# projects

application_id: 10817133
project_number: 5R21AG081761-02
administering_ic: NIA
award_notice_date: 2024-03-05
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AG
serial_number: 081761
program_official: ROBERTS, LUCI
project_start_date: 2023-04-01
project_end_date: 2026-07-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8163817
contact_pi: SAITO, HIROSHI
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
A Refined Murine Model of Post-sepsis Cognitive Impairment for Investigating Mitochondrial Abnormalities and Human ApoE4 Gene Polymorphisms

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

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

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


application_id: 10817104
project_number: 5T35EY026509-08
project_title: Summer Vision Sciences Training Program
administering_ic: NEI
award_notice_date: 2024-06-28
opportunity_number: PA-20-162
application_type: 5
activity_code: T35
ic: EY
serial_number: 026509
program_official: CLAYTON, EDWIN C
project_start_date: 2017-07-01
project_end_date: 2027-03-31
study_section: ZEY1-VSN(06)
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
other_pis: MCCALL, MAUREEN A
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractThis is a renewal application for a T35 summer medical student training program in vision research withtwo Specific Aims: 1) To provide hands-on training in basic and clinical vision research to medicalstudents in a structured mentored environment and 2) To provide an interactive educational experiencethat introduces medical students the fundamental skills necessary for basic translational and clinicalresearch in vision biology. The co-directors of this program request support for 8 second-year medicalstudents each summer in vision related research laboratories that focus on topics such as visualcircuitry retinal degeneration corneal epithelial homeostasis uveitis ocular drug discovery anddevelopment of the visual system. Trainees will be selected from the first-year class at University ofLouisville School of Medicine. Students will review research projects submitted by 18 faculty funded bythe NEI or vision related foundations. The directors will make a special effort to recruit students who areunderrepresented in science including females ethnic minorities and from disadvantagedbackgrounds. Students will review the available projects and rank their 1st-5th choices allowing matchingof trainees with mentors. Final decisions will be made based on interviews between mentors andTrainees. During the 10-week summer training students work with mentors on their research project inlaboratory settings complete training in the Responsible Conduct of Research including topics such asfabrication and falsification of data plagiarism managing scientific data publication practices andresponsible authorship mentorship stewardship and conflict of interest. Trainees will complete humansubject IRB training and animal care and handling as required by their specific research projects. AllTrainees will attend a 2-hour weekly Vision Sciences Research Training Seminar designed tointroduce clinical/translational research in Ophthalmology led by mentors in this T35 program. Theseminar series will culminate with each Trainee presenting his/her research project to peers andmentors. In addition trainees present the results of their research as posters with peers at a School ofMedicine-wide week-long celebration of research (Research!Louisville) that includes nationallyrecognized physician-scientists as keynote speakers. Trainees will be encouraged to continue researchas part of the Distinction in Research track that is an enrichment program focusing on providingmeaningful and productive research experiences throughout second through fourth years of medicalschool with ongoing presentations by students with mentors and 4+ weeks of research time in thefourth year toward the goal of developing clinician-researchers. Trainees will be tracked to assess theimpact of this T35 program on careers as physician-scientists.

project_terms:
Authorship;Basic Science;Biology;Clinical;Clinical Research;Conflict of Interest;Data;Education;Environment;Faculty;Female;Foundations;Funding;Goals;Homeostasis;Hour;Institutional Review Boards;Interview;Laboratories;Laboratory Research;Medical Students;Mentors;Mentorship;Ophthalmology;Physicians;Plagiarism;Productivity;Publications;Research;Research Personnel;Research Project Grants;Research Training;Retinal Degeneration;Science;Scientist;Series;Structure;Student recruitment;Students;Systems Development;Time;Training;Training Programs;Translational Research;Universities;Uveitis;Vision;Vision research;Visual;Work;animal care;career;corneal epithelium;design;disadvantaged background;drug discovery;ethnic minority;experience;fabrication;human subject;medical schools;peer;posters;programs;responsible research conduct;skills;vision development;vision science

public_health_relevance:
Project Narrative:This NEI Short-Term Institutional Training Grant renewal application requests 5 years of support for 8 risingsecond year Medical Student trainees in our Vision Science laboratories for a 10 week research experience.We will focus on recruitment of under-represented trainees into this program to enhance the diversity of ourmedical workforce. The T35 training grant will be used to entice our medical students into our Distinction inResearch Track a program that encourages students to participate in laboratory research in years 2-4 ofmedical school with an eye toward scholarly activities in academic medicine to continue to build a pipeline oftranslational clinician-researchers.


application_id: 10817087
project_number: 5R21NS131903-02
project_title: Mechanism and Therapeutic Potential of CBD to Repair Blood-Brain Barrier Dysfunction in Epilepsy
administering_ic: NINDS
award_notice_date: 2024-03-19
opportunity_number: PA-21-219
application_type: 5
activity_code: R21
ic: NS
serial_number: 131903
program_official: LEENDERS, MIRIAM
project_start_date: 2023-04-01
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-MDCN-M(91)]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Blood-brain barrier dysfunction is both a cause and consequence of seizures in patients with epilepsy yet ther-apeutic options to repair barrier dysfunction do not exist. Key characteristics of barrier dysfunction in epilepsyare neurovascular inflammation and barrier leakage both result from seizure-mediated release of glutamate.Data support that an inflamed and leaky and thus dysfunctional barrier contributes to seizure genesis througha pernicious feedback loop that promotes epilepsy progression. However current therapeutic options to treatepilepsy are largely neuron-centric and do not address barrier dysfunction. In addition existing antiseizure drugs(ASDs) do not reliably control all seizures leaving patients with difficult-to-treat epilepsies prone to uncontrolledseizures. We recently discovered that Cannabidiol (CBD) mitigates barrier dysfunction in epilepsy. We also foundthat CBD blocks glutamate-mediated barrier leakage in isolated capillaries and repairs seizure-induced barrierdysfunction in vivo. These findings suggest that CBD has the potential to block the feedback signaling that drivesbarrier dysfunction and seizure progression in epilepsy. However data that support the use of CBD to repairbarrier dysfunction in epilepsy are not available. This knowledge gap represents a critical unmet need that pre-vents us from achieving therapeutic advances for patients with epilepsy. The overall objective in this applicationis to define the mechanistic link between cannabinoid signaling and barrier dysfunction to explain observed CBDeffects and to evaluate CBD as therapeutic agent to repair barrier dysfunction in epilepsy. Based on preliminarydata the central hypothesis of this project is that CBD repairs barrier dysfunction thereby lowering seizure burdenin epilepsy. The rationale for the proposed research is that its successful completion will provide mechanisticand preclinical data supporting future research for the clinical translation of CBD to treat patients with epilepsy.The hypothesis will be tested by pursuing two specific aims: 1) Describe cannabinoid signaling in glutamate-mediated barrier dysfunction and 2) Evaluate CBD for its potential to repair barrier dysfunction in epilepsy. UnderAim 1 we will describe key mechanistic steps between cannabinoid signaling and glutamate-mediated barrierdysfunction by using brain capillaries isolated from knockout mouse models. We will verify these signaling stepsin isolated human brain capillaries. Under Aim 2 we will evaluate the therapeutic benefit of CBD on seizure-mediated neurovascular inflammation barrier leakage and seizure burden in chronic epileptic rats. The pro-posed research is innovative because it focuses on a thus far unaddressed topic: cannabinoid signaling at theblood-brain barrier and CBD as therapeutic agent to repair barrier dysfunction and reduce seizures in epilepsy.The proposed research is significant because it holds the promise of a novel therapeutic approach to repairbarrier dysfunction that has translational potential to advance treatment of patients with epilepsy and other sei-zure disorders with underlying barrier dysfunction.

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

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


application_id: 10817033
project_number: 5R01HD101508-05
project_title: Noninvasive Noncontact High-Density Optical Imaging of Neonatal Intraventricular Hemorrhage
administering_ic: NICHD
award_notice_date: 2024-03-25
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: HD
serial_number: 101508
program_official: GUMINA, DIANE LAURA
project_start_date: 2020-04-10
project_end_date: 2027-03-31
study_section: Imaging Technology Development Study Section[ITD]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTGerminal matrix-intraventricular hemorrhage (GM-IVH) is a major complication of premature birth occurring inup to 45% of very low birthweight neonates (<1500 g) due to fragility of immature blood vessels within thegerminal matrix. GM-IVH can also lead to hydrocephalus (HCP) and increased intracranial pressure whichfurther induces inflammation and brain tissue injury. Though neonatal GM-IVH and HCP are increasinglycommon due to the rising survival rate of preterm births there are no established biomarkers or guidelines fortheir treatments to prevent brain injury. Preterm infants with GM-IVH/HCP are vulnerable to alterations in cerebralblood flow (CBF) because they have impaired cerebrovascular autoregulation. However there are no reliablefunctional imaging methods at the bedside of neonatal intensive care units (NICUs) for repeatedly assessingeither degree of cerebral injury or effectiveness of interventions. Near-infrared spectroscopy and tomographytechnologies have been used for decades as noninvasive bedside tools for continuous monitoring of cerebralblood oxygen saturation (StO2). However most systems lack the combination of spatial resolution and wide field-of-view (FOV) to image distributed brain functions and discriminate the brain signal from overlaying scalp andskull. A few high-density tomographic systems use numerous discrete sources and detectors coupled with fiberbundles to a head cap. However adjusting and maintaining a stable optical coupling of numerous fibers to asmall fragile neonatal head (i.e. a contact measurement) is labor-intensive and poses great challenges to headcap design with safety concern. To overcome these limitations we propose to develop a novel noncontacthigh-density-detection (using a CCD/CMOS camera) multi-wavelength speckle contrast diffuse correlationtomography (MW-scDCT) system to accommodate fast high-resolution functional imaging of both CBF andStO2 over a large FOV on the neonatal head. The MW-scDCT will be rigorously calibrated and optimized usingstandard tissue phantoms (Aim 1). In vivo calibration/evaluation will be conducted against MRI and histologicalexamination in an IVH/HCP model of neonatal piglets who preserve great similarities with human neonates (Aim2). A pilot clinical observational study will be performed in preterm neonates with GM-IVH/HCP under standardof care in the NICU (Aim 3). Cerebral hemodynamics/metabolism cerebrovascular autoregulation and cerebralfunctional connectivity will be analyzed from serial functional images taken over several weeks after birth. Wehypothesize that cerebral hemodynamic/metabolic alterations detected by MW-scDCT correlate withprogression of brain injury after GM-IVH/HCP and recovery after treatment. Multiple parameters will providemore comprehensive assessments of neonatal brain injury/recovery compared to a single parameter alone. Thisstudy will fulfill a critical need in the field of neonatology to provide objective measures/biomarkers to guide timingof treatment for GM-IVH and HCP. We anticipate that noninvasive repeated and longitudinal cerebral monitoringfor the guidance of interventions could be eventually implemented as standard of care in NICUs.

project_terms:
Acute;Aftercare;Algorithms;Autopsy;Biological Markers;Birth;Blood;Blood Vessels;Brain;Brain Injuries;Brain imaging;Calibration;Case Study;Cephalic;Cerebral Ventricles;Cerebrospinal Fluid;Cerebrospinal fluid shunts procedure;Cerebrovascular Circulation;Cerebrum;Chronic Phase;Clinical;Clinical assessments;Complication;Coupled;Coupling;Critical Care;Critical Illness;Detection;Development;Devices;Diffuse;Dimensions;Effectiveness of Interventions;Evaluation;Fiber;Functional Imaging;Goals;Guidelines;Harm Reduction;Head;Histologic;Homeostasis;Human;Hydrocephalus;Image;Imaging Device;Imaging Techniques;Impairment;Inflammation;Injury;Intervention;Intracranial Hypertension;Intracranial Pressure;Ischemic Brain Injury;Laboratories;Legal patent;Magnetic Resonance Imaging;Measurement;Measures;Medical;Metabolic;Metabolism;Methodology;Methods;Modeling;Monitor;Multi-modal optical imaging;Mus;Near-Infrared Spectroscopy;Neonatal;Neonatal Brain Injury;Neonatal Intensive Care Units;Neonatology;Neurologic Deficit;Neurological outcome;Neurosciences Research;Observational Study;Optics;Outcome;Outcome Measure;Outcome Study;Oxygen;Oxygen Consumption;Premature Birth;Premature Infant;Property;Rattus;Recovery;Research;Resolution;Safety;Scalp structure;Signal Transduction;Source;Survival Rate;System;Technology;Testing;Three-Dimensional Imaging;Tissues;Ultrasonography;Very Low Birth Weight Infant;brain health;brain tissue;cerebral hemodynamics;cerebrovascular;clinical application;cranium;density;design;detector;functional disability;high risk;human imaging;imager;imaging modality;improved;in vivo;innovation;intraventricular hemorrhage;metabolic rate;multimodality;neonatal brain;neonate;neuroimaging;novel;optical imaging;portability;pre-clinical;premature;preservation;preterm newborn;prevent;standard care;standard of care;tissue injury;tissue phantom;tomography;tool

public_health_relevance:
PROJECT NARRATIVEPreterm infants are at high risk for brain injuries due to alterations in brain blood flow and oxygenation especiallyafter the occurrence of intraventricular hemorrhage and currently there is no reliable bedside method to monitorthese functional parameters continuously in premature brains. This project will develop and test a newnoncontact fast high-resolution and portable optical device which enables immediate and continuous imagingof brain blood flow oxygenation metabolism and functional connectivity in neonatal piglets and preterm infants.Compared to currently available technologies this noninvasive multi-parameter functional imager will providea more comprehensive and accurate assessment of neonatal brain health/injury which may help optimize carefor critically ill neonates and reduce harm to their brains.


application_id: 10816395
project_number: 5R01NS112304-04
project_title: Propriopsinal neuron function in normal and post-SCI locomotion
administering_ic: NINDS
award_notice_date: 2024-02-08
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: NS
serial_number: 112304
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2021-03-15
project_end_date: 2027-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: DANNER, SIMON MICHAEL
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:
Abstract: Despite the more than 100 years since the recognition of intrinsic spinal locomotor circuits many ofthe functional details of those circuits and their contributions to recovery following spinal cord injury (SCI)remain to be determined. Recent development of powerful molecular tools enables functional dissection ofneural circuitry via reversibly silencing neurotransmission and trans-synaptic labeling. We will combine thesetools with sophisticated gait and kinematic analyses that includes the full repertoire of speed dependent gaitsto provide the functional and anatomical information necessary for building and refining an advanced neuro-biomechanical computer model of the rat spinal cord body and limbs. We will focus on two classes of spinalcord interneurons the long ascending (LAPNs) and descending (LDPNs) propriospinal neurons thatinterconnect the forelimb and hindlimb circuits and central pattern generators in the two enlargements andinvestigate their role in the intact spinal cord and after SCI using both hemisection and contusion models. Ourpreliminary data show that these LAPNs/LDPNs are essential components involved in speed-dependent gaitexpression. Silencing these neurons partially decouples the right and left limbs at each girdle. Surprisinglysilencing these neurons after an incomplete contusion injury results in better overground locomotion a resultthat is hard to reconcile based on current knowledge and observations in uninjured animals. Using viral-basedtrans-synaptic labeling we will determine the sensory descending and propriospinal inputs onto both LAPNsand LDPNs. We will utilize both existing and new physiological and biomechanical data (Aim 1) as well as newanatomical data (Aim 2) to build and refine our computational model (Aim 3). Then in vivo experiments andcomputer modeling will be performed in parallel (Aim 4) to determine the roles that ipsilateral and commissuralLAPNs and LDPNs play in locomotor behavior including the full range of locomotor gaits and in recoveredfunction after hemisection and incomplete contusion injuries. We suggest that a deeper understanding of longpropriospinal neurons represents an important step towards the development of new therapeutic tools forrecovery after SCI.

project_terms:
Adult;Anatomy;Animals;Axon;Behavior;Binding;Biomechanics;Cervical;Characteristics;Computer Models;Computer Simulation;Contusions;Data;Data Set;Development;Dissection;Experimental Models;Forelimb;Gait;Goals;Hindlimb;Injury;Interneurons;Ipsilateral;Knowledge;Label;Lateral;Left;Limb structure;Locomotion;Mediating;Modeling;Molecular;Movement;Musculoskeletal System;Neurons;Physiological;Play;Population;Publishing;Rattus;Recovery;Reverse engineering;Role;Running;Sensory;Source;Speed;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Structure;Structure-Activity Relationship;Synapses;Techniques;Testing;Thoracic spinal cord structure;Validation;Viral;Virus;Walking;animal data;biomechanical model;central pattern generator;design;experimental study;in silico;in vivo;kinematics;model development;neural circuit;neurotransmission;novel;novel therapeutics;predictive modeling;sensory input;tool

public_health_relevance:
Project Narrative This multi-PI project focuses on the role of the long ascending and descending propriospinalneurons (LAPNs LDPNs) in the control of locomotion and recovery after a spinal cord injury. We will use acombination of viral based synaptic silencing retrograde and trans-synaptic tracing and comprehensive gaitand kinematic analysis to aid the development of a neuro-biomechanical computer model and to generateimportant new knowledge of spinal locomotor circuitry.


application_id: 10816373
project_number: 5R01HD096077-05
project_title: The Role of FOS in the Ovary
administering_ic: NICHD
award_notice_date: 2024-02-16
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HD
serial_number: 096077
program_official: TAYMANS, SUSAN
project_start_date: 2019-05-06
project_end_date: 2027-02-28
study_section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER]
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
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:
Abstract Understanding the cellular events underlying ovulation and subsequent corpus luteum (CL) formation iscritically important because these biological processes provide the foundation of our ability to regulate femalefertility. A fundamental cornerstone of the cellular events induced by the preovulatory gonadotropin surge vitalfor ovulation and CL formation is the expression of specific transcription factors. However our knowledge ofthe identity and regulatory actions of gonadotropin-induced key transcription factors remains limited. A recent study has shed light on a member of the activator protein-1 (AP-1) transcription factor family FOS(a.k.a. c-fos) as a key transcription factor involved in follicular development ovulation and luteal formation.Fos-deficient mice failed to ovulate and form CL even when exogenous gonadotropins were administered (1)indicating that the ovarian expression of Fos is necessary for normal ovulation and luteinization. However littleto nothing is known exactly how the FOS/AP-1 transcription factor affects these processes in the ovary. Ourpreliminary study revealed for the first time that the expression of FOS is highly up-regulated in dominantfollicles collected after hCG administration from normally cycling women and in preovulatory follicles after hCGadministration in mice. Moreover we demonstrated that FOS regulated the hCG-induced increase in theexpression of key ovulatory genes in human granulosa cells by directly binding to the promoters of thesegenes. Based on these novel findings we hypothesized that FOS/AP-1 plays essential roles in ovulation andluteal formation/function both in humans and mice. Fos null mice displayed a pleiotropic phenotype with significant loss of viability at birth. To determine theovary-specific function/action of FOS/AP-1 we propose to establish novel transgenic mouse models in whichFos expression is ablated in an ovarian cell-specific manner. These mutant mice will be used to assess theovarian phenotype including follicular development ovulation luteal development and fertility as well as toidentify downstream target genes of FOS/AP-1 in ovarian cells (Specific Aim #1). To relate and compare thefindings from mice to humans we will first characterize the spatiotemporally regulated expression of all FOSand JUN family members in ovulatory follicles obtained before and throughout the periovulatory period fromnormally cycling women. The specific role of FOS/AP-1 in human ovaries will also be determined by identifyingdownstream target genes of FOS/AP-1 and assessing the cellular impact(s) of FOS' action (Specific Aim #2). The information obtained from the proposed studies will not only advance our understanding of themechanism necessary for successful ovulation and luteinization but also be instrumental for futuretranslational/clinical application thus leading to improved management of fertility in vivo and in vitro.

project_terms:
Ablation;Address;Affect;Albers-Schonberg disease;Binding;Binding Sites;Biological Process;Birth;Cell Culture Techniques;Cells;DNA Binding;Data;Development;Event;Exhibits;FOS gene;Family;Family member;Fertility;Foundations;Future;Gene Expression;Genes;Gonadotropins;Hour;Human;Human Chorionic Gonadotropin;In Vitro;JUNB gene;Knockout Mice;Knowledge;Luteinization;Mediating;Mus;Mutant Strains Mice;Ovarian;Ovarian Tissue;Ovary;Ovulation;PMSG (Gonadotropins);Pathway interactions;Phenotype;Physiological;Physiology;Pilot Projects;Play;Process;Progesterone Receptors;Prostaglandins;Reporting;Role;System;Time;Transcription Factor AP-1;Transgenic Mice;Woman;clinical application;corpus luteum;design;female fertility;granulosa cell;human tissue;improved;in vivo;insight;jun Oncogene;member;mouse model;novel;prevent;promoter;spatiotemporal;transcription factor;women's reproductive health

public_health_relevance:
Narrative Successful ovulation and subsequent corpus luteum formation and development are essential for femalefertility. In the present proposal we will demonstrate for the first time that the FOS/AP-1 transcription factorplays an essential role in ovulation and corpus luteum formation in both humans and mice. Information derivedfrom the present proposal will provide novel insights into the mechanism(s) underlying ovulation and lutealformation and can be applied for promoting and inhibiting the critical facet of ovarian physiology therebyallowing us to effectively manage fertility in women.


application_id: 10815677
project_number: 261201800013I-P00009-26100001-2
project_title: SEER CORE INFRASTRUCTURE SUPPORT
administering_ic: NCI
project_start_date: 2018-05-01
project_end_date: 2023-04-30
contact_pi_person_id: 78147083
contact_pi: DURBIN, ERIC
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_abstract:
The purpose of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER)Program is to assemble and report annual estimates of cancer statistics that pertain to incidenceprevalence and patient survival; monitor trends to identify important changes in cancer rates forpopulation subgroups defined by geographic demographic and social characteristics; provideinformation on changes over time in stage of disease at diagnosis and types of therapy as well asassociated changes in cancer patient survival; carry out special studies that provide insight into trends incancer rates treatment patterns and other relevant aspects of cancer control; and provide an infrastructureto support cancer research through its data.

project_terms:
Annual Reports;Cancer Control;Cancer Patient;Data;Diagnosis;Disease;Geography;Incidence;Infrastructure;Malignant Neoplasms;Monitor;National Cancer Institute;Patients;Population;Prevalence;SEER Program;Social Characteristics;Subgroup;Time;anticancer research;cancer statistics;insight;treatment pattern;trend


application_id: 10814850
project_number: 5R01CA272772-02
administering_ic: NCI
award_notice_date: 2024-03-12
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: CA
serial_number: 272772
program_official: SINGH, ANJU
project_start_date: 2023-04-01
project_end_date: 2028-03-31
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer

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

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

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


application_id: 10814249
project_number: 5R01AA028905-03
project_title: Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease
administering_ic: NIAAA
award_notice_date: 2024-03-08
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: AA
serial_number: 028905
program_official: LIN, LI
project_start_date: 2022-06-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1-DKUS-R(04)]
contact_pi_person_id: 10484237
contact_pi: KIRPICH, IRINA A.
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:
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis tosteatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity mortality andhealth care costs in the US and worldwide. However there is no FDA-approved therapy for any stage of ALD.There is also an incomplete understanding of the mechanisms and mediators of disease progression andseverity. Soluble epoxide hydrolase (s-EH) a master enzyme that regulates the metabolism of endogenousbioactive lipids (e.g. epoxy-fatty acids Ep-FAs) has recently been recognized as an emerging therapeutic targetin multiple diseases. The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition atdifferent stages of ALD severity and to provide a mechanistic foundation for using s-EH inhibition as a noveltherapy for alcohol-induced liver pathology. Aim 1. To test the therapeutic effectiveness of s-EH inhibitionas a novel therapeutic strategy for ALD. We will: i) test whether modulation of s-EH activity by pharmacologicalinhibition or s-EH (Ephx2) genetic ablation can effectively attenuate or prevent EtOH-induced liver injury inexperimental ALD; ii) evaluate whether s-EH inhibition leads to stabilization of blood and liver Ep-FAs; and iii)correlate changes in Ep-FA levels with markers of liver injury. Systemic and targeted liver-specific delivery of s-EH inhibitors (t-TUCB and TPPU) and WT and Ephx2 -/- mice (global and liver-specific) will be used in multipleanimal models of ALD which produce different stages of disease severity and which recapitulate differentfeatures of human ALD. This allows for a rigorous evaluation of the effects of s-EH inhibition at different stagesof ALD severity. Treatment and prevention paradigms will be applied. Aim 2. To explore mechanism(s)underlying the beneficial effects of s-EH inhibition in experimental ALD. We will determine whether Ep-FAstabilization mediated by s-EH inhibition plays a critical role in attenuation of EtOH-induced liver injury. We willtest whether n3 vs n6 Ep-FAs exert a greater beneficial effect by enhancing M2 macrophage polarizationincreasing a pro-restorative/pro-resolving macrophage phenotype and by Ep-FAs-PPAR-CXCL1-mediatedreduction of neutrophil infiltration. s-EH inhibitors WT transgenic fat-1 mice (which endogenously convert n6PUFAs to n3 PUFAs) and hepatocyte-specific Ppar-/- mice will be used. In vivo and in vitro studies will beperformed. Aim 3. To evaluate EtOH-induced alterations in s-EH and Ep-FAs in human ALD. Utilizing de-identified human plasma and whole blood samples we will: i) evaluate alterations in plasma Ep-FAs andestablish relationships between biomarkers of liver injury and systemic inflammation in patients with alcohol-associated hepatitis (AH); ii) determine the effects of n3-PUFA dietary supplementation on plasma Ep-FAs inheavy drinking individuals; and iii) test whether s-EH inhibition and Ep-FAs (including both n3 and n6 Ep-FAs)can effectively decrease basal and LPS-stimulated pro-inflammatory cytokine production in whole blood andperipheral blood monocytes obtained from AH patients.

project_terms:
Ablation;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcohols;Animal Experiments;Animal Model;Anti-Inflammatory Agents;Attenuated;Biological Markers;Blood;Blood specimen;CXCL1 gene;Cirrhosis;Dietary Supplementation;Disease;Disease Progression;Enzymes;Epoxide hydrolase;Epoxy Compounds;Etiology;Evaluation;FAT gene;FDA approved;Fatty Acids;Fatty Liver;Fibrosis;Foundations;Genetic;Glycols;Goals;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis;Hepatocyte;Human;In Vitro;Individual;Infection;Inflammation;Inflammatory;Injury;Kidney;Lipids;Liver;Liver diseases;Lung;Macrophage;Mediating;Mediator;Messenger RNA;Metabolic Diseases;Metabolism;Morbidity - disease rate;Mus;N-3 polyunsaturated fatty acid;Names;Neutrophil Infiltration;Obesity;Organ failure;PPAR gamma;Pathogenesis;Pathology;Patients;Phenotype;Plasma;Play;Prevention;Preventive;Production;Property;Resolution;Role;Severity of illness;Steatohepatitis;Testing;Therapeutic;Transgenic Organisms;Treatment Efficacy;Whole Blood;attenuation;chemokine;cytokine;effective therapy;in vivo;inhibitor;liver injury;monocyte;mortality;neutrophil;non-alcoholic fatty liver disease;novel;novel therapeutic intervention;novel therapeutics;organ regeneration;peripheral blood;pharmacologic;preservation;prevent;receptor;systemic inflammatory response;therapeutic effectiveness;therapeutic evaluation;therapeutic target;therapeutically effective;tissue regeneration

public_health_relevance:
Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis tosteatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity mortality andhealth care costs in the US and worldwide. However there is no FDA-approved therapy for any stage of ALD.The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition at different stages of ALDseverity and to provide a mechanistic foundation for using s-EH inhibition as a novel therapy for alcohol-inducedliver pathology.


application_id: 10814181
project_number: 5R01DE030103-03
project_title: Therapeutic vascularization to support repair of damaged salivary glands
administering_ic: NIDCR
award_notice_date: 2024-03-21
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DE
serial_number: 030103
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
arra_indicator: N
project_abstract:
Project Summary Damage to salivary glands is a devastating condition  identification of therapies topromote regeneration of these important organs is imperative. Great progress is being made inengineering and transplantation of salivary gland epithelium. A major remaining hurdle ingland engineering is the need to establish a functional vasculature which is essential for survivalof any replacement tissue in vivo. In addition to essential support therapeutic angiogenesis alsostimulates healing of non-vascular tissue. This study will characterize methods of promotingvascularization in regenerating salivary gland tissues. Using mice as a pre-clinical model systemwe will evaluate two distinct therapeutic approaches  individually and in combination  topromote vascularization and regeneration of damaged glands. One therapeutic approachinvolves implantation of an exogenous vascular cell milieu as a method to enhance formation offunctional blood vessel networks. The other approach which may be effective when used inconjunction with implanted cells or on its own will involve systemic delivery of a drug withpotential to stimulate angiogenesis. The therapeutic potentials of the of the two approaches willbe evaluated separately and in combination in vivo in mice in a biopsy wound healing model.Cellular and molecular events of vascular assembly associated with each therapy will be definedusing cell culture assays in vitro. For implantation of vascular cells we will use a cell milieu ofstromal vascular fraction derived from adipose (AdSVF). The AdSVF cell milieu has realadvantages as a cell source. It includes many cell types needed to form functional blood vesselnetworks (endothelial pericytes vascular smooth muscle fibroblasts) it reduces inflammationto promote regeneration of parenchymal tissue it is readily available for self-donation andimportantly has proven safe for clinical use. As an adjunct to implanted AdSVF or as astand-alone vascularizing therapeutic we will also test the ability of a systemic pharmacologicagent Tazarotene to stimulate formation of functional vascular networks. Tazarotene is asynthetic retinoid. Its vascular promoting activity is consistent with the action of naturalretinoids including vitamin A and its derivative retinoic acid which are essential for vascularassembly in vivo. This project will identify methods to promote functional vasculature inregenerating salivary glands. Resulting knowledge can be used to enhance success of therapiesaimed at repairing salivary epithelium thereby advancing the field toward developing effectivetherapies for patients suffering from salivary gland damage.

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;Epithelium;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;Pilot Projects;Pre-Clinical Model;Production;Proliferating;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;pharmacologic;repaired;replacement tissue;small molecule;success;therapeutic angiogenesis;wound;wound healing

public_health_relevance:
Project NarrativeLoss of salivary gland function is a devastating condition. Millions of people lose salivary glandfunction from autoimmune disease or cancer radiation treatment and therapies to promotegland repair are needed. Repair of salivary gland tissues requires re-growth of blood vessels thatcan support salivary gland tissue as it heals from damage.


application_id: 10813192
project_number: 5F31DK131920-03
project_title: High fat diet-induced adrenergic dysfunction and resolution of adipose inflammation
administering_ic: NIDDK
award_notice_date: 2024-03-19
opportunity_number: PA-21-052
application_type: 5
activity_code: F31
ic: DK
serial_number: 131920
program_official: BODDIE, THOMAS ARTIS
project_start_date: 2022-04-01
project_end_date: 2025-04-25
study_section: ZDK1-GRB-2(J1)L
contact_pi_person_id: 14522014
contact_pi: PENA CALDERIN, ERNESTO HECTOR
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Excess nutrient consumption promotes systemic and tissue-specific inflammatory responses inhibiting insulinreceptor signaling pathways and prevents glucose uptake. Although specific molecular and cellular mechanismsthat lead to the development of insulin resistance remain unclear chronic inflammation is central to obesity-induced T2D. Diet-induced adipose tissue (AT) expansion with infiltration of classically activated macrophagesand production of pro-inflammatory cytokines perpetuates chronic inflammation and insulin resistance.Therapeutic approaches that directly interrupt innate immune responses are problematic however as they couldlead to immunosuppression and thus have limited therapeutic applicability. We have shown that persistentinflammation in diabetes and obesity is due to a deficiency in the processes that normally resolve inflammation.Nonetheless mechanisms by which obesity induces perturbations in pro-resolving pathways and promote thedevelopment of unmitigated chronic inflammation remains undefined. Physical inactivity contributes to increasedadiposity markers of inflammation chronic disease and premature death while physical activity protects againstthe development of obesity and chronic inflammation independent of reductions in weight. Cellular mechanismsby which physical activity protects against chronic inflammation however remain largely unknown. Recent workhas shown that resolution of inflammation is mediated in part by enzymatic (15-12- 5-lipoxygenase andcyclooxygenases) conversion of polyunsaturated fatty acids into specialized proresolving lipid mediators (SPMs;e.g. resolvins lipoxins maresins and protectins) that act to quell inflammatory signaling. Importantly our laband others have also shown that obese-diabetic mice treated with SPMs display elevated alternatively activatedmacrophages with reduced AT inflammation improved insulin sensitivity and enhanced wound healing capacity.Additionally our lab has shown that high fat diet-induced insulin resistance develops due to elevated pro-inflammatory lipid mediator leukotriene B4 (LTB4) production and that BLT-1 (LTB4 receptor) deficient mice areprotected against diet-induced insulin resistance a paradigm that also persists in atherosclerotic lesions. Thesefindings suggest that imbalanced production of pro-inflammatory and proresolving lipid mediators contribute toobesity-induced insulin resistance. Our preliminary data show that exercise increases AT SPM biosynthesis andis inhibited by short duration high fat diet (HFD) feeding. We also find that HFD inhibits exercise-inducedalternatively activated adipose tissue macrophages (ATM) levels. Interestingly adrenal gland expression ofbiosynthetic enzymes and catecholamine levelswhich our lab has previously shown to stimulate SPMbiosynthesis in macrophagesare reduced following HFD feeding. Thus we hypothesize that HFD-inducedadrenergic dysfunction inhibits the proresolving response to exercise in AT. In pursuit of the scientific questionsherein I will hone my basic laboratory skills learn advanced techniques develop professional skills and networkall of which will propel me towards achieving my goal of becoming an independent investigator in academia.

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

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


application_id: 10813075
project_number: 5R01DA033862-11
administering_ic: NIDA
award_notice_date: 2024-04-24
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DA
serial_number: 033862
program_official: LYNCH, SEAN EDWARD WINTERS
project_start_date: 2012-09-01
project_end_date: 2027-11-30
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: 2024-04-01
project_title:
Examining the Impact of the Twin Epidemics of Methamphetamine and Opioid Use on Overdose Risky Sex and Treatment Engagement among PWUD in Two Rural Appalachian Cohorts

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

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

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


application_id: 10811185
project_number: 3R01CA133429-16S1
project_title: Diversity Supplement Carolina Galeano-Naranjo
administering_ic: NCI
award_notice_date: 2023-07-19
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: CA
serial_number: 133429
suffix: S1
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2009-04-01
project_end_date: 2025-04-30
study_section: Molecular Oncogenesis Study Section[MONC]
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
project_abstract:
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately145000 new cases and 51000 deaths are predicted for the year 2019; and this mortality is predominantly dueto poor responses to available treatment options. A better understanding of the molecular events leading tocancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients.My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases PHLPP(PH domain Leucine-rich-repeats Protein Phosphatase) in inhibiting colon cancer initiation and progression. Wehave made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor aswell as the molecular mechanism underlying PHLPP regulation. The overall objective of this study is to furtherdevelop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supportingcell survival and tumorigenesis. In exciting recent findings we demonstrated that chemotherapy-induced ERstress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulatingeIF2/ATF4-mediated signaling. In addition we found that downregulation of PHLPP promotes mitochondrialfission by regulating Drp1 phosphorylation. Collectively the central hypothesis driving this proposed study is thatPHLPP serves an essential stress sensor in CRC in which cellular stress signals trigger PHLPP degradation topromote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate the molecularmechanism underlying PHLPP-mediated regulation of eIF2/ATF4 signaling. We will determine ifdownregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagyactivation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics;and 3) to define the role of mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis invivo. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes to tumorinitiation and progression in colon cancer. This supplement will allow Ms. Carolina Galeano-Naranjo to receivefurther training in conducting basic and translational cancer research. Her results will assist in determining therole of PHLPP in CRC by regulating mitochondrial activity. She will determine if PHLPP mutations found in CRCpatients interfer with their ability to control Drp1 phosphorylation and mitochondrial fission. Ultimately byproviding mechanistic insights into PHLPP-dependent regulation of stress response our findings will help identifynew treatment options and better predict the effectiveness of chemotherapy agents based on PHLPP status incancer patients.

project_terms:
Automobile Driving;Autophagocytosis;Basic Cancer Research;Cancer Etiology;Cancer Patient;Cell Death Induction;Cell Migration Inhibition function;Cell Proliferation;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemoresistance;Collaborations;Colon Carcinoma;Colorectal Cancer;Development;Disease;Down-Regulation;EIF-2alpha;Effectiveness;Ensure;Epithelial Cells;Equilibrium;Event;Funding;Grant;HK2 gene;Inflammation;Integrins;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Malignant neoplasm of pancreas;Mediating;Metabolic;Metabolism;Mitochondria;Molecular;Mutation;Oncogenic;Organism;PH Domain;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphoric Monoester Hydrolases;Phosphorylation;Physiological;Play;Protein Dephosphorylation;Protein Family;Protein Kinase;Protein phosphatase;Proto-Oncogene Proteins c-akt;Regulation;Resistance;Role;Signal Pathway;Signal Transduction;Stress;Supporting Cell;Testing;Training;Tumor Suppressor Proteins;United States;biological adaptation to stress;cancer cell;cancer initiation;cancer survival;cancer type;cell growth regulation;chemotherapy;coping mechanism;endoplasmic reticulum stress;improved;in vivo;insight;leucine-rich repeat protein;mitochondrial autophagy;mortality;mouse model;multicatalytic endopeptidase complex;novel;protein expression;response;sensor;success;translational cancer research;tumor initiation;tumor metabolism;tumor progression;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE Colorectal cancer mortality is predominantly due to the development of disseminated disease and resistantto conventional chemotherapy. Our study focuses on developing a mechanistic understanding of PHLPP-mediated regulation of cellular stress signaling to circumvent chemoresistance. Results from our studies will helpidentify new treatment options and better predict the effectiveness of chemotherapy agents.


application_id: 10810905
project_number: 1R21EY034674-01A1
project_title: Detailed Molecular Structures of Tear Film Lipid Layer for Improved Treatment of Dry Eye Syndrome
administering_ic: NEI
award_notice_date: 2023-12-13
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: EY
serial_number: 034674
suffix: A1
program_official: MCKIE, GEORGE ANN
project_start_date: 2023-12-01
project_end_date: 2025-11-30
study_section: Special Emphasis Panel[ZRG1 NV-P (81)]
contact_pi_person_id: 16225396
contact_pi: JAEGER, VANCE W
other_pis: BORCHMAN, DOUGLAS
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYDry eye syndrome (DES) afflicts over 7 million Americans. DES can cause chronic and severe symptoms leadingto visual disturbances. DES is caused by instability of the precorneal tear film (PCTF) at the surface of the eye.While it is known that the stability of the PCTF plays a central role in DES there is rigorous debate about whatcauses PCTF instability. The tear film lipid layer (TFLL) is central to the stability of tear films. The TFLL is anextremely thin layer of ordered lipid molecules separating the PCTF from the air. Researchers have proposedseveral functions for the TFLL including but not limited to reducing tear preventing the collapse of the tear layerand providing a layer of defense against pathogens. However it is unclear how changes in TFLL compositionthickness and arrangement induce PCTF instability and thinning. Several competing hypotheses naturally leadto different strategies for treating DES. Stimulation of tear production modulation of glandular function andsupplementation with externally applied lipid solutions are all possible treatment routes. However questionsabout the causes of DES are difficult to answer because of lack of a detailed molecular structure of the TFLL.Because of the TFLLs dynamic nature common experimental techniques are incapable of providing high-resolution structural detail about how molecules arrange in the TFLL at the air-lipid and lipid-water interfaces.Instead researchers use lower resolution methods to probe composition and structure sometimes indirectlythrough model chemical compounds. However these low-resolution techniques provide ambiguous resultsbecause multiple related molecular arrangements can produce the same signal. Thus there is not a one-to-onecorrelation between experimental results and molecular structures. In this study we will generate and validate aphysiochemical computational model of the TFLL which considers the energetics of the system and which willbe used to rationalize experimental observations about TFLL structure function and properties. Recentdevelopments in computational power allow researchers to simulate the motion of up to millions of atoms overtimescales long enough to allow the prediction of physical properties with a method called molecular dynamics.The model begins with a description of the inter- and intramolecular forces acting on the TFLLs components. Avirtual box of atoms is generated with a hypothetical molecular arrangement. Using classical physics forcesbetween molecules are translated into motion of all atoms and simulated snapshots of atomic positions arecollected. Analysis of these snapshots and associated energies allows the calculation of theoretical propertiesthat can be matched to experimental data. A successful model will match experimentally observed behavior andprovide a well-supported hypothetical TFLL structure for researchers to use for further studies. If successful themodel developed in this work can help provide evidence for or against prevailing and competing hypothesesabout the function of the TFLL and the underlying causes of DES. Ultimately the knowledge gained in this studycan be applied to improved design of treatments and therapeutics for DES.

project_terms:
3-Dimensional;Affect;Age Years;Air;Algorithms;American;Behavior;Binding;Biological;Chemical Models;Chemicals;Chronic;Compensation;Computer Models;Consensus;Cornea;Data;Development;Diffusion;Dry Eye Syndromes;Elasticity;Environment;Etiology;Eye;Film;Generations;Goals;Knowledge;Lateral;Lead;Lipids;Measures;Methods;Modeling;Molecular;Molecular Conformation;Molecular Structure;Motion;NMR Spectroscopy;Nature;Nuclear Magnetic Resonance;Oils;Physics;Play;Population;Positioning Attribute;Probability;Production;Property;Publishing;Rationalization;Research Personnel;Resolution;Role;Route;Sampling;Signal Transduction;Spectrum Analysis;Structural Models;Structure;Supplementation;Surface;Surface Tension;Symptoms;System;Techniques;Testing;Therapeutic;Thermodynamics;Thick;Thinness;Translating;Visual;Water;Work;chemical property;density;enthalpy;evaporation;experimental study;eye dryness;fluidity;human old age (65+);improved;macromolecule;meibomian gland;molecular dynamics;molecular modeling;pathogen;physical property;prevent;restraint;simulation;theories;therapy design;virtual

public_health_relevance:
PROJECT NARRATIVEThis project aims to provide a high-resolution description of the tear film lipid layer which is a thin layer of oil-likemolecules that separate tears on the surface of the eye from the ambient air. Physical and chemical propertiesof the tear film lipid layer have been implicated in the development of dry eye syndrome which affects 7 millionAmericans. With an improved high-resolution description of the tear film lipid layer researchers can testcompeting hypotheses about structure properties and function of the lipid layer and its relationship to thedevelopment of dry eye syndrome.


application_id: 10810823
project_number: 5R21AI177008-02
administering_ic: NIAID
award_notice_date: 2024-01-29
opportunity_number: PAR-22-109
application_type: 5
activity_code: R21
ic: AI
serial_number: 177008
program_official: GEZMU, MISRAK
project_start_date: 2023-03-16
project_end_date: 2026-02-28
study_section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH]
contact_pi_person_id: 14497209
contact_pi: ZHANG, HONGBIN
other_pis: NASH, DENIS
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-03-01
project_title:
Developing Statistical Methods on Event History Data Subject to Data Complexities for HIV Disease Progression and Policy Evaluation

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

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

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


application_id: 10810081
project_number: 3R35GM142679-02S1
project_title: Chromatin Regulation of Tissue Regeneration and Stem Cell Function
administering_ic: NIGMS
award_notice_date: 2023-06-27
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: GM
serial_number: 142679
suffix: S1
program_official: PHILLIPS, ANDRE W
project_start_date: 2021-09-01
project_end_date: 2026-06-30
contact_pi_person_id: 10461818
contact_pi: DUNCAN, ELIZABETH MARIE
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Genomic regulators such as transcription factors and chromatin-modifying enzymes work together toinstruct cell fate during developmental processes including both the routine cell turnover that occurs duringhomeostasis and the major tissue replacement and repatterning that occurs during regeneration. One specificgroup of chromatin-modifying complexes whose activity is strongly associated with gene expression is theSet1/MLL family of histone methyltransferases. These enzyme complexes share a core of several essentialsubunits yet each particular enzyme (Set1 MLL1 MLL2 etc.) is functionally non-redundant in multicellularanimals i.e. individual null mutations are lethal. These data and others including some from my laboratoryindicate that each Set1/MLL complex regulates its own distinct set of genes. However many of the molecularand mechanistic details driving this biochemical and functional specificity remain unknown. To uncover the fundamental molecular mechanisms underlying this process my laboratory studies theplanarian model of animal regeneration. Planarians are free-living flatworms with incredible regenerativecapacities. They are also amenable to genetic perturbation through RNAi easily dissociated for single cellanalyses and encode chromatin modifying proteins with strong homology to those of other organisms. Forexample planarian Set1 and MLL1/2 enzymes show strong sequence homology to their mammaliancounterparts and my previous research has shown that loss of either enzyme leads to loss of their conservedhistone modifying activity trimethylation of histone H3 at lysine 4 (H3K4me3). Moreover we find that eachenzyme targets a specific set of genes that correlate with their phenotype after enzyme loss. Specifically lossof MLL1/2 through RNAi of its transcript leads to loss of H3K4me3 at highly conserved cilia genes as well asloss of cilia and ciliated cells. However we do not know how MLL1/2 targets these cilia genes specifically invivo. To begin identifying the molecular and mechanistic basis of this targeting we first need to characterizethe planarian MLL1/2 complex in terms of its biochemical composition and function. Notably the phenotype induced in planarians after RNAi of a core Set1/MLL complex subunit dpy-30may provide an opportunity to uncover the mechanism that distinguishes Set1 from MLL1/2 function in vivo. Totest this idea I have recruited a promising undergraduate student to identify planarian DPY-30 interactingproteins. He will begin by cloning the two planarian versions of DPY-30 with an epitope tag. He will thenexpress these planarian proteins in mammalian cells and ask if they stably interact with mammalian MLL1/2proteins and form a functional histone methyltransferase complex. These studies will inform whether planarianDPY-30 is required MLL1/2 but not Set1 assembly and/or function as a histone methyltransferase complex.This project will also allow Ethan to gain the experience and skills needed to build a career in biomedicalresearch.

project_terms:
Address;Animal Model;Animals;Automobile Driving;Binding;Biochemical;Biological;Biomedical Research;Cells;Chromatin;Cilia;Cloning;Competence;Complex;DNA;Data;Development;Developmental Process;Dissociation;Enzymes;Epitopes;Essential Genes;Family;Functional Regeneration;Gene Activation;Gene Expression;Genes;Genetic;Genetic Transcription;Genome;Genomics;Goals;Heterogeneity;Histone H3;Histones;Homeostasis;Individual;Injury;Knowledge;Laboratories;Laboratory Study;Link;Lysine;MLL gene;MLL2 gene;Mammalian Cell;Methods;Molecular;Multienzyme Complexes;Multipotent Stem Cells;Mus;Natural regeneration;Neurons;Organism;Pattern;Pharmaceutical Preparations;Phenotype;Planarians;Platyhelminths;Play;Pluripotent Stem Cells;Principal Investigator;Process;Proteins;RNA Interference;Recreation;Regenerative capacity;Regulation;Research;Research Personnel;Retina;Role;Sequence Homology;Signal Transduction;Somatic Cell;Specificity;Testing;Time;Tissues;Transcript;Translating;Width;Work;career;cell fate specification;cell type;experience;genomic locus;histone methylation;histone methyltransferase;in vivo;injured;insight;novel;null mutation;overexpression;programs;protein complex;recruit;regenerative;replacement tissue;response;single cell analysis;skills;stem cell function;stem cell population;stem cells;tissue regeneration;tool;transcription factor;undergraduate student

public_health_relevance:
Research in my lab leverages the fundamental protein homology yet remarkable regenerativeand developmental abilities of planarian flatworms to uncover fundamental mechanisms that linkexternal signals to functional changes in gene expression. Our previous data indicated thatchromatin modifying protein MLL1/2 maintains its conserved enzymatic role in planarians and atthe same time revealed novel genomic targets of this enzyme. We have recruited a promisingundergraduate student to test the biochemical homology of the planarian MLL1/2 complex byassessing the ability of planarian MLL1/2 complex subunits to interact with mammalian MLL1/2complex proteins in a functional way.


application_id: 10809677
project_number: 5UT2GM148083-03
project_title: I-RED Southeast XLerator Network
administering_ic: NIGMS
award_notice_date: 2024-03-18
opportunity_number: RFA-GM-22-001
application_type: 5
activity_code: UT2
ic: GM
serial_number: 148083
program_official: ZHOU, YANG
project_start_date: 2023-03-15
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1-IMST-B(51)B]
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryI-RED Southeast XLerator Network powered by XLerateHealth LLC in collaboration with the University ofKentucky as the lead academic partner institution proposes to develop a suite of experience-basedentrepreneurship education products and commercialization education tools to address the needs ofacademic institutions and their faculty researchers innovators and graduate/undergraduate students in theSoutheast IDeA states region. The ultimate aim of these entrepreneurship education and training productsis to foster the translation of promising biomedical discoveries and technologies from research laboratoriesinto the creation of commercial products which both improve human health and promote economic growth.As a result it will significantly enhance commercialization knowledge mature the entrepreneurialecosystem identify more market-ready technologies and patents see more startup entities formed increasedilutive and non-dilutive funding to these entities and accelerate the commercialization of biomedical andhealth tech innovations in the region  with the fundamental goal of positively impacting human health andpatients lives.This team has years of experience working with academic institutions innovators and healthcare startupsin the Southeast IDeA states region (including the previous NIGMS STTR IDeA Regional TechnologyTransfer Accelerator award) developing extensive entrepreneurial educational content and deliveringentrepreneurial training to biomedical innovators aspiring to become entrepreneurs. Key team memberspossess strong and diverse backgrounds that include education and training technology transfer clinicalpractice startup company creation venture capital investing building talent support systems sales andmarketing social media and program and product development among other disciplines. We will createand deploy the most impactful educational products necessary to further advance the translation ofbiomedical technologies being developed by academic researchers to the commercial marketplace.I-RED Southeast XLerator Network will leverage its teams experiences assessing building and workingwith a wide network of highly diverse partners across each state and territory in the Southeast IDeA statesregion with a governance structure to optimize communication and ensure extensive prototype testing andvalidation of unique educational programs and products that will address the needs identified through gapassessment and achieve strong engagement from our regions innovators in those educational programsand products.

project_terms:
Acceleration;Address;Award;Biomedical Technology;Capital;Capital Financing;Collaborations;Communication;Discipline;Economics;Ecosystem;Education;Effectiveness;Ensure;Entrepreneurship;Evaluation;Faculty;Fostering;Fund Raising;Funding;Goals;Growth;Health;Health Technology;Healthcare;Human;Institution;Investments;Kentucky;Knowledge;Laboratory Research;Lead;Legal patent;Licensing;Marketing;Monitor;National Institute of General Medical Sciences;Outcome;Participant;Patients;Phase;Pilot Projects;Positioning Attribute;Process;Program Development;Reporting;Research Personnel;Sales;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Structure;Students;Support System;Talents;Technology;Technology Transfer;Testing;Training;Training and Education;Translations;Universities;Validation;clinical practice;cohort;commercialization;design;experience;improved;innovation;member;new product development;product development;programs;prototype;social media;success;tool;undergraduate student

public_health_relevance:
Project NarrativeThrough this program I-RED Southeast XLerator Network will develop a suite of experience-basedentrepreneurship education products and commercialization education tools to address the needs ofacademic institutions and their faculty researchers innovators and graduate/undergraduate students in theSoutheast IDeA states region. The ultimate aim of these entrepreneurship education and training productsis to foster the translation of promising biomedical discoveries and technologies from research laboratoriesinto the creation of commercial products which both improve human health and promote economic growth.As a result it will significantly enhance commercialization knowledge mature the entrepreneurialecosystem identify more market-ready technologies and patents see more startup entities formed increasedilutive and non-dilutive funding to these entities and accelerate the commercialization of biomedical andhealth tech innovations in the region  with the fundamental goal of positively impacting human health andpatients lives.


application_id: 10809651
project_number: 5R21AA030638-02
project_title: Role of urolithin A in progression of alcohol-associated liver disease
administering_ic: NIAAA
award_notice_date: 2024-02-26
opportunity_number: PA-20-195
application_type: 5
activity_code: R21
ic: AA
serial_number: 030638
program_official: WANG, JOE
project_start_date: 2023-03-15
project_end_date: 2026-02-28
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractExcessive consumption of alcohol is a global problem and is the worlds third largest risk factor for diseases anddisabilities and accounting for 5.9% of all deaths worldwide. Alcohol-associated liver disease (ALD) is aspectrum of disease that starts with steatosis progressing to fibrosis and finally cirrhosis in ~20 to 30% patientsof in chronic excessive alcohol drinkers. However rest of the 70-80% with alcohol use disorders (AUD) patientsmay not progress into severe ALD. Therefore we asked what are factors that potentially prevent AUD patientsto progress in to ALD. The composition of gut microbiota and their metabolites are significantly vary in ALDpatients compared to AUD and healthy subjects and play a critical role in manifesting ALD pathogenesis. Ourpilot studies in mouse of ALD showed that treatment with gut microbial metabolite Urolithin A (UroA) significantlyreduced ALD pathogenesis. UroA treatment decreased EtOH-induced gut permeability hepatic steatosis andhepatitis in chronic chronic+binge ALD mouse models. UroA is a dietary microbial metabolite produced fromellagitannin/ellagic acid-rich diets such as pomegranate walnuts and berries. We postulate that harboring UroA-producing bacteria in healthy or AUD subjects may prevent from developing severe ALD. In this exploratoryproject we will test the hypothesize that microbiota and their metabolites (urolithins) in healthy and AUD withoutALD differ from AUD patients with ALD and presence of UroA-producing bacteria when combined with diets richin EA/ET or with direct supplementation of UroA will protect from ALD progression. To test this hypothesis weproposed two specific aims. In aim 1 we will collect stool samples from healthy AUD and severe ALD patientsand determine their ability to produce UroA in vitro cultures. Next we will generate humanized microbiota mice(HMM) by fecal microbiota transplantation (FMT) of UroA-producing or non-producing stool samples (collectedfrom healthy/AUD/ALD subjects) in to germ free mice. In aim 2 these humanized microbiota mice (UroAproducers vs non-producers) will subjected to chronic+binge (10+1) ALD model and determine extent of ALDdevelopment in these mice upon supplementing with EA. Further we will test whether direct supplementation ofUroA mitigate severe ALD in these humanized microbiota mice. Upon successful completion of these studieswe will determine whether UroA-producing microbiota and/or direct supplementation of UroA provides protectionagainst ALD in humanized microbiota mice. These studies would unravel potential of microbiota dependentpersonalized dietary patterns to control ALD.

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

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


application_id: 10807093
project_number: 5R01DE028916-05
project_title: Biosynthesis structure and function of cell wall in Streptococcus mutans
administering_ic: NIDCR
award_notice_date: 2024-03-27
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: DE
serial_number: 028916
program_official: MCNEALY, TAMARA L
project_start_date: 2020-04-08
project_end_date: 2026-03-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 8869391
contact_pi: KOROTKOVA, NATALIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The cell wall of many species of Lactobacillales consists of multiple peptidoglycan layersdecorated with serotype-specific polysaccharides that are characterized by the presence ofrhamnose. Streptococcus mutans is a key etiological agent of human dental caries and hasalso been implicated in bacteremia and infective endocarditis. Based on the chemical structuresof serotype-specific carbohydrates S. mutans is classified into serotypes c e f and k withapproximately 70-80% of strains found in the oral cavity classified as serotype c. The serotypec-specific carbohydrate (SCC) of S. mutans is composed of a polyrhamnose backbone with -linked glucose side-chains. Although carbohydrate structures have been reported for allS. mutans serotypes our recent insights into the structure of these glycopolymers indicate thatthe functionally important modification glycerol phosphate was overlooked possibly due to itsloss during the purification steps. This new finding justifies a re-examination of the chemicalstructures of serotype-specific carbohydrates. One of the goals of the proposed study is todetermine the molecular structure of SCC isolated from S. mutans using mild non-destructivemethods. Moreover little is known about the multienzyme processes involved in attachment ofthe glucose side-chains to the polyrhamnose backbone of SCC and the function of the glycerolphosphate modification in S. mutans. Our preliminary findings revealed that the glycerolphosphate modification plays important roles in S. mutans morphology autolysis resistance toantimicrobials and biofilm formation. We propose to identify and functionally characterize theenzymes involved in glucose side-chain attachment to polyrhamnose and investigate themolecular mechanisms underlying the functions of glycerol phosphate modification inmorphology autolysis and biofilm formation. To accomplish our goals we will employstreptococcal genetics in vitro enzymology NMR spectroscopy of polysaccharides analyticalchemistry mass spectrometric analysis of phospholipids and various methods of microscopyincluding AFM-based nanomechanics. The cell wall biosynthetic machinery is an historicallypreferred target for the development of novel antimicrobials. In order to validate the pathway ofSCC decoration with glycerol phosphate as a potential drug target we will determine the role ofthis modification in a rat caries model. Successful outcomes will guide future studies of cell wallbiogenesis in other important Gram-positive bacteria and the development of novel strategies totreat S. mutans infections.

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

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


application_id: 10806728
project_number: 3R01AG069909-02S1
project_title: The role of satellite cells in skeletal muscle hypertrophy with aging
administering_ic: NIA
award_notice_date: 2023-03-15
opportunity_number: PA-20-185
application_type: 3
activity_code: R01
ic: AG
serial_number: 069909
suffix: S1
program_official: BOYCE, AMANDA T
project_start_date: 2021-08-15
project_end_date: 2026-04-30
study_section: Cellular Mechanisms in Aging and Development Study Section[CMAD]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryThe loss of skeletal muscle mass with age is of clinical importance because it is associated with increasedmorbidity and mortality as well as a marked deterioration in the quality of life. There is also a heightenedinterest in the identification of cellular and molecular mechanisms responsible for the lack of an anabolicresponse of aged muscle to hypertrophic stimuli. The use of satellite cells to treat loss of skeletal muscle massis considered a promising therapeutic strategy given their stem cell characteristics and essential role in post-natal muscle growth and regeneration. The results of our studies have prompted us to perform mechanisticanalyses of both of the well-known function of satellite cells; fusion to myofibers to provide additional nuclei forhypertrophic growth to other functional consequences of satellite cell expansion that occurs in response tovarious exogenous stimuli such as exercise as the increase in satellite cell abundance in response tomechanical overload far exceeds myonuclear accretion associated with increased myofiber size. We reportedsatellite cells were necessary for optimal long-term hypertrophic growth of skeletal muscle by regulating theextracellular matrix. Activated satellite cells repressed fibroblast collagen production via extracellular vesicle(EV) delivery of miR-206 revealing a previously unrecognized function of satellite cells in addition to providinga mechanism through which satellite cells communicate with other cells within muscle. We now have in vivosingle-cell (sc)RNA-seq evidence from Pax7-tdT reporter mice of a satellite cell intercellular communicationnetwork in which satellite cells communicate with FAPs/fibrogenic cells and endothelial cells duringhypertrophic growth. Aim 1 will test the hypothesis that aging negatively impacts this communication networkinhibiting proper remodeling of the extracellular matrix thereby inhibiting hypertrophy. We have also developeda novel mouse model that allows us to simultaneously deplete satellite cells and label resident myonuclei Aim2 will use this model and single-myonuclear (smn)RNA-seq to characterize age-dependent changes in theresident myonuclear transcriptome and identify mechanisms that enable short term hypertrophy in the absenceof satellite cells in adult mice which is lost in old age. Aim 3 will use an additional newly developed reportermouse that enables specific and stable labeling of satellite cell nuclei to determine how aging alters thesatellite cell-derived myonuclear transcriptome in response to a hypertrophic stimulus. We hypothesize that inaged muscle satellite cell-derived myonuclei have altered transcriptional output that does not promote ahypertrophic response and that impaired fusion of satellite cells or defective satellite cells may negativelyimpact resident myonuclear transcriptional activity contributing to impaired growth. Defining fusion-dependentand -independent roles of satellite cells and age-associated changes that negatively impact muscle adaptabilitywill identify potential new targets to promote skeletal muscle growth in the face of inactivity during aging and inthe face of muscle wasting diseases.

project_terms:
Ablation;Adult;Affect;Age;Aging;Cell Communication;Cell Nucleus;Cells;Characteristics;Chronic;Clinical;Collagen;Communication;Deterioration;Doxycycline;Elderly;Endothelial Cells;Exercise;Extracellular Matrix;Female;Fibroblasts;Fibrosis;Foundations;Gene Expression;Genes;Genetic Transcription;Grant;Growth;Human;Hypertrophy;Immunohistochemistry;Impairment;In Vitro;Label;Mechanics;Messenger RNA;MicroRNAs;Modeling;Molecular;Mononuclear;Morbidity - disease rate;Mus;Muscle;Muscle satellite cell;Muscular Atrophy;Natural regeneration;Output;Phenocopy;Plantaris muscle;Population;Population Dynamics;Process;Production;Quality of life;Reporter;Reporting;Repression;Rodent;Role;Skeletal Muscle;Stimulus;Systemic disease;Tamoxifen;Testing;Therapeutic;Therapeutic Uses;Time;Transcript;Wasting Syndrome;age related;aged;extracellular vesicles;human old age (65+);in vivo;intercellular communication;interest;male;mortality;mouse model;muscle aging;muscle form;muscle hypertrophy;novel;patient population;physical inactivity;postnatal;prevent;progenitor;response;sarcopenia;satellite cell;single-cell RNA sequencing;skeletal muscle growth;skeletal muscle wasting;stem cells;transcriptome;transcriptome sequencing;young adult

public_health_relevance:
NarrativeA decrease in skeletal muscle mass is of clinical importance because it is associated with increased morbidityand mortality as well as a marked deterioration in the quality of life. A broad patient population is affected bysignificant losses in muscle mass including those afflicted by various systemic diseases chronic physicalinactivity and sarcopenia. The purpose of this grant is to better understand the role of skeletal muscle stemcells (satellite cells) in the blunted growth response to exercise in the elderly thereby providing a foundation fortheir therapeutic use to prevent or restore losses in skeletal muscle mass during aging.


application_id: 10806471
project_number: 3P40OD019794-09S1
project_title: Administrative Supplement: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2023-07-13
opportunity_number: PA-20-272
application_type: 3
activity_code: P40
ic: OD
serial_number: 019794
suffix: S1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2023-07-01
project_end_date: 2024-02-29
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYThe Ambystoma Genetic Stock Center (AGSC) is a P40 Research Resource that distributeslaboratory axolotls (Ambystoma mexicanum) to researchers and educators nationally andinternationally. The AGSC houses approximately 880 adults and several thousandlarvae/juveniles in aquatic recirculating systems and static bowls to sustain a captive wildtypebreeding population and a growing number of mutant and transgenic lines. To ensure the healthof axolotls within the AGSC and their reproducibility in biological experiments it is necessary tofollow rigorous husbandry guidelines. The most critical variable in axolotl husbandry is waterquality. Water quality must be extremely high to ensure normal axolotl development growth andreproductive capacity and to eliminate disease risks associated with pathogens. The AGSCmaintains high water quality by ensuring a constant and readably available water supply andrigorous sanitary procedures to ensure the cleanliness of bowls and tanks. Tank and bowlsanitation is a labor-intensive process that is primarily done by hand and to a lesser extentusing an outdated commercial restaurant dishwasher that is rapidly becoming non-functional.This Administrative Supplement will be used to purchase two Calypso - Aquatic Cabinet Washersystems that are designed to efficiently and effectively clean biological agents and associatedbiofilms from aquatic organism tanks and bowls. The addition of these new washer systems willprovide infrastructure that is critically needed to maintain high water quality and sanitaryprocedures increase efficiency of axolotl husbandry and generate healthy and reproducibleaxolotl lines for biomedical researchers.

project_terms:
Administrative Supplement;Adolescent;Adult;Ambystoma;Ambystoma mexicanum;Biological;Biological Products;Biomedical Research;Breeding;Development;Disease;Embryonic Development;Ensure;Generations;Genetic;Growth;Guidelines;Hand;Health;Human;Infrastructure;Interdisciplinary Study;International;Laboratories;Larva;Microbial Biofilms;Modeling;Organ Model;Population;Postembryonic;Procedures;Process;Readability;Reproducibility;Research;Research Personnel;Resources;Restaurants;Sanitation;System;Transgenic Organisms;Translating;Water Supply;aquatic organism;design;disorder risk;experimental study;mutant;organ regeneration;pathogen;reproductive;tissue repair;water quality

public_health_relevance:
PROJECT NARRATIVELiving stock resources are needed for the Mexican axolotl so that investigators can developresearch models and translate biological information that is relevant to human health anddisease. The Mexican axolotl is a primary vertebrate model for organ regeneration tissuerepair and post-embryonic development.


application_id: 10806365
project_number: 3R24OD010435-21S1
project_title: Administrative Supplement: Genome Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2023-06-26
opportunity_number: PA-20-272
application_type: 3
activity_code: R24
ic: OD
serial_number: 010435
suffix: S1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2023-07-01
project_end_date: 2024-02-29
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: SMITH, JERAMIAH JAMES
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYUnder the parent R24 award we are developing fundamental genomic and bioinformaticresources that will better enable studies of the axolotl (Ambystoma mexicanum). Specifically weare pursuing approaches to improve the current A. mexicanum genome assembly and generatenew data sets that characterize epigenetic changes during axolotl tissue regeneration. Toimprove the current genome assembly we need to resolve gaps/errors that are caused bycomplex repetitive and polymorphic regions that largely reflect the introgression and segregationof A. tigrinum (Tiger salamander) DNA into the primary Ambystoma Genetic Stock Centerpopulation. To address this challenge we are performing long read DNA sequencing of axolotl-tiger salamander hybrids and sequencing the genomes of approximately 10 AGSC axolotls.While the long read DNA sequencing approach will resolve assembly gaps/errors wholegenome sequencing of only 10 A. mexicanum will identify some of the moderate to highfrequency single nucleotide polymorphisms segregating within and among individuals in theAGSC leaving many SNPs unidentified and moderate to low frequency SNPs unvalidated. Theimpact of our parent award project would be significantly enhanced if we had a dedicatedMiSeq DNA sequencer to validate a greater number of SNPs. Through targeted sequencing ofseveral hundred AGSC A. mexicanum we will generate data to validate DNA variants that couldpotentially compromise the design and function of molecular probes by members of the A.mexicanum community. MiSeq data will likely prove useful in the management of A. mexicanumstocks in the AGSC and may lead to the discovery of genetic factors that contribute tophenotypic variation including variability within and among A. mexicanum lines. Additionally adedicated DNA sequencer would speed progress in validating antibodies for ChIP-Seq andallow us to rapidly develop a new cutting-edge approach  Cut&Run - to characterizeepigenetic changes during tissue regeneration. The purchase of a high-performance DNAsequencing machine via this administrative supplement request will speed enhance and furtherinnovate resource development to accomplish objectives of the parent R24 award.

project_terms:
Address;Administrative Supplement;Ambystoma;Ambystoma mexicanum;Amphibia;Antibodies;Award;Biological;ChIP-seq;Communities;Complex;DNA;DNA Resequencing;DNA sequencing;Data;Data Set;Dedications;Disease;Embryonic Development;Epigenetic Process;Frequencies;Genetic;Genome;Health;Human;Hybrids;Individual;Modeling;Molecular Probes;Organ Model;Parents;Performance;Phenotype;Population;Postembryonic;R24;Research;Research Personnel;Resource Development;Resources;Running;Salamander;Single Nucleotide Polymorphism;Speed;Tigers;Translating;Variant;bioinformatics resource;design;genome resource;genome sequencing;improved;innovation;member;novel strategies;organ regeneration;segregation;targeted sequencing;tissue regeneration;tissue repair;whole genome

public_health_relevance:
PROJECT NARRATIVELiving stock resources are needed for the Mexican axolotl so that investigators can developresearch models and translate biological information that is relevant to human health anddisease. The Mexican axolotl is a primary vertebrate model for organ regeneration tissuerepair and post-embryonic development.


application_id: 10806167
project_number: 5R25NS130963-02
project_title: UKNeu-PREP: University of Kentucky Neuroscience Postbaccalaureate Research Education Program
administering_ic: NINDS
award_notice_date: 2024-02-16
opportunity_number: RFA-NS-22-035
application_type: 5
activity_code: R25
ic: NS
serial_number: 130963
program_official: MATTHEWS, MARGUERITE
project_start_date: 2023-03-15
project_end_date: 2027-02-28
study_section: ZNS1-SRB-D(21)
contact_pi_person_id: 8201969
contact_pi: GENSEL, JOHN C
other_pis: BRADLEY, LUKE H
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 SummaryNationally underrepresented minorities (e.g. first-generation low income women people of color and peoplewith disabilities) significantly and consistently lag behind non-underrepresented peers in earning life sciencedoctorate degrees. While the foundation for the development of biomedical Ph.D. and MD/Ph.D. graduatesprimarily focuses on the recruitment of younger students gaps in the Ph.D. or MD/Ph.D. pipeline still existswith underrepresented populations due to limited role models expectations and resources to pursue excep-tional doctoral training. Nationally the step between undergraduate and graduate school is often a barrier inthe biomedical doctoral degree pipeline. This barrier is exacerbated by limited access to substantive biomedi-cal research opportunities to prepare for graduate school. To address this critical need in our region andbeyond the University of Kentucky (UK) Neuroscience - Postbaccalaureate Research Education Program(UKNeu- PREP) is uniquely positioned to provide access to an extensive biomedical research experience inneuroscience while preparing program Participants through educational and professional development oppor-tunities to acquire the knowledge research experience communication skills and confidence to successfullynavigate the admissions process into a strong neuroscience graduate program. UKNeu-PREP will leverageexisting state regional and national networks to recruit Participants to become integrated into campus studentsupports active research programs and pipeline programs. Existing pipeline programs include our associatedT32 training program Neurobiology of CNS Injury the Department of Neuroscience UK START (STEMThrough Authentic Research and Training) and the Spinal Cord and Brain Injury Research Center (SCo-BIRC)- African American Research Training Scholars (AARTS) programs. Collectively UKNeu-PREP will trainParticipants to be lifelong career scientists while creating representational diversity at all levels. UKNeu-PREPwill contribute to innovation and excellence in research environments and strengthen the entire research train-ing enterprise.

project_terms:
Address;Admission activity;African American;American;Appalachian Region;Appointment;Biological Sciences;Biomedical Research;Communication;Communities;Degree Completion;Development;Disabled Persons;Disadvantaged;Discipline;Doctor of Philosophy;Doctor's Degree;Education;Educational process of instructing;Educational workshop;Electronic Mail;Employment;Enrollment;Ensure;Environment;Exposure to;First Generation College Students;Foundations;Generations;Goals;Health;Individual;Institution;Kentucky;Knowledge;Knowledge acquisition;Letters;Low income;Medicine;Mentors;Minority;Mission;Modeling;Neurobiology;Neurosciences;Neurosciences Research;Outcome;Output;Participant;Pathway interactions;Patient Recruitments;Population;Positioning Attribute;Postbaccalaureate;Postdoctoral Fellow;Preparation;Process;Publications;Qualifying;Recruitment Activity;Research;Research Training;Resources;STEM career;Scholars Program;Schools;Science;Scientist;Solid;Source;Students;Surveys;Talents;Telephone;Training;Training Programs;Training and Infrastructure;Underrepresented Minority;Underrepresented Populations;Underrepresented Students;Universities;Videoconferencing;Woman;Work;career;central nervous system injury;disadvantaged background;economic disparity;education research;empowerment;ethnic minority;expectation;experience;graduate school;graduate school preparation;graduate student;health care disparity;higher education;improved;innovation;meetings;peer;people of color;programs;racial minority population;recruit;role model;skills;social;social media;spinal cord and brain injury;stem;success;symposium;technological innovation;undergraduate student;university student

public_health_relevance:
Project NarrativeThe goal of the University of Kentucky Neuroscience Postbaccalaureate Research Education Program(UKNeu-PREP) is to serve individuals from underrepresented and disadvantaged backgrounds from under-graduate institutions without substantive research opportunities. The realization of this mission is the develop-ment of a diverse pool of well-trained postbaccalaureate participants that transition into strong neuroscienceand research-focused higher degree doctoral programs. A diverse scientific community and workforce are vitalfor increasing the quality of higher education medicine (including reducing health care disparities) scientificresearch and technological innovation to solve health-related problems and challenges.


application_id: 10805353
project_number: 5T35ES014559-18
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2024-02-14
opportunity_number: PA-20-162
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2021-08-13
project_end_date: 2027-02-28
study_section: ZES1-VSM-S(T)
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: CAVE, MATTHEW C;CONKLIN, DANIEL JOSEPH
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract:This proposal is a competing renewal application for a T35 short term medical student summer trainingprogram in environmental health science research that has been funded by NIEHS for 15 years. The SpecificAims are: 1) To provide hands-on training in basic and clinical environmental health-based research to medicalstudents in a structured mentored environment; 2) To provide an interactive educational experience thatintroduces medical students to the fundamental skills necessary for basic translational and clinicalEnvironmental Health Sciences-based research. The Distinction in Research Track (DIR) a feature added inthe previous award period enhances training for our students to function as environmental health sciencesspecialists in an academic health center setting. This NIEHS T35 training program encourages students toparticipate in the DIR for a continued longitudinal research experience in the 2nd  4th years of medical trainingallowing them to develop research-oriented skills to complete a clinical or translational research project in thethird/fourth years. Publication of peer-reviewed articles as some trainees have achieved as well as thestrength of residency training and first permanent position as physician-scientists are tracked as outcomes.The program will support training of 8 second year medical students in environmental health sciences researchtopics related to chemical exposure induced chronic diseases including diabetes non-alcoholic fatty liverdisease obesity cancer and hormonal regulation of metabolism. UofL medical students in the top half of thefirst year class choose from research projects submitted by 23 mentors in the Schools of Medicine and PublicHealth (ranking them 1-5 for interest). Trainees to be appointed to the T35 training grant are selected after in-person meetings between trainees and mentors to assure `fit'. A successful effort has been made to recruitstudents from underrepresented minorities and disadvantaged backgrounds. During the 11-week summertraining students work with mentors on their research project in clinical or laboratory settings and completetraining in the Responsible Conduct of Research (topics include: reproducibility fabrication and falsification ofdata plagiarism managing scientific data publication practices mentorship responsible authorshipstewardship conflict of interest). Trainees working with human subjects complete human subject and IRBtraining prior to beginning their research. Trainees who use vertebrate animals in mentors' labs complete andpass IACUC training courses. All trainees will attend a weekly Environmental Health Sciences Conferencedesigned to introduce clinical and translational research in environmental health sciences to T35 trainees. Theconference culminates with each Trainee presenting his/her research project to peers and mentors. Traineesalso present the results of their research as posters with peers at a School of Medicine week-long researchcelebration that includes nationally recognized physician-scientists as keynote speakers. Poster contestWinners are eligible to attend the National Student Research Forum the following Spring.

project_terms:
Authorship;Award;Chemical Exposure;Chronic Disease;Clinical;Clinical Research;Conflict of Interest;Data;Diabetes Mellitus;Education;Eligibility Determination;Environment;Environmental Health;Funding;Grant;Health;IACUC;Institutional Review Boards;Laboratories;Malignant Neoplasms;Medical;Medical Students;Mentors;Mentorship;Metabolism;National Institute of Environmental Health Sciences;Obesity;Outcome;Peer Review;Persons;Physicians;Plagiarism;Positioning Attribute;Public Health;Publications;Reproducibility;Research;Research Project Grants;Residencies;Scientist;Specialist;Structure;Student recruitment;Students;Training;Training Programs;Training Support;Translational Research;Vertebrates;Work;design;disadvantaged background;experience;fabrication;health science research;hormone regulation;human subject;interest;medical schools;meetings;non-alcoholic fatty liver disease;peer;posters;programs;responsible research conduct;skills;summer student;symposium;underrepresented minority student

public_health_relevance:
NarrativeThis NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is to request annual supportfor 8 medical student trainees for a 10 week training experience for the next 5 years. The overarching scientifictheme of research that links our faculty to this T35 Training Grant is the common interest of the faculty inresearch training of medical students in our laboratories in elucidating the health outcomes of exposure ofnormal and obese individuals to various environmental chemicals. In addition we will use the T35 TrainingGrant to entice our medical students into our Distinction in Research Track designed to allow students topursue research interests throughout the years 2-4 of medical school curriculum with an eye toward building apipeline of diverse translational clinician-researchers in the future.


application_id: 10804728
project_number: 5R01DK131442-03
project_title: The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation
administering_ic: NIDDK
award_notice_date: 2025-04-16
opportunity_number: PA-20-185
application_type: 5
activity_code: R01
ic: DK
serial_number: 131442
program_official: GARCIA, MARTHA
project_start_date: 2022-06-01
project_end_date: 2028-03-31
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 11629370
contact_pi: DENG, ZHONG-BIN
other_pis: Not Applicable
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
There is an increasing evidence that demonstrates a critical pathogenic role for the gut-liver axis in thedevelopment of nonalcoholic fatty liver diseases (NAFLD). Gut-derived endotoxin leakiness is increased underpathological conditions including high fat diet (HFD) consumption. Gut fucosylation is a key force in maintaininga homeostatic relationship between the gut and its microbiota. Nevertheless it is unclear how host fucosylationmachinery contributes to obesity-associated intestinal barrier function microbial translocation and inflammation.Glycosphingolipids (GSLs) are major constituents of enterocytes and consist of glycans conjugated to a lipid(ceramide) core. Ceramide is at the center of sphingolipid metabolism and is hydrolyzed to generate sphingosineand fatty acid by ceramidases including neutral ceramidase (NcDase). However whether gut NcDasecontributes to intestinal fucosylation in NAFLD is unclear. We found that deletion of intestinal epithelial cells(IECs) NcDase induced marked upregulation of intestinal fucosylation in response to HFD exposure. Ourpreliminary studies further demonstrated that HFD-fed NcDase-/- mice have increases in intestinal AhR activityIL-22 secretion and the production of fucosylated gangliosides (fucosyl-GM1). We also found that fucosyl-GM1can bind to DC-SIGN a C-type lectin expressed in hepatic macrophages and can induce anti-inflammatory M2macrophage. This has led to the central hypothesis that gut NcDase regulates the intestinal fucosylationand subsequent barrier function via IEC AhR signal; and that IECs NcDase-derived fucosylatedglycosphingolipids induce hepatic macrophage polarization via fucosyl-GM1/DC-SIGN pathway andprevent the development of NAFLD. Importantly the proposal also pursues translational studies that examinethe efficacy of prebiotic 2-FL feeding and fucosyl-GM1 treatment targeted at intestinal fucosylation and hepaticinflammatory macrophages in mitigating gut-liver axis changes. Following specific aims will be carried out: Aim1: Determine the impact of NcDase on the gut fucosylation and the effects of this impact on intestinal barrierintegrity. We will determine the impact of NcDase-related gut microbiota on the gut fucosylaton and barrierfunction. Aim 2: Determine whether NcDase regulation of IEC AhR contributes to gut fucosylation via microbialmetabolite in response to HFD exposure. Aim3: Determine whether IEC NcDase-derived fucosylatedgangliosides contribute to the induction of liver tolerogenic macrophages and evaluate the efficacy offucosylation-based therapeutic interventions in NAFLD. Our studies on the NcDase-mediated gut fucosylationand prebiotic intervention will likely bring new mechanistic understanding and identify new therapeutic targetsfor the prevention and treatment of NAFLD.

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

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


application_id: 10804637
project_number: 5P20GM130456-05
project_title: Developing immunotherapeutic nanoparticles for spinal cord injury
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9
subproject_number: 6052
contact_pi_person_id: 14321924
contact_pi: PARK, JONGHYUCK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Traumatic spinal cord injury (SCI) leads to primary injury followed by secondary injuries including inflammation which create an inhibitory environment. Regeneration is limited due to additional tissue damages and an inhibitory environment leading to various neurological deficits. The goal of this proposal is to develop a non-invasive acute intervention with the goal of modulating inflammatory responses to reprogram an inhibitory environment after SCI. Particularly the SCI demographic shifts toward a more equal balance among males and females indicating that improved therapeutics are needed since the difference in physiological factors between sexes play important roles in pharmacological treatments and functional recovery after SCI. In this study Poly(lactide-co-glycolide) (PLG)-based multiple nanoparticle (NP) formulations will be designed with various physicochemical factors to identity sex-specific key functionality of NPs to reprogram inflammation thereby facilitating functional recovery in females and males respectively after SCI. Specific aim 1 will investigate NP-induced innate cells modulation following SCI to identify sex-specific key properties of NPs. The distinct physicochemical properties of NPs will differently limit inflammation after SCI. Specific aim 2 will assess NPs-mediated long-term dynamic responses in the spinal cord and their effects on anatomical and functional recovery in both sexes after SCI. Intravenously (IV) administered NPs will bind to pro-inflammatory subsets of immune populations and direct their trafficking to the spleen. NP-positive innate cells within the injured tissues will lead to a sustained response facilitating an environment that improves recovery after SCI. Successful completion of proposed aims will provide efficient sex-specific NP designs to maximize functional recovery after SCI. In addition NPs are made of FDA-approved material that enables NPs to be administered in triage or on site to patients diagnosed with SCI without direct intervention into the spinal cord. This study will provide a potentially practical therapy for the entire SCI population.

project_terms:
Acute;Anatomy;Binding;Cells;Centers of Research Excellence;Clinical Trials;Diagnosis;Environment;Equilibrium;FDA approved;Female;Formulation;Glycolic-Lactic Acid Polyester;Goals;Hospitals;Immune;Immunotherapeutic agent;Impairment;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Intravenous;Mediating;Natural regeneration;Neurologic Deficit;Patients;Pharmacologic Substance;Pharmacological Treatment;Physiological;Play;Population;Property;Quality of life;Recovery;Recovery of Function;Research;Role;Site;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Spleen;Staging;Therapeutic;Tissues;Triage;acute care;design;improved;inflammatory modulation;injured;innovation;intravenous administration;loss of function;male;nanoparticle;programs;response;severe injury;sex;sexual identity;trafficking

public_health_relevance:
Spinal cord injury (SCI) severely impairs the quality of life for patients causing permanent loss of function below the injury. The proposed nanoparticle-mediated strategy will provide a non-invasive acute care platform that can be given immediately intravenously in the pre-hospital environment. Successful completion of the proposed studies will have the potential to develop an over-the-counter transformational platform that can lead to fast-track staging of clinical trials for SCI patients.


application_id: 10804632
project_number: 5P20GM130456-05
project_title: Computational Core
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9
subproject_number: 6049
contact_pi_person_id: 6614980
contact_pi: ZHAN, CHANG-GUO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  COMPUTATIONAL COREWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Within this context the CPRI Computational Core directed by Dr. Chang-Guo Zhan willleverage unique computational expertise commercial and in-house software/methods and UKs formidablecomputational processing network to support a range of computational services to advance COBRE project andpilot objectives. The Core will provide services individually tailored to project/pilot needs that facilitate thedevelopment of new hypotheses/models and streamline the prioritization of experimental studies. Specificallythe Core will enable molecular modeling/simulation of macromolecular targets and target-ligand complexesADMET prediction studies structure-based virtual screening for ligand discovery de novo ligand design andartificial intelligence-based methods. This suite of services has been strategically designed to integrate with andcomplement the support provided by the CPRI Translational Core and the CPRI-affiliated COBRE for MolecularMedicine Organic Synthesis Core. Together CPRIs corresponding fully integrated suite of research supportcapabilities and expertise will accelerate innovative preclinical translational research and facilitate juniorinvestigator career development.

project_terms:
Acceleration;Address;Artificial Intelligence;Basic Science;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Complement;Complex;Computer Hardware;Computer software;Computing Methodologies;Consultations;DNA;Data Analyses;Development;Devices;Diffusion;Disease;Doctor of Philosophy;Excretory function;Faculty;Goals;Gold;Health;Individual;Infrastructure;Kentucky;Lead;Leadership;Ligands;Macromolecular Complexes;Mentors;Mentorship;Metabolism;Methods;Modeling;Molecular;Molecular Medicine;Organic Synthesis;Pharmacologic Substance;Process;Proteins;Protocols documentation;Research;Research Design;Research Personnel;Research Support;Resources;Science;Scientist;Services;Structure;Techniques;Toxic effect;Training;Translational Research;Universities;Validation;absorption;career development;clinical application;design;experimental study;faculty research;innovation;intermolecular interaction;models and simulation;molecular dynamics;molecular modeling;multidisciplinary;nanoparticle;particle;pre-clinical;prevent;primary outcome;protein complex;research faculty;self assembly;simulation;stem;synergism;tool;virtual screening


application_id: 10804630
project_number: 5P20GM130456-05
project_title: Translational Core
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9
subproject_number: 6048
contact_pi_person_id: 8227789
contact_pi: LEGGAS, MARKOS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  TRANSLATIONAL COREWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Within this context the CPRI Translational Core will provide key infrastructure and expertiseto support experimental studies central to probe/lead/materials discovery. Under the co-direction of Drs. MarkosLeggas and Jon Thorson the Core will support assay design development validation and implementation; pilotscreening campaigns; a suite of in vitro absorption distribution metabolism excretion and toxicity (ADMET)assays; and first in animal ADMET/pharmacokinetics (PK) studies. Support in the Core will be tailored towardspecific COBRE project/pilot needs and screening services will also leverage CPRI-exclusive compoundcollections (both natural products and synthetics). The Cores services have been strategically designed tointegrate with and complement the support provided by the CPRI Computational Core and the CPRI-affiliatedCOBRE for Molecular Medicine Organic Synthesis Core. Together CPRIs corresponding fully integratedresearch support capabilities and expertise will accelerate innovative translatable transdisciplinary researchand facilitate junior investigator career development.

project_terms:
Acceleration;Address;Adhesions;Animals;Basic Science;Biological Assay;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Collection;Complement;Consultations;Data Analyses;Dedications;Development;Devices;Disease;Doctor of Philosophy;Drug Kinetics;Excretory function;Faculty;Goals;Health;In Vitro;Infrastructure;Kentucky;Lead;Leadership;Libraries;Mentors;Mentorship;Metabolism;Methods;Microbial Biofilms;Modeling;Molecular Medicine;Natural Products;Organic Synthesis;Pharmacologic Substance;Reporter;Research;Research Design;Research Personnel;Research Support;Resources;Science;Scientist;Services;Toxic effect;Translational Research;Type IV Secretion System Pathway;Universities;Validation;absorption;antimicrobial;career development;clinical application;cytotoxicity;design;experimental study;faculty research;immunoregulation;innovation;instrumentation;multidisciplinary;pre-clinical;prevent;primary outcome;research faculty;screening;screening services;stem;synergism;tool;transcription factor


application_id: 10804629
project_number: 5P20GM130456-05
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
project_start_date: 2020-03-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9
subproject_number: 6047
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT  ADMINISTRATIVE CORE We propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Research and Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary center focused on translational chemical biology [the nexus of chemical biology (the application of chemical biology principles to develop validated probe/models to advance our understanding of biology) and pharmaceutical science (the application of pharmaceutical principles to advance leads/materials/devices that address unmet clinical needs)]. The COBRE will leverage and develop unique translational chemical biology research support infrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedical research probe/tool/model/materials development and validation and the early advancement of potential translatable assets. Within this context the CPRI Administrative Core will support center communication coordination oversight and integration of all COBRE operations activities projects pilots and research support cores. The Core will provide fiscal management and resource oversight overall coordination of mentoring and career development activities resource allocation and program evaluation to ensure program effectiveness. The Administrative Core will also facilitate interactions with related UK programs and centers to foster synergy and coordination of resources. The Core will facilitate the Centers engagement of junior faculty researchers and mentors from UK Colleges (Agriculture Food & Environment; Arts and Sciences; Engineering; Medicine; Pharmacy and others) to create a vibrant center that seamlessly integrates resources personnel and knowledge across disciplinary boundaries and fosters scientific innovation and career development.

project_terms:
Address;Agriculture;Arts;Biological;Biology;Biomedical Research;Cancer Center;Cardiovascular Diseases;Career Mobility;Centers of Research Excellence;Chemicals;Clinical;Clinical Sciences;Communication;Decision Making;Development;Development Plans;Devices;Discipline;Disease;Education;Engineering;Ensure;Environment;Evaluation;Faculty;Food;Fostering;Goals;Health;Human Resources;Infrastructure;Institution;Kentucky;Knowledge;Leadership;Medicine;Mentors;Mentorship;Modeling;Molecular Medicine;Obesity;Oral;Outcome;Pharmacologic Substance;Pharmacy facility;Process;Program Effectiveness;Program Evaluation;Research;Research Personnel;Research Priority;Research Support;Resource Allocation;Resource Sharing;Resources;Science;Structure;Systemic disease;Translational Research;Translations;Universities;Validation;career;career development;clinical application;clinical center;college;faculty research;improved;innovation;interdisciplinary collaboration;multidisciplinary;operation;outreach;prevent;primary outcome;programs;stem;success;supportive environment;synergism;tool;tumor metabolism


application_id: 10804628
project_number: 5P20GM130456-05
project_title: Center of Biomedical Research Excellence in Pharmaceutical Research and Innovation
administering_ic: NIGMS
award_notice_date: 2024-02-28
opportunity_number: PAR-18-266
application_type: 5
activity_code: P20
ic: GM
serial_number: 130456
program_official: FRINCU, CRINA
project_start_date: 2020-03-01
project_end_date: 2025-07-31
study_section: ZGM1-RCB-9(C1)
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT - OVERALLWe propose to establish a Center of Biomedical Research Excellence (COBRE) in Pharmaceutical Researchand Innovation at the University of Kentucky (UK). CPRI will serve as a comprehensive multidisciplinary centerfocused on translational chemical biology [the nexus of chemical biology (the application of chemical biologyprinciples to develop validated probe/models to advance our understanding of biology) and pharmaceuticalscience (the application of pharmaceutical principles to advance leads/materials/devices that address unmetclinical needs)]. The COBRE will leverage and develop unique translational chemical biology research supportinfrastructure/expertise to facilitate junior faculty mentorship and career development innovative biomedicalresearch probe/tool/model/materials development and validation and the early advancement of potentialtranslatable assets. Key COBRE infrastructure to be developed and implemented in Phase I includes the CPRIAdministrative Core and two research support cores (the Translational Core and the Computational Core) andthe COBRE will also further develop and leverage the COBRE for Molecular Medicines Organic Synthesis Coreto support CPRI junior faculty projects/pilots. CPRI will initially support four outstanding junior investigatorsworking in three therapeutic areas (cancer infectious disease and cardiovascular disease). Our overarching hypothesis is that CPRIs translational chemical biology focus presents a distinctly uniqueUK platform to: i) engage integrate and mentor junior faculty from a broad range of fundamental applied andclinical disciplines; ii) facilitate the development of new impactful probes/tools/models and advance innovativetransdisciplinary research; and iii) bridge the gap between basic academic research discoveries andcommercial/clinical application via education mentorship and key support infrastructure. CPRIs distinct focuson translational chemical biology and early translation fills a notable preclinical research gap for many of UKsexceptional research centers strategically focused on understanding treating and preventing the major diseasesthat contribute to Kentuckys disproportionate health challenges. Anticipated COBRE outcomes include anincrease in the number and diversity of UK junior faculty engaged in translational chemical biology research andbetter-prepared to develop and employ innovative biomedical probes/tools/models/materials new sustainableUK translational chemical biology research support infrastructure and capabilities an increase in the number ofUK junior faculty with independent research funding and a boost in the number potentially translatable UKpreclinical assets.

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

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


application_id: 10803764
project_number: 1R01ES033531-01A1
project_title: Vascular Toxicity of Benzene
administering_ic: NIEHS
award_notice_date: 2024-02-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: ES
serial_number: 033531
suffix: A1
program_official: SCHUG, THADDEUS
project_start_date: 2024-02-21
project_end_date: 2028-11-30
study_section: Environmental Determinants of Disease Study Section [EDD]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Abstract:Benzene is a ubiquitous environmental pollutant. Natural sources of benzene include gasemissions from volcanos and forest fire. Benzene is also one of the top 20 chemicals generatedby industrial sources in the United States. While levels of benzene in the ambient air are usuallyin low ppb range amount of benzene in automobile exhaust and tobacco smoke can exceed 50ppm and occupational exposure to benzene can be as high as several hundred ppm. Peopleliving near hazardous waste sites gasoline refineries petrochemical industries and gasolinefueling stations may also have high exposure to benzene. Emerging data suggest that benzenecan exert cardiovascular toxicity. Our preliminary studies show that exposure to benzeneexacerbates atherosclerosis the underlying cause of most cardiovascular disease and stroke. Invitro studies show that benzene metabolite tt-muconaldehyde induces endothelial activation(expression of adhesion molecules leukocyte adhesion and their trans-endothelial migration andendothelial cell apoptosis). Using RNA-seq approach we identified several molecular targets(eNOS SOD1 HO-1 COX-2 ATF3 etc.) by which benzene and its metabolites can exert adverseeffects on endothelial functions. We also observed that heat shock proteins HSPA1A andHSPA1B induced by benzene exposure could play a protective role in benzene-inducedendothelial dysfunction and atherosclerosis. Based on these observations we hypothesize thatHSPA1A and HSPA1B prevent benzene-induced exacerbation of atherogenesis by inhibitingvascular inflammation and injury. To test this hypothesis we propose two specific aims: Aim 1will examine how HSPA1A and HSPA1B affect benzene-induced endothelial functions (vascularrelaxation leukocyte rolling and adhesion to vascular endothelium apoptosis) and Aim 2 willexamine how endothelial cell specific overexpression of HSPA1A and HSPA1B affects benzene-induced atherosclerosis (lesion size composition and nature). Successful completion of thisproject will establish a mechanistically validated model of benzene-induced endothelialdysfunction and atherosclerosis. This will provide a strong rationale to examine the association ofbenzene exposure with vascular dysfunctions and atherosclerosis in humans.

project_terms:
Adhesions;Adverse effects;Affect;Air;Air Pollution;Aorta;Apoptosis;Arterial Fatty Streak;Atherosclerosis;Automobile Exhaust;Benzene;Benzene Exposure;Benzoquinones;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Cell Adhesion Molecules;Cell Physiology;Cells;Cessation of life;Chemicals;Cytoskeleton;Data;Deposition;Disease;Dose;Dyslipidemias;Endothelial Cells;Endothelium;Environmental Pollutants;Environmental Pollution;Evaluation;Exposure to;Failure;Fibrosis;Foam Cells;Gases;Gasoline;Hazardous Waste Sites;Health;Heat shock proteins;Hematopoietic;Human;Hydroquinones;In Vitro;Individual;Industrialization;Industry;Inflammation;Inflammation Mediators;Inflammatory;Innate Immune Response;Insulin Resistance;Knockout Mice;Lesion;Leukocyte Rolling;Leukocytes;Lipid-Laden Macrophage;Lipoproteins;Low Density Lipoprotein Receptor;Low-Density Lipoproteins;Matrix Metalloproteinases;Mediating;Metals;Modeling;Molecular;Molecular Chaperones;Molecular Target;Mus;Myocardial Ischemia;Natural Source;Nature;Necrosis;Non-Insulin-Dependent Diabetes Mellitus;Occupational Exposure;Ozone;PTGS2 gene;Particulate Matter;Persons;Petroleum;Play;Process;Protein Overexpression;Proteins;Rattus;Relaxation;Role;Rupture;Small Interfering RNA;Smooth Muscle Myocytes;Source;Stimulus;Stroke;Structure;Testing;Time;Tobacco smoke;Toxic effect;Toxin;Trichloroethylene;United States;Vascular Diseases;Vascular Endothelium;activating transcription factor 3;air filter;atherogenesis;chronic inflammatory disease;cytokine;drinking water;endothelial dysfunction;forest fires;high efficiency particulate air filter;immunotoxicity;leukemia;migration;overexpression;pollutant;premature;prevent;protein expression;protein folding;recruit;response;sex;superfund site;superoxide dismutase 1;transcriptome sequencing;vascular inflammation;vascular injury;volatile organic compound;volcano;western diet

public_health_relevance:
Narrative: Benzene is a ubiquitous environmental pollutant and a known hematopoietic toxin butlittle is known about the effect of benzene exposure on cardiovascular disease. The proposedstudy will examine the effect of benzene exposure on atherosclerosis the underlying cause ofmost cardiovascular disease and stroke and delineate the associated molecular mechanisms.


application_id: 10802728
project_number: 1R01CA278941-01A1
administering_ic: NCI
award_notice_date: 2024-03-08
opportunity_number: PAR-21-294
application_type: 1
activity_code: R01
ic: CA
serial_number: 278941
suffix: A1
program_official: WANG, YISONG
project_start_date: 2024-03-08
project_end_date: 2029-02-28
study_section: Special Emphasis Panel[ZRG1 TIR-W (01)]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: GUO, HAIXUN
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Understanding Pancreatic Cancer Immune Microenvironment and Treatment Response through Integrating in vivo Imaging with Immunophenotyping

project_abstract:
Project Summary Although cancer immunotherapy has been proclaimed a breakthrough in many types of cancer pancreaticductal adenocarcinoma (PDAC) responds poorly to immune checkpoint blockade (ICB) therapy. PDAC isclassified as immunologically cold tumor with pronounced presence of immunosuppressive myeloid cells.Therefore developing novel approaches to reprogram the PDAC tumor immune microenvironment (TiME) andpromoting immunotherapeutic efficacy are drastically needed. A key knowledge gap in understanding the PDAC TiME is a lack of tools to visualize and monitor theseimmunosuppressive myeloid cells during tumor progression and treatment. Molecular imaging approachesprovide such an opportunity through a specific cell-tracking strategy or targeting of surface molecules expressedon immune cells. In the preliminary studies we demonstrated that yeast-derived whole b-glucan particles (WGP)predominately traffic to the pancreas and incite massive infiltration of myeloid cells with trained immunityphenotype leading to a reduction in PDAC tumor progression and prolonged survival. Trained immunity isdefined as innate immune responses that can adapt and develop a memory-like phenotype of previous infectionor vaccination. Despite these successes mice treated with WGP eventually died even in combination with anti-PD-L1 therapy. The overarching goal of this proposal is to develop an integrated in vivo imaging withimmunophenotyping approach to understand PDAC immune evasion mechanisms and develop more efficacioustherapy for PDAC. Three Aims are proposed. Aim 1 will determine if induction of trained immunity reprogramspancreas myeloid cells thus reshaping their function in the PDAC TiME. We will utilize a radiolabeled WGP andan anti-CD11b probe to track WGP trafficking and influx of myeloid cells in the pancreas. We will also test thehypothesis that the abundance of pancreas tissue resident macrophages (TRMs) as measured by the lymphaticvessel endothelial hyaluronan receptor (LYVE-1) probe is a predictive marker for PDAC immune evasion andprogression. Aim 2 will determine whether combining trained immunity with anti-CD47 and/or anti-EGFR mAbtherapy promotes myeloid cell phagocytic/tumoricidal activity to maximize innate antitumor immunity. Targetedin vivo imaging will be used to monitor phagocytosis and EGFR levels within the PDAC TiME. Aim 3 willdetermine the ability of induction of trained immunity to recruit and stimulate adaptive T cells in the pancreas.We will also determine whether combining induction of trained immunity with anti-CD47 mAb therapy will furtherpotentiate anti-PD-L1 therapeutic efficacy in PADC. Immuno-imaging will be used to track CD8+ T cell infiltrationfunction and PD-L1 expression within the PDAC TiME. The successful completion of this proposal will likelyprovide a novel insight into understanding the mechanisms of PDAC immune evasion and treatment responseand resistance.

project_terms:
Anti-CD47;Biological Assay;CD44 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Control;Cancer Model;Cells;Cessation of life;Classification;Clinical;Clinical Trials;Cytometry;Desmoplastic;Diagnosis;Disease;Eligibility Determination;Endothelium;Epidermal Growth Factor Receptor;Epigenetic Process;Excision;Exposure to;Glucans;Goals;Granzyme;ITGAM gene;Immune;Immune Evasion;Immune response;Immunity;Immunologic Memory;Immunologics;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Infection;Infiltration;Innate Immune Response;Investigation;KPC model;Knowledge;Label;Liver;Macrophage;Malignant Neoplasms;Malignant neoplasm of pancreas;Measures;Mediating;Memory;Metabolic;Modeling;Monitor;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mus;Myeloid Cells;Myeloid-derived suppressor cells;Neoplasm Metastasis;Organ;Pancreas;Pancreatic Ductal Adenocarcinoma;Paper;Particulate;Patients;Phagocytes;Phagocytosis;Phase;Phenotype;Publishing;Radiolabeled;Reporting;Research;Shapes;Signal Transduction;Solid;Solid Neoplasm;Stimulus;Surface;Survival Rate;Symptoms;T cell infiltration;T-Lymphocyte;Testing;Time;Tissues;Training;Treatment Efficacy;Tumor Immunity;Tumor-associated macrophages;Tumor-infiltrating immune cells;Vaccination;Visualization;Yeasts;anti-CTLA4;anti-PD-1;anti-PD-L1;anti-PD-L1 therapy;anti-tumor immune response;antitumor effect;cancer immunotherapy;cancer type;effective therapy;efficacious treatment;imaging approach;immune checkpoint blockade;immune imaging;improved;in vivo imaging;ineffective therapies;innate immune mechanisms;innovation;insight;intraperitoneal;lymphatic vessel;molecular imaging;mouse model;nanobiologic;novel;novel strategies;novel therapeutics;pancreatic cancer patients;pancreatic ductal adenocarcinoma model;particle;predictive marker;programmed cell death ligand 1;programs;rational design;recruit;response;subcutaneous;success;therapy design;therapy resistant;tool;trafficking;transcriptomics;treatment response;tumor;tumor progression;tumor-immune system interactions;tumorigenic

public_health_relevance:
Project NarrativeThe overall goal of this proposal is to develop an integrated in vivo imaging with immunophenotypingapproach to understand the immune evasion mechanisms of pancreatic cancer and develop more effectivetherapies for this disease. The successful completion of this study may provide an innovative approach totreating pancreatic cancer and the knowledge gained from this study may also help us develop a rationallydesigned intervention for pancreatic cancer patients.


application_id: 10802365
project_number: 5R01AI152258-06
administering_ic: NIAID
award_notice_date: 2024-04-09
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: AI
serial_number: 152258
program_official: ROBINSON, RICHARD THOMAS
project_start_date: 2020-04-16
project_end_date: 2026-03-31
study_section: Special Emphasis Panel[ZRG1-CVRS-R(03)]
contact_pi_person_id: 8774042
contact_pi: MESSAOUDI, ILHEM
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-04-01
project_title:
Mechanisms of increased susceptibility to pulmonary Nontuberculous Mycobacterial disease in the elderly

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

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

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


application_id: 10801394
project_number: 1R01AA030774-01A1
project_title: Selective Glucocorticoid Receptor Antagonism in Alcohol Use Disorder: A Human Neuroscience Study
administering_ic: NIAAA
award_notice_date: 2024-07-22
opportunity_number: PA-20-184
application_type: 1
activity_code: R01
ic: AA
serial_number: 030774
suffix: A1
program_official: SENEVIRATNE, CHAMINDI
project_start_date: 2024-08-01
project_end_date: 2028-07-31
study_section: Addiction Risks and Mechanisms Study Section[ARM]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
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
project_abstract:
ABSTRACT/SUMMARY Perturbations of the hypothalamic-pituitary-adrenal (HPA) axis characterize alcohol use disorder (AUD).The HPA axis is the primary stress-response system and cortisol is the major adrenal glucocorticoid hormonein most mammals. A negative feedback system involving glucocorticoid receptors (GRs) regulates HPA axisactivity and cortisol secretion. Preclinical studies have shown glucocorticoid receptor (GR) antagonists reducealcohol (ALC) reward withdrawal and stress-induced relapse in preclinical studies. Despite this robustliterature these areas are understudied in humans perhaps because the only clinically available GRantagonist mifepristone is not selective. The proposed rigorous crossover study will translate provocative preclinical findings implicating GRs inAUD to humans using a selective GR antagonist PT150. Participants (N=34 17 females 17 males) willcomplete an experimental session after at least 5 days of maintenance on each PT150 dose (0 450 900mg/day) to determine responses to experimentally induced stress. Participants will complete a separateexperimental session to determine if PT150 attenuates the pharmacodynamic effects of ALC (0.5 g/kg). We willrecord behavioral (i.e. ALC demand craving mood and subjective effects) neuroendocrinological (i.e.cortisol) and physiological (i.e. heart rate blood pressure breath ALC level) responses before stress or ALCand periodically afterwards for 120 mins. Finally we will determine whether PT150 reduces ALC use (i.e.number of drinks and heavy drinking days/week) craving and stress in the natural ecology. We predict: 1)stress induction will increase cortisol ALC demand and negative mood and PT150 will attenuate theseresponses 2) ALC will increase ALC demand and produce prototypical subjective effects and PT150 willattenuate these effects and 3) PT150 will decrease drinking craving and stress in the natural ecology.Exploratory aims will determine if: 1) responses/changes differ in females and males; 2) baseline cortisol orstress levels will predict behavioral or neuroendocrinological responses to stress and attenuation by PT150;and 3) behavioral and neuroendocrine responses and attenuation by PT150 during the stress-inductionsession predict changes in the naturalistic ecology. This project will expand the scope of clinical neuroscience research on AUD by focusing on GRantagonism in humans. Rigorous preclinical research supports this proposal. The proposed research couldprovide the impetus for subsequent clinical research to develop PT150 as an adjunct therapy for AUD.Because HPA dysregulation occurs in stimulant opioid and tobacco use disorders this project could also spurinterest in elucidating the role of GR antagonism in other substance use disorders. The proposed work willproduce an immediate and sustained impact.

project_terms:
Adrenal Glands;Affinity;Alcohol consumption;Alcohol withdrawal syndrome;Alcohols;Area;Attenuated;Auditory;Behavior assessment;Behavioral;Bilateral;Biological Availability;Blood;Blood Pressure;Businesses;Clinical;Clinical Pharmacology;Clinical Research;Cognitive;Consumption;Corticosterone;Cross-Over Studies;Development;Dose;Ecology;Environment;Feedback;Female;Glucocorticoid Receptor;Glucocorticoids;Goals;Heart Rate;Heavy Drinking;Hormones;Human;Hydrocortisone;Hypothalamic structure;Kentucky;Literature;Maintenance;Mammals;Memory;Mifepristone;Moods;Neuroendocrinology;Neurosciences;Neurosciences Research;Neurosecretory Systems;Oncology;Oral;Participant;Patients;Performance;Pharmacodynamics;Pharmacology Study;Pharmacotherapy;Physiological;Pituitary Gland;Placebos;Progesterone Receptors;Public Health;Questionnaires;Relapse;Reporting;Research;Research Personnel;Research Support;Rights;Role;Self Administration;Severities;Stress;Substance Use Disorder;Surveys;System;Testing;Therapeutic;Tobacco Use Disorder;Translating;Universities;Withdrawal;Work;alcohol demand;alcohol effect;alcohol measurement;alcohol reward;alcohol seeking behavior;alcohol use disorder;antagonist;attenuation;behavior prediction;biological adaptation to stress;comparison control;conditioned place preference;craving;drinking;electronic data;foot;human subject;hypothalamic-pituitary-adrenal axis;improved;innovation;interest;male;negative mood;opioid use disorder;pre-clinical;pre-clinical research;preclinical study;prolonged abstinence;reduced alcohol use;response;social;stimulant use disorder;stressor;tool

public_health_relevance:
PROJECT NARRATIVE The research proposed in this application consists of a rigorous crossover study to determine whetherglucocorticoid receptor antagonism attenuates behavioral and neuroendocrinological responses toexperimentally induced stress in non-treatment-seeking patients with alcohol use disorder (AUD) thepharmacodynamic effects of alcohol (ALC) and drinking craving and stress in the natural environment. Theproposed study is innovative and important because it might spur the development of PT150 as an adjuncttherapy for alcohol use disorder.


application_id: 10799988
project_number: 1R01HL168085-01A1
administering_ic: NHLBI
award_notice_date: 2024-01-31
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: HL
serial_number: 168085
suffix: A1
program_official: LIU, SONGTAO
project_start_date: 2024-02-01
project_end_date: 2028-01-31
study_section: Bioengineering, Technology and Surgical Sciences Study Section[BTSS]
contact_pi_person_id: 8487070
contact_pi: WANG, DONGFANG
other_pis: YOGANATHAN, AJIT P
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_title:
Development of a Percutaneous Double Lumen Cannula-Based Cavopulmonary Assist System Toward Clinical Application

project_abstract:
The standard palliative surgery for a single ventricle defect is a total cavopulmonary connection (TCPC) whichseparates the pulmonary and systemic circulations. This Fontan circulation eventually fails with high long-termmortality. A failing Fontan includes cavopulmonary failure (CPF) and/or ventricular failure. No cavopulmonaryassist (CPA) device is available for CPF. Our ultimate goal is to develop a percutaneous CPA system for totalambulatory support of CPF patients. Our enabling technology is a CPA dual lumen cannula (DLC) with pairedmembrane umbrellas. Via ony 1 venous cannulation this DLC connects the TCPC to an external pump withoutmajor surgery. This system provided total CPA and reversed CPF hemodynamics/renal dysfunction in ourlethal CPF sheep model enabling 96 hr survival. To move our CPA DLC toward clinical application thefollowing specific aims were developed: Specific Aim 1: To design optimize and fabricate a new CPADLC for least thrombogenic/ hemolytic potential and smooth installation/deployment. Two membraneumbrellas ensure efficient/reliable performance. Slipknots ensure easy DLC installation/umbrella deployment.Validated computational fluid dynamics will be used for design optimization. The CPA DLC body will be madeof ultrathin reinforced polyurethane (PU) with a PU membrane sleeve infusion lumen. The two membraneumbrellas will be molded onto DLC. Specific Aim 2: [To assess the anatomic fittingness of the CPA DLCin patient specific TCPC silicone models and evaluate the potential of reversing pathophysiology inCPF patients using our established mathematical model validated with CPF patients comprehensivehemodynamic data]. Patient specific silicone TCPC models will be made from MRIs in our Fontan database.A mock loop with these models will assess the CPA DLC for: 1) ability to fit/function well; 2) flow stasis/highshear stress areas. Our patient specific Fontan simulation platform will quantify CPA flow rates that mitigateliver congestion. Specific Aim 3: To evaluate final CPA DLC prototype in a [patient specific TCPC mockloop] for performance reliability and 30 day durability. This mock loop with 37% glycerin will test CPADLC for: 1) flow efficiency/reliability at 360 [axial] rotation/8 cm dislocation and 2) 30 day durability at 4 L/minflow. Specific Aim 4: To evaluate the CPA DLC prototype for in vivo performance reliability and ease ofinstallation/deployment in a CPF sheep model. Ease of installation/deployment and performance/reliabilitywill be assessed in 6 hr studies (n=15). A 2-week preclinical study (n=15) will confirm full reversal of CPFhemodynamics/end-organ dysfunction and will assess biocompatibility.

project_terms:
3-Dimensional;Acute;Anatomy;Area;Blood;Cannulas;Cannulations;Catheters;Circulation;Common Ventricle;Data;Databases;Development;Dislocations;Eligibility Determination;Ensure;Failure;Functional disorder;Glycerol;Goals;Grant;Heart;Heart Transplantation;Hemolysis;Hypoxia;Implantable Pump;In Vitro;Inferior vena cava structure;Infusion procedures;Kentucky;Liquid substance;Live Birth;Liver;Lung;Magnetic Resonance Imaging;Massachusetts;Medical Device;Membrane;Modeling;Molds;Operative Surgical Procedures;Organ;Palliative Surgery;Patient Simulation;Patients;Performance;Polyurethanes;Pulmonary artery structure;Pump;Reconstructive Surgical Procedures;Recovery;Rotation;Self-Help Devices;Sheep;Silicones;Single ventricle congenital heart disease;Superior vena cava structure;System;Technology;Testing;Thrombosis;Universities;Venous;Ventricular;Work;biomaterial compatibility;clinical application;clinical efficacy;clinically relevant;design;flexibility;hemodynamics;improved outcome;in vivo;kidney dysfunction;mathematical model;mortality;novel;pre-clinical;preclinical study;pressure;prevent;prototype;shear stress;sheep model;simulation;thrombogenesis;ventricular assist device

public_health_relevance:
We are proposing to further develop a percutaneous cavopulmonary assist system toward clinical application.The enabling technology is a cavopulmonary assist dual lumen cannula with paired membrane umbrellas. Ourcavopulmonary assist system will provide total ambulatory support to cavopulmonary failure patients bridgingthese patients with failing Fontan circulation to recovery reconstructive surgery and heart transplantation toimprove outcomes.


application_id: 10799156
project_number: 3R15GM085722-04S1
project_title: Mechanisms of Action in UmuD in Regulating DNA Damage-Induced Genes in a umuC-Deficient Bacterium
administering_ic: NIGMS
award_notice_date: 2023-05-19
opportunity_number: PA-20-272
application_type: 3
activity_code: R15
ic: GM
serial_number: 085722
suffix: S1
program_official: REDDY, MICHAEL K
project_start_date: 2009-08-01
project_end_date: 2025-12-31
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
primary_duns: 041957010
primary_uei: MRGUP99ZAZ59
duns_number: 041957010
uei: MRGUP99ZAZ59
fips: US
organization_id: 569601
organization_name: MOREHEAD STATE UNIVERSITY
organization_city: MOREHEAD
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 403511684
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Multi-drug resistant bacteria such as the ESKAPE pathogens are difficult to treat; finding new drugtargets and alternate methods of interfering with cell growth are crucial to infectious disease control. AGram-negative nosocomial ESKAPE pathogen Acinetobacter baumannii has multiple antibiotic-resistancegenes and a mutagenic response to DNA damage that antibiotics can cause. The PIs undergraduate researchteam has uncovered a novel DNA damage response (DDR) system in this pathogen that uses a non-canonical repressor UmuDAb and a small protein coregulator DdrR to repress mutagenic error-pronepolymerases. Typical DDR regulators namely the LexA repressor of SOS genes and the SulA cell divisioninhibitor are not encoded by the non-enteric Acinetobacter genus yet they possess a checkpoint response offilamentation after DNA damage. There is increasing interest in targeting cell division and controlcheckpoints to control bacterial infections and novel mechanisms of cell division inhibition are recentrefinements to Escherichia coli and Bacillus DDR models. Staphylococcus aureus (also an ESKAPE pathogen)and other Gram-positive and non-enteric bacteria that lack SulA instead use small proteins lacking inter-genus homologies to inhibit cell division after DNA damage. Our teams evidence suggests that the DdrRcomponent of SOS regulation mimics the actions of SulA and these Gram-positive growth inhibitors afterDNA damage: ddrR mutants have growth sensitivity to DNA damage and cannot inhibit cell division after it. This projects long-term goal is to construct a new model of inhibiting cell division in Gram-negativeGammaproteobacteria such as A. baumannii which could help find non-antibiotic means of inhibiting itsgrowth and treating infectious disease. Our objectives are to identify how UmuDAb and DdrR directly andindirectly control error-prone polymerase production and cell division checkpoints as part of theAcinetobacter DDR. We hypothesize that the UmuDAb and DdrR regulators physically interact to control thisLexA-deficient pathogen's SOS response. Our objectives will be achieved using complementary approachesto determine whether their phenotype of cell division inhibition results from directly interacting withdivisome proteins or occurs through co-regulatory actions. Specifically we will: (Aim 1) use biochemicalmethods to identify UmuDAb-DdrR interactions; (Aim 2) establish these proteins' roles in inhibiting celldivision with fluorescence microscopy localization experiments two-hybrid and growth inhibition assays;and (Aim 3) examine previously obtained transcriptome data for targets of DdrR and UmuDAb regulatoryactivities that may control DNA damage checkpoints and growth after DNA damage. The PIs previouslydemonstrated mutant strains purified proteins and expertise in microbiology molecular biologybiochemistry and bioinformatics will allow her team of undergraduate students to complete these objectiveswhile producing authentic scientific knowledge and gaining a wide range of knowledge and skills.

project_terms:
Acinetobacter;Acinetobacter baumannii;Antibiotic Resistance;Antibiotics;Bacillus;Bacteria;Bacterial Infections;Binding;Biochemical;Biochemistry;Bioinformatics;Biological;Biological Assay;Cell Division Process;Cell division;Cells;Collection;Communicable Diseases;DNA Damage;DNA damage checkpoint;Data;ESKAPE pathogens;Equipment;Escherichia coli;Filament;Fluorescence Microscopy;Gammaproteobacteria;Gene Expression;Genes;Goals;Gram-Negative Bacteria;Growth;Growth Inhibitors;Immune checkpoint inhibitor;Knowledge;Learning;Membrane;Methods;Microbiology;Microscopic;Modeling;Molecular Biology;Multiple Bacterial Drug Resistance;Mutation;Nature;Phenotype;Polymerase;Polymerase Gene;Process;Production;Proteins;Regulation;Repression;Research;Role;SOS Box;SOS Response;Staphylococcus aureus;System;Testing;Two-Hybrid System Techniques;cell fixing;cell growth;crosslink;disorder control;drug resistant pathogen;experimental study;gene repression;inhibitor;interest;mutant;new therapeutic target;novel;overexpression;pathogen;protein purification;repaired;resistance gene;response;skills;stoichiometry;transcriptome;transcriptome sequencing;undergraduate research;undergraduate student;yeast two hybrid system

public_health_relevance:
Project Narrative The purpose of this research is to understand how Acinetobacter baumannii an antibiotic-resistant pathogen responds to DNA damage to learn how to inhibit this pathogens growth withoutusing antibiotics. The typical bacterial repair response to DNA damage causes a pause in growth whilethe cell fixes the damage but can also cause mutations. Our research will test for interactions betweenproteins that regulate the production of these mutations and proteins used to halt cell division afterDNA damage.


application_id: 10798949
project_number: 1R01CA279455-01A1
project_title: Pdcd4-Rictor Interaction in Suppression of Lung Tumorigenesis
administering_ic: NCI
award_notice_date: 2023-09-20
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: CA
serial_number: 279455
suffix: A1
program_official: FORRY, SUZANNE L
project_start_date: 2023-09-20
project_end_date: 2028-08-31
study_section: Mechanisms of Cancer Therapeutics B Study Section[MCTB]
contact_pi_person_id: 8737920
contact_pi: YANG, HSIN-SHENG
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractLung cancer is the leading cause of cancer-related deaths in the United States. The high mortality rate is notonly due to the lack of effective early detection but also due to poor tumor response to currently availabletherapies. These underscore the urgent need to better understand the biological events and mechanism of lungcancer suppression as is the need for important new therapeutic approaches that specifically target theseprocesses to improve survival rates. Lung cancer is mainly divided into two types: small cell lung cancer (SCLC)and non-small cell lung cancer (NSCLC) the latter of which accounts for 80-85% of all cases. A new subset oflung cancer in both SCLC and NSCLC was recently identified in which Rapamycin-insensitive companion ofmTOR (Rictor) gene is amplified. Rictor is an essential component of the mammalian target of rapamycincomplex 2 (mTORC2) and is required for mTORC2 complex activity and integrity. Activation of mTORC2 resultsin promotion of cancer cell proliferation and survival. This application builds on exciting preliminary data thatProgrammed cell death 4 (Pdcd4) bound with Rictor through a Rictor binding domain (RBD) to inhibit mTORC2activity 6-phosphofructo-2-kinase/fructose-26-biphosphatase 3 (PFKFB3) level cell proliferation and colonyformation. In addition a peptide containing the RBD specifically inhibits mTORC2 but not mTORC1. Our datafurther demonstrated that the RBD peptide suppressed NSCLC proliferation in cultured cells and nude mice. Thecentral hypothesis is that Pdcd4-Rictor binding specifically inhibits mTORC2 to preferentially suppressproliferation in Rictor-elevated NSCLC via induction of proteasomal degradation of PFKFB3. To test thishypothesis three specific aims are proposed: i) Delineate the mechanism of how Pdcd4-Rictor binding interfereswith mTORC2 activity to suppress tumor growth in NSCLC; ii) Dissect how Pdcd4-Rictor-mTORC2 axis impactsPFKFB3 stability and metabolic pathways; iii) Demonstrate that mTORC2-specific inhibition by RBD peptidepreferentially suppresses the growth of Rictor-elevated NSCLC to improve survival rate. The accomplishment ofthe proposed study will not only uncover novel regulatory mechanisms of mTORC2 activity and PFKFB3expression by Pdcd4 but also reveal the importance of mTORC2-specific inhibition by RBD peptide on NSCLCtumorigenesis. The expected findings will guide us to develop new strategies that are particularly relevant toprecision medicine approaches for NSCLC patients with elevated Rictor.

project_terms:
6-Phosphofructo-2-kinase;Acetylation;Apoptosis;Binding;Biological;Biological Assay;Cancer Etiology;Cancer Patient;Cause of Death;Cell Proliferation;Cell Survival;Cells;Cessation of life;Companions;Complex;Cultured Cells;Data;Drug Kinetics;Early Diagnosis;Event;Exhibits;FRAP1 gene;Feedback;Fructose;Gene Amplification;Genes;Genetic;Genetic Transcription;Glycolysis;Growth;In Vitro;Inhibition of Cell Proliferation;Invaded;Investigation;Knock-out;Laboratories;Malignant neoplasm of lung;Maps;Mediating;Metabolic Pathway;Mutation;Mutation Analysis;Neoplasm Metastasis;New Agents;Non-Small-Cell Lung Carcinoma;Nude Mice;Outcome Study;Patients;Penetration;Peptides;Phosphorylation;Phosphorylation Site;Phosphotransferases;Process;Prognosis;Proliferating;Proteasome Inhibitor;Proteins;Regulation;Reporting;Resistance;Role;Signal Transduction;Sirolimus;Site;Subgroup;Survival Rate;Tertiary Protein Structure;Testing;Therapeutic;Tumor Suppressor Proteins;Ubiquitination;United States;Up-Regulation;Woman;Work;Xenograft procedure;cancer cell;cancer diagnosis;cancer type;improved;in vivo;inhibitor;knock-down;lung cancer cell;lung tumorigenesis;men;metabolomics;migration;mortality;multicatalytic endopeptidase complex;mutant;novel;novel therapeutic intervention;novel therapeutics;patient derived xenograft model;precision medicine;prevent;research clinical testing;response;small cell lung carcinoma;therapy resistant;tumor;tumor growth;tumorigenesis;ubiquitin-protein ligase

public_health_relevance:
Project NarrativeLung cancer is the most commonly diagnosed cancer and the first leading cause of death in both men andwomen in the United Sates. In this proposal we intend to understand of how Pdcd4 a tumor suppressor bindswith Rictor an important protein in suppression of the lung cancer cells. This work will provide new strategiesfor lung cancer with Rictor elevation therapeutics and potentially develop new agents for treatment of this typeof lung cancer.


application_id: 10798811
project_number: 3P20GM113226-08S1
project_title: 2023 Equipment Supplement to Hepatobiology and Toxicology COBRE
administering_ic: NIGMS
award_notice_date: 2023-07-04
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 113226
suffix: S1
program_official: NANDA, JAGPREET SINGH
project_start_date: 2016-06-10
project_end_date: 2026-03-31
study_section: ZGM1(C2)
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The University of Louisville (UofL) Hepatobiology and Toxicology (H&T) COBRE is a unique thematiccenter focused on liver research. The UofL H&T COBRE concentrates on the mechanisms and therapeuticstrategies for multiple forms of liver disease/injury including: Non-alcoholic fatty liver disease/non-alcoholicsteatohepatitisthe most common liver disease in the US/worldwide and is highly linked to the metabolicsyndrome; Alcoholic Liver Diseasea common problem among those who drink; Environmental ToxicantInduced Liver Injuryan increasingly recognized problem and Louisville has been a leader in this area;Hepatitis B and Cimportant causes of cirrhosis and hepatocellular carcinoma worldwide; PersonalizedMedicinean increasingly important factor in medication efficacy and most drugs are metabolized in the liver;and Drug-Induced Liver Injurythe most common reason drugs are removed from the market and animportant cause of liver failure. This COBRE brings together experienced senior mentors/investigators andpromising junior investigators to perform cross-cutting research on the unique topics of Hepatobiology andToxicology. We address critical barriers in our understanding of the development/ progression of liver diseaseand we define targets for prevention/treatment that could transform clinical practice. Specific Aims of the Hepatobiology and Toxicology COBRE are to:1. Expand and strengthen a thematically-focused program in Hepatobiology and Toxicology that helps buildand sustain the overall research infrastructure at UofL.2. Expand and strengthen the multidisciplinary program in research education mentoring and careerdevelopment in Hepatobiology and Toxicology and systematically track and evaluate the progress.3. Provide the necessary research resources and translational science/basic technologies to support state-of-the-art research in Hepatobiology and Toxicology and to ensure sustainability of the program.4. Discover new mechanisms/molecular targets and effective means for preventing and/or treating liverdiseases/toxicant exposures and communicate our findings to the public. In summary Phase I strengthened UofLs biomedical research infrastructure through the establishment ofa thematic multidisciplinary center in hepatobiology and toxicology to enhance the ability of investigators tocompete for independent funding. In Phase I we met or exceeded our metrics including 1) four of ourinvestigators transitioning to independent research funding; 2) 91 mentee and 162 total publications; 3) newrenovated laboratory space; 4) numerous presentations; 5) establishing new collaborations; and 6) >$75million in total new grant funding by H&T members. This Phase II proposal builds on our Phase I successextends and strengthens the scope of the program and provides a roadmap for sustainability.

project_terms:
Address;Alcoholic Liver Diseases;Area;Biomedical Research;Centers of Research Excellence;Cirrhosis;Collaborations;Communication;Development;Ensure;Equipment;Funding;Grant;Hepatitis B;Hepatitis C;Injury;Laboratories;Link;Liver;Liver Failure;Liver diseases;Marketing;Mentors;Metabolic syndrome;Molecular Target;Pharmaceutical Preparations;Phase;Prevention;Primary carcinoma of the liver cells;Program Sustainability;Publications;Research;Research Infrastructure;Research Personnel;Resources;Technology;Therapeutic;Toxic Environmental Substances;Toxicant exposure;Toxicology;Translational Research;Universities;career development;clinical practice;drug induced liver injury;education research;experience;liver injury;member;multidisciplinary;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;personalized medicine;prevent;programs;success

public_health_relevance:
The University of Louisville (UofL) Hepatobiology and Toxicology COBRE is a unique thematic researchcenter. We have strengthened UofLs biomedical research infrastructure through the establishment of athematic multidisciplinary center in hepatobiology and toxicology to enhance the ability of investigators tocompete for independent funding. This Phase II proposal builds on our Phase I success and extends andstrengthens the scope of the program.


application_id: 10797084
project_number: 3P20GM125504-06S1
project_title: Functional Microbiomics Inflammation and Pathogenicity
administering_ic: NIGMS
award_notice_date: 2023-06-26
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 125504
suffix: S1
program_official: CUPIT, PAULINE
project_start_date: 2018-03-01
project_end_date: 2028-02-29
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe Primary goal of the Functional Microbiomics Inflammation and Pathogenicity CoBRE at the UofL is toestablish a thematic multidisciplinary research center for the study of the interface between the microbiomeinflammation and pathogenicity. In the last five years we assembled a cadre of junior investigators withcomplementary expertise and outstanding potential and have partnered these project leaders with well-qualifiedand dedicated mentors. An integrated set of complementary projects made novel connections betweeninflammatory processes and bacterial pathogenicity to establish the basis for the development of noveltherapeutics and delivery methods. This has led to successful graduation of five junior faculty with NIH R01awards and three of these investigators are still at UofL and are transitioning into mentoring roles whileestablishing their own strong scientific programs. Thus far research in their laboratories has been supported bya Functional Microbiomics Core that provides germ free animal facilities anaerobic culture capabilitymicrobiome sequencing and bioinformatics and assay of inflammatory markers. For many of our junior facultyand their mentors there is now increasing demand for the ability to image inflammation deeper into tissues in liveanimals and spatial resolution within the tissues has become an important requirement for many projects. Thusfor the phase II of the FMIP CoBRE we have made significant commitment to expand our imaging capabilities byadding Multiphoton Intravital Microscopy (MP-IVM) a well-established method for imaging of living intactbiological tissues through the whole organisms to our repertoire of technologies in FMC. We propose to furtherexpand this area by purchasing a CellScape_Chip Cytometry Instrument from Canopy Biosciences. ChipCytometry can multiplex the spatial proteomics at single cell resolution. This supplement application is requestingpartial funding from the NIH to acquire and establish Chip Cytometry at the UofL that will support the research oflarge number of faculty working in the areas of microbiota inflammation and pathogenesis.

project_terms:
Alzheimer's Disease;Animals;Area;Award;Bioinformatics;Biological;Biological Assay;Biological Sciences;Cells;Cytometry;Dedications;Development;Disease;Faculty;Funding;Germ-Free;Goals;Image;Inflammation;Inflammatory;Interdisciplinary Study;Laboratories;Malignant Neoplasms;Mentors;Methods;Molecular;Pathogenesis;Pathogenicity;Periodontal Diseases;Phase;Process;Proteomics;Qualifying;Research;Research Personnel;Research Support;Resolution;Role;Technology;Tissues;United States National Institutes of Health;Whole Organism;animal facility;human disease;imaging capabilities;imaging modality;inflammatory marker;instrument;intravital microscopy;microbiome;microbiome research;microbiome sequencing;microbiota;multi-photon;novel;novel therapeutics;programs

public_health_relevance:
NARRATIVEInflammation has been associated with the development of a wide range of human diseases includingperiodontal disease cancer and Alzheimers disease. The goal of this proposal is to establish a Chip Cytometryfacility that allows spatial imaging of inflammation as it develops leading to the discovery of cellular and molecularmechanisms underlying the pathogenicity of these diseases.


application_id: 10796981
project_number: 5R01CA249734-04
project_title: Targeting Lipid Metabolism in Colorectal Cancer
administering_ic: NCI
award_notice_date: 2024-03-25
opportunity_number: PA-19-056
application_type: 5
activity_code: R01
ic: CA
serial_number: 249734
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2021-04-01
project_end_date: 2026-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). Our long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in fatty acid metabolism contribute to metastatic disease. Fatty acid synthase (FASN) a key enzyme of de novo lipid synthesis is significantly upregulated and activated in CRC and its activity is associated with poor prognosis higher risk of disease recurrence and death. We identified FASN as a potential target for advanced CRC and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However the underlying mechanisms of FASN regulation of metastasis and potential mechanism of resistance to FASN inhibition are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of CRC metastasis by lipid metabolism. Our preliminary data suggest that the primary product of de novo fatty acid synthesis palmitate is selectively used for sphingolipid synthesis. Overexpression of FASN selectively regulates activity of SphK1 and SphK2 and increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipid implicated in metastasis. Therefore in Aim 1 we will test the hypothesis that FASN enhances metastasis by upregulating the SphK/S1P axis and we will determine the contributions of SphK1 and SphK2 to CRC metastasis. Furthermore our preliminary studies show a correlation between expression of FASN and CD36 a fatty acid translocase responsible for exogenous FA uptake. Our data show that inhibition of FASN leads to upregulation of CD36 and it can be a potential mechanism of resistance to novel FASN inhibitors that are currently being tested in Phase II clinical trials. Therefore in Aim 2 we will elucidate how FASN regulates CD36 and determine molecular mechanisms by which upregulation of CD36 contributes to CRC metastasis including the effect of CD36 upregulation on sphingolipid metabolism and S1P synthesis. In Aim 3 we will test whether inhibition of FA uptake via CD36 will increase efficacy of a novel FASN inhibitor TVB-3664 in CRC. We will utilize biological samples from patients human primary CRC cells tumor organoids established from genetically modified mice and CRC metastasis models which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches including targeted and stable isotope-resolved metabolomics (SIRM) to evaluate the effect of alteration in lipid synthesis and FA uptake on cancer cell metabolism. These studies have a high translational impact since CD36 and FASN inhibitors are currently tested in multiple pre-clinical studies and Phase I-II clinical trials and there is urgent need for more research and knowledge on their effects in CRC. Beside validation of FASN SphKs and CD36 as therapeutic targets in CRC the comprehensive analysis of metabolic and signaling pathways proposed in the current application also have the potential to identify new druggable targets and therapeutic strategies for CRC.

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

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


application_id: 10796239
project_number: 3R35GM136295-04S1
project_title: Acquisition of confocal scan to upgrade existing fluorescence microscope
administering_ic: NIGMS
award_notice_date: 2023-08-25
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: GM
serial_number: 136295
suffix: S1
program_official: LEWIS, MECHELLE MAYLEBEN
project_start_date: 2020-05-01
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZRG1(55)-R]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary This proposal is for an equipment administrative supplement to an existing MIRA R35 supporting the PIsresearch addressing the molecular mechanisms of the extracellular signal-regulated kinases 1 and 2 (ERK1/2)signal transmission as guided by scaffold proteins. This research program focuses on understanding themechanisms by which key regulators such as the scaffold protein Shoc2 modify ERK1/2 signaling. Thesestudies decipher and determine the mechanisms by which endosomal sorting regulates the ubiquitin-drivenremodeling of Shoc2 complexes and signaling and illuminate the key steps that segregate Shoc2 into distinctintracellular sorting pathways. Preliminary studies have already yielded new insights into the molecular detailsof how Shoc2-activated ERK1/2 signals promote early developmental stages. For this work zebrafish is usedas a vertebrate model to investigate the in vivo effect of Shoc2 gene editing on the early stages ofdevelopment since they offer distinct advantages for studies of development including their transparency aswell as external and rapid development. Outcomes from this work are expected to produce an ambitious andcomprehensive mechanistic understanding of how Shoc2 is involved in determining the specificity of ERK1/2signaling outcomes. As such this work is laying the groundwork for future studies on developmental disordersthat will contribute to the advancement of novel therapeutic strategies and biomarkers. This administrativesupplement application to acquire a confocal scanning disk as an add-on to an existing 3i Marianasmicroscope platform will foster ongoing experiments in this research program. The advanced scanningcapacities will significantly improve the quality of the imaging analysis to examine the distribution of Shoc2signaling complexes in cells and will dramatically enhance these studies to examine the role of Shoc2-mediated signals in embryonic development.

project_terms:
Address;Administrative Supplement;Biological Markers;Cells;Complex;Development;Disease;Embryonic Development;Endosomes;Equipment;Fostering;Future;Genes;Image;MAPK3 gene;Malignant Neoplasms;Mediating;Microscope;Modeling;Molecular;Outcome;Pathway interactions;Research;Role;Scaffolding Protein;Scanning;Signal Transduction;Sorting;Specificity;Syndrome;Ubiquitin;Work;Zebrafish;developmental disease;experimental study;fluorescence microscope;improved;in vivo;insight;novel diagnostics;novel therapeutic intervention;programs;public health relevance;segregation;targeted treatment;therapeutic development;transmission process;tumor;virtual

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


application_id: 10796006
project_number: 1R15CA274344-01A1
project_title: The Role of HA Remodeling and Mesenchymal Transitions in Glioblastoma
administering_ic: NCI
award_notice_date: 2024-03-27
opportunity_number: PAR-21-155
application_type: 1
activity_code: R15
ic: CA
serial_number: 274344
suffix: A1
program_official: GEORGE, CHRISTINA DAWN
project_start_date: 2024-04-01
project_end_date: 2027-03-31
study_section: Special Emphasis Panel[ZRG1 CDPT-J (80)]
contact_pi_person_id: 12556833
contact_pi: CHEN, JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARYGlioblastoma (GBM) is a deadly disease with no effective therapy and is associated with one of the worst 5-yearsurvival rates of all human cancers. Current treatments which include aggressive surgical care radiotherapyand chemotherapy are ineffective in part because of the highly adaptable nature of GBM which facilitatestherapy evasion and a persistent evolution of disease. Recent work has revealed the crucial role of the tumormicroenvironment (TME) in regulating tumor cell plasticity leading to efforts to create targeted TME-dependenttreatments to combat GBM progression. However due to the complex nature of the TME and a limitedunderstanding of the relevant promoters of disease embedded within this milieu progress in identifying promisingtherapeutic targets remains challenging. Within in the TME biophysical cues including matrix stiffness andcomposition have emerged as significant regulators of GBM cell aggressiveness. Focused investigations on thebiophysical mechanisms regulating GBM cell aggressiveness represent a novel approach to develop effectiveGBM TME targeting therapies. The emergence of biophysical alterations in the TME remains poorly understoodwith the process of TME tissue remodeling being an underappreciated aspect of GBM progression. Currentinvestigations indicate that alterations in hyaluronic acid (HA) secretion and digestion may affect tumorprogression through two major processes: 1) shape the biophysical characteristics of the evolving TME and 2)induce mesenchymal shifts that leads to increased dysregulations in ECM secretion increased invasivenessand increased proliferation. This proposal seeks to clarify the contributions and mechanisms of ECM remodelingby quantifying ECM alterations in tumor core and rim and by dissecting the mechanotransductive mechanismsunderlying HA-dependent tumorigenic control. To do this we will test the following hypotheses: 1) Core ECMremodeling leads to elevated HA content that increases tissue stiffening due to increased HAS2 and HYAL2activity in mesenchymal tumor regions 2) Increased mechanical stiffness and HA presentation will synergisticallypromote mesenchymal transitions that will lead to increased HASes and decreased HYALs leading toaccumulation of HA with varying molecular weights and subsequent biophysical alterations and 3) IncreasedHA stiffness will increase CD44 mechanotransduction through CD44 clustering and ERM activity leading toupregulated pro-mesenchymal signaling via STAT3-NF-B and LOX-Twist1 and LMW HA secretion. Theproposed studies will be the first to systematically dissect the ECM components of various patient matchedregions of GBM tumors and study their contributions to biophysical characteristics mesenchymal transitionsand HA-CD44 mechanotransduction.

project_terms:
Adaptor Signaling Protein;Affect;Ankyrins;Atomic Force Microscopy;Binding Sites;Biophysical Process;Biophysics;CD44 gene;Caring;Cells;Complex;Cues;Development;Digestion;Disease;ERM protein;Electron Microscopy;Environment;Evolution;Extracellular Matrix;Genes;Glioblastoma;Goals;HAS2 gene;Histological Techniques;Human;Hyaluronan;Hyaluronic Acid;Hyaluronic Acid Binding;Hyaluronidase;Hydrogels;In Vitro;Investigation;LOX gene;Link;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of brain;Mass Spectrum Analysis;Mechanics;Mesenchymal;Mesenchymal Cell Neoplasm;Molecular Profiling;Molecular Weight;Nature;Nuclear Translocation;Operative Surgical Procedures;Pathway interactions;Patients;Phenotype;Primary Brain Neoplasms;Process;Production;Prognosis;Proliferating;Property;Radiation therapy;Reporting;Research Personnel;Role;STAT3 gene;Shapes;Signal Transduction;Survival Rate;Testing;Therapeutic;Therapeutically Targetable;Tissues;Tumor Tissue;Tumor-Associated Process;Tumorigenicity;Work;biophysical model;biophysical properties;biophysical tools;chemotherapy;combat;effective therapy;gain of function;improved;in vivo;insight;loss of function;malignant phenotype;mechanotransduction;migration;mutant;neoplastic cell;novel;novel strategies;novel therapeutics;profiles in patients;promoter;receptor;targeted treatment;therapeutic target;tumor;tumor microenvironment;tumor progression;tumorigenic

public_health_relevance:
PROJECT NARRATIVECurrent approaches to treat glioblastoma an aggressive brain cancer have been unsuccessful due to its abilityto adapt and evolve. This is possible because the environment within the tumor presents signals that helpglioblastoma cells evade therapies and continue to grow. Understanding how these signals in the tumorenvironment change due to treatments may help researchers identify new drugs and approaches that can targetboth the tumor environment and the tumor cells that benefit from it.


application_id: 10795834
project_number: 5P20GM125504-07
administering_ic: NIGMS
award_notice_date: 2024-02-16
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3
subproject_number: 5221
contact_pi_person_id: 10933857
contact_pi: TENG, YUN
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: 2024-03-01
project_title:
Edible Plant-derived exosome-like nanoparticles (ELNs) and phage inhibit brain inflammation by targeting microglia and  gut microbiota

project_abstract:
Project Summary/AbstractIncreasing blood-brain barrier (BBB) permeability contributes to the speed of the aging process and theprogression of the development of age-related diseases. Microglia-mediated inflammation is a key element inthe development of BBB permeability which results in brain injury and promotes the progression of many braindiseases. Restoring impaired BBB function by targeting microglial cells without inducing side effects wouldtherefore be a major advance. Compelling evidence shows that healthy edible plants have importantphysiological roles for normal brain function and can prevent neuroinflammatory processes without side-effects.Turmeric root and ginger used in medicines for centuries display a multitude of health benefits includinginhibiting the progression of Alzheimers disease. We have shown that exosome-like nanoparticles (ELNs) fromturmeric root (TELNs) are selectively taken up by microglial cells and their constituent microRNAs inhibit theexpression of aging related inflammatory sensome genes including S100A8 and TLR4 thus enhancing BBBfunction. Additionally S100A8 is induced by metabolites isoamylamine (IAA) and crotonic acid (CA) releasedfrom the bacterial family Ruminococcaceae which is overgrown in aged mice due to a reduction of the Myoviridaefamily phages. ELNs from ginger (GELNs) can inhibit the growth of Ruminococcaceae reduce the levels of IAAand CA thus decreasing sensome inflammation as well as increasing expression tight junction genes Cldn5 andOcln in endothelial cells. In this study we will provide cellular and molecular insight into how ELNs modulatebrain function via the gut-brain axis by targeting microglial cells and the Ruminococcaceae to the benefit of thebrain. Our hypothesis is that impaired brain function in aged mice can be restored by TELNs and GELNsand gut bacterial phages through inhibition of expression of sensome proinflammatory genes andreduction in production of IAA and CA from Ruminococcaceae. We will test our hypothesis through twospecific aims. (1) We will investigate the role of the S100A8/TLR4 pathway targeted by TELN microRNAs inrecovery from cognitive decline in aged mice; (2) We will determine whether oral administration of GELNs andMyoviridae family phages has a beneficial effect on improving cognitive decline through reducing the productionof IAA and CA metabolites from Ruminococcaceae. The Aims will be performed in a mouse model that mimicsthe human aging process. The completion of this study will lead to identification of new therapeutic targets andpotential for the development of ELN based interventions for treating BBB permeability and brain inflammation.In addition the findings will provide a foundation to further study whether oral administration of customized ELNsisolated from different plants will have a synergistic/additive effect with gut beneficial phages in preventing ortreating chronic inflammatory brain related diseases.

project_terms:
Acids;Alzheimer's Disease;Apoptosis;Bacteriophages;Blood - brain barrier anatomy;Brain;Brain Diseases;Brain Injuries;Chronic;Communication;Data;Development;Disease;Edible Plants;Effectiveness;Elements;Encephalitis;Endothelial Cells;Family;Foundations;Gene Expression;Genes;Ginger;Goals;Growth;Growth Factor;Health Benefit;Human;Impaired cognition;Impairment;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Intervention;Intranasal Administration;Learning;Mediating;Medicine;Memory;MicroRNAs;Microglia;Modeling;Molecular;Myoviridae;Neurons;Oral;Oral Administration;Pathogenicity;Pathway interactions;Physiological;Plants;Prevention strategy;Process;Production;Publishing;Reporting;Role;Route;S100A8 gene;Shapes;Surface;Synaptic plasticity;TLR4 gene;Testing;Tight Junctions;Tumeric;age-related disease;aged;aging process;aging related;blood-brain barrier crossing;blood-brain barrier function;blood-brain barrier permeabilization;brain dysfunction;cognitive recovery;exosome;gut dysbiosis;gut microbiota;gut-brain axis;improved;in vivo;insight;microbial;microbiome research;mouse model;nanoparticle;nerve stem cell;neuroinflammation;neuronal survival;new therapeutic target;novel;old mice;oligodendrocyte progenitor;precursor cell;prevent;rate of aging;receptor;side effect


application_id: 10795833
project_number: 5P20GM125504-07
project_title: The role of sugar transport in C. difficile colonization and disease
administering_ic: NIGMS
award_notice_date: 2024-02-16
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3
subproject_number: 5220
contact_pi_person_id: 14774031
contact_pi: COLLINS, JAMES TRISTAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractClostridioides difficile infection (CDI) is still the most common cause of healthcare-associated infection despitea concerted effort to reduce the incidence. Increasingly C. difficile is found in the community among personswith no recent healthcare contact. The long-term goal of this project is to identify novel therapeutic targets whichcan be exploited to treat CDI and control the spread of C. difficile. The overall objectives in this application areto (i) elucidate the specificity and redundancy of the sugar transporters under positive selection in C. difficile (ii)determine their role in disease and iii) examine the impact of dietary sugar on asymptomatic carriage. Thecentral hypothesis is that C. difficile has evolved to better occupy niche space within the gastrointestinal tract(GIT) by taking advantage of the modern sugar-rich diet. The rationale for this project is that determining thespecificity and importance of sugar transporters and downstream metabolism in C. difficile carriage and infectionsets up a robust scientific framework whereby new prophylaxis and treatment strategies can be developed. Thecentral hypothesis will be tested by pursuing three specific aims: 1) Elucidate the specificity redundancy andinfluence on toxin production of evolving sugar transport genes 2) Determine the effect of evolving sugartransport genes on community invasion and disease and 3) Investigate the role of sugars in niche establishmentand asymptomatic carriage. Under the first aim clean deletions of sugar transporters previously shown to beunder positive selection in epidemic C. difficile will be generated and their effect on growth and toxin productionassessed. The second aim will determine the role of sugar transport in invasion using a novel in vitro bioreactorassay and disease by utilizing a mouse model of CDI. Finally aim three will assess the role of sugar availabilityin asymptomatic C. difficile colonization by using toxin negative C. difficile strains and a novel 13 strain mousemicrobiota colonization model. The research proposed in this application is innovative because it focuses onthe metabolic adaptation of C. difficile to carbohydrates and their role in asymptomatic carriage as well asdisease. This focus has the potential to lead to novel prophylactic strategies that can be used against C. difficilebefore the emergence of the disease. The proposed research is significant as it will provide a solid scientificjustification for the continued examination of metabolism as a virulence mechanism in C. difficile and provide aframework for the future study of novel prophylactic intervention and treatment options.

project_terms:
Accounting;Adult;Antibiotics;Biological Assay;Bioreactors;Carbohydrates;Clostridium difficile;Communities;Data;Development;Diet;Dietary Sugars;Disease;Enabling Factors;Environment;Environmental Risk Factor;Epidemic;Future;Gastrointestinal tract structure;Genes;Goals;Growth;Healthcare;Horizontal Disease Transmission;Hospitalization;Hospitals;Human;In Vitro;Incidence;Infection;Inflammation;Intake;Intervention;Intestines;Invaded;Link;Metabolic;Metabolism;Modeling;Modernization;Mouse Strains;Nutrient;Nutrient availability;Organism;Outcome;Pathogenicity;Persons;Population;Process;Production;Prophylactic treatment;Research;Role;Severity of illness;Shapes;Solid;Specificity;System;Testing;Toxic effect;Toxin;Trehalose;Virulence;Work;colonization resistance;dysbiosis;evidence base;gut microbiota;healthcare-associated infections;host microbiota;human old age (65+);innovation;insight;microbiome research;microbiota;mouse model;new therapeutic target;novel;pathogen;prevent;prophylactic;sugar;treatment strategy


application_id: 10795832
project_number: 5P20GM125504-07
project_title: Regulation of LPS structure and function in Porphyromonas gingivalis
administering_ic: NIGMS
award_notice_date: 2024-02-16
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2024-09-30
study_section: ZGM1-RCB-3
subproject_number: 5219
contact_pi_person_id: 14927473
contact_pi: MORADALI, FATA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/Abstract Periodontitis is a highly prevalent infectious inflammatory disease of the tissues supporting the teeth that can lead to tissue destruction formation of a deep periodontal pocket alveolar bone resorption and tooth loss. Etiological models suggest that periodontitis is driven by a synergistic community of virulent bacteria that trigger host inflammatory responses in the gingival tissues resulting in disease progression. Among recognized pathogens the Gram-negative anaerobe Porphyromonas gingivalis (Pg) has been strongly implicated in periodontitis. Lipopolysaccharide (LPS) macromolecules produced by Pg strains have been repeatedly shown to stimulate pro-inflammatory innate immune responses. Intriguingly Pg strains can diversify the structure of LPS in response to biologically relevant stimuli to 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 antagonists in the interaction with the innate immune system. Agonistic LPS plays prominent roles in the pathological outcome of infection by being involved in the activation of TLR signaling pathways leading to production of proinflammatory cytokines tissue destruction and bone resorption. However we do not yet know the mechanisms of the regulation of LPS heterogeneity and its biological importance during pathogenesis. We discovered that Pg strains possess a c-di-AMP signaling mechanism in which the c-di-AMP synthase PGN_0523 (dacpg) and the c-di-AMP phosphodiesterase PGN_0521 (pdepg) control the essential turnover of c-di-AMP and consequently LPS heterogeneity and virulence potential. This study will investigate how c-di-AMP turnover regulates the heterogeneity and immunomodulatory properties of Pg LPS using in vitro and in vivo models. To this end two independent but related specific aims are proposed: Specific Aim 1: To understand how c-di-AMP-controls heterogeneity of LPS in Pg. Specific Aim 2: To understand the impact of c- di-AMP-dependent variation of LPS on the innate immune response. Upon completion of the proposed studies we will learn how c-di-AMP signaling controls Pg LPS heterogeneity and determines the innate immune responses. Since c-di-AMP signaling does not exist in humans it is a potential novel druggable target. Our findings will inform the discovery of potent antagonistic LPS isoforms as a foundation for development of anti- inflammatory therapeutics.

project_terms:
Adenosine;Adenosine Monophosphate;Adult;Agonist;Anaerobic Bacteria;Anti-Inflammatory Agents;Applications Grants;Bacteria;Biological;Bone Resorption;Cell Physiology;Cell membrane;Cells;Chemical Structure;Chronic;Communities;Cytoprotection;Data;Detection;Development;Disease;Disease Progression;Equilibrium;Etiology;Foundations;Genes;Gingiva;Heterogeneity;Human;Immune;Immune Evasion;Immune system;In Vitro;Infection;Inflammation;Inflammatory;Inflammatory Response;Innate Immune Response;Innate Immune System;Learning;Lipopolysaccharides;Membrane;Microinjections;Modeling;Molecular;Mus;Outcome;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Periodicity;Periodontal Pocket;Periodontitis;Play;Porphyromonas gingivalis;Production;Property;Protein Isoforms;Regulation;Role;Serum;Signal Pathway;Signal Transduction;Stimulus;Stress;Structure;System;Systemic disease;TLR4 gene;Therapeutic;Tissues;Toll-like receptors;Tooth Loss;Tooth structure;Variant;Virulence;Virulence Factors;Virulent;alveolar bone;antagonist;cytokine;immunoregulation;in vitro testing;in vivo Model;in vivo evaluation;macromolecule;microbiome research;mutant;new therapeutic target;pathogen;pathogenic bacteria;phosphoric diester hydrolase;receptor;response


application_id: 10795828
project_number: 5P20GM125504-07
project_title: Functional Microbiomics Core
administering_ic: NIGMS
award_notice_date: 2024-02-16
opportunity_number: PAR-19-312
application_type: 5
activity_code: P20
ic: GM
serial_number: 125504
project_start_date: 2018-03-01
project_end_date: 2028-02-29
study_section: ZGM1-RCB-3
subproject_number: 5218
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractIn this Phase 2 of the Functional Microbiomics Inflammation and Pathogenicity COBRE the primary goal of theFunctional Microbiomics Core (FMC) is unchanged. We will sustain and enhance the well-established integratedservice center that functions as a critical resource for the Research Project Leaders (RPLs) as a priority andsecondarily for all investigators of the Center. Since all new COBRE projects also utilize mouse models to explorethe inter-relationships between inflammation and pathogenesis and the contribution of microbiota to thisprocess our well-established germ-free and gnotobiotic mice facility (GMF) will continue to play a central role inservices provided by the FMC. We will continue to provide anaerobic culturing of mixed and/or mono bacterialstrains to facilitate the specific colonization of the germ-free mice. 16S ribosomal DNA will be profiled with thein-house developed Oxford nanopore sequencing as well as PacBio-long read sequencing tools andbioinformatic support provided. Our most extensively used resource; multiplex-based analysis of inflammatorymediators in biological samples will continue to function using the Bio-Plex 200 (Bio-Rad) multiplex system. Inaddition several recent advances allow us to augment the services provided by the FMC. First the recentlydeveloped highly successful rederivation service of transgenic and KO mouse models as germ-free will greatlyexpand the scope and utility of the GMF. Related to this service is the development of a new area of researchon the role of microbiota in Alzheimers Disease (AD) supported by an administrative supplement to the FMCfrom NIA/NIGMS. The GMF has already rederived several AD mouse models. For this project the FMC alsodeveloped a suite of mouse behavior analysis models including the Morris Water Maze and Novel ObjectRecognition tests. These services will support all future ageing related research at the center including a newproject on the role of edible-plant derived exosomes in restoring the integrity of the Blood Brain Barrier. We alsonow include imaging support in particular Multiphoton Intravital Microscopy for imaging of live tissue and an InVivo Imaging System (IVIS) for live mouse imaging. Besides functioning as a service center another major goalof the FMC is to promote the education and training of researchers primarily the RPLs. The FMC will also interactwith other Core facilities at the University of Louisville such as the Genomics Metabolomics and Bioinformaticscore facilities established with the support of other highly successful COBRE/INBRE programs. In particular thenewly funded Cancer Immunology and Immunotherapy COBRE-operated Functional Immunomics Core (FIC)facility also directed by Dr. Bodduluri has several joint initiatives with the FMC including the establishment of ahistopathology service center. The FMC will work with these and other UofL resources in order to avoidduplication of equipment and to train individual investigators in specific protocols foster innovative protocoldevelopment and integrate analysis of data.

project_terms:
3xTg-AD mouse;Administrative Supplement;Adopted;Alzheimer's Disease;Area;Award;Behavior;Bioinformatics;Biological;Blood - brain barrier anatomy;Breeding;Centers of Research Excellence;Core Facility;Data Analyses;Dedications;Derivation procedure;Development;Edible Plants;Equipment;Extramural Activities;Fee-for-Service Plans;Fostering;Funding;Future;Genomics;Germ-Free;Gnotobiotic;Goals;Histopathology;Housing;Image;Individual;Inflammation;Inflammation Mediators;Infrastructure;Institution;Joints;Knockout Mice;Laboratories;Mentors;Methodology;Mission;Modeling;Mus;National Institute of General Medical Sciences;Pathogenesis;Pathogenicity;Phase;Play;Process;Protocols documentation;Research;Research Personnel;Research Project Grants;Research Support;Resources;Ribosomal DNA;Role;Sampling;Services;System;Techniques;Testing;Tissues;Training;Training and Education;Transgenic Organisms;Translational Research;Universities;Whole Organism;Work;aging related;animal facility;cancer immunotherapy;clinical translation;exosome;experimental study;imaging facilities;in vivo imaging system;innovation;intravital microscopy;metabolomics;microbiome research;microbiota;microscopic imaging;morris water maze;mouse model;multi-photon;nanopore;novel;object recognition;programs;protocol development;success;synthetic polymer Bioplex;tool;tumor immunology


application_id: 10795738
project_number: 4R01NS088555-08
project_title: B Cells Directly Alter Adaptive Plasticity to Support Functional Recovery After Stroke
administering_ic: NINDS
award_notice_date: 2024-07-12
opportunity_number: PA-20-185
application_type: 4
activity_code: R01
ic: NS
serial_number: 088555
program_official: BOSETTI, FRANCESCA
project_start_date: 2015-02-01
project_end_date: 2026-06-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 9562586
contact_pi: STOWE, ANN MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
The central hypothesis of this R01 renewal focuses on a subset of B cells that provide neurotrophic support to counter cognitive impairment and improve motor function after ischemic stroke a key risk factor for the development of vascular contributions to cognitive impairment and dementia (VCID). These neurotrophic B cells secrete brain-derived neurotrophic factor (BDNF) and may be critical to countering the development of VCID. Unfortunately the patient population most at risk for stroke and VCID aged individuals have impaired B cell development and secretion of growth factors that could limit protection from post-stroke depression and dementia. Sex is also a factor as elderly women with post-stroke dementia have the lowest levels of circulating BDNF though no prior studies have directly linked a loss of neurotrophic immune cell populations and the development of VCID. Based on our pilot data we will test: if a subset of post-stroke B cells (i.e. B cellsBDNF+) upregulate BDNF after encountering glutamate; if B cellsBDNF+ limit the development of VCID and support motor recovery; and if B cell-derived BDNF is impaired in aged females. We will use 4 mos. (young) and 16 mos. (aged) female and male mice to test if B cellsBDNF+ support neuronal function plasticity motor and multi-domain cognitive recovery post-stroke. Aim 1 will test if after stroke (1A) glutamate binds to B cells to increase BDNF production and drive recovery-linked intracellular Ca2+ signaling that is sex- and age-dependent. We will (1B) use B cellsNtrk2tm1Ddg/J in vitro totest if the BDNF receptor TrkB is required for BDNF production and in vitro neuroprotection. Aim 2 will test if B cellsBDNF+ support remote plasticity as well as cognitive and motor recovery in a primary motor cortex (M1) photothrombosis stroke model. Inducible depletion of (2A) all B cells or (2B) specific B cell-derived BDNF in young and aged female hCD20TamCre/ BDNFfl/fl mice and littermate controls will occur either acute (day 0) or delayed (beginning day 7 post-stroke). Primary outcomes will include 1) preservation of Pavlovian stimulus-reinforcer learning on an automated touchscreen task 2) improved forelimb precision reaching and 3) peri-infarct and contralesional M1 plasticity. Aim 3 will test if B cell-derived BDNF augments long-term cognitive and motor recovery. Aged C57BL/6J female mice will receive tMCAo or sham surgery and adoptive transfer of B cells that (3A) overexpress BDNF or (3B) lack BDNF the latter derived from hCD20TamCre/BDNFfl/fl donor mice beginning day 7 post-stroke. Primary outcomes will include 1) ameliorated hippocampal-specific cognitive deficits tested via touchscreen pattern separation 2) improved precision skilled reaching and 3) regional ipsi- and contralesional diapedesis of B cells as determined via whole brain serial two-photon tomography that correlates to within-animal magnitude of brain circuit-specific cognitive function and motor recovery. These studies will confirm an age-dependent loss of a novel subset of B cells B cellsBDNF+ in females that develop VCID. They will also confirm that therapeutically targeting B cells can counter post-stroke dementia and motor deficits a potential treatment supporting plasticity-based recovery after any CNS injury or disease.

project_terms:
Acute;Adult;Affect;Age;Anatomy;Animals;Anxiety;Area;Automobile Driving;Award;B-Cell Acute Lymphoblastic Leukemia;B-Cell Development;B-Lymphocyte Subsets;B-Lymphocytes;Binding;Brain;Brain region;Brain-Derived Neurotrophic Factor;Cell Survival;Cell secretion;Cell surface;Cells;Central Nervous System Diseases;Cognitive deficits;Data;Dementia;Development;Elderly woman;FDA approved;Female;Forelimb;Genetic Polymorphism;Genetic Transcription;Glutamates;Growth Factor;Health;Hippocampus;Immune;Immune system;Impaired cognition;Impairment;In Vitro;Individual;Infarction;Infiltration;Interleukin-10;Ischemia;Ischemic Stroke;Learning;Leukocytes;Link;Mediating;Memory;Middle Cerebral Artery Occlusion;Modeling;Motor;Motor Activity;Motor Cortex;Mus;N-Methyl-D-Aspartate Receptors;Neuronal Plasticity;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Pattern;Population;Production;Publishing;Recovery;Recovery Support;Recovery of Function;Research;Risk Factors;Role;Signal Transduction;Stimulus;Stroke;Support System;Synaptic Transmission;Tamoxifen;Techniques;Testing;Therapeutic;Up-Regulation;adoptive B cell transfer;age related;aged;aging population;automated assessment;central nervous system injury;cognitive function;cognitive recovery;dentate gyrus;disability;excitotoxicity;extracellular;functional plasticity;improved;in vitro testing;learning strategy;long term recovery;male;migration;motor deficit;motor function improvement;motor recovery;neuroinflammation;neuronal survival;neuroprotection;neurotrophic factor;novel;overexpression;patient population;post stroke;post stroke dementia;post stroke depression;preservation;primary outcome;reinforcer;response;rituximab;sex;sham surgery;skills;stroke model;stroke recovery;stroke risk;synaptogenesis;therapeutic target;tomography;touchscreen;two-photon;vascular cognitive impairment and dementia

public_health_relevance:
PROJECT NARRATIVEStroke the leading cause of long-term adult disability has no FDA-approved therapeutic treatments to boostlong-term recovery in part because we do not understand long-term mechanisms that influence recovery. Thisresearch proposes to identify mechanisms of neurotrophin support by B cells an immune cell subset thatmoves into uninjured areas of the post-stroke brain to support recovery. These studies will be critical inunderstanding how the immune system supports neuronal plasticity to improve long-term motor and cognitiverecovery after stroke with critical consideration of age and sex in the response of B cells to stroke.


application_id: 10795701
project_number: 4R01NS119165-02
project_title: Translational Approaches to Mitigate Enhanced Alzheimers Disease Risk Following a Mild TBI
administering_ic: NINDS
award_notice_date: 2024-04-16
opportunity_number: PA-19-056
application_type: 4
activity_code: R01
ic: NS
serial_number: 119165
program_official: AWWAD, HIBAH OMAR
project_start_date: 2021-04-01
project_end_date: 2026-02-28
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
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:
ABSTRACTA traumatic brain injury (TBI) is a well-known risk factor for Alzheimer's disease. There is not a one-to-onerelationship where a TBI will lead to the development of Alzheimer's disease. The lack of a direct connectionsuggests a selective vulnerability. Problematically when a person has a mild TBI it is not possible to know ifthey will recover without an impact on their brain health or if they have now increased their vulnerability todeveloping Alzheimer's disease. What can be done? One approach is a broad administration of therapy shortlyafter the injury. Since this approach requires treating some people who would recover from the TBI withoutintervention the benefit-to-risk ratio must be very high. That is you do not want to cause harm by giving anunneeded drug. Our long-term goal is to identify safe treatments to be used after a mild TBI in an older adultpopulation to lessen the chance of developing Alzheimer's disease. There are currently no FDA approveddrugs to be used after a mild TBI to reduce secondary injury mechanisms. We believe that not treating after amild TBI is a missed opportunity but the treatment needs to be safe. Our preliminary evidence shows that aTBI causes deficits in energy metabolism and increased neuroinflammation both of which are exacerbated bypreexisting proteinopathies such as amyloid-beta. To target these mechanisms we have identified Beta-hydroxybutyrate (BHB; 3-hydroxybutyric acid) as a safe multimodal intervention. BHB is a ketone body whichis continuously produced by the liver at low levels but can rise above 1mM during periods of fasting calorierestriction prolonged exercise or by the ketogenic diet. Clinically BHB is safe to be administered orally BHBrapidly crosses the blood-brain-barrier and in cases of starvation ketones can provide as much as 70% of thebrain's energy. BHB is an alternative biofuel that can bypass blockages in the electron transport systemcaused by amyloid-beta and TBI which decrease mitochondrial bioenergetics. BHB has also been shown tosuppress inflammation via an inflammasome-dependent mechanism and by binding to a recently deorphanizedGPCR called HCA2. We will test the central hypothesis that BHB will be effective at reducing functionaldeficits seen in APP/PS1 KI mice following a mild TBI through both energetic and neuroinflammatorydependent mechanisms in three specific aims (SA). SA1: Dose-dependent effects of BHB on mitochondrialfunction and neuroinflammation after TBI. SA2: Define the immunomodulatory properties of the HCA2receptor via dose-dependent effects of niacin a high-affinity HCA2 agonist. SA3: Define theimmunomodulatory properties BHB through the HCA2 receptor through loss of function experiment. Our workseeks to address the mechanisms associated with the increased fragility of the older brain which keeps it fromrecovering from a mild TBI. We also will define the therapeutic potential of the BHB/HCA2 axis as a post-TBIneuroprotective strategy for use in a population at risk for Alzheimer's disease.

project_terms:
APP-PS1;Acceleration;Acids;Address;Adult;Affinity;Age;Agonist;Agreement;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Assisted Living Facilities;Binding;Bioenergetics;Brain;Bypass;Caloric Restriction;Chronic;Clinical;Closed head injuries;Cognitive;Cognitive deficits;Complex;Data;Dementia;Development;Disease;Dose;Electron Transport;Energy Metabolism;Environmental Risk Factor;Epidemiology;Exercise;Experimental Designs;Exposure to;FDA approved;Family member;Fasting;G-Protein-Coupled Receptors;Goals;Head;Implant;Incidence;Independent Living;Individual;Inflammasome;Inflammation;Injury;Interleukin-1 beta;Intervention;Ketone Bodies;Ketones;Knock-in Mouse;Knockout Mice;Life;Liver;Measures;Microglia;Mitochondria;Mus;Neurodegenerative Disorders;Neurologic;Nicotinic Acids;Odds Ratio;Older Population;Oral Administration;Osmosis;Pathologic;Persons;Pharmaceutical Preparations;Population;Populations at Risk;Positron-Emission Tomography;Predisposition;Property;Pump;Radiology Specialty;Receptor Activation;Recovery;Reporting;Risk;Risk Factors;Risk Reduction;Societies;Starvation;System;TBI treatment;Testing;Therapeutic;Time;Traumatic Brain Injury;Work;beta amyloid pathology;beta-Hydroxybutyrate;blood-brain barrier crossing;brain health;demented;design;efficacious intervention;experience;experimental study;falls;human old age (65+);immunoregulation;ketogenic diet;loss of function;loved ones;medical attention;member;mild traumatic brain injury;mitochondrial dysfunction;modifiable risk;mouse model;multi-component intervention;neurodegenerative dementia;neuroinflammation;neuroprotection;older adult;pre-clinical;prevent;receptor;subcutaneous;translational approach;young adult;-amyloid burden

public_health_relevance:
A significant way to reduce the overall burden of Alzheimers disease is to identify modifiable risk factors whichcould be avoided or treated that would slow or prevent the onset of Alzheimers disease. Traumatic braininjury is a well-established environmental risk factor for the development of Alzheimers disease. Completion ofthese studies will uncover the largely unexplored therapeutic approach of Beta hydroxybutyrate for individualsexposed to a traumatic brain injury to reduce the risk of developing a neurodegenerative disease.


application_id: 10795313
project_number: 3P42ES007380-25S1
project_title: KC Donnelly Externship Admin Supplement for Victoria Klaus P42ES007380 UKSRC
administering_ic: NIEHS
award_notice_date: 2023-06-10
opportunity_number: PA-20-272
application_type: 3
activity_code: P42
ic: ES
serial_number: 007380
suffix: S1
program_official: HENRY, HEATHER F
project_start_date: 2023-06-10
project_end_date: 2024-01-31
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
KC Donnelly for Victoria Klaus P42ES00738025 PD/PI: Kelly PennellKCD Project Description (abstract):My current research within UKSRC Project 3 is to synthesize advanced sorbent materials with an affinityfor PFAS. These materials are currently being studied for their ability to remove PFAS from aqueoussystems but we plan to assess their efficacy as enterosorbents to remove these contaminants from thehuman body. PFAS have been connected to a series of adverse health effects and one of the mostcommon routes of PFAS exposure is through contaminated drinking water. Thus the removal of thesecontaminants from both drinking water and the human body is needed. Enterosorbents are orallyadministered sorbents that pass through the GI tract where they bind various substances withoutdisturbing other systems within the body prior to excretion. Importantly enterosorbents have beenshown to be a promising noninvasive therapeutic treatment approach for acute and chronic impacts ofchemical contaminant exposures. Together with TAMUSRC Project 5 and their established bioassaytechniques and ecotoxicological analyses we will analyze advanced sorbent materials developed atUKSRC for treatment of PFAS in water at TAMUSRC to determine their safety and efficacy asenterosorbents. Our advanced sorbents developed within UKSRC Project 3 will be screened to identifythose that exhibit the highest affinity for PFAS in preliminary aqueous studies at UK. These will beanalyzed for their enterosorbents applications using analytical technologies and bioassay methods aspart of TAMUSRC Project 5.

project_terms:
Acute;Affinity;Binding;Biological Assay;Chemicals;Chronic;Collaborations;Drug Metabolic Detoxication;Ensure;Excision;Excretory function;Exhibits;Exposure to;Gastrointestinal tract structure;Health;Human body;Hydrogels;Individual;Learning;Methodology;Methods;Oral Administration;Organism;Poly-fluoroalkyl substances;Polymers;Postdoctoral Fellow;Research;Research Project Grants;Review Literature;Route;Safety;Series;System;Techniques;Technology;Texas;Therapeutic;Toxic effect;Universities;Water;aqueous;contaminated drinking water;drinking water;experience;experimental study;externship;novel

public_health_relevance:
KC Donnelly for Victoria Klaus P42ES00738025 PD/PI: Kelly PennellProject NarrativeThe proposed research project that I would be performing during the KC Donnelly (KCD) externshipwould be focusing on the analysis of UKSRC-developed candidate advanced sorbent materials anddetermining their feasibility as enterosorbents to remove per- and polyfluoroalkyl substances (PFAS)from the GI Tract. While at Texas A&M I will conduct ecotoxicological analyses using a series of livingorganism assays established as part of TAMUSRC to determine the toxicity and detoxification potentialof UKSRC-developed advanced sorbent materials. This KCD will initiate a collaboration between theUKSRC and TAMUSRC and expects to increase the impacts of both centers.


application_id: 10794454
project_number: 3P20GM130456-04S1
project_title: Administrative Supplement: COBRE in Pharmaceutical Research and Innovation
administering_ic: NIGMS
award_notice_date: 2023-08-30
opportunity_number: PA-20-272
application_type: 3
activity_code: P20
ic: GM
serial_number: 130456
suffix: S1
program_official: FRINCU, CRINA
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: ZGM1(C1)
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
SUMMARY/ABSTRACT OF PARENT AWARD (P20 GM130456)The Center of Biomedical Research Excellence in Pharmaceutical Research and Innovation (CPRI) at theUniversity of Kentucky (UK) is a comprehensive multidisciplinary center focused on translational chemicalbiology [the nexus of chemical biology (the application of chemical biology principles to develop validatedprobe/models to advance our understanding of biology) and pharmaceutical science (the application ofpharmaceutical principles to advance leads/materials/devices that address unmet clinical needs)]. This Phase ICOBRE leverages and develops unique translational chemical biology research support infrastructure/expertiseto facilitate junior faculty mentorship and career development innovative biomedical researchprobe/tool/model/materials development and validation and the early advancement of potential translatableassets. Key COBRE infrastructure to be developed and implemented in Phase I includes the CPRI AdministrativeCore and two research support cores (the Translational Core and the Computational Core) and the COBRE willalso further develop and leverage the COBRE for Molecular Medicines Organic Synthesis Core to support CPRIjunior faculty projects/pilots. CPRI currently supports four outstanding junior investigators working in threetherapeutic areas (cancer infectious disease and tissue/bone regeneration). Our overarching hypothesis is that CPRIs translational chemical biology focus presents a distinctly uniqueUK platform to: i) engage integrate and mentor junior faculty from a broad range of fundamental applied andclinical disciplines; ii) facilitate the development of new impactful probes/tools/models and advance innovativetransdisciplinary research; and iii) bridge the gap between basic academic research discoveries andcommercial/clinical application via education mentorship and key support infrastructure. CPRIs distinct focuson translational chemical biology and early translation fills a notable preclinical research gap for many of UKsexceptional research centers strategically focused on understanding treating and preventing the major diseasesthat contribute to Kentuckys disproportionate health challenges. Anticipated COBRE outcomes include anincrease in the number and diversity of UK junior faculty engaged in translational chemical biology research andbetter-prepared to develop and employ innovative biomedical probes/tools/models/materials new sustainableUK translational chemical biology research support infrastructure and capabilities an increase in the number ofUK junior faculty with independent research funding and a boost in the number potentially translatable UKpreclinical assets.

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

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


application_id: 10793921
project_number: 1UC7AI180309-01
project_title: UofL RBL Pandemic Preparedness and Response Integrated Research Core
administering_ic: NIAID
award_notice_date: 2023-08-18
opportunity_number: RFA-AI-22-075
application_type: 1
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: Special Emphasis Panel[ZAI1 SJ-W (S1)]
subproject_number: 9959
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH 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:
SUMMARY: PANDEMIC PREPAREDNESS AND RESPONSE INTEGRATED RESEARCH SERVICES COREThe Pandemic Preparedness and Response Integrated Research Services Core (PaPR Core) shall support allRisk Group 3 (RG3) pathogen studies conducted at the University of Louisville (UofL) Regional BiocontainmentLaboratory (RBL). In alignment with the NIAID Pandemic Preparedness Mission the PaPR Core shall serveinvestigators at UofL our regional academic and industrial partners collaborating investigators in the NBL/RBLnetwork and other investigators who wish to avail of our facilities and expertise. The PaPR Core supports fundedresearch programs by providing scientific expertise on study design labor to support execution of both in vitroand in vivo BSL-3 studies and data analysis and interpretation services that culminate in issuing acomprehensive study report to the sponsor investigator. The PaPR Core shall operate on a cost-recoverybusiness model with revenue re-invested in core services. The aims of the PaPR Core are to: (1) Supportcontinuous refinement of RG3 pathogen infection models established at UofL RBL.; (2) Support continuousrefinement of RG3 pathogen infection models established at UofL RBL; (3) Enable investigations on the impactof aging and chronic metabolic disease on RG3 pathogen infections; and (4) Enable studies on the impact ofenvironmental toxicant exposure on RG3 pathogen infections.

project_terms:
Aging;Alcoholic Liver Diseases;Ally;Alphavirus;Animal Model;Arthritogenic;Attention;Autopsy;Blood Chemical Analysis;Businesses;COVID-19;Cardiometabolic Disease;Centers of Research Excellence;Chronic;Chronic Disease;Clinical;Collaborations;Communicable Diseases;Communities;Data;Data Analyses;Development;Disease;Disease Outcome;Elderly;Emerging Communicable Diseases;Ensure;Environmental Exposure;Environmental Impact;Environmental Medicine;Funding;Health;Hematology;Immunology;In Vitro;Industrialization;Infection;Investigation;Investigational Drugs;Investments;Japanese encephalitis virus;Laboratories;Measurement;Metabolic;Metabolic Diseases;Mission;Modeling;National Institute of Allergy and Infectious Disease;Outcome;Outcome Study;Pathogenesis;Pathology;Persons;Pharmacodynamics;Physiological;Positron;Positron-Emission Tomography;Powassan virus;Readiness;Recovery;Reporting;Reproducibility;Research;Research Design;Research Personnel;Risk;SARS-CoV-2 infection;Scanning;Semliki forest virus;Service delivery model;Services;System;Testing;Toxic Environmental Substances;Toxicant exposure;Translational Research;United States National Institutes of Health;Universities;Viral Pathogenesis;Virus;Virus Diseases;Vulnerable Populations;West Nile virus;Whole Body Plethysmography;Workforce Development;X-Ray Computed Tomography;chikungunya;cost;environmental toxicology;future pandemic;global environment;good laboratory practice;in vivo;in vivo Model;in vivo imaging;infectious disease model;instrument;instrumentation;medical countermeasure;mouse model;operation;pandemic potential;pandemic preparedness;pandemic response;pathogen;programs;pulmonary function;response


application_id: 10793920
project_number: 1UC7AI180309-01
project_title: UofL RBL BSL3 Practices and Workforce Development Core
administering_ic: NIAID
award_notice_date: 2023-08-18
opportunity_number: RFA-AI-22-075
application_type: 1
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: Special Emphasis Panel[ZAI1 SJ-W (S1)]
subproject_number: 9958
contact_pi_person_id: 7016711
contact_pi: SEVERSON, WILLIAM 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:
SUMMARY: BSL-3 PRACTICES AND WORKFORCE DEVELOPMENT COREThe BSL-3 Practices and Workforce Development Core (BSL-3 PWD) shall develop and maintain SOPsbiosafety and biosecurity plans and provide training for BSL-3 best practices to ensure a safe and secure workenvironment within the University of Louisville (UofL) Regional Biocontainment Laboratory (RBL). The BSL-3PWD Core will support the RBLs mission to provide a regional resource to facilitate research goals forbiodefense emerging infectious diseases and pandemic preparedness and response. The Core will provideBSL-3 practices training to investigators at UofL regional academic investigators with BSL-3 facilities andspecialized biosafety and biocontainment professionals and tradesmen who support the operations the UofLRBL and the RBL network. The specific aims of the BSL-3 PWD core to: (1) Provide laboratorians and personneltraining for BSL-3 best practices to ensure a safe and secure work environment within the RBL and support theRBLs mission; (2) Develop and maintain Standard Operating Procedures (SOPs) for personnel working in theBSL-3/ABSL-3 space in the RBL (3) Provide select agent training for handling of select agents inventory andaccountability; (4) Provide Operations and Maintenance training for specialized biosafety and biocontainmentprofessionals and tradespeople who support the operations of the RBL; and (5) Provide biosafety education andtraining for removal of materials and equipment from the BSL-3 policies for shipping and receiving materialsand waste management.

project_terms:
Accountability;Aromatase;Biological;Computer software;Dedications;Development;Emerging Communicable Diseases;Ensure;Environment;Equipment;Equipment and supply inventories;Evaluation;Excision;Exposure to;Goals;Hazardous Substances;Human Resources;Individual;Laboratories;Maintenance;Mentors;Mission;National Institute of Allergy and Infectious Disease;Policies;Principal Investigator;Procedures;Process;Protective Devices;Reporting;Research;Research Personnel;Resource Sharing;Resources;Secure;Security;Services;Shipping;Specialist;Toxin;Training;Training Programs;Training and Education;Universities;Update;Waste Management;Workforce Development;animal facility;biodefense;biosafety level 3 facility;biosecurity;meetings;microorganism;operation;pandemic preparedness;pandemic response;professional atmosphere;programs;wasting


application_id: 10793919
project_number: 1UC7AI180309-01
project_title: UofL RBL BSL3 Facility Management Maintenance and Operations Core
administering_ic: NIAID
award_notice_date: 2023-08-18
opportunity_number: RFA-AI-22-075
application_type: 1
activity_code: UC7
ic: AI
serial_number: 180309
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: Special Emphasis Panel[ZAI1 SJ-W (S1)]
subproject_number: 9957
contact_pi_person_id: 79041956
contact_pi: STEFFEN, MARLENE CLARKE
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:
SUMMARY: Facility Management Maintenance and Operations (FMMO) CoreThe Center for Predictive Medicine (CPM) Regional Biocontainment Lab at the University of Louisville wasdesigned and constructed following established guidelines to provide a safe facility for the trained and qualifiedpersonnel to work with hazardous pathogens while protecting themselves the community and environment. Inorder to assure that the structure and specialized content within hold up to the exceptional standards over theyears a highly skilled and dedicated team of individuals from all walks of life e.g. project management technicaltrades biosafety animal welfare security business services information technology and senior scientificprofessionals to name a few must combine their expertise to reach this goal. The CPM Facility OperationsManager is paramount in the success of the management maintenance and operations 24/7/365. Theestablished activities processes and workflows are based on risk assessment and communicated to allstakeholders. Preventive maintenance is the strategy employed to make certain preparedness is the foundationfor fulfilling the CPM mission. Each facet (management maintenance and operations) is essential to thereliability longevity and purpose set forth in 2009 and have an impeccable record to affirm its efficacy.In addition personnel must be familiar with the standard operating procedures safety protocols security accessmeasures emergency procedures BSL-3/ABSL-3 practices and are trained and educated annually to reviewrefresh and reinforce the basis of proper steps to safely complete their assigned tasks.Collaboration and communication with law enforcement Homeland Security FBI public health agenciesgovernment entities university and local subject matter experts other groups in the NBL/RBL Networkinspectors and service technicians all enhance the outcome.Based on our historical successes the contributions (impact commitment involvement dedication) of theFMMO Core provide the necessary assets for our expert scientists to be at the leading edge of infectiousdiseases research and readiness to respond for another pandemic.

project_terms:
Address;Administrator;Animal Welfare;Area;Businesses;Calibration;Certification;Collaborations;Communication;Communities;Containment;Contractor;Decontamination;Dedications;Development;Disinfectants;Emergency Situation;Ensure;Environment;Environmental Health;Equipment;Foundations;Gases;Goals;Government;Guidelines;Human Resources;IACUC;Individual;Infectious Diseases Research;Information Technology;Infrastructure;Law Enforcement;Life;Life Cycle Stages;Longevity;Maintenance;Measures;Medicine;Mission;Monitor;Motion;Names;Outcome;Pathogenicity;Persons;Phase;Preventive;Procedures;Process;Protocols documentation;Public Health;Publishing;Qualifying;Readiness;Recommendation;Regulation;Research;Research Personnel;Resources;Risk Assessment;Role;Running;Safety;Schedule;Scientist;Security;Services;Specialist;Structure;Surface;System;Testing;Time;Training;Universities;Update;Veterinarians;Walking;Work;Workforce Development;animal care;biosafety level 3 facility;biosecurity;chlorine dioxide;comparative;design;design and construction;experience;insight;intrusion detection system;member;operation;pandemic disease;pandemic preparedness;pathogen;repaired;research study;skills;success


application_id: 10793918
project_number: 1UC7AI180309-01
project_title: UofL RBL Operations Workforce Development and Pandemic Preparedness Research
administering_ic: NIAID
award_notice_date: 2023-08-18
opportunity_number: RFA-AI-22-075
application_type: 1
activity_code: UC7
ic: AI
serial_number: 180309
program_official: DIAZ SAN SEGUNDO, FAYNA C
project_start_date: 2023-08-18
project_end_date: 2028-07-31
study_section: Special Emphasis Panel[ZAI1 SJ-W (S1)]
contact_pi_person_id: 7245379
contact_pi: PALMER, KENNETH E
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
SUMMARY (OVERALL):The University of Louisville Regional Biocontainment Laboratory (RBL) is operated by the University Center forPredictive Medicine for Biodefense and Emerging Infectious Diseases (CPM). The RBL is a regional resourcethat facilitates translational research to develop diagnostics prognostics therapeutics and vaccines to mitigatebiodefense and emerging infectious disease threats. Our Center operates the only BSL-3 and ABSL-3 facilitiescurrently operating in the Commonwealth of Kentucky. The CPM mandate is to prepare for and respond to publichealth emergencies such as the COVID-19 pandemic.The broad long-range objectives and goals of the University of Louisville (UofL) CPM RBL are:1. To offer state-of-the-art research services to the regional and national biomedical research community to learn from past pandemics and biological warfare experiences and effectively predict and mitigate future emerging infectious disease threats.2. To manage maintain and operate the UofL RBL to serve the national and regional need for biocontainment facilities suitable for research on Risk Group 3 pathogens and other biothreats.3. To follow a philosophy of continuous improvement in BSL-3 and ABSL-3 work practices and to ensure that all personnel who need to access BSL-3 and ABSL-3 containment laboratories are appropriately trained and prepared to serve the national and regional need for biocontainment research professionals.To achieve these aims we propose to establish three collaborative Cores. The Facilities ManagementMaintenance and Operations Core (FMMO Core) is responsible for ensuring that the facility is always availableto meet the research and emergency preparedness mission of the RBL. The BSL-3 Practices and WorkforceDevelopment Core (BSL-3PWD Core) formalizes our mentor-mentee training plan to ensure our laboratory isstaffed with BSL-3 research professionals who are proficient at biocontainment research professionals. This coreresponds to the reality that response to rapidly emerging public health emergencies like COVID-19 is limited bythe number of available BSL-3 trained and experienced research professionals. Our Pandemic Preparednessand Response Integrated Research Core (PaPR Core) responds to the substantially increased requests for ourBSL-3 research services by organizing an integrated full-service BSL-3 research support function to supportinvestigator needs. These cores will work in unison to achieve the CPM mission: to prepare for and respond topublic health emergencies like the COVID-19 pandemic.

project_terms:
Attention;Biological Warfare;Biomedical Research;Biotechnology;COVID-19;COVID-19 pandemic;COVID-19 patient;China;Clinical Trials;Communities;Containment;Creativeness;Crowns;Dedications;Diagnostic;Disease Outbreaks;Economics;Emerging Communicable Diseases;Ensure;Federal Government;Funding Opportunities;Future;Goals;Health Services Research;Health care facility;Hospitals;Hour;Human Resources;Industry;Infection;Institution;International;Investigational New Drug Application;Kentucky;Laboratories;Leadership;Learning;Maintenance;Managed Care;Medicine;Mentors;Mission;Modeling;National Center for Advancing Translational Sciences;National Institute of Diabetes and Digestive and Kidney Diseases;Nose;Patients;Philosophy;Play;Public Health;Research;Research Personnel;Research Support;Resources;Rest;Reverse Transcriptase Polymerase Chain Reaction;Risk;Role;Scientist;Serology test;Services;System;Talents;Techniques;Testing;Therapeutic;Training;Translational Research;United States National Institutes of Health;Universities;University resources;Vaccines;Work;Workforce Development;biocontainment facility;biodefense;biothreat;cohort;emergency preparedness;experience;improved;laboratory experience;medical countermeasure;metropolitan;novel;novel coronavirus;operation;pandemic disease;pandemic preparedness;pandemic response;pathogen;previous pandemic;prognostic;prophylactic;public health emergency;recruit;response;service organization;skills;wastewater surveillance

public_health_relevance:
NARRATIVE (OVERALL):The University of Louisville Regional Biocontainment Laboratory (RBL) is a regional resource that facilitatestranslational research to develop diagnostics therapeutics and vaccines to mitigate biodefense and emerginginfectious disease threats. We propose to establish three cores that will work in unison to achieve the RBLmission to prepare and respond to public health emergencies like pandemics. The cores will be responsible forfacility management and operations; for training laboratory workers in safe BSL-3 work practices; and foroperating a full-service research support function for scientists who need to use the RBL.


application_id: 10793620
project_number: 5R13OH012359-03
project_title: SouthON Conference Grant
administering_ic: NIOSH
award_notice_date: 2023-12-01
opportunity_number: PAR-21-148
application_type: 5
activity_code: R13
ic: OH
serial_number: 012359
project_start_date: 2021-12-01
project_end_date: 2024-11-30
study_section: Safety and Occupational Health Study Section[SOH]
contact_pi_person_id: 8433958
contact_pi: SANDERSON, WAYNE T.
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-12-01
project_abstract:
Project Summary/AbstractThe occupational fatality rates in the Southeast region of the United States are 44% higher thanthe US fatality rate. In 2019 the overall occupational fatality rate for states in our region was 6.3deaths/100000 workers compared to 4.4/100000 for the US overall and higher in all individualstates (Bureau of Labor Statistics) except Virginia. The goal of the Southeastern StatesOccupational Health Network (SouthON) collaborative working meetings over the next threeyears will be to continue to build upon the foundation we have established for regionaloccupational health surveillance (OHS) capacity and research in the 12-state Southeastern USregion (Alabama Arkansas Florida Georgia Kentucky Louisiana Mississippi NorthCarolina South Carolina Tennessee Virginia and West Virginia). We will do this through:1) continued strong regional partnerships and collaborations among state health departmentsacademic partners internal National Institute for Occupational Safety and Health (NIOSH)researchers and surveillance experts NIOSH-funded agricultural research centers andeducation research centers (ERCs) other governmental agencies professional organizationsand occupational health and safety stakeholders; 2) data-driven development of occupationalinjury and illness research hypotheses; 3) southeastern occupational injury and illnesssurveillance and prevention activities; 4) state and southeast regional OHS capacity building;and 5) translation of occupational injury and illness research into public health practice. Theobjectives of our annual SouthON meetings are to: 1) develop common priorities for OHSepidemiological analyses and worksite interventions; 2) build collaborations with otheroccupational epidemiologists NIOSH academic colleagues Occupational Safety and HealthAdministration (OSHA) worker organizations and other OHS partners; 3) provide epidemiologyand program planning tools for OHS capacity building; and 4) promote scientific collaborationamong OHS partners in the Southeast region. NIOSH funds will support the SouthON meetingparticipants.

public_health_relevance:
Project Narrative This proposed project is relevant to public health by: 1) identifying industriesoccupations and worker populations at high risk for work injuries and illnesses in the southeastregion of the United States; 2) assessing risk factors trends and emerging occupational safetyand health issues; 3) improving and enhancing timely occupational injury and illnesssurveillance systems in the southeast region; and 4) working with regional industrial academicgovernmental and organizational partners to intervene to reduce workplace illnesses andinjuries.


application_id: 10792258
project_number: 3R35ES032876-03S1
project_title: Chromosome Instability Drives Metal-Induced Lung Cancer
administering_ic: NIEHS
award_notice_date: 2023-07-03
opportunity_number: PA-20-272
application_type: 3
activity_code: R35
ic: ES
serial_number: 032876
suffix: S1
program_official: CARLIN, DANIELLE J
project_start_date: 2021-08-01
project_end_date: 2029-06-30
study_section: ZES1(R3)
contact_pi_person_id: 6094413
contact_pi: WISE, JOHN PIERCE
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
PROJECT SUMMARY OF THE FUNDED PARENT GRANTLung cancer is the leading cause of cancer death with little improvement in survivability over many decades.Understanding and support for lung cancer have suffered from the stigma that the disease is merely aconsequence of tobacco use when in fact other agents are a major factor in the disease. Many people with lungcancer have never used tobacco and only a minority of tobacco users actually get lung cancer. However whilelung cancer kills more people than colon breast and prostate cancer combined it receives less federal fundingthan each of these cancers alone. Chromosome instability (CIN) is a hallmark of lung cancer. All establishedlung carcinogens cause CIN yet the mechanisms for how they do have received little attention. Metal exposureis a worldwide health concern. Metals cause lung cancer and carcinogenic metals are a component in tobacco.Metals are poor mutagens but potently induce CIN yet how metals cause lung cancer and CIN is poorlyunderstood. We focus our R35 program on understanding the mechanisms for how metal carcinogens induceCIN in lung cancer. We use hexavalent chromium [Cr(VI)] a human lung carcinogen of major public healthconcern as our primary metal of interest although we will compare Cr(VI) outcomes with other metal lungcarcinogens. We will study how Cr(VI) induces structural and numerical CIN considering human lung fibroblastepithelial and induced pluripotent stem cell models. We will progress our studies from individual cell types tomore complex three-dimensional mixed cell culture studies. We enhance and deepen our understanding ofthese mechanisms with a One Environmental Health approach which leverages the ability of wildlife to resistCr(VI)-induced CIN and provide novel insights into its carcinogenic mechanism. Moreover we maximize theimpact of these findings by translating our outcomes into animals and into a powerful and unique collection ofhuman subjects and populations ranging from workers with primarily Cr(VI) exposure to workers with a mixedmetal exposure including Cr. This combined approach of humans animals and cell lines with One EnvironmentalHealth tools will give us unprecedented insight into how metals induce structural and numerical CIN. In particularwe will define: 1) key mechanisms for metal-induced CIN; 2) how these mechanisms persist and are heritable atthe cellular level to cause neoplastic disease; and 3) how they translate to animals and humans. Thus ourproposed R35 program will revolutionize our understanding of Cr(VI) CIN metal carcinogenesis and lungcancer while also providing important insights for other cancers that involve CIN. Outcomes will include majorscientific breakthroughs in understanding: 1) how metals cause normal human lung cells to become neoplastic;2) how to detect this neoplastic transformation when it occurs; 3) how to more effectively target lung cells thathave transformed and 4) how to prevent neoplastic change from occurring leading to improved risk assessmenttreatments and health outcomes for people exposed to metals.

project_terms:
3-Dimensional;Acute;Address;Alligators;Animals;Attention;Autopsy;Cancer Etiology;Carcinogens;Cavia;Cell Culture Techniques;Cell Line;Cells;Cementation;Cessation of life;Chemicals;Chromosomal Instability;Collection;Colon Carcinoma;Complex;Cultured Cells;DNA Double Strand Break;DNA Repair;Data;Data Set;Disease;Dust;Dyes;Environmental Health;Epithelium;Ethics;Event;Experimental Designs;Exposure to;Fibroblasts;Filament;Funding;Hazardous Substances;Health;Heritability;Human;Individual;Ink;Laboratories;Leadership;Learning;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mentors;Metal Carcinogenesis;Metal exposure;Metals;Minority;Modeling;Morbidity - disease rate;Mutagens;Neoplastic Cell Transformation;Nucleoproteins;Outcome;Paint;Particulate;Persons;Pigments;Population;Professional Competence;Proteins;Public Health;Research;Resistance;Risk Assessment;Scientist;Study Skills;Testing;Tobacco;Tobacco use;Training;Translating;Translational Research;Translations;Underrepresented Minority;United States;Work;Workplace;carcinogenesis;carcinogenicity;cell type;chromium hexavalent ion;experience;experimental study;fighting;homologous recombination;human subject;improved;induced pluripotent stem cell;innovation;insight;interest;malignant breast neoplasm;metabolomics;mixed cell culture;neoplastic;novel;novel strategies;parent grant;prevent;programs;recombinational repair;repaired;response;skills;social stigma;stem cell model;tobacco user;tool;transcriptomics;zinc chromate

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


application_id: 10792148
project_number: 1G08LM014412-01
administering_ic: NLM
award_notice_date: 2023-12-20
opportunity_number: PAR-20-283
application_type: 1
activity_code: G08
ic: LM
serial_number: 014412
program_official: SMITH, CRISTAN
project_start_date: 2024-01-01
project_end_date: 2026-12-31
study_section: Special Emphasis Panel[ZLM1 ZH-G (01)]
contact_pi_person_id: 11808630
contact_pi: WHITE, BRANDI MICHELLE
other_pis: Not Applicable
congressional_district: 06
department: OTHER CLINICAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-01-01
project_title:
DASH-ing to Heart Health: Supporting Low-Income African American Women with an Interactive "Meals that Heal" Resource Book

project_abstract:
Although the DASH diet [Dietary Approaches to Stop Hypertension] has been shown tosignificantly reduce the risk of hypertension and other cardiovascular disease risk factors thereis a lack of available health information on how to follow a feasible DASH diet for low-incomeAfrican American women who may be at the most risk for hypertension because of poor socialdeterminants of health. The long-term goal of this project is to increase the accessibility andacceptability of culturally- and economically-responsive dietary approaches to reducehypertension risk for low-income African American women. The overall goal of this project is tocreate a useful and usable interactive resource book that increases awareness/knowledge ofhypertension and improves ease of following a DASH diet by providing culturally relevant andlow-cost DASH recipes that low-income African American women can utilize when making hearthealthy food choices. The specific aims are to: (1) evaluate how currently available DASHrecipes perform in terms of cultural relevance and economic feasibility; (2) describe what factorsinfluence adherence to the DASH diet; and (3) determine how effective an interactive resourcebook is at increasing DASH knowledge and the likelihood of using DASH recipes. The first aimwill use an integrative review to synthesize related literature. The second aim will explorebarriers and facilitators to DASH adherence including dietary preferences and food budgetarydecision making. The third aim will evaluate the effectiveness of the resource throughcommunity-based food demonstration workshops. This proposed project is innovative becauseit focuses on adherence to DASH diet and low-income African American women a group that isdisproportionately impacted by hypertension. The proposed project is significant becausefindings will increase the availability of accessible and usable evidence-based health informationfor health disparity populations. This knowledge has the potential to increase the adherence tothe DASH diet and overall effectiveness of existing interventions which is critical to reducinghypertension disparities.

project_terms:
Adherence;Adopted;Adult;Affect;African American;African American Women;African American population;American;Asian Women;Awareness;Behavioral;Books;Budgets;Cardiac health;Cardiovascular Diseases;Communities;Complex;DASH diet;Decision Making;Diastolic blood pressure;Diet;Diet Modification;Disease Management;Disparity;Eating;Economics;Educational workshop;Effectiveness;Family;Family member;Financial Hardship;Food;Goals;Government;Health;Health Care Costs;Health Food;Healthy Eating;Heart;Hispanic Women;Hypertension;Information Resources;Intervention;Interview;Knowledge;Literature;Low Income Population;Low income;Marketing;Outcome;Pathway interactions;Peer Review;Persons;Primary Prevention;Professional Organizations;Psychosocial Stress;Public Housing;Publications;Recipe;Research;Research Project Grants;Resources;Risk;Risk Factors;Risk Reduction;Social Environment;Social support;Subgroup;United States National Library of Medicine;Woman;adherence rate;blood pressure reduction;built environment;cardiovascular disorder risk;community-centered;cost;dietary;dietary adherence;dietary approach;disorder prevention;economic disparity;effectiveness evaluation;evidence base;food insecurity;food quality;good diet;healing;health disparity populations;high risk;hypertension control;hypertension prevention;improved;informant;innovation;lifestyle intervention;preference;prevent;racial discrimination;social health determinants;socioeconomics;usability

public_health_relevance:
The "Meals that Heal" project will develop disseminate and evaluate a useful and usableinteractive health information resource for low-income African American women and othereconomically-disadvantaged African Americans. The interactive resource book will providetailored health information about hypertension risk reduction and the DASH diet [DietaryApproaches to Stop Hypertension] including culturally relevant and low-cost DASH recipesfor hypertension disease prevention or management. The resource book will be marketed toa broader audience through existing community-based partnerships and networks.


application_id: 10791929
project_number: 5R21CA277314-02
project_title: A Stem Cell Based Exosomal Vaccine for the Prevention of Cancer
administering_ic: NCI
award_notice_date: 2024-01-31
opportunity_number: PAR-20-292
application_type: 5
activity_code: R21
ic: CA
serial_number: 277314
program_official: VLAD, ANDA MIOARA
project_start_date: 2023-02-17
project_end_date: 2026-01-31
study_section: ZCA1-TCRB-Q(O1)S
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: LI, CHI
congressional_district: 03
department: SURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACT Lung cancer is a prevalent disease and consume many lives every year. Disease relapse invasion andmetastases are the main causes of death. Recent discoveries provide compelling evidence that at least sometypes of cancer are initiated and maintained by a small population of malignant cells called cancer-initiatingstem cells (CICs). Relapse invasion and metastases are explained by the fact that CICs have a differentbiology than all the other tumor cells and importantly are resistant to chemotherapies and radiation. LungCICs have been shown to represent about 115% of all tumor cells and can form tumors with injections as lowas 100 cells. Evidence from published studies have demonstrated that human as well as rodent cancerscontain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteinsalso express markers used to identify lung CICs; therefore we hypothesized that ES cells and CICs shareseveral common molecular traits. To test this hypothesis we vaccinated mice with exosomes derived from EScells expressing GM-CSF and investigated whether an anti-tumor immune response was elicited. Wediscovered that ES cell-derived exosome-based vaccination strategy (ES-exo vaccine) is very effective inpreventing both implantable and carcinogen-induced lung adenocarcinoma development without anydetectable toxicity or signs of autoimmunity. Recently published results from our laboratory reveal thatsplenocytes from ES cell-immunized mice are preferentially cytotoxic to lung CICs. Experiments proposed inthis application seek to expand these novel findings to convincingly demonstrate that ES-exo vaccineimmunize against lung cancer-associated CICs and that anti-CIC immunity is responsible for preventing lungadenocarcinoma development. The anti-tumor activities of ES-exo vaccine as well as their immunostimulatoryproperties will be investigated in in vitro and in vivo lung cancer mouse models. Experiments proposed in thisstudy will address the translational potential of our novel ES-exo vaccine as a cell-free prophylactic vaccinemodality in implantable transgenic and xenograft mouse models of lung cancer. One of the major goals of thisapplication is to identify tumor antigens important for anti-lung cancer efficacy of ES-exo vaccine using aproteomics-based screening methodology. To fulfill the stated objectives the following aims are proposed: 1)Investigate whether lung cancer-initiating cells are targets of ES cell-derived exosomes (ES-exo) vaccination-induced anti-tumor immunity and 2) Evaluate the translational potential of ES cell-derived exosomes (ES-exo)as a novel cell-free vaccine for lung cancer. Our proposed study will provide important insights towardsdeveloping a safe prophylactic vaccine for lung cancer onset and/or recurrence.

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

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


application_id: 10789054
project_number: 3R01DA057605-01S1
project_title: Diversity Supplement - Rapid Actionable Data for Opioid Response in Kentucky (RADOR-KY)
administering_ic: NIDA
award_notice_date: 2023-05-31
opportunity_number: PA-21-071
application_type: 3
activity_code: R01
ic: DA
serial_number: 057605
suffix: S1
program_official: KURAMOTO-CRAWFORD, SATOKO JANET
project_start_date: 2022-09-30
project_end_date: 2025-09-29
contact_pi_person_id: 12111311
contact_pi: SLAVOVA, SVETLA STEFANOVA
other_pis: TALBERT, JEFFERY C
congressional_district: 06
department: BIOSTATISTICS & OTHER MATH SCI
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractOpioid use disorder (OUD) is a major public health concern with opioids being involved inapproximately 75% of the 107622 overdose deaths reported by the Centers for Disease Control(CDC) in 2021. Overdose rates have risen in recent years and substantial resources areinvested in combatting OUD at the national and local levels. Coordination of efforts to combatOUD may be the key to reducing overdose deaths. To this end the RADOR-KY project will builda robust state-wide surveillance system integrating diverse data sources to monitor and predictdrug overdose mortality and morbidity. This system will be used by stakeholders to inform data-driven action supporting the coordination and targeting of prevention and treatment efforts. Asproposed in the parent grant for this supplement the RADOR-KY system will integrate severaldata sources related to OUD prevention and treatment efforts. However there are gaps in thedata that is available to RADOR-KY. Kentucky does not have an all-payer claims database andso data about residential OUD treatment and treatment support systems can only be obtainedfrom Medicaid beneficiaries. In this proposal we will supplement the RADOR-KY efforts usingan informatics approach to capture data about treatment and recovery support services fundedby the Kentucky Opioid Response Effort (KORE) a state-administered and federally fundedprogram aimed at reducing overdose death and expanding access to treatment and supportservices. KORE funds treatment support services (e.g. peer support recovery communitycenters) and for uninsured and underinsured people medication and residential treatment.KORE data is currently collected for reporting to the Substance Abuse and Mental HealthAdministration but the existing approach is unstandardized leading to inefficiencies delaysand quality issues that make KORE data unsuitable for use in RADOR-KY. The specific aims ofthis project are to build a new platform for KORE agencies to submit standardized data improving data ingestion through automated validation  and then to create near-real timevisualizations and analyses that will allow KORE agencies and other stakeholders to refine andtarget their efforts to combat OUD. This data will be integrated into RADOR-KY supporting theaims of the parent grant by improving the surveillance database and predictive models. We willshare the code and methods developed for this project publicly allowing other agencies withinand beyond Kentucky to improve their analytic and planning capabilities. This will be especiallyhelpful for administering State Opioid Response efforts in other states.

project_terms:
Algorithms;Area;Centers for Disease Control and Prevention (U.S.);Cessation of life;Code;Communities;County;Custom;Data;Data Collection;Data Linkages;Data Reporting;Data Sources;Databases;Decision Making;Developmental Disabilities;Ecosystem;Emergency Care;Evidence based treatment;Focus Groups;Funding;Grant;Harm Reduction;Health Services Accessibility;Individual;Informatics;Insurance;Intellectual functioning disability;Investments;Kentucky;Leadership;Link;Machine Learning;Medicaid;Mental Health;Methods;Monitor;Morbidity - disease rate;Online Systems;Opioid;Overdose;Overdose reduction;Performance;Persons;Pharmaceutical Preparations;Predictive Analytics;Prevention;Process;Public Health;Recovery;Recovery Support;Reporting;Residential Treatment;Resource Allocation;Resources;Risk;Secure;Services;Source;Standardization;Statistical Models;Substance abuse problem;Support System;System;Techniques;Time;Transportation;Underinsured;Uninsured;United States Substance Abuse and Mental Health Services Administration;Validation;Visual;Visualization;Visualization software;Work;behavioral health;beneficiary;combat;community center;computerized data processing;dashboard;data infrastructure;data ingestion;data lake;data standards;data submission;data visualization;design;disorder prevention;diverse data;health administration;improved;inpatient service;insight;medication for opioid use disorder;mortality;novel;opioid overdose;opioid use disorder;overdose death;overdose prevention;parent grant;peer support;population based;predictive modeling;prevent;programs;recovery services;response;service utilization;surveillance data;treatment services;trend;web app

public_health_relevance:
Project NarrativeThis project will create a new system for capturing data from agencies receiving KentuckyOpioid Response Effort (KORE) funding to provide treatment and support services for peoplewith opioid use disorder. Data will undergo automated validation and be used to generate near-real time insights about trends in service utilization. The data will also be used in the RADOR-KY surveillance ecosystem expanding and improving the surveillance dashboards andpredictive modeling used to coordinate and target resources for preventing overdose deaths.


application_id: 10788368
project_number: 5R24OD010435-22
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2024-02-09
opportunity_number: RFA-OD-19-027
application_type: 5
activity_code: R24
ic: OD
serial_number: 010435
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2026-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-G(55)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: SMITH, JERAMIAH JAMES
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
This application proposes to develop fundamental genomic and bioinformatic resources that will better enablestudies of the axolotl (Ambystoma mexicanum). The axolotl provides the best model for identifying mechanismsof regeneration that can translate to humans. This is because it can regenerate multiple damaged body partsincluding whole limbs spinal cord and brain and because it shares tetrapod biology with human. Understandinghow axolotls regenerate complex tissues may reveal mechanisms to activate stem cells within human tissues toorganize and reform damaged tissues. Beyond regeneration the axolotl presents many untapped diseasemodels that were identified and rigorously examined with traditional developmental approaches before thegenetics/genomics era. With our recent development of the first chromosome-scale assembly of the axolotlgenome these and new models that will be created in coming years through genome editing can be advancedfor the first time to significantly impact biomedical research. However to advance these models improvementsof the genome assembly are needed along with new datasets to enable genome-wide studies of the large axolotlgenome. To accomplish these objectives we propose three specific aims. In Aim 1 we will resolve inter- andintra-specific variation within the current assembly and resolve complex repetitive regions that have hamperedthe placement of ~6 Gb of the 32 Gb genome. Specifically we will employ a powerful trio binning strategy thattakes advantage of long read sequencing of DNA from axolotl x tiger salamander (A. tigrinum) hybrids. Thisapproach leverages decades of experience in generating interspecific hybrids to resolve assembly gaps/errorsand accurately place gene models within their non-coding regulatory environments. Additionally we will analyzesequence data from 10 AGSC axolotls from branches of the pedigree that optimally sample laboratory geneticdiversity. In Aim 2 we will perform Chip-Seq to identify changes in histone post-translational modifications duringtail and limb regeneration. Characterization of epigenetic marks for embryo larval and adult models ofregeneration will provide new resources for regeneration research and advance community efforts in performinggenome wide studies. Aim 3 will address significant community needs user-friendly access to large scalegenomic datasets and improvement of genomic and bioinformatic capabilities of investigators in the axolotlcommunity. Accomplishment of these aims will significantly advance axolotl as an animal model for biomedicalresearch.

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

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


application_id: 10788348
project_number: 5P40OD019794-10
project_title: Ambystoma Genetic Stock Center
administering_ic: OD
award_notice_date: 2024-01-25
opportunity_number: PAR-17-006
application_type: 5
activity_code: P40
ic: OD
serial_number: 019794
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-03-01
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZRG1-GGG-D(50)R]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: SOCIAL SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
OVERALL COMPONENT - PROJECT SUMMARYThis application seeks support to continue operations of the Ambystoma Genetic Stock Center (AGSC) at theUniversity of Kentucky (UK). The AGSC is the only federally funded resource center that distributes Mexicanaxolotls (Ambystoma mexicanum) a salamander that provides living materials in support of biomedicalresearch nationally and internationally. Most notably axolotls are unique among vertebrates in being able toregenerate numerous tissues and body parts. These include the spinal cord limbs jaw retina brain heartand tail all of which can be regenerated at any point during embryonic larval and adult life. Also axolotls areused by researchers that work in additional areas including neurobiology ecotoxicology developmentphysiology cell biology genetics genomics and evolution. This is an exciting time for the axolotl as itsincredibly large genome (32 Gb) was recently sequenced and assembled. New and assessable resources areallowing cutting edge technologies like gene-editing and single cell RNA sequencing to be performed for thefirst time approaches that are rapidly accelerating discoveries using axolotl models. In just the past 4 yearsNIH support for axolotl research has tripled and there has been a significant increase in transgenic and knock-out lines in the community. PIs in the salamander community recently came together to discuss futureopportunities and challenges and the enabling role the AGSC will play in moving community efforts forward.During the previous funding period the AGSC moved internally from the College of Arts and Sciences to theCollege of Medicine (COM) at UK. This move has strengthened the AGSC in several significant ways thatclearly demonstrate long term commitment by the host institution for this irreplaceable resource. Specificallyfunding was made available to replace re-circulating systems and create a more user friendly website tofacilitate axolotl stock purchasing and more efficiently disseminate information that is useful for working withaxolotls. Additionally COM-UK has extensive experience working with university core research centers andthus provides a more stable administrative environment to support AGSC business activities and to betterensure regulatory compliance and animal health and welfare. Over the next 5 years the AGSC will build uponcurrent momentum by maintaining and generating high quality axolotl stocks that are needed by a growingnumber of NIH-funded investigators. Husbandry and management practices will be modified to increaseavailability of post-embryonic stocks that are seeing increasing demand by researchers. Also transgenic andknock-out stocks will be prioritized for import into the AGSC and cryopreservation methods will be developed topreserve and more efficiently manage stocks. The AGSC will continue to serve as an informatics hub whereinvestigators obtain information about the collection technical procedures potential collaborators andresearch findings. Overall the project will ensure distribution and long-term sustainability of axolotl resourcesto NIH-funded investigators.!

project_terms:
Acceleration;Adolescent;Adult;Ambystoma;Ambystoma mexicanum;Animals;Area;Arts;Awareness;Biological;Biomedical Research;Body part;Brain;Breeding;Businesses;Cellular biology;Collaborations;Collection;Communities;Computers;Cryopreservation;Custom;Development;Disease;Education;Embryo;Embryonic Development;Ensure;Environment;Evolution;Funding;Future;Genes;Genetic;Genome;Genomics;Germ;Health;Heart;Hour;Human;IACUC;Informatics;Infrastructure;Institution;International;Jaw;Kentucky;Knock-out;Life;Limb structure;Louisiana;Medicine;Methods;Modeling;Natural regeneration;Neurobiology;Newsletter;Online Systems;Organ Model;Physiology;Play;Population;Postembryonic;Practice Management;Procedures;Protocols documentation;Reproducibility;Research;Research Personnel;Research Support;Resources;Retina;Role;Salamander;Science;Shipping;Site;Spinal Cord;System;Tail;Technology;Time;Tissues;Transgenic Organisms;Translating;United States National Institutes of Health;Universities;Vertebrates;Work;animal resource;college;cost;experience;genetic resource;knowledge base;learning strategy;meetings;operation;organ regeneration;preservation;single-cell RNA sequencing;sperm cell;sperm cryopreservation;statistics;timeline;tissue repair;user-friendly;web site;welfare

public_health_relevance:
PROJECT NARRATIVELiving stock resources are needed for the Mexican axolotl so that investigators can developresearch models and translate biological information that is relevant to human health anddisease. The Mexican axolotl is a primary vertebrate model for organ regeneration tissuerepair and post-embryonic development.


application_id: 10786763
project_number: 1R21NS135089-01
project_title: Cannabidiol (CBD) as a Potential Therapeutic for Experimental Subarachnoid Hemorrhage
administering_ic: NINDS
award_notice_date: 2023-12-05
opportunity_number: PA-21-219
application_type: 1
activity_code: R21
ic: NS
serial_number: 135089
program_official: KOENIG, JAMES I
project_start_date: 2023-12-05
project_end_date: 2025-11-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 11256608
contact_pi: ROBERTS, JILL MARIE
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTSubarachnoid hemorrhage (SAH) commonly caused by a ruptured aneurysm carries a high rate of disabilityand death. Preclinical studies demonstrate SAH induces dysregulation of the cerebrovasculature which con-tributes to early brain injury and delayed cerebral ischemia. Few treatment options currently exist for SAHpatients making it imperative to identify novel therapies to improve outcomes following SAH. Cannabidiol(CBD) has gained attention for its potential therapeutic properties and widespread mechanistic actions. Firstutilized for the treatment of pain preclinical studies demonstrate CBD has anti-inflammatory neuroprotectiveand vascular stabilization properties in experimental models of injury. However understanding of the effectsof CBD on blood vessels in the brain is limited and no studies have directly investigated CBD as a treatmentfor SAH representing critical gaps in knowledge. The overall objectives of this application are to determinethe therapeutic potential of CBD for SAH injury and identify processes by which CBD improves vascularhealth. The central hypothesis is that daily CBD treatment improves vascular integrity to increase cerebralblood flow (CBF) and prevent DCI thereby improving functional outcomes and mortality following SAH. Therationale for this project is that determination of CBDs therapeutic efficacy in SAH will generate a strongscientific framework from which new strategies for SAH therapy can be developed. The central hypothesiswill be tested by pursuing two specific aims: 1) Determine CBDs efficacy to improve functional outcomes andmortality following SAH and 2) Identify the impact of CBD therapy on cerebral microvessel pathology follow-ing SAH. Under the first aim multiple doses of CBD will be tested in mice following SAH injury (endovascularperforation) to determine the most effective dose that improves sensory/motor function and cognitive out-comes and reduces mortality. For the second aim the efficacy of CBD to reduce the development of vaso-spasm and blood-brain barrier leakage will be investigated utilizing intravital microscopy and ex vivo micro-Computed Tomography imaging. The research proposed in this application is innovative because it proposesthe use of a compound with a wide variety of molecular targets capable of ameliorating multiple aspects ofSAH pathology. The proposed research is significant because it is expected to provide scientific justificationfor the continued mechanistic investigation of CBD as a much-needed novel therapeutic for SAH patientsadvancing the field of stroke research.

project_terms:
Address;Adult;Affect;Age;Aneurysmal Subarachnoid Hemorrhages;Anti-Inflammatory Agents;Arteries;Attention;Blood - brain barrier anatomy;Blood Vessels;Blood brain barrier dysfunction;Blood-Retinal Barrier;Brain;Brain Injuries;Cannabidiol;Cerebral Ischemia;Cerebrovascular Circulation;Cerebrovascular Spasm;Cerebrovascular system;Cessation of life;Cognitive;Data;Death Rate;Development;Dose;Experimental Models;Extravasation;Feedback;Female;Functional disorder;Future;Health;Hemorrhage;Image;In Vitro;Incidence;Injury;Investigation;Iron Overload;Knowledge;Light;Marketing;Mediating;Medical;Mission;Molecular Target;Motor;Mus;Outcome;Pain management;Pathology;Patients;Perforation;Peripheral;Permeability;Policies;Process;Productivity;Property;Public Health;Quality of life;Relaxation;Reporting;Research;Retina;Risk;Ruptured Aneurysm;Safety;Science;Sensory;Severities;Stroke;Subarachnoid Hemorrhage;Testing;Therapeutic;Treatment Efficacy;United States National Institutes of Health;Vasospasm;Work;blood-brain barrier permeabilization;cerebral microvasculature;cerebrovascular;cost;disability;functional improvement;functional outcomes;immune cell infiltrate;improved;improved outcome;innovation;intravital microscopy;male;microCT;mortality;neuroprotection;novel therapeutics;pre-clinical;preclinical study;prevent;repaired;therapeutically effective

public_health_relevance:
NARRATIVEThe proposed research is relevant to public health because subarachnoid hemorrhage is a worldwide problemwith a high rate of disability and death in working age adults leading to high costs and loss in productivity.This project is focused on developing cannabidiol as an effective therapeutic for subarachnoid hemorrhageto improve vascular health and functional outcomes. Thus the proposed research is relevant to the NIH mis-sion to reduce illness and enhance quality of life.


application_id: 10786376
project_number: 1R01HL171763-01
project_title: Cardiopulmonary Toxicity of Electronic Nicotine Delivery Systems
administering_ic: NHLBI
award_notice_date: 2023-12-14
opportunity_number: RFA-OD-21-002
application_type: 1
activity_code: R01
ic: HL
serial_number: 171763
program_official: POSTOW, LISA
project_start_date: 2023-12-14
project_end_date: 2028-11-30
study_section: Special Emphasis Panel[ZRG1 ICN-E (56)]
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
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:
Cardiopulmonary Toxicity of Electronic Nicotine Delivery SystemsAlthough electronic nicotine delivery systems (ENDS) are widely used by youth and young adults the toxicityand the health effects of these products remain unclear. Many types of devices with varying constituents havebeen introduced into the market making it difficult to ascribe toxicity to a specific class of products or to studytheir long-term health effects. ENDS produce volatile organic compounds (VOCs) such as formaldehyde andacrolein which are generated by the thermal degradation of e-liquids containing propylene glycol:vegetableglycerin (PG:VG) and may lead to adverse health effects. Nevertheless the dependence of VOC generation one-liquid composition and constituents nicotine and other ingredients has not been studied and the contributionsof different constituents to the potential harmful effects of e-cigarettes remain unclear. Therefore within theframework of a regulatory context we plan to study the cardiovascular and pulmonary toxicity of e-cigaretteaerosols over a wide range of operating conditions and use patterns to provide rigorous and comprehensive datapertinent to the regulation of new and emerging devices by the US Food and Drug Administration (FDA). Basedon our previous work we propose that device-specific cardiovascular and pulmonary effects of e-cigarettes arein large part mediated by the extent of VOCs generation and toxicity which are modified by co-exposure tonicotine and other e-liquid ingredients as well as individual use patterns.

project_terms:
Acrolein;Address;Aerosols;Affect;Animal Model;Biological Markers;Carbon Monoxide;Cardiac;Cardiopulmonary;Cardiovascular Physiology;Cardiovascular system;Characteristics;Data;Dependence;Development;Devices;Electronic Nicotine Delivery Systems;Electronic cigarette;Evaluation;Exposure to;Flavoring;Formaldehyde;Generations;Health;Individual;Link;Lung;Marketing;Measures;Mediating;Metals;Modeling;Mus;Nicotine;Pattern;Policies;Production;Propylene Glycols;Protocols documentation;Public Health;Regulation;Risk;Role;Solvents;Tars;Technology;Testing;Toxic effect;United States Food and Drug Administration;Urine;Work;Youth;biomarker identification;combustible cigarette;design;disorder risk;e-cigarette aerosols;electronic cigarette use;electronic liquid;evidence base;hemodynamics;manufacture;nicotine exposure;novel;pod mods;pollutant;pulmonary function;tobacco advertising;tobacco products;vegetable glycerin;volatile organic compound;young adult

public_health_relevance:
Cardiopulmonary Toxicity of Electronic Nicotine Delivery SystemsIn the proposed studies we will investigate the cardiovascular and pulmonary toxicity of ENDS using animalmodels and state-of-the-art exposure technology protocols and biomarkers of exposure and of harm. As suchwe will directly address the Scientific Domain of Toxicity and thus will provide the FDA/CTP with rigorous andvalidated data to support policies regulating the design manufacturing and marketing of e-cigarette devices inorder to protect public health.


application_id: 10785724
project_number: 1R21AI180274-01
project_title: Molecular mechanisms of Helicobacter pylori trans-kingdom DNA conjugation
administering_ic: NIAID
award_notice_date: 2023-11-22
opportunity_number: PA-20-195
application_type: 1
activity_code: R21
ic: AI
serial_number: 180274
program_official: BAQAR, SHAHIDA
project_start_date: 2023-12-01
project_end_date: 2025-10-31
study_section: Bacterial-Host Interactions Study Section [BHI]
contact_pi_person_id: 11309989
contact_pi: SHAFFER, CARRIE
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARYOf the recognized infection-associated malignancies the most significant carcinogenic microbe is the gastricbacterium Helicobacter pylori which chronically colonizes the stomach of over half of the global population andcontributes to the development of more than one million new cases of cancer per year. Despite many decadesof research we do not fully understand how H. pylori balances interactions with the human host to stimulate thedevelopment of gastric disease. The cancer-associated H. pylori cag type IV secretion system (cag T4SS) hasemerged as a paradigm for understanding how a single molecular device transports diverse immunostimulatorycargo into target eukaryotic cells. Whereas some T4SSs have the capacity to secrete multiple protein effectorsthe ability to translocate a pro-inflammatory bacterial oncoprotein and a repertoire of DNA and polysaccharidesubstrates distinguishes the cag T4SS from other nanomachines. In exciting new studies we discovered thatcag T4SS-dependent trans-kingdom DNA conjugation stimulates cytosolic nucleic acid reconnaissance systemsto provoke the production of multifarious interferons and inflammatory cytokines that orchestrate diverse immuneresponses. Our long-term objective is to mechanistically characterize how the dynamic cag T4SS transportscarcinogenic molecular cargo into gastric cells. Towards our objective we aim to define the kinetics andbiogeography of cag T4SS-dependent DNA translocation in vivo and delineate the mechanism by whichchromosomal DNA cargo is excised and coupled to the cag T4SS apparatus. Our studies will employ rodentinfection models high-resolution microscopy biochemical approaches and immunological assays to addresslongstanding knowledge gaps in gastric cancer biology and uncover microbial mechanisms that are involved inthe development of pre-malignant lesions. Collectively these investigations will advance our understanding ofimportant host-pathogen conflicts that engage nucleic acid surveillance pathways to regulate host immunity andtrigger microbial carcinogenesis. Furthermore our studies will provide the foundational framework for developingnew treatment and intervention strategies to reduce the incidence and severity of malignancies that arise as aconsequence of infection-induced chronic inflammation.

project_terms:
Address;Bacteria;Biochemical;Biological;Biological Assay;Biology;Cancer Biology;Carcinogens;Cells;Chronic;Coupled;DNA;DNA delivery;DNA relaxase;Data;Development;Devices;Disease Outcome;Eukaryotic Cell;Future;Gastritis;Goals;Helicobacter Infections;Helicobacter pylori;Human;Immune response;Immune signaling;Immunity;Immunologic Surveillance;Immunology procedure;Incidence;Infection;Inflammation;Inflammatory;Interferons;Intervention;Investigation;Isomerism;Kinetics;Knowledge;Lesion;Malignant Neoplasms;Mediating;Microbe;Microscopy;Modeling;Molecular;Nucleic Acids;Oncogenic;Oncoproteins;Orthologous Gene;Outcome;Pathway interactions;Polysaccharides;Population;Production;Proteins;Reporter;Research;Resolution;Risk Factors;Rodent;Role;Severities;Signal Transduction;Stomach;Stomach Diseases;System;Type IV Secretion System Pathway;Virus;Work;carcinogenesis;carcinogenicity;cytokine;endonuclease;in vivo;infection related cancer;innovation;malignant stomach neoplasm;microbial;mouse model;nanomachine;novel therapeutic intervention;pathogen;premalignant;secretion process;segregation;translational study;transposon/insertion element;tumorigenesis

public_health_relevance:
PROJECT NARRATIVEHelicobacter pylori chronically colonizes the stomach of more than half of the global population and is thestrongest known risk factor for the development of gastric cancer. The proposed studies will explore themechanisms by which H. pylori delivers microbial DNA into gastric cells trigger innate immune signaling. Theseinvestigations will advance our understanding of how an important bacterial carcinogen regulates host immunityto promote chronic inflammation and stimulate the development of stomach malignancies.


application_id: 10784982
project_number: 1R61MH132722-01A1
project_title: Using Exercise to Enhance Consolidation of Exposure-Based Therapeutic Learning in PTSD
administering_ic: NIMH
award_notice_date: 2024-02-16
opportunity_number: PAR-21-135
application_type: 1
activity_code: R61
ic: MH
serial_number: 132722
suffix: A1
program_official: TUMA, FARRIS KEITH
project_start_date: 2024-02-16
project_end_date: 2026-01-31
study_section: Special Emphasis Panel[ZMH1 ERB-N (06)]
contact_pi_person_id: 10372293
contact_pi: BADOUR, CHRISTAL L.
other_pis: ADAMS, THOMAS G;CISLER, JOSHUA M
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project SummaryThe proposed R61/R33 project would build on our published pilot data and animal models to demonstrate thatmoderate intensity physical exercise delivered after exposure therapy engages fear circuitry and enhances theconsolidation of therapeutic safety learning thereby enabling enhanced symptom reduction for PTSD. In theR61 target engagement phase adults with PTSD related to interpersonal violence (IPV) exposure wouldcomplete an initial session of imaginal exposure to traumatic memory cues adapted for an MRI setting. Thiswould be followed by 30-mins of moderate intensity exercise or low intensity walking control. Participantswould return 24-hrs later to complete a second session of imaginal exposure with MRI. We hypothesize greaterbetween-session reductions in fear responding and fear circuit activation to traumatic memory cues 24-hrslater among those who exercised following the first session compared to those in the walking control condition.The R33 phase will build upon successful target engagement and adapt a brief version of prolonged exposure(PE) therapy to include moderate-intensity exercise or walking control after imaginal exposure. We hypothesizethat PE with exercise will result in more rapid and larger reductions in PTSD symptoms and reduced fear-related neurocircuitry activation and affective arousal to trauma cues compared to PE plus walking control.Overall this project is designed to demonstrate that a novel intervention (moderate intensity exercise) engageskey mechanisms of therapeutic exposure thereby enhancing the efficacy of exposure therapy.

project_terms:
Acute;Adult;Aerobic Exercise;Affective;Aftercare;Amygdaloid structure;Animal Model;Anterior;Anxiety;Arousal;Biological Markers;Brain-Derived Neurotrophic Factor;Cardiovascular Diseases;Clinical assessments;Cues;Diagnosis;Disease;Dorsal;Emotional;Event;Exercise;Exercise Test;Exposure to;Extinction;Fright;Functional Magnetic Resonance Imaging;Heart Rate;Insula of Reil;Interpersonal Violence;Intervention;Knowledge;Learning;Magnetic Resonance Imaging;Measures;Mediating;Memory;Mental Depression;Monitor;Neurobiology;Participant;Patient-Focused Outcomes;Peripheral;Phase;Physical Exercise;Post-Traumatic Stress Disorders;Psyche structure;Psychopathology;Psychophysiology;Psychotherapy;Publishing;Randomized;Reporting;Safety;Signal Transduction;Symptoms;Testing;Therapeutic;Trauma;Visit;Walking;Writing;anxiety reduction;anxious;candidate marker;comorbidity;data modeling;design;exercise intensity;follow-up;heart rate monitor;improved;indexing;learning extinction;neural;neural circuit;novel;prevent;psychoeducation;psychologic;reduce symptoms;self-reported anxiety;therapy outcome;trauma exposure;traumatic event;treadmill;treatment planning;violence exposure

public_health_relevance:
Project NarrativeThe proposed project would explore the viability of moderate intensity exercise delivered following exposuretherapy as a novel means of enhancing consolidation of therapeutic safety learning and exposure therapies.This knowledge has the potential to increase therapy outcomes for patients with PTSD and related disorders.


application_id: 10783919
project_number: 1K99AG084892-01
project_title: Gabapentin prescription and health-related outcomes in older adults
administering_ic: NIA
award_notice_date: 2023-12-15
opportunity_number: PA-20-188
application_type: 1
activity_code: K99
ic: AG
serial_number: 084892
program_official: MARTIN, DAMALI
project_start_date: 2023-12-15
project_end_date: 2025-11-30
study_section: Career Development Facilitating The Transition to Independence Study Section[AGCD-1]
contact_pi_person_id: 78323710
contact_pi: OH, GYEON
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractGabapentin currently approved to treat partial seizures and postherpetic neuralgia wasthe 6th most commonly prescribed medication in the US in 2018. Notably close to 95% of gabapentinprescriptions are for off-label indications such as neuropathic pain migraines substance use disorder andpsychiatric symptoms. Gabapentin's widespread use may be driven by a belief that it is a safer drug thanopioids and antipsychotics. However there is an increasing concern about the safety of gabapentin use andseveral studies have reported that gabapentin has the potential for misuse and abuse. In particular althoughgabapentin prescription has dramatically increased in older adults our understanding of gabapentin use in thispopulation is limited. Due to gabapentin's known binding site alpha-2-delta-1 which has a relationship withcalcium channel NMDA receptor and thrombospondin it is possible that gabapentin could affect older adults'cognition and motor functions. To fill in the research gap this study proposes to assess longitudinal patterns ofgabapentin use in older adults and to estimate the risk of health-related outcomes associated with gabapentinprescriptions using Medicare claims data and linked Rush Alzheimer Disease Center-Medicare data. Aim 1 willdetermine the distinct patterns (e.g. duration of use concurrent medications history of medication prior togabapentin initiation) of gabapentin use and examine the factors including demographics and medical historyassociated with each pattern. This aim will provide clinically relevant characteristics of gabapentin users tofurther investigate. Aim 2 will examine the association of gabapentin use with health-related outcomesincluding falls fractures neurocognitive changes hospitalizations emergency department visits and mortality.These associations will be estimated marginal structural models by considering time-varying exposure patternsand time-varying confounders including concurrent use of other medications and medical history. Thisproposal fits into the National Institute on Aging's special interest of research on pain pain management andopioids in aging. Through completing this project Dr. Oh will gain experience in real-world evidence studies and expandher toolbox to serve her professional future as a neuro-pharmacoepidemiologist. Since medication use and itseffects is highly influenced by policy this project will build Dr. Oh's knowledge of the process of translatingresearch into policy. Lastly Dr. Oh will sharpen essential professional skills such as grant writing networkingand mentoring. She will be guided by a strong interdisciplinary mentoring team with collective expertise inneuroepidemiology pharmacoepidemiology health-related outcomes policy and biomedical informatics.Findings from this study will help healthcare providers and policymakers better understand the risks andbenefits of prescribing gabapentin to older adults and will provide the baseline knowledge for furtherinvestigation into establishing the causal relationship between gabapentin and health-related outcomes.

project_terms:
Adult;Affect;Aging;Alzheimer's Disease;Alzheimer's disease related dementia;Analgesics;Antipsychotic Agents;Autopsy;Behavior;Belief;Benefits and Risks;Benzodiazepines;Binding Sites;Breathing;Calcium Channel;Central Nervous System;Central Nervous System Depressants;Characteristics;Clinical;Cognition;Cognitive;Data;Data Coordinating Center;Data Reporting;Data Set;Dementia;Diagnosis;Drug Prescriptions;Drug usage;Emergency department visit;Enrollment;Ensure;Focal Seizure;Fracture;Future;Goals;Grant;Health;Health Expenditures;Health Personnel;Healthcare;Hospitalization;Impaired cognition;Investigation;Knowledge;Label;Link;Manuscripts;Measures;Medical History;Medicare;Medicare claim;Medicine;Mentors;Methods;Migraine;Motor;N-Methyl-D-Aspartate Receptors;National Institute on Aging;Neurocognitive;Neuroepidemiology;Nursing Homes;Opioid;Oral;Outcome;Pain;Pain management;Patient-Focused Outcomes;Pattern;Pharmaceutical Preparations;Pharmacoepidemiology;Policies;Policy Maker;Population;Postherpetic neuralgia;Preparation;Process;Psychiatric therapeutic procedure;Recording of previous events;Reporting;Research;Risk Estimate;Role;Safety;Sample Size;Selection Bias;Structural Models;Substance Use Disorder;Surveys;Thrombospondins;Time;Translating;United States Centers for Medicare and Medicaid Services;United States Food and Drug Administration;Writing;anti-depressive agents;behavior change;beneficiary;biomedical informatics;career;clinically relevant;demographics;evidence base;experience;fall risk;falls;functional decline;gabapentin;improved;interest;mortality;motor behavior;neuropathology;off-label use;older adult;painful neuropathy;psychiatric symptom;skills;treatment risk;trend

public_health_relevance:
Project NarrativeAlthough gabapentin has been increasingly prescribed in the older adults as off-label indication the potentialhealth effects of gabapentin use on older adults are not well studied. This proposal will investigate the patternsof gabapentin use in older adults and the healthcare-related outcomes associated with gabapentin use. Thisstudy will provide healthcare providers and policymakers with a better understanding of the use and potentialhealth outcomes associated with gabapentin use in older adults.


application_id: 10782971
project_number: 5R25GM148314-02
administering_ic: NIGMS
award_notice_date: 2024-02-09
opportunity_number: PAR-20-066
application_type: 5
activity_code: R25
ic: GM
serial_number: 148314
program_official: AKACEM, LAMEESE DANA
project_start_date: 2023-02-10
project_end_date: 2025-01-31
study_section: Training and Workforce Development Study Section - C[TWD-C]
contact_pi_person_id: 7770672
contact_pi: ALARD, PASCALE
other_pis: BERTOCCI, KAREN L.;CORBITT, CYNTHIA ;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
budget_start_date: 2024-02-01
project_title:
University of Louisville Biomedical Integrative Opportunity for Mentored Experience Development -PREP (UL-BIOMED-PREP)

project_abstract:
AbstractThere is strong evidence for a significant race and gender gap in academia and first generation graduates faceinequity in becoming tenured faculty. Moreover Kentucky (KY) is a state with a large economicallydisadvantaged population including first generation/rural graduates who are underrepresented in STEM fields.A highly effective approach to remediating the paucity of diversity in STEM is to provide underrepresentedstudents with the tools they need to apply to and succeed in graduate school. The goal of the University ofLouisville (UofL) Biomedical Integrative Opportunity for Mentored Experience Development-PREP (UL-BIOMED-PREP) is to train the next generation of underrepresented scientists in STEM fields including MedicineDentistry Arts and Sciences and Engineering. UL-BIOMED-PREP is a unique integrated education programamong these four schools; it will provide students from Kentucky and surrounding areas who areunderrepresented in the STEM fields with extensive mentored development and research opportunities in thesedisciplines with access to a large array of scientific projects tailored courses designed to develop skills that willprepare students to successfully apply to and complete graduate school and cohort-building activities gearedtoward building resiliency and developing critical thinking and life-long learning skills necessary for becoming ascientific leader. There are currently no PREP programs in Kentucky and this initiative aligns very well with thecurrent strategic plan of UofL to pursue inclusiveness in education. Seven to eight UL-BIOMED-PREP scholarswill be recruited from the UofL and regional programs/colleges geared to facilitate achievement ofunderrepresented students in STEM with an emphasis on African American and Latino first generationgraduates and economically underserved students from both rural and urban areas in KY. A personaldevelopment plan will be developed for each scholar at the start of the program based on individual skills andneeds that will be re-evaluated regularly. An experienced research mentor will be chosen at the end of twolaboratory rotations a research committee assigned to evaluate monthly progress and a student mentorassigned to provide personalized advising. UL-BIOMED-PREP scholars will present any program outcomeregularly at regional/national meetings and via social media. In addition to courses designed to aid in thepreparation of graduate school applications and complete graduate school monthly career developmentactivities will help foster an inclusive community networking and help scholars develop confidence and a growthmindset. Internal and External Advisory Committees will regularly evaluate the program and provide ongoingfeedback that will be used to improve the program. Upon program completion UL-BIOMED-PREP scholars willpossess improved research and analytical skills a better understanding of graduate school expectations andthe resiliency and self-confidence to handle the challenging demands of graduate school. Our goal is to reachthe target of 85% of UL-BIOMED-PREP scholars being admitted and completing graduate school.

project_terms:
Academia;Achievement;Address;Admission activity;Advisory Committees;African American;Applied Skills;Area;Arts;Biomedical Research;Books;Cardiovascular system;Collaborations;Communication;Communities;Critical Thinking;Data;Dental Faculty;Dentistry;Development;Development Plans;Discipline;Economically Deprived Population;Education;Educational workshop;Engineering;Environmental Health;Ethical Issues;Face;Faculty;Feedback;Fostering;Future;Gender;Generations;Goals;Growth;Hispanic;Historically Black Colleges and Universities;Individual;Inequity;Information Literacy;Journals;Kentucky;Laboratories;Latino;Learning Skill;Medical Faculty;Medicine;Mentors;Methodology;Minority Participation;Outcome;Postbaccalaureate;Principal Investigator;Publishing;Race;Reporting;Research;Research Project Grants;Research Training;Rotation;Rural;STEM field;Scholars Program;School Dentistry;Schools;Science;Scientist;Series;Speed;Strategic Planning;Students;Time;Training;Underrepresented Students;United States National Institutes of Health;Universities;career;career development;cohort;college;design;disadvantaged student;economic disparity;education research;expectation;experience;falls;graduate school;graduate school preparation;improved;innovation;interest;learning strategy;life-long learning;medical schools;meetings;next generation;oral communication;programs;promote resilience;recruit;remediation;research and development;research facility;resilience;rural area;skill acquisition;skills;social media;student mentoring;student participation;success;summer research;tool;training opportunity;translational neuroscience;undergraduate student;underserved students;urban area

public_health_relevance:
Project NarrativeBecause of the Kentucky's large economically disadvantaged population and the race and gender gapin academia it is imperative to provide underrepresented students in Kentucky with the tools they willneed to apply and succeed in graduate school. The overall objective of this research education programis to recruit and train the next generation of underrepresented scientists in the STEM fields bydeveloping a unique integrated education program among faculty of the Medical Dental Arts andSciences and Engineering schools at the University of Louisville. This program will provide studentsfrom Kentucky and surrounding area underrepresented in STEM extensive research training in variousbiomedical disciplines and development of various skills necessary to become successful scientistsand of a strong sense of belonging in science.


application_id: 10782687
project_number: 1R21CA280141-01A1
project_title: Lectikines for Immunotherapy against Ovarian Cancer
administering_ic: NCI
award_notice_date: 2024-02-01
opportunity_number: PAR-22-216
application_type: 1
activity_code: R21
ic: CA
serial_number: 280141
suffix: A1
program_official: HARRIS, RAYMOND D
project_start_date: 2024-02-01
project_end_date: 2026-01-31
study_section: Special Emphasis Panel[ZCA1 RTRB-S (O1)]
contact_pi_person_id: 8640855
contact_pi: MATOBA, NOBUYUKI
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
SUMMARYThe goal of this project is to create a novel immunotherapeutic drug candidate against ovarian cancer (OVCA).OVCA is the leading cause of death from gynecological malignancy in the United States with poor survival ratesdue to late diagnosis and chemo-resistant fatal recurrent disease after the first-line debulking surgery andchemotherapies. Immune checkpoint inhibitors have thus far failed to show a significant clinical benefit due tohighly immunosuppressive tumor microenvironment and poor infiltration of T cells. Thus the development ofeffective OVCA immunotherapy requires novel strategies. To address this problem the proposed project willcreate novel immunotherapeutic proteins based on Avaren lectin. It is a small 14-kDa recombinant proteinengineered in the PIs laboratory from a natural actinomycete lectin which selectively recognizes a cluster ofhigh-mannose glycans that are prevalent on the surface of enveloped viruses and malignant cells. A fusionprotein consisting of Avaren lectin and human IgG1 Fc (AvFc) was previously shown to exhibit potent antiviraland antitumor activities without toxicity in in vitro and in vivo animal models. Based on growing evidenceindicating that high-mannose overaccumulation also occurs on the surface of OVCA cells we hypothesize thatAvaren lectin can be utilized in novel OVCA-targeting strategies. Our preliminary data show that AvFc efficientlybinds to OVCA but not to adjacent normal tissues. AvFc elicited potent antibody-dependent cell-mediatedcytotoxicity (ADCC) against OVCA cell lines. Furthermore AvFc treatment exhibited moderate yet statisticallysignificant efficacy extending the survival of animals in a syngeneic orthotopic murine OVCA model using theID8 cell line. Building on these data in this project we will create immunostimulatory variants of Avaren lectinthat can transform OVCA into more immunologically hot tumors thereby exhibiting potent immunotherapeuticefficacy. Specifically we will engineer translational fusion proteins consisting of Avaren lectin / AvFc and anantitumor cytokine (lectikines). In Aim 1 we will generate lectikines by fusing a variant of IL-2 devoid of CD25binding (IL-2v) or IL-15 to AvFc which will be produced in Nicotiana benthamiana plants using a transientoverexpression system. After thorough purification we will assess their molecular properties OVCA cell-bindingaffinity and cytokine functions in a battery of biochemical biophysical and cell-based assays. In Aim 2 we willevaluate the therapeutic effects of lectikines in comparison with AvFc in a murine ID8 OVCA model. Diseaseprogression will be monitored through abdomen circumference body weight and live animal bioluminescenceimaging. Immunophenotyping of peritoneal cells will be performed by flow cytometry. We anticipate that lectikineswill elicit significant efficacy through increased immune activation in the tumor microenvironment. Successfulcompletion of this pilot project will establish an initial proof-of-concept and generate a compelling data set forfurther investigation and development of a first-in-class OVCA immunotherapy.

project_terms:
Abdomen;Actinobacteria class;Address;Affinity;Animal Model;Animals;Anti-viral Agents;Antineoplastic Agents;Binding;Biochemical;Biological;Biological Assay;Biological Products;Biophysics;Body Weight;C57BL/6 Mouse;Cancer Model;Cancer cell line;Cause of Death;Cell Line;Cell surface;Cells;Chemoresistance;Chimeric Proteins;Clinical;Data;Data Set;Development;Diagnosis;Disease Progression;Engineering;Enzyme-Linked Immunosorbent Assay;Euthanasia;Exclusion;Exhibits;Flow Cytometry;Foundations;Goals;HIV;High Pressure Liquid Chromatography;Human;IL2RA gene;IgG1;Immune;Immune checkpoint inhibitor;Immunocompetent;Immunohistochemistry;Immunologics;Immunophenotyping;Immunotherapeutic agent;Immunotherapy;Implant;In Vitro;Infiltration;Interleukin-15;Interleukin-2;Investigation;Laboratories;Lectin;Malignant Breast Neoplasm;Malignant Female Reproductive System Neoplasm;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of ovary;Mannose;Measurement;Melanoma;Modeling;Molecular;Monitor;Mus;Nicotiana;Non-Small-Cell Lung Carcinoma;Normal Cell;Normal tissue morphology;Operative Surgical Procedures;Ovary;Patients;Peritoneal;Peritoneal lavage;Pilot Projects;Plant Viruses;Plants;Polysaccharides;Primary Neoplasm;Property;Protein Engineering;Proteins;Recombinant Fusion Proteins;Recombinant Proteins;Recurrent disease;Series;Site;Skin Cancer;Spleen;Surface;Surface Plasmon Resonance;Survival Rate;System;T cell infiltration;Therapeutic Effect;Tissues;Toxic effect;Tumor Debulking;United States;Variant;Viral;Viral Physiology;Virus;Western Blotting;Xenograft Model;analog;antibody-dependent cell cytotoxicity;antitumor effect;antiviral immunity;bioluminescence imaging;biophysical properties;cancer cell;cancer immunotherapy;cancer therapy;chemotherapy;cytokine;design;drug candidate;experience;experimental study;expression vector;human model;immune activation;immunogenicity;improved;in vitro Assay;in vivo;manufacture;monocyte;neoplastic cell;novel;novel strategies;ovarian neoplasm;overexpression;preclinical development;recruit;targeted agent;therapeutic evaluation;tumor;tumor growth;tumor microenvironment;tumor-immune system interactions

public_health_relevance:
NARRATIVEThis project will generate novel immunotherapeutic drug candidates against ovarian cancer based on lectikineswhich are recombinant fusion proteins consisting of the tumor glycobiomarker-targeting lectin Avaren and anantitumor cytokine. We will design and produce several lectikine constructs and evaluate them in in vitro assaysand in a mouse ovarian cancer model. Successful completion of this pilot project will establish an importantproof-of-concept data package justifying further preclinical development of our first-in-class immunotherapeuticcandidate for ovarian cancer.


application_id: 10782521
project_number: 5K08AI151100-06
project_title: Defining the impact of zinc on Streptococcus agalactiae biofilm and colonization
administering_ic: NIAID
award_notice_date: 2024-02-14
opportunity_number: PA-19-117
application_type: 5
activity_code: K08
ic: AI
serial_number: 151100
program_official: GU, XIN-XING
project_start_date: 2020-03-09
project_end_date: 2026-02-28
study_section: Microbiology and Infectious Diseases B Research Study Section[MID-B]
contact_pi_person_id: 12264080
contact_pi: DOSTER, RYAN S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryDuring pregnancy zinc deficiency is associated with an increased risk of infection. Streptococcus agalactiaealso known as Group B Streptococcus (GBS) colonizes 20-30% of pregnant women. GBS vaginal colonizationincreases the risk for stillbirth preterm labor and neonatal sepsis. One strategy that GBS may use to stablycolonize the reproductive tract is to produce biofilm and we have found that GBS biofilm production issuppressed in the presence of zinc. This proposal tests the hypothesis that GBS biofilm production isnegatively regulated by zinc and this biofilm contributes to stable colonization of host tissues by limiting innateimmune responses against GBS. To test this hypothesis Aim 1 will use mutagenesis and transcriptomicapproaches to identify genetic pathways regulating GBS biofilm. Aim 2 will define the impact of zinc-regulatedbiofilm at the host-microbial interface by evaluating GBS mutants lacking cadD a zinc efflux transporter whichresults in impaired biofilm production. We will examine these interactions using in vitro models of humanvaginal epithelial cells explanted human fetal membranes and an Instrumented Fetal Membrane Organ on aChip (IFMOC) model under conditions that modify zinc availability. Aim 3 will use a mouse vaginal colonizationmodel to define how the zinc transporter cadD impacts vaginal colonization in settings of zinc deficiency orsupplementation. Completion of these Aims will shed new light on how zinc impacts GBS-host interactions thatculminate in colonization (and infection) of the reproductive tract.Dr. Ryan Doster is an Instructor in the Division of Infectious Diseases at Vanderbilt University Medical Center.His past work investigated gestational tissue innate immune responses to infection. This project will expand hisresearch focus to mechanisms of GBS colonization. This project complements Dr. Dosters clinical training inpediatrics and adult infectious diseases medicine. Under the mentorship of Dr. David Aronoff Dr. JenniferGaddy and a multidisciplinary Scholarship Oversight Committee Dr. Doster will master techniques includingbacterial mutagenesis transcriptomics and modeling infection within the reproductive tract to determine howzinc alters bacterial physiology and pathogenesis. Vanderbilt offers cutting-edge technology and expertise inthese areas through Vanderbilt Technologies for Advanced Genomics and other shared research corefacilities. These studies and a strong career development program will prepare Dr. Doster for transition to anindependent researcher investigating the pathogenesis of bacterial infections during pregnancy.

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

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


application_id: 10782489
project_number: 5R21AG077495-02
project_title: Drug repurposing for Alzheimers disease-related inflammation caused by a TBI
administering_ic: NIA
award_notice_date: 2023-11-29
opportunity_number: PAR-22-094
application_type: 5
activity_code: R21
ic: AG
serial_number: 077495
program_official: ARUNKUMAR, NANDINI
project_start_date: 2023-02-15
project_end_date: 2024-12-31
study_section: Special Emphasis Panel[ZRG1-BDCN-A(55)R]
contact_pi_person_id: 10095513
contact_pi: BACHSTETTER, ADAM D
other_pis: GENSEL, JOHN C
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTThe CDC estimates that at least 200000 older Americans (> 65 years) will have a traumatic brain injury (TBI)each year primarily caused by a closed head injury (CHI) from a fall. The aged brain with Alzheimers diseaseneuropathological changes has significant reactive microglia and astrocytes and other markers ofneuroinflammation. An acquired brain injury can further exacerbate this state of reactive gliosis andneuroinflammation. Alzheimers disease poses a significant therapeutic challenge given that pathology candevelop over decades. However we believe that it is an obtainable therapeutic goal to prevent the worseningof neuroinflammation caused by an acquired brain injury in those at risk for developing Alzheimers disease .Control of neuroinflammation following the TBI in older adults is a promising avenue for improving patientoutcomes. However no drug has earned FDA approval for specific use in mild TBI. There is also limitedevidence to guide the repurposing of FDA-approved drugs that target neuroinflammation for this uniquepopulation. Broad-spectrum immunosuppressants are not advisable and while selective biologics (such asanti-TNF) are promising they also come with the risk of increasing infection which is problematic in an olderadult population at risk for infections. Our goal is to identify targeted immunomodulatory (notimmunosuppressants) with a high benefit-to-risk ratio. We recently identified the commonly prescribedantibiotic Azithromycin (AZM) as an immunomodulatory agent with neuroprotective effects in spinal cordinjury. Because of its safety profile AZM is frequently prescribed as a prophylactic treatment in severalconditions and broadly administered in at-risk disease populations. This proposal aims to provide proof-of-principal data for AZM as a safe and effective neuroinflammatory modulatory drug. We will test the centralhypothesis that AZM can alter neuroinflammation and improve cognitive outcomes following a CHI in anAPP/PS1 KI mouse model of Alzheimers disease-related pathology in the following two specific aims (SA). SA1: Define the immunomodulatory dose-dependent effect of AZM in 8-month-old APP/PS1 KI mouse model following a CHI. SA2: Evaluate the effects of AZM on CHI-induced behavioral and Alzheimers disease-related neuropathology in 8-month-old APP/PS1 KI mice.This proof-of-concept study could establish AZM as a safe and well-tolerated FDA-approved drug to reducedamage and speed recovery in the fragile older brain following a CHI. Once the feasibility of AZM treatmenthas been established new areas of drug development and clinical research with the potential to more quicklydevelop a new drug to slow the devastating effects of Alzheimers disease can be created.

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

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


application_id: 10781992
project_number: 5R01DA054347-03
administering_ic: NIDA
award_notice_date: 2024-01-31
opportunity_number: PA-20-183
application_type: 5
activity_code: R01
ic: DA
serial_number: 054347
program_official: WANG, JIA BEI
project_start_date: 2022-04-15
project_end_date: 2027-02-28
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
budget_start_date: 2024-03-01
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;Cannabis policy;Clinical Research;Complement;Data;Dose;Double-Blind Method;Dronabinol;Enrollment;FDA approved;Impairment;Individual;Inhalation;Inpatients;Life;Maintenance;Marijuana;Measures;Medical Marijuana;Methadone;Modeling;Naltrexone;Opiate Addiction;Opioid;Oral;Oral Administration;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;US State;Ventilatory Depression;Withdrawal;abuse liability;cannabis administration;cannabis withdrawal;clinical practice;design;drug misuse;effective therapy;epidemiology study;high risk population;illicit drug use;innovation;marijuana use;medication for opioid use disorder;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

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: 10781979
project_number: 5R01DK095662-13
project_title: The Role of Crypt Fissioning in IBD Ulcer Healing
administering_ic: NIDDK
award_notice_date: 2024-02-08
opportunity_number: PA-18-330
application_type: 5
activity_code: R01
ic: DK
serial_number: 095662
program_official: SENGER, STEFANIA
project_start_date: 2021-02-24
project_end_date: 2026-01-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Program Director/Principal Investigator (Barrett Terrence A):The importance of mucosal healing in inflammatory bowel disease (IBD) derives from clinical data thatdemonstrate it to be a predictor of remission1. Thus ulcer healing predicts the capacity for therapies to preventunwanted clinical sequelae (i.e. surgery). Unfortunately many IBD patients remain refractory or loseresponsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies show thatreduced mitochondrial gene expression predict unfavorable outcomes in ulcerative colitis (UC)2. These findingswere supported by Kugathasan et al who found that increased expression of mitochondrial respiratory chaingenes predicted favorable (B1 protected) Crohns disease (CD) outcomes3. Based on these results and ourown data we hypothesize that a critical driver of chronic ulceration in IBD is the failure of intestinalepithelial cells (IEC) to increase mitochondrial respiration with ROS generation. We posit that chronicmucosal inflammation suppresses mitochondrial respiration needed for crypt fissioning (in ulcer healing) inIBD. This hypothesis will be tested in the following studies: Aim 1. Determine the impact ofmitochondrial respiration for mucosal healing. These studies benefit from strikingly novel Prelim.Data using VilCre/mTmG/TFAMfl/fl mice where mitochondrial respiration was shown to be required forcrypt fissioning in ulcer healing. In Aim 2 we will determine the requirement of mitochondrial-derived ROS in IEC crypt division using primary human colonoids. Aim 3 studies will determinethe impact of chronic inflammation on ulcer healing in patients. IEC transcriptomics from ulceredges from CD and ulcerative colitis will be compared to normal ulcer healing. Normal ulcer healingwill be interrogated using a novel biopsy of a biopsy (Bx/Bx) approach (IEC will be isolated fromBx/Bx sites 4-6day after initial biopsies). ScRNAseq results have already shown that mitochondrialbiogenesis (PGC1) increases in Bx/Bx ulcers whereas levels drop in IBD IEC. In summary: Studieswill investigate the cause of non-healing ulceration in IBD by interrogating novel murine humanand in vitro colonoid culture models of determining the impact of suppressed mitochondrial respirationon IEC responses (crypt fissioning). The studies will test the notion that chronic mucosalinflammation (as in IBD) suppresses mitochondrial respiration which impedes ROS-inducedPI3K signaling and crypt fissioning. Our goal is to identify therapeutic targets to allow for enhancedmitochondrial respiration to aide mucosal repair in IBD.OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

project_terms:
Biochemical;Biogenesis;Biopsy;Childhood;Chronic;Clinical;Clinical Data;Clinical Research;Colitis;Crohn's disease;Data;Disease;Disease Outcome;Disease remission;Drops;Epithelial Cells;Failure;Gene Expression;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Human;In Vitro;Inflammation;Inflammatory Bowel Diseases;Injury;Intestines;Investigation;Knockout Mice;Leukocyte L1 Antigen Complex;Maintenance;Measures;Mitochondria;Modeling;Monoclonal Antibodies;Mucositis;Mucous Membrane;Mus;Operative Surgical Procedures;Outcome;Oxidation-Reduction;PTEN gene;Pathogenesis;Patients;Phosphatidylinositols;Phosphotransferases;Principal Investigator;Procedures;Refractory;Respiration;Respiratory Chain;Role;Signal Transduction;Site;TNF gene;Tattooing;Testing;Treatment Efficacy;Ulcer;Ulcerative Colitis;Visualization;WNT Signaling Pathway;Work;beta catenin;chronic ulcer;clinical phenotype;crypt cell;dextran sulfate sodium induced colitis;drug development;experience;healing;infliximab;intestinal epithelium;new therapeutic target;novel;novel strategies;prevent;programs;prospective;repaired;response;single-cell RNA sequencing;stem cells;therapeutic biomarker;therapeutic target;transcriptomics

public_health_relevance:
The importance of understanding the role of mitochondrial respiration in ulcer healing and determiningclinical phenotypes in inflammatory bowel disease has been recently strengthened by major prospectiveclinical studies in pediatric Crohns (Kugathasan et al Lancet) and ulcerative colitis (Haberman) patients.Studies proposed here use a novel genetically-engineered mouse model of mitochondrial deficiency incombination with single cell RNAseq analysis of normal and diseased (CD/UC) patients. We posit thiswork will identify key mechanisms that underlie the cause of nonhealing ulceration in IBD with the goalof identifying targets for new drug development.


application_id: 10779668
project_number: 4UT2GM148083-02
project_title: I-RED Southeast XLerator Network
administering_ic: NIGMS
award_notice_date: 2023-03-15
opportunity_number: RFA-GM-22-001
application_type: 4
activity_code: UT2
ic: GM
serial_number: 148083
program_official: ZHOU, YANG
project_start_date: 2023-03-15
project_end_date: 2025-02-28
study_section: Special Emphasis Panel[ZRG1-IMST-B(51)B]
contact_pi_person_id: 15333536
contact_pi: WILLMOT, JACQUELINE
other_pis: KRENTSEL, EUGENE ;MCCLURE, IAN D;SAUNDERS, ROBERT
congressional_district: 03
department: Unavailable
primary_duns: 080949252
primary_uei: JYN1A3M4LD29
duns_number: 080949252
uei: JYN1A3M4LD29
fips: US
organization_id: 10048196
organization_name: XLERATEHEALTH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402023346
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryI-RED Southeast XLerator Network powered by XLerateHealth LLC in collaboration with the University ofKentucky as the lead academic partner institution proposes to develop a suite of experience-basedentrepreneurship education products and commercialization education tools to address the needs ofacademic institutions and their faculty researchers innovators and graduate/undergraduate students in theSoutheast IDeA states region. The ultimate aim of these entrepreneurship education and training productsis to foster the translation of promising biomedical discoveries and technologies from research laboratoriesinto the creation of commercial products which both improve human health and promote economic growth.As a result it will significantly enhance commercialization knowledge mature the entrepreneurialecosystem identify more market-ready technologies and patents see more startup entities formed increasedilutive and non-dilutive funding to these entities and accelerate the commercialization of biomedical andhealth tech innovations in the region  with the fundamental goal of positively impacting human health andpatients lives.This team has years of experience working with academic institutions innovators and healthcare startupsin the Southeast IDeA states region (including the previous NIGMS STTR IDeA Regional TechnologyTransfer Accelerator award) developing extensive entrepreneurial educational content and deliveringentrepreneurial training to biomedical innovators aspiring to become entrepreneurs. Key team memberspossess strong and diverse backgrounds that include education and training technology transfer clinicalpractice startup company creation venture capital investing building talent support systems sales andmarketing social media and program and product development among other disciplines. We will createand deploy the most impactful educational products necessary to further advance the translation ofbiomedical technologies being developed by academic researchers to the commercial marketplace.I-RED Southeast XLerator Network will leverage its teams experiences assessing building and workingwith a wide network of highly diverse partners across each state and territory in the Southeast IDeA statesregion with a governance structure to optimize communication and ensure extensive prototype testing andvalidation of unique educational programs and products that will address the needs identified through gapassessment and achieve strong engagement from our regions innovators in those educational programsand products.

project_terms:
Acceleration;Address;Award;Biomedical Technology;Capital;Capital Financing;Collaborations;Communication;Discipline;Economics;Ecosystem;Education;Effectiveness;Ensure;Entrepreneurship;Evaluation;Faculty;Fostering;Fund Raising;Funding;Goals;Growth;Health;Health Technology;Healthcare;Human;Institution;Investments;Kentucky;Knowledge;Laboratory Research;Lead;Learning;Legal patent;Licensing;Marketing;Monitor;National Institute of General Medical Sciences;Outcome;Participant;Patients;Phase;Pilot Projects;Positioning Attribute;Process;Program Development;Reporting;Research Personnel;Sales;Small Business Innovation Research Grant;Small Business Technology Transfer Research;Structure;Students;Support System;Talents;Technology;Technology Transfer;Testing;Training;Training and Education;Translations;Universities;Validation;clinical practice;cohort;commercialization;design;experience;improved;innovation;member;new product development;product development;programs;prototype;social media;success;tool;undergraduate student

public_health_relevance:
Project NarrativeThrough this program I-RED Southeast XLerator Network will develop a suite of experience-basedentrepreneurship education products and commercialization education tools to address the needs ofacademic institutions and their faculty researchers innovators and graduate/undergraduate students in theSoutheast IDeA states region. The ultimate aim of these entrepreneurship education and training productsis to foster the translation of promising biomedical discoveries and technologies from research laboratoriesinto the creation of commercial products which both improve human health and promote economic growth.As a result it will significantly enhance commercialization knowledge mature the entrepreneurialecosystem identify more market-ready technologies and patents see more startup entities formed increasedilutive and non-dilutive funding to these entities and accelerate the commercialization of biomedical andhealth tech innovations in the region  with the fundamental goal of positively impacting human health andpatients lives.


application_id: 10779035
project_number: 1R01AG084670-01
administering_ic: NIA
award_notice_date: 2024-02-07
opportunity_number: PA-20-185
application_type: 1
activity_code: R01
ic: AG
serial_number: 084670
program_official: LI, TONG
project_start_date: 2024-02-15
project_end_date: 2029-01-31
study_section: Special Emphasis Panel[ZRG1 AN-Q (55)]
contact_pi_person_id: 12103073
contact_pi: SELENICA, MAJ-LINDA B
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2024-02-15
project_title:
Emerging role of PAD4 mediated TDP-43 citrullination in the neuropathology of LATE and Alzheimers Disease Related Dementias

project_abstract:
ABSTRACTTAR DNA-binding protein 43 (TDP-43) pathology is associated with a spectrum of clinicaldementias. Despite the enormous risk that TDP-43 proteinopathies present to public health thereis a lack of strategies against TDP-43 pathology. Our laboratory has discovered that peptidylarginine deiminase 4 (PAD4) induces the conversion of arginine (positive) to citrulline (neutral) anovel and irreversible posttranslational modification of TDP-43. We identified elevated PAD4expression and TDP-43 citrullination (citR) at the outset of Limbic-Predominant Age-related TDP-43 Encephalopathy (LATE) and in AD Related Dementias (ADRDs). We cross-validated ourfindings in a novel TDP-43 mouse model and will utilize it to investigate the mechanistic impactof PAD4 on TDP-43 phenotype. To date we know very little about the role of PAD4 in theprogression of LATE and ADRD. Notably as citR TDP-43 remains elusive our studies suggestdomain-specific effects of citR moieties on TDP-43 nuclear import cytoplasmic accumulation andphase-separation dynamics. We will address the significant gap and define mechanisms ofCa2+-coordinated PAD4 activity on TDP-43 toxic gain-of-function in the human brain mousemodels and neuronal cells. We state that PAD4-mediated TDP-43 citrullination impairs TDP-43 nucleocytoplasmic shuttling and accelerates cytoplasmic accumulation ultimatelyleading to neuropathology and cognitive decline in LATE. In Aim 1 we will establish howgenetic PADi4 (gene) gain- and loss-of-function regulates TDP-43 nuclear import and cytoplasmicaccumulation and determine PAD4-restricted TDP-43 epitopes in primary neurons. We will alsoassess how neuronal PADi4 expression or deletion promotes TDP-43 phenotype synapticdysfunction and neurobehavioral deficits in a mouse model. Aim 2 will investigate the directeffects of NLS and LCD-directed pseudo-citR mimetics on TDP-43 nuclear import accumulationand solubility in primary neurons. We will also determine how these citR moieties regulate TDP-43 liquid-solid separation kinetics. Lastly we will determine the functional role of pseudo-citRmimetics on the TDP-43 phenotype in vivo. Aim 3 will determine if PAD4 activity and citR TDP-43 epitope restriction signatures follow regional vulnerability of the human brain in LATE andADRD. The proposed studies will elucidate how PAD4 activity and this novel PTM definefunctional consequences that lead to the neuropathogenesis of TDP-43 proteinopathies.

project_terms:
Acceleration;Affect;Alzheimer's disease related dementia;Animal Model;Antibodies;Arginine;Arginine deiminase;Biochemical;Biological Markers;Biology;Brain;Brain region;Cells;Chronic;Citrulline;Clinical;Cognitive deficits;Custom;Cytoplasm;DNA-Binding Proteins;Data;Dementia;Epitopes;Fostering;Functional disorder;Genes;Genetic;Human;Impaired cognition;Impairment;In Vitro;Kinetics;Laboratories;Liquid substance;Mass Spectrum Analysis;Mediating;Neurons;Neuropathogenesis;Nuclear Import;Outcome;Pathogenesis;Pathologic;Pathology;Phase;Phase Transition;Phenotype;Phosphorylation;Post-Translational Protein Processing;Proteins;Public Health;Recombinants;Risk;Role;Solid;Solubility;Spectrum Analysis;Synapses;TDP-43 aggregation;Testing;Work;aging population;comorbidity;digital;gain of function;human tissue;in vivo;indexing;limbic-predominant age-related TDP-43 encephalopathy;loss of function;mimetics;mouse model;neurobehavioral;neuropathology;novel;nucleocytoplasmic transport;protein TDP-43;protein aggregation;protein function;response

public_health_relevance:
NARRATIVEWe discovered a new posttranslational modification of TDP-43 citrullination (citR) and confirmed itsaccumulation in Limbic-Predominant Age-related TDP-43 Encephalopathy (LATE) human brain and TDP-43animal models. We state that the "coordinated activation state of peptidyl arginine deiminase 4 (PAD4) inducescitrullination of TDP-43 impairs protein function promotes cytoplasmic accumulation and aberrant proteinphase-separation dynamics. This application will unravel mechanisms of PAD4-mediated citrullination implicatedin TDP-43 pathogenesis that characterize LATE and ADRDs.


application_id: 10776091
project_number: 1R01AR083375-01
project_title: Mechanistic Assessment of NMES to Rescue Localized Neuromuscular Disruption after ACL Injury
administering_ic: NIAMS
award_notice_date: 2024-08-31
opportunity_number: PA-20-183
application_type: 1
activity_code: R01
ic: AR
serial_number: 083375
program_official: WASHABAUGH, CHARLES H
project_start_date: 2024-08-30
project_end_date: 2029-07-31
study_section: Special Emphasis Panel[ZRG1 SMEP-C (05)]
contact_pi_person_id: 11267737
contact_pi: FRY, CHRISTOPHER
other_pis: NOEHREN, BRIAN
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: UNIVERSITY-WIDE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryAnterior Cruciate Ligament (ACL) injury and subsequent reconstruction result in disrupted neuromuscularpathways which have been linked to protracted quadriceps weakness and atrophy. There is a significant gap inknowledge concerning the signaling cascades that precipitate peripheral quadriceps deficits limiting progressin the field to address the inceptive events underlying poor functional recovery. Lacking mechanistic evidencehinders the development of targeted rehabilitation protocols to address quadriceps atrophy and weakness thatoften persist far beyond return to activity. Pilot data in this proposal has identified a molecular signature ofquadriceps neuromuscular dysfunction that appears following the initial ACL injury and is further exacerbatedby reconstruction. Early molecular changes following ACL reconstruction culminate in local quadricepsdenervation and weakness. Additionally provided data show this molecular signature to be responsive toneuromuscular electrical stimulation (NMES) providing a heretofore previously unknown mechanistic target ofNMES. Conflicting results from studies lacking rigor and mechanistic insight have limited the efficacy andutilization of NMES following ACL injury hindering its therapeutic potential. The overarching hypothesis of thisproposal is that ACL injury results in rapid quadriceps neuromuscular remodeling and local denervation whichresults in subsequent quadriceps atrophy and weakness. Further NMES is hypothesized to mitigatedenervation-induced molecular signaling within the quadriceps providing critical mechanistic insight. Threeinterconnected but independent aims will address the overarching hypothesis. Specifically innovative pre-clinical gain and loss of function experiments will establish causative roles for specific signaling cascadeswithin the quadriceps that are critical for responsiveness to NMES. Additionally a rigorous and targeted clinicaltrial will address gaps in knowledge surrounding NMES that have previously limited acceptance and utilization.Results of the current study will provide necessary mechanistic insight to overcome a critical barrier in thedevelopment of evidence-based guidelines. Results from this work will directly lead to new testable treatmentsto advance the care of individuals with ACL injuries that will remedy the pervasive issue of protractedquadriceps weakness.

project_terms:
Address;Atlases;Atrophic;Biological;Biopsy;Caring;Cell Nucleus;ChIP-seq;Clinical Practice Guideline;Clinical Trials;Data;Deacetylase;Denervation;Development;Etiology;Event;Fiber;Functional disorder;Genetic;HDAC4 gene;Histone Deacetylase Inhibitor;Impairment;Individual;Injury;Knockout Mice;Knowledge;Link;Measures;Modeling;Molecular;Molecular Profiling;Molecular and Cellular Biology;Morphology;Mus;Muscle;Muscle Weakness;Muscle function;Muscular Atrophy;Neuromuscular Junction;Nuclear;Nuclear RNA;Operative Surgical Procedures;Orthopedic Surgery;Outcome;Participant;Pathway interactions;Peripheral;Phenotype;Physical therapy;Positioning Attribute;Postoperative Period;Protocols documentation;Randomized;Reconstructive Surgical Procedures;Recovery;Recovery of Function;Rehabilitation therapy;Resolution;Role;Signal Transduction;Skeletal Muscle;Testing;Therapeutic;Time;Torque;Translations;Work;anterior cruciate ligament injury;anterior cruciate ligament reconstruction;anterior cruciate ligament rupture;chromatin immunoprecipitation;defined contribution;evidence based guidelines;experimental study;gain of function;gene induction;gene induction/repression;human data;improved outcome;innovation;insight;loss of function;molecular targeted therapies;multidisciplinary;muscle strength;neural;neuromuscular;neuromuscular stimulation;novel;pharmacologic;pre-clinical;preclinical study;quadriceps muscle;reconstruction;regenerative rehabilitation;response;single nucleus RNA-sequencing;statistics;transcriptional reprogramming;transcriptome;transcriptome sequencing

public_health_relevance:
Project NarrativeAnterior cruciate ligament tears are a common injury and in spite of surgical reconstruction and rehabilitationthere remain significant impairments in the quadriceps muscle which contribute to poor long term outcomes.This project has identified a molecular signature of quadriceps neuromuscular dysfunction that contributes tothe initial loss of quadriceps muscle strength. An innovative combination of pre-clinical studies and amechanistic clinical trial will determine the ability of neuromuscular electrical stimulation to mitigate this earlymolecular signature and restore quadriceps strength.


application_id: 10773360
project_number: 3R43CA261417-01S1
administering_ic: NCI
award_notice_date: 2023-06-02
opportunity_number: PAR-22-073
application_type: 3
activity_code: R43
ic: CA
serial_number: 261417
suffix: S1
program_official: ZHAO, MING
project_start_date: 2021-04-01
project_end_date: 2023-06-30
contact_pi_person_id: 10810394
contact_pi: MOLLOY, JANELLE ARLENE
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 093718777
primary_uei: L8D1CH5FK9X3
duns_number: 093718777
uei: L8D1CH5FK9X3
fips: US
organization_id: 10052089
organization_name: WILD DOG PHYSICS, LLC
organization_city: NICHOLASVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 403568039
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2023-05-01
project_title:
Enabling remote medical physics services for medical accelerator quality assurance through a novel table-top imaging device

project_abstract:
Executive Summary Radiation Therapy is an effective component of the treatment strategy for patients suffering fromcancer. Advanced techniques such as intensity modulated radiation therapy (IMRT) image-guided RT (IGRT)stereotactic body RT (SBRT) and stereotactic radiosurgery (SRS) improve outcomes and are delivered usingmedical linear accelerators (i.e. linacs). SBRT is especially appealing given that the precise treatments aredelivered in 1-5 daily treatment fractions as opposed to the 20-40 fractions required for conventionaltechniques. Providing SBRT in rural settings can improve access by administering these precise abbreviatedtreatments to patients who have difficulty traveling to large regional medical centers. Further adoption ofautomated techniques for quality control and enhanced tele-dosimetry can support peer review improvequality reduce dependence on (local) expertise and reduce operating costs. The quality assurance (QA) that medical physicists provide is critical for safe treatments yet there is ashortage of qualified medical physicists (QMPs) both in the US and globally. At the same time more centersare introducing modern techniques that are more precise but intrinsically have more risk due the high dosesand geometric precision required. There is widespread noncompliance with industry standard QA protocols inthe US and internationally. Existing QA devices have not evolved sufficiently to provide the precision versatilityand efficiency that is needed for high precision RT. Given these exacerbated safety risks the market needs aparadigm shift in how QA is performed in modern RT. Wild Dog Physics (WDP) proposes to design and test a new-generation QA device that addresses theseunmet medical needs. When complete it will be more precise efficient and comprehensive than any QAsolution currently on the market. The proposed project seeks to develop a clinical prototype to be tested in theRadiation Therapy clinic at the University of Kentucky as well as regional partner organizations located inrural underserved areas. The prototype will be developed using the following milestones: Design and build i)a novel a small-form-factor optical tunnel (SFFOT) ii) a laminated side wall with a scintillating phosphorscreen and switchable film outer layer to facilitate ambient light rejection and iii) a hybrid beam quality /compact CT phantom. The project will culminate with the construction of an integrated prototype that will betested for technical and clinical performance. Towards this end the specific aims of this project are:Specific Aim 1: Build and test the 3 primary subcomponents of an integrated device; a) a SFFOT that cancollect an image(s) of the entire useful interior surface transmit the image(s) to an electronic camera sensorthrough a small form-factor (< 5 cm diameter) passive optical chain; b) a laminated side wall consisting of anouter electronically polarizing optical layer and an inner radio-luminescent layer and c) a hybrid dosephantom to be integrated onto one side of the device which will serve as a tissue-equivalent phantom so thatbeam quality metrics can be monitored and to host CT image quality test objects.Specific Aim 2: Construct and test a clinical prototype; The systems ability to monitor machine performance ina clinical setting will be validated. Sensitivity to detecting changes in relative and absolute radiation output aswell as field edge positioning will be measured with success criteria defined as 0.5% and 0.5 mm. Dataacquisition time for monthly QA tests will be measured and success defined as less than 30 minutes. The consolidation of multiple device functions combined with the ease of use and measurementprecision enable a paradigm shift in how medical physics services and quality assurance are rendered. Sparsebut efficient daily QA protocols will be replaced with comprehensive data collection and automated analysis atno additional cost in time or staffing. High precision radiation treatments can be safely brought to rural andunderserved areas with safety efficiency and precision improved in any center using the innovation. To date we have established the feasibility of constructing a single device that can acquirecomprehensive QA metrics in less than 60 minutes. Presently all subsystems have been tested and found toperform as required. A three-dimensional prototype has been built and is being validated by our clinicalpartner at the UK Radiation Medicine department. WDP is in the process of seeking SBIR Phase 2 funding tofurther develop the technology to the point of commercialization.

project_terms:
3-Dimensional;Abbreviations;Address;Adoption;Canis familiaris;Clinic;Clinical;Collection;Data Collection;Dependence;Devices;Diameter;Dose;Electronics;Film;Funding;Generations;Hybrids;Image;Imaging Device;Improve Access;Industry Standard;Intensity-Modulated Radiotherapy;International;Kentucky;Light;Linear Accelerator Radiotherapy Systems;Malignant Neoplasms;Marketing;Measurement;Measures;Medical;Medical center;Medicine;Modernization;Monitor;Optics;Output;Patients;Peer Review;Performance;Phase;Physics;Positioning Attribute;Process;Protocols documentation;Public Health;Qualifying;Quality Control;Radiation;Radiation therapy;Radiosurgery;Resource-limited setting;Risk;Rural;Safety;Services;Side;Small Business Innovation Research Grant;Surface;System;Techniques;Technology;Testing;Time;Tissues;Travel;Universities;Work;X-Ray Computed Tomography;automated analysis;commercialization;cost;data acquisition;design;dosimetry;health care availability;image guided;improved;improved outcome;innovation;non-compliance;novel;optical polarization;peer support;prototype;public health relevance;quality assurance;rural area;rural setting;sensor;success;transmission process;treatment strategy;underserved area

public_health_relevance:
Project Narrative  Public Health Relevance The proposed work has the potential to improve public health by developing a commercial device thatwill improve access to and safety of advanced radiation therapy treatments especially in low-resource settings.By markedly improving efficiency in the collection of routine quality assurance measurements access tohealthcare and treatment safety can be improved while costs can be decreased.


