity_number: PA-20-184
application_type: 1
activity_code: R01
ic: AA
serial_number: 029488
suffix: A1
program_official: ZHA, WENXING
project_start_date: 2022-09-20
project_end_date: 2027-06-30
study_section: Special Emphasis Panel[ZRG1 RPHB-M (02)]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: LEEMAN, ROBERT F.
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Linking Impulsivity Domains and Subjective Response to Alcohol in Young Adults Using Lab and Daily Assessment Methods

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

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

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


application_id: 10452766
project_number: 5R01NS107548-05
administering_ic: NINDS
award_notice_date: 2022-07-19
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 107548
program_official: KOTLIAROVA, SVETLANA
project_start_date: 2018-08-15
project_end_date: 2024-07-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)S]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-01
project_title:
A novel strategy to overcome the P-gp/BCRP drug efflux system at the blood-brain barrier to improve brain uptake of CNS therapeutics

project_abstract:
Failure of anticancer drug treatment is largely due to overexpression of the P-gp/BCRP drug efflux system atthe blood-brain barrier. New evidence suggests that glioblastoma multiforme (GBM) induces P-gp/BCRP over-expression in capillaries of the brain hemisphere that is contralateral to the tumor. Thus after surgical removalof the primary tumor remnant tumor cells that are scattered throughout the brain remain shielded from anti-cancer drugs. This poses a significant clinical problem and represents an unmet critical need to develop strat-egies to overcome P-gp/BCRP. The absence of such strategies will likely prevent improvements in GBM ther-apy. The long-term goal of the investigator is to identify molecular mechanisms that control blood-brain barrierfunction and can be targeted to improve brain uptake of anticancer drugs. The overall objective of this applica-tion is to develop an effective therapeutic strategy to overcome P-gp/BCRP-mediated anticancer drug effluxand prolong survival in mice with GBM. Based on preliminary data the central hypothesis is that GBM inducesP-gp/BCRP overexpression and that inhibiting PI3K/Akt will decrease P-gp/BCRP overexpression which willincrease brain uptake of anticancer drugs thereby reducing tumor size and prolonging GBM mouse survival.The rationale for this research is that its successful completion is expected to provide a solid evidence-basedscientific framework for translating our strategy into the clinic. Based on strong preliminary data this hypothesiswill be tested by pursuing three specific aims: 1) Determine the mechanism(s) by which GBM inducesP-gp/BCRP overexpression; 2) Identify pathways that regulate P-gp/BCRP at the human blood-brain barrier;and 3) Develop a therapeutic strategy to increase anticancer drug brain uptake in GBM mice. Under the firstaim mechanistic steps involved in GBM-induced overexpression of P-gp/BCRP will be assessed in brain capil-laries of the hemisphere contralateral to the primary tumor. The impact of blocking these steps on brain uptakeof anticancer drugs in GBM-bearing mice will be determined. Under the second aim P-gp/BCRP regulation bythe PTEN/PI3K/Akt/mTOR pathway will be determined in brain capillaries from normal individuals and fromGBM patients. Under the third aim the therapeutic benefit of combining PI3K/Akt inhibitors with anticancerdrugs to reduce P-gp/BCRP levels with the goal of improving brain uptake of anticancer drugs and prolongingsurvival will be assessed in three different GBM models. The proposed research is innovative in the appli-cant's opinion because it represents a new and substantive departure from the status quo by shifting the focusto GBM-induced overexpression of blood-brain barrier P-gp/BCRP in the contralateral hemisphere and by uti-lizing a molecular switch-based approach to overcome P-gp/BCRP-mediated drug efflux to target remnant tu-mor cells distant from the primary tumor. The proposed research is significant because it is expected that thenew knowledge may have broad translational importance in the treatment of patients with GBM and potentiallyother brain tumors as well.

project_terms:
ABCB1 gene;ABCG2 gene;AKT inhibition;Antineoplastic Agents;Blood - brain barrier anatomy;Blood capillaries;Brain;Brain Neoplasms;Cells;Cerebral hemisphere;Clinic;Clinical;Contralateral;Data;Development;Distant;Drug Efflux;Excision;FRAP1 gene;Failure;Glioblastoma;Goals;Human;Individual;Ipsilateral;Knowledge;Lateral;Lead;Mediating;Mission;Modeling;Molecular;Mus;National Institute of Neurological Disorders and Stroke;Natural regeneration;Outcome;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Primary Neoplasm;Public Health;Regulation;Research;Research Personnel;Signal Transduction;Solid;System;TNF gene;TNFRSF1A gene;Testing;Therapeutic;Translating;Treatment outcome;United States National Institutes of Health;Work;base;blood-brain barrier function;cerebral capillary;effective therapy;evidence base;expectation;improved;in vivo;inhibitor;innovation;lapatinib;neoplastic cell;nervous system disorder;novel;novel strategies;overexpression;prevent;therapeutically effective;treatment strategy;tumor;uptake

public_health_relevance:
The proposed research is relevant to public health because it is expected to provide a novel treatment strategyto overcome blood-brain barrier drug efflux for improved delivery of therapeutics into the brain specificallyanticancer drugs. Thus the proposed research is relevant to the mission of the NIH/NINDS that pertains todeveloping fundamental knowledge that will help reduce the burden of neurological disease.


application_id: 10452738
project_number: 5P30GM127607-05
project_title: Pilot Projects Program
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3
subproject_number: 5795
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
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:
ABSTRACTPILOT PROJECT PROGRAM. The overarching mission of the University of Louisville Diabetes and ObesityCenter is to enhance and enrich research into the mechanisms underlying cardiometabolic health and disease.In line with this mission the Pilot Project Program of Phase III of the COBRE will provide financial technical andintellectual support to pilot projects in the areas of diabetes obesity and cardiovascular biology. Applicants forthe Program will derive primarily from junior faculty within academic departments at the University of Louisvillewho have an interest in developing research programs in cardiometabolic disease. Additionally meritoriousprojects submitted by mid-career and senior investigators proposing to change fields or direct their futureresearch toward cardiovascular or metabolic disease will be considered for funding. Pilot project grantapplications will be solicited annually and awarded for a period of not more than two years based on the reviewand recommendations of internal grant evaluators and the External Advisory Committee. In addition we willprovide each awardee with a strong mentorship team to chaperone the development of their projects to the levelrequired for federal funding and to provide career guidance. The specific objectives of the program are to: (1)support innovative cardiometabolic research; (2) provide scientific and professional mentorship to awardrecipients; (3) strengthen the competitiveness of the Diabetes and Obesity Center; and (4) monitor efficiencyand effectiveness of the pilot program. We will encourage projects that have a high probability of both integratingwith and advancing the knowledge and capabilities of the current Center. This approach will help ensure thatwe increase the mass of investigators in the Center as well as augment our ability to conduct basic andtranslational research.

project_terms:
Address;Advisory Committees;Affect;Applications Grants;Area;Award;Basic Science;Biology;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Centers of Research Excellence;Complex;Custom;Data;Development;Diabetes Mellitus;Disease;Effectiveness;Ensure;Environment;Environmental Pollution;Etiology;Extramural Activities;Faculty;Fostering;Funding;Genetic;Goals;Grant;Growth;Health;Institution;Insulin Resistance;Investments;Knowledge;Life Style;Manuscripts;Mentors;Mentorship;Metabolic;Metabolic Diseases;Methodology;Mission;Molecular Chaperones;Monitor;Obesity;Phase;Pilot Projects;Probability;Publishing;Recommendation;Regulation;Research;Research Personnel;Research Project Grants;Resources;Role;Social status;Time;Translational Research;United States National Institutes of Health;Universities;Vocational Guidance;base;cardiometabolism;cardiovascular health;career;career development;innovation;interest;mid-career faculty;novel;novel therapeutics;progenitor;programs;recruit;senior faculty;stem cell function;success;synergism


application_id: 10452737
project_number: 5P30GM127607-05
project_title: Imaging and Physiology Core
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3
subproject_number: 5794
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
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 Imaging and Physiology Core (Core E) will nurture the Centers continued growth and hasten projectdevelopment by promoting scientific excellence in investigations of cardiometabolic diseases. Core E willanticipate the needs of the Centers investigatorsparticularly junior investigators whose collective needschangeby maintaining uninterrupted communication with Center members regarding their projects directions.Core E will provide access to state-of-the-art instrumentation and deliver expert instruction related to non-invasive imaging murine surgical models and advanced microscopy. The Core will promote education on thetheory and technical appreciation of relevant approaches instrumentation and techniques. The Core willcollaborate with Center members particularly junior investigators to develop new tailored procedures to answertheir experimental questions. The Director will provide guidance not only for the techniques provided by Core Ebut also mentorship to the junior faculty members in the Center. In addition to meeting the needs of the Centersprojects the Core has established a viable plan to transition to financial independence during Phase III ofCOBRE support. These collective aspirational goals will be accomplished through the following Aims: i) SupportCenter projects through excellence in imaging and physiology; ii) Become a self-sustaining feature of the Centerby cultivating the Cores financial independence; iii) Develop new protocols and techniques for future imagingand physiology needs of the Center; iv) Educate and train investigators on the theory application and analysesrelated to imaging and physiology. Support during Phases I and II of COBRE the University the Center andfaculty members have contributed significantly to the extensive instrumentation in Core E. Such investmentsreflect the important role of Core E in the progress of the Center. The Director will continue developing newprotocols acquiring the latest instrumentation and initiating collaborations with additional investigatorsthroughout the campus community. The Core will make every effort to meet the imaging and physiology needsof all of the Center members while leveraging complementary resources on campus. This Core will maintain itscurrent excellent level of service and actively seek to improve its infrastructure while provide the Center memberswith state-of-the-art instrumentation. Such progress will continue with the long-term goal of establishing a self-sustaining Core. As Core E moves into Phase III the Core will formally engage its business model to bring itsplan for self-sufficiency to fruition. Core E will work closely with Core A to maintain its financial goals to ensureits effectiveness and to enhance its efficiency. Furthermore this Core will be pivotal in bringing this Center tonational prominence in cardiometabolic research. The results of such efforts have been and will continue to beevident in the Centers COBRE graduates numerous publications and growth in NIH funding of Core-supportedCenter members. Core E will remain a bedrock of technological development scientific innovation and relevanttraining for the Center as it tackles the greatest threats to health: diabetes and cardiovascular disease.

project_terms:
Address;Affect;Area;Attention;Businesses;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular Physiology;Cells;Centers of Research Excellence;Charge;Collaborations;Communication;Communities;Complications of Diabetes Mellitus;Counseling;Data Analyses;Development;Diabetes Mellitus;Disease model;Echocardiography;Education;Effectiveness;Ensure;Extramural Activities;Faculty;Felis catus;Fruit;Funding;Future;Goals;Grant;Growth;Health;Human Resources;Image;Individual;Infrastructure;Instruction;Investigation;Investments;Mentors;Mentorship;Microscopy;Mission;Modeling;Monitor;Mus;Obesity;Operative Surgical Procedures;Phase;Physiology;Policies;Procedures;Protocols documentation;Publications;Research;Research Design;Research Personnel;Resources;Role;Services;Surgical Models;Techniques;Tissue imaging;Training;Training and Education;United States National Institutes of Health;Universities;Work;cardiometabolism;confocal imaging;consumer product;flexibility;fluorescence imaging;heart function;imaging approach;imaging modality;improved;in vivo imaging;innovation;instrumentation;investigator training;meetings;member;non-invasive imaging;protocol development;sound;success;technological innovation;theories


application_id: 10452736
project_number: 5P30GM127607-05
project_title: Animal Models and Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3
subproject_number: 5793
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
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 function of the Animal Core of the University of Louisvilles Diabetes and Obesity Center (DOC) is toprovide members of the DOC with the resources facilities and knowhow needed for the developmentinterrogation and phenotyping of animal models for diabetes and obesity research using state-of-the-arttechniques procedures and protocols relevant to the evaluation of metabolism and assessment of adiposityinsulin resistance and the cardiovascular complications of diabetes. By successive accumulation of expertiseresources and experience the Core has become an integral component of the Center and an indispensableresource for diabetes and obesity research comparable with research cores at leading institutions around thecountry. Developing on this trajectory of success the Core will continue to provide unique and unduplicatedservices to UofL investigators and continue to grow by progressively acquiring and accumulating newcapabilities resources and expertise.

project_terms:
Animal Model;Animals;Capital;Cardiometabolic Disease;Cardiovascular system;Centers of Research Excellence;Complex;Complications of Diabetes Mellitus;Consultations;Consumption;Continuing Education;Core Facility;Country;Development;Diabetes Mellitus;Educational workshop;Equipment;Evaluation;Fees;Funding;Future;Grant;Human Resources;Infrastructure;Institution;Instruction;Insulin Resistance;Investments;Learning;Marshal;Metabolic;Metabolism;Methods;Modeling;Molecular;National Heart Lung and Blood Institute;National Institute of Environmental Health Sciences;Obesity;Phase;Phenotype;Procedures;Protocols documentation;Research;Research Personnel;Resource Sharing;Resources;Series;Services;Standardization;Structure;Study models;Superfund;Techniques;Technology;Time;Training;Training Activity;Universities;animal imaging;base;career;career development;detection method;expectation;experience;instrument;investigator training;lectures;member;metabolomics;pre-clinical;programs;success;user-friendly


application_id: 10452735
project_number: 5P30GM127607-05
project_title: Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3
subproject_number: 5792
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Overarching goal of the Center is to understand the mechanisms of pathophysiology of diabetesand obesity and their cardiovascular complications. The Bioanalytics Core is an integral part ofthe Center and will play a key role in the evolution of COBRE in Phase III. The Core will renderservices for rigorous and comprehensive bioanalytical analysis of diabetic specimens. It willprovide intellectual input with experimental design and state-of-the-art technical expertise toaddress the needs of Center investigators. The Core consists of a group of outstanding scientistswith expertise in chromatography mass spectrometry clinical chemistry cardiovascularphysiology and diabetes. Director of the Core Dr. Sanjay Srivastava has more than twenty fiveyears of research experience in analytical biochemistry and pathology vascular inflammationatherosclerosis and diabetes. He will oversee all the Core operations and will work closely withCenter investigators and COBRE-supported pilot project leaders to fulfill their analyticalbiochemistry needs. Dr. Lorkiewicz technical director of the Core has extensive experience instable isotope labeling and mass spectrometric analyses of small molecular weight compounds.He will assist the Center investigators with their metabolomics mercapturomics and otherchromatography/mass spectrometry analyses. Drs. Srivastava and Lorkiewicz will provide handson training to junior investigators for bioanalytical assays. The training acquired at the Core willfacilitate them to grow as scientists and expand their repertoire of technical skills. The Core isequipped with state-of-the-art clinical chemistry and analytical biochemistry equipment and islocated in the Delia Baxter Building. In addition to address the current requirements of the COBREprojects the Core will continue to expand its knowledgebase and technical expertise to satisfythe future needs of the Center. Long term goal of the Core is to become a fiscally independententity capable of providing cutting-edge pathology and bio-analytical services to researchersinterested in diabetes and cardiovascular pathophysiology. Continued excellence in pathologicalanalyses will foster collaborations which will not only help the Core financially but will alsoadvance the field in combatting diabetic complications.

project_terms:
Acetylcysteine;Address;Alkaloids;Analytical Biochemistry;Applications Grants;Area;Atherosclerosis;Benzene;Biological Assay;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Charge;Chemicals;Chromatography;Clinical Chemistry;Collaborations;Communities;Complete Blood Count;Complications of Diabetes Mellitus;Continuing Education;Data Analyses;Diabetes Mellitus;Directed Molecular Evolution;Educational workshop;Ensure;Equipment;Evolution;Experimental Designs;Extramural Activities;Faculty;Fee-for-Service Plans;Fostering;Functional disorder;Funding;Future;Glucose;Goals;Grant;Hepatic;Human Resources;Infrastructure;Kidney;Lipids;Maintenance;Malondialdehyde;Mass Chromatography;Mass Fragmentography;Mass Spectrum Analysis;Measures;Metabolic;Molecular Weight;Neurotransmitters;Obesity;Participant;Pathologic;Pathology;Pathway Analysis;Phase;Pilot Projects;Plasma;Play;Procedures;Program Research Project Grants;Protocols documentation;Research;Research Personnel;Resolution;Resources;Role;Science;Scientist;Services;Specimen;Stable Isotope Labeling;Structure;Superfund;Technical Expertise;Techniques;Tobacco;Training;United States National Institutes of Health;Universities;Volatile Fatty Acids;Work;Xenobiotic Metabolism;cost;design;detection method;diabetic;experience;experimental study;instrument;interest;investigator training;knowledgebase;mass spectrometer;member;metabolomics;monoamine;muconic acid;non-diabetic;novel;operation;oxidation;ranpirnase;research facility;stable isotope;symposium;toxicant;urinary;vascular inflammation;volatile organic compound;webinar


application_id: 10452734
project_number: 5P30GM127607-05
project_title: Flow Cytometry Core
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3
subproject_number: 5791
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe Flow Cytometry Core (Core B) has four major goals. Its primary function is to provide state of the artequipment and expertise for flow cytometric analysis of cellular antigen expression function metabolism andsignaling thereby supporting cardiovascular research in diabetes and obesity at the University of Louisville. CoreB personnel are highly-experienced investigators who have worked for several years on flow cytometry usingvarious tissues and cells from multiple species and have extensive expertise in rare event analysis. Thecomplementary nature of their backgrounds and areas of expertise coupled with their collegial nature providesa strong foundation for productive synergy within this Core and its productive interactions with other investigatorsin the DOC at the UofL and with collaborative interactions with other Institutes. Secondly the Core is committedto an educational goal. Not only will all users be trained on the operation of instruments it is the intent that theseusers completely understand cytometric theory application and data analysis. Through hands-on training andeducational presentations it is hoped that all current and future users will be able to competently incorporateflow cytometry as an analytical tool. Third the Core is committed to developing its scope and operation to supportmultidimensional flow cytometry needs in the future. It will continue to upgrade its equipment and analyticalrepertoire. Finally this Core has the ultimate goal of developing into a self-supporting and large-scale flowcytometry operation that will cater not only to the specific needs of the Center but to other University andextramural investigators interested in diabetes and obesity research. A fully developed Flow Cytometry Corewill be a significant asset in developing future multi-investigator projects and for helping researchers conductmultifaceted basic and clinical investigations aimed at the amelioration of health hazards caused by diabetesand obesity.

project_terms:
Address;Adipocytes;Adopted;Antigens;Apoptotic;Area;Award;Biological Assay;Blood Cell Count;Blood Platelets;Cardiovascular system;Cell Therapy;Cells;Centers of Research Excellence;Chemicals;Clinical Research;Color;Communities;Continuing Education;Coupled;Data;Data Analyses;Detection;Diabetes Mellitus;Dyes;Epidemic;Equipment;Event;Extramural Activities;Fee-for-Service Plans;Fees;Felis catus;Flow Cytometry;Foundations;Funding;Future;Generations;Goals;Grant;Health Hazards;Human Resources;Immune;Individual;Institutes;Institution;Metabolism;Monitor;Nature;Obesity;Phase;Population Analysis;Procedures;Protocols documentation;Reagent;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Sampling;Services;Signal Transduction;Structure;Techniques;Tissues;Training;Universities;Work;analytical tool;antigen detection;base;career development;cell determination;clinical investigation;diabetic patient;event cycle;experience;experimental study;innovation;instrument;interest;investigator training;macrophage;meetings;member;mitochondrial membrane;monocyte;novel;obese patients;operation;peripheral blood;programs;rapid detection;stem cell population;synergism;theories;tissue stem cells


application_id: 10452733
project_number: 5P30GM127607-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3
subproject_number: 5790
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Core A will continue to provide scientific fiscal administrative and logistic oversight to all aspectsof the Center. As before Core personnel will facilitate communication among investigators andthe sharing of reagents tools specimens and data to ensure appropriate allocation and effectiveuse of Center funds. The Core will also continue to: provide clerical support; coordinateinteractions between facility cores and research projects; organize regular investigator meetingsand; provide biostatistical support. In addition to these functions the Core will develop andimplement a clear path for transition to and attainment of independent status of the Cores. TheCore will provide leadership and administrative support needed to maintain the thematic focus ofthe Center and to achieve Center goal. It will provide oversight to a pilot project program thatprovides seed funding for promising projects by new investigators. Core personnel will encouragethe exploratoin of new research avenues and phase out unpromising resarch and maximize theintellectual environment of the Center. The Core will also provide statistical support to assist instudy design and analysis and help in developing grant proposals and maintain data andbiospecimen biorepositories. It will monitor evaluate overall Center progress in achieving specificmilestones. Core personel will prepare annual scientific reports and financial statements and planand organize symposia seminars and regulary-scheduled meetings. They will invite prominentscientists to present seminars and interact with Center members and communiate with Universityand NIH officials to report progress and discuss Center related issues. In consultation with theexternal and internal advisory committee the Program Director will evaluate core progress andthe achievement of Center goals. If required Core A personnel will work with university officialsto increase the critical mass of investigators working in the Center. If it becomes necessary CoreA will adopt remedial measures for Principal Investigators who fail to satisfactory review by theExternal Advisory Committee. The Core will also maintain a Center Website and faciliate thedissemination of information about Center activities as well as diabetes and obesity.

project_terms:
Achievement;Adopted;Advisory Committees;Applications Grants;Award;Biometry;Cardiovascular system;Centers of Research Excellence;Communication;Consult;Consultations;Core Facility;Data;Data Analyses;Development;Diabetes Mellitus;Ensure;Environment;Extramural Activities;Faculty;Fostering;Funding;Future;Generations;Goals;Human Resources;Individual;Information Dissemination;Journals;Leadership;Logistics;Measures;Mentors;Monitor;Obesity;Peer Review;Performance;Phase;Pilot Projects;Postdoctoral Fellow;Principal Investigator;Productivity;Progress Reports;Publications;Reagent;Reporting;Research;Research Activity;Research Design;Research Personnel;Research Project Grants;Resources;Sampling;Schedule;Scientist;Seeds;Selection Criteria;Series;Services;Specimen;Training Activity;Training and Education;United States National Institutes of Health;Universities;Visit;Work;biobank;career;career development;experimental study;graduate student;meetings;member;professor;programs;recruit;symposium;tool;web site


application_id: 10452732
project_number: 5P30GM127607-05
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2022-08-02
opportunity_number: PAR-17-249
application_type: 5
activity_code: P30
ic: GM
serial_number: 127607
program_official: ZHOU, YANG
project_start_date: 2018-07-01
project_end_date: 2024-06-30
study_section: ZGM1-RCB-3(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_abstract:
ABSTRACTThis application is to support Phase III of the COBRE-supported Diabetes and Obesity Center atthe University of Louisville. The Center was established in 2008 with the central objective ofsupporting molecular cellular experimental translational and clinical investigations into thecardiovascular causes and consequences of diabetes and obesity. During Phase I and II theCenter underwent phenomenal growth. It has facilitated the career development of juniorinvestigators provided core support to investigators involved in diabetes obesity andcardiovascular research and has provided training and mentorship to graduate students andpost-doctoral fellows. The goal in Phase III is to provide sustainable core support to Centerinvestigators and strengthen diabetes and obesity research at the institution; to maintain andenhance state-of-the-art infrastructure foster research and support basic and translationalresearch within the thematic focus of the Center. In Phase III the Center will support 5 Cores Core A: An Administrative Core Core B: Flow Cytometry Core Core C Pathology and BioanlyticsCore Core D: Animal Models and Phenotyping Core and Core E: Imaging and Physiology Core.The Center will also support a Pilot Project Program to stimulate new research by providing seedfunding to promising projects that could obtain extramular funding. The Center provides uniqueopportunities for research in the areas of cardiovascular metabolism inflammation andcardiometabolic disease stem cell biology and environmental determinants of cardiometabolicdisease. A dynamic self-sustaining Diabetes and Obesity Center at the University of Louisvillewill not only provide fertile ground for innovative studies in the area of diabetes obesity andcardiovascular research but it will enable the institution to become an enduring hub of learningmentoring training and fostering academic excellence.

project_terms:
Acute;Animal Model;Animals;Area;Arts;Award;Basic Science;Biomedical Research;Blood Vessels;Cardiometabolic Disease;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Centers of Research Excellence;Clinical;Complement;Core Facility;Country;Data;Development;Diabetes Mellitus;Discipline;Disease;Endocrine;Ensure;Environment;Environmental Exposure;Epidemic;Event;Excess Mortality;Faculty;Flow Cytometry;Fostering;Foundations;Funding;Goals;Grant;Growth;Health;Human;Image;Individual;Inflammation;Infrastructure;Institution;Insulin Resistance;Interdisciplinary Study;Investigation;Laboratories;Lead;Learning;Medicine;Mentors;Mentorship;Metabolic;Metabolism;Molecular;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathology;Phase;Phenotype;Physiology;Pilot Projects;Postdoctoral Fellow;Public Health Schools;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Research Training;Resources;Risk Factors;Science;Seeds;Services;Solid;Stroke;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;Vascular Diseases;Work;base;cardiovascular disorder risk;career;career development;clinical investigation;diabetic;graduate student;innovation;interdisciplinary approach;interest;member;multidisciplinary;novel;prevent;programs;recruit;stem cell biology;sudden cardiac death

public_health_relevance:
This project is to support core services and pilot funding for promising projects as the Diabetesand Obesity Center at the University of Louisville. Diabetes and obesity as well as theircardiovascular complications are the leading causes of death worldwide and their increase hasreached epidemic proportions. Further research in this area could lead to new understanding ofthe mechanisms that result in the development of these diseases and how their adverse healtheffects could be therapeutically minimized and managed.


application_id: 10452614
project_number: 5R34DA053140-02
project_title: Integrated PrEP Interventions for People Who Inject Drugs in Rural Kentucky
administering_ic: NIDA
award_notice_date: 2022-07-22
opportunity_number: PA-18-780
application_type: 5
activity_code: R34
ic: DA
serial_number: 053140
program_official: JENKINS, RICHARD A
project_start_date: 2021-08-01
project_end_date: 2024-07-31
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 6851115
contact_pi: SURRATT, HILARY L
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTRural areas in the United States are increasingly impacted by HIV tied to the ongoing opioid epidemicgrowing stimulant use and widespread drug injection. Kentucky (KY) is among seven states identified withheavy rural HIV burden and increasing rates of new HIV diagnoses attributable to injection drug use. RuralHIV outbreaks among people who inject drugs (PWID) have occurred recently in KYs neighboring stateshighlighting the urgent need to implement proven HIV prevention and harm reduction strategies for PWID inKYs rural areas. A key pillar of Ending the HIV Epidemic (EHE): A Plan for America is the prevention of newHIV infections through scale up of evidence-based interventions including syringe service programs (SSPs)and Pre-exposure prophylaxis (PrEP). Our R21 in KYs Appalachian region demonstrated consistent utilizationof rurally located SSPs by high-risk PWID making SSPs a critical venue to scale delivery of comprehensiveHIV prevention services in rural areas. In a prior RCT conducted by the PI of this application strengths-basedcase management (SBCM) interventions were shown to be effective in increasing HIV testing and overcomingbarriers to medical care among people who use drugs. Building on this prior work and ongoing collaborationwith rural SSPs in KY this R34 will adapt and integrate a novel PrEP initiation intervention at point ofcare in rural SSPs in two KY counties that are among the nations top 10 most vulnerable to HIVamong PWID and conduct a preliminary test of its efficacy. The Specific Aims are to: 1) Assess clientprovider organization and structural-level facilitators and barriers to integration of a PrEP focusedSBCM (SBCM-PrEP) intervention into routine SSP practice. Guided by the PRISM model we will conductsemi-structured key informant interviews with PWID clinical care and harm reduction service providers andfacility administrators in our targeted SSP implementation locations to identify individual organizational andstructural challenges and opportunities to adapt the SBCM-PrEP to enhance client acceptability accessibilityand compatibility with clinical workflow; 2) Adapt an evidence-based SBCM protocol to provide PrEPintervention services for PWID in SSP sites. Using in-depth interview data from Aim 1 we will adapt refineand incorporate HIV prevention content most salient to PrEP care into the SBCM-PrEP following the ADAPTITT framework; and 3) Examine feasibility acceptability and preliminary efficacy of the adapted SBCM-PrEP. 80 participants will be randomized into: CDC-PrEP (an in-use PrEP intervention based on CDCguidelines) or SBCM-PrEP. Primary outcomes include feasibility and acceptability (measured by interventionattendance engagement and satisfaction) during the active intervention period and preliminary efficacy onPrEP initiation (measured by dispensed PrEP prescription) 3- and 6- months post-baseline. The proposedstudy fills a gap in evidence for PrEP studies among rural PWID by testing brief interventions that address bothindividual and structural challenges to PrEP uptake through an integrated point of care service delivery model.

project_terms:
AIDS prevention;Address;Administrator;Americas;Appalachian Region;Caring;Case Management;Centers for Disease Control and Prevention (U.S.);Client;Clinical;Collaborations;County;Data;Disease Outbreaks;Drug user;Education;Environment;Epidemic;Equipment;Evidence based intervention;Guidelines;HIV;HIV Infections;HIV diagnosis;Harm Reduction;Human immunodeficiency virus test;Incidence;Indiana;Individual;Infrastructure;Injecting drug user;Injections;Intervention;Interview;Kentucky;Knowledge;Literature;Location;Measures;Medical;Monitor;Needle-Exchange Programs;North Carolina;Participant;Pharmaceutical Preparations;Practical Robust Implementation and Sustainability Model;Prevention;Protocols documentation;Provider;Randomized;Risk;Rural;Rural Community;Service delivery model;Services;Site;Sterility;Structure;Syringes;Testing;United States;West Virginia;Woman;Work;acceptability and feasibility;barrier to care;base;brief intervention;clinical care;drug testing;evidence base;health care availability;high risk;informant;injection drug use;men;novel;opioid epidemic;point of care;pre-exposure prophylaxis;prevention service;preventive intervention;primary outcome;risk perception;rural area;satisfaction;scale up;screening;service intervention;service providers;social stigma;stimulant use;tool;transmission process;uptake

public_health_relevance:
PROJECT NARRATIVEKentucky (KY) is among seven states identified with heavy rural HIV burden and increasing rates of new HIVdiagnoses attributable to injection drug use. The expansion of PrEP has been strongly endorsed as a keystrategy for impacting the course of the HIV epidemic however PrEP trials among people who inject drugs arelargely absent in rural areas. This R34 application will adapt and integrate a novel PrEP initiation interventionat point of care in rural syringe service programs in two KY counties that are among the nations top 10 mostvulnerable to HIV among PWID and fills a gap in evidence by testing brief interventions that address bothindividual and structural challenges to PrEP uptake.


application_id: 10452276
project_number: 1R21AA029201-01A1
administering_ic: NIAAA
award_notice_date: 2022-08-29
opportunity_number: PA-20-194
application_type: 1
activity_code: R21
ic: AA
serial_number: 029201
suffix: A1
program_official: HAGMAN, BRETT THOMAS
project_start_date: 2022-09-01
project_end_date: 2024-07-31
study_section: Clinical, Treatment and Health Services Research Study Section[AA-3]
contact_pi_person_id: 9711222
contact_pi: WEAFER, JESSICA J
other_pis: MOLONEY, MAIREAD
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Testing an Online Insomnia Intervention to Reduce Alcohol Use via Improved Sleep Among Heavy Drinkers

project_abstract:
ABSTRACTAlcohol use disorder (AUD) inflicts enormous physical emotional and financial burdens on the individual andsociety at large. Insomnia a public health crisis in its own right is highly prevalent among individuals withAUD. Both AUD and insomnia are particularly problematic in women as women have a 40% higher insomniarisk than men and incidence of AUD is increasing among women at alarming rates. AUD and insomnia have abidirectional and feed-forward relationship such that excessive alcohol consumption negatively impacts sleepand disrupted sleep contributes substantially to alcohol-related problems. Moreover our preliminary datasuggests that this association may be particularly pronounced in women. Importantly insomnia often precedesproblematic drinking in both adolescents and adults. As such insomnia serves as a potential interventiontarget for hazardous drinking. The recommended first-line insomnia treatment - cognitive behavioral therapy forinsomnia (CBT-I) - holds promise as a therapy that may reduce alcohol use via improved sleep. CBT-I trainedpractitioners however are rare and the multiple required visits may not be covered by insurance. One solutionto these obstacles is the implementation of efficacious accessible electronic cognitive behavioral therapy forinsomnia (e-CBT-I). For this project we will utilize Sleep Healthy Using the Internet (SHUTi) the most widelyused and well-validated version of e-CBT-I in a sample of heavy drinking community dwelling adults withinsomnia. We have exciting preliminary data showing that SHUTi improves sleep and reduces alcoholconsumption in this population. Here we will extend these findings by conducting a well-powered randomizedcontrolled trial. We will utilize a two-arm single blinded randomized control mixed methods design. For theactive treatment condition (n=50) participants will have 9 weeks to complete the 6-week SHUTi program. In thecontrol condition (n=50) participants will have access to a web-based sleep education program for the sametime period. Both programs will be accessed through the Internet and will contain information about sleep andsleep hygiene; only the SHUTi group will receive feedback and targeted recommendations based on sleepdiary data. Alcohol use insomnia severity and sleep quality will be quantitatively assessed via online surveyand sleep and alcohol use diaries at baseline and three time points: T1 (at the end of the 9-week interventionperiod) T2 (3-months post-intervention) and T3 (6 months post-intervention). All participants will additionallytake part in semi-structured qualitative interviews at T1. Our central hypothesis is that SHUTi will reducealcohol use via improved sleep in this population and that effects will be more pronounced in women. Thisproject will be the first to test SHUTi in community dwelling heavy drinking adults with insomnia. If successfulour intervention will provide an easily-accessible cost effective intervention for a high-risk population andholds potential for positive public health impact especially for women.

project_terms:
Adolescent;Adult;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic beverage heavy drinker;Appalachian Region;Asthma;Cancer Survivor;Cellular Phone;Cognitive Therapy;Communities;Data;Diagnosis;Education;Effectiveness;Emotional;Feedback;Female;Financial Hardship;Goals;Heavy Drinking;Incidence;Individual;Insurance;Internet;Intervention;Interview;Learning Module;Mediating;Methods;Office Visits;Online Systems;Participant;Personal Computers;Persons;Play;Population;Prevention;Public Health;Randomized;Randomized Controlled Trials;Recommendation;Reporting;Research;Risk;Role;Sampling;Self Administration;Severities;Sex Differences;Single-Blind Study;Sleep;Sleep disturbances;Sleeplessness;Societies;Structure;Surveys;Tablets;Telephone Interviews;Testing;Time;Training;United States;Visit;Woman;active method;aged;alcohol related problem;alcohol use disorder;arm;base;binge drinking;comorbidity;cost;cost effective intervention;design;diaries;drinking;effectiveness evaluation;hazardous drinking;high risk;high risk population;improved;innovation;male;men;novel;post intervention;prevent;programs;recruit;reduced alcohol use;sleep health;sleep quality;stem;symptomatology

public_health_relevance:
Alcohol use disorder (AUD) is an urgent and escalating public health problem estimated to cost the UnitedStates $249 billion per year. Insomnia a public health crisis in its own right often precedes problematicdrinking thus treating insomnia may serve as a novel prevention target for AUD. Our innovative mixedmethods project will be among the first to test a technologically-facilitated non-pharmaceutical insomniaintervention to reduce alcohol consumption in heavy-drinking community dwelling adults with insomnia.


application_id: 10451184
project_number: 1R01HL163818-01
project_title: Systematic identification of cardiotoxic e-cigarette flavorants
administering_ic: NHLBI
award_notice_date: 2022-04-15
opportunity_number: RFA-OD-21-002
application_type: 1
activity_code: R01
ic: HL
serial_number: 163818
program_official: POSTOW, LISA
project_start_date: 2022-04-22
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1 IFCN-E (56)]
contact_pi_person_id: 11702638
contact_pi: CARLL, ALEX PERROW
other_pis: NYSTORIAK, MATTHEW A
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_terms:
Action Potentials;Acute;Adult;Adverse effects;Aerosols;Affect;Aldehydes;Arrhythmia;Biological;Biological Assay;Blood Circulation;Cardiac;Cardiac Electrophysiologic Techniques;Cardiac Myocytes;Cardiotoxicity;Cardiovascular Physiology;Cardiovascular system;Cessation of life;Chemicals;Chronic;Conscious;Consumption;Data;Dependence;Devices;Dose;Electrocardiogram;Electronic cigarette;Electrophysiology (science);Emerging Tobacco Products;Equilibrium;Evaluation;Exposure to;Flavoring;Food Additives;Functional disorder;Future;Heart;Heart Rate;Heating;Human;In Vitro;Incidence;Individual;Ingestion;Inhalation;Knowledge;Link;Long-Term Effects;Lung;Malignant Neoplasms;Marketing;Modeling;Monitor;Mus;Negative Finding;Nicotine;Oral Ingestion;Outcome;Pathologic;Pathway interactions;Performance;Periodicity;Policies;Prevalence;Propylene Glycols;Regulation;Research Priority;Risk;Safety;Serum;Smoker;Smoking;Solvents;Structure;Sum;Testing;Tissues;Toxic effect;Toxicology;Toxin;Ventricular;Ventricular Arrhythmia;Work;air filter;base;clinical predictors;e-cigarette aerosols;electronic cigarette use;electronic cigarette user;electronic liquid;experimental study;heart cell;heart function;high risk;in vivo;nicotine exposure;nicotine inhalation;respiratory;response;stem;sudden cardiac death;tobacco products;tobacco regulatory science;vegetable glycerin;young adult


application_id: 10449473
project_number: 1K01ES033289-01A1
project_title: Evaluating mechanisms of sex differences in environmentally-induced metabolic diseases
administering_ic: NIEHS
award_notice_date: 2022-06-03
opportunity_number: PAR-21-172
application_type: 1
activity_code: K01
ic: ES
serial_number: 033289
suffix: A1
program_official: SCHUG, THADDEUS
project_start_date: 2022-06-03
project_end_date: 2025-05-31
study_section: Special Emphasis Panel[ZES1 LWJ-S (K1)]
contact_pi_person_id: 14294360
contact_pi: WAHLANG, BANRIDA
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Address;Affect;Agricultural Workers;Androgen Receptor;Automobile Driving;Award;Binding;Biological;Biological Markers;Body Composition;Cardiovascular system;Chemicals;Chlordan;Development;Diabetes Mellitus;Disease;Dose;Dyslipidemias;Educational Background;Endocrine;Endocrine Disruptors;Endocrine disruption;Energy Intake;Environment;Environmental Epidemiology;Environmental Exposure;Environmental Health;Estrogen Receptors;Ethnic Origin;Exhibits;Exposure to;Female;Food Contamination;Future;Gender;Glucose Intolerance;Goals;Grant;Habits;Health;Health Care Costs;Hepatic;Hepatotoxicity;High Fat Diet;High Prevalence;Home;Hormones;Human;Hyperglycemia;Hyperlipidemia;Hypertension;Incidence;Ingestion;Injury;Investigation;Isoptera;Knowledge;Lead;Lipids;Liver;Measures;Metabolic;Metabolic Diseases;Metabolic syndrome;Metabolism;Mind;Molecular;Morbidity - disease rate;Mus;Obesity;Organ;Outcome;Pathology;Policy Maker;Polychlorinated Biphenyls;Population;Postmenopause;Prevalence;Process;Proteome;Proteomics;Public Health;Race;Receptor Activation;Receptor Signaling;Reporting;Research;Resistance;Risk;Risk Factors;Serum;Sex Differences;Signal Pathway;Socioeconomic Status;Symptoms;Techniques;Testing;Therapeutic;Toxic effect;Training;Vulnerable Populations;Woman;Work;Xenobiotics;abdominal fat;arm;authority;base;contaminated water;design;diet-induced obesity;effective intervention;environmental chemical;epidemiology study;gene interaction;glucose tolerance;in vitro Model;in vivo Model;male;men;mouse model;non-alcoholic fatty liver disease;nutrition;organochlorine pesticide;organochlorine pesticide exposure;persistent organic pollutants;prevent;receptor;sedentary lifestyle;sexual dimorphism;toxicant

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


application_id: 10449466
project_number: 1K01AG073698-01A1
administering_ic: NIA
award_notice_date: 2022-07-18
opportunity_number: PA-20-190
application_type: 1
activity_code: K01
ic: AG
serial_number: 073698
suffix: A1
program_official: JOSEPH, LYNDON
project_start_date: 2022-08-01
project_end_date: 2027-06-30
study_section: Career Development For Early Career Investigators Study Section [AGCD-2]
contact_pi_person_id: 12504171
contact_pi: SAMAAN, MICHAEL A
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advisory Committees;Aerobic Exercise;Age;Aging;Area;Biochemical;Biological Markers;Biomechanics;Biometry;Cartilage;Cartilage Matrix;Chronic;Clinical;Data;Degenerative polyarthritis;Development;Disease;Disease Progression;Elderly;Exercise;Exhibits;Extensor;Fibrosis;Functional disorder;Goals;Health;Hip Joint;Hip Osteoarthritis;Hip Pain;Hip region structure;Image;Intervention;Knee Osteoarthritis;Knowledge;Lead;Literature;Magnetic Resonance Imaging;Measures;Mechanical Stress;Mechanics;Mentored Research Scientist Development Award;Muscle;Muscle function;Musculoskeletal;Pain;Patient Self-Report;Patients;Physical therapy;Population;Principal Investigator;Protocols documentation;Recommendation;Research;Research Personnel;Resources;Serum;Stress Tests;Techniques;Therapeutic;Torque;Total Hip Replacement;Training;United States;Work;age related;aging population;base;career;chronic pain patient;exercise intervention;exercise program;gait rehabilitation;improved;innovation;insight;joint loading;mammalian COMP;multidisciplinary;multimodality;muscle physiology;novel;novel imaging technique;preservation;programs;prospective;simulation;skills;symptom treatment


application_id: 10449267
project_number: 5R01CA211137-05
project_title: Targeting Abl kinases in BRAF-driven melanomas
administering_ic: NCI
award_notice_date: 2022-07-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 211137
program_official: MERCER, NATALIA
project_start_date: 2018-08-13
project_end_date: 2024-07-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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:
Despite the success of new targeted agents and immunotherapies metastatic melanoma remains an incurabledisease for many patients. Although BRAF inhibitors (BRAFi) show promise for reducing metastatic burdensome melanomas are intrinsically resistant and most responding patients eventually acquire resistance. Thesedata underline the importance of identifying new markers for treatment response and novel drug combinationsfor treating metastatic and BRAFi-resistant disease. We show that Abl/Arg non-receptor tyrosine kinases arehighly expressed in melanoma and are activated in a subset (40-60%). Moreover SFKs and BRAFV600E themost common genetic alteration in melanoma both contribute to Abl/Arg activation in melanoma cells. Onceactivated Abl/Arg promote proliferation survival a switch in EMT transcription factor expression invasion andmetastasis and bidirectionally regulate and potentiate BRAFV600E signaling. Moreover inhibitors of Abl/Arg anda parallel pathway which drives intrinsic BRAFi resistance (PI3K/Akt/PTEN) cooperate to prevent melanomaviability and tumor growth. Based on these findings we hypothesize that BRAFV600E/ERK and SFKscooperatively activate Abl/Arg which synergize with Akt to drive melanoma development progressionphenotypic switching and subsequent resistance. We propose a comprehensive hypothesis-drivenexperimental design that will establish Abl/Arg as novel and exploitable drug targets. Aim 1 will define themechanism by which Abl/Arg are activated in melanoma. To achieve our objective biochemical molecularbiological and cell biological approaches using melanocytes melanoma cell lines tissue microarrayspharmacological inhibitors/RNAi mass spectrometry and immunohistochemistry will be used to test theprediction that BRAFV600E/ERK-mediated phosphorylation prevents nuclear targeting of Abl and facilitatesactivation of Abl/Arg by SFKs. In Aim 2 2D/3D culture rescue experiments and xenograft approaches will beused to identify the mechanism by which Abl/Arg drive the EMT transcription factor switch potentiateBRAFV600E signaling and promote acquired BRAFi resistance. Finally in Aim 3 genetically engineered (GEM)and xenograft mouse models as well as loss- and gain-of-function approaches will be used to test theprediction that Abl/Arg cooperate with activated Akt in mutant PTEN melanomas to promote melanomagrowth/metastasis and BRAFi/MEKi resistance. Data obtained from this project not only will allow us to gainimportant insight into fundamental mechanisms by which Abl/Arg are activated in melanoma which likely isapplicable to other solid tumors but also may lead to clinical studies testing the efficacy of Akt inhibitors incombination with Abl/Arg inhibitors for treating mutant BRAF/PTEN melanomas which often are resistant tocurrent therapeutic approaches.

project_terms:
Automobile Driving;BRAF gene;Binding;Binding Sites;Biochemical;Biological;Cell Cycle Progression;Cell Line;Cells;Chronic;Clinical Research;Complex;Data;Development;Disease;Disease Resistance;Disease remission;Drug Targeting;Environment;Experimental Designs;FDA approved;Genetic Engineering;Goals;Growth;Immunohistochemistry;Immunotherapy;Incidence;Intrinsic drive;Knock-in;Lead;Link;Malignant Neoplasms;Masks;Mass Spectrum Analysis;Mediating;Melanoma Cell;Messenger RNA;Metastatic Melanoma;Molecular;Mucous Membrane;Mutation;Nature;Neoplasm Metastasis;Nuclear;Nuclear Localization Signal;Oncologist;Outcome;PTEN gene;Pathway interactions;Patients;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Physiological;Play;Positioning Attribute;Proteins;Proto-Oncogene Protein c-kit;RNA Interference;Refractory Disease;Repression;Research;Resistance;Resistance development;Role;Signal Transduction;Solid Neoplasm;Sun Exposure;TWIST1 gene;Testing;Therapeutic;Threonine;Time;Tissue Microarray;Work;Xenograft Model;Xenograft procedure;base;design;efficacy testing;experimental study;gain of function;genetic approach;in vivo;in vivo Model;inhibitor;innovation;insight;leukemia;loss of function;melanocyte;melanoma;mouse model;mutant;novel;novel drug combination;novel marker;prevent;recruit;src-Family Kinases;success;targeted agent;therapy resistant;three dimensional cell culture;transcription factor;treatment response;tumor growth;young woman

public_health_relevance:
Metastatic melanoma is one of the deadliest cancers and although new treatments are promising somemelanomas do not respond to the treatments or develop resistance. This proposal examines the role of Ablkinases (proteins known to promote leukemia development) in melanoma identifying mechanisms by whichthey are activated and contribute to melanoma development and therapeutic resistance. The ultimate goal is totest whether FDA-approved drugs targeting Abl kinases can be utilized in combination with other agents totreat resistant disease.


application_id: 10448281
project_number: 5R01CA168658-09
project_title: Cellular Metabolites regulating cancer cell adaptation
administering_ic: NCI
award_notice_date: 2022-07-11
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 168658
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2013-05-02
project_end_date: 2024-06-30
study_section: Cellular Signaling and Regulatory Systems Study Section[CSRS]
contact_pi_person_id: 8821411
contact_pi: LEE, YOUNG-SAM
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Cellular metabolites regulating cancer cell adaptation SAICAR is a metabolite accumulates in cancer cells upon glucose starvation or EGF stimulation. Uponaccumulation SAICAR promotes cancer cell survival and proliferation by inducing tumor PKM2. However it isnot yet clear how cancer cells but not normal proliferating cells accumulate SAICAR. We hypothesize that transformation-induced alteration of pentose phosphate pathway is responsible forthe accumulation of SAICAR. In this project we will test this hypothesis while evaluating the importance ofSAICAR accumulation for the growth of tumor in vivo. The outcome of this project include a better understanding on metabolic reprogramming contributes tocancer. In addition the outcome of this project will determine whether SAICAR accumulation can be a potentialtherapeutic target.

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

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


application_id: 10448074
project_number: 3U01HL133359-05S1
project_title: Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
administering_ic: NHLBI
award_notice_date: 2021-07-27
opportunity_number: PAR-15-085
application_type: 3
activity_code: U01
ic: HL
serial_number: 133359
suffix: S1
program_official: ADHIKARI, BISHOW B
project_start_date: 2017-08-03
project_end_date: 2023-01-31
study_section: ZEB1-OSR-C(M1)S
contact_pi_person_id: 8356696
contact_pi: CAMPBELL, KENNETH S
other_pis: WENK, JONATHAN F
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACTThe goal of this research is to develop a predictive multiscale model that will improve understanding of familialcardiomyopathies and that can be used to help screen potential new therapies for cardiac disease. Familialcardiomyopathies are the most frequently inherited heart defect and affect about 700000 Americans. Most ofthe genetic mutations affect myosin or regulatory proteins that modulate myosin function. The majority of thesemutations also induce abnormal cardiac growth termed hypertrophy. This project will develop calibrate andvalidate an innovative multiscale model that uses data quantifying myosin-level function to predict how heartshypertrophy over time. This is a critical step on the path to developing patient-specific computer models that canbe used to optimize treatments for heart failure and to predict the effects of different types of pharmaceuticalintervention. In the future one could envision clinicians testing drug treatments in silico and selecting theintervention that produces the greatest long-term benefit for their patient.The research team consists of two physiologists/biophysicists (Campbell & Yengo) and two engineers (Wenk &Lee) who share a common interest in cardiac biology. Together their research skills span from structure-functionanalysis of myosin molecules to computer simulations of hearts that grow and remodel over time. The researchplan integrates state-of-the-art hierarchically-coupled mathematical models with validation experiments thatrange from stopped-flow molecular kinetic assays to magnetic resonance imaging of myocardial strain patterns.The model will be tested using molecular to organ-level experimental data obtained from wild-type mice and fromtransgenic animals that develop cardiac hypertrophy because of a K104E mutation in myosin regulatory lightchain. Additional tests will be performed using drugs that enhance (omecamtiv mecarbil) and inhibit (MYK-461)myosin-level contractile function.There are three specific aims.Aim 1: Integrate a multistate kinetic model of myosin into an organ-level finite framework to predict the effects ofgenetic and/or pharmaceutical modulation of myosin function.Aim 2: Develop growth and remodeling algorithms to predict chronic changes in ventricular structure and functionresulting from genetic and/or pharmaceutical modulation of myosin function.Aim 3: Calibrate and validate the model using experimental data quantifying different spatial and temporal scales.

project_terms:
Acute;Affect;Algorithms;American;Biological Assay;Biology;Cardiac;Cardiac Death;Cardiomyopathies;Cardiovascular Diseases;Cells;Chronic;Computer Models;Computer Simulation;Computer software;Coupled;DNA Sequence Alteration;Data;Data Analyses;Development;Drug usage;Elements;Engineering;Fiber;Future;Genetic;Geometry;Goals;Growth;Heart;Heart Abnormalities;Heart Diseases;Heart Hypertrophy;Heart failure;Histology;Hypertrophy;Inherited;Intervention;Kinetics;Laws;Magnetic Resonance Imaging;Mathematics;Measurement;Measures;Modeling;Molecular;Motor;Mutation;Myocardial;Myosin ATPase;Myosin Regulatory Light Chains;Organ;Patients;Pattern;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Proteins;Records;Research;Research Personnel;Sarcomeres;Scientist;Structure;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Transgenic Animals;Transgenic Mice;Treatment Failure;Validation;Ventricular;Ventricular Remodeling;Wild Type Mouse;Work;cell motility;drug testing;experience;experimental study;genetic regulatory protein;heart function;improved;in silico;inherited cardiomyopathy;innovation;interest;kinetic model;mathematical model;model development;molecular scale;multi-scale modeling;novel therapeutics;personalized medicine;predictive modeling;response;simulation;skills;software development;treatment optimization;treatment planning

public_health_relevance:
NARRATIVEThis project develops computer software and mathematical techniques that can be used to predict how heartsgrow and adapt in response to genetic mutations and/or drugs. In the future scientists and clinicians will be ableto use the software to help optimize personalized treatment plans for patients who have different types ofcardiovascular disease.


application_id: 10447778
project_number: 5R01HL142710-05
project_title: Regulation of Coronary Blood Flow
administering_ic: NHLBI
award_notice_date: 2022-06-13
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 142710
program_official: OH, YOUNGSUK
project_start_date: 2018-07-20
project_end_date: 2024-06-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 10920880
contact_pi: NYSTORIAK, MATTHEW 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
project_abstract:
PROJECT SUMMARYThe goal of this project is to gain a better understanding of mechanisms that underlie metabolic couplingbetween myocardial oxygen demand and oxygen supply via changes in coronary blood flow to the heart.Redox-sensitive voltage-gated potassium channels (i.e. Kv1.x) in coronary vascular smooth muscle (CVSM)are known to be essential to the enhancement of myocardial blood flow (MBF) in response to increasedcardiac workload. How Kv1 channel activity is enhanced in CVSM in response to metabolic signals from anactive myocardium is unknown. Here we propose an essential role for metabolic regulation of Kv1 channelactivity by the tetrameric assembly of cytosolic auxiliary Kv subunits which are members of the aldo-ketoreductase (AKR) superfamily and bind oxidized and reduced pyridine nucleotides (e.g. NAD(H)) with highaffinity. Our preliminary data are consistent with the global hypothesis that interactions between NAD(H) andKv1 and Kv2 impart precise control over the coupling between regional MBF with cardiac oxygen demand.In Aim 1 we will delineate the role of coronary Kv subunits in the regulation of the metabolic hyperemiaresponse. To do this we will use non-invasive myocardial contrast echocardiography (MCE) to measure MBFas a function of cardiac workload in anesthetized WT and Kv-null animals upon administration ofnorepinephrine (NE). The cell-specific contribution of Kv1 and Kv2 in CVSM to metabolic hyperemia will beexamined in double transgenic animals with inducible smooth muscle-specific expression of Kv in nullbackground animals. In vitro electrophysiology and myography will test the relative roles for Kv in altering thevoltage-dependence of Kv1 activation and inactivation and metabolic vasodilation respectively. In Aim 2 wewill elucidate the mechanism of Kv-mediated metabolic coupling. We will measure using electrophysiologythe relative functional contribution of Kv subunits to regulation of Kv1 activity upon specific manipulations incellular metabolism that alter the redox ratio of NADH:NAD+ in CVSM. We will quantify changes inNADH/NAD+ redox in CVSM using genetically-encoded fluorescent biosensors and MALDI-MS imaging anddetermine the role of NAD(H) turnover by Kv catalysis in regulation of coronary vasodilation andenhancement of MBF. In Aim 3 we will clarify the role of Kv in cardiovascular adaptation to exerciseconditioning. To do this we will subject WT and genetically-modified animals to a forced treadmill runningexercise protocol before measuring adaptations in MBF coronary vasodilatory capacity and Kv activation andinactivation properties. This aim will also address the overall dependence of physiological myocardialadaptations and enhancement of exercise capacity on coronary Kv-dependent changes in MBF.

project_terms:
Address;Affect;Affinity;Animals;Binding;Biochemistry;Biosensor;Blood;Blood Vessels;Blood flow;Caliber;Cardiac;Cardiovascular system;Catalysis;Cells;Complex;Contrast Echocardiography;Coronary;Coronary Arteriosclerosis;Coronary Vessels;Coronary artery;Coronary heart disease;Couples;Coupling;Cues;Data;Dependence;Development;Electrophysiology (science);Exercise;Family;Genetically Engineered Mouse;Genetically Modified Animals;Goals;Heart;Heart Contractilities;Heart Diseases;Heart Rate;Hyperemia;Image;Impairment;In Vitro;Ischemia;Link;Measurement;Measures;Mediating;Mediator of activation protein;Membrane Potentials;Metabolic;Metabolism;Molecular;Molecular Biology;Monitor;Myocardial;Myocardial Ischemia;Myocardial perfusion;Myocardium;Myography;NADH;Norepinephrine;Oxidation-Reduction;Oxides;Oxidoreductase;Oxygen;Patients;Physiological;Play;Process;Property;Proteins;Protocols documentation;Pump;Recurrence;Regulation;Resistance;Rest;Role;Running;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Stress;Structural Protein;Testing;Transgenic Animals;Vascular Smooth Muscle;Vasodilation;Voltage-Gated Potassium Channel;Work;Workload;arteriole;base;comorbidity;conditioning;coronary artery occlusion;exercise capacity;exercise regimen;exercise training;heart function;heart metabolism;hypoperfusion;in vivo;insight;member;novel;novel imaging technique;novel therapeutics;patch clamp;prevent;pyridine nucleotide;reconstitution;response;sedentary;therapeutically effective;tool;treadmill;voltage

public_health_relevance:
PROJECT NARRATIVERecent evidence indicates that defective coupling between cardiac metabolic demand and coronary vascularfunction contributes to myocardial ischemia in patients with heart disease. We will establish a novel paradigmof myocardial blood flow regulation by elucidating the molecular components that establish the connectionbetween cellular metabolism and vascular smooth muscle excitability. Thus insights generated during thisproject could reveal new targets for the development of more effective therapeutic strategies to prevent orreverse ischemia-related cardiac disorders.


application_id: 10447716
project_number: 5R01DE030939-02
project_title: A T.fosythia-derived protease inhibitor in periodontal health and disease
administering_ic: NIDCR
award_notice_date: 2022-07-28
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 030939
program_official: MCNEALY, TAMARA L
project_start_date: 2021-07-12
project_end_date: 2026-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: BAGAITKAR, JUHI
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:
Chronic inflammation in periodontitis is driven in part by the excessive uncontrolled proteolytic activity in theinfected periodontium. Well recognized periodontal pathogens including Porphyromonas gingivalis (Pg)Treponema denticola Tannerella forsythia (Tf) and Prevotella intermedia secrete proteases that contribute toinitiation and propagation of inflammatory reaction. The inflammation is inadvertently associated with release ofhost proteases from immune which not only add to tissue destruction by degradation of proteinaceouscomponents of extracellular matrix and enhancement of inflammation but are also the major executioners ofirreversible periodontal tissue damage. On the other side neutrophil serine proteases (NSPs) are essential forneutrophil antibacterial functions and control of inflammatory processes. In this respect it is fascinating that Tfproduces a lipoprotein a bacterial serpin (serine protease inhibitor) referred to as miropin. Miropin located onthe Tf cell surface efficiently inhibits a broad range of serine and cysteine proteases of diverse specificities andorigin including human NSPs (elastase and cathepsin G) cysteine cathepsin L and bacterial enzymes includingLys-specific gingipain (Kgp) produced by Pg. Kgp together with Arg-specific gingipains (RgpA and RgpB) isabsolutely essential virulence factor responsible for P. gingivalis pathogenicity in several animal models ofinfection. Nevertheless it was surprising that wild-type Tf totally abolished Pg-induced morbidity and mortality inmiropin-dependent manner during co-infection in a murine subcutaneous chamber model (our preliminary data).Based on these results we hypothesized that Tf-derived miropin plays a dual yinyang role in the pathobiologyof periodontitis. Furthermore we theorized that taking advantage of miropin unique structural features allowingit to inhibit proteases of different specificities using at least 3 different active sites within the reactive site loop wewill produce supermiropins of selective specificities targeting either host- or bacteria-derived proteases.Cumulatively the main objective of this proposal is to unravel the role of miropin-expressing Tf in thepathobiology of periodontitis as outlined in Specific Aims: (i) determine effect of miropin in Tf-Pg co-infection ongingival inflammation and alveolar bone loss (ABL) in a mouse oral gavage periodontitis model; (ii) geneticallyengineer Tf mutant strains expressing a supermiropin that inhibits a wide range of host and gingipains; (iii)investigate effects of purified recombinant inhibitors and Tf strains expressing them on neutrophil functions; and(iv) elucidate the mechanisms underlying the roles of host proteases and gingipains in pathogenic interactionsbetween Pg and Tf in oral lung and chamber models of infection using Tf strains expressing supermiropinstargeting selective sets of proteases. This knowledge will create novel perspectives in the treatment ofperiodontitis.

project_terms:
Active Sites;Affect;Alveolar Bone Loss;Animal Model;Anti-Bacterial Agents;Automobile Driving;Bacteria;Binding Sites;Biological Response Modifiers;Blood coagulation;Caspase;Cathepsin G;Cathepsin L;Cell surface;Cells;Chronic;Clinical;Communities;Complex;Cysteine;Data;Dental Plaque;Disease;Elastases;Enzymes;Event;Extracellular Matrix;Extracellular Matrix Proteins;Forsythia;Genetic Engineering;Gingiva;Goals;Gram-Negative Anaerobic Bacteria;Growth Factor;Health;Human;Immune;Infection;Inflammation;Inflammatory;Knowledge;Light;Lipoprotein (a);Lung;Lys-gingipain;Modeling;Morbidity - disease rate;Mus;Names;Nature;Nutrient;Oral;Organism;Outcome;Pathogenesis;Pathogenicity;Peptide Hydrolases;Periodontal Diseases;Periodontal Pocket;Periodontitis;Periodontium;Play;Porphyromonas gingivalis;Prevention;Prevotella intermedia;Process;Prokaryotic Cells;Protease Inhibitor;Reaction;Recombinants;Research;Resolution;Role;Serine Protease;Serine Proteinase Inhibitors;Serpins;Side;Signal Transduction;Site;Specificity;Testing;Thrombus;Tissues;Treponema denticola;Virulence;Virulence Factors;Yin-Yang;base;chronic inflammatory disease;co-infection;controlled release;design;dysbiosis;fascinate;gingipain;in vivo Model;inhibitor;member;mortality;mutant;neutrophil;novel;pathobiont;pathogen;periodontopathogen;receptor;scaffold;subcutaneous;subgingival biofilm;subgingival microbiome

public_health_relevance:
Tannerella forsythia is a Gram-negative anaerobic bacterium a member of dysbiotic subgingival bacterial floraconsidered the causative agent of a chronic inflammatory disease of the periodontium (chronic periodontitis).This bacterium is a unicorn among prokaryotes since it produces a unique protease inhibitor referred to miropinefficiently targeting host and bacterial serine and cysteine proteases of divergent specificities. As such miropinmay play a dual yinyang role in the pathobiology of periodontitis and this study is designed to cast light on thecontribution of miropin-expressing T. forsythia to health or disease of the periodontium.


application_id: 10447178
project_number: 5R01NS119337-03
project_title: Enhanced Mitochondrial Viability via Engineered Hyrdogels for Intrathecal Spinal Cord Delivery
administering_ic: NINDS
award_notice_date: 2022-06-16
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 119337
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-09-30
project_end_date: 2025-06-30
study_section: Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section[BNVT]
contact_pi_person_id: 6146950
contact_pi: RABCHEVSKY, ALEXANDER GEORGE
other_pis: PATEL, SAMIRKUMAR
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractMitochondrial dysfunction is pivotal to the neuropathological sequelae following traumatic spinal cordinjury (SCI). During this initial time window there is a significant loss of mitochondria with aninflammatory/oxidative environment that perpetuates the pathophysiology. It is hypothesized that torescue the cellular damage occurring following SCI one must replace damaged mitochondria while alsochanging the damaging microenvironment. We have documented that maintaining endogenousmitochondrial bioenergetics with acetyl-l-carnitine (ALC) an alternative mitochondrial biofuel or reducingoxidative stress by replenishing endogenous antioxidant glutathione (GSH) with N-acetylcysteine amide(NACA) after SCI results in increased but limited long-term functional neuroprotection. We have alsoreported that acute mitochondrial transplantation (MitoTxp) using intraspinal injections of mitochondriaisolated from rat soleus muscle significantly preserved bioenergetic function 48hr post-SCI. Howeverthis was sporadically successful due to the challenges of both accumulating mitochondria at the site ofinjury and maintaining their viability prior to cellular uptake. In the current proposal we will develop athermo-gelling erodible hydrogel system for the localized delivery of viable mitochondria to test theneuroprotective efficacy of combined MitoTxp and pharmaceutical interventions (ALC and/or NACA) aftercontusion SCI. The use of an injectable hydrogel will permit the development of a local environment whichcan aide in maintaining mitochondrial health through optimization of the hydrogel niche. We will determine1) optimum constituents for isolated mitochondria to remain viable for extended periods in polymerichydrogels 2) whether exogenous mitochondria transplanted via less invasive intrathecal route equallypreserve integrity of bioenergetics compared to intraspinal route and 3) consequences of acute ordelayed MitoTxp in combination with ALC and/or NACA on bioenergetics oxidative stress and functionalneuroprotection after SCI.

project_terms:
Acute;Antioxidants;Biochemical;Bioenergetics;Cell Count;Cells;Confocal Microscopy;Cytosol;Development;Diffuse;Dose;Engineering;Environment;Fostering;Functional disorder;Gel;Glutathione;Health;Histologic;Homeostasis;Hyaluronic Acid;Hydrogels;Hypersensitivity;In Vitro;Inflammatory;Injectable;Injury;Intervention;Intrathecal Injections;Kinetics;Knowledge;Label;Levocarnitine Acetyl;Locomotion;Maintenance;Mechanics;Methylcellulose;Mitochondria;Molecular Chaperones;Muscle Mitochondria;N-Acetylcysteinamide;Organelles;Osmotic Pressure;Outcome Measure;Oxidative Stress;PC12 Cells;Pharmacologic Substance;Polymers;Production;Property;Proteins;Rattus;Recovery of Function;Reporting;Research;Route;Site;Soleus Muscle;Spinal Cord;Spinal Cord Contusions;Spinal Injections;Spinal cord injury;System;Testing;Therapeutic Intervention;Time;Tissues;Transplantation;base;cell injury;combinatorial;design;dosage;experimental study;extracellular;functional outcomes;improved;in vivo;in vivo evaluation;injured;innovation;insight;mitochondrial dysfunction;neuroprotection;novel;preservation;uptake

public_health_relevance:
NarrativeThe current proposal is an innovative research plan to determine for the first time whether administration ofantioxidant (NACA) or alternative biofuel (ALC) known to maintain mitochondrial bioenergetics and promotefunctional neuroprotection after contusion spinal cord injury (SCI) in combination with novel intrathecal injectionof isolated muscle mitochondria embedded in a thermo-gelling erodible hydrogel system to protect mitochondrialviability fosters greater neuroprotective efficacy. The use of an injectable hydrogel will permit the developmentof a local environment which can aide in maintaining mitochondrial health through optimization of the hydrogelniche. The knowledge gained from the proposed experiments will provide direct insight into the use of hydrogelsystems for organelle delivery in vivo and the potential of this novel combinatorial therapeutic intervention(s) tomaintain cellular bioenergetics while reducing oxidative stress following SCI to promote tissue sparing andfunctional recovery.


application_id: 10447008
project_number: 5R01DE029498-02
project_title: Role of Notch-1/PLA2-IIA in oral dysbiosis inflammation and periodontal disease
administering_ic: NIDCR
award_notice_date: 2022-04-28
opportunity_number: PAR-19-172
application_type: 5
activity_code: R01
ic: DE
serial_number: 029498
program_official: CHANDER, PREETHI
project_start_date: 2021-08-01
project_end_date: 2026-04-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adverse effects;Agreement;Animal Model;Antimicrobial Effect;Antimicrobial susceptibility;Apoptosis;Autophagocytosis;Bacteria;Cell Proliferation;Cell physiology;Cells;Clinical;Complex;Data;Development;Disease;Ecology;Enzymes;Epithelial;Epithelial Cells;Event;Exhibits;Firmicutes;Gene Expression;Gingiva;Health;Human;Immune;In Vitro;Inbred BALB C Mice;Infection;Inflammation;Inflammatory;Knowledge;Lead;Lesion;Mediating;Microbe;Modeling;Molecular;Mouse Strains;Mucosal Immunity;Mucous Membrane;Mus;Mutation;Natural Immunity;Oral;Oral health;PLA2G2A gene;Pathogenicity;Pathway interactions;Periodontal Diseases;Periodontitis;Phospholipase A2;Play;Porphyromonas gingivalis;Property;Proteobacteria;Public Health;Receptor Activation;Reporting;Research;Research Design;Resistance;Role;Surface;Testing;Time;Transgenic Mice;Variant;adaptive immunity;antimicrobial;base;bone loss;chemokine;chronic infection;chronic inflammatory disease;dysbiosis;gingipain;in vivo;innovation;macrophage;malignant mouth neoplasm;microbial;microbial community;microbiota;mouse model;nonhuman primate;notch protein;oral cavity epithelium;oral microbiome;oral pathogen;overexpression;pathogen;prevent;receptor;recruit;response


application_id: 10446103
project_number: 2R01DA033862-09
administering_ic: NIDA
award_notice_date: 2022-06-15
opportunity_number: PA-20-185
application_type: 2
activity_code: R01
ic: DA
serial_number: 033862
program_official: LYNCH, SEAN EDWARD WINTERS
project_start_date: 2012-09-01
project_end_date: 2027-03-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 7018622
contact_pi: HAVENS, JENNIFER R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-06-15
project_title:
Examining the Impact of the Twin Epidemics of Methamphetamine and Opioid Use on Overdose Risky Sex and Treatment Engagement among PWUD in Two Rural Appalachian Cohorts

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

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

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


application_id: 10446041
project_number: 1R01DA054347-01A1
administering_ic: NIDA
award_notice_date: 2022-04-12
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: DA
serial_number: 054347
suffix: A1
program_official: HAMPSON, AIDAN
project_start_date: 2022-04-15
project_end_date: 2026-02-28
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 8906159
contact_pi: BABALONIS, SHANNA
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_title:
Cannabis Modulation of Outcomes Related to Opioid Use Disorder: Opioid Withdrawal Opioid Abuse Potential and Opioid Safety

project_abstract:
Abstract Opioids and cannabinoids are the two most widely used and misused drug classes. Worldwide anestimated 53 million people misuse opioids. In the US 2.6 million individuals meet criteria for opioid usedisorder and nearly 47000 people died in 2019 due to opioid overdose. At the same time global cannabis(i.e. marijuana) use is also at record high levels - in 2018 43.5 million individuals in the US reported past-yearcannabis use. Despite high rates of both licit and illicit use of these drug classes there are no controlled dataon the effects of cannabis in one of the most high-risk groups  individuals with opioid use disorder. Thus thecurrent project aims to explore how both acute (Study 1) and repeated (Study 2) cannabis administrationimpacts 1) opioid abuse potential 2) opioid withdrawal severity and 3) opioid safety/physiological effects. Twoindependent inpatient studies will be conducted during this 4-year project and each will utilize a randomizedwithin-subject double-blind placebo-controlled design and will enroll samples of participants with moderate tosevere opioid use disorder (with current physical dependence) and limited past-month cannabis use. Study 1will examine the effects of 7 acute cannabis doses including a 6-fold dose range of THC (5 10 20 30 mg)THC/CBD doses across a 3-fold dose range (10:10 mg; 30:30 mg THC:CBD) and matched placebo onoutcomes related to 1) opioid abuse liability (i.e. ratings of high drug liking) during an acute opioid challenge2) withdrawal severity (during acute instances of opioid withdrawal) and 3) safety/physiological effects (e.g.respiratory drive) of the drug conditions and combinations. Study 2 will explore the effects of repeated inhaledcannabis (3 times/day for 6.5 consecutive days) across three randomized dosing blocks (two active cannabisdoses matched placebo) to determine how a repeated cannabis dosing model impacts outcomes related to 1)opioid abuse potential (i.e. ratings of high drug liking) assessed during an acute opioid challenge; 2)withdrawal severity (measured during acute instances of opioid withdrawal) 3) safety/physiological effects(e.g. respiratory drive) of the drug conditions and combinations; and 4) cannabis tolerance and withdrawal.Cannabis modulation of sleep quality during bouts of acute opioid withdrawal will also be explored. Bothstudies will employ a full complement of pharmacodynamic outcomes including subjective and observer-ratedmeasures as well as a full battery of physiological and psychomotor outcomes related to safety andimpairment to fully assess the potential risk/benefit profile of cannabis in OUD. Overall these timely andinnovative studies will provide the first empirical data on the effects of inhaled cannabis in an opioid-dependentpopulation. These studies will provide new controlled information on potential interactions relevant to clinicalpractice prescribing and public safety.

project_terms:
Acute;Address;Affect;Agonist;Anxiety;Benefits and Risks;Buprenorphine;Cannabinoids;Cannabis;Clinical;Complement;Conflict (Psychology);Data;Dose;Double-Blind Method;Dronabinol;Enrollment;FDA approved;Geographic state;Impairment;Individual;Inhalation;Inpatients;Laws;Life;Maintenance;Measures;Medical Marijuana;Methadone;Modeling;Naltrexone;Opiate Addiction;Opioid;Oral;Outcome;Panic;Participant;Patients;Persons;Pharmaceutical Preparations;Pharmacodynamics;Physical Dependence;Physiological;Placebo Control;Placebos;Population;Public Advocacies;Public Health;Qualifying;Randomized;Reporting;Research;Research Project Grants;Route;Safety;Sampling;Severities;Statutes and Laws;Study Subject;Tachycardia;Testing;Therapeutic Effect;Time;Ventilatory Depression;Withdrawal;abuse liability;cannabis withdrawal;clinical practice;design;drug misuse;effective therapy;epidemiology study;high risk population;illicit drug use;innovation;marijuana use;mortality;opioid abuse;opioid epidemic;opioid misuse;opioid mortality;opioid overdose;opioid use;opioid use disorder;opioid withdrawal;overdose death;placebo group;respiratory;sleep quality;vapor

public_health_relevance:
PROJECT NARRATIVEThis research project will provide important public health and safety information regarding the effects ofcannabis in individuals with opioid use disorder. This project will examine the manner in which both acute andrepeated doses of vaporized cannabis alter the expression of opioid withdrawal modify the abuse potential ofopioids and affect the physiological safety profile of opioids; cannabis tolerance and withdrawal will also beassessed.


application_id: 10445046
project_number: 5R03CA256230-02
administering_ic: NCI
award_notice_date: 2022-07-18
opportunity_number: PAR-20-052
application_type: 5
activity_code: R03
ic: CA
serial_number: 256230
program_official: SHARMAN, ANU
project_start_date: 2021-07-05
project_end_date: 2024-06-30
study_section: ZCA1-TCRB-Q(M3)P
contact_pi_person_id: 11597020
contact_pi: FONG, KA-WING
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: 2022-07-01
project_title:
E2F family transcription factors are directly regulated by TRIM28 to promote castration-resistance in prostate cancer

project_abstract:
Prostate cancer (PCa) is the second-leading cause of cancer-related death in American men.Androgen deprivation therapies that target the androgen receptor (AR) are the mainstay treatmentfor metastatic PCa. New generation anti-androgen enzalutamide (Enz) significantly increasesPCa patient survival. However resistance to Enz develops rapidly. Importantly castration-resistant prostate cancer (CRPC) is driven primarily by aberrant activation of the AR in the milieuof low androgen. The AR exerts its tumorigenic roles mainly through genomic regulation of targetgene expression. This genomic action is tightly regulated by a number of cofactors and one ofwhich is TRIM24. We recently reported that TRIM28 is an upstream regulator of TRIM24 proteinstability in CRPC where both TRIM24 and TRIM28 expression is highly elevated. MechanisticallyTRIM28 stabilizes TRIM24 by preventing TRIM24 from SPOP-driven ubiquitination anddegradation and thereby TRIM24 is able to reactivate AR signaling in CRPC. To explore theTRIM28-mediated downstream signaling genome-wide transcriptome analysis revealed thatTRIM28 engaged in various oncogenic pathway including cell cycle and DNA replication. Byinterrogating cell cycle signature genes we showed that TRIM28 induces E2F1 E2F2 and E2F3gene expression in PCa. In addition TRIM28 ChIP-seq revealed that TRIM28 directly binds topromoter region of transcription factor E2F1-E2F3 which play a pivotal role in activatingtranscription of the genes required for cell cycle progression. Further deregulated expression oractivity of the E2F family has often been detected in many human cancers which leads touncontrolled cell proliferation. In this proposal we hypothesize that E2F transcription factor is acritical downstream target of TRIM28 and clinically-available E2F small molecules inhibitorLY101-4B may suppress CRPC progression. To test this hypothesis three specific aims areproposed. In Aim1 we will first validate the direct regulation of E2F1-E2F3 gene expression byTRIM28 with the use of genomic approaches. Aim2 will examine clinical expression of E2F andevaluate the efficacy of E2F inhibitor in CRPC cell lines and xenografts.

project_terms:
American;Androgen Antagonists;Androgen Receptor;Androgens;Antibodies;Binding;Biological Assay;CRISPR/Cas technology;Cancer Cell Growth;Cancer Etiology;Cancer Patient;Castration;Cell Cycle;Cell Cycle Progression;Cell Extracts;Cell Line;Cell Proliferation;Cells;Cessation of life;ChIP-seq;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;DNA Binding;DNA biosynthesis;E2F transcription factors;Family;Gene Expression;Generations;Genetic Transcription;Genomic approach;Genomics;Growth;Harvest;Human;Immunohistochemistry;LNCaP;Luciferases;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Prostate Cancer;Oncogenic;Pathway interactions;Patients;Play;Promoter Regions;Proteins;RNA;Receptor Signaling;Regulation;Reporter;Reporting;Resistance;Role;Running;Signal Transduction;Specimen;Testing;Tissue Microarray;Transactivation;Transcriptional Activation;Ubiquitination;Western Blotting;Xenograft procedure;advanced prostate cancer;androgen deprivation therapy;androgen sensitive;biobank;castration resistant prostate cancer;cell growth;cofactor;cohort;efficacy evaluation;enzalutamide;experimental study;genetic signature;genome-wide;inhibitor;knock-down;men;mutant;prevent;promoter;prostate cancer cell;prostate cancer cell line;prostate cancer progression;small hairpin RNA;small molecule inhibitor;targeted treatment;therapeutic target;transcription factor;transcriptome;tumor growth;tumor xenograft;tumorigenic

public_health_relevance:
TRIM28 is a transcription factor which was recently found to be aberrantly upregulated inadvanced prostate cancer. In this proposal we will characterize E2F as a crucial downstreamtarget of TRIM28 and targeting TRIM28-E2F axis may suppress castration resistant prostatecancer progression.


application_id: 10445006
project_number: 5R25GM132961-04
project_title: STEM Through Authentic Research Training (START) Program for Underrepresented Communities
administering_ic: NIGMS
award_notice_date: 2022-06-22
opportunity_number: PAR-17-339
application_type: 5
activity_code: R25
ic: GM
serial_number: 132961
program_official: BECK, LAWRENCE A
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Special Emphasis Panel[ZRG1-CB-J(56)R]
contact_pi_person_id: 9077753
contact_pi: BRADLEY, LUKE H
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract/ Project SummaryThe increasing importance of technology in contemporary society necessitates a STEM literate population.This represents a challenge for traditionally underrepresented populations (people of color individuals withdisabilities individuals in less affluent communities) impacting upward social mobility. Often members ofthese groups are doubly disadvantaged as the few who become first generation college students often lack aroadmap for success through family near peers and potential mentors. Success for this populationrepresenting a highly motivated group needs to be nurtured to embrace and advance STEM disciplinesbefore they reach their college classrooms. This necessitates the education not only of students but theirteachers providing synergies in teaching and learning to empower students to avail of opportunities perceivedas being beyond their reach. We hypothesize that bridging this expanding gap requires an integrated programbringing together academic social and real-world professional experiences to establish a pipeline linkingsuccess in middle/high school to success for first generation college students and beyond. Such a pipeline willgenerate not only STEM-proficient citizens but also a cadre of near peers to motivate by example. With thiscentral premise we have formed the STEM Through Authentic Research and Training (START) Program totidentify recruit and retaining traditionally underrepresented populations by providing year-round authenticresearch opportunities and professional development for high school students (grades 9-12) and middle andsecondary STEM teachers (grades 5-12). START represents a partnership between the University of Kentuckyproviding opportunities for STEM research The Academies of Lexington a partnership with the FayetteCounty Public Schools- focused on changing the traditional didactic model for STEM instruction the KY-WVLSAMP program an NSF funded consortium led by UK including over 10 diverse academic institutionssupporting undergraduate research aimed at increasing the representation and overall success of traditionallyunderrepresented populations in STEM disciplines. START establishes a natural pipeline to the collegiatelevel by virtue of the alliance with KY-WV LSAMP and its member institutions. Finally we have recruited SpaceTango a Lexington STEM start-up company which builds and integrates systems for scientific and biomedicalresearch under microgravity conditions on the international space station. As such a spectrum of researchopportunities from the molecular and microscopic level in participating UK STEM laboratories to the vastnessof space itself afforded by Space Tango provide an exciting palate of opportunities for traditionallyunderrepresented students and the teachers responsible for their STEM education. We believe that theintegration of real world authentic research opportunities in the context of overall STEM education via a uniquepartnership between academia educational and commercial entities will motivate underrepresented studentpopulations to levels of achievement they often believe are beyond their horizons.

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

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


application_id: 10444535
project_number: 1R01DE030103-01A1
project_title: Therapeutic vascularization to support repair of damaged salivary glands
administering_ic: NIDCR
award_notice_date: 2022-03-17
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DE
serial_number: 030103
suffix: A1
program_official: CHANDER, PREETHI
project_start_date: 2022-04-01
project_end_date: 2027-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 11258094
contact_pi: SANDELL, LISA L
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
project_terms:
Adipose tissue;Angiogenesis Promoter;Autoimmune Diseases;Biological Models;Biology;Biopsy;Blood Vessels;Blood flow;Cell Culture Techniques;Cells;Clinical;Complex;Endothelial Cells;Endothelium;Engineering;Ensure;Epithelial;Event;FDA approved;Fibroblasts;Gene Expression;Genetic Transcription;Gland;Growth;Implant;In Vitro;Individual;Inflammation;Knowledge;Malignant Neoplasms;Methods;Microbubbles;Molecular;Mus;Natural regeneration;Organ;Pathology;Patients;Perfusion;Pericytes;Persons;Pharmaceutical Preparations;Pharmacology;Pilot Projects;Pre-Clinical Model;Production;Radiation therapy;Recovery;Retinoids;Saliva;Salivary;Salivary Gland Tissue;Salivary Glands;Skin;Smooth Muscle Myocytes;Source;Submandibular gland;Supporting Cell;System;Tazarotene;Testing;Therapeutic;Therapeutic Uses;Tissue Engineering;Tissues;Transplantation;Vascular Smooth Muscle;Vascularization;Vitamin A;Wound models;angiogenesis;blood vessel development;cell type;effective therapy;experience;healing;implantation;in vitro Assay;in vivo;knowledge of results;novel;novel therapeutics;repaired;replacement tissue;small molecule;success;therapeutic angiogenesis;wound healing;wound treatment


application_id: 10444427
project_number: 1R01MD016864-01A1
project_title: K-VAC: Kentucky Vaccinating Appalachian Communities
administering_ic: NIMHD
award_notice_date: 2022-07-15
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: MD
serial_number: 016864
suffix: A1
program_official: JONES, NANCY LYNNE
project_start_date: 2022-07-15
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1 HDM-V (90)]
contact_pi_person_id: 6914381
contact_pi: KIVINIEMI, MARC T
other_pis: CARDARELLI, KATHRYN MARIE
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
2019-nCoV;Achievement;Address;Adult;Affect;Appalachian Region;Behavior;COVID-19;COVID-19 mortality;COVID-19 prevention;COVID-19 vaccine;Chronic Disease;Cluster randomized trial;Communicable Diseases;Communities;Community Health Aides;Complex;Education;Educational Background;Elements;Emerging Communicable Diseases;Epidemic;Face;Failure;Foundations;Future;Geography;Goals;Government;Health Personnel;Health protection;Individual;Influenza;Infrastructure;Institution;Intervention;Kentucky;Medical;Obesity;Obstructive Lung Diseases;Persons;Politics;Population;Population Characteristics;Poverty;Preparation;Prevalence;Process;Public Health;Research;Research Personnel;Respiratory Disease;Risk;Rural;Rural Population;SARS-CoV-2 infection;Safety;Series;Source;System;Trust;Unemployment;Vaccinated;Vaccination;Vaccines;base;community based participatory research;community partnership;community-level factor;distrust;effectiveness measure;experience;falls;health care availability;health care delivery;health goals;implementation fidelity;indexing;inhibitor;intervention delivery;prevent;smoking prevalence;tailored messaging;transmission process;trial design;uptake;vaccination strategy;vaccine acceptance;vaccine access;vaccine delivery;vaccine hesitancy;vaccine safety;vulnerable community;willingness


application_id: 10444295
project_number: 1R01CA258751-01A1
project_title: Combating melanoma resistance by targeting ABL1/2
administering_ic: NCI
award_notice_date: 2022-05-23
opportunity_number: PAR-21-033
application_type: 1
activity_code: R01
ic: CA
serial_number: 258751
suffix: A1
program_official: SONG, MIN-KYUNG H
project_start_date: 2022-05-23
project_end_date: 2027-04-30
study_section: Clinical Oncology Study Section[CONC]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
other_pis: KOLESAR, JILL MARIE;WILSON, MELISSA A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
ABL1 gene;Animal Model;Animals;BRAF gene;Basic Science;Biochemical;Biological;Cell Line;Cells;Clinical;Clinical Trials;Coculture Techniques;Collaborations;Conditioned Culture Media;Coupling;Cytometry;Data;Dose;Dose-Limiting;Drug Kinetics;ERBB2 gene;ERBB3 gene;Experimental Designs;FDA approved;Family;Goals;Immune;Immunotherapeutic agent;In Vitro;Infiltration;MEKs;Malignant Neoplasms;Mass Spectrum Analysis;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Mutation;NRG1 gene;Oncologist;PI3K/AKT;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Phase I/II Clinical Trial;Phosphotransferases;Protein Family;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;Publishing;RELA gene;RNA Interference;Randomized Clinical Trials;Records;Refractory;Regimen;Research;Research Personnel;Resistance;Resistance development;Role;Safety;Sampling;Serum;Site;Survival Rate;Testing;Toxic effect;Translational Research;Xenograft procedure;arm;base;biomarker development;drug-sensitive;effective therapy;experimental study;human tissue;improved;in vivo;in vivo Model;inhibitor;innovation;interdisciplinary approach;leukemia;melanoma;next generation sequencing;novel;pharmacokinetics and pharmacodynamics;phase 2 study;resistance mechanism;safety testing;secondary endpoint;single-cell RNA sequencing;targeted agent;therapy resistant;transcriptome sequencing;translational goal;tumor


application_id: 10444190
project_number: 3K01DK114391-05S1
administering_ic: NIDDK
award_notice_date: 2021-09-14
opportunity_number: PAR-16-211
application_type: 3
activity_code: K01
ic: DK
serial_number: 114391
suffix: S1
program_official: SASLOWSKY, DAVID E
project_start_date: 2017-08-01
project_end_date: 2022-05-31
study_section: Digestive Diseases and Nutrition C Study Section[DDK-C]
contact_pi_person_id: 12197847
contact_pi: ALAM, M. ASHFAQUL
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_title:
Microbially generated protons mediate interkingdom host-microbiome cross-talk and maintain intestinal homeostasis via reciprocal functions of two proton-sensing GPCRs

project_abstract:
Project Summary: Intestinal damage is observed in inflammatory bowel disease (IBD) entericinfectionsaswellasfollowingsurgicaltraumaandenvironmentalinsults.Tissuerestitutionisacomplexbutcoordinated cellular process to repair gut mucosa. We recently reported that the intestinal woundmicroenvironment specifically enriches a mucosa-associated microbial consortium which enhanced epithelialwoundhealing.Theadvancesinnextgenerationgenesequencinghaveidentifieddiversemicrobialspeciesandmetagenomesinthehost;howevertounderstandandexploitthepotentialofthemicrobiotas>8milliongenesandtheirmetabolicfunctionsapplicationofthemass-spectrometry-basedidentificationofsmallmetabolitesandfunctional characterization by the methods of cell biology are crucial. Hence this proposed study will lay afoundationformyrigoroustraininginmetabolomeandcellbiologyofgutbarrierfunction.Forthispurposeweperformedapreliminaryanalysisbymassspectrometry-basedglobalmetabolomicprofilingofintactandinjuredmucosa as well as colon of germ-free and conventional mice. We found an elevated synthesis of microbialmetaboliteswithlowpKawhichareessentialinestablishinganextracellularpHgradientinthecoloniccryptsoftheconventionalmicebutnotingermfreemice.Wealsofoundthatthecolonicepithelialcellsofconventionalmiceexpressincreasedlevelsofproton-sensingGPCRs(GPCR4andGPCR68).Basedonpreliminaryfindingstheworkinghypothesesofthisprojectare:1)theinjuredmucosaltissueanditsassociatedmicrobiotaproducemetabolitestoregulatespatiotemporalchangesintheprotonconcentrationofthecolonandtherebyregulateintestinalhomeostasisandrepair2)microbiota-producedmetabolitesmodulateprotonconcentrationwhichisperceivedbytheproton-sensingGPCRsofenterocytestoregulategutpermeability.Aim1istoconfirmtheroleofmicrobiota-producedmetabolitesinregulatingcellularproliferation&repairviaproton-sensingGPCR4andGPCR68intheGPCR4-/-andGPCR68-/-micewhosecoloniesareestablishedinouranimalfacility.Wewillalsoperform the metabolomic profiling and RNA-seq analysis of the colon of GPCR4-/- and GPCR68-/- mice.Furthermorewewilldeterminethemetabolomeoftheinjuredmucosainthegerm-freemouse.SpecificAim2willdeterminethefunctionoftheprotongradient&alsotheroleofspecificmetabolitesintheregulationofgutpermeability by tight-junction. Emory University boasts an intellectually rich research environment whoseresourceswillbeusedtocarryouttheproposedresearchaswellasthemas-spectrometrycenterlocatedacrossthetowninGeorgiaInstituteofTechnologyAtlanta.Theproposedresearchincombinationwithastructuredteam of mentor advisors and collaborators as well as the training plan that includes didactic courses andworkshopsisdesignedtofacilitatemylong-termgoalofdevelopinganindependently-fundedresearchprograminchronicgastrointestinalinflammatorydiseasessuchasIBDconsistentwiththemissionoftheNIDDK.

project_terms:
Affect;Animals;Biology;Biopsy;Cell Proliferation;Cell physiology;Cells;Cellular biology;Chronic;Colon;Complex;Development;Diabetes Mellitus;Disease;Distal;Educational workshop;Endoscopy;Enterocytes;Environment;Epithelial;Epithelial Cell Proliferation;Epithelial Cells;Event;Forcep;Foundations;Funding;G-Protein-Coupled Receptors;Genes;Germ-Free;Goals;Grant;Gut Mucosa;Health;Homeostasis;Immune system;In Vitro;Inflammatory;Inflammatory Bowel Diseases;Institutes;Intestinal Mucosa;Intestinal permeability;Intestines;Knowledge;Liquid substance;Liver diseases;Maintenance;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Mentors;Mentorship;Metabolic;Methods;Mission;Mucous Membrane;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;Natural regeneration;Obesity;Operative Surgical Procedures;Performance;Permeability;Process;Proteins;Protons;Regulation;Reporting;Research;Resources;Role;Scientist;Spectrometry;Structure;Technology;Testing;Tight Junctions;Tissues;Training;Trauma;Universities;animal facility;base;career development;cell motility;claudin 4;colonic crypt;design;differential expression;enteric infection;epithelial wound;evidence base;extracellular;gastrointestinal;gastrointestinal epithelium;gut microbiota;host microbiome;host-microbe interactions;immune activation;injured;injury and repair;intestinal homeostasis;metabolome;metabolomics;metagenome;microbial;microbial community;microbial host;microbiome;microbiota;next generation;novel;pH gradient;programs;receptor;repaired;restoration;small molecule;spatiotemporal;transcriptome sequencing;wound;wound closure;wound healing

public_health_relevance:
ProjectNarrativeImportance of extracellular proton concentration is critical in intestinal mucosa during health and disease.Howeverthereisnoevidence-basedknowledgehowextracellularpHofthemucosalmicroenvironmentregulateintestinalrepairandrestorationofhomeostasis.Leveragingthemetabolomicstudiesthisprojectisdesignedtoinvestigate two proton-sensing G-protein coupled receptors and their role in microbial metabolite-drivenextracellularpHgradientduringmucosalhomeostasisandrepair.


application_id: 10443781
project_number: 5R01AI139671-04
administering_ic: NIAID
award_notice_date: 2022-06-23
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: AI
serial_number: 139671
program_official: CHUANG, ELEANORE JENNIFER
project_start_date: 2019-07-05
project_end_date: 2024-06-30
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 10797120
contact_pi: FRIEBOES, HERMANN
other_pis: LEWIS, AMANDA L.
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Understanding the Host-Microbiome-Therapeutic Triad: Implications for Designing Alternative Intravaginal Delivery Platforms to Treat Bacterial Vaginosis

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

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

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


application_id: 10443718
project_number: 5R01DK125801-03
administering_ic: NIDDK
award_notice_date: 2022-06-28
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 125801
program_official: KUCZMARSKI, ROBERT J
project_start_date: 2020-07-15
project_end_date: 2025-06-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 10552456
contact_pi: WILLIAMS, LOVORIA B
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Enhancing the Diabetes Prevention Program to promote weight loss among non-responders in a community based lifestyle intervention

project_abstract:
PROJECT SUMMARYObesity is the number one and most preventable Type 2 diabetes (T2D) risk factor yet despite a $20 billionannual expenditure on diet and weight loss efforts 87% of US adults are overweight or obese. Disparities alsopersist as Non-Hispanic Black adults have a higher obesity prevalence (46.8%) than non-Hispanic Whites(37.9%) and suffer higher rates of Type 2 diabetes (T2D). The Diabetes Prevention Program (DPP) lifestyleintervention (LI) demonstrated the clinical benefits of lifestyle intervention and garnered the Center for DiseaseControl (CDC) endorsement as the gold standard LI program for US adults. Reimbursable by the Center forMedicare and Medicaid Services (CMS) the DPP LI is currently disseminated nationally and the national DPP.While the DPP LI is effective critical populations dont achieve clinically significant weight loss in the currentgroup-based translation paradigm. This is particularly true for Black DPP participants who show the lowestadjusted percent weight loss across (3.2%) among all racial/ethnic groups. A lack of weight loss in the earlyweeks of intervention is a known predictor of post-treatment outcomes and continues to be a major barrier toweight loss for Black participants. Additional research on early intervention with a focus on populations thatexperience disparities is urgently needed as the new CMS payment structure (based on weight loss metrics)may further limit access to the DPP for Blacks. This project proposes a cluster randomized control trial with500 Black participants who are nested in 20 community sites primarily churches. Trained community healthworkers will deliver a group-based 6-month long DPP Group Lifestyle Balance (DPP-GLB) over 18 sessionsand nonresponders will be identified at four weeks. Nonresponders in the intervention group only will receiveweekly telephone support from the CHWs to provide individual-level enhanced treatment to help themovercome barriers to adherence to the program goals. These activities will meet the following Specific Aims: 1)To evaluate differences over time in the primary outcome of weight and secondary outcomes (i.e. physicalactivity level blood pressure and dietary behaviors) between nonresponders in the intervention groupcompared to nonresponders in the active control group. 2) To examine potential mediators (social supportself-efficacy motivation stress) and moderators (age sex socioeconomic status) of the relationship betweentreatment group and early weight loss response in the both nonresponders and responders.3) To evaluate thecost of the intervention arm by comparing the incremental cost and weight loss with the active control arm.Outcome measures include weight (primary); secondary outcomes include blood pressure physical activitydietary behaviors mediation and moderator effects and cost. If found to efficacious the enhanced strategiesfor nonresponders could be standardized as a supplement for use with the national DPP and may besupported by current DPP payers.

project_terms:
Address;Adherence;Adopted;Adult;African American population;Aftercare;Age;Behavior;Black American;Black Populations;Black race;Blood Pressure;Body Weight decreased;Centers for Disease Control and Prevention (U.S.);Church;Clinical;Communities;Community Health Aides;Control Groups;Diet;Early Intervention;Equilibrium;Ethnic group;Expenditure;Future;Gender;Goals;Gold;Individual;Intervention;Intervention Studies;Life Style;Mediating;Mediation;Mediator of activation protein;Mission;Modeling;Morbidity - disease rate;Motivation;National Institute of Diabetes and Digestive and Kidney Diseases;Non-Insulin-Dependent Diabetes Mellitus;Not Hispanic or Latino;Obesity;Outcome;Outcome Measure;Participant;Pattern;Persons;Phase;Physical activity;Population;Prevalence;Psychosocial Factor;Public Health;Randomized Controlled Trials;Research;Research Personnel;Risk Factors;Self Efficacy;Site;Social support;Socioeconomic Status;Standardization;Stress;Structure;Telephone;Time;Training;Translations;Treatment outcome;United States Centers for Medicare and Medicaid Services;Variant;Weight;Work;active control;arm;base;clinically significant;cost;cost effective;diabetes prevention program;dietary;experience;group intervention;improved;intervention cost;intervention effect;intervention program;lifestyle intervention;male;meetings;mortality risk;overweight adults;payment;personalized medicine;personalized strategies;primary outcome;programs;racial and ethnic;response;secondary outcome;sex;sociodemographic variables;standard care;success;treatment arm;treatment group;weight loss intervention

public_health_relevance:
Project NarrativeThe proposed research is relevant to public health because African Americans/Blacks suffer with higherobesity rates and have more trouble losing weight loss than others. Trained Community Health Workers willdeliver the Diabetes Prevention Program (DPP); early during the program the researchers will identifyparticipants who are not losing weight and the Community Health Workers will offer these participants extrasupport to help them overcome weight loss barriers. If this extra support works the National DPP and otherscan adopt it to achieve better weight loss outcomes among DPP participants thereby having a significantpublic health impact.


application_id: 10443080
project_number: 1R01DC019634-01A1
project_title: The fungiform papilla as a multi-sensory end-organ
administering_ic: NIDCD
award_notice_date: 2022-06-28
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: DC
serial_number: 019634
suffix: A1
program_official: SULLIVAN, SUSAN L
project_start_date: 2022-07-01
project_end_date: 2027-06-30
study_section: Neuroscience of Interoception and Chemosensation Study Section[NIC]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: BREZA, JOSEPH MICHAEL
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Afferent Neurons;Amyloid beta-Protein;Anatomy;Attention;Behavior;Binding Proteins;Brain Stem;Burning Mouth Syndrome;C Fiber;Cell Nucleus;Characteristics;Code;Data;Electrophysiology (science);Epithelial;Esthesia;Fiber;Food;Fungiform Papilla;Gene Expression;Genes;Genetic;Genetic Identity;Genetic Markers;Goals;Housing;Image;Lateral;Light;Liquid substance;Location;Mechanoreceptors;Mediating;Modality;Mucous Membrane;Mus;Nerve Growth Factor Receptors;Neuraxis;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 3;Oral;Oral cavity;Organ;Palate;Parvalbumins;Perception;Peripheral;Peripheral Nervous System Diseases;Potato;Property;Proprioceptor;Research;Rodent;Role;Sensory;Skin;Smell Perception;Stimulus;Structure;Structure of trigeminal ganglion;Surface;Synapses;Taste Buds;Taste Perception;Temperature;Testing;Texture;Thermoreceptors;Tongue;Touch sensation;Trigeminal Nuclei;Trigeminal System;Viral;awake;base;experience;experimental study;feeding;mechanical stimulus;multimodality;multisensory;nerve supply;olfactory stimulus;optogenetics;oral sensory;postsynaptic neurons;receptive field;repaired;response;somatosensory;taste stimuli;tongue papilla;tool


application_id: 10442725
project_number: 5R01DE030100-02
administering_ic: NIDCR
award_notice_date: 2022-06-27
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 030100
program_official: OKI, NOFFISAT
project_start_date: 2021-07-01
project_end_date: 2025-06-30
study_section: Clinical Data Management and Analysis Study Section[CDMA]
contact_pi_person_id: 10376668
contact_pi: CLARKSON, MELISSA
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Developing standardized graphic libraries for anatomy: A focus on human craniofacial anatomy and phenotypes

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

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

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


application_id: 10441376
project_number: 5U01AA026936-05
project_title: Lipid metabolites can both potentiate and treat alcoholic hepatitis
administering_ic: NIAAA
award_notice_date: 2022-06-15
opportunity_number: RFA-AA-18-003
application_type: 5
activity_code: U01
ic: AA
serial_number: 026936
program_official: DUNTY, JR, WILLIAM
project_start_date: 2018-09-22
project_end_date: 2024-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: JOSHI-BARVE, SWATI
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:
Alcoholic Hepatitis (AH) is an important cause of morbidity mortality and health care costs. Only a limitednumber (<25% of those who drink heavily) develop this more advanced liver disease. Thus there must bemodifying factors that either prevent or facilitate disease activity/progression. Dietary fat represents a criticalmacronutrient disease modifier for AH. The American diet has increased dramatically in omega 6-polyunsaturated fat (PUFA) content and has a very imbalanced omega-6:omega-3 ratio. In pre-clinical rodentmodels dietary PUFA enriched in linoleic acid (LA) promotes alcohol-induced liver damage. Mice fed analcohol + high PUFA (LA) diet generate toxic oxidized products of linoleic acid metabolism (OXLAMs) as wellas a highly reactive and toxic aldehyde lipid peroxidation product (i.e. acrolein) which causes ER stress andliver injury. This high PUFA diet plus alcohol in rodents also causes gut dysbiosis and decreases levels of thecritical short chain fatty acid butyrate. We postulate that human subjects with AH will have (i) increasedlevels of the lipid peroxidation product acrolein (toxic aldehyde) (ii) increased levels of OXLAMs and(iii) altered gut flora with decreased fecal levels of butyrate and butyrate producing bacteria all ofwhich correlate with severity of liver injury. We also postulate that certain lipid products (resolvinsbutyrate) will be therapeutic in AH. We address this hypothesis with three specific aims using unique humansamples generated through the NIAAA-funded U01-consortium in AH.Specific Aim #1: Determine whether levels of acrolein metabolites and adducts in serum/urine/tissue areelevated in AH and correlate these levels with biomarkers of gut permeability hepatic cell death/injury anddisease severity.Specific Aim #2: Determine whether serum levels of OXLAMS are elevated in human AH and correlatethose levels with biomarkers of severity of AH hepatocyte death and gut permeability. Determine whetherserum levels of resolvins are decreased in AH and whether resolvin administration to AH blood ex vivodecreases proinflammatory cytokines.Specific Aim #3: Determine fecal levels of short-chain fatty acids (focusing on butyrate) in patients with AHand determine abundance of butyrate-producing bacteria in patients with acute AH and after recovery withabstinence. We will also determine the effects of different doses of butyrate on ex-vivo cytokine production inAH patients.!

project_terms:
Abstinence;Acrolein;Acute Alcoholic Hepatitis;Address;Alcoholic Hepatitis;Alcoholic liver damage;Alcohols;Aldehydes;American diet;Arachidonate 15-Lipoxygenase;Attenuated;Bacteria;Biological Markers;Blood;Butyrates;Cell Death;Cell membrane;Cessation of life;Data;Development;Diet;Diet and Nutrition;Dietary Fats;Disease;Dose;Endotoxemia;Fatty acid glycerol esters;Free Radicals;Funding;Genetic;Health Care Costs;Heavy Drinking;Hepatocyte;Human;Injury;Institution;Intake;Intervention;Intestinal permeability;Investigation;Laboratories;Linoleic Acids;Lipid Peroxidation;Lipids;Liver;Liver diseases;Macronutrients Nutrition;Mediating;Membrane Lipids;Metabolism;Morbidity - disease rate;Mus;National Institute on Alcohol Abuse and Alcoholism;Nutritional;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidative Stress;Oxides;Patient Care;Patients;Persons;Play;Polyunsaturated Fatty Acids;Production;Receptor Activation;Recovery;Research;Risk;Rodent;Rodent Model;Role;Sampling;Serum;Severities;Severity of illness;Smoking;Testing;Therapeutic;Tissues;Toll-like receptors;United States;Universities;Urine;Volatile Fatty Acids;adduct;alcohol research;cytokine;dysbiosis;endoplasmic reticulum stress;gut bacteria;gut dysbiosis;gut inflammation;gut microbiota;human subject;improved;liver injury;mortality;mouse model;nutrition;organ injury;oxidation;polyunsaturated fat;pre-clinical;prevent;response;translational applications;tributyrin

public_health_relevance:
PROJECT NARRATIVEThis translational application related to the Alcoholic Hepatitis Network project AlcHepNet comprised of nineleading partner institutions in the field will examine new and promising treatments for severe liver damagecaused by alcohol. Combined these two approaches will improve treatment and how we care for patients withthis devastating liver condition.!


application_id: 10441341
project_number: 5R01HD097675-04
project_title: Neurotensin: A Novel Mediator of Ovulation
administering_ic: NICHD
award_notice_date: 2022-07-01
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HD
serial_number: 097675
program_official: TAYMANS, SUSAN
project_start_date: 2019-09-06
project_end_date: 2024-05-31
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: DUFFY, DIANE M
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
A womans fertility is dependent on the cascade of events leading up to ovulation. Defects in this ovulatoryprocess result in 25% of all female infertility cases supporting the paramount role of ovulation in reproductivesuccess and providing a strong premise to explore mediators of the ovulatory process. We propose thatneurotensin is one of these pivotal regulators of the ovulatory process. Ovulation is set in motion by the preovulatory LH surge which increases ovarian intrafollicular mediatorsthat act to bring about oocyte release. Our novel and exciting preliminary data indicate that neurotensin (NTS)a small neuropeptide is a key intrafollicular mediator of ovulation. This is based upon our findings that NTS isone of the most differentially-expressed genes in the granulosa cells of the human ovulatory follicle up to15000 fold after the ovulatory gonadotropin surge. Likewise LH also rapidly and significantly increases NTSmRNA in granulosa cells from rodent and monkey ovulatory follicles. Importantly injection of a neurotensinantibody into monkey preovulatory follicles blocked oocyte release resulting in luteinized unruptured folliclesconsistent with failure of ovulation. Similarly mice lacking NTS expression form luteinized unruptured folliclesfollowing LH/hCG administration and a NTS receptor antagonist inhibits oocyte release in a novel in vitromodel of mouse ovulation. Yet other than our preliminary data nothing is known regarding the temporalexpression of NTS receptors or the function of NTS in ovulation and female fertility. These questions will beaddressed in this proposal through a collaborative approach utilizing the exceptional backgrounds technicalexpertise and models of the Project Leaders. We will make use of a high-impact translational model wherethe granulosa and theca from human periovulatory follicles will be collected prior to and at three designatedtimes after hCG (early late and postovulatory) to complement in vivo and in vitro studies performed with miceand monkeys. The regulation of NTS and NTS receptor expression in the ovulatory follicle will be illuminatedand compared across women monkeys and mice in Aim 1. The ovulatory functions stimulated by NTS ingranulosa theca cumulus and endothelial cells of the follicle will be elucidated in Aim 2. The actions of NTSon ovulation as well as other key reproductive processes will be revealed in mice and monkeys using micelacking NTS expression NTS receptor antagonists and NTS-neutralizing antibodies in Aim 3. A major strengthof this proposal is the collaborative interactions between Dr. Curry and Dr. Duffy to address the function of NTSand its receptors in periovulatory events across multiple species including exceptional human ovarian tissuesand in vivo studies of non-human primates an animal model with high relevance to human reproductivefunction. Thus there is an exceptional degree of significance in understanding the basic tenets of oocyterelease which provides a fundamental platform to either improve outcomes for infertile women or converselyprovide targets to prevent oocyte release for female contraception.

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

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


application_id: 10441291
project_number: 5U18FD006519-05
project_title: Assuring Radiation Protection
administering_ic: FDA
award_notice_date: 2022-08-25
opportunity_number: RFA-FD-18-021
application_type: 5
activity_code: U18
ic: FD
serial_number: 006519
program_official: MILLER, DONALD
project_start_date: 2018-09-01
project_end_date: 2023-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11755645
contact_pi: MCBURNEY, RUTH EVELYN
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 115963720
primary_uei: SBT5JJP6JP86
duns_number: 115963720
uei: SBT5JJP6JP86
fips: US
organization_id: 1565201
organization_name: CONFERENCE OF RADIATION CONTROL PROG DIR
organization_city: Frankfort
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406013717
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe objective of this cooperative agreement is to coordinate state and federal activities to achieveeffective solutions to present and future radiation control problems. The Conference of RadiationControl Program Directors (CRCPD) a professional organization whose membership includesrepresentatives of state radiation control programs and whose mission is dedicated to radiationprotection will provide a forum for development of coordinated national radiation policy modelregulations guidance and procedures for the control of sources of radiation in the United States andwill coordinate the interchange of radiation protection experience among the states and between thestates tribes and the federal government. CRCPD will establish and maintain approximately 70committees other working groups and liaisons to other organizations made up of its state and localgovernment members to address specific radiation control problems in the application of radiation in thehealing arts education and industry; the control and mitigation of radiation exposure from all sourcesincluding radiation in the environment and as a result of licensed activities accidents and incidents; andpreparedness for radiological emergencies and homeland security. Work products of the committeeswith oversight by an elected Board of Directors will include updates to the Suggested StateRegulations for Control of Radiation protocols for evaluation of x-ray trends practice guidelines andother model procedures and reports for use by state and local government agencies in maintainingeffective radiation programs.CRCPD will also plan facilitate and provide travel assistance for state representatives for annualmeetings of the National Conference on Radiation Control as an opportunity for member States andother stakeholders to convene and exchange information on radiation issues and new technologies.The conference will include discussions lectures and workshops on radiation priorities as determinedby state and federal planners. CRCPD will also provide radiation protection training sessions inconjunction with the annual meeting and at other times outside of the annual meeting through state-federal workshops and web-based training sessions. We will also maintain various mechanisms foraccess to information for the benefit of the States and other interested parties including: a frequently-updated website for posting of working group products meetings services and opportunities forservice as well as a secure site for committees and state agency members to access sensitiveinformation; a periodic newsletter; liaison with other related organizations; broadcast e-mails for time-sensitive information; and use of social media and conference calls for major concerns affecting amajority or all of the states.1

public_health_relevance:
Project NarrativeThe objective of this cooperative agreement is to coordinate Federal State and Tribalactivities to achieve effective solutions to present and future radiation control problems.The adoption and implementation of the guidance recommendations and proceduresprovided under this project will provide for improved quality in radiation protectionprograms throughout the United States. The overall impact of these cooperative effortswill ultimately reduce the risk of illness and deaths associated with unnecessaryradiation exposure from all sources and improve the quality of medical radiationimaging and therapy.1


application_id: 10441277
project_number: 5U01AA026934-05
project_title: Pilot Trial UO1 DUR-928
administering_ic: NIAAA
award_notice_date: 2022-06-15
opportunity_number: RFA-AA-18-005
application_type: 5
activity_code: U01
ic: AA
serial_number: 026934
program_official: GAO, PETER
project_start_date: 2018-09-25
project_end_date: 2024-06-30
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AH is an acute form of alcoholic liver disease and includes a spectrum that ranges from mild injury to severelife threatening injury. The prevalence of AH has not been accurately determined; it is believed to occur in 10%to 35% of heavy drinkers. On histology AH is characterized by infiltration of the liver by inflammatory cells andhepatocellular injury. AH is usually associated with progressive fibrosis in the presence of continued alcoholabuse. No new drugs for AH have been successfully developed since the introduction of corticosteroids as atreatment in the early 1970s. Corticosteroids have been utilized as a standard of care in various treatmentguidelines for patients with severe AH. Pentoxifylline has also been used because of its safety but severalwell-conducted studies have not supported the efficacy of pentoxifylline for the treatment of severe AH.Importantly a recent study has questioned the efficacy of both prednisone and pentoxifylline in the treatment ofAH. Mortality at 6 months was similar in patients on either prednisone pentoxifylline or both as compared withplacebo. Therefore there is a need for novel therapies. DUR-928 is an endogenous intracellular regulatorymolecule and sulfated oxysterol: 5-cholesten-3 25-diol 3-sulfate (25HC3S). DUR-928 is under developmentfor multiple indications including treatment of chronic metabolic disease such as NAFLD/NASH and PSC andtreatment of acute organ injuries such as AKI and AH. DUR-928 is able to lower intracellular lipidaccumulation regulate inflammatory responses and improve cell survival. Based on the current accumulatedknowledge of DUR-928 biology we believe that DUR-928 represents a novel therapeutic agent for AH with anexcellent safety profile (is produced endogenously). In this PILOT UO1 we propose 2 independent but linkedstudies.Study #1: An open-label dose escalation study to assess the safety pharmacokinetics and efficacy of DUR-928 in patients with Moderate Alcoholic Hepatitis.Study #2: An open-label dose escalation study to assess the safety pharmacokinetics and efficacy of DUR-928 in patients with Severe Alcoholic Hepatitis.

project_terms:
25-hydroxycholesterol;ADD-1 protein;Acute;Acute Alcoholic Hepatitis;Acute Renal Failure with Renal Papillary Necrosis;Adrenal Cortex Hormones;Agonist;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Anorexia;Apoptosis;Biology;Cell Nucleus;Cell Survival;Cholesterol;Cholesterol Homeostasis;Chronic;Clinical Data;Cytoplasm;Data;Development;Diet;Disease;Dose;Drug Kinetics;Enzymes;FDA approved;Fatty acid glycerol esters;Fibrosis;Glucocorticoids;Glycols;Hepatic;Hepatocyte;Hepatomegaly;Histology;Hospitals;Human;Hydroxylation;Icterus;In Vitro;Infection;Infiltration;Inflammatory;Inflammatory Response;Injury;Intracellular Accumulation of Lipids;Knowledge;Life;Link;Lipids;Liver;Liver Regeneration;Malaise;Malnutrition;Metabolic Diseases;Mitochondria;Morbidity - disease rate;Multiple Organ Failure;Natural regeneration;Pathway interactions;Patients;Pentoxifylline;Placebos;Prednisone;Prevalence;Safety;Signal Pathway;Signal Transduction;Sterols;Sulfate;Syndrome;Systemic Inflammatory Response Syndrome;Therapeutic Agents;base;cell injury;effective therapy;hepatocellular injury;high risk;improved;in vivo;lipid biosynthesis;lipid metabolism;liver cell proliferation;macrophage;mortality;mouse model;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutics;open label;organ injury;overexpression;pilot trial;pre-clinical;preclinical study;standard of care;sulfotransferase;treatment guidelines

public_health_relevance:
Alcoholic Hepatitis (AH) is an acute form of alcoholic liver disease and includes a spectrum that ranges frommild injury to severe life threatening injury. Based on the current accumulated knowledge of DUR-928 biologywe believe that DUR-928 represents a novel therapeutic agent for AH with an excellent safety profile (isproduced endogenously). In this PILOT UO1 we propose 2 independent but linked studies in moderate andsevere AH.


application_id: 10440815
project_number: 1R34AR079672-01A1
project_title: The Local Infiltration Therapy (LIT) Trial for Pain Control Following Hip Fracture Fixation
administering_ic: NIAMS
award_notice_date: 2022-08-03
opportunity_number: PAR-20-090
application_type: 1
activity_code: R34
ic: AR
serial_number: 079672
suffix: A1
program_official: WASHABAUGH, CHARLES H
project_start_date: 2022-08-05
project_end_date: 2024-07-31
study_section: Arthritis and Musculoskeletal and Skin Diseases Clinical Trials Study Section [AMSC]
contact_pi_person_id: 14874046
contact_pi: MATUSZEWSKI, PAUL EDWARD
other_pis: Not Applicable
congressional_district: 06
department: ORTHOPEDICS
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:
Geriatric hip fractures are an increasingly prominent public health problem with more than 300000 fracturesustained within the U.S. each year and predicted over 1000000 by 2050. These fractures are life changingin elderly patients and sustaining a post-operative complication can be severely debilitating. Post-operativepain can be a significant driver of poor outcome via an increased risk of post-operative complications includingdelirium which is associated with increased mortality morbidity and outcome which persists beyond indexhospitalization. Pain control is frequently managed with opioids which elderly patients are particularlysusceptible to the negative side-effects they entail which include somnolence delirium nausea vomitingurinary retention and respiratory depression. Additionally increased opioid use in the context of the currentopioid epidemic is further concerning and elderly patients are just as susceptible as other age groups. Thusdecreasing opioid use in these patients is paramount in decreasing complications and ultimately improvingoutcome for this deserving group of patients. In a pilot double-blinded multi-centered placebo-controlled trialwe recently conducted we reported a decreased use of opioids following hip fracture fixation and decreasedpain visual analog scores (VAS) with the usage of liposomal bupivacaine. In a follow-up retrospective studywe demonstrated that the use of an injection cocktail of commonly available medications (ClonidineEpinephrine Ropivacaine Toradol) demonstrated a similar and possibly greater decrease of opioid use andpain VAS when compared to liposomal bupivacaine. The injection cocktail is associated with less cost than thecommercial liposomal bupivacaine and may be a more cost-effective alternative to liposomal bupivacaine.Given these findings and large support for both of these modalities in the arthroplasty literature evaluation ofthe approach to improve outcomes in the hip fracture population is crucial to helping prevent complications andpoor outcomes in these patients. This proposal aims to initiate and complete the planning of a multi-centerdouble-blind non-inferiority trial with placebo for effect size determination to test our hypotheses that apharmacy prepared cocktail is not inferior to a commercially available liposomal bupivacaine and that localinjection therapy can improve pain control following hip fracture fixation. We will utilize existing researchrelationships between clinical sites to complete the protocol optimize procedures prepare a budget developprotocol forms optimize recruitment procedures develop a standard procedures manual perform regulatorysubmissions and recruit additional sites as necessary to complete the proposed trial. Given the severity ofcomplications associated with poor pain control successful planning and completion of this trial can potentiallyintroduce a method of pain control which is opioid free and widely adaptable with minimal resources.

project_terms:
Address;Agreement;Budgets;Bupivacaine;Certification;Climacteric;Clinical;Clinical Trials;Clinical trial protocol document;Clonidine;Collection;Complication;Consent Forms;Contracts;Data;Data Collection;Databases;Delirium;Double-Blind Method;Drowsiness;Elderly;Enrollment;Ensure;Epinephrine;Evaluation;Exclusion Criteria;Fracture;Fracture Fixation;Goals;Grant;Hip Fractures;Hospitalization;Incentives;Individual;Infiltration;Injection of therapeutic agent;Injections;Institution;Institutional Review Boards;Kentucky;Ketorolac;Liposomes;Literature;Manuals;Methods;Modality;Morbidity - disease rate;Multi-Institutional Clinical Trial;Nausea and Vomiting;Opioid;Orthopedic Procedures;Orthopedics;Outcome;Pain;Pain management;Paper;Patients;Pharmaceutical Preparations;Pharmacy facility;Placebo Effect;Placebos;Population;Postoperative Complications;Postoperative Pain;Preparation;Prevention;Procedures;Process;Protocols documentation;Public Health;Randomized;Replacement Arthroplasty;Reporting;Research;Resources;Retrospective Studies;Risk;Rotator Cuff;Safety;Safety Management;Severities;Site;Spine surgery;Statistical Data Interpretation;Testing;Therapy trial;Training;Trauma;Universities;Urinary Retention;Ventilatory Depression;Visual;Work;age group;analog;base;clinical investigation;clinical research site;cohort;cost;cost effective;data dictionary;data management;data repository;data standards;design;effectiveness evaluation;experience;follow-up;improved;improved outcome;indexing;mortality;novel;older patient;opioid epidemic;opioid use;participant enrollment;payment;placebo controlled trial;prevent;primary endpoint;prospective;randomized placebo controlled trial;recruit;repaired;ropivacaine;screening;secondary endpoint;side effect

public_health_relevance:
Geriatric hip fractures are common and associated with high morbidity and mortality with more than 3000000fractures sustained each year in the U.S. Opioid limiting pain control using local injection therapy following hipfracture fixation may improve outcomes by decreasing complications associated with poor pain control andopioid use in this population. This grant aims to support the planning of a clinical trial which will assess theeffectiveness of these novel injections in the treatment of post-operative pain following geriatric hip fracturefixation to improve outcomes in geriatric hip fractures.


application_id: 10440464
project_number: 5R01CA215095-06
project_title: Roles of RORalpha in breast cancer development and progression
administering_ic: NCI
award_notice_date: 2022-08-12
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 215095
program_official: WATSON, JOANNA M
project_start_date: 2017-07-01
project_end_date: 2025-10-17
study_section: Tumor Microenvironment Study Section[TME]
contact_pi_person_id: 10533977
contact_pi: XU, REN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Tumor has been described as the wounds that do not heal. The two share some common features such asloss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarityinduced macrophage infiltration. However little is known of how disruption of epithelial cell polarity at earlystage of breast cancer development induces macrophage infiltration. We have identified the RAR-relatedorphan nuclear receptor  (ROR) as a potent tumor suppressor by analyzing global gene expression profilesin polarized and non-polarized mammary epithelial cells. Our recent findings show that ROR inhibits ROSgeneration and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggestthat ROR is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found thatknockdown of ROR significantly induced ROS production in mammary epithelial cells. Reactive oxygenspecies (ROS) are the driver of cancer progression and critical regulator of the NF-B pathway. Based onthese novel findings the central hypothesis of our proposal is that downregulation of ROR in non-polarizedbreast cancer cells increased ROS generation in mitochondria thereby inducing NF-B and macrophageinfiltration. We integrate high-throughput metabolic analysis a novel 3D co-culture system and global geneexpression profiling to delineate mechanisms by which ROR inhibits ROS production and macrophageinfiltration. The long-term goal of this proposal is to define the impact of the ROR/ROS axis in mediatingmammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposedfollowing specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORreduces ROS levels and NF-B activity in polarized mammary epithelial cells; Aim 2. To determine howreduced ROR expression in non-polarized breast cancer cells induces macrophage infiltration and M2polarization; Aim 3. Define the impact of ROR in suppressing breast cancer formation and metastasis. Theproposed study is high impact for its inherent scientific importance and its translational potential. This study willelucidate the molecular mechanism by which disruption of tissue polarity induces macrophageinfiltration/differentiation. Determining roles of ROR in reducing ROS generation and inhibiting NF-Bactivation may identify a novel strategy to inhibit breast cancer development and progression.

project_terms:
3-Dimensional;Agonist;Biological Assay;Biology;Breast;Breast Cancer Cell;Breast Cancer Model;Breast Epithelial Cells;Cell Polarity;Cellular Metabolic Process;Chronic;Coculture Techniques;Complex;Development;Down-Regulation;Epithelial Cells;Gene Expression;Gene Expression Profiling;Generations;Glutathione Disulfide;Goals;Human;Hydrogen Peroxide;Immunocompetent;Infiltration;Inflammation;Knockout Mice;Knowledge;Lead;Link;Malignant Neoplasms;Measurement;Mediating;Metabolic;Metformin;Mitochondria;Modeling;Molecular;Mus;NADP;Nature;Neoplasm Metastasis;Nuclear Orphan Receptor;Oxidation-Reduction;Pathway interactions;Positioning Attribute;Production;Reactive Oxygen Species;Research;Role;Scheme;Source;Structure;Superoxides;System;TP53 gene;Testing;Tissue Microarray;Tissues;Tumor Suppressor Proteins;base;breast cancer progression;cancer cell;cancer prevention;cancer therapy;cytokine;druggable target;healing;improved;inhibitor;insight;knock-down;loss of function;macrophage;malignant breast neoplasm;mammary;metabolomics;monocyte;multidisciplinary;novel;novel strategies;stable isotope;transcriptome;translational potential;tumor;tumor microenvironment;tumor progression;wound

public_health_relevance:
Characterizing the molecular link between disruption of mammary tissue polarity and macrophage infiltrationand elucidating the mechanism by which ROR repressing ROS generation and NF-B activity will fill criticalgaps in our knowledge about cancer-associated chronic inflammation and breast cancer progression.Determining whether inducing ROR activity represses breast progression and metastasis will help identifypotential druggable targets.


application_id: 10440105
project_number: 3R01DE029650-03S1
project_title: HPV16 E6 Antibody Detection as an Early Marker of Oropharyngeal Cancer Among Men Living with HIV
administering_ic: NIDCR
award_notice_date: 2021-09-16
opportunity_number: PA-20-272
application_type: 3
activity_code: R01
ic: DE
serial_number: 029650
suffix: S1
program_official: YIN, HONGEN
project_start_date: 2021-02-05
project_end_date: 2024-04-30
study_section: ZDE1(13)
contact_pi_person_id: 14510566
contact_pi: KUHS, KRYSTLE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractPeople living with HIV (PLWH) have an increased life expectancy due to effective therapies. This has resulted in anincreased incidence of non-AIDS defining cancers (NADCs) in particular cancers caused by human papillomavirus (HPV).The most rapidly increasing HPV-related malignancy in the general US population is HPV-driven oropharyngeal cancer(HPV-OPC) a type of head and neck that has increased in incidence by more than 200% over the past few decades.1 2PLWH are 1.5 to 4 times more likely to develop HPV-OPC than the general population.3 They are also more likely todevelop HPV-OPC at younger ages (51 versus 60)4 and have a less favorable cancer prognoses.5 Unlike cervical cancerwhere the introduction of highly effective screening has significantly reduced the incidence and mortality of cervicalcancer there are no methods for early detection of HPV-OPC. A major barrier for early detection has been the inabilityto identify PLWH at highest risk for HPV-OPC given that a precancerous precursor lesion for OPC has yet to be identified.Recently HPV16 E6 antibody positivity has been identified as a promising early biomarker. Previous work from ourgroup showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients6 and appear more than 10 yearsprior to diagnosis.7-9 Additionally we have shown that HPV16 E6 antibodies are highly specific for HPV-OPC10 and arenot strongly associated with the 5 other cancers caused by HPV.11 The objective of this study is to evaluate the ability ofthe HPV16 E6 marker to identify a sub-population of PLWH at highest risk for developing HPV-OPC and for which headand neck cancer screening would be most effective. To accomplish this we will conduct a natural history study of theHPV16 E6 antibody marker. This study will focus on men aged 40+ living with HIV given that ~85% of HPV-OPC casesoccur in middle aged men and HIV infection additionally elevates risk by up to 4-fold. Using the Tennessee Center forAIDS Research (TN-CFAR) Biorepository banked blood samples from men aged 40+ living with HIV (N=3261) will betested for HPV16 E6 antibodies. All HPV16 E6 seropositives and a subset of HPV16 E6 seronegatives (1:2 ratio) will beinvited to participate in yearly (4 total) comprehensive head and neck cancer screening exams performed by aVanderbilt Ingram Cancer Center (VICC) head and neck surgeon. Cancer screening visits will include: visual inspection ofthe mouth and palpation of tonsils ultrasound imaging laryngoscope exam a detailed questionnaire and biospecimencollection. E6 seropositive men will be compared to E6 seronegative men in terms of: a) markers of elevated HPV-OPCrisk and b) development of HPV-OPC. The specific aims are: (1) Estimate the prevalence of HPV16 E6 antibodies amongmen aged 40+ living with HIV; (2) Determine the association between HPV16 E6 seropositivity and markers of HPV-OPCrisk; (3) Estimate the risk of developing: a) precancerous markers of HPV-OPC and/or; b) HPV-OPC by HPV16 E6serostatus. We hypothesize that men with HPV16 E6 antibodies will be more likely to have known risk factorsassociated with HPV-OPC development [sexual behavior persistent oral HPV infection] and will be more likely todevelop HPV-OPC than men without HPV16 E6 antibodies. The COVID-19 pandemic has prevented recruitment into thisstudy; thus this supplement is aimed at overcoming these barriers to allow the study to proceed as planned.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Affect;Age;Antibodies;Behavioral;Biological Markers;Blood;Blood Banks;Blood specimen;COVID-19 pandemic;Cancer Center;Cancer Etiology;Clinic;Collection;Communities;Comprehensive Health Care;Development;Diagnosis;Early Diagnosis;General Population;HIV;HIV Infections;HIV Seronegativity;HPV-High Risk;Head and Neck Cancer;Head and Neck Surgeon;Head and neck structure;High Prevalence;Human Papilloma Virus-Related Malignant Neoplasm;Human Papillomavirus;Human papilloma virus infection;Human papillomavirus 16;Incidence;Individual;Laryngoscopes;Lesion;Life Expectancy;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Methods;Natural History;Oncoproteins;Oral cavity;Oral health;Palpation;Patients;Persons;Population;Positioning Attribute;Prevalence;Quality of life;Questionnaires;Research;Resources;Risk;Risk Estimate;Risk Factors;SARS-CoV-2 infection;Screening for cancer;Screening procedure;Seroprevalences;Sex Behavior;Surrogate Markers;Tennessee;Testing;Time;Tonsil;Ultrasonography;Visit;Visual;Work;aged;antibody detection;base;biobank;cancer risk;chemoradiation;clinical examination;cohort;early detection biomarkers;effective therapy;high risk;improved;malignant oropharynx neoplasm;men;middle age;mortality;novel;oral HPV;oral HPV infection;premalignant;prevent;rapid detection;recruit;screening;screening guidelines;seropositive

public_health_relevance:
PROJECT NARRATIVECases of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) now outnumber cervical cancer cases in the US -men and people living with HIV (PLWH) are at highest risk. We are proposing to use HPV16 E6 seropositivity an earlybiomarker of HPV-OPC to develop a cohort of men living with HIV who are at highest risk for OPC to better understandHPV16 E6 antibodies as an early marker of HPV-OPC and b) to develop new methods of early detection for this rapidlyincreasing cancer. The COVID-19 pandemic has prevented recruitment into this study; thus this supplement is aimed atovercoming these barriers to allow the study to proceed as planned.


application_id: 10439341
project_number: 2R15ES028440-02A1
project_title: Prenatal Cigarette Smoke Exposure: Impact on Offspring Gut Bacterial Microbiome
administering_ic: NIEHS
award_notice_date: 2022-06-17
opportunity_number: PAR-21-155
application_type: 2
activity_code: R15
ic: ES
serial_number: 028440
suffix: A1
program_official: DZIERLENGA, ANIKA LIN
project_start_date: 2017-08-01
project_end_date: 2026-05-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 2095188
contact_pi: CORBITT, CYNTHIA
other_pis: Not Applicable
congressional_district: 03
department: BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
ABSTRACTAn estimated 17% of women in Kentucky smoke during pregnancy. The studies proposed within this renewalapplication use a well-developed murine model of developmental exposure to tobacco smoke. We have showneffects of prenatal cigarette smoke exposure (CSE) on birth weight catch-up growth and gut bacterialmicrobiome in mouse dams and their offspring as well as effects on offspring phenotype (preliminary data).However we do not know if the observed changed in microbiome and offspring phenotype are linked. We willmeasure the effect of cecal transfer of microbiomes or dietary resistant starch on those same measures in thismodel.Our central hypothesis that CSE-induced gut microbiome alterations are linked to offspring phenotype will betested within 2 aims:Aim 1: use cecal transfer in weanlings to separate effects of CSE-induced microbiome from CSE itselfAim 2: use dietary resistant starch to increase short-chain fatty acids before vs after pubertyIf our central hypothesis is supported future studies will delve into gut-liver-brain axis consequences of intestinaldysbiosis as well as investigate potential interventions.Drs. Corbitt (PI) Neal (co-I) and Kosiewicz (co-I) jointly will train students and conduct the proposed studies.

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

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


application_id: 10439253
project_number: 1R21AI169423-01
project_title: Extracellular vesicles released in response to Yersinia pestis
administering_ic: NIAID
award_notice_date: 2022-01-18
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 169423
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2022-01-18
project_end_date: 2023-12-31
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
other_pis: URIARTE, SILVIA M
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:
SUMMARY Extracellular vesicles (EVs) are membrane-bound vesicles released by cells that are potent vehiclesfor intercellular communication. The signaling capacity of EVs is mediated by incorporation of differentbiomolecules (e.g. proteins lipids nucleic acids and carbohydrates) within individual vesicles.Neutrophils produce EVs upon recognition of a variety of stimuli but the biological properties of EVschange depending on the stimuli encountered. Thus depending on stimulation neutrophil-derived EVshave been shown to induce both pro- and anti-inflammatory responses in recipient cells. Neutrophilscan also produce a subset of EVs that are directly microbiostatic to bacteria and fungi. However theEV response by neutrophils has only been characterized for very few bacterial species and thereforewe have a limited understanding of the full potential of neutrophil-derived EVs in response to differentbacterial infections. Yersinia pestis is the causative agent of the human disease known as plague. Y.pestis evades immune cell recognition via direct interactions with innate immune cells that disrupt thenormal responses by these cells. Specifically Y. pestis uses a type three secretion system (T3SS) todirectly secrete bacterial proteins (called Yops) into host cells which disrupt specific host cell signalingpathways. The outcomes of Yop translocation into host neutrophils include: blocking phagocytosisinhibition of the generation of reactive oxygen species and decreased production of pro-inflammatorycytokines by neutrophils. Recently we and others have shown that Y. pestis is able to block neutrophilgranule exocytosis in a T3SS-dependent manner. Together these data show that Y. pestis efficientlyalters endocytic and exocytic activities by neutrophils. Despite its ability to disrupt endocytic andexocytic pathways the ability of Y. pestis to alter the production of EVs by host cells has not beenpreviously investigated. With a growing appreciation for EVs in inflammation and bacterial clearanceour lack of a proper understanding of the EVs released by innate immune cells in response to Y. pestisrepresents a critical knowledge gap in the immune response to Y. pestis. Based on previously publishedstudies and our preliminary data we hypothesize that Y. pestis actively alters the production of EVs byinnate immune cells and that this alteration has a direct impact on how EVs can influence the immuneresponse to the bacterium. To test this hypothesis in Aim 1 we will define the composition of thepayloads packaged into EVs by neutrophils in response to Y. pestis infection and whether the T3SSand Yop effectors alter the production of EVs. In Aim 2 we will determine the impact of EVs isolatedfrom neutrophils infected with Y. pestis or a Y. pestis strain lacking the Yop effectors on immune cellresponse to Y. pestis infection. Completion of these Aims will provide for the first time a comprehensivedescription of the EVs produced by human neutrophils in response to infection with Y. pestis.

project_terms:
Anti-Inflammatory Agents;Antigen Presentation;Autoimmunity;Bacteria;Bacterial Infections;Bacterial Proteins;Biological;Biology;Carbohydrates;Cell Communication;Cells;Characteristics;Cytoplasmic Granules;Data;Exocytosis;Future;Generations;Goals;Grant;Growth;Human;Immune;Immune Evasion;Immune response;Immune signaling;Individual;Infection;Inflammasome;Inflammation;Inflammatory;Inflammatory Response;Innate Immune System;Knowledge;Lipids;Malignant Neoplasms;Mediating;Membrane;Molecular;Nucleic Acids;Outcome;Pathogenesis;Pathologic;Pathway interactions;Patients;Phagocytosis Inhibition;Physiological;Plague;Play;Population;Production;Property;Proteins;Publishing;Reactive Oxygen Species;Reporting;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Site;Stimulus;System;Testing;Therapeutic;Therapeutic Intervention;Time;Vesicle;Yersinia pestis;base;cytokine;exosome;extracellular vesicles;fungus;human disease;improved;intercellular communication;macrophage;monocyte;mutant;neutrophil;novel;novel strategies;recruit;response;tool;vesicular release

public_health_relevance:
PROJECT NARRATIVEExtracellular vesicles (EVs) are released by cells to mediate cell-to-cell communication and contribute toestablishing the proper immune response during infection. Our goal is to define how Yersinia pestis thecausative agent of plague alters EV production by immune cells to disrupt cell communication and inhibit therecruitment of immune cells to the site of infection (referred to as inflammation). Because inducing inflammationduring early stages of plague can improve the therapeutic window for a patient defining mechanisms used byY. pestis to inhibit inflammation is not only important for our understanding the pathogenesis of this bacteriumbut will help us to identify new approaches to improve current plague therapy.


application_id: 10438971
project_number: 2R15GM128050-02
administering_ic: NIGMS
award_notice_date: 2022-03-09
opportunity_number: PAR-21-155
application_type: 2
activity_code: R15
ic: GM
serial_number: 128050
program_official: VATAKIS, DIMITRIOS NIKOLAOS
project_start_date: 2018-05-01
project_end_date: 2026-04-30
study_section: Molecular Genetics B Study Section[MGB]
contact_pi_person_id: 14341647
contact_pi: GUY, MICHAEL P.
other_pis: Not Applicable
congressional_district: 04
department: CHEMISTRY
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: 2022-05-01
project_title:
Determining how 2'-O-methylations in the eukaryotic anticodon loop region of tRNA are formed and how they affect translation

project_abstract:
ABSTRACTTranslation is a key step in the overall process that cells use to convert genes into proteins and defects intranslation are linked to many human diseases. A critical component of translation is transfer RNA (tRNA)which must be extensively chemically modified by numerous cellular enzymes to function properly. Many ofthese enzymes and the tRNA modifications that they form are conserved in eukaryotic organisms ranging fromsingle-celled budding yeast to multi-cellular organisms such as humans thus making yeast a powerful modelorganism for studying the roles of tRNA modifications. Importantly defects in tRNA modifications causediverse neurological disorders such as intellectual disability (ID) and are linked to many other diseases. ThisNIH R15 AREA proposal seeks to expose undergraduate students to modern biomedical research byadvancing the field of tRNA modification research in three ways. First we propose to study yeast Trm732 aprotein which binds to the methyltransferase Trm7 to form a highly conserved modification at position 32located in the critical anticodon loop (ACL) region of the tRNA. In addition we will study yeast Trm734 whichalso binds to Trm7 to form a conserved modification at tRNA position 34 in the ACL. Defects in thesemodifications due to mutations in human TRM7 (known as FTSJ1) cause ID. Moreover human TRM732(THADA) is linked to type 2 diabetes obesity and polycystic ovary syndrome and human TRM734 (WDR6)also has links to human health. Thus in Aim 1 of the proposal students will perform biochemical experimentsto determine the roles of Trm732 and Trm734 in tRNA modification by Trm7. In our previous round of fundingstudents identified Trm732 and Trm734 variant proteins lacking tRNA modification activity which will bevaluable tools to understand how each protein functions in tRNA modification. Second although thecumulative role of these modifications at 32 and 34 have been studied previously little is known about theindividual role of each modification by itself. Thus in Aim 2 we propose to determine how each modificationindividually affects translation in yeast as well as in cultured human and fruit fly cells. Third we propose toidentify the gene required to form a human tRNA ACL modification not found in yeast and to study its role intranslation. In Aim 3 we will finish our work to identify the enzyme that adds a modification to position 39 ofcertain human animal and plant tRNAs. Students will continue to test candidate genes for the modificationactivity using approaches that we developed previously to identify other tRNA modification genes. Once thegene is identified we will use reporter assays to determine the role of this modification in translation. Theresearch proposed herein meets the criteria of the NIH R15 AREA award because it gives undergraduatestudents the opportunity to fully participate in research that will increase knowledge of the underlying molecularcauses of disease. Students will be trained in genetic molecular biological and biochemical techniqueshelping to prepare a new generation of biomedical researchers.

project_terms:
Affect;Amino Acids;Animal Model;Animals;Anticodon;Award;Binding;Biochemical;Biochemistry;Biological;Biological Assay;Biomedical Research;Candidate Disease Gene;Cell physiology;Cells;Chemicals;Codon Nucleotides;Defect;Disease;Drosophila genus;Enzymes;Eukaryota;Exposure to;Fission Yeast;Funding;Gene-Modified;Generations;Genes;Genetic;Grant;Growth;Health;Homologous Gene;Human;Individual;Institution;Intellectual functioning disability;Kentucky;Knowledge;Link;Malignant Neoplasms;Mammalian Cell;Methylation;Methyltransferase;Modernization;Modification;Molecular;Molecular Biology;Mutation;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organism;Phenotype;Plants;Polycystic Ovary Syndrome;Positioning Attribute;Process;Proteins;RNA;RNA Binding;RNA-Binding Proteins;Reporter;Research;Research Personnel;Research Project Grants;Role;Saccharomyces cerevisiae;Saccharomycetales;Science;Sequence Alignment;Site-Directed Mutagenesis;Stress;Students;Techniques;Testing;Training;Transfer RNA;Translations;United States National Institutes of Health;Universities;Variant;Work;X-linked mental retardation 9;Yeasts;career;cell growth;experimental study;human disease;insight;knock-down;mutant;nervous system disorder;overexpression;protein function;protein protein interaction;tool;undergraduate student

public_health_relevance:
PROJECT NARRATIVEPosttranscriptional modification of transfer RNA (tRNA) is crucial for proper translation and cell growth anddefects in modifications have been linked to several human diseases. Modifications in and around theanticodon loop (ACL) region of tRNA are especially important and defects in modifications in this region causeintellectual disability and are linked to human health in several other ways. This proposal will engageundergraduate students in all aspects of a research project that employs molecular biology genetics andbiochemistry to characterize the proteins that form three of these important tRNA modifications and todetermine the roles of these modifications in translation in organisms ranging from yeast to humans.


application_id: 10438562
project_number: 5T32AI132146-05
project_title: Inflammation and Pathogenesis Training Program
project_terms: Inflammation;Pathogenesis;Training Programs
administering_ic: NIAID
award_notice_date: 2022-08-16
opportunity_number: PA-16-152
application_type: 5
activity_code: T32
ic: AI
serial_number: 132146
program_official: GONDRE-LEWIS, TIMOTHY A
project_start_date: 2018-08-01
project_end_date: 2024-07-31
study_section: Microbiology and Infectious Diseases B Research Study Section[MID-B]
contact_pi_person_id: 1941645
contact_pi: MITCHELL, THOMAS C.
other_pis: LAMONT, RICHARD J
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
project_abstract:
AbstractThe major objective of this new training program is to produce skilled rigorous and creative scientists who willmake novel connections between inflammatory processes and human pathogenesis. The University ofLouisville is well-positioned to have high impact by selecting trainees with leadership potential from its existingIntegrated Programs in Biomedical Sciences (IPIBS) for continued training on research topics that bridgemicrobiology and immunology. This interdisciplinary approach will bring together 35 faculty who are all highlyproductive scientists with extensive mentoring experience and well-funded research programs focused on i)inflammatory ontogeny and immune surveillance of cancer ii) mechanisms of autoimmune disorders iii)cellular and molecular mechanisms of host-microbial interactions iv) animal models of infectious disease v)the role of the microbiota in regulation of inflammatory diseases vi) polymicrobial communities andinflammation and vii) inflammation-driven disease and its impact on host physiology. Pre-candidacy supportfrom IPIBS in which all students receive stipends and benefits funded by the University of Louisville includeslaboratory rotations advanced didactic training in immunology; inflammation; microbiology; and pathogenesis.Pre-candidacy training also includes research survival skills including grant development and compositionoral presentations scientific writing and publishing professional networking along with extensive training inthe responsible conduct of research. To attain the highest positive peer-to-peer impact each year two studentswho have demonstrated exceptional performance while successfully completing their first two years ofgraduate education as IPIBS Fellows will be selected for two years of support from the T32 training grant.Students from diverse backgrounds who show the most potential based on their achievements as IPIBSFellows in graduate coursework a qualifying exam and in their research projects will be selected in order tofoster their academic leadership skills and excellence as research scientists. This additional training will occurthrough student organization of a program-specific discussion club hosting two high profile speakers per yearin disciplines that highlight important relationships between inflammation and pathogenesis and rigorousreview of their research progress by a training mentor and dissertation committee. The program will beoverseen by two Directors working closely with a Steering Committee including an independent evaluation ofthe training programs organization leadership objectives and outcomes by Internal and External AdvisoryCommittees.

public_health_relevance:
Public Health RelevanceInflammation is a multi-component process that helps protect the host from injury and infection under normalhomeostatic conditions. However inflammatory responses can also cause acute tissue damage or becomeestablished as chronic inflammation which together contribute to many human diseases. It is essential to traina new generation of scientists with interdisciplinary expertise in microbial and inflammatory biologicalmechanisms in order to continue progress against pervasive inflammatory-based disorders.


application_id: 10438112
project_number: 3R01HL139047-04S1
project_title: Remote Hind Limb Ischemia Mechanism of Cardioprotection
administering_ic: NHLBI
award_notice_date: 2021-08-19
opportunity_number: PA-20-222
application_type: 3
activity_code: R01
ic: HL
serial_number: 139047
suffix: S1
program_official: SCHWARTZ, LISA
project_start_date: 2018-07-01
project_end_date: 2023-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-R(02)S]
contact_pi_person_id: 1885220
contact_pi: TYAGI, SURESH C.
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
project_abstract:
Although hind limb remote ischemic conditioning (RIC) is cardioprotective the mechanism isunknown. The long-term goal of this project is to understand the mechanism of protection by remotehind-limb ischemia. The central hypothesis of this proposal is that transient ischemic episodes awayfrom the myocardial infarction (MI) contribute to the recovery through secretion of beneficialexosomes from skeletal muscle endocrine improving mitochondrial metabolism hydrogen sulfide(H2S an anti-oxidant anti-inflammatory anti-apoptotic vasoactive gas) and mobilization of bonemarrow stem cells (BMSC) to the site of injury (Figure 1). It is known that DNA hypermethylation byepigenetic modification inhibits the gene and produces homocysteine (Hcy) leading tohyperhomocysteinemia (HHcy) that decreases H2S. Interestingly increase in cystathione  synthase(CBS) and cystathionine  lyase (CSE) enzymes increases H2S and decreases Hcy. Our preliminarydata suggests that RIC induced musclin (a skeletal muscle hormone) attenuated myocardial muscledamage and dysfunction. The central hypothesis will be tested by the following three specific aims:Specific Aim 1: To determine whether the RIC releases exosomes induces musclin and reversescompromised skeletal and cardiac muscle function during MI and diabetes. Specific Aim 2: Todetermine whether the RIC enhances H2S production by increasing CBS and CSE expression andepigenetic hypomethylation and gene induction during MI and diabetes. Specific Aim 3: To determinewhether the RIC instigates BMSC mobilization to the site of myocardial injury and mitigates muscledamage by regeneration after MI during diabetes.

project_terms:
Address;Anti-Inflammatory Agents;Antioxidants;Apoptotic;Area;Attenuated;Biogenesis;Biological Assay;Bone Marrow Stem Cell;Bone Marrow Transplantation;Cardiac;Coronary heart disease;Cystathionine;DNA;Data;Diabetes Mellitus;Endocrine;Enzymes;Epigenetic Process;Event;Female;Fibrosis;Fluorescence;Functional disorder;Gases;Genes;Goals;Heart;Hematopoietic Stem Cell Mobilization;Hindlimb;Histology;Homocysteine;Hormones;Hydrogen Sulfide;Hyperhomocysteinemia;Hypermethylation;Incidence;Injury;Ischemia;Label;Limb structure;Lyase;Measures;Methylation;Mitochondria;Modification;Mouse Protein;Mus;Muscle;Muscle function;Muscular Atrophy;Myocardial;Myocardial Infarction;Myocardium;Natural regeneration;PPAR gamma;Plasma;Procedures;Production;Proteins;Recovery;Risk;Sampling;Site;Skeletal Muscle;Supplementation;Testing;cardioprotection;conditioning;diabetic;effective therapy;exosome;gene induction;glucose metabolism;improved;ischemic conditioning;limb ischemia;male;mitochondrial metabolism;myocardial damage;myocardial injury;response

public_health_relevance:
Narrative:The incidence of coronary heart disease (CHD) in diabetics is robust and this proposal addresses theissue of remote ischemia can create beneficial effects on ischemic insult in the heart. There must bea strategy to restore lost ischemic tolerance capacity in diabetes to counter the risk. Our proposalfocuses on this aspect and evaluates mechanisms of remote ischemic condition (RIC) in effectivetreatment of myocardial infarction (MI).


application_id: 10437929
project_number: 5R01CA264652-02
project_title: Plk1 as a prognostic biomarker for prostate cancer
administering_ic: NCI
award_notice_date: 2022-07-13
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 264652
program_official: JOHNSON, RONALD L
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Cancer Biomarkers Study Section[CBSS]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Androgen Receptor;Androgens;BRCA mutations;Biochemical;Cancer Patient;Castration;Cell Culture System;Cells;Chromatin;Clinic;Clinical;Clinical Research;Clinical Trials;Complex;DNA Damage;DNA Repair;DNA Repair Gene;DNA Repair Pathway;DNA amplification;DNA damage checkpoint;Data;Defect;Development;Disease;Event;Exhibits;Fostering;Frequencies;Genetically Engineered Mouse;Goals;Health;Investigation;Ionizing radiation;Malignant Neoplasms;Malignant neoplasm of prostate;Mediator of activation protein;Meiotic Recombination;Mission;Mitotic;Mus;Mutation;Outcome;PLK1 gene;Patient-Focused Outcomes;Patients;Phosphorylation;Phosphotransferases;Poly(ADP-ribose) Polymerases;Prognostic Marker;Proteins;Public Health;Receptor Signaling;Recovery;Research;Resistance;Role;Sampling;Signal Pathway;Signal Transduction;Testing;Therapeutic;Tumor Subtype;Withdrawal;Work;abiraterone;ataxia telangiectasia mutated protein;base;brca gene;cancer cell;castration resistant prostate cancer;clinically relevant;comparative efficacy;cytotoxic;design;efficacy evaluation;enzalutamide;genetic approach;improved;inhibitor;innovation;mouse model;novel;novel strategies;overexpression;patient population;predictive marker;premature;prostate cancer cell;prostate cancer progression;response;success;tumor


application_id: 10437880
project_number: 5R03CA262720-02
project_title: Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer
administering_ic: NCI
award_notice_date: 2022-06-23
opportunity_number: PAR-20-052
application_type: 5
activity_code: R03
ic: CA
serial_number: 262720
program_official: LUO, RUIBAI
project_start_date: 2021-07-01
project_end_date: 2023-06-30
study_section: ZCA1-TCRB-V(M1)P
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 SUMMARYAltered metabolism is rapidly emerging as a target for therapeutic intervention in cancer. An increased rate oflipid synthesis in cancer has been recognized as an important aspect of rewired metabolism in transformedcells. Fatty acid synthase (FASN) a key enzyme of lipid synthesis is actively investigated in pre-clinicalstudies and clinical trials as a therapeutic target for cancer. Altered glycosylation also a universal feature ofcancer is associated with cancer progression reduced immune response and resistance to drug treatments.The hexosamine biosynthesis pathway (HBP) generates a nucleotide sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) a key substrate for protein glycosylation. However the mechanisms of howupregulation of de novo lipid synthesis can contribute to synthesis of UDP-GlcNAc and the effect of FASN-targeted therapy on hexasomine biosynthesis are not yet understood. We developed colorectal cancer (CRC)mouse models with heterozygous and homozygous deletion of FASN in intestine and colon and found thatdeletion of FASN is associated with a significant decrease in tumor number and an increase in mouse survival.The RNA-seq data and metabolic analysis of tumors show that FASN selectively regulates the levels ofenzymes and metabolites within the HBP. Consistantly we found that expression of FASN alters synthesis ofUDP-GlcNAc in human CRC cells and correlates with UDP-GlcNAc level in human CRC tissues. Furthermorewe show that FASN alters O-linked and N-linked protein glycosylation. Therefore we hypothesize thatupregulation of FASN during tumorigenesis enhances synthesis of UDP-GlcNAc via rewiring the metabolicnetwork in CRC cells. In Aim 1 using stable isotope labeling and ultrahigh-resolution mass-spectrometry andnuclear magnetic resonance we will delineate FASN-mediated metabolic changes in polar metabolites ofmultiple pathways that supply metabolic subunits to UDP-GlcNAc in vivo. In Aim 2 we will determine the effectof pharmacological inhibition of FASN on synthesis of UDP-GlcNA in human CRC organoids and establishedthe link between expression of FASN and enzymes within the HBP in human CRC tissues. Knowledge of howFASN regulates UDP-GlcNAc synthesis will have a significant translational impact by contributing to betterunderstanding of the mechanisms of metabolic adoptations in cancer cells and identifying new targetableliabilities that would lead to development of more effective therapeutic strategies for CRC. Completion of thesestudies will also help us advance our ongoing research to better understand how lipid synthesis regulates thelandscape of glycosylation in CRC and contribution of these metabolic pathways to CRC progression andmetastasis.

project_terms:
Acetyl Coenzyme A;Acyl Coenzyme A;Adopted;Amino Sugars;Anabolism;Biochemical Pathway;Cancer Etiology;Cell Proliferation;Cessation of life;Characteristics;Clinical Trials;Colon;Colorectal Cancer;Data;Development;Disease;Disease-Free Survival;Drug resistance;Enzymes;Fatty Acids;Fatty-acid synthase;Funding;Gene Expression;Genes;Genetic;Glucose;Glutamine;Glycolysis;Growth;Hexosamines;Human;Immune response;Intestines;Knowledge;Lead;Link;Lipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Mus;Neoplasm Metastasis;Nitrogen;Nuclear Magnetic Resonance;Organoids;Pathway interactions;Pharmacology;Pharmacotherapy;Phase II Clinical Trials;Post-Translational Protein Processing;Process;Production;Prognosis;Protein Glycosylation;Regulation;Research;Resolution;Role;Signal Transduction;Solid;Stable Isotope Labeling;Testing;Therapeutic;Therapeutic Intervention;Tissues;United States;Up-Regulation;Uridine Diphosphate N-Acetylglucosamine;Woman;anti-cancer;cancer cell;cell transformation;colorectal cancer progression;glycosylation;improved;in vivo;inhibitor;link protein;lipid biosynthesis;long chain fatty acid;men;mouse model;neoplastic cell;novel;novel therapeutic intervention;overexpression;oxidation;preclinical study;sugar nucleotide;targeted treatment;therapeutic target;therapeutically effective;transcriptome sequencing;translational impact;tumor;tumor progression;tumorigenesis;uptake

public_health_relevance:
PROJECT NARRATIVE Colorectal cancer is the 2nd most common cause of cancer death among men and women in the UnitesStates. We have proposed to investigate a novel mechanism of how an increase in lipid synthesis rewiresthe metabolic network to enhance synthesis of uridine diphosphate N-acetylglucosamine a substrate forglycosylation. The completion of this study we will determine novel metabolic vulnerabilities in fatty acidsynthase-driven colorectal cancer and further guide the development of novel therapeutic strategies to treatcolorectal cancer and potentially other solid cancers.


application_id: 10437775
project_number: 5F31DC019050-03
project_title: Terminal Arbor remodeling of Peripheral Taste Neurons
administering_ic: NIDCD
award_notice_date: 2022-06-29
opportunity_number: PA-19-195
application_type: 5
activity_code: F31
ic: DC
serial_number: 019050
program_official: SCHURMAN, JACLYN REBECCA
project_start_date: 2020-07-01
project_end_date: 2023-05-15
study_section: ZDC1-SRB-R(32)
contact_pi_person_id: 14783350
contact_pi: WHIDDON, ZACHARY DAVID
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractTaste receptor cells (within taste buds) are constantly replaced through adulthood. This raisesthe question of whether this continuous cell turnover causes remodeling in the taste nerveterminal arbors which innervate taste receptor cells. More specifically how does taste receptorcell entry and cell exit within the taste bud influence arbor structure? To answer thesequestions I propose to develop an in vivo two-photon imaging method to repeatedly sample thesame terminal arbors over time. Aim 1 will examine terminal arbor structure over the averagelifespan of a taste receptor cell (10 days). I hypothesize that terminal arbor structure in theepithelium will remodel in this period while structure beneath the epithelium will remain stable.Aim 2 will examine arbor structure when taste cell turnover is manipulated to elucidate theeffects of cell entry and cell exit. I hypothesize that taste cell exit from the bud will promotebranch retraction and taste cell entry into the bud will promote branch formation/growth. Theseexperiments are the first to investigate changes in taste neuron anatomy over time using a intravital imaging approach and will provide direct evidence of extent of nerve fiber remodeling in thetaste bud. Future studies will use this approach to investigate the specific molecularmechanisms in both neurons and taste cells used to orchestrate plasticity in the taste bud.

project_terms:
Adult;Affect;Afferent Neurons;Anatomy;Cells;Chemicals;Dose;Environment;Epithelial;Erinaceidae;Exposure to;Future;Genetic;Growth;Hour;Image;Individual;Label;Location;Longevity;Maps;Methods;Molecular;Morphology;Mus;Nerve;Nerve Fibers;Nervous system structure;Neurons;Organ;Peripheral;Pharmacology;Process;Receptor Cell;Recovery;Sampling;Sensory;Signal Transduction;Structure;System;Tamoxifen;Taste Buds;Taste Perception;Techniques;Time;Tongue;experimental study;imaging approach;imaging modality;in vivo imaging;in vivo two-photon imaging;intravital imaging;novel;prevent;response;side effect;smoothened signaling pathway;taste system;time use;two-photon

public_health_relevance:
Project NarrativeHere I propose an in vivo imaging method to observe changes in terminal arbor structure ofperipheral taste neurons over time in response to taste receptor cell turnover. Theseexperiments will contribute to our current understanding of structural plasticity in the adultnervous system and how this plasticity is regulated. Of central importance is the application ofthis technique to assess how novel chemotherapeutic side-effects might disrupt the sense oftaste.


application_id: 10437631
project_number: 5R01DE026963-05
project_title: P. gingivalis genes essential for tobacco smoke survival
administering_ic: NIDCR
award_notice_date: 2022-06-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 026963
program_official: MCNEALY, TAMARA L
project_start_date: 2017-09-01
project_end_date: 2025-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(02)M]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Periodontitis is a highly prevalent disease associated with several debilitating systemic conditionsincluding vascular and lung diseases diabetes mellitus and pre-term birth. The most recent epidemiologicalevidence suggests that tobacco smoking accounts for the majority of destructive periodontal disease cases indeveloped nations. Smoking enhances infection rates and enriches numbers of a key periodontal pathogenPorphyromonas gingivalis. However the mechanisms underlying this phenomenon are in need of elucidation. Inthe first iteration of award facilitated by a two year NIGMS-funding mechanism we generated an 80000 colonytransposon sequencing library for P. gingivalis strains ATCC 33277 and exploited this resource to: (i) Successfully identify 256 genes that are putatively essential for surviving tobacco-induced stress; (ii) Delineate a core stress genome commonly required for tobacco-survival epithelial colonization and subcutaneous abscess formation; and (iii) Validated several genes as conditionally essential for P. gingivalis to survival of cigarette smoke- induced stress in vitro by generating single gene deletion mutants that exhibit either reduced absolute fitness in competition assays with the parental P. gingivalis strain in smoked medium; (iv) We have also generated a novel murine model of tobacco-exacerbated periodontitis. We now plan to build on these successes via three specific aims as follow:Aim 1: Further elucidate P. gingival CSE-related survival strategies by generating mutants in single genesthat are both CSE-essential (TnSeq data) ;and tobacco-regulated (RNAseq and qPCR); yet not compromised intheir ability to colonize oral epithelial cells (TIGK model) or immune resistance (murine abscess model).Aim 2: Determine in vivo relevance of putatively CSE-essential genes using a murine smoke-exposurechamber model in a chronic Baker model of P. gingivalis-induced periodontitis.Aim 3: Establish the broad applicability of data gathered in Aims 1 and 2 by confirming biological functionand distribution of CSE essential genes in multiple P. gingivalis strains. Long term advances are likely to include (a) A better understanding of how P. gingivalis thrives in atobacco-toxin rich environment; (b) Future therapeutic targeting of essential genes to control P. gingivalisinfection in smokers (CSE-essentiality data) and in general (multiple disease-relevant conditions core stressgenome data); (c) Alternate treatment regimens for smokers based on mechanistic insight into smoke-inducedand/or exacerbated periodontal diseases;and (d) The establishment of an essential gene database for tobacco-enhanced pathogens that will facilitate the identification of common bacterial strategies for surviving tobaccosmoke exposure thus broadening the significance of the research beyond the oral cavity.

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

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


application_id: 10436997
project_number: 5R21DK127295-02
administering_ic: NIDDK
award_notice_date: 2022-05-27
opportunity_number: PAR-19-222
application_type: 5
activity_code: R21
ic: DK
serial_number: 127295
program_official: SERRANO, KATRINA JANE
project_start_date: 2021-06-23
project_end_date: 2024-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-H(54)]
contact_pi_person_id: 10299348
contact_pi: RASHID, CETEWAYO SAIF
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-06-01
project_title:
Hyaluronan as a mediator of intrauterine growth restriction-induced islet dysfunction in type 2 diabetes

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

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

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


application_id: 10436430
project_number: 3P01NS097197-05S1
project_title: Lafora Epilepsy Basic mechanisms to therapy
administering_ic: NINDS
award_notice_date: 2021-07-09
opportunity_number: PA-20-272
application_type: 3
activity_code: P01
ic: NS
serial_number: 097197
suffix: S1
program_official: LEENDERS, MIRIAM
project_start_date: 2016-07-01
project_end_date: 2023-06-30
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
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:
This is an Administrative Supplement request in response to PA-20-272 "Administrative Supplements to Existing NIH Grants and Cooperative Agreements" for P01NS097197 entitled "Lafora Epilepsy - Basic mechanisms to therapy". The requested funds are to maintain and cryo-preserve Lafora disease animal models and novel cell lines as well as maintain key resources. Per the budget justification these funds will be utilized by the Roach laboratory (Project 3) the Guinovart laboratory (Project 4) the Sanz laboratory (Project 4) and the Serratosa laboratory (Biological Core). The Gentry laboratory (Project 1) and the Minassian laboratory (Project 2) have carryforward funds that they will utilize to preserve and maintain key resources. The Medicinal Chemistry Core generated a number of small molecules that are still being tested and no funds are being requested for additional compounds. Therefore the Medicinal Chemistry Core is being sunset. The Biological Core originally was comprised of a branch at UCSD that generated animal and cell line LD models and one in Madrid that has been and is performing behavioral tests and cell line analyses. Since no new animal or cell line models are needed at this time the UCSD branch is being sunset. In summary the requested funds will be utilized to maintain novel and key reagents that have been generated and are critical to developing a therapy or cure for Lafora disease.

project_terms:
Administrative Supplement;Animal Disease Models;Animals;Antisense Oligonucleotides;Biological;Biological Assay;Biological Models;Brain;Budgets;Cell Line;Chemistry;Clinical Research;Clinical Trials;Coupled;Cytoplasm;Data;Defect;Dendrites;Development;Diagnosis;Diagnostic;Disease;Disease model;Dreams;Enzymes;Epilepsy;Funding;Genes;Genetic;Glycogen;Grant;Intractable Epilepsy;Laboratories;Lafora Disease;Modeling;Molecular;Molecular Target;Mutation;Pathway interactions;Patients;Pharmaceutical Chemistry;Pharmacology;Positioning Attribute;RNA;Reagent;Refractory;Resources;Starch;Structural Biochemistry;Techniques;Technology;Testing;Therapeutic;Time;U-Series Cooperative Agreements;United States National Institutes of Health;Work;base;behavior test;induced pluripotent stem cell;innovation;member;mouse model;novel;personalized diagnostics;preservation;response;small molecule;small molecule inhibitor;therapeutic evaluation

public_health_relevance:
Lafora disease is a catastrophic epilepsy that strikes healthy teenagers and leads to constant ever-worsening seizures until it results in death after 10 years. The collaboration in this Program Project Grant brings together the clinician-scientists and researchers who discovered the causes of this disease: the shape of glycogen becomes abnormal in this disease in fact it becomes similar to plant starch and builds up in the patients' brain cells. We will utilize state of the art technologies including techniques to manipulate genes introducing biological agents to interfere with gene expression utilization of hormones and carbohydrate-poor dies small molecules and sugar-mimics to down-regulate glycogen production; our research is in a state where we see a clear track to develop effective methods to diagnose treat and ultimately cure LO.


application_id: 10436133
project_number: 1R34DK132548-01
administering_ic: NIDDK
award_notice_date: 2022-04-06
opportunity_number: RFA-DK-20-032
application_type: 1
activity_code: R34
ic: DK
serial_number: 132548
program_official: BURCH, HENRY B
project_start_date: 2022-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZDK1 GRB-9 (J2)]
contact_pi_person_id: 12349240
contact_pi: LACY, MARY E.
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-05-01
project_title:
Using Practice Facilitation and Operationalizing Referral Information Technology (UP FOR IT) to Increase DSMES Utilization

project_abstract:
PROJECT SUMMARYThe prevalence of diabetes in Kentucky is ~25% higher than the national average and rural areas withinKentucky face an even higher burden of diabetes and its related complications. Diabetes self-managementeducation and support (DSMES) services are integral to quality diabetes care. Substantial evidence shows thatDSMES participation improves diabetes outcomes and is cost-effective. Despite strong evidence of benefit andclear guidelines from the American Diabetes Association recommending its use <10% of eligible individualscomplete DSMES. Determinants that contribute to low DSMES uptake exist at multiple levels and includeclinician awareness geographic availability cost and reimbursement and referral mechanisms. Although theKentucky Department of Public Health administers a statewide DSMES program that is free to participants andavailable face-to-face in 80/120 counties and by telehealth in all counties DSMES utilization remains lowacross Kentucky. In response to the current RFA seeking to test innovative and pragmatic approaches tofacilitate greater use of DSMES we propose testing and evaluating a clinic-level intervention that implementshealth information technology (automated patient identification and a bidirectional referral system) to reducebarriers related to identification and referral of eligible patients and engages clinical teams in a practicefacilitation collaborative to increase clinician awareness and overcome clinic-level barriers. We will achieve thisthrough three aims: 1) Planning  implementation science-guided evaluation and adaptation of an existing pilotdiabetes clinical quality improvement program; 2) Implementation  of the adapted intervention; and 3)Evaluation - of intervention components using the Practical Robust Implementation and Sustainability Model(PRISM). We will adapt the proposed intervention from a successful pilot project that used health informationtechnology and a collaborative quality improvement approach to increase DSMES utilization at participatingclinics by >100%. We will use a pragmatic cluster randomized study design to evaluate implementationeffectiveness and will use an implementation science framework to guide evaluation of the feasibilityacceptability and sustainability of the intervention. To achieve the study aims we have partnered with theKentucky Department of Public Health (DSMES provider) the Kentucky Regional Extension Cooperative(practice facilitation partner) Kentucky Health Information Exchange (health information technology partner)and two healthcare systems in rural Kentucky. This pilot and feasibility study will provide insight on pragmaticscalable and sustainable strategies to increase DSMES utilization. Findings will generate key preliminary datathat will guide planning of an R01-level dissemination and implementation trial with the goal of reducingdiabetes-related morbidity and mortality.

project_terms:
Address;Adult;American;Appalachian Region;Awareness;Blood Glucose;Caring;Charge;Clinic;Clinical;Communities;Complications of Diabetes Mellitus;County;Data;Diabetes Mellitus;Diagnosis;Disease;Education;Effectiveness;Evaluation;Face;Feasibility Studies;Geography;Glycosylated hemoglobin A;Goals;Guidelines;Health;Health Care Costs;Health system;Healthcare Systems;Individual;Information Technology;Intervention;Interview;Kentucky;Morbidity - disease rate;Motivation;Outcome;Participant;Patients;Persons;Pilot Projects;Population;Practical Robust Implementation and Sustainability Model;Prevalence;Primary Health Care;Process;Provider;Public Health;Quality of life;Randomized;Research Design;Rural;Secure;Services;Surveys;System;Testing;base;care costs;combat;community clinic;cost;cost effective;diabetes self-management;dissemination trial;effectiveness testing;empowered;evidence base;glycemic control;health disparity populations;health information technology;implementation evaluation;implementation framework;implementation process;implementation science;implementation trial;improved;innovation;insight;mortality;program costs;programs;response;rural area;rural health disparities;skills;system-level barriers;telehealth;uptake

public_health_relevance:
PROJECT NARRATIVEDiabetes Self-Management Education and Support (DSMES) is an evidence-based small group educationalprogram that helps people with diabetes better control blood sugar (improved hemoglobin A1c) and reducediabetes-related complications and healthcare costs. DSMES is strikingly underutilized with fewer than 10% ofeligible patients receiving this helpful service due to patient- clinician- and health system-level barriers thatinclude low clinician awareness and lack of integrated referral processes between clinics and community-based DSMES programs. Our project tests a clinic level-intervention that implements an electronic clinic-community referral system and creates a practice facilitation collaborative to empower clinical teams to identifyand address DSMES barriers with the goal of increasing DSMES utilization.


application_id: 10434906
project_number: 5R01DA049333-03
administering_ic: NIDA
award_notice_date: 2022-07-20
opportunity_number: PAR-18-747
application_type: 5
activity_code: R01
ic: DA
serial_number: 049333
program_official: DUNSTON, SHEBA KING
project_start_date: 2020-09-30
project_end_date: 2025-07-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-08-01
project_title:
Research Examining Factors Associated with the Opioid Crisis among Underserved African Americans (REFOCUS)

project_abstract:
ABSTRACTOpioid-related overdose rates among African Americans have increased exponentially. Given AfricanAmerican opioid users have the lowest treatment completion rates when compared to other races/ethnicitiesthere is increased risk for mortality and morbidity. As a result there is a dire need to better understand thisfatal epidemic among this historically underserved group. Using the theory of Subcultural Evolution and DrugUse which suggests cultural and generational influences are linked to drug use patterns and risks amongAfrican Americans the Research Examining Factors Associated with the Opioid Crisis among UnderservedAfrican Americans (REFOCUS) project will employ a within-racial group mixed-methods design among AfricanAmerican adults in the community. The overall objective is to better understand the complex structural socialand cultural factors that differentially influence NMPOU other nonmedical prescription drug use and treatmentservice use among African Americans. Ultimately our goal is to gather data that will inform culturally-tailoredinterventions to reduce NMPOU and better facilitate initiation and completion of treatment. The REFOCUSproject has three aims: 1) To understand cultural and generational characteristics associated withNMPOU other NMPDU illicit drug use and treatment service use. We will conduct in-depth interviews withapproximately 40 African American nonmedical prescription opioid users stratified by gender and age tounderstand NMPOU across the lifespan within the context of lived experience. Using thematic analysis datawill be gathered to culturally-tailor the survey. 2) To assess structural social and cultural patterns ofNMPOU other NMPDU illicit drug use and treatment service use among 800 (400 = male and 400 =female) African American NMPO users. We will conduct cross-sectional face-to-face culturally-informedsurveys (modified by information obtained in Aim 1) and drug testing using targeted recruitment and stratifiedsampling by age and gender. 3) To pretest messaging generated from initial findings that will informtargeted interventions specific to African American nonmedical prescription opioid users. We willconduct in-depth semi-structured interviews and using health communication techniques we will develop alibrary of cultural gender and generational specific messages related to decreasing NMPOU and increasingtreatment engagement and retention. We will test these messages that will be constructed from Aim 1 and Aim2 data with approximately 40 African American nonmedical prescription opioid users stratified by gender andage. This pretesting task will prepare us to conduct a fully powered RCT as the next step in our research.This underrepresented new investigator led project directly aligns with the PAR and NIDAs priority focusarea of addressing real-world complexities. As this high-impact project focuses on a marginalized groupunderrepresented in opioid use research and it has the potential to yield insights on ways to culturally-tailorfuture interventions for African Americans.

project_terms:
Address;Adult;African American;African American population;Age;Area;Attention;Buprenorphine;Cessation of life;Characteristics;Child Rearing;Communities;Complex;Comprehension;Criminal Justice;Data;Data Sources;Dimensions;Discrimination;Dose;Drug usage;Employment;Epidemic;Ethnic Origin;Evolution;Female;Future;Gender;Generations;Goals;Healthcare Systems;Heroin;Intervention;Interview;Kentucky;Libraries;Link;Longevity;Mediating;Mental Health;Methadone;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Outcome;Overdose;Pain;Participant;Patients;Pattern;Pharmacotherapy;Policies;Population;Public Health;Race;Reporting;Research;Research Personnel;Research Project Grants;Risk;Sampling;Stress;Structure;Surveys;Techniques;Testing;Treatment outcome;Underrepresented Populations;Underserved Population;base;cohort;design;distrust;drug testing;evidence base;experience;health care availability;health communication;illicit drug use;improved;insight;low socioeconomic status;male;marginalized population;men;misuse of prescription only drugs;mortality risk;older women;opioid epidemic;opioid overdose;opioid use;opioid user;physical conditioning;pill;prescription opioid;prescription opioid misuse;recruit;response;social;synthetic opioid;theories;treatment services;trend;young woman

public_health_relevance:
PROJECT NARRATIVEThe REFOCUS project-Research Examining Factors Associated with the Opioid Crisis amongUnderserved African Americans has significant public health implications by examining howstructural social and cultural factors influence nonmedical prescription opioid use (NMPOU) andtreatment service use among African Americans across the adult lifespan. Overdose rates haverisen exponentially among African Americans but this group has received much less attention.The REFOCUS project will generate data directly applicable to culturally-tailor interventionstargeting African American opioid users in order to reduce NMPOU and improve treatmentoutcomes.


application_id: 10434889
project_number: 5R01DK048498-27
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2022-06-10
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2024-06-30
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The mammalian intestinal mucosa undergoes a process of continual renewal characterized by activeproliferation of stem cells localized near the base of the crypts; progression of these cells up the crypt-villusaxis with cessation of proliferation; and subsequent differentiation into one of the four primary cell types (i.e.enterocytes goblet cells Paneth cells and enteroendocrine cells). An imbalance in this highly-regimented andorderly process within the crypts is associated with a number of common intestinal pathologies (e.g. colorectalcancer and inflammatory bowel disease [IBD]). Delineating the molecular factors regulating intestinalproliferation and differentiation is crucial to our understanding of not only normal gut development andadaptation but also aberrant gut growth. With the support of this grant we have shown the importance of thePI3K/Akt/mTOR and Wnt/-catenin pathways in the regulation of intestinal cell proliferation and differentiation.In addition we showed that enhanced ketogenesis by mTORC1 inhibition contributes to the regulation ofintestinal cell differentiation and that tuberous sclerosis complex 2/mTORC1 signaling contributes to themaintenance of intestinal epithelial homeostasis. Moreover we found that activation of Wnt/-catenin signalingsuppresses the expression of the ketogenic enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) whichinhibits glycolysis in intestinal cells. Recently we have shown that deficiency of SIRT2 a member of the sirtuinfamily of proteins results in the activation of Akt/mTORC1 and Wnt/-catenin increased intestinal cellproliferation and stemness and increased expression of glycolytic hexokinases (HK) 1 and 2. Using single cellsequencing we found that HK1 and HK2 were differentially expressed in various types of intestinal cells;knockdown of HK2 but not HK1 increased Paneth and goblet cell differentiation. Based on our recentlypublished and preliminary findings we have further refined our central hypothesis to state that the glycolyticenzyme HK2 acting downstream of SIRT2 significantly contributes to the maintenance of normal intestinalhomeostasis. To examine our central hypothesis we have planned experiments with the following SpecificAims: 1) to further delineate the cellular mechanisms for SIRT2-mediated alterations of glycolysis andoxidative phosphorylation in intestinal cells; 2) to better define the role of HK2 in mediating the effects of SIRT2in the intestine; and 3) to determine the impact of alterations of SIRT2/HK2 on intestinal homeostasis in vivo.The studies in the current proposal represent direct and novel extensions of our previous findings and aredesigned to define in a systematic fashion the molecular mechanisms and signaling events regulating theprocesses of intestinal proliferation differentiation and adaptation utilizing a number of innovative techniquesincluding murine and human intestinal organoids novel transgenic models single-cell sequencing and stableisotope resolved metabolomics (SIRM).

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

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


application_id: 10434741
project_number: 5U01AA026980-05
project_title: Alcoholic Hepatitis Network 3/9 University of Louisville
administering_ic: NIAAA
award_notice_date: 2022-06-14
opportunity_number: RFA-AA-18-002
application_type: 5
activity_code: U01
ic: AA
serial_number: 026980
program_official: GAO, PETER
project_start_date: 2018-08-01
project_end_date: 2024-09-24
study_section: ZAA1-JJ(01)R
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTAlcoholic hepatitis (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity ofeffective therapeutics. This application represents a coordinated submission of several NIAAA-fundedconsortia that have come together as the Alcoholic Hepatitis Network (AlcHepNet). Collectively the networkwill synergize efforts and expertise to better understand AH and develop novel effective and safe therapies forsevere AH. Buttressing that goal the overarching aims of this new consortium are to: 1) perform studies tobetter understand the pathogenesis and main determinants of outcomes particularly in severe AH; 2) identifynovel targets for therapy of AH and 3) perform phase 2B studies of compounds that are already FDAapproved and available and can be repurposed as safe and effective therapies for severe AH. Under theumbrella of these larger aims the aims of this AlcHepNet proposal are to: Aim 1. Conduct a prospectivemulticenter observational study of patients with AH and suitable controls that serves as thefoundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend ourlongitudinal database containing 1) clinical and laboratory information and 2) bio-sample repository fromsubjects with AH of varying severity and matched controls. This database will serve three functions: (a) provideunique information on the outcomes and pathobiology of AH (b) support translational research designed toidentify novel targets for treatment and (c) serve as a catalyst to develop systems biology-based informatics-integrated databases that will serve as a resource for all researchers interested in AH; Aim 2. Perform amulticenter prospective randomized phase 2B clinical trial of granulocyte colony stimulating factor G-CSF versus Anakinra (plus zinc) versus standard medical therapy with Prednisone in patients withsevere AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptorantagonist Anakinra (plus zinc) are superior to the standard of care (i.e. Prednisone) in patients with severeAH. The choice of these agents is based on: 1) literature demonstrating a role for inflammation andinflammasome activation in severe AH 2) several pilot studies demonstrating therapeutic benefit with G-CSFand 3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. Thisphase 2B efficacy trial will be conducted across nine clinical centers and coordinated by two Data CoordinatingCenters (DCCs). The primary endpoint will be mortality at Day 90. The investigators and the AlcHepNet areuniquely positioned to perform the proposed study given the substantial breadth depth and history ofexpertise related to AH clinical trial conduct and related therapeutic development. By testing promisingtherapies for AH and collecting well-annotated patient samples and datasets this proposal will have a strongand lasting impact on the field.!

project_terms:
Adrenal Cortex Hormones;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Biological Specimen Banks;Clinical;Clinical Research;Clinical Trials;Clinical Trials Design;Collection;Conduct Clinical Trials;Consumption;Data;Data Coordinating Center;Data Set;Databases;Development;Disease;Economic Burden;Educational workshop;Eligibility Determination;FDA approved;Foundations;Funding;Future;Goals;Granulocyte Colony-Stimulating Factor;Hepatitis B;Infection;Inflammasome;Inflammation;Informatics;Institution;Interleukin-1 Receptors;Interleukin-1 beta;Label;Laboratories;Life;Light;Literature;Liver;Liver diseases;Medical;Mission;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Observational Study;Oral cavity;Outcome;Pathogenesis;Patient Care;Patient Recruitments;Patients;Pentoxifylline;Pharmaceutical Preparations;Phase;Pilot Projects;Positioning Attribute;Predisposition;Prednisone;Public Health;Randomized;Recording of previous events;Research Design;Research Personnel;Resources;Role;Sampling;Severities;Systems Biology;Testing;Therapeutic;Therapeutic Studies;Translational Research;Universities;Validation;Work;Zinc;active method;anakinra;antagonist;base;catalyst;clinical center;drug testing;effective therapy;efficacy trial;end stage liver disease;evidence base;improved;insight;interest;liver injury;longitudinal database;meetings;mortality;new therapeutic target;novel;primary endpoint;prospective;receptor;research study;secondary endpoint;standard of care;targeted treatment;therapeutic development;therapeutically effective;translational study;treatment arm

public_health_relevance:
PROJECT NARRATIVEThe Alcoholic Hepatitis Network project AlcHepNet comprised of nine leading partner institutions in the fieldwill examine new and promising treatments for severe liver damage caused by alcohol. Further the networkwill collect and organize patient information associated data and samples that can help shed greater light onthis disease. Combined these two approaches will improve treatment and how we care for patients with thisdevastating liver condition.!


application_id: 10434080
project_number: 5R01DC018273-03
project_title: Neural mechanisms underlying integration of taste and smell
administering_ic: NIDCD
award_notice_date: 2022-06-08
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DC
serial_number: 018273
program_official: SABRI, MERAV
project_start_date: 2020-07-02
project_end_date: 2025-06-30
study_section: Chemosensory Systems Study Section[CSS]
contact_pi_person_id: 8305266
contact_pi: SAMUELSEN, CHAD L
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY ABSTRACT Although interactions between the senses of smell and taste are a key factor for guiding food choices theneural mechanisms underlying the multisensory integration of odors and tastes remain largely unknown. A morethorough understanding of these neurobiological processes will provide better insight into diseases characterizedby unhealthy food choices such as obesity or diabetes. Eating food simultaneously activates the olfactory andgustatory systems to generate enduring odor-taste associations. The primary cortical area for taste gustatorycortex (GC) is a principal site of convergent gustatory and olfactory information. Recent work from our labdetermined that functionally distinct populations of neurons in GC represent different properties of individualunpaired odors or tastes. However how neurons in GC represent odor-taste mixtures as well as the neuralmechanisms that underlie integration and processing of smell and taste remain unclear. Recent behavioral andphysiological studies show that cortico-cortical interactions between sensory cortices are fundamental tomultisensory integration suggesting that projections from the functionally distinct anterior (aPC) and posterior(pPC) regions of piriform cortex (i.e. olfactory cortex) modulate multimodal chemosensory processing in GC.Using rats as a model system this proposal will combine behaving electrophysiology and optogenetic techniquesto investigate how the circuit between neurons in GC and the functionally distinct regions of piriform cortexmediates multisensory integration of odors and tastes. The Specific Aims will test the following hypotheses: Aim1: Different populations of neurons in GC encode the chemical identity and hedonic value of odor-taste mixtures.Aim 2: Neurons in GC that respond to both odors and tastes receive aPC input representing the chemical identityof odor-taste mixtures. Aim 3: Neurons in GC that respond to both odors and tastes receive pPC inputrepresenting the hedonic value of odors and odor-taste mixtures. The results of each Specific Aim will contributefundamental knowledge about the cortico-cortical circuitry underlying the integration of smell and taste andprovide a necessary prelude for investigating the role that these cortico-cortical circuits play in guiding foodchoices.

project_terms:
Anterior;Area;Behavior;Behavioral;Biological Models;Categories;Chemicals;Data;Diabetes Mellitus;Disease;Eating;Electrophysiology (science);Fiber;Food;Goals;Health;Individual;Knowledge;Mediating;Neurobiology;Neurons;Obesity;Odors;Olfactory Cortex;Olfactory Pathways;Outcome;Perception;Physiological;Play;Population;Process;Property;Publishing;Rattus;Resolution;Role;Sampling;Signal Transduction;Site;Smell Perception;Stimulus;Taste Perception;Techniques;Testing;Work;base;experience;hedonic;insight;multimodality;multisensory;neuromechanism;nutrition;optogenetics;outcome prediction;piriform cortex;preference;response;sensory cortex;taste system

public_health_relevance:
PROJECT NARRATIVE Associations between the senses of smell and taste (i.e. flavors) are an essential factor in determining whichfoods we choose to eat; however the neural mechanisms underlying the multisensory integration of odors andtastes remain unclear. We use a combination of behaving electrophysiology and optogenetics to investigate howinteractions between the olfactory and gustatory cortices contribute to multisensory integration of smell and taste.These results will provide new insight into the circuit mechanisms underlying the perception of flavor.


application_id: 10432119
project_number: 5R01HL124015-07
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2022-07-15
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: HL
serial_number: 124015
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2023-06-30
study_section: Basic Biology of Blood, Heart and Vasculature Study Section [BBHV]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
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:
ABSTRACTThe hematopoietic system is very sensitive to a variety of stresses. Radiation therapy commonly results in notonly acute hematopoietic suppression but also long-term bone marrow (BM) injury with increased risk of BMfailure or malignancy. Accumulation of damages during aging process is another type of stress on HSCs.Enhancing HSC survival and maintaining their genomic integrity upon stress are crucial for preservation of HSCself-renewal function and for protection against stress-induced BM injury. However the underlying molecularmechanisms are not well defined. No effective treatment has been developed to prevent or treat stress-inducedHSC damages and related pathological consequences. The primary goal of this project is to identify novelpharmaceutical compounds and transcriptional mechanism that target a HSC stress regulatory protein latexin(Lxn) and to uncover the mechanisms that Lxn suppression results in radiation protection and HSC rejuvenation.We have identified a novel Lxn inhibitor small compound and found that it significantly increases survival byprotecting HSCs via a newly identified canonical mechanism of carboxypeptidase A inhibition upon radiation.Lxn deletion also mitigates aging-related functional decline of HSCs. We hypothesize that pharmaceutical andtranscriptional suppression of Lxn protects HSCs and blood system from stress (radiation and aging)-inducedfunctional decline via the upregulation of canonical CPA3 pathway. Aim 1 is to determine the molecularmechanisms by which Lxn inactivation protects against radiation-induced BM injury via up-regulation of canonicalCPA3 pathway. Aim 2 is to identify the mechanism of action of Lxn lead inhibitor in radiation protection ofhematopoietic system. Aim 3 is to define the role of Lxn suppression in rejuvenating old HSCs. Findings willadvance our knowledge of novel mechanisms how Lxn regulates stress hematopoiesis. Results will provide acompelling starting point and lay grounds for the novel drug discovery by targeting Lxn which will benefit patientssubject to radiation treatment and old people with dysfunctional HSC and immune aging.

project_terms:
Acute;Aging;Amino Acids;Angiotensin II;Apoptosis;BCL2 gene;Binding;Binding Proteins;Blood;Blood Cells;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;Bone marrow failure;Cancer Patient;Carboxypeptidase;Carboxypeptidase A;Cellular Stress;Development;Dose;Elderly;Fluorouracil;Funding;Genes;Genetic;Genetic Transcription;Goals;HMGB2 Protein;HMGB2 gene;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic System;Hematopoietic stem cells;Hemorrhage;Homing;Ice;Immune;In Vitro;Infection;Injury;Intervention;Knockout Mice;Knowledge;Lead;Legal patent;Life;Lymphoid;Maintenance;Malignant - descriptor;Malignant Neoplasms;Measures;Mediating;Molecular;Mus;Myelogenous;Myelosuppression;NF-kappa B;Natural regeneration;Output;PC3.1 antigen;Pathologic;Pathway interactions;Patients;Persons;Pharmacologic Substance;Pharmacy (field);Physiological;Process;Protein Subunits;Quality of life;Radiation;Radiation Protection;Radiation therapy;Regenerative capacity;Regulation;Regulator Genes;Rejuvenation;Reporting;Ribosomal Proteins;Risk;Role;Signal Transduction;Stress;System;Therapeutic;Time;Transplantation;Up-Regulation;Work;base;cancer therapy;cell injury;cell regeneration;drug discovery;effective therapy;functional decline;genetic regulatory protein;genome integrity;hematopoietic stem cell aging;hematopoietic stem cell self-renewal;in vivo;inhibitor;irradiation;knock-down;novel;novel therapeutics;overexpression;preconditioning;preservation;prevent;radiation response;self-renewal;senescence;stem cell survival;stem cells

public_health_relevance:
PROJECT NARRATIVEMitigation and protection of bone marrow cells particularly hematopoietic (blood forming) stem cells fromradiation and aging-induced acute and permanent injury is critical for the quality of life of cancer patients receivingradiotherapy and for the elderly. This study will investigate pharmaceutic and genetic inhibition of hematopoieticstress regulatory gene latexin in radiation protection and stem cell rejuvenation.


application_id: 10431808
project_number: 5R01EY029719-04
project_title: Glycine subunit specific inhibition and ganglion cell visual responses
administering_ic: NEI
award_notice_date: 2022-05-16
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: EY
serial_number: 029719
program_official: WRIGHT, CHARLES BAKER
project_start_date: 2019-03-01
project_end_date: 2024-02-29
study_section: Special Emphasis Panel[ZRG1-MDCN-V(04)S]
contact_pi_person_id: 1905800
contact_pi: MCCALL, MAUREEN A
other_pis: GREGG, RONALD G
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Retinal ganglion cells (GCs) integrate excitatory and inhibitory inputs and perform computations that encodediverse features of the visual scene. The output of these functionally and morphologically diverse GCs establishvisual signaling streams maintained throughout the visual pathway. Ultimately they create our perception of thesize shape and color of objects and their relationships in space. They establish relationships of objects in time sothat we know when it is stationary or moving and when moving its direction and velocity. To this end there is ageneral division of labor between the retina's inhibitory neurotransmitter systems. GABA and its receptorsmodulate spatial vision whereas glycine and its receptors modulate temporal vision. There are five glycinereceptor subunits (one  and 4s). The GlyR subunits combine with a single  subunit to make functionalreceptors with diverse biophysical properties. Our work shows that all GCs expresses one or more GlyRs and thecomposition differs across GC type. We hypothesize that variety enhances the diversity of inhibitory functions acrossand within GC types and are used to encode the visual scene. However the specific function of GlyR subunits isalmost completely unknown.We know that the responses (and transmitter release) of the GABA and glycinergic amacrine cells presynapticto GCs are modulated by other glycinergic amacrine cell input. This means that until GlyRs can be selectivelyeliminated in GCs or ACs we cannot disambiguate the role of direct GlyR inhibition to GCs from GlyR modulationin the upstream circuit that provides input to the GCs. We developed a novel AAV-shRNA knockdown (KD)approach that eliminates expression of individual G lyR subunits in GCs while leaving their upstream expressionintact. We propose to use this approach to define the role of GlyR direct inhibition in 7 identified GC types and byextension the role of isolated GABA inputs in those same GCs. In Aim 1 we ask if a single GlyR GlyR1 expressed by the 4 functionally diverse GCs modulates the same or different aspects of their visual responses. In aim 2 we ask iftwo different GlyR subunits expressed in the same GC increase the diversity of inhibition to modulate differentaspects of the visual response in a single GC type. We use electrophysiological assays to characterize the spikingresponses of the GCs underlying currents and the relationships between the kinetics of excitatory and inhibitoryinput with the postsynaptic response.This proposal addresses the novel concept: that diverse glycine subunit specific inhibition interacts withpresynaptic inputs to controls visual computation.

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

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


application_id: 10431791
project_number: 5R01HL152081-03
administering_ic: NHLBI
award_notice_date: 2022-06-03
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 152081
program_official: HASAN, AHMED A K
project_start_date: 2020-07-01
project_end_date: 2024-06-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Understanding the role of immune complexes between apolipoprotein A-I and IgG in atherosclerotic cardiovascular disease

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

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

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


application_id: 10431349
project_number: 1S10OD032361-01
project_title: Waters Xevo TQ-XS system
administering_ic: OD
award_notice_date: 2022-06-10
opportunity_number: PAR-21-127
application_type: 1
activity_code: S10
ic: OD
serial_number: 032361
program_official: CHEN, YONG
project_start_date: 2022-06-15
project_end_date: 2023-06-14
study_section: Special Emphasis Panel[ZRG1 BCMB-P (30)]
contact_pi_person_id: 12584275
contact_pi: LORKIEWICZ, PAWEL K
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThe Bioanalytics Core laboratory at the University of Louisville Diabetes and Obesity Center (DOC) and otherlaboratories on campus operate mass spectrometers dedicated to meeting the ever-increasing and complexneeds of NIH-funded investigators. These needs far exceed current capabilities with major limitations comprisinga lack of ability for ultrasensitive targeted analyses in the areas of exposomics metabolomics and lipidomics.These applications are central to Major and Minor Users including five NIH-funded centers and twenty-twoindividual research projects focusing on environmental toxicology cardiovascular hepatic and metabolicdisease exercise science and immunology. We propose to add an ultrasensitive robust Waters Xevo TQ-XStriple-quadrupole mass spectrometer with the Acquity I-Class Premier ultraperformance liquid chromatographywhich will address the analytical needs of major and minor users by significantly enhancing breadth of analytecoverage and sensitivity of targeted bioanalyses currently out of reach with available LC-MS instrumentsavailable at the University Campus. The proposed system will complement current bioanalytical instrumentationcurrently at full capacity and provide needed hardware to develop and transfer high-throughput ultrasensitivetargeted methods to cater to the needs of our users. Specifically we will set up: i) A platform to quantify ultralow-level xenobiotic adducts with mercapturic acid and carnosine to aid human exposomics studies; ii) A targetedmethod for urinary biogenic volatile organic compound metabolites; iii) A workflow for measurement of bile acids;iv) specific targeted lipidomics assays (major lipid classes short-chain fatty acids and isoprostanesrespectively); v) Quantification of corticosteroids including cortisol and cortisone as markers of chronic vi) Atargeted assay for catecholamines and their metabolites in plasma; vii) A method to quantify reactive carbonylsin tobacco product aerosols; viii) quantification of gut microbial amine metabolites; ix) A high-throughput assayfor measuring amino acids and dipeptides in various biological matrices. Proposed work with the instrumentincludes detailed training and education in mass spectrometry and method development which will furtheradvance research in the Center and maximize the utility of the proposed system. The DOC has the infrastructureto maintain and support the new equipment backed by the support of the University.

project_terms:
Acetylcysteine;Address;Adrenal Cortex Hormones;Aerosols;Amines;Amino Acids;Area;Back;Bile Acids;Biological;Biological Assay;Cardiovascular Diseases;Carnosine;Catecholamines;Chronic;Complement;Complex;Cortisone;Diabetes Mellitus;Dipeptides;Equipment;Exercise;Felis catus;Funding;Human;Hydrocortisone;Immunology;Individual;Infrastructure;Isoprostanes;Laboratories;Lipids;Liquid Chromatography;Liver diseases;Mass Spectrum Analysis;Measurement;Measures;Metabolic Diseases;Methods;Minor;Obesity;Plasma;Research;Research Personnel;Research Project Grants;Science;System;Training and Education;United States National Institutes of Health;Universities;Volatile Fatty Acids;Water;Work;Xenobiotics;adduct;environmental toxicology;high throughput screening;instrument;instrumentation;lipidomics;mass spectrometer;meetings;metabolomics;method development;microbial;tobacco products;urinary;volatile organic compound

public_health_relevance:
NarrativeWe request laboratory equipment that will help environmental toxicology research of heart liver and metabolicdisease. We will measure metabolites lipids hormones and other chemicals present in very low amounts inurine feces blood and tissues with this instrument. These measurements will help the University of Louisvilleresearchers obtain much-needed data to uncover and understand the mechanisms of the environment on humanhealth and ways to prevent or minimize associated negative consequences.


application_id: 10430357
project_number: 1R03DE031854-01
project_title: The Control of LPS Heterogeneity and Virulence by C-di-AMP Signaling in P. gingivalis
administering_ic: NIDCR
award_notice_date: 2022-03-04
opportunity_number: PAR-21-084
application_type: 1
activity_code: R03
ic: DE
serial_number: 031854
program_official: MCNEALY, TAMARA L
project_start_date: 2022-04-01
project_end_date: 2024-03-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14927473
contact_pi: MORADALI, FATA
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryPeriodontitis is a highly prevalent infectious inflammatory disease of the tissues supporting the teeth that canlead to tissue destruction alveolar bone resorption formation of the deep periodontal pocket and tooth loss.Etiological models suggest that periodontitis is driven by a synergistic community of virulent bacteria that triggerhost inflammatory responses below the gum line resulting in disease progression. Among recognized pathogensthe Gram-negative highly proteolytic anaerobe Porphyromonas gingivalis (Pg) has been stronglyimplicated in periodontitis. Pg strains produce lipopolysaccharide (LPS) macromolecules as the maincomponents of the outermost layer of the cells that have been repeatedly shown to stimulate innate immuneresponses. Intriguingly Pg strains can diversify the structure of LPSs in response to biologically relevant stimulito temporarily disguise themselves evade the immune system protect from stresses and promote survival.Accordingly at least four LPS variants have been identified in Pg strains that may act as agonists or antagoniststo activate innate immune responses. A specific form of LPSs called A-LPS serves to anchor a series ofdestructive proteolytic enzymes known as gingipains on the cell surface. These virulence factors collectively playprominent roles in the pathological outcome of infection by being involved in various activities including tissuedestruction host-defense perturbation immune system evasion and bone resorption. However we do not yetknow the mechanisms of the regulation of LPS heterogeneity and its biological importance during pathogenesis.We discovered that Pg strains have evolved with c-di-AMP signaling pathway in which the c-di-AMP synthasePGN_0523 (dacpg) and the c-di-AMP phosphodiesterase PGN_0521 (pdepg) control the essential turnover of c-di-AMP and in turn cell viability within biofilms LPS heterogeneity the diffusion of gingipains into thesurrounding milieu and virulence potential. We will investigate how c-di-AMP turnover regulates theheterogeneity and immunostimulatory properties of LPSs and affects gingipain-associated virulence potential.To this end two specific aims are proposed and each aim includes a set of separate experiments and assays:Specific Aim 1: To understand c-di-AMP-controlled heterogeneity of LPSs in Pg. Specific Aim 2: Tounderstand the impact of c-di-AMP-dependent variation of LPS on the innate immune response and gingipains-associated virulence. Upon completion of the proposed studies we will learn how c-di-AMP signalingcontrols LPS heterogeneity impacts immunostimulatory responses and the virulence potential of Pg. Since c-di-AMP signaling does not exist in mammals our findings will inform about a novel druggable target.

project_terms:
Adenosine;Adenosine Monophosphate;Adult;Affect;Agonist;Anaerobic Bacteria;Anti-Inflammatory Agents;Applications Grants;Bacteria;Biological;Biological Assay;Bone Resorption;Cell Survival;Cell Wall;Cell membrane;Cell physiology;Cell surface;Cells;Chemical Structure;Communities;Data;Detection;Development;Diffusion;Disease;Disease Progression;Equilibrium;Etiology;Genes;Heterogeneity;Host Defense;Immune system;Infection;Inflammatory;Inflammatory Response;Innate Immune Response;Lead;Learning;Link;Lipopolysaccharides;Mammals;Membrane;Microbial Biofilms;Modeling;Modification;Molecular;Outcome;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Peptide Hydrolases;Periodicity;Periodontal Pocket;Periodontitis;Physiology;Play;Population;Porphyromonas gingivalis;Post-Translational Protein Processing;Production;Property;Regulation;Role;Series;Signal Pathway;Signal Transduction;Stimulus;Stress;Structure;System;Systemic disease;TLR4 gene;Therapeutic;Tissues;Tooth Loss;Tooth structure;United States;Variant;Virulence;Virulence Factors;Virulent;alveolar bone;antagonist;cytokine;economic impact;experimental study;extracellular;gingipain;macromolecule;mutant;neutrophil;new therapeutic target;novel;pathogen;pathogenic bacteria;phosphoric diester hydrolase;receptor;response;socioeconomics

public_health_relevance:
PROJECT NARRATIVEPeriodontitis afflicts ~ 50% of the adult population in the United States with substantial socio-economic impacts. Porphyromonas gingivalis has been strongly implicated in periodontitis. Theproposed studies will decipher the regulatory role of a novel signaling pathway that controls cellwall components virulence and fundamental aspects of P. gingivalis physiology andpathogenesis.


application_id: 10430005
project_number: 5R37CA234002-03
project_title: Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors
administering_ic: NCI
award_notice_date: 2022-06-20
opportunity_number: PA-19-056
application_type: 5
activity_code: R37
ic: CA
serial_number: 234002
program_official: FORRY, SUZANNE L
project_start_date: 2020-07-09
project_end_date: 2025-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8320211
contact_pi: IMBERT-FERNANDEZ, YOANNIS
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
We have recently discovered a novel oncogenic mechanism whereby cyclin D1 bypasses CDK4/6 inhibitionresulting in the stimulation of 6-phosphofructo-2-kinase (PFKFB3) and glucose metabolism. The objective of thisproposal is to characterize the role of PFKFB3 in mediating adaptation or resistance to CDK4/6 inhibition and todefine new approaches to increase the efficacy of CDK4/6 inhibitors in order to enable durable responses instage IV HR+ breast cancer patients. Deregulation of the estrogen receptor (ER)-cyclin D1-CDK4/6 pathway isa hallmark of ER+ breast cancer that has prompted the development of CDK4/6 inhibitors. Althoughadministration of CDK4/6 inhibitors to patients with ER+ advanced breast cancers have resulted in animprovement in progression free survival almost all patients invariable develop resistance and relapse over time.Activation of glucose metabolism upon CDK4/6 inhibition is becoming increasingly evident. A key stimulator ofglycolysis is the PFKFB3 enzyme which synthesizes fructose 26-bisphosphate (F26BP) a potent allostericactivator of the rate-limiting 6-phosphofructo-1-kinase (PFK1). F26BP controls flux throughout the entireglycolytic pathway and as a result is required for the proliferation of cancer cells. In preliminary studies weprovide evidence that PFKFB3 expression and activity is increased in response to CDK4 inhibition in ER+ breastcancer cells and breast cancer patient tumors. Notably we show that a PFKFB3 inhibitor PFK-158 increasesthe anti-tumor activity of anti-CDK4 targeted therapy in vitro and in vivo. We postulate that PFKFB3 is anessential regulatory effector of the cyclin D1-CDK4/6 axis that serves to attenuate CDK4/6 inhibition effects bystimulating glucose metabolism. Furthermore we hypothesize that genetic or pharmacological inhibition ofPFKFB3 will increase the efficacy of CDK4/6 inhibitors by disabling the ability of the cell to sustain sufficientglucose metabolism necessary for survival and growth. Aim 1 will determine the mechanism by which CDK4/6inhibition induces PFKFB3 expression. Aim 2 will determine the effects of combined CDK4/6 and PFKFB3inhibition on glucose metabolism cell cycle growth and survival in vitro. Aim 3 will examine the metabolic andgrowth effects of pharmacological CDK4/6 and PFKFB3 inhibition as monotherapies and in combination inmouse models of breast cancer in vivo. We anticipate that our studies will support the clinical testing of PFKFB3inhibitors in combination with CDK4/6 inhibitors to increase the survival of advanced ER+ breast cancer patients.

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

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


application_id: 10429992
project_number: 5K01DA043652-05
project_title: Neural Mechanisms of Cannabinoid-Impaired Decision-Making in Emerging Adults
administering_ic: NIDA
award_notice_date: 2022-06-09
opportunity_number: PA-16-190
application_type: 5
activity_code: K01
ic: DA
serial_number: 043652
program_official: LIN, YU
project_start_date: 2018-07-15
project_end_date: 2024-06-30
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 10239541
contact_pi: WESLEY, MICHAEL J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT ABSTRACT This mentored career development award (K01) will enable Dr. Michael Wesley to achieve his long-termgoal of becoming an independent investigator with a clinical neuroscience research program examiningcannabis use disorder (CUD) in emerging adults which is a current NIDA funding priority. Dr. Wesley is a newAssistant Professor in the University of Kentucky (UK) College of Medicine. The activities proposed in thisaward build on Dr. Wesleys background expertise in neuroimaging and drug abuse research and will allow himto accomplish the following short-term objectives: Become an expert in (1) clinical pharmacology and (2)non-invasive brain stimulation research in an emerging adult population with CUD and enhance/develop his(3) knowledge of the responsible conduct of research (4) skills for scientific communication and grant writingand (5) ability to manage an independent research program. UK has numerous faculty and projects focused on drug abuse research and is an ideal environment forDr. Wesley to complete this award. Dr. Wesley has assembled a stellar mentoring team consisting of Dr. JoshLile (Mentor) who has a successful NIH-funded clinical pharmacology research program at UK and Dr. MarkGeorge (Co-Mentor) who pioneered the use of non-invasive brain stimulation for treating depression. Inaddition Dr. Lumy Sawaki (Internal Preceptor) and Dr. Lon Hays (Study Physician) will provide local safetyoversight and medical supervision and Dr. Terry Lohrenz (External Preceptor) will provide guidance withadvanced statistical analysis of neuroimaging data. Dr. Wesley will also engage in a series of formal classeslab exchanges and research seminars/meetings to assist him in accomplishing the objectives of this award. The proposed research project is based on the premise that cannabis impairs decision-making processesand these impairing effects contribute to an increased risk of developing CUD in emerging adults. Thisresearch will combine the acute administration of 9-tetrahydrocannabinol (THC) the main psychoactiveingredient in cannabis with high-definition transcranial direct current stimulation (HD-tDCS) and neuroimagingusing rigorous methods to examine the role of prefrontal cortex regions of interest in cannabis-impaireddecision-making in emerging adults. Aim 1 will test the hypotheses that raising intrinsic PFC activity (Exp. 1)will attenuate whereas lowering activity (Exp.2) will enhance the impairing effects of THC on measures ofdecision-making and associated neurocognitive processes in emerging adults. Aim 2 will test the hypothesisthat brain activity and connectivity during baseline task performance is associated with the subsequentresponse to THC and HD-tDCS. This highly innovative project will improve our understanding of themechanisms involved in cannabis-impaired decision-making which will inform CUD management and addressa growing public health concern.

project_terms:
Acute;Address;Anodes;Attenuated;Award;Behavior;Behavioral Mechanisms;Brain;Cannabinoids;Cannabis;Cathodes;Chemicals;Clinical;Clinical Pharmacology;Communication;Data;Decision Making;Development;Disease Management;Dorsal;Drug Use Disorder;Drug abuse;Drug usage;Environment;Faculty;Functional Magnetic Resonance Imaging;Funding;Genetic;Goals;Grant;Impairment;Individual;Individual Differences;Intervention;Intoxication;K-Series Research Career Programs;Kentucky;Knowledge;Lateral;Lesion;Link;Maps;Measures;Medial;Medical;Medicine;Membrane Potentials;Mental Depression;Mentors;Methodology;Methods;National Institute of Drug Abuse;Nature;Neurocognitive;Neurons;Neurosciences Research;Neurotransmitters;Perception;Pharmaceutical Preparations;Physicians;Physiological;Population;Predisposition;Prefrontal Cortex;Process;Public Health;Research;Research Personnel;Research Project Grants;Research Training;Rest;Risk;Role;Safety;Series;Short-Term Memory;Site;Statistical Data Interpretation;Substance abuse problem;Supervision;Task Performances;Techniques;Testing;Tetrahydrocannabinol;Tissues;Training;United States National Institutes of Health;Universities;Writing;base;career development;college;disorder prevention;emerging adult;emerging adulthood;endogenous cannabinoid system;experimental study;frontal lobe;improved;individual response;innovation;interest;marijuana use;marijuana use disorder;marijuana user;meetings;neuroimaging;neuromechanism;noninvasive brain stimulation;preclinical study;professor;programs;relating to nervous system;response;responsible research conduct;skills;social;success

public_health_relevance:
PROJECT NARRATIVECannabis intoxication impairs decision-making processes which may confer increased risk of developingcannabis use disorder (CUD) in emerging adults. The proposed research will combine clinical pharmacologybrain stimulation and neuroimaging to establish the neural mechanisms contributing to cannabinoid-impaireddecision-making in emerging adults with CUD. Results from this project will inform CUD prevention/treatmentefforts and address a growing public health concern.


application_id: 10428628
project_number: 5R01NR019456-03
administering_ic: NINR
award_notice_date: 2022-06-29
opportunity_number: RFA-NR-20-001
application_type: 5
activity_code: R01
ic: NR
serial_number: 019456
program_official: KEHL, KAREN
project_start_date: 2020-09-07
project_end_date: 2025-06-30
study_section: ZNR1-REV-W(23)
contact_pi_person_id: 9701191
contact_pi: MUDD, GIA
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Heart of the Family: A Cardiovascular Disease and Type 2 Diabetes Risk Reduction Intervention in High-Risk Rural Families

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

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

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


application_id: 10428147
project_number: 2K12DA035150-11
project_title: Kentucky BIRCWH Program: Training the Next Generation of Women's Health Scholars
administering_ic: NIDA
award_notice_date: 2022-06-17
opportunity_number: RFA-OD-21-006
application_type: 2
activity_code: K12
ic: DA
serial_number: 035150
program_official: BABECKI, BETH
project_start_date: 2022-08-01
project_end_date: 2027-07-31
study_section: Special Emphasis Panel[ZRG1 PSE-W (50)]
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The University of Kentuckys (UK) BIRCWH program is built around three pillars: mentoringinterdisciplinary research and career development. Given the significant health challenges inKentucky we focus on three areas of important health disparity for Appalachian Kentuckians: 1)substance use 2) violence against women and 3) lifespan changes in health with aging. UKBIRCWH objectives are: 1) to provide the environment mentorship and facilities to enhancethe ability of BIRCWH scholars to compete for NIH research grants in diverse areas of womenshealth research 2) to deepen our understanding of the unique role of sex and gender in themanifestation of health and disease 3) to develop and implement new communication andsocial networking technologies to address sex and gender differences and improve womenshealth 4) to personalize prevention diagnostics and therapeutics to address health disparities5) to stimulate new collaborations in focused interdisciplinary and interactive research areasthat are essential for uncovering sex and gender differences and improving womens health; and6) to use a thematic multidisciplinary focus as a platform for enhancing translational researchbetween basic clinical and public health scientists. Our formal framework for growing the nextgeneration of womens health and sex differences researchers includes a mentoring team foreach Scholar composed of: 1) experienced faculty members (Mentors) and 2) a former BIRCWHscholar (Coach). This mentoring team will collectively provide in-depth research experiencesand didactic training to assistant professor tenure-track faculty. Career development will alsoinclude mechanisms for accountability for manuscript submissions workshops on grantdevelopment and aspects of academic development such as personnel management negotiationskills self-care and promotion. UK BIRCWH Scholar appointments will be 2 years for PhD and3 years for MD scholars. Based on our prior experience we anticipate training 8 scholars over 5years of funding. Outcomes: Since 2000 40 Scholars have completed BIRCWH training (17MDs 23 PhDs) who have produced 1712 peer-reviewed publications secured $41636782 inNIH funding as PI and $239982415 as Co-I or PI from other external sources. UK has retained57% of our BIRCWH graduates who continue active research programs and support BIRCWHas Coaches and Mentors. Given this success why should UKs BIRCWH funding continue?Succinctly Kentuckys need continues. Our rates of substance use violence and chronic disease(3 foci) are among this nations highest. With BIRCWH funding we can support those who willaddress the health inequities Kentuckians and others across the nation still face.

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

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


application_id: 10427416
project_number: 5R01CA256893-02
project_title: Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
administering_ic: NCI
award_notice_date: 2022-07-05
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 256893
program_official: KONDAPAKA, SUDHIR B
project_start_date: 2021-07-01
project_end_date: 2026-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetates;Affect;Androgen Antagonists;Androgen Receptor;Androgens;Autocrine Communication;Biochemical;Bioinformatics;Cancer Patient;Castration;Cells;Clinic;Clinical;Coculture Techniques;Cultured Cells;Data;Development;Disease;Drug usage;Event;Fibroblasts;Fostering;Genetically Engineered Mouse;Goals;Health;Human;Investigation;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Modeling;Molecular;Mus;Mutation;Neoplasm Circulating Cells;Neoplasm Metastasis;Organoids;Outcome;Paracrine Communication;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacology;Pharmacotherapy;Play;Protein Family;Public Health;RNA analysis;Receptor Activation;Receptor Signaling;Research;Resistance;Resistance development;Role;Sampling;Signal Pathway;Signal Transduction;Specimen;System;Testing;Therapeutic;Tissue Microarray;United States National Institutes of Health;WNT Signaling Pathway;Withdrawal;Xenograft procedure;abiraterone;base;castration resistant prostate cancer;clinical translation;clinically relevant;docetaxel;enzalutamide;gain of function;hormone therapy;improved;inhibitor;inhibitor therapy;innovation;loss of function;mouse model;new therapeutic target;novel;novel strategies;patient derived xenograft model;planar cell polarity;prostate cancer cell;prostate cancer progression;receptor;response;therapeutic target;transcriptome;transcriptome sequencing;tumor;tumor microenvironment


application_id: 10425019
project_number: 1R34MH126965-01A1
administering_ic: NIMH
award_notice_date: 2022-04-19
opportunity_number: RFA-MH-20-500
application_type: 1
activity_code: R34
ic: MH
serial_number: 126965
suffix: A1
program_official: BURSTEIN, MARCY ELLEN
project_start_date: 2022-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZMH1 ERB-N (03)]
contact_pi_person_id: 10775786
contact_pi: LEVINSON, CHERI ALICIA
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Facing Eating Disorder Fears for Anorexia Nervosa: A Virtual Relapse Prevention Program Targeted at Approach and Avoidance Behaviors

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

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

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


application_id: 10424380
project_number: 5P50AA024337-07
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8881
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Affinity;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Analytical Chemistry;Bacteria;Bilophila wadsworthia;Bioinformatics;Biological;Biometry;Broccoli - dietary;Butyrates;Cecum;Complex Mixtures;Consumption;Data Collection;Data Reporting;Development;Enhancers;Ensure;Epigenetic Process;Ethanol;FOXP3 gene;Family;Feces;Functional disorder;Ginger;Glutathione;Goals;Heavy Drinking;Human;Human Resources;Immunoglobulin Class Switching;Individual;Inflammatory;Infrastructure;Institution;Interleukin-17;Intestines;Lactobacillus casei rhamnosus;Lipids;Liver;Liver Dysfunction;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Methods;Molecular Evolution;Monitor;Mus;Pathogenicity;Pathway interactions;Patients;Peptides;Performance;Phosphorylation;Plasma;Play;Post-Translational Protein Processing;Preparation;Probiotics;Production;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Reaction;Research;Research Personnel;Resolution;Resources;Role;STAT3 gene;Sampling;Science;Stable Isotope Labeling;Standardization;T-Lymphocyte;Techniques;Technology;Testing;Therapeutic Intervention;Time;Tissue Sample;Training and Education;Translational Research;Tryptophan;Universities;Variant;Volatile Fatty Acids;alcohol research;base;data sharing;design;efficacy evaluation;exosome;follow-up;gut dysbiosis;gut microbiota;instrument;lipid mediator;lipidomics;liver injury;member;metabolomics;method development;microbial;multidisciplinary;nanoparticle;novel;novel therapeutic intervention;nutrition;organ injury;pathogenic bacteria;prevent;protective effect;sample collection;sex;stool sample;success;teratogenesis;transcription factor;treatment group


application_id: 10424379
project_number: 5P50AA024337-07
project_title: Probiotic-derived nano-particles in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8880
contact_pi_person_id: 8029790
contact_pi: FENG, WENKE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Agonist;Alcohol-Induced Disorders;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Aryl Hydrocarbon Receptor;Bacteria;Bacterial Translocation;Bilophila wadsworthia;Biological Markers;Cells;Chronic;Clinical;Development;Digestive System Disorders;Disease;Endocytosis;Environment;Epithelial;Epithelial Cells;Evaluation;Experimental Models;Functional disorder;Future;Ginger;Growth;Homeostasis;Intestines;Lead;Liver diseases;Mediating;Mus;National Institute on Alcohol Abuse and Alcoholism;Natural regeneration;Outcome;Oxidative Stress;Pathogenicity;Pathway interactions;Patients;Play;Prevention;Prevention therapy;Probiotics;Production;Receptor Signaling;Role;Sampling;Signal Transduction;Testing;Therapeutic Effect;Tight Junctions;Tryptophan;Up-Regulation;alcohol abuse therapy;alcohol exposure;aryl hydrocarbon receptor ligand;base;clinical application;disorder prevention;dysbiosis;exosome;gut colonization;gut inflammation;gut microbes;gut microbiota;improved;interleukin-22;intestinal barrier;intestinal epithelium;islet;metabolomics;microbial;mouse model;nanoparticle;nutrition;organ injury;pathogenic bacteria;prebiotics;prevent;probiotic therapy;programs;protective effect;transcytosis


application_id: 10424377
project_number: 5P50AA024337-07
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8879
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-05-01
project_terms:
Address;Alcohol abuse;Alcohols;Behavioral;Binding;Broccoli - dietary;Cell physiology;Congenital Abnormality;DNA;Defect;Development;Disease;Edible Plants;Elements;Embryo;Embryonic Development;Enhancers;Epigenetic Process;Ethanol;Event;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Genes;Genetic Transcription;Genome;Human;Impairment;Learning Disabilities;Mediating;Neural Crest Cell;Neuronal Dysfunction;Pathogenesis;Prevalence;Prevention;Prevention approach;Prevention strategy;Psyche structure;Regulation;Role;Site;Sulforaphane;Testing;Therapeutic;Variant;Work;Zebrafish;alcohol consumption during pregnancy;alcohol exposure;base;cell type;craniofacial development;exosome;innovation;insight;maternal alcohol use;migration;nanoparticle;novel therapeutic intervention;nutrition;organ injury;prevent;programs;teratogenesis;transcription factor


application_id: 10424376
project_number: 5P50AA024337-07
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8878
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-05-01
project_terms:
Address;Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Biological Markers;Butyrates;Clinical;Clinical Data;Clinical Research;Collection;Data;Development;Dietary Intervention;Dietary Supplementation;Disease Marker;Enteral;Exhibits;Fatty Liver;Funding;Hepatic;Histone Deacetylase Inhibitor;Human;Immune;Inflammation;Inflammatory;Injury;Interleukin-17;Intervention;Knowledge;Liver;Liver diseases;Mediating;Mus;Neutrophil Infiltration;Nutritional;Pathogenesis;Pathogenicity;Patient Recruitments;Patients;Play;Preventive treatment;Probiotics;Prodrugs;Production;Resources;Role;Severity of illness;T-Lymphocyte;Testing;Therapeutic;Therapeutic Intervention;Transplantation;United States National Institutes of Health;base;cohort;dietary;dysbiosis;efficacy evaluation;efficacy testing;evidence base;fecal transplantation;gut bacteria;gut dysbiosis;gut-liver axis;human model;human study;immune activation;innovation;insight;liver development;liver inflammation;liver injury;microbial;microbial community;mouse model;nutrition;organ injury;preclinical study;prevent;problem drinker;programs;response;systemic inflammatory response;targeted treatment;therapeutic target;treatment strategy;tributyrin


application_id: 10424375
project_number: 5P50AA024337-07
project_title: Role of n3 PUFAs and inflammation-resolving lipid mediator RvD1 in alcoholic liver disease
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8877
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alcohol consumption;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Model;Attenuated;Bacteria;Biological Response Modifiers;Chronic;Cytokine Signaling;Data;Development;Diet;Dietary Fats;Dietary Fatty Acid;Dietary Supplementation;Disease Progression;Down-Regulation;Effectiveness;Engineering;Ethanol;Experimental Animal Model;FDA approved;FPR2 gene;Fatty acid glycerol esters;Functional disorder;Health;Heavy Drinking;Hepatic;Hepatocellular Damage;Homeostasis;Host Defense;Human;Immune;Immune response;Impairment;In Vitro;Individual;Inflammation;Inflammatory;Intestinal permeability;Intestines;Kentucky;Linoleic Acids;Liver;Mediating;Mediator of activation protein;Microbe;Modeling;Molecular;Mus;Nuclear;Nutritional;Organoids;Pathogenesis;Patients;Phagocytosis;Phenotype;Plants;Plasma;Play;Production;Prognosis;Research;Resolution;Rodent;Role;Sampling;Severities;Severity of illness;Signal Transduction;Survivors;Technology;Testing;Therapeutic Agents;Tissues;Transcript;Transgenic Organisms;Translating;Whole Blood;attenuation;base;cytokine;exosome;gut inflammation;gut-liver axis;improved;in vivo evaluation;intestinal barrier;lipid mediator;liver inflammation;liver injury;macrophage;monocyte;nanoparticle;novel;novel therapeutic intervention;nutrition;organ injury;peripheral blood;preclinical study;receptor;repaired;systemic inflammatory response;therapeutic effectiveness;tissue repair


application_id: 10424374
project_number: 5P50AA024337-07
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD
subproject_number: 8876
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Area;Arts;Basic Science;Bioinformatics;Biometry;Budgets;Cancer Center;Clinical;Clinical Investigator;Collaborations;Communities;Conflict (Psychology);Consultations;Country;Development;Education;Engineering;Ensure;Epigenetic Process;Evaluation;Functional disorder;Grant;Health Sciences;Individual;International;Intervention;Lead;Leadership;Medicine;Preventive;Proteomics;Public Health Nursing;Reporting;Research;Research Personnel;Research Proposals;Resources;Role;Schools;Science;Social Work;Specialized Center;Standardization;Structure;Therapeutic Intervention;Time;Tissue Sample;Tissues;Universities;alcohol research;body system;cohesion;gut microbiota;high school;innovation;interest;intestinal barrier;medical schools;member;metabolomics;multidisciplinary;novel;nutrition;organ injury;programs


application_id: 10424373
project_number: 5P50AA024337-07
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2022-05-21
opportunity_number: RFA-AA-20-001
application_type: 5
activity_code: P50
ic: AA
serial_number: 024337
program_official: MURRAY, GARY
project_start_date: 2016-05-15
project_end_date: 2026-04-30
study_section: ZAA1-DD(50)P
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Alcohol abuse;Alcoholic Liver Diseases;Alcohols;Brain;Broccoli - dietary;Butyrates;Cause of Death;Chronic;Collaborations;Communities;Country;Development;Dietary Fats;Dietary Intervention;Education;Enhancers;Epigenetic Process;Ethanol;FDA approved;Faculty;Feces;Fetal Alcohol Spectrum Disorder;Fetal Alcohol Syndrome;Fostering;Functional disorder;Funding;Future;Goals;Grant;Health Care Costs;Impairment;Individual;Industry;Injury;Institution;Interdisciplinary Study;Intervention;Intestines;Knowledge;Lactobacillus;Lead;Lipids;Mediating;Mediator of activation protein;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;Neural Crest Cell;Nutritional;Organ;Pathogenesis;Prevention;Prevention approach;Prevention therapy;Preventive;Probiotics;Proteomics;Research;Research Personnel;Resources;Role;School Dentistry;Signal Transduction;Sulforaphane;Therapeutic Intervention;United States;United States National Institutes of Health;Universities;Volatile Fatty Acids;alcohol abuse therapy;alcohol exposure;alcohol intervention;alcohol research;alcohol use disorder;base;cofactor;cohesion;college;exosome;gut bacteria;gut inflammation;gut-liver axis;high school;improved;intestinal barrier;liver inflammation;metabolome;metabolomics;mortality;mouse model;multidisciplinary;nanoparticle;new therapeutic target;novel;nutrition;organ injury;prevent;teratogenesis;therapeutic effectiveness;therapeutic target


application_id: 10422236
project_number: 1R01HL163272-01
project_title: Extracellular Matrix Dynamics During Remodeling
administering_ic: NHLBI
award_notice_date: 2022-03-05
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 163272
program_official: WONG, RENEE P
project_start_date: 2022-04-01
project_end_date: 2026-03-31
study_section: Integrative Myocardial Physiology/Pathophysiology B Study Section[MPPB]
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_terms:
Abate;Acute;Address;Anabolism;Attention;Biomechanics;CD44 Antigens;Cardiac;Cardiac Myocytes;Catabolism;Cells;Chronic;Chronic Phase;Cicatrix;Collagen;Collagen Fibril;Complex;Congestive Heart Failure;Coupled;Data;Dependence;Deposition;Disease;Embryo;Enzymes;Event;Extracellular Matrix;Family;Fibroblasts;Fibrosis;Glucose;Glycolysis;HAS2 gene;Heart;Heart failure;Hyaluronan;Hyaluronidase;Impairment;Inflammation;Inflammatory;Investigation;Knowledge;Leukocytes;Matrix Metalloproteinases;Mediating;Mesenchymal;Metabolic;Metabolism;Mus;Myeloid Cells;Myocardial Infarction;Outcome;Pathologic;Pathology;Pathway interactions;Phase;Population;Process;Production;Proxy;Regulation;Role;Testing;Tissues;Ventricular Function;Ventricular Remodeling;cell type;gain of function;glucose metabolism;hyaluronan synthase 1;insight;loss of function;macrophage;metabolomics;migration;response to injury;stable isotope;wound healing


application_id: 10421444
project_number: 5R01GM138882-03
administering_ic: NIGMS
award_notice_date: 2022-06-27
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: GM
serial_number: 138882
program_official: BARSKI, OLEG
project_start_date: 2020-09-01
project_end_date: 2025-06-30
study_section: Macromolecular Structure and Function A Study Section[MSFA]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: GLAZER, EDITH C;HEIDARY, DAVID
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2022-07-01
project_title:
Role of small molecule interactions and multiprotein assemblies in CYP1B1 disease-associated function and dysfunction

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

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

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


application_id: 10421429
project_number: 5R01NS114404-03
project_title: BMAL1/ARNTL plays a critical non-circadian role in secondary tissue damage after contusive SCI
administering_ic: NINDS
award_notice_date: 2022-05-20
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 114404
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2020-08-15
project_end_date: 2025-05-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 7612305
contact_pi: HETMAN, MICHAL
other_pis: SARASWAT, SUJATA OHRI
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Circadian rhythms regulate a wide spectrum of biological processes of critical importance for organismalhealth. Perturbations of those rhythms underlie many pathologies including systemic inflammation depressionand neurodegeneration. Mechanistically circadian rhythms are driven by intrinsic oscillatory changes in geneexpression that are orchestrated by several regulators of gene transcription and mRNA translation forming thecore oscillator circuitry. Those key regulators most importantly the non-redundant transcription/translationfactor BMAL1/ARNTL are active in most cells throughout the body and undergo circadian entrainment byexternal time cues such as light or feeding. At the organismal level the pro-rhythmic role of the oscillator iswidely recognized as a critical contributor to homeostasis. BMAL1 effects that are independent of the centralrhythm include anti-oxidant protection in the brain life span regulation contributions to atherosclerosis andendoplasmic reticulum (ER) stress-sensitization of cancer cells. Those or similar tissue-specific functions ofBMAL1 may affect the outcome after SCI. However clock function at the molecular level has never beeninvestigated in the context of SCI. Unexpectedly we found that: (i) moderate contusive thoracic SCIupregulates BMAL1 in penumbral oligodendrocytes (OLs) coinciding with induction of the ER stress response(ERSR)-activated pro-apoptotic transcription factor CHOP and ER stress-mediated apoptosis of OLs (ii) afterSCI Bmal1-/- mice show improved locomotor recovery and white matter sparing (WMS) as well as selectivedownregulation of Chop and its pro-apoptotic target gene death receptor 5 (Dr5) and reduced bloodextravasation and inflammation with extensive changes in microglia/macrophage (MM) and endothelial (EC)-specific gene expression. Also pharmacological enhancement of the negative feedback inhibition of BMAL1reduces ER stress toxicity in OPC cultures. These exciting findings suggest a novel role of BMAL1 in thepathogenesis of SCI which may include OL-cell autonomous regulation of CHOP-mediated OL apoptosisand/or EC/MM-cell autonomous modulation of post-SCI hemorrhage/vascular dysfunction/cytotoxic neuro-inflammation. Therefore we will test the hypothesis that BMAL1 regulates OL EC and/or MM gene expressionthat contributes to SCI-associated white matter loss and impaired locomotor recovery. To test this hypothesiswe will: (i) determine the cell autonomous roles of OL- MM- and EC-BMAL1 in SCI-associated white matterdamage and locomotor recovery (ii) identify mechanism(s) that underlie BMAL1-mediated enhancement ofSCI-driven white matter loss and (iii) evaluate mediators of the negative feedback inhibition of BMAL1 aspharmacological targets for interventions to reduce SCI-associated white matter loss and locomotorimpairment. We will use a moderate T9 SCI contusion model in wild type or cell type-selective Bmal1-/- miceand non-toxic CNS-permeable drugs targeting the feedback regulation of BMAL1. This research may uncovernovel previously unrecognized contributions of BMAL1 to `secondary tissue injury after SCI.

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

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


application_id: 10421408
project_number: 5R01HL147381-03
project_title: Mechanisms regulating the atherogenic activities of serum amyloid A
administering_ic: NHLBI
award_notice_date: 2022-06-06
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 147381
program_official: LIU, LIJUAN
project_start_date: 2020-07-05
project_end_date: 2024-06-30
study_section: Special Emphasis Panel[ZRG1-VH-D(02)M]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: SHRIDAS, PREETHA
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but alsoplays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whoseconcentration in the plasma increases 1000-fold or more during a systemic inflammatory response beforereturning to near undetectable levels. However SAA is also persistently elevated in chronic inflammatoryconditions such as diabetes obesity rheumatoid arthritis etc. While the liver is the major source of SAAduring an acute inflammatory response extra-hepatic expression has also been documented. Most notablyadipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognizedfor decades that plasma levels of SAA predict cardiovascular risk in humans. More recently our groupdetermined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerousreports by multiple laboratories SAA exerts a myriad of effects in vitro that would be expected to exacerbateinflammation and atherosclerosis in vivo. However most of these published studies investigated lipid-free SAAoverlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances plasma SAA isfound associated with the high-density lipoprotein (HDL) fraction and accumulating evidence demonstratesthat HDL inhibits SAAs pro-inflammatory activity. Thus one function of HDL may be to sequester andneutralize SAA and limit the propagation of inflammation in vivo. Notably SAA can also be detected on apoBparticles particularly in human populations with increased risk for cardiovascular disease. Although thepathophysiological significance of the association of SAA with non-HDL lipoproteins is not known we haveshown that SAA on apoB-containing lipoproteins augments their proteoglycan binding which could lead toincreased vascular retention. Taken together these observations lead us to propose that the pro-inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium betweenHDL-SAA very low-density lipoprotein/low-density lipoprotein-SAA and lipid-free SAA. To test this hypothesiswe have developed critical research tools including novel mouse models with inducible tissue-specific SAAexpression to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodelingfactors (e.g. cholesterol ester transfer protein phospholipase A2 and oxidation) leads to the release ofbioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoBlipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA(liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. Theresults of this proposal will validate SAA as a therapeutic target in cardiovascular disease and will developSAA lipoprotein distribution as a potential biomarker of risk.

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

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


application_id: 10421328
project_number: 5R01CA237643-04
project_title: Targeting epigenetic heterogeneity to improve lung cancer immunotherapy response
administering_ic: NCI
award_notice_date: 2022-06-28
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 237643
program_official: SOMMERS, CONNIE L
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Developmental Therapeutics Study Section[DT]
contact_pi_person_id: 10317047
contact_pi: BRAINSON, CHRISTINE FILLMORE
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Immunotherapies particularly those that inhibit the PD1/PD-L1 interaction and drive T cells to recognizeand kill tumor cells have shown striking responses in a small subset of late stage treatment refractory squamouslung tumors. However the majority of patients do not have a lasting response. One way to boost response is toinclude an epigenetic inhibitor such as one targeting the Polycomb Repressive Complex 2 (PRC2) to influencethe tumor cell and microenvironment heterogeneity. My central hypothesis is that EZH2 inhibitors will boostimmunotherapy response in squamous tumors both by increasing the PD-L1 expressing tumorpropagating cells (TPCs) and by depleting immunosuppressive tumor associated neutrophils. Theoverarching goal of the proposed study is to validate combining EZH2 inhibition with PD1/PD-L1 targetedimmunotherapy and learn the molecular mechanisms when the treatment is successful as well as when it is notsuccessful. In Aim 1 I will use both mouse models and human patient derived organoid cultures and serial orthotopictransplantation to examine NGFR and PD-L1 expression and tumor propagation abilities of lung SCC cells afterEZH2 inhibitor treatment. I will also test if non-TPC cells can de-differentiate and continue to fuel tumor growthby sorting for presence or absence of the putative TPC cell surface marker nerve growth factor receptor (NGFR).The epigenetic and transcriptional consequences of EZH2 inhibition on squamous lung tumor cells will beassessed by ChIP-seq and RNA-seq. In Aim 2 I will focus on the tumor associated neutrophils (TANs). I willcompare TANs from placebo treated mice to those from EZH2 inhibitor treated mice for abundance migrationcapacity and ability to suppress T cells. I will also use an EZH2 conditional knock-out mouse model to furthercharacterize how EZH2 loss affects TANs. Again ChIP-seq and RNA-seq will be used to dissect the molecularchanges driven by EZH2 inhibition in the neutrophil populations. In Aim 3 I will treat immune-competentsquamous lung cancer bearing mice with the EZH2 inhibitor GSK126 or EPZ-6438 (Tazemetostat) and theimmunotherapy PD-1 antibody and follow tumor growth by magnetic resonance imaging. I will characterizetumor phenotypes in responders and non-responders and examine tumors that develop acquired resistance tothis therapeutic drug combination. Completion of these aims will solidify the efficacy of a promising therapeuticcombination and uncover mechanisms by which tumor hierarchies and microenvironments are changed by EZH2inhibitors in squamous lung cancers. Given that one arm of a Phase 1/2 clinical trial combining EZH2 inhibitionwith anti-PDL1 just began recruiting late stage non-small cell lung cancer patients learning the phenotypes andmechanisms of responders and non-responders will be extremely timely for any Phase 2/3 trials that ensue.

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

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


application_id: 10421320
project_number: 5R01DK121695-04
project_title: Macrophage Migration Inhibitory Factor mediates bladder pain
administering_ic: NIDDK
award_notice_date: 2022-06-13
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: DK
serial_number: 121695
program_official: KIRKALI, ZIYA
project_start_date: 2019-07-01
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1-DKUS-B(90)]
contact_pi_person_id: 8093598
contact_pi: VERA, PEDRO L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078344581
primary_uei: JCSKALYM8HU6
duns_number: 078344581
uei: JCSKALYM8HU6
fips: US
organization_id: 10030991
organization_name: LEXINGTON BIOMEDICAL RESEARCH INSTITUTE
organization_city: LEXINGTON
organization_state: KY
organization_type: Research Institutes
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Our long-term goal is to discover novel therapeutic targets for pelvic pain. Pelvic painbladder pain specifically is also the cardinal symptom of interstitial cystitis/bladder painsyndrome (IC/BPS) where most patients show no underlying bladder infection pathology orinjury. The local and central mechanisms that mediate pelvic pain are not fully understood.There is an urgent need to correct this knowledge gap so as to develop effective noveltherapeutic targets for chronic pelvic pain. Our overall objective in this application is to determine the mechanisms of MIF-mediated bladder hyperalgesia. Our central hypothesis is that MIF mediates bladderhyperalgesia through local (bladder) and central (spinal) mechanisms. We plan to test our central hypothesis by pursuing the following three specific aims: 1. Identify urothelial MIF receptors that mediate bladder hyperalgesia.Based on the published data referred to above our working hypothesis is that released MIFacts at urothelial MIF receptors to elicit urothelial HMGB1 release and bladder hyperalgesia. 2. Identify downstream targets of MIF/HMGB1 that mediate bladder hyperalgesia. Ourworking hypothesis based on our published and preliminary evidence is that blockingdownstream signaling pathways activated by MIF/HMGB1 will prevent bladder hyperalgesia. 3. Identify spinal mechanisms that mediate persistent bladder hyperalgesia.Based on our preliminary data our working hypothesis is that increased production andrelease of spinal MIF activates increased release of spinal HMGB1 to maintain bladder pain. In order to accomplish these aims we will conduct studies using rodent models ofbladder pain and in vitro studies using human urothelial cells. We will examine organ-leveland spinal-level mechanisms of bladder pain while focusing on treating persistent bladderpain. We will also identify novel lumbosacral peptides/proteins associated with persistentbladder pain. Succesful completion of these studies is expected to have a positive impactbecause it is probable that the identified components of the mechanism will provide newperipheral and/or central targets for therapeutic interventions in conditions of bladder pain.

project_terms:
Acute;Binding;Bladder;Bladder Injury;Cyclophosphamide;Cystitis;Data;Goals;HMGB1 Protein;Human;Hyperalgesia;In Vitro;Infection;Infective cystitis;Inflammation;Inflammatory;Injury;Interstitial Cystitis;Knowledge;Mediating;Microglia;Migration Inhibitory Factor;Organ;Outcome;Pain;Pathology;Patients;Pelvic Pain;Peptides;Peripheral;Production;Proteins;Publishing;Research;Rodent Model;Signal Pathway;Signal Transduction;Spinal;Spinal Cord;Symptoms;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Urothelial Cell;Urothelium;Work;base;bladder pain;chronic pelvic pain;cytokine;inhibitor;interstitial;new therapeutic target;novel;prevent;protease-activated receptor 4;radiation cystitis;receptor;targeted treatment;therapeutic target

public_health_relevance:
The proposed studies will contribute to fundamental knowledge about the mechanisms ofbladder pain and identify novel potential therapeutic targets for patients with InterstitialCystits/Bladder Pain Syndrome.


application_id: 10421274
project_number: 5R01HL148443-03
project_title: Mechanisms of cardiac remodeling triggered by gestational diabetes
administering_ic: NHLBI
award_notice_date: 2022-04-18
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HL
serial_number: 148443
program_official: TJURMINA, OLGA A
project_start_date: 2020-05-01
project_end_date: 2024-04-30
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9983033
contact_pi: DESPA, SANDA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTGestational diabetes mellitus (GDM) heightens the risk of developing cardiovascular disease in both motherand offspring. A recent large population-based prospective study (CARDIA) found that GDM is independentlyassociated with cardiac hypertrophy and impaired heart function later in life. In agreement with this finding ourpreliminary data show cardiac hypertrophy and activation of Ca2+-dependent transcriptional signaling twomonths after a GDM-complicated pregnancy in female rats. Although hyperglycemia is generally consideredthe critical mediator numerous studies reported that GDM has negative long term consequences even withgood glycemic control in the mother. Thus additional mechanisms promote metabolic and cardiovasculardysfunction in GDM. We previously demonstrated an essential role for amylin a pancreatic hormone withamyloidogenic properties and whose secretion increases in parallel with that of insulin in the cardiacremodeling and dysfunction induced by type-2 diabetes. Moreover we found that amylin activates Ca2+-dependent transcriptional signaling in cardiac myocytes. Our preliminary studies show higher amylin levels inblood from female rats with GDM and their offspring. Based on these findings we hypothesize that GDMpromotes pathological remodeling of maternal and offspring heart through activation of Ca2+-dependenthypertrophy signaling that is triggered by systemic amylin dyshomeostasis. To test this overall hypothesis wewill i) determine the molecular mechanisms underlying the GDM-induced pathological remodeling of the heartii) probe the amylin-cardiac myocyte interaction in GDM and iii) assess the effect of hyperamylinemia onpregnancy-induced cardiac remodeling in the absence of other metabolic alterations associated with GDM.Experiments will combine in vivo assessment of heart structure and function and pharmacological treatmentwith measurements in explanted hearts and isolated cardiac myocytes in female rats with normal and GDM-complicated pregnancies and their offspring as well as in pregnant amylin-KO females injected withrecombinant amylin. Thus the project will provide unique insights into the complex mechanisms through whichGDM programs cardiac remodeling in mother and offspring. The study may be paradigm shifting by assertingamylin dyshomeostasis as a key player in this pathology which will help design new therapeutic strategies forreducing the postpartum risk of heart disease in mothers with GDM and their offspring.

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

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


application_id: 10420527
project_number: 1R01AI168475-01
administering_ic: NIAID
award_notice_date: 2022-02-25
opportunity_number: PA-20-185
application_type: 1
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: 2022-02-25
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;Cell Line;Cells;Clinical;Clinical Research;Clinical Trials;Complex;Computer Models;Data;Development;Devices;Epithelial;Epithelial Cells;Equilibrium;Experimental Models;Female;Formulation;Gardnerella;Gardnerella vaginalis;Gelatin;Goals;HIV;Health;Histopathology;Human;In Vitro;Infection;Infertility;Inflammation Mediators;Investigation;Kinetics;Lactobacillus;Link;Measurement;Measures;Mediator of activation protein;Medicine;Metronidazole;Microbe;Modeling;Mucous body substance;Mus;Oral;Outcome;Pelvic Inflammatory Disease;Phase;Pre-Clinical Model;Prevotella;Probiotics;Process;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;base;bioprinting;co-infection;cytotoxicity;delivery vehicle;design;dysbiosis;engineering design;experience;experimental study;gut health;high risk;improved;improved outcome;in vitro Model;in vivo;mathematical model;microbial;microbicide;mouse model;multidisciplinary;novel;pathogen;pre-clinical;predictive modeling;prevent;prototype;reduce symptoms;reproductive;reproductive tract;scaffold;vaginal lactobacilli;vaginal microbiome;virtual


application_id: 10418813
project_number: 5R01CA196634-08
project_title: Improving chemotherapy of castration-resistant prostate cancer.
administering_ic: NCI
award_notice_date: 2022-07-11
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 196634
program_official: FORRY, SUZANNE L
project_start_date: 2016-08-10
project_end_date: 2026-06-30
study_section: Mechanisms of Cancer Therapeutics - 1 Study Section[MCT1]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ablation;Affect;Androgen Receptor;Androgens;Binding;Biochemical;Bromodomain;Castration;Cell Cycle;Cell Cycle Progression;Cell Proliferation;Cells;Chemoresistance;Chromatin;Clinical Research;Data;Development;Disease;Docking;Epigenetic Process;Event;Family;Fostering;Genetic Transcription;Genetically Engineered Mouse;Goals;Growth and Development function;Health;Investigation;Lead;Lysine;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Mitosis;Mitotic;Molecular;Mutation;Operative Surgical Procedures;Outcome;PLK1 gene;Paclitaxel;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphorylation Site;Phosphotransferases;Proteins;Public Health;Reader;Receptor Signaling;Regulation;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;Site;Specimen;System;Testing;Therapeutic;Therapeutic Agents;Transcriptional Elongation Factors;United States National Institutes of Health;Work;Xenograft procedure;abiraterone;castration resistant prostate cancer;chemotherapy;clinically significant;cyclin T1;design;docetaxel;effective therapy;enzalutamide;genetic approach;genomic locus;improved;in vivo;inhibitor;innovation;loss of function mutation;member;mouse model;multicatalytic endopeptidase complex;novel;novel strategies;patient derived xenograft model;prostate cancer cell;prostate cancer progression;protein degradation;recruit;standard care;success;therapy resistant;ubiquitin-protein ligase


application_id: 10418801
project_number: 5R21AI163886-02
project_title: Identifying novel tick attractants and repellents by exploiting their olfactory and eco-physiology
administering_ic: NIAID
award_notice_date: 2022-05-16
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AI
serial_number: 163886
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2021-06-07
project_end_date: 2025-05-31
study_section: Vector Biology Study Section[VB]
contact_pi_person_id: 11079155
contact_pi: SYED, ZAINULABEUDDIN
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 SUMMARYBlack-legged tick Ixodes scapularis have doubled their distribution range within the past 2 decades. Notsurprisingly Lyme disease incidence has tripled since the 1990s according to the recent NIH tickborne diseasesstrategic planning committees report. These vector/disease expansions have been attributed to climate changeneighborhoods encroaching the animal habitats and other ecologic shifts. Multi-pronged strategies especiallythose that are based on understanding the ticks unique olfactory system and eco-physiological adaptations willprovide effective practices that can be embedded into the existing vector control strategies. Ticks display robustolfactory driven behaviors despite endowed with a simple olfactory machinery made of ca. 20 olfactory sensilla(housing ca. 80-90 olfactory receptor neurons ORNs). How can such relatively simple olfactory systemaccomplish the remarkable task of detecting and discriminating between the preferred hosts and mates or toavoid the unfavorable ones? We will answer this question by determining the detection properties of each of thesensilla challenging with odors of demonstrated behavioral response. We propose to use the single sensillumrecording (SSR) method to record the odor induced activity from individual ORNs The SSR will be furthercoupled with gas-chromatography (GC-SSR) to directly isolate biologically active constituents odorant from thecomplex odors mixtures. These constituents will be chemically identified using mass spectrometry and finallyverified by injecting them back into GC-SSR. Electrophysiologically active chemicals will be tested for thebehavioral response in a 4-arm olfactometer- either individually or in blends. In arthropods a distinct yet limitedrange of volatiles from the environment are parsimoniously used in various contexts eliciting distinct behaviorssuch as attraction to host and mates and repulsion/avoidance from unsuitable sites. Odors such aspheromones are effective means to sample and control vector arthropods including ticks yet identifying aneffective and selective bait has been elusive so far. Therefore we believe that our proposed integrated platformwill lead to the discovery of novel natural attractants and repellents. This project will extend the fundamentalunderstanding of the ticks olfactory biology and integrating this knowledge with the eco-physiologicaldeterminants such as saturation deficit will lead to design of novel management strategies.

project_terms:
Address;Affect;Animals;Arthropod Vectors;Arthropods;Back;Behavior;Behavioral;Behavioral Paradigm;Biological;Biology;Black-legged Tick;Blood;Canis familiaris;Centers for Disease Control and Prevention (U.S.);Chemicals;Chemistry;Climate;Code;Complex;Coupled;Custom;Deer;Detection;Development;Disease;Disease Vectors;Electrophysiology (science);Elements;Environment;Evaluation;Exposure to;Gas Chromatography;Goals;Habitats;Hair;Housing;Human;Incidence;Individual;Knowledge;Laboratories;Letters;Life;Ligands;Link;Lyme Disease;Mass Fragmentography;Mass Spectrum Analysis;Measurement;Mediating;Methods;Monitor;Neighborhoods;Nose;Odors;Olfactory Pathways;Olfactory Receptor Neurons;Outcome;Partner in relationship;Pheromone;Physiological;Physiological Adaptation;Physiology;Population;Population Explosions;Prevalence;Prevention;Property;Publishing;Recommendation;Recording of previous events;Reporting;Resources;Sampling;Site;Smell Perception;Strategic Planning;Switzerland;Tail;Techniques;Testing;Tick-Borne Diseases;Ticks;Training;United States National Institutes of Health;Universities;Vector-transmitted infectious disease;Volatile Oils;White-Footed Mouse;Work;arm;base;behavior test;behavioral response;burden of illness;climate change;design;exposed human population;feeding;field study;improved;innovation;instrument;novel;prevent;screening;success;tick bite;tick population;tick transmission;tick-borne pathogen;tool;vector;vector control;vector management strategies;vector tick

public_health_relevance:
PROJECT NARRATIVEHistorically some of the most successful campaigns against vector-borne diseases have beenthose targeted against the vectors and Odor Baited Traps (OBTs) offer invaluable tools in thepopulation monitoring that define the success of any vector management strategy. We proposeto screen natural extract and essential oils in a behavioral paradigm and isolate novelnatural ligands by employing ticks olfactory apparatus as biological sensing element. Identifiedligands will be tested for behavioral sensitivity thus paving the way for developing effectiveand specific baits that can be employed as lures in OBTs.


