# projects

application_id: 8997042
project_number: 5R25AA022823-03
project_title: Basic and Applied Summer Training in Alcohol Research
administering_ic: NIAAA
award_notice_date: 2016-01-27
opportunity_number: PAR-13-104
application_type: 5
activity_code: R25
ic: AA
serial_number: 022823
program_official: POWELL, ELIZABETH
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 1869834
contact_pi: NIXON, KIMBERLY
other_pis: PRENDERGAST, MARK A
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The University of Kentucky Summer Training in Alcohol Research (STAR) program provides 12 weeks of intensive hands-on alcohol research for 11 outstanding undergraduate students. A broad range of research opportunities exist that are truly bench to bedside because of the breadth of empirical approaches employed by our alcohol research faculty. Research topics available to the trainees range from the cell biology of alcohol neurodegeneration to applied survey research on the role that alcohol may have in moderating interpersonal domestic violence. This program will mesh well with the long-standing existing infrastructure of the Department of Pharmaceutical Science's summer undergraduate research program. Trainees will perform independent research under the supervision of alcohol research faculty participate in weekly educational and professional development seminars and be trained in responsible conduct of research. Hard work discovery and great science will culminate in a research presentation to faculty laboratory personnel and peers at our annual Summer Alcohol Research Symposium. Aggressive advertising of the program through scientific organizations networking websites and directly to regional liberal arts colleges undergraduate institutions and especially those schools serving underrepresented groups in STEM fields will allow for the recruitment of a diverse pool of summer undergraduate trainees. In concert with the main goals of providing hands on experience in basic and applied alcohol research we will be promoting the biomedical and behavioral sciences as career choices for these students. Evaluations of short-term and long-term successes of the STAR program on our primary objective of increasing the pool of diverse applicants to graduate programs and biomedical research careers will be conducted and followed throughout the years of the program.

project_terms:
Advertising;Alcohol consumption;Alcohol dependence;Alcohols;Arts;Behavioral Sciences;Biomedical Research;Brain Injuries;Career Choice;Cellular biology;Development;Domestic Violence;Engineering;Evaluation;Faculty;Goals;Hand;Health;Institution;Kentucky;Laboratories;Laboratory Personnel;Mathematics;Nerve Degeneration;Pharmacologic Substance;Play;Qualifying;Research;Research Infrastructure;Role;STEM field;Schools;Science;Students;Supervision;Surveys;Technology;Training;Underrepresented Groups;Universities;Work;alcohol research;bench to bedside;career;college;experience;peer;programs;responsible research conduct;scientific organization;success;summer research;symposium;undergraduate research;undergraduate student;web site

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The University of Kentucky Basic and Applied Summer Training in Alcohol Research (STAR) is a 12 week summer research program for 11 undergraduates to work hands on in the laboratory of faculty pursuing a broad spectrum of alcohol and addiction-related research questions. These research experiences range in focus from the cell biology of alcohol-induced brain damage to role that alcohol use/abuse plays in interpersonal domestic violence. This program aims to attract and develop a diverse pool of qualified experienced applicants for graduate study and/or careers in science technology engineering or math fields.


application_id: 8996734
project_number: 5R01NS089324-02
project_title: Functional consequences of silencing propriospinal pathways after SCI in the adult rat
administering_ic: NINDS
award_notice_date: 2016-01-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089324
program_official: JAKEMAN, LYN B
project_start_date: 2015-02-01
project_end_date: 2020-01-31
study_section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT]
contact_pi_person_id: 1932676
contact_pi: MAGNUSON, DAVID SK
other_pis: WHITTEMORE, SCOTT R
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_terms:
Address;Adult;Animals;Behavior;Behavioral;Beryllium;Bilateral;Cells;Cervical;Contusions;Data;Development;Dissection;Doxycycline;Excision;Forelimb;Gait;Grant;Health;Hindlimb;Histology;Injury;Interneurons;Locomotion;Locomotor Recovery;Lumbar Regions;Molecular;Motor Activity;Movement;Neural Pathways;Neurons;Neurotransmitters;Outcome;Pathway interactions;Phenotype;Physiological;Play;Population;Presynaptic Terminals;Process;Rattus;Recovery;Recovery of Function;Role;Severities;Spinal;Spinal Cord;Spinal cord injury;Subfamily lentivirinae;Synaptic Transmission;System;Testing;Tetracycline Control;Time;Virus;Walking;Weight-Bearing state;Work;arm;central pattern generator;drinking water;insight;kinematics;limb movement;neural circuit;neurotransmission;neurotropic;novel;research study;tool;vector;white matter


application_id: 8996557
project_number: 4R01DA033364-04
project_title: Medications Development for Cocaine: A Translational Approach in Monkey and Human
administering_ic: NIDA
award_notice_date: 2015-12-03
opportunity_number: PA-10-268
application_type: 4
activity_code: R01
ic: DA
serial_number: 033364
program_official: HAMPSON, AIDAN
project_start_date: 2013-02-01
project_end_date: 2018-06-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 8046705
contact_pi: LILE, JOSHUA ANTHONY
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): Cocaine-use disorders continue to be a significant public health concern yet no effective pharmacological treatments have been identified. This application is founded on the proposition that translational research on development of cocaine pharmacotherapies will benefit from the use of coordinated and homologous procedures in animals and humans to study effects of Candidate medications on choice between cocaine and a non-drug reinforcer. Self-administration procedures will be used in this project because the reinforcing effects of drugs are central to their abuse and the development of dependence. An alternative reinforcer to cocaine will be offered because the choice to use cocaine to the exclusion of other behaviors is a hallmark of dependence and an effective medication should assist patients in reducing drug use and reallocating behavior from drug use to more responsible and productive activities. Advantages of including preclinical research in the medications development process include strict control over environment and subject history and testing novel compounds and/or extensive dose ranges not feasible in humans. Rhesus monkeys were selected as the animal subjects because they are phylogenetically more closely related to humans than rodents and can be instrumented with chronically indwelling IV catheters which facilitates implementation of drug vs. food choice procedures. Human laboratory research permits the testing of putative pharmacotherapy effects on challenges with the abused drug in a clinically relevant subject population. Another advantage of pairing rhesus monkey and human laboratory models is that powerful within-subjects designs can be used with both species. Despite the relative strengths of human and non-human primate approaches translational research has been hampered by the use of widely different self-administration procedures and medication treatment regimens. The proposed project seeks to harmonize rhesus monkey and human procedures used to screen medications by first establishing parallel self-administration methods that will employ the same cocaine doses route of cocaine administration and schedule of reinforcement as well as a species-specific alternative reinforcer that effectively reduces drug taking. Cocaine doses schedule parameters and alternative reinforcer magnitude will then be adjusted to obtain equivalent functional effects prior to d-amphetamine maintenance testing. The use of d-amphetamine will permit equilibration of cross-species sensitivity and provide a comparator for effects of other non-dopaminergic Candidate medications examined in future studies. Achieving the aims of this project will exert a sustained and powerful impact by establishing a research platform for cocaine medication screening that will tightly link animal and human approaches thereby accelerating translational research on medications development. The proposed project is highly innovative in that it will develop coordinated and homologous procedures in nonhuman primates and humans using sophisticated cocaine choice procedures aimed towards medications development for cocaine-use disorders.

project_terms:
Address;Animals;Behavior;Catheters;Clinical;Clinical Research;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;Dependence;Development;Dextroamphetamine;Disease;Dopamine;Dopamine Agonists;Dose;Drug Use Disorder;Drug usage;Effectiveness;Ensure;Environment;Evaluation;Exclusion;Food;Future;Goals;Gold;Health;Human;Intravenous;Laboratories;Laboratory Research;Laboratory Study;Link;Macaca mulatta;Maintenance;Methods;Modeling;Monkeys;Patients;Pharmaceutical Preparations;Pharmacological Treatment;Pharmacotherapy;Population;Prevalence;Prevention;Procedures;Process;Public Health;Recording of previous events;Reinforcement Schedule;Research;Rodent;Route;Safety;Schedule;Self Administration;Standardization;Testing;Translational Research;Treatment Protocols;base;clinically relevant;cocaine use;design;innovation;instrument;non-drug;nonhuman primate;novel;pre-clinical research;reinforcer;research study;screening;stimulant abuse;translational approach;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cocaine-use disorders continue to be a significant public health concern yet no effective medications have been identified. This application is founded on the proposition that research to develop medications for cocaine addiction will benefit from the use of highly coordinated and homologous animal and human procedures to study effects of promising drugs on choice between cocaine and a non-drug alternative. The ultimate goal of this project is to establish a research platform that facilitates animal-to-human translational research on the development of medications for treatment of cocaine abuse and dependence.


application_id: 8995695
project_number: 5R01NS065842-09
administering_ic: NINDS
award_notice_date: 2016-02-26
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 065842
program_official: KOENIG, JAMES I
project_start_date: 2010-04-01
project_end_date: 2020-03-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
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
budget_start_date: 2016-04-01
project_abstract:
DESCRIPTION (provided by applicant): Although stroke is the fourth leading cause of death in the U.S. the current treatment strategy of thrombolysis for the majority of strokes due to a blood clot (ischemic) has mixed results. Thus there is an urgent need for new and better stroke therapies. We have previously demonstrated that the domain V protein fragment of the brain extracellular matrix component perlecan is both neuroprotective and neuroreparative after ischemic stroke by interaction with the brain endothelial cell receptor 51 integrin. Intriguingy preliminary results now suggest that mice with an endothelial selective deletion of 51 integrin
are profoundly resistant to experimental ischemic stroke; they show little to no signs of brain injury. Furthermore inhibition of the 51 integrin with ATN-161 or its more potent isoform Ac-PhScN-NH2 conveys nearly identical resistance to stroke injury in wild type mice. This may occur via stabilization of the blood-brain barrier through increased function of the brain endothelial cell tight junction protein claudin-5 which in turn minimizes vasogenic edema inflammation and injury. Therefore we hypothesize that endothelial cell 51 integrin could be a particularly effective therapeutic target for stroke. In this application we propose the followig specific aims: 1. Determine the effect of endothelial cell selective 51 integrin deletion on experimental ischemic stroke 2. Determine the potential of the 51 integrin as a therapeutic target in experimental ischemic stroke and 3. Determine in mechanistic detail the role of 51 integrin in modulating blood-brain barrier integrity and subsequent resistance to ischemic stroke. We will use several novel genetically modified mice (5 integrin endothelial cell specific knockdown mice claudin5 eGFP tagged mice) and newly characterized 51 integrin inhibitors in experimental stroke models and in vitro endothelial cell barrier assays. We expect to demonstrate that suppression or inhibition of 51 integrin in endothelial cells affords significnt blood-brain barrier-mediated resistance to experimental ischemic stroke supporting our long-term goal of developing 51 integrin as a novel human stroke therapeutic target.

project_terms:
Anatomy;Antineoplastic Agents;Apoptosis;Biochemical;Biological Assay;Blood - brain barrier anatomy;Blood coagulation;Blood flow;Brain;Brain Injuries;Cause of Death;Dose;Endothelial Cells;Extracellular Matrix;Genetic;Glucose;Goals;Histology;Human;Immunohistochemistry;In Vitro;Infarction;Inflammation;Injury;Integrin Inhibition;Integrin alpha5;Integrin alpha5beta1;Integrins;Ischemia;Ischemic Brain Injury;Ischemic Stroke;Knock-out;Knockout Mice;Label;Link;Magnetic Resonance Imaging;Mediating;Methods;Middle Cerebral Artery Occlusion;Morbidity - disease rate;Motor;Mus;Oxygen;Peptides;Permeability;Protein Fragment;Protein Isoforms;Proteins;Proteoglycan;Receptor Inhibition;Recovery of Function;Resistance;Role;Signal Transduction;Testing;Therapeutic;Tight Junctions;Time;Treatment Efficacy;Wild Type Mouse;analog;brain endothelial cell;cancer clinical trial;cell injury;cell type;cerebrovascular;deprivation;experience;in vitro Model;in vivo;inhibitor/antagonist;innovation;knock-down;mouse model;novel;novel therapeutic intervention;perlecan;post stroke;prevent;public health relevance;receptor;repaired;response to brain injury;stroke;stroke therapy;therapeutic target;thrombolysis;treatment strategy;vasogenic edema

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although stroke is the fourth leading cause of death in the U.S. current treatment options are limited in their application and efficacy. Towards that end we have identified a novel component of the brain's injury response derived from the brain's extracellular matrix which appears to protect cells from injury and help the brain to repair itself We further showed that this component termed perlecan domain V exerted its beneficial effects through interaction with the 51 integrin receptor on brain vascular (endothelial) cells Preliminary results now suggest that inhibition of this receptor profoundly protects the brain from
stroke injury and may do so by preventing breakdown of the blood-brain barrier. Therefore we propose to determine the therapeutic efficacy and mechanism(s) of action of targeting the 51 integrin in experimental ischemic stroke with the long term goal of developing better stroke therapies.


application_id: 8995186
project_number: 5R21AI112618-02
project_title: Improving the lead rF1-V plague vaccine using an SA-4-1BBL/alum adjuvant platform
administering_ic: NIAID
award_notice_date: 2015-12-21
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 112618
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2015-01-15
project_end_date: 2017-12-31
study_section: Vaccines Against Microbial Diseases Study Section[VMD]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: LAWRENZ, MATTHEW B
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): Yersinia pestis is the causative agent of bubonic and pneumonic plague and a potential bioweapon. Currently there is not a vaccine available to protect the public from a potential epidemic or bioterrorism event. While Y. pestis infection can be treated with antibiotics the effective treatment window for primary pneumonic infection is very short (less than 24 hrs after exposure). Furthermore naturally acquired resistance to antibiotics has been reported and weaponized Y. pestis could likely be modified to be resistant to antibiotic treatment. Therefore the development of an efficacious plague vaccine is an important scientific endeavor and public policy goal. The current lead vaccine against plague is a subunit vaccine formulation consisting of a recombinant F1-LcrV fusion protein (rF1-V) adjuvanted with alum. This vaccine has proven effective in rodent models but has decreased efficacy in primate models and variable antibody production in clinical trials. Therefore while rF1-V appears to be an excellent vaccine candidate for plague it needs further improvement for a better immunogenicity profile. A series of studies have demonstrated the important and critical role of Th1 cellular responses in protection against plague. Inasmuch as alum is a Th2 adjuvant that primarily generates a robust humoral response we hypothesized that the lead rF1-V vaccine formulation can benefit from an adjuvant system that generates a balanced mixed humoral and Th1 cellular immune responses. Towards this end we propose the use an adjuvant platform that includes alum and the novel adjuvant SA-4-1BBL. SA-4- 1BBL is a recombinant form of costimulatory ligand 4-1BBL with demonstrated robust efficacy in generating Th1 immune responses. Preliminary data with the lead rF1-V vaccine support our hypothesis and show that the addition of SA-4-1BBL to the lead vaccine formulation generates a robust rF1-V-specific Th1 cellular immune response. In Aim 1 we will extend these preliminary studies by establishing the SA-4-1BBL dose required to produce an optimized Th1 response that complements the Th2 response elicited by alum. In Aim 2 we will directly test the hypothesis that the Th1 response elicited by SA-4-1BBL contributes to protection against plague. This will be accomplished by using a combination of immune cell depletion and mutant mouse backgrounds to define the contribution of different cell types and cytokines to vaccine-induced protection against plague. Together these studies will demonstrate that a combinatorial adjuvant platform using alum and SA-4-1BBL can produce a balanced and protective Th1/Th2 immune response. Furthermore in addition to improving the lead candidate plague vaccine and its development for NHP and human clinical trials the proposed adjuvant system may also be used as a platform to generate subunit vaccines and or improve the efficacy of the existing ones against a host of other intracellular pathogens.

project_terms:
Adjuvant;Adjuvanticity;Agonist;Alhydrogel;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Antibody Formation;Antigen Targeting;Antigens;Attenuated Live Virus Vaccine;Automobile Driving;Bacteria;Bacterial Vaccines;Bioterrorism;Bubonic Plague;CD8B1 gene;Cells;Chimeric Proteins;Clinical Trials;Complement;Data;Development;Dose;Epidemic;Equilibrium;Event;Extracellular Domain;FDA approved;Formulation;Future;Generations;Goals;Health;Human;Immune;Immune response;Immune system;Immunologic Adjuvants;Inactivated Vaccines;Individual;Infection;Infectious Agent;Interferon Type II;Lead;Ligands;Malignant Neoplasms;Modeling;Mus;Mutant Strains Mice;Plague;Plague Vaccine;Pneumonic Plague;Primates;Production;Public Policy;Recombinant Proteins;Recombinants;Reporting;Rodent Model;Role;Safety;Series;Signal Transduction;Streptavidin;Subunit Vaccines;System;T cell response;T-Lymphocyte;TNF gene;Testing;Th1 Cells;Time;Treatment Efficacy;Vaccination;Vaccines;Work;Yersinia pestis;aluminum sulfate;base;cell mediated immune response;cell type;combinatorial;cytokine;defined contribution;effective therapy;immunogenicity;improved;long term memory;mouse model;nonhuman primate;novel;novel vaccines;pathogen;pre-clinical;preclinical study;prophylactic;protective efficacy;receptor;response;vaccine candidate;vaccine development;vaccine-induced immunity

public_health_relevance:
PUBLIC HEALTH RELEVANCE: No vaccine for plague is available in the US to protect the public from a future epidemic or bioterrorism attack. The main objective of this proposal is to fas track the development of the existing lead plague vaccine candidate by using a novel adjuvant system to improve efficacy. These studies will establish the vaccine formulation and characterize the role of different components of the immune system in vaccine protection. These data will guide future tests in primate models and human clinical trials.


application_id: 8994684
project_number: 4R01DE022597-04
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2016-02-01
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: DE
serial_number: 022597
program_official: CHANDER, PREETHI
project_start_date: 2013-02-01
project_end_date: 2018-01-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 6947603
contact_pi: POTEMPA, JAN S
other_pis: Not Applicable
congressional_district: 03
department: 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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Porphyromonas gingivalis is a leading pathogen in chronic periodontitis a disease process involving progressive destruction of tissues that support the teeth. Recently the organism has been reported to produce a unique bacterial enzyme P. gingivalis peptidylarginine deiminase (PPAD) which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function hence PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level.  We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD within the chronic inflammatory environment and immune system stimulation by bacteria- derived "danger signals" leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine which is also a preferential target for PPAD. Hence this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA; (ii) functional and structural studies of various forms of PPAD; and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.

project_terms:
Affect;Anaphylatoxins;Antibodies;Arginine;Atherosclerosis;Autoantibodies;Autoimmune Responses;Autoimmunity;Bacteria;Bioinformatics;Biological;Bone Resorption;Bradykinin;C-terminal;Caspase;Chronic;Cigarette Smoker;Citrulline;Clinical;Collagen-Induced Arthritis;Complement;Complement 3a;Complement 5a;Complex;Connective Tissue;Data;Dental Plaque;Development;Disease;Environment;Enzymes;Epidemiology;Epitopes;Exposure to;Forsythia;Generations;Gingiva;Gingival Crevicular Fluid;Health;Homeostasis;Homologous Gene;Human;Immune;Immune Tolerance;Immune response;Immune system;Individual;Infection;Inflammation;Inflammatory;Intervention;Joints;Kinins;Knowledge;Lesion;Light;Link;Lung;Microbial Genome Sequencing;Molecular;Natural Immunity;Organism;Pathogenesis;Pathogenicity;Pathology;Patients;Peptides;Peptidoglycan;Periodontal Diseases;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Post-Translational Protein Processing;Predisposition;Prevention;Process;Properdin;Protein-arginine deiminase;Proteins;Reaction;Reporting;Research;Research Proposals;Resistance;Rheumatoid Arthritis;Role;Serum;Signal Transduction;Site;Source;Substrate Specificity;Synovial Fluid;System;TNFRSF10A gene;Tissues;Tooth Loss;Tooth structure;Transgenic Mice;Treponema denticola;Validation;Virulence Factors;alveolar bone;arthropathies;bactericide;base;citrullinated protein;complement pathway;fimbria;gingipain;in vivo;innovation;interest;microbial;novel strategies;pathogen;pathogenic bacteria;polypeptide;preference;protein structure function;three dimensional structure;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis a known periodontal pathogen is the only known bacterium which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed infected periodontal tissues not onlycontributes to the pathology of periodontitis but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.


application_id: 8994612
project_number: 3DP1GM114862-01S1
project_title: Form and Function Function of our Janus faced genome
administering_ic: NIGMS
award_notice_date: 2015-06-22
opportunity_number: PA-15-034
application_type: 3
activity_code: DP1
ic: GM
serial_number: 114862
suffix: S1
program_official: GOROSPE, RAFAEL
project_start_date: 2014-09-30
project_end_date: 2019-07-31
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project title: Form and function of our Janus faced genome The conversion of RNA into DNA via reverse transcription has transformed the human genome: insertion of RNA-derived DNA copies has roughly doubled the mass of our hereditary material. However integration of reverse transcribed RNAs is an inefficient process even for the most successful genomic parasites (e.g. retroviruses retrotransposons and pseudogenes). The reverse transcribed copies that fail to integrate may be considered microcosms of the Roman god Janus: with one face they gaze towards the past as an imperfect copy of a previous life (i.e. the RNA they are derived from) and with another face they look towards the future capable of directing the fate of their molecular environment. Remarkably the identity and function of these genomic misfits that lie outside the confines of the traditional landscape of DNA is largely unexplored but expected to be vast and powerful. We find that endogenous cDNA formation (i.e. reverse transcribed DNA derived from host RNA) is robust and has important biological and disease-modifying function. Blocking reverse transcription prevents endogenous cDNA formation and interestingly also blocks an endogenous cDNA-mediated mouse model of blindness. Here we will extend these observations to systematically analyze the host-derived reverse transcriptome to produce the first draft atlas of the identity and function of endogenous cDNA in health and disease. We will also experimentally demonstrate the relevance of endogenous cDNA to molecular and metabolic pathways and provide an alternate explanation of toxicity attributed nucleoside reverse transcriptase inhibitors (e.g. peripheral neuropathy and developmental defects). We expect our work to demonstrate that the collision of host-derived RNA and the bidirectional flow of genetic information produces a powerful regulatory class of hereto underappreciated molecules that control health and disease and can be harnessed to understand and manipulate basic tenets of cellular biology.

project_terms:
Atlases;Biological;Blindness;Cellular biology;Complementary DNA;DNA;Defect;Development;Disease;Ensure;Environment;Face;Future;Gene Expression Profile;Genome;Genomics;Head;Health;Human Genome;Inherited;Life;Mediating;Metabolic Pathway;Molecular;Nucleosides;Organism;Parasites;Peripheral Nervous System Diseases;Process;Pseudogenes;RNA;Retrotransposon;Retroviridae;Reverse Transcriptase Inhibitors;Reverse Transcription;Side;Toxic effect;Work;fitness;gaze;genetic information;mouse model;prevent

public_health_relevance:
Project Narrative Form and function of our Janus faced genome The Roman god Janus is said to have two faces on either side of his head - one which faces forward staring into the future and one which faces backwards gazing towards the past. In much the same way genetic information within an organism contains not only the blueprints needed to ensure its current and future fitness but also a distinct form: an imperfect copy of a previous life.


application_id: 8993650
project_number: 5R01NS084857-03
project_title: Carbonyl Scavenging for Traumatic Brain Injury
administering_ic: NINDS
award_notice_date: 2016-01-11
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 084857
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-02-01
project_end_date: 2018-01-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 2450852
contact_pi: HALL, EDWARD D.
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our laboratory has documented that generation of the potent reactive nitrogen species (RNS) peroxynitrite (PN) is responsible for oxidative damage by lipid peroxidation (LP) and neurotoxic protein modification by binding of LP-derived carbonyl-containing aldehydes such as 4-hydroxynoneal (4-HNE) and acrolein to mitochondrial and other cellular elements during the first 72 hrs after traumatic brain injury (TBI). This oxidative damagecauses brain mitochondrial respiratory compromise and decreased calcium (Ca++) buffering which worsens post-TBI neuronal intracellular Ca++ overload calpain-mediated neuronal cytoskeletal degradation neurodegeneration and neurological impairment. Recently a novel antioxidant approach for post-central nervous system (CNS) injury for decreasing and possibly reversing oxidative damage has been identified that involves scavenging the LP-derived carbonyl compounds ("carbonyl scavenging") preventing their neurotoxic effects. Preliminary support from other laboratories and our own has shown that certain clinically used drugs that contain hydrazine function groups can covalently bind to 4-HNE or acrolein and prevent their neurotoxicity. The proposed 3 Aim project will employ phenelzine a long used hydrazine-containing anti-depressant that contains has been found to be an effective carbonyl scavenger as a tool to investigate the antioxidant neuroprotective effects of carbonyl scavenging in isolatedrat brain mitochondria and the rat controlled cortical impact TBI model. Specifcally the project will define the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration. Since phenelzine has a long history of clinical use and a well understood human safety profile the translation of the drug's use into clinical TBI trials would be facilitated.

project_terms:
4 hydroxynonenal;Acrolein;Acute;Aldehydes;Antihypertensive Agents;Antioxidants;Binding;Brain;Brain Injuries;Buffers;Calcium;Calpain;Cell Culture Techniques;Cell membrane;Chemicals;Chronic;Clinical;Data;Dose;Drug usage;Elements;Exposure to;Functional disorder;Generations;Health;Human;Hydralazine;Impairment;Injury;Ischemia;Laboratories;Lesion;Lipid Peroxidation;Lipids;Mediating;Membrane Lipids;Mitochondria;Mitochondrial Proteins;Modeling;Modification;Motor;Mus;Nerve Degeneration;Neurologic;Neurons;Patients;Peroxonitrite;Pharmacology;Phase;Phase III Clinical Trials;Phenelzine;Polyunsaturated Fatty Acids;Post-Translational Protein Processing;Rattus;Reaction;Reactive Nitrogen Species;Reactive Oxygen Species;Recording of previous events;Regimen;Reperfusion Therapy;Reporting;Research Personnel;Safety;Spinal cord injury;Staging;Stress;Testing;Therapeutic;Time;Tissues;Toxic effect;Translations;Traumatic Brain Injury;Traumatic Subarachnoid Hemorrhage;Treatment Efficacy;attenuation;axonal degeneration;base;carbonyl compound;carbonyl group;central nervous system injury;clinically relevant;cognitive function;cognitive recovery;controlled cortical impact;cytotoxic;improved;in vivo;injured;lipid peroxidation inhibitor;morris water maze;mortality;motor function improvement;motor recovery;nerve injury;neurotoxic;neurotoxicity;novel;oxidative damage;perhydroxyl radical;prevent;protective effect;respiratory;stroke;tool;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This project will examine the neuroprotective effects of phenelzine a long-used anti-depressant compound that has recently been discovered to also be a scavenger of lipid peroxidation-derived carbonyl-containing aldehydes such as 4-hydroxynonenal and acrolein in the rat controlled cortical impact traumatic brain injury model (CCI-TBI). Preliminary data has demonstrated that phenelzine can protect brain mitochchondria from impairment of their function an effect that is correlated with a lessened 4-hydroxynonenal modification of mitochondrial proteins and to decrease post-TBI brain damage. This proposal will expand our understanding of the neuroprotective pharmacology (e.g. mechanism of action dose-response and therapeutic window) of phenelzine's "carbonyl scavenging" in terms of neuronal mitochondrial and cytoskeletal protection along with the ability to improve chronic motor and cognitive recovery and to decrease post-traumatic neurodegeneration.


application_id: 8993338
project_number: 1R01HL123358-01A1
project_title: A novel mechanism for ART-associated dyslipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2015-07-13
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 123358
suffix: A1
program_official: FLEG, JEROME L
project_start_date: 2015-08-01
project_end_date: 2019-05-31
study_section: AIDS Discovery and Development of Therapeutics Study Section[ADDT]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Adverse effects;Agonist;Amprenavir;Animal Model;Anti-Retroviral Agents;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Awareness;CD36 gene;Cardiovascular Diseases;Cells;Chemicals;Cholesterol;Chronic;Clinical;Comorbidity;Development;Diet;Disease;Dose;Dyslipidemias;Foam Cells;Gene Expression;Generations;Goals;HIV;HIV Infections;HIV Protease Inhibitors;HIV therapy;Health;Heart;Homeostasis;Hyperlipidemia;In Vitro;Individual;Infection;Inflammation;Intestines;Knockout Mice;Laboratories;Lead;Lipids;Liver;Long-Term Survivors;Longevity;Lopinavir;Mediating;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Nuclear Receptors;Pathway interactions;Patients;Pharmaceutical Preparations;Pilot Projects;Protease Inhibitor;Receptor Activation;Regulation;Risk;Ritonavir;Role;SXR receptor;Signal Pathway;Testing;Therapeutic Uses;Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;antiretroviral therapy;atherogenesis;base;cardiovascular disorder risk;cholesterol transporters;defined contribution;drug metabolism;efavirenz;follow-up;in vivo;insight;macrophage;mouse model;non-nucleoside reverse transcriptase inhibitors;novel;pregnane X receptor;public health relevance;receptor function;research study;scavenger receptor;sensor;survivorship;uptake


application_id: 8991507
project_number: 5R01GM113832-02
project_title: Synthetic HDL_a potential sepsis therapy
administering_ic: NIGMS
award_notice_date: 2015-11-24
opportunity_number: RFA-HL-14-028
application_type: 5
activity_code: R01
ic: GM
serial_number: 113832
program_official: DUNSMORE, SARAH
project_start_date: 2015-01-01
project_end_date: 2019-11-30
study_section: ZHL1-CSR-O(S1)
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: SCHWENDEMAN, ANNA
congressional_district: 06
department: PEDIATRICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Animals;Bacteria;Biodistribution;Biological;Biology;Biotechnology;Blood;Blood Vessels;Cardiovascular Diseases;Cessation of life;Chemicals;Clinical;Clinical Data;Data;Dose;Drops;Drug Kinetics;Effector Cell;Endothelial Cells;Endotoxins;Event;Extravasation;Figs - dietary;Frequencies;Generations;Goals;Grant;High Density Lipoprotein therapy;High Density Lipoproteins;Immune;Immunity;Immunocompromised Host;In Vitro;Inflammatory;Inflammatory Response;Knockout Mice;Knowledge;Lead;Ligation;Lipids;Lipoprotein (a);Mediating;Modeling;Mus;Pathogenesis;Pathway interactions;Patients;Peptides;Play;Positioning Attribute;Proteins;Puncture procedure;Regimen;Reporting;Research Personnel;Risk Factors;Role;Safety;Sepsis;Shapes;Signal Transduction;Testing;Therapeutic;Time;Translations;Treatment Protocols;Vascular Endothelial Cell;aged;base;cytokine;design;effective therapy;endothelial dysfunction;experience;in vitro Assay;in vivo;innovation;macrophage;mechanistic (body);mortality;multidisciplinary;novel;outcome forecast;overexpression;pre-clinical;preclinical study;reconstitution;septic;success;tool;treatment strategy;vascular endothelial dysfunction


application_id: 8991477
project_number: 5R21AI116517-02
project_title: Exploitation of host glycolysis by Legionella
administering_ic: NIAID
award_notice_date: 2015-12-09
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: AI
serial_number: 116517
program_official: ERNST, NANCY L
project_start_date: 2015-01-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1-IDM-B(80)S]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Upon transmission to humans Legionella pneumophila (Lp) proliferates within alveolar macrophages causing pneumonia with high morbidity and mortality. Intracellular proliferation of Lp occurs within the endoplasmic reticulum-derived Legionella-containing vacuole (LCV) which evades lysosomal fusion. Biogenesis of the LCV is governed by the Dot/Icm type IV secretion system which injects into the host cell ~300 protein effectors that exploit a myriad of cellular processes to enable intra- vacuolar proliferatin of Lp. The generation time of intra-vacuolar Lp within human macrophages is ~40 min which is 3-4 times faster than growth in rich media. Amino acids are the major sources of carbon and energy for Lp which metabolize them through the TCA cycle as the major energy-yielding metabolic pathway in Lp which does not have a functional glycolytic pathway. However our recent studies indicate that the host basal cellular levels of amino acids are below the threshold needed as a major source of carbon and energy to feed the TCA cycle of intra-vacuolar Lp. To achieve that threshold Lp promotes host proteasomal degradation which is totally bypassed upon supplementation of amino acids or pyruvate. This indicates the import of pyruvate by the LCV and its utilization by intra-vacuolar Lp as a source of carbon and energy. Our preliminary data show a Dot/Icm-dependent up-regulation of the host glycolytic enzymes and production of pyruvate in Lp-infected human monocytes-derived macrophages (hMDMs). Importantly glucose deprivation or inhibition of glycolysis in hMDMs suppresses intra-vacuolar proliferation of Lp butthe suppression is totally relieved upon supplementation of pyruvate. This indicates that the LCV imports pyruvate to be utilized by intra-vacuolar Lp as a source of carbon and energy. Our findings indicate a multi-prong bacterial strategy to retrieve diverse host resources to feed the TCA cycle of Lp. The import of pyruvate across eukaryotic membranes is mediated by the plasma membrane-localized SLC16A1 and SLC16A7 transporters and by the mitochondrial membrane-localized MPC1 and MPC2 oligomeric complex. Our preliminary data derived from microarrays of Lp-infected hMDMs show that Lp triggers Dot/Icm-dependent up-regulation of the host MPC1 and MPC2 but not SLC16A1 or SLC16A7. Our profiling of the proteome of the LCV membrane shows that the MPC1 and MPC2 eukaryotic transporter is acquired by the LCV in a Dot/Icm-dependent manner but the SLC16A1 and SLC16A7 are not detectable in the LCV proteome. Therefore our hypothesis is: the host MPC pyruvate transporter is acquired by the LCV membrane through interaction with a Dot/Icm-translocated effector to import pyruvate into the LCV to be utilized by intra-vacuolar Lp as a source of carbon and energy. To test our hypothesis our specific aims are to determine and characterize the following: I. Acquisition of host MPC transporter by the LCV and its import of pyruvate as a source of carbon and energy for intra-vacuolar Lp; II. The Lp effectors that interact with the host MPC transporter in the LCV membrane. The significance of our studies stem from deciphering exploitation of host glycolysis by intra- vacuolar Lp; and determination of the mechanisms of import of host pyruvate from the cytosol of primary hMDMs into a pathogen-containing vacuole and its utilization by the pathogen as a source of carbon and energy. The innovations of our studies stem from: Novelty of the hypotheses; cutting-edge technologies and experimental design; Dot/Icm-dependent up-regulation of host glycolysis production of pyruvate; and up- regulation of the host MPC1 and MPC2 transporter; recruitment of the host MPC1 and MPC2 transporter into the pathogen-containing vacuole; import of pyruvate generated from host glycolysis by the pathogen- containing vacuolar membrane; and identification of novel bacterial effectors that interact with the host MPC1 and MPC2 transporter in the vacuolar membrane of an intra-vacuolar pathogen.

project_terms:
Alveolar Macrophages;Amino Acids;Biogenesis;Bypass;Carbon;Cell membrane;Cell physiology;Cells;Citric Acid Cycle;Communicable Diseases;Complex;Cytosol;Data;Disease;Endoplasmic Reticulum;Enzymes;Experimental Designs;Generations;Glucose;Glycolysis;Glycolysis Inhibition;Growth;Health;Human;Knowledge;Legionella;Legionella pneumophila;Mediating;Membrane;Metabolic Pathway;Metabolism;Microbe;Morbidity - disease rate;Nutrient;Nutritional;Pathway interactions;Pneumonia;Process;Production;Proliferating;Proteins;Proteome;Pyruvate;Resources;Retrieval;Source;Supplementation;Technology;Testing;Time;Type IV Secretion System Pathway;Up-Regulation;Vacuole;Virulence;antimicrobial;deprivation;feeding;innovation;macrophage;microbial;mitochondrial membrane;monocyte;mortality;novel;pathogen;pyruvate carrier;stem;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although microbial access to host nutrients is one of the most fundamental aspects of infectious diseases our understanding of this process remains very limited. In the host pathogens are faced with major nutritional challenges that include host nutritional limitation and the host innate defense of microbial deprivation of essential nutrients.To counteract these nutritional challenges pathogens have evolved highly efficient nutrient retrieval strategies which are major potential targets for anti-microbial therapy. Our proposed studies will decipher the mechanisms of import of host pyruvate into the vacuole harboring Legionella pneumophila within human macrophages. Since host-generated pyruvate is an important source of carbon and energy needed by this pathogen to proliferate within the vacuole and cause pneumonia our studies are high impact.


application_id: 8991046
project_number: 5R01AI051517-12
project_title: Paramyxovirus F protein mediated membrane fusion
administering_ic: NIAID
award_notice_date: 2015-12-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 051517
program_official: PARK, EUN-CHUNG
project_start_date: 2002-05-15
project_end_date: 2019-12-31
study_section: Virology - B Study Section[VIRB]
contact_pi_person_id: 8106840
contact_pi: DUTCH, REBECCA
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:
Address;Affect;Antiviral Agents;Automobile Driving;C-terminal;Ca(2+)-Transporting ATPase;Cells;Characteristics;Chimeric Proteins;Cholesterol;Cytoplasmic Tail;Data;Development;Dissociation;Elements;Environment;Family;Funding;Glycoproteins;Goals;Health;Hendra Virus;Human;Human Metapneumovirus;Individual;Infection;Kinetics;Lipids;Measles;Mediating;Membrane;Membrane Fusion;Membrane Fusion Activity;Membrane Lipids;Molecular;Molecular Conformation;Mutation;Neuropilins;Paramyxovirus;Paramyxovirus Fusion Protein;Peptides;Process;Proteins;Regulation;Research;Respiratory syncytial virus;Rest;Role;Sarcoplasmic Reticulum;Signal Transduction;Sphingolipids;Structure;System;Testing;Therapeutic;Time;Transmembrane Domain;Vaccines;Viral;Viral Fusion Proteins;Viral Proteins;Virus;Virus-like particle;Work;disulfide bond;insight;mutant;novel;particle;pathogen;prevent;protein folding;protein function;research study;sedimentation equilibrium;trafficking


application_id: 8990832
project_number: 5R21CA191683-02
project_title: CCR2 mediated inflammation and gut microbiota in promoting intestinal cancer
administering_ic: NCI
award_notice_date: 2016-01-08
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 191683
program_official: DASCHNER, PHILLIP J
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: ZCA1-RTRB-Z(O1)
contact_pi_person_id: 9246960
contact_pi: JALA, VENKATAKRISHNA RAO
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is strongly associated with inflammation accompanied by increased infiltration of leukocytes. CCR2 a seven transmembrane G-protein coupled chemokine receptor mediates several biological functions including chemotaxis of leukocytes upon binding to its ligand CCL2 (MCP1). CCR2 is expressed on peripheral blood monocytes/macrophages as well as on activated T-cells B-cells immature dendritic cells and mast cells. Elevated expression of CCL2 in tumor cells is very well correlated with increased metastasis and poor prognosis in several types of human cancers. Recently it was shown in animal models that CCL2-CCR2 axis play an important role in promotion of colon tumorigenesis. Our preliminary data showed that CCR2-/- mice in the ApcMin/+ (a spontaneous intestinal cancer mouse model) background developed significantly fewer and smaller size small intestinal and colon tumors and showed substantial survival advantage compared to ApcMin/+ mice. Further polyps in CCR2-/-ApcMin/+ displayed decreased tumor infiltrating F4/80+ cells decreased inflammatory molecules (e.g. IL-1 SOCS1) increased apoptosis and CD8 levels compared to ApcMin/+ mice. Interestingly inflammatory cytokines IL-23 and IL-17 were significantly reduced in CCR2-/-ApcMin/+. Our gut microbiota analysis revealed that tumor promoting Bacteroides genus are significantly reduced in CCR2-/-ApcMin/+ mice compared to ApcMin/+ mice.  Based on these preliminary data we hypothesize that CCR2/CCL2 mediated recruitment of tumor associated macrophages (TAMs) and Th17 cells modulate inflammation and microbiota in the tumor microenvironment to promote intestinal tumors and blocking CCR2-CCL2 axis would reduce the tumor burden. To test this hypothesis we propose two specific aims. In AIM 1 we will determine the requirement of CCR2 for recruitment and activation of IL-23 (TAMs DCs) and IL-17 (Th17  T-cells) producing cells during intestinal tumorigenesis. In AIM 2 we will determine the influence of gut microflora on CCR2 dependent production of IL-23 and IL-17 to promote intestinal tumorigenesis. The current proposal will also examine the efficacy of existing CCR2 inhibitors in colon cancer progression to translate our basic observation in pre-clinical models. Determining the molecular cellular mechanisms and complex inter-relationship between immune system-microbiota in the context of cancer will have a strong impact on our basic understanding of intestinal carcinogenesis as well as potential for developing novel therapeutic strategies.

project_terms:
Adoptive Transfer;Animal Model;Antibiotics;ApcMin/+ mice;Apoptosis;B-Lymphocytes;Bacteria;Bacteroides;Bacteroides fragilis;Binding;Biological Process;CCL2 gene;CD4 Positive T Lymphocytes;CD8B1 gene;Cancer Etiology;Cells;Cessation of life;Chemotaxis;Colitis;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Complex;Coupled;Data;Dendritic Cells;Development;Epithelial;Epithelial Cells;Equilibrium;Event;Family;Figs - dietary;GTP-Binding Proteins;Genes;Genetic;Granzyme;Health;Human;IL8 gene;Immune;Immune system;Individual;Infiltration;Inflammation;Inflammatory;Interferon Type II;Interleukin-1 beta;Interleukin-17;Interleukin-6;Intestinal Cancer;Intestinal Neoplasms;Intestines;Lactobacillus acidophilus;Lamina Propria;Leukocyte Chemotaxis;Leukocytes;Ligands;Link;Lymphoid Cell;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Monocyte Chemoattractant Proteins;Mus;Mutation;Myeloid Cells;NF-kappa B;Neoplasm Metastasis;Pathway interactions;Play;Polyps;Pre-Clinical Model;Probiotics;Process;Production;Recruitment Activity;Role;STAT3 gene;Signal Transduction;Spleen;T-Cell Proliferation;T-Lymphocyte;TNF gene;Testing;Translating;Tumor Burden;base;carcinogenesis;cell motility;chemokine;chemokine receptor;colon tumorigenesis;commensal microbes;cytokine;design;fecal transplantation;gut microbiota;inhibitor/antagonist;interleukin-23;macrophage;microbiota;monocyte;mouse model;neoplastic cell;next generation sequencing;novel therapeutic intervention;novel therapeutics;outcome forecast;peripheral blood;research study;response;seven-transmembrane G-protein-coupled receptor;small molecule;transcription factor;tumor;tumor microenvironment;tumor progression;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Monocyte chemoattractant protein (MCP1/CCL2) is a classic chemokine that mediates its directed cell migration via CCR2. Our data suggested that deficiency of CCR2 reduced the progression of spontaneous intestinal tumors and increased survival in the context of Min mutation in the Apc gene. This proposal investigates role of CCL2-CCR2 axis in balancing the inter-relationship between immune system and microbiota in colon tumorigenesis and successful completion of this project would provide new level of understanding to design potential novel therapeutic approaches for the treatment of colon cancer.


application_id: 8989362
project_number: 3U90TP000563-03S1
administering_ic: COTPER
award_notice_date: 2014-12-19
opportunity_number: RFA-TP-12-1201
application_type: 3
activity_code: U90
ic: TP
serial_number: 000563
suffix: S1
project_start_date: 2014-12-22
project_end_date: 2015-06-30
study_section: ZTP1-SRC(99)
contact_pi_person_id: 9142162
contact_pi: HUMBAUGH, KRAIG E
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-12-22
project_title:
TP12-1201: PHEP SUPPLEMENTAL FOR EBOLA VIRUS DISEASE ACTIVITY MONITORING AND DIRECT ACTIVE MONITORING ACTIVITIES


application_id: 8987999
project_number: 1R01AR067667-01A1
project_title: Mitigating mitochondrial epigenetics in bone remodeling by hydrogen sulfide
administering_ic: NIAMS
award_notice_date: 2015-07-31
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AR
serial_number: 067667
suffix: A1
program_official: CHEN, FAYE H
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-U (90)]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Clinical studies report that children born with severe hyperhomocysteinemia (HHcy) due to deficiency in cystathionine--synthase (CBS) gene resulting in an elevation in plasma homocysteine (Hcy) levels develop skeletal malformations with weaker bone. Although mitochondrial dysfunction has been involved in bone pathology altered mitochondrial (Mito) epigenetics and dynamics contributing to frailer bone have not been studied. The long term goal of this project is to understand the mechanisms of mito-epigenetic remodeling and changes in bone structure/function during genetic HHcy. Alterations in mitochondrial dynamics disturb bone cell (osteoclast/ osteoblast) differentiation and matrix metabolism. Studies have confirmed that type-I collagen (coll-1) a dominant protein of the organic bone matrix is homocysteinylated (N-Hcy-coll-1) during HHcy. Our preliminary data suggest that genetic HHcy affects mito-epigenetic remodeling by altering mito-redox stress mito-DNA methylation / hydroxymethylation fission-fusion and cause N-Hcy-coll-1 cross linking. These processes cumulatively disrupt bone matrix bone density bone blood flow and lead to mitophagy accompanying with significant bone loss. Interestingly hydrogen sulfide (H2S an anti-redox stress and Hcy lowering agent) mitigates bone damage. The central hypothesis of this proposal is that HHcy contributes to bone-matrix inferiority through N-Hcy-coll-1 in part by
increasing mito- epigenetic remodeling and altering mitochondrial dynamics. However treatment with H2S ameliorates HHcy-induced bone abnormalities. We will test this hypothesis by following three specific Aims: Specific Aim # 1: To determine whether the HHcy instigates mito-epigenetic remodeling and DNA methylation in part by altering mitochondrial fission and fusion and whether H2S mitigates mito-epigenetic remodeling. Specific Aim # 2: To determine whether the HHcy homocysteinylates bone type-I collagen activates MMP-1-3-13 disrupts bone matrix (MMP/TIMP axis; collagen/elastin ratio) and H2S ameliorates these changes. Specific Aim # 3: To determine whether the HHcy alters bone mineral density bone mineral content biomechanical load-bearing capacity bone blood flow and disrupts osteoblast/osteoclast differentiation and whether H2S alleviates these alterations.

project_terms:
Affect;Alkaline Phosphatase;Antibodies;Attenuated;Azacitidine;Biomechanics;Blood Vessels;Blood flow;Bone Density;Bone Diseases;Bone Matrix;Bone Mineral Contents;Bone Resorption;Bone remodeling;C-terminal;Child;Chimeric Proteins;Clinical Research;Co-Immunoprecipitations;Collagen;Collagen Type I;Consumption;Cyclophosphamide;Cystathionine;DNA Methylation;Data;Deformity;Elastin;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Event;Gel;Gelatin;Gelatinase B;Generations;Genes;Genetic;Goals;Homocysteine;Homocystine;Hydrogen Sulfide;Hyperhomocysteinemia;Immunohistochemistry;Impairment;In Situ;Interstitial Collagenase;Knock-out;Knockout Mice;Lasers;MMP9 gene;MTHFR gene;Matrix Metalloproteinases;Measures;Mechanics;Metabolism;Mitochondria;Mitochondrial DNA;Molecular;Mus;Osteoblasts;Osteocalcin;Osteoclasts;Osteocytes;Osteogenesis;Oxidation-Reduction;Oxidative Stress;Pathology;Pathway interactions;Peptides;Plasma;Process;Proteins;Proteome;Pyridoxal Phosphate;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Role;Staining method;Stains;Stress;Structure;Testing;Therapeutic;Therapeutic Agents;Weight-Bearing state;Western Blotting;Wild Type Mouse;blood lead;bone;bone cell;bone loss;bone strength;bone turnover;crosslink;density;femoral artery;inhibitor/antagonist;innovation;malformation;microCT;mitochondrial dysfunction;novel;osteoblast differentiation;public health relevance;skeletal;tibia


application_id: 8986654
project_number: 5F32HL126300-02
project_title: Prevention of heart failure and remodeling through calcium channel modulation
administering_ic: NHLBI
award_notice_date: 2015-11-27
opportunity_number: PA-14-149
application_type: 5
activity_code: F32
ic: HL
serial_number: 126300
program_official: MEADOWS, TAWANNA
project_start_date: 2014-12-01
project_end_date: 2016-11-30
study_section: Special Emphasis Panel[ZRG1-F10A-S(20)L]
contact_pi_person_id: 11933080
contact_pi: MANNING, JANET R
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): The loss of cardiac output immediately post-myocardial infarction (MI) triggers longer-term cardiac remodeling. MI remodeling consists of a loss of contractility and ventricular dilation leading to heart failure (HF). Strategies that maintin higher systolic function post-MI may circumvent the stimulus that ultimately leads to HF. One potential therapeutic target is Rad a small GTPase that acts as a regulator of the L-type calcium channel; Rad loss promotes greater inward current higher twitch calcium levels greater fractional shortening of ventricular myocytes and increased heart contractility. It is hypothesize that this improvement in calcium homeostasis and contraction can mitigate the loss of contractility post-MI. To test this hypothesis Rad null mice will be subjected to coronary artery ligation and serial echocardiography to monitor heart dimensions and function. Scar size will be evaluated using histology and cytosolic calcium will be measured in stimulated isolated ventricular myocytes to determine if Rad null mice are protected from MI-induced calcium dysregulation preventing loss of transient amplitude and the slowing of reuptake into the SR. In addition the hypothesis that Rad null mice are protected from acute MI-induced necrosis and apoptosis will be tested using isolated perfused hearts subjected to ischemia which will subsequently be stained and analyzed for infarct development. These results will also be investigated in vivo using late gadolinium enhanced MRI. It is hypothesized that deletion of Rad GTPase will prevent MI-induced heart failure through both preservation of cardiac output post-MI and through the priming of the heart to reduce infarct development through cytoprotective pathways. These experiments will enable a better understanding of a potentially beneficial therapeutic protein that may both prevent acute cytotoxicity as well as promote functional improvement after MI.

project_terms:
Acute;Acute myocardial infarction;Adrenergic Agents;Anterior;Apoptosis;Area;Arteries;Attenuated;Biological Preservation;Calcium;Calcium Channel;Calcium Signaling;Cardiac;Cardiac Output;Cause of Death;Cell Death;Cell physiology;Cessation of life;Cicatrix;Clinical;Coronary artery;Data;Development;Disease;EFRAC;Echocardiography;Electrophysiology (science);Functional disorder;Funding;Gadolinium;Genetic;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Heart;Heart Contractilities;Heart Diseases;Heart failure;Histology;Homeostasis;Hypertrophy;Infarction;Injury;Ischemia;Knock-out;Knockout Mice;L-Type Calcium Channels;Laboratories;Left;Ligation;Magnetic Resonance Imaging;Measures;Mentors;Methods;Monitor;Monomeric GTP-Binding Proteins;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Necrosis;Paper;Pathway interactions;Patient-Focused Outcomes;Phenotype;Phosphorylation;Prevention;Proteins;Publications;Publishing;Regulation;Reperfusion Injury;Research Personnel;Research Training;Signal Transduction;Staining method;Stains;Stimulus;Stroke Volume;Testing;Therapeutic;Tissue Survival;Tissues;Ventricular;Work;Workload;career;clinically relevant;cytotoxicity;functional improvement;gadolinium oxide;graduate student;heart dimension/size;heart function;hemodynamics;improved;in vivo;loss of function;member;novel;novel therapeutics;post-doctoral training;prevent;research study;reuptake;therapeutic protein;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal will test the hypothesis that Rad GTPase deletion will promote tissue survival and will promote myocardial function after ischemia preserving cardiac output and obviating the hemodynamic trigger for cardiac remodeling that leads to pathological hypertrophic growth remodeling and heart failure. These findings will identify a novel method of cardioprotection that may be clinically relevant for post-myocardial infarction treatment of contractile dysfunction and the prevention of heart failure.


application_id: 8986471
project_number: 1R13OD021318-01
project_title: Comparative Medicine Resource Directors Meetings
administering_ic: OD
award_notice_date: 2015-07-24
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: OD
serial_number: 021318
program_official: MURPHY, STEPHANIE
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-C (90)]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Biocompatible Materials;Biomedical Research;Collaborations;Development;Face;Fostering;Funding;Grant;Location;Medicine;Mission;Request for Applications;Request for Proposals;Research Infrastructure;Resources;Scientist;Solutions;Strategic Planning;United States National Institutes of Health;comparative;design;innovation;meetings;posters;programs;public health relevance;symposium;working group

public_health_relevance:
PUBLIC HEALTH RELEVANCE   
This grant will support three conferences over a five-year period to convene the Directors of Resource Centers funded by the National Institutes of Health Office of Research Infrastructure (ORIP) Division of Program Coordination Planning and Strategic Initiatives. The objectives of the conference are to provide a forum for Directors to discuss common issues and problems relevant to fulfilling the mission of ORIP to receive input and guidance from NIH staff and scientists and to share ideas for common solutions.


application_id: 8986280
project_number: 1R13ES026036-01
project_title: 2016 Central and Eastern European Conference on Health and the Environment
administering_ic: NIEHS
award_notice_date: 2015-12-30
opportunity_number: PA-13-347
application_type: 1
activity_code: R13
ic: ES
serial_number: 026036
program_official: HENRY, HEATHER F
project_start_date: 2016-01-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZES1 JAB-D (R3)]
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The Central and Eastern European Conference on Health and the Environment (CEECHE) is a critically important international venue designed to focus representative global research and stakeholder expertise in environmental health and science on major challenges related to environmental exposures in Central Eastern Europe (CEE) countries. In particular this conference series is a vital platform for continuing coordination of US and Central Eastern Europe stakeholder expertise directed at multiple facets of environmentally-induced diseases. This region not only has a pre-1989 legacy of serious environmental contamination and neglect with associated devastating human health impacts but also faces the challenges of more recent environmental disasters. The proposed 2016 conference theme Prevention of Environmental Exposures and Disease Risks builds on 25 years of international interactions dedicated to the exchange of knowledge and expertise and concerted efforts to build a network of scientists health experts and federal and private stakeholders to address collaboratively these persistent problems. Key areas of focus will include population health impacts including insights into the exposome and epigenetic impacts environmental disease prevention strategies including lifestyle factors environmental remediation technologies and risk assessment public policy implications and next-generation scientific leadership. The University of Kentucky Superfund Research Center Lexington Kentucky proposes to partner with the Institute of Experimental Medicine Prague Czech Republic to organize and implement the 2016 Central and Eastern European Conference on Health and the Environment in Prague Czech Republic April 10-14 2016. Conference aims are to: 1) provide an intellectual exchange between scientists and trainees in the field of health and the environment by exploring innovative and sustainable strategies for environmental detection and remediation of hazardous pollutants; 2) review multiple environmental stressors and health status as a variant of disease by including studies related to persistent organic pollutants metals mixtures and new and emerging pollutants; 3) compare understand and assess population health impacts associated with exposure science and prevention of environmental disease through multi-level interventions and new risk assessment paradigms; and 4) provide a platform to strengthen the relation and collaboration between US and Central Eastern Europe trainees and young environmental scientists relative to environmental challenges in the 21st century. The conference will allow diverse early career and established investigators to communicate timely research results on pertinent scientific topics and promote future interactions aligned with an emerging prevention paradigm relevant to environmental health. The conference site in Prague will facilitate maximum participation of European Union and other Central Eastern Europe scientists and stakeholders with their US counterparts to promote productive interactions focused on emerging global priorities and enduring challenges in the area of environmentally-induced disease.

project_terms:
Address;Adopted;Air;Air Pollution;Area;Biological;Caustics;Chemicals;Collaborations;Complex;Country;Coupled;Cyanides;Czech Republic;Detection;Disasters;Discipline;Disease;Eastern Europe;Ecology;Education;Environment;Environmental Exposure;Environmental Health;Environmental Impact;Environmental Pollution;Environmental sludge;Epigenetic Process;Europe;European;European Union;Event;Exposure to;Face;Funding;Future;Goals;Gold;Health;Health Status;Human;Hungary;Institutes;Institution;International;Intervention;Kentucky;Knowledge;Leadership;Left;Link;Longevity;Medicine;Metals;Mexico;Mining;Minority;National Institute of Environmental Health Sciences;Oils;Outcome;Pathway interactions;Plants;Pollution;Predisposition;Prevention;Prevention strategy;Process;Public Health;Public Policy;Publications;Research;Research Personnel;Residual state;Resources;Risk;Risk Assessment;Rivers;Romania;Science;Scientist;Series;Site;Soil;Students;Superfund;Technology;Tennessee;Therapeutic Intervention;Toxic Environmental Substances;Toxic effect;Toxicant exposure;Travel;Universities;Variant;West Virginia;Woman;career;chemical spill;coal ash;contaminated water;cost;design;disorder prevention;disorder risk;environmental stressor;exposed human population;health disparity;health literacy;innovation;insight;interdisciplinary approach;lifestyle factors;neglect;next generation;novel;operation;persistent organic pollutants;policy implication;pollutant;population health;prevent;public health relevance;remediation;symposium;technological innovation;therapeutic development;toxicant;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Central and Eastern European Conference on Health and the Environment 2016 will provide an ideal setting to discuss and tackle challenges of reducing/preventing health risks associated with high-level exposure to persistent environmental contaminants in Central and East Europe. The conference theme focuses on prevention paradigms to reduce and modulate environmental exposures and modulate exposure-associated health impacts.


application_id: 8985734
project_number: 1R01NS093920-01
project_title: Microglia responses to CNS injury: targeting p38 MAPK signaling
administering_ic: NINDS
award_notice_date: 2015-04-24
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: NS
serial_number: 093920
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Cellular and Molecular Biology of Glia Study Section[CMBG]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Microglia are the resident tissue myeloid cell in the brain. Acute isolation and molecular profiling of adult microglia have clearly identified a microglia-specific gene expression profile not found in other macrophage populations or other cells in the CNS. As a molecular and functionally unique population of cells microglia exhibit a remarkable ability to survey the brain and rapidly undergo a spectrum of responses to insults or tissue damage. These coordinated responses normally result in protection against injury but can be dysfunctional and exacerbate or even cause neurological disease. An added layer of complexity occurs when monocytes are recruited to the brain following disease or injury. As a functionally distinct population newly recruited monocytes/macrophages make different contributions to disease progression compared to microglia. One of the top canonical pathways in microglia/macrophages is the p38 MAPK pathway a well-established signaling pathway important in stress responses. In the last funding period we documented the importance of the p38alpha isoform in microglia proinflammatory cytokine production and found that suppression of p38alpha can prevent the inflammatory response that causes subsequent neuronal/synaptic damage. In two mouse models of diffuse traumatic brain injury (TBI) we found that deletion of p38alpha in myeloid cells was associated with decreased microglia activation and a rescue of vestibulomotor deficits cognitive impairments and synaptic protein loss. Our data demonstrating the importance of p38alpha in regulating key functions of macrophages/microglia that are altered by a brain injury provides a strong precedent for further mechanistic and translational studies. We have now developed an exceptionally specific small molecule p38alpha inhibitor (termed MW150) that is CNS- penetrant has drug-like properties and no adverse effects at very high doses. MW150 is a novel reagent with high translational relevance for future therapeutic development. As a foundation for future development we now propose to address mechanistically how to target p38alpha to improve outcomes following a TBI. To this end we need to answer: 1) When can p38alpha be targeted; i.e. what is the optimal therapeutic window after TBI? 2) Where and how can p38alpha be targeted; i.e. does p38alpha in other inflammatory cell types besides microglia (infiltrating macrophages astrocytes endothelial cells)
contribute to neuroinflammatory responses after TBI? Our studies will provide key mechanistic information about how injury-induced p38alpha-dependent inflammatory responses in multiple cell types synergize and cross-talk to drive neurologic impairments. We will test the hypothesis that suppression of p38alpha signaling in appropriate therapeutic windows and appropriate cell types after CNS injury can lead to selective beneficial outcomes. Our aims are: Aim 1. Establish the post-injury therapeutic window for efficacy of our small molecule p38a inhibitor. Aim 2. Define the contribution of p38a in resident microglia versus infiltrating macrophages to TBI-induced impairments. Aim 3. Determine how p38alpha in other CNS inflammatory cell types (astrocytes and endothelial cells) contributes to injury-induced responses.

project_terms:
AD pathology;Acute;Address;Adult;Adverse effects;Alzheimer's Disease;Astrocytes;Brain;Brain Injuries;Cells;Central Nervous System Diseases;Chronic;Clinical;Cognitive deficits;Craniocerebral Trauma;Data;Dementia;Development;Diffuse;Disease;Disease Progression;Dose;Drug Kinetics;Endothelial Cells;Exhibits;Foundations;Functional disorder;Funding;Future;Gene Expression Profile;Immune response;Impaired cognition;Impairment;Inflammatory;Inflammatory Response;Injury;Intervention;Lead;MAPK14 gene;Medical;Microglia;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Profiling;Morbidity - disease rate;Mus;Myeloid Cells;Nervous System Physiology;Nervous System Trauma;Neuroglia;Neurologic;Neurons;Outcome;Paracrine Communication;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phosphotransferases;Population;Production;Property;Protein Isoforms;Proteins;Reagent;Recruitment Activity;Reporting;Research;Risk;Role;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Site;Surveys;Synapses;Testing;Therapeutic;Therapeutic Intervention;Tissues;Traumatic Brain Injury;analog;biological adaptation to stress;cell type;central nervous system injury;cytokine;defined contribution;effective therapy;human MAPK14 protein;improved;inhibitor/antagonist;injured;macrophage;monocyte;mouse model;nervous system disorder;neuroinflammation;novel;prevent;public health relevance;response;small molecule;stressor;therapeutic development;therapeutic target;translational study


application_id: 8984635
project_number: 1R01CA193220-01A1
project_title: Ubiquilin1 regulates EMT and metastasis of human lung adenocarcinoma
administering_ic: NCI
award_notice_date: 2015-08-07
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 193220
suffix: A1
program_official: AULT, GRACE S
project_start_date: 2015-08-07
project_end_date: 2020-07-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9743542
contact_pi: BEVERLY, LEVI J
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality worldwide causing more than 1.3 million deaths each year. Over ~700000 of these victims succumb to lung cancers that have alterations in one of the genes encoding members of the Ubiquilin family (UBQLN). The UBQLN family of proteins consists of 5 family members (UBQLN1-4 and UBQLNL) which all contain ubiquitin-like (UBL) and ubiquitin-associated domains (UBA). There is very limited data on biological processes regulated by UBQLN proteins. A direct role for UBQLN proteins in human cancer has not previously been examined. The goal of this proposal is to understand how disruption of UBQLN1 or UBQLN2 contributes to the metastatic progression of human lung adenocarcinoma. The ultimate goal of this project is to identify the cellular processes altered specifically in cancers that harbor loss of UBQLN function. The preliminary data in this proposal are the first to suggest that UBQLN loss is capable of directly altering processes involved in metastatic progression of human lung cancer. We demonstrate that loss of UBQLN1 or UBQLN2 increases EMT migration and invasion of transformed and non-transformed lung epithelial cells and that UBQLN1 regulates multiple pathways known to be critical in human lung cancer including IGF1R mTOR MYC and ERK. We propose to examine in detail how UBQLN1 and UBQLN2 regulate key steps of metastatic progression in vitro as well as determine if UBQLN1 loss alters the in vivo kinetics of metastatic
tumor progression. Importantly we have observed that one allele of UBQLN1 or UBQLN2 is lost in over 50% of human lung adenocarcinomas. The data gained from this application will determine if cancers harboring altered UBQLN function represent a novel subset of lung cancers and if the expression of UBQLN family members can be used as a predictive biomarker to determine which patients are more likely to succumb to metastatic lung cancer. By understanding how alterations in UBQLN1 signaling contributes to metastatic progression we may be able to target these downstream pathways specifically in tumors with altered UBQLN1 function to block metastasis thus potentially affecting millions of lung cancer patients in the coming decades.

project_terms:
Accounting;Adenocarcinoma;Adenocarcinoma Cell;Affect;Alleles;Amino Acids;Back;Biochemical;Biological;Biological Assay;Biological Markers;Biological Process;Cancer Etiology;Cancer Patient;Cancer cell line;Cell Line;Cell physiology;Cells;Cessation of life;Client;Clustered Regularly Interspaced Short Palindromic Repeats;Data;Diagnosis;Disease;Disseminated Malignant Neoplasm;Engineering;Epithelial Cells;Family;Family member;Future;Genes;Genetic Engineering;Goals;Growth;Human;Human body;IGF1R gene;In Vitro;Individual;Kinetics;Laboratories;Lead;Link;Lung;Lung Adenocarcinoma;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Metastatic to;Mortality Vital Statistics;Mutation;Neoplasm Metastasis;Non-Small-Cell Lung Carcinoma;Oncogenes;Pathway interactions;Patients;Phenotype;Play;Primary Neoplasm;Process;Property;Protein Family;Proteins;Recurrence;Role;Sampling;Signal Pathway;Signal Transduction;Site;Staging;Therapeutic;Transgenic Mice;Tumor Burden;UBA Domain;Ubiquitin;Xenograft Model;Xenograft procedure;base;cancer cell;cell motility;epithelial to mesenchymal transition;human FRAP1 protein;in vivo;in vivo Model;insight;member;metastatic process;migration;mouse model;mutant;novel;protein function;public health relevance;research study;small hairpin RNA;success;therapeutic target;tumor;tumor progression;tumorigenesis;ubiquilin


application_id: 8984490
project_number: 1R44HL129870-01
administering_ic: NHLBI
award_notice_date: 2015-07-22
opportunity_number: PA-14-071
application_type: 1
activity_code: R44
ic: HL
serial_number: 129870
program_official: LEE, ALBERT
project_start_date: 2015-08-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1 CVRS-C (10)]
contact_pi_person_id: 10459031
contact_pi: BATES, MARK
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 968130778
duns_number: 968130778
fips: US
organization_id: 10032915
organization_name: ROSELLINI SCIENTIFIC, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111162
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-08-01
budget_end_date: 2016-12-31
assistance_listing_number: 93.837
project_title:
Development of a microperforated nanocomposite balloon for intravascular anti-restenotic drug delivery

project_abstract:
DESCRIPTION (provided by applicant): Hemodialysis is the most common treatment for kidney failure requiring the passing of blood out of the body through a filter and back into the
body. Almost 30% of hemodialysis patients undergo arteriovenous graft procedures involving the insertion of prosthetic shunts (i.e. synthetic tubes) between artery and vein particularly in
the forearm. With the hemodialysis patient population estimated to reach over 500000 by 2020 the number of patients requiring grafts will reach over 150000 (30% of 500000) and most of these grafts will eventually clot. Clotting occurs in these grafts due to blockages that occur in te blood vessel at the outflow site of the graft. As a result many hemodialysis patients require intervention to open up the narrowing or stenosis of the blood vessel. Currently interventions for clotted grafts involve removal of the clot with a device followed by angioplasty of the vein. Once angioplasty is needed the lesion will keep restenosing and often the patients need additional declot procedures and repeat angioplasty. While stents are routinely used to open up narrowed arteries they cannot be implemented in this case. A more mechanically compliant structure is needed. Relatively new drug-coated balloons (DCBs) are a possible solution. However DCBs inherently exhibit sporadic and unpredictable drug delivery. Furthermore DCB drug delivery is currently quite inefficient with much of the drug being lost downstream. This increases the potential for systemic toxicity. In addition chemical agents (excipients) are needed to control diffusion of the drug coating. These excipients pose a risk of downstream embolism for the patient. A more efficient safer method of intravascular anti-restenotic drug delivery is needed to improve efficacy and reduce risk of embolism. We propose to develop a nanocomposite-based polymer balloon with microperforations to enable pulsed-flow drug delivery to the lesion. Using our approach drugs can be efficiently delivered directly to the diseased site reducing the potential for systemic toxicity. Our intravascular drug delivery system is capable of delivering drugs of almost any form from lipophilic drugs to hydrophilic drugs and even combinations thereof.

project_terms:
Adverse reactions;Angioplasty;Animals;Arteries;Back;Biological;Blood;Blood Vessels;Carbon Nanotubes;Caring;Catheters;Chemical Agents;Chemistry;Coagulation Process;Development;Devices;Dialysis procedure;Diffusion;Disease;Drug Delivery Systems;Dysbarism;Embolism;Evaluation;Excipients;Excision;Exhibits;FDA approved;Family suidae;Fee-for-Service Plans;Forearm;Health;Hemodialysis;In Situ;Intervention;Kidney Failure;Laboratories;Lesion;Liquid substance;Manufactured Materials;Manufacturer Name;Measures;Mechanics;Medical;Medical Device;Methods;Modeling;Modification;Monitor;Mortality Vital Statistics;Nylons;Organ Transplantation;Output;Paclitaxel;Patients;Pharmaceutical Preparations;Phase;Physiologic pulse;Polymers;Procedures;Process;Prosthesis;Research Institute;Risk;Safety;Shunt Device;Site;Solutions;Stenosis;Stents;Structure;Surface;Technology;Testing;Therapeutic Effect;Toxic effect;Tube;Twin Multiple Birth;Validation;Veins;Work;aqueous;base;biocompatible polymer;biomaterial compatibility;common treatment;cost;design;improved;in vivo;individualized medicine;nanocomposite;patient population;polymerization;pressure;public health relevance;restenosis;scale up

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The major challenge for hemodialysis patients is the eventual blockage of arteries occurring near the site in the forearm where the dialysis tubing is inserted. We propose to develop a drug delivery system that will eliminate these blockages. Our drug delivery system will lower the added care costs currently required to manage hemodialysis patients and reduce their mortality risk.


application_id: 8984464
project_number: 2R44DK089892-06
project_title: NOVEL ASSAY TO DETECT CHRONIC KIDNEY DISEASE
administering_ic: NIDDK
award_notice_date: 2015-08-10
opportunity_number: PA-14-071
application_type: 2
activity_code: R44
ic: DK
serial_number: 089892
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2010-09-20
project_end_date: 2018-06-30
study_section: Special Emphasis Panel[ZRG1 DKUS-L (11)]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: COUGHLIN, RICHARD THOMAS
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant:  There are an estimated 26 million Americans with chronic kidney disease (CKD). Early diagnosis and treatment are the only cost-effective means to reverse this growing problem. NIH recognizes the challenge to diagnose CKD early during its initiation and development phases in order to prevent further renal damage reduce cardiovascular risk and minimize the economic impact of CKD. Currently two complimentary tests - estimated GFR (eGFR) and urine albumin-to-creatinine ratio (UACR) - are used to identify CKD and are effective once the onset of disease has occurred. We will produce a new ELISA for CKD to be employed as a diagnostic test based upon the use of a novel biomarker that reflects critical events in the pathophysiology of kidney disease. Preliminary results suggest
that our CKD-ASSAY could replace or compliment both predicate assays. Further the specificity and reproducibility of the results may reduce or eliminate the need for repeat testing.
Aside from increased convenience and reduced time to treatment this may mean that the cost of screening for CKD may be greatly reduced.  Our CKD-ASSAY would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension diabetes or a family history of CKD. In Phase I we evaluated the feasibility and proof-of principal of this test
and found that the prototype assay in both at-risk populations was highly sensitive and specific. In Phase II we confirmed the specificity of our CKD-ASSAY established concordance with other assays and looked for other factors that might have impacted on assay performance. We request Phase IIB support so that we can prepare cGMP kits perform the pivotal clinical evaluations submit our 510(k) application to the FDA and prepare for commercial launch.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Adult;Affect;Agreement;Albumins;American;Biological Assay;Biological Markers;Blinded;Calibration;Cardiovascular Diseases;Child;Chronic Kidney Failure;Clinical;Clinical Research;Clinical Trials;Code;Communities;Creatinine;Cyclic GMP;Detection;Development;Devices;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Disease;Doctor of Philosophy;Early Diagnosis;Early treatment;End stage renal failure;Enzyme-Linked Immunosorbent Assay;Equation;Event;Family history of;Functional disorder;Funding;Goals;Health Insurance Portability and Accountability Act;Hemodialysis;Howard Temin Award;Hypertension;ICD-9;In Vitro;Injury;Intellectual Property;Kidney;Kidney Diseases;Legal patent;Measures;Methods;Minority Groups;Morbidity - disease rate;Mortality Vital Statistics;Onset of illness;Patients;Performance;Phase;Physicians;Polycystic Kidney Diseases;Population;Populations at Risk;Premature Infant;Prevalence;Process;Publishing;Quality Control;Records;Regulatory Pathway;Reproducibility of Results;Series;Sickle Cell;Site;Specificity;System;Testing;Time;United States;United States National Institutes of Health;Urine;Work;base;cardiovascular risk factor;cohort;commercialization;cost;cost effective;cost efficient;economic impact;high risk;loss of function;manufacturing process;novel;polyclonal antibody;post gamma-globulins;pre-clinical;prevent;programs;prototype;public health relevance;research clinical testing;screening;success;validation studies

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease hemodialysis and end stage renal disease. We will develop an assay for identification of people with advanced kidney disease that are under-diagnosed by current methods and to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 8984298
project_number: 5R01DE017921-06
project_title: Role of JAKs in innate responses to P. gingivalis
administering_ic: NIDCR
award_notice_date: 2015-12-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DE
serial_number: 017921
program_official: CHANDER, PREETHI
project_start_date: 2010-06-23
project_end_date: 2019-12-31
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: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adopted;Affect;Agonist;Alveolar Bone Loss;Anti-Inflammatory Agents;Anti-inflammatory;Autocrine Communication;Bacteria;Bacterial Infections;Bone Marrow;Cells;Chronic;Data;Disease;Equilibrium;Event;Family;Gingiva;Goals;Health;Homeostasis;Human;Immune;Immune response;Inflammation;Inflammatory;Inflammatory Response;Interleukin-10;Interleukin-4;JAK3 gene;Janus kinase;Knockout Mice;Mass Spectrum Analysis;Mediating;Microbe;Modeling;Modification;Mus;Natural Immunity;Neutrophil Infiltration;Organism;Pathway interactions;Pattern;Periodontal Diseases;Periodontitis;Periodontium;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Process;Production;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Reaction;Regulation;Role;Signal Pathway;Signal Transduction;Signaling Protein;Site-Directed Mutagenesis;Testing;Therapeutic Intervention;Time;Tissues;Translating;Work;bone loss;cytokine;design;in vivo;knock-down;macrophage;member;microbial;microbial community;monocyte;novel;oral infection;pathogen;pathogenic bacteria;prevent;response;therapy design


application_id: 8984161
project_number: 5R37DE011111-23
project_title: P.gingivalis interactions with gingival epithelial cells
administering_ic: NIDCR
award_notice_date: 2015-12-17
opportunity_number: PA-07-070
application_type: 5
activity_code: R37
ic: DE
serial_number: 011111
program_official: LUNSFORD, DWAYNE
project_start_date: 2014-01-01
project_end_date: 2018-12-31
study_section: NSS
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Periodontal diseases are one of the most common bacterial infections of humans and impose a significantburden on the health care system. One of the predominant pathogens in periodontal disease is P.gingivalis; however P. gingivalis can also inhabit the oral cavity in the absence of disease. The interactionbetween P. gingivalis and gingival epithelial cells makes a significant contribution to the degree ofequilibrium between host and microbe and to overall gingival health status. P. gingivalis can manipulateepithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram hostinnate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase SerB.The goal of this proposal is define the outcomes of the interaction between P. gingivalis and gingivalepithelial cells as they relate colonization of the organism and the generation of immune dysbiosis. We shallalso continue our major focus on the role of the functionally versatile SerB invasin and modulin of P.gingivalis. Cofilin an actin depolymerizing protein is required for P. gingivalis invasion. We will examinethe ability of SerB to dephosphorylate and inactivate LIMK kinase which will lead to activation of cofilin. Wewill then investigate the impact of P. gingivalis on ROCK PAK1 and MK2 pathways that lead to activation of LIMK. These interactions will be observed within the cell by live cell imaging. P..gingivalis can suppressIL-8 production in part through regulation of actin dynamics. We shall study the cofilin dependent actinmediated suppression of IL-8 by P. gingivalis. The immune disruptive ability of P. gingivalis also extends toT-cell chemokines and the mechanism of suppression of IP-10 ITAC and Mig will be studied. We will alsobegin to assess biological relevance by examining T-cell migration in response to epithelial cells infectedwith P. gingivalis. These studies will provide a detailed molecular analysis of the targeting of host signaltransduction by P. gingivalis along with the role of a specific effector phosphatase. Ultimately the knowledge gained could be developed into strategies that could be utilized to intervene in the P.gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host.

project_terms:
Actins;American;Bacterial Infections;Binding;Biological;Biological Assay;CXCL10 gene;Cell Communication;Cells;Complement;Data;Development;Disease;Elements;Ensure;Epithelial Cells;Equilibrium;Family;Generations;Gingiva;Goals;Health Status;Healthcare Systems;Human;I-kappa B Proteins;IL8 gene;IRF1 gene;Immune;Immunologic Surveillance;Infection;Instruction;Interferons;Knowledge;LIM Domain Kinase 1;LIMK1 gene;Label;Lead;Location;Luciferases;MEK inhibition;MEKs;Measurement;Measures;Mediating;Microbe;Molecular;Molecular Analysis;Natural Immunity;Nuclear Translocation;Oral cavity;Organism;Outcome;Pathway interactions;Periodontal Diseases;Phospho-Specific Antibodies;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Plasmids;Porphyromonas gingivalis;Process;Production;Protein Dephosphorylation;Proteins;ROCK1 gene;Regulation;Reporter;Role;Serine;Signal Transduction;Signal Transduction Pathway;Signaling Molecule;Small Interfering RNA;Structure;T-Lymphocyte;TNF gene;Testing;Therapeutic Agents;Variant;actin depolymerizing proteins;cell motility;chemokine;cofilin;design;in vivo;live cell imaging;mutant;novel;novel therapeutics;overexpression;p65;pathogen;prevent;promoter;response;transcription factor

public_health_relevance:
RELEVANCE (See instructions):P. gingivalis is a cause of periodontal diseases that afflict millions of Americans. In this study we willexamine the interactions between P. gingivalis and the human cells that are colonized by the organism. Theinformation to be gathered could be used to identify targets for novel therapeutic agents designed tointerfere with the colonization and survival strategies of P. gingivalis.


application_id: 8983412
project_number: 1F30DE025543-01
project_title: Characterization of P. gingivalis minor fimbrial accessory proteins
administering_ic: NIDCR
award_notice_date: 2015-04-22
opportunity_number: PA-14-150
application_type: 1
activity_code: F30
ic: DE
serial_number: 025543
program_official: FRIEDEN, LESLIE A
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11948429
contact_pi: LEE, JAE YONG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adhesions;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Animals;Area;Binding (Molecular Function);Biogenesis;Biological Assay;Cell surface;Chronic;Chronic Disease;Clinical;Communities;Complement;Complex;Development;Disease;Electron Microscopy;Epithelial Cells;Exhibits;Filament;Gene Cluster;Genes;Goals;Homeostasis;Immune;Immune response;Immunity;Individual;Infection;Inflammatory;Lead;Left;Length;Location;Mediating;Membrane Proteins;Minor;Modeling;Molecular;Mouth Diseases;Mus;Oral;Oral cavity;Oral health;Organism;Outcome;Pathogenesis;Pathogenicity;Periodontitis;Population;Porphyromonas gingivalis;Process;Properdin;Protein Binding;Protein Subunits;Proteins;Recombinant Proteins;Research;Resistance;Role;Severities;Streptococcus gordonii;Structure;Surface;Testing;Therapeutic Studies;Tissues;Tooth Exfoliation;Tooth Loss;United States;Virulence Factors;bone loss;co-infection;design;fimbria;immunoregulation;improved;in vivo;mouse model;mutant;new therapeutic target;novel;novel therapeutics;oral bacteria;pathogen;prevent;protein complex;protein structure;public health relevance;therapeutic target


application_id: 8983254
project_number: 1F31AA023694-01A1
project_title: Intoxication in a Rewarding Environment as a Risk Factor for Alcohol Misuse
administering_ic: NIAAA
award_notice_date: 2015-07-14
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: AA
serial_number: 023694
suffix: A1
program_official: URBANAS, DIANA
project_start_date: 2015-07-26
project_end_date: 2016-05-14
study_section: Epidemiology, Prevention and Behavior Research Study Section[AA-2]
contact_pi_person_id: 12082179
contact_pi: LAUDE, JENNIFER
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
project_abstract:
DESCRIPTION (provided by applicant): There is evidence for the role of the environment on responses to alcohol in terms of behavioral functioning. However experiencing a history of reward while intoxicated on the appetitive properties of alcohol is a relatively unexplored area of
study. Such an experience could generalize to the intoxicated state and increase the rewarding properties of alcohol. Theory also suggests that enhanced appetitive properties of alcohol resulting from such a history could increase disinhibition in the presence of alcohol cues. Different environmental factors present during drinking that tend to be reinforcing in themselves such as socializing with friends in a bar setting. Although there is empirical evidence that situational factors alter subjective responses to alcohol no study has assessed the transfer of these changes on a prospective drinking episode. It is also unknown whether a rewarding history while intoxicated affects the response to alcohol cues. Further manipulations have been brief and have confounded positive experiences and socialization for example. This study will test the general working hypothesis that a rewarding history while intoxicated will increase the appetitive effects that drinkers attribute to alcohol and to alcohol cues. To this end subjects wil play a rewarding game across the BAC curve following a low dose of alcohol and will be later tested on various measures following an acute dose of alcohol. 3 key indicators of the rewarding properties of alcohol will be used to examine how a rewarding experience while mildly intoxicated affects behavior on a later drinking occasion. That a correlation exists between my implicit measure of the appetitive properties of alcohol cues and disruption of behavioral control suggests that the resultant increase in the rewarding properties of alcohol owing to a rewarding experience while intoxicated may increase alcohol cue-induced disinhibition in response to an acute dose of alcohol. This will be tested using two disinhibition tasks. One will measure alcohol-cue-induced disinhibition and the second will measure disinhibition in the absence of alcohol cues. A rewarding experience while mildly intoxicated should selectively increase alcohol-cue-induced disinhibition.  Results of this research would have important implications for the growing interest in interventions aimed reducing drinking by attentional-retraining and inhibitory control exercises. Such approaches do not consider the role of the environment on the rewarding properties of alcohol and alcohol cues and this may contribute why they fail to reduce drinking long-term. As such the effectiveness of behavioral interventions may increase when training occurs in multiple environments especially in those where there was a prior history of reward while intoxicated. This is because a rewarding history while intoxicated may enhance the appetitive responses to alcohol and result in an increase in alcohol-cue-induced disinhibition. As such these results could inform training aimed at attenuating alcohol-cue-induced disinhibition a key indicator of abuse potential.

project_terms:
Acute;Affect;Alcohol consumption;Alcoholic Intoxication;Alcohols;Area;Attenuated;Behavior;Behavior Control;Behavior Therapy;Behavioral;Cognition;Consumption;Dependence;Development;Disinhibition;Dose;Effectiveness;Environment;Environmental Risk Factor;Exercise;Friends;Genetic;Incentives;Intervention;Intoxication;Light;Measures;Patient Self-Report;Pattern;Perception;Placebos;Play;Property;Recording of previous events;Relative (related person);Research;Research Proposals;Rewards;Risk Factors;Role;Socialization;Testing;Training;Work;alcohol cue;alcohol misuse;alcohol response;alcohol use disorder;attentional bias;conditioning;drinking;experience;high risk drinking;interest;motivated behavior;prospective;public health relevance;response;success;theories;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Studying whether rewarding environments enhance the appetitive properties of alcohol and alcohol cues is important because it will shed light on mechanisms of binge patterns of drinking in young adults who oftentimes drink in rewarding environments (e.g. bar with friends). Further current conditioning treatments aimed at reducing at-risk drinking have been limited in their success and do not consider the role of the environment on responses to alcohol and alcohol cues. This application will inform why treatments like attentional and inhibitory control training are not the most efficacious and that success rates may increase when training occurs in multiple environments; especially in contexts that imbue positive properties to alcohol and alcohol cues.


application_id: 8983158
project_number: 1F31NS092418-01A1
project_title: Determination of the epigenetic regulation of gene transcription by MeCP2 in neurons
administering_ic: NINDS
award_notice_date: 2015-06-12
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: NS
serial_number: 092418
suffix: A1
program_official: MAMOUNAS, LAURA
project_start_date: 2015-07-01
project_end_date: 2017-09-30
study_section: Special Emphasis Panel[ZRG1 F03B-D (20)]
contact_pi_person_id: 12337891
contact_pi: RIEDMANN, CAITLYN M
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Over 90% of the cases of the devastating neurodevelopmental disorder Rett Syndrome (RTT) which affects 1 in 10000 girls is due to loss of function mutations in the X-linked methyl CpG binding protein 2 (MeCP2). MeCP2 is expressed in low levels throughout the body and during neurogenesis but is expressed at a level equivalent to linker histone H1 in mature neurons reaching a stoichiometry of one molecule MeCP2 per two nucleosomes the basic repeating unit of chromatin. Many RTT symptoms have been traced to MeCP2 mutations in neurons within specific regions of the brain and glial cells. Therefore determining the principles of MeCP2 mediated regulation is critical for understanding RTT pathology.  MeCP2 and H1 compete to bind nucleosomes at their DNA entry/exit dyad and lead to distinct chromatin structures with specific transcriptional outcomes. The first aim of this study will be to determine what nucleosomes throughout the genome are regulated by MeCP2. The genome-wide transcriptional deregulation observed in cells with mutated MeCP2 indicate that MeCP2 binds to specific nucleosomes throughout neurogenesis and during differentiation to drive proper expression patterns. Furthermore glial cell transcriptional deregulation due to MeCP2 mutations also contribute to RTT phenotypes indicating that MeCP2's regulation is cell type specific. Nucleosome chromatin immunoprecipitation coupled with high throughput sequencing (nuc-ChIP-seq) will be used to generate MeCP2-bound nucleosome maps for neurons during neurogenesis mature neurons and for glial cells. In addition to determining the target nucleosomes/genes of MeCP2 regulation these maps will also identify what histone tail post translational modification (PTMs) patterns associate with/signal for MeCP2 binding.  By binding to the DNA entry/exit dyad of nucleosome MeCP2 and H1 alter 'nucleosome breathing' the spontaneous dissociation of the DNA from the histone octamer thereby regulating the accessibility of DNA target sites usually buried within chromatin to their binding proteins. Therefore the second aim will be to determine how MeCP2 influences nucleosome stability and dynamics. Frster resonance energy transfer (FRET) will be performed on mononucleosomes and restriction enzyme digest analysis on in vitro multi- nucleosome arrays to determine the intrinsic binding activity of MeCP2 to both the individual nucleosome and to chromatin. These in vitro arrays will be modified to determine how specific epigenetic factors such as DNA methylation and specific histone tail PTM patterns regulate this binding. Furthermore RTT-causing MeCP2 mutations will be utilized in order to determine how these binding properties are altered in disease states.  By combining next generation sequencing (aim 1) with detailed binding assays (aim 2) this study will generate a highly detailed and global view of MeCP2 mediated transcriptional regulation in cells important in brain development thereby providing important insights into RTT pathology and therapeutic targets.

project_terms:
Affect;Atomic Force Microscopy;Base Pairing;Binding (Molecular Function);Binding Proteins;Biochemical;Bioinformatics;Biological Assay;Brain;Breathing;Cells;Chromatin;Chromatin Structure;Conflict (Psychology);Coupled;DNA;DNA Methylation;DNA-Binding Proteins;Development;Disease;Dissociation;Energy Transfer;Environment;Epigenetic Process;Female;Gene Expression;Gene Expression Regulation;Gene Targeting;Genes;Genetic;Genetic Transcription;Genome;Genomic DNA;Growth Factor;Hand;High-Throughput Nucleotide Sequencing;Higher Order Chromatin Structure;Histocompatibility Testing;Histone H1;Histone H1(s);Histones;Homeostasis;In Vitro;Individual;Lead;Link;Location;Maintenance;Maps;Mediating;Methyl-CpG-Binding Protein 2;Molecular;Movement;Mutate;Mutation;Nature;Neurodevelopmental Disorder;Neuroglia;Neuronal Differentiation;Neurons;Nucleosomes;Outcome;Pathology;Pattern;Phenotype;Positioning Attribute;Post-Translational Protein Processing;Process;Property;Proteins;Recruitment Activity;Regulation;Reporting;Resolution;Rett Syndrome;Signal Transduction;Site;Speech;Structure;Symptoms;Tail;Tandem Repeat Sequences;Techniques;Testing;Time;Transcriptional Regulation;Work;analytical ultracentrifugation;biophysical techniques;brain cell;cell type;chromatin immunoprecipitation;developmental disease/disorder;epigenetic marker;epigenetic regulation;genome-wide;girls;insight;loss of function mutation;neurogenesis;next generation sequencing;prevent;public health relevance;relating to nervous system;restriction enzyme;stoichiometry;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Most cases of the devastating neural developmental disorder Rett Syndrome characterized by apparently normal development for the first 6-18 months followed by developmental regression and stagnation complete loss of speech and hand stereotypies replacing purposeful hand movements are due to mutations in the neural protein MeCP2 (methyl CpG binding protein 2). This project will determine how MeCP2 interprets its genetic environment to properly regulate gene transcription in neurons and how this interpretation is changed in Rett Syndrome so that targeted therapies and treatments can be established.


application_id: 8981814
project_number: 2R44NS083218-03
project_title: SYSTEM FOR AUTOMATED NONINVASIVE MONITORING OF MOUSE SLEEP AND BEHAVIOR
administering_ic: NINDS
award_notice_date: 2015-07-16
opportunity_number: PA-14-071
application_type: 2
activity_code: R44
ic: NS
serial_number: 083218
program_official: CAPORELLO, EMILY LAURA
project_start_date: 2013-04-01
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
contact_pi_person_id: 12510521
contact_pi: LHAMON, MICHAEL E
other_pis: SUNDERAM, SRIDHAR
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The basic functions of sleep are still unknown. Abnormal sleep patterns can manifest as a variety of disorders- sleep apnea parasomnias REM (rapid eye movement sleep) behavioral disorder (RBD) narcolepsy-many of which are influenced by heredity. There is an increasing focus on characterizing mouse behaviors for genetic and drug studies. However discovering the genes responsible for sleep and related disorders requires time- consuming large-scale behavioral screening of phenotypes to correlate observed traits with genetics. Behavioral monitoring of mice is usually limited to actigraphic measurements such as video tracking wheel-running and photoelectric beam-breaking. Although many of these methods are noninvasive and have potential for high- throughput (HT) application they monitor mainly locomotor activity without providing information about sleep-wake state and sleep architecture which are important for investigating sleep disorders. While EEG can be used to accurately determine sleep-wake state it is invasive and resource-intensive (surgery recovery etc.) which limits its application in large-scale genetic studies wih rodents. Signal Solutions LLC has developed a sensor cage environment for noninvasive behavioral monitoring that is being used by prominent research groups to identify genes responsible for different traits related to sleep and circadian rhythms. The specific aims of this work are to further improve the capabilities of the piezo system to noninvasively: 1. Discriminate sleep-wake state (sleep/wake REM/NREM) and behavior within wake (e.g. quiet vs. active high activity feeding grooming) to a level comparable to EEG/EMG by classifying piezo signal features with added low-cost video features; 2. Incorporate real-time feedback stimulation for behavior modification 3. Integrate electronics and with new multimodal sensing into a compact system for testing in research laboratories 4. Develop low-cost device for automatic animal welfare monitoring. The envisioned end product is a sensor cage and software interface for HT monitoring of sleep-wake state and behavior in small animals to identify genetic factors responsible for sleep/circadian disorders as well as behavioral effects of pharmacological manipulation sensory stimulation or neural injury (e.g. traumatic brain injury epilepsy). This system will be particularly advantageous for prescreening potentially interesting phenotypes and reserving invasive EEG analysis for further confirmation. Medical targets of interest are sleep/circadian disorders sleep apnea obesity/diabetes REM/NREM sleep deprivation and stress among others. Potential clients include academic research labs as well as industrial labs interested in behavioral monitoring on a large scale (e.g. drug screening).

project_terms:
Affect;Algorithms;Amplifiers;Animal Experimentation;Animal Housing;Animal Welfare;Animals;Behavior;Behavior Disorders;Behavior Therapy;Behavior monitoring;Behavioral;Behavioral Assay;Behavioral Genetics;Behavioral Research;Brain;Circadian Rhythm Sleep Disorders;Circadian Rhythms;Client;Code;Computer Interface;Computer software;Confidentiality;Data;Decision Trees;Development;Devices;Diabetes Mellitus;Discrimination (Psychology);Disease;Electroencephalography;Electronics;Environment;Epilepsy;Evaluation;Event;Feedback;Film;Floor;Genes;Genetic;Genetic Screening;Genetic study;Goals;Government;Grant;Grooming;Heredity;Home environment;Implant;Intervention;Kentucky;Label;Laboratory Research;Letters;Measurement;Medical;Methodology;Methods;Modification;Monitor;Motor Activity;Mus;Narcolepsy;Noise;Obesity;Operative Surgical Procedures;Outcome;Pattern;Persons;Pharmaceutical Preparations;Phase;Phenotype;Physiologic pulse;Play;Polysomnography;Power Sources;Preclinical Drug Evaluation;Quantitative Trait Loci;REM Sleep;REM Sleep Parasomnias;Recovery;Research;Resources;Rodent;Role;Running;Sensory;Signal Transduction;Sleep;Sleep Apnea Syndromes;Sleep Architecture;Sleep Deprivation;Sleep Disorders;Sleep Stages;Solutions;Stress;Structure;System;Systems Integration;Techniques;Testing;Time;Traumatic Brain Injury;Universities;Wakefulness;Work;actigraphy;awake;base;brain research;commercialization;cost;feeding;flexibility;foot;gene discovery;high throughput analysis;improved;interest;meetings;nerve injury;nervous system disorder;novel;pressure;prototype;public health relevance;respiratory;response;screening;sensor;signal processing;somatosensory;success;tool;trait;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Discovery of genes that play a role in sleep and circadian rhythm disorders requires extensive screening of behavior usually in mice preferably with invasive and resource-intensive brain signal (EEG) recordings to score sleep stage (REM NREM) and wake behavior. The goal of this research is to develop and validate a methodology for using a noninvasive pressure-sensitive piezoelectric ("piezo") sensor platform to distinguish different stages of sleep and behavior without the need for EEG making large-scale behavioral screening feasible and limit the need for EEG verification to only the most interesting phenotypes thus identified.


application_id: 8980968
project_number: 2R44AA021331-02A1
project_title: Novel Drug Carrier System for the Treatment of Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2015-09-25
opportunity_number: PA-14-071
application_type: 2
activity_code: R44
ic: AA
serial_number: 021331
suffix: A1
program_official: RADAEVA, SVETLANA
project_start_date: 2012-09-25
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1 DKUS-N (10)]
contact_pi_person_id: 10119089
contact_pi: BAUER, PHILIP
other_pis: GOBEJISHVILI, LEILA ;MALDONADO, CLAUDIO
congressional_district: 03
department: Unavailable
primary_duns: 144667602
primary_uei: TGWXNHCYTTR3
duns_number: 144667602
uei: TGWXNHCYTTR3
fips: US
organization_id: 10004330
organization_name: ENDOPROTECH, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402041019
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and no FDA-approved therapy exists. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF-) and TNF--inducible proinflammatory cytokines/chemokines such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis and levels
correlate with markers of the acute phase response reduced liver function and poor clinical outcome. The focus of this application is the delivery of a drug that uses a unique carrier system to target the liver and correct the dysregulated cytokine production. Preliminary studies in isolated cells indicated that cyclic AMP (cAMP) decreases when cells are exposed to alcohol and is associated with an increase in pro-inflammatory cytokine levels. Experiments in which cellular cAMP concentrations were increased attenuated this increase in pro-inflammatory cytokines. Also we have preliminary data implicating an increase in phosphodiesterase 4B (PDE 4B) in the decreased cAMP concentrations observed in alcohol-exposed cells. Our working hypothesis is that altered PDE 4B and cAMP metabolism cause abnormal cytokine production/activity which plays a critical role in the development and perpetuation of ALD. Our long-term goal is to develop therapeutic interventions based on this research thereby providing a much needed drug therapy for ALD. We have identified a highly effective PDE 4 inhibitor to treat ALD but in humans systemic administration of the inhibitor induces severe nausea when threshold levels cross the blood-brain-barrier and reach the central nervous system (CNS). In Phase I of this proposal we demonstrated that our carrier system targeted the drug to the liver and reduced PDE4 activity in liver but not in the brain. We concluded that administration of a PDE4 inhibitor in our carrier system limited access of the drug to the CNS reducing the potential for side effects. In Phase II we will optimize the carrier system and compare pharmacokinetic characteristics of free drug vs. drug in the carrier system. Also we will perform efficacy pharmacological safety and product stability studies of drug in the optimized carrier system. The data obtained will be used for an IND application to the FDA to initiate clinical trial and eventually for commercialization.

project_terms:
Abstinence;Acute-Phase Reaction;Adverse effects;Alcoholic Hepatitis;Alcoholic Liver Cirrhosis;Alcoholic Liver Diseases;Alcohols;Antibodies;Attenuated;Blood;Blood - brain barrier anatomy;Brain;Cause of Death;Cells;Chemicals;Chronic;Cirrhosis;Clinical;Clinical Trials;Crohn's disease;Cyclic AMP;Data;Development;Disease;Dose;Drug Carriers;Drug Delivery Systems;Drug Kinetics;Drug Targeting;Drug usage;Endotoxins;Enteral;Excipients;FDA approved;Goals;Hepatic;Hepatocyte;Human;IL8 gene;In Vitro;Inflammation;Inflammatory;Injury;Interleukin-10;Interleukin-18;Intestines;Kupffer Cells;Life;Lipids;Liver;Liver Regeneration;Liver diseases;Mediating;Metabolism;Modeling;Monitor;Mortality Vital Statistics;Multicenter Trials;Mus;Nausea;Nausea and Vomiting;Neuraxis;Oral;Outcome;PDE4B;Patients;Peripheral;Permeability;Pharmaceutical Preparations;Pharmacotherapy;Phase;Physicians;Plasma;Play;Prednisone;Process;Production;Reporting;Research;Research Personnel;Rheumatoid Arthritis;Role;Rolipram;Safety;Serum;Severity of illness;Solubility;Solutions;Staging;Stream;Surrogate Markers;Survival Rate;System;TLR4 gene;Testing;Therapeutic Effect;Therapeutic Intervention;Therapeutic Uses;Treatment Efficacy;Tumor Necrosis Factor-alpha;Vesicle;Water;Work;alcohol exposure;aqueous;base;chemokine;clinical application;clinically relevant;commercialization;cost;cytokine;feeding;in vivo;inhibitor/antagonist;liver function;liver injury;macrophage;monocyte;mouse model;novel;pharmacokinetic characteristic;phosphodiesterase IV;public health relevance;receptor;research study;response;safety study;sucrose octaacetate;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S. and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD but oral systemic administration of the inhibitor induces severe nausea in humans when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating in the blood stream and concentrates drug in the liver thereby maximizing the therapeutic effect while minimizing severe side effects.


application_id: 8980687
project_number: 1R43OD021317-01
project_title: TOWARDS A UNIVERSAL CHRONIC WOUND MODEL
administering_ic: OD
award_notice_date: 2015-07-28
opportunity_number: PA-14-071
application_type: 1
activity_code: R43
ic: OD
serial_number: 021317
program_official: CONTRERAS, MIGUEL A
project_start_date: 2015-08-01
project_end_date: 2017-01-31
study_section: Special Emphasis Panel[ZRG1 MOSS-T (12)]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal is in response to the mission of the Office of Research Infrastructure Programs (ORIP) to "Develop and provide access to critical animal models that offer essential clues to a broad range of human disorders". Our goal is to develop a universal animal model that best recapitulates non-healing human chronic wounds. The burden of chronic wounds is growing rapidly due to increasing health care costs an aging population and a sharp rise in the incidence of obesity and diabetes. Despite more than a century of extensive research and thousands of dressings developed even the best treatments achieve only a 50% healing rate-and this healing is often only temporary with high recurrence rate. A statement made in one of the first papers describing chronic wound treatment-that "Old ulcers in 1830 will be older ulcers in 1860"-unfortunately still applies today. Unless some dramatic measures are taken old ulcers in 2014 will be older ulcers in 2044.  It is expensive and time consuming to develop new wound care drugs. The ability to translate experimental findings into clinical usage relies heavily on animal models that serve as surrogates of the human condition. Human chronic wounds are defined as wounds that heal with a significant delay usually over a period of more than 2-3 months. However all current animal models have problems such as being acute in nature with very short or no ischemic time and mostly created in young animals. No current model is able to recapitulate human chronic wounds.  Although multiple factors are involved in nonhealing chronic wounds our unifying hypothesis is that tissue ischemia is the most critical factor hindering healing. Persistent tissue ischemia in te vicinity of the wound is an important underlying feature of chronic wounds that severely impairs the healing process. For many chronic wounds ischemia may not be the initiating factor because many ulcers start from a combination of repeated trauma neuropathy pressure loading and infection. However tissue ischemia is the main cause that hinders healing-wounds do not heal in tissue that does not bleed whereas they always heal in tissue that bleeds extensively.  We have developed an ischemic rabbit ear model using a minimally invasive surgical procedure. This model has the advantages of being simple safe economical and very flexible with minimal skin contraction. The duration of ischemia is about one month-the longest of all currently available models. This procedure has been used in more than one hundred rabbits without complications. However ischemia finally disappears after one month-which is still too short a duration to match human chronic wounds.  This project aims at further improvements in this model that will make it more closely approximate human chronic wounds with various pathophysiologic origins. The following goals are planned: 1) to extend the ischemic time up to 2-3 months 2) to use this model in aged animals; and 3) to ensure that the model remains simple safe and easy to create. For the phase I project our goal is to obtain the proof-of-concept that the ischemic time can be extended further by subcutaneous tissue separation with minimal or no side effects.  The minimally invasive surgery developed by our group has provided the longest ischemic wound model. The success of the current project will build a critical infrastructure program to fill a major gap in scientific research and provide a simple and easy to use animal model for wound dressing development.

project_terms:
Acute;Adverse effects;Affect;Animal Model;Animals;Caring;Chronic;Clinical;Development;Diabetes Mellitus;Disease;Ear structure;Ensure;Goals;Healed;Health Care Costs;Hemorrhage;Human;Impaired wound healing;Incidence;Infection;Ischemia;Length;Measures;Minimally Invasive Surgical Procedures;Mission;Modeling;Nature;Neuropathy;Obesity;Operative Surgical Procedures;Oryctolagus cuniculus;Paper;Pathology;Patients;Pharmaceutical Preparations;Phase;Procedures;Process;Protocols documentation;Recurrence;Research;Research Infrastructure;Silicone Gels;Skin;Sterile coverings;Subcutaneous Tissue;Techniques;Testing;Time;Tissues;Translating;Trauma;Ulcer;United States;Venous;Wound Healing;aged;aging population;base;cost;drug development;flexibility;healing;juvenile animal;minimally invasive;pressure;programs;public health relevance;research and development;response;subcutaneous;success;wound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The most critical deficiency in wound research and drug development is a lack of suitable animal model that can recapitulate the clinical features of chronic wounds. A minimally invasive technique to create an animal model with the longest ischemic time has been developed by our group. This project will further extend the ischemic time to reflect the most critical feature of non-healing chronic wounds. The success of this project will build a critical infrastructure program to fill a major gap in scientific research and
provide a simple and easy to use animal model for wound dressing development.


application_id: 8979673
project_number: 5R01CA133429-09
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2015-11-09
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: CA
serial_number: 133429
program_official: YASSIN, RIHAB R
project_start_date: 2009-04-01
project_end_date: 2019-11-30
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 7353657
contact_pi: GAO, TIANYAN
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Adenocarcinoma;Adipocytes;Affect;Automobile Driving;Cancer Cell Growth;Cancer Center;Cancer Etiology;Cell Proliferation;Cell Survival;Cells;Cessation of life;Citric Acid Cycle;Collection;Colon Carcinoma;Colorectal Cancer;Development;Down-Regulation;Ensure;Event;FRAP1 gene;Family;Genetic;Health;Human;Hypoxia;In Vitro;Intestines;Knockout Mice;Knowledge;Malignant Neoplasms;Mediating;Metabolic;Metabolic Pathway;Metabolic stress;Metabolism;Molecular;NOD/SCID mouse;Oncogenes;PH Domain;Pathway interactions;Patients;Pharmaceutical Preparations;Play;Production;Protein phosphatase;Proteins;Regulation;Research;Resistance;Role;Signal Transduction;Testing;Tissues;Translations;Treatment Efficacy;Tumor Suppressor Proteins;United States;Xenograft Model;cancer cell;cancer initiation;cancer therapy;chemotherapy;colon cancer patients;coping;design;glucose uptake;improved;in vivo;insight;leucine-rich repeat protein;lipid biosynthesis;lipid metabolism;mTOR Inhibitor;macromolecule;metabolomics;mouse model;novel;outcome forecast;research study;stable isotope;success;therapy resistant;treatment strategy;tumor metabolism;tumor progression;tumorigenesis


application_id: 8978819
project_number: 1R41AI120353-01
project_title: Improving the therapeutic efficacy of a lead vaccine against plague using a novel adjuvant system
administering_ic: NIAID
award_notice_date: 2015-05-08
opportunity_number: PA-14-072
application_type: 1
activity_code: R41
ic: AI
serial_number: 120353
program_official: ZOU, LANLING
project_start_date: 2015-05-15
project_end_date: 2017-10-31
study_section: Special Emphasis Panel[ZRG1 IMM-R (12)]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
other_pis: BOWEN, WILLIAM SEAN;LAWRENZ, MATTHEW B
congressional_district: 03
department: Unavailable
primary_duns: 079603469
primary_uei: LNESEBSKBHK8
duns_number: 079603469
uei: LNESEBSKBHK8
fips: US
organization_id: 10037836
organization_name: FASCURE THERAPEUTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   FasCure Therapeutics focuses on the development of adjuvant systems to generate prophylactic and therapeutic immune responses. The major objective of this Phase 1 STTR proposal is to reformulate a lead plague subunit vaccine with a novel adjuvant system to improve its protective efficacy.  Yersinia pestis is the causative agent of bubonic and pneumonic plague and a potential bioweapon. Currently there is not a vaccine available to protect the public from a potential epidemic or bioterrorism event. While Y. pestis infection can be treated with antibiotics the effective treatment window for primary pneumonic infection is very short (less than 24 hrs. after exposure). Furthermore naturally acquired resistance to antibiotics has been reported and weaponized Y. pestis could likely be modified to be resistant to antibiotic treatment. Therefore the development of an efficacious plague vaccine is an important scientific endeavor and public policy goal.  The current lead vaccine against plague is a subunit vaccine formulation consisting of a recombinant F1- LcrV fusion protein (rF1-V) adjuvanted with alum. This vaccine has proven effective in rodent models but has decreased efficacy in primate models and variable antibody production in clinical trials. Therefore while rF1-V appears to be an excellent vaccine candidate for plague it needs further improvement to produce a better immunogenicity profile. While the current vaccine primarily generates a Th2 humoral immune response several studies have demonstrated a critical role of Th1 cellular responses in protection against plague. Therefore the primary focus of this proposal is to establish a novel adjuvant system that generate a mixed Th1 and Th2 immune responses and use adjuvant to improve the efficacy of lead rF1V vaccine. This goal will be achieved by using alum MPL and SA-4-1BBL as agonists NLRs TLR4 and the 4-1BB receptor respectively that are critical for the generation of effective Th1 cellular and Th2 humoral immune responses. Aim 1 will establish the optimum dose of each adjuvant to generate balanced robust Th1 and Th2 responses against the rF1-V antigen. Aim 2 will use the lead vaccine formulation to determine its protective efficacy against pneumonic plague in mice.  If successful a Phase II proposal will be submitted to further develop this vaccine formulation by testing its protective efficacy against
plague using a nonhuman primate model as a prelude to clinical trials. Importantly the proposed adjuvant system may also be used as a platform to generate new subunit vaccines or improve the efficacy of the existing ones against other intracellular pathogens that need a balanced immune response.

project_terms:
Accounting;Adjuvant;Agonist;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Antibody Formation;Antigens;Binding (Molecular Function);Bioterrorism;Bubonic Plague;CD28 gene;Cercopithecus pygerythrus;Chimeric Proteins;Clinical Trials;Data Protection;Dendritic cell activation;Development;Dose;Drug Formulations;Epidemic;Equilibrium;Event;Family;Future;Generations;Goals;Human;Immune;Immune response;Immune system;Immunity;Immunization;Infection;Inflammatory Response;Lead;Lipid A;Memory;Modeling;Mus;Natural Immunity;Nucleotides;Pathway interactions;Pattern recognition receptor;Phase;Plague;Plague Vaccine;Pneumonic Plague;Pre-Clinical Model;Primates;Property;Public Policy;Receptor Signaling;Recombinants;Reporting;Rodent Model;Role;Safety;Shapes;Signal Transduction;Signaling Molecule;Small Business Technology Transfer Research;Subunit Vaccines;System;T cell response;T-Lymphocyte;Testing;Therapeutic;Toll-like receptors;Treatment Efficacy;Tumor Necrosis Factor Receptor;Up-Regulation (Physiology);Vaccination;Vaccines;Yersinia pestis;Yersinia pestis V antigen;adaptive immunity;aluminum sulfate;effective therapy;immunogenicity;improved;mouse model;nonhuman primate;novel;novel vaccines;pathogen;pre-clinical;prophylactic;protective efficacy;public health relevance;receptor;response;toll-like receptor 4;vaccine candidate;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  No vaccine for plague is available in the US to protect the public from a future epidemic or bioterrorism attack. The main objective of this proposal is to fas track the development of the existing lead plague vaccine candidate by using a novel adjuvant system to improve efficacy. These studies will establish the vaccine formulation and characterize the role of different components of the immune system in vaccine protection - these data will guide future tests in primate models and human clinical trials.


application_id: 8978015
project_number: 1P50AA024337-01
project_title: Mechanisms of Alcohol-Induced Lung and Liver Injury
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8305
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Lung Injury;Aging;Alcohol Nutrition;Alcohol abuse;Alcohols;Alveolar;Animals;Antioxidants;Area;Cell Culture Techniques;Cell surface;Cells;Chronic;Collagen;Defect;Deposition;Development;Dietary Intervention;Epigenetic Process;Epithelial Cells;Ethanol;Ethanol dependence;Extracellular Matrix;Fibroblasts;Fibronectins;Fibrosis;Functional disorder;Gene Expression;Genes;Glycoproteins;Growth;Harvest;Immune;In Vitro;Inflammation;Inflammatory;Injury;Interleukin-1 beta;Laboratories;Lead;Lung;Matrix Metalloproteinases;Modeling;Modification;Mus;Nicotinic Receptors;Organ;Organ Transplantation;Oxidation-Reduction;Oxidative Stress;Permeability;Phenotype;Play;Predisposition;Process;Production;Rodent;Role;Sepsis;Stress;Testing;Tissues;Transforming Growth Factors;Work;alcohol effect;cytokine;design;experience;histone modification;in vivo;indium-bleomycin;injury and repair;liver injury;lung injury;monolayer;mortality;nutrition;problem drinker;programs;promoter;response to injury;sensor


application_id: 8978014
project_number: 1P50AA024337-01
project_title: Sulforaphane-mediated epigenetic modulation of ethanol-induced apoptosis and teratogenesis
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8304
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Address;Alcohol Nutrition;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Attenuated;Broccoli - dietary;Cell Death;Cells;Chemicals;Congenital Abnormality;Consumption;CpG Islands;DNA Modification Methylases;Data;Development;Diet;Disease;Disease model;Embryo;Epigenetic Process;Ethanol;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Gene Expression;Gene Expression Regulation;Gene Silencing;Genes;Goals;Histone Deacetylase;Incidence;Injury;Intake;Laboratories;Lead;Malignant Neoplasms;Mediating;Mental Retardation;Methylation;Modification;Mus;Neural Crest Cell;Nutraceutical;Oral;Organ;Pathogenesis;Pathway interactions;Population;Prevention;Promoter Regions;Regimen;Role;Severities;Signal Transduction;Sulforaphane;Testing;Therapeutic;Transcriptional Activation;Vegetables;Work;alcohol exposure;antioxidant enzyme;base;effective intervention;epigenetic regulation;histone modification;in vivo;innovation;malformation;non-genetic;novel strategies;novel therapeutics;nutrition;prevent;programs;promoter;response


application_id: 8978013
project_number: 1P50AA024337-01
project_title: HDAC Mediated Epigenetic Mechanisms in Alcohol-Induced Abnormal Gut-Liver Axis
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8303
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acetylation;Affect;Alcohol Nutrition;Alcoholic Liver Diseases;Alcohols;Attenuated;Automobile Driving;Bacteria;Butyrates;Carnitine O-Palmitoyltransferase;Chronic;Data;Development;Diet;Endotoxemia;Endotoxins;Enteral;Epigenetic Process;Ethanol;Fatty Acids;Fatty Liver;Functional disorder;Gene Expression;Genes;Goals;Gram-Negative Bacteria;HDAC1 gene;HDAC3 gene;Hepatic;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone H3;Histones;Impairment;Inflammation;Injury;Intestines;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Liver;Liver diseases;Mass Spectrum Analysis;Mediating;Modification;Molecular;Organ;Pathogenesis;Pathology;Permeability;Play;Prevention strategy;Probiotics;Prodrugs;Proteomics;Role;Testing;Therapeutic Intervention;Work;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;epigenetic regulation;feeding;histone modification;insight;interest;lipid metabolism;metabolomics;microbial;microbiome;microbiota;nutrition;probiotic supplementation;programs;promoter;translational study;treatment strategy;tributyrin


application_id: 8978012
project_number: 1P50AA024337-01
project_title: Role of Dietary Fat in Alcoholic Liver Disease
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8302
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Affect;Alcohol Nutrition;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Arachidonate 15-Lipoxygenase;Attenuated;Cations;Data;Development;Diet;Dietary Fats;Dietary Intervention;Down-Regulation;Endotoxemia;Endotoxins;Enzymes;Experimental Animal Model;FDA approved;Genetic;Heavy Drinking;Hepatic;Human;Inflammation;Inflammatory;Inflammatory Response;Inflammatory disease of the intestine;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Kupffer Cells;Laboratories;Lead;Ligands;Linoleic Acids;Lipopolysaccharides;Mediating;Molecular;Morbidity - disease rate;Oral;Organ;Pathogenesis;Pathway interactions;Patients;Permeability;Pilot Projects;Play;Production;Proteins;Role;Severities;Signal Pathway;Staging;Supplementation;TRPV1 gene;Testing;Tight Junctions;Translating;Unsaturated Fats;Up-Regulation;Vanilloid;Whole Blood;base;cytokine;gut microbiome;human study;liver inflammation;liver injury;member;metabolome;monocyte;mortality;new therapeutic target;nutrition;octadecadienoic acid;overexpression;oxidation;peripheral blood;prevent;programs;receptor;saturated fat


application_id: 8978011
project_number: 1P50AA024337-01
project_title: Omics Core
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8301
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acids;Acrolein;Affinity;Alcohol Nutrition;Alcoholic Liver Diseases;Alcohols;Animals;Attention;Attenuated;Automobile Driving;Bioinformatics;Biological;Biotin;Blood;Blood specimen;Body Weight;Cell Line;Cells;Chronic;Complex Mixtures;Curcumin;Data;Data Collection;Data Reporting;Data Set;Development;Drug Interactions;Embryo;Endotoxemia;Ensure;Environment;Epigenetic Process;Extracellular Matrix;Feces;Fibroblasts;Gas Chromatography;Ginger;Goals;Grapefruit;Hepatic;High Pressure Liquid Chromatography;Histone Acetylation;Histones;Human Resources;Inflammation;Injury;Institution;Interleukin-2;Intestines;Lactobacillus casei rhamnosus;Liquid substance;Liver;Liver Dysfunction;Liver diseases;Lung;Lysine;Mass Spectrum Analysis;Measures;Mediating;Metabolic;Methodology;Methods;Molecular;Molecular Evolution;Mus;Neural Crest Cell;Organ;Pattern;Peptides;Performance;Post-Translational Protein Processing;Preparation;Protein Analysis;Protein Fragment;Proteins;Proteomics;Protocols documentation;Research;Research Infrastructure;Research Personnel;Resolution;Resources;Role;Sampling;Science;Serum;Services;Standardization;Sulforaphane;TNFRSF5 gene;Techniques;Technology;Time;Tissue Sample;Tissues;Training and Education;Transcriptional Regulation;Unsaturated Fats;Urine;abstracting;adduct;alcohol effect;design;exosome;histone methylation;histone modification;instrument;liquid chromatography mass spectrometry;liver injury;long chain fatty acid;male;meetings;member;metabolomics;method development;multiple reaction monitoring;nanoparticle;novel;nutrition;phosphoproteomics;programs;protein metabolite;response;sample collection;saturated fat;sharing data;success;toxicant;tributyrin;two-dimensional


application_id: 8978010
project_number: 1P50AA024337-01
project_title: Pilot Project Core
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8300
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Awareness;Chronic Disease;Clinical;Clinical Research;Decision Making;Development;Educational Status;Environment;Evaluation;Extramural Activities;Funding;Goals;Health;Heart Diseases;Individual;Information Resources;Injury;Institution;Intervention;Kentucky;Lung diseases;Malignant Neoplasms;Mentors;Mission;Modeling;New Agents;Obesity;Organ;Patients;Peer Review;Pilot Projects;Prevention;Recruitment Activity;Research;Research Personnel;Resources;Role;Rural;Schools;Science;Secure;Study Section;Substance abuse problem;Translational Research;United States National Institutes of Health;Universities;alcohol abuse therapy;alcohol research;base;black lung;health disparity;improved;innovation;medically underserved;meetings;novel;nutrition;prevent;programs;stroke


application_id: 8978009
project_number: 1P50AA024337-01
project_title: Administrative Core
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
subproject_number: 8308
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Advisory Committees;Alcohol Nutrition;Alcohol abuse;Alcohols;Archives;Area;Arts;Basic Science;Bioinformatics;Biometry;Budgets;Cancer Center;Clinical;Clinical Investigator;Collaborations;Communities;Conflict (Psychology);Consultations;Country;Development;Education;Engineering;Ensure;Epigenetic Process;Faculty;Functional disorder;Funding;Grant;Health;Health Sciences;Individual;Injury;Intervention;Intestines;Lead;Leadership;Left;Letters;Medicine;Organ;Pilot Projects;Proteomics;Public Health Nurses;Public Health Nursing;Reporting;Research;Research Personnel;Research Proposals;Resources;Role;Schools;Science;Social Work;Specialized Center;Structure;Students;TNFRSF5 gene;Therapeutic Intervention;Time;Tissue Sample;Tissues;Universities;alcohol research;body system;high school;innovation;interest;medical schools;member;metabolomics;multidisciplinary;next generation;novel;nutrition;programs;training opportunity


application_id: 8978008
project_number: 1P50AA024337-01
project_title: The Role of Nutrition in the Development/Progression of Alcohol-Induced Organ Injury
administering_ic: NIAAA
award_notice_date: 2016-05-13
opportunity_number: RFA-AA-15-001
application_type: 1
activity_code: P50
ic: AA
serial_number: 024337
program_official: DUNTY, JR, WILLIAM
project_start_date: 2016-05-15
project_end_date: 2021-04-30
study_section: Special Emphasis Panel[ZAA1 GG (50)]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute Lung Injury;Alcohol Nutrition;Alcohol abuse;Alcohol consumption;Alcoholic Liver Diseases;Alcohols;Apoptosis;Area;Award;Biomedical Engineering;Carnosine;Cause of Death;Chronic;Clinical Research;Collaborations;Communities;Development;Diet;Dietary Intervention;Education;Epigenetic Process;Extracellular Matrix;FDA approved;Faculty;Functional disorder;Funding;Goals;Health;Health Care Costs;Histones;Immune system;Industry;Injury;Institution;Intervention;Intestines;Knowledge;Laboratories;Lead;Lipids;Liver;Mental Retardation;Morbidity - disease rate;National Institute on Alcohol Abuse and Alcoholism;New Agents;Nutraceutical;Nutritional;Organ;Pilot Projects;Predisposition;Prevention;Probiotics;Process;Proteomics;Research;Research Personnel;Research Training;Resources;Rewards;Role;S-Adenosylmethionine;Steatohepatitis;Structure of parenchyma of lung;Sulforaphane;Therapeutic Intervention;Translating;Translational Research;United States;United States National Institutes of Health;Universities;Unsaturated Fats;Work;alcohol abuse therapy;alcohol intervention;alcohol research;base;college;education research;high school;improved;inhibitor/antagonist;interdisciplinary approach;interest;metabolomics;mortality;multidisciplinary;new therapeutic target;next generation;novel;nutrition;offspring;prevent;programs;public health relevance;success;therapeutic target


application_id: 8976948
project_number: 1U58DP005981-01
administering_ic: NCCDPHP
award_notice_date: 2015-03-23
opportunity_number: RFA-DP-15-1509
application_type: 1
activity_code: U58
ic: DP
serial_number: 005981
project_start_date: 2015-03-29
project_end_date: 2020-03-28
study_section: ZDP1-SRC(99)
contact_pi_person_id: 9154516
contact_pi: SHEPHERD, RUTH ANN
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-03-29
budget_end_date: 2016-03-28
project_title:
KENTUCKY TOBACCO CONTROL: EVIDENCE-BASED STRATEGIES TO REDUCE TOBACCO USE INITIATION PROMOTE QUITTING ELIMINATE SECONDHAND SMOKE EXPOSUREAND REACH DISPARATE POPULATIONS QUITTING ELIMINATE SECONDHA


application_id: 8976604
project_number: 5R44AI102326-03
project_title: Enhanced baculovirus vectors with higher titers and increased genome stability
administering_ic: NIAID
award_notice_date: 2015-12-21
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: AI
serial_number: 102326
program_official: PARK, EUN-CHUNG
project_start_date: 2013-01-01
project_end_date: 2017-12-31
study_section: Special Emphasis Panel[ZRG1-IMST-K(14)B]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The baculovirus expression vector system (BEVS) has been successfully utilized to produce thousands of proteins for use as vaccines and therapeutics as well as for studies of protein structure and function. One limitation of BEVS is the propensity of baculoviruses to accumulate transposon insertions into the fp25k gene leading to the "few polyhedra (FP)" phenotype. This mutation shifts the balance of virus production from occlusion-derived viruses which are not infectious in tissue culture to budded viruses (BV) which are the form of virus that is used in baculovirus expression. Higher levels of BV would be advantageous for BEVS users but FP mutants are also deficient in transcription from the polyhedrin promoter that drives expression of target genes. Baculoviruses also rapidly accumulate defective interfering particles (DIP) which are often linked to a sharp decrease in target gene expression due to deletion of the target gene and/or the viral genes needed for its expression. One factor promoting DIP formation is transposition into fp25k. The goal of this proposal is to limit deleterious effects of transposition into fp25k while taking advantage of thefact that elimination of the FP25K activity significantly increases BV production. During Phase I two strategies - an inducible construct for controlling fp25k and an fp25k deletion mutant coupled with a cell line constitutively expressing FP25K - were explored for regulating FP25K expression. Both strategies sought to produce high titer virus during the amplification stage of baculovirus infection and enable a switch to high level transcription from the polyhedrin promoter during the recombinant protein expression phase. Results document achievement of Phase I objectives with deletion of fp25k from the virus and complementary expression from an engineered cell line enabling the predicted control of budded virus and recombinant protein production. However the inducible construct did not provide sufficient FP25K control due to the toxicity of the heavy metal inducer to insect cells. Therefore in Phase II we will (1) develop animproved inducible construct with tighter transcriptional regulation using an ecdysone receptor-based inducible promoter; (2) validate the beneficial effects of FP25K regulation using viruses that express intracellular and secreted yellow fluorescent protein (YFP) for BEVS and BacMam (mammalian expression) technology; (3) develop user friendly fp25k mutant backbones for simplified BEVS and BacMam cloning and demonstrate their utility with several medically relevant transgenes; and (4) test the fp25k expression system in the context of vankyrin-enhanced BEVS (VE-BEVSTM) technology. ParaTechs' VE-BEVS products delay death and lysis of baculovirus-infected cells thereby boosting target protein expression up to 20 fold. ManyBEVS users would want to incorporate both vankyrin and FP25K technologies; therefore it is important to determine whether they are compatible. Taken together completion of Phase II objectives will enable users of the BEVS to control and optimize production of BV and recombinant protein expression.

project_terms:
Achievement;Address;Adoption;Ankyrins;Baculoviruses;Biocontrols;Cell Line;Cells;Cessation of life;Cloning;Coupled;Cytolysis;Defective Viruses;Engineering;Equilibrium;Funding;Gene Expression;Gene Targeting;Genes;Genetic Recombination;Genetic Transcription;Genome;Genome Stability;Genomic Instability;Goals;Health;Heavy Metals;Infection;Insect Viruses;Insecta;Link;Maintenance;Mammalian Cell;Marketing;Methods;Modification;Mutation;Phase;Phenotype;Process;Production;Proteins;Recombinant Proteins;Regulation;Research Personnel;Staging;Structure;System;Technology;Testing;Time;Toxic effect;Transcriptional Regulation;Transgenes;United States National Institutes of Health;Vertebral column;Viral;Viral Genes;Viral Proteins;Viral Vector;Virus;base;commercialization;cost;design;ecdysone receptor;expression vector;improved;in vivo;innovative technologies;mutant;prevent;promoter;protein expression;protein function;protein structure function;therapeutic vaccine;tissue culture;user-friendly;vaccine trial;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The baculovirus expression vector system (BEVS) is commonly used for production of proteins for structure-function studies vaccines and therapeutics. Unfortunately many researchers are not aware that certain mutations rapidly accumulate leading to lower levels of target gene expression. ParaTechs has developed a strategy to prevent these mutations while simultaneously providing higher levels of virus production stable genome maintenance and target gene expression.


application_id: 8976593
project_number: 5R21CA178753-02
project_title: Epigenetic regulation of S100A4/Metastasin
administering_ic: NCI
award_notice_date: 2015-11-23
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 178753
program_official: AULT, GRACE S
project_start_date: 2014-12-01
project_end_date: 2017-11-30
study_section: ZCA1-SRB-1(O1)
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_abstract:
DESCRIPTION (provided by applicant): Epigenetic modulation of gene expression is an important mediator of cancer progression. It is well understood that tumor suppressors can be inactivated by the methylation of their promoters which can contribute to tumor progression. However select promoters of pro-invasive and pro-metastatic genes can be selectively demethylated and thus activated during tumor progression. S100A4 is one such gene that contributes to tumor metastasis in several cancer types and its expression is tightly controlled by promoter methylation. We have found that the integrin 64 can control S100A4 expression in breast cancer by stimulating the demethylation of the S100A4 promoter. Based on our preliminary data and supporting literature we propose a novel mechanism of producing sncRNAs through transcriptional regulation of antisense RNAs. We postulate that these sncRNAs are generated by double stranded RNAs created through hybridization of sense and antisense transcripts from a given promoter. In the case of the S100A4 promoter the region that governs the methylation status of the promoter is located in a non-coding alternatively spliced exon. Notably sncRNAs corresponding to this alternatively spliced exon of S100A4 are present in cells expressing high S100A4 but not in cells lacking S100A4 according to public databases. Furthermore we provide evidence that integrin 64 controls the expression of an antisense transcript to S100A4. We propose that these sncRNAs then direct methylcytosine modifying enzymes and DNA repair molecules to the site of specific DNA demethylation. Accordingly the central hypothesis of this application is that integrin 64 stimulates S100A4 promoter demethylation through non-coding RNA-guided modification of methylated cytosines and subsequent DNA mismatch repair. We will test our central hypothesis through completion of the following three aims: 1) Define how integrin 64 directs DNA demethylation of the S100A4 promoter through generation of antisense RNAs and sncRNAs 2) Determine the involvement of DNA repair in DNA demethylation of the S100A4 promoter which will aid us in defining the molecules that drive removal of repressive CpG methylation marks and 3) Define changes in DNA methylation caused by integrin 64 signaling on a genomic scale. If our model is proven largely correct it will represent a new paradigm of how integrins non-coding RNAs and RNA processing transmit oncogenic signals. Furthermore understanding how epigenetic modulation of an invasive and metastatic phenotype is controlled will give us the power to target it therapeutically.

project_terms:
Antisense RNA;Bioinformatics;Cells;Cleaved cell;Complementary DNA;Coupled;Cues;Cytosine;Cytosine deaminase;DNA;DNA Methylation;DNA Repair;DNA Repair Enzymes;DNA Repair Pathway;DNA glycosylase;Data;Databases;Dicer Pathway;Double-Stranded RNA;ECM receptor;Elements;Environment;Enzymes;Epigenetic Process;Event;Excision;Exons;Gene Expression;Generations;Genes;Genomics;Health;Integrin alpha6beta4;Integrins;Literature;Malignant Neoplasms;Mammalian Cell;Mediating;Mediator of activation protein;Methodology;Methylation;Mismatch Repair;Modeling;Modification;Nature;Neoplasm Metastasis;Oncogenic;Phenotype;Process;Promoter Regions;Publishing;RNA Interference;RNA Processing;RNA Splicing;Reaction;Regulation;Reporting;Role;Signal Transduction;Site;Solid;Specificity;System;Testing;Thymidine;Transcript;Transcriptional Regulation;Tumor Suppressor Proteins;Untranslated RNA;Up-Regulation;Variant;Work;Zebrafish;base;cancer type;demethylation;epigenetic regulation;epigenome;genome-wide;inhibitor/antagonist;innovation;insight;malignant breast neoplasm;methylome;next generation sequencing;novel;promoter;receptor;transcription factor;transcriptome;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In this study we will use the collective expertise of our team and take advantage of the recent progress in the field of DNA demethylation to understand how integrin 64 contributes to promoter demethylation of pro-invasive and pro-metastatic genes thus demonstrating how specificity of demethylation is achieved. Specifically we will determine how sncRNAs and the DNA repair pathway epigenetically control the S100A4 promoter and how these specific sncRNAs are generated. Ultimately if our model is proven largely correct it will uncover a new paradigm of how integrins non-coding RNAs and RNA processing transmit oncogenic signals that will give us the power to target these epigenetic events therapeutically.


application_id: 8975821
project_number: 1R01AI120244-01
project_title: Molecular and Cellular Pathogenesis of Legionella
administering_ic: NIAID
award_notice_date: 2015-04-09
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AI
serial_number: 120244
program_official: ERNST, NANCY L
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Host Interactions with Bacterial Pathogens Study Section[HIBP]
contact_pi_person_id: 1877865
contact_pi: ABU KWAIK, YOUSEF A
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): In the aquatic environment Legionella pneumophila (Lp) proliferates within amoeba but upon transmission to humans it causes pneumonia with high morbidity and mortality. Within amoeba and human macrophages Lp proliferates within the Legionella-containing vacuole (LCV) which evades lysosomal fusion and is remodeled by the endoplasmic reticulum (ER). Biogenesis of the LCV is controlled by the Dot/Icm type IV secretion system which injects into the host cell ~300 protein effectors that modulate a myriad of cellular processes to enable intracellular proliferation of Lp. Very few of this large battery o Lp effectors such as AnkB and AnkH are required for the intracellular infection. To attain biological function in the host cell many injected bacterial effectors require post- translational
modification by various host machineries. Post-translational modification of eukaryotic proteins by Asparagine (Asn) hydroxylation impacts their protein-protein interaction and has been widely studied during hypoxic conditions in inflammatory foci. It is not known whether any injected bacterial effector is post-translationally modified by the host asparagine hydroxylase FIH. The Asn hydroxylation motif has been identified within many human Ankyrin repeats-containing proteins (Ank) that have been shown to be modified by FIH. Our bioinformatics preliminary data have identified an Asn hydroxylation motif within the ankyrin repeats of the AnkB and AnkH effectors of Lp and we show that both effectors are modified by the host FIH Asparagine hydroxylase. We show that the host FIH is rapidly recruited to the LCV membrane where AnkH and AnkB are exclusively localized. Our in silico genomic analyses have identified the Asn hydroxylation motif in eight other translocated effectors of Lp. Importantly RNAi-mediated knockdown or chemical inhibition of FIH abolishes intracellular proliferation of Lp and promotes fusion of the LCV to the lysosomes. Therefore our hypothesis is: host-mediated Asn hydroxylation of Lp effectors by FIH is required for their functions in biogenesis of the LCV and intracellular proliferation of Lp. To test our hypothesis our specific aims are to characterize th following: I) Asn hydroxylation of AnkH and its role in the intracellular infection; II) Asn hydroxylation of AnkB and its role in the intracellular infection; and III) Asn hydroxylation of oter Lp effectors and its role in biogenesis of the LCV. Upon completion of our proposed studies the biological function and host targets of AnkH will be known and the ubiquitination substrates of AnkB will be identified. The role of host FIH-mediated Asn hydroxylation in the biological function of AnkH and AnkB will be uncovered. This is significant since both effectors are two of very few of the battery of ~300 Lp effectors to be required for intra-vacuolar proliferation. We wil report on our novel discovery of the acquisition of the FIH complex by a pathogen-containing vacuole and its role in modification of several Lp effectors. We will uncover the role of FIH-mediated Asn hydroxylation of several Lp effectors in lysosomal evasion by the LCV. Our proposed studies on Lp-primary hMDMs interaction and specific manipulation of the host post- translational modification by FIH are innovative with broad high impact and significance not only for Lp but for other pathogens. This is evident from our discovery of Asn hydroxylation of the YopM effector of Yersinia and potential Asn hydroxylation of the IpaH4.5 effector of Shigella and the EsxF effector of Mycobacterium.

project_terms:
Alveolar Macrophages;Amoeba genus;Ankyrin Repeat;Asparagine;Bacterial Proteins;Binding (Molecular Function);Biogenesis;Bioinformatics;Biological Process;Cell physiology;Cells;Chemicals;Complex;Computer Simulation;Data;Disease;Endoplasmic Reticulum;Environment;Enzymes;Genomics;Genus Mycobacterium;Human;Hydroxylation;Hypoxia;Infection;Inflammatory;Killings;Legionella;Legionella pneumophila;Lysosomes;MMP14 gene;Mediating;Membrane;Mixed Function Oxygenases;Modification;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Organism;Pathogenesis;Phagocytes;Pneumonia;Post-Translational Protein Processing;Proliferating;Proteins;Proteome;RNA Interference;Recruitment Activity;Reporting;Role;Shigella;System;Testing;Type IV Secretion System Pathway;Ubiquitination;Vacuole;Yersinia;genome-wide;innovation;liquid chromatography mass spectrometry;macrophage;microbial;monocyte;novel;pathogen;protein protein interaction;public health relevance;transmission process


application_id: 8975596
project_number: 4R01AI095032-05
project_title: Cooperation of CD8+ T cells and phagocytes to eliminate Toxoplasma cysts
administering_ic: NIAID
award_notice_date: 2015-12-10
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AI
serial_number: 095032
program_official: PESCE, JOHN T
project_start_date: 2012-01-01
project_end_date: 2017-12-31
study_section: AIDS-associated Opportunistic Infections and Cancer Study Section[AOIC]
contact_pi_person_id: 1882071
contact_pi: SUZUKI, YASUHIRO
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Toxoplasma gondii establishes an important chronic infection capable of causing life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The basis of persistence of the infection is the tissue cyst which remains largely quiescent for the life of the host but can reactivate and cause disease. This stage of the parasite is not affected by any of the current drug treatments and it has been generally regarded as untouchable. However our recent studies revealed that the immune T cells are able to eliminate T. gondii cysts from the brains of infected hosts when the T cells are transferred into infected immunodeficient animals that have already developed large numbers of the cysts. This T cell-mediated immune process is associated with accumulation of mononuclear cells primarily microglia and macrophages morphologically around tissue cysts. Since the accumulated phagocytes penetrate within the cyst these cells appear to be the main effector cells that destroy the cysts and eliminate them from the brain after initiation of this process by immune T cells. CD8+ immune T cells possess a potent activity to initiate this anti-cyst immune process and the protective activity of the T cells requires perforin. The overall goalof this research project is to determine the molecular mechanisms by which perforin-mediated activity of CD8+ immune T cells cooperates with the phagocytes to remove T. gondii cysts from the brain. In the first aim we will determine if CD8+ immune T cells accumulate and attach to the cyst-containing cells in the brain. We will also determine if the CD8+ T cells lyse cyst-containing cells in a perforin-dependent manner in vitro and whether the perforin- mediated activity of CD8+ T cells induces the accumulation of phagocytes around the cysts in the brain. In the second aim we will determine the MHC class I molecule(s) critical for recognition of cyst-containing cells by CD8+ T cells. We will then determine the T. gondii cyst epitope(s) presented by the identified MHC class I molecule for recognition by the CD8+ T cells by screening predicted bradyzoite epitope peptides and/or bradyzoite cDNA library. The third aim is to determine the mechanisms by which phagocytes eliminate T. gondii cysts after initiation of the immune process by CD8+ T cells. We will examine the roles of inducible nitric oxide synthase and autophagy in killing of bradyzoites and elimination of cysts using mice lacking a molecule required for each mechanism. The information generated from the studies in these three specific aims all together will provide the essential basis for developing a novel method(s) to activate CD8+ T cells and phagocytes to eliminate T. gondii cysts that can reactivate and cause toxoplasmic encephalitis.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Affect;Animals;Antigens;Autophagocytosis;Brain;CD8-Positive T-Lymphocytes;CD8B1 gene;Cells;Chronic;Cyst;Cytolysis;Cytotoxic T-Lymphocytes;Disease;Effector Cell;Encephalitis;Epitopes;Excision;Genes;Goals;Health;Histocompatibility Antigens Class I;Hybridomas;Immune;Immune system;Immunocompromised Host;In Vitro;Inbred BALB C Mice;Individual;Infection;Interferons;Killings;Knockout Mice;Life;Mediating;Mediator of activation protein;Methods;Microglia;Microscopy;Molecular;Mononuclear;Mus;NOS2A gene;Nitric Oxide;Parasites;Patients;Peptides;Phagocytes;Pharmacotherapy;Play;Process;Production;Research Project Grants;Resistance;Risk;Role;Staging;Surface;T-Lymphocyte;Tissues;Toxoplasma;Toxoplasma gondii;base;cDNA Library;cytotoxic;in vitro Model;in vivo;macrophage;novel;perforin;prevent;screening;two-photon

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Reactivation of chronic infection with Toxoplasma gondii causes life-threatening toxoplasmic encephalitis in AIDS patients and other immunocompromised individuals. The proposed studies are to analyze how T cells and phagocytes cooperate to eliminate the persisting cyst stage of T. gondii which can reactivate and cause the disease. These studies will provide the information essential for developing a novel method(s) to eliminate the persisting cyst stage of the parasite and prevent or reduce the risk of developing toxoplasmic encephalitis.


application_id: 8975201
project_number: 5R01EY024051-02
project_title: The danger signals in autoimmune uveitis
administering_ic: NEI
award_notice_date: 2015-11-19
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 024051
program_official: MCKIE, GEORGE ANN
project_start_date: 2014-12-01
project_end_date: 2018-11-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 6193432
contact_pi: SHAO, HUI
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): Autoimmune uveitis mediated by T cells is a major cause of blindness in the USA and worldwide particularly among relative young and working populations. Proposed studies will focus on the danger signals in pathogenesis of chronic autoimmune uveitis using a murine model induced by the adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells. Aims described in this proposal will examine the release of danger signals initiated by uveitogenic IRBP-specific T cells and the role of them in ocular inflammation. Aim 1 will determine the Fas/FasL signaling in rapid release of HMGB1 from viable retinal cells after interaction with IRBP-specific T cells. Aim 2 will examine the roleof HMGB1 in sustaining and promoting IRBP-specific T cell function during chronic intraocular inflammation. Results of these studies will further our understanding of the molecular pathogenesis of autoimmune uveitis and identify novel targets for anti-inflammatory intervention to limit visual loss.

project_terms:
Adoptive Transfer;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antigen-Presenting Cells;Antigens;Apoptotic;Astrocytes;Blindness;CD95 Antigens;Caspase;Cell Death;Cell physiology;Cells;Chronic;Disease;Eye;Frequencies;Functional disorder;Generations;Goals;HMGB1 gene;Health;Human;Immunity;Inflammation;Inflammatory;Intervention;Local Therapy;MAPK14 gene;MAPK8 gene;Maintenance;Mediating;Memory;Molecular;Pathogenesis;Pathogenicity;Phenotype;Population;Proteins;Regulatory T-Lymphocyte;Resistance;Retinal;Role;Signal Transduction;Systemic Therapy;T memory cell;T-Lymphocyte;Testing;Th1 Cells;Uveitis;Western World;Work;autoimmune uveitis;chemokine;cytokine;inhibitor/antagonist;interstitial retinol-binding protein;mouse model;novel;novel therapeutic intervention;research study;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Autoimmune uveitis is a common ocular inflammation mediated by auto-reactive T cells. Despite a wide range of local and systemic therapies to treat this disease uveitis is still one of the leading causes of blindness in the Western world. Experiments described in this proposal will examine danger signals in the progress of T cell immunity in the eye. The long-term goal of proposed studies is to identify targets for interventional therapy for the disease.


application_id: 8974789
project_number: 5R21DE024804-02
project_title: Antimicrobial and inflammatory epithelial responses modulated by P. gingivalis-induced PLA2-IIA
administering_ic: NIDCR
award_notice_date: 2015-11-19
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: DE
serial_number: 024804
program_official: CHANDER, PREETHI
project_start_date: 2014-12-01
project_end_date: 2017-11-30
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although specific oral pathogenic bacterial species [i.e. P. gingivalis (Pg)] have been related to established periodontal lesions and can recapitulate disease in animal models the early events associated with epithelial-oral pathogen interactions in a complex microbial ecology that creates a microenvironment enabling the initiation of periodontitis (i.e. periodontal dysbiosis) remain unclear. Current studies in our laboratory identifying global gene expression profiles of immunoinflammatory genes in oral epithelial cells (OECs) exposed to oral bacteria species indicated that Pg is able to induce a remarkable increase in the transcription of secreted phospholipase A2-group IIA (PLA2G2A) whose expression levels clearly exceeded 20-30 times those of classical immunoinflammatory mediators (e.g. cytokines/chemokines and antimicrobial peptides). Protein levels determination indicated that PLA2-IIA expression appears to be Pg-specific response since other oral G+ and G- bacterial species failed to induce similar PLA2-IIA responses. PLA2-IIA is a highly cationic lipolytic enzyme produced by multiple cells and plays a critical role in infection and inflammationthrough its potent antimicrobial properties (especially against Gram-positive bacteria) as well asits effects on activating inflammatory cells and lipid mediator production. Moreover evidence indicates that Notch-1 is a central regulator of mucosal immune responses and is involved in PLA2-IIA expression by intestinal epithelial cells. Consistently we observed that Pg induced the expression of the NOTCH1 gene and its activation in OECs. Thus modulation of epithelial PLA2-IIA levels particularly at mucosal surfaces could be a plausible strategy for pathogenic bacterial species to break the host-microbiota symbiotic interactions leading to inflammatory disease. Therefore we hypothesize that antimicrobial and immunoinflammatory responses of OECs are modulated by P. gingivalis through differential activation of PLA2-IIA in a mechanism that involves the Notch-1 receptor. To test this hypothesis we propose the following two specific aims: (i) to identify the OEC signaling pathways involved in P. gingivalis-induced PLA2-IIA and (ii) to determine the cellular location and function of OEC- produced PLA2-IIA in response to P. gingivalis. To address these knowledge gaps we will use oral epithelial cell culture models as well as different Pg strains combined with neutralization experiments using monoclonal antibodies chemical inhibitors or siRNA approaches to: (i) identify OEC receptors/pathways involved in Pg-induced PLA2-IIA and (ii) determine the cellular location and function of OEC-produced PLA2-IIA after Pg challenge to more fully understand the potential role of this interesting molecule in the initial states of infection and inflammation of the oral mucosa. This contribution's significance will enable a better understanding of the cellular and molecular mechanisms involved in Pg-induced PLA2-IIA as a potential mechanism involved in Pg-induced dysbiosis. The results are expected to contribute to a strong evidence-based foundation for future studies designed to identify molecular target(s) associated with Pg-induced epithelial PLA2-IIA production in vitro (using primary OECs and organotypic cultures) and in vivo (using a nonhuman primate model) that could increase the risk for oral mucosa dysbiosis. More focused control of this dysbiosis process should ultimately provide new opportunities for the development of innovative approaches to prevent/treat periodontitis.

project_terms:
Address;Affect;Animal Model;Atherosclerosis;Bacteria;Blood Platelets;CCAAT-Enhancer-Binding Proteins;Cell Culture Techniques;Cell membrane;Cells;Chemicals;Complement;Complex;Crohn's disease;Cytokine Signaling;Development;Disease;ES01;Ecology;Endothelial Cells;Environment;Enzymes;Epithelial;Epithelial Cells;Epithelial Receptor Cell;Event;Foundations;Future;Gene Expression;Genes;Genetic Transcription;Gram-Positive Bacteria;Health;Heparan Sulfate Proteoglycan;Hepatocyte;Host Defense;Human;Immune response;In Vitro;Infection;Inflammation;Inflammatory;Inorganic Sulfates;Interleukin-1;Intestines;Invaded;Knowledge;Laboratories;Lesion;Link;Location;Mediating;Mediator of activation protein;Membrane;Microbe;Modeling;Molecular;Molecular Profiling;Molecular Target;Monoclonal Antibodies;Mucosal Immune Responses;Mucositis;NOTCH1 gene;Nutrient;Oral;Oral mucous membrane structure;PLA2G2A gene;Paneth Cells;Pathogenesis;Pathway interactions;Pattern Recognition;Periodontal Diseases;Periodontitis;Phospholipase A2;Play;Porphyromonas gingivalis;Process;Production;Property;Proteins;Proteoglycan;Public Health;Receptor Up-Regulation;Regulation;Research;Research Design;Rheumatoid Arthritis;Risk;Role;SP1 gene;Signal Pathway;Signal Transduction;Small Interfering RNA;Solid;Subgroup;Surface;Symbiosis;TNF gene;Testing;Time;Translating;Unspecified or Sulfate Ion Sulfates;Up-Regulation;Virulence Factors;antimicrobial;antimicrobial peptide;autocrine;cell type;chemokine;cytokine;design;evidence base;extracellular;in vivo;inhibitor/antagonist;innovation;interest;lipid mediator;macrophage;member;microbial;microbial host;microbiota;nonhuman primate;notch protein;oral bacteria;oral pathogen;pathogen;prevent;receptor;research study;response;translational study

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will provide an evidence- based mechanistic foundation for further translational studies designed to identify molecular target(s) mediating the Pg-induced PLA2-IIA by oral epithelial cells. This potential early event in the pathogenesis of periodontitis should provide new opportunities for the development of innovative approaches to prevent/treat periodontal disease and its contribution to adverse systemic health. In addition this research will create a foundation for future studies focused on evaluating similar Pg- related PLA2-IIA responses in other cell types (e.g. human endothelial cells) that may help to elucidate the potential role of Pg in other systemic disorders such as atherosclerosis.


application_id: 8972927
project_number: 1R21DC014857-01
project_title: Taste neuron connectivity and branching revealed by sparse cell genetic labeling
administering_ic: NIDCD
award_notice_date: 2015-06-12
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: DC
serial_number: 014857
program_official: SULLIVAN, SUSAN L
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 IFCN-B (03)]
contact_pi_person_id: 1859791
contact_pi: KRIMM, ROBIN FRANCES
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant: A general feature of sensory organization is that neurons can be divided into different types based on molecular morphological and functional characteristics. Whether this type of organization exists in the taste system is unclear. It is generally accepted that taste receptor cells exist as different types. The next critical step is to
determine how these different taste receptor cell types can connect with the ganglion neurons that carry taste information to the brain. Because peripheral gustatory axons invade the tongue in fascicles with individual axons intertwining at every level past attempts at reconstructing single fibers have not been successful. This project will overcome this critical barrier by combining genetically-directed sparse labeling of nerve fibers with three-dimensional visualization and reconstruction in taste buds. Using these approaches we will test the hypothesis that gustatory neurons can be divided into subtypes based on their morphology (i.e. branching) and connectivity with specific types of taste receptor cells. These experiments will reveal how connections between taste cells and nerve fibers are organized. The approaches established in this project can be used in future studies to understand 1) if morphological subtypes correspond to specific molecular and/or functional subtypes 2) the branching of individual taste neurons in the central nervous system (CNS) 3) how branching patterns are established during development and 4) whether normal branching patterns are reestablished following injury disease or chemotherapy.

project_terms:
Address;Alkaline Phosphatase;Axon;Brain;Cells;Characteristics;Code;Data;Development;Dimensions;Disease;Dose;Embryonic Development;Esthesia;Fascicle;Fiber;Future;Ganglia;Genes;Genetic;Genetic Recombination;Hand;Health;Imagery;Immunohistochemistry;Individual;Injury;Invaded;Label;Methods;Molecular;Morphology;Mus;Nerve Fibers;Neuraxis;Neurons;Pathway interactions;Pattern;Peripheral;Persons;Phenotype;Property;Quality of life;Receptor Cell;Research;Sensory;Signal Transduction;Specificity;Staining method;Stains;Stimulus;Sucrose;Tamoxifen;Taste Buds;Taste Disorders;Taste Perception;Testing;Time;Tongue;base;cell type;chemotherapy;ganglion cell;public health relevance;reconstruction;research study;response;sensory system;taste stimuli;taste system;tongue root;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Taste disorders can have detrimental effects on a person's health and quality of life. The underlying mechanisms are not understood but could result from disruption of the gustatory neurons that carry taste information to the brain. Taste ganglion neurons are largely unstudied due to a lack of appropriate tools; this project overcomes this critical barrier by developing new tools that can be used to examine taste ganglion neuron branching and peripheral connectivity following injury and in disease states.


application_id: 8972917
project_number: 1R43DE025431-01
project_title: Development and Feasibility of PerioDX for Identification of Periodontal Disease
administering_ic: NIDCR
award_notice_date: 2015-07-14
opportunity_number: RFA-DE-15-002
application_type: 1
activity_code: R43
ic: DE
serial_number: 025431
program_official: RODRIGUEZ-CHAVEZ, ISAAC R
project_start_date: 2015-07-15
project_end_date: 2016-07-14
study_section: Special Emphasis Panel[ZDE1 JR (11)]
contact_pi_person_id: 7875071
contact_pi: NOVAK, MICHAEL JOHN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 078739664
duns_number: 078739664
fips: US
organization_id: 10033642
organization_name: INNOVATIVE DIAGNOSTICS, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-15
budget_end_date: 2016-07-14
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis is a chronic polymicrobial bacterial infection that leads to soft and hard tissue destruction and is the leading cause of tooth loss in adults. Periodontitis also is associated with sequelae of several important systemic diseases seen in the population. Although microbial and host biomarkers have both been identified as independent predictors of periodontal disease combining these measures into a single POC device would greatly increase the specificity and sensitivity of a diagnostic tool. Due to the increasing prevalence and associated co-morbidities of periodontitis the availability of screening and diagnostic technologies for the early detection of periodontitis initiation and progression would have both a profound impact on public health and have significant commercial potential.  The goal of this project is to develop a programmable bio-nanochip diagnostic device technology that uses antibody-coated agarose beads and membrane-based technology in a multiplex format to detect periodontal disease by targeting both microbes and host response biomarkers. This translational research effort is the continuation of a 12-year collaboration of an expert and diverse research team to further develop a next-generation POC diagnostic device for periodontal disease. The goal is to produce a highly reliable reproducible accurate and sensitive tool for early detection screening and monitoring of periodontal disease that would enable enhanced decision-making regarding treatment. This study is being performed by Innovative Diagnostics Inc. (IDI) and researchers from the University of Kentucky (UK) McDevitt Laboratory (Rice University) and SensoDx (Houston TX).  In this Phase I effort a biochip device (PerioDXTM) will be developed that uses next generation disposable cartridges to rapidly detect and quantitate Porphyromonas gingivalis and matrix metalloproteinase (MMP)-8 in saliva from patients who have health or periodontal disease. Successful completion of these studies will lead to a Phase II application that targets expansion of the biological targets including additional bacteria and host molecules contributory to periodontal disease. These biological targets will be selected with the commercialization goal of creating a device that can be used in various professional venues as well as resource poor settings to improve oral health with respect to screening diagnosing and monitoring periodontal disease infections and progression.  The Phase I study has two Specific Aims: Aim 1: Adapt and optimize the SensoDx platform for simultaneous detection of a periodontal pathogen (P. gingivalis) and a host response biomarker (matrix metalloproteinase-8) in whole saliva Aim 2: Evaluate salivary samples using PerioDX(tm) to differentiate healthy and periodontitis subjects

project_terms:
Adult;Affect;Antibodies;Bacteria;Bacterial Infections;Biological;Biological Markers;Care Technology Points;Cataloging;Catalogs;Cells;Chronic;Clinical Research;Collaborations;Comorbidity;Complex;Contracts;Data;Decision Making;Dental;Dentistry;Dentists;Detection;Development;Devices;Diagnosis;Diagnostic;Diagnostic Sensitivity;Disease;Disease Outcome;Early Diagnosis;Evaluation;Forsythia;Gingivitis;Goals;Health;Healthcare;Human;Human Microbiome;Immune response;Individual;Infection;Inflammation;Inflammatory;Kentucky;Knowledge;Laboratories;Lead;Measures;Membrane;Microbe;Microbial Biofilms;Monitor;Neutrophil Collagenase;Oral cavity;Oral health;Patients;Periodontal Diseases;Periodontitis;Phase;Population;Porphyromonas gingivalis;Prevalence;Research;Research Personnel;Resources;Rice;Saliva;Salivary;Sampling;Scientist;Sensitivity and Specificity;Sepharose;Small Business Innovation Research Grant;Specimen;Systemic disease;Technology;Tissues;Tooth Loss;Translational Research;Treponema denticola;Universities;Variant;Visit;Visual;arm;base;biobank;biochip;college;commercialization;disorder risk;improved;innovation;microbial;microbial host;next generation;oral pathogen;pathogen;phase 1 study;point of care;point-of-care diagnostics;public health medicine (field);rapid detection;response;screening;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontal disease is an inflammatory and destructive disease that silently affects millions of people. Periodontal disease is currently diagnosed subjectively by visual evaluation by a dentist. The goal of this study is to develop a single point
of-care device that evaluates both bacteria and biological markers of inflammation in human saliva in order to provide a highly specific and sensitive detection of periodontal disease.


application_id: 8969800
project_number: 1R21DA038817-01A1
project_title: Single molecule determination of nAChR structural assembly for therapeutic targeting
administering_ic: NIDA
award_notice_date: 2015-07-01
opportunity_number: PAR-13-350
application_type: 1
activity_code: R21
ic: DA
serial_number: 038817
suffix: A1
program_official: HILLERY, PAUL
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Biophysics of Neural Systems Study Section[BPNS]
contact_pi_person_id: 8957529
contact_pi: RICHARDS, CHRISTOPHER I
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The consumption of tobacco products leads to the elevation of several health risks. Smokers have a higher likelihood of developing cardiovascular disease respiratory disease and several types of cancer. As a result approximately 20% of all deaths in the United States are associated with tobacco products. Despite the clear hazards it is estimated that more than 40 million adults in the United States are smokers. One of the primary barriers to decreasing the number of smokers is that nicotine a component of tobacco is highly addictive. We propose a novel approach to elucidate the mechanism of nicotine addiction and to identify target nAChR assemblies and phenotypes for nicotine cessation therapeutics. In the R21 phase we will focus on the development of a novel approach to monitor the assembly and trafficking of nicotinic receptors at the single molecule level. Nicotinic
receptors cannot be purified outside of the cellular environment making them inaccessible to common single molecule techniques that require the purification and reconstitution of proteins. We will utilize receptors isolated in cell derived vesicles. Isolation of vesicles from different organelles will allow us to determine nicotine and therapeutic ligands affect the assembly and trafficking of nAChRs. Identification of the specific structural assemblies targeted by existing therapeutics will allow us to identify specific targets for cessation therapeutics. In the R33 phase we will extend studies to receptors generated in live animals by isolating vesicles from different regions of the brain of nicotinic receptor GFP knock-mice. These will be the first single
molecule studies of nicotinic receptors generated in live animals. We will be able to correlate the
assembly of different receptor subtypes to specific brain regions. These studies will for the first
time allow us to perform single molecule fluorescence studies on brain derived nAChRs. Understanding how existing therapeutics alter structural assembly in specific brain regions will provide an understanding of which nAChRs to target and the structural assembly they should induce. This will provide insight into the mechanism of nicotine addiction and on the receptor phenotypes optimally induced by cessation therapeutics.

project_terms:
Adult;Affect;Animals;Brain;Brain imaging;Brain region;Cardiovascular Diseases;Cell membrane;Cells;Cessation of life;Development;Environment;Exposure to;Fluorescence;Goals;Golgi Apparatus;Health;Image;Knock-in Mouse;Label;Life;Ligands;Lung diseases;Measures;Mediating;Membrane;Molecular Chaperones;Monitor;Mus;Nicotine;Nicotine Dependence;Nicotinic Receptors;Organelles;Phase;Phenotype;Play;Risk;Role;Series;Smoker;Sorting - Cell Movement;Structure;Synapses;Synaptosomes;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tobacco;Tobacco use;United States;Vesicle;addiction;cancer type;fluorescence imaging;hazard;in vivo;innovation;insight;novel;novel strategies;novel therapeutics;presynaptic;protein reconstitution;public health relevance;receptor;research study;single molecule;stoichiometry;therapeutic target;trafficking


application_id: 8969758
project_number: 1R21HD079747-01A1
project_title: A Brain-Machine Interface to Facilitate Motor Recovery from Incomplete SCI
administering_ic: NICHD
award_notice_date: 2015-07-07
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: HD
serial_number: 079747
suffix: A1
program_official: MARDEN, SUSAN F
project_start_date: 2015-07-08
project_end_date: 2017-06-30
study_section: Motor Function, Speech and Rehabilitation Study Section[MFSR]
contact_pi_person_id: 9484873
contact_pi: SUNDERAM, SRIDHAR
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
project_abstract:
DESCRIPTION (provided by applicant): Recent research suggests that neuroplasticity plays a crucial role in functional recovery after neurological injury. Sensory input in the form of sustaind peripheral nerve stimulation (PNS) can up-modulate neuroplastic change and thereby accelerate recovery of motor function. Furthermore our preliminary data demonstrate that motor function can be substantially enhanced when PNS is delivered prior to motor training. During PNS subjects remain awake but not actively engaged in any task. The objective of this project is to test whether PNS in subjects with incomplete spinal cord injury can accelerate recovery of motor function when PNS is delivered in closed-loop: i.e. only in response to subject's volition. This brief PNS delivery will be triggered by a brain-machine interface (BMI) that detects intent-to-move from suppression of the electroencephalogram (EEG) sensorimotor ("mu") rhythm which can occur with actual or imagined movement effort. Evidence of a beneficial effect from synchronizing PNS with intent-to-move could help optimize timing- dependent neuroplasticity which is critical for motor learning. This proposal has the following specific aims: 1. Develop a BMI for accurately detecting intent-to-move with minimal latency from continuous EEG measurements and briefly triggering closed-loop PNS in response to intent-to-move; and 2. Test the hypothesis that closed-loop PNS can promote motor neuroplasticity better than open-loop (pre-programmed) PNS or sham PNS as reflected by progressive increase in motor-evoked potential amplitude and motor performance. No study to date has investigated closed-loop PNS in individuals with neurological injuries. Refinement of PNS techniques and protocols that incorporate BMIs will contribute enormously to science and clinical care and therefore have high translational potential for neurorehabilitation.

project_terms:
Acute;Area;Body part;Brain;Corticospinal Tracts;Data;Detection;Development;Discriminant Analysis;Electric Stimulation;Electroencephalogram;Evaluation;Exercise;FPS-FES Oncogene;Fiber;Force of Gravity;Goals;Hand;Imagery;Individual;Learning;Long-Term Potentiation;Measurement;Measures;Monitor;Motor;Motor Cortex;Motor Evoked Potentials;Movement;Nerve Fibers;Nervous System Trauma;Nervous system structure;Neuronal Plasticity;Neurorehabilitation;Outcome;Patients;Performance;Peripheral Nerve Stimulation;Phase;Plastics;Play;Principal Investigator;Protocols documentation;Recovery;Recovery of Function;Rehabilitation therapy;Research;Residual state;Rewards;Role;Science;Signal Transduction;Speed (motion);Spinal cord injury;Spinal cord injury patients;Synapses;System;Techniques;Testing;Time;Training;Transcranial magnetic stimulation;Volition;acronyms;awake;base;brain machine interface;clinical care;cohort;effective therapy;hand grasp;improved;injured;insight;motor control;motor function recovery;motor learning;motor recovery;novel;post intervention;programs;public health relevance;response;screening;sensory input;theories

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The goal is to develop a brain-machine interface that will detect when a patient with incomplete spinal cord injury attempts hand movement and apply peripheral nerve stimulation (PNS) to send a reward signal to the brain. This is expected to speed up rehabilitation compared to PNS without any effort from the patient.


application_id: 8969464
project_number: 1R01AR067188-01A1
project_title: Interplay of androgens microbiota and immunoregulation in lupus
administering_ic: NIAMS
award_notice_date: 2015-05-15
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AR
serial_number: 067188
suffix: A1
program_official: MANCINI, MARIE
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section[HAI]
contact_pi_person_id: 1933503
contact_pi: KOSIEWICZ, MICHELE M
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
project_terms:
Address;Affect;Agonist;Androgen Receptor;Androgens;Autoimmune Diseases;Castration;Cell physiology;Complex;Cytoprotection;Data;Defect;Dendritic Cells;Development;Diabetes Mellitus;Disease;Environment;Estrogens;Exhibits;Feces;Female;Gonadal Steroid Hormones;Health;Human;Immune response;Immune system;In Vitro;Inbred NOD Mice;Incidence;Inflammatory;Insulin-Dependent Diabetes Mellitus;Intestines;Knowledge;Lead;Link;Lupus;Mediating;Men's Role;Microbiological Techniques;Modeling;Mortality Vital Statistics;Mus;Pathogenesis;Phytol;Play;Prevention strategy;Production;Property;Puberty;RXR;Receptor Signaling;Regulatory T-Lymphocyte;Role;Severity of illness;Sex Characteristics;Systemic Lupus Erythematosus;Techniques;Therapeutic;Transplantation;Treatment Protocols;Tretinoin;Volatile Fatty Acids;Woman;base;commensal microbes;disorder prevention;gut microbiota;immunoregulation;imprint;in vivo;innovation;male;men;metabolomics;mouse model;next generation sequencing;novel;novel therapeutics;public health relevance;sex

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Systemic lupus erythematosus (SLE or lupus) is an insidious disease without many treatment options. Women have a much higher incidence of SLE than men and male sex steroids (androgens) appear to protect genetically susceptible men from disease. Recently a role for the intestinal natural (non-pathogenic) bacterial flora in health and
disease (including inflammatory and autoimmune diseases) has been demonstrated and an important relationship between the natural bacterial flora in the gut and male androgens in disease has been identified. We have found that fecal transplants from healthy male mice into lupus-susceptible female mice protected them from disease. In this application we propose to study the relationship between gut flora and androgens in lupus in order to develop novel therapies for the treatment of lupus.


application_id: 8969160
project_number: 7R21AI113386-02
project_title: Effect of the gut microbiota on malaria
administering_ic: NIAID
award_notice_date: 2015-03-13
opportunity_number: PA-14-078
application_type: 7
activity_code: R21
ic: AI
serial_number: 113386
program_official: WALI, TONU M
project_start_date: 2014-12-01
project_end_date: 2016-04-30
study_section: Pathogenic Eukaryotes Study Section[PTHE]
contact_pi_person_id: 11178918
contact_pi: SCHMIDT, NATHAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Plasmodium infections which cause malaria have been a scourge to humanity for thousands of years. Unfortunately we are still years away from an efficacious anti-malaria vaccine that is available to the >40% of the world's population that isat risk of malaria. Further complicating treatment and control of malaria is that both Plasmodium and the mosquito vector that transmits the parasite rapidly develop resistance to new drugs developed to treat malaria and control mosquito populations. Therefore it is imperative novel approaches to control malaria are explored. We propose an exploratory project to determine the impact of the gut microbiota on regulating the severity of malaria which has the potential to provide insights to novel and affordable approaches to treat malaria. The gut microbiota has been shown to shape susceptibility to obesity diabetes and regulate multiple aspects of host immunity. This is particularly true for components of the immune system that interface with the GI tract. Importantly the gut microbiota also augments host immunity to bacterial and viral infections that occur outside of the GI tract. However there are no reports as to how the gut microbiota influence host immune responses to non-GI tract parasitic infections including Plasmodium. Our preliminary data demonstrate that C57BL/6 mice purchased from different vendors which are known to have alterations in their gut microbiota exhibit substantially different levels of parasite burden following infection with Plasmodium yoelii 17XNL. We have also demonstrated that C57BL/6 mice from different vendors treated with a cocktail of antibiotics exhibit dynamic responses following infection with Plasmodium compared to control treated mice. Collectively our data suggest the gut microbiota regulates the severity of malaria. We hypothesize that specific gut bacteria and their metabolic by-products regulate susceptibility to malaria. We will address this hypothesis through the following specific aims: 1) Identify differences in gut microbiota populations that are associated with differential susceptibility to malaria 2) Determine ability of the gut microbiota to transfer resistance or susceptibility to malaria to another mouse and 3) Identify gut metabolites that drive differential susceptibility to malaria.

public_health_relevance:
PUBLIC HEALTH RELEVANCE: In spite of tremendous effort an efficacious malaria vaccine that can be deployed in large quantities is still years away and current malaria control measures are hampered by drug resistance. Completion of this project will identify populations of the gut microbiota and/or metabolome that confer protection from severe malaria. These results will be critical in developing affordable novel probiotic and prebiotic approaches to control severe malaria.


application_id: 8968972
project_number: 1R21ES023627-01A1
project_title: Differential miRNA expression & progression of arsenic induced skin cancers
administering_ic: NIEHS
award_notice_date: 2015-06-29
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: ES
serial_number: 023627
suffix: A1
program_official: HUMBLE, MICHAEL C
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 SIEE-C (01)]
contact_pi_person_id: 1880454
contact_pi: STATES, J CHRISTOPHER
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are two types of skin cancer caused by both sunlight and arsenic exposure. It is clear that mutations from UV-induced DNA damage drive sunlight induced skin cancers. In contrast the mechanism of arsenic induced skin cancer remains unclear. This exploratory project will characterize the differential microRNA expression in primary human keratinocytes exposed long term to arsenic in vitro and in a unique sample set of arsenic induced skin lesions including hyperkeratosis (premalignant lesion to both arsenic induced BCC and SCC) BCC and SCC. MicroRNA expression profiles will be determined by microarray analyses of RNA purified from primary human keratinocytes exposed and unexposed to arsenite in vitro and in laser capture microdissection purified keratinocytes from formalin fixed paraffin embedded samples of the arsenic induced skin lesions. Differential microRNA expression for the 6 microRNAs with greatest fold change between comparison sets will be confirmed by qRT-PCR. Comparisons between exposed and unexposed primary human keratinocytes will identify arsenic exposure induced changes in microRNA expression that may contribute to cellular transformation. Comparisons between HK vs BCC and HK vs SCC will reveal changes associated with progression from pre-malignant to malignant phenotype and between BCC vs SCC will reveal similarities and dissimilarities between the two tumor types. Comparison of the microRNA expression profiles unique to arsenic induced BCC and SCC with the published data from sunlight induced BCC and SCC will provide critical molecular information on the similarity or dissimilarity of these phenotypically similar cancers induced by different environmental carcinogens. Completion of these studies will provide novel data on arsenic induced changes in microRNAs in primary human keratinocytes and in progression of arsenic induced skin cancers. Extension of these studies in the future using multiple lesions from single individuals and by combining data with mRNA expression profiles will provide detailed molecular information on tumor progression.

project_terms:
Affect;Arsenic;Arsenites;Basal cell carcinoma;Biological Assay;Biological Markers;Cancer Etiology;Chronic;Country;DNA Damage;Data;Development;Disease;Environmental Carcinogens;Epigenetic Process;Etiology;Exposure to;Female;Formalin;Future;Gene Expression;Gene Expression Profile;Health;Human;Hyperkeratosis;In Vitro;Incubated;Individual;Induced Mutation;Lesion;Light;Malignant - descriptor;Malignant Neoplasms;Messenger RNA;MicroRNAs;Microarray Analysis;Molecular;Molecular Profiling;Mutagenesis;Mutation;Outcome;Paraffin Embedding;Pattern;Premalignant;Principal Component Analysis;Publishing;RNA;Role;Sampling;Sex Characteristics;Skin Cancer;Skin Carcinogenesis;Squamous cell carcinoma;Sunlight;TP53 gene;Testing;Tissues;UV induced;arsenic-induced carcinogenesis;differential expression;drinking water;driving force;keratinocyte;laser capture microdissection;mRNA Expression;male;malignant phenotype;melanoma;metaplastic cell transformation;molecular phenotype;novel;public health relevance;skin lesion;sunlight-induced;tumor;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Arsenic exposure in drinking water is a worldwide health problem affecting numerous countries including the U.S. A common outcome of chronic arsenic exposure is skin cancer. This project will provide information on the molecular mechanisms of skin cancer development in arsenic exposed individuals using a unique set of samples of premalignant and malignant lesions from people chronically exposed to arsenic in their drinking water.


application_id: 8968265
project_number: 5R01HL125228-02
project_title: Mineralocorticoid receptor and abdominal aortic aneurysm
administering_ic: NHLBI
award_notice_date: 2015-11-02
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 125228
program_official: TOLUNAY, ESER
project_start_date: 2014-11-15
project_end_date: 2018-10-31
study_section: Special Emphasis Panel[ZRG1-VH-A(03)]
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
project_abstract:
DESCRIPTION (provided by applicant): Abdominal aortic aneurysm (AAA) is a vascular disease with rising prevalence and a high mortality rate. Current treatment is limited to open or endovascular surgery a procedure for which only 10% of AAA patients are eligible highlighting an urgent need for new mechanistic understandings of AAA. With a long term goal to identify new therapeutic targets for AAA the current proposal will investigate the pathological roles of aldosterone (Aldo) mineralocorticoid receptor (MR) and high salt intake in AAA. Elevated plasma Aldo and high salt intake have been linked to a spectrum of cardiovascular diseases. MR antagonists have been shown to be effective in reducing cardiovascular mortality and hospitalizations for heart failure. However little is known of the roles of Aldo MR and high sal intake in AAA. Recently the applicants discovered that administration of MR agonists deoxycorticosterone acetate (DOCA) or Aldo to C57BL/6 male mice induced AAA in the presence of high salt. Importantly DOCA- or Aldo-salt-induced AAA mimicked human AAA with respect to oxidative stress vascular inflammation smooth muscle cell (SMC) degeneration metalloproteinase (MMP) activation and elastin degradation. Treatment of mice with spironolactone or eplerenone two clinically used MR antagonists effectively attenuated DOC- or Aldo-salt-induced aortic aneurysm formation and rupture. Building on these exciting and novel findings the applicants further demonstrated that in isolated mouse aorta administration of pathological plasma concentrations of Aldo and sodium activated MMP2 and induced oxidative stress suggesting a direct pathological effect of Aldo and salt on aorta. Interestinglydenuding endothelial cells from isolated aorta had no effect on Aldo-salt-induced MMP2 activation and oxidative stress indicating that MR in SMC (SMC-MR) is involved. Consistent with this concept the applicants found that p47phox a component of NADPH oxidase that has been implicated in human AAA was markedly upregulated by Aldo-salt in the medial layer of abdominal aortic wall and co-localized with SMC a-Actin which was completely abolished by treatment of mice with eplerenone. Moreover treatment of mice with temporal a free radical scavenger diminished DOCA-salt-induced AAA. Therefore the applicants hypothesize that increased plasma Aldo and salt activate SMC-MR and p47phox and thus result in oxidative stress MMP activation vascular inflammation SMC degeneration and elastin degradation thereby contributing to AAA. Three specific aims are: 1) test the hypothesis that SMC-MR is required for Aldo-salt-induced AAA; 2) define the mechanism by which SMC-MR targets p47phox to induce AAA; 3) determine whether targeting the Aldo/MR/salt axis is effective for treatment of AAA. To achieve these aims genetic animal models (SMC- specific MR knockout mice and global p47phox knockout mice) and various molecular biochemical and physiopathological approaches will be used. If proposed studies are successful they will have a profound impact on current basic researches and clinical practices on the etiology diagnosis and treatment of AAA.

project_terms:
Abdomen;Abdominal Aortic Aneurysm;Accounting;Acetates;Actins;Affect;Age;Agonist;Aldosterone;Aldosterone Antagonists;Animal Model;Aorta;Aortic Aneurysm;Attenuated;Basic Science;Binding;Biochemical;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Clinic;Country;Deoxycorticosterone;Diagnosis;Disease;Elastin;Endothelial Cells;Etiology;Free Radical Scavengers;Genetic;Goals;Health;Heart failure;Hospitalization;Human;Hypertension;Intake;Kidney;Knockout Mice;Left Ventricular Hypertrophy;Link;MMP2 gene;MMP9 gene;Matrix Metalloproteinases;Medial;Membrane;Messenger RNA;Metalloproteases;Mineralocorticoid Receptor;Molecular;Mus;Myocardial Infarction;NADPH Oxidase;Operative Surgical Procedures;Oxidative Stress;Patients;Pharmaceutical Preparations;Plasma;Prevalence;Procedures;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Scheme;Smooth Muscle Myocytes;Sodium;Sodium Chloride;Spironolactone;Stress;Tamoxifen;Testing;Time;Vascular Diseases;Withdrawal;Woman;abdominal aorta;age related;clinical practice;diagnosis evaluation;effective therapy;eplerenone;insight;loss of function;male;men;mortality;mouse model;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;prevent;promoter;salt intake;stroke;tempol;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Abdominal aortic aneurysm (AAA) is defined as a permanent localized dilations of aorta affect 4 to 8% of men and 0.5 to 1.5% of women over the age of 60 and account for about 2% of all deaths in Western countries. AAA is a vascular disease with rising prevalence and a high mortality rate (65% to 85%) related to AAA rupture. Currently surgery is the only option for treatment of AAA and no drug has been approved for the treatment of this devastating disease. The goals of this application are to elucidate the mechanisms responsible for AAA and thereby identify new therapeutic targets to develop new drugs to treat AAA.


application_id: 8967461
project_number: 1R03DE024586-01A1
project_title: Modulation of innate epithelial cell responses by oral commensal bacteria
administering_ic: NIDCR
award_notice_date: 2015-06-17
opportunity_number: PAR-13-348
application_type: 1
activity_code: R03
ic: DE
serial_number: 024586
suffix: A1
program_official: CHANDER, PREETHI
project_start_date: 2015-07-01
project_end_date: 2017-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 9641157
contact_pi: GONZALEZ, OCTAVIO ALBERTO
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The mechanisms through which a persistent recognition of oral commensal bacteria by oral epithelial cells (OECs) mitigates an uncontrolled inflammatory response of the oral mucosa remain unknown. Evidence suggests that epithelial cells may discriminate between commensals and pathogenic bacteria through differential activation of responses particularly cytokine/chemokine patterns which ultimately influence both innate and adaptive arms of the immune response. Recent work in our laboratory has been identifying patterns of OECs responses following challenge with commensal and pathogenic oral bacteria. The results showed a significantly more robust (quality and quantity) chemokine transcriptional activity in response to the oral commensal S. gordonii (Sg) compared to the outcomes following challenge with the oral pathogens F. nucleatum (Fn) and P. gingivalis. Subsequent protein analysis of selected chemokines showed that there was a clear disconnect between the Sg-induced chemokine transcriptional activation and the reduced and limited protein levels found in OEC extracts and supernatants in comparison with the effect of Fn which despite inducing lower mRNA chemokines levels (2 to 4-fold less) enhanced a robust protein chemokine production as previously shown. Therefore we hypothesized that Sg and perhaps other oral commensal bacterial species have the ability to efficiently activate regulatory mechanisms for chemokine transcription and translation in order to minimize pathological inflammatory responses driven by OECs in mucosal tissues. Consistently preliminary analysis showed that Sg has the ability to significantly up-regulate (>2- fold) the expression of 115/2578 miRNAs in OECs whereby miR-663a miR-4516 miR492 and miR193a-5p have validated gene targets involved in TLR- and cytokine-induced chemokine transcription and translation. To test this hypothesis we propose the following two specific aims: (i) To determine the chemokine transcriptional and translational responses of OECs to oral commensal bacteria and (ii) To determine the role of specific miRNAs in regulating the chemokine production induced by oral commensal bacteria in OECs. To address these knowledge gaps we will use OEC cultures to: (a) determine whether the disconnect between transcription and translation of chemokines in OECs is common feature of oral commensal bacterial species and (b) determine the effect of oral commensals on the expression of specific miRNAs as regulators of these inflammatory molecules. The contribution of this investigation is expected to be the identification of the activ regulation of inflammatory responses in OECs by specific miRNAs as a potential "tolerogenic mechanism" by which oral commensal bacteria maintain symbiosis with the host. Importantly diminutions of miRNAs that would be activated specifically by oral commensal bacteria (e.g. during dysbiosis) could be related to pathologic inflammatory changes observed in disease. This project's significance will enable a better understanding of the cellular and molecular mechanisms involved in the "tipping point" between epithelial tolerogenic and pathologic responses to oral bacteria. The results are expected to contribute to a strong evidence-based foundation for future studies designed to target these mechanisms and identify new molecular target(s) associated with oral bacteria-regulated epithelial chemokine production and will ultimately provide new opportunities for the development of innovative approaches to prevent/treat periodontitis.

project_terms:
Address;Adverse effects;Affect;Bacteria;Birth;CCL20 gene;CXC Chemokines;Cell Culture Techniques;Cell Extracts;Characteristics;Development;Disease;Dose;Ecology;Environment;Epithelial;Epithelial Cells;Equilibrium;Evaluation;Foundations;Fusobacterium nucleatum;Future;Gene Targeting;Genes;Genetic Transcription;Goals;Health;Homeostasis;IL8 gene;Immune response;Inflammation;Inflammatory;Inflammatory Response;Investigation;Knowledge;Laboratories;Lead;Mediating;Messenger RNA;MicroRNAs;Molecular;Molecular Target;Mucous Membrane;Oral;Oral mucous membrane structure;Outcome;Pathologic;Pattern;Periodontal Diseases;Periodontitis;Porphyromonas gingivalis;Production;Protein Analysis;Proteins;Regulation;Research;Research Design;Role;Streptococcus gordonii;Surface;Symbiosis;Taxon;Testing;Tissues;Transcriptional Activation;Translating;Translations;Up-Regulation (Physiology);Work;arm;beta-Chemokines;chemokine;combat;commensal microbes;cytokine;design;evidence base;immunopathology;innovation;microbial;oral bacteria;oral commensal;oral pathogen;pathogen;pathogenic bacteria;periopathogen;prevent;public health medicine (field);public health relevance;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will provide and evidence-based foundation for further mechanistic studies designed to identify specific miRNAs mediating the epithelial tolerogenic and pathologic responses to oral commensals which will provide new opportunities for the development of innovative approaches to prevent/treat periodontal disease and its potential adverse effects in systemic health.


application_id: 8966928
project_number: 1R21AI113348-01A1
project_title: Engineering pancreatic islets with TG protein to overcome rejection
administering_ic: NIAID
award_notice_date: 2015-05-12
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 113348
suffix: A1
program_official: BOURCIER, KATARZYNA
project_start_date: 2015-05-12
project_end_date: 2017-04-30
study_section: Transplantation, Tolerance, and Tumor Immunology Study Section[TTT]
contact_pi_person_id: 1894295
contact_pi: SHIRWAN, HAVAL
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
project_abstract:
DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) continues to be a major source of morbidity and mortality in over 0.9% US population with an economic burden in billions of dollars. The two current methods used to treat T1D are insulin therapy and allogeneic islet/pancreas transplantation (Tx) both of which have major limitations. Insulin administration does not completely prevent the complications associated with diabetes. Allogeneic islet/pancreas Tx suffers from rejection as well as renal and islet toxicities associated with chronic use of immunosuppressive drugs. Therefore the primary objective of this grant proposal is to establish a novel immunomodulatory protocol to confer tolerance to allogeneic islet grafts inthe absence of continuous immunosuppression. This will be achieved by engineering allogeneic islets ex vivo to transiently display on their surface a novel form of TGF1 SA-TGF protein and use the engineered islets to induce tolerance and treat T1D using rodent models.  T1D and allogeneic islet cell destruction is primarily mediated by T cells directed at unique beta cell and Tx antigens. Controlling the function of T pathogenic cells is therefore critical to tolerance induction to auto/alloantigens and treatment of T1D using allogeneic islets. We herein propose to use SA-TGF as an immunomodulatory molecule to achieve this goal. TGF1 has pleiotropic immune functions and is critical for tolerance to self-antigen. TGF also plays an important role in acquired tolerance to auto and alloantigens using various immunomodulatory approaches. Most importantly ectopic expression of TGF in pancreatic islets using transgenic systems or viral vectors proved effective in inducing tolerance to autoantigens in NOD mouse model of human T1D. However continuous expression of this molecule is associated with massive fibrosis and long-term beta cell failure. Importantly transient expression of TGF in beta cells using inducible transgenic systems overcame its deleterious effects without compromising its tolerogenic function. Inasmuch as this transgenic approach is not applicable to clinical islet Tx we envisioned that the transient display of TGF at protein level on the surface of islets in a clinically applicable manner may achieve tolerance without its reported complications arising from continuous expression. In limited preliminary studies we demonstrated that the transient display of SA-TGF on pancreatic islets was effective in overcoming rejection in a chemically induced islet Tx model. Building on these strong preliminary data we herein propose to use SA-TGF-engineered allogeneic islets as a means of immunomodulation to prevent graft rejection and treat diabetes in chemically and spontaneously diabetic mouse models. A series of studies will be conducted to delineate the implicated mechanisms of the tolerance. Rapid and transient display of SA-TGF protein on pancreatic islets offers a whole new means of intervention in the areas of autoimmunity and Tx. This approach possesses the simplicity safety and efficacy required to make it a clinically relevant alternative that may accomplish the same goals as gene therapy in the treatment of a broad spectrum of immune-based diseases including T1D.

project_terms:
Affect;Affinity;Alloantigen;Allogenic;Antigens;Applications Grants;Area;Autoantigens;Autoimmune Diseases;Autoimmune Process;Autoimmunity;Beta Cell;Biological;Biotin;C57BL/6 Mouse;Cells;Characteristics;Chimeric Proteins;Chronic;Clinical;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Economic Burden;Ectopic Expression;Engineering;Failure (biologic function);Family suidae;Fibrosis;Generations;Goals;Graft Rejection;Graft Survival;Health;Homeostasis;Human;IL2RA gene;Immune;Immune response;Immune system;Immunosuppressive Agents;Inbred BALB C Mice;Inbred NOD Mice;Insulin;Insulin-Dependent Diabetes Mellitus;Intervention;Islet Cell;Islets of Langerhans;Islets of Langerhans Transplantation;Kidney;Ligands;Maintenance;Mediating;Membrane;Memory;Methods;Modeling;Molecular;Molecular Chaperones;Morbidity - disease rate;Mortality Vital Statistics;Mus;Natural immunosuppression;Natural regeneration;Pancreas;Pancreas Transplantation;Pharmaceutical Preparations;Play;Population;Proteins;Protocols documentation;Recovery;Regulation;Regulatory T-Lymphocyte;Reporting;Rodent Model;Role;Safety;Series;Signal Transduction;Sirolimus;Source;Splenocyte;Streptavidin;Suggestion;Surface;System;T-Lymphocyte;Therapeutic;To autoantigen;Toxic effect;Transforming Growth Factor beta;Transgenic Organisms;Transplantation;Viral Vector;base;clinically relevant;crosslink;design;diabetic;effective therapy;efficacy testing;gene therapy;human disease;immune function;immunoregulation;improved functioning;islet;lymph nodes;macrophage;mouse model;novel;novel strategies;pleiotropism;prevent;receptor;standard care

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects more than 1% of the population worldwide. Insulin as a standard treatment although effective in treating T1D has major long-term complications therefore the development of novel approaches to prevent and treat T1D is a significant therapeutic goal. In this application we propose a novel engineering approach to display an immunomodulatory protein on the surface of allogeneic pancreatic islets (a source of insulin producing beta cells) and use the engineered islets to cure T1D in a mouse model (NOD) of the human disease without continuous use of immunosuppressive drugs; If effective this approach may have immediate and important implications for the use of allogeneic islets for the treatment of T1D in humans.


application_id: 8965602
project_number: 3R01HG006838-01S1
project_title: Supplement to Harmonizing Privacy Laws to Enable International Biobank Research
administering_ic: NHGRI
award_notice_date: 2015-02-09
opportunity_number: PA-14-077
application_type: 3
activity_code: R01
ic: HG
serial_number: 006838
suffix: S1
program_official: MCEWEN, JEAN
project_start_date: 2015-03-01
project_end_date: 2015-07-31
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:
DESCRIPTION (provided by applicant): In recent years researchers from around the world have begun developing repositories of tissues and socio-demographic data for genetics and other biomedical research. These biobanks often linked with patient health care records have been an invaluable resource in helping to understand cancer diabetes and various genetic-related disorders. The specimens and data are especially valuable when combined and analyzed with specimens and data from other countries because rare variations can be detected and examined. Sharing by researchers of specimens and data across international borders may be hampered by privacy laws in several countries that limit disclosure or receipt of certain specimens or health information. The study relying on a worldwide team of experts will compile and analyze the privacy laws in 23 countries undertaking substantial biobank development. It will then propose legal and technical strategies to accommodate important privacy interests while facilitating international access and use for research.

project_terms:
Administrator;Affect;Area;Biomedical Research;Clinical;Code;Collaborations;Complex;Confidentiality;Consent;Country;Data;Databases;Development;Diabetes Mellitus;Disclosure;Disease;Ensure;Environment;Europe;European Union;Fostering;Genetic;Genome;Genomics;Growth;Health;Healthcare;Individual;Information Technology;International;Laws;Lead;Legal;Link;Malignant Neoplasms;Maps;Measures;Modeling;Monograph;Nature;Other Genetics;Participant;Patients;Policies;Policy Maker;Population Study;Privacy;Records;Regulation;Research;Research Methodology;Research Personnel;Resources;Role;Sampling;Security;Specimen;Structure;Tissues;Translational Research;Variant;Work;base;biobank;comparative;data integration;development policy;interest;next generation sequencing;privacy protection;repository;sharing data;tool

public_health_relevance:
Biobanks often with linked clinical records have been established in numerous countries to facilitate genetic and genomic research. International collaborations of researchers using biobanks have been hampered by privacy laws in various countries. Developing an expert compilation of privacy laws in countries performing biobank-based research and recommending measures to harmonize these laws will enable international research cooperation and coordination.


application_id: 8965102
project_number: 2R01DK080770-05A1
project_title: Renal Osteodystrophy: A Fresh Approach
administering_ic: NIDDK
award_notice_date: 2015-06-23
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: DK
serial_number: 080770
suffix: A1
program_official: CHAN, KEVIN E
project_start_date: 2009-03-01
project_end_date: 2020-06-30
study_section: Skeletal Biology Development and Disease Study Section[SBDD]
contact_pi_person_id: 7875292
contact_pi: MALLUCHE, HARTMUT H
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Affect;Age;Alendronate;Alkaline Phosphatase;Aorta;Biochemical;Blood;Blood Tests;Bone Density;Bone Diseases;Bone Pain;Bone Resorption;Categories;Chronic;Chronic Kidney Failure;Clinical;Control Groups;Coronary;Data;Dialysis procedure;Disease;End stage renal failure;Endocrine System Diseases;Enrollment;Event;FDA approved;Fracture;Funding;Gender;General Population;Goals;Health;Heart Arrest;Heart Valves;Hip Fractures;Histologic;Hormones;Individual;Kidney Diseases;Link;Malignant Neoplasms;Measures;Metabolic Diseases;Minerals;Mission;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Myocardial Infarction;N-terminal;Operative Surgical Procedures;Osteogenesis;Osteoporosis;Parathyroid gland;Pathway interactions;Patients;Physicians;Postmenopausal Osteoporosis;Procollagen;Quality of life;Race;Randomized;Randomized Controlled Trials;Renal Osteodystrophy;Renal function;Research;Risk;Safety;Science;Serum;Severities;Staging;Telephone;Teriparatide;Testing;Therapeutic;Time;Treatment Cost;Treatment Protocols;United States;United States National Institutes of Health;Vascular calcification;Visit;X-Ray Computed Tomography;arm;base;bone;bone loss;bone mass;bone turnover;calcification;cardiovascular risk factor;cinacalcet;clinical practice;coronary artery calcification;cost;detector;fibroblast growth factor 23;high risk;improved;individualized medicine;novel;public health relevance;response;socioeconomics;stroke;tartrate-resistant acid phosphatase


application_id: 8964727
project_number: 1U01AA022618-01A1
project_title: Role of Gut Microbiome and DHA Deficiency in Alcohol Induced Neuroinflammation
administering_ic: NIAAA
award_notice_date: 2016-08-15
opportunity_number: PAR-13-133
application_type: 1
activity_code: U01
ic: AA
serial_number: 022618
suffix: A1
program_official: WANG, JOE
project_start_date: 2016-08-15
project_end_date: 2021-07-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Acids;Adverse effects;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcohols;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Astrocytes;Attenuated;Bacteria;Brain;Brain Injuries;Cells;Cerebrum;Chronic;Communities;Complex;Cyclic AMP;Data;Development;Diet;Encephalitis;Endotoxemia;Endotoxins;Enteral;Epithelial;Ethanol;Extramural Activities;Feedback;Functional disorder;Gene Expression;Gram-Negative Bacteria;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Intervention;Intestines;Knockout Mice;Lactobacillus;Lactobacillus casei rhamnosus;Lead;Link;Mediating;Membrane;Mental disorders;Microglia;Mus;National Institute on Alcohol Abuse and Alcoholism;Nerve Degeneration;Omega-3 Fatty Acids;Oxidative Stress;Pathology;Peripheral;Permeability;Play;Populations at Risk;Preventive;Probiotics;Process;Production;Proteins;Proteobacteria;Role;Rolipram;Sequence Analysis;Signal Transduction;Supplementation;TLR4 gene;TNF gene;Therapeutic;Tight Junctions;Treatment Efficacy;Universities;Work;alcohol effect;alcohol exposure;base;body system;brain cell;chronic alcohol ingestion;cytokine;feeding;gut microbiome;gut microbiota;immune activation;inhibitor/antagonist;macrophage;metagenomic sequencing;microbiota;monocyte;neuroinflammation;neuropathology;next generation sequencing;phosphodiesterase IV;prevent;probiotic supplementation;public health relevance;rRNA Genes;sequencing platform;translational study


application_id: 8964384
project_number: 2R01DK048498-20A1
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2015-07-15
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: DK
serial_number: 048498
suffix: A1
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2020-05-31
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
project_abstract:
DESCRIPTION (provided by applicant): The mammalian intestinal mucosa undergoes a process of continual renewal characterized by active proliferation of stem cells localized near the base of the crypts; progression of these cells up the crypt-villus axis with cessation of proliferation; and subsequent differentiation into one of the four primary cell types (i.e. enterocytes goblet cells Paneth cells and enteroendocrine cells). An imbalance in this highly-regimented and orderly process within the crypts is associated with a number of common intestinal pathologies (e.g. colorectal cancer and inflammatory bowel disease [IBD]) which are associated with significant morbidity and mortality. Delineating the molecular factors regulating intestinal proliferation and differentiation is crucial to our understanding of not only normal gut
development and adaptation but also aberrant gut growth. With the support of this grant we have shown the importance of the PI3K/Akt/mTOR pathway in the regulation of intestinal cell proliferation and differentiation. In addition we have shown the differential effects of various NFAT isoforms which integrate and cooperate with the PI3K/mTOR pathway to maintain intestinal homeostasis. As an extension to our published results our recent findings have demonstrated a novel metabolomic profile associated with intestinal cell differentiation and found that the ketogenic enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) and its product -hydroxybutyrate (HB) an endogenous inhibitor of histone deacetylases (HDACs) are increased with differentiation. In addition inhibition of mTOR Complex 1 (mTORC1) increases HMGCS2 expression in vitro and in vivo and moreover HB induces intestinal cell differentiation. Finally we have shown that HB increases the expression of the sirtuin proteins that contribute to intestinal cell differentiation; mTOR interacts with and regulates the expressio and deacetylase activity of the sirtuin proteins. Based on our recently published and preliminary findings we have further refined our central hypothesis to state that intestinal cell proliferatio and differentiation are regulated by PI3K/Akt/mTOR signaling pathway acting on critical downstream proteins (e.g. HMGCS2 and sirtuin proteins); a novel interaction between these pathways may exist that further adds to the intricate but highly regimented regulation of intestinal homeostasis. To examine our central hypothesis we have planned experiments with the following Specific Aims: 1) to delineate mTOR-mediated metabolic reprogramming in intestinal cell proliferation and differentiation; 2) to define the role of HMGCS2/HB in mediatin the effects of mTOR in the intestine; 3) to determine whether sirtuin proteins act cooperatively with HMGCS2/HB to maintain intestinal homeostasis. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation.

project_terms:
Atrophic;Biochemistry;Biometry;Cell Differentiation process;Cell Proliferation;Cell model;Cells;Colorectal Cancer;Complex;Deacetylase;Development;Enterocytes;Enteroendocrine Cell;Enzymes;Event;Excision;Glycolysis;Goals;Goblet Cells;Grant;Growth;Histones;Human;Hydroxybutyrates;Hydroxymethylglutaryl-CoA Synthase;In Vitro;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Ketone Bodies;Lead;Maintenance;Mediating;Metabolic;Metabolism;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Operative Surgical Procedures;Organoids;Paneth Cells;Pathology;Pathway interactions;Phenotype;Play;Process;Protein Isoforms;Proteins;Publishing;Regulation;Role;Signal Pathway;Signal Transduction;Sirtuins;Stem cells;Stress;System;Testing;Time;Transgenic Mice;Tuberous sclerosis protein complex;Villus;base;cell type;clinically relevant;design;human FRAP1 protein;in vivo;inhibitor/antagonist;insight;intestinal homeostasis;ketogenesis;ketogentic;mTOR Signaling Pathway;mTOR inhibition;metabolomics;migration;mouse model;multidisciplinary;novel;novel therapeutics;nuclear factors of activated T-cells;public health relevance;research study;stable isotope


application_id: 8963523
project_number: 1R01GM112721-01A1
project_title: Deciphering the Code of N-terminal Post-translational Modification
administering_ic: NIGMS
award_notice_date: 2015-08-17
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: GM
serial_number: 112721
suffix: A1
program_official: GERRATANA, BARBARA
project_start_date: 2015-09-01
project_end_date: 2020-06-30
study_section: Membrane Biology and Protein Processing Study Section[MBPP]
contact_pi_person_id: 8476980
contact_pi: SCHANER-TOOLEY, CHRISTINE E
other_pis: Not Applicable
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
project_abstract:
DESCRIPTION (provided by applicant): Post-translational modification of the -amino group of proteins has been documented for many decades. However these modifications are little studied and thought to be constitutive with few regulatory roles. Recent data from our laboratory challenges these beliefs. We have identified two novel N-terminal modifying enzymes NRMT1 and NRMT2 and shown that many of their targets are known disease-related proteins (including Retinoblastoma SET Tau -catenin and ataxin- 3). We have constructed the first viable knockout mouse for any N-terminal PTM (NRMT1-/-) which has severe developmental defects. We have also identified the first protein MYL9 which can be either N-terminally methylated or N-terminally acetylated. According to these data we aim to demonstrate that N-terminal post- translational modifications are dynamic serve distinct functional roles and control many pathways regulating human development and disease. Specific Aim #1 will use our newly generated NRMT1-/- mouse embryonic fibroblasts to determine the functional differences between N-terminal mono- and trimethylation. Specific Aim #2 will use a combination of biochemical assays and mass spectrometry to show for the first time that N-terminal methylation and N-terminal acetylation are interchangeable and differentially regulate protein function. Specific Aim #3 will use a combination of isothermal calorimetry protein arrays and SILAC mass spectrometry to determine if N-terminal monomethylation trimethylation and acetylation promote different binding partners. These experiments will begin to place N-terminal post-translational modifications in their relevant signaling pathways and reveal how their misregulation leads to developmental defects and tumor formation. Successful completion of these aims will initiate a new field of protein regulation and identify novel regulatory mechanisms for many cellular pathways known to impact human health.

project_terms:
Acetylation;Acetyltransferase;Address;Belief;Binding (Molecular Function);Binding Proteins;Biochemical;Biological Assay;Calorimetry;Cell Culture Techniques;Cell Proliferation;Cell physiology;Cells;Chromatin Structure;Code;Consensus Sequence;Cytotoxic agent;DNA Binding;DNA-Binding Proteins;Data;Defect;Development;Disease;Disease Progression;EMSA;Embryo;Enzymes;Fibroblasts;Frequencies (time pattern);Genes;Genetic Transcription;Goals;Health;Histone Code;Histones;Human;Human Development;ICAM1 gene;Knock-out;Knockout Mice;Laboratories;Lead;MJD1 protein;Mass Spectrum Analysis;Mediating;Methylation;Modification;Monitor;Mono-S;Myosin Regulatory Light Chains;N-terminal;Nuclear;Nuclear Export;Nuclear Localization Signal;Pathway interactions;Peptides;Perception;Post-Translational Protein Processing;Process;Protein Array;Proteins;Reading;Recruitment Activity;Regulation;Retinoblastoma;Role;Signal Pathway;Signal Transduction;Specificity;Tail;Tertiary Protein Structure;Testing;Time;Translating;amino group;base;beta catenin;cell growth regulation;cell motility;chromatin immunoprecipitation;human disease;innovation;mutant;novel;overexpression;protein function;public health relevance;research study;tau Proteins;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Post-translational modification of the N-terminus of proteins is a vastly understudied branch of protein processing. However our data show that its misregulation produces severe developmental defects and leads to oncogenesis. We aim to prove these modifications are dynamic and serving distinct regulatory roles so that their involvement in disease progression can be comprehensively studied and satisfactorily utilized.


application_id: 8962894
project_number: 1R01CA187273-01A1
project_title: Suppression of Prostate Tumor Growth and Metastasis by Inhibition of Vimentin
administering_ic: NCI
award_notice_date: 2015-06-10
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: CA
serial_number: 187273
suffix: A1
program_official: CHEN, WEIWEI
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1883986
contact_pi: RANGNEKAR, VIVEK M
other_pis: Not Applicable
congressional_district: 06
department: RADIATION-DIAGNOSTIC/ONCOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Advanced prostate tumors that often metastasize to the lung bone and other vital tissues are resistant to conventional therapy. Prostate apoptosis response-4 (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells. Although baseline levels of Par-4 secreted by cells are inadequate to induce apoptosis normal cells can be induced to produce robust secretion of Par-4 protein that targets cancer cells in a paracrine manner. Accordingly secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 in cancer cells to trigger apoptosis in primary and metastatic tumors. Importantly secreted Par-4 induces cancer-specific apoptosis but it does not induce apoptosis in normal cells as GRP78 is expressed only on the surface of cancer cells not on normal cells. "Small-molecule" drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would therefore represent an important therapeutic advance. In preliminary studies we synthesized and screened newly developed 3-arylquinolines as well as related quinolones and quinothiolones for the secretion of Par-4 protein from normal mouse and human fibroblast and epithelial cells. This screening led to the identification of 2-amino-7-(NN-dimethylamino)-3-(2'-fluorophenyl)quinoline (called "Arylquin-1") as a member of a new class of agents that trigger robust secretion of Par-4 from normal cells at nanomolar non-toxic concentrations. As expected Par-4 secreted from these normal cells induced paracrine apoptosis in diverse prostate and lung cancer cell cultures but not in normal cell cultures. Using
a biotinylated biologically active version of Arylquin-1 we identified vimentin a protein linkedto motility invasion EMT and metastasis as the molecular target of Arylquin-1 that in turn produces Par-4 secretion. In this study we will determine the effect of Arylquin-1 on Par-4 secretion from normal cells and apoptosis in prostate cancer cell culture and in vivo on tumor growth in prostate cancer models. Computational dynamics revealed that Arylquin-1 forms a stable interaction with a hydrophobic pocket on vimentin. We will therefore determine the domains of Par-4 and vimentin that bind to each other to elucidate the mechanism underlying inhibition of Par-4 secretion by vimentin and its release by Arylquin-1. Consistent with the interaction of Arylquin-1 with vimentin our preliminary studies also indicated that Arylquin-1 inhibits motility and invasion in prostate cancer cells by an apoptosis-independent mechanism. We will therefore study whether Arylquin-1 inhibits motility invasion and EMT in cell culture and metastasis in mouse models of prostate cancer via vimentin-dependent mechanisms. Developing agents that selectively promote Par-4 secretion from normal cells induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.

project_terms:
Androgens;Apoptosis;Apoptotic;Binding (Molecular Function);Biology;Cancer Etiology;Cell Culture Techniques;Cell Surface Receptors;Cells;Cessation of life;Chemicals;Conditioned Culture Media;Development;Epithelial;Epithelial Cells;Family;Fibroblasts;GRP78;Growth;Human;Impaired wound healing;Inhibition of Apoptosis;Killings;Knockout Mice;Liver;Lung;Malignant Neoplasms;Malignant neoplasm of lung;Malignant neoplasm of prostate;Mesenchymal;Metastatic Neoplasm to the Lung;Modeling;Molecular Target;Mus;Neoplasm Metastasis;Normal Cell;Organ;PAWR protein;Patients;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Primary Neoplasm;Prostate;Prostate Cancer therapy;Prostatic Neoplasms;Proteins;Quinolones;Resectable;Resistance;Role;Structure-Activity Relationship;Surface;Testing;Therapeutic;Tissues;Toxic effect;Tumor Suppressor Proteins;Vimentin;analog;bone;cancer cell;cell motility;conventional therapy;deprivation;extracellular;in vivo;insight;member;men;metastatic process;mouse model;novel;paracrine;prostate cancer cell;prostate cancer model;public health relevance;quinoline;receptor;response;screening;small molecule;therapy resistant;tumor;tumor growth;tumor xenograft


application_id: 8962566
project_number: 1R01GM113087-01A1
project_title: Deciphering the molecular mechanisms underlying active scaffolding
administering_ic: NIGMS
award_notice_date: 2015-07-29
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: GM
serial_number: 113087
suffix: A1
program_official: DUNSMORE, SARAH
project_start_date: 2015-08-01
project_end_date: 2020-05-31
study_section: Molecular and Integrative Signal Transduction Study Section[MIST]
contact_pi_person_id: 8586925
contact_pi: GALPERIN, EMILIA
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Affect;Apoptosis;Biochemical;Biological;Biological Markers;Biological Process;Blood;Cell Adhesion;Cell Culture System;Cell membrane;Cell model;Cell physiology;Cells;Cognitive deficits;Complex;Congenital Heart Defects;Cultured Cells;Data;Defect;Development;Disease;Effectiveness;Embryo;Embryonic Development;Endocytosis;Endosomes;Ensure;Enzymes;Event;Face;Fluorescence Resonance Energy Transfer;Foundations;Genetic Models;Goals;Growth;Hematopoiesis;Hematopoietic;Image;Lead;Link;MAP Kinase Gene;MEKs;Mediating;Microscopy;Mission;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Genetics;Mus;Mutation;Outcome;Pathology;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Physiological;Play;Prevention;Prognostic Marker;Protein Biochemistry;Proteins;Proto-Oncogene Proteins c-raf;Ras/Raf;Regulation;Research;Role;Scaffolding Protein;Signal Pathway;Signal Transduction;Spatial Distribution;Specificity;Staging;Study models;System;Techniques;Testing;Ubiquitin;Ubiquitination;Work;Zebrafish;base;cell motility;cellular transduction;chromophore;developmental disease/disorder;disease diagnosis;in vivo;innovation;insight;novel;novel therapeutics;public health relevance;scaffold;targeted treatment;therapeutic development;transmission process;tumor;tumor progression;ubiquitin-protein ligase


application_id: 8961098
project_number: 2R01AR060701-06
project_title: Novel Roles for Satellite Cells in Adult Skeletal Muscle Adaptation
administering_ic: NIAMS
award_notice_date: 2015-07-26
opportunity_number: PA-13-302
application_type: 2
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2020-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
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:
DESCRIPTION (provided by applicant):  Under the current award we have acquired exciting new evidence that satellite cells are necessary for the proper remodeling of the extracellular matrix during hypertrophy. We reported that in muscle depleted of satellite cells there was a significant increase in fibrosis that was associated with a blunted long-term hypertrophic response. Our preliminary data show that activated satellite cells/myogenic progenitor cells (MPCs) are capable of repressing the synthesis of extracellular matrix components by fibroblasts through exosomal delivery of microRNAs. We hypothesize that the loss of satellite cells removes this "brake" leading to the over-production of collagen and fibrosis ultimately limiting long-term hypertrophic growth. We further hypothesize that fibrosis as a result of loss of
satellite cells preferentially limits growth in fast muscle fibers whereas growth of slow fibers i limited by myonuclear domain size. Thus fast fibers display a relatively flexible myonuclear domain whereas slow fibers may have a more stringent requirement for satellite cells for growth. The objectives of this proposal are to use genetic mouse models and in vitro cell culture to investigate these novel roles for satellite cells in skeletal muscle adaptation by pursuing the following aims. Aim 1 will determine the mechanisms underlying satellite cell regulation of extracellular matrix remodeling during skeletal muscle hypertrophy. Aim 2 will determine if fibrosis attenuates long-term hypertrophy in satellite cell-depleted muscle and the influence of fiber type composition. Aim 3 will determine if there is a fiber type-specific requirement for satellite cell fusion during skeletal muscle hypertrophy. Our published work and new preliminary data clearly show that our understanding of satellite cell function in adult skeletal muscle adaptation remains incomplete. The studies described in this proposal address this fundamental gap in our knowledge and are expected to provide critical information necessary to more effectively evaluate the use of satellite cells as a therapeutic agent to prevent or restore the los of skeletal muscle mass associated with dystrophies cancer age and rehabilitation following disuse.

project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Affect;Age;Aging;Area;Atrophic;Attenuated;Award;Cell Culture Techniques;Cell Therapy;Cell fusion;Cell physiology;Clinical;Coculture Techniques;Collagen;Congestive Heart Failure;Data;Deterioration;Environment;Extracellular Matrix;Fiber;Fibroblasts;Fibronectins;Fibrosis;Foundations;Gene Expression;Gene Targeting;Genes;Genetic;Grant;Growth;HIV;Hypertrophy;Immobilization;In Vitro;Individual;Knockout Mice;Knowledge;Limb structure;Maintenance;Malignant Neoplasms;Mediating;MicroRNAs;Molecular;Molecular Profiling;Morbidity - disease rate;Mortality Vital Statistics;Mouse Strains;Mus;Muscle;Muscle Fibers;Muscle function;Operative Surgical Procedures;Phenotype;Plantaris muscle;Process;Production;Publishing;Quality of life;Regulation;Rehabilitation therapy;Reporter;Reporting;Rheumatoid Arthritis;Role;Sepsis;Series;Skeletal Muscle Satellite Cells;Skeletal muscle structure;Stem cells;Systemic disease;Tamoxifen;Testing;Therapeutic Agents;Therapeutic Uses;Time;Untranslated Regions;Wasps;Weight;Work;base;cell growth;extracellular;flexibility;human DICER1 protein;in vitro Assay;in vivo;loss of function;mouse model;muscle form;muscle hypertrophy;novel;patient population;prevent;public health relevance;research study;response;sarcopenia;satellite cell;skeletal muscle plasticity;stem


application_id: 8958810
project_number: 4R01ES020870-05
project_title: Cell survival and arsenic carcinogenesis
administering_ic: NIEHS
award_notice_date: 2015-11-20
opportunity_number: PA-10-067
application_type: 4
activity_code: R01
ic: ES
serial_number: 020870
program_official: REINLIB, LESLIE J
project_start_date: 2012-01-15
project_end_date: 2017-10-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
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): Although the molecular mechanism of arsenic-induced carcinogenesis remains to be investigated reactive oxygen species (ROS) generated by arsenic are considered to be important. Arsenic-generated ROS could cause DNA damage lipid peroxidation and protein modification leading to various carcinogenic responses. Our preliminary studies have shown that the capacity of ROS generation induced by arsenic is substantially reduced in arsenic-transformed human lung bronchial epithelial (BEAS-2B) cells relative to the non-transformed cells. Such a reduction in ROS generation endows cells with premalignant features including rapid growth. Arsenic- transformed cells exhibit a decreased apoptosis (apoptosis resistance) upon arsenic exposure. This proposal hypothesizes that due to a low potency of ROS generation arsenic-transformed cells develop apoptosis resistance and increased cell survival contributing to the overall mechanism of arsenic-induced carcinogenesis. Three aims are proposed to test this hypothesis. Aim 1 will investigate the mechanism of decreased ROS generation in the arsenic-transferred cells. We will investigate whether impairment of the ROS generating pathway is responsible for a low level of arsenic-induced ROS generation in arsenic transformed BEAS-2B cells. We will also investigate whether the increased level of antioxidant enzymes in transformed cells contributes to the decreased level of ROS generation. The completion of this aim will establish the mechanism of decreased ROS generation in arsenic-transformed cells. Aim 2 will investigate the role of reduced ROS generation in apoptosis resistance of arsenic-transformed cells. We investigate (a) whether reduced ROS generation of arsenic- transformed cells is responsible for apoptosis resistance in arsenic-transformed cells; (b) whether arsenic- transformed cells have higher antioxidant activities of SOD and catalase than their passage-matched control cells; (c) whether knock-down of antioxidant enzymes or overexpressing NADPH oxidase in the transformed cells increases ROS generation and enhances apoptosis in response to arsenic stimulation; (d) whether knocking down of Bcl-2 increases apoptosis of arsenic-transformed cells; and (e) whether arsenic- transformed cell will show fast growth and enhanced invasion and migration due to the decreased ROS generation and apoptosis resistance. Overall this aim will demonstrate the role of ROS in apoptosis resistance of arsenic-transformed cells. Aim 3 will investigate the arsenic-transformed cells-induced tumorigenesis and the role of apoptosis. We will investigate the role of apoptosis resistance in tumorigenesis of arsenic-transformed cells. We will also investigate the roles of ROS and apoptosis regulatory proteins Bcl-2 in arsenic-transformed cells-induced tumorigenesis using both skin tumorigenesis model and orthotopic lung cancer model. It is expected that the increase of apoptosis of arsenic-transformed cells by Bcl-2 knockdown will decrease tumor growth. Similarly alterations in the ROS generating capacity of the cells i.e. by ectopic overexpression and knockdown of the ROS-scavenging and producing enzymes will have an effect on tumorigenesis of arsenic-transformed cells.

project_terms:
Antioxidants;Apoptosis;Apoptotic;Arsenic;Arsenites;BCL2 gene;Cancer Model;Cell Death;Cell Survival;Cells;Characteristics;Chronic;DNA Damage;Dose;Enzymes;Epithelial;Epithelial Cells;Exhibits;Exposure to;GADD45A gene;Generations;Growth;Health;Human;Impairment;Kidney;Lipid Peroxidation;Liver;Lung;Malignant neoplasm of lung;Malignant neoplasm of urinary bladder;Microfilaments;Modeling;Molecular;NADPH Oxidase;Pathway interactions;Post-Translational Protein Processing;Premalignant;Prevention strategy;Property;Reactive Oxygen Species;Resistance;Role;Skin;Testing;Toxic effect;Transcription Factor AP-1;antioxidant enzyme;arsenic-induced carcinogenesis;cancer cell;carcinogenesis;catalase;cell growth;cell motility;cell transformation;genetic regulatory protein;hypoxia inducible factor 1;knock-down;migration;novel;overexpression;rapid growth;response;tumor growth;tumorigenesis

public_health_relevance:
Health effects of chronic exposure to arsenic are one of the major health concerns. The present study will investigate the mechanism of arsenic-induced carcinogenesis with a focus on decreased generation of reactive oxygen species and apoptosis resistance in arsenic transformed cells. The results will help understand the mechanism of arsenic carcinogenesis and to develop preventive strategy.


application_id: 8958209
project_number: 1R15DE025388-01
project_title: Treg regulation and its role in gingival inflammation during pregnancy
administering_ic: NIDCR
award_notice_date: 2015-07-14
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: DE
serial_number: 025388
program_official: CHANDER, PREETHI
project_start_date: 2015-07-15
project_end_date: 2020-01-14
study_section: Special Emphasis Panel[ZRG1 MOSS-U (82)]
contact_pi_person_id: 9846210
contact_pi: LIANG, SHUANG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pregnant women are more prone to develop exacerbated gingival inflammation which is known as pregnancy gingivitis. Inflammation and oral pathogenic bacteria infiltration during pregnancy are detrimental to pregnant women's health and negatively impact on their life quality and can cause adverse pregnancy outcomes in some cases. Using a modified ligation induced periodontal disease model our preliminary data implies that the gingival inflammation during pregnancy is linked with lower number of Tregs one subset of T cells critical for host immune regulation. This proposal hypothesizes that host Tregs proliferate in response to pathogen infection to prevent excessive immune responses but the process is down-regulated during pregnancy. This down-regulation of Treg development is responsible for the disrupted immune homeostasis and gingival inflammation. This notion will be tested using in vitro analysis and in vivo mouse model. In Aim 1 we will determine the effect of pregnancy on pathogen-induced Treg number and function. Pregnant mice will be ligated and infected with pathogens to determine the number as well as the immune suppressive function of induced Tregs; detailed mechanisms of the regulation on Treg proliferation will also be determined. Aim 2 is expected to investigate the role of Tregs in the gingival inflammation during pregnancy. Depletion of Tregs as well as adoptive transfer of Tregs into pregnant mice will reveal the effect of Tregs on the gingival inflammation. The objective is to reveal the regulation of infection-induced Treg development by pregnancy status and the effect of this regulation on gingival inflammation during pregnancy. The goal of the project is to not only pinpoint the critical cell type in the disease but also provide information for the pathogenesis and future cure of the disease therefore significantly improving woman health. Moreover another goal of current proposal is to enhance the research and training environment for the students in our school by exposing more students to the concept and technologies for oral biology research and foster next generation of scientists.

project_terms:
Adoptive Transfer;Affect;Animal Model;Bacteria;Cells;Communicable Diseases;Data;Development;Disease;Disease model;Down-Regulation;Environment;Flow Cytometry;Fostering;Funding;Future;Gingiva;Gingivitis;Goals;Hemorrhage;Homeostasis;Immune;Immune response;Immunity;In Vitro;Infection;Infiltration;Inflammation;Knockout Mice;Ligation;Link;Lymphocyte Subset;Modeling;Mus;Natural Immunity;Oral;Pathogenesis;Pathway interactions;Patients;Periodontal Diseases;Pregnancy;Pregnancy Outcome;Pregnant Women;Prevalence;Process;Proliferating;Quality of life;Regulation;Regulatory T-Lymphocyte;Research;Research Training;Role;School Dentistry;Schools;Scientist;Students;T-Cell Proliferation;T-Lymphocyte;T-Lymphocyte Subsets;Technology;Testing;Thymus Gland;Tissues;Universities;Women's Health;Work;adaptive immunity;cell type;improved;in vivo;insight;mouse model;next generation;novel;oral bacteria;oral biology;oral immunology;pathogen;pathogenic bacteria;pregnant;prevent;programs;public health relevance;response;therapeutic target;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Pregnant women are prone to more prevalent and more severe gingival inflammation. This application proposes to investigate the regulation of infection-driven Treg development during pregnancy and its role in gingival inflammation. This work is expected to pinpoint the role of dysregulation of Treg development in the gingival inflammation during pregnancy.


application_id: 8958194
project_number: 1R15CA188890-01A1
project_title: Finding novel platinum(II) complex anti-cancer drugs with reduced ototoxicity
administering_ic: NCI
award_notice_date: 2015-07-01
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: CA
serial_number: 188890
suffix: A1
program_official: CHEN, WEIWEI
project_start_date: 2015-07-01
project_end_date: 2020-01-01
study_section: Special Emphasis Panel[ZRG1 MDCN-R (86)]
contact_pi_person_id: 7028711
contact_pi: SMITH, MICHAEL E
other_pis: WILLIAMS, KEVIN M
congressional_district: 02
department: BIOLOGY
primary_duns: 077876258
primary_uei: U5GMACGETKJ1
duns_number: 077876258
uei: U5GMACGETKJ1
fips: US
organization_id: 9186501
organization_name: WESTERN KENTUCKY UNIVERSITY
organization_city: BOWLING GREEN
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 421011001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overarching goal is to find platinum(II) complex drugs that show toxicity against cancer cells while avoiding ototoxicity and hearing loss. This research will be conducted both in vitro and in vivo in the zebrafish model. Current platinum-based drugs like cisplatin have diamine ligands and are highly ototoxic i.e. produce sensory hair cell and hearing loss. Some novel platinum(II) complexes have triamine or heterocyclic ligands that exhibit unique DNA and protein binding properties that differ from that of complexes with diamine ligands. Dr. Kevin Williams (Biochemistry) at Western Kentucky University (WKU) has recently found differences in platinum(II) diamine and triamine complexes in their reactions with amino acid and nucleotide targets. These properties may result in reduced drug side effects such as ototoxicity. Dr. Michael Smith (Neurobiology) recently showed that ototoxicity could be examined in the zebrafish inner ear using two ototoxic chemicals- the aminoglycoside antibiotic gentamicin and the platinum-based anti- cancer drug cisplatin. The proposed project is an interdisciplinary collaboration between these two laboratories at WKU. This proposal has two primary aims: 1) to determine whether novel platinum(II) complexes cause cytotoxicity to cancer cells and 2) to determine whether the novel platinum(II) complexes are ototoxic (i.e. damage hair cells and cause hearing loss). In aim 1 we will test six novel compounds in six different cancer cell lines for anticancer activity using cytotoxicity assays inductively coupled plasma-emission spectroscopy (ICP-ES) to measure uptake of platinum into cancer cell nuclei and DNA binding assays. In aim 2 those compounds that are found to be cytotoxic to cancer cells in aim 1 will be tested for ototoxicity in a zebrafish inner ear model. Following microinjection with either a platinum-compound or buffer control zebrafish hearing thresholds will be measured using auditory evoked potential (AEP) recording. Then the inner ears will be dissected and cell death and hair cell loss will be quantified in the sensory epithelia. The proposed study establishes a framework for understanding the effects of these novel platinum(II) complexes on cancer cells and hair cells with the ultimate goal of providing the foundation for future investigations developing new chemotherapy drugs that avoid the side effect of hearing loss. This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduate and graduate students to research; and 3) strengthening the research environment in non- research intensive universities. Western Kentucky University aspires to be the best comprehensive public institution in Kentucky. This project supports this mission by enhancing the research environment and by providing undergraduate and graduate students with opportunities to be engaged in biomedical research and supports both P.I.s' career goals of leading independently-funded research laboratories.

project_terms:
Adverse drug effect;Adverse effects;Affect;Affinity;American;Amino Acids;Aminoglycoside Antibiotics;Aminoglycosides;Animal Model;Antibiotics;Antineoplastic Agents;Auditory;Auditory Evoked Potentials;Binding (Molecular Function);Biochemistry;Biological Assay;Biomedical Research;Buffers;Cancer cell line;Cell Death;Cell Density;Cell Line;Cell Nucleus;Cell Survival;Cell model;Chemical Agents;Chemicals;Chemotherapy-Oncologic Procedure;Cisplatin;Complex;Coupled;Cytotoxic agent;DNA;DNA Binding;DNA-Binding Proteins;Development;Diamines;Disease;Drug Prescriptions;Environment;Epithelium;Equilibrium;Exhibits;Exposure to;Foundations;Funding;Future;Genetic Transcription;Gentamicins;Goals;Hair Cells;Hearing;In Vitro;Institution;Investigation;Kentucky;Killings;Laboratories;Laboratory Research;Labyrinth;Ligands;Malignant Neoplasms;Measures;Microinjections;Mission;Modeling;Neurobiology;Nucleotides;Pharmaceutical Preparations;Plasma;Platinum;Platinum Compounds;Property;RNA;Reaction;Relative (related person);Research;Research Support;Sensory;Sensory Hair;Sensory Receptors;Series;Signal Pathway;Staining method;Stains;System;TdT-Mediated dUTP Nick End Labeling Assay;Testing;Toxic effect;Universities;Vertebrates;Work;Zebrafish;anticancer activity;apramycin;base;cancer cell;career;cell injury;chemotherapy;cytotoxic;cytotoxicity;drug candidate;drug development;emission spectroscopy;experience;graduate student;hearing impairment;in vivo;interdisciplinary collaboration;novel;ototoxicity;ototoxin;programs;public health relevance;undergraduate student;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A half a million Americans a year experience hearing loss as a result of taking prescription drugs that are ototoxic such as the anti-cancer chemotherapy compound cisplatin. The proposed project investigates novel platinum-based compounds for cancer cytotoxicity and ototoxicity using a zebrafish auditory hair cell model. The goal is to find
novel platinum-based chemotherapy compounds that are less ototoxic than cisplatin but are still effective at killing cancer cells.


application_id: 8957744
project_number: 1R15AI119861-01
project_title: The reverse transmigration of Salmonella-infected cells into the bloodstream
administering_ic: NIAID
award_notice_date: 2015-06-12
opportunity_number: PA-13-313
application_type: 1
activity_code: R15
ic: AI
serial_number: 119861
program_official: ALEXANDER, WILLIAM A
project_start_date: 2015-06-20
project_end_date: 2019-05-31
study_section: Special Emphasis Panel[ZRG1 IDM-S (81)]
contact_pi_person_id: 2147829
contact_pi: WORLEY, MICAH
other_pis: Not Applicable
congressional_district: 03
department: BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Salmonella is a major public health problem. There are more than one billion new Salmonella infections of humans each year that lead to more than three million deaths. The problem is greatly exacerbated by the emergence of multi-drug resistant strains. In addition to public health concerns S. Typhimurium is also studied because it
is a model pathogen without parallel for dissecting basic pathogenic processes as it combines the advantages of excellent genetics with tractable animal models of infection. Salmonella is believed to exploit migratory host cells as Trojan horses to spread from the gastrointestinal (GI) tract to internal organs. Dendritic cells are one such cell type which can reenter the bloodstream by traversing endothelium in the basal to apical direction in a normal host process referred to as reverse transmigration. Reverse transmigration is likely relevant to numerous infectious processes including the spread of pathogenic microbes from the GI tract lung tissue and the oral mucosa to the systemic circulation. Not surprisingly infected cells do not normally reverse transmigrate presumably because this could create a serious bloodstream infection. The host likely has mechanisms to detect conserved microbial components and balances the need to resolve inflammation with inhibiting the spread of microbes appropriately. Salmonella Typhimurium exploits the reverse transmigration pathway to deeper tissue manipulating the migratory properties of infected cells to enter the bloodstream within them directly from the GI tract as an unappreciated component of its pathogenesis. Salmonella achieves this in part by secreting the type III effector SrfH into infected cells to subvert the host protein TRIP6 to stimulate reverse transmigration. In Aim 1 we will employ a variety of biochemical and genetic tools to delineate mechanistically exactly how the SrfH/TRIP6 interaction promotes travel through the reverse transmigration pathway. As a mutant deficient in type III secretion generally has a larger defect in triggering the reverse transmigration of infected cells than a srfH mutant additional microbial and host factors must be involved. In Aim 2 we will utilize an in vitro revere transmigration assay along with murine intra-host dissemination experiments to determine the impact of the 9 host factors that are known to regulate the reverse transmigration of uninfected cells on the reverse transmigration of ones infected with Salmonella. Also we will determine if these molecules are perturbed during infections. Finally we will utilize the in vitro assay to identify the additional type III effector(s) involved in exploiting the reverse transmigration pathway to the bloodstream.

project_terms:
Animal Model;Apical;Bacteria;Binding (Molecular Function);Biochemical Genetics;Biological Assay;Blood Circulation;Cell membrane;Cell surface;Cells;Cessation of life;Communicable Diseases;Coupling;Data;Defect;Dendritic Cells;Endothelium;Equilibrium;Equus caballus;Gastrointestinal tract structure;Genetic;Human;Immune response;In Vitro;Infection;Inflammation;Integration Host Factors;Investigation;Knowledge;Lead;Lymphatic System;Mediating;Microbe;Modeling;Molecular;Multi-Drug Resistance;Mus;Oral mucous membrane structure;Organ;Pathogenesis;Pathway interactions;Process;Property;Proteins;Regulation;Route;Salmonella;Salmonella infections;Salmonella typhimurium;Sepsis;Site;Spleen;Structure of parenchyma of lung;Testing;Tissues;Travel;Virulence Factors;Work;cancer type;cell motility;cell type;combat;human BCAR1 protein;in vitro Assay;in vivo;innovation;insight;microbial;microbial host;migration;monolayer;mutant;novel;palmitoylation;pathogen;public health medicine (field);public health relevance;research study;resistant strain;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There are more than one billion new Salmonella infections of humans each year that lead to more than three million deaths. One of the key features of serious Salmonellosis is the colonization of internal organs from the gastrointestinal (GI) tract. n the work proposed here we will identify and characterize microbial and host factors that regulate the spread of Salmonella to the bloodstream and deeper tissue from the GI tract through a newly discovered largely uncharacterized pathway.


application_id: 8957715
project_number: 1R21CA198249-01
project_title: A Novel Vaccination Stratagem for Lung Cancer
administering_ic: NCI
award_notice_date: 2015-06-15
opportunity_number: PAR-13-146
application_type: 1
activity_code: R21
ic: CA
serial_number: 198249
program_official: YOVANDICH, JASON L
project_start_date: 2015-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZCA1 RTRB-Z (M1)]
contact_pi_person_id: 10807180
contact_pi: YADDANAPUDI, KAVITHA
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): Lung cancer is a prevalent disease and consumes many lives every year. Disease relapse invasion and metastases are the main causes of death. Recent discoveries provide compelling evidence that at least some types of cancer are initiated and maintained by a small population of malignant cells called cancer-initiating stem cells (CICs). Relapse invasion and metastases are explained by the fact that CICs have a different biology than all the other tumor cells and importantly are resistant to chemotherapies and radiation. Lung CICs have been shown to represent about 1-15% of all tumor cells and can form tumors with injections as low as 100 cells. Evidence from published studies have demonstrated that human as well as rodent cancers contain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteins also express markers used to identify lung CICs; therefore we hypothesized that ES cells and CICs share several common molecular traits. To test this hypothesis we vaccinated mice with irradiated allogeneic murine ES cells in combination with a source of granulocyte-macrophage colony stimulating factor (GM-CSF) as an immunostimulatory adjuvant (ES cell vaccine) and investigated whether an anti-tumor immune response was elicited. We discovered that ES cell vaccination is very effective in preventing both implantable and carcinogen-induced lung adenocarcinoma development without any detectable toxicity or signs of autoimmunity. Preliminary studies from our laboratory reveal that splenocytes from ES cell-immunized mice are preferentially cytotoxic to lung CICs. Experiments proposed in this application seek to expand these novel findings to convincingly demonstrate that ES cells immunize against lung cancer- associated CICs and that anti-CIC immunity is responsible for preventing lung adenocarcinoma development. A major goal of this study is to assess the potential of CIC-targeting ES cell vaccine as a treatment option for lung cancer patients. We will test the translational potential of our approach using a novel ES cell-derived exosome- based vaccination strategy (Es-exo vaccine). Experiments proposed in this study will address the in vivo efficacy of ES-exo vaccine as a cell-free vaccine modality in both prophylactic and therapeutic settings against lung cancer. The biological features responsible for the anti-tumor activities of ES-exo vaccine as well as their immunostimulatory properties will be investigated in in vitro and in vivo lung cancer mouse models. To fulfill the stated objectives
the following aims are proposed: 1) Investigate whether lung cancer-initiating cells are targets of
ES cell vaccination- induced anti-tumor immunity. 2) Evaluate the translational potential of ES cell-derived exosomes (ES-exo) as a novel cell-free vaccine for lung cancer. Our proposed study will provide important insights towards developing a safe immunotherapeutic vaccine for lung cancer onset and/or recurrence.

project_terms:
Address;Adjuvant;Age-Months;Allogenic;Animal Model;Antigens;Autoimmunity;Binding (Molecular Function);Biological;Biology;CD8B1 gene;Cancer Biology;Cancer Patient;Carcinogens;Cause of Death;Cell-Free System;Cells;Cessation of life;Clinical Trials;Data;Dendritic Cells;Development;Disease;Disease remission;Embryo;Epithelial;Goals;Granulocyte-Macrophage Colony-Stimulating Factor;Health;Health Care Costs;Hematopoietic;Human;Immune;Immune response;Immunity;Immunization;Immunotherapeutic agent;In Vitro;Injection of therapeutic agent;Laboratories;Lead;Lewis Lung Carcinoma;Life;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Membrane;Messenger RNA;MicroRNAs;Modality;Molecular;Mus;Mutation;Neoplasm Metastasis;Patients;Platelet Factor 4;Population;Pre-Clinical Model;Property;Proteins;Publishing;Radiation;Recurrence;Recurrent disease;Relapse;Relative (related person);Reporting;Research Design;Resistance;Risk;Rodent;Signal Transduction;Solid;Source;Splenocyte;Stem cells;T cell response;Teratoma;Testing;Therapeutic;Toxic effect;Transgenic Organisms;Translations;Treatment Efficacy;Tumor Antigens;Tumor Immunity;Undifferentiated;Vaccinated;Vaccination;Vaccines;Validation;Vesicle;Work;antitumor effect;base;cancer cell;cancer therapy;cancer type;cell type;chemotherapy;conventional therapy;cytotoxic;embryonic stem cell;in vitro Assay;in vivo;insight;intercellular communication;lung tumorigenesis;mouse model;nanoscale;neoplastic cell;novel;prevent;prophylactic;public health relevance;research study;self-renewal;stem;trait;tumor;tumorigenesis;vaccination strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A Novel Vaccination Stratagem for Lung Cancer Lung cancer patients remain at elevated risk for relapse following conventional treatment. Recent studies of lung cancer biology provide compelling evidence that lung cancer is initiated and maintained by a small population of malignant cells called cancer-initiating cells (CICs). Currently available cancer treatments may be ineffective against lung CICs. Our preliminary work using a vaccine consisting of mouse embryonic stem (ES) cells has provided validation that vaccination prevents lung cancers in mice. We propose to investigate whether ES cell vaccination as well as a novel cell-free version of the ES cell vaccine is effective in depleting lung CICs and prevent cancer. Such a vaccine will reduce health care costs and loss of life from a disease that is now a major health problem worldwide.


application_id: 8949915
project_number: 1K01CA197073-01
project_title: Intestinal phosphatidylcholine exposure and breast cancer risk
administering_ic: NCI
award_notice_date: 2015-06-26
opportunity_number: PAR-12-050
application_type: 1
activity_code: K01
ic: CA
serial_number: 197073
program_official: SOYOMBO-SHOOLA, ABIGAIL ADEBISI
project_start_date: 2015-07-01
project_end_date: 2020-06-30
study_section: Transition to Independence Study Section (I)[NCI-I]
contact_pi_person_id: 10392720
contact_pi: ONONO, FREDRICK ONYANGO
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_terms:
Address;Adipose tissue;Animals;Attenuated;Award;Bile fluid;Bioavailable;Blood;Blood Circulation;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast cancer metastasis;Calories;Cancer Patient;Cancer Prognosis;Chylomicrons;Clinical;Consumption;Data;Diet;Dietary Fats;Disease;Enterocytes;Enzymes;Exposure to;Fasting;Fatty acid glycerol esters;Food;Funding;Future;Genetic;Growth;Health;Human;Hydrolysis;In Vitro;Incidence;Individual;Intervention;Intestinal Absorption;Intestines;Lead;Lecithin;Link;Lipids;Lipoproteins;Low-Density Lipoproteins;Lymphatic System;Lysophospholipids;Malignant Neoplasms;Mass Spectrum Analysis;Mediator of activation protein;Mentors;Metabolic;Metabolism;Metastatic Neoplasm to the Bone;Monitor;Mus;Neoplasm Metastasis;Nonesterified Fatty Acids;Obesity;Outcome;Overweight;Pathway interactions;Patients;Phospholipase A2;Phospholipase D;Phospholipids;Plants;Plasma;Postmenopause;Pre-Clinical Model;Prevalence;Process;Production;Reaction;Request for Proposals;Research;Research Personnel;Research Training;Risk Assessment;Risk Factors;Scientist;Signal Transduction;Stomach;Testing;Tracer;Training;Underrepresented Minority;United States;United States National Institutes of Health;Weight;Woman;Work;alkylglycerophosphoethanolamine phosphodiesterase;anticancer research;base;cancer risk;career development;diet and cancer;dietary constituent;disorder risk;experience;feeding;food consumption;inhibitor/antagonist;lysophosphatidic acid;malignant breast neoplasm;metabolomics;migration;mouse model;nutrition;obesity risk;particle;response;sedentary lifestyle;skills;stable isotope;translational study;tumor growth;uptake


application_id: 8947449
project_number: 1K22AI118949-01
project_title: Contact-Dependent Interbacterial Signaling in Burkholderia
administering_ic: NIAID
award_notice_date: 2016-07-20
opportunity_number: PAR-14-341
application_type: 1
activity_code: K22
ic: AI
serial_number: 118949
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2016-08-01
project_end_date: 2018-07-31
study_section: Microbiology and Infectious Diseases B Research Study Section[MID-B]
contact_pi_person_id: 10751521
contact_pi: GARCIA, ERIN C
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Both non-pathogenic and pathogenic Burkholderia including members of the opportunistic infection-causing Burkholderia cepacia complex encode genes to produce contact-dependent growth inhibition (CDI) system proteins. CDI is a widespread phenomenon in which Gram-negative bacteria use the toxic C-terminus of a polymorphic surface-exposed exoprotein to inhibit the growth of susceptible bacteria upon cell-cell contact. The exoprotein toxin is delivered to the cytoplasm of target cells and autoinhibition
is prevented by production of a small immunity protein. We previously demonstrated that in addition to their role in interbacterial competition the CDI system proteins in Burkholderia thailandensis encoded by bcpAIOB mediate biofilm formation. This requires the putative nuclease activity of the BcpA toxic exoprotein but is independent of interbacterial killing suggesting that biofilm formation in B. thailandensis involves an uncharacterized function of BcpA. Preliminary data suggest that bcpAIOB mediate interbacterial signaling in B. thailandensis leading to a change in gene expression in immune target bacteria. Given these data and the conservation of CDI systems it seems likely that CDI systems in other Burkholderia also function in interbacterial signaling and could play a role during infection. Toward understanding the role of CDI system-mediated signaling this proposal will test the hypothesis that BcpA toxin delivered to an immune target cell interacts with specific periplasmic and cytoplasmic factors leading to global gene expression changes and represents a useful therapeutic target in pathogenic Burkholderia. Experiments proposed in Aim 1 will continue to investigate the mechanism of bcpAIOB-mediated interbacterial signaling in B. thailandensis defining the affected gene regulation pathways and identifying required regions of BcpA as well as other factors necessary for signaling. Studies in Aim 2 will explore the role of CDI systems and their potential for exploitation as therapies in pathogenic Burkholderia cepacia complex strains. These studies represent the first investigation of what may be a widespread phenomenon in Gram-negative bacteria and will work toward addressing an essential need for new drug targets and antimicrobials.

project_terms:
Address;Affect;Animal Model;Animals;Anti-Bacterial Agents;Bacteria;Behavior;Binding;Biochemical;Burkholderia;Burkholderia cepacia complex;Cells;Chronic;Chronic Granulomatous Disease;Communication;Communities;Complex;Congo Red;Cytoplasm;Data;Decontaminant;Development;Disease;Disease Outbreaks;Drug Targeting;Escherichia coli;Foundations;Future;Gene Expression;Gene Expression Regulation;Genes;Genome;Gram-Negative Bacteria;Growth;Human;Immune;Immune Targeting;Immunity;In Vitro;Infection;Infection prevention;Investigation;Killings;Knowledge;Life;Lung;Lung diseases;Mediating;Microbial Biofilms;Modeling;Molecular;Neisseria meningitidis;Opportunistic Infections;Organism;Pathway interactions;Phenotype;Pigments;Plants;Play;Production;Proteins;Reporter;Research;Role;Signal Pathway;Signal Transduction;Soil;Surface;System;Testing;Therapeutic;Toxic effect;Toxin;Work;antimicrobial;base;cystic fibrosis patients;human disease;in vivo;insight;member;mouse model;new therapeutic target;nuclease;pathogen;periplasm;prevent;public health relevance;recombinase;research study;therapeutic target;transcriptome sequencing;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Burkholderia are a group of environmental bacteria that can cause life-threatening opportunistic infections in patients with cystic fibrosis or other lung disorders. This proposal focuses on understanding of how these and related bacteria interact with each other and how that interaction may affect disease. Additionally by studying antibacterial proteins produced by these bacteria this research will lay the foundation for the development of new antimicrobial therapies against Burkholderia.


application_id: 8944142
project_number: 1U01AG050636-01
project_title: Preclinical Development of a Selective Suppressor of Neuroinflammation for MCI/AD
administering_ic: NIA
award_notice_date: 2015-08-31
opportunity_number: PAR-12-015
application_type: 1
activity_code: U01
ic: AG
serial_number: 050636
program_official: PETANCESKA, SUZANA
project_start_date: 2015-09-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZAG1 ZIJ-6 (M1)]
contact_pi_person_id: 1870576
contact_pi: VAN ELDIK, LINDA J
other_pis: WATTERSON, DANIEL MARTIN
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the largest global public health crises facing us today and is predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent cure or slow the progression of disease and new therapeutic strategies are urgently needed. Our strategy is to target the abnormal glial activation and neuroinflammation that arises early in AD progression and that is becoming of increased interest as a therapeutic target. Dysregulated neuroinflammation responses such as proinflammatory cytokine overproduction from abnormally activated glia are seen early in AD and are thought to be a key contributor to downstream synaptic dysfunction and cognitive deficits. This raises the possibility that selective targeting of the dysregulated cytokine response may be a useful therapeutic approach. This application seeks three years of support to bring to IND status a novel experimental therapeutic (termed MW151) whose pharmacological mechanism of action is to attenuate disease- and injury-induced proinflammatory cytokine overproduction thereby reducing downstream synaptic and cognitive dysfunction in multiple animal models of CNS disorders. MW151 is a water-soluble orally bioavailable CNS-penetrant small molecule with outstanding chemical and metabolic stability. MW151 has been extensively de-risked through several non-GLP pharmacological and toxicology screens and a GMP compatible production scheme has been developed. However MW151 has not progressed into final GLP preclinical development. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with mild cognitive impairment due to AD. With U01 funding we will pursue three aims that are milestone-driven with clear Go/No Go decision criteria. Aim 1: Perform preclinical pharmacokinetics and safety assessment of MW151. Aim 2: Produce GMP drug substance (API) and oral drug product. Aim 3: Obtain an IND for future first-in-human clinical investigations. This project will advance development of a promising drug candidate with the potential to prevent the transition to or slow the progression of AD. In addition successful development of MW151 could have broad clinical applications not only to AD but to a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.

project_terms:
Acute Brain Injuries;Address;Advanced Development;Adverse event;Age;Alzheimer's Disease;Animal Model;Attenuated;Bioavailable;Biological Availability;Brain;Canis familiaris;Central Nervous System Diseases;Cessation of life;Chemicals;Clinical;Clinical Research;Cognitive deficits;Communication;Critical Care;Data;Dementia;Development;Disease;Disease Progression;Dose;Drug Formulations;Drug Kinetics;Functional disorder;Funding;Future;Guidelines;Head;Homeostasis;Human;Impaired cognition;Individual;Injury;Intellectual Property;Intervention;Intravenous;Investigation;Investigational Drugs;Knock-in Mouse;Medicine;Metabolic;Modeling;Neurodegenerative Disorders;Neuroglia;Neurological outcome;Neurons;Oral;Oral Administration;Outcome;Parents;Pathology;Pathway interactions;Patients;Penetration;Pharmaceutical Preparations;Pharmacodynamics;Pharmacology;Phase;Phase I Clinical Trials;Physiological;Population;Production;Publishing;Rattus;Reporting;Risk;Role;Route;Safety;Scheme;Staging;Stress;Synapses;Testing;Therapeutic;Time;TimeLine;Toxicogenetics;Toxicology;Traumatic Brain Injury;Water;Work;analog;attenuation;base;clinical application;clinical investigation;cytokine;drug candidate;effective therapy;experience;healthy volunteer;interest;mild cognitive impairment;neuroinflammation;novel;novel therapeutics;phase 2 study;pre-clinical;prevent;progressive neurodegeneration;public health medicine (field);public health relevance;response;safety study;small molecule;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed preclinical campaign addresses the urgent and critical need to develop effective disease-modifying therapeutics to prevent delay and treat AD. We are proposing to develop a promising drug candidate that in animal models attenuates the overactive proinflammatory cytokine aspect of neuroinflammation and prevents the downstream neuron dysfunction and cognitive impairment that characterizes neurodegenerative disease progression. The aims are focused on FDA guidelines for investigational new drug status.


application_id: 8943869
project_number: 1R01AI119022-01
project_title: Structure and mechanism of the ESX secretion system from pathogenic mycobacteria
administering_ic: NIAID
award_notice_date: 2015-07-22
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AI
serial_number: 119022
program_official: KRAIGSLEY, ALISON
project_start_date: 2015-07-25
project_end_date: 2019-12-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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:
Affect;Amino Acids;Antigens;Antitubercular Agents;Architecture;Binding (Molecular Function);Biochemical;Biological;Biological Process;C-terminal;Cell Wall;Cell physiology;Cell surface;Cessation of life;Communicable Diseases;Complex;Data;Development;Diagnostic;Diagnostic Reagent;Environment;Enzymes;Essential Amino Acids;Extreme drug resistant tuberculosis;Family;Future;Genetic;Genus Mycobacterium;Goals;Growth;Homologous Gene;Human;Immune;Individual;Infection;Investigation;Knowledge;Macromolecular Complexes;Mass Spectrum Analysis;Membrane;Methods;Modeling;Molecular;Molecular Chaperones;Multi-Drug Resistance;Mutation;Mycobacterium tuberculosis;Pathogenesis;Pathway interactions;Peptide Hydrolases;Pilum;Play;Process;Protein Family;Protein Secretion;Proteins;Role;Specificity;Staging;Structure;Surface;System;Testing;Therapeutic;Tuberculosis;Vaccines;Virulence;Work;X-Ray Crystallography;base;design;dimer;drug development;drug discovery;extracellular;improved;inhibitor/antagonist;insight;mycobacterial;new therapeutic target;novel therapeutics;pathogen;protein aggregation;protein protein interaction;protein transport;public health relevance;research study;resistant strain;tool;tuberculosis drugs;vaccine candidate;vaccine development

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed studies are expected to uncover the architecture and mechanism of the ESX secretion system a pathway essential for virulence and involved in the transport of multiple proteins to the cell surface or extracellular milieu in human
pathogen M. tuberculosis. The generated data will provide a framework for developing novel therapeutics and improved vaccines against tuberculosis.


application_id: 8942732
project_number: 1R21AI118818-01
project_title: Recognition of Pneumocystis trophs by murine dendritic cells
administering_ic: NIAID
award_notice_date: 2015-04-27
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 118818
program_official: DUNCAN, RORY A
project_start_date: 2015-05-01
project_end_date: 2017-04-30
study_section: Special Emphasis Panel[ZRG1 AARR-K (04)]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pneumocystis (PC) is an opportunistic fungal pathogen that causes pneumonia (PCP) in immunocompromised individuals and is one of the original AIDS-defining pathogens. Even though the incidence of PCP has dropped with the advent of highly active anti-retroviral therapy mortality rates due to PCP has not changed and HIV-infected individuals are still susceptible to PCP when they are not compliant with their HIV therapy or when the virus becomes resistant to therapy. Though much is known about Pneumocystis and the immune response to it there are still large gaps in our understanding of how the organism is recognized and cleared by the immune system. PC has two identifiable life forms the cyst or ascus that is surrounded by a fungal cell wall composed of -glucans and chitin and the trophozoite or spore form that is devoid of a cell wall but unlike most medically relevant fungi has a cell membrane that contains cholesterol rather than the ergosterol. It is well
established that both macrophages and dendritic cells recognize the cyst form of PC through the -glucan receptor dectin-1. However the cyst form of the organism represents a small proportion of the total lung burden particularly late in infection when the trophic forms are as much as 90% of the organisms in the lungs. It is not known how dendritic cells and macrophages recognize the trophic forms of PC. The goal of this project is to identify the receptors that dendritic cells and macrophages use to recognize the trophic forms of PC particularly early during infection before specific antibody is formed and whether the trophic forms stimulate the cells to produce immune mediators. Our hypothesis is that the trophic forms of PC bind to one or more c-type lectin receptors (CLRs) via mannosylated proteins resulting in a dampened inflammatory response by suppressing signaling through dectin-1. Two specific aims are proposed to address the hypothesis. Aim 1 will determine whether the trophic forms of PC bind CLR and transmit a signal. Aim 2 will determine the mechanism of suppression of inflammation induced by the trophic forms of PC. Together these aims will provide important new information about whether dendritic cells and macrophages are stimulated by PC or alternatively whether the trophic forms dampen immunity and escape innate immune surveillance.

project_terms:
Acquired Immunodeficiency Syndrome;Address;Alveolar;Alveolar Macrophages;Antibodies;Binding (Molecular Function);Biological Response Modifiers;C Type Lectin Receptors;Cell Wall;Cell membrane;Cell physiology;Cells;Chitin;Cholesterol;Chromoblastomycosis;Cyst;Data;Dendritic Cells;Drops;Ergosterol;Genes;Glucans;Goals;HIV;HIV therapy;Highly Active Antiretroviral Therapy;Host Defense;Human;Immune;Immune System Part;Immune response;Immune system;Immunity;Immunocompromised Host;Immunologic Surveillance;Incidence;Individual;Infection;Inflammation;Inflammatory Response;Interleukin-6;Lectin Receptors;Life;Ligation;Link;Lung;Mannose;Morbidity - disease rate;Mortality Vital Statistics;Mus;Myeloid Cells;Organism;Pneumocystis;Pneumocystis carinii Pneumonia;Pneumonia;Proteins;Reproduction spores;Signal Transduction;Signaling Molecule;Surface;TNF gene;Technology;Thick;Vaccines;Virus;Yeasts;adaptive immunity;cytokine;dectin 1;design;extracellular;fungus;immunosuppressed;macrophage;mannose receptor;mouse dectin-2;nano-string;pathogen;public health relevance;receptor;response;therapy resistant

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Pneumocystis is a fungal pathogen that causes pneumonia in immunodeficient individuals particularly those infected with HIV. The goal of this study is to understand how one of the life forms of Pneumocystis interacts with dendritic cells a part of the immune system. Understanding these interactions are important for devising new treatments as well as for generating vaccine strategies.


application_id: 8941165
project_number: 1R01AR068313-01
project_title: MYD88 Signaling in Mammalian Myoblast Fusion
administering_ic: NIAMS
award_notice_date: 2015-09-12
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AR
serial_number: 068313
program_official: BOYCE, AMANDA T
project_start_date: 2015-09-14
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1 MOSS-V (03)]
contact_pi_person_id: 1917770
contact_pi: KUMAR, ASHOK
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
3' Untranslated Regions;Ablation;Adaptor Signaling Protein;Address;Adult;Age;Attenuated;Binding (Molecular Function);Bioinformatics;Caliber;Cell fusion;Cells;Consensus;DNA Sequence;Defect;Development;Drosophila genus;Drosophila melanogaster;Drug Targeting;Embryonic Development;Event;Family;Gene Expression;Genes;Genetic;Goals;Growth;Hypertrophy;Immune response;Impairment;In Vitro;Injury;Interleukin-1;Knock-out;Knockout Mice;Knowledge;Lead;MAP Kinase Gene;Mediating;MicroRNAs;Molecular;Molecular and Cellular Biology;Mus;Muscle;Muscle Cells;Muscle Fibers;MyD88 protein;Myelogenous;Myoblasts;Myogenic Regulatory Factors;Myogenin;Myopathy;Natural regeneration;Neonatal;Pathway interactions;Pattern;Play;Process;Promoter Regions (Genetics);Promotor (Genetics);Research;Role;Seminal;Signal Pathway;Signal Transduction;Skeletal muscle structure;Small Interfering RNA;System;TLR3 gene;Testing;Therapeutic;Toll-like receptors;Transcript;Vertebrates;Wild Type Mouse;Work;base;improved;in vivo;insight;interleukin-18 receptor;mouse model;muscle form;muscle hypertrophy;myogenesis;novel;novel therapeutics;overexpression;public health relevance;receptor;repaired;research study;response;response to injury;skeletal muscle growth;wasting


application_id: 8940334
project_number: 1R01AI118814-01
project_title: Lead Optimization of ML336 a Potent VEEV Inhibitor
administering_ic: NIAID
award_notice_date: 2015-04-30
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: AI
serial_number: 118814
program_official: DAVIS, MINDY I
project_start_date: 2015-05-01
project_end_date: 2020-04-30
study_section: Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section[DDR]
contact_pi_person_id: 9658299
contact_pi: CHUNG, DONGHOON
other_pis: GOLDEN, JENNIFER E.;JONSSON, COLLEEN B
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 New World alphaviruses Venezuelan (VEEV) Eastern and Western Equine Encephalitis viruses are emerging pathogens that are endemic throughout the Americas. They cause encephalitis in humans and equines thus presenting serious health and economic problems. Despite the urgent need neither approved drugs nor vaccines are available for treatment of these diseases in humans. Broad long-term objectives: The research objectives stated herein and in future studies that build upon these findings will deliver analogs of ML336 a promising lead compound as small molecule therapeutic candidates for future clinical evaluation targeting diseases caused by VEEV and other alphaviruses. Specific aims/hypothesis: The specific aims address two hypotheses. In aims 1 and 2 we hypothesize that medicinal chemical optimization of ML336 can afford a safe and specific therapeutic preclinical candidate to treat New World alphaviral diseases. In aim 3 we test the hypothesis that ML336 blocks VEEV RNA synthesis through disruption of interactions required for replicase assembly and/or directly inhibits an enzymatic activity required for viral RNA synthesis. Research design and methods: Aim 1 will derive a robust pharmacological profile suitable for in vivo efficacy through structure-activity and structure-property relationshi (SAR-SPR) studies. Specifically Dr. Golden will lead efforts to generate analogs of ML336 with an improved pharmacological profile that includes increased solubility and BBB permeability and reduced metabolic liability to improve exposure and clearance parameters. In Aim 2 Dr. Guo will assess the biodistribution and pharmacokinetics/dynamics of ML336 and 2-3 lead compounds each year showing suitable and robust pharmacological and antiviral (in vitro and in vivo) profiles. Dr. Jonsson will lead in vivo efficacy testing studies of two of the most promising
lead candidates to define the optimal dosing regimen using the VEEV Trinidad Donkey strain. Finally Dr. Chung will dissect the mechanism of action of ML336 using in vitro assays focused on replication (Aim 3) in consultation with Dr. Sawicki.

project_terms:
Address;Alphavirus;Americas;Amidines;Antiviral Agents;Asses;Biodistribution;Biotechnology;Chemicals;Chemistry;Consultations;Disease;Dose;Drug Kinetics;Encephalitis;Future;Human;In Vitro;Knowledge;Lead;Metabolic;Molecular Bank;Mus;Nonstructural Protein;Outcome;Permeability;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Preclinical Drug Development;Property;RNA Viruses;RNA chemical synthesis;RNA replication;Regimen;Replication-Associated Process;Research;Research Design;Research Methodology;Resistance;Series;Solubility;Structure;Structure-Activity Relationship;Testing;Therapeutic;Toxic effect;Trinidad;United States National Institutes of Health;Vaccines;Venezuelan Equine Encephalitis Virus;Virus Inhibitors;Western Equine Encephalitis Virus;analog;cytotoxicity;efficacy testing;health economics;high throughput screening;improved;in vitro Assay;in vitro activity;in vivo;insight;interest;mouse model;novel;pathogen;pre-clinical;preclinical study;public health relevance;replicase;research clinical testing;small molecule;viral RNA;viral resistance


application_id: 8938978
project_number: 1R01HL128592-01
administering_ic: NHLBI
award_notice_date: 2015-07-27
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 128592
program_official: DESVIGNE-NICKENS, PATRICE
project_start_date: 2015-08-01
project_end_date: 2020-04-30
study_section: Special Emphasis Panel[ZRG1 DTCS-A (81)]
contact_pi_person_id: 11817133
contact_pi: VANDSBURGER, MORIEL
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
budget_start_date: 2015-08-01
project_title:
Novel MRI techniques for imaging cardiac fibrosis to improve clinical practice in patients with renal failure

project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular disease affects millions of Americans with heart failure as a common endpoint. The development of cardiac fibrosis occurs early in cardiovascular disease promotes heart failure and provides arrhythmogenic substrate leading to increased frequency of adverse cardiac events and higher mortality. Cardiac magnetic resonance imaging (CMR) is routinely used to measure changes in ventricular structure and function with balanced steady state free precession (bSSFP) imaging. With intravenously delivered gadolinium contrast agents late gadolinium enhancement (LGE) CMR is the clinical standard for identifying focal fibrosis and quantifying fibrotic burden and when combined with mapping of T1-relaxation times can quantify diffuse fibrosis through measurement of increased extracellular volume fraction (ECV). In individuals with chronic kidney disease a strong link exists between cardiac fibrosis and adverse cardiac events however LGE is contraindicated due to the danger of nephrogenic systemic fibrosis. Emerging studies suggest that specific circulating hormones and peptides may be biomarkers of cardiac fibrosis and potential therapeutic targets in chronic kidney disease. However the inability to measure fibrosis in such patients represents a major gap to the discovery of potential biomarkers and leaves most studies measuring cardiac hypertrophy as an insensitive surrogate of fibrosis. This proposal seeks to develop a gadolinium free MRI method to measure fibrotic burden via reduced magnetization transfer (MT) in areas fibrotic tissue. This method termed 2-point bSSFP exploits an endogenous contrast mechanism in bSSFP imaging to identify fibrotic and edematous tissue. The proposed aims will validate 2-point bSSFP against standard of care LGE and measurement of diffuse fibrosis through ECV mapping. Finally comparison of fibrotic burden (measured with 2-point bSSFP) to blood chemical workup in CKD patients will examine the correlation between fibrosis and potential biomarkes. The successful completion of these aims will enable rapid and gadolinium free imaging of cardiac fibrosis over the entire heart. Further correlation of cardiac fibrosis with blood serum biomarkers in chronic kidney disease patients can help identify potential therapeutic targets to halt or reverse fibrosis the efficacy f which can be serially monitored using 2-point bSSFP.

project_terms:
Affect;Age;Agreement;American;Area;Biological Markers;Blood;Cardiac;Cardiovascular Diseases;Cause of Death;Chemicals;Chronic Kidney Failure;Cicatrix;Clinical;Clinical Research;Comorbidity;Contrast Media;Coronary Arteriosclerosis;Defibrillators;Development;Diagnostic;Diffuse;Disease;Edema;Equilibrium;Evaluation;Event;Fibrosis;Frequencies (time pattern);Funding;Gadolinium;Gold;Heart;Heart Hypertrophy;Heart failure;Hormones;Image;Image Enhancement;Imaging Techniques;Individual;Intraobserver Variability;Kentucky;Kidney Failure;Left ventricular structure;Link;Magnetic Resonance Imaging;Maps;Measurement;Measures;Methods;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Motion;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Parathyroid gland;Pathway interactions;Patients;Recruitment Activity;Relaxation;Renal function;Risk;Sensitivity and Specificity;Serum;Serum Markers;Signal Transduction;Slice;Structure;Testing;Therapeutic Intervention;Time;Tissues;Treatment Efficacy;Universities;Ventricular;Ventricular septum;Weight;Work;base;clinical practice;coronary fibrosis;density;design;extracellular;fibroblast growth factor 23;follow-up;gadolinium oxide;imaging modality;improved;non-invasive monitor;novel;peptide hormone;public health relevance;standard of care;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the leading cause of death amongst Americans particularly for patients with chronic kidney disease. The emerging link between fibrosis and adverse cardiac events has motivated development of gadolinium contrast agent based diagnostics of cardiac fibrosis that are not suitable for patients with compromised renal function. The proposed work fully validates a completely non-invasive and gadolinium free fibrosis imaging technique and applies this method to the identification of novel blood biomarkers of cardiac fibrosis in chronic kidney disease patients.


application_id: 8934196
project_number: 5R43NS084701-02
project_title: Catheter for Large Volume Intraparenchymal Brain Therapies
administering_ic: NINDS
award_notice_date: 2015-09-11
opportunity_number: PA-14-071
application_type: 5
activity_code: R43
ic: NS
serial_number: 084701
program_official: FERTIG, STEPHANIE
project_start_date: 2014-09-30
project_end_date: 2017-03-31
study_section: Special Emphasis Panel[ZRG1-ETTN-C(10)B]
contact_pi_person_id: 8714039
contact_pi: STICE, JIM
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079228773
duns_number: 079228773
fips: US
organization_id: 10035571
organization_name: TWIN STAR TDS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405071968
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-09-01
budget_end_date: 2017-03-31
project_abstract:
DESCRIPTION (provided by applicant): Neurodegenerative and malignant diseases of the central nervous system affect millions of Americans. These diseases are often devastating and difficult to treat and effective drug delivery remains a significant challenge. Infusion of drugs nto the brain parenchyma using convection-enhanced delivery (CED) allows direct treatment of lesions circumventing the blood brain barrier. In particular important new treatments and diseases call for large regions of brain to be subjected to therapeutic doses. Multiple clinical trials have been conducted using CED to deliver large volumes of chemotherapy and immunotoxins in patients with gliomas but actual drug delivery to the tumor has been poor for several reasons including the unpredictable dispersion of the drug in the tissue. These adverse events result in reduced efficacy and increased toxicity. To overcome the limitations associated with conventional CED catheters in heterogeneous tissue the Applicants have developed a macroporous hollow fiber catheter (maPHFC) for improved drug delivery. Hypothesis: The Applicants propose that maPHFCs will overcome the limitations of current CED catheters for the treatment of brain disorders requiring large distributions in tissue. Preliminary Data: In Applicant's prior research porous hollow fiber catheters (PHFCs) showed superior performance in positioning priming and infusion as compared to conventional CED catheters. PHFCs produced less reflux in bench and large animal studies. In vitro and in vivo studies have shown the unique ability of the PHFC to traverse voids and distribute therapeutics across both sides of the void. An innovative macroporous PHFC (maPHFC) that provides several days of infusion of large molecules without occlusion has been developed and preliminarily tested. Specific Aims: With this proposed Phase I feasibility research the Applicants expect to develop the maPHFC design to meet human use requirements for large infusions in acute settings and assess performance with bench and animal testing. Design verification testing will be conducted to facilitate eventual clinical studies. Aim 1: Finalize human maPHFC designs. maPHFC designs will be finalized to meet human use requirements based on expert design input. Key design changes from prior research will focus on improved priming maPHFC stabilization during tunneling and optimization of the maPHFC design for large volume distribution. Aim 2: In vivo maPHFC comparative safety and infusion studies. maPHFC and control catheters will be evaluated in normal swine brains with MR tracer infusions. Results will be used to compare safety and volume of distribution. Aim 3: maPHFC design verification testing. The objective is to generate the test data required for FDA clinical study approvals.

project_terms:
Acute;Adverse event;Affect;Alzheimer's Disease;American;Animal Testing;Animals;Area;Blood - brain barrier anatomy;Brain;Brain Diseases;Brain Neoplasms;Brain region;Canis familiaris;Catheters;Cell Therapy;Central Nervous System Diseases;Chronic;Clinical;Clinical Research;Clinical Trials;Comparative Study;Convection;Data;Disease;Dose;Drug Delivery Systems;Experimental Models;Family suidae;Fiber;Glioma;Health;Human;Immunotoxins;In Vitro;Infusion procedures;Lesion;Letters;Malignant - descriptor;Modeling;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Operative Surgical Procedures;Outcome;Parkinson Disease;Patients;Performance;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Positioning Attribute;Recurrence;Reflux;Research;Research Personnel;Safety;Side;Small Business Innovation Research Grant;Solutions;Sterility;Testing;Therapeutic;Therapeutic Agents;Tissues;Toxic effect;Tracer;base;biomaterial compatibility;brain tissue;brain volume;chemotherapy;clinical efficacy;comparative;contrast enhanced;design;gene therapy;human study;improved;in vivo;innovation;meetings;novel;prototype;standard of care;tumor;usability;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Effective drug delivery of large volumes of solutions containing therapeutic agents into the brain remains a significant obstacle to achieving clinical efficacy of therapies for neurodegenerative and malignant diseases affecting the central nervous system. The Applicants have developed novel porous hollow fiber catheters which demonstrate more uniform and better distribution of infusates in tissue than standard of care catheters. In this project bench and animal studies will be conducted followed by design verification testing to generate data for FDA clinical study approvals.


application_id: 8932755
project_number: 5R01NR012967-02
administering_ic: NINR
award_notice_date: 2015-07-20
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NR
serial_number: 012967
program_official: HUSS, KAREN
project_start_date: 2014-09-26
project_end_date: 2019-07-31
study_section: Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]
contact_pi_person_id: 8446344
contact_pi: CHUNG, MISOOK LEE
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-08-01
project_terms:
Acute;Address;Adherence (attribute);Adult;Affect;Age;Analysis of Variance;Attitude;Behavior;Cardiovascular system;Caregivers;Caring;Chronic;Chronically Ill;Complex;Control Groups;Data;Desire for food;Diet;Dietary Intervention;Dietary Sodium;Distress;Eating;Educational Intervention;Educational aspects;Educational process of instructing;Elderly;Electronics;Enrollment;Epidemic;Excretory function;Face;Family;Family Caregiver;Family member;Feeling;Food;Food Labeling;Food Preferences;Goals;Health;Health Care Costs;Health Status;Heart failure;Hospitalization;Hour;Individual;Intake;Interpersonal Relations;Intervention;Intervention Studies;Knowledge;Lead;Long-Term Effects;Measures;Medical;Modeling;Monitor;Outcome;Patients;Perception;Physiological;Play;Prevalence;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Reading;Recommendation;Research;Research Personnel;Resources;Role;Self Care;Self Management;Sensory;Social support;Sodium;Sodium Chloride;Sodium-Restricted Diet;Source;Symptoms;Tablets;Taste Buds;Taste Perception;Testing;Time;Urine;Videoconferences;Videoconferencing;Wit;Work;base;care giving burden;caregiving;design;follow-up;group intervention;hedonic;improved;innovation;intervention program;longitudinal analysis;meetings;member;monitoring device;outcome forecast;preference;prevent;programs;public health medicine (field);skills;success;treatment as usual;urinary


application_id: 8932734
project_number: 5R01HL123927-02
project_title: Crosstalk between membrane traffic proteins and integrin activation
administering_ic: NHLBI
award_notice_date: 2015-06-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 123927
program_official: CHANG, HENRY
project_start_date: 2014-09-25
project_end_date: 2018-06-30
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 8558885
contact_pi: LI, ZHENYU
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_terms:
Actins;Acute;Adhesions;Adhesives;Anabolism;Arthrogryposis;Atherosclerosis;Binding (Molecular Function);Binding Proteins;Biochemical;Blood Platelets;Blood Vessels;Cause of Death;Cell Adhesion;Cell surface;Cells;Chinese Hamster;Chinese Hamster Ovary Cell;Cholestasis;Co-Immunoprecipitations;Coagulation Process;Complex;Confocal Microscopy;Cytomegalovirus;Cytoplasmic Granules;Cytoplasmic Organelle;Cytoplasmic Tail;Data;Defect;Development;Disease;Endocytosis;Epitopes;Event;Exocytosis;Extracellular Matrix;Fibrin;Fibrinogen;Functional disorder;Goals;Health;Hemostatic function;Host Defense;Human;Inflammation;Integrin Binding;Integrins;Kidney;Knockout Mice;Ligands;Link;MAP Kinase Gene;Malignant Neoplasms;Maps;Mediating;Megakaryocytes;Membrane Fusion;Membrane Protein Traffic;Membrane Proteins;Modeling;Molecular;Mouse Strains;Mus;Myocardial Infarction;Ovary;P-Selectin;Pathway interactions;Patients;Phosphorylation;Plasma;Platelet Activation;Play;Process;Promotor (Genetics);Protein Family;Proteins;Recombinants;Research Project Grants;Role;SRC gene;Signal Pathway;Signal Transduction;Syndrome;Testing;Thrombosis;Time;United States;VWF gene;Work;Wound Healing;angiogenesis;antimicrobial;base;extracellular;in vivo;insight;member;mouse model;mutant;novel;overexpression;polymerization;prevent;receptor;receptor mediated endocytosis;recombinase;research study;rho GTP-Binding Proteins;stem;stroke;syntaxin binding protein 1


application_id: 8932710
project_number: 5R44GM099206-04
project_title: Novel method to create knockout rats using endonucleases and spermatogonial stem
administering_ic: NIGMS
award_notice_date: 2016-08-16
opportunity_number: PA-13-234
application_type: 5
activity_code: R44
ic: GM
serial_number: 099206
program_official: SLEDJESKI, DARREN D
project_start_date: 2011-09-05
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-J(15)B]
contact_pi_person_id: 12627415
contact_pi: JAMLING, TSETEN YESHI
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 079703270
primary_uei: JK2VCZCBR8R4
duns_number: 079703270
uei: JK2VCZCBR8R4
fips: US
organization_id: 10038664
organization_name: HERA TESTING LABORATORIES, INC.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405059002
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The laboratory rat is a preferred rodent model in pre-clinical drug studies. Their larger size facilitates procedures otherwise difficult in mice includng studies using instrumentation blood sampling and surgeries and allows for ten times the amount of tissue collection. Although rats are often more suitable than mice for pharmacological toxicological physiological and many other biological assays the ease of genetic engineering technologies has made the mouse the preeminent rodent model. However the recent emergence of new and more precise gene targeting techniques for the rat has resulted in significant growth in the production of genetically-modified rats. In Phase I we demonstrated the feasibility of combining custom site-specific Xanthomonas TAL Nuclease (XTNTM) [a.k.a. TALEN] technology with spermatogonial stem cells (SSCs) for rapid cost-effective and precise genome engineering in the rat. Indeed the Phase I studies enabled Transposagen to launch custom XTNTM and knockout rat production services in 2012 and we have successfully created and delivered custom knockout rats to both industry and academic investigators. In work outside the Phase I project we paired XTN TALEN technology with piggyBacTM technology to create the Footprint-FreeTM Gene Editing System the only commercially available system that can engineer as little as a single nucleotide without leaving unwanted mutations and allowing for selection of rare events. For Phase II studies we propose to use SSC- and Footprint-FreeTM Gene Editing technology to create a suite of rats that would express a specific human CP2D6* allele in the absence of the homologous rat Cyp2d genes (i.e. humanized CYP2D6 rat models). Humans carry a single but highly polymorphic p450 CYP2D6 gene. CYP2D6 metabolizes nearly 25% of current drugs and is represented by over 70 variants in the population which possess a wide range of enzyme activities. As a consequence adverse drug effects or lack of drug effect depend on the specific allele(s) an individual is carrying. Humanized CYP2D6 animal models would be of great value for drug testing. To accomplish this task we will optimize strategies to simultaneously delete a ~60 kb segment of the rat genome that contains the 5-gene Cyp2d cluster and knock-in a specific human CYP2D6* allele so that it would be placed under transcriptional control of the rat Cyp2d2 promoter to ensure a physiological pattern of expression. Not only would the humanized rat be useful for assessing the consequences of CYP2D6*-specific metabolites in the whole animal but hepatocytes isolated from these animals would provide a reliable and consistent source of CYP2D6* hepatocytes for in vitro drug metabolism testing. More generally successful optimization of Footprint-FreeTM Gene Editing protocols for the creation of large-scale humanizing knock-in mutations would enable for the first time the possibility of sophisticated and cost-effective genome engineering in many mammalian organisms.

project_terms:
Adverse drug effect;Alleles;Animal Model;Animals;Biological Assay;Biomedical Research;Blood specimen;CYP2D6 gene;Cell Line;Cell model;Cells;Cleaved cell;Communities;Complex;Coupled;Custom;Detection;Engineering;Ensure;Enzymes;Event;Excision;Gene Family;Gene Targeting;Genes;Genetic Engineering;Genetically Engineered Mouse;Genome engineering;Goals;Growth;Health;Hepatocyte;Housing;Human;In Vitro;Individual;Industry;Knock-in;Knock-out;Laboratory Rat;Lead;Left;Link;Metabolism;Methods;Modeling;Multigene Family;Mus;Mutation;Nonhomologous DNA End Joining;Nucleotides;Operative Surgical Procedures;Organism;Pathway interactions;Pattern;Pharmaceutical Preparations;Pharmacologic Substance;Phase;Physiological;Physiology;Population;Procedures;Production;Property;Protocols documentation;Public Health;Rattus;Research;Research Personnel;Rodent Model;Services;Shipping;Ships;Site;Source;Stem cells;System;Techniques;Technology;Testing;Time;Tissue Banks;Toxic effect;Toxicity Tests;Transcriptional Regulation;Transplantation;Transposase;United States National Institutes of Health;Variant;Work;Xanthomonas;arm;base;cell transformation;cost;cost effective;design;drug discovery;drug metabolism;drug testing;endonuclease;enzyme activity;enzyme model;homologous recombination;instrumentation;interest;knockout gene;male;member;mouse model;novel;nuclease;phase 1 study;phase 2 study;pre-clinical;predictive modeling;promoter;rat genome;stem;transcription activator-like effector nucleases;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The laboratory rat has been a valuable animal model for biomedical research due to its similarity to human physiology. Pharmaceutical companies currently rely primarily on animal or transformed cell models for pre- clinical metabolism and toxicity testing during drug discovery. Thus there is a compelling need for animal models that are more predictive for ADME properties in humans. However the ease and lower costs associated with generating mutations in mice has lead to a greater reliance on genetically engineered mouse models despite the inability of many of these models to mimic human pathways. We outline a strategy that integrates our expertise in spermatogonial stem cells (SSCs) with a site-specific enzyme technology to create knockout and humanized rat models for drug discovery applications. Thus this project would benefit many goals of public health by making the production of mutations in the rat that better model human physiology readily accessible to the research community.


application_id: 8932608
project_number: 5F31NS087878-02
project_title: The role of microglia in acute pathology of repeated concussion and CTE development
administering_ic: NINDS
award_notice_date: 2015-09-09
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: NS
serial_number: 087878
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-09-22
project_end_date: 2016-08-07
study_section: Special Emphasis Panel[ZRG1-F01-F(20)L]
contact_pi_person_id: 11450867
contact_pi: BOLTON-HALL, AMANDA
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): In the United States 70-90% of the approximately 1.7-3.8 million traumatic brain injuries (TBI) reported every year are considered "mild" and result
in a wide range of acute symptoms the cause of which are not well understood. Individuals involved in activities such as the military and athletics are at increased risk of accruing multipl TBIs. Due to natural variability involved in cases of repeated concussions in humans animal models are instrumental in expanding our knowledge regarding the cellular consequences of mild TBI which can include axonal injury astrocytosis and microgliosis. Acute microglial activation may contribute to early tissue damage but has also been observed chronically after TBI and in many cases of neurodegenerative diseases where neurobehavioral consequences are evident. However to our knowledge no studies have focused on how microglia activation specifically affects the pathological outcomes of repeated mild TBI. We have developed a closed head injury (CHI) mouse model of concussion in which repeated concussive impacts but not a single impact result in acute microglial activation that is associated with greater neuron death and astrogliosis. To better understand the role of microglia in the pathology of repeated concussion posttraumatic microgliosis will be amplified or attenuated in Aim 1. Progranulin-deficient (GRN KO) mice which exhibit increased microgliosis compared to wildtype (WT) mice after a stab wound to the brain will be used to elicit an enhanced microglial response after three
concussions delivered at 24h inter-injury intervals. Ibuprofen a common anti-inflammatory drug will be given to a subset of WT mice after each injury to attenuate the normal CHI-induced microglial response. Memory motor coordination and anxiety-like behaviors as well as axonal injury neuronal degeneration and astrocytosis will be evaluated in these three groups over the first 2 weeks after injury to test the hypothesis that neuropathological damage is proportional to early microglial activation. Persistent microgliosis is associated with a condition of progressive neurodegeneration after repeated mild TBI termed chronic traumatic encephalopathy (CTE). CTE is officially diagnosed by cytosolic accumulations of phosphorylated TAR DNA binding protein 43 (pTDP43) and hyperphosphorylated Tau in the post-mortem brain. Currently no animal model of TBI replicates all of these key pathological hallmarks hindering progress in understanding the causative cellular and molecular factors underlying CTE. GRN KO mice have an age- dependent increase in microgliosis (~7mo) in the absence of injury that precedes the accumulation of pTDP43 (~12-18mo). In Aim 2 chronic histopathological and behavioral effects of repeated concussions will be compared in GRN KO and WT mice over time. We anticipate that persistent activation of microglia in brain- injured GRN KO mice will accelerate pTDP43 accumulation and worsen behavioral deficits providing a more rapid and efficient model for assessing the links between repeated concussions and the development of CTE pathology. An animal model of CTE will also provide a platform for testing therapeutic interventions.

project_terms:
Acute;Affect;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Anxiety;Appearance;Astrocytes;Astrocytosis;Athletic;Attenuated;Behavioral;Biological Assay;Blood - brain barrier anatomy;Brain;Brain Concussion;Brain Injuries;Case Study;Cell Death;Cessation of life;Chronic;Clinical;Closed head injuries;DNA-Binding Proteins;Data;Development;Diagnosis;Enzyme-Linked Immunosorbent Assay;Exhibits;Functional disorder;Goals;Human;Ibuprofen;Individual;Inflammation;Inflammatory Response;Injury;Knowledge;Laboratories;Lead;Learning;Link;Mediator of activation protein;Memory;Memory impairment;Microglia;Military Personnel;Modeling;Molecular;Molecular Profiling;Motor;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurons;Outcome;Pathology;Penetrating Brain Injury;Pharmaceutical Preparations;Phosphotransferases;Progranulin;Proteins;Randomized;Reporting;Risk;Rodent Model;Role;Sports;Stab Wounds;Symptoms;Testing;Therapeutic Intervention;Time;Tissues;Training;Traumatic Brain Injury;United States;Western Blotting;age related;anxiety-like behavior;astrogliosis;axon injury;behavior test;catalyst;chronic traumatic encephalopathy;combat;cytokine;cytotoxic;early onset;high risk;hyperphosphorylated tau;in vivo;injured;innovation;mild traumatic brain injury;motor deficit;mouse model;neurobehavioral;neuropathology;novel;progressive neurodegeneration;public health relevance;repaired;response;tau aggregation;tau-1;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Multiple concussions can occur in the course of sporting activities military training and combat and other circumstances. The cellular mechanisms underlying the vulnerability of the brain to repeated injury and the long-term consequences of multiple concussions are not well understood. This project aims to investigate the role of microglial activation in brain damage and behavioral dysfunction after repeated concussion and to develop a novel mouse model to study chronic degenerative effects of concussions.


application_id: 8932575
project_number: 5F31AG047762-02
project_title: Astrocytic Calcineurin and Connexin43 Gap Junctions in Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2016-01-25
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: AG
serial_number: 047762
program_official: PETANCESKA, SUZANA
project_start_date: 2015-02-01
project_end_date: 2017-01-02
study_section: Special Emphasis Panel[ZRG1-F05-R(20)L]
contact_pi_person_id: 11629027
contact_pi: PLEISS, MELANIE
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): As the sixth leading cause of death that affects over 5.2 million people Alzheimer's disease (AD) is becoming a health crisis. To much disappointment previous clinical trials have shown little success in finding a treatment for this devastating disease. Thus it is critical that new and alternative molecular targets be explored. The proposed project will test the overarching hypothesis that calcineurin (CN) and connexin43 (Cx43) interactions disrupt gap junction (GJ) coupling in astrocytes during the progression of AD leading to detrimental changes in neurologic function. This project will use a multi-disciplinary approach to investigate the hypothesis using an array of AD model systems including human hippocampal specimens APP/PS1 transgenic mice and rat primary astrocyte cultures. In addition to the excellent model systems this project will use a variety of cutting-edge techniques including fluorescence resonance energy transfer (FRET) adeno-associated virus (AAV) - mediated gene delivery and slice electrophysiology. The overarching hypothesis will be examined through three independent specific aims which are as follows: to test the hypothesis that CN interacts with Cx43 during the progression of AD using techniques such as FRET and co-immunoprecipitations (Co-IPs); to test the hypothesis that beta amyloid (A-beta) disrupts gap junction (GJ) coupling in a CN-dependent manner using techniques such as dye coupling and Western blot; to test the hypothesis that CN/Cx43 interactions disrupt GJ coupling and neurologic function in a mouse model of AD using cognitive measures such as the active avoidance paradigm and techniques such as dye coupling Western blot and slice electrophysiology. This project not only provides superior training in neuroscience research but also will provide extremely valuable information into a potential new therapeutic target for AD.

project_terms:
APP-PS1;Acute;Affect;Age;Alzheimer's Disease;Alzheimer's disease model;Amyloid beta-Protein;Animal Model;Astrocytes;Autopsy;Biological Assay;Biological Models;Brain;Calcineurin;Calcineurin inhibitor;Cause of Death;Clinical Trials;Co-Immunoprecipitations;Cognitive;Communication;Connexin 43;Connexins;Coupled;Coupling;Critical Thinking;Custom;Cyclosporine;Data;Dependovirus;Development;Disease;Disease Progression;Dyes;Electrophysiology (science);Experimental Designs;Exposure to;Fluorescein-5-isothiocyanate;Fluorescence Resonance Energy Transfer;Gap Junctions;Gene Delivery;Gene Transfer;Glial Fibrillary Acidic Protein;Goals;Harvest;Health;Hippocampus (Brain);Human;Inflammatory;Injury;Interleukin-1;Label;Measurement;Measures;Mediating;Modeling;Molecular Target;Mus;Nervous System Physiology;Neurosciences Research;Outcome;PPP3CA gene;Production;Protein Dephosphorylation;Protein phosphatase;Rattus;Research;Role;Sampling;Scientist;Signal Transduction;Slice;Specimen;Staging;Synapses;Techniques;Testing;Time;Tissue Sample;Tissues;Training;Transgenic Mice;United States;Western Blotting;Work;base;behavior test;brain tissue;cytokine;design;insight;mild cognitive impairment;mouse model;neuroinflammation;new therapeutic target;non-demented;novel;peptide A;peptidomimetics;promoter;public health relevance;relating to nervous system;research study;success;transgene expression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: As the sixth leading cause of death that affects over 5.2 million people in the United States Alzheimer's disease (AD) is becoming an impending health crisis. To much disappointment previous clinical trials have shown little success in finding a treatment for this devastating disease. Thus it is critical that new and alternative molecular targets be explored which is the goal of the proposed research.


application_id: 8931926
project_number: 5R21CA177359-02
project_title: Promoting Colorectal Cancer Screening in Rural Emergency Departments
administering_ic: NCI
award_notice_date: 2015-08-10
opportunity_number: PAR-13-132
application_type: 5
activity_code: R21
ic: CA
serial_number: 177359
program_official: BRESLAU, ERICA S
project_start_date: 2014-09-23
project_end_date: 2017-05-31
study_section: Health Disparities and Equity Promotion Study Section[HDEP]
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
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 NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Rural Appalachian Kentuckians suffer a disproportionate incidence and mortality from colorectal cancer (CRC) the second leading cause of cancer death. The Centers for Disease Control estimate that as many as 60 percent of CRC related deaths could be prevented if everyone age 50 and older were screened regularly. Rural Appalachian residents are currently being screened at suboptimal rates. The proposed intervention builds on our successful cancer prevention projects: Faith Moves Mountains: A CBPR Appalachian Wellness and Cancer Prevention Program and Promoting Mammography among African American Women Visiting the Emergency Departments. Both projects involve lay health advisor (LHA) delivered motivational interviewing interventions that have been culturally tailored. We propose to pilot test a culturally tailored intervention using brief motivational interviewing by LHAs to promote CRC screenings in an emergency department (ED) serving rural Appalachian Kentucky in order to (1) evaluate the feasibility of the intervention in this rurl Appalachian setting; and (2) assess the effects of the intervention on perceived barriers to CRC screening and subsequent cancer screening engagement.  Consistent with our current Faith Moves Mountains and Promoting Mammography projects we will train carefully selected community members (LHAs) to deliver a brief motivational interview while participants wait for non-urgent care in the ED or wait with a family member who is receiving care. Each participant in conjunction with the LHA will develop a written plan of action that addresses their identified barriers to screening. The brief intervention will take about 15 minutes and will be delivered in aprivate area of the ED. Control group participants will receive standard-of-care ED services that include brochure information identifying general cancer screening services provided by the hospital. Outcome measures will include assessment of barriers and receipt of CRC screening and will be measured at three and six months post intervention. The results will serve as preliminary data for a multisite rural ED-based clinical trial evaluating the cancer promotion intervention.

project_terms:
Accident and Emergency department;Address;Advisory Committees;Affect;African American;Age;Appalachian Region;Area;Cancer Burden;Cancer Etiology;Caring;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical Trials;Colorectal Cancer;Communities;Control Groups;County;Data;Educational aspects;Emergency Care;Emergency department visit;Family member;Goals;Guidelines;Health;Health Services Accessibility;Healthcare Systems;Hospitals;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Malignant Neoplasms;Mammography;Measures;Mortality Vital Statistics;Outcome Measure;Pamphlets;Participant;Patients;Population;Prevention program;Preventive;Primary Health Care;Provider;Randomized Controlled Trials;Readiness;Recommendation;Recruitment Activity;Research;Risk;Rural;Screening for cancer;Services;Staging;Survival Rate;Targeted Research;Testing;Training;Vulnerable Populations;Woman;Writing;base;behavioral/social science;brief intervention;cancer prevention;colorectal cancer screening;disorder prevention;experience;health disparity;high risk;innovation;intervention effect;member;motivational enhancement therapy;post intervention;prevent;programs;screening;social science research;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project will be the first to address the disproportionate incidence and mortality from CRC in rural Appalachia by providing an innovative CRC screening intervention in a rural ED.


application_id: 8931795
project_number: 5R01HD080205-02
administering_ic: NICHD
award_notice_date: 2015-06-17
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HD
serial_number: 080205
program_official: NITKIN, RALPH M
project_start_date: 2014-09-23
project_end_date: 2019-06-30
study_section: Urologic and Genitourinary Physiology and Pathology[UGPP]
contact_pi_person_id: 6490947
contact_pi: HUBSCHER, CHARLES H.
other_pis: HARKEMA, SUSAN J
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
project_abstract:
DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in impairments of locomotor sensory and autonomic functions severely affecting overall health and quality of life. Recent discoveries related to activity-dependent plasticity in humans have led to a widely implemented rehabilitation intervention Locomotor Training which includes stepping using body weight support on a treadmill with manual facilitation. Evidence suggests that this particular type
of task specific training optimizes the lumbosacral spinal circuitry. We have intriguing evidence from four SCI individuals who are unable to stand or walk showing improved bladder and sexual function after undergoing Locomotor Training. These changes in urogenital function may be due to activity-dependent plasticity of lumbosacral circuitry that mediates micturition and erectile functions.  Proper bladder management post-SCI is necessary to decrease the risk of upper urinary tract disease a major source of morbidity. The life-long urologic care is required for SCI
individuals yet most efforts treat symptoms but do not improve intrinsic function. In addition paraplegics rank sexual function as the function post-injury that should be given the highest priority in order to enhance quality of life. This proposal focuses on the mechanisms involved in the reorganization of spinal cord circuits for bladder and sexual function in response to activity-dependent plasticity induced by step training after SCI with and without epidural stimulation. Stand training and/or arm crank exercise serve as controls. Of potential mechanistic importance is that neurotrophins have been implicated in modulating bladder function. It is therefore hypothesized that weight bearing task specific training for locomotion post-SCI induces plasticity of neural networks that mediate not just walking but bladder and sexual function as well and may do so for bladder function by reducing specific neurotrophins that are elevated post-SCI.  Our unique approach will utilize the expertise of each investigator to 1) To determine whether the effect of weight-bearing task-specific training for locomotion on voiding frequency and urodynamic parameters is due to an interaction between locomotor and urinary bladder circuitry after traumatic incomplete upper motor neuron SCI in humans (versus standing or general exercise); 2) To assess the effect of LT on urine (biomarkers) and bladder (biopsy tissue) NGF and BDNF levels after severe incomplete SCI; 3) To determine the effect of weight-bearing task-specific training for locomotion on erectile function and sexual satisfaction after traumatic incomplete upper motor neuron SCI in humans; and 4) To assess the effect of epidural stimulation in combination with LT on voiding frequency urodynamic parameters erectile function and bladder/urine NGF and BDNF levels after complete and motor complete/sensory incomplete upper motor neuron SCI in humans. Our innovative multi-disciplinary study may lead to the translation of a combination approach of weight bearing step training epidural stimulation
and neurotrophic factor manipulation to promote functional recovery for multiple systems following SCI.

project_terms:
Abbott brand of sildenafil citrate;Affect;Animals;Ataxia;Awareness;Biological Markers;Biological Neural Networks;Biopsy;Bladder;Bladder Dysfunction;Bladder Tissue;Body Weight;Brain-Derived Neurotrophic Factor;Caring;Case Study;Catheterization;Chemicals;Clinical;Contusions;Country;Data;Disease;Ejaculation;Electric Stimulation;Esthesia;Evaluation;Exercise;Female;Fertility;Flexor;Foundations;Frequencies (time pattern);Genitourinary system;Hardness;Health;Hospitalization;Human;Hyperreflexia;Impairment;Individual;Infection;Injury;International;Intervention;Interview;Knowledge;Lead;Learning;Life;Locomotion;Locomotor training;Lower Extremity;Manuals;Mediating;Morbidity - disease rate;Motor;Motor Neurons;Operative Surgical Procedures;Oral;Outcome Measure;Paralysed;Paraplegia;Patient Self-Report;Patients;Penile Erection;Pharmaceutical Preparations;Quality of life;Questionnaires;Rattus;Recovery;Recovery of Function;Rehabilitation therapy;Relative (related person);Reporting;Research Personnel;Residual volume;Rest;Risk;Seminal fluid;Sensory;Sex Functioning;Sexual Dysfunction;Source;Sphincter;Spinal;Spinal Cord;Spinal cord injury;Stents;Step training;Symptoms;System;Testing;Therapeutic;Tissues;Training;Translations;United States;Urethra;Urination;Urine;Urodynamics;Urologic Diseases;Walking;Weight-Bearing state;arm;base;improved;improved functioning;indexing;inhibitor/antagonist;innovation;life time cost;male;neurotrophic factor;novel;phosphodiesterase V;pressure;prevent;public health relevance;response;satisfaction;urologic


application_id: 8931792
project_number: 5R21HD080035-02
project_title: Preventing hyperphagia in Prader Willi syndrome using an oligonucleotide
administering_ic: NICHD
award_notice_date: 2015-08-17
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: HD
serial_number: 080035
program_official: KING, TRACY
project_start_date: 2014-09-23
project_end_date: 2017-08-31
study_section: Therapeutic Approaches to Genetic Diseases Study Section[TAG]
contact_pi_person_id: 8899488
contact_pi: STAMM, STEFAN
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:
DESCRIPTION (provided by applicant): One of the most severe daily problems in Prader-Willi syndrome (PWS) is the inability to reach satiety after a meal which leads to hyperphagia and obesity. The loss of expression of two small nucleolar RNA (snoRNA) clusters is a crucial genetic contributor to the disease. One of these snoRNAs (SNORD115) promotes the most active form of the serotonin receptor 2C (HTR2C). Activated HTR2C receptors in the arcuate nucleus inhibit food uptake. We developed an oligonucleotide ("oligo#5") that similar to SNORD115 promotes the formation of the most active HTR2C receptor that localizes on the cell surface. Oligo#5 inhibits food uptake of fasted mice when delivered by intracerebroventricular (ICV) or carotid injection to the arcuate nucleus. We postulate that oligo#5 could be developed into an anti hyperphagia drug for Prader-Willi syndrome. This hypothesis will be tested in two Specific Aims: 1. Deliver oligo#5 and its derivatives to the arcuate nucleus in the brain and determine their mode of action. We will test delivery using osmotic pumps bringing oligo#5 into the 3rd ventricle similar to the acute injections. Oligo#5 accumulates in the hypothalamus and decreases food uptake after carotid injection suggesting it can cross the blood brain barrier. We will therefore test delivery by injecting into the bloodstream. Different chemistries of oligo#5 wil be tested in cell-based models prior to testing in mice. This allows to determine efficacy and to get mechanistic insights. 2. Determine long term toxicity efficacy and off-site targets of the oligonucleotide. We did not observe adverse effects in up to three repeated injections and will test long-term delivery using osmotic pumps and injection into the blood. We will determine immune response behavioral changes inflammation and other adverse effects and measure changes in efficacy over time. Off-target effects will be measured by RNA sequencing and array analysis. We expect that oligo#5 is safe can be delivered through the bloodstream and shows a long-term reduction in food intake. These investigations are significant as they target hyperphagia the most complicating feature in the daily lives of patients they are innovative as they deliver a nucleic acid to a brain region possibly through the blood where it acts by changing target RNA processing; they are feasible as we developed the oligonucleotide and the detection system.

project_terms:
Acute;Address;Adverse effects;Anti-Obesity Agents;Area;Behavioral;Blood;Blood - brain barrier anatomy;Blood Circulation;Brain;Brain region;Canis familiaris;Carotid Arteries;Cell membrane;Cell surface;Cells;Chemistry;Child;Comorbidity;Detection;Disease;Drug Targeting;Eating;Endoplasmic Reticulum;Exons;FOS gene;Fasting;Food;Genetic;Genetic Transcription;Genome;Goals;Health;Heterodimerization;Hyperphagia;Hypothalamic structure;Immune response;Inflammation;Injection of therapeutic agent;Insulin;Investigation;Leptin;Measures;Messenger RNA;Modeling;Morbid Obesity;Mus;Neurologic;Neurons;Nucleic Acids;Obesity;Obsession;Oligonucleotides;Patients;Pharmaceutical Preparations;Pharmacodynamics;Prader-Willi Syndrome;Primates;Pro-Opiomelanocortin;Problem behavior;Protein Isoforms;Proteins;Pump;RNA;RNA Processing;RNA Sequences;RNA Splicing;Reagent;Safety;Satiation;Serotonin;Serotonin Receptor 5-HT2C;Signal Transduction;Site;Small Nucleolar RNA;Structure;Structure of nucleus infundibularis hypothalami;System;Techniques;Testing;Therapeutic;Time;Toxic effect;United States;Untranslated RNA;Work;base;ghrelin;innovation;insight;mRNA Precursor;nervous system disorder;non-genetic;prevent;public health relevance;receptor;response;tool;transcriptome sequencing;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: People with Prader-Willi Syndrome never feel full after eating which leads to the constant urge to eat and extreme obesity. We developed an oligonucleotide that substitutes the missing genetic part in the disease and that reduces food intake. We will optimize delivery of the oligonucleotides and test its safety in mice.


application_id: 8930985
project_number: 5R21EB017902-02
project_title: Biodegradable Polymerized Simvastatin
administering_ic: NIBIB
award_notice_date: 2015-07-24
opportunity_number: PA-12-284
application_type: 5
activity_code: R21
ic: EB
serial_number: 017902
program_official: RAMPULLA, DAVID
project_start_date: 2014-09-22
project_end_date: 2018-06-30
study_section: Biomaterials and Biointerfaces Study Section[BMBI]
contact_pi_person_id: 1874927
contact_pi: PULEO, DAVID A.
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: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION:  Synthetic degradable polymers are commonly used for drug delivery and to aid in tissue regeneration. Drugs are routinely encapsulated in the material for subsequent diffusion- and/or degradation-mediated release. Limitations with encapsulation however include limited payload and the potential for premature exhaustion of the delivery system. To prolong release drugs have been conjugated to polymers. Drug can be attached to the polymer via a linker that subsequently releases the molecule following cleavage or it can be incorporated into the polymeric backbone during synthesis.  The overarching goal of this project is to develop and characterize a polymer synthesized using drug molecules in the present case simvastatin as monomers. The working hypothesis is that the structure of simvastatin with a lactone moiety in the prodrug is amenable to ring-opening polymerization. As such polymerized simvastatin could then be processed into films that degrade by hydrolysis to release bioactive simvastatin molecules which have osteogenic anti-inflammatory and angiogenic properties in addition to their well-known known hypolipidemic effects.  Aim 1 will develop and characterize a degradable polymerized form of simvastatin. With respect to this objective it is hypothesized that the polymer can be processed into biodegradable films that release simvastatin. Aim 2 will investigate whether polymerized films of simvastatin degrade in vivo to stimulate osteogenesis in a rodent supracalvarial implantation model. It is hypothesized that as the polymer degrades bioactive simvastatin is released to enhance local bone formation.  If the proof-of-principle studies proposed for this Exploratory/Developmental Award are successful the polymer may be fabricated into a variety of physical forms (e.g. microspheres and tissue engineering scaffolds) to exploit the pleiotropic effects of simvastatin for bone and other tissue applications as well as the methods potentially being applicable to other members of the statin family.

project_terms:
Adverse effects;Anti-Inflammatory Agents;Anti-inflammatory;Award;Biocompatible Materials;Biological;Biomedical Engineering;Cells;Data;Defect;Development;Diffusion;Drug Delivery Systems;Drug usage;Encapsulated;Ethylene Glycols;Family;Film;Glycolates;Goals;Health;Hydrolysis;Implant;Lactones;Local Anti-Infective Agents;Mediating;Methods;Microspheres;Modeling;Molecular Weight;Nanosphere;Nylons;Osteogenesis;Pharmaceutical Preparations;Polyanhydrides;Polyesters;Polymers;Process;Prodrugs;Property;Reaction;Research Project Grants;Rodent;Simvastatin;Site;Structure;System;Systemic Therapy;Testing;Tissue Engineering;Tissues;Trauma;Ursidae Family;Vertebral column;Work;biodegradable polymer;biomaterial compatibility;bone;cancer therapy;caprolactone;controlled release;copolymer;design;direct application;ethylene glycol;exhaustion;implantation;in vivo;member;monomer;multidisciplinary;osteogenic;particle;pleiotropism;poly(lactic acid);polycarbonate;polymerization;premature;response;scaffold;tissue regeneration;tumor;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Synthetic degradable polymers are commonly employed for drug delivery and to aid in tissue regeneration. Although current materials are useful limitationsinclude limited payload and instability of drug. This project will develop a polymer directly composed of the drug simvastatin which has several important biological activities including osteogenic anti-inflammatory and angiogenic effects.


application_id: 8930773
project_number: 272201000033I-0-27200002-1
project_title: Task A65:Evaluation of Candidate Products in Mouse Inhalation Model of Yesinia Pestis Infection
administering_ic: NIAID
project_start_date: 2014-09-15
project_end_date: 2015-05-14
contact_pi_person_id: 12446857
contact_pi: LAWRENZ, MATTHEW
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_terms:
Animal Model;Breathing;Communicable Diseases;Contracts;Development;Evaluation;Infection;Modeling;Mus;Standardization;efficacy testing;therapeutic development


application_id: 8929266
project_number: 5P01HD071875-02
project_title: CIPAR1 A Novel Modulator of Progesterone Accumulation in Periovulatory Follicle
administering_ic: NICHD
award_notice_date: 2015-07-28
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7820
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Affect;Antibodies;Apoptosis;Castration;Cell Culture Techniques;Cell Differentiation process;Cell physiology;Cells;Collaborations;Cytoprotection;Data;Development;Enzymes;Experimental Models;Female;Fertility;Future;Gene Proteins;Genes;Goals;Gonadotropins;Hormones;Human;Immunoprecipitation;In Vitro;Instruction;Link;Location;Luteinization;Macaca;Mediating;Mediator of activation protein;Molecular;Monkeys;Ovary;Ovulation;Physiological;Play;Primates;Production;Progesterone;Prostaglandins;Prostate;Prostatic;Proteins;Proteomics;Rattus;Reproduction;Rodent;Role;Steroid biosynthesis;Testing;Tissues;Woman;base;corpus luteum;critical period;differential expression;granulosa cell;hormone regulation;human tissue;improved;in vitro Model;in vivo;novel;research study;response


application_id: 8929265
project_number: 5P01HD071875-02
project_title: Mechanism of Periovulatory Leukocyte Infiltration into the Ovary
administering_ic: NICHD
award_notice_date: 2015-07-28
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7819
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG JAY
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: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Accounting;Adhesions;Adult;Affect;Age;Angiotensins;Animals;Anovulation;Biological Assay;Biological Process;Blood Circulation;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cells;Chronic;Clinical Treatment;Cytokine Receptors;Cytometry;Data;Defect;Diagnosis;Disease;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Failure (biologic function);Female;Fertility;Flow Cytometry;Homologous Gene;Human;Immune system;Immunohistochemistry;In Vitro;Indomethacin;Infiltration;Inflammation;Inflammation Mediators;Instruction;Knockout Mice;Lead;Leukocyte Trafficking;Leukocytes;Measures;Mediator of activation protein;Migration Assay;Monitor;Monkeys;Ovarian;Ovarian Stimulations;Ovary;Ovulation;PTGS2 gene;Pathway interactions;Pattern;Plasma;Play;Population;Primates;Procedures;Progesterone;Prostaglandins;RU-486;Rattus;Receptor Cell;Recruitment Activity;Reproductive system;Rodent;Role;Serum;Signal Pathway;Spleen;Testing;Woman;celecoxib;chemokine;cohort;cytokine;inhibitor/antagonist;nonhuman primate;novel;novel strategies;peripheral blood;receptor;reproductive;spatiotemporal


application_id: 8929264
project_number: 5P01HD071875-02
project_title: Angiogenesis in the Primate Ovulatory Follicle
administering_ic: NICHD
award_notice_date: 2015-07-28
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7818
contact_pi_person_id: 1919355
contact_pi: DUFFY, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-07-01
budget_end_date: 2016-06-30
project_terms:
Aftercare;Antibodies;Area;Biopsy;Blood Vessels;Blood capillaries;Cell Count;Cell Proliferation;Cell physiology;Cells;Coculture Techniques;Conditioned Culture Media;Contraceptive Agents;Data;Detection;Development;Diagnosis;Dinoprostone;Dose;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Exposure to;Failure (biologic function);Fertility;Follicular Fluid;Gonadotropins;Growth Factor;Histologic;Hormones;Human;Human Chorionic Gonadotropin;In Vitro;Infertility;Instruction;Laboratories;Lead;Luteinizing Hormone;Macaca;Mediating;Mediator of activation protein;Messenger RNA;Modeling;Monkeys;Ovarian;Ovarian Follicle;Ovarian Hyperstimulation Syndrome;Ovary;Ovulation;Population;Pregnancy;Primates;Production;Proliferating;Prostaglandin Inhibition;Prostaglandins;Proteins;Reproduction;Rodent;Structure;Testing;Time;Tissues;Vascular Endothelial Growth Factor Receptor;Vascular Endothelial Growth Factors;Western Blotting;Woman;angiogenesis;capillary;effective therapy;granulosa cell;in vivo;inhibitor/antagonist;migration;neovascularization;novel;prevent;receptor;research study;response


application_id: 8929254
project_number: 5R01GM079684-07
project_title: The Regulation of Smoothened in Hedgehog Signaling
administering_ic: NIGMS
award_notice_date: 2015-06-25
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 079684
program_official: MAAS, STEFAN
project_start_date: 2008-07-01
project_end_date: 2018-06-30
study_section: Development - 1 Study Section[DEV1]
contact_pi_person_id: 8575677
contact_pi: JIA, JIANHANG
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Hedgehog (Hh) proteins function as morphogens and play critical roles in pattern formation and cell growth control. Dysregulation and dysfunction of the Hh signaling pathway induces diverse types of cancers. The seven-pass transmembrane protein Smoothened (Smo) is required in both insects and mammals for transduction of the Hh signal. Our strategy is to use Drosophila as a simple and genetically tractable model system to explore the mechanisms of Hh signal transduction by the receptor complex. The long-term goal of our research is to elucidate how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. Although many components in the Hh pathway have been identified how the Hh signal is transduced through Patched (Ptc) to Smo is still unclear. We have discovered that Smo activation requires phosphorylation by multiple kinases including protein kinase A (PKA) casein kinase 1 (CK1) casein kinase 2 (CK2) and G protein-coupled receptor kinase 2 (Gprk2) and that phosphorylation leads to increased Smo cell surface levels and signaling activity. We show that Smo transduces Hh signals by directly recruiting a downstream Fused-Costal2 (Fu-Cos2) complex and that Fus- Cos2 protein complex promotes hyperphosphorylation of Smo uncovering a feedback mechanism essential for optimal Hh pathway activation. Furthermore we have identified protein phosphatase PP4 as a negative regulator of Smo. Results from our studies have suggested that the cell surface accumulation and intracellular trafficking of Smo play critical roles in regulating Hh-induced Smo activation. However many questions persist regarding the mechanism controlling Smo localization and trafficking. To begin address these questions we have recently discovered that the deubiquitinase USP8 promotes Smo signaling activity by preventing Smo ubiquitination and regulating Smo subcellular localization. Combined with the preliminary studies in the project our findings provide new tools and hypotheses for investigating the mechanisms of Smo signaling. In this project our central hypothesis is that Smo activation downstream of Hh is tightly controlled by its subcellular localization in which a novel kinase and small molecules promotes Hh signaling by enhancing the cell surface accumulation of Smo whereas ubiquitin inactivates Smo by promoting Smo endocytosis and degradation. We will use a combination of genetic and biochemical approaches in three Specific Aims: 1) To determine how a newly identified kinase regulates Smo phosphorylation and basolateral membrane localization; 2) to investigate the molecular mechanisms by which small molecules activate Smo in response to Hh stimulation; 3) to determine how Hh regulates the ubiquitin-mediated endosomal sorting of Smo via a novel E3 ligase of Smo.

project_terms:
Address;Basal cell carcinoma;Beta-Adrenergic Receptor Kinase 1;Binding (Molecular Function);Biochemical;Biological;Biological Models;Cancer Etiology;Cell surface;Cells;Complex;Congenital Abnormality;Cyclic AMP-Dependent Protein Kinases;Development;Diagnostic;Dimerization;Drosophila genus;Embryonic Development;Endocytosis;Erinaceidae;Event;Family member;Feedback;Functional disorder;G-Protein-Coupled Receptors;Genetic;Goals;Health;High Pressure Liquid Chromatography;Homologous Gene;Insecta;Integral Membrane Protein;Investigation;Malignant Neoplasms;Mammals;Mass Spectrum Analysis;Mediating;Molecular;Pathway interactions;Pattern;Pattern Formation;Phospholipids;Phosphorylation;Phosphotransferases;Physiological;Play;Preventive;Process;Protein Tyrosine Kinase;Protein phosphatase;Proteins;Publishing;RNA Interference;Recruitment Activity;Regulation;Research;Role;Signal Transduction;Signaling Molecule;Sorting - Cell Movement;Technology;Tertiary Protein Structure;Testing;Therapeutic;USP8 gene;Ubiquitin;Ubiquitination;Wing;base;basolateral membrane;cancer type;casein kinase I;casein kinase II;cell growth;design;fly;hedgehog signal transduction;human SMO protein;insight;medulloblastoma;morphogens;novel;phosphatidylinositol 4-phosphate;prevent;protein complex;protein function;receptor;response;small molecule;smoothened signaling pathway;tool;trafficking;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Hedgehog (Hh) signaling is known for its role in directing processes such as cell growth proliferation and differentiation during embryogenesis. Abnormal activation of Smo an atypical GPCR in the receptor complex results cancers such as basal cell carcinoma (BCC) and medulloblastoma. Investigation of the Smo signaling mechanisms the goal of this project will provide both insights into fundamental developmental problems and new strategies to design preventive and curative tools and treatments for cancers caused by deregulated Hh signaling.


application_id: 8928623
project_number: 5R01EY024068-02
project_title: Inflammasome Activation in Geographic Atrophy
administering_ic: NEI
award_notice_date: 2015-08-14
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 024068
program_official: MCKIE, GEORGE ANN
project_start_date: 2014-09-01
project_end_date: 2016-06-30
study_section: Diseases and Pathophysiology of the Visual System Study Section[DPVS]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Geographic atrophy (GA) is an untreatable advanced form of age-related macular degeneration (AMD) that is characterized by degeneration of the retinal pigmented epithelium (RPE). Neither the mechanisms that promote this RPE degeneration nor the basis for the centrifugal expansion of GA that can ultimately lead to blindness have been resolved. This enigmatic nature of GA pathogenesis has precluded the development of any FDA-approved therapy for the one million Americans diagnosed with GA and the millions more at risk of developing GA. In new and exciting studies we discovered an unconventional immune activation of the NLRP3 inflammasome complex in the RPE of human eyes with GA (Tarallo et al. Cell 2012) that occurs in response to a specific accumulation of toxic non-coding Alu RNAs during deficiency in the RNase DICER1 and induces RPE degeneration (Kaneko et al. Nature 2011). This surprising finding of pathologic inflammasome activation in a non-immune cell is a critical step in understanding GA pathogenesis and elucidating the essential effector pathways that determine retinal vitality. Our findings which introduce a novel definition of auto-immunity: The RPE activation of the NLRP3 inflammasome in response to self-derived Alu RNAs represents the first description of inflammasome activation to endogenous all the while causing pathology in a classically immune privileged ocular milieu. Crucially blockade at multiple molecular steps along NLRP3 inflammasome activation blocked RPE cell death thus providing an important mechanism-based strategy to alleviating the worldwide burden of GA. However we still lack an integrated understanding of whether other AMD-related stressors also cause inflammasome activation in GA and if so precisely how these mechanisms converge upon common effector pathways that induce RPE degeneration. A rigorous definition of these mechanisms is crucial to enhancing our understanding of the molecular drivers of GA and to developing rational treatments. We will provide novel functional insights into how dysregulated NLRP3 inflammasome activation contributes to GA pathogenesis and develop a novel therapeutic strategy via the following Aims: (1) Generate a spatiotemporal map of known AMD-related stressors and markers of NLRP3 inflammasome activation in relation to the locus of pathology in GA and early AMD eyes; (2) Decipher the molecular mechanisms underlying inflammasome activation by known GA-associated stresses; (3) Determine whether blockade of inflammasome machinery and its effector pathways in acute and chronic animal models of AMD inhibit RPE degeneration. These studies will illuminate novel aspects of the molecular and biochemical bases of GA and help validate a molecular targeting strategy that could be translated into clinical trials. As such this proposal is aligned with the -year goals of the NEI's Retinal Diseases Program strategic plan.

project_terms:
Acute;Affect;Age;Age related macular degeneration;American;Amyloid;Animal Disease Models;Animal Model;Biochemical;Blindness;Blood Vessels;Cell Death;Cell model;Cells;Characteristics;Cholesterol;Choroidal Neovascularization;Chronic;Clinical Trials;Complex;DICER1 gene;Data;Deposition;Developed Countries;Development;Diagnosis;Disease;Drusen;Economics;Elements;Etiology;Exhibits;Eye;FDA approved;Fatty acid glycerol esters;Genes;Genetic;Goals;Health;Health Expenditures;Human;Hyperactive behavior;Immune;Immunity;Lead;Link;MAPK3 gene;Maps;Molecular;Molecular Target;Mus;Nature;Nerve Degeneration;Pathogenesis;Pathologic;Pathology;Pathway interactions;Patients;Peptides;Population;Prevalence;Productivity;RNA;Regulation;Retina;Retinal;Retinal Diseases;Retrotransposon;Ribonucleases;Risk;Severities;Signal Transduction;Strategic Planning;Stress;Structure of retinal pigment epithelium;Testing;Transcript;Translating;Translational Research;United States National Institutes of Health;Untranslated RNA;Vision;Vision research;apolipoprotein E-4;base;biological adaptation to stress;effective therapy;feeding;geographic atrophy;immune activation;improved;insight;novel;novel therapeutics;programs;response;spatiotemporal;stressor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There is no FDA-approved treatment for the one million Americans with geographic atrophy (GA) or for the millions more who are at risk of developing GA. We recently discovered an enzymatic deficiency that leads to accumulation of toxic RNA molecules and immune activation in the eyes of patients with GA. By understanding how these newly discovered pathways cause GA and testing therapies that will be suitable for advancing to clinical trials this proposal is aligned with the National Vision Research Agenda's Needs Gaps and Opportunities for the NEI's Retinal Diseases Program strategic plan and embraces the NIH Director's recent challenge to advance translational science using creative approaches.


application_id: 8928431
project_number: 272201400004I-0-9999-1
project_title: Central Clinical Laboratory Services
administering_ic: NIAID
project_start_date: 2014-05-13
project_end_date: 2021-05-12
contact_pi_person_id: 12262097
contact_pi: KOMAROMY, GABOR
other_pis: Not Applicable
department: Unavailable
primary_duns: 184227809
primary_uei: YPNJBDKDGJV7
duns_number: 184227809
uei: YPNJBDKDGJV7
fips: US
organization_id: -418027
organization_city: HIGHLAND HEIGHTS
organization_state: KY
organization_type: Unavailable
organization_zip: 410769167
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_terms:
Clinical;Clinical Research;Communicable Diseases;Laboratories;National Institute of Allergy and Infectious Disease;Research Infrastructure;Services;research study


application_id: 8928277
project_number: 261201300013I-0-26100004-1
administering_ic: NCI
project_start_date: 2014-08-15
project_end_date: 2015-08-14
contact_pi_person_id: 12446667
contact_pi: TUCKER, THOMAS
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
funding_mechanism: R and D Contracts
project_title:
Patterns of Care/Quality of Care Study: Diagnosis Year 2013 (SEER)Period of Performance: 08/15/2014-08/14/2015Line item #: 1

project_abstract:
SEER Patterns of Care Studies describe characterize and compare practice patterns and treatments provided for cancer in different geographic areas of the United States. SEER Patterns of Care/Quality of Care Studies are conducted to satisfy a Congressional directive (under Public Law 100-607 Sec. 413 (a)(2)(C) adopted November 4 1988) to the National Cancer Institute to assess the incorporation of state-of-the-art cancer treatments into clinical practice and the extent to which cancer patients receive such treatments and include the results of such assessment in the biennial reports. To select the cancers to satisfy this directive the Division of Cancer Control and Population Sciences has been working closely with the Division of Cancer Treatment. This years Patterns of Care (POC) Study shall investigate state-of-the-art therapies for patients with cancers of sites: sarcoma for all ages and for ages 15-39 non-Hodgkin lymphoma Hodgkin lymphoma acute lymphocytic leukemia and female breast cancer.

project_terms:
Adjuvant Therapy;Adopted;Age;Beds;Biological Markers;Cancer Patient;Characteristics;Communities;Comorbidity;Data;Diagnosis;Diagnostic tests;Division of Cancer Control and Population Sciences;Educational process of instructing;Ethnicity aspects;Female Breast Carcinoma;Geographic Locations;Hodgkin Disease;Hospitals;Immunotherapy;Insurance Coverage;Laws;Leukemia Lymphocytic Acute;Link;Malignant Neoplasms;Medicare;National Cancer Institute;Non-Hodgkin's Lymphoma;Operative Surgical Procedures;Patients;Pattern;Patterns of Care;Performance;Physicians;Quality of Care;Race;Radiation therapy;Reporting;Time;United States;Work;cancer site;cancer therapy;chemotherapy;clinical practice;hormone therapy;sarcoma;sex


