# projects

application_id: 9869825
project_number: 5F32AG058456-03
administering_ic: NIA
award_notice_date: 2020-02-28
opportunity_number: PA-16-307
application_type: 5
activity_code: F32
ic: AG
serial_number: 058456
program_official: OPANASHUK, LISA A
project_start_date: 2018-02-01
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1-F01A-F(20)L]
contact_pi_person_id: 11123177
contact_pi: BRAUN, DAVID JAMES
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-02-01
project_title:
Vascular-associated neuroinflammation in Alzheimer's disease: differential effects on disease progression modulated by underlying amyloid burden

project_abstract:
PROJECT SUMMARY Of the modifiable factors that collectively account for over half of Alzheimers disease (AD) cases themajority are vascular risk factors (VRFs). Given that the number of AD patients is expected to double by 2040this situation presents an important opportunity to reduce negative impacts on public health. Clearerunderstanding of the precise temporal and mechanistic alterations linking VRFs to AD may enable developmentof therapeutic approaches to sever that link. The overall goal of this proposal is therefore to elucidate potentiallytargetable mechanisms underlying the connection between early vascular damage and subsequent ADpathology. Vascular inflammation is one unifying feature of many VRFs and this can induce or propagateneuroinflammatory changes in the brain. Considering the established role of neuroinflammation in ADpathogenesis it may be clinically useful to target neuroinflammatory alterations secondary to vascular insult.This proposal will therefore test the hypothesis that vascular risk factors contribute to AD primarily by increasingneuroinflammatory responses and altering subsequent amyloid pathology. For these studies I will use a well-characterized amyloid beta (Ab) overexpression mouse model of AD (APPswe/PS1dE9) along with a dietaryhyperhomocysteinemia (HHcy) model to induce vascular damage and inflammation. In Aim 1 I will induce HHcyin AD mice within a period corresponding to prodromal AD and in Aim 2 within a period corresponding to earlyAD. In both aims l will acutely treat the vascular-associated neuroinflammation in half of the animals. I willcharacterize how vascular damage and associated neuroinflammation interact with underlying Ab pathology toproduce additive cognitive deficits at different stages of AD progression. In addition both aims will includeclinically relevant neuroimaging measures to connect pathological alterations with detectable alterations incerebral blood flow (arterial spin labeling) and metabolic changes (magnetic resonance spectroscopy).Successful completion of this project will provide clinically-relevant insight into the links between VRFs and AD.Further it will provide proof-of-concept of the utility of targeting neuroinflammation secondary to vasculardamage as a means of preventing or delaying future cognitive decline. Ideally such an approach will somedaybe incorporated into a comprehensive strategy of managing AD risk. A carefully designed career developmentplan has also been formalized that includes participation in specialty workshops regular presentation of dataparticipation in scientific meetings and enhancement of non-technical science proficiencies. An experiencedmentoring group of senior scientists in a well-established institution for AD research ensure that I will haveoptimal opportunity to grow into a successful independent investigator devoted to AD therapeutic development.

project_terms:
Abeta synthesis;Acute;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Alzheimer's disease therapeutic;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animals;Anti-Inflammatory Agents;Blood - brain barrier anatomy;Blood Vessels;Brain;Cerebrovascular Circulation;Cerebrovascular Disorders;Cerebrum;Clinical;Cognitive;Cognitive deficits;Data;Deposition;Development Plans;Diet;Disease Progression;Educational workshop;Ensure;Functional disorder;Future;Goals;Hyperhomocysteinemia;Hypertension;Impaired cognition;Inflammation;Inflammatory;Institution;Link;Magnetic Resonance Spectroscopy;Measures;Mediating;Memory impairment;Mentors;Metabolic;Modeling;Mus;Neuroglia;Obesity;Pathogenesis;Pathogenicity;Pathologic;Pathology;Pattern;Pharmaceutical Preparations;Process;Public Health;Research;Research Personnel;Risk;Risk Factors;Role;Science;Secondary to;Senior Scientist;Spin Labels;Testing;Training;Translating;Vascular Diseases;abeta accumulation;abeta deposition;amyloid pathology;beta amyloid pathology;brain metabolism;career development;cerebral hypoperfusion;clinically relevant;comorbidity;cytokine;design;epidemiology study;experience;glial activation;hypercholesterolemia;inflammatory marker;insight;medical specialties;meetings;middle age;modifiable risk;mouse model;neuroimaging;neuroinflammation;overexpression;prevent;prodromal Alzheimer's disease;response;stem;therapeutic development;tool;treatment strategy;vascular inflammation;vascular injury;vascular risk factor;-amyloid burden

public_health_relevance:
PROJECT NARRATIVEThe most prevalent modifiable risk factors for Alzheimers disease (AD) are vascular risk factors and there isstrong evidence that neuroinflammation is a crucial aspect of this risk. Successful completion of this project willclarify this relationship advance anti-inflammatory treatment strategies and hopefully help to stem the tide ofnew AD cases projected to occur in the coming decades.


application_id: 9868586
project_number: 3R01GM127495-02S1
project_title: Exercise-enhanced resolution of inflammation
administering_ic: NIGMS
award_notice_date: 2019-06-07
opportunity_number: PA-18-591
application_type: 3
activity_code: R01
ic: GM
serial_number: 127495
suffix: S1
program_official: ZHAO, XIAOLI
project_start_date: 2018-09-01
project_end_date: 2023-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 11169883
contact_pi: HELLMANN, JASON L
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Acute;Adrenergic Receptor;Affect;Anabolism;Animals;Arachidonate 15-Lipoxygenase;Arachidonate 5-Lipoxygenase;Binding;Blood Pressure;Bone Marrow;Catecholamines;Cell physiology;Cells;Chronic;Chronic Disease;Complex;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Docosahexaenoic Acids;Eicosanoids;Eicosapentaenoic Acid;Enzymes;Exercise;Extravasation;FPR2 gene;Female;G-Protein-Coupled Receptors;Health;Heart Hypertrophy;Homeostasis;Human;Immune;Individual;Infection;Inflammation;Inflammatory;Injury;Knowledge;Lead;Link;Lipids;Lipoxins;Literature;Longevity;Measures;Mediating;Mus;Obesity;Omega-3 Fatty Acids;Pathway interactions;Peritonitis;Phagocytosis;Physical activity;Premature Mortality;Process;Production;Quality of life;RNA Interference;Research Personnel;Resistance;Resolution;Risk Factors;Role;Running;Signal Transduction;Techniques;Testing;Tissues;Work;adrenergic block;angiogenesis;cardiometabolism;cardiovascular disorder risk;cardiovascular health;cohort;cytokine;diabetic;exercise regimen;exercise training;feeding;gain of function;healing;improved;in vivo;insight;lipid mediator;macrophage;male;microbial;neutrophil;non-diabetic;novel;novel therapeutic intervention;physical inactivity;receptor;response;skeletal muscle growth;trafficking;treadmill


application_id: 9868346
project_number: 3R01AT008617-04S1
project_title: Gender dependent anti-inflammatory effect of thegrapefruit exosomes-like nanoparticles
administering_ic: NCCIH
award_notice_date: 2019-09-18
opportunity_number: PA-19-165
application_type: 3
activity_code: R01
ic: AT
serial_number: 008617
suffix: S1
program_official: WANG, YISONG
project_start_date: 2015-12-01
project_end_date: 2020-11-30
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
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:
The overall goal of this proposal is to determine whether gender differences contribute to edible plant exosomalnon-coding small RNA (nc-sRNA) in the prevention of gut inflammation using the dextran sulfate sodium (DSS)induced colitis mouse models. Our recently published data indicates that exosome-like nanoparticles (ELNs)present in a number of edible plants including grapefruit have anti-inflammatory properties. Mice fed grapefruitELNs (FELNs) are protected against DSS induced mouse colitis. Up take of FELNs by intestinal macrophagesinhibits the release of IL-1 and IL-6 and the induction of HO-1 and IL-10 expression. Our preliminary data furtherindicate that FELNs carry high levels of specific nc-sRNA that inhibit the induction of proinflammatory cytokinesby targeting intestinal macrophages. The nc-sRNA is associated with inactivation of macrophage miR155. Aspecific FELN nc-sRNA complexed with naringin binds to miR155 and subsequently prevents miR155 bindingto 3UTRs of certain anti-inflammatory genes thus inhibiting the induction of proinflammatory cytokines. Wehave also demonstrated that ginger ELN nc-sRNAs promotes the production of IL-10 in lamina propriamacrophages under steady-state as well as inflammatory conditions. Therefore we hypothesize that plant ELNscarrying the nc-sRNA bioactive complex are taken up by intestinal macrophages and subsequently bind toinflammatory microRNAs resulting in inhibition of induction of chronic inflammation cytokines thereby preventingchronic intestinal inflammation. Sex is emerging as an important factor in the etiology and expression ofmany different pathological conditions and sex-biased disease susceptibility is well demonstrated indifferent types of illness in particular inflammation driven immune related diseases. However whethergender differences contribute to the stability of ELN nc-sRNAs in intestinal macrophages is not known. Ourhypothesis will be tested in vitro and in vivo to determine whether sex differences contribute to hormone-depenandet regulation of stability of ELN nc-sRNAs up taken by intestinal macrophages. Demonstration of thehormone-depenandet regulation of ELNs complex targeting to gut inflammatory cells would be a significant stepforward in the understanding of how gender differences regulate anti-inflammatory responses through ELNs.The data generated should provide a foundation for selecting specific ELNs from different types of plants forpersonalized (female versus male) complementary medicine for patients and determine whether oraladministration of a customized exosome isolated from different plants will have a synergestic/additive effect onprevention or treatment of disease.

project_terms:
Address;Anti-inflammatory;Antigen-Presenting Cells;Antiinflammatory Effect;Binding;Biological;CD4 Positive T Lymphocytes;Cells;Chronic;Colitis;Complementary Medicine;Complex;Consumption;Custom;Data;Dendritic Cells;Disease;Disease susceptibility;Eating;Edible Plants;Encapsulated;Escherichia coli;Etiology;Event;Female;Food;Foundations;Frequencies;Gender;Genes;Ginger;Goals;Grapefruit;Hormones;Human;ITGAX gene;Immune;Immune Tolerance;Immune system;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Ingestion;Interleukin-1;Interleukin-10;Interleukin-6;Intestines;Knock-out;Lamina Propria;Link;Lipids;Mediating;MicroRNAs;Molecular;Molecular Profiling;Mus;Oral;Oral Administration;Pathologic;Pathway interactions;Patients;Phenotype;Plants;Play;Prevention;Production;Property;Prospective Studies;Proteins;Publishing;RNA;Rag1 Mouse;Regulation;Role;Sex Bias;Sex Differences;Signal Transduction;Small RNA;Sodium Dextran Sulfate;Stem cells;T-Lymphocyte;TNF gene;Testing;Time;Untranslated RNA;Untranslated Regions;Work;base;chemokine;cytokine;exosome;extracellular;gender difference;in vitro testing;in vivo;macrophage;male;monocyte;mouse model;nanoparticle;prevent;sex

public_health_relevance:
Project narrative. Concept that extracellular RNA (exRNA) may alter target cell phenotypes isemerging as a universal intercellular communicator in intercellular signaling. The significantimpact of sex differences on the disease susceptibility through regulating a number of differentpathways in immune cells have been studied. The overall goal of this study is to test whethergender differences contribute to the molecular mechanism for grapefruit exosomes non-codingRNA induction of oral immune tolerance to food.


application_id: 9866168
project_number: 1R01EB028792-01
administering_ic: NIBIB
award_notice_date: 2020-03-13
opportunity_number: PA-19-056
application_type: 1
activity_code: R01
ic: EB
serial_number: 028792
program_official: ANDERSON, AFROUZ AZARI
project_start_date: 2020-03-15
project_end_date: 2024-11-30
study_section: Imaging Guided Interventions and Surgery Study Section[IGIS]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-03-15
project_terms:
Adjuvant Therapy;Algorithms;Area;Blood;Blood capillaries;Blood flow;Body Image;Brain;Breast;Clinical;Clinical Trials;Color;Dermal;Development;Devices;Diagnosis;Diffuse;Distress;Dyes;Ensure;Esthetics;Excision;Family suidae;Fluorescence;Fluorescence Angiography;Health Care Costs;Heterogeneity;Human;Hypoxia;Image;Imaging Techniques;Implant;Incidence;Indocyanine Green;Interruption;Judgment;Laboratories;Lateral;Mammaplasty;Mastectomy;Measurement;Measures;Metabolic;Monitor;Necrosis;Operative Surgical Procedures;Optics;Outcome;Outcome Study;Oxygen;Patients;Pattern;Perfusion;Perioperative;Postoperative Complications;Postoperative Period;Quality of life;Risk;Rodent;Sexuality;Skin;Speed;Surgeon;Surgical Flaps;System;Techniques;Technology;Temperature;Testing;Thick;Three-Dimensional Image;Three-Dimensional Imaging;Time;Tissue imaging;Tissues;Woman;base;burn wound;cost efficient;design;diffuse optical spectroscopy and imaging;hemodynamics;image reconstruction;imager;imaging system;in vivo;innovation;malignant breast neoplasm;multimodality;next generation;non-invasive optical imaging;novel;operation;preclinical study;preservation;prevent;prototype;self esteem;surgery outcome;tissue reconstruction;tomography;translational study;wound;wound treatment


application_id: 9864362
project_number: 1R21AI146016-01A1
project_title: Role of the Trophic Forms of Pneumocystis in Lung Response to Infection
administering_ic: NIAID
award_notice_date: 2019-06-17
opportunity_number: PA-18-489
application_type: 1
activity_code: R21
ic: AI
serial_number: 146016
suffix: A1
program_official: LOVE, DONA
project_start_date: 2019-06-17
project_end_date: 2021-05-31
study_section: Special Emphasis Panel[ZRG1 AARR-M (03)]
contact_pi_person_id: 1945284
contact_pi: GARVY, BETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Pneumocystis (PC) pneumonia continues to be a leading cause of opportunistic infections inpatients living with HIV. Though we are thirty years into the HIV epidemic very little is knownabout the lifestyle of the PC organism and how it interacts with the immune system. The field ishampered by the inability to culture the organisms for more than a couple weeks and theproblem of separating the two identifiable life forms the ascus and trophic forms resulting in apaucity of information regarding how these separate life forms interact with the host and theimmune response. Recently -glucan synthesis inhibitors (a class of drugs calledechinocandins) have been used to eliminate the ascus form of the organisms in vivo giving usthe ability to obtain a purified population of trophic forms and to examine trophic forminteractions with host immune cells. Our preliminary data demonstrates that trophic forms of PCinhibit TNF production of alveolar macrophages after stimulation by lipopolysaccharide (LPS) -glucans or lipoteichoic acid (LTA) in vitro. Additionally in vivo we found that trophic formsinhibit TNF production in the lungs of mice challenged with a small dose of LPS. Wehypothesize that the trophic forms of PC act to temper the inflammatory response to -glucansin the ascus forms of PC. The goal of this proposal is to determine the significance andmechanism of the inhibitory activity of trophic forms of PC. We propose two aims to addressour hypothesis. In aim 1 we will determine whether trophic forms of PC alter the balance ofinflammation induced by -glucan in vivo. In aim 2 we will determine whether trophic forms ofPC dampen inflammation induced by innate immune responses and identify pattern recognitionreceptors on macrophages that interact with tropic forms of PC.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Alveolar Macrophages;Asthma;Binding;Bone Marrow;Cell Wall;Cells;Chronic Obstructive Airway Disease;Cyst;Data;Dendritic Cells;Dose;Environment;Epidemic;Epithelial Cells;Equilibrium;Glucans;Goals;HIV;Immune;Immune response;Immune system;In Vitro;Individual;Infection;Infectious Agent;Inflammation;Inflammation Mediators;Inflammatory Response;Innate Immune Response;Knockout Mice;Knowledge;Lead;Learning;Life;Life Style;Lipopolysaccharides;Lung;Mannose;Molecular;Mus;Opportunistic Infections;Organism;Patients;Pattern;Pattern recognition receptor;Phagocytosis;Pharmaceutical Preparations;Pharmacology;Pneumocystis;Pneumocystis carinii Pneumonia;Pneumonia;Population;Production;Proteins;Reproduction spores;Role;System;TNF gene;Time;base;beta-Glucans;beta-glucan receptor;co-infection;cytokine;design;experimental study;genetic manipulation;glucan synthase;immunosuppressed;in vivo;in vivo Model;inflammatory milieu;inhibitor/antagonist;insight;lipoteichoic acid;lung injury;macrophage;mannose receptor;mouse dectin-2;mouse model;nano-string;novel;pathogen;pathogenic fungus;prevent;response;tool

public_health_relevance:
Pneumocystis pneumonia is an AIDS-defining illness caused by an opportunistic fungal pathogen that has twoidentifiable life forms trophic forms and asci or cysts. While much is known about the immune response to theasci very little is known about the interactions of trophic forms with innate immune cells. This project isdesigned to understand how the trophic forms of Pneumocystis contribute to host-pathogen interactions in thelungs.


application_id: 9864109
project_number: 5R01NS102196-03
project_title: RIT1-mediated Protection following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2020-01-22
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 102196
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2018-02-15
project_end_date: 2023-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7875195
contact_pi: ANDRES, DOUGLAS ALLEN
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:
Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affectingmore than 1.7 million individuals each year. TBI not only results in tissue damage and cell death but canperturb surviving neuronal function leading to alterations in neural connectivity abnormal plasticity andnetwork dysfunction. Due to the inherent diversity in post-TBI dysfunction a critical need exists for therapeuticinterventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approachescould have enormous clinical social and economic benefit. However implementation of this strategy requiresthe identification of endogenous molecular cascades capable of regulating multiple protective/restorativepathways. The discovery that the Rit GTPase (RIT1) is dramatically down-regulated following corticalcontusion injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functionalrecovery following TBI. Drawing upon a collection of RIT1 transgenic mice exciting preliminary datademonstrate that Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunctionfollowing CCI. Additional data suggest that Rit is critical for post-TBI neurogenesis and promotes synapticintegrity by reducing post-contusion synaptic loss. Collectively these data are the first to demonstrate asignificant role for Rit in directing neuroprotection and neuroplasticity following TBI and suggest that Ritfunctions as a linchpin regulator of multiple injury response mechanisms following CCI. The overall hypothesisis that: (1) Rit plays a key role in cellular and functional recovery from brain trauma and (2) that activation ofRit signaling therefore has broad therapeutic potential in the setting of TBI. Three complementary aims guideour studies. Aim 1 will test the hypothesis that contusion-dependent Rit loss disrupts gene expressionprograms that promote neural survival and neurogenesis. In Aim 2 we will evaluate the extent to which Ritsignaling controls neuronal survival after contusive brain injury. The efficacy of Rit-targeted therapies will beevaluated using an inducible knock-in mouse model to permit Rit activation over a clinically relevant period ofhours to days after the onset of brain injury. Aim 3 will test the hypothesis that Rit signaling preserves synapticfunction following traumatic brain injury using transgenic mice electrophysiology and biochemical assays.Overall these studies are expected to identify Rit as a crucial signal integration hub in the setting of brain injury orchestrating diverse endogenous pathways that regulate neuronal survival promote neuronal regenerationand control neuroplasticity mechanisms.

project_terms:
Acute;Affect;Area;Attenuated;Behavioral;Biochemical;Biological Assay;Brain Contusions;Brain Injuries;CREB1 gene;Cause of Death;Cell Death;Cells;Chronic;Clinical;Collection;Contusions;Cortical Contusions;Data;Development;Economics;Electrophysiology (science);Emotional;Experimental Models;Functional disorder;Gene Expression;Genetic Transcription;Guanosine Triphosphate Phosphohydrolases;Hippocampus (Brain);Hour;Impaired cognition;Individual;Injury;Knock-in Mouse;Language;Learning;Leg;Link;Mediating;Memory impairment;Modeling;Molecular;Multiple Trauma;Nerve Degeneration;Nerve Regeneration;Neuronal Dysfunction;Neuronal Injury;Neuronal Plasticity;Neurons;Pathway interactions;Play;Proteins;Recovery;Recovery of Function;Role;Signal Transduction;Speech;Suggestion;Survivors;Synapses;Testing;Therapeutic;Therapeutic Intervention;Thinking;Tissues;Transgenic Mice;Traumatic Brain Injury;United States;adult neurogenesis;arm;bioinformatics tool;brain repair;clinically relevant;dentate gyrus;disability;experience;experimental study;implementation strategy;in vivo;injured;injury-related death;insight;loss of function;mouse model;network dysfunction;neurogenesis;neuronal survival;neuroprotection;preservation;programs;relating to nervous system;response to injury;social;synaptic function;targeted treatment;transcriptome sequencing

public_health_relevance:
Traumatic brain injury (TBI) is a leading cause of death and disability in the United States and survivors mayhave persistent loss of function in arms or legs abnormal speech or language loss of thinking ability oremotional problems. The wide range of injuries suggests that the development of multi-prong therapeuticapproaches to TBI could have enormous clinical social and economic benefit. This project will investigate theRIT1 protein as a linchpin capable of counterbalancing diverse injury mechanisms providing a unique avenuefor therapeutic intervention by allowing a combined approach of protecting neurons and promoting brain repairin a single target.


application_id: 9859375
project_number: 5R01CA213990-04
project_title: Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer
administering_ic: NCI
award_notice_date: 2020-02-27
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 213990
program_official: XI, DAN
project_start_date: 2017-02-06
project_end_date: 2022-01-31
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary Immunosuppressive macrophages have been linked to cancer-related inflammation and therapeuticresistance in cancer including chemotherapy and immunotherapy thus representing attractive therapeutictargets. Macrophages can be polarized into extreme M1 or M2 phenotype depending on the environmentalcues. Although macrophage phenotype within the tumor microenvironment is more complicated it is clearthat immunosuppressive tumor-associated macrophages (TAM) phenotypically more resemble M2-likemacrophages. In the preliminary studies we discovered that transcription factor c-Maf is highly expressed inmouse and human polarized M2 macrophages and immunosuppressive TAM. In addition natural productyeast-derived particulate -glucan treatment significantly downregulates c-Maf expression leading toenhanced T cell responses in mice. We also demonstrated that M1 and M2 macrophages have distinctmetabolic profiles and c-Maf regulates many genes related to glycolysis. Based on these preliminary studieswe hypothesize that transcription factor c-Maf is an essential controller and a metabolic checkpointfor immunosuppressive TAM functional activity. Three Aims are proposed. Aim 1 determines thecellular and molecular mechanisms by which c-Maf is regulated in immunosuppressive TAM. We willinvestigate whether tumor secreted factors regulate c-Maf expression in TAM. We will also determine howthe Raf-1 kinase pathway regulates c-Maf and c-Maf-related gene expression. Finally we will test whetherloss of function of c-Maf in TAM significantly delays tumor progression and metastasis. Aim 2 determineswhich TAM metabolic pathway(s) is regulated by c-Maf using systems metabolomics approach. We will firstdetermine TAM metabolic pathways using Stable Isotope Resolved Metabolomics (SIRM) approach.Furthermore we will determine which metabolic pathways are regulated by c-Maf. Finally we will determinethe causative role of metabolic reprogramming in -glucan-mediated TAM functional conversion. Aim 3determines whether the dectin-1 agonist -glucan modulates TAM function of human non-small cell lungcancer (NSCLC) via the c-Maf pathway. We will determine whether -glucan treatment downregulates c-Maf expression and alters c-Maf-regulated genes in human NSCLC TAM. We will also determine whetherhuman TAM functions are reversed upon -glucan treatment. Finally we will examine whether -glucantreatment in patients with NSCLC downregulates c-Maf expression and alters monocyte suppressivefunction. The overall goal of this proposal is to understand the transcriptional regulation ofimmunosuppressive TAM by c-Maf and establish the transcription factor c-Maf as a novel target for humancancer immunotherapy.

project_terms:
Agonist;Anti-Inflammatory Agents;Arginine;Cell Survival;Cell physiology;Clinical Research;Cues;Data;Dinoprostone;Essential Amino Acids;Gene Expression;Generations;Genes;Genetic Transcription;Glucose;Glutamine;Glycolysis;Goals;Human;IRF4 gene;Immunosuppression;Immunotherapy;Infiltration;Inflammation;Interleukin-10;Interleukin-12;Leukocytes;Link;MHC Class II Genes;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitogen-Activated Protein Kinase Kinases;Modeling;Molecular;Mus;Natural Products;Neoplasm Metastasis;Network-based;Nitric Oxide;Non-Small-Cell Lung Carcinoma;PPAR gamma;PTGS2 gene;Particulate;Pathway Analysis;Pathway interactions;Patients;Phenotype;Play;Population Heterogeneity;Prostaglandin-Endoperoxide Synthase;Proto-Oncogene Proteins c-raf;Reactive Oxygen Species;Regulation;Role;Signal Transduction;System;T cell response;TNF gene;Testing;Transcriptional Regulation;Tumor Burden;Tumor-associated macrophages;Vascular Endothelial Growth Factors;Yeasts;arginase;bZIP Domain;base;beta-Glucans;c-myc Genes;cancer immunotherapy;chemotherapeutic agent;chemotherapy;cytokine;dectin 1;density;effector T cell;factor C;fibrosarcoma;immunosuppressive checkpoint;immunosuppressive macrophages;inhibitor/antagonist;innovation;loss of function;macrophage;metabolic profile;metabolomics;monocyte;novel;outcome forecast;stable isotope;therapeutic target;therapy resistant;transcription factor;transcriptome;tumor;tumor microenvironment;tumor progression

public_health_relevance:
Project NarrativeThis study will determine the mechanisms by which transcription factor c-Maf regulates cancer-elicitedimmunosuppressive macrophages via the transcriptional regulation and metabolic reprograming. Thesuccessful completion of this study may provide an innovative approach for cancer immunotherapy.


application_id: 9858389
project_number: 5R01HG009914-03
project_title: Regulation of International Direct-to-Participant Genomic Research
administering_ic: NHGRI
award_notice_date: 2020-01-16
opportunity_number: PA-14-276
application_type: 5
activity_code: R01
ic: HG
serial_number: 009914
program_official: LOCKHART, NICOLE C
project_start_date: 2018-03-01
project_end_date: 2022-01-31
study_section: Societal and Ethical Issues in Research Study Section[SEIR]
contact_pi_person_id: 6098284
contact_pi: ROTHSTEIN, MARK A
other_pis: KNOPPERS, BARTHA MARIA M.
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 SummaryNew techniques for genomic research are being developed to take advantage of the ability tocontact research participants directly without utilizing physicians hospitals or biobanks.Researchers are now able to use the internet to recruit and enroll research participants ingenomic studies by using an online application and consent process. Participants send theirhealth records electronically and ship a sample of blood or saliva to the researchers. Althoughthis process has been approved by IRBs for domestic studies it is unclear whether this processis lawful for international research because of the diverse laws and policies of the countrieswhere the participants reside.This research will study the important but complex question of whether international direct-to-participant genomic research is lawful in a sample of 32 countries. It will also consider whatsteps are necessary to facilitate this efficient diversity-enhancing research while still protectingthe welfare of research participants.The project has the following three aims:Aim 1: Convene three expert working groups of researchers and IRB leaders to identify andprioritize the key issues for a standard questionnaire and template to distribute to the study's 32international experts on country-specific laws and research ethics.Aim 2: Distribute the questionnaires to the international experts consult with and advise themas they prepare their responses to the questionnaires and summaries of country-specific legaland ethical issues compile and analyze the responses and draft conclusions and policyoptions.Aim 3: Distribute the draft conclusions and policy options to the three expert working groupsinternational consultants and advisory board members and obtain their feedback; analyze theresponses and use them to prepare a final draft; write and publish articles presenting thefindings of the study; and disseminate the results in presentations to various groups ofstakeholders.

project_terms:
American;Biological;Blood specimen;Collaborations;Complex;Consent;Consult;Country;Electronic Health Record;Enrollment;Ethical Issues;Ethics;Feedback;Genomics;Health;Hospitals;Individual;Institutional Review Boards;International;Internet;Laws;Legal;Participant;Physicians;Policies;Process;Publishing;Questionnaires;Regulation;Research;Research Ethics;Research Personnel;Saliva;Sampling;Ships;Specimen;Techniques;Writing;biobank;member;rare genetic disorder;recruit;response;welfare;working group

public_health_relevance:
PROJECT NARRATIVEResearchers are now able to use the internet to recruit and enroll widely dispersedindividuals which is valuable for a wide range of research especially research involvingrare genetic disorders. With IRB approval online recruitment and enrollment ofindividuals from the same country as the researchers is permissible including obtainingbiological specimens and health information but it is unknown whether recruitment andenrollment of individuals from foreign countries would violate the laws of thosecountries. In collaboration with American stakeholders and legal experts from 32countries the investigators will analyze applicable legal provisions and provide policyoptions to enable ethical international direct-to-participant research.


application_id: 9858236
project_number: 5R21AI142576-02
project_title: Endothelial JAK3 expression and inflammatory lung injury in sepsis
administering_ic: NIAID
award_notice_date: 2020-01-28
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AI
serial_number: 142576
program_official: MINNICOZZI, MICHAEL
project_start_date: 2019-02-01
project_end_date: 2022-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummarySepsis remains a major cause of death in critically ill patients. New therapeutic strategies areneeded to treat this devastating disease. Excessive inflammatory responses which lead toinflammatory tissue injury contribute to the pathogenesis of multiple organ failure in sepsis.Recent studies have demonstrated that JAK3 is a promising target against various inflammatorydiseases. However the regulation and function of JAK3 in sepsis have not been studied. In ourpreliminary studies we demonstrated that JAK3 expression is highly up-regulated during sepsis.Selective JAK3 inhibition by JAK3 inhibitors including a FDA-approved inhibitor Tofacitinibblocked endothelial inflammatory signaling and inflammatory lung injury during sepsis.Furthermore we demonstrated that JAK3 expression is controlled by HDAC6 a histonedeacetylase that modulates nuclear and non-nuclear protein function through deacetylation.HDAC6 knockdown or inhibition prevented TNF- induced endothelial JAK3 expression STAT1activation and leukocyte adhesion molecule ICAM-1 expression. In a mouse model ofpolymicrobial sepsis HDAC6 inhibition blocked sepsis-induced JAK3 expression. In the proposedstudies we will conduct a serial of experiments to assess the therapeutic potential of JAK3inhibition against sepsis-induced inflammatory lung injury and to investigate the regulation ofJAK3 by HDAC6 during sepsis.

project_terms:
Bacterial Infections;Cause of Death;Clinical;Clinical Trials;Critical Illness;Cytokine Receptors;Data;Deacetylation;Disease;Endothelial Cells;Endothelium;FDA approved;Family;Future;Gene Expression;HDAC4 gene;HDAC6 gene;Inflammatory;Inflammatory Response;Injury;Intercellular adhesion molecule 1;JAK3 gene;Janus kinase;Lead;Leukocyte Adhesion Molecules;Lung;Mediating;Multiple Organ Failure;Nuclear;Nuclear Protein;Pathogenesis;Pathway interactions;Patients;Phase III Clinical Trials;Play;Regulation;Reporting;Rheumatoid Arthritis;Role;STAT1 gene;STAT1 protein;Sepsis;Signal Pathway;Signal Transduction;Structure of parenchyma of lung;Systemic Inflammatory Response Syndrome;TNF gene;Testing;Therapeutic;Therapeutic Effect;Up-Regulation;antitumor effect;chronic inflammatory disease;experimental study;inhibitor/antagonist;knock-down;lung injury;member;mouse model;novel;novel therapeutic intervention;novel therapeutics;polymicrobial sepsis;prevent;protein function;tissue injury;transcription factor;vascular injury

public_health_relevance:
Project NarrativeSuccessful completion of the proposed studies will reveal a novel role of JAK3 in sepsis-inducedinflammatory signaling. The studies will validate the therapeutic potential of JAK3 inhibition againstinflammatory injury in sepsis. The proposed studies will provide important information for futureclinical trials.


application_id: 9857607
project_number: 5R01EY027805-03
administering_ic: NEI
award_notice_date: 2020-01-27
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: EY
serial_number: 027805
program_official: LIBERMAN, ELLEN S
project_start_date: 2018-02-01
project_end_date: 2023-01-31
study_section: Biology of the Visual System Study Section[BVS]
contact_pi_person_id: 14475772
contact_pi: FAMULSKI, JAKUB K
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: 2020-02-01
project_title:
Comprehensive analysis of periocular mesenchyme composition specification and function during anterior segment formation

project_abstract:
PROJECTSUMMARY:Inheritedcongenitalanteriorsegmentdysgenesis(ASD)disordersareamajorcauseofvisionimpairmentandblindness.Theyincludedevelopmentaloculardeficienciesoftheiriscorneaandlensinadditiontosignificantpredisposition~50%toglaucoma.Fromvariousstudiesinrecentyearsithasbecomeclearthatmanycongenitaldisordersandpredispositionsarisefromearlydevelopmentaldefectsbothmajorandsubtle.Examiningthedevelopmentalprocessgivingrisetotheseessentialcomponentsofthevisualsystemisthereforeafruitfulapproachtostudyingthedisease.Theanteriorsegmentderiveslargelyfromtheearlymigratingneuralcrestcellsthattargetspecificallytotheanteriorofthedevelopingretinaandarelooselyclassifiedasperiocularmesenchyme(POM).POMdeficiencyhasbeendemonstratedincertaincasesofASD.IbelieveamajorroadblockineffortstotreatandunderstandASDhasbeenthelimitedexaminationofPOMbiologyandfunctionduringearlyoculardevelopment.ThishamperseffortstocharacterizetheetiologyofdiseaseandscreeninginASDfamiliesinadditiontodelayingattemptsatiPSC-mediatedapproachesfortreatmentofASD.TocircumventtheseproblemsweaimtocomprehensivelycharacterizePOMcellspecificationmigrationtargetingdifferentiationandultimatelycontributiontoanteriorsegmentdysgenesis.ThisisthenextlogicalandnecessarystepinorderforthefieldtocontinuetheevolutionoftherapyandscreeningforglaucomaandASDdisorders.OurimmediategoalistotestthehypothesisthatPOMcellsdelineateintovarioussubpopulationsandspecifytobecometheanteriorsegmentmesenchyme(ASM).TotestourhypothesisweproposetoemploythehighlyversatilezebrafishembryomodelsystemandcomprehensivelyexaminePOMcelldevelopmentwhilecatalogingtheircontributiontotheanteriorsegmentthroughgeneticmolecularandcuttingedgeinvivoimagingapproaches.Ourspecificaimsare:Aim1:CharacterizespecificationanddefinethecompositionoftheASMtheusingacombinationofgeneexpressionanalysispairedwithlight-sheetinvivotimelapseimagingandconfocalmicroscopy.Aim2:TrackthemigratorybehaviorandlineagetracedistinctpopulationsofASMduringanteriorsegmentformationusinglight-sheetinvivotimelapseimagingandconfocalmicroscopypairedwithanovelfatemappingoptogenetictracingmechanism.Aim3:GenerateacomprehensiveASMtranscriptomeforscreeningnoveltargetsinASDpatientsamplesusingacombinationofflowcytometrycoupledtoRNAseqandnextgenerationexomesequencing.

project_terms:
Affect;Animal Model;Anterior;Anterior segment dysgenesis;Behavior;Biological Assay;Biological Models;Biology;Blindness;Candidate Disease Gene;Cataloging;Catalogs;Cells;Cellular biology;Ciliary Muscle;Classification;Color;Comprehension;Confocal Microscopy;Congenital Disorders;Cornea;Corneal Endothelium;Coupled;Defect;Development;Developmental Process;Disease;Disease model;Embryo;Etiology;Event;Evolution;Eye Development;Family;Flow Cytometry;Future;Gene Combinations;Gene Expression Profiling;Genes;Genetic;Genetic Counseling;Genome engineering;Genomics;Glaucoma;Goals;Health;Human;Image;In Situ Hybridization;Individual;Inherited;Iris;Knowledge;Lesion;Light;Location;Maps;Mediating;Mesenchyme;Microscopy;Molecular;Mus;Neural Crest Cell;Optics;Patients;Pattern;Phenotype;Population;Predisposition;Regulation;Reporter;Research;Retina;Sampling;Sclera;Structure;Testing;Time;Tissues;To specify;Transgenic Organisms;Vision;Visual impairment;Visual system structure;Zebrafish;clinical practice;confocal imaging;exome sequencing;gain of function;imaging approach;in vivo;in vivo imaging;induced pluripotent stem cell;lens;migration;next generation;novel;optogenetics;orbit muscle;screening;stem cell therapy;time use;transcription factor;transcriptome;transcriptome sequencing

public_health_relevance:
PROJECTNARRATIVE/RELEVANCETOHUMANHEALTH:Anteriorsegmentdysgenesis(ASD)disordershavedevelopmentalunderpinningsthatarecrucialtoourcomprehensionofvisiondiseaseandadvancementoftherapy.Clinicalpracticewilldirectlybenefitfromstudiesofanimalmodelslikezebrafishwhichprovidestremendousresearchadvantagesincludingexuterodevelopmentopticaltransparencythroughoutdevelopmentandcapacityforgenomeengineeringanddiseasemodeling.ThegoalofourproposalistogeneratethefirstcomprehensiveclassificationofperiocularmesenchymecellsinordertofacilitateeffortsinscreeningforASDpredispositionandenablefutureinvivostemcelltherapy.


application_id: 9857599
project_number: 5R01ES016893-13
project_title: Particulate Cr(VI) Toxicology in Human Lung Epithelial Cells and Fibroblasts
administering_ic: NIEHS
award_notice_date: 2019-11-14
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: ES
serial_number: 016893
program_official: TYSON, FREDERICK L
project_start_date: 2009-07-06
project_end_date: 2023-10-31
study_section: Systemic Injury by Environmental Exposure[SIEE]
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
arra_indicator: N
project_abstract:
PROJECT SUMMARYLung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combatingit is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major publichealth concern because exposure to it is common in the workplace and in the general environment. Our studyfocuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis which are currently unknown. Inparticular this work focuses on the particulate Cr(VI) compounds because they are the most potent Cr(VI)carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells toevade DNA double strand break repair which are hallmarks of human lung cancer. Thus this research focuseson how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosomeinstability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts theeffector arm of homologous recombination (HR repair) disrupting RAD51 nucleoprotein filament formation lossof which can cause chromosome instability. Therefore the goal of this research is to characterize this impact onHR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is:particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivatingHR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test thishypothesis through three interrelated specific aims. Aim 1 will determine how Cr(VI) impacts BRCA2 DSS1RAD51B RAD51C RAD51D RPA and XRCC2 to disrupt RAD51 nucleoprotein filament formation in humanlung cells. Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation inhuman lung cells neoplastically transformed by Cr(VI) and the protein levels of BRCA2 DSS1 RAD51BRAD51C RAD51D RPA and XRCC2 in lung tumors from human Cr(VI) workers. Aim 3 determines the impactof Cr(VI) on protein levels of BRCA2 DSS1 RAD51B RAD51C RAD51D RPA and XRCC2 in the lungs andlung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of theinteractions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the firstcharacterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers.Results will also show which changes are transient and depend on exposure and which changes persist in cellsthat escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1)An understanding of Cr(VI)s carcinogenic mechanism; 2) Essential information to better assess exposure riskto particulates; and 3) A mechanistic approach for further study of Cr(VI) other metals and lung cancer in general.

project_terms:
Animal Model;Animals;Autopsy;BRCA2 gene;Cancer Etiology;Carcinogens;Cell Death;Cell Nucleus;Cells;Cessation of life;Chemicals;Chromium Compounds;Chromosomal Instability;Cytoplasm;DNA;DNA Double Strand Break;DNA Repair;Data;Disease;Double Strand Break Repair;Dust;Dyes;Environment;Epithelial Cells;Event;Exposure to;Fibroblasts;Filament;Goals;Hazardous Substances;Heritability;Human;Ink;Learning;Lung;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Metals;Molecular;Morbidity - disease rate;Neoplastic Cell Transformation;Nuclear;Nucleoproteins;Outcome;Paint;Particulate;Phenotype;Pigments;Proteins;Public Health;RAD51C gene;Rad51 recombinase;Rattus;Reporting;Research;Risk;Structure of parenchyma of lung;Testing;Toxicology;United States;Work;Workplace;XRCC2 gene;arm;carcinogenesis;carcinogenicity;cell growth;chemical carcinogen;chromium hexavalent ion;chromosome loss;combat;fight against;homologous recombination;insight;lung carcinogenesis;neoplastic;neoplastic cell;novel strategies;prevent;protein expression;protein protein interaction;public health relevance;recombinational repair;repaired;response;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE STATEMENTLung cancer is the number one cause of cancer death in the United States. Our study focuses on twohallmarks of lung cancer chromosome instability and evading DNA double strand break repair and advancesour basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes theseoutcomes as part of its carcinogenic mechanism. Our findings will help identify new mechanistic insights whichcan spur new potential treatment targets new approaches to reduce and prevent Cr(VI)-induced lung cancerand new insights to better determine safer exposure levels for this major public health concern.


application_id: 9856426
project_number: 5R34DA045563-03
project_title: Social media HIV prevention intervention for rural women drug users
administering_ic: NIDA
award_notice_date: 2020-01-28
opportunity_number: PA-15-268
application_type: 5
activity_code: R34
ic: DA
serial_number: 045563
program_official: JENKINS, RICHARD A
project_start_date: 2018-04-01
project_end_date: 2023-02-28
study_section: Special Emphasis Panel[ZRG1-AARR-G(02)M]
contact_pi_person_id: 14909213
contact_pi: STATON, MICHELE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACTThe overall aim of this R34 application is to adapt and feasibility test an evidence-based intervention for HIVprevention for a high-risk group of rural women in Appalachia. This study has potential to make a significantcontribution to science by advancing knowledge on the use of social media to increase access to preventioninterventions to reduce high-risk substance use and related health disparities among rural women during a timeof emerging and significant public health risk in Appalachia. Successfully accomplishing study aims will respondto a critical and unmet need to increase the reach and scope of prevention interventions using social media aswell as advance knowledge about the high-risk drug use behaviors of this underserved group. Considering theneed for prevention interventions among this high-risk group and the popularity of Facebook the purpose of thisR34 proposal is to adapt an evidence-based HIV prevention intervention for social media delivery and tofeasibility test through a randomized control trial with 60 high-risk rural women drug users. The following aimsguide the proposed study: (1) Adapt the NIDA Standard for HIV prevention for delivery via Facebook; and (2)Examine the feasibility of the adapted intervention with high-risk rural women through a randomized control pilot.The proposed use of Facebook in this study is promising because it is a stable widely used cost-efficientplatform that could be leveraged to increase access to critically needed HIV prevention education. This studypresents an exciting opportunity to examine the use of Facebook as a technique to expand the reach of evidence-based preventions interventions for high-risk drug users who are not likely to engage in formal treatment.Findings from this study will inform development of the larger R01 which would allow examination of theeffectiveness and sustainability of this HIV prevention intervention in understudied high risk populations.

project_terms:
AIDS prevention;Address;Affect;Alcohol or Other Drugs use;Appalachian Region;Area;Attention;Cessation of life;Communicable Diseases;Consent;Country;County;Coupled;Development;Disease Outbreaks;Documentation;Drug user;Education;Effectiveness;Effectiveness of Interventions;Epidemic;Evidence based intervention;Facebook;Feedback;Focus Groups;Frequencies;Funding;HIV;Health;Hepatitis C;Human immunodeficiency virus test;Impairment;Imprisonment;Indiana;Infection;Injections;Intervention;Interview;Jail;Kentucky;Knowledge;Link;Media Intervention;Methods;Morbidity - disease rate;National Institute of Drug Abuse;Needle Sharing;Participant;Pharmaceutical Preparations;Pilot Projects;Prevalence;Prevention;Prevention education;Preventive Intervention;Public Health;Publications;Quality of life;Randomized;Reporting;Research;Resources;Risk;Risk Behaviors;Rural;Rural Community;Science;Services;Techniques;Testing;Time;Underserved Population;United States National Institutes of Health;Virus Diseases;Vulnerable Populations;Woman;Work;behavioral health;community reentry;control trial;cost efficient;disability;disease transmission;drug use behavior;evidence base;health disparity;high risk;high risk behavior;high risk population;improved;injection drug use;innovation;men;opioid epidemic;pilot trial;prevention service;primary outcome;public health research;recruit;rural area;rural underserved;social interventions;social media;testing services;transmission process;trend

public_health_relevance:
PROJECT NARRATIVEThe overall aim of this R34 application is to adapt and feasibility test an evidence-based HIV preventioneducation for high-risk underserved rural women in Appalachia. This study has potential to make a significantcontribution to science by advancing knowledge on the use of social media to increase access to preventioninterventions to reduce high-risk substance use and related health disparities among rural women during a timeof emerging and significant public health risk in Appalachia. Successfully accomplishing study aims will respondto a critical and unmet need to increase access to prevention interventions using social media as well asadvance knowledge about the high-risk drug use behaviors among vulnerable populations.


application_id: 9854342
project_number: 1P20GM135004-01
project_title: Overcoming resistance to cancer immunotherapy by targeting MDSC-derived adenosine
administering_ic: NIGMS
award_notice_date: 2020-01-31
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 135004
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
subproject_number: 8112
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-02-01
budget_end_date: 2021-01-31
project_terms:
5'-Nucleotidase;Adenosine;Adopted;Advanced Malignant Neoplasm;Attenuated;CD8-Positive T-Lymphocytes;CD8B1 gene;CREB1 gene;Cancer Center;Cancer Model;Cancer Patient;Cattle;Cell physiology;Cell surface;Cells;Child;Clinical;Consumption;Critical Pathways;Cyclic AMP;Data;Dinoprostone;Disease;Enzymes;Epidermal Growth Factor Receptor;FDA approved;Frequencies;Generations;Goals;Homing;Human;Immune;Immune Cell Suppression;Immune checkpoint inhibitor;Immune system;Immunotherapeutic agent;Immunotherapy;Impairment;Implant;In Vitro;In complete remission;Inosine;Knock-out;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Mediator of activation protein;Molecular;Mus;Myeloid-derived suppressor cells;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nucleosides;Outcome;PD-1 inhibitors;Pathway interactions;Patients;Polyethylene Glycols;Prostaglandin Inhibition;Purine Nucleosides;Regulation;Resistance;STAT3 gene;Severe Combined Immunodeficiency;Signal Pathway;Signal Transduction;T-Cell Activation;T-Lymphocyte;Testing;Transgenic Model;Tumor Immunity;Tumor-Derived;adenosine deaminase;anti-CTLA4 antibodies;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;cancer immunotherapy;clinically relevant;conditional knockout;effector T cell;enzyme replacement therapy;extracellular;improved;in vivo;inhibitor/antagonist;insight;monocyte;mouse model;neoplastic cell;novel;objective response rate;programmed cell death ligand 1;response;therapeutic target;therapy development;therapy resistant;transcription factor;tumor;tumor growth;tumor immunology;tumor microenvironment


application_id: 9854340
project_number: 1P20GM135004-01
project_title: Mechanisms of resistance to immune therapy in NSCLC
administering_ic: NIGMS
award_notice_date: 2020-01-31
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 135004
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
subproject_number: 8110
contact_pi_person_id: 14384874
contact_pi: LI, QINGSHENG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Bioinformatics;Biopsy Specimen;CD3 Antigens;CD8-Positive T-Lymphocytes;CD8B1 gene;Cancer Center;Cancer Model;Cancer Patient;Cells;Clinic;Clinical;Data;Disease;FDA approved;Failure;Generations;Germ-Free;Goals;Grant;Growth;Human;IL17 gene;Immune checkpoint inhibitor;Immunity;Immunotherapy;Individual;Interleukin-17;Lung;Lung Adenocarcinoma;Lung Neoplasms;Lymphocyte;Lymphocyte Activation;Macrophage Activation;Malignant neoplasm of lung;Mediating;Mus;Neoadjuvant Therapy;Non-Small-Cell Lung Carcinoma;Operative Surgical Procedures;Patients;Production;Progression-Free Survivals;Psoriasis;Resistance;Severities;Specimen;T-Cell Activation;T-Lymphocyte;Testing;Therapeutic;anti-PD-1;anti-PD1 antibodies;anti-PD1 therapy;base;cancer immunotherapy;checkpoint therapy;clinically relevant;commensal bacteria;cytotoxic;cytotoxicity;design;human microbiota;in vivo;interstitial;lung microbiota;lymphoid neoplasm;macrophage;microbiota;microbiota profiles;mouse model;neoantigens;neoplastic;neutralizing antibody;novel;prognostic;programmed cell death protein 1;prospective;resistance factors;resistance mechanism;response;restoration;standard of care;therapy outcome;tumor;tumor immunology;tumorigenic; T cells


application_id: 9854337
project_number: 1P20GM135004-01
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2020-01-31
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 135004
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
subproject_number: 8107
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-02-01
budget_end_date: 2021-01-31
project_abstract:
The goal of the CCII COBRE is to establish a thematic multidisciplinary research center of excellence at theUniversity of Louisville that focuses on improving our understanding of cancer immunology and developingnovel immunotherapeutic approaches. Importantly with the recent clinical successes of immune checkpointinhibitors and oncolytic viruses there is great interest and momentum in understanding the interaction betweenthe host immune system and neoplastic cells. Our projects proposing basic immunology research coupled withtranslational and human specimen studies are expected to ultimately lead to entirely new immunotherapeuticapproaches as well as strategies for overcoming resistance to existing agents. The Administrative Core (AC)will coordinate the professional activities of the more than 40 individuals who will constitute the new Center forCancer Immunology and Immunotherapy (CCII). The AC will provide administrative fiscal and scientificoversight and planning for junior investigators mentors projects the research core a pilot program andadvisory committees. In addition to governance functions the AC will provide key research and mentoringsupport. This will include the awarding of project grants assignment of mentors provision of a grant writingmentorship program biostatistics and bioinformatics support compliance and regulatory oversight mentoringof pilot projects and encouragement of diversity and inclusion. Internal advisors and an External AdvisoryCommittee (EAC) that consists of five leading scientists in the CCII thematic area will guide the AC. The EACwill provide scientific guidance and constructive feedback regarding center/project progress and be involved inCCII strategic planning and in the selection of replacement and pilot projects. The two PIs of the overall CCIIprogram will direct the AC with key support from two co-Is who have extensive experience administering multi-component grant programs and from two additional co-Is who are well qualified to oversee the essentialbiostatistics and bioinformatics support. Their efforts will supplement a mentoring program that is anchored byeight senior investigators who are experienced mentors and have been highly productive and well funded inthe thematic area. The three specific aims of this Administrative Core that encompass all of these functions areto: (1) Establish procedures for CCII administration planning and decision-making; (2) Provide a mentorshipprogram to accelerate the careers of the CCII junior investigators; and (3) Create a CCII pilot grant programthat will stimulate new projects and collaborations. Innovative features of the AC are built on lessons learnedfrom establishing other multidisciplinary thematic centers and include a shared governance approach that aimsto ensure engagement of all participants and a holistic mentoring strategy that provides comprehensiveguidance for our CCII junior investigators. By the end of the 5-year funding program we expect that 4-6 CCIIjunior investigators will have been awarded R01 grants and that many of these graduates will remain keymembers of this new COBRE focused on cancer immunology and immunotherapy.

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


application_id: 9854336
project_number: 1P20GM135004-01
project_title: Center for Cancer Immunology and Immunotherapy (CCII)
administering_ic: NIGMS
award_notice_date: 2020-01-31
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 135004
program_official: PEI, WUHONG
project_start_date: 2020-02-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZGM1 RCB-4 (C1)]
contact_pi_person_id: 6983402
contact_pi: YAN, JUN
other_pis: CHESNEY, JASON A.
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_terms:
Adoptive Cell Transfers;Advanced Malignant Neoplasm;Advisory Committees;Animals;Antibodies;Area;Award;Basic Science;Bioinformatics;Biological Markers;Biomedical Research;Biometry;Bladder;CAR T cell therapy;CTLA4 gene;Cancer Center;Cancer Death Rates;Centers of Research Excellence;Clinical;Clinical Trials;Collaborations;Conduct Clinical Trials;Country;Cytometry;Development;Diagnosis;Discipline;Disease remission;Disseminated Malignant Neoplasm;Early Diagnosis;Financial Support;Flow Cytometry;Funding;Future;Genomics;Goals;Grant;Growth;Head and neck structure;Home environment;Human;Human Resources;Immune;Immune Evasion;Immune checkpoint inhibitor;Immune response;Immune system;Immunity;Immunologic Surveillance;Immunologist;Immunotherapeutic agent;Immunotherapy;Infrastructure;Institution;Interdisciplinary Study;International;Kidney;Lead;Lung;Malignant Neoplasms;Mediating;Mentors;Mission;Molecular;Mus;Names;Oncolytic viruses;Outcome;Paper;Patients;Persons;Phase;Pilot Projects;Proteins;Publications;Recording of previous events;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resistance;Resources;Sampling;Savings;Seminal;Services;Specimen;Study Section;T Virus;T cell therapy;Talents;Testing;Training;Translating;Translational Research;Universities;Vaccines;Work;anti-cancer;base;cancer cell;cancer clinical trial;cancer immunotherapy;cancer therapy;cancer type;career development;checkpoint therapy;cohort;equipment acquisition;immune checkpoint;improved;innovation;interest;melanoma;member;microbiome research;new therapeutic target;novel strategies;optimism;programmed cell death ligand 1;programmed cell death protein 1;programs;recruit;research and development;response;senior faculty;side effect;success;systemic toxicity;treatment strategy;tumor;tumor immunology


application_id: 9854241
project_number: 1P20GM130456-01A1
administering_ic: NIGMS
award_notice_date: 2020-02-21
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 130456
suffix: A1
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZGM1 RCB-9 (C1)]
subproject_number: 8072
contact_pi_person_id: 10451500
contact_pi: VENDITTO, VINCENT JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

project_abstract:
PROJECT SUMMARY / ABSTRACT  PROJECT 4The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediatedpathogenesis of cardiovascular disease (CVD). Detailed characterization of the antigen epitope specificityantibody subclass and receptor engagement will enhance the understanding of CVD and guide therapeuticdevelopment. One target of IgG antibody induction in patients is apolipoprotein A-I (ApoA-I) the major protein ofhigh density lipoprotein (HDL). Although anti-ApoA-I antibodies have been identified in mice and human subjectsthe role of these antibodies have not been elucidated. Furthermore the immunologic impact of antibodies boundto ApoA-I in an immune complex (ApoA-I/IgG ICs) is unclear. The long-term goal is to develop novel peptideand antibody therapeutics based on mechanistic insight from mice to reduce the burden of CVD in patients. Toachieve this goal the overall objectives of this proposal build from our observations in human subjects tocharacterize the molecular components of the anti-ApoA-I antibody response in mice and correlate theircharacteristics with cellular interactions functional outcomes and atherosclerosis progression. The hypothesisis that anti-ApoA-I antibodies exhibit both pro- and anti-inflammatory effects depending on the antibodycharacteristics (i.e. subclass epitope specificity Fc receptor interaction) leading to exacerbation or suppressionof atherosclerosis. The rationale for this proposed research is that understanding one component of the immuneresponse associated with CVD will promote improved patient outcomes through novel therapeutic strategies.Encouraged by strong preliminary data this hypothesis will be tested through two specific aims: 1) Elucidatethe molecular components and functional implications of antibodies targeting peptide epitopes derived fromApoA-I; and 2) Determine if ApoA-I/IgG ICs mediate an anti-inflammatory phenotype by engaging with theinhibitory Fc receptor using in vitro assays and in vivo studies in atherosusceptible mouse models. In the firstaim a structure immunogenicity relationship will be generated by correlating in silico modeling biophysicalcharacterization and immunogenicity studies of known peptide epitopes derived from ApoA-I. These data will becorrelated with antibody profiles and subclass composition of the antibody response toward ApoA-I. In thesecond aim the mechanistic impact of anti-ApoA-I antibodies will be determined by characterizing cellpolarization in the presence of specific anti-ApoA-I profiles and inducing antibody profiles in atherosusceptiblemice lacking Fc receptors. The innovation and significance of the proposed work is driven by the novelimmunomodulation strategies that will improve our understanding of antibody-mediated immune responseswhich will guide continued efforts to develop novel immunotherapies through coordination with the CPRI COBREto decrease the burden of CVD in patients.

project_terms:
Address;Anti-Inflammatory Agents;Antibodies;Antibody Response;Antibody Therapy;Antigen-Antibody Complex;Antigens;Antiinflammatory Effect;Apolipoprotein A-I;Arterial Fatty Streak;Atherosclerosis;Autoantibodies;Autoantigens;Biology;Blood Circulation;Cardiovascular Diseases;Cells;Centers of Research Excellence;Cessation of life;Characteristics;Chemicals;Consumption;Coronary Arteriosclerosis;Coupled;Data;Development;Diet;Disease Progression;Epitopes;Evaluation;Exhibits;Fc Receptor;Female;Foundations;Goals;Health;High Density Lipoproteins;Human;IgG1;IgG4;Immune;Immune response;Immunization;Immunoglobulin G;Immunologics;Immunotherapy;Investigation;Kentucky;Laboratories;Link;Mass Spectrum Analysis;Mediating;Mission;Modeling;Molecular;Mus;Myocardial Infarction;Outcome;Pathogenesis;Patient-Focused Outcomes;Patients;Peptide antibodies;Peptides;Pharmacologic Substance;Phenotype;Prevention;Procedures;Proteins;Reporting;Research;Role;Specificity;Structure;TLR4 gene;Testing;Universities;Work;athero susceptible;base;biophysical properties;cancer immunotherapy;cardiovascular disorder risk;functional outcomes;human subject;immunogenic;immunogenicity;immunomodulatory therapies;immunoregulation;improved;in silico;in vitro Assay;in vivo;innovation;insight;macrophage;male;mouse model;novel;novel therapeutics;polarized cell;receptor;success;therapeutic development;treatment strategy;western diet


application_id: 9854238
project_number: 1P20GM130456-01A1
administering_ic: NIGMS
award_notice_date: 2020-02-21
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 130456
suffix: A1
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZGM1 RCB-9 (C1)]
subproject_number: 8069
contact_pi_person_id: 11956743
contact_pi: AWUAH, SAMUEL GORMAN
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_title:
Gold-based pharmacophore synthetic strategies as a basis for transcription factor modulator discovery

project_abstract:
PROJECT SUMMARY/ABSTRACT  PROJECT 1Transcription factor (TF) deregulation underlies numerous diseases including cancer; however the selectivetargeting of TFs with small molecule probes/leads remains elusive. Our research program seeks to exploit theunique spatial properties and chemical reactivity of gold-based [Au(I) and Au(III)] complexes as a basis for TFprobe/lead modulator discovery. Specifically we seek to develop novel and efficient reaction methods to rapidlyconstruct diverse Au-based pharmacophore libraries and to leverage these unique compound sets and astreamlined screening strategy to discover selective modulators of the model oncogenic transcription factor c-MYC. This study will develop a generalizable platform to target undruggable targets such as protein-proteininterfaces or TFs using caged gold centers via two ways: i) directly ligate gold to specific amino acids or ii)covalently modify specific amino acids by transfer of coordinated ligands via reductive elimination in a mannersimilar to chemistry performed by transition metal-based catalysts. The studies will extend the breadth of stablegold ligands through optimization of Au catalytic processes advance our understanding of the tunable reactivityand bioorthogonality of Au-based pharmacophores and potentially set the stage for a generalized strategy totarget undruggable proteins. A primary innovation of the proposed studies is the potential to dramatically altervia covalent modification protein surface structure/electronics and thereby influence function. CPRI mentorship and research support cores will further facilitate this project in a number of key ways.Specifically the Computational Core will assist in the development of new predictive structure-activityrelationship (SAR) models for Au-based probes and computational c-MYC/MAX-ligand structural models to guideprobe design; the Translational Core will facilitate assay development validation and implementation (andeventually first in animal assessments including PK and ADMET); and the COBRE for Molecular MedicinesOrganic Synthesis Core will strategically support ligand synthesis/scale-up. This will also be augmented by aCOBRE mentorship team with extensive expertise in transcription factor lead discovery cancer biology andpharmaceutical science.

project_terms:
3-Dimensional;Affinity;Amino Acids;Animals;Area;Auranofin;Binding;Binding Sites;Biochemical;Biological Process;Cancer Biology;Cells;Centers of Research Excellence;Chemicals;Chemistry;Complex;Computer Models;Cysteine;DNA Binding;Data;Development;Disease;E-Box Elements;Electronics;Evaluation;Exhibits;FDA approved;Gene Expression Regulation;Genetic Transcription;Glutathione;Goals;Gold;Heterodimerization;Histidine;Individual;Laboratories;Lead;Libraries;Ligands;Lysine;Malignant Neoplasms;Medical;Membrane Proteins;Mentorship;Methods;Modeling;Modification;Molecular;Molecular Medicine;Natural Products;Nature;Nitrogen;Nucleic Acids;Oncogenic;Organic Synthesis;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Post-Translational Protein Processing;Process;Property;Proteins;Reaction;Regulation;Research;Research Support;Rheumatoid Arthritis;Safety;Science;Selenocysteine;Side;Site;Structural Models;Structure;Structure-Activity Relationship;Surface;System;Testing;Transition Elements;Validation;assay development;base;c-myc Genes;catalyst;cellular targeting;cytotoxicity;design;functional group;improved;inhibitor/antagonist;innovation;interest;metal complex;novel;pharmacophore;programs;protein phosphatase inhibitor-2;protein protein interaction;scale up;screening;small molecule;success;therapeutic target;time use;transcription factor


application_id: 9854236
project_number: 1P20GM130456-01A1
project_title: Translational Core
administering_ic: NIGMS
award_notice_date: 2020-02-21
opportunity_number: PAR-18-266
application_type: 1
activity_code: P20
ic: GM
serial_number: 130456
suffix: A1
project_start_date: 2020-03-01
project_end_date: 2025-01-31
study_section: Special Emphasis Panel[ZGM1 RCB-9 (C1)]
subproject_number: 8067
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
project_terms:
Address;Adhesions;Animals;Basic Science;Biological Assay;Biology;Biomedical Research;Centers of Research Excellence;Chemicals;Clinical;Clinical Research;Collection;Complement;Consultations;Data Analyses;Development;Devices;Disease;Doctor of Philosophy;Drug Kinetics;Excretory function;Faculty;Gap Junctions;Goals;Health;In Vitro;Infrastructure;Kentucky;Lead;Leadership;Libraries;Mentors;Mentorship;Metabolism;Methods;Microbial Biofilms;Modeling;Molecular Medicine;Natural Products;Organic Synthesis;Pharmacologic Substance;Pilot Projects;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;base;career development;clinical application;cytotoxicity;design;experimental study;faculty research;immunoregulation;innovation;instrumentation;multidisciplinary;pre-clinical;prevent;primary outcome;screening;stem;synergism;tool;transcription factor


application_id: 9853789
project_number: 5R01EY028911-02
project_title: Chemical Optimization of c-Cbl Antagonists for Corneal Wound Healing
administering_ic: NEI
award_notice_date: 2020-01-15
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: EY
serial_number: 028911
program_official: MCKIE, GEORGE ANN
project_start_date: 2019-02-01
project_end_date: 2024-01-31
study_section: Special Emphasis Panel[ZRG1-BDCN-J(81)S]
contact_pi_person_id: 1925445
contact_pi: CERESA, BRIAN P.
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_terms:
Address;Advanced Development;Adverse drug effect;Affinity;Anatomy;Animal Model;Antineoplastic Agents;Bacteria;Binding;Biochemical;Biological Assay;Biology;Biomedical Engineering;Blindness;Calorimetry;Cell Proliferation;Cell model;Cetuximab;Chemical Injury;Chemical Structure;Chemicals;Complex;Cornea;Corneal Diseases;Corneal Injury;Data;Development;Diabetes Mellitus;Disease;Distress;Drug usage;EGF gene;Epidermal Growth Factor Receptor;Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor;Epithelial;Epithelial Cells;Epithelium;Event;Eye;Eye Infections;FDA approved;Generations;Goals;Growth Factor Receptors;Health care facility;Homeostasis;Human;In Vitro;Incidence;Infection;Investigation;Laboratories;Lead;Ligands;Light;Lysosomes;Maintenance;Measures;Mediating;Membrane;Mission;Modeling;Modification;Molecular;Operative Surgical Procedures;Oryctolagus cuniculus;Pain;Patients;Pharmaceutical Preparations;Pharmacology;Prevalence;Primary Health Care;Procedures;Proteins;Public Health;Reagent;Receptor Signaling;Recombinants;Recurrence;Replacement Therapy;Research;Retina;Rodent;Signal Transduction;Structure;Testing;Therapeutic;Therapeutic Agents;Tissue Model;Tissues;Topical application;Trauma;Virus;Vision;Work;base;cancer type;cell growth;cell motility;corneal epithelial wound healing;corneal epithelium;corneal surgery;cytokine;cytotoxicity;desensitization;drug development;experience;heat injury;improved;in silico;in vivo;inhibitor/antagonist;innovation;interest;knock-down;limbal;nanomolar;novel;novel therapeutics;particle;preservation;prevent;receptor;restoration;side effect;stem cells;tissue culture;trafficking;ubiquitin-protein ligase;wound healing


application_id: 9853009
project_number: 5K08DK102542-05
project_title: Nephritogenic autoantibodies in systemic lupus
administering_ic: NIDDK
award_notice_date: 2020-02-20
opportunity_number: PA-14-046
application_type: 5
activity_code: K08
ic: DK
serial_number: 102542
program_official: RANKIN, TRACY L
project_start_date: 2016-02-25
project_end_date: 2022-02-24
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 11177796
contact_pi: CASTER, DAWN
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:
DESCRIPTION (provided by applicant): Up to 60% of SLE patients develop clinical evidence of kidney injury termed lupus nephritis (LN). LN is thought to be caused by glomerular immune complex deposition activating an inflammatory cascade that injures glomerular cells leading to proteinuria and loss of filtration capacity. LN is classified based on renal histopathology into si classes of which proliferative LN (ISN/RPS class III or IV) is most likely to cause renal failure.Most studies examining the causes of proliferative LN have focused on the nephritogenic potential of anti-nuclear antibodies diverting attention from a potential role for tissue/cell-specific autoantibodies. There is increasing evidence that autoantibodies to tissue specific target antigens contribute to the pathogenesis of many glomerular diseases including LN. Our preliminary data show that sera from patients with proliferative LN contain autoantibodies to human glomerular proteins including annexin A2 and moesin. These findings support our central hypothesis that autoantibodies targeting glomerular proteins including annexin A2 and moesin result in immune complex deposition that causes proliferative LN. This mentored career development proposal will focus on further characterization of autoantibodies to annexin A2 and moesin in proliferative LN validation of those autoantibodies as biomarkers for disease examination of the functional changes in podocytes and mesangial cells exposed to those autoantibodies and evaluation of the nephritogenic potential of those antibodies in animal models. As evidenced by the advances in understanding primary membranous nephropathy after the identification of target antigens this will lead to improved understanding of the pathogenic mechanisms of disease and provide new diagnostic and prognostic biomarkers. This mentored career development award also will provide protected time for the applicant to develop the skills required to become an independent physician-scientist investigating clinical and basic aspects of lupus nephritis through an individualized career development plan which has been developed by the mentorship team.

project_terms:
Actins;Address;Affect;American;Animal Model;Annexins;Antibodies;Antigen Targeting;Antigen-Antibody Complex;Antinuclear Antibodies;Attention;Autoantibodies;Autoimmune Diseases;Award;Biological Markers;Cell physiology;Cells;Clinical;Cytoskeleton;Data;Deposition;Development;Development Plans;Diagnosis;Dialysis procedure;Discipline;Disease;End stage renal failure;Evaluation;Exposure to;Filtration;Functional disorder;Goals;Histopathology;Human;Immunoglobulin G;Impairment;Inflammatory;Inflammatory Response;Injections;Injury;Injury to Kidney;K-Series Research Career Programs;Kidney;Kidney Failure;Knowledge;Lead;Life;Lupus;Lupus Nephritis;Membranous Glomerulonephritis;Mentors;Mentorship;Nucleosomes;Pathogenesis;Pathogenicity;Patients;Physicians;Prognostic Marker;Proteins;Proteinuria;Publications;Renal glomerular disease;Research;Role;Scientist;Serum;Systemic Lupus Erythematosus;Testing;Therapeutic immunosuppression;Time;Tissues;Training;Treatment Protocols;Validation;base;career;career development;diagnostic biomarker;disease diagnosis;ds-DNA;experience;experimental study;improved;improved outcome;lupus prone mice;mesangial cell;moesin;mouse model;novel diagnostics;podocyte;programs;public health relevance;skills;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The objective of this mentored Career Development proposal is to characterize cell/tissue specific nephritogenic autoantibodies that cause proliferative LN (class III/IV). This research is expected to establish the pathophysiologic basis for proliferativeLN as well as identify biomarkers for the diagnosis of this disease providing the technologic and intellectual framework necessary for the applicant to develop an independent research program in this discipline.


application_id: 9852945
project_number: 5R21AA026787-02
project_title: PD-L1 and Ethanol-enhanced Mammary Tumorigenesis
administering_ic: NIAAA
award_notice_date: 2020-01-29
opportunity_number: PA-17-219
application_type: 5
activity_code: R21
ic: AA
serial_number: 026787
program_official: MURRAY, GARY
project_start_date: 2019-02-01
project_end_date: 2022-01-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 10212779
contact_pi: CHEN, GANG
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Alcohol consumption is a well-known risk factor for human cancer including female breast cancer. Thebiological and epidemiological evidence indicates that alcohol consumption is causally and dose-dependentlyassociated with breast cancer. However the mechanism underlying ethanol-promoted mammarycarcinogenesis is unclear. Cancer is a systemic disease. The immune system monitors the host bodyrecognizing and reacting against newly arising mutated/tumor cells to stop/control tumor formation. A processtermed immunoediting is initiates when the immune system encounters mutated/tumor cells and may result inone of the three outcomes: elimination equilibrium or escape of tumor cells from immune control. Hencetumor formation indicates a compromise of host immunosurveillance. T cells particularly cytotoxic T cellsrepresent a major component of cell-mediated anti-tumor immunity. One of the mechanisms modulating T cellantitumor effector function involves the activation/inhibition receptors on a T cell membrane. Inhibition of T cellantitumor function through the activation of immune checkpoint pathways such as PD-L1/PD-1 pathway hasbeen shown to promote tumor cell immune escape and tumorigenesis. In addition previous reports indicatethat the aberrant activation of STAT3 may up-regulate PD-L1 in many human tumors. The proposed study willtest our hypothesis that ethanol promotes mammary tumorigenesis through STAT3/PD-L1/PD-1-mediatedinhibition of T cell antitumor function.

project_terms:
Alcohol consumption;Binding;Biological;Breast Cancer Model;Breast Epithelial Cells;Cell membrane;Cells;Cellular Structures;Cytotoxic T-Lymphocytes;Data;Dose;Epidemiology;Equilibrium;Ethanol;Female Breast Carcinoma;Foundations;Functional disorder;Genes;Human;Immune system;Immunologic Surveillance;Knowledge;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mammary gland;Mediating;Monitor;Mouse Mammary Tumor Virus;Mus;Mutate;Outcome;PD-1 pathway;PD-1/PD-L1;Pathway interactions;Process;Receptor Inhibition;Reporting;Risk Factors;Role;STAT3 gene;Signal Transduction;Solid;Systemic disease;T-Lymphocyte;Testing;Tissues;Tumor Escape;Tumor Immunity;Tumor-infiltrating immune cells;Tumorigenicity;Up-Regulation;alcohol exposure;cancer cell;immune activation;immune checkpoint;in vivo;malignant breast neoplasm;mouse model;neoplastic cell;programmed cell death ligand 1;promoter;tumor;tumorigenesis

public_health_relevance:
This proposed study aims to investigate a mechanism for ethanol-promoted mammary tumor formation byusing a mammary tumorigenesis mouse model. Ethanol exposure may compromise host anti-tumor immunitywhich in turn promotes an immune escape of tumor cells from the surveillance of immune system. The ideahas never been investigated before and will provide valuable information for further study the mechanismunderlying ethanol-promoted mammary tumorigenicity.


application_id: 9852556
project_number: 5R01NS092680-04
project_title: ER Ca2+ store mediated white matter injury
administering_ic: NINDS
award_notice_date: 2020-02-04
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 092680
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2017-05-01
project_end_date: 2022-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 11601659
contact_pi: STIRLING, DAVID PAUL
other_pis: Not Applicable
congressional_district: 03
department: NEUROSURGERY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract: Protecting white matter following SCI is a major goal to improve neurological recovery followingspinal cord injury (SCI). Whether the axoplasmic reticulum (AR) the major endomembrane system and Ca2+store within axons contributes to secondary bystander central myelinated fiber degeneration following SCIremains unknown. Furthermore the role of the AR's major release channels ryanodine receptors (RyR) andinositol 145-trisphophate receptors (IP3R) in white matter injury remain poorly understood; however ourpreliminary data support an important role for RyR in mediating secondary degeneration of axons following aclinically-relevant contusion SCI in vivo. Our overall objective is to protect central myelinated fibers followingSCI by targeting AR Ca2+ release channels. We will test the following hypothesis within this proposal. RyRand IP3R mediate intra-axonal Ca2+ store release of Ca2+ within spinal axons and cause secondary axonaldegeneration following contusion SCI. Therefore inhibiting Ca2+ store mediated Ca2+ release by targeting RyRor upstream signaling pathways that converge on RyR and IP3R will protect white matter following SCI. Ourspecific aims are to: 1. Determine the role of RyR and IP3R in secondary axonal degeneration followingcontusion SCI in real-time. 2. Determine the role of upstream signaling pathways in AR Ca2+ release inreal-time. 3. Evaluate clinically relevant approaches to inhibit AR-mediated intra-axonal CICR toimprove neurological recovery following contusion SCI. To accomplish this goal we will utilize two-photonmicroscopy combined with an ultrafast resonant scanner (capable of collecting images at up 420 frames persecond) to assess axonal swelling spheroid formation axonal retraction degeneration (Advillin-Cre: tdTomatotransgenic mice) axonal Ca2+ wave generation and Ca2+ accumulation in axons (Advillin-Cre: tdTomato:CaMP6f and Thy1GCaMP6f transgenic mice) myelin integrity (fluorescent lipophilic dyes) and changes in AR(e.g. ER tracker dyes and 3D electron microscopy) as these dynamic events are unfolding in real-time in vivofollowing a contusion SCI. The technology and approach proposed may help advance the field as live imagingof axons over time allows unequivocal determination of the fate of injured axons and whether they can berescued in real-time with treatment. Furthermore it allows direct visualization of myelin and the fate of this vitalelement simultaneously with axons as these events are unfolding in the injured spinal cord. This proposal isinnovative and uses advanced imaging techniques to explore overlooked areas of SCI research. The approachtaken may also unveil potential novel therapeutic targets and clinically relevant treatments (e.g. FDA approvedcarvedilol) to promote neurological recovery after SCI. The underlying mechanisms of white matter injury mayalso be relevant to multiple sclerosis and other neurological diseases.

project_terms:
3-Dimensional;AVIL gene;Area;Atrophic;Axon;Behavioral;Binding Proteins;Calcium;Data;Degenerative Disorder;Distal;Dyes;Electron Microscopy;Elements;Estrogen receptor positive;Event;FDA approved;Fiber;Gait;Generations;Goals;Human;ITPR1 gene;Image;Imaging Techniques;Injury;Inositol;Intervention;Kainic Acid Receptors;Knockout Mice;Mediating;Modeling;Molecular;Morphology;Multiple Sclerosis;Mus;Myelin;Nature;Neurologic Deficit;Pathologic;Pathology;Patients;Pharmacology;Process;Recovery;Recovery of Function;Reproducibility;Research;Reticulum;Role;Ryanodine Receptors;Secondary to;Signal Pathway;Signal Transduction;Site;Spinal;Spinal Cord;Spinal Cord Contusions;Spinal cord injury;Stroke;Swelling;System;Technology;Testing;Therapeutic;Time;Transgenic Mice;Visualization;Wallerian Degeneration;Work;axon injury;axonal degeneration;carvedilol;clinically relevant;effective therapy;functional outcomes;genetic approach;improved;in vivo;injured;innovation;kinematics;lipophilicity;loss of function;nervous system disorder;neurological recovery;new therapeutic target;novel;novel therapeutics;oxidation;preservation;prevent;receptor;serial imaging;spinal tract;two photon microscopy;white matter;white matter injury

public_health_relevance:
Project NarrativePatients with spinal cord injury often suffer from permanent neurological deficits due to loss of white matteraxons and there are currently no effective therapies to treat these problems. The molecular mechanisms thatcause secondary bystander axonal loss following spinal cord injury are poorly understood; however growingscientific evidence suggests a key role of pathological calcium in this process. This proposal will explore onepotential molecular mechanism through which the axon's major calcium store calcium release receptors mightexert such damaging effects.


application_id: 9850912
project_number: 5R01AG061111-02
administering_ic: NIA
award_notice_date: 2020-12-08
opportunity_number: PAR-18-175
application_type: 5
activity_code: R01
ic: AG
serial_number: 061111
program_official: CLARKE, AKANNI YAO
project_start_date: 2019-02-01
project_end_date: 2024-11-30
study_section: Special Emphasis Panel[ZRG1-BBBP-Z(55)R]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: NELSON, PETER T.
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
budget_start_date: 2020-12-01
project_title:
Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging

project_terms:
3-Dimensional;ABCC9 gene;Affect;Age;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease related dementia;Alzheimers disease biomarker;Amyloid;Amyloid beta-Protein;Autopsy;Biological Assay;Biological Markers;Brain;CRSP3 gene;Cardiovascular system;Clinical;Clinical Trials;Cognition;Complement;Congestive Heart Failure;Data;Degenerative Disorder;Dementia;Diagnosis;Differential Diagnosis;Diffusion Magnetic Resonance Imaging;Disease;Double-Blind Method;Drug usage;Elderly;Future;Genes;Heart failure;Hippocampus (Brain);Human;Impaired cognition;Individual;Kentucky;Life;Link;Longitudinal cohort;Magnetic Resonance Imaging;Magnetic Resonance Spectroscopy;Measures;Metabolic;Morbidity - disease rate;Nerve Degeneration;Neurocognitive;Neurofibrillary Tangles;Nicorandil;Outcome Measure;Participant;Pathology;Pathway interactions;Persons;Pharmacology;Pharmacotherapy;Phase;Placebos;Population;Prevention trial;Prospective cohort;Proteins;Proteomics;Publishing;Randomized;Research;Risk;Running;Safety;Spin Labels;Structure;Techniques;Testing;Universities;Urea;Work;aging population;base;cognitive testing;cohort;cost;design;disease diagnosis;drug discovery;drug repurposing;early phase clinical trial;efficacy outcomes;genetic risk factor;high risk;hippocampal atrophy;hippocampal sclerosis;magnetic resonance imaging biomarker;neurocognitive test;neuroimaging;neuropathology;novel;novel therapeutics;prevent;primary endpoint;primary outcome;randomized placebo-controlled clinical trial;receptor;safety testing;sex;tau Proteins;tau-1;treatment duration;trial design;volunteer


application_id: 9850578
project_number: 5R01DK112034-04
project_title: Mechanisms regulating neurotensin secretion and function
administering_ic: NIDDK
award_notice_date: 2020-02-10
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 112034
program_official: SERRANO, JOSE
project_start_date: 2017-02-01
project_end_date: 2022-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
ABSTRACT Neurotensin (NT) is a tridecapeptide localized to specialized enteroendocrine (EE) cells predominantlyin the small bowel. The most potent stimulus for NT release is the ingestion of dietary fats. NT facilitates freefatty acid (FFA) absorption in the proximal intestine stimulates growth of colorectal pancreatic and breastcancers that have the high affinity NT receptor 1 (NTR1) and contributes to lipid metabolism and glucosecontrol although its precise role in these processes has not been delineated. Recently a large populationstudy identified a significant association of increased fasting pro-NT (a stable NT precursor fragment producedin equimolar amounts relative to NT) levels with the development of diabetes increased risk of cardiovasculardisease and mortality and increased risk of breast cancer in women. Together these findings identify animportant role for NT in lipid metabolism and moreover links increased NT levels to various metabolicdiseases and increased morbidity and mortality. Epidemiological evidence clearly shows direct linkage between overnutrition and obesity; however themolecular mechanisms linking adiposity to overnutrition remain unknown. In exciting recent findings wedemonstrate that NT deficiency (using an NT knockout mouse model) protects against obesity insulinresistance and non-alcoholic fatty liver disease (NAFLD) associated with high fat consumption; we furtherdemonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FFAabsorption through a mechanism involving NTR1 and NTR3/sortilin. Conversely the overexpression of NT inDrosophila midgut EE cells increases lipid accumulation in the midgut fat body and oenocytes (hepatocyte-likecells). Remarkably in humans we show that increased levels of pro-NT strongly predict new onset obesity ina graded manner which is independent of body mass index (BMI) and insulin resistance. Therefore thecentral hypothesis for our current proposal is that FFA-mediated NT release by EE cells through a cross-talkmechanism involving AMPK activation mTOR inhibition and ERK1/2 activation promotes intestinal absorptionof FFAs acting through NTR1 and/or NTR3 and the inhibition of intestinal AMPK. Moreover we speculate thatthe overconsumption of dietary fats which leads to excess NT secretion results in obesity (from continued fatstorage) and metabolic disorders (e.g. hepatic steatosis and insulin resistance). To examine our long-termgoal of better defining intestinal NT secretion and function we have assembled a multidisciplinary and highlycollaborative team with defined expertise in NT physiology and function; metabolism and systemsbiochemistry; Drosophila genetics; and biostatistics/computational biology. Ultimately our findings will: i)significantly advance the fields of GI physiology endocrinology and metabolism; ii) change existing paradigmsregarding the systemic effects of NT; and iii) revolutionize our concept of gut hormones and their role inobesity and metabolic diseases.

project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Affinity;Amino Acids;Assimilations;Attenuated;Biochemistry;Biometry;Body mass index;Breast Cancer Risk Factor;Cells;Clinical;Colorectal Cancer;Complex;Computational Biology;Consumption;Development;Diabetes Mellitus;Diet therapy;Dietary Fats;Digestion;Distant;Drosophila genus;Endocrinology;Enterocytes;Enteroendocrine Cell;Epidemiology;Epigenetic Process;FRAP1 gene;Fasting;Fat Body;Fatty Liver;Fatty acid glycerol esters;Food;Future;Gastrointestinal Physiology;Genes;Genetic;Goals;Growth;Hepatocyte;High Fat Diet;Homeostasis;Hormones;Human;Ingestion;Innovative Therapy;Insulin Resistance;Intestinal Absorption;Intestinal Mucosa;Intestines;Knockout Mice;Laboratories;Lead;Length;Link;Lipids;Liver;MAPK3 gene;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of pancreas;Mediating;Metabolic Diseases;Metabolism;Midgut;Molecular;Morbidity - disease rate;Mus;Neurotensin;Neurotensin Receptors;Nonesterified Fatty Acids;Nutrient;Obesity;Overnutrition;Peptides;Physiology;Play;Population Study;Process;Protein Kinase;Regulation;Role;Signal Pathway;Signal Transduction;Site;Small Intestines;Stimulus;Stomach;System;Time;Transgenic Organisms;Woman;absorption;base;blood glucose regulation;cardiovascular disorder risk;cell motility;epidemiology study;lipid metabolism;mTOR inhibition;malignant breast neoplasm;mortality;mouse model;multidisciplinary;non-alcoholic fatty liver disease;novel;overexpression;receptor;response;sortilin;uptake

public_health_relevance:
Project NarrativeOur recent findings have shown that neurotensin (NT) a 13-amino acid peptide localized predominantly to thesmall bowel acts as a thrifty gene to absorb ingested fats; NT deficiency in mice protects against obesityinsulin resistance and hepatic steatosis associated with high fat diet consumption. Moreover we made thenovel observation that elevated NT levels in humans is strongly predictive of future obesity. Our currentstudies which define the mechanisms regulating NT secretion and intestinal function will significantly impactthe fields of GI physiology and metabolism and may eventually lead to innovative therapies for diet-inducedobesity and resultant metabolic disorders based on inhibition of NT signaling.


application_id: 9850516
project_number: 5R01CA192894-05
project_title: Enhancing anti-neoplastic activity of metformin in prostate cancer
administering_ic: NCI
award_notice_date: 2020-01-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 192894
program_official: FORRY, SUZANNE L
project_start_date: 2016-02-08
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1-BMCT-C(01)S]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Because prostate cancer (PCa) requires androgen for development castration is the primary treatment for patients with late stage PCa. Because androgen receptor (AR) signaling continues to be active in castration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However two FDA-approved ASIs abiraterone and enzalutamide only improve overall patient survival for several months. Thus it is urgent to identify new targets and develop new approaches to treat ASI-resistant CRPC. Metformin an antidiabetic drug widely used for over 40 years is now believed to have anti-neoplastic activity in different types of cancers. Recent clinical data suggests that metformin use may reduce development of CRPC and PCa mortality. However the detailed molecular mechanisms underlying this very important observation is not completely understood. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the mTOR (mammalian target of rapamycin) pathway and AR signaling and to exploit this unique pathway as a novel therapeutic target for ASI- resistant CRPC patients. The central hypothesis is that a combination of Plk1 inhibition with metformin is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing two Specific Aims - (1) to dissect how Plk1 phosphorylation of TSC1 (tuberous sclerosis complex 1) a negative regulator of the mTOR pathway leads to activation of the mTOR pathway in vivo; (2) to determine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. These two complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance f Plk1 to the mTOR/AR pathways and to examine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 regulates the mTOR/AR signaling; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1 as a critical therapeutic target to enhance the efficacy of metformin. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised toprovide a new paradigm for improved patient therapies by identifying the key regulator of the mTOR/AR signaling that is critical for generating and maintaining the CRPC phenotype.

project_terms:
5'-AMP-activated protein kinase;Acceleration;Androgen Receptor;Androgens;Antidiabetic Drugs;Antineoplastic Agents;Biochemical;Cancer Cell Growth;Cancer Patient;Castration;Cell Proliferation;Clinical;Clinical Data;Clinical Research;Consumption;Data;Development;Disease;Disease Progression;Event;FDA approved;FRAP1 gene;Fostering;Gluconeogenesis;Glucose;Goals;Growth and Development function;Health;Hyperinsulinism;Investigation;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Prostate Cancer;Metformin;Methodology;Mission;Mitotic;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Prostate;Prostate Cancer therapy;Protein Biosynthesis;Public Health;Receptor Signaling;Research;Resistance;Role;Side;Signal Pathway;Signal Transduction;System;TSC1 gene;Testing;Therapeutic;Tuberous sclerosis protein complex;Work;Xenograft procedure;abiraterone;anticancer research;base;cancer therapy;cancer type;castration resistant prostate cancer;chemotherapy;design;diagnostic biomarker;docetaxel;effective therapy;genetic approach;improved;in vivo;inhibitor/antagonist;innovation;mTOR Inhibitor;mTOR inhibition;mortality;mouse model;new therapeutic target;novel;novel strategies;overexpression;predictive marker;prostate cancer cell;prostate cancer progression;protein degradation;public health relevance;therapeutic target;therapy development;treatment effect;tumor growth;tumor xenograft

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


application_id: 9850331
project_number: 75N93019D00019-0-759301900131-1
project_title: In Vitro Assessment for Antimicrobial Activity Support (Task Area B)
administering_ic: NIAID
project_start_date: 2019-01-15
project_end_date: 2020-09-30
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
funding_mechanism: R and D Contracts
project_abstract:
This contract provides in vitro testing of potential antimicrobial agents maintenance of stocks and cell lines development of related assays and new techniques to culture difficult to grow pathogens.

project_terms:
Area;Biological Assay;Cell Line;Contracts;Development;In Vitro;Infrastructure;Maintenance;Techniques;antimicrobial;antimicrobial drug;in vitro testing;pathogen


application_id: 9850204
project_number: 5R01CA157429-08
project_title: Overcoming drug resistance of castration-resistant prostate cancer
administering_ic: NCI
award_notice_date: 2020-01-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 157429
program_official: FORRY, SUZANNE L
project_start_date: 2011-09-01
project_end_date: 2021-01-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Overcoming drug resistance of castration-resistant prostate cancer. Over the last decade tremendous progress has been made in the understanding of castration-resistant prostate cancer (CRPC) a disease state that retains androgen receptor (AR)-dependent in most cases. That understanding led to the notion that targeted inhibition of AR signaling would be an effective approach for treatment of CRPC. In support the landscape for CRPC treatment is now changing from docetaxel-based therapy to treatment with Androgen Signaling Inhibitors (ASI) such as abiraterone an inhibitor of de novo androgen synthesis pathway and enzalutamide a direct AR inhibitor. However ASI- based treatment only improves the overall patient survival by several months. Therefore understanding the underlying mechanisms of ASI resistance and development of novel avenues to increase the efficacy of ASI-based therapy are urgently needed. Besides AR signaling activation of the PI3K pathway due to lose-of-function PTEN tumor suppressor has a well-established role in CRPC. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with CRPC. The objective is to define the role of Polo-like kinase 1 (Plk1) in activating AR signaling and the PI3 pathway and to exploit this unique pathway as a novel therapeutic target for CRPC patients. The central hypothesis is that Plk1-associated activity towards AR and PTEN causes constitutive activation of AR signaling and the PI3K pathway respectively thus CRPC progression and development of ASI resistance. This hypothesis will be tested by pursuing three Specific Aims - (1) to identify the molecular mechanism(s) by which Plk1 activity activates AR signaling; (2) to examine whether Plk1-associated activity affects PCa progression in vivo; and (3) to test whether Plk1 phosphorylation of AR regulates ASI sensitivity. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing gain-of-function and loss-of-function strategies with inducible PCa mouse models culture systems and human PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to the AR and the PI3K signaling pathways and to examine how Plk1 induces ASI resistance in CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 activates AR; (ii) examine how Plk1 activates the PI3K pathway; (iii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iv) validate Plk1 as a critical therapeutic target to enhance theefficacy of ASI. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised to provide a new paradigm for improved patient therapies by identifying the key regulator of the AR/PI3K pathways that are critical for generating and maintaining the CRPC phenotype.

project_terms:
Acetates;Adrenal Glands;Affect;Androgen Receptor;Androgens;Biochemical;Biological Markers;Cancer Patient;Castration;Cell Death;Cell Nucleus;Cells;Clinical Research;Critical Pathways;Cytochrome P450;Cytoplasm;Data;Development;Disease;Drug resistance;Event;Fostering;Goals;Health;Human;Investigation;Knock-in Mouse;Malignant Neoplasms;Malignant neoplasm of prostate;Methodology;Mission;Mitotic;Molecular;Mus;Mutate;Outcome;PI3 gene;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmacology;Pharmacotherapy;Phenotype;Phosphorylation;Phosphorylation Site;Phosphotransferases;Prevention;Prostate;Prostate Cancer therapy;Prostatic;Public Health;RNA Splicing;Receptor Signaling;Regulation;Research;Resistance;Resistance development;Role;Signal Pathway;Signal Transduction;System;Testing;Therapeutic;Tumor Suppressor Proteins;Tumor-Derived;Up-Regulation;Variant;Withdrawal;Work;Xenograft Model;Xenograft procedure;abiraterone;base;castration resistant prostate cancer;design;docetaxel;effective therapy;gain of function;improved;in vivo;inhibitor/antagonist;innovation;loss of function;mouse model;new therapeutic target;novel;novel strategies;overexpression;predictive marker;prostate cancer cell;prostate cancer progression;public health relevance;response;success;therapeutic target;tumor growth;tumor xenograft

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


application_id: 9849326
project_number: 5R01HL141103-02
administering_ic: NHLBI
award_notice_date: 2019-11-27
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: HL
serial_number: 141103
program_official: OH, YOUNGSUK
project_start_date: 2019-01-15
project_end_date: 2022-10-31
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 6625920
contact_pi: GONG, MING C
other_pis: GUO, ZHENHENG
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-11-01
project_title:
Targeting timing of food intake as a novel strategy against disruption of blood pressure circadian rhythm in diabetes

project_abstract:
The normal blood pressure (BP) circadian rhythm is essential to human health as morning BPsurge is associated with increased incidence of life-threatening cardiovascular events. Moreover disruptionof BP circadian rhythm which occurs in up to 75% of diabetic patients is emerging as an index for futuretarget organ injury and poor cardiovascular outcomes. However the mechanism by which BP circadianrhythm is disrupted in diabetes is largely unknown and an effective strategy to restore the disrupted BPcircadian rhythm in diabetes has not yet been identified. Our preliminary studies found that by limiting thetime of food available to the active period (ATRF) provided striking protection of the diabetic db/db micefrom the severe disruption of BP circadian rhythm. Moreover BMAL1 an obligatory clock gene is requiredfor and glucagon-like peptide-1 (GLP-1) receptor activation mimics the protection of BP circadian rhythm byATRF. These intriguing findings suggest that ATRF can serve as a novel strategy to promote normal BPcircadian rhythms thus significantly improving the cardiovascular prognosis of diabetic patients. Thecurrent proposal will examine this new exciting possibility by testing the specific hypothesis that active time-restricted feeding (ATRF) or GLP-1 activation restores normal smooth muscle and renal BMAL1 andsympathetic oscillations thus protects diabetic mice from disruptions of blood pressure circadian rhythm.The three specific aims are 1). Determine the mechanism by which BMAL1 is dysregulated in diabetes andrestored by ATRF. 2). Test the hypothesis that ATRF protects BP circadian rhythm via smooth muscle andrenal BMAL1 in diabetes. 3). Define ATRF as a novel chrononutritional therapy and targeting GLP-1 as anew pharmacological therapy to protect BP circadian rhythm in diabetes. We will monitor the circadianrhythms of BP food intake BMAL1 regulation vascular smooth muscle function and signaling renalfunction and sympathetic regulation under ad libitum and ATRF feeding regimens. The various mousemodels will be used are diabetic db/db mice db/db-per2Luc mice high-fat diet fed mice smooth muscle andrenal BMAL1 knockout mice.

project_terms:
ARNTL gene;Affect;Agonist;Blood Pressure;Calories;Cardiovascular Diseases;Cardiovascular system;Circadian Rhythms;Data;Diabetes Mellitus;Diabetic Angiopathies;Diabetic mouse;Eating;Event;Excretory function;Food;Functional disorder;Future;GLP-I receptor;Genes;Glucagon;Goals;Health;High Fat Diet;Human;Incidence;Intake;Kidney;Knockout Mice;Life;Light;Link;Liver;Macronutrients Nutrition;Metabolism;Monitor;Mus;Muscle function;Norepinephrine;Nuclear;Obesity;Organ;Outcome;Peptides;Pharmacology;Prevalence;Receptor Activation;Regimen;Regulation;Renal function;Reporting;Rho-associated kinase;Role;Severities;Signal Transduction;Smooth Muscle;Smooth Muscle Myocytes;Sympathetic Nervous System;Testing;Time;Time-restricted feeding;Type 2 diabetic;Variant;Vascular Smooth Muscle;circadian;db/db mouse;diabetic;diabetic patient;fasudil;feeding;gender difference;glucagon-like peptide 1;improved;indexing;inhibitor/antagonist;mouse model;neurotensin mimic 1;novel;novel strategies;novel therapeutics;organ injury;outcome forecast;pre-clinical;prevent;protective effect;urinary

public_health_relevance:
Normal blood pressure has regular circadian rhythm which is disrupted in up to 75% diabeticpatients in association with detrimental cardiovascular outcomes. We found that the bloodpressure circadian rhythm is effectively protected if the diabetic mice were only allowed accessto food during their active time (eat at the right time). The proposed study will investigate themechanisms underlying this protection and test the potential of limiting feeding to active time asa novel therapeutic strategy to improve the prognosis in diabetic patients.


application_id: 9849297
project_number: 5P20GM121327-04
project_title: Project 4: The Role of Fatty Acid Synthase in Colorectal Cancer
administering_ic: NIGMS
award_notice_date: 2019-12-17
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
project_start_date: 2020-01-01
project_end_date: 2020-12-31
study_section: ZGM1-RCB-6
subproject_number: 7099
contact_pi_person_id: 10755133
contact_pi: ZAYTSEVA, YEKATERINA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY  Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). My long-term goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by understanding how changes in de novo fatty acid synthesis 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. I have identified FASN as a potential target for advanced stages of disease and showed that upregulation of this enzyme is a key mechanism supporting metastasis in CRC. However the underlying mechanisms of regulation of metastasis by FASN are not understood. The current application proposes a comprehensive research plan to study novel mechanisms of regulation of growth survival and metastasis by FASN in CRC. Our preliminary studies show that overexpression of FASN is associated with an increase in cellular respiration including - oxidation inhibition of autophagy and accumulation of lipid droplets. Therefore in Aim 1 we will elucidate the role of FASN in reprogramming of metabolic pathways and lipid storage in order to maintain energy homeostasis and promote survival of cancer cells. Furthermore our preliminary data suggest that the primary product of de novo fatty acid synthesis palmitate is selectively used for sphingolipid synthesis and overexpression of FASN increases the level of sphingosine-1-phosphate (S1P) a bioactive sphingolipid known to enhance migration and invasion of cancer cells. Therefore in Aim 2 we will test the hypothesis that FASN promotes metastasis via activation of sphingosine kinases and an increase in S1P signaling. Finally in Aim 3 we will test the effect of FASN inhibitor on proliferation in CRC patient-derived xenografts (PDXs) as a monotherapy and in combination with an autophagy inhibitor and identify potential biomarkers associated with CRC responsiveness to FASN inhibition.  I will utilize biological samples from patients human primary cells and PDX 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 Stable Isotope-Resolved Metabolomics (SIRM) to evaluate the effect of FASN overexpression on cancer metabolism. The differential expression of FASN in normal versus cancer cells makes de novo lipogenesis a desirable target for therapeutic intervention. I anticipate that the proposed work will identify a subset of CRC patients who would benefit from targeted FASN inhibition and further advance our understanding of the role of FASN in CRC that would potentially lead to the development of novel therapeutic strategies to treat this disease.

project_terms:
Autophagocytosis;Biological;Biological Sciences;Cancer Cell Growth;Cancer Center;Cause of Death;Cell Proliferation;Cell Respiration;Cell Survival;Cells;Cessation of life;Characteristics;Colorectal Cancer;Data;Development;Disease;Disease-Free Survival;Drug Evaluation;Energy Supply;Enzymes;Evaluation;Fatty Acids;Fatty-acid synthase;Goals;Growth;Homeostasis;Human;Incidence;Kentucky;Lead;Link;Lipids;Malignant - descriptor;Malignant Neoplasms;Mass Spectrum Analysis;Mediating;Membrane;Metabolic;Metabolic Pathway;Metabolism;Metastatic Neoplasm to the Liver;Metastatic Neoplasm to the Lung;Metastatic to;Modeling;Molecular;Neoplasm Metastasis;Oncogenic;Outcome;Palmitates;Patients;Play;Post-Translational Protein Processing;Pre-Clinical Model;Process;Production;Proteins;Publishing;Recurrence;Regulation;Research;Resected;Role;Sampling;Signal Transduction;Solid Neoplasm;Sphingolipids;Sphingosine;Stress;Testing;Therapeutic;Therapeutic Intervention;Tumor Angiogenesis;Universities;Up-Regulation;Work;Xenograft Model;Xenograft procedure;antitumor effect;base;cancer cell;cancer survival;colon cancer cell line;colon cancer patients;colorectal cancer metastasis;colorectal cancer treatment;differential expression;disorder risk;high risk;in vivo;inhibition of autophagy;inhibitor/antagonist;knock-down;lipid biosynthesis;metabolomics;migration;molecular marker;novel;novel therapeutics;outcome forecast;overexpression;oxidation;potential biomarker;prevent;sphingosine 1-phosphate;sphingosine kinase;stable isotope;targeted treatment;tumor;tumor growth;tumor metabolism


application_id: 9849290
project_number: 5P20GM121327-04
project_title: Core B: Metabolism Core
administering_ic: NIGMS
award_notice_date: 2019-12-17
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
study_section: ZGM1-RCB-6
subproject_number: 7094
contact_pi_person_id: 7042565
contact_pi: LANE, ANDREW N.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-01
budget_end_date: 2020-12-31
project_abstract:
PROJECT SUMMARY Metabolomics largely consists of metabolic profiling which is the process of identification andquantification of a large number of metabolites of many different biochemical classes from diversebiological samples including cells culture media tissue and biofluids. However to understand themetabolic underpinning of diseases such as cancer a biochemical mechanism is needed in whichcase it is necessary to introduce appropriate stable isotope tracers which while increasing thenumber of analytes to be quantified also greatly increase the retrieval of biologically relevantinformation. This Stable Isotope Resolved Metabolomics (SIRM) approach is a unique specialty ofthe Metabolism Core. The goals of the Core are to provide services for a wide coverage ofmetabolites with isotopomer and isotopologue analysis. To achieve this we make use of two majoranalytical platforms namely high resolution nuclear magnetic resonance (NMR) and ultra-highresolution Fourier-transform mass spectrometry (UHR-FTMS) with or without chromatography. TheCore personnel will advise on analytical methods and experimental design and additional techniquesmay be developed to address issues of identification and quantification. Because experimentaldesign and sample preparation are integral to the data acquisition and interpretation the Coreprovides expertise in these and informatics relevant to the SIRM approach. These goals will beachieved according to the following: Specific Aim 1. To provide access and expertise across a widerange of NMR and MS technologies to investigators. Specific Aim 2. To provide experimental designsample processing and informatics support to the investigators for data reduction metabolicpathway and biochemical mechanism analyses. Specific Aim 3. To develop and implement newmethods to enhance metabolic capabilities relevant to the COBRE Projects. This Core will supportthe young investigators by providing advanced analytical technologies and expertise in the metabolicrequirements for cancer development.

project_terms:
Address;Algorithms;Biochemical;Biochemistry;Bioinformatics Shared Resource;Biological;Biomass;Biometry;Cancer Biology;Cancer Center;Cell Culture Techniques;Centers of Research Excellence;Chromatography;Classification;Collaborations;Complement;Consult;Culture Media;Data;Data Analyses;Databases;Development;Disease;Experimental Designs;Fourier Transform;Goals;Hour;Human Resources;In Situ;Informatics;Infusion procedures;Isotope Labeling;Isotopes;Kentucky;Label;Liquid Chromatography;Logistic Regressions;Malignant Neoplasms;Mass Fragmentography;Mass Spectrum Analysis;Metabolic;Metabolic Pathway;Metabolism;Methods;Mole the mammal;Nuclear Magnetic Resonance;Pathway Analysis;Pathway interactions;Preparation;Procedures;Process;Protons;Research Personnel;Resolution;Retrieval;Sampling;Schedule;Services;Spectrum Analysis;Standardization;Statistical Data Interpretation;System;Techniques;Technology;Time;Tissue Harvesting;Tissues;Tracer;Universities;Update;advanced analytics;analytical method;animal imaging;base;cell growth;data acquisition;data reduction;experimental study;in vivo;medical specialties;metabolic abnormality assessment;metabolic profile;metabolomics;random forest;stable isotope;tumor metabolism;ultra high resolution;wiki


application_id: 9849287
project_number: 5P20GM121327-04
project_title: University of Kentucky Center for Cancer and Metabolism
administering_ic: NIGMS
award_notice_date: 2019-12-17
opportunity_number: PAR-14-035
application_type: 5
activity_code: P20
ic: GM
serial_number: 121327
program_official: MCGUIRL, MICHELE
project_start_date: 2017-03-01
project_end_date: 2021-12-31
study_section: ZGM1-RCB-6(CI)
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
other_pis: ZHOU, BINHUA P
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 Cancer cell survival traits such as suppressed apoptosis rapid cell cycling and proliferation and the abilityto metastasize from a primary location require extensive metabolic reprogramming of the tumormicroenvironment. Intriguing new insights into the novel role of metabolic dysregulation in tumorigenesis andmetastasis increasingly draw attention to currently understudied areas of cancer research: the potential formetabolic modulation to influence therapeutic outcomes and the impact of metabolic events at the clinical levelto impact quality of life for cancer patients. The University of Kentucky (UK) proposes to establish a uniquemultidisciplinary Center of Biomedical Research Excellence (COBRE) on Cancer and Metabolism (CCM) as astrategically designed sustainable framework that cultivates cutting-edge research focused on the role ofmetabolic mediators of cancer development and progression. The proposed multidisciplinary center leverageshighly specialized expertise in redox biology cancer cell signaling systems biochemistry and data sciences aswell as the presence of advanced metabolomics and sophisticated cancer imaging capabilities to create anintegrated cancer-metabolism research framework. Overarching goals are to strengthen UK's cancer researchenterprise by providing a thematically focused multidisciplinary infrastructure dedicated to defining thecontribution of metabolism in the development and treatment of cancer and to use this novel multidisciplinaryplatform to develop promising early-stage investigators with enhanced skills in an exciting new area of cancerresearch. To accomplish these goals we will (1) develop a critical mass of funded investigators with researchprograms directly related to the Center's unifying theme (2) provide strong team-based mentoring combiningbasic and clinical expertise (3) recruit new investigators to the Center through pilot project grant supportleveraged by institutional funds (4) create synergy among research projects via critical links to strong researchcenters at UK including existing COBREs and (5) facilitate the translation of basic findings in cancermetabolism into early therapeutic approaches. Proposed new synergies will be developed through fourresearch projects an Administrative Core important research cores in metabolism and imaging and strongbiostatistics/ bioinformatics support all of which are critical to the proposed studies and will contribute to thedevelopment of institutional resources. The scientific focus of the four research projects is cancer-metabolisminteractions spanning basic and translational perspectives. This concentration of multidisciplinary expertisefocused on a newly recognized cancer paradigm holds promise for significant new understandings ofoncogenesis overall. The CCM's integrative thematic focus and the clinical and translational implications ofinnovative understandings of the cancer-metabolism axis have strong potential to create a cadre of well-trainedscientists who are well equipped to lead future generations of scientists integrating these exciting new avenuesof investigation in metabolic dysregulation into multi-faceted studies on cancer development and therapy.

project_terms:
Address;Apoptosis;Area;Attention;Basic Science;Biochemistry;Bioinformatics;Biology;Biometry;Cancer Center;Cancer Death Rates;Cancer Patient;Cell Cycle;Cell Proliferation;Cell Survival;Centers of Research Excellence;Clinical;Collaborations;Core Facility;Coupled;Data;Data Science;Development;Discipline;Early Diagnosis;Environment;Event;Faculty;Fostering;Foundations;Funding;Future Generations;Goals;Grant;Growth;Image;Incidence;Infrastructure;Interdisciplinary Study;Intervention;Investigation;Kentucky;Lead;Link;Location;Malignant Neoplasms;Mediator of activation protein;Mentors;Metabolic;Metabolic Diseases;Metabolism;Neoplasm Metastasis;Obesity;Outcome;Oxidation-Reduction;Pilot Projects;Proliferating;Quality of life;Research;Research Personnel;Research Project Grants;Research Support;Resources;Role;Scientist;Seeds;Signal Transduction;System;Therapeutic;Training;Translations;United States National Institutes of Health;Universities;anticancer research;base;cancer cell;cancer imaging;cancer initiation;cancer therapy;career;cohesion;defined contribution;design;early detection biomarkers;imaging capabilities;improved;innovation;insight;interdisciplinary approach;metabolomics;mortality;multidisciplinary;novel;novel therapeutics;prevent;programs;recruit;skills;success;synergism;therapeutic target;therapy outcome;tool;trait;tumor metabolism;tumor microenvironment;tumor progression;tumorigenesis

public_health_relevance:
PROJECT NARRATIVE The Center of Biomedical Research Excellence on Cancer and Metabolism seeks to define underlyingmechanisms that support a body of emerging evidence that links metabolic disorders to the development andprogression of cancer. To this end integrated and synergistic research support across multiple disciplines andfocusing on innovation and translation of ideas from basic research into novel therapy will be provided to juniorfaculty with research programs in this highly significant area. A well-designed and intensive mentoring programand cutting-edge research cores will foster and augment collaborations between project leaders and leadingresearchers from both within and outside UK.


application_id: 9846018
project_number: 5R01HL134731-04
project_title: Serum Amyloid A Inflammasome Activation and Abdominal Aortic Aneurysms
administering_ic: NHLBI
award_notice_date: 2019-12-24
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 134731
program_official: MCDONALD, CHERYL
project_start_date: 2017-01-01
project_end_date: 2021-12-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: DE BEER, FREDERICK C.
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:
Recent estimates indicate that 5-10% of men and 1-2% of women 65-79 years of age in the United States areliving with an abdominal aortic aneurysm (AAA). Approximately 15000 will die each year due to AAA rupture.The treatment for AAA is limited to surgical intervention due to lack of other therapies with proven benefit.Although most patients with AAAs are asymptomatic the risk of death due to rupture increases greatly asAAAs expand. Insights into mechanisms contributing to AAA progression would have a major impact on theclinical management of AAA by providing new biomarkers that predict AAA expansion and thus the risk foraortic rupture as well as novel strategies for intervention. Recent published findings from our laboratoryprovide the impetus for a detailed evaluation of serum amyloid A (SAA) in AAA progression: 1) SAA deficiencyattenuates AAA in a mouse model; 2) in mice SAA is present in AAA in regions with substantial elastindegradation macrophage infiltration and matrix metalloproteinase (MMP) activity; and 3) SAA can be detectedin human AAA. In unpublished work we also determined that SAA induces IL-1 and NLRP3 expression aswell as IL-1 secretion in macrophages consistent with priming and activation of the NLRP3 inflammasome.These findings are notable given the recent recognition that NLRP3 inflammasome activation is a critical eventin AAA development in mice. Thus our central hypothesis is that SAA activates the NLRP3 inflammasomethereby amplifying local inflammatory responses that enhance pathological tissue remodeling and promoteAAA progression. AIM 1: Investigate the role of the NLRP3 inflammasome in SAA's ability to promote AAA inmice. Aim 1a. Using mice deficient in various inflammasome components (NLRP3-/- ASC-/- caspase-1-/- mice)or IL-1 signaling (IL-1R-/- mice) we will determine whether SAA-mediated AAA is dependent on the NLRP3inflammasome. We will also investigate whether small-molecule anionic sulphonates a treatment that blocksthe deposition of SAA in tissues is effective in reducing AAA in mice. Aim 1b. Using macrophage cell cultureswe will investigate whether any of the known biological activities attributed to SAA including reactive oxygenspecies generation or association with HDL are involved in SAA-mediated NLRP3 inflammasome activation.AIM 2: To test the hypothesis that systemic SAA promotes the progression of an established AAA. Aim 2a.Our approach will be to transiently increase SAA expression in livers of mice at specific intervals during thecourse of AngII infusion through the use of viral vectors and an inducible transgene. As a complementaryapproach SAA expression will be suppressed using antisense oligonucleotides. The impact of SAA on indicesof AAA progression and aortic inflammation and remodeling will be determined. Aim 2b. To investigate thepotential role of SAA and inflammasome activation in human AAA the relationship between plasma SAA IL-1and the rate of AAA expansion in humans will be determined in the prospective N-TA3CT trial. These studieshold the potential for identifying new strategies for the clinical management of AAA.

project_terms:
Abdominal Aortic Aneurysm;Acute;Age-Years;Angiotensin II;Antisense Oligonucleotides;Aortic Rupture;Aortitis;Apolipoprotein E;Attenuated;Biological;Biological Markers;Blood Vessels;CASP1 gene;CCL2 gene;Caring;Cell Culture Techniques;Cells;Cessation of life;Chronic;Clinical Management;Data;Deposition;Development;Elastin;Evaluation;Event;Generations;High Density Lipoproteins;Human;Infection;Infiltration;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory Response;Infusion procedures;Injury;Interleukin-1 beta;Intervention;Laboratories;Liver;Matrix Metalloproteinases;Medial;Mediating;Mus;Operative Surgical Procedures;Pathologic;Patients;Plasma;Proteins;Publications;Publishing;Reactive Oxygen Species;Risk;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Serum amyloid A protein;Signal Transduction;Smooth Muscle Myocytes;Stains;Symptoms;TNF gene;Testing;Tissues;Transgenes;United States;Viral Vector;Woman;adeno-associated viral vector;base;effective therapy;human old age (65+);indexing;innovation;insight;macrophage;men;mortality risk;mouse model;novel;novel strategies;predictive marker;prospective;response;small molecule;therapeutic target;translational study;unpublished works;vascular inflammation

public_health_relevance:
Approximately 15000 people in the United States alone die every year due to rupture of an abdominal aorticaneurysm (AAA). The clinical management of patients with AAA is challenged by the lack of effectivetreatments and the fact that most patients with AAA do not exhibit symptoms. This project investigateswhether serum amyloid A a protein known to be involved in the normal response to infection and injury maybe useful for developing new approaches for the identification care and management of patients with AAA.


application_id: 9844417
project_number: 5F31DE027585-03
project_title: Exploitation of the host immune response by Aggregatibacter actinomycetemcomitans mediated by QseBC
administering_ic: NIDCR
award_notice_date: 2020-01-06
opportunity_number: PA-16-308
application_type: 5
activity_code: F31
ic: DE
serial_number: 027585
program_official: FRIEDEN, LESLIE A
project_start_date: 2018-01-01
project_end_date: 2022-12-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 14913835
contact_pi: OZUNA, HAZEL
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:
Aggregatibacter actinomycetemcomitans (Aa) has been strongly associated with localized aggressiveperiodontitis (1-3). At the anaerobic environment of the sub-gingival pocket Aa is exposed to changes inhomeostasis yet little is known about the processes used by Aa to acquire the necessary nutrients such as:iron in order to adjust to changes and persist. The study the mechanism used by Aa to sense and respond toenvironmental stress is essential in order to to develop therapeutic treatments for periodontal disease andfurther the knowledge in the field of microbial endocrinology. A two component system (TCS) known asQseBC is expressed by Aa and it plays an important role in the process of adaptation and survival in theanaerobic environment. The sensor molecule QseC was found to play a role in growth and virulence of Aa (1).Further the signals responsible for the activation of this TCS were identified as being catecholamines and iron(CAT-Fe) (Weigel 2015). The protein YgiW has no known function and it is co-expressed with the QseBCTCS. The regulation of the enterobactin operon genes were found to remain unchanged in the presence ofCAT-Fe (Weigel 2015) when other genes involved in iron uptake were downregulated suggesting that it mustplay an important role for Aa persistence in the anaerobic environment. Among the four genes encoded in theenterobactin operon there is an outer membrane enterobactin receptor FepA (4) yet Aa does not producesiderophores (5). Localized aggressive periodontitis promotes increased infiltration of polymorphonuclear(PMNs) leukocytes or neutrophils (6). PMNs have been shown to release catecholamines (CAT) a type ofsiderophore suggesting that the inflamed sub-gingival pocket may serve as a CAT-Fe rich environment.Therefore the proposed hypothesis is that Aa utilizes catecholamines from the host environment and viaQseBC priming metabolism for growth in the anaerobic sub-gingival environment and then acquiringiron through the uptake of CAT-Fe via the enterobactin complex. The hypothesis will be tested byaddressing the following aims: 1) to characterize the synthesis storage and release of CAT by PMNsstimulated with Aa 2) to define the interaction of CAT-Fe with QseC and/or YigiW and 3) determine thecontribution of YgiW on QseC activation. The research design will consist of exposing human PMNs directly towild type and virulence factors mutants of Aa and measuring CAT levels by ELISA to confirm their ability torelease CAT (Aim 1a) and identify the signals required for their release (Aim 1b). The granules of PMNs willbe isolated and screened using CAT antibodies to identify where CAT are stored (Aim 1c). Next biding kineticanalysis will be used to characterize the interaction of CAT-Fe to QseC and/or YgiW (Aim 2a) and surfaceplasmon resonance will be used to define YgiW contribution to QseC activation (Aim 2b). Lastly bindingkinetic analysis will be employed to determine the binding interaction of CAT-Fe to FepA (Aim 3a) and thechronic periodontitis animal model will be use to asses the role of the enterobactin operon in Aa virulence (Aim3b).

project_terms:
Actinobacillus actinomycetemcomitans;Address;Anaerobic Bacteria;Animal Model;Antibodies;Asses;Binding;Catecholamines;Complex;Cytoplasmic Granules;Development;Endocrinology;Enterobactin;Environment;Enzyme-Linked Immunosorbent Assay;Exposure to;Foundations;Future;Gene Expression;Genes;Growth;Homeostasis;Hormones;Human;Immune response;Infection;Infiltration;Inflammatory;Iron;Kinetics;Knowledge;Ligands;Location;Measures;Mediating;Membrane;Metabolism;Microbial Biofilms;Nutrient;Operon;Organism;Outcome;Periodontal Diseases;Periodontitis;Phagocytes;Play;Process;Proteins;Regulation;Research Design;Respiration;Role;Siderophores;Signal Transduction;Stress;Surface Plasmon Resonance;System;Testing;Therapeutic;Transferrin;Virulence;Virulence Factors;Work;design;enteric pathogen;environmental change;exposed human population;macrophage;microbial;mutant;neutrophil;periplasm;receptor;response;sensor;therapeutic target;uptake

public_health_relevance:
Project NarrativeThe mechanisms of Aggregatibacter actinomycetemcomitans (Aa) to sense and adjust to environmentalchanges will expand the knowledge and serve as a guide to work with similar organisms found in comparableniches. In addition findings will further the field of microbial endocrinology and iron acquisition systems. Thestudy of the proposed mechanism by which Aa exploits the host response to acquire iron presents theopportunity for future therapeutic targets for periodontal disease.


application_id: 9843701
project_number: 5R01HL124015-05
project_title: Latexin function in the maintenance and regeneration of the hematopoietic system
administering_ic: NHLBI
award_notice_date: 2019-12-31
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 124015
program_official: BAI, C BRIAN
project_start_date: 2016-01-01
project_end_date: 2021-08-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 9839693
contact_pi: LIANG, YING
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY The long-term goal of this study is to develop new strategies to mitigate and protect radiation-inducedhematopoietic injury by delineating the molecular mechanisms responsible for enhancing hematopoietic stemcells (HSC) self-renewal and survival. Radiation therapy commonly results in not only acute hematopoieticsuppression but also long-term bone marrow (BM) injury. To date no effective treatment has been developedto prevent or treat these pathological consequences. Enhancing HSC survival and maintaining their genomicintegrity upon radiation are crucial for preservation of HSC self-renewal function and for protection againstradiation-induced BM injury. However the molecular mechanisms for regulating HSC survival and self-renewalare not well defined. HSC number and function demonstrate natural variations and underlying genetic diversityis an important yet largely unknown mechanism involved in the regulation of HSC function. Latexin (Lxn) waspreviously identified as the first stem cell regulatory gene whose natural variation negatively contributes to theHSC population size in different mouse strains. In preliminary studies constitutive gene ablation approacheswere developed to define the role of Lxn in HSCs and hematopoiesis in normal and radiation stress conditions.Results showed that Lxn inactivation protects HSCs and hematopoietic progenitor cells (HPCs) from radiation-induced cell death thus mitigating acute hematopoietic suppression and conferring a survival advantage.Moreover Lxn knockout mice do not develop hematological malignancies following single or fractionateddosages of radiation. Mechanistically Lxn inactivation in vivo increases HSC self-renewal and survival. At themolecular level our published and preliminary work showed that ribosomal protein subunit 3 (Rps3) is a novelLxn-binding protein and Lxn overexpression inhibits Rps3 activity thus enhancing radiation sensitivity andtoxicity. In addition the number of human HSCs/HPCs negatively correlates with Lxn expression levelindicating the potential role of Lxn in regulating human hematopoiesis. These findings lead to the hypothesisthat Lxn maintains homeostatic HSC and hematopoiesis and inhibition of Lxn function protects againstradiation-induced hematopoietic injury via Rps3-dependent prosurvival pathways. Specific aims are to: 1)determine the cellular mechanisms by which Lxn inactivation enhances HSC survival and self-renewal andconfers radioprotection 2) identify the molecular mechanisms by which Lxn inactivation enhances Lxn-Rps3-NF-kB prosurvival pathway and 3) determine the role of Lxn in mitigating human hematopoietic cell toxicityfrom radiation injury. This research will advance understanding of a critical but understudied mechanisminvolved in the natural regulator of HSC function and self-renewal. By using mouse and human model systemsand state-of-the-art molecular and genomic techniques findings from the proposed study may facilitate to thedevelopment of novel mechanism-based therapeutic strategy to protect against radiation-induced BM injurywhich could be beneficial for the patients receiving cancer therapy and BM transplantation.

project_terms:
Ablation;Acute;Apoptosis;Attenuated;Binding;Binding Proteins;Biological Models;Blood;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CD34 gene;Cancer Patient;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Complex;DNA Damage;Development;Exposure to;Genes;Genetic;Genetic Transcription;Genetic Variation;Genomics;Goals;Hematologic Neoplasms;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Transplantation;Hematopoietic System;Hematopoietic stem cells;Human;In Vitro;Injury;Knockout Mice;Late Effects;Lead;Liquid substance;Maintenance;Mediating;Modeling;Molecular;Mouse Strains;Myelosuppression;NF-kappa B;Natural regeneration;Nuclear Translocation;PC3.1 antigen;Pathologic;Pathway interactions;Patients;Pharmacology;Population Sizes;Process;Protein Subunits;Publishing;Quality of life;Radiation;Radiation Dosage;Radiation Injuries;Radiation Protection;Radiation Tolerance;Radiation Toxicity;Radiation therapy;Reactive Oxygen Species;Regulation;Regulator Genes;Reporting;Research;Ribosomal Proteins;Role;Second Primary Cancers;Signal Transduction;Solid;Stress;Techniques;Therapeutic;Variant;Work;Xenograft procedure;base;cancer therapy;cell injury;cell transformation;chemotherapy;effective therapy;functional decline;genome integrity;hematopoietic stem cell self-renewal;human model;in vivo;knock-down;mortality;mouse model;novel;overexpression;p65;preconditioning;preservation;prevent;promoter;radiation mitigation;radiation response;radiation-induced injury;recruit;replication stress;response;self-renewal;senescence;small hairpin RNA;stem cell model;stem cell population;stem cells;tumor

public_health_relevance:
PROJECT NARRATIVEMitigation and protection of bone marrow cells particularly hematopoietic (blood forming) stem cells fromradiotherapy-induced acute and permanent injury is critical for the quality of life of cancer patients receivingradiotherapy and bone marrow transplantation. This study will investigate the radiomitigation andradioprotection of inhibition of a novel HSC regulatory gene latexin and will have great therapeutic value forpatients receiving radiation chemotherapy and bone marrow transplantation.


application_id: 9843117
project_number: 5R01CA223164-02
project_title: Integrin alpha6beta4 regulation of cancer epigenetics
administering_ic: NCI
award_notice_date: 2019-12-23
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: CA
serial_number: 223164
program_official: AULT, GRACE S
project_start_date: 2019-01-01
project_end_date: 2023-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
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_terms:
Actins;Apoptosis;Base Excision Repairs;Basement membrane;Bioinformatics;Biometry;Breast;Carcinoma;Cell Nucleus;Cells;Chromatin;Clinical;Complex;Cytokeratin;Cytoskeleton;Cytosol;DNA;DNA Methylation;DNA Repair;DNA Sequence Alteration;Data;Enhancers;Environment;Epigenetic Process;Event;Fostering;Funding;GADD45A gene;Gene Expression Regulation;Genes;Genome;Heterogeneity;Histones;Integrin Binding;Integrin alpha6beta4;Integrin beta4;Integrins;Intermediate Filaments;Investigation;Keratin;Laboratories;Laminin;Link;Literature;Malignant Neoplasms;Mediating;Methodology;Methylation;Modeling;Modification;Molecular;Mutation;Neoplasm Metastasis;Nuclear;Nuclear Translocation;Oncogenic;Pathology;Pathway interactions;Phenotype;Post-Translational Protein Processing;Process;Property;Regulation;Research;Resistance;Role;Signal Transduction;Site;Solid;Specificity;Testing;Therapeutic;Therapeutic Intervention;Tumor Biology;Tumor Cell Invasion;Untranslated RNA;Vimentin;Work;base;cell motility;demethylation;emerin;epigenome;falls;genome-wide;genomic locus;innovation;insight;leukemia/lymphoma;mechanotransduction;migration;next generation sequencing;novel;plectin;prevent;promoter;recruit;repair enzyme;sensor;transcriptome;transcriptomics;triple-negative invasive breast carcinoma;tumor;tumor microenvironment


application_id: 9842409
project_number: 5R01DA033862-07
project_title: Effect of structural interventions on substance use and HIV/HCV risk among rural PWUD
administering_ic: NIDA
award_notice_date: 2019-11-19
opportunity_number: PA-15-003
application_type: 5
activity_code: R01
ic: DA
serial_number: 033862
program_official: FLOURNOY FLOYD, MINNJUAN WYNCEPHEL
project_start_date: 2012-09-01
project_end_date: 2021-11-30
study_section: Behavioral and Social Consequences of HIV/AIDS Study Section[BSCH]
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
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal of this renewal application (R01DA033862) is to determine the influence of structural interventions on engagement in risk reduction and health promotion activities among rural Appalachian drug users. Results from the three-year R01 that the investigators seek to continue reveal an ever-changing landscape of prescription drug abuse; an epidemic that is still in its infancy. Unlike many rural and suburban areas there is little evidence for the transition to heroin abuse. In this cohort there has been  marked shift from abuse of OxyContin(r) (extended-release oxycodone) to immediate release oxycodone to more recently buprenorphine and gabapentin-containing products. In addition rates of HCV prevalence and incidence are high especially given the population density of rural Appalachia. Given the syndemic of opioid abuse and infectious disease transmission two structural interventions are particularly relevant to this population of rural people who use drugs(PWUD). Medicaid (MC) expansion (under the Affordable Care Act [ACA]) and syringe access programs (SAP) are two structural interventions that may allow for increased engagement in health promotion among PWUD but are likely heavily influenced by individual network and community-level factors. Utilizing Latkin's Dynamic Social Systems model and leveraging the extant highly successful cohort of rural PWUD the aims include: 1) examining how dynamic factors of these structural interventions influence longitudinal trends in illicit and prescriptiondrug abuse; 2) determining the influence of these structural interventions on HIV/HCV incidence and engagement in risk reduction; and 3) assessing the influence of these structural interventions on uptake of substance abuse treatment. This study is highly significant given that understanding the mechanisms by which these specific structural interventions influence health promotion is key to improving public health in rural Appalachia. Substance abuse and HCV are two of the most important if not the most important health issues facing this region already plagued with marked health disparities. Using innovative measures of network and geospatial risk as well as conjoint analysis and multilevel longitudinal statistical models results will notonly inform development of interventions that optimize uptake and utilization of risk reduction services such as SAP and substance abuse treatment but may inform policies surrounding further implementation of health promotion programs in the rural U.S.

project_terms:
Accounting;Address;Affordable Care Act;Alcohol or Other Drugs use;Area;Behavior;Biological Models;Buprenorphine;Communicable Diseases;Communities;Complement;County;Data;Data Collection;Development;Disease Outbreaks;Disease Outcome;Drug abuse;Drug user;Effectiveness;Enrollment;Epidemic;Frequencies;Goals;HIV;HIV/HCV;Health;Health Promotion;Hepatitis C Incidence;Hepatitis C Prevalence;Hepatitis C Therapy;Hepatitis C Transmission;Hepatitis C virus;Heroin Abuse;Illicit Drugs;Indiana;Individual;Injecting drug user;Injections;Insurance Coverage;Intervention;Kentucky;Laws;Literature;Longitudinal trends;Measures;Medicaid;Modeling;Natural experiment;Nature;Needle Sharing;Outcome;Oxycodone;Participant;Personal Communication;Pharmacoepidemiology;Policies;Population;Population Density;Prevalence;Public Health;Research;Research Personnel;Resources;Risk;Risk Behaviors;Risk Reduction;Rural;Rural Appalachia;Rural Population;Services;Statistical Models;Sterility;Structure;Substance Use Disorder;Substance abuse problem;Syringes;Time;Treatment outcome;Uninsured;cohort;disease transmission;drug of abuse;follow-up;gabapentin;health disparity;improved;infancy;innovation;opioid abuse;opioid injection;prescription drug abuse;prescription opioid;programs;public health relevance;response;rural area;social;social metrics;substance abuse treatment;suburb;success;therapy design;therapy development;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Both MC expansion and SAPs have great potential to improve substance abuse and infectious disease outcomes among rural PWUD/PWID; however first we must understand the mechanisms by which these SIs are influencing outcomes. Therefore results may inform ways in which to optimize uptake and utilization of structural interventions as well as to inform policies surrounding further implementation of SIs that will improve public health outcomes in rural Appalachia.


application_id: 9842281
project_number: 5R01CA222596-03
project_title: Role of Sulfiredoxin in Colorectal Cancer Development
administering_ic: NCI
award_notice_date: 2019-12-10
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 222596
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2018-01-01
project_end_date: 2022-12-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 10043947
contact_pi: WEI, QIOU
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:
Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer deathin both men and women in USA and worldwide. One of the major causes of colorectal cancer mortality is dueto the spreading of cancer cells from primary tumor sites to distant organs a process known as cancer cellinvasion and metastasis. This process is coordinately regulated by various biological molecules and theirassociated signaling pathways. The long-term objective of my research is to understand colon tumorigenesisand metastatic process by identifying critical molecular drivers and to understand their function mechanisms todevelope effective ways for targeted cancer therapy. Sulfiredoxin is a novel redox enzyme that has a criticalrole of promoting tumorigenesis and metastasis of colorectal cancer. In this project our goals are tounderstand molecular mechanisms by which Sulfiredoxin promotes cancer cell invasion and metastasis and totest the efficacy of a novel small molecule inhibitor of Srx in blocking human colorectal cancer invasion andmetastasis using cell culture as well as mouse models.

project_terms:
American Cancer Society;Azoxymethane;Back;Binding;Biological;Biology;C-terminal;Cancer Etiology;Cell Culture Techniques;Cells;Cessation of life;Cetuximab;Clinic;Colorectal Cancer;Data;Deacetylation;Development;Diagnosis;Distant;Drug Kinetics;Enzymes;Epithelial;Epithelium;Fc Receptor;Free Radicals;Future;Goals;Growth;Growth Factor Receptors;Human;Individual;International;Knockout Mice;Malignant Neoplasms;Maximum Tolerated Dose;Mediating;Mesenchymal;Mitogen-Activated Protein Kinases;Modeling;Molecular;Mus;Neoplasm Metastasis;Oncogenic;Organ;Oxidation-Reduction;Oxidative Stress;Oxidoreductase;Pathologist;Patients;Peroxidases;Physicians;Play;Post-Translational Protein Processing;Primary Neoplasm;Process;Receptor Activation;Reporting;Research;Research Personnel;Resistance;Resources;Role;Route;Scientist;Signal Pathway;Signal Transduction;Site;Sodium Dextran Sulfate;Specimen;Subcutaneous Injections;Testing;Therapeutic;Toxic effect;Tyrosine Phosphorylation;Woman;Xenograft Model;Xenograft procedure;base;cancer cell;cancer diagnosis;colon cancer patients;colon carcinogenesis;colon tumorigenesis;colorectal cancer metastasis;colorectal cancer treatment;dosage;efficacy study;efficacy testing;enzyme activity;fascin;implantation;insight;men;metastatic colorectal;metastatic process;mortality;mouse model;multidisciplinary;novel;novel therapeutics;panitumumab;peroxiredoxin;receptor;small molecule inhibitor;targeted cancer therapy;tumorigenesis

public_health_relevance:
This project is aimed to understand role of Sulfiredoxin in colon tumorigenesis and molecularmechanism of Sulfiredoxin in promoting colorectal cancer cell invasion and metastasis. Bytesting a novel small molecule inhibitor of Sulfiredoxin in the treatment of colorectal cancer inmouse models we expect to provide proof-of-the-concept data for future translationalapplications.


application_id: 9842102
project_number: 3RF1AG059717-01S1
project_title: Translating SHIP1 Genetics to Generate a Novel Alzheimers Pharmacologic Agent
administering_ic: NIA
award_notice_date: 2019-03-14
opportunity_number: PA-18-906
application_type: 3
activity_code: RF1
ic: AG
serial_number: 059717
suffix: S1
program_official: GROTHAUS, PAUL G
project_start_date: 2018-09-15
project_end_date: 2023-08-31
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
other_pis: HUMPHREY, MARY BETH;KERR, WILLIAM GARROW
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:
Genome wide association studies (GWAS) have identified single nucleotidepolymorphisms (SNP)s associated with Alzheimer disease (AD) risk. We propose thatthese SNPs point to mechanisms that affect AD development and thus represent targetsfor AD drugs. More specifically we propose that drugs that mimic the actions of theprotective SNP allele represent potential genetically validated pharmacologic agents.Notably a SNP with modest molecular actions may impact disease modestly but a drugthat acts strongly at the same target may impact disease robustly. While this has beenaccomplished in other diseases the lack of GWAS translation to pharmacologicagents represents a key knowledge gap in AD.In this proposal we will focus on rs35349669 (rs669) a common SNP withinINPP5D that is strongly associated with AD. Collectively our work on INPP5Dencoding the lipid phosphatase SHIP1 over the last 17 years has provided theframework for its role in neuro-immune modulation through a physical interaction withTREM2 another critical factor recently implicated in AD. Building on these discoverieswe have now developed SHIP1 small molecule inhibitors that are safe and effective inmurine models as well as SHIP1 conditionally deficient mice. New data from our groupestablish a direct mechanistic connection between SHIP1 and AD pathophysiology byshowing that INPP5D expression is increased with the rs669 allele associated with ADrisk and with AD pathology. Overall this study brings together an interdisciplinary teamto critically test our global hypothesis: Pharmacologic or genetic inhibition of SHIP1decreases AD risk or progression. For this effort we propose the following SpecificAims: (i) Elucidate the mechanism underlying rs669 (ii) Elucidate SHIP1 molecularactions relative to AD pathogenic mechanisms (iii) Define the optimal SHIP inhibitionstrategy to impact macrophage and microglial function in the CNS and (iv) TranslateINPP5D genetics into a novel therapeutic agent. Overall this focused proposal willdevelop our compelling molecular genetic results elucidate the actions of SHIP1 in anAD context and translate these changes into a possible AD-preventive agent.

project_terms:
APP-PS1;Affect;Agonist;Alleles;Alzheimer's Disease;Alzheimer's disease risk;Amyloid beta-Protein;Apoptotic;Biological Availability;Brain;CSF3 gene;Cell Line;DNA;Data;Development;Disease;Disease Progression;Functional disorder;Genes;Genetic;Goals;Homeostasis;Human;Hydroxymethylglutaryl-CoA reductase;In Vitro;Individual;Inherited;Knowledge;Length;Lipids;Low-Density Lipoproteins;Mediating;Metabolic;Microglia;Minor;Molecular;Molecular Genetics;Morphology;Mus;Neuroimmune;Neurons;Osteoclasts;Parents;Pathogenicity;Pathology;Phagocytosis;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Phenotype;Phosphoric Monoester Hydrolases;Plasma;Population;Population Attributable Risks;Preventive;Production;Protein Isoforms;Proteins;RNA Splicing;Role;Signal Transduction;Single Nucleotide Polymorphism;TREM2 gene;TYROBP gene;Testing;Therapeutic Agents;Time;Translating;Translations;Variant;Work;abeta oligomer;base;chemical genetics;cohort;cytokine;fitness;genome wide association study;in vivo;inhibitor/antagonist;macrophage;migration;monocyte;mouse model;mutant;neuropathology;novel;novel therapeutics;overexpression;preclinical study;response;risk variant;small molecule;small molecule inhibitor;src Homology Region 2 Domain;tool

public_health_relevance:
Variants in the DNA that we inherit from our parents constitutes about 70% of the risk ofAlzheimer's disease. Here we will determine how one of these variants in a genecalled INPP5D acts to increase AD risk and test whether an inhibitor of SHIP1 theprotein produced from INPP5D reduces AD risk. Overall our goal is to turn geneticfindings into pharmacologic approaches to reduce the risk of Alzheimer's disease.


application_id: 9841581
project_number: 7R01CA192894-04
project_title: Enhancing anti-neoplastic activity of metformin in prostate cancer
administering_ic: NCI
award_notice_date: 2019-01-15
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: CA
serial_number: 192894
program_official: FORRY, SUZANNE L
project_start_date: 2016-02-08
project_end_date: 2021-01-31
study_section: Special Emphasis Panel[ZRG1-BMCT-C(01)S]
contact_pi_person_id: 8042648
contact_pi: LIU, XIAOQI
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Because prostate cancer (PCa) requires androgen for development castration is the primary treatment for patients with late stage PCa. Because androgen receptor (AR) signaling continues to be active in castration-resistant prostate cancer (CRPC) androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However two FDA-approved ASIs abiraterone and enzalutamide only improve overall patient survival for several months. Thus it is urgent to identify new targets and develop new approaches to treat ASI-resistant CRPC. Metformin an antidiabetic drug widely used for over 40 years is now believed to have anti-neoplastic activity in different types of cancers. Recent clinical data suggests that metformin use may reduce development of CRPC and PCa mortality. However the detailed molecular mechanisms underlying this very important observation is not completely understood. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with ASI-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating the mTOR (mammalian target of rapamycin) pathway and AR signaling and to exploit this unique pathway as a novel therapeutic target for ASI- resistant CRPC patients. The central hypothesis is that a combination of Plk1 inhibition with metformin is a new approach to treat ASI-resistant CRPC. This hypothesis will be tested by pursuing two Specific Aims - (1) to dissect how Plk1 phosphorylation of TSC1 (tuberous sclerosis complex 1) a negative regulator of the mTOR pathway leads to activation of the mTOR pathway in vivo; (2) to determine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. These two complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with inducible PCa mouse models culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance f Plk1 to the mTOR/AR pathways and to examine whether a combination of Plk1 inhibition with metformin is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 regulates the mTOR/AR signaling; (ii) genetically evaluate how Plk1 cooperates with loss of PTEN signaling; and (iii) validate Plk1 as a critical therapeutic target to enhance the efficacy of metformin. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies are poised toprovide a new paradigm for improved patient therapies by identifying the key regulator of the mTOR/AR signaling that is critical for generating and maintaining the CRPC phenotype.

project_terms:
5'-AMP-activated protein kinase;Acceleration;Androgen Receptor;Androgens;Antidiabetic Drugs;Antineoplastic Agents;Biochemical;Cancer Cell Growth;Cancer Patient;Castration;Cell Proliferation;Clinical;Clinical Data;Clinical Research;Consumption;Data;Development;Disease;Disease Progression;Event;FDA approved;FRAP1 gene;Fostering;Genetic;Gluconeogenesis;Glucose;Goals;Growth and Development function;Health;Hyperinsulinism;Investigation;Liver;Malignant Neoplasms;Malignant neoplasm of prostate;Mediating;Metastatic Prostate Cancer;Metformin;Methodology;Mission;Mitotic;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Outcome;PLK1 gene;PTEN gene;Pathway interactions;Patient-Focused Outcomes;Patients;Pharmaceutical Preparations;Pharmacology;Phenotype;Phosphorylation;Phosphotransferases;Prostate;Prostate Cancer therapy;Protein Biosynthesis;Public Health;Receptor Signaling;Research;Resistance;Role;Side;Signal Pathway;Signal Transduction;System;TSC1 gene;Testing;Therapeutic;Tuberous sclerosis protein complex;Work;Xenograft procedure;abiraterone;anticancer research;base;cancer therapy;cancer type;castration resistant prostate cancer;chemotherapy;design;diagnostic biomarker;docetaxel;effective therapy;improved;in vivo;inhibitor/antagonist;innovation;mTOR Inhibitor;mTOR inhibition;mortality;mouse model;new therapeutic target;novel;novel strategies;overexpression;predictive marker;prostate cancer cell;prostate cancer progression;protein degradation;public health relevance;therapeutic target;therapy development;treatment effect;tumor growth;tumor xenograft

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


application_id: 9841308
project_number: 1R41CA243600-01
administering_ic: NCI
award_notice_date: 2019-07-02
opportunity_number: PA-18-575
application_type: 1
activity_code: R41
ic: CA
serial_number: 243600
program_official: EVANS, GREGORY
project_start_date: 2019-08-01
project_end_date: 2022-07-31
study_section: Special Emphasis Panel[ZRG1 SBIB-T (10)]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078515036
primary_uei: HSZNRZ4JS954
duns_number: 078515036
uei: HSZNRZ4JS954
fips: US
organization_id: 10032228
organization_name: BIOPTICSTECHNOLOGY, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405131245
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-01
project_title:
Development of a Wearable Fluorescence Imaging Device for Intraoperative Identification of Brain Tumors

project_abstract:
ABSTRACT Approximately 700000 people in the United States have been diagnosed with a primary brain tumor. Ofthese malignant gliomas (MGs) account for approximately 40% of all intracranial tumors with an overall patientsurvival rate of only ~34%. More than any other cancer brain cancer has lasting physical cognitive andpsychological impacts on a patients life and the highest per-patient initial cost of care. Surgical resectionremains the cornerstone of therapy and the extent of resection correlates with patient survival. A limiting factorfor resection however is the surgeons ability to differentiate the tumor from normal tissue. In pursuit ofintraoperative guidance for the safe and maximal resection fluorescence-guided surgery has emerged as anadvanced adjunctive technique. The uses of surgical operative microscopes with FDA-approved fluorescein dyehave shown significantly higher tumor resection rates (75-100%) in MGs than conventional surgeries (30-55%).However most clinical-grade fluorescence microscopes (e.g. PENTERO 900 microscope with YELLOW560 fluorescein module Carl Zeiss Meditec AG) are hampered by high costs (~$330K) limited portability(~800 lbs) and lack of operation flexibility. Many surgeons prefer and continue to use wearable surgical eyeloupes which allow for convenient and fast operation but are not capable of fluorescence visualization. To overcome limitations of currently available surgical imaging techniques we have preliminarilydemonstrated safety and feasibility of an innovative wearable fluorescence prototype that piggybacks on eyeloupes for identifying MGs (Pending Patent: PCT/US2018/41418). In this Phase-I study we will collaboratewith a startup company (Bioptics Technology LLC) to miniaturize optimize and validate this low-cost device(~$8K) with user experience (e.g. ease of wearing alignment and operation) for easy and accurate fluorescentidentification of MGs during resection. Compact LEDs and a small CMOS camera with dedicated optical filterswill be optically integrated into different functional modules for florescence excitation and detection. Theselightweight compact and inexpensive modules will be attached to the eye loupes to form an integrated wearabledevice allowing for real-time ocular observation and video recording of fluorescence and color images. Thedevice operating system will be optimized to be up and running so that neurosurgeons can easily use it withoutmuch specialized training. To ensure appropriate performance and sufficient accuracy this device will be firstoptimized and calibrated using tumor-simulating phantoms against the PENTERO 900 microscope withYELLOW 560 (Aim 1) and then validated in patients with MGs against histopathological analyses of biopsiedsamples taken from the surgical tumor margin (Aim 2). The potential market size of this device would be tens ofmillions of dollars in the US alone providing a significant opportunity for commercialization. Ultimately thisaffordable wearable and ergonomic device will significantly increase the ability of more surgeons to conductfast and thorough operations and thus improve surgical outcomes and reduce the burden on healthcare systems.

project_terms:
Accounting;Area;Biopsy Specimen;Blinded;Blood - brain barrier anatomy;Brain Neoplasms;Clinical;Cognitive;Color;Color Visions;Conventional Surgery;Custom;Data;Detection;Development;Devices;Diagnosis;Dyes;Ensure;Excision;Eye;FDA approved;Fluorescein;Fluorescence;Goals;Gold;Halogens;Healthcare Systems;Hospitals;Hour;Image;Image-Guided Surgery;Imagery;Imaging Device;Imaging Techniques;Intracranial Neoplasms;Intravenous;Legal patent;Life;Light;Lighting;Magnetic Resonance Imaging;Malignant Glioma;Malignant Neoplasms;Malignant neoplasm of brain;Measurement;Microscope;Movement;Neurosurgeon;Normal tissue morphology;Obstruction;Operating System;Operative Surgical Procedures;Optics;Outcome;Patients;Performance;Phase;Primary Brain Neoplasms;Psychological Impact;Running;Small Business Technology Transfer Research;Sports;Surgeon;Surgical margins;Survival Rate;System;Techniques;Technology;Testing;Time;Training;Tumor Tissue;United States;Universities;Video Recording;Work;base;care costs;commercialization;contrast enhanced;cost;design;experience;flexibility;fluorescence imaging;fluorescence microscope;fluorescence-guided surgery;imaging system;improved;innovation;light weight;miniaturize;novel;off-patent;operation;optical imaging;performance tests;phase 1 study;phase 2 study;portability;prototype;research and development;safety and feasibility;surgery outcome;tumor;wearable device

public_health_relevance:
PROJECT NARRATIVEThe goal of this STTR Phase-I project is to develop and commercialize an innovative low-cost wearablefluorescence imaging device that can be attached to the standard surgical eye loupes for helping neurosurgeonsto easily and accurately identify brain tumors for safe and maximal resection. This wearable ergonomic devicewill result in a wide range of movement and fast/easy operation thus providing a novel way to image fluorescingbrain tumors without a large expensive operative microscope. The potential market size of this affordable deviceare tens of millions of dollars in the US alone and potential customers are neurosurgeons working across a widerange of surgical units especially at regional and mobile army surgical hospitals.


application_id: 9841183
project_number: 2P42ES007380-22
project_title: Fate and Transport of Contaminants in Aging Piping Systems
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5743
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Address;Aging;Air;Analytical Chemistry;Biological Monitoring;Biomedical Research;California;Communication;Communities;Computer Models;Coupled;Data;Data Analyses;Deterioration;Ecology;Ensure;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Hazards;Environmental Health;Environmental Pollution;Equation;Ethylenes;Evidence based practice;Foundations;Fracture;Gases;Goals;Hazardous Waste;Health;Human;Individual;Indoor Air Quality;Industry;Infrastructure;Inhalation Exposure;Interview;Joints;Kentucky;Knowledge;Measurement;Measures;Membrane;Modeling;North Carolina;Outcome;Outcome Study;Pathway interactions;Policies;Polymers;Public Health;Regulation;Reporting;Research;Research Project Grants;Risk;Risk Reduction;Route;Sampling;Science;Services;Site;Superfund;Surveys;System;Techniques;Temperature;Testing;Tetrachloroethylene;Time;Toxic effect;Transcend;Translational Research;Transport Process;Trichloroethylene;Uncertainty;United States;Volatilization;Water;Water Supply;aged;base;contaminant transport;data interoperability;data management;data modeling;drinking water;engineering design;epidemiology study;field study;ground water;health literacy;hookah;informant;mass flux;novel;nutrition;predictive modeling;pressure;prevent;research facility;sensor;sensor technology;superfund chemical;superfund site;tool;vapor intrusion;ventilation;water quality


application_id: 9841181
project_number: 2P42ES007380-22
project_title: Postnatal Complications and Interventions against Halogenated Organics during Pregnancy
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5741
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Acids;Address;Adipocytes;Adolescent;Adult;Agonist;Aryl Hydrocarbon Receptor;Behavior Therapy;Biochemical;Body Composition;Breast;Cells;Child;Collaborations;Detection;Development;Diabetes Mellitus;Discipline of Nursing;Endocrine Disruptors;Environmental Exposure;Environmental Impact;Environmental Pollution;Epidemic;Erythroid;Evaluation;Exercise;Exposure to;Fatty acid glycerol esters;Female;Funding;Future;Gender;Glucose Clamp;Glucose Intolerance;Goals;Gold;Hazardous Substances;Health;Home environment;Human;Human Development;Impairment;Infant;Insulin Resistance;Intervention;Kentucky;Knockout Mice;Life Style;Liver;Measures;Mesenchymal Stem Cells;Metabolic;Methods;Modeling;Molecular;Mus;Muscle Cells;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Pathway interactions;Perinatal;Perinatal Exposure;Phenotype;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Preventive Intervention;Process;Research;Risk;Role;Running;Sampling;Serum;Superfund;Techniques;Testing;Thinness;Time;Tissues;Toxic effect;Umbilical cord structure;Universities;Work;adipocyte differentiation;base;biological adaptation to stress;blood glucose regulation;cohort;cost effective;dechlorination;diabetes risk;diphenyl;disorder risk;exercise intervention;fetal;glucose uptake;impaired glucose tolerance;improved;in utero;in vivo;innovation;insight;insulin sensitivity;insulin signaling;lipid biosynthesis;male;mouse model;neonate;nutrition;obesity development;obesity in children;obesity risk;obesogen;offspring;offspring obesity;perfluorooctanoic acid;perinatal development;pollutant;postnatal;prenatal exposure;programs;sedentary;specific biomarkers;superfund chemical;transcription factor;trend


application_id: 9841180
project_number: 2P42ES007380-22
project_title: Superfund Chemicals Nutrition and Multi-Organ Cardiovascular Risk
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5740
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Acute;Address;Animal Model;Antibiotics;Atherosclerosis;Binding;Biological;Biological Markers;Blood Vessels;Cardiovascular Diseases;Cause of Death;Ceramides;Chemicals;Chronic;Data;Data Set;Development;Diet;Dietary Fiber;Dietary Intervention;Dioxins;Disease;Down-Regulation;Ecology;Endothelium;Environment;Environmental Engineering technology;Environmental Exposure;Enzymes;Epigallocatechin Gallate;Event;Exposure to;Fiber;Functional disorder;Future;Gene Expression;Genes;Goals;Green tea;Hazardous Waste Sites;Health;Hepatic;Hepatocyte;Human;In Vitro;Inflammation;Inflammatory;Insulin Resistance;Inulin;Link;Lipids;Liver;Liver Dysfunction;Low Density Lipoprotein Receptor;Mediating;Metabolic;Metabolic dysfunction;Metabolism;Methionine;Modeling;Molecular;Mus;NF-kappa B;Nutrient;Outcome;Oxidation-Reduction;Pathology;Peripheral;Permeability;Plants;Plasma;Poison;Polychlorinated Biphenyls;Population;Pre-Clinical Model;Process;Production;Public Health;Reporting;Research;Resistance development;Risk;Sampling;Signal Pathway;Signal Transduction;Sphingolipids;Stains;Superfund;Technology;Testing;Toxic effect;United States;Vascular Endothelial Cell;Volatile Fatty Acids;animal data;atherosclerosis risk;base;biobank;body system;cardiometabolism;cardiovascular disorder risk;cardiovascular risk factor;chemical stability;choline deficient diet;chronic inflammatory disease;disorder risk;experimental study;exposed human population;gut bacteria;gut microbiota;in vivo;lipid metabolism;liver injury;macrophage;metabolic profile;metabolomics;nutrition;oxidation;persistent organic pollutants;pollutant;polyphenol;prebiotics;prevent;programs;response;stable isotope;superfund chemical;toxicant;transcriptomics;trimethyloxamine;vascular inflammation


application_id: 9841179
project_number: 2P42ES007380-22
project_title: Research Experience and Training Coordination Core
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5739
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Address;Affect;Bioinformatics;Clinical;Clinical Sciences;Collaborations;Communities;Complex;Data Analyses;Data Collection;Data Science;Development;Discipline;Doctor of Philosophy;Ecology;Education;Educational workshop;Environmental Engineering technology;Environmental Health;Exposure to;Funding;Goals;Government;Grant;Health;Individual;Industrialization;Industry;Interdisciplinary Study;Kentucky;Knowledge;Laboratory Research;Leadership;Life Style;Location;Medical Ethics;Mentors;Methods;Mind;Modeling;Modernization;Outcome;Policies;Positioning Attribute;Postdoctoral Fellow;Problem Solving;Productivity;Public Health;Recording of previous events;Reporting;Research;Research Project Grants;Resources;STEM field;Science Technology Engineering and Mathematics;Scientist;Series;Signal Recognition Particle;Social Impacts;Source;Students;Superfund;Technology;Thinking;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Training and Education;Translational Research;Universities;Water;Writing;base;career;career development;clinical center;data management;data sharing;design;experience;flexibility;innovation;interdisciplinary approach;interest;laboratory experience;meetings;multidisciplinary;next generation;novel;nutrition;outreach;pollutant;programs;recruit;remediation;responsible research conduct;skills;skills training;student training;success;superfund chemical;superfund site;training opportunity;webinar


application_id: 9841178
project_number: 2P42ES007380-22
project_title: Community Engagement Core
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5738
contact_pi_person_id: 12559398
contact_pi: BREWER, DAWN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Address;Adopted;Affect;Age;Air Pollution;Area;Back;Behavior;Biological;Chemicals;Chronic Disease;Coal Mining;Collaborations;Communication;Communities;Consumption;Country;County;Development;Drug Metabolic Detoxication;Education;Elderly;Environmental Hazards;Environmental Health;Environmental Pollutants;Environmental Pollution;Evaluation;Exposure to;Family;Focus Groups;Fostering;Goals;Hazardous Substances;Health;Health Benefit;Health behavior;Health behavior change;Home environment;Individual;Intervention;Interview;Journals;Kentucky;Kidney;Knowledge;Lead;Life Style;Liver;Longevity;Methods;Modeling;Needs Assessment;Outcome;Peer Review;Physical activity;Physiological;Plants;Policies;Polychlorinated Biphenyls;Population;Population Growth;Populations at Risk;Preventive Intervention;Public Health;Recommendation;Reporting;Research;Research Activity;Research Project Summaries;Resources;Risk;Science;Scientist;Services;Site;Solvents;Superfund;Surveys;System;Toxic effect;Translating;United States;Universities;Water Pollution;Work;Youth;behavior change;community center;community organizations;design;environmental change;evidence base;experience;farmers markets;good diet;health knowledge;health literacy;healthy lifestyle;improved;innovation;meetings;novel;nutrition;pollutant;prevent;programs;rapid growth;social;superfund chemical;superfund site;symposium;tool;tool development;walking program


application_id: 9841177
project_number: 2P42ES007380-22
project_title: Data Management and Analysis Core
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5737
contact_pi_person_id: 8776790
contact_pi: PENNELL, KELLY G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Academy;Address;Adverse effects;Animals;Awareness;Basic Science;Biometry;Chemicals;Collaborations;Common Data Element;Communities;Complex;Computational Science;Consensus;Data;Data Analyses;Data Science;Data Scientist;Data Set;Deposition;Development;Discipline;Documentation;E-learning;Ecology;Educational workshop;Ensure;Environment;Environmental Health;Formulation;Fostering;Gap Junctions;Goals;Government Agencies;Grant;Hazardous Chemicals;Hazardous Substances;Information Resources;Infrastructure;Interdisciplinary Study;Investigator-Initiated Research;Kentucky;Knowledge;Knowledge Discovery;Life Cycle Stages;Metadata;Methods;National Institute of Environmental Health Sciences;Online Systems;Ontology;Outcome;Planet Earth;Population;Problem Solving;Process;Protocols documentation;Public Health;Quality Control;Registries;Reproducibility;Research;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Resources;Risk;Science;Scientist;Secure;Series;Site;Superfund;Technology;Terminology;Testing;Toxic effect;Training;Translational Research;Universities;Validation;Work;application programming interface;base;biomedical informatics;dashboard;data archive;data dictionary;data ecosystem;data integration;data management;data quality;data resource;data sharing;data standards;data tools;design;experience;experimental study;improved;innovation;interoperability;meetings;member;nutrition;programs;quality assurance;remediation;repository;superfund chemical;symposium;tool;training opportunity;training project;webinar


application_id: 9841176
project_number: 2P42ES007380-22
project_title: Biomonitoring and Environmental Analytical Chemistry Core
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5736
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Address;Amendment;Analytical Chemistry;Basic Science;Biological;Biological Markers;Biological Monitoring;Biological Process;Businesses;Cardiovascular Diseases;Chemicals;Clinical;Clinical Management;Cohort Studies;Collaborations;Communities;Consent;Coupled;Data Analyses;Data Analytics;Data Reporting;Data Science;Data Storage and Retrieval;Detection;Development;Diet and Nutrition;Disease;Doctor of Philosophy;Ecology;Ensure;Environmental Engineering technology;Environmental Exposure;Environmental Health;Environmental Pollutants;Equipment;Evaluation;Exercise;Exposure to;Funding;Gas Chromatography;Gas-Liquid Chromatography;Goals;Grant;Health;High Pressure Liquid Chromatography;Human;Human Resources;In Vitro;Institutional Review Boards;Intervention;Investigation;Laboratories;Lead;Life Style;Link;Liquid Chromatography;Literature;Malignant Neoplasms;Management Information Systems;Mass Spectrum Analysis;Measurement;Medical center;Methods;National Institute of Environmental Health Sciences;Outcome;Pre-Clinical Model;Preparation;Procedures;Protocols documentation;Publications;Quality Control;Reaction;Reporting;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resolution;Risk;Role;Sampling;Schedule;Service provision;Services;Soil;Source;Superfund;Support System;System;Technology;Testing;Toxic Environmental Substances;Toxic effect;United States National Institutes of Health;Veterans;Vulnerable Populations;Water;Work;analytical method;base;cardiovascular disorder risk;clinical translation;computerized data processing;data management;disorder risk;environmental chemical;environmental chemical exposure;environmental intervention;experience;health administration;human disease;improved;instrument;instrumentation;interest;laboratory facility;mass spectrometer;metabolomics;nutrition;offspring;operation;pollutant;population health;preclinical study;programs;quality assurance;ranpirnase;remediation;stressor;superfund chemical;water sampling


application_id: 9841175
project_number: 2P42ES007380-22
project_title: Administration Core
administering_ic: NIEHS
award_notice_date: 2020-03-26
opportunity_number: RFA-ES-18-002
application_type: 2
activity_code: P42
ic: ES
serial_number: 007380
study_section: Special Emphasis Panel[ZES1 JAB-D (SF)]
subproject_number: 5735
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-12-01
budget_end_date: 2020-11-30
project_terms:
Academia;Address;Advisory Committees;Analytical Chemistry;Animal Model;Animals;Appalachian Region;Biological Monitoring;Biomedical Research;Chemicals;Clinical Sciences;Communication;Communities;Community of Practice;Complex;Coupled;Data;Data Analyses;Databases;Detection;Development;Ecology;Educational workshop;Engineering;Ensure;Environment;Environmental Engineering technology;Environmental Exposure;Environmental Health;Evaluation;Event;Exercise;Exposure to;Funding;General Population;Goals;Government Agencies;Grant;Health;Human;Human Resources;Individual;Industry;Information Dissemination;Infrastructure;Institutes;Internships;Intervention;Investigator-Initiated Research;Kentucky;Leadership;Life Style;Link;Longevity;Maintenance;Mentorship;National Institute of Environmental Health Sciences;Physical activity;Polychlorinated Biphenyls;Positioning Attribute;Prevention;Preventive Intervention;Process;Productivity;Reporting;Research;Research Activity;Research Personnel;Research Project Grants;Resources;Risk;Role;Science;Scientist;Structure;Superfund;Targeted Research;Technology;Technology Transfer;Testing;Toxic effect;Toxicity Tests;Training;Training Activity;Translating;Translational Research;Translations;United States National Institutes of Health;Universities;Water;arm;base;clinical center;crosslink;data management;design;disorder risk;experience;healthy lifestyle;innovation;materials science;meetings;member;multidisciplinary;novel;nutrition;pollutant;prevent;programs;ranpirnase;remediation;superfund chemical;technology development;webinar


application_id: 9841167
project_number: 7R01NS088555-05
project_title: B cells alter adaptive autoimmunity to protect from ischemic injury after stroke
administering_ic: NINDS
award_notice_date: 2019-01-29
opportunity_number: PA-18-590
application_type: 7
activity_code: R01
ic: NS
serial_number: 088555
program_official: BOSETTI, FRANCESCA
project_start_date: 2018-12-20
project_end_date: 2020-01-31
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: 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:
DESCRIPTION (provided by applicant): More than 800000 people in the U.S. will suffer from stroke each year yet there remains only one FDA- approved acute intervention. Clinical trials to minimize post-stroke inflammation failed highlighting the need to better understand inflammatory and neuroprotective mechanisms within the central nervous system (CNS). Repetitive hypoxic preconditioning (RHP) naturally protects from stroke for months beyond treatment minimizing infarct volumes blood-brain barrier (BBB) disruption and monocyte T cell and neutrophil diapedesis into the ischemic brain. In contrast RHP specifically induces an immunosuppressed B cell phenotype that is enhanced in the injured CNS of preconditioned mice following stroke. The adoptive transfer of RHP-treated B cells (B(RHP)cells) 6h after transient stroke in male mice reduced infarct volumes and improved functional recovery compared to PBS- or wild type (WT) B cell-treated controls. B(RHP)cell therapy also suppressed a post-stroke autoimmune response to CNS-derived neuronal and myelin antigen (Ag) a novel finding for adaptive autoimmunity that has only been studied in preclinical models of stroke in the context of secondary infection. The goal of this New Investigator grant is to determine if B(RHP)cells as part of a transferrable adaptive immunity to mild hypoxia mediate endogenous protection through the production of interleukin 10 (IL10) a cytokine that promotes neuronal repair as well as interferon (IFN)- a cytokine that converts effector (i.e. pro-inflammatory Th1) T cells to regulatory T cells (Tregs) that suppress other neuropathological immune cells. Specific Aim 1 will test the hypothesis that B cells confer acute neuroprotection through the production of IL10 and direct neuronal interaction. We will confirm using state-of-the-art 3-D serial two-photon tomography for whole brain imaging MRI and behavioral assays that IL10- enhanced B(RHP)cells colocalize to a higher number of surviving neurons in the ischemic hemisphere to improve long-term functional recovery. We will also confirm the role of B(RHP)cell-derived IL10 on neuronal viability and axon outgrowth in vitro following oxygen-glucose deprivation (OGD) with B(RHP)cells harvested from IL10-null and WT mice. Specific Aim 2 will test the hypothesis that B(RHP)cells from WT but not IFN--null mice will induce a novel Treg population to suppress pro-inflammatory autoreactive responses from Th1 cells. The transfer of Tregs exposed in vitro to B(RHP)cells will also promote long-term neurovascular and functional recovery (Aim 1A methods) in addition to suppressing CNS-derived autoreactivity. Finally Glatiramer Acetate or Copaxone(r) is an FDA-approved drug that upregulates B cell-derived IL10 and Treg conversion in patients with multiple sclerosis. Specific Aim 3 will test the hypothesis that WT B cells treated with Copaxone will upregulate IL10 and IFN- to phenocopy B(RHP)cell-mediated protection. We will test the efficacy of Copaxone-treated B cells on neuronal viability in vitro following OGD (Aim 1B methods). Copaxone- or control Betaseron-treated B cells will be adoptively transferred post-stroke to determine efficacy on long-term recovery (Aim 1A methods).

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Stroke the fourth leading cause of death has few successful clinical treatments to reduce injury due to an incomplete understanding of injury and recovery mechanisms. This proposed research challenges the current dogma that all post-stroke inflammation is detrimental to recovery by identifying a new immune cell (B cell) population that is a part of the brain's natural protection from stroke (ischemic) injury. These studies will be th first to determine how the transfer of B cells as a post-stroke neurotherapeutic reduces injury and improves recovery and how this therapy alters a previously unstudied post-stroke autoimmune response that contributes to neuronal protection.


application_id: 9841083
project_number: 1R56AG057191-01A1
project_title: Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS
administering_ic: NIA
award_notice_date: 2019-05-06
opportunity_number: PAR-15-356
application_type: 1
activity_code: R56
ic: AG
serial_number: 057191
suffix: A1
program_official: PETANCESKA, SUZANA
project_start_date: 2019-05-15
project_end_date: 2021-02-28
study_section: Special Emphasis Panel[ZRG1-PSE-P(55)]
contact_pi_person_id: 9594976
contact_pi: FARDO, DAVID WILLIAM
other_pis: Not Applicable
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
project_abstract:
Brain diseases other than Alzheimers disease (AD) are common but understudied causes of dementia. Aparticularly prevalent subtype of non-Alzheimers dementia is termed hippocampal sclerosis dementia orcerebral age-related TDP-43 with sclerosis (CARTS). This neuropathology (NP) defined disease which is oftenmisdiagnosed clinically as AD affects ~20% of the elderly with substantial impact on cognition. The long-termgoal is to resolve the genomic factors that modulate CARTS severity and heterogeneity. To accomplish this wewill establish test and apply a robust pipeline to elucidate the mechanisms influenced by genetic risk factors forCARTS factoring in other non-AD brain pathologies. This requires a seasoned multidisciplinary team withexpertise in NP molecular biology neuroimaging large data analyses and in particular statistical genomics.The central hypothesis based on considerable preliminary data is that alleles modifying CARTS risk that werediscovered via candidate gene and genome-wide association studies (GWAS) are proxies for phenomena moredirectly involved in disease pathogenesis. To test this hypothesis the team will execute the following SpecificAims: 1. Develop and validate a classification framework to analyze the genetic drivers of CARTS. Theproposed effort to optimize classification of CARTS for genotyping will test and validate a revised set ofpathology-based criteria to differentiate CARTS AD-related TDP-43 pathology and brain arteriolosclerosis (B-ASC) to refine understanding of disease-defining border zones. Disease severity will be operationalized for useas a quantitative trait and rubrics for disease subtypes will be developed for correlation with genomic studies.2. Construct a robust and harmonized omics database and localize genetic regions influencing CARTS.Genetics data augmented with rich NP endophenotypes will enable discovery and refinement of novel insightsregarding the mechanisms driving CARTS dementia. Large-scale datasets (NACC ADGC ADNI ADSP AMP-AD) will be aggregated and harmonized to test the genetic drivers of clinical and NP-based CARTSendophenotypes prioritizing subtype-specific candidate genetic regions.3. Develop a systems biology analytic pipeline that extends beyond DNA variation to establish and testcandidate functional molecular outcomes of specific gene variants/regions that are associated withCARTS pathology. Most GWAS findings are not causal but rather proxies for true underlying genetic influencesof disease manifested through mechanisms that include (a) expression quantitative trait loci (eQTL) (b)differential isoform splicing QTL (sQTL) (c) brain imaging QTL (iQTL) and (d) protein QTL (pQTL). These willbe detected with recently developed statistical methodologies. Successful completion of the aims will producemechanistic insights into CARTS potentially leading to new therapeutics. The proposed studies are distinct fromprior efforts exploiting next-generation sequencing focusing on a common yet recently characterized braindisease (CARTS). We will deposit results online via NIAGADS for use by the research community.

project_terms:
Affect;Aging;Alleles;Alzheimer's Disease;American;Architecture;Automobile Driving;Autopsy;Biological;Brain Diseases;Brain Pathology;Brain imaging;Brain region;Candidate Disease Gene;Cerebrum;Classification;Clinical;Cognition;Communities;Comorbidity;Complex;DNA;Data;Data Analyses;Data Set;Data Storage and Retrieval;Databases;Dementia;Deposition;Diagnosis;Diagnostic;Disease;Disease Progression;Elderly;Future;Genetic;Genetic Risk;Genetic Variation;Genetic study;Genomics;Genotype;Goals;Impaired cognition;Individual;Knowledge;Life;Measures;Methodology;Molecular;Molecular Biology;Molecular Genetics;National Institute on Aging;Nature;Neurocognitive;Outcome;Pathogenesis;Pathologic;Pathology;Phenotype;Play;Process;Protein Isoforms;Proxy;Public Health;Quantitative Trait Loci;RNA Splicing;Research;Research Personnel;Research Project Grants;Risk;Risk Factors;Role;Sclerosis;Seasons;Severity of illness;Site;Systems Biology;Terminology;Testing;Time;Variant;age related;aging brain;analysis pipeline;base;brain arteriolosclerosis;clinically relevant;cognitive testing;delta protein;disease diagnosis;disease heterogeneity;disease phenotype;disorder risk;disorder subtype;endophenotype;evidence base;experimental study;genetic risk factor;genetic variant;genome wide association study;genome-wide analysis;hippocampal sclerosis;insight;member;multidisciplinary;neuroimaging;neuropathology;next generation sequencing;non-alzheimer dementia;novel;novel therapeutics;precision medicine;prevent;protective factors;protein TDP-43;risk variant;targeted treatment;trait;transcriptomics;web site

public_health_relevance:
PROJECT NARRATIVEUnderstanding better the biological mechanisms that underlie complex diseases of brain aging can aid in theability to diagnose disease early track disease progression and identify drug targets for treatment. Thegenetic knowledge to be garnered from this proposal is critical to discover and refine risk factors and theassociated biological mechanisms of diseases of brain aging.


application_id: 9840945
project_number: 5F30NS096876-04
project_title: Multi-mechanistic protection of mitochondria following traumatic brain injury
administering_ic: NINDS
award_notice_date: 2020-01-02
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: NS
serial_number: 096876
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2016-07-01
project_end_date: 2020-12-31
study_section: NST-2 Study Section [NST-2]
contact_pi_person_id: 12672057
contact_pi: KULBE, JACQUELINE RENEE
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL 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 MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Over five million people currently live with a disability resulting from a traumatic brain injury (TBI) with an associated economic burden of 60 billion dollars annually. Clinically there are limited treatment options for TBI and single mechanism agents are unlikely to prevent its devastating neurologic consequences. Therefore multi-mechanistic combinational therapies must be developed. Synaptic and non-synaptic mitochondrial dysfunction and lipid peroxidation (LP) induced oxidative damage are key contributors to the downstream pathology associated with TBI including cytoskeletal degradation neurodegeneration and behavioral impairments. Following injury increased Ca++ is sequestered by mitochondria resulting in formation of the mitochondrial permeability transition pore (mPTP) and increased formation of reactive oxygen and nitrogen species. These reactive species initiate LP leading to formation of the neurotoxic LP-breakdown products 4- HNE and acrolein which covalently bind mitochondrial proteins causing oxidative damage further enhancing mitochondrial respiratory dysfunction generation of reactive species and enhancing formation of mPTP with synaptic mitochondria being particularly susceptible. Upon mPTP formation the mitochondria stop producing ATP and lose their Ca++ buffering capacity. Ca++ is released back into the cytosol where it activates the protease calpain causing cytoskeletal degradation. Ultimately synaptic dysregulation neurodegeneration and neurologic impairment ensue. Individually the aldehyde scavenger phenelzine (PZ) and the mPTP inhibitor cyclosporine A (CsA) partially attenuate mitochondrial dysfunction and neuronal damage following controlled cortical impact injury (CCI) in rats. Therefore our overall hypothesis is that LP-induced neurotoxic aldehyde scavenging and inhibition of mPTP are complimentary and that combining these two mechanisms will additively or synergistically attenuate synaptic and non-synaptic mitochondrial respiratory dysfunction and LP- induced oxidative damage following severe controlled cortical impact (CCI) in rats leading to decreased cytoskeletal degradation decreased neurodegeneration and improved motor and cognitive function. Aim 1 a dose response tests the hypothesis that early administration (15min.) of the combination PZ & CsA additively or synergistically attenuates synaptic and non-synaptic mitochondrial respiratory dysfunction and LP-induced oxidative damage as well as neuronal cytoskeletal degradation following severe CCI. Aim 2 tests the hypothesis that the combination PZ & CsA improves the therapeutic window for neuroprotection following severe CCI. Aim 3 tests the hypothesis that the combination PZ & CsA additively or synergistically decreases neurodegeneration and improves motor and cognitive function over the first 28 days following severe CCI. This study will identify differential responses of synaptic and non-synaptic mitochondria to drug therapy following injury. It re-purposes two FDA approved drugs which use complimentary neuroprotective mechanisms to ultimately identify a more neuroprotective combinational therapy that can successfully translate to human TBI.

project_terms:
Acrolein;Affect;Aldehydes;Antidepressive Agents;Attenuated;Back;Binding;Buffers;Calcium;Calpain;Clinical;Clinical Treatment;Combined Modality Therapy;Cyclosporine;Cytosol;Dose;Economic Burden;FDA approved;Generations;Health;Homeostasis;Hour;Human;Immunosuppressive Agents;Impairment;Individual;Injury;Learning;Lipid Peroxidation;Lipids;Memory;Mitochondria;Mitochondrial Proteins;Motor;Nerve Degeneration;Neurologic;Neurons;Nitrogen;Outcome Measure;Oxygen;Pathology;Peptide Hydrolases;Peroxonitrite;Pharmaceutical Preparations;Pharmacotherapy;Phenelzine;Process;Rattus;Respiration Disorders;Respiratory physiology;Role;Silver Staining;Spectrin;Stains;Stress;Synapses;TBI treatment;Testing;Therapeutic;Translating;Traumatic Brain Injury;Western Blotting;behavioral impairment;cognitive function;controlled cortical impact;disability;improved;improved outcome;inhibitor/antagonist;mitochondrial dysfunction;mitochondrial permeability transition pore;morris water maze;neuroprotection;neurotoxic;novel;object recognition;oxidative damage;perhydroxyl radical;prevent;response;uptake

public_health_relevance:
Traumatic brain injury (TBI) represents a significant health crisis and affects millions of people worldwide. Currently there are no approved pharmacotherapies for the clinical treatment of TBI. This project combines two FDA approved drugs phenelzine and cyclosporine A to protect synaptic and non-synaptic mitochondria prevent neuronal damage and improve motor and cognitive function following experimental TBI.


application_id: 9839996
project_number: 1R01AI145335-01A1
administering_ic: NIAID
award_notice_date: 2019-06-17
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: AI
serial_number: 145335
suffix: A1
program_official: O'NEIL, MICHAEL T
project_start_date: 2019-06-17
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-U (02)]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: PATWARDHAN, ABHIJIT R.
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Quantitative Approaches for Drug Testing in Chronic Toxoplasmosis: Leveraging New Insights Into Bradyzoite Biology Within Tissue Cysts In Vivo

project_abstract:
Symptomatic toxoplasmosis in the context of immune suppression is typically associated with the reactivation of the chronic form of the infection mediated by bradyzoites that reside within tissue cysts. Despite their central role in the pathogenesis very little is known about the basic biology of bradyzoites. In fact our work (Watts et al. mBio 2015) was the first to definitively demonstrate that bradyzoites within tissue cysts in vivo are dynamic replication competent entities. This view directly challenged the prevailing dogma of bradyzoites and the tissue cysts that house them were metabolically inert. This view has been proffered as the reason for why bradyzoites are resistant to drugs that effectively kill the actively growing tachyzoites. Understanding the underlying basis for the inherent resistance to drug-mediated clearance needs to be addressed on a mechanistic basis which is now possible given our recent identification of quantifiable markers for the physiological status of individual bradyzoites within tissue cysts. This can further be extended to developing a framework for the evaluation of potential new drugs in vivo that rely on quantifiable physiological readouts that will greatly enhance sensitivity by addressing the behavior of populations of bradyzoites within tissue cysts as opposed to the currently used tissue cyst burden. This crude metric limits the sensitivity of efficacy to 2 orders of magnitude as percentage decreases in cyst burden and little else are measured. Our development of BradyCount1.0 an imaging based application to quantify the actual bradyzoite levels within tissue cysts revealed a previously underappreciated level of heterogeneity in bradyzoite numbers relative to tissue cyst size. We exploited what was known about the dynamics of the scaffold protein TgIMC3 and nuclear morphology in the context of replication to capture not only replicating bradyzoites but also information of their relative age. Additional studies revealed that bradyzoite mitochondrial activity and the accumulation amylopectin granules (AG) a measure of stored energy were also heterogeneous. This provides three distinct and likely interrelated physiological metrics that can be assessed at the level of individual bradyzoites within in vivo derived tissue cysts. With this study we aim to develop a new standard to assess the progression of the chronic Toxoplasma infections and to translate this novel approach to assess the effectiveness of existing and future drugs. Toward this end we propose develop BradyCount 2.0 to morphologically quantify nuclear profiles and bradyzoite scaffolds (as a markers of active and past replication) mitochondrial profiles and the distribution of AG as reporters of energy and intermediary metabolism. By recording multiple parameters individually and collectively on bradyzoites within tissue cysts we will establish a framework to define the chronic infection and the impact of drug intervention employing quantifiable physiological metric. These inputs will be used to refine a Markov Chain-based data-driven computational model to understand this enigmatic phase for which effective treatments are lacking. These studies will greatly improve the sensitivity of testing of both existing and future drugs while providing crucial mechanistic insights.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Age;Amylopectin;Architecture;Automobile Driving;Behavior;Biology;Brain;Budgets;Cell Cycle Progression;Cell Nucleus;Chronic;Clinical;Computer Simulation;Cyst;Cytoplasmic Granules;DNA biosynthesis;Data;Development;Drug Exposure;Drug resistance;Effectiveness;Energy Metabolism;Evaluation;Funding Mechanisms;Future;Glucose;Gold;Grant;Growth;HIV;Heterogeneity;Image;Imaging technology;Immunosuppression;Individual;Infection;Intervention;Knowledge;Life;Life Cycle Stages;Markov Chains;Measures;Mediating;Metabolic;Metabolism;Mitochondria;Modeling;Morphology;Nature;Nuclear;Parasites;Parasitic infection;Pathogenesis;Pattern;Periodicity;Pharmaceutical Preparations;Phase;Physiological;Physiology;Population;Process;Property;Publishing;Pyrimethamine;Reporter;Reporting;Resolution;Role;Scaffolding Protein;Source;Starch;Sulfadiazine;Technology;Testing;Time;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Training;Translating;Work;atovaquone;base;chronic infection;computer framework;drug efficacy;drug testing;effective therapy;efficacy study;imaging approach;improved;in vivo;insight;markov model;mouse model;novel strategies;novel therapeutics;pathogen;scaffold;simulation;targeted treatment

public_health_relevance:
A significant barrier to the identification of potential drug treatments targeted at the Toxoplasma gondii chronic infection is the lack of suitable quantifiable readouts for the effect of drugs on the encysted bradyzoites. In this study we leverage our findings regarding bradyzoite replication and energy metabolism to establish imaging based approaches and develop a computational model framework to assess drug efficacy in the murine model.


application_id: 9838747
project_number: 5K01DK116923-02
project_title: Social Network Analysis and Social Support Intervention for Rural Dwelling Older Adults with T2DM
administering_ic: NIDDK
award_notice_date: 2019-12-24
opportunity_number: PAR-18-418
application_type: 5
activity_code: K01
ic: DK
serial_number: 116923
program_official: SPAIN, LISA M
project_start_date: 2019-01-01
project_end_date: 2023-12-31
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 11808527
contact_pi: SMALLS, BRITTANY L.
other_pis: Not Applicable
congressional_district: 06
department: FAMILY MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adherence;Adult;Affect;Age;Aging;Attention;Behavior;Blindness;Blood Pressure;Clinical;Communities;Community Health Aides;Complications of Diabetes Mellitus;Coronary Arteriosclerosis;County;Decision Making;Diabetes Mellitus;Diagnosis;Disease;Education;Effectiveness;Elderly;Epidemic;Exposure to;Foundations;Geriatrics;Glycosylated hemoglobin A;Health Communication;Health Food;Health Personnel;Health behavior;High Prevalence;Individual;Influentials;Intervention;Interview;Kentucky;Kidney Diseases;Knowledge;Life Expectancy;Maps;Medical Records;Methods;Morbidity - disease rate;Neighborhoods;Non-Insulin-Dependent Diabetes Mellitus;Outcome;Pathway Analysis;Play;Population;Positioning Attribute;Poverty;Prevalence;Quality of life;Regimen;Research;Research Personnel;Risk;Role;Rural Appalachia;Rural Community;Self Care;Social Environment;Social Network;Social support;Source;Stress;Stroke;Structure;Surveys;Syndrome;Testing;Training;United States National Institutes of Health;aging population;base;blood lipid;cognitive function;diabetes management;diabetes self-management;disease transmission;empowerment;experience;fall risk;frailty;glycemic control;health care service;health literacy;improved;individual patient;innovation;member;negative affect;post intervention;premature;programs;recruit;rural area;rural dwellers;rural residence;sarcopenia;social;statistics


application_id: 9838673
project_number: 5U01MD010556-05
administering_ic: NIMHD
award_notice_date: 2019-12-27
opportunity_number: RFA-MD-15-010
application_type: 5
activity_code: U01
ic: MD
serial_number: 010556
program_official: DAGHER, RADA K
project_start_date: 2016-04-26
project_end_date: 2021-12-31
study_section: ZMD1-DRI(03)
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-01
project_title:
Appalachians Together Restoring the Eating Environment (Appal-TREE): Advancing Sustainable CBPR Interventions to Improve Healthy Diet in Rural Appalachian Children

project_abstract:
DESCRIPTION (provided by applicant):The National Institutes of Health has acknowledged that residents of rural Appalachia experience among the nation's worst health and economic profiles including disability and premature mortality stemming from elevated rates of heart disease and stroke various cancers diabetes all of which are closely associated with suboptimal dietary intake obesity and overweight. Community members are particularly concerned about their children who have among the highest rates of obesity overweight and suboptimal dietary intake in the nation. Eliminating these health disparities requires scientificaly informed community-engaged research to develop and evaluate innovative and sustainable programs and policies. For the proposed application our community-research team will (1) use an innovative information technology CBPR method - Structured Public Involvement - to refine and tailor a package of pilot tested healthy eating interventions; (2) conduct and evaluate this package of interventions that were found to be feasible culturally consonant and promising during R24MD008018 and (3) build community capacity in social marketing an innovative approach to enhance sustainability of the intervention. Our partners include the Community Farm Alliance local school districts the Cooperative Extension Service and other community organizations. For the first aim the innovative CBPR approach Structured Public Involvement will allow us to tailor the intervention while maintaining project fidelity. For the second aim wewill administer and evaluate three interrelated interventions to transform access to and intake of healthy foods for Appalachian children; (1) a school-based water campaign to decrease sugar sweetened beverage consumption (2) healthy cooking classes to encourage healthy cooking on a budget; and (3).a farmer's market-based healthy summer feeding program. Finally in Aim 3 we will administer a CBPR-oriented approach social marketing to enhance sustainability a challenge for all behavioral interventions. Through the schools we will train teachers and administrators to teach social marketing to students who will be encouraged to develop marketing campaigns supporting healthy diets. All of these efforts will be developed implemented and evaluated in conjunction with our Community Advisory Boards. As one of our local stakeholders told us "If you really are what you eat it's no wonder so many of us are unhealthy." By developing sustainable evidence-based programming we aim to transform consumption patterns and the eating environment so the next generation of rural residents can overcome pernicious health disparities.

project_terms:
Administrator;Appalachian Region;Area;Behavior Therapy;Budgets;Child;Clinic;Communities;Community Health;Community Participation;Consumption;County;Diabetes Mellitus;Diet;Diet Habits;Dietary Intervention;Dietary intake;Disease;Eating;Educational workshop;Elements;Environment;Equilibrium;Evidence based program;Farming environment;Food;Food Services;Future;Health;Health Food;Health Priorities;Healthy Eating;Heart Diseases;Heart Rate;Home environment;Improve Access;Information Technology;Intake;Intervention;Kentucky;Lead;Life;Malignant Neoplasms;Marketing;Methods;Nutritional;Obesity;Outcome;Overweight;Parents;Pattern;Pilot Projects;Policies;Premature Mortality;Program Sustainability;Public Housing;Research;Research Personnel;Rural;Rural Appalachia;Schools;Science;Services;Social Marketing;Specific qualifier value;Stroke;Structure;Students;Teacher Professional Development;Techniques;Technology;Testing;To specify;Trainers Training;Trees;U-Series Cooperative Agreements;United States National Institutes of Health;Water;Youth;base;behavior change;community intervention;community organizations;cooking;design;disability;evidence base;experience;farmers markets;feeding;good diet;health disparity;health economics;improved;information gathering;innovation;innovative technologies;insight;meetings;member;multidisciplinary;next generation;novel;outreach;preference;prevent;programs;public health relevance;rural dwellers;rural health disparities;rural underserved;school district;service programs;skills;social;stem;sugar;sweetened beverage;teacher;theories;user-friendly

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Appalachians Together Restoring the Eating Environment (Appal-TREE) uses a new CBPR technology to solicit community input delivers a tested package of healthy diet interventions (water promotion cooking classes and expansion of the Summer Food Service Program via farmers markets) to Appalachian communities. Social marketing techniques will be taught to area youth as a means of promoting sustainable support for this intervention.


application_id: 9838467
project_number: 3R44AA025804-02S1
project_title: Mutant transgenic plant cells as a novel source of drugs
administering_ic: NIAAA
award_notice_date: 2019-02-27
opportunity_number: PA-18-591
application_type: 3
activity_code: R44
ic: AA
serial_number: 025804
suffix: S1
program_official: FERTIG, JOANNE
project_start_date: 2019-01-01
project_end_date: 2019-08-31
contact_pi_person_id: 1970787
contact_pi: LITTLETON, JOHN M.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 196165877
primary_uei: N1NBJ43SQGX7
duns_number: 196165877
uei: N1NBJ43SQGX7
fips: US
organization_id: 10001163
organization_name: NAPROGENIX, INC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060286
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Abstract of administrative supplementThe original objective was to use a novel plant biotechnology target-directed evolution to produce novelinhibitors of the human dopamine transporter (DAT) as leads for medications for alcohol use disorder. Thisapproach evolves plant biosynthesis toward a specific target by a combination of mutagenesis and selection.Lobelia cardinalis was used as the plant species because it contains lobinaline a previously uninvestigatedinhibitor of the DAT that also has partial agonist activity at nicotinic receptors [Brown et al 2015]. These proteinsare molecular targets in alcohol and nicotine use disorders and lobinaline inhibits alcohol consumption in rodentswith no evidence of abuse potential. Lobinaline would be an excellent lead compound for pharmacotherapy ofalcohol and nicotine use disorders except that it is a highly complex insoluble alkaloid with no chemicalsynthesis. However target-directed evolution of L. cardinalis mutants should generate lobinaline derivatives withgreater potency and/or solubility as well as other metabolites with activity on the DAT. This was shown to betrue using a combination of GC/MS and pharmacological analyses [Brown et al 2016]. However to definitivelyidentify the active metabolites in mutant plant cell cultures the applicants had to develop novel analyticalmethodology. This has identified at least 15 novel metabolites that are markedly overproduced in those mutantsthat contain increased inhibitory activity on the DAT. Two of these are already known to be active either againstthe DAT or against MPP+ neurotoxicity and four metabolites are derivatives of lobinaline. These lobinalinemetabolites are N-oxides and derivatives with new double bonds in the ring structure. The lobinaline N-oxideshave been tested in vitro and in vivo with exciting results. Their pharmacology in vitro differs only modestly fromlobinaline but they have an important druggable advantage in increased aqueous solubility. However whentested in vivo by microperfusion in rat brain the lobinaline N-oxides have clear initial inhibitory effects on rate ofdopamine clearance (as does lobinaline) but this is rapidly converted to an increase in dopamine clearancecapacity. This partial antagonist effect of these metabolites on the DAT is unlike lobinaline or indeed any otherknown DAT inhibitor. It is theoretically of considerable value in drug dependence but this has not been tested inintact animals (and this was not included in the original application). One specific aim in this supplementaryproposal is to test the lobinaline N-oxides in animal models of alcohol and nicotine use disorder and to test the9 other novel metabolites for activity in vitro. In addition the mutant transgenic cultures that contain novel activemetabolites are a major resource (estimated cost to date is $10K/clone) and for sufficient metabolites to beobtained for testing they must continue to be maintained and sub-cultured. If this supplemental application issuccessful the applicants intend to use the data for another NIH application to continue development of thesenovel plant metabolites as treatments for alcohol use disorder.

project_terms:
1-Methyl-4-phenylpyridinium;Administrative Supplement;Agonist;Alcohol consumption;Alcoholism;Alcohols;Algorithmic Analysis;Alkaloids;Anabolism;Animal Model;Animals;Award;Biotechnology;Brain;Carrier Proteins;Cell Culture Techniques;Cells;Characteristics;Coca;Cocaine;Complex;Data;Development;Directed Molecular Evolution;Dopamine;Drug Addiction;Future;Human;In Vitro;Insecta;Lead;Lobelia;Mass Fragmentography;Methodology;Microchip Analytical Procedures;Molecular Target;Mutagenesis;Mutation;Natural Selections;Nicotine;Nicotine Use Disorder;Nicotinic Receptors;Oxides;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacology;Pharmacotherapy;Plants;Production;Proteins;Rattus;Research;Resistance;Resources;Rodent;Rodent Model;Solubility;Source;Structure;Substance Use Disorder;Synthesis Chemistry;Technology;Testing;Therapeutic;Transgenic Organisms;Transgenic Plants;United States National Institutes of Health;alcohol abuse therapy;alcohol use disorder;analytical method;aqueous;chemical synthesis;commercialization;cost;cytotoxicity;dopamine transporter;feeding;high throughput screening;in vitro activity;in vitro testing;in vivo;in vivo evaluation;inhibitor/antagonist;liquid chromatography mass spectrometry;mutant;neurotoxicity;novel;pi bond;preference;technology development

public_health_relevance:
Project narrativeThe company is developing a technology that directs mutant cells of a plant species to produce drugs with activityat a specific target. This proposal applies the technology to plant drugs that are of potential value in drugdependence and alcoholism. Under the original award we have found several plant metabolites with the requiredactivity and the supplemental application is to test these for their ability to reduce drug dependence.


application_id: 9838293
project_number: 5R01HL135158-03
project_title: Effect of early life stress on obesity-induced hypertension in mice
administering_ic: NHLBI
award_notice_date: 2019-12-10
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: HL
serial_number: 135158
program_official: MCDONALD, CHERYL
project_start_date: 2017-12-01
project_end_date: 2022-11-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 10353675
contact_pi: LORIA, ANALIA
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/ABSTRACTObesity promotes hypertension a major risk factor for cardiovascular disease. Epidemiological studies havelinked early life stress as a modifiable risk factor for increased body mass index and blood pressure. Using anadvantageous mouse model of early life stress that combines postnatal maternal separation and earlyweaning (MSEW) with a high fat diet we have identified two potential adipose tissue-derived targetsimplicated in the pathways by which these mice display exacerbated obesity-induced hypertension.Experimental studies have demonstrated that adipose afferent reflex (AAR) is enhanced in diet-inducedobesity models. Specifically the acute stimulation of adipose tissue afferent nerve fibers (e.g. capsaicin leptin)elevates blood pressure renal nerve activity and plasma catecholamines. Adipose tissue also expressescomponents of the renin-angiotensin system (RAS). Notably it has been shown that adipose tissue-specificabrogation of the sole RAS precursor angiotensinogen (AGT) effectively prevents high fat diet-inducedincreases in blood pressure. Our preliminary findings support for the novel central hypothesis postnatalMSEW aggravates obesity-induced HT in adult life by stimulating AAR reflex-mediated sympatheticactivation and adipose tissue-derived AGT secretion. We will test key predictions in two multilevel specificaims: (1) To test the hypothesis that MSEW heightens obesity-induced hypertension by stimulating adiposetissue excitatory signals to increase AAR reflex. We will assess the effects of MSEW on AAR reflex in acuteand chronic in vivo experiments using a novel state of the art technique in order to determine the adiposetissue-brain axis effects on blood pressure; and (2) To test the hypothesis that MSEW exacerbates obesity-induced hypertension by increasing AGT secretion in adipose tissue. We will generate an adipose tissue-specific tamoxifen-inducible AGT knockout mouse expose the mice to MSEW and wean them on a high fatdiet. The AGT deletion will be induced at three time points from early postnatal life to adulthood in order toassess its effects on programming progression and reversion of hypertension. The outcomes of these studiesmay provide novel early life stress-programmed adipose tissue targets with impact on blood pressure control.

project_terms:
Acute;Adipose tissue;Adult;Affect;Afferent Neurons;American;Angiotensin II;Angiotensinogen;Autonomic ganglion;Baroreflex;Biological Assay;Birth;Blood Pressure;Body mass index;Capsaicin;Cardiovascular Diseases;Catecholamines;Child;Chronic;Diet;Dose;Exposure to;Feedback;Female;Gene Expression;Generations;Glomerular Filtration Rate;Glucocorticoids;Health;High Fat Diet;Homeostasis;Hormones;Hypertension;Hypothalamic structure;Immediate-Early Genes;Kidney;Knockout Mice;Leptin;Life;Link;Longevity;Mediating;Mediator of activation protein;Metabolic;Microinjections;Modeling;Morbidity - disease rate;Mus;Myocardial Ischemia;Nerve;Nerve Fibers;Neuraxis;Neurons;Nociception;Norepinephrine;Obesity;Organ;Outcome Study;Pathway interactions;Personal Satisfaction;Plasma;Procedures;Reflex action;Renal Hypertension;Renin-Angiotensin System;Resiniferatoxin;Risk Factors;Role;Scheme;Sensory;Signal Transduction;Source;Stimulus;Sympathetic Nervous System;Tamoxifen;Techniques;Testing;Therapeutic Intervention;Time;Tissues;Visceral;Weaning;abuse neglect;afferent nerve;analog;base;blood pressure reduction;blood pressure regulation;brain tissue;cardiovascular risk factor;chromatin immunoprecipitation;comorbidity;early life stress;epidemiologic data;epidemiology study;experimental study;hypertension prevention;in vivo;indexing;kidney dysfunction;leptin receptor;male;maternal obesity;maternal separation;modifiable risk;molecular marker;mortality;mouse model;neglect;neonate;neurotransmission;next generation;novel;paraventricular nucleus;postnatal;prevent;promoter;response;somatosensory;stressor;urinary

public_health_relevance:
PROJECT NARRATIVEEarly life stress (ELS) has been established as an independent risk factor for cardiovascular disease bypromoting adiposity and high blood pressure; however the causative mechanisms remain unknown. We willuse an advantageous paradigm involving postnatal maternal separation and early weaning (MSEW) a modelof ELS to decipher the role of adipose tissue-brain axis on heightening obesity-induced hypertension. Theoutcomes of these studies may provide novel early life stress-programmed adipose tissue targets with impacton blood pressure control.


application_id: 9838263
project_number: 5R01HL131526-04
project_title: ASK1 and Ventilator-Induced Lung Injury
administering_ic: NHLBI
award_notice_date: 2019-12-05
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 131526
program_official: ZHOU, GUOFEI
project_start_date: 2016-12-15
project_end_date: 2021-11-30
study_section: Lung Injury, Repair, and Remodeling Study Section[LIRR]
contact_pi_person_id: 1860187
contact_pi: WATERS, CHRISTOPHER M
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Acute Respiratory Distress Syndrome (ARDS) is a severe form of acute lung injury with very high mortality andfew therapeutic options. Patients with acute lung injury are often initially treated with oxygen by mask and ifthe disease progresses they will be mechanically ventilated with high levels of oxygen (typically 50 to 100%).Although both mechanical ventilation and hyperoxia (HO) can independently cause injury the combination ofthe two has been shown to accelerate and cause more extensive lung injury than either condition alone. Thereis a critical need for understanding these mechanisms in order to develop strategies to reduce or preventventilator-induced lung injury (VILI). The long term goal is to improve understanding of the mechanisms bywhich the combination of exposure to high levels of oxygen (HO) and overdistention (or stretch) of lungscontributes to VILI. The overall objective of this application is to demonstrate that apoptosis signal regulatingkinase-1 (ASK1) is a central mediator of HO-induced exacerbation of VILI. The central hypothesis of thisapplication is that HO-induced activation of ASK1 promotes VILI by enhancing cell death through p38-mediated apoptosis and increased inflammation and by preventing cell survival through suppression ofextracellular signal-regulated kinase- (ERK1/2)-mediated pathways. These mechanisms will be investigatedusing ASK1-deficient mice in a clinically relevant mouse model with pre-exposure to HO (24 hr) followed bymechanical ventilation with high tidal volume. We will also investigate these mechanisms in mice with lunginjury caused by LPS or influenza virus prior to exposure to HO and mechanical ventilation in order to modelthe clinical scenario of ARDS. In addition primary cultures of alveolar type II epithelial cells and macrophagesas well as cell lines with knockdown of ASK1 and other key mediators will be subjected to HO and cyclicstretch. Aim 1 will test the hypothesis that HO/VILI is exacerbated by ASK1-induced activation of p38 thatpromotes stretch-induced apoptosis via inhibition of survivin and through activation of the inflammasome. Aim2 will test the hypothesis that ASK1 activation prevents ERK1/2-mediated pro-survival pathways includingexpression of survivin and Nrf2-mediated production of antioxidant enzymes. These studies will elucidate newsignaling pathways involved in HO-induced exacerbation of VILI.

project_terms:
Acute Lung Injury;Adult Respiratory Distress Syndrome;Alveolar;Animal Model;Apoptosis;Apoptosis Inhibitor;Apoptotic;Cell Death;Cell Line;Cell Survival;Cells;Clinical;Disease;Epithelial;Epithelial Cells;Epithelium;Exposure to;Extracellular Signal Regulated Kinases;Genetic Transcription;Goals;Hyperoxia;Infection;Inflammasome;Inflammation;Influenza;Injury;Investigation;JUN gene;Lead;Life;Lipopolysaccharides;Lung;MAP Kinase Gene;MAP Kinase Kinase Kinase;MAP3K5 gene;MAPK8 gene;Masks;Mechanical Ventilators;Mechanical ventilation;Mechanics;Mediating;Mediator of activation protein;Modeling;Mus;Oxidative Stress;Oxygen;Pathway interactions;Patients;Periodicity;Phosphothreonine;Production;Public Health;Reactive Oxygen Species;Research;Role;Severities;Signal Pathway;Signal Transduction;Stretching;Structure of parenchyma of lung;TXN gene;Testing;Therapeutic;Therapeutic Intervention;Tidal Volume;Tissues;Ventilator;Ventilator-induced lung injury;Viral;Work;alveolar epithelium;antioxidant enzyme;clinically relevant;improved;influenzavirus;knock-down;lung injury;macrophage;mortality;mouse model;novel;novel therapeutic intervention;novel therapeutics;p38 Mitogen Activated Protein Kinase;prevent;response;survivin;targeted treatment

public_health_relevance:
The proposed project is relevant to public health because ventilator-induced lung injury contributes to themortality of patients with the acute respiratory distress syndrome a devastating disease which results insignificant loss of life. The proposed studies will investigate the mechanisms of how high levels of oxygencontribute to this increased injury and will identify potential targets for therapeutic intervention to reduce injury.


application_id: 9837898
project_number: 1R13ES031011-01
project_title: Disaster Response Research (DR2) Workshop
administering_ic: NIEHS
award_notice_date: 2019-07-04
opportunity_number: PA-18-648
application_type: 1
activity_code: R13
ic: ES
serial_number: 031011
program_official: REINLIB, LESLIE J
project_start_date: 2019-07-15
project_end_date: 2020-06-30
study_section: Special Emphasis Panel[ZES1 VSM-S (R3)]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Disasters expose the general population and responders to a range of potential contaminants and stressorswhich may impact both physical and mental health. Since nearly all disasters whether natural or man-madehave an environmental health component it is critical that specialized research tools and trained researchersbe readily available to evaluate and ascertain causal links between complex exposures and short- and long-term health outcomes especially for vulnerable sub-populations such as the elderly children pregnantwomen and those with socioeconomic and environmental disparities. Ideally environmental health scienceresearch can also be utilized to guide the policies needed to address health consequences and mitigate healthimpacts of future disasters as well as for protection of first responders; however a major challenge isconnecting our nations policymakers with research that can increase community resiliency and protect publichealth. This proposal seeks funds to support a workshop to be held in conjunction with the 2019 NationalConference of State Legislatures (NCSL) Legislative Summit entitled: Disaster Preparedness and ResponseResearch: A Workshop for the National Conference of State Legislatures. The NCSL Legislative Summit isscheduled for August 5th-8th 2019 in Nashville Tennessee. The proposed workshop is planned as a pre-conference event to be held August 5th 2019 on the first day of the Summit. The overarching goal of theworkshop is to foster dialog between active environmental health science researchers and state legislators inorder to share accurate scientific information and to translate current research results relevant to pressingenvironmental health issues that face constituents and communities. The objectives/specific aims of thisconference proposal are to: 1) Communicate the importance and impact of disaster response research oncommunity resiliency for state legislators and their staff members. 2) Promote dialogue about how NIEHS-funded research can help guide disaster response for States. 3) Foster research translation and engagementamong state legislators federal agencies and NIEHS-funded disaster scientists. The proposed workshoplends expertise from multiple NIEHS-funded centers including the University of Kentucky (UK) University ofIowa (UI) and University of Washington (UW) and provides an ideal opportunity for environmental healthscience researchers to communicate quality information to state legislators and legislative staff regarding theenvironmental health issues that face their constituents and communities. This workshop will provide statepolicymakers insight into the depth and breadth of research available from NIEHS-funded research centersincluding policy solutions necessary to respond to disaster recovery and mitigate the impact of future disasters.

project_terms:
Address;Affect;Area;Child;Communities;Complex;Decision Making;Disasters;Educational workshop;Elderly;Environmental Health;Event;Exercise;Face;Financial compensation;Fostering;Funding;Future;General Population;Generations;Goals;Health;Intervention;Iowa;Kentucky;Knowledge;Learning;Link;Mental Health;Michigan;National Institute of Environmental Health Sciences;New York City;Oils;Outcome;Policies;Pregnant Women;Process;Protocols documentation;Public Health;Readiness;Recovery;Research;Research Personnel;Schedule;Scientist;Tennessee;Terrorism;Time;TimeLine;Training;Translating;Translations;Universities;Washington;ZIKV disease;contaminated drinking water;disability;first responder;health science research;improved;insight;lead contamination;man;member;outreach;physical conditioning;programs;resilience;response;service delivery;socioeconomics;stressor;symposium;tool

public_health_relevance:
The workshop lends expertise from multiple NIEHS-funded centers including the University ofKentucky (UK) University of Iowa (UI) and University of Washington (UW) and provides anideal opportunity for environmental health science researchers to communicate qualityinformation to state legislators and legislative staff regarding the environmental health issuesthat face their constituents and communities. This workshop will provide state policymakersinsight into the depth and breadth of research available from NIEHS-funded research centersincluding policy solutions necessary to respond to disaster recovery and mitigate the impact offuture disasters.


application_id: 9837501
project_number: 5R01NS103785-02
project_title: Cell-Specific Actions of IL-1 / IL-1R1 Signaling Following Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2019-12-17
opportunity_number: PA-18-484
application_type: 5
activity_code: R01
ic: NS
serial_number: 103785
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2018-12-15
project_end_date: 2023-11-30
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
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_terms:
Acute;Address;Alzheimer's Disease;Alzheimer's disease related dementia;Attenuated;Blood Vessels;Brain;Cells;Central Nervous System Diseases;Chronic;Clinical;Closed head injuries;Data;Development;Disease;Electrophysiology (science);Endothelial Cells;Endothelium;Extravasation;FDA approved;Failure;Functional disorder;Generations;Genetic;Goals;Immunomodulators;Impaired cognition;Impairment;Inflammation;Inflammatory;Injury;Interleukin Suppression;Interleukin-1;Interleukin-1 Receptors;Knockout Mice;Knowledge;Lead;Learning;LoxP-flanked allele;Memory;Modeling;Molecular;Mus;Nature;Nerve Degeneration;Neurodegenerative Disorders;Neuronal Injury;Outcome;Pathologic;Pathway interactions;Patient-Focused Outcomes;Pharmaceutical Preparations;Public Health;Radial;Receptor Signaling;Regulation;Residual state;Risk Factors;Role;Severities;Signal Transduction;Synapses;Synaptic plasticity;Testing;Time;Traumatic Brain Injury;Vascular Diseases;Vascular remodeling;Vertebral column;arm;blood-brain barrier permeabilization;brain endothelial cell;cell type;central nervous system injury;cerebral atrophy;density;improved;mild traumatic brain injury;mouse model;neuroinflammation;neuroprotection;novel;response;restoration;severe injury;targeted treatment;water maze


application_id: 9837105
project_number: 1RF1AG064859-01
administering_ic: NIA
award_notice_date: 2019-08-06
opportunity_number: PA-18-484
application_type: 1
activity_code: RF1
ic: AG
serial_number: 064859
program_official: GROTHAUS, PAUL G
project_start_date: 2019-08-15
project_end_date: 2024-08-31
study_section: Special Emphasis Panel[ZRG1 BDCN-Q (90)]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-08-15
project_title:
Pre-clinical efficacy of a selective p38MAPK inhibitor in a model of comorbid Alzheimer/vascular pathology

project_abstract:
ABSTRACTCerebrovascular pathology is a very common comorbidity with Alzheimer's pathology. However there is limitedknowledge about the molecular mechanisms underlying the vascular contributions to cognitive impairment anddementia (VCID) the mechanisms that link VCID and Alzheimer progression or how to intervene effectively ina complex multi-pathology environment. A key mechanism that drives pathophysiology progression in manyCNS disorders is dysregulated neuroinflammatory responses from innate immune cells in the brain andchronic neuroinflammation is a common feature seen early in both VCID and Alzheimer's disease (AD)progression. An important cell signaling pathway that contributes to neuroinflammatory responses in manyCNS disorders is the p38 MAPK pathway especially the p38 isoform. Activation of this important stress-regulated protein kinase occurs early in AD p38 activation can lead to chronic neuroinflammation that hasneurodegenerative consequences and selective p38 inhibition is beneficial in AD animal models. Howeverthere is no information on whether p38 is important in the detrimental inflammatory responses andsubsequent neurodegenerative sequelae seen in VCID or comorbid VCID/AD pathology. We hypothesize thatvascular dysfunction in the context of Alzheimer pathology creates an enhanced microglia inflammatory statedriven by p38 MAPK that worsens the pathologic outcomes. We further postulate that the pathogenicevents induced by comorbid VCID/AD will be modifiable by selective inhibition of p38. To test our hypotheseswe will use the established hyperhomocysteinemia mouse model of cerebral small vessel disease to inducevascular injury in the APP/PS1 transgenic mouse. We will also use our recently developed exceptionallyspecific small molecule p38 inhibitor MW150 which is CNS-penetrant safe and efficacious in mousemodels of AD pathology. The goal is to determine the therapeutic efficacy of MW150 in order to extend itspotential for disease modification to a complex comorbid brain environment exhibiting both VCID and ADpathologies. Aim 1 will determine the minimum dose of MW150 that mitigates VCID-induced functional deficitsin AD transgenic mice in a preventative treatment paradigm. Aim 2 will determine the mechanisms underlyingMW150's actions in mitigating degenerative sequelae by testing its effects on neuroinflammatory vascularand synaptic dysfunction endpoints. Aim 3 will test MW150 in a therapeutic treatment paradigm to determineefficacy in older mice when pathology is already present mimicking what we see in the clinic with AD patientsexhibiting comorbid vascular pathology. Because MW150 is a drug candidate in early stage clinicaldevelopment successful completion of these mechanistic and highly translational studies will extend thepotential clinical utility of MW150 to a disease indication with complex comorbid pathologies. Given the urgentunmet medical need and MW150's unique potential success will offer the potential for a new chemical entityand therapeutic intervention for VCID/AD either as a mono-therapy or as part of a multi-drug armamentarium.

project_terms:
APP-PS1;Adopted;Alzheimer's Disease;Alzheimer's disease model;Amyloid;Amyloid beta-Protein;Animal Disease Models;Area;Blood - brain barrier anatomy;Blood Vessels;Brain;Cells;Central Nervous System Diseases;Cerebral small vessel disease;Chemicals;Chronic;Clinic;Clinical;Cognitive;Comorbidity;Complex;Country;Data;Dementia;Deposition;Disease;Disease Progression;Dose;Elderly;Environment;Event;Exhibits;Functional disorder;Goals;Hyperhomocysteinemia;Impaired cognition;Impairment;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Innate Immune Response;Intervention;Knowledge;Lead;Link;MAPK14 gene;Mediating;Mediator of activation protein;Medical;Microglia;Mitogen-Activated Protein Kinases;Modeling;Modification;Molecular;Mus;Nerve Degeneration;Neurologic Dysfunctions;Outcome;Pathogenicity;Pathologic;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphotransferases;Play;Prevalence;Preventive treatment;Protein Isoforms;Protein Kinase;Publishing;Reporting;Role;Severities;Signal Pathway;Signal Transduction;Stress;Synapses;Testing;Therapeutic;Therapeutic Intervention;Transgenic Mice;Treatment Efficacy;Vascular Diseases;base;cerebrovascular pathology;clinical development;cytokine;dementia risk;drug candidate;druggable target;inhibitor/antagonist;mitogen-activated protein kinase p38;mouse model;neuroinflammation;novel;preclinical development;preclinical efficacy;prevent;response;small molecule;stress kinase;success;targeted treatment;therapeutic development;translational study;vascular cognitive impairment and dementia

public_health_relevance:
NARRATIVEAlzheimers disease pathology and cerebrovascular pathology are frequently found together in the brains ofolder people and vascular damage increases the risk of dementia but little is known about how these twopathologies interact and drive disease progression. Our project will use novel mouse models and a uniqueCNS-active drug candidate to test the idea that dysregulated inflammation in the brain driven by the stresskinase p38aMAPK worsens the pathological and cognitive outcomes and can be targeted for therapeuticintervention. These mechanistic/ translational studies are a key first step to understanding how to somedayprevent or treat these prevalent CNS diseases that afflict a growing number of elderly individuals.


application_id: 9835806
project_number: 1F31AA027960-01
project_title: Early Maturing Out of Problematic Alcohol Use
administering_ic: NIAAA
award_notice_date: 2019-08-28
opportunity_number: PA-18-671
application_type: 1
activity_code: F31
ic: AA
serial_number: 027960
program_official: CASTLE, I-JEN
project_start_date: 2020-01-05
project_end_date: 2022-01-04
study_section: Special Emphasis Panel[ZAA1 GG (32)]
contact_pi_person_id: 15766856
contact_pi: PETERSON, SARAH JANE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Most research suggests that alcohol use peaks in the college years then declines into the mid-thirties;understanding this maturing out process may clarify who is at risk for ongoing alcohol-related problems(Jochman & Fromme 2010). However there is evidence that some individuals mature out much earlier:downward drinking trends for some individuals begin early in the college years with as many as one third ofcollege students decreasing their drinking (Baer et al. 2001). Work using the developmentally sensitivemethod of trajectory analysis which helps identify different subgroups of a population who experience differentdevelopmental trends has consistently identified a group that decreases drinking beginning during the firstyear of college: an early maturing out group (e.g. Schulenberg et al. 1996; Greenbaum et al. 2005). It iscrucial for risk research and thus for the public health to identify factors that differentiate those who decreasetheir drinking early from those who persist in high levels of alcohol consumption; doing so would clarify risk forcollege-related alcohol problems and alcohol use disorder and aid in developing earlier targeted preventionand intervention efforts. Past research has examined contextual and individual difference factors in relation tovarying trajectories (Chassin et al. 2002; Gates et al. 2016; Jackson & Sher 2005). However those studiesdid not address early maturing out. The proposed research emphasizes two possibilities: 1) perhaps those whomature out early are facing adult-like responsibilities such as paying for their educations/supporting theirfamilies and/or 2) perhaps those who persist have higher levels of personality and learning-based risk factorscompared to those who mature out early. I propose to test both possibilities. Concerning the latter I apply anew model that integrates the personality trait of negative urgency the tendency to act rashly when in a highlynegative mood with psychosocial learning in the form of alcohol expectancies which has proven quiteeffective in understanding drinking risk (Peterson et al. 2018). The research component of this proposalinvolves using a four-wave longitudinal design to (a) identify a group that decreases drinking levels early incollege and a group that persists using trajectory analyses and (b) test whether these groups can bedifferentiated on the basis of contextual or individual difference factors. Studying factors that influence earlymaturing out is novel. A successful test would have clear clinical and public health implications as theproposed project is likely to provide direction for targeted intervention during the college years. The trainingcomponent of this proposal includes training in the following: 1) the execution and management of alongitudinal study including participant recruitment data collection and follow-up; 2) complex statisticalanalyses such as multilevel modeling; 3) the emerging adulthood developmental literature which is likely toprove helpful in understanding early maturing out; 4) further advanced training in research ethics; 5)preparation of research reports for publication; 6) mentoring of junior graduate and undergraduate students.

project_terms:
Adolescent;Adult;Alcohol abuse;Alcohol consumption;Alcoholic beverage heavy drinker;Classification;Clinical;Complex;Consumption;Data Collection;Development;Early identification;Education;Exanthema;Expectancy;Face;Family;Fibrinogen;Heavy Drinking;Home environment;Impulsivity;Income;Individual;Individual Differences;Intervention;Learning;Life Style;Light;Literature;Longitudinal Studies;Marriage;Measures;Mentors;Methods;Modeling;Occupations;Patient Recruitments;Personality;Personality Traits;Population;Preparation;Prevention;Preventive Intervention;Process;Psychological reinforcement;Public Health;Publications;Readiness;Reporting;Research;Research Design;Research Ethics;Risk;Risk Factors;Sampling;Social Reinforcement;Specialist;Specific qualifier value;Statistical Data Interpretation;Students;Subgroup;Surveys;Testing;Time;Training;Work;aged;alcohol expectancy;alcohol measurement;alcohol related problem;alcohol use disorder;base;career;college;college drinking;community college;drinking;drinking behavior;early drinking;emerging adulthood;experience;falls;follow-up;graduate student;high risk;longitudinal design;multilevel analysis;negative mood;novel;programs;psychosocial;trait;trend;underage drinking reduction;undergraduate student;university student

public_health_relevance:
Many individuals decrease their drinking following the college years; however there is evidence that for somethese reductions begin early in the college years. Identifying factors that differentiate those who decrease theirdrinking early from those who persist in heavy alcohol use will clarify the risk process for harmful collegiatedrinking and shed light on risk for adult alcohol use disorders. The proposed project is part of adevelopmentally sensitive program of research designed to examine trends and risk factors for emergingadulthood problem drinking.


application_id: 9835257
project_number: 1F31NS110264-01A1
project_title: Acomys as a Novel Mammalian Model of Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2019-06-17
opportunity_number: PA-18-671
application_type: 1
activity_code: F31
ic: NS
serial_number: 110264
suffix: A1
program_official: BAMBRICK, LINDA LOUISE
project_start_date: 2019-07-01
project_end_date: 2020-06-26
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 14923407
contact_pi: ORR, MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/Abstract Less than 1% of hospitalized victims of spinal cord injury (SCI) experience full recovery by the time ofdischarge which reflects the human spinal cords inability to regenerate and an absence of therapies to induceregeneration after SCI. Non-mammalian animal models such as lampreys newts and zebrafish readilyregenerate tissues; however the phylogenetic gap between non-mammalian species and mammals limits theability of researchers to translate regenerative targets into therapeutics for human SCI. A mammalian modelwith enhanced spinal regeneration would serve as a powerful tool to identify targets and provide a roadmap forinducing mammalian regeneration after SCI. The genus Acomys consists of mammals closely related to humans and the laboratory mouse (genusMus). Acomys exhibit scar free regeneration of nerves muscle cartilage adipose tissue glands follicles andskin and enhanced recovery from muscle and kidney injury. Importantly Acomys mount inflammatory andfibrotic responses to injury that are unique from those of non-regenerating Mus and are required for Acomysregeneration. SCI results in robust inflammatory and fibrotic injury in current non-regenerating animal modelsand affects SCI progression and repair but these responses have not been examined in Acomys followingSCI. I hypothesize that Acomys will exhibit pro-regenerative inflammatory and scarring responses to SCI andfunctional regeneration of damaged spinal pathways. Using histological and biochemical approaches Aim 1 of this proposal will investigate spatiotemporaldifferences in the inflammatory and fibrotic response of Acomys and Mus. Results of this aim will identify ifAcomys and Mus injury responses differ following SCI. Aim 2 will use in vitro methods to test speciesdifferences in intrinsic neurite outgrowth potential and in vivo methods to test species differences in functionalaxon regeneration following SCI. While Acomys respond to other injuries with pro-regenerative injuryresponses that ultimately result in regeneration these experiments will be the first to directly test the Acomysability to mount pro-regenerative injury responses in the spinal cord and will establish Acomys ability toregenerate after SCI. This proposal will establish the utility of Acomys as a novel mammalian model of SCI. A mammalianmodel of SCI with spinal regeneration would be a powerful tool to identify translatable therapeutic targets andprovide a roadmap for inducing regeneration in human SCI patients.

project_terms:
3-Dimensional;Acomys;Adipose tissue;Affect;Animal Model;Astrocytes;Axon;Biochemical;Biological Assay;Cartilage;Cell Count;Cicatrix;Collagen;Complex;Data;Development;Dyes;Ear;Electrophysiology (science);Exhibits;Extracellular Matrix;Extracellular Matrix Proteins;Fibroblasts;Fibronectins;Filament;Fishes;Flow Cytometry;Gland;Hair;Harvest;Histologic;Human;Image;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Injury;Kidney;Laboratory mice;Lampreys;Life;Lucigenin;Mammals;Measures;Methods;Microglia;Microscopy;Modeling;Motor;Mus;Muscle;Natural regeneration;Nerve Regeneration;Neurites;Neurons;Newts;Organ;Outcome;Outcome Measure;Peripheral;Phylogenetic Analysis;Property;Reactive Oxygen Species;Recovery;Regenerative response;Research Personnel;Resolution;Salamander;Sebaceous Glands;Sensory;Skin;Solvents;Spinal;Spinal Cord;Spinal cord injury;Spinal cord injury patients;Spottings;Testing;Therapeutic;Thick;Time;Tissues;Tracer;Translating;Translations;Western Blotting;Zebrafish;axon growth;axon injury;axon regeneration;experience;experimental study;in vivo;injured;insight;macrophage;neutrophil;novel;phenotypic biomarker;reconstruction;regenerative;regenerative therapy;repaired;response;response to injury;spatiotemporal;species difference;spinal pathway;therapeutic target;tool

public_health_relevance:
Spinal cord injury causes serious life-long complications because human spinal pathways do not regenerateand there are no effective regenerative therapies available. A limiting factor in development of regenerativetherapies is the difficulty of translating targets from species with regenerative abilities (including newtssalamanders and fish) to mammals (including humans). This proposal will test spinal cord injury responsesand regeneration in Acomys a group of mammals newly recognized for their regenerative abilities followingperipheral injuries to evaluate their utility for discovering regenerative therapeutic targets for human spinalcord injury.


application_id: 9835074
project_number: 1F30HL143943-01A1
project_title: Mechanisms of renin angiotensin modulation in thoracic aortic aneurysms
administering_ic: NHLBI
award_notice_date: 2019-08-15
opportunity_number: PA-18-673
application_type: 1
activity_code: F30
ic: HL
serial_number: 143943
suffix: A1
program_official: MEADOWS, TAWANNA
project_start_date: 2019-09-01
project_end_date: 2022-11-01
study_section: Special Emphasis Panel[ZRG1 F10A-R (20)]
contact_pi_person_id: 14923219
contact_pi: CHEN, JEFF ZHEYING
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
ABSTRACT Thoracic aortic aneurysms (TAAs) are a common clinically-silent dilatation of the aorta. Howevercomplications of this disease - such as aortic dissection and rupture - are sudden and deadly. Because there iscurrently no validated medical therapy to prevent or reverse aortic dilation all patients with thoracic aorticaneurysms will eventually need surgical repair. Marfan syndrome is caused by mutations in fibrillin-1 a large extracellular matrix protein responsible forelastin structure and aortic integrity. Our project proposes the use of Marfan syndrome model mice toinvestigate the pathogenesis of TAAs. We have shown that TAAs occur in an angiotensin receptor (AT1areceptor) dependent manner. How AT1a receptors are activated in Marfan syndrome is a gap in currentknowledge. AT1a receptors are canonically activated by its main effector peptide angiotensin II. It can also beactivated in a ligand independent manner. We hypothesize that AT1a receptors in Marfan syndrome areactivated in an AngII dependent manner. Furthermore we hypothesize that depletion of endogenous AngIIsufficiently attenuates TAA development in Marfan syndrome through inhibition of AT1a receptor activity. To test this hypothesis we will determine if AngII depletion by angiotensinogen antisenseoligonucleotide administration attenuates aortic dilation aortic medial remodeling and aortic AT1a receptoractivity. We will also perform a retrospective clinical study using a large electronic health record dataset todetermine if inhibition of AngII formation angiotensin receptor blockade or beta-blockade are associated withprotection against TAA in Marfan syndrome patients. Altogether completion of this project will provide a better understanding of the molecular mechanismbehind Marfan syndrome associated thoracic aortic aneurysm pathogenesis.

project_terms:
3-Dimensional;Angiotensin II;Angiotensin Receptor;Angiotensin Type 1a Receptor;Angiotensin-Converting Enzyme Inhibitors;Angiotensinogen;Angiotensins;Antisense Oligonucleotides;Aorta;Aortic Rupture;Attenuated;Binding;Bioinformatics;Breeding;Cardiomyopathies;Clinical;Clinical Research;Collagen;Communication Research;Confocal Microscopy;Data;Data Set;Databases;Deposition;Development;Dilatation - action;Dilated Cardiomyopathy;Dimensions;Disease;Dissection;Elastin;Electron Microscopy;Electronic Health Record;Enzyme Inhibition;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;FBN1;Genetic;Goals;Growth;Half-Life;Health;Hemorrhage;Human;Imagery;Knowledge;Ligands;Losartan;MADH2 gene;MAPK3 gene;Marfan Syndrome;Matrix Metalloproteinases;Measurement;Measures;Mechanics;Medial;Medical;Modeling;Molecular;Mus;Mutation;Nitric Oxide;Operative Surgical Procedures;Pathogenesis;Patients;Peptides;Peptidyl-Dipeptidase A;Pharmaceutical Preparations;Pharmacology;Phosphorylation;Plant Roots;Process;Production;Publishing;RNA Interference;Receptor Activation;Renin;Reporting;Research Ethics;Risk;Rupture;Signal Transduction;Specificity;Stretching;Structure;Sudden Death;Testing;Thoracic Aortic Aneurysm;Training;Transforming Growth Factor beta;Ultrasonography;Vascular Smooth Muscle;base;extracellular;inhibitor/antagonist;mortality;mouse model;prevent;protective effect;receptor;repaired;transdifferentiation

public_health_relevance:
PROJECT NARRATIVEThoracic aortic aneurysms greatly increase the risk of sudden death by aortic rupture followed with rapidinternal bleeding. Currently there is no validated medical therapy to treat thoracic aortic aneurysms.Uncovering the key processes which drive thoracic aortic aneurysm formation is critical for identifying targetsthat can modulate this disease.


application_id: 9832976
project_number: 1F31AI147417-01
administering_ic: NIAID
award_notice_date: 2019-08-06
opportunity_number: PA-18-671
application_type: 1
activity_code: F31
ic: AI
serial_number: 147417
program_official: VINCENT, LEAH REBECCA
project_start_date: 2019-08-09
project_end_date: 2022-08-08
study_section: Special Emphasis Panel[ZRG1 F13-Z (20)]
contact_pi_person_id: 15691582
contact_pi: KEB, GABRIELLE
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: 2019-08-09
project_title:
Chlamydia trachomatis Secreted Effector Proteins: Infection Properties and Identification of Host Targets

project_abstract:
Project Summary Chlamydia trachomatis is the causative agent of most commonly reported sexually transmitted diseasein the United States. Disease is most severe in women and can cause detrimental effects to reproductive healthsuch as infertility. Establishment of an intracellular niche within non-immune cells such as mucosal epitheliumis sufficient to drive immunopathology and disease sequela. C. trachomatis lacking both TmeA and TmeB typeIII secretion system effectors generate fewer infectious progeny in tissue culture and have significantlydecreased infectivity in mice. Previous attempts to identify their individual functions utilized fluorescence-reported allelic exchange mutagenesis (FRAEM) but resulted in unclear phenotypes due to cassette-inducedpolar effects. Recently I have developed floxed-cassette allelic exchange mutagenesis (FLAEM) to reversecassette-induced polar effects and generate the first ever markerless C. trachomatis deletion mutant. Ihypothesize that TmeA and TmeB are functionally related and important for establishing the inclusion becausethey are co-transcribed share a common chaperone and are secreted into the host cell at the same time. Theproposed work will utilize the novel marker-less C. trachomatis deletion mutant to determine whenduring chlamydial development TmeA and TmeB are important and identify their eukaryotic host celltargets. The outcomes of this research will directly contribute to our understanding of basic C. trachomatisbiology and how they use secreted effectors to establish an intracellular which will identify potential drug targetsto prevent the spread of infection to millions world-wide.

project_terms:
Alleles;Attenuated;Bacteria;Biological Assay;Biology;Biotin;Cells;Chlamydia Infections;Chlamydia trachomatis;Co-Immunoprecipitations;Cytolysis;Defect;Development;Disease;Drug Targeting;Epithelium;Fluorescence;Genes;Genetic Transcription;Genome;Growth;Hela Cells;Immune response;Immunoprecipitation;In Vitro;Indirect Immunofluorescence;Individual;Infection;Infertility;Invaded;Label;Link;LoxP-flanked allele;Maintenance;Mass Spectrum Analysis;Membrane;Modeling;Molecular;Molecular Chaperones;Mucous Membrane;Mus;Mutagenesis;Outcomes Research;Pathogenesis;Pathology;Pathway interactions;Phenotype;Plasma;Production;Property;Proteins;Reporting;Reproductive Health;Research;Sexually Transmitted Diseases;Stains;Surface;Techniques;Technology;Time;Transcript;Type III Secretion System Pathway;United States;Vacuole;Western Blotting;Woman;Work;immunopathology;in vitro Model;in vivo;interest;mouse model;mutant;new technology;novel marker;prevent;receptor;tissue culture

public_health_relevance:
Project NarrativeChlamydia trachomatis a leading cause of sexually transmitted disease relies on a specialized secretionmechanism to deploy anti-host proteins that are essential to pathogenesis. This proposal contains work thatwill characterize selected proteins to determine their specific contributions to chlamydial disease.


application_id: 9831563
project_number: 5R01EY026180-05
project_title: Tear Film Lipid Compositional Structural Functional Relationships and Dry Eye
administering_ic: NEI
award_notice_date: 2019-12-09
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 026180
program_official: MCKIE, GEORGE ANN
project_start_date: 2015-12-01
project_end_date: 2022-11-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 1962526
contact_pi: BORCHMAN, DOUGLAS
other_pis: Not Applicable
congressional_district: 03
department: OPHTHALMOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Dry eye affects over six million people in the United States alone and may be classified as aqueous production-deficient (AD) and evaporative which is associated with meibomian gland dysfunction (MGD). Both mechanisms of development of dry eye share the common feature of instability of the tear film (TF) with rapid tear break-up time suggesting there may be a shared structural abnormality of the TF that is responsible for the instability. Our spectroscopic studies have identified several potential abnormalities in the TF lipid composition that may contribute to TF instability including terpenoids saturation protein and cholesteryl esters. We also identified hydrocarbon conformational abnormalities with dry eye. For example when terpenoid levels in meibum are low as in MGD the TF is unstable and patients have the signs and symptoms of dry eye. When terpenoids are restored with azithromycin treatment TF stability is restored and patients no longer have the signs and symptoms of dry eye. We have the best chance of testing which moieties are important to TF stability by studying samples with a wide range of TF stabilities. We propose to study samples from patients with dry eye (both AD and MGD) and samples from Asians because they have an 80% higher incidence of dry eye compared to Caucasians. We will also compare compositional changes in meibum and TF lipid when the signs and symptoms of dry eye are ameliorated with treatment. TF lipid and meibum will be studied since their composition is slightly if not significantly different. We propose to use spectroscopy Raman IR and NMR to determine how TF composition relates to tear film stability measured in vitro and in vivo on the same sample. The TF stability parameters we propose to measure in vitro include: surface pressure-area isotherms isocycles surface rheology surface Raman and quantitative Brewster angle microscopy to assess the meibum's lateral elasticity and capability of compressing and spreading during dynamic area changes. We propose to measure in vivo several parameters including tear osmolarity break-up time and blink rate. Natural and experimental differences in TF lipid and meibum amount and composition (especially terpenoids saturation protein and levels of cholesteryl esters) hydrocarbon conformation and lipid-protein interactions will be correlated to TF stability using principle component analysis t determine if and which moieties in meibum are important to TF stability with the ultimate goal of developing therapies to enhance TF stability.

project_terms:
Affect;Age;Anti-Bacterial Agents;Area;Asians;Azithromycin;Back;Blinking;Caucasians;Cells;Cholesterol Esters;Chronic;Clinical;Contact Lenses;Development;Diet;Disease;Elasticity;Environment;Etiology;Film;Genetic;Goals;Hydrocarbons;In Vitro;Incidence;Knowledge;Lateral;Lead;Lipids;Measures;Microscopy;Modification;Molecular Conformation;Nuclear Magnetic Resonance;Osmolar Concentration;Patients;Production;Property;Proteins;Rheology;Sampling;Sampling Studies;Signs and Symptoms;Sjogren's Syndrome;Spectrum Analysis;Structural defect;Structure;Surface;Symptoms;Techniques;Technology;Terpenes;Testing;Time;United States;Variant;Visual;aqueous;evaporation;experience;eye dryness;in vivo;meibomian gland;meibomian gland dysfunction;pressure;public health relevance;spectroscopic survey;therapy development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Dry eye affects over seven million people in the United States alone and meibomian gland disease is the most frequent cause. Dry eye can cause chronic and severe symptoms as well as secondary changes that can lead to visual disturbance. Elucidating the mechanism of tear film instability in dry eye will enable development of therapies to ameliorate the ocular effects of deranged structure of the lipid layer and meibum.


application_id: 9830071
project_number: 5R01ES028102-03
project_title: The role of autophagy in cadmium induced prostate carcinogenesis
administering_ic: NIEHS
award_notice_date: 2019-11-18
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: ES
serial_number: 028102
program_official: REINLIB, LESLIE J
project_start_date: 2017-12-01
project_end_date: 2022-11-30
study_section: Systemic Injury by Environmental Exposure[SIEE]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
other_pis: FREEDMAN, JONATHAN H
congressional_district: 03
department: UROLOGY
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 SummaryIt has been clearly demonstrated that exposure to the environmental toxicant cadmium is associatedwith a variety of human diseases including prostate cancer. Prostate cancer is the second leading causeof cancer death in United States. Although an association has been established the mechanism bywhich this metal induces cellular transformation has yet to be defined. One underexplored process thatmay be affected by cadmium is oncogenic autophagy a process that promotes cancer cell survival. Ourpreliminary data clearly shows that chronic exposure to cadmium leads to cellular transformation andthat this transformation occurs via autophagy through changes in Placenta Specific 8 (Plac8) expression.Additionally Plac8 is observed in human prostate cancer but not in benign prostatic hyperplasia tissues.Based on our preliminary results we hypothesize that cadmium-induced cellular transformation ismediated by the induction of autophagy and that Plac8 is an essential regulator of this process.We will test this hypothesis using a combination of approaches in normal prostate epithelial (RWPE-1)transforming cells and cadmium-transformed prostate epithelial (CTPE) cells mice and human prostatecancer. The goals of this project are to explore an innovative model for the regulation of autophagy bycadmium; where short term metal exposure induces the apoptosis while chronic low dose exposurewhich more accurately represents human etiology of cadmium toxicity; autophagy acts oncogenicleading to transformation. The interaction between cadmium autophagy/apoptosis and Plac8expression will be defined using three approaches: Specific Aim 1: Establish the mechanistic relationshipbetween cadmium exposure and the induction of autophagy in prostate epithelial cells. Specific Aim 2:Determine the mechanism by-which cadmium induces Plac8 expression to regulate pro-survivalsignaling autophagy. Specific Aim -3: Determine the oncogenic role of Plac8 in vivo. The successfulcompletion of these goals represents the first studies on the role of autophagy/Plac8 in cadmium-induced prostate cancer. It will also inform on the applicability of using Plac8 as a prostate cancerbiomarker and of targeting this protein to inhibit metal-induced prostate cancer.

project_terms:
Acute;Affect;Apoptosis;Autophagocytosis;Benign Prostatic Hypertrophy;Cadmium;Cancer Etiology;Cell Death;Cell Line;Cell Survival;Cells;Cessation of life;Chronic;Data;Dose;Epithelial;Epithelial Cells;Epithelium;Etiology;Exposure to;Genes;Gleason Grade for Prostate Cancer;Goals;Human;Human Pathology;Hypoxia;Malignant neoplasm of prostate;Mediating;Metal exposure;Metals;Modeling;Molecular;Mus;Nude Mice;Oncogenic;Organelles;Oxidative Stress;Patients;Pharmacology;Placenta;Population;Prevention;Process;Prostate;Prostatic Neoplasms;Proteins;Regulation;Research;Resistance;Role;Screening for Prostate Cancer;Serum;Signal Transduction;Site-Directed Mutagenesis;Specimen;Starvation;Stress;System;Testing;Time;Tissues;Toxic Environmental Substances;Toxic effect;Translational Research;Tumor Tissue;United States;Urine;Xenograft Model;base;cancer biomarkers;cancer cell;carcinogenesis;cell transformation;early detection biomarkers;environmental chemical;genetic activator;genetic inhibitor;human disease;in vivo;innovation;lysosomal proteins;malignant phenotype;metaplastic cell transformation;mouse model;novel;overexpression;prostate carcinogenesis;transcription factor;tumor growth;tumor xenograft;virtual

public_health_relevance:
Project NarrativeThis research outlined in this proposal aims to delineate the mechanism by which cadmium affectsautophagy ultimately leading to transformation. The study is examining for the first time several novelprocesses autophagy and the gene Plac8 not typically associated with environmental chemical inducedprostate cancer. The successful completion of these goals will inform on the applicability new prostatecancer biomarkers and targets to treat metal-induced prostate cancer.


application_id: 9828496
project_number: 5R01DA041513-05
project_title: Neural microcircuit selection by astrocyte signaling following cocaine exposure
administering_ic: NIDA
award_notice_date: 2020-11-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DA
serial_number: 041513
program_official: TSAI, SHANG-YI ANNE
project_start_date: 2017-02-01
project_end_date: 2022-11-30
study_section: Molecular Neuropharmacology and Signaling Study Section[MNPS]
contact_pi_person_id: 10632329
contact_pi: ORTINSKI, PAVEL IVANOVICH
other_pis: Not Applicable
congressional_district: 06
department: NEUROSCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary/AbstractA significant obstacle to developing effective drug addiction therapies is that drug-induced neuronal plasticitymay be restricted to discrete neuronal populations within brain reward areas. The processes driving selectionof specific cells from a larger pool of available neurons are not clear. Our long-term goal is to identify themechanisms that assemble medium spiny neuron (MSN) microcircuits underlying behavioral expression ofcocaine seeking and taking. In this application our objective is to identify cocaine-related neuronal adaptationsthat depend on astrocytic signaling. We propose a hypothesis that astrocytic signals recruit discretesubpopulations of MSNs within the nucleus accumbens (NAc) shell to facilitate neuronal and behavioralplasticity associated with cocaine self-administration in the rat. This hypothesis is supported by our preliminaryand published data and studies from other groups. The rationale for pursuing this hypothesis is that despite agrowing recognition that astrocytes actively modulate neuronal activity little is known about the role ofastrocytes in coordination of local circuits and even less about regulation of local circuits by cocaine. On thebasis of substantial preliminary data we will test our central hypothesis in three specific aims: 1) Characterizethe impact of astrocyte signaling on cocaine-induced NMDA receptor (NMDAR) plasticity in MSN microcircuits.2) Characterize the impact of astrocyte signaling on cocaine-induced AMPA receptor (AMPAR) plasticity insynchronously active MSNs. 3) Identify the consequences of astrocyte-synchronized neuronal activity oncocaine seeking and taking. In the first aim we will use a unique characteristic of neuronal response toastrocyte-derived signals slow inward currents (SICs) to test the hypothesis that cocaine-induced plasticity ofextrasynaptic NMDARs previously linked to cocaine exposure is restricted to NAc shell MSNs displaying SICevents. The second aim is built on classical knowledge linking NMDAR-mediated signaling to plasticity ofsynaptic AMPARs and current evidence indicating that NMDAR-mediated SICs co-occur in neuronalsubpopulations. In this aim we will determine whether cocaine-induced plasticity of synaptic AMPAR signalingis restricted to subpopulations of NAc shell MSNs synchronized by astrocyte-derived signals. In the third aimwe will test the hypothesis that facilitation and inhibition of astrocyte-driven neuronal synchronization willrespectively facilitate and inhibit cocaine-seeking behaviors. The approach is significant because it improvesour ability to identify cell populations responsible for specific behavioral responses. This ability is critical fortargeted therapeutic approaches. Our approach is innovative because: it considers a novel hypothesis ofastroglia as active participants in selection of cocaine-relevant neuronal microcircuits it facilitates developmentof novel viral tools to identify such microcircuits and it seeks to identify novel mechanisms of cocaine-inducedneuroglial plasticity. Completion of these studies will expand understanding of the relationship between glialsignaling individual neuron excitability local network function and behavioral outcomes in the context ofcocaine addiction.

project_terms:
AMPA Receptors;Acute;Addictive Behavior;Affect;Animals;Area;Astrocytes;Automobile Driving;Behavior;Behavioral;Brain;Cells;Characteristics;Cocaine;Cocaine Abuse;Cocaine Dependence;Code;Coupling;Data;Development;Dopamine;Dose;Eating;Electrophysiology (science);Event;Exposure to;Future;Glutamates;Goals;Image;Individual;Knowledge;Link;Maintenance;Mediating;N-Methyl-D-Aspartate Receptors;Neuronal Plasticity;Neurons;Nucleus Accumbens;Participant;Pharmaceutical Preparations;Play;Population;Process;Public Health;Publishing;Rattus;Regulation;Rewards;Role;Self Administration;Signal Transduction;Slice;Sucrose;Synaptic plasticity;System;Testing;Therapeutic;Training;Viral;addiction;base;behavioral outcome;behavioral plasticity;behavioral response;brain cell;cell type;cocaine exposure;cocaine self-administration;design;designer receptors exclusively activated by designer drugs;drug addiction therapy;effective therapy;experience;experimental study;improved;innovation;neurotransmission;novel;quantum;receptor-mediated signaling;recruit;relating to nervous system;response;sex;targeted treatment;theories;tool

public_health_relevance:
Project NarrativeCocaine abuse a major public health problem remains without an effective treatment partly because neuronalbrain cells responsible for addictive behavior and those responsible for pursuit of natural rewards (e.g. eatingor sex) are intermingled. This application proposes that activity of astrocytes another major type of brain celldrives changes within a sub-population of neurons specifically associated with cocaine experience.Identification of discrete neurons that drive cocaine-directed behavior will facilitate development of targetedaddiction therapeutics. Successful completion of the proposed studies will expand fundamental understandingof astrocyte-neuron interactions.


application_id: 9828489
project_number: 5R01CA214638-03
project_title: A redox-mediated mechanism of UVB-induced metabolic switch in skin carcinogenesis
administering_ic: NCI
award_notice_date: 2019-11-08
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: CA
serial_number: 214638
program_official: JOHNSON, RONALD L
project_start_date: 2017-12-18
project_end_date: 2022-11-30
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 3147341
contact_pi: ST CLAIR, DARET K
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:
More than 1.2 million new cases of non-melanoma skin cancer including squamous cell carcinoma andbasal cell carcinoma are diagnosed annually in the United States and the lifetime risk for skin cancerexceeds the lifetime risk for all other cancers combined. Ultraviolet (UV) radiation is considered as themain cause of non-melanoma skin cancer. The current paradigm for prevention against UVB-inducedskin cancer is application of general antioxidant products which is inadequate because it is based onincomplete understanding of the role of oxidative stress in cancer development. The overall goal of thisresearch is to gain an in-depth understanding of the mechanism by which superoxide radical/anion (O2-) in mitochondria contributes to metabolic switch during UVB carcinogenesis and to test the conceptthat a targeted antioxidant approach can prevent skin cancer. Our preliminary data demonstrate thatthe expression of manganese containing superoxide dismutase (MnSOD) is suppressed inhistologically normal skin at preneoplastic stage which results in increased superoxide production andincreased synthesis of uncoupling proteins (UCPs). Furthermore knockdown of UCPs suppresseslactate production and increases ATP levels. Thus adaptation to increased superoxide production byinduction of UCPs is likely the critical step leading to the Warburg effect. We also have found thatexposure to UVB causes nitration and inactivation of MnSOD and activation of prosurvival autophagyresponses. Co-immunoprecipitation of nitrated MnSOD identified members of the Chaperone-MediatedAutophagy (CMA) pathway which supports the role of CMA in selective degradation of nitrated proteins.Based on these novel findings we propose that O2- is a critical driver of metabolic alteration in UVBcarcinogenesis that promotes cancer development and progression. Specific Aim 1 will test thehypothesis that O2- triggers an uncoupling protein (UCP)-dependent metabolic switch. Specific Aim 2will test the hypothesis that MnSOD is a critically important target of UVB-induced peroxynitrite (OONO-) that leads to activation of autophagy responses. Specific Aim 3 will test the concept that UVB-inducedO2- and OONO- are critical mediators that promote UV carcinogenesis. We will use molecular geneticapproach coupled with proteomics to identify UCP transcriptomes and stable-isotope-resolvedmetabolomics to identify pathways leading to preneoplastic metabolic alterations. We will use well-characterized mimetics of MnSOD to test the concept that mechanistically targeted antioxidants canprevent UV carcinogenesis. The relationship between UV radiation and energy metabolism remainsunknown. The results from this study will close that knowledge gap and will provide valuable insightsinto the metabolic vulnerabilities that are amenable to cancer prevention.

project_terms:
Affinity;Anions;Antioxidants;Autophagocytosis;Basal cell carcinoma;Bioenergetics;Chemistry;Chemoprevention;Co-Immunoprecipitations;Consumption;Coupled;Data;Development;Diagnosis;Energy Metabolism;Epithelial Cells;Event;Exposure to;Genetic Enhancer Element;Genetic Transcription;Glucose;Glycolysis;Goals;Histologic;Human;Intervention;Kinetics;Knowledge;Luciferases;Malignant Epithelial Cell;Malignant Neoplasms;Manganese;Mediating;Mediator of activation protein;Metabolic;Metabolism;Mitochondria;Modeling;Molecular;Molecular Biology;Molecular Chaperones;Molecular Genetics;Nitrates;Normal tissue morphology;Ontology;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Peroxonitrite;Prevention;Production;Proteins;Proteomics;Reporter Genes;Research;Risk;Role;Skin;Skin Cancer;Skin Carcinogenesis;Skin Carcinoma;Squamous cell carcinoma;Superoxide Dismutase;Superoxides;Testing;Tissues;Transgenic Mice;UV carcinogenesis;UV induced;UVB carcinogenesis;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;United States;Validation;Warburg Effect;base;cancer prevention;carcinogenesis;design;genetic approach;insight;knock-down;lifetime risk;member;metabolomics;mimetics;nitration;novel;prevent;promoter;prototype;response;skin cancer prevention;stable isotope;transcriptome;tumor

public_health_relevance:
The overall goal of this research is to gain a comprehensive understanding of the mechanism by whichsuperoxide radical/anion (O2-) in mitochondria contributes to metabolic switch during UVBcarcinogenesis and to obtain valuable in-depth insights into the metabolic vulnerabilities that areamenable to cancer prevention. The results achieved from this study will have the potential tofundamentally change the practice of chemoprevention of UV-induced skin cancer.


application_id: 9828116
project_number: 5R01NS104289-03
project_title: Validation of a Point of Care Diagnostic Test for Sports Related Concussion
administering_ic: NINDS
award_notice_date: 2019-11-26
opportunity_number: PA-16-160
application_type: 5
activity_code: R01
ic: NS
serial_number: 104289
program_official: UMOH, NSINI ALEASE
project_start_date: 2017-12-01
project_end_date: 2021-11-30
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: SMOOT, KYLE
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:
AbstractMild traumatic brain injury (mTBI) resulting from sports related concussion (SRC) is a substantial public healthconcern with ~ 1.6  3.8 million injuries per year in the United States. Although extremes of head injury arerecognizable mTBI associated with SRC is more difficult to diagnose and is complicated by subtle physicalcognitive and emotional symptoms that may manifest up to 48 h following a concussive blow. In preliminarystudies using a rat model of mTBI and in a small clinical trial of patients with mTBI due to motor vehicleaccidents or unintentional falls we identified a novel post translationally modified marker of neuronal injuryubiquitinated visinin like protein 1 (ubVILIP-1) that is released into blood rapidly after injury. To facilitate rapidmeasurement of circulating ubVILIP-1 we developed a lateral flow device (LFD) that provides detection of thebiomarker in less than 20 min. The aim of the current proposal is determine if ubVILIP-1 levels can be used toidentify athletes with SRC by establishing baseline levels of the marker and then quantifying changes thatoccur following SRC and to correlate ubVILIP-1 levels with clinical metrics including SCAT3 measures.

project_terms:
Accident and Emergency department;Age;Assessment tool;Athletic Injuries;Awareness;Bedside Testings;Biological Assay;Biological Markers;Blood;Blood specimen;Brain Concussion;Chronic;Clinical;Clinical Data;Clinical Trials;Conscious;Craniocerebral Trauma;Data;Detection;Devices;Diagnosis;Diagnostic;Diagnostic tests;Drops;Early identification;Enzyme-Linked Immunosorbent Assay;Equilibrium;Evaluation;Exertion;Fingers;Future;Glial Fibrillary Acidic Protein;Human;Injury;Kentucky;Lateral;Legal patent;Manufactured football;Measurement;Measures;Modeling;Monitor;Neurobehavioral Manifestations;Neuronal Injury;Neurons;Operative Surgical Procedures;Patients;Physicians;Play;Post-Translational Protein Processing;Proteins;Public Health;Rattus;Recording of previous events;Recovery;Research;Sampling;Seasons;Serum;Soccer;Specificity;Sports;Standardization;Symptoms;System;Tablets;Testing;Time;Training;Ubiquitination;United States;Universities;Validation;Weight;Woman;associated symptom;base;blood-based biomarker;conditioning;controlled cortical impact;effectiveness testing;emotional symptom;falls;injury recovery;male;men;mild traumatic brain injury;novel;novel marker;physical symptom;point-of-care diagnostics;recruit;research clinical testing;risk minimization;sensor;tau Proteins;vehicular accident;visinin

public_health_relevance:
NarrativeMild traumatic brain injury (mTBI) resulting from sports related concussion (SRC) is a substantial publichealth concern with ~ 1.6  3.8 million injuries per year in the United States. Despite considerableresearch there remains a critical need for a point of care test that can rapidly measure a maker of injuryin blood on the playing field during a clinically useful time frame. Preliminary and future studiesdescribed in this proposal aim to test the usefulness of a lateral flow device (LFD) that quantifies aspecific post-translational modification of visinin like protein 1 (VILIP-1) a neuron specific Ca2+-sensorprotein released into blood following mTBI as an objective marker of SRC.


application_id: 9827910
project_number: 1R21CA231911-01A1
project_title: STAN-CT: Standardization and Normalization of CT images for Lung Cancer Patients
administering_ic: NCI
award_notice_date: 2019-06-20
opportunity_number: PAR-15-334
application_type: 1
activity_code: R21
ic: CA
serial_number: 231911
suffix: A1
program_official: REDMOND, GEORGE O
project_start_date: 2019-07-01
project_end_date: 2021-06-30
study_section: Special Emphasis Panel[ZCA1 TCRB-D (M1)]
contact_pi_person_id: 10950301
contact_pi: CHEN, JIN
other_pis: FEI, BAOWEI ;ZHANG, GUO-QIANG
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractLung cancer is the leading cause of cancer death and one of the most common cancers among both men andwomen in the United States. Recent advances in high-resolution imaging set the stage for radiomics tobecome an active emerging field in cancer research. However the promise of radiomics is limited by a lack ofimage standardization tools because computed tomography (CT) images are often acquired using scannersfrom different vendors with customized acquisition parameters posing a fundamental challenge to radiomicstudies across sites. To overcome this challenge especially for large-scale multi-site radiomic studiesadvanced algorithms are required to integrate standardize and normalize CT images from multiple sources.We propose to develop STAN-CT a deep learning software package that can automatically standardize andnormalize a large volume of diagnostic images to facilitate cross-site large-scale image feature extraction forlung cancer characterization and stratification. By precisely mitigating the differences in advanced radiomicfeatures of CT images STAN-CT will overcome research silos and promote medical image resource sharingultimately improving the diagnosis and treatment of lung cancer. Our goal will be achieved through two Aims.In Aim 1 we will develop a working prototype to standardize CT images. First we will collect raw image datafrom lung cancer patients and reconstruct CT images using multiple image reconstruction parameters and wewill scan a multipurpose chest phantom along with five different nodule inserts. Then we will develop and trainSTAN-CT for CT image standardization. An alternative training architecture will be developed to achieve theimproved model training stability. In Aim 2. We will deploy and test STAN-CT for image standardization locallyand across three medical centers. First we will make the STAN-CT software package available to the public byproviding a menu-driven web-interface so that that users can conveniently convert medical images that weretaken using non-standard protocols to one or multiple standards that they specify. Second we will deploySTAN-CT at the University of Kentucky for local performance validation. We will test the functionality reliabilityand performance of STAN-CT using both patient chest CT image data collected at large-scale and thephantom image data both independent to training. Third we will deploy and test STAN-CT at the University ofKentucky as well as the University of Texas Southwestern Medical Center and Emory University for cross-center performance validation. We will use the same multipurpose chest phantom and both standard and non-standard protocols to validate STAN-CT at the three centers. We will test the generalizability of STAN-CTusing clinical CT images of human patients and will determine whether a model trained using the data fromone medical center are applicable for images collected at another place. Finally we will distribute the softwarepackage of STAN-CT for public use. STAN-CT will enable a wide range of radiomic researches to identifydiagnostic image features that strongly associated with lung cancer prognosis.

project_terms:
Algorithms;Anatomic Models;Anatomy;Architecture;Cancer Etiology;Cancer Patient;Cancer Prognosis;Cessation of life;Characteristics;Chest;Clinical;Communities;Computer software;Custom;Data;Diagnosis;Diagnostic Imaging;Disease Management;Evolution;Faculty;Goals;Human;Image;Imaging Phantoms;Imaging technology;Kentucky;Life;Malignant Neoplasms;Malignant neoplasm of lung;Medical Imaging;Medical center;Modeling;Multi-Institutional Clinical Trial;Names;Nodule;Non-Small-Cell Lung Carcinoma;Outcome;Patients;Performance;Phase;Phenotype;Protocols documentation;Quality Control;Radiology Specialty;Research;Resource Sharing;Scanning;Site;Source;Specific qualifier value;Standardization;Stratification;Survival Rate;System;Testing;Texas;Tissues;Tomography Computed Scanners;Training;United States;Universities;Validation;Vendor;Woman;X-Ray Computed Tomography;anticancer research;base;cancer diagnosis;cancer imaging;cancer therapy;chest computed tomography;computational platform;data to knowledge;deep learning;high resolution imaging;human imaging;image reconstruction;imaging modality;improved;lung imaging;member;men;outcome forecast;prototype;quantitative imaging;radiomics;response;spatial temporal variation;tool;trait;tumor;web interface

public_health_relevance:
Project NarrativeComputed tomography (CT) is one of the most popular diagnostic image modalities routinely used forassessing anatomical tissue characteristics for disease management. However CT images are often acquiredusing scanners from different vendors with different imaging standards posing a fundamental challenge toradiomic studies across sites. The goal of the Standardization and Normalization of CT images for lung cancerpatients (STAN-CT) project is to develop a deep learning software package that can automatically standardizeand normalize a large volume of chest CT images to facilitate cross-site large-scale image feature extractionfor lung cancer characterization and stratification.


application_id: 9824211
project_number: 3R01NS091146-05S1
project_title: Anti-oxidant Promoting Cytokine LIF Ebhances Neural Cell Survival During Ischemia
administering_ic: NINDS
award_notice_date: 2019-01-15
opportunity_number: PA-18-906
application_type: 3
activity_code: R01
ic: NS
serial_number: 091146
suffix: S1
program_official: BOSETTI, FRANCESCA
project_start_date: 2016-05-01
project_end_date: 2020-12-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 1879898
contact_pi: PENNYPACKER, KEITH R
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
project_abstract:
Summary Leukemia inhibitory factor (LIF) is an anti-inflammatory cytokine that activates the expression ofendogenous antioxidants in neural cells. Our laboratory has been examining the efficacy of LIF in the rodentstroke model of middle cerebral artery occlusion (MCAO) which reflects the most commonly occluded vesselin humans. We have found that LIF administered at 6 h after MCAO improves anatomical and functionaloutcomes in rats. Of interest this treatment reflects a 33% extension of the therapeutic window whenextrapolated to the current clinical stroke window for therapy. LIF increased the expression of antioxidantproteins via Akt in cultured neurons and oligodendrocytes. Aim 1: Is the efficacy of LIF dependent on SOD?We have found total superoxide dismutase (SOD) levels are significantly elevated and protein levels of oneisoform SOD3 are increased several-fold at 3 days following MCAO. In this Aim we will determine if specificSOD subtype(s) are responsible for the LIF-induced effects and determine cell-specific expression of theseSOD isoforms. MCAO studies will first use knockout mice to examine the SOD subtypes and these results willthen be confirmed in rats. Aim 2: Does this LIF dosing regimen translate into long-term behavioralrecovery? This Aim will determine whether this treatment regimen has lasting effects. These data will be usedto devise a treatment regimen to extend the short-term efficacy to long-term histological and functionalrecovery at 90 days post-MCAO in rats. Aim 3: Which signals are transduced following LIF activation?The efficacy of LIF is dependent on the protein kinase Akt. From analysis of antioxidant promoters thetranscription factor MZF-1 is the putative transcription factor that activates their gene expression via Akt. Wewill use immunohistochemistry and gel shift assays to quantify their expression and promoter bindingrespectively in the infarct regions of rats treated with LIF after MCAO. siRNA techniques with neuronalcultures will be employed to knock down expression of this factor to validate previous findings. Aim 4: Will LIFadministration be effective in elderly rats after MCAO? In this Aim we will treat elderly male and femalerats in short-term studies. These studies will be used to determine if there are any age- or sex- dependentdifferences in LIF efficacy after MCAO. Both histological and functional recovery will be examined. Thisproposal is aimed to further elucidate the mechanism(s) of LIF treatment and optimize the treatment regimenfor long-term efficacy. While treatment with exogenous antioxidants has failed we believe that the systemicactivation of endogenous antioxidants is a better approach and could have substantial implications for treatingclinical stroke.

project_terms:
Address;Age;Anatomy;Anti-inflammatory;Antioxidants;Behavioral;Binding;Cell Survival;Cells;Clinic;Clinical;Data;Dose;Elderly;Electrophoretic Mobility Shift Assay;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;FDA approved;Female;Gene Expression;Histologic;Human;Immunohistochemistry;Infarction;Intravenous;Ischemia;Knockout Mice;LIF gene;Laboratories;Measures;Middle Cerebral Artery Occlusion;Motor Skills;Neurologic;Neurons;Occlusion injury;Oligodendroglia;Performance;Protein Isoforms;Protein Kinase;Proteins;Public Health;Rattus;Records;Recovery;Recovery of Function;Regimen;Rodent;Safety;Sex Differences;Signal Transduction;Small Interfering RNA;Stroke;Superoxide Dismutase;Techniques;Therapeutic;Translating;Treatment Protocols;activating transcription factor;base;combat;cytokine;experimental study;functional outcomes;gray matter;improved;individualized medicine;interest;knock-down;male;pre-clinical;promoter;response;sex;stroke model;transcription factor;treatment optimization;treatment strategy;white matter

public_health_relevance:
NarrativeStroke is a major public health problem in the USA with only one FDA-approved treatment that has a limitedtreatment window. We have found that leukemia inhibitory factor (LIF) protects neural cells from stroke. Theproposed experiments will identify how LIF increases the cells own antioxidants to protect it from strokeinduced damage.


application_id: 9823863
project_number: 5R21AI142590-02
administering_ic: NIAID
award_notice_date: 2019-11-05
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AI
serial_number: 142590
program_official: FERGUSON, STACY E
project_start_date: 2018-11-15
project_end_date: 2020-10-31
study_section: Genetics of Health and Disease Study Section[GHD]
contact_pi_person_id: 10517640
contact_pi: WATSON, COREY TAYLOR
other_pis: MARASCO, WAYNE A.
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
budget_start_date: 2019-11-01
project_title:
Population level characterization of human immunoglobulin heavy chain germline variants with impacts on variability in the Ab repertoire of healthy adults

project_abstract:
Project Summary AbstractAntibodies (Abs) are a diverse family of proteins expressed by B cells and are critical components of theadaptive immune system. They are encoded by hundreds of genes at three primary immunoglobulin (IG) generegions: the IG heavy chain (IGH) locus and two light chain loci IG kappa (IGK) and IG lambda (IGL). TheIGH locus in particular has been demonstrated by us and others to exhibit extreme genetic variability at boththe individual and population levels. This extreme variation is characterized by the occurrence of singlenucleotide polymorphisms (SNPs) as well as large insertions deletions and duplications spanning tens ofthousands of kilobases and resulting in losses or gains of functional genes (copy number variants CNVs).Given its inherent locus sequence complexity and extreme genetic diversity IGH remains a difficult genomicregion to study thus little is known about the effects of IGH genetic polymorphism on the function of Abs andthe associated effects on disease pathologies and treatment outcomes. However with the advent of high-throughput sequencing approaches for profiling the expressed Ab repertoire it has become increasingly clearthat IGH genetic variants including coding and non-coding SNPs as well as CNVs likely play a role in thedeveloping Ab response and may contribute to Ab biases observed in many disease contexts. This includesexamples in cancer autoimmunity infectious disease and vaccine responsiveness. These data stronglysupport the idea that not all individuals are poised to mount the same Ab response and that this at least inpart can be attributed to IGH genetic determinants. With this in mind we propose that the integration of locus-wide IGH population genetic data can inform our understanding of the functional B cell response in diseaseprocesses and help direct better clinical care such as the design of more effective therapeutic andprophylactic strategies. However no study to date has sought to comprehensively survey IGH variants locus-wide and identify key polymorphisms contributing to variability in the expressed Ab repertoires of healthyadults. Critically for such an approach to be successful new genomic tools are required that are capable ofovercoming pitfalls associated with current approaches and that allow for the comprehensive assaying of IGHvariants locus-wide. The proposed project will seek to demonstrate the utility of novel IGH genotyping methodsto comprehensively characterize for the first time associations between germline IGH haplotype variation andsignatures in expressed antibody repertoires of healthy adult subjects. This project will yield basic insights intothe effects of IGH polymorphisms on inter-individual Ab repertoire variation with implications for the discoveryof novel genomic factors and molecular mechanisms influencing Ab repertoire development and diversity. Inaddition this work will lay a foundation for the future integration of IGH genomics into immunological studiesseeking to more fully characterize the Ab response in disease and clinical phenotypes.

project_terms:
Adaptive Immune System;Adult;Age;Alleles;Antibodies;Antibody Repertoire;Antibody Response;Antigens;Autoimmunity;B-Lymphocytes;Biological Assay;Code;Collection;Communicable Diseases;Complex;Copy Number Polymorphism;Data;Data Set;Development;Disease;Exhibits;Foundations;Frequencies;Future;Gene Dosage;Genes;Genetic;Genetic Determinism;Genetic Polymorphism;Genetic Recombination;Genetic Variation;Genome;Genomic Segment;Genomics;Genotype;Goals;Haplotypes;Health Status;Heavy-Chain Immunoglobulins;Heritability;High-Throughput Nucleotide Sequencing;Human;Human Genome;IGH@ gene cluster;IgE;Immune response;Immunogenetics;Immunoglobulin A;Immunoglobulin Class Switching;Immunoglobulin D;Immunoglobulin G;Immunoglobulin Genes;Immunoglobulin M;Immunoglobulin Somatic Hypermutation;Immunoglobulins;Immunologics;Immunology;Individual;Knowledge;Light;Malignant Neoplasms;Mediating;Methods;Mind;Molecular;Nucleic Acid Regulatory Sequences;Outcome;Pathology;Pattern;Play;Population;Population Genetics;Process;Protein Family;Proteins;Protocols documentation;Publishing;Recording of previous events;Regulatory Element;Resolution;Role;Single Nucleotide Polymorphism;Structure;Surveys;Technology;Time;Treatment Efficacy;Treatment outcome;Twin Multiple Birth;Untranslated RNA;Vaccines;Variant;Work;analysis pipeline;base;bioinformatics pipeline;clinical care;clinical phenotype;cohort;complementarity-determining region 3;design;disease phenotype;functional gain;genetic association;genetic variant;genomic tools;improved;insertion/deletion mutation;insight;inter-individual variation;interest;kappa-Chain Immunoglobulins;novel;personalized medicine;population based;prophylactic;response;statistics

public_health_relevance:
Individual immune responses are known to track with signatures in the expressed antibody (Ab) repertoirewhich we and others have recently demonstrated robustly associate with genetic variants in theimmunoglobulin heavy chain locus (IGH); we propose that such findings have broad implications. Here weapply novel genomic tools to leverage long-read sequencing for comprehensive IGH genotyping which we useto characterize IGH variants with impacts on Ab repertoire variability in a multi-ethnic healthy adult population.This project will have outcomes with transformative impacts on B cell immunology and immunogenetics.


application_id: 9822213
project_number: 3R01AG026307-12S1
project_title: Self-Regulation and Brain and Cognitive Health in Older Adults - Diversity Supplement
administering_ic: NIA
award_notice_date: 2018-11-30
opportunity_number: PA-18-906
application_type: 3
activity_code: R01
ic: AG
serial_number: 026307
suffix: S1
program_official: NIELSEN, LISBETH
project_start_date: 2006-07-15
project_end_date: 2021-03-31
contact_pi_person_id: 1886687
contact_pi: SEGERSTROM, SUZANNE C.
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Age;Aging;Alzheimer's Disease;Alzheimer's disease risk;Behavior;Brain;Cognitive;Complement;Development;Elderly;Emotions;Episodic memory;Failure;Goals;Health;Hippocampus (Brain);Image;Impaired cognition;Informal Social Control;Knowledge;Longevity;Maintenance;Measures;Mediating;Motivation;Neurocognitive;Outcome;Pathway interactions;Patient Self-Report;Personality Traits;Physical activity;Process;Psychoneuroimmunology;Research;Role;Testing;Time;Work;brain health;coping;cytokine;dementia risk;emotion regulation;executive function;heart rate variability;inflammatory marker;interest;neuroimaging;parent grant;prospective;socioeconomics;success


application_id: 9822147
project_number: 5R01AG049806-05
project_title: The effects of exercise on satellite cell dynamics during aging
administering_ic: NIA
award_notice_date: 2019-11-29
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AG
serial_number: 049806
program_official: WILLIAMS, JOHN
project_start_date: 2016-01-01
project_end_date: 2021-02-28
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: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
AbstractA key determinant of geriatric frailty is sarcopenia the age-associated loss of skeletal muscle mass andstrength. Although the etiology of sarcopenia remains to be determined studies in humans and rodents havereported a strong correlation between the loss and/or dysfunction of satellite cells and sarcopenia. Despite thecorrelation between declining satellite cell-dependent regenerative capacity and age no studies to date havedirectly tested this relationship to determine if the loss of satellite cells causes sarcopenia. To test this idea wedepleted (>85%) satellite cells in five month old mice to a level dramatically lower than that observed withnormal aging. A detailed analysis of multiple muscles through 24 months of age revealed that despitesignificantly reduced regenerative capacity the life-long depletion of satellite cells did not accelerate norexacerbate sarcopenia; however the depletion of satellite cells at a young age was associated with asignificant increase in fibrosis in old mice. These highly provocative findings together with our data on thefiber-type specific role of satellite cells in response to exercise reveal our limited understanding of how agingaffects the function of satellite cells in skeletal muscle maintenance the development of fibrosis and inresponse to a growth stimulus; addressing these fundamental gaps in our knowledge clearly requires newtools. Towards this end we will utilize a novel mouse strain (Pax7-H2B-GFP) that will allow us to track satellitecell dynamics for the first time in adult skeletal muscle aging. To better understand how aging and exerciseaffects satellite cell dynamics and the regulation of fibrosis the following aims will be pursued: 1) determinehow age and life-long exercise affects satellite cell dynamics in the maintenance of skeletal muscle 2)determine how age and life-long exercise affects satellite cell regulation of fibrosis and 3) determine how ageaffects satellite cell dynamics in response to a growth stimulus. The approaches described herein usepowerful new genetic tools to determine how aging and life-long exercise alters the function of satellite cells inskeletal muscle homeostasis regulation of fibrosis and adaptability. The development of the Pax7-H2B-GFPmouse represents a long sought-after method for tracking satellite cells especially following fusion into themyofiber. This novel mouse strain will allow us to address formally intractable questions regarding how satellitecell dynamics are affected by age and life-long exercise. Such fundamental knowledge is necessary to criticallyevaluate the therapeutic value of satellite cells for the treatment of muscle mass loss and function associatedwith aging.

project_terms:
Ablation;Address;Adult;Affect;Age;Age-Months;Aging;Biological Assay;CD34 gene;Cell Nucleus;Cell physiology;Cells;Coculture Techniques;Collagen;Data;Development;Disease;Elderly;Environment;Etiology;Exercise;Expression Profiling;Fiber;Fibroblasts;Fibrosis;Functional disorder;Gastrocnemius Muscle;Genes;Genetic;Goals;Growth;Homeostasis;Human;Hypertrophy;Immunohistochemistry;Individual;Integrins;Intervention;Knock-out;Knowledge;Label;Life;Longevity;Maintenance;Measures;Mediating;Methods;MicroRNAs;Modeling;Mouse Strains;Mus;Muscle;Muscle Fibers;Nucleosomes;Outcome;Phase;Phenotype;Physical activity;Production;Proteins;Publishing;Quality of life;Regulation;Reporter;Reporting;Research;Rodent;Role;Running;Skeletal Muscle;Skeletal Muscle Satellite Cells;Stimulus;Testing;Therapeutic;Time;Untranslated Regions;base;exosome;experimental study;extracellular;falls;frailty;improved;loss of function;muscle aging;muscle form;muscle hypertrophy;muscle strength;normal aging;novel;p38 Mitogen Activated Protein Kinase;progenitor;regenerative;response;sarcopenia;satellite cell;sedentary;senescence;skeletal muscle growth;skeletal muscle wasting;stem cells;tool

public_health_relevance:
RelevanceA hallmark of aging in humans is the progressive loss of skeletal muscle mass and strength which is known tohave a negative impact on an individual's quality of life by robbing them of their daily independence as well asincreasing the occurrence of falls and other diseases. The primary goal of the proposed research is tounderstand how stem cell dynamics change with age how stems cells influence the muscle environment andthe impact of exercise on satellite cell function during aging. This knowledge is required to evaluate thetherapeutic potential of these cells to treat the loss of skeletal muscle mass and fucntion duirng aging.


application_id: 9821197
project_number: 5R01AT008617-05
project_title: Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms
administering_ic: NCCIH
award_notice_date: 2019-11-21
opportunity_number: PAR-13-375
application_type: 5
activity_code: R01
ic: AT
serial_number: 008617
program_official: KIM, HYE-SOOK
project_start_date: 2015-12-01
project_end_date: 2022-07-19
study_section: Special Emphasis Panel[ZRG1-EMNR-V(55)R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
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:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the role of edible plant exosomal non-coding small RNA (nc-sRNA) in the prevention of gut inflammation using the dextran sulfate sodium (DSS) induced colitis and three other gut inflammatory related mouse models. Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet the evidence that specific plant-based supplements are beneficial is controversial and the underlying mechanisms are not clear. The challenge is to isolate and characterize the biological activities of the essential functional unit contained in specific naturl products to determine if and how it's cellular and molecular effects on the host can be used in a beneficial manner. Our recently published data (1-5) indicates that exosome-like nanoparticles (ELNs) present in a number of edible plants including grapefruit and ginger have anti-inflammatory properties. Mice fed grapefruit ELNs (FELNs) are protected against DSS induced mouse colitis. Up take of FELNs by intestinal macrophages inhibits the release of IL-1 and IL-6 and the induction of HO-1 and IL-10 expression. Our preliminary data further indicate that FELNs carry high levels of specific nc-sRNA that inhibit the induction of proinflammatory cytokines by targeting intestinal macrophages. The nc-sRNA is associated with inactivation of macrophage miR155. A specific FELN nc-sRNA complexed with naringin binds to miR155 and subsequently prevents miR155 binding to 3-UTRs of certain anti-inflammatory genes thus inhibiting the induction of proinflammatory cytokines. We have also demonstrated that ginger ELN nc-sRNAs promotes the production of IL-10 in lamina propria macrophages under steady-state as well as inflammatory conditions. Therefore we hypothesize that plant ELNs carrying the nc-sRNA bioactive complex are taken up by intestinal macrophages and subsequently bind to inflammatory microRNAs resulting in inhibition of induction of chronic inflammation cytokines thereby preventing chronic intestinal inflammation. Our hypothesis will be tested in vitro and in vivo to determine: (1) whether FELN taken up by intestinal macrophages leads to induction of tolerant dendritic cells (DCs) through nc-sRNA-155 mediated anti-inflammatory effects since DCs are critical for gut immune tolerance and homeostasis through cross-talk with intestinal macrophages; (2) the factors that regulate sorting of anti-inflammatory nc-sRNA-155 into macrophage exosomes; and (3) which ginger ELNs nc-sRNA(s) are required for induction of anti- inflammatory IL-10 expressed in macrophages. Demonstration of the ELNs complex targeting to gut inflammatory cells would be a significant step forward in the understanding of how the plant kingdom interacts with the mammalian species to regulate anti-inflammatory responses through ELNs. The data generated should provide a foundation for selecting specific ELNs from different types of plants for personalized complementary medicine for patients and determine whether oral administration of a customized exosome isolated from different plants will have a synergistic/additive effect on prevention or treatment of disease.

project_terms:
Anti-Inflammatory Agents;Antigens;Antiinflammatory Effect;Bacteria;Binding;Biological;Cells;Chronic;Colitis;Communication;Complementary Medicine;Complex;Crohn's disease;Custom;Data;Dendritic Cells;Diet;Disease;Edible Plants;Encapsulated;Escherichia;Escherichia coli;Exposure to;Food;Foundations;Genes;Ginger;Goals;Grapefruit;Gut Mucosa;Health;Homeostasis;Immune;Immune Tolerance;Immune response;In Vitro;Inflammation;Inflammatory;Inflammatory Response;Ingestion;Interleukin-1;Interleukin-1 beta;Interleukin-10;Interleukin-6;Intestines;Investigation;Lamina Propria;Lipids;Literature;Macrophage Activation;Mediating;MicroRNAs;Modeling;Molecular;Mononuclear;Mus;Myeloid Cell Activation;Natural Products;Oral Administration;Pathway interactions;Patients;Phagocytes;Plant Extracts;Plants;Play;Prevention;Production;Property;Proteins;Publishing;RNA;RNA Binding;Role;Sampling;Signal Transduction;Small RNA;Sodium Dextran Sulfate;Sorting - Cell Movement;Study models;TNF gene;Testing;Untranslated RNA;Untranslated Regions;base;bioactive natural products;cytokine;dextran sulfate sodium induced colitis;exosome;experimental study;fruits and vegetables;gut bacteria;in vitro testing;in vivo;inflammatory disease of the intestine;interspecies communication;lymph nodes;macrophage;mouse model;nanoparticle;prevent;public health relevance;transcription factor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet molecule mechanisms underlying beneficial of edible plants and extracts for sustaining health is not clear. The studies that we have accomplished to date suggest that edible plant exosome-like nanoparticles encapsulated with non-coding small RNAs that binds to miRNAs prevent mouse colitis- standard mouse models for studying Crohn's disease. The focus of this application is to further characterize these mechanisms and then to determine whether targeting of these mechanisms is through communication with different subsets of miRNAs expressed in the intestinal macrophages and this will also allow for further investigations as to how interspecies communication takes place via plant derived exosomes.


application_id: 9820726
project_number: 5R01DC014468-05
project_title: In vivo patterns of receptor activation by odorants
administering_ic: NIDCD
award_notice_date: 2019-11-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DC
serial_number: 014468
program_official: SULLIVAN, SUSAN L
project_start_date: 2015-12-01
project_end_date: 2022-11-30
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 1883753
contact_pi: MCCLINTOCK, TIMOTHY S
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)  This project uses a new in vivo assay that allows the identification of the odorant receptors activated in live mice by any odor making it possible to identify in one experiment many receptors activated by the odor. This accelerates the identification of receptors sensitive to any odor and when combined with in vitro assays for the function of individual odorant receptors allows testing of hypotheses about the sets of receptors activated by odorants and odor mixtures. The first aim targets a specific region of the broad universe of odorants testing whether the overlap in sets of receptors responsive to these odorants depends on their structural similarity. The second aim tests hypotheses about the possible interactions between odorants at odorant receptors. It begins with pairs of odorants that are known or suspected of interacting mostly by the ability of one odorant to block activation of one or more receptors by another odorant. It then moves on to testing more complex mixtures seeking to identify interactive effects between odorants at receptors - effects that are fundamental to the characteristic sensation of the odor and the discrimination of one odor from another. In addition to improving our understanding of the mechanisms of odor perception these experiments provide knowledge expected to facilitate the development of more sophisticated ways of manipulating odor environments to benefit the quality of human life.

project_terms:
Alcohols;Biological Assay;Breathing;Carboxylic Acids;Characteristics;Chemicals;Code;Color;Complex;Complex Mixtures;Data;Detection;Development;Discrimination;Environment;Esthesia;Face;Hearing;Human;Individual;Ketones;Knowledge;Lead;Learning;Life;Ligands;Mammals;Mus;Nature;Odorant Receptors;Odors;Pattern;Perception;Pest Control;Pharmacology;Prevalence;Problem Solving;Receptor Activation;Receptor Cell;Smell Perception;Structure;Testing;Time;Vision;experimental study;improved;in vitro Assay;in vivo;novel strategies;public health relevance;receptor;sensor;stem;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE  The array of sensors for odors is composed of hundreds of distinct odorant receptors in most mammals but which of these receptors respond to the thousands of odor chemicals is virtually unknown making it difficult to understand how we detect and discriminate odors. This project uses a newly developed novel strategy to identify the sets of receptors responsive to any odor we choose to test. This information will help us understand how we discriminate odors as well as lay the groundwork for developing pharmacological agents for altering odor detection a direction that should lead to improved flavors and fragrances blockers of noxious smells and even improved pest control.


application_id: 9820153
project_number: 1R24ES030904-01
administering_ic: NIEHS
award_notice_date: 2020-05-05
opportunity_number: RFA-ES-18-009
application_type: 1
activity_code: R24
ic: ES
serial_number: 030904
program_official: GRAY, KIMBERLY A
project_start_date: 2020-05-06
project_end_date: 2025-04-30
study_section: Special Emphasis Panel[ZES1 VSM-K (R)]
contact_pi_person_id: 7102409
contact_pi: HAYNES, ERIN N
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-05-06
project_terms:
Adolescent;Adult;Age;Air;Anatomy;Applications Grants;Biological;Biological Markers;Blood;Brain;Caregivers;Chemistry;Chicago;Child;Childhood;Cohort Studies;Collaborations;Communities;Community Developments;Data;Data Management Resources;Data Set;Development;Dust;Environmental Epidemiology;Environmental Exposure;Environmental Health;Environmental Impact;Equipment and supply inventories;Etiology;Evaluation;Exposure to;Funding;Grant;Growth and Development function;Hair;Home environment;Illinois;Infrastructure;Knowledge;Lab-On-A-Chips;Laboratories;Longevity;Magnetic Resonance Imaging;Maintenance;Manganese;Measurement;Measures;Metals;Methods;Motor;National Institute of Environmental Health Sciences;Neuroanatomy;Neurodevelopmental Deficit;Neuropsychology;Ohio;Outcome;Parents;Participant;Pediatric cohort;Pediatric epidemiology;Physiology;Play;Police;Population;Psychosocial Factor;Reporting;Research;Resources;Role;Saliva;Scientific Advances and Accomplishments;Scientist;Serum;Side;Soil;Structure of nail of toe;Time;Training;United States;Urine;Whole Blood;biobank;cohort;data management;data sharing;deciduous tooth;early childhood;improved;innovation;neurodevelopment;next generation;novel;participant retention;point of care;preservation;primary caregiver;research study;sensor;toxicant;water sampling


application_id: 9818438
project_number: 1R01CA247365-01A1
project_title: Chemical Biology of the Control of Neddylation by DCN1
administering_ic: NCI
award_notice_date: 2019-06-19
opportunity_number: PA-18-484
application_type: 1
activity_code: R01
ic: CA
serial_number: 247365
suffix: A1
program_official: FU, YALI
project_start_date: 2019-07-01
project_end_date: 2024-06-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 6620313
contact_pi: GUY, RODNEY KIPLIN
other_pis: SCHULMAN, BRENDA A;SINGH, BHUVANESH
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
3q26;Acetylation;Affinity;Amines;Amino Acids;Animals;Automobile Driving;Binding;Bioavailable;Biochemical;Biological;Biological Availability;Biological Process;Biology;Bromodomain;C-terminal;CUL1 gene;CUL3 gene;CUL5 gene;Cell Nucleus;Cells;Charge;Chemicals;Clinical;Complex;Contact Inhibition;Cullin Proteins;Cytosol;Data;Development;Disease;Disease Progression;Drug Targeting;Enzymes;Excretory function;Family member;Foundations;Generations;Genetic;Genetic Models;Goals;Growth Factor;Health;Homeostasis;Human;Hydrophobicity;Immune System Diseases;In Vitro;Ligase;Ligation;Lysine;Malignant Neoplasms;Mammals;Measures;Mediating;Metabolism;Methionine;Modeling;Molecular;Mus;N-terminal;Names;Nature;Oncogenes;Oncoproteins;Oral;Pathway interactions;Pattern;Pharmaceutical Chemistry;Pharmacodynamics;Pharmacology;Phenotype;Post-Translational Protein Processing;Process;Proteasome Inhibitor;Protein Isoforms;Proteins;RBX1 gene;Regulation;Reporting;Research Design;Research Methodology;Role;Sequence Homology;Side;Signal Transduction;Squamous cell carcinoma;Structure;Substrate Specificity;System;Testis Brain;Tissues;Toxic effect;Ubiquitin;Ubiquitin Like Proteins;Ubiquitin family;Ubiquitination;antitumor drug;base;cancer therapy;clinically significant;combinatorial;drug discovery;improved;in vivo;inhibitor/antagonist;knock-down;malignant phenotype;novel therapeutics;pre-clinical;receptor;response;small molecule;spatiotemporal;success;three dimensional cell culture;tool;tumor;tumor progression;ubiquitin ligase;ubiquitin-protein ligase


application_id: 9817680
project_number: 5R21AI142063-02
project_title: Inhibition of GSDMD as a new treatment for infection
administering_ic: NIAID
award_notice_date: 2019-11-05
opportunity_number: PA-18-489
application_type: 5
activity_code: R21
ic: AI
serial_number: 142063
program_official: MINNICOZZI, MICHAEL
project_start_date: 2018-11-05
project_end_date: 2020-10-31
study_section: Special Emphasis Panel[ZRG1-IDM-Y(82)S]
contact_pi_person_id: 10386925
contact_pi: WEI, YINAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Sepsis plagues 19 million per year globally with a mortality rate of ~ 30% resulting in ~ five milliondeaths every year. Sepsis is caused by a dysregulated host response to infection. Over reactionof the immune system upon detection of the invasion of microbes triggers inflammatory reactionthe excessive reaction of which eventually lead to multiple organ failure and patient death.Pyroptosis is a form of programmed cell death in the immune response signaling pathway duringinfection. The detection of microbe invasion triggers the activation of the inflammatory caspaseswhich cleaves the linker between the N-terminal (NT) and C-terminal (CT) domains of the effectorprotein gasdermin D (GSDMD). This cleavage lifts the auto-inhibition of the GSDMD CT domainon the NT domain which subsequently binds to the inner leaflet of the cell membraneoligomerizes and forms pores that are large enough for inflammatpry cytokines such as IL-1 tobe released and trigger downstream responses. Studies have shown that GSDMD is the sole anddirect effector of pyroptosis and deletion of the GSDMD gene significantly improved the survivalrate in a murine sepsis model. Therefore we hypothesize that small molecule inhibitors thatdisrupt GSDMD function can effectively alleviate negative effects of pyroptosis on septicpatient and thus improve the outcome of sepsis treatment. To search for GSDMD inhibitorswe will pursue three specific aims to develop assays and validate them through screening a smallcollection of compounds. Aim 1. To develop an assay to identify compounds that strengthenGSDMD auto-inhibition. Aim 2. To develop an assay to identify compounds that prevent GSDMDinteraction and pore-forming in membrane. Aim 3. To screen a small collection of compounds tovalidate and optimize assays. In preliminary studies we established that the GSDMD is atractable target. In addition we have engineered several GSDMD constructs and developedseveral novel methods and primitive assays which established the feasibility of the proposedapproach. Outcomes of the proposed study include the establishment of useful assays for HTSand identification of a collection of active compound structures. In the next stage at the conclusionof this exploratory/developmental R21 project we will seek additional funding and collaborationto test a larger number of compounds and develop medicinal chemistry and biology componentsto further test and develop identified compounds. It is our expectation that novel classes ofinhibitors binding to original target sites on GSDMD to prevent its pore-forming activity will beidentified which will lead to the development of new anti-infection therapeutics.

project_terms:
Apoptosis;Binding;Biological Assay;Biology;C-terminal;Caspase;Cell membrane;Cells;Cessation of life;Chemicals;Cleaved cell;Collaborations;Collection;Data;Detection;Development;Digestion;Dissociation;Engineering;Extravasation;FDA approved;Fluorescence;Funding;Genes;Immune response;Immune system;Infection;Inflammation;Inflammatory;Interleukin-1 beta;Lead;Length;Libraries;Lifting;Lipid Bilayers;Membrane;Methods;Microbe;Modeling;Morbidity - disease rate;Multiple Organ Failure;Mus;N Domain;N-terminal;Outcome;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Process;Proteins;Protocols documentation;Reaction;Research Project Grants;Ribosomes;Sepsis;Signal Pathway;Signal Transduction;Site;Structure;Survival Rate;Testing;Therapeutic;base;cytokine;driving force;expectation;high throughput screening;immune activation;immunoreaction;improved;improved outcome;inhibitor/antagonist;mortality;novel;prevent;protein expression;protein purification;response;screening;septic patients;small molecule inhibitor;tissue culture

public_health_relevance:
Project NarrativeCumulative data indicate that excessive activation of the immune response is a majordriving force for morbidity and mortality in sepsis. Pyroptosis a component of immuneresponse relies on the function of gasdermin D (GSDMD). This research project seeksto develop and validate assays to identify inhibitors of GSDMD and thus block thepyroptosis cascade.


application_id: 9816337
project_number: 2R01EY024173-06A1
project_title: Parallel Tectothalamic Pathways
administering_ic: NEI
award_notice_date: 2019-09-16
opportunity_number: PA-18-484
application_type: 2
activity_code: R01
ic: EY
serial_number: 024173
suffix: A1
program_official: FLANDERS, MARTHA C
project_start_date: 2014-09-02
project_end_date: 2022-09-29
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
Summary/AbstractThe proposed experiments are designed to examine how sensory selectivity is adjusted to initiate appropriatebehavior. In mice two fundamental visually-evoked behaviors freezing and escape are initiated respectivelyby the movement of a small disc that moves slowly across the visual field (sweeping) or a disc that rapidlyexpands to fill the visual field (looming). However the synaptic interactions that mediate the selection of thesevisually-evoked responses are largely unknown. In the superior colliculus (SC) wide field vertical (WFV) cellsrespond to sweeping or looming stimuli and project to the thalamic pulvinar nucleus (PUL) a brain regioninvolved in the initiation of visually-guided behavior. WFV cells receive input from the retina and V1 intrinsicSC neurons and the parabigeminal nucleus (PBG). Based on previous studies of the avian nucleus isthmi(considered the PBG homologue) we hypothesize that SC-PBG connections gate the responses of WFV cellsto their retinal input and this stimulus selection network determines the subsequent initiation of appropriatebehavioral responses. We propose to examine SC-PBG circuits in detail and test whether manipulating theiractivity can shift the responsiveness of WFV cells alter PUL responses to sweeping and looming stimuli orimpact the initiation of visually-evoked freezing and escape behavior. We will study this system at multiplelevels from the ultrastructure of synapses to behavioral assessments using an array of innovative strategiesto examine circuit function with cell type specificity. The specific goals of the proposed experiments are: tocharacterize the ultrastructure of synaptic input to WFV cells and synaptic connections that link the SC andPBG (Aim 1a) test how optogenetic activation of the synaptic connections between the SC and PBG affect theresponsiveness of WFV and PBG cells (Aim 1b) determine whether PUL receptive field properties differbased on their unique responses to WFV cell input (Aim 2a) test whether PUL responses are altered bymanipulating SC-PBG circuits (Aim 2b) and determine if chemogenetic manipulation of SC-PBG pathwaysaffects visually-evoked freezing or escape responses (Aim 3). We believe that this integrated approach canaddress how sensory selectivity is adjusted to initiate appropriate behavior while providing the precision ofsingle cell circuit analysis.

project_terms:
Address;Affect;Animals;Axon;Behavior;Behavior assessment;Bilateral;Birds;Brain;Brain region;Cell Nucleus;Cells;Disease;Dyslexia;Electric Stimulation;Electrodes;Electrons;Evaluation;Freezing;Frequencies;Glutamates;Goals;Head;Homologous Gene;In Vitro;Knowledge;Link;Mammals;Measures;Mediating;Methods;Microscopic;Midbrain structure;Motion;Motion Perception;Motor;Movement;Mus;Neurons;Output;Pathway interactions;Pattern;Property;Pulvinar structure;Reaction;Retina;Retinal;Running;Schizophrenia;Sensory;Signal Transduction;Slice;Specificity;Stimulus;Synapses;System;Techniques;Testing;Thalamic structure;Visual;Visual Fields;Visual Motion;Visual Pathways;Work;autism spectrum disorder;base;behavioral response;brain circuitry;cell type;design;experimental study;innovation;optical fiber;optogenetics;photoactivation;receptive field;response;superior colliculus Corpora quadrigemina;visual motor;visual stimulus

public_health_relevance:
Project Narrative The results of these experiments will significantly enhance our understanding of the braincircuitry underlying visual motion perception thus providing information relevant to the treatment ofdisorders in which visual motion processing is compromised such as dyslexia and schizophrenia. Inaddition the results of these experiments will enhance our understanding of subcortical visualpathways which may be altered in autism spectrum disorder.


application_id: 9814889
project_number: 2R01DE011111-26A1
project_title: P. gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2019-06-05
opportunity_number: PA-18-484
application_type: 2
activity_code: R01
ic: DE
serial_number: 011111
suffix: A1
program_official: MELILLO, AMANDA A
project_start_date: 1995-04-01
project_end_date: 2024-06-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Apoptosis;Bacteria;Binding;Biological;Cell Proliferation;Cell Survival;Cells;Characteristics;Communities;Community Actions;Complex;Disease;Effector Cell;Epithelial;Epithelial Cells;Exhibits;FOXO1A gene;Fusobacterium nucleatum;Genetic Transcription;Gingiva;Grant;Homeostasis;Human;Immune;Immune response;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-1 beta;Interleukin-6;Maintenance;Modeling;Molecular;Mouth Diseases;Mucous Membrane;Oral;Organism;Outcome;Pathologic;Pathway interactions;Periodontitis;Physiological;Porphyromonas gingivalis;Post-Translational Protein Processing;Process;Production;Property;Protein Dephosphorylation;Regulation;Role;Serine;Signal Pathway;Signal Transduction;Site;Specificity;Streptococcus;Streptococcus gordonii;Streptococcus oralis;Surface;Tissues;alveolar bone;beta catenin;bone metabolism;dysbiosis;immunological status;in vivo;microbial;microorganism;microorganism interaction;mouth squamous cell carcinoma;novel;oral bacteria;oral streptococci;periodontopathogen;programs;promoter;recruit;response;therapy design;transcription factor


application_id: 9813698
project_number: 1R03CA235171-01A1
administering_ic: NCI
award_notice_date: 2019-07-31
opportunity_number: PAR-18-021
application_type: 1
activity_code: R03
ic: CA
serial_number: 235171
suffix: A1
program_official: LEE, CECILIA H
project_start_date: 2019-08-01
project_end_date: 2021-07-31
study_section: Special Emphasis Panel[ZCA1 TCRB-Q (M2)]
contact_pi_person_id: 11642450
contact_pi: MCLOUTH, LAURIE
other_pis: Not Applicable
congressional_district: 06
department: PSYCHIATRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_title:
Piloting Pathways a Hope-Enhancing Intervention to Address Activity and Role Function in Metastatic Lung Cancer Patients

project_abstract:
Project SummaryLung cancer is the second most commonly diagnosed cancer and leading cause of cancer death among menand women in the U.S. Nearly 90000 people will be diagnosed with metastatic non-small cell lung cancer(NSCLC) this year representing 40% of lung cancers. One of the more distressing consequences of metastaticNSCLC to patients is its effect on their participation in daily activities and roles. Between 40-65% of lungcancer patients report that impairment in their daily activities and roles is a top unmet supportive care need.This care gap is reflected in existing interventions which do not directly address function and are not wellintegrated into primary oncologic care. The overall goal of this research is to address this care gap byimplementing a supportive care intervention to help address activity and role function concerns in primaryoncologic care. Our research suggests that intervening on patient hope which reflects agency for pursuinggoals and identifying pathways to pursue goals may be a promising approach to address activity and rolefunction concerns in metastatic NSCLC patients. Informed by our preliminary data our multidisciplinary teamhas adapted a hope-enhancing intervention for use with metastatic NSCLC patients in primary oncologic care.The intervention called Pathways is based in Hope Theory and comprised of 5 sessions designed to helppatients identify meaningful and feasible goals to pursue and increase patient agency and pathways forpursuing goals in the presence of likely disease obstacles including lung cancer stigma. The intervention isdelivered by a nurse with training in supportive care through in-person and phone sessions. The researchproposed in this application will evaluate the feasibility of Pathways. In Aim 1 we will refine Pathways bypiloting it with 6 metastatic NSCLC patients and conducting interviews with them to evaluate its acceptabilityand gather suggestions for aspects that need to be improved. Our multidisciplinary team will review theinformation from Aim 1 and refine Pathways. Then in Aim 2 we will test the feasibility (patient accrualadherence retention patient acceptability ratings) of Pathways with 20 metastatic NSCLC patients and assesspre-post changes in hope cancer-related goal interference and outcome measures related to function anddistress. Results of this study will determine the feasibility of a nurse-delivered hope-enhancing intervention toimprove function in activities and roles in metastatic NSCLC patients and provide preliminary data to inform arandomized controlled trial of efficacy of the intervention.

project_terms:
Address;Adherence;Cancer Etiology;Cancer Patient;Caring;Cessation of life;Clinic;Comorbidity;Data;Diagnosis;Disease;Distress;Electronic Health Record;Enrollment;Etiology;Family;Feedback;Future;Goals;Impairment;Infusion procedures;Intervention;Intervention Studies;Interview;Leisure Activities;Length;Life;Malignant Neoplasms;Malignant neoplasm of lung;Mental Depression;Motivation;Non-Small-Cell Lung Carcinoma;Nonmetastatic;Nurses;Outcome;Outcome Measure;Palliative Care;Pathway interactions;Patient Preferences;Patients;Persons;Pilot Projects;Procedures;Protocols documentation;Randomized Controlled Trials;Reporting;Research;Research Personnel;Resources;Role;Smoking;Social Work;Stigmatization;Suggestion;Supportive care;Symptoms;Telephone;Testing;Thoracic Oncology;Training;Treatment Efficacy;Treatment Side Effects;Woman;Work;arm;base;cancer care;cancer diagnosis;cancer therapy;care delivery;clinical practice;design;efficacy testing;efficacy trial;evidence base;improved;improved functioning;innovation;interest;men;multidisciplinary;novel;oncology;outcome forecast;patient oriented;patient-level barriers;preference;public health relevance;social stigma;symptom treatment;theories;therapy design

public_health_relevance:
Public Health RelevanceMaintaining participation in valued daily activities and life roles is of paramount concern to the 90000 peoplewho are diagnosed with metastatic lung cancer each year in the U.S. but current clinical practice in primaryoncology does not address this significant patient concern. To address this care gap we will pilot a nurse-delivered intervention Pathways that helps patients identify and pursue meaningful goals related to dailyactivities and roles. Findings from this study will provide data on the feasibility of a patient-centeredintervention designed to overcome patient barriers and align with oncology clinic work flow.


application_id: 9812867
project_number: 1R15DA047610-01A1
project_title: Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine
administering_ic: NIDA
award_notice_date: 2019-05-24
opportunity_number: PA-18-504
application_type: 1
activity_code: R15
ic: DA
serial_number: 047610
suffix: A1
program_official: MOORE, HOLLY MARIE
project_start_date: 2019-06-01
project_end_date: 2023-05-31
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 11434612
contact_pi: YATES, JUSTIN RYAN
other_pis: Not Applicable
congressional_district: 04
department: PSYCHOLOGY
primary_duns: 072879760
primary_uei: LN53C9E23GH6
duns_number: 072879760
uei: LN53C9E23GH6
fips: US
organization_id: 656601
organization_name: NORTHERN KENTUCKY UNIVERSITY
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 410990001
organization_country: UNITED STATES
project_abstract:
Project Summary/AbstractRisky choice is one facet of impulsivity that is observed in several psychiatric disorders including substanceuse disorders. Understanding the shared neurobiology of risk-taking behavior and drug abuse is important fordesigning effective pharmacotherapies for individuals that are at risk for developing substance use disorders.The neurotransmitter glutamate is considered to be involved in drug addiction and recent research has shownthat the N-methyl-D-aspartate (NMDA) glutamate receptor is involved in risky choice. Considering NR2B-selective antagonists lack the psychotomimetic side effects observed with NMDA receptor channelblockers (such as MK-801 and ketamine) these drugs may provide a novel therapeutic approach totreating individuals predisposed to engaging in risky behaviors. The NR2B subunit antagonist ifenprodil iseffective in blocking the rewarding effects of morphine an opiate that has high abuse potential. Becauseifenprodil has high affinity for adrenergic receptors additional research with highly selective NR2B subunitantagonists is needed to determine if this subunit is a potential molecular target for treating disorderscharacterized by excessive risk. The highly selective NR2B antagonist Ro 63-1908 decreases risky choice asmeasured in probability discounting in rats; however this effect is only observed when the probability ofobtaining a large reward increases across the session raising issues about the validity of this task to measurerisky choice. Thus the first goal of this proposal is to further elucidate the role of the NR2B subunit of theNMDA receptor in risky decision making by testing the effects of Ro 63-1908 in the risky decision task (RDT)in which rats choose between a small safe reward and a large risky reward (i.e. paired with foot shock).Using the RDT is ideal because performance in this task is predictive of cocaine self-administration. Thesecond goal is to determine if blocking NR2B-containing NMDA receptors is efficacious in attenuating cocaineself-administration in rats displaying increased risky choice. The third goal of the proposal is to determine ifcocaine exposure differentially alters NR2B subunit distribution (via receptor autoradiography) in high and lowrisk-taking rats and to determine if Ro 63-1908 can reverse cocaine-induced alterations in NR2B subunitdistribution.

project_terms:
Adrenergic Receptor;Affect;Affinity;Amygdaloid structure;Attenuated;Autoradiography;Behavior;Behavioral;Binding;Binding Sites;Brain region;Cocaine;Consumption;Data;Decision Making;Disease;Dose;Drug Addiction;Drug Targeting;Drug abuse;Drug usage;Economics;Elasticity;Female;Glutamate Receptor;Glutamates;Goals;Impulsivity;Individual;Individual Differences;Intercept;Ketamine;Ligands;Link;MK801;Measures;Medial;Mediating;Mental disorders;Modeling;Molecular Target;Morphine;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;N-methyl-D-glutamate;Neurobiology;Neurotransmitters;Nucleus Accumbens;Opioid;Performance;Pharmaceutical Preparations;Pharmacotherapy;Prefrontal Cortex;Price;Probability;Procedures;Psychological reinforcement;Rattus;Research;Rewards;Risk;Risk Behaviors;Risk-Taking;Role;Self Administration;Sex Differences;Shock;Substance Use Disorder;Substance abuse problem;Testing;Training;Withdrawal;behavior measurement;behavioral economics;channel blockers;cocaine exposure;design;discount;discounting;drug reinforcement;experimental study;flexibility;foot;high risk;ifenprodil;insight;male;molecular drug target;neuromechanism;novel;novel therapeutic intervention;prevent;psychostimulant;receptor;reinforcer;side effect;stimulant abuse

public_health_relevance:
Project NarrativeCurrently there are few treatments that are efficacious in treating individuals with co-morbid impulse-controland substance use disorders. The purpose of this research is to determine the role of the NR2B subunit of theglutamate N-methyl-D-aspartate (NMDA) receptor in risky decision making and psychostimulant reward. Theresults of the current proposal will be important because novel pharmacotherapies (e.g. drugs that target theNR2B subunit of the NMDA receptor) can be used to better treat those that engage in risky behaviors and/orhave substance use disorders.


application_id: 9812488
project_number: 1R15DK122547-01
administering_ic: NIDDK
award_notice_date: 2020-07-06
opportunity_number: PA-18-504
application_type: 1
activity_code: R15
ic: DK
serial_number: 122547
program_official: ZAGHLOUL, NORANN
project_start_date: 2020-07-07
project_end_date: 2024-06-30
study_section: Molecular and Cellular Endocrinology Study Section[MCE]
contact_pi_person_id: 11381044
contact_pi: ZERUTH, GARY T
other_pis: Not Applicable
congressional_district: 01
department: BIOLOGY
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-07-07
project_title:
Evaluation of endocrine pancreas development beta cell mass expansion and regeneration in glis3 mutant zebrafish

project_abstract:
Project SummaryThe endocrine pancreas is responsible for the production of several hormones including insulin important in theregulation of carbohydrate metabolism and glucose homeostasis. Both the development of the endocrine pancreas andits proper function within the context of the mature organ rely on networks of transcription factors that are not yet wellunderstood. Among these the Krppel-like protein Gli-similar 3 (Glis3) has been found to be important in thedevelopment of insulin-producing  cells and is essential for insulin transcription in adults. Currently little is known aboutthe specific roles Glis3 plays in pancreatic cell fate specification or its involvement in the postnatal expansion of  cellmass.In this proposal experiments are described intended to characterize pancreatic development and function in theglis3sa17645 mutant zebrafish line. Zebrafish homozygous for the glis3sa17645 allele (glis3-/-) ubiquitously lack glis3expression. In Specific Aim 1 we will characterize pancreatic development in glis3 knockout fish to determine whetherglis3 is required for the formation of endocrine progenitor cells or their subsequent specification to islet fates. Emphasiswill be placed on identifying the mechanisms that regulate islet maturation and mass expansion. The experimentsdescribed in Specific Aim 2 are designed to examine the role of glis3 in the expansion of  cell mass in adults respondingto nutrient excess. Finally in Specific Aim 3  cell regeneration will be studied in glis3 mutant zebrafish followingchemical ablation.The research described in this proposal will be conducted at a regional comprehensive university that serves apredominately rural economically underdeveloped community for whom access to scientific research is traditionallyrestricted. The research will be completed with extensive support from undergraduate researchers who will gain theopportunity to co-author manuscripts and present findings at local state and national meetings.Broadly the completion of the studies outlined in this proposal will increase our understanding of how Glis3 specifiesendocrine fates in the pancreas and may help shed light on how Glis3 mutations lead to diseases in humans includingdiabetes mellitus. Furthermore a greater understanding of the mechanisms that regulate pancreatic development is likelyto be achieved including a more thorough knowledge of the transcription factor networks that regulate  cell massexpansion and regeneration in zebrafish. Ultimately completion of the research described may lead to the establishmentof a complementary zebrafish model for the study of diabetes or other Glis3-related diseases.

project_terms:
Ablation;Adult;Alleles;Animal Model;Apoptosis;Architecture;B Cell Proliferation;Beta Cell;Blood Glucose;Cell Lineage;Cell Maturation;Cells;Chemicals;Communities;Complex;Conflict (Psychology);Coupled;Cretinism;Data;Defect;Development;Diabetes Mellitus;Disease;Dorsal;Duct (organ) structure;Ductal Epithelial Cell;Embryo;Endocrine;Evaluation;Event;Fishes;Generations;Genetic Techniques;Genetic Transcription;Goals;High Fat Diet;Hormones;Human;Hypothyroidism;Injury;Insulin;Islets of Langerhans;Knock-out;Knowledge;Kruppel-like transcription factors;Lead;Light;Mammals;Manuscripts;Mediating;Metabolic;Metabolic Diseases;Molecular;Mutation;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Organ;Pancreas;Pathology;Play;Polycystic Kidney Diseases;Process;Production;Proliferating;Proteins;Regulation;Research;Research Personnel;Rodent;Role;Rural;Specific qualifier value;Streptozocin;Structure of beta Cell of islet;Study models;Syndrome;Universities;Zebrafish;blood glucose regulation;carbohydrate metabolism;cell fate specification;cell regeneration;clinically significant;design;endocrine pancreas development;experimental study;functional loss;genome wide association study;glucose metabolism;islet;knock-down;meetings;mouse model;mutant;neonatal diabetes mellitus;notch protein;novel therapeutics;offspring;pancreas development;postnatal;programs;response;stem cells;transcription factor;type I and type II diabetes;undergraduate student;zebrafish development

public_health_relevance:
Project NarrativeGLIS3 mutations in humans are associated with a number of pathologies including polycystic kidney disease congenitalhypothyroidism and diabetes mellitus. In this project a zebrafish mutant deficient in glis3 is used as a model organism togain a better understanding of pancreatic development and function. Given the similarities between zebrafish and humanpancreas development the results of this study may eventually lead to the facilitation of novel therapies to treat diabetesand other metabolic diseases.


application_id: 9811889
project_number: 2R15HL120068-03
project_title: Fibrin Clot Architecture Regulated by Factor XIII
administering_ic: NHLBI
award_notice_date: 2019-07-08
opportunity_number: PA-18-504
application_type: 2
activity_code: R15
ic: HL
serial_number: 120068
program_official: WARREN, RONALD Q
project_start_date: 2013-08-05
project_end_date: 2023-07-31
study_section: Special Emphasis Panel[ZRG1 VH-N (80)]
contact_pi_person_id: 1912066
contact_pi: MAURER, MURIEL C.
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project SummaryFactor XIII is found in quite different locations including plasma (A2B2) the cellular (A2) of plateletsmegakaryocytes and monocytes and (A2) in bone extracellular matrix. Plasma FXIII A2B2 is activatedproteolytically by thrombin and low mM Ca2+ whereas FXIII A2 is activated nonproteolytically by a range of Ca2+concentrations. The resultant transglutaminases (FXIII A* and A) introduce covalent -glutamyl--lysylcrosslinks into protein networks. The main objective of our research is to decipher the kinetic andconformational differences between the two activated forms of Factor XIII (FXIII) and to characterize theirability to affect fibrin clot architecture and related processes. FXIII has roles in hemostasis venous thrombosiscardiac repair bone remodeling innate immunity etc. There are however few examples of strategies totherapeutically target FXIII. To further enhance such developments critical gaps in knowledge need to beaddressed. We need to know more about 1) the substrate specificities and structural features of activatedFXIII species from different activation pathways and 2) how fibrin clot architecture is controlled by FXIIIcatalyzed crosslinking reactions involving the fibrin C region and  module. The proposed research will thusaddress two hypotheses: 1) Factor XIII is hypothesized to have optimized activation pathways proteinstructural features and substrate specificities to effectively target its actions in different physiologicalenvironments. Research will focus a) on the kinetic properties of proteolytic FXIII A* and nonproteolytic FXIIIA b) on probing conformational roles of FXIII Activation Peptide interactions and c) on enhancing calciumbinding. 2) The fibrin(ogen) C region and  module are hypothesized to enhance their interactions with FXIIIby utilizing distinct reactive glutamine environments and employing binding segments for FXIII. a) With C(233-425) we will focus on quantitatively exploring how individual reactive Qs will facilitate the reactivities ofremaining Qs. b) With -module (142-411) we will rank the reactivities of Q398/Q399 and assess the role thatanchoring sites plays in controlling substrate specificity. The biochemical methods required to address theseaims include activity assays fibrin crosslinking gels mass spectrometry solution NMR and analyticalultracentrifugation. Our contributions to this research field will have a positive impact because they will help toaddress unresolved issues associated with FXIII structure-function and as a result lead to new innovativestrategies to manage FXIII in particular physiological locations

project_terms:
Active Sites;Address;Affect;Antiplasmin;Architecture;Binding;Binding Sites;Biochemical;Biological Assay;Blood Coagulation Disorders;Blood Platelets;Blood coagulation;Bone remodeling;Calcium Binding;Cardiovascular Diseases;Catalytic Domain;Coagulation Process;Development;Environment;Extracellular Matrix;Factor XIII;Fibrin;Fibronectins;Gel;Glutamine;Hemophilia A;Hemorrhage;Hemostatic function;Individual;Kinetics;Knowledge;Lead;Location;Mass Spectrum Analysis;Medical;Megakaryocytes;Methods;Mission;Modeling;Molecular Conformation;Natural Immunity;Pathway interactions;Peptides;Physiological;Plasma;Play;Process;Property;Proteins;Public Health;Reaction;Research;Research Personnel;Research Project Grants;Risk;Role;Site;Specificity;Structural Protein;Structure;Substrate Specificity;Therapeutic Agents;Thrombin;Time;Transglutaminases;United States National Institutes of Health;Variant;Venous Thrombosis;Wound Healing;analytical ultracentrifugation;base;bone;cardiac repair;crosslink;disability;human disease;inhibitor/antagonist;innovation;interest;monocyte;mutant;novel therapeutics;preservation;programs;protein structure;success;therapeutic development;therapeutic target;transglutaminase 2;trend analysis

public_health_relevance:
Project NarrativeFactor XIII has been associated with cardiovascular disease bleeding disorders wound healing innateimmunity and bone dynamics. Using innovative approaches the proposed research will provide criticalinformation on how to control the ability of Factor XIII to introduce rigid crosslinks into fibrin blood clots andother physiological environments. The research proposed is relevant to public health because its discoveriesmay lead to the development of novel therapeutic agents to address such medical conditions. Successes inthe research projects will support the NIH mission to increase biomedical knowledge and to reduce humandisease and disability.


application_id: 9811734
project_number: 1G08LM013185-01
project_title: Integrating Information Resources to Promote Environmental Health Literacy in Appalachian Kentucky
administering_ic: NLM
award_notice_date: 2019-09-09
opportunity_number: RFA-LM-19-001
application_type: 1
activity_code: G08
ic: LM
serial_number: 013185
program_official: VANBIERVLIET, ALAN
project_start_date: 2019-09-09
project_end_date: 2022-05-31
study_section: Special Emphasis Panel[ZLM1 ZH-G (01)]
contact_pi_person_id: 11057059
contact_pi: HOOVER, ANNA GOODMAN
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
PROJECT SUMMARY/ABSTRACTHealth disparities in Appalachian Kentucky have been well-documented with many chronic healthconditions disproportionately experienced across the region linked to environmental contributors.Deteriorating infrastructure inappropriate waste disposal and risks related to mining agricultureand other occupational activities underscore the need for this at-risk population to receive cleartimely and accessible information about potential environmental health threats to supportimportant decisions about preventive and protective actions. Unfortunately creating easilyunderstandable resources and tools can prove especially challenging in a region whereeducational attainment falls well below national averages with nearly one-quarter of adults overage 25 lacking high school diplomas and only about one-fifth holding an associate's degree orhigher. Therefore improving environmental health literacy (EHL) in the region is critical. EHL usesinformation and methods from health social and environmental sciences to promoteunderstanding of the relationship between environmental exposures and human health. Suchunderstanding can spur individual and/or community actions to minimize unnecessary exposuresand mitigate illness related to unavoidable exposures. To this end it is critical that existinginformation resources be evaluated integrated improved and made more accessible to helpimprove EHL and inform environmental health decisions. To address these needs ourmultidisciplinary team will deploy stakeholder-engaged research strategies to achieve thefollowing Specific Aims: 1) evaluate existing environmental health-related risk maps currentlyavailable from academic government and non-profit organizations to determine resourceaccessibility navigability understandability and perceived utility for Appalachian Kentuckians; 2)conduct needs assessments to identify additional information and appropriate framing required toimprove understandability and utility of environmental health-related risk maps for AppalachianKentuckians; 3) use information gathered in Aims 1 and 2 to enhance maps through the inclusionof critical health-related information in accessible formats as well as through potential changesto the visualizations themselves to improve understandability; and 4) leverage stakeholder-partnerships developed through the study to disseminate revised maps and additionalenvironmental health resources through community organizations thereby promoting EHL acrossthe region.

project_terms:
Address;Adult;Affect;Age;Agriculture;Appalachian Region;Associate Degree;Chronic;Communities;Community Actions;Decision Making;Development;Diabetes Mellitus;Ecology;Educational Status;Environmental Exposure;Environmental Health;Face;Goals;Government;Health;Health Resources;Health Sciences;Human;Hypertension;Imagery;Incidence;Individual;Industry;Information Resources;Infrastructure;Interdisciplinary Study;Kentucky;Link;Maps;Methods;Mining;Morbidity - disease rate;Needs Assessment;Nonprofit Organizations;Obesity;Occupational;Occupational Exposure;Personal Satisfaction;Population;Populations at Risk;Preventive;Refuse Disposal;Research;Resources;Risk;Social Sciences;Time;community organizations;evidence base;experience;falls;health disparity;health literacy;high school;improved;model development;mortality;multidisciplinary;population health;prevent;socioeconomics;tool

public_health_relevance:
PROJECT NARRATIVEHealth disparities in Appalachian Kentucky have been well-documented and are driven by manyfactors including challenging socioeconomic conditions and low levels of educational attainmentexacerbated by environmental concerns about deteriorating infrastructure inappropriate wastedisposal and risks related to mining agriculture and other occupational activities. This studystrives to mitigate these disparities by building regional environmental health literacy through thedevelopment integration refinement and provision of timely understandable and accessibleinformation about potential environmental health threats and evidence-based preventive andprotective actions. A multidisciplinary research team will deploy stakeholder-engaged researchstrategies to achieve the following Specific Aims: 1) evaluate existing environmental health-related risk maps currently available from academic government and non-profit organizations todetermine resource accessibility navigability understandability and perceived utility forAppalachian Kentuckians; 2) conduct needs assessments to identify additional information andappropriate framing required to improve understandability and utility of environmental health-related risk maps for Appalachian Kentuckians; 3) use information gathered in Aims 1 and 2 toenhance maps through the inclusion of critical health-related information in accessible formatsas well as through potential changes to the visualizations themselves to improveunderstandability; and 4) leverage stakeholder-partnerships developed through the study todisseminate revised maps and other environmental health resources through communityorganizations thereby promoting EHL across the region.


application_id: 9811338
project_number: 3T03OH010637-06S1
project_title: The Environmental Health Science Program at Western Kentucky University
administering_ic: NIOSH
award_notice_date: 2019-05-05
opportunity_number: PAR-15-352
application_type: 3
activity_code: T03
ic: OH
serial_number: 010637
suffix: S1
program_official: MAPLES, ELIZABETH
project_start_date: 2017-07-01
project_end_date: 2022-06-30
study_section: Special Emphasis Panel[ZOH1 EHG (01)]
contact_pi_person_id: 14375391
contact_pi: TAYLOR, RITCHIE DON
other_pis: Not Applicable
congressional_district: 02
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 421011001
organization_country: UNITED STATES
project_abstract:
Project SummaryThe success of the undergraduate Environmental Health Science (EHS) Program and the need for advancedtraining opportunities for the occupational and environmental health and safety workforce has led to thecreation of the graduate program in Environmental and Occupational Health Science (EOHS) at WesternKentucky University (WKU). This graduate program has seen strong interest in the region since its inception.The success of graduates from both programs employed as occupational safety and health specialistsenvironmental health and safety specialists industrial hygienists and in closely related fields has establishedthe credibility of the institution to offer this curriculum. The undergraduate EHS Program is currently supportedby the National Institute for Occupational Safety and Health (NIOSH) Training Project Grant (TPG). A criticalneed for the graduate EOHS program is NIOSH TPG funding to enhance environmental and occupationalsafety and health training for graduate students create a more diverse EOHS student population and meetEOHS workforce needs in this region.The EOHS Master of Science degree program at WKU is a comprehensive Science Technology Engineeringand Mathematics (STEM) program built upon education and training in basic and applied sciences. The overalleducational objective is a multidisciplinary approach that provides students the opportunity to develop acomprehensive understanding of the chemical biological physical and social factors or stressors in theoccupational and natural environments that impact public health outcomes.The courses offered in both the EHS and EOHS programs are designed to educate and train students inanticipation recognition evaluation and control of workplace factors that may affect the health comfort orproductivity of workers and the public. These programs respond to needs identified by our advisory committeemembers area industries and EOHS consultants in the field. The NIOSH TPG funding at WKU would supportspecific objectives to enhance occupational safety and health and related training through both the EHS andEOHS degree programs. These objectives are to support recruitment and training of students in EOHSenhance the diversity of students in the program and advance the EOHS field in this region.Specifically the TPG will provide tuition scholarships and stipends to train six (6) graduate students or moreeach project annum. Training though the EOHS curriculum will allow students to graduate with a Master ofScience degree in EOHS. A broad goal of the TPG is to attract and retain minority students. The EHSundergraduate program has seen an increase in minority student enrollments. The administrators of WKU'sNIOSH TPG believe that it is important to continue to be diligent and innovative in expanding opportunities forminorities to enter the EOHS field. NIOSH TPG sponsorship of the WKU Programs will ensure opportunitiesand training that will promote expertise in the EOHS field for the people of Kentucky and beyond.

public_health_relevance:
Public Health Relevance StatementThe Environmental Health Science (EHS) undergraduate and Environmental and Occupational Health Science(EOHS) graduate programs prepare students with a strong foundation in applied physics chemistry biologymathematics and community health that lead to the development of skills that can be utilized in a variety ofpublic health settings. EHS and EOHS program graduates have become environmental and occupationalhealth science professionals protecting public health across Kentucky the region and the nation.


application_id: 9810977
project_number: 1R15CA242482-01
project_title: Dynamic scheduling of the upcoming screening exam based on screening history and other parameters
administering_ic: NCI
award_notice_date: 2019-07-19
opportunity_number: PA-18-504
application_type: 1
activity_code: R15
ic: CA
serial_number: 242482
program_official: ZHU, CLAIRE
project_start_date: 2019-09-01
project_end_date: 2023-08-31
study_section: Cancer, Heart, and Sleep Epidemiology B Study Section[CHSB]
contact_pi_person_id: 8158793
contact_pi: WU, DONGFENG
other_pis: Not Applicable
congressional_district: 03
department: BIOSTATISTICS & OTHER MATH SCI
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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Motivated by the need of physicians and patients to make informed decision probability methods are proposedto address the problem of when to schedule the next exam for an asymptomatic individual with a history ofnegative screenings. The method provides a screening time interval to limit the risk of being a clinical incidentcase to a small value such as 5% or 10%. The time interval is a function of the three key parameters (i.e.screening sensitivity sojourn time in preclinical state and transition time distribution in disease-free state) aperson's current age/gender smoking status and one's screening history. Distribution of Lead time (ie.diagnosis time advanced by screening) and probability of over-diagnosis are derived if one would bediagnosed with cancer at the future scheduled time. A new likelihood function to estimate the three keyparameters are proposed and will be validated to increase the accuracy of the estimation. The methods will beapplied to four cohorts from the Prostate Lung Colorectal and Ovarian Cancer Screening Trial for lung cancer(PLCO-Lung) and four cohorts from the National Lung Screening Trials (NLST). The specific aims are:1. To estimate the three key parameters using a new likelihood function in the eight cohorts using either chest X-ray or Low Dose Computed Tomography (CT). Eight cohorts (four from PLCO-Lung using X-ray: male/female smokers male/female never-smokers; four from NLST: male/female smokers via X-ray male/female smokers via CT) were identified. The three key parameters will be estimated when sensitivity is modeled as a function of the sojourn time and time spent in the preclinical state using our new likelihood method. This lays a foundation for predictions and estimations in Aim 2 since the future time interval is a function of the three key parameters; and we will plug in estimates of the three key parameters in Aim 2 to obtain the optimal screening time.2. To schedule the next screening exam dynamically for an asymptomatic individual with any screening history. A new method using conditional probability of incidence before the next exam is proposed. The next screening time is found by limiting this probability to a small value to guarantee early detection and control the risk of over-diagnosis. The lead-time distribution and the probability of over-diagnosis are derived if one would be diagnosed with cancer at the next proposed screening time so that predictive information can be provided to individuals on how early his/her disease could be detected and the risk of over-diagnosis if one undergoes screening exams as suggested.3. To develop a user-friendly software for Aims 1 and 2 and made available to the public.In summary policy makers can use information from this research to recommend future screening frequenciesfor different risk groups (e.g. age gender smoking status) under different screening techniques (X-ray or CT).Physicians may use results from Aim 3 (the developed software) to schedule the next exam for individuals.

project_terms:
Address;Age;Chronic Disease;Clinical;Computer software;Diagnosis;Disease;Early Diagnosis;Female;Foundations;Frequencies;Future;Gender;Goals;Incidence;Individual;Knowledge;Lead;Likelihood Functions;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Methods;Modality;Modeling;Motivation;Output;Patients;Persons;Physicians;Plug-in;Policy Maker;Probability;Prostate Lung Colorectal and Ovarian Cancer Screening Trial;Pulmonary Mass;Recording of previous events;Research;Risk;Risk Factors;Roentgen Rays;Schedule;Screening Result;Screening for cancer;Smoker;Smoking Status;Spiral Computed Tomography;Statistical Methods;Techniques;Testing;Thoracic Radiography;Time;Validation;X-Ray Computed Tomography;base;cohort;density;low-dose spiral CT;lung cancer screening;male;never smoker;pre-clinical;screening;simulation;software development;time interval;trial design;tv watching;user friendly software

public_health_relevance:
Project Narrative:When to schedule the upcoming screening exam in lung cancer for an individualwith negative result(s) in the past and still looks healthy right now? We propose anew probabilistic method to provide a screening time interval by limiting the riskof being a clinical incidence to a small value such as 5 or 10%. The lead-timedistribution and the probability of over-diagnosis can be estimated if one wouldbe diagnosed with cancer at the scheduled time.


