# projects

application_id: 8847357
project_number: 5P01HL078825-10
project_title: Regulation of CPC Function via Protein O-GlcN Acylation
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7458
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
The myocardium is largely unable to effectively repair itself following an infarction. Recent work indicates that resident cardiac progenitor cells (CPCs) represent an under-developed therapeutic target. Unfortunately the post-ischemic myocardium is an unfavorable environment for the survival and potential cardiomyogenic differentiation of CPCs thereby limiting effective post-ischemic myocardial repair of exogenously administered CPCs. Project 3 will address the biological regulation of stress signaling and its impact on CPC function. Recently several reports indicated a unique stress response (0-GlcNAc) in the heart that allows differentiated cardiac myocytes to withstand the violent environment of the post-ischemic myocardium. Protein 0-GlcNAcylafion occurs in every multicellular organism that has been examined; yet nothing is known about the role of this stress signal in CPCs. This Project will directly address this deficiency to create new biological insights. Project 3 will test the central hypothesis that a unique alarm signal (0-GlcNAc) plays a fundamental role in regulating CPC function and that it promotes CPC survival but may limit bona fide post-ischemic cardiomyogenesis by maintaining CPCs in a persistent state of alarm. Project 3 will establish the impact of the pro-adaptive stress signal 0-GlcNAc on CPC function by specifically focusing on proliferation (Aim 1) survival (Aim 2) and differentiation (Aim 3). This Project will use an exhaustive series of carefully controlled loss- and gain-of-function approaches. Regardless of the specific outcomes of the Alms this Project will provide completely novel Insights into an exciting area of cardiovascular medicine because of the significance of the questions being pursued. Project 3 will continue to collaborate with Projects 1 2 and 4 to understand innovative inter-regulatory mechanisms between O- GlcNAcylation and: the NO-CO axis (Project 1) TNF-NFkB induced inflammation (Project 2) and hyperglycemic suppression of CPC function (Project 4). The role of protein 0-GlcNAcylafion in CPCs is completely unknown. This Project will undoubtedly establish new biological insights by assuming an innovative approach to understanding CPC regulation and pathophysiology.

project_terms:
Acylation;Address;Area;Attenuated;Biological;Biology;Cardiac;Cardiac Myocytes;Cardiovascular system;Cell Count;Cell Death;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell physiology;Cellular Stress;Cessation of life;Characteristics;Defect;Environment;Eukaryota;Functional disorder;Heart;Heart failure;Hyperglycemia;Hypoxia;Infarction;Inflammation;Injury;Instruction;Maintenance;Mechanics;Medicine;Modeling;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Organism;Outcome;Play;Process;Proteins;Regulation;Reporting;Role;Series;Shelter facility;Signal Transduction;Staging;Stem cells;Stress;System;TNF gene;Testing;Therapeutic;Translating;Transplantation;Undifferentiated;Violence;Work;base;biological adaptation to stress;cell injury;cell type;clinically relevant;experience;gain of function;innovation;insight;novel;oxidant stress;primitive cell;repaired;response;restoration;therapeutic target

public_health_relevance:
RELEVANCE (See instructions): Project 3 will establish completely innovative insights into the regulation of the proliferation survival and differentiation of primitive cells in the heart and translate the findings into a clinically relevant model of heart failure. Regardless of the specific outcomes of the Aims Project 3 will provide completely novel insights into a unique form of stress signaling as a previously unrecognized regulator of progenitor cell function.


application_id: 8847356
project_number: 5P01HL078825-10
project_title: Tumor Necrosis Factor Modulation of CPCs
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7457
contact_pi_person_id: 1914941
contact_pi: PRABHU, SUMANTH D
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
project_abstract:
The overarching objective of this project is to establish the mechanistic relationships between pathologicalinflammation and cardiac progenitor cell (CPC)-mediated tissue repair. After myocardial infarction (Ml)CPCs are increased in number but fail to produce sufficient endogenous healing suggesting that factors inthe microenvironment compromise their reparative capacity. During LV remodeling there is sustainedelaboration of the pro-inflammatory cytokine tumor necrosis factor-a (TNF). The effects of TNF in the post-MIheart are heterogeneous and depend on its two cell-surface receptors (TNFRs) - TNFRl promotes LVremodeling and activation of nuclear factor (NF)-KB and p38 MAPK whereas TNFR2 opposes these effectsand is beneficial. However whether divergent TNFR-specific effects extend to CPCs and modulate theirreparative capacity is unknown. In our preliminary studies we have uncovered the novel finding that TNFinhibits cardiomyocyte differentiation of CPCs and instead promotes an adrenergic phenotype that canpotentiate remodeling. This response is dependent on TNFR1 and associated with NF-KB and can beopposed by TNFR2 Hence we hypothesize that differential TNF signaling via TNFR1 TNFR2 and NF-KBplavs a critical role in determining adrenergic versus cardiomyogenic fate and conseguentiv the reparativecapacity of CPCs following Ml. We propose three Aims. In Aim 1 we will determine the effects of TNFR-dependent signaling on CPC competence and adrenergic versus cardiogenic differentiation in vitro usingGFP-labeled lin-/c-kit+ CPCs from wild-type (WT) TNFRl-/- TNFR2-/- dominant-negative (DN)-lKBatransgenic (Tg) and Tg-DN-p38a MAPK mouse hearts. We will also establish that neuroadrenergic-typecells are derived from cardiac and not resident neural progenitors. In Aim 2 we will delineate the role ofCPC-localized TNFR-signaling during cardiac repair in vivo. In a murine reperfused Ml model we will deliverGFP-labeled lin-/c-kit+ WT TNFR1-/- TNFR2-/- or Tg-DN-kBa CPCs and determine cell fate and theireffects on LV remodeling and tissue adrenergic activation. In Aim 3 we will determine the effects of TNF inthe tissue microenvironment on CPC-mediated repair and adrenergic differentiation by defining remodelingresponses upon transplantation of GFP-labeled WT lin-/c-kit+ CPCs following reperfused Ml in WT and TNF-/- mice or upon circumscribed systemic TNF inhibition with etanercept. Collectively these studies will: 1)uncover a novel role for TNF as an inhibitor of CPC function and CPC-mediated repair via TNFR1 and NF-KB; 2) define a heretofore unknown CPC-derived origin for adrenergic cells in the failing heart; and 3) targetpotential therapeutic avenues related to TNF signaling to enhance the efficacy of CPC transplantationRELEVANCE (See instructions):These studies will establish the novel paradigm that tumor necrosis factor-a (TNF) profoundly influencescardiac progenitor cell (CPC) behavior through the divergent effects of its two receptors and channels thesecells toward either beneficial (cardiac cell) or detrimental (adrenergic cell) fates for tissue repair. The resultswill shed light on potential therapeutic avenues related to TNF signaling that can both enhance the efficacyof exogenous progenitor cell transplantation and augment the heart's intrinsic capacity to repair itself aftermyocardial infarction in the absence of progenitor cell therapy.

project_terms:
Adrenergic Agents;Arrhythmia;Biological;Cardiac;Cardiac Myocytes;Catecholamines;Cell Density;Cell Differentiation process;Cell Surface Receptors;Cell Therapy;Cell Transplantation;Cell membrane;Cell physiology;Cells;Clinical;Competence;Cytoprotection;Disease;Doctor of Medicine;Dominant-Negative Mutation;Etanercept;Healed;Heart;Heart failure;Human;In Vitro;Inflammation;Inflammatory;Injury;Instruction;Label;Left Ventricular Remodeling;Left ventricular structure;Light;MAP Kinase Gene;MAPK14 gene;Mediating;Mediator of activation protein;Modeling;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocarditis;Nuclear;Phenotype;Play;Principal Investigator;Process;Promotor (Genetics);Proteins;Proto-Oncogene Protein c-kit;Role;Secondary to;Signal Transduction;Staging;Stem cell transplant;Stem cells;TNFRSF1A gene;TNFRSF1B gene;Testing;Therapeutic;Tissues;Transgenic Organisms;Transplantation;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Tyrosine 3-Monooxygenase;adrenergic;cardiac repair;cell behavior;cell type;cytokine;healing;improved;in vivo;indexing;inhibitor/antagonist;injured;nerve stem cell;nestin protein;novel;receptor;repaired;research study;response;time use;tissue repair


application_id: 8847355
project_number: 5P01HL078825-10
project_title: Role of the NO-CO Module in Regulating CPC Function
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
subproject_number: 7456
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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
project_abstract:
The discovery of cardiac progenitor cells (CPCs) provides a potential new approach to the treatment of heart failure (HF) The initial results of our first-in-humans clinical study of CPCs in patients with HF (SCIPIO) are encouraging. However CPC-based therapies are severely limited by the fact that almost all (at least 97%) of the transplanted CPCs die shortly after transplantation. This implies that increasing the survival of transplanted cells by preventing apoptosis will enhance the efficacy of CPC therapy. In the current funding period of this Program Project we have found that carbon monoxide (CO) and nitric oxide (NO) exert powerful anti-apoptotic actions and form a closely inter-related functional module (CO-NO module) which is regulated by heme oxygenase-1 (HO-1) extracellular superoxide dismutase (ecSOD) and inducible NO synthase (iNOS). We will exploit this discovery to enhance cell-based therapies. The overall goal of Project 1 is to elucidate the role of the CO-NO module in regulating CPC function and to evaluate its therapeutic utility after myocardial infarction (Ml). We propose that augmenting this module will greatly potentiate the effectiveness of transplanted CPCs and dramatically enhance CPC-mediated cardiac repair. This Project represents the natural evolution of our previous work in this Program Project; having discovered that the CO- NO module affors powerful protection against mmyocardial ischemia we will now build on this work to enhance the reparative ability of CPCs. In Aim 1 we will determine the roles of HO-1 and CO in modulating CPC function. In Aim 2 we will establish the role of ecSOD in regulating CPC function and mediating HO-1- induced protection of CPCs. In Aim 3 we will determine the role of NO in modulating CPC function and the role of HO-1 and ecSOD in mediating the effects of NO on CPCs. Using both gain- and loss-of-function approaches in all three Aims we will systematically evaluate fundamental parameters of CPC competence in vitro and the ability of CPCs to repair cardiac damage in vivo in a murine model of post-MI LV remodeling and dysfunction. In Aim 4. we will elucidate the molecular mechanisms whereby CO and NO upregulate ecSOD and NO upregulates HO-1 and ecSOD in CPCs focusing on the transcription factor Nrf2. These will be the first studies to examine the role of CO and NO and their supporting proteins HO-1 ecSOD and INOS in modulating CPC function. The results will be entirely new and will add a new dimension to our understanding of CPC biology. In addition these studies will provide proof-of-principle for the therapeutic utility of manipulations that potentiate the CO-NO module in CPCs which may lay the groundwork for future trials of genetically or pharmacologically enhanced CPCs in patients with HF.

project_terms:
Apoptosis;Apoptotic;Carbon Monoxide;Cardiac;Cell Survival;Cell Therapy;Cell Transplants;Cell physiology;Cells;Cellular biology;Chemotaxis;Clinical Research;Competence;Deet;Dimensions;Effectiveness;Evolution;Functional disorder;Funding;Future;Gene Transfer;Generations;Genetic;Genetic Transcription;Goals;Heart failure;Heme;Heme Oxygenase (Decyclizing);Human;In Vitro;Instruction;Ischemia;Left Ventricular Remodeling;Length;Measures;Mediating;Mediator of activation protein;Minority;Modeling;Molecular;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Oxidative Stress;Patients;Phase I Clinical Trials;Proteins;Proto-Oncogene Protein c-kit;Reactive Oxygen Species;Resistance;Role;Stem cells;Structure;Superoxide Dismutase;Telomerase;Testing;Therapeutic;Translations;Transplantation;Up-Regulation (Physiology);Work;cardiac repair;clinical application;cytokine;extracellular;gain of function;human NOS2A protein;in vivo;inhibitor/antagonist;loss of function;novel strategies;oxidative damage;phase 1 study;pre-clinical;preconditioning;prevent;programs;senescence;telomere;transcription factor

public_health_relevance:
RELEVANCE (See instructions): In 2009 we started SCIPIO a study of c-kit+ cardiac progenitor cells (CPCs) in patients with heart failure and the initial results are encouraging. Project 1 builds on SCIPIO. We will test a new therapy - genetically- modified or preconditioned CPCs which promise to be superior to the cells currently being used in SCIPIO. If the results confirm our working hypothesis these studies will lay the groundwork for testing more effective CPCs for the treatment of heart failure and thus may facilitate translation of cell therapies to humans.


application_id: 8847354
project_number: 5P01HL078825-10
project_title: Protection of Ischemic Myocardium
administering_ic: NHLBI
award_notice_date: 2015-06-18
opportunity_number: PAR-10-285
application_type: 5
activity_code: P01
ic: HL
serial_number: 078825
program_official: WONG, RENEE P
project_start_date: 2005-04-15
project_end_date: 2018-05-31
study_section: Heart, Lung, and Blood Program Project Study Section[HLBP]
contact_pi_person_id: 1893527
contact_pi: BOLLI, ROBERTO
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:
Lack of understanding of basic stem cell mechanisms limits current therapeutic approaches. In this renewal application we will focus on the use of c-kit* cardiac progenitor cells (CPCs) to protect the heart against post-myocardial infarction (Ml) remodeling and heart failure (HF). The overall goal is to elucidate the molecular mechanisms that regulate the properties of CPCs and to evaluate the therapeutic utility of enhancing CPC function in order to optimize cardiac repair. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Belli) will elucidate the role of CO and NO in regulating CPC function and therapeutic efficacy. The central hypothesis is that these gases are kev determinants of CPC competence and that augmenting their levels will dramatically enhance CPC-mediated cardiac repair. Project 2 (Prabhu) will illuminate the deleterious effects of TNF on CPC competence and reparative ability. This project will test the hypothesis that differential TNF signaling via TNFR1 TNFR2 and NF-KB plavs a critical role in determining adrenergic versus cardiomyogenic fate and consequently the reparative capacity of CPCs following Ml. Project 3 (Jones) will examine the role of protein 0-GlcNAcylation in modulating the fundamental properties of CPCs and will test the hypothesis that the 0-GlcNAc alarm signal plays a critical role in regulating CPC proliferation survival differentiation and paracrine function. Project 4 (Bhatnagar) will determine how diabetes affects CPC-mediated myocardial repair and how CPC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes undermines CPC competence by inducing insulin resistance. Thus all four Projects focus cohesively on CPCs. These Projects will be supported by four Cores that will provide expertise in mouse surgery cell transplantation CPC culture and phenotyping pathology flow cytometry and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. These will be the first studies to examine the role of CO and NO TNF 0-GlcNAcylation and type 2 diabetes on CPC function: consequently the results will be entirely new and will advance our understanding of CPC biology. In addition these studies may lay the groundwork for new translational investigations of CPC therapy in patients with HF. Since we have already initiated the first-in-humans clinical trial of unmodified CPCs in patients with HF we are well positioned to rapidly translate any insights derived from this Program into new clinical investigations.

project_terms:
Acute;Address;Adrenergic Agents;Affect;Aftercare;Apoptotic;Biology;Carbon Monoxide;Cardiac;Cell Culture Techniques;Cell Proliferation;Cell Separation;Cell Survival;Cell Therapy;Cell Transplantation;Cell Transplants;Cell physiology;Cells;Cellular biology;Cessation of life;Clinical Research;Clinical Trials;Collaborations;Competence;Cytoprotection;Diabetes Mellitus;Effectiveness;Engraftment;Environment;Flow Cytometry;Funding;Gases;Goals;Heart;Heart failure;Human;Hypoxia;Infarction;Inflammatory;Instruction;Insulin Resistance;Investigation;Ischemia;Knowledge;Lead;Left Ventricular Remodeling;Length;Manuscripts;Mediating;Molecular;Motivation;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Natural regeneration;Nitric Oxide;Non-Insulin-Dependent Diabetes Mellitus;Operative Surgical Procedures;Outcome;Pathology;Patients;Phenotype;Play;Positioning Attribute;Progress Reports;Property;Proteins;Proto-Oncogene Protein c-kit;Recording of previous events;Regulation;Reperfusion Injury;Research Infrastructure;Research Personnel;Resistance;Role;Signal Pathway;Signal Transduction;Stem cells;Stress;TNF gene;TNFRSF1A gene;TNFRSF1B gene;Testing;Therapeutic;Therapeutic Uses;Tissues;Translating;Translations;Transplantation;Treatment Efficacy;Work;abstracting;adrenergic;base;cardiac repair;clinical investigation;cytokine;diabetic;experience;improved;insight;paracrine;programs;repaired;response;stem

public_health_relevance:
RELEVANCE (See instructions): In 2009 we started SCIPIO the first-in-humans study of c-kit+ cardiac progenitor cells (CPCs). The initial results are encouraging. This Program builds on SCIPIO and seeks to optimize the effectiveness of these promising CPCs therapies. If our hypotheses are confirmed the results will lead to the use of more efficacious cell therapies in patients with heart failure. Since we have developed the infrastructure to launch new clinical studies of CPCs any new insights gained in this Program will be rapidly translated.


application_id: 8847282
project_number: 5K23AR060275-04
project_title: Clinical and Biochemical Predictors of Outcome after Knee Injury in Young Patient
administering_ic: NIAMS
award_notice_date: 2015-01-25
opportunity_number: PA-10-060
application_type: 5
activity_code: K23
ic: AR
serial_number: 060275
program_official: WASHABAUGH, CHARLES H
project_start_date: 2012-03-05
project_end_date: 2016-02-29
study_section: Arthritis and Musculoskeletal and Skin Diseases Special Grants Study Section[AMS]
contact_pi_person_id: 9042382
contact_pi: LATTERMANN, CHRISTIAN
other_pis: Not Applicable
congressional_district: 06
department: ORTHOPEDICS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Posttraumatic osteoarthritis is an acknowledged outcome of contact-related sports injuries but is an underestimated and understudied problem occurring after non-contact rupture of the anterior cruciate ligament (ACL).  It is estimated that approximately 40-50% of young athletes are at significant risk for developing progressive osteoarthritis (OA) 10-20 years after ACL injury suffered during high school sports participation. Unfortunately reliable predictors of which athletes are at highest risk for developing OA after ACL injury do not exist.   We propose to establish for the first time baseline serum measures of specific biomarkers in 350 injury- free adolescent high school athletes before during and after their competitive season (Aim 1). We will follow this cohort of subjects prospectively for 4 years. Simultaneously we will study a second age- matched cohort of young high school athletes with documented ACL tears. Biomarkers will be measured in these subjects post-injury until biomarker values normalize.  These subjects will be followed for two years post-operatively using patient reported outcome (PRO) instruments. We hypothesize that biomarker levels will increase after ACL injury relative to a normative population. In addition we hypothesize that biomarkers will be highest in subjects with more severe bone bruising after ACL injury (Aim 2).  Finally we will determine outcomes of subjects with severe bone bruises following ACL injury (Aim 3). The presence of bone bruise is not known to be a predictor of posttraumatic OA and lower clinical outcomes scores however bone bruises have been implicated in the progression of osteoarthritis after ACL injury. We will examine if any correlation exists between the magnitude distribution or severity of bone bruise lower patient reported outcomes and evidence of posttraumatic OA initiation at 2 year follow-up. We will also re-examine pre-operative MRI scans pre and post-operative standardized  x-ray and patient reported outcomes followed over 2 years (with a follow-up rate of 85%) in a  prospective longitudinal cohort of 112 isolated ACL injured patients with no additional comorbidities.   Typically 90-100% of these patients may be expected to have a bone bruise after ACL injury.   The impact of these studies is expected to be significant. The identification and validation of biomarkers with and without supporting correlating data from the extent of bone bruise associated with ACL rupture  will provide clinicians with the means to identify adolescents at high risk for the development of  disabling and crippling posttraumatic osteoarthritis and tailor treatment and rehabilitation protocols  that may prevent or delay early onset osteoarthritis in this vulnerable population.

project_terms:
Adolescent;Age;Anterior Cruciate Ligament;Arthritis;Athletic Injuries;Biochemical;Biological Markers;Bone Injury;Cartilage;Cartilage injury;Characteristics;Clinical;Comorbidity;Contusions;Data;Degenerative polyarthritis;Development;Elderly;Employee Strikes;Enrollment;Film;Goals;Image Analysis;Individual;Injury;Knee;Knee Injuries;Lead;Lesion;Location;Lower Extremity;MRI Scans;Magnetic Resonance Imaging;Measures;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Pattern;Physiologic pulse;Population;Postoperative Period;Protocols documentation;Recommendation;Regimen;Rehabilitation therapy;Relative (related person);Reporting;Risk;Seasons;Serum;Severities;Sports;Testing;Time;Universities;Validation;Visual;Vulnerable Populations;Work;anterior cruciate ligament rupture;articular cartilage;bone;cohort;design;disability;early onset;follow-up;high risk;high school;individualized medicine;injured;instrument;ligament injury;mammalian COMP;prevent;prospective;young adult

public_health_relevance:
Non-contact injuries to the knee in the young are becoming prevalent at an alarming rate as participation in high school sports increases. Anterior cruciate ligament (ACL) injuries with bone bruises may hasten cartilage loss predisposing some individuals to early onset osteoarthritis. This study investigates the ability of a serum biomarkerand magnetic resonance imaging to predict (separately or in combination) progressive unremitting cartilage loss in high school athletes at the time of ACL injury. The result of this study may significantly impact the design and implementation of new better treatment and rehabilitation protocols in these young athletes.


application_id: 8847232
project_number: 5R01CA172379-03
project_title: Novel resveratrol analogs and colorectal cancer treatment
administering_ic: NCI
award_notice_date: 2015-04-28
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 172379
program_official: EMENAKER, NANCY J
project_start_date: 2013-08-06
project_end_date: 2016-05-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7013090
contact_pi: LIU, CHUNMING
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): Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States and accounts for more than 50000 deaths per year. CRC is initiated by mutations of adenomatous polyposis coli (APC) and b-catenin genes which result in abnormal activation of the Wnt signaling pathway. Inhibition Wnt signaling is essential for CRC prevention and treatment; however prior efforts along these lines were not successful because of the side effects displayed by these inhibitors. We hypothesize that natural products and their analogs are ideal therapeutic agents if they target key pathways in CRC and possess minimal toxicity. Recently we reported that resveratrol which is found in the skin of red grapes significantly inhibits Wnt signaling. Resveratrol is reported to have anti-cancer activity and not toxic at concentration (1 gram/day) effective for CRC treatment but resveratrol has a half-life in vivo that limits its utility as a therapeutic agent. Supported by anR21 grant (RCA139359) we designed and synthesized resveratrol analogs called FlDAS agents that are more potent than resveratrol in cell based assays and possess significantly greater half-lives than reservatrol. One particular compound FlDAS-4r inhibits growth of human CRC xenografts in nude mice and is well tolerated in mice. Using a biotinylated biologically active form of FIDAS-4r we identified methionine adenosyltransferase 2A (MAT2A) as the direct target for resveratrol analogs. Our central hypothesis is that resveratrol and its analogs inhibit MAT2A and regulate the levels and metabolism of S-adenosylmethionine (SAM) thus inhibiting Wnt signaling and the proliferation of CRC cells. To further define the molecular mechanism of these anti- cancer agents and to develop these agents for CRC treatment and chemoprevention we will pursue the following three Specific Aims: 1) To define the mechanisms regulating inhibition of MAT2A by FIDAS agents; 2) To delineate the mechanisms of how FIDAS agents inhibit CRC cell growth; and 3) To characterize novel FIDAS agents using in vivo mouse models.

project_terms:
APC gene;Accounting;Adenomatous Polyposis Coli;Adverse effects;Affect;Anabolism;Animal Model;Antineoplastic Agents;Binding (Molecular Function);Biological;Biological Assay;Biological Factors;Biological Process;CTNNB1 gene;Cancer Cell Growth;Cancer Etiology;Cell Proliferation;Cell model;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Colorectal Cancer;Development;Disclosure;Drug Targeting;Epigenetic Process;Event;Family;Funding;Future;Generations;Genes;Genetic Transcription;Genetically Engineered Mouse;Goals;Grant;Grapes;Growth;Half-Life;Human;Hypermethylation;In Vitro;Lead;Legal patent;Malignant Neoplasms;Malignant neoplasm of liver;Mediating;Metabolism;Methionine;Modeling;Molecular;Molecular Target;Mortality Vital Statistics;Mus;Mutation;Neoplasms;Nude Mice;Organoids;Pathway interactions;Patients;Polyamines;Promotor (Genetics);Publications;Reporting;Resveratrol;Role;S-Adenosylmethionine;Signal Pathway;Signal Transduction;Skin;Testing;Therapeutic;Therapeutic Agents;Toxic effect;United States;Xenograft procedure;analog;base;cancer cell;cancer prevention;cancer therapy;colon carcinogenesis;colorectal cancer prevention;design;drug candidate;efficacy testing;histone methylation;in vivo;inhibitor/antagonist;methionine adenosyltransferase;mouse model;novel;public health relevance;research study;trans-resveratrol;tumor metabolism;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer death in the United States. Resveratrol and its novel analogs are promising agents for colorectal cancer prevention and treatment. This project will explore novel mechanisms of action of resveratrol analogs using cell and animal models of colorectal cancer in order to develop better chemopreventive and therapeutic agents in the future.


application_id: 8846739
project_number: 7R01NS079507-03
project_title: Blood-brain barrier function in epilepsy: new targets for therapy
administering_ic: NINDS
award_notice_date: 2014-05-14
opportunity_number: PA-11-260
application_type: 7
activity_code: R01
ic: NS
serial_number: 079507
program_official: WHITTEMORE, VICKY R
project_start_date: 2012-09-30
project_end_date: 2017-07-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 9358186
contact_pi: BAUER, BJOERN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is a lack in understanding the mechanism responsible for blood-brain barrier dysfunction in epilepsy. This is a significant clinical challene since it prevents development of a therapy to overcome antiepileptic drug (AED) resistance and reduce seizure burden. Our long-term goal is to elucidate the mechanisms that regulate blood-brain barrier function which may lead to new strategies to treat epilepsy and other neuro- logical diseases. The objectives in this application are to identify the mechanism(s) by which seizures trig- ger barrier dysfunction and map key signaling proteins that can potentially serve as targets to reverse such dysfunction in epilepsy. Accomplishing these objectives is expected to increase AED brain uptake and reduce seizure burden. Our central hypothesis is that 1) glutamate activates the two-arm LOX/COX pathway thereby decreasing expression and activity of influx transporters and upregulating expression and activity of efflux transporters through theCOX arm that 2) glutamate triggers development of barrier leakage through the LOX arm; and that 3) inhibiting cPLA2 to block both arms of the LOX/COX pathway reverses barrier dysfunction and thereby reduces seizure burden. The rationale for this research is that identifying the mechanism(s) responsible for changes in transporter expression and activity and barrier leakage will potentially provide new targets to improve epilepsy treatment and better control seizures. To accomplish the objectives of this application our hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism of seizure-induced changes of transporter expression and activity; 2) deter- mine the mechanism of seizure-induced blood-brain barrier leakage; and 3) develop a therapeutic strategy to reduce seizures in chronic epileptic rats. In Aim 1 we will block cPLA2 and COX-2 to reverse seizure- induced changes in transporter expression and activity. We will monitor influx and efflux transporter ex- pression and activity and determine AED brain uptake. In Aim 2 we will inhibit cPLA2 and 5-LOX to map the signaling pathway causing seizure-induced barrier leakage. We will determine expression of tight junc- tion proteins and matrix metalloproteases and assess barrier leakage. In Aim 3 we will evaluate the ther- apeutic benefit of cPLA2 inhibition on seizure burden in a rat chronic epilepsy model by determining influx and efflux transporter expression and activity assessing barrier leakage and monitoring seizure frequen- cy duration and severity. The proposed research is innovative because it is focused on a new integrated strategy that considers blood-brain barrier transporters as well as barrier leakage and it is designed spe- cifically to revers barrier dysfunction to overcome AED resistance and reduce seizures. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with AED-resistant epilepsy. The proposed research is translational because cPLA2 inhibitors are under development and our strategy has potential to be translated into the clinic.

public_health_relevance:
The proposed research is relevant to public health because it will significantly advance our understanding of blood-brain barrier function in neurological diseases and potentially provide new treatment opportunities for epilepsy. Thus the proposed research is relevant to the mission of the NIH/NINDS which is to develop fundamental knowledge that will help reduce the burden of neurological diseases in people worldwide.


application_id: 8846598
project_number: 5U01ES015673-11
project_title: Novel Therapies for Chlorine-Induced Lung Injury
administering_ic: NIEHS
award_notice_date: 2015-07-31
opportunity_number: PAR-10-180
application_type: 5
activity_code: U01
ic: ES
serial_number: 015673
program_official: NADADUR, SRIKANTH
project_start_date: 2006-09-29
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-MDCN-J(50)R]
contact_pi_person_id: 2736750
contact_pi: HOYLE, GARY W.
other_pis: Not Applicable
congressional_district: 03
department: PUBLIC HEALTH & PREV 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 PUBLIC HEALTH
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlorine gas is a highly toxic respiratory irritant that is considered a chemical threat agent. The goal of the research proposed in this renewal application is to develop a medical countermeasure to treat lung injury induced by chlorine inhalation. During the previous U01 award a mouse model of chlorine gas inhalation was developed a detailed characterization of lung injury following chlorine exposure was performed signaling pathways representing possible targets for therapeutic intervention were investigated strategies for manipulating signaling pathways of interest were tested and compounds that significantly inhibited lung injury or inflammation in chlorine-exposed mice were identified. Rolipram a type 4 phosphodiesterase inhibitor was shown to stimulate alveolar fluid transport decrease pulmonary edema and inhibit airway hyperreactivity. Triptolide a diterpenoid anti-inflammatory compound inhibited chlorine-induced lung inflammation. In the present application formulations of rolipram and triptolide will be developed for intramuscular (i.m.) injection a preferred delivery route for potential mass casualty situations. In addition methylprednisolone an FDA-approved anti-inflammatory compound will be evaluated as an alternative to triptolide. The overall hypothesis to be tested is that i.m. injection of an encapsulated formulation of rolipram in combination with an anti-inflammatory compound will represent the most effective countermeasure for chlorine-induced lung injury. Countermeasure formulations will be tested in mice to determine efficacy against chlorine-induced acute lung injury to assess longer term effects on airway remodeling and airway hyperreactivity and to measure the length of effective post-exposure treatment window. The most effective countermeasure formulation will be evaluated in rabbits to demonstrate efficacy in a non-rodent animal model. An optimized countermeasure formulation with efficacy against chlorine-induced lung injury in mice and rabbits will be subject to additional studies necessary for progression toward regulatory approval including collection of pharmacokinetic/pharmacodynamic and toxicity data and production of the countermeasure using current good manufacturing practices.

project_terms:
Affect;Alveolar;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Award;Breathing;Chlorine;Collection;Data;Development;Diterpenes;Drug Formulations;Drug Kinetics;Encapsulated;FDA approved;Gases;Goals;Human;Inflammation;Intramuscular Injections;Irritants;Length;Liquid substance;Long-Term Effects;Lung Inflammation;Lung Injury Acute;Maximum Tolerated Dose;Measures;Medical;Methylprednisolone;Mus;No-Observed-Adverse-Effect Level;Oryctolagus cuniculus;Pathway interactions;Pharmacodynamics;Phosphodiesterase Inhibitors;Poisons;Principal Investigator;Production;Pulmonary Edema;Research;Research Institute;Rodent;Rolipram;Route;Signal Pathway;Testing;Therapeutic Intervention;Toxic effect;Universities;airway hyperresponsiveness;airway remodeling;chemical threat;chemokine;chlorine gas;efficacy testing;interest;lung injury;mass casualty;mouse model;neutrophil;novel;pre-clinical;prevent;public health relevance;research study;respiratory;triptolide

public_health_relevance:
Public Health Relevance: The goal of the proposed experiments is to develop novel ways to treat acute lung injury caused by chlorine gas inhalation. The research will focus on medical countermeasures that can be easily and rapidly administered in a mass casualty situation. This type of research is important because of concerns that U.S. civilians could be adversely affected by the accidental or intentional release of highly toxic chemicals.


application_id: 8846567
project_number: 5R01DC007176-11
project_title: Neurotrophin Regulation of Taste System Development
administering_ic: NIDCD
award_notice_date: 2015-05-12
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: DC
serial_number: 007176
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2016-07-07
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)M]
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): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. Brain-derived neurotrophic factor (BDNF) regulates both the number and location of gustatory innervation during embryonic development. Our current research is designed to determine if and/or how these connections are important for central gustatory development or taste function and whether BDNF regulates development of the postnatal taste system. The proposed studies combine cell counting tract tracing immunohistochemistry electrophysiology and behavioral testing in conditional and inducible transgenic mice to: 1) determine if BDNF influences postnatal changes in geniculate ganglion and taste bud development 2) determine if embryonic or postnatal BDNF is important for central terminal field organization and 3) determine if embryonic or postnatal BDNF is important for adult gustatory function. Together these studies test the hypotheses that: 1) embryonic BDNF determines the number of neurons innervating a taste bud and taste buds increase in size to meet that number postnatally. 2) CNS terminal field formation is regulated by BDNF and the specificity of peripheral connections. 3) Gustatory sensitivity is reduced but that the taste system still functions despite wide-scale reorganization. These studies will determine how early peripheral innervation patterns influence continued development and function of the taste system. In addition we will determine whether BDNF is required for postnatal gustatory development. Because these experiments examine how neurotrophin regulation of sensory innervation influences continued development and adult function this project has important implications for the potential therapeutic use of these powerful signaling molecules in re-establishing gustatory function following neuronal impairment.

project_terms:
Adult;Attention;Birth;Brain-Derived Neurotrophic Factor;Cell Count;Chemicals;Development;Electrophysiology (science);Embryo;Embryonic Development;Epithelium;Excision;Goals;Health;Homeostasis;Immunohistochemistry;Impairment;Individual;Lead;Location;Mus;National Institute on Deafness and Other Communication Disorders;Nerve;Neurons;Oral cavity;Pattern;Peripheral;Peripheral Nervous System Diseases;Persons;Physiological;Process;Quality of life;Recovery;Regulation;Research;Sensory;Signaling Molecule;Specificity;Stimulus;Structure of geniculate ganglion;Systems Development;Taste Buds;Taste Disorders;Taste Perception;Testing;Therapeutic;Therapeutic Uses;Tongue;Transgenic Mice;Visit;behavior test;chorda tympani;critical period;design;meetings;nerve supply;neurotrophic factor;overexpression;postnatal;preference;research study;response;taste stimuli;taste system

public_health_relevance:
Taste disorders can have detrimental effects on a person's health and quality of life. According to NIDCD more than 200000 people visit a doctor each year for problems with their chemical senses including taste. The underlying mechanism of many gustatory disruptions is not well understood. As a result much emphasis has been placed on a basic understanding of the taste bud. However the neurons innervating taste buds receive little attention and are also required for normal gustatory function. Some adult gustatory disruptions may result from an alteration in factor(s) regulating gustatory system innervation both during development and as a part of normal adult homeostasis. Peripheral neuropathies are relatively common and frequently accompany other illnesses. A basic understanding of the factors that are required to promote innervation during development and possibly maintain it in adulthood may lead to therapeutic approaches that allow taste recovery following its loss.


application_id: 8846086
project_number: 5K08DA032296-05
project_title: African American Offenders: Drug Use Mental Health and HIV Risk
administering_ic: NIDA
award_notice_date: 2015-04-22
opportunity_number: PA-11-193
application_type: 5
activity_code: K08
ic: DA
serial_number: 032296
program_official: JONES, DIONNE
project_start_date: 2012-05-01
project_end_date: 2016-04-30
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 10667839
contact_pi: STEVENS-WATKINS, DANELLE J
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  The primary goal of this K08 award is to further develop a productive independent research career in drug abuse research. The training and career development plan will enhance Dr. Stevens-Watkins's research experience in primary data collection with prisoners focused on drug use mental health and HIV thus resulting in the clarification of the specific aims of an R01 submission in years 4 and 5. The proposed training objectives are: (1) to receive training in the epidemiology of drug abuse mental health and HIV as they relate to health disparities among African Americans; (2) to further develop expertise in research with special populations biostatistics and advanced quantitative analyses including non-linear categorical models and structural equation modeling; (3) to use the data collected in the proposed research plan as pilot data for an R01 research proposal. The specified training goals are aligned with the research aims and compliment the clinical experience of the candidate. Dr. Stevens-Watkins will be sponsored by her established mentors Drs. Carl Leukefeld and Carrie Oser both with expertise in drug abuse and HIV research. Of high significance HIV has recently been termed a "crisis" in the African American community. The overall goal of the proposed research plan is to better understand the complex and dynamic relationship between drug use mental health and HIV risk among African American male prisoners nearing community re-entry. The specific aims are (1) to explore drug use symptoms of depression and anxiety and HIV risk behaviors among African American male inmates by conducting a thorough literature review and devising an analytical model using biostatics multivariate analytic techniques with available data; (2) to identify prevalence incidence and predictors of drug use disorders anxiety depressive disorders and HIV sexual risk behaviors among 205 incarcerated African American men; (3) to examine the knowledge patterns and perceived cultural and community barriers to utilizing individual and health resources and their relationship to substance abuse recovery and HIV risk behaviors among 205 African American men upon release from prison. Baseline data will be collected in prison and follow-up data collection will occur when participants have been released in the community after 3-months. The proposed research plan will offer HIV testing and counseling to an at-risk population that has historically been difficult to engage in research and HIV testing subsequently significantly impacting public health by possibly preventing the spread of HIV. The candidate's immediate career goals include published manuscripts and R01 funding by the end of K08 funding with an ultimate career goal of becoming an independent clinical drug abuse researcher. This proposal includes an outstanding mentoring team as well as a feasible training and research plan utilizing resources offered by both Spalding University and the University of Kentucky.

project_terms:
African American;Anxiety;Award;Biometry;Career Choice;Chronic;Clinical;Communities;Complex;Counseling;Data;Data Analyses;Data Collection;Depressive disorder;Development Plans;Drug Use Disorder;Drug abuse;Drug usage;Environment;Epidemiology;Equation;Funding;Goals;HIV;HIV Infections;HIV risk;Health;Health Resources;Housing;Human immunodeficiency virus test;Imprisonment;Incidence;Individual;Intervention;Interview;Kentucky;Knowledge;Life;Manuscripts;Mediating;Mental Depression;Mental Health;Mental Health Services;Mentors;Methods;Modeling;Outcome;Participant;Pattern;Phase;Populations at Risk;Pre-Post Tests;Prevalence;Prisoner;Prisons;Process;Protocols documentation;Psychologist;Publishing;Recording of previous events;Recovery;Research;Research Personnel;Research Proposals;Research Training;Resources;Review Literature;Risk;Risk Behaviors;Social support;Specific qualifier value;Structural Models;Substance abuse problem;Techniques;Testing;Training;Universities;Unsafe Sex;Writing;anxiety symptoms;career;career development;community reentry;correctional system;depressive symptoms;drug testing;experience;follow-up;health care service utilization;health disparity;high risk;high risk sexual behavior;impression;improved;intravenous drug use;male;men;men who have sex with men;named group;offender;prevent;psychologic;public health medicine (field);public health research;racism;sex risk

public_health_relevance:
The proposed project has significant public health implications for reducing the spread of HIV among the African American community by offering testing and by targeting men exiting prison re-entering the community. The proposed project will generate an improved understanding of the complex relationship between drug use mental health and HIV risk among an at-risk group.


application_id: 8845555
project_number: 5T35ES014559-10
project_title: Summer Environmental Health Sciences Training Program
administering_ic: NIEHS
award_notice_date: 2015-03-31
opportunity_number: PA-10-037
application_type: 5
activity_code: T35
ic: ES
serial_number: 014559
program_official: SHREFFLER, CAROL A
project_start_date: 2006-04-01
project_end_date: 2016-03-31
study_section: Environmental Health Sciences Review Committee[EHS(TK)]
contact_pi_person_id: 1886009
contact_pi: PROUGH, RUSSELL ALLEN
other_pis: MCCLAIN, CRAIG J.;SRIVASTAVA, SANJAY
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant)      This NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is to request support for 6 medical student trainees for the next 5 years. The overarching scientific theme of research that links the faculty to this T35 Training Grant is the common interest in research training of medical students in their laboratories in elucidating the health outcomes of exposure of obese individuals to various environmental or common chemicals in the environment. The faculty mentors involved come from the Department of Biochemistry & Molecular Biology (Klinge Prough and Ramos) Department of Medicine Division of Cardiovascular Medicine (Bhatnagar Conklin Prabhu and Srivastava) Division of Pulmonary Medicine (Roman Chair of Medicine) and Division of Gasteroenterology (Barve Cave Joshi-Barve and McClain) Department of Pharmacology & Toxicology (Arteel Hein and States) Department of Occupational and Environmental Health Sciences School of Public Health and Information Sciences (Hoyle and Tollerud) and Molecular Cellular & Craniofacial Biology Birth Defects Research Center School of Dentistry (Pisano).  Most are funded from the NIEHS or grants that support research directly relevant to environmental health sciences. The NIEHS Center directed by Ken Ramos encourages faculty to compete for more NIEHS grants through career development and pilot project grants to the junior and senior faculty respectively. The proposal contains two specific aims.      Specific aim 1: To provide hands-on training in basic and clinical environmental health sciences- based research to medical students in a structured mentored environment.      Specific Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical environmental health sciences-based research.      The principal objectives of the Summer Environmental Health Sciences Research Training Program are to provide research experience for medical students and to stimulate interest among medical students in becoming clinical research scientists. Students who engage in research activities with faculty members will participate in projects germane to the field of environmental health and the health concerns of this country. The program includes didactic instruction (Syllabus for the "Summer Environmental Health Sciences Research Training Seminar Series"; Syllabus for the "Bench to Bedside Course") as well as a hands-on- research experience directed by experienced scientists interested in environmental medicine.

project_terms:
Biochemistry;Biology;Cardiovascular system;Chemicals;Clinical;Clinical Research;Congenital Abnormality;Country;Environment;Environmental Health;Environmental Medicine;Faculty;Funding;Grant;Health;Health Sciences;Individual;Information Sciences;Instruction;Laboratories;Link;Medical Students;Medicine;Mentors;Molecular;Molecular Biology;National Institute of Environmental Health Sciences;Obesity;Occupational Health;Outcome;Pharmacology and Toxicology;Pilot Projects;Pulmonary Disease (Specialty);Research;Research Activity;Research Support;Research Training;School Dentistry;Schools;Scientist;Series;Structure;Students;Training;Training Programs;base;bench to bedside;career development;craniofacial;experience;health science research;interest;member;programs;skills

public_health_relevance:
Program Director/Principal Investigator (Last First Middle): Prough Russell AllenProgram Narrative: This NIEHS Short-Term Institutional Training Grant (5T35ES014559) application is torequest annual support for 6 medical student trainees for a 12 week training experience for the next 5 years.The overarching scientific theme of research that links our faculty to this T35 Training Grant is the commoninterest in research training of Medical Students in our laboratories in elucidating the health outcomes ofexposure of obese individuals to various environmental or common chemicals in the environment. We believethat this training experience will shape our medical student trainees to consider a career in areas ofenvironmental medicine.PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 8845506
project_number: 5R37AI052218-14
project_title: In vitro glycorandomization of natural products
administering_ic: NIAID
award_notice_date: 2015-05-11
opportunity_number: PA-11-260
application_type: 5
activity_code: R37
ic: AI
serial_number: 052218
program_official: DAVIS, MINDY I
project_start_date: 2002-06-03
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1-BCMB-B(02)M]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The attachment of sugars to naturally-occurring and/or synthetic small molecules can dramatically influence the corresponding mechanism pharmacodynamics pharmacokinetics and even patent life of the parental structure. Yet due to the technical challenges associated with conventional glycosylation strategies the application of glycosylation in the context of drug discovery and/or development remains underexplored. An overarching aim of this program has been to develop simple and user-friendly chemoenzymatic methods for the differential glycosylation of target scaffolds to ultimately enable such drug discovery/development exploration. Toward this goal the first phase of this study (years 1-5) led to the key proof of concept for  chemoenzymatic glycorandomization (a one pot three enzyme strategy capable of activating and attaching free monosaccharides to complex natural product scaffolds) and also provided fundamental information regarding two critical but poorly understood enzyme classes (anomeric sugar kinases and sugar-1-phosphate nucleotidylyltransferases). The second phase of this project (years 6-10) dramatically expanded the attempted application of this first generation system toward a range of diverse scaffolds leading to success in many cases but also exposing key limitations of the platform. Importantly the work conducted during the second phase also led to fundamental new knowledge regarding glycosyltransferase (GT)-catalyzed reactions that serves as the basis from which to launch the third phase of this study. Specifically the proposed third phase of this study (years 11-15) takesadvantage of our recent abilities to evolve highly permissive GTs and also drive GT-catalyzed reactions in reverse to enable next generation single enzyme or dual enzyme transglycosylation strategies for differential glycosylation of an array of structurally-diverse scaffolds (including natural product-based or synthetic glycosylated or non-glycosylated parental scaffolds). We propose to take full advantage of the current state of the art to: i) narrow the gaps of knowledge in understanding functional GT structure-activity-relationships; ii) specifically develop a range o catalysts for the production of novel sugar nucleotides (anticipated to be of broad use to the glycobiology community); iii) develop a range of catalysts for the differential glycosylation of a key set of structurally diverse anti-infective and anticancer scaffolds; and iv)exploit the corresponding differentially glycosylated scaffolds as a novel source for the discovery of new antiinfective  and anticancer leads.

project_terms:
Amino Acids;Anti-Bacterial Agents;Anti-Infective Agents;Antiviral Agents;Automobile Driving;Biological;Biological Assay;Biological Factors;Bufadienolides;Cardenolides;Catalysis;Cell Proliferation;Chemistry;Ciprofloxacin;Collaborations;Communities;Complement;Complex;Daptomycin;Development;Drug Kinetics;Enzymes;Equilibrium;Evaluation;Evolution;Generations;Glucose;Glycobiology;Glycosides;Goals;In Vitro;Investments;Knowledge;Legal patent;Libraries;Life;Macrolides;Methods;Minocycline;Modeling;Monosaccharides;Mutagenesis;National Institute of Allergy and Infectious Disease;Novobiocin;Nucleotides;Pharmacodynamics;Phase;Phosphotransferases;Positioning Attribute;Predisposition;Production;Pyrimidine;Reaction;Reagent;Sirolimus;Source;Specificity;Structural Models;Structure;Structure-Activity Relationship;System;Thymidine;Toxic effect;Uridine;Ursidae Family;Variant;Vertebral column;Work;analog;anticancer activity;base;bufadienolide;catalyst;design;design and construction;directed evolution;drug development;drug discovery;functional group;glycosylation;glycosyltransferase;innovation;inorganic phosphate;liquid chromatography mass spectrometry;member;next generation;novel;pathogen;pre-clinical;progenitor;programs;research study;scaffold;screening;small molecule;success;sugar;sugar nucleotide;tool;user-friendly

public_health_relevance:
We propose to develop simple and user-friendly chemoenzymatic methods for the differential glycosylation of complex target scaffolds to enable glycoconjugation as a tool for drug discovery and development. The models selected as part of the current study are anticipated to hold particularly high potential for the discovery of new antibacterial antiviral and anticancer leads.


application_id: 8845445
project_number: 5R24MD008018-03
project_title: Appalachians Together Restoring the Eating Environment (APPAL-TREE)
administering_ic: NIMHD
award_notice_date: 2015-04-09
opportunity_number: RFA-MD-12-006
application_type: 5
activity_code: R24
ic: MD
serial_number: 008018
program_official: CASTILLE, DOROTHY M
project_start_date: 2013-05-01
project_end_date: 2017-04-30
study_section: ZMD1-RN(07)
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): identified as a key priority population by the NIMHD the Appalachian counties of Kentucky suffer from some of the nation's highest rates of obesity and overweight lowest rates of produce consumption and high rates of premature mortality and diet-related diseases such as diabetes heart disease and various cancers. With the main partnership of three community-based organizations - the Community Farm Alliance (a community development organization designed to improve food production systems). Faith Moves Mountains (a community-based research team with ten years of culturally-based intervention experience) and the Big Sandy Area Development District (a well-respected network that plans promotes and coordinates programs for regional economic health and social development of Appalachia) - and with extensive input from the Community Advisory Board (CAB) faith partners and Cooperative Extension this community-academic partnership proposes to address the most modifiable risk factor for these main causes of morbidity and mortality: suboptimal diet. In this three-year planning grant the community-academic collaboration will undertake three specific aims and associated activities. In Aim 1 the project team will conduct a community needs assessment and assets inventory hold community forums to present this information and meet regularly with the community partners and CAB. The nutrition and agricultural economic co-investigators will partner with the community research team to use innovative and established methods including GIS mapping focus groups and nutritional and economic assessment techniques. In Aim 2 community forums CAB meetings and collaborative engagement sessions among project partners will facilitate the selection and initiation of an evidence-based pilot intervention to promote better nutrition emphasizing food access particularly fruits and vegetables. In Aim 3 the community-academic collaborative will implement and evaluate this pilot intervention tracking nutritional outcomes participant satisfaction and costs and reporting results to Appalachian community members.       RELEVANCE: By addressing one of the nation's leading public health challenges - poor diet leading to overweight/obesity and subsequent health impacts - in a region (Appalachian Kentucky) suffering extreme disparities in diet and diet-related disease this project will develop implement and evaluate a comprehensive approach to dietary change by increasing access to healthy foods.

project_terms:
Address;Advocate;Agriculture;Americas;Appalachian Region;Area;Behavior;Benefits and Risks;Cause of Death;Chronic;Collaborations;Communities;Community Developments;Complex;Consumption;County;Development;Diabetes Mellitus;Diet;Dietary intake;Disease;Eating;Economics;Educational aspects;Effectiveness;Environment;Equipment and supply inventories;Evaluation;Evidence based intervention;Experimental Designs;Farming environment;Focus Groups;Food;Food Access;Food Safety;Frequencies (time pattern);Grant;Health;Health Food;Health Status;Health care facility;Heart Diseases;Improve Access;Individual;Institute of Medicine (U.S.);Institution;Intervention;Kentucky;Link;Malignant Neoplasms;Maps;Measures;Methods;Minority Groups;Mission;Morbidity - disease rate;Mortality Vital Statistics;Needs Assessment;Nutritional;Obesity;Outcome;Overweight;Participant;Pattern;Population;Premature Mortality;Principal Investigator;Process;Production;Publications;Reporting;Research;Research Personnel;Resources;Risk Factors;Social Development;Socioeconomic Status;System;Techniques;Testing;United States;base;community intervention;community organizations;cost;design;evidence base;experience;farmer;food environment;fruits and vegetables;health disparity;health economics;improved;innovation;meetings;member;modifiable risk;nutrition;programs;public health medicine (field);risk perception;safety net;satisfaction;therapy design


application_id: 8843837
project_number: 5R01DK093462-05
project_title: Role of Ceramide-induced Kidney Cell Death in Acute Kidney Injury
administering_ic: NIDDK
award_notice_date: 2015-04-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 093462
program_official: SADUSKY, ANNA BURKART
project_start_date: 2012-09-17
project_end_date: 2017-04-30
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 6769757
contact_pi: SISKIND, LEAH J
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a devastating disease with a high mortality rate. Apoptosis and necrosis play major roles in AKI but there is a fundamental knowledge gap of the factors regulating their induction in AKI. Continued existence of this gap represents a significant problem as AKI has a high mortality rate and there are very few therapeutic interventions to alter the clinical course of this disease. The long-term goal is t uncover mechanisms involved in AKI for the development of novel therapeutics to protect the kidney. Ceramides regulate apoptosis and necrosis and are elevated in the kidney in several models of AKI. The factors that regulate production of ceramides during kidney apoptosis and necrosis and whether ceramides lead to apoptotic versus necrotic kidney cell death are completely unknown. Likewise there are many different ceramide species and the roles for particular ceramide species in AKI have not been determined. This proposal will answer these questions to achieve the objective of developing ceramides as novel therapeutic approaches for the treatment of AKI. Preliminary data demonstrate that: (i) long-chain ceramides (C16 - C20- ceramides) are generated via de novo synthesis during kidney cell apoptosis and blocking their generation inhibits apoptosis; (ii) the pro-apoptotic BCL-2 protein BAK is a key regulator of ceramide synthases (CerS) and long-chain ceramide generation during kidney cell apoptosis; (iii) acid sphingomyelinase (aSMase) generated very long-chain ceramides (C24-C26-ceramides) occurs in kidney cell necrosis; (iv) kidney cortical CerS and acid SMase are activated and specific ceramides elevated several-fold in in vivo rodent models of AKI (cisplain nephrotoxicity and rhabdomyolysis-induced AKI); and (v) mice given inhibitors of enzymes responsible for ceramide synthesis are protected from cisplatin-induced AKI. This expanding and developing body of work has led us to propose the following hypothesis: nephrotoxic stimuli elevate specific species of kidney ceramides through CerS and SMase-mediated pathways inducing kidney cell death and ultimately kidney failure. This hypothesis will be tested with threespecific aims: (1) determine the mechanism by which BAK regulates CerS activity and generation of specific long-chain ceramides during kidney cell apoptosis; (2) determine the contribution of SMase-generated ceramide to kidney cell necrosis; and (3) determine the in vivo contribution of CerS and aSMase to cisplatin-induced AKI in mice. The approach is innovative because it will identify the mechanism by which BAK regulates ceramide synthases as well as the specific role of individual ceramide species in vivo in AKI. The proposed research is significant as it advances our current knowledge of mechanisms of kidney cell death AKI. Ultimately such knowledge has the potential to greatly improve the treatment of AKI.

project_terms:
Acids;Acute Renal Failure with Renal Papillary Necrosis;Apoptosis;Apoptotic;BAX gene;BCL-2 Protein;Bioenergetics;Biological Assay;Cell Death;Cells;Ceramides;Cisplatin;Clinical Course of Disease;Data;Development;Disease;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Figs - dietary;Generations;Glycerol;Goals;In Vitro;Individual;Injury;Intervention;Kidney;Kidney Failure;Knockout Mice;Knowledge;Lead;Measures;Mediating;Modeling;Mortality Vital Statistics;Mus;N-palmitoylsphingosine;Necrosis;Nephrotoxic;Pathway interactions;Play;Production;Protein Isoforms;Proximal Kidney Tubules;Research;Rhabdomyolysis;Rodent Model;Role;Sphingolipids;Stimulus;Supportive care;Testing;Therapeutic Intervention;Time;acid sphingomyelinase;base;dihydroceramide desaturase;improved;in vivo;inhibitor/antagonist;innovation;kidney cell;nephrotoxicity;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;public health medicine (field);research study;therapeutic development

public_health_relevance:
This proposal will advance current knowledge of mechanisms of acute kidney injury by identifying factors that regulate generation of specific ceramide speciesduring kidney apoptosis and necrosis. The proposed research is relevant to public health because acute kidney injury has a high mortality rate with very few therapeutic interventions. Thus information gained from the enclosed studies has the potential to improve the treatment of acute kidney injury.


application_id: 8843630
project_number: 7R01HD070792-02
project_title: Indomethacin and delayed umbilical cord clamp for preterm infant IVH
administering_ic: NICHD
award_notice_date: 2014-05-09
opportunity_number: PAR-11-246
application_type: 7
activity_code: R01
ic: HD
serial_number: 070792
program_official: REN, ZHAOXIA
project_start_date: 2013-04-01
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1-EMNR-R(55)R]
contact_pi_person_id: 6654912
contact_pi: GIANNONE, PETER J
other_pis: BAUER, JOHN ANTHONY
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_abstract:
DESCRIPTION (provided by applicant): Intraventricular hemorrhage (IVH) during the neonatal period is a common occurrence in preterm infants and is a well-recognized major contributor to brain injury and related disabilities later in life. Infants who develop severe IVH are at significant risk for developmental disabilities including cerebral palsy and/or major cognitive handicaps. Despite its prevalence long term consequences and enormous medical and social costs mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined. Only one therapy prophylactic indomethacin during the first 3 days of life has consistently been shown to prevent or decrease the severity of IVH in preterm infants but its use is severely limited by the drug's toxic side effects and its controversial efficacy with respect to long-term outcomes. Indomethacin side effects are severe and include gastrointestinal perforation renal toxicity and related organ failure and actual extension of an established intra-cranial bleeding episode. Recent studies suggest that delayed umbilical cord-clamping (DCC) may decrease the incidence of IVH. However at least in the largest study all the infants received prophylactic indomethacin along with delaying of the cord clamp. These two modalities in combination may have advantages with respect to efficacy or safety when compared to prophylactic indomethacin used alone. Our Aims are 1) Compare efficacy and safety of prophylactic indomethacin with vs. without DCC cord clamp in affecting the incidence and severity of IVH in preterm (gestational age <30wks) and 2) Investigate mechanistic interactions of DCC and indomethacin in VLBW infants. This project may improve the safety and use of prophylactic indomethacin and further define the medical value potential mechanisms and optimal implementation strategies for DCC.

public_health_relevance:
Intraventricular hemorrhage (IVH) during the neonatal period is a common occurrence in preterm infants and is a well-recognized major contributor to brain injury and related disabilities later in life including cerebral palsy and/or major cognitive handicaps. Despite its prevalence long term consequences and enormous medical and social costs mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined. Only one therapy prophylactic indomethacin during the first 3 days of life has consistently been shown to prevent or decrease the severity of IVH in preterm infants but its use is severely limited by the drug's toxic side effects and its controversial efficacy with respect to long-term outcomes. In this study we will investigate the potential beneficial effects of delayed umbilical cord clamping on the efficacy and safety of indomethacin in preterm infants. This project may improve the safety and use of prophylactic indomethacin and further define the medical value potential mechanisms and optimal implementation strategies for delayed umbilical cord clamping.


application_id: 8843555
project_number: 5R01NS075871-05
project_title: DNA Nanoparticle Gene Therapy in Brain
administering_ic: NINDS
award_notice_date: 2015-05-14
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 075871
program_official: MORRIS, JILL A
project_start_date: 2011-07-01
project_end_date: 2017-05-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 7875446
contact_pi: YUREK, DAVID M.
other_pis: Not Applicable
congressional_district: 06
department: NEUROSURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed studies will determine the feasibility of compacting plasmid DNA into "nanoparticles" and using these nanoparticles to deliver their payload into cells of the central nervous system (CNS) as a non-viral gene therapy technique. DNA compacting techniques will be used to form nanoparticles containing condensed DNA plasmids with diameters in the range of 8-12 nanometers. In a series of recent publications coming out of our laboratories we have shown that synthetic nanoparticles containing DNA plasmids can be used to transfect brain cells and establish both short- and long-term transgene activities following a single injection of DNA nanoparticles (DNP) directly into brain tissue. These encouraging results have lead us to propose a series of studies to further characterize and test the potential of using synthetic vectors to deliver therapeutic genes to the brain as a possible treatment for neurodegenerative disorders. My laboratory has considerable experience testing neurotrophic factor therapy as well as cellular replacement therapies in animal models of Parkinson's disease (PD) and we propose to examine the feasibility of delivering a gene encoding for the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) to brain cells as a means to protect the brain against neuronal degeneration that occurs in an animal model of PD. The first set of experiments will expand upon our current knowledge of DNP technology. In Specific Aim 1 we will attempt to further optimize plasmids design and mode of intracerebral delivery of compacted DNA nanoparticles (DNPs) and then assess the immunogenicity of this treatment. In the second specific aim we will determine if DNP transfection of the lesion brain is greater than in the intact brain and whether or not the aged brain is more susceptible to DNP transfection than younger brain; this studies will determine if an up-regulation of astrocytes at the site of neurodegeneration actually benefits transfection efficiency of DNPs because our preliminary studies indicate DNPs have a tropism for astrocytes. Finally our third specific aim will determine whether or not intracerebral infusion of modified hGDNF DNPs prevent neurodegeneration of dopaminergic neurons following a neurotoxic lesion of the nigrostriatal pathway. Successful results in these studies could then be applied to animal models of neurodegenerative disorders and possibly lead to translational studies for the treatment of neurological disorders such as Parkinson's disease.

project_terms:
Affect;Age;Animal Model;Animals;Astrocytes;Biodistribution;Brain;Brain region;Caliber;Cells;Corpus striatum structure;DNA;DNA delivery;Data;GDNF gene;Gene Transfer;Genes;Glial Fibrillary Acidic Protein;Human;Incidence;Infusion procedures;Injection of therapeutic agent;Knowledge;Laboratories;Lead;Lesion;Methods;Monitor;Nerve Degeneration;Neuraxis;Neurodegenerative Disorders;Nucleic Acids;Parkinson Disease;Patients;Phase I Clinical Trials;Plasmids;Population;Production;Promotor (Genetics);Proteins;Publications;Rattus;Replacement Therapy;Reporter Genes;Rodent;Series;Site;Structure;Techniques;Technology;Testing;Therapeutic;Time;Transfection;Transgenes;Translating;Tropism;Up-Regulation (Physiology);Viral Vector;Virus;Work;aged;aging brain;brain cell;brain tissue;design;dopaminergic neuron;experience;gene therapy;glial cell line derived neurotrophic factor rat;glial cell-line derived neurotrophic factor;immunogenicity;improved;juvenile animal;nanometer;nanoparticle;nervous system disorder;neurotoxic;neurotrophic factor;nigrostriatal pathway;non-viral gene therapy;novel;particle;plasmid DNA;prevent;research study;response;therapeutic gene;transgene expression;translational study;vector;young adult

public_health_relevance:
The proposed studies will use a novel nanoparticle technology that allows nucleic acids (DNA) to be compacted near their theoretical limit; this technology almost duplicates the compaction efficiency of viruses. We present preliminary data showing proof-of-concept that these nanoparticles can be used as a non-viral gene therapy for transfecting cells in the brain. Successful results from our animal studies could then be translated to human studies using these targeted nanoparticles as a form of non-viral gene therapy to treat various neurological disorders.


application_id: 8843520
project_number: 5R01HL073085-11
project_title: Angiotensin - A link between obesity and hypertension
administering_ic: NHLBI
award_notice_date: 2015-04-09
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 073085
program_official: OH, YOUNGSUK
project_start_date: 2003-06-03
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-VH-F(02)M]
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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): The prevalence of obesity is rising in Kentucky and the nation. Prior to the obesity epidemic hypertension prevalence was lower in females than males until menopause when both obesity and hypertension increase. The most recent NHANES data demonstrate the surprising finding that the prevalence of hypertension is rising at a faster rate in females than males. This competing renewal focuses on mechanisms contributing to obesity-induced hypertension in males versus females a highly significant topic since obesity is a primary cause of hypertension in both genders. We have examined whether an activated adipocyte renin-angiotensin system (RAS) is a link between obesity and hypertension. During the current period we demonstrated that deficiency of adipocyte-derived angiotensinogen (AGT) prevented elevations in adipose and systemic angiotensin II (Ang II) concentrations and abolished the development of hypertension in obese male mice. We also demonstrated that adipocytes express angiotensin converting enzyme 2 (ACE2) which cleaves Ang II to form the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). In male obese hypertensive mice exhibiting increased adipose-derived systemic Ang II adipose ACE2 expression was reduced and systemic Ang-(1-7) concentrations plummeted. These results suggest that reductions in ACE2 in an expanded adipose mass make Ang II the predominant adipose-derived RAS peptide contributing to hypertension in obese male mice. In contrast to males obese female mice were totally resistant to the development of hypertension despite greater adiposity. Remarkably female normotensive obese mice exhibited increased adipose ACE2 activity associated with elevated plasma Ang-(1-7) concentrations. Deficiency of ACE2 converted obese females to a hypertensive phenotype. Removal of ovarian sex hormones reduced adipose ACE2 activity and plasma Ang- (1-7) concentrations and resulted in robust obesity-induced hypertension. Moreover estrogen markedly stimulated ACE2 mRNA abundance in 3T3-L1 adipocytes. We hypothesize that differential regulation of adipocyte ACE2 in obese males versus females determines whether adipose tissue produces Ang II or Ang-(1- 7) in the development of hypertension. Aim 1 tests the hypothesis that adipocyte ACE2 deficiency promotes hypertension in obese female mice while ACE2 activation prevents hypertension in obese males through an adipocyte ACE2-dependent mechanism. Aim 2 tests the hypothesis that estrogen promotes adipocyte ACE2 expression and protects male and ovariectomized female obese mice from hypertension. Aim 3 tests the hypothesis that DIZE-induced ACE2 activation reduces blood pressure in male and ovariectomized female obese hypertensive mice through an Ang-(1-7)/MasR-dependent mechanism. The impact of these studies is definition of mechanisms for the development of hypertension in obese males versus females. We will also develop ACE2 activation as a novel therapy to treat hypertension in obese males and/or menopausal females.

project_terms:
Adipocytes;Adipose tissue;Angiotensin II;Angiotensinogen;Angiotensins;Blood Pressure;Body mass index;Castration;Cleaved cell;Data;Development;Epidemic;Equilibrium;Estrogen Therapy;Estrogens;Excision;Exhibits;Female;Gender;Gonadal Steroid Hormones;Health;Hypertension;Kentucky;Knock-out;Left;Link;Mediator of activation protein;Menopause;Messenger RNA;Modeling;Mus;NHANES;Obese Mice;Obesity;Ovarian;Peptides;Peptidyl-Dipeptidase A;Pharmacotherapy;Phenotype;Plasma;Prevalence;Production;Regulation;Renin-Angiotensin System;Resistance;Source;Testing;Translating;Vasodilator Agents;Women's Rights;angiotensin I (1-7);blood pressure reduction;male;normotensive;novel;novel therapeutics;prevent;receptor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is at epidemic proportions in the US and may eventually overcome previously ascribed protection of females against the development of hypertension. These studies focus on the renin-angiotensin system of adipocytes as a mediator of obesity-hypertension in males versus females. Since obesity is the primary cause of hypertension in the US and the prevalence of hypertension is increasing more rapidly in females than males our studies will define mechanisms for these differences and uncover novel targets for drug therapy.


application_id: 8843414
project_number: 5R01DK074720-08
project_title: Novel hematopoietic effects of C5 cleavage fragment
administering_ic: NIDDK
award_notice_date: 2015-04-17
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DK
serial_number: 074720
program_official: BISHOP, TERRY ROGERS
project_start_date: 2007-03-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-VH-C(02)]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
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): Both pharmacological mobilization of hematopoietic stem progenitor cells (HSPCs) and myeloablative conditioning for transplantation activate the complement cascade (CC) in bone marrow (BM) and in the previous funding period we focused on the role of the third complement component (C3) in mobilization and homing of HSPCs. In this competing renewal we will focus on the fifth complement component (C5) which is located downstream from C3. C5 cleavage leads to generation of the potent anaphylatoxins C5a and desArgC5a and generation of non-lytic and lytic C5b-C9 known as the membrane attack complex (MAC). Our recently published data support a crucial role for C5a/C5b-C9 in trafficking of HSPCs. In particular C5-deficient mice are poor mobilizers in response to granulocyte colony stimulating factor (G-CSF) and exhibit delayed hematopoietic reconstitution after transplantation with wild type (WT) BM cells. Based on these findings the central hypothesis of this competing renewal is that the activation of distal steps of the complement cascade and release of C5a and C5b-C9 (MAC) are important regulators of mobilization and homing of HSPCs. To address this hypothesis we propose: Specific Aim 1. The molecular basis of the mobilization defect in C5-deficient mice. Based on our observation that C5-deficient mice are poor G-CSF mobilizers we will address whether C5 cleavage is i) required for circadian HSPC mobilization ii) mobilization of HSPC induced by other agents and iii) whether C5 activation and S1P plasma level correlates with mobilization efficacy in patients. We will also focus on the role of erythrocyte-released S1P in mobilization by performing mobilization studies in CD55/CD59-deficient mice that are highly sensitive to C5b-C9 (MAC) lysis. Finally we will focus on the role of C5b-C9-induced release of S1P in mobilization observed in patients with hemolytic syndromes. Specific Aim 2. The molecular basis of the homing defect in C5-deficient mice. We found that the CC is activated in lethally irradiated mice and that C5-deficient mice engraft poorly with WT BM cells. To shed more light on the role of the distal part of the CC (C5a/C5b-C9) in homing/engraftment we will study whether conditioning for transplantation by chemotherapy also activates the CC in BM and study the effect of C5a/C5b-C9 on expression of i) HSPC chemoattractants in BM ii) adhesion/tethering molecules for HSPCs on BM endothelium and ii) on secretion of factors facilitating homing. Specific Aim 3. The C5a/C5b-C9-induced BM stroma-derived cathelicidin (LL-37) as a potent homing sensitizing factor. We found that LL-37 like C3a is a very strong priming factor for SDF-1 that becomes upregulated in BM stroma after conditioning for transplantation in a C5a/C5b-C9-dependent manner. In an immunodeficient mouse model we will test whether short exposure of HSPCs to LL-37 before transplantation increases homing of human BM- and umbilical cord blood (UCB)-derived HSPCs. We will also address whether LL-37 also primes the responsiveness of HSPCs to other homing factors and focus on the molecular mechanism of these phenomena.

project_terms:
Address;Adhesions;Adult;Anaphylatoxins;Blood Vessels;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotactic Factors;Circadian Rhythms;Collaborations;Complement;Complement 3a;Complement 5a;Complement Activation;Complement Membrane Attack Complex;Complement component C5;Cytolysis;Data;Defect;Development;Dinoprostone;Distal;Endothelium;Engraftment;Erythrocytes;Exhibits;Fibroblasts;Funding;Generations;Granulocyte Colony-Stimulating Factor;Growth Factor;Health;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Human;Integrin alpha4beta1;Integrins;Investigation;Lead;Life;Ligands;Light;Link;Lipids;Lytic;Molecular;Mus;Natural Immunity;Nucleotides;Osteoblasts;Patients;Physiological;Plasma;Polysaccharides;Process;Publishing;Role;Stem cells;Syndrome;Testing;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Vascular Cell Adhesion Molecule-1;Work;base;cathelicidin;ceramide 1-phosphate;chemotherapy;complement C3 precursor;complement C5b;immunodeficient mouse model;leukemia;novel;novel therapeutics;peripheral blood;reconstitution;response;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Section In this competing renewal we will focus on the role of a major component of innate immunity namely activation of the complement cascade in trafficking of hematopoietic stem/progenitor cells. This application will allow us to better understand this process as well as lead to the development of novel therapeutic strategies to treat patients with leukemias and inborn defects of hematopoiesis by transplantation of hematopoietic stem cells.


application_id: 8842725
project_number: 5R01NS084823-03
project_title: Mechanisms of Homocysteine-Induced Fibrinogen-Amyloid Plaque Formation
administering_ic: NINDS
award_notice_date: 2015-05-04
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: NS
serial_number: 084823
program_official: CORRIVEAU, RODERICK A
project_start_date: 2013-07-01
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-VH-B(03)]
contact_pi_person_id: 6869069
contact_pi: LOMINADZE, DAVID
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The plaques in the brain during Alzheimer's diseases (AD) are primarily composed of amyloid-b (Ab) peptide. Although a strong association between Ab fibrinogen (Fg) and elevated level of homocysteine (Hcy) i.e. hyperhomocysteinemia (HHcy) during AD is well- documented the mechanism of amyloid plaque formation is unclear. The long-term goal of this project is to understand the mechanisms of cerebrovascular permeability leading to amyloid plaque formation. We have shown that elevated levels of Hcy and Fg i.e. hyperfibrinogenemia (HFg) increase cerebrovascular permeability and Fg can cross vascular endothelial cell (EC) layer secondary to activation of matrix metalloproteinase-9 (MMP-9). In addition increased levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) which enhances collagen content in subendothelial matrix (SEM) are associated with AD. In pilot studies we found that while HHcy enhances vascular permeability through mainly the paracellular pathway HFg activates mainly the transcellular transport. We also found that blood level of Fg is increased during HHcy. Therefore Fg can have an additive effect in HHcy-induced cerebrovascular permeability. We found that HHcy increases collagen level in SEM and Fg and Ab depositions in brain vasculature. While HHcy increases MMP-9 activity and enhances the paracellular transport as well as homocyteinylates Fg (making fibrin clots more rigid) Fg enhances the transcellular transport through caveolin-1 (Cav-1) signaling (via phosphorylation of Cav-1). However the role of Hcy and Fg in Hcy-Fg-Ab-collagen complex formation is unclear. The hypothesis of this proposal is that HHcy increases vascular permeability by primarily affecting the endothelial cell (EC) junction proteins and activating MMP-9 and indirectly by increasing blood content of Fg which enhances transcellular transport leading to an enhanced Hcy- Fg-Ab-collagen complex formation. We will test this hypothesis with three specific aims: 1) To determine whether the HHcy instigates cerebrovascular permeability via paracellular transport leading to enhanced cerebrovascular crossing of fibrinogen 2) To determine whether the fibrinogen deposition enhances cerebrovascular permeability mainly through caveolar transcytosis via Cav-1 signaling secondary to MMP-9 activation 3) To determine whether the HHcy increases fibrinogen-Ab-collagen complex accumulation in mouse brains secondary to increasing tissue inhibitor of metalloproteinase-1. To define specific causative effects of Hcy Fg MMP-9 Cav-1 and TIMP-1 in Fg-Ab-collagen complex formation the studies will be done on pial vessels of wild type (WT) Cystathionine b-Synthase heterozygote (CBS+/-) mice (a model of HHcy) MMP-9 gene knockout (MMP9-/-) CBS and MMP-9 double knockout (CBS+/-/MMP9-/-) Cav-1 gene knockout (Cav1-/-) Fg g-chain-deficient (Fg-/-) CBS+/-/Fg-/- HFg transgenic (HFg) HFg/MMP9-/- CBS+/-/Cav1-/-/MMP9-/- CBS+/- /HFg CBS+/-/HFg/MMP9-/- TIMP-1 gene knockout (TIMP1-/-) CBS+/-/TIMP1-/- double knockout Fg-/-/MMP1-/- and CBS+/-/Fg-/-/TIMP1-/- mice using a newly developed dual-tracer probing method that allows separation of paracellular from transcellular transport. Formation of Fg-Ab-collagen complex in brain cortex will be assessed with immunohistochemical analysis. The results of the proposed research should uncover the molecular mechanisms regulating Hcy-Fg-Ab-collagen complex formation and lead to effective strategies for the treatment of cerebrovascular complications during diseases such as AD.

project_terms:
Affect;Aging;Alzheimer's Disease;Amyloid;Binding (Molecular Function);Blood;Brain;CAV1 gene;Caveolae;Coagulation Process;Collagen;Complex;Cryoultramicrotomy;Cystathionine;Dementia;Deposition;Development;Disease;Endothelial Cells;Extravasation;Fibrin;Fibrinogen;Gelatinase B;Goals;Health;Heterozygote;Homocysteine;Homocystine;Hyperhomocysteinemia;Immunohistochemistry;Intercellular Junctions;Interstitial Collagenase;Knock-out;Knowledge;Lead;MMP9 gene;Matrix Metalloproteinases;Measures;Methods;Mission;Modeling;Molecular;Mus;Neurodegenerative Disorders;Pathway interactions;Peptides;Permeability;Phosphorylation;Pilot Projects;Presenile Alzheimer Dementia;Proteins;Research;Role;Sampling;Secondary to;Senile Plaques;Signal Transduction;TIMP1 gene;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tracer;Transgenic Organisms;United States National Institutes of Health;Vascular Endothelial Cell;Vascular Permeabilities;caveolin 1;cerebrovascular;design;knockout gene;novel;occludin;public health medicine (field);transcytosis;treatment strategy;vascular endothelial cadherin-2;venule

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the most common form of dementia and it is not a normal part of aging. Up to 5 percent of people with the disease have early onset AD. The plaques in the brain during AD are primarily composed of amyloid-b (Ab) peptide. Although a strong association between Ab fibrinogen (Fg) and homocysteine (Hcy) is well-documented the mechanism is unclear. Our findings show that at elevated levels Hcy increases cerebrovascular permeability to proteins leading to Fg deposition in brain cortical vessels. We also found that this Fg is associated with increased levels of Ab and collagen in brain vasculature. These effects of Hcy and Fg were diminished in the absence of matrix metalloproteinase-9 (MMP-9) activity. The long-term goal of this project is to understand mechanisms leading to brain Fg-Ab-collagen complex formation. The knowledge of mechanisms that control the amyloid plaque formation will lead to the design of therapeutic strategies for the control of this devastating neurodegenerative disease. The proposed research is relevant to public health and to the mission of NIH because it will clarify a novel pathogenic causal relationship into the role of Hcy Fg and MMPs in development of AD.


application_id: 8842654
project_number: 5R01GM099744-05
project_title: Sirt1 regulation of NFkB activation and inflammatory responses in sepsis
administering_ic: NIGMS
award_notice_date: 2015-04-22
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: GM
serial_number: 099744
program_official: DUNSMORE, SARAH
project_start_date: 2013-06-01
project_end_date: 2016-04-30
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 8693493
contact_pi: FU, JIAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Septic shock is a systemic inflammatory response syndrome that causes multiple organ damage and death. Currently there is no efficient treatment for the disease. Identifying novel therapeutic targets that can help control sepsis-induced inflammation is crucial to treat this devastating disease. Activation of complex inflammatory networks is responsible for the excessive systemic inflammatory response in sepsis. NF-kB has been demonstrated as a central player that regulates these inflammatory networks in sepsis. However molecular regulation of NF-kB activity in sepsis remains largely unknown. Recent studies indicate that acetylation is a new mechanism in NF-kB activation. It has been reported that Sirt1 a deacetylase widely expressed in all tissues interacts with NF-kB and inhibits NF-kB activity by deacetylation in several in vitro and in vivo systems. Yet the function and regulation of Sirt1 in sepsis-induced inflammatory responses have not been studied. Using mouse models of sepsis we demonstrate that Sirt1 controls inflammatory responses during sepsis by regulating NF-kB acetylation and activation. Our preliminary data showed that induction of sepsis triggered NF-kB acetylation and activation in wild type mice which were further increased in Sirt1 knockout mice. Interestingly Sirt1 activation by resveratrol or Sirt1 gene delivery inhibited sepsis-induced NF-kB acetylation. Furthermore we showed that caspase activation resulted in Sirt1 degradation which may function as a new pathway to aggravate systemic inflammation in sepsis. In the proposed studies we will test the hypothesis that Sirt1 controls NF-k B activation and inflammatory responses during sepsis. Our specific aims are: (1) to define the role of Sirt1 in sepsis-induced NF-kB activation and systemic inflammation. We will use inducible Sirt1 knockout mice to assess the role of Sirt1 in sepsis-induced systemic inflammation; we will examine the role of caspase in Sirt1 regulation of NF-kB activation and inflammatory signaling during sepsis; (2) to specifically dissect Sirt1 control of NF-kB activation in endothelial cell inflammatory responses during sepsis. We will define Sirt1 control of sepsis-induced NF-kB activation and inflammatory signaling in endothelial cells. We will use endothelial-specific Sirt1 knockout mice to assess the role of endothelial Sirt1 in NF-kB modulation and inflammatory signaling in sepsis; (3) to explore the therapeutic potential of modulating NF-kB activation by Sirt1 activators and Sirt1 gene delivery in sepsis-induced inflammation. We will explore the therapeutic potential of Sirt1 activators on sepsis-induced NF-kB activation and inflammatory signaling; we will evaluate whether Sirt1 gene delivery can effectively protect against sepsis-induced inflammation by inhibiting NF-kB-regulated inflammatory signaling. Successful completion of the proposed studies will disclose Sirt1 as a novel modulator of sepsis-induced NF-kB activation and inflammation and validate the potential of Sirt1 as a therapeutic target to treat sepsis-associated inflammatory tissue damage.

project_terms:
Acetylation;Bacterial Infections;Cause of Death;Cessation of life;Complex;Critical Illness;Data;Deacetylase;Deacetylation;Disease;Endothelial Cells;Gene Delivery;In Vitro;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Knockout Mice;Molecular;Multiple Organ Failure;NF-kappa B;Organ;Pathway interactions;Patients;Regulation;Reporting;Resveratrol;Role;Sepsis;Sepsis Syndrome;Septic Shock;Signal Transduction;System;Testing;Therapeutic;Tissues;Wild Type Mouse;caspase;in vivo;inflammatory modulation;mouse model;new therapeutic target;novel;therapeutic target

public_health_relevance:
Successful completion of the proposed studies will disclose Sirt1 as a novel modulator of sepsis-induced NF-kB activation and inflammation and validate the potential of Sirt1 as a therapeutic target to treat sepsis- associated inflammatory tissue damage.


application_id: 8842212
project_number: 5R01NS079637-04
project_title: Vascular breakdown in Alzheimers Disease with cerebrovascular disease
administering_ic: NINDS
award_notice_date: 2015-05-01
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: NS
serial_number: 079637
program_official: CORRIVEAU, RODERICK A
project_start_date: 2012-07-01
project_end_date: 2016-04-30
study_section: Clinical Neuroimmunology and Brain Tumors Study Section[CNBT]
contact_pi_person_id: 8849885
contact_pi: WILCOCK, DONNA M
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): Microhemorrhages and vasogenic edema are pathological phenomena that occur in both cerebrovascular disease (CBVD) and Alzheimer's disease (AD). In CBVD these can occur throughout the brain yet are most frequently subcortical. In AD they usually occur at sites of vascular amyloid deposition. Given that CBVD and AD are not always mutually exclusive but often co-exist it is important that we understand the mechanisms of microhemorrhages and vasogenic edema. We hypothesize that inflammatory-mediated activation of matrix metalloproteinases leads to degeneration of tight junction proteins and basement membrane proteins resulting in vascular leakage producing microhemorrhages and/or vasogenic edema.  Our goal for this proposal is to model CBVD in mouse models of amyloid deposition to produce vasogenic edema and microhemorrhage and determine the role of the MMP system in their onset and the impact CBVD has on response to amyloid-targeted therapies. We will assess inflammatory changes and activation of the MMP systems as mechanisms for these abnormalities. Importantly we propose to acquire MR FLAIR and Susceptibility Weighted (SWI) images to assess vasogenic edema and microhemorrhage as well as any other brain changes occurring through the course of the studies. Immediately prior to tissue harvest we will acquire arteral spin label (ASL) scans to measure brain perfusion and thus enable a comparison of the density of microhemorrhages and brain health. Additionally we will acquire contrast enhanced T1-weighted scans following administration of Magnevist and Galbumin contrast agents to assess vascular leakage. We propose to use AAV and pharmacological agents to inhibit MMPs directly or inhibit the inflammatory signals thought to be increasing MMP activity. We will also examine whether the efficacy and side-effect profile of two A- targeted therapies in trials are influenced by the presence of CBVD in amyloid-depositing mice.  The overall goal of our proposal is to determine the time-course of CBVD pathology when we generate CBVD in APP/PS1 transgenic mice determine the roles of inflammation and MMPs in the generation of microhemorrhage and vasogenic edema and finally to establish the effect CBVD has on the response to A-targeted therapies. We believe that CBVD is common co- morbidity with AD that influences the pathogenesis of AD and response to therapy.

project_terms:
APP-PS1;Adverse effects;Affect;Aging;Alzheimer's Disease;Amyloid;Amyloid deposition;Animals;Basement membrane;Blood Vessels;Blood flow;Brain;Brain Pathology;Cerebrovascular Circulation;Cerebrovascular Disorders;Clinical Trials;Cognition;Comorbidity;Contrast Media;Deposition;Diet;Edema;Extravasation;Gadopentetate Dimeglumine;Generations;Genetic;Goals;Health;Hippocampus (Brain);Hyperhomocysteinemia;Image;Immunotherapy;Inflammation;Inflammatory;Inhibition of Matrix Metalloproteinases Pathway;Injection of therapeutic agent;Interleukin-1;Left;MMP2 gene;MMP9 gene;Magnetic Resonance Imaging;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measures;Mediating;Membrane Proteins;Modeling;Modification;Mus;Pathogenesis;Pathology;Patients;Perfusion;Predisposition;Production;Proteins;Research Proposals;Role;Scanning;Signal Transduction;Site;Spin Labels;System;TIMP1 gene;TIMP2 gene;Thalamic structure;Tight Junctions;Time;Tissue Harvesting;Transgenic Mice;Weight;amyloid pathology;anakinra;arteriole;contrast enhanced;density;inhibitor/antagonist;mouse model;neuroinflammation;receptor;response;secretase;targeted treatment;therapeutic target

public_health_relevance:
Cerebrovascular disease commonly occurs with aging as does Alzheimer's disease. In fact it is estimated that 40% of Alzheimer's patients also have cerebrovascular disease. Our research proposal will examine the impact cerebrovascular disease has on the progression of amyloid pathology a brain pathology in Alzheimer's disease. Our overall goal is to enhance our understanding of the relationship between cerebrovascular disease and Alzheimer's disease and how one can affect the other.


application_id: 8842033
project_number: 5R01HD075783-03
project_title: Evaluating the long-term effects of Green Dot on teen dating violence prevention
administering_ic: NICHD
award_notice_date: 2015-05-15
opportunity_number: PA-09-169
application_type: 5
activity_code: R01
ic: HD
serial_number: 075783
program_official: CHINN, JUANITA JEANNE
project_start_date: 2013-09-06
project_end_date: 2016-11-30
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: FOLLINGSTAD, DIANE RUTH
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Our purpose is to evaluate the longer-term impact of Green Dot across the Bluegrass an active bystanding-based randomized intervention trial in 26 high schools across Kentucky designed to reduce dating and sexual violence in a cohort of seniors as they transition into young adulthood. Our central question is: Does Green Dot continues to have an effect in changing the culture of violence acceptance and reducing violence perpetration among students exposed to Green Dot relative to those not exposed as this cohort enters young adulthood? In this prospective cohort of approximately 7500 students we will measure the individual level exposure to the Green Dot program and into young adulthood allowing us to estimate the risk of dating and sexual violence victimization and perpetration. Very few studies have prospectively estimated the risk of dating and sexual violence among a cohort randomized to a primary prevention intervention and followed into young adulthood. This R01 is also unique because cohort members will be followed independent of whether they do or do not attend college. Individually following this cohort of seniors represents a significant value-added and time-sensitive opportunity because the full implementation of Green Dot began in late 2011. Only now (2013-15) would we anticipate seeing an effect of Green Dot among rising seniors on changing bystanding and potentially reducing violence. Aim 1. Prospectively determine whether and how the Green Dot intervention reduces rates of teen dating and sexual violence into young adulthood by (a) changing social norms of violence acceptance (b) increasing active bystanding and (c) diffusing the intervention through peer networks. Approximately 7500 high school seniors who attended Kentucky high schools randomized to the Green Dot intervention (n~3750) or control schools (n~3750) will be followed 42 months into young adulthood. Aim 2. To determine the potentially modifying effects of participants' post-high school life experience on the association between exposure to the Green Dot intervention and bystanding actions teen dating and sexual violence incidence. Post-high school experience will be categorized as attending any form of college or university versus no additional education. Specific life stressors such as relationship status pregnancy military deployment family and peer violence and substance abuse will also be explored. This cohort study is appropriately powered (90%) to address both aims. Comparisons will be made at 6-month intervals and across the 42-month follow-up and the interaction of intervention by time will be evaluated. Generalized Estimating Equations will be used to test the impact of Green Dot over time while taking clustering of high schools and correlation among repeated measurements among individual students into account and adjusting for confounders. This prospective cohort builds upon a large population-based and promising primary prevention intervention designed to reduce dating and sexual violence among high school students and provides an important test of the longer-term efficacy of this program into young adulthood.

project_terms:
Accounting;Address;Adolescent;Adult;Binding (Molecular Function);Cohort Studies;Collection;Data;Data Analyses;Diffuse;Educational Status;Educational aspects;Elements;Equation;Evaluation;Exposure to;Family Violence;Frequencies (time pattern);Funding;High School Student;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Length;Life;Life Experience;Long-Term Effects;Measurement;Measures;Military Personnel;Outcome;Participant;Poa plant;Population;Pregnancy;Prevention program;Preventive Intervention;Primary Prevention;Randomized;Recruitment Activity;Relative (related person);Risk Estimate;Schools;Students;Substance abuse problem;Teen Dating Violence;Testing;Time;Training;Universities;Victimization;Violence;base;cohort;college;dating violence;dating violence prevention;design;emerging adult;experience;follow-up;high risk;high school;innovation;member;novel;partner violence;peer;peer networks;peer violence;population based;programs;prospective;public health relevance;randomized trial;sexual violence;social norm;stressor;therapy design;twelfth grade;violence prevention;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Because teen dating and sexual violence rates remain high tests of promising primary prevention interventions with sufficient lengths of follow-up to detect changes in violence are needed. We propose a cohort study of high school seniors (n=7500) followed for up to 42 months who participated in a high school based randomized intervention trial of an active bystanding prevention program.


application_id: 8840989
project_number: 5K99HL122505-02
project_title: Mechanisms of Monocytosis in Obesity:Implications for Cardiovascular Disease
administering_ic: NHLBI
award_notice_date: 2015-04-30
opportunity_number: PA-11-197
application_type: 5
activity_code: K99
ic: HL
serial_number: 122505
program_official: HUANG, LI-SHIN
project_start_date: 2014-05-01
project_end_date: 2016-04-30
study_section: ZHL1-CSR-P(F1)
contact_pi_person_id: 10936209
contact_pi: NAGAREDDY, PRABHAKARA REDDY
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The proposed career development plan is designed to equip the PI with unique skill sets expand knowledge base and research experience to meet the short-term goal of becoming a productive researcher and a long- term goal of becoming an independent investigator in monocyte/macrophage biology in the areas of obesity diabetes mellitus and cardiovascular disease (CVD). The plan will be carried out at the University of Kentucky (UK) an institution that is renowned for its strong CVD research program. The PI will be mentored by Dr. Susan Smyth the Chief of Cardiovascular Medicine and co-mentored by Dr. Phil Kern the Director of Barnstable Brown Diabetes and Obesity Center. The plan proposes to explore the relationship between monocytosis adipose tissue (AT) inflammation and its impact on atherosclerosis using insights the PI recently gained from studies at Columbia University. The PI has found that neutrophil-derived damage associated molecular patterns (DAMP) such as S100A8/A9 drives myelopoiesis and severely affects atherosclerotic lesion regression in diabetes. Further he found a dramatic increase in the mRNA expression of both S100A8 and S100A9 in white AT from obese mouse models. However unlike in type I diabetic mouse models the circulating levels of S100A8 and S100A9 in obese models are neither increased nor driven by hyperglycemia. Why S100A8 and S100A9 are increased in AT and whether they are involved in obesity-induced monocytosis is not clear. The overall goal of this project is to understand how obesity affects the number and phenotype of circulating WBCs particularly the monocytes and in turn arterial biology. We will use mouse models to study the mechanisms driving these human abnormalities develop a "proof of concept" for a treatment strategy aimed at reducing the offending DAMPs or cytokines and assess whether this strategy will alter atherosclerosis in mouse models. Finally we will determine whether insights developed in mice correlate with changes in humans. Specific Aim 1 will determine the sources of cells and signaling molecules in AT that drives monocyte production in obesity. In this aim we will also determine the effect of adiposity and impact of weight loss on myelopoiesis and characterize the phenotype of circulating monocytes in mouse models of obesity. Specific Aim 2 will identify the processes and signaling pathways that mediate obesity-induced monocytosis. Specific Aim 3 will assess the impact of obesity-induced monocytosis on atherosclerotic lesion regression. Collectively the outcomes of this project will provide novel insights into the causes and consequences of enhanced monocytosis in obesity.

project_terms:
Address;Adipocytes;Adipose tissue;Affect;Area;Arterial Fatty Streak;Atherosclerosis;Automobile Driving;Biology;Blood;Body Weight decreased;Bone Marrow;Cardiovascular Diseases;Cardiovascular system;Cells;Cholesterol;Comorbidity;Development;Development Plans;Diabetes Mellitus;Diabetic mouse;Diet;Environment;Epidemic;Functional disorder;Genetic;Goals;Health;Human;Hyperglycemia;Inflammation;Inflammatory;Institution;Interleukin-1;Intervention;Kentucky;Lesion;Leukocytes;Ligands;Link;Mediating;Mediator of activation protein;Medicine;Mentors;Metabolic syndrome;Modeling;Molecular;Monocytosis;Mus;Myelogenous;Myeloid Cells;Myeloid Progenitor Cells;Myelopoiesis;Natural Immunity;Necrosis;Necrosis Induction;Neutrophilia;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Obesity associated cardiovascular disease;Outcome;Patients;Pattern;Phenotype;Plasma;Play;Process;Production;Recruitment Activity;Reporting;Research;Research Personnel;Research Proposals;Resolution;Role;S100A8 gene;S100A9 gene;Severities;Signal Pathway;Signal Transduction;Signaling Molecule;Source;Stimulus;TLR4 gene;Techniques;Time;Training;Travel;Universities;cardiovascular disorder risk;career development;cell type;cytokine;design;experience;feeding;insight;knowledge base;mRNA Expression;macrophage;meetings;monocyte;mouse model;neutrophil;novel;progenitor;programs;public health relevance;receptor;response;skills;treatment strategy;type I diabetic

public_health_relevance:
Public Health Relevance: besity and its associated co- morbidities are a growing health concern globally. Whilst there are a number of interventions currently available to clinicians to treat obese patients suffering with CVDs there s lingering debate over which strategies are most beneficial. These findings are likely to also have a broader impact on the field of innate immunity and obesity as there is a high potential for a number of targets to be discovered in respects to obesity-induced monocyte production.


application_id: 8840391
project_number: 1R01DK104653-01
project_title: Hydrogen sulfide mechanism of renal hypertension
administering_ic: NIDDK
award_notice_date: 2015-06-16
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: DK
serial_number: 104653
program_official: NIHALANI, DEEPAK
project_start_date: 2015-07-01
project_end_date: 2019-06-30
study_section: Hypertension and Microcirculation Study Section[HM]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
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
arra_indicator: N
project_terms:
3-Mercaptopyruvate sulfurtransferase;Affect;Amino Acids;Angiography;Antihypertensive Agents;Antioxidants;Atherosclerosis;Blood Pressure;Blood Vessels;Blood capillaries;Cells;Chemicals;Chronic Kidney Failure;Co-Immunoprecipitations;Collagen;Connexins;Cystathionine;Cystathionine beta-Synthase;Development;Diet;Disease;Endothelial Cells;Environmental Hazards;Enzymes;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Functional disorder;Future;Gap Junctions;Gelatinase A;Gelatinases;Gene Delivery;Genes;Genetic Models;Glomerular Filtration Rate;Goals;Homocysteine;Homocystine;Hydrogen Sulfide;Hyperhomocysteinemia;Hypertension;Impairment;In Vitro;Inflammatory;Injury;Interstitial Collagenase;Investigation;Kidney;Kidney Diseases;Knowledge;Lead;Lyase;Mass Spectrum Analysis;Matrilysin;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metabolism;Methods;Molecular;Mus;Nitric Oxide;Outcome;Outcomes Research;Oxidative Stress;Pathology;Perfusion;Physiological;Plasma;Process;Production;Renal Hypertension;Renal function;Renovascular Hypertension;Reporting;Research;Reverse Transcriptase Polymerase Chain Reaction;Roentgen Rays;Role;Staining method;Stains;Structure;Sulfhydryl Compounds;Supplementation;Testing;Therapeutic;Therapeutic Agents;Tissue Inhibitor of Metalloproteinases;Tissues;Up-Regulation (Physiology);Vascular Diseases;Vascular remodeling;Western Blotting;blood pressure regulation;capillary;caveolin 1;collagenase;connexin 37;density;gene delivery system;human NOS3 protein;in vivo;insight;kidney vascular structure;neurotoxicity;novel;prevent;public health relevance


application_id: 8840378
project_number: 3UH2TR000875-02S1
project_title: Fruit exosome-like particles for therapeutic delivery of extracellular miRNAs
administering_ic: NCATS
award_notice_date: 2014-08-28
opportunity_number: PA-14-077
application_type: 3
activity_code: UH2
ic: TR
serial_number: 000875
suffix: S1
program_official: TAGLE, DANILO A
project_start_date: 2013-08-01
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZRG1(50)-R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: GUO, PEIXUAN
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:
Adverse effects;Animals;Antibodies;Biohazardous Substance;Biological Assay;Brain;Brain Neoplasms;Breast;Cells;Clinic;Clinical;Colon Carcinoma;Colonic Neoplasms;Curcumin;DNA;Data;Dendritic Cells;Development;Disease;Dose;Down-Regulation;Edible Plants;Encapsulated;Environment;Evaluation;Folic Acid;Fruit;Gene Expression;Goals;Grapefruit (food);Grapes;Human;Immune response;Immunotherapy;In Vitro;Inflammatory;Intranasal Administration;Killings;Knock-in Mouse;Knock-out;Laboratories;Light;Lipids;Liposomes;Literature;Liver;MHC Class I Genes;Malignant Neoplasms;Mammalian Cell;Metastatic Neoplasm to the Liver;MicroRNAs;Modeling;Mus;Myelogenous;Myeloid Cells;NK Cell Activation;Neoplasm Metastasis;Non-Viral Vector;Nucleic Acids;Oral Administration;Paclitaxel;Pharmaceutical Preparations;Phenotype;Play;Prevention;Production;Proteins;Protocols documentation;Publishing;RNA;Research Personnel;Role;Safety;Science;Signal Transduction;Small Interfering RNA;Small RNA;Specificity;Suppressor-Effector T-Lymphocytes;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Tomatoes;Toxic effect;Tumor Tissue;Viral Vector;aqueous;base;cancer cell;cancer therapy;cell type;chemotherapeutic agent;chemotherapy;cost;expression vector;extracellular;in vivo;intravenous administration;large scale production;migration;mouse model;nanoparticle;nanosized;nanovector;neoplastic cell;overexpression;particle;prevent;public health relevance;receptor;targeted delivery;tool;trafficking;tumor;vector-induced


application_id: 8840323
project_number: 5K23NR014883-02
project_title: Interventions in Nutrition Education and Skills
administering_ic: NINR
award_notice_date: 2015-05-13
opportunity_number: PA-11-194
application_type: 5
activity_code: K23
ic: NR
serial_number: 014883
program_official: ROARY, MARY
project_start_date: 2014-04-18
project_end_date: 2017-03-31
study_section: Nursing Science Review Committee[NRRC(58)]
contact_pi_person_id: 11333924
contact_pi: HARDIN-FANNING, FRANCES
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): Individuals living in rural Appalachian food deserts have among the highest cardiovascular disease (CVD) rates in the nation. Nine risk factors account for 90% of all CVD risk and eight of those factors excluding smoking are influenced by nutritional habits. Diet is dependent upon individual and environmental factors particularly in rural food deserts where socioeconomic factors contribute to poor eating habits. Few researchers have developed and tested strategies aimed at improving dietary patterns in rural food deserts and there has been no significant improvement in the dietary behaviors of most rural Appalachians over the past several decades. Given the disproportionate CVD rates and economic disadvantage in this region it is vital to develop and test cost-effective interventions that target the individual and environmental barriers to healthy eating that are specific to this region. Through a training plan that includes mentoring by a team of nursing and nutritional scientists and formal course work seminars and a research study this K23 Award will engender the skills to develop and test novel interventions aimed at increasing consumption of CVD risk- reducing foods in rural Appalachia. The applicant completed her doctorate in nursing in 2011 and has since conducted preliminary studies that inform the need to develop and test individualized nutritional interventions that address the unique barriers to healthy eating in rura Appalachia. The broad hypothesis of this program of research is that nutritional behavior change interventions individualized to each participant's specific motivation and ability are more likely to yield long-term behavior change than standardized interventions delivered en masse. A pilot study will be conducted in six Appalachian food desert counties with participants in three counties serving as controls and participants in the other three counties receiving an individualized intervention. The specific aims of the study are to: 1) test the outcome of an individualized intervention aimed at increasing consumption of CVD-risk reducing foods and 2) determine whether health literacy financial status and risk of food insecurity moderate the effectof the intervention. Outcome variables will be measured using a food frequency questionnaire food security survey and by monitoring monthly grocery purchases. The combination of a structured training plan and the research project will support the applicant's long-term goal of becoming an independent investigator in primary CVD prevention focused on improving nutrition. Specifically the applicant will obtain training in the principles of a) conducting rigoous trials of individualized dietary interventions in the context of austere environments b) assessingnutritional status and c) improving scientific productivity (grant-writing and publishing). The research study will provide the preliminary data research skills and expertise needed to apply for R01 grant funding to conduct controlled trials of individualized interventions aimed at improving dietary patterns of individuals living in rural food deserts and other austere environments with similar barriers to healthy eating.

project_terms:
Accounting;Address;Alcohol consumption;Apolipoprotein A-I;Apolipoproteins B;Appalachian Region;Area;Behavior;Behavior Therapy;Cardiovascular Diseases;Chronic Disease;Consumption;Control Groups;Country;County;Data;Diet;Diet Habits;Dietary Intervention;Dietary Practices;Disadvantaged;Discipline of Nursing;Eating;Economically Deprived Population;Economics;Effectiveness;Environment;Environmental Risk Factor;Exhibits;Food;Food Preservation;Frequencies (time pattern);Funding;Goals;Grant;Habits;Health;Health Food;Heart Diseases;Hypertension;Individual;Intervention;Knowledge;Knowledge acquisition;Life;Measures;Mentored Patient-Oriented Research Career Development Award;Mentors;Monitor;Motivation;Non-Insulin-Dependent Diabetes Mellitus;Nutritional;Nutritional status;Outcome;Participant;Physical activity;Pilot Projects;Play;Population;Poverty;Productivity;Psychosocial Factor;Publishing;Questionnaires;Research;Research Personnel;Research Project Grants;Risk;Risk Factors;Rural;Scientist;Smoking;Socioeconomic Factors;Structure;Surveys;Team Nursing;Testing;Training;Training Programs;United States;Waist-Hip Ratio;Work;Writing;base;behavior change;burden of illness;cardiovascular disorder prevention;cardiovascular disorder risk;control trial;cost;cost effective;effective intervention;empowered;food consumption;food security;group intervention;health literacy;high risk;improved;innovation;intervention effect;literacy;metropolitan;motivational enhancement therapy;nonmetropolitan area;novel;nutrition;nutrition education;programs;public health medicine (field);research study;skills;theories;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The knowledge gained from this project will help fulfill the need for developing and testing individualized interventions aimed at improving eating habits and thereby lowering risk and cost burden of heart disease in rural Appalachian food deserts. Currently there has been little research on the effectiveness of dietary behavior change strategies aimed at reducing cardiovascular disease risk for this region which has the country's highest heart disease rates and is one of the most economically disadvantaged areas. This research has the potential to significantly impact short and long-term heart disease rates in this and similar regions.


application_id: 8840114
project_number: 1R01DA037621-01A1
project_title: Long-term activation of spinal opioid analgesia after inflammation
administering_ic: NIDA
award_notice_date: 2015-08-04
opportunity_number: PA-13-118
application_type: 1
activity_code: R01
ic: DA
serial_number: 037621
suffix: A1
program_official: LIN, YU
project_start_date: 2015-08-15
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1 IFCN-B (03)]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Severe tissue injury generates central sensitization (increased responsiveness of CNS nociceptive neurons to normal or sub-threshold afferent input) that contributes to hyperalgesia. Latent sensitization (LS) is a silent form of central sensitization that persists after tissue has healed and overt signs of hyperalgesia have resolved. LS can be revealed with opioid receptor antagonists or inverse agonists that "rekindle" or reinstate hyperalgesia. Thus pain remission during LS is likely maintained by tonic opioid receptor activity that masks the pronociceptive components of LS. LS is important because it primes nociceptive systems such that when inhibitory systems fail a pain episode ensues. A key first step in understanding LS is to demonstrate the translational significance and we now show that the opioid receptor inverse agonist naloxone can reinstate experimental pain when delivered 1 wk after the resolution of secondary hyperalgesia following first degree thermal injury. Specific Aim 1 tests the hypothesis that burn or surgery triggers LS and long-term opioid analgesia in humans. To further study the neurobiological mechanisms of LS we will also use a mouse model that is long-lasting powerful broad range repeatable and translates to human studies. We found that mu opioid receptor (MOR) inverse agonists reinstated behavioral and molecular signs of hyperalgesia even when administered months after tissue injury and this required NMDA receptor activation of adenylyl cyclase type 1 (AC1). Our results are important because they suggest that any event such as stress that interferes with MOR analgesia during LS will lead to relapse of hyperalgesia in chronic pain syndromes in humans. Specific Aim 2 tests the hypothesis that MOR constitutive activity (MORCA) and/or activation of MOR delta (DOR) or kappa (KOR) receptors by opioid peptides in the DH or rostroventromedial medulla maintains endogenous analgesia and thereby restricts LS to a state of pain remission. Specific Aim 3 determines the extent to which MORs inhibit spatially coordinated neural activity in the DH (using an innovative 64-channel field recording system) and synaptic strength in presynaptic terminals of primary afferent nociceptors or on DH neurons (using patch clamp electrophysiology) during LS. Specific Aim 4 then tests whether MORs specifically inhibit spinal NMDA receptor subunits (GluN2A or GluN2B) and/or Epac1 (exchange protein directly activated by cAMP recently found to contribute to peripheral pain senstization) to block pain during LS. Completion of this project will bring us closer to our long-term goal of alleviating chronic pain b either: a) facilitating endogenous opioid analgesia thus restricting LS within a state of remission; or b) extinguishing LS altogether for example with a selective AC1 or Epac1 inhibitor. Our general model and hypothesis shares similarities with the concept of allostasis: a pathologically-elevated balance between opposing processes (MOR and LS) that facilitate each other by mutual feedback. Our long-term vision is a new conceptual strategy for chronic pain therapy to restore homeostasis where there is neither central sensitization nor MOR compensatory responses.

project_terms:
Absence of pain sensation;Acute;Acute Pain;Address;Adenylate Cyclase;Affect;Affective;Agonist;American;Analgesics;Behavior;Behavioral;Binding (Molecular Function);Brain;Burn injury;Chronic;Cutaneous;Cyclic AMP;Cyclic AMP Receptors;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease remission;Dynorphins;Electrophysiology (science);Endogenous Opiates;Enkephalins;Equilibrium;Event;Excitatory Postsynaptic Potentials;Failure (biologic function);Feedback;Figs - dietary;Goals;Guanosine Triphosphate;Healed;Hernia;Homeostasis;Human;Hyperalgesia;Inflammation;Inguinal region;Injury;Knockout Mice;Knowledge;Lead;Masks;Mediating;Messenger RNA;Modeling;Molecular;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NR1 gene;Naloxone;Naltrexone;Neurons;Nociception;Nociceptors;Operative Surgical Procedures;Opioid;Opioid Peptide;Opioid Receptor;Pain;Pain Nature;Pain management;Phase;Phosphorylation;Physical Function;Physiologic pulse;Posterior Horn Cells;Postoperative Pain;Presynaptic Terminals;Process;Productivity;Protein Isoforms;Proteins;Publishing;Quality of life;Receptor Activation;Receptors Opioid delta;Receptors Opioid mu;Relapse;Resolution;Science;Secondary Hyperalgesias;Signal Transduction;Site;Slice;Spinal;Spinal Cord;Stress;Synapses;Synaptosomes;Syndrome;System;Testing;Tissues;Translating;Vision;Work;adenylyl cyclase 1;allostasis;central sensitization;chronic pain;cost;dorsal horn;healing;heat injury;inhibitor/antagonist;innovation;mental function;mouse model;naltrexol;neurobiological mechanism;pain behavior;patch clamp;peripheral pain;prevent;public health medicine (field);public health relevance;receptor;relating to nervous system;repaired;response;spinal nerve posterior root;spontaneous pain;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain is a public health problem which affects the physical and mental functioning quality of life and productivity of over 100 million Americans costing $600 billion dollars annually. Our recent work suggests that our body's own natural opioid pain killers exert an extremely powerful and very long-lasting ability to prevent chronic pain. This project seeks to elucidate the molecular mechanisms that create this pain relief system such as opioid systems being stuck in a constant "ON" state and to demonstrate its importance in humans after suffering from a traumatic injury.


application_id: 8839319
project_number: 5F31NS083292-03
project_title: Methylglyoxal and TRPA1 contribution to neuropathic pain in type 2 diabetes
administering_ic: NINDS
award_notice_date: 2015-03-20
opportunity_number: PA-11-111
application_type: 5
activity_code: F31
ic: NS
serial_number: 083292
program_official: OSHINSKY, MICHAEL L
project_start_date: 2013-04-01
project_end_date: 2015-09-30
study_section: Special Emphasis Panel[ZRG1-F02B-M(20)L]
contact_pi_person_id: 10806881
contact_pi: GRIGGS, RYAN B
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): Diabetes affects almost 9% of the United States population and 20-50% of diabetic patients experience painful diabetic neuropathy. Painful diabetic neuropathy (PDN) results in increased somatosensory responsiveness increased patient-reported pain and has a greater prevalence in type 2 versus type 1 diabetic patients. Ninety percent of diabetic patients are type 2 pointing to the need to understand the mechanisms that underlie PDN. Plasma methylglyoxal a catabolic cellular metabolite of glucose is markedly increased in hyperglycemic diabetic patients mice and rats. Very recent studies also suggest that methylglyoxal causes pain via TRPA1-dependent neuronal sensitization but this mechanism has only been investigated in the streptozotocin (STZ) model of type 1 diabetes. Other chronic studies in the STZ model indicate increased neuronal responsiveness to peripheral stimulation (sensitization) and pain. Lack of comparable longitudinal studies in a rat model of type 2 diabetes is an important gap in knowledge. The proposed studies will use the Zucker Diabetic Fatty (ZDFfa/fa) rat model of type 2 diabetes to test the central hypothesis that hyperglycemia-induced increases in methylglyoxal cause painful diabetic neuropathy in type 2 diabetes. By understanding how changes in peripheral nerves lead to alteration of sensory processing in the spinal cord we can learn how to effectively treat painful diabetic neuropathy. The goal of this project is to discover new therapeutic targets for PDN treatment.  Specific Aim 1 will test the hypothesis that methylglyoxal produces spontaneous pain-like behavior in type 2 diabetes. Reactive methylglyoxal directly activates nociceptive sensory neurons to cause pain. We will attempt to inhibit methylglyoxal-induced pathology by several different methods including the FDA-approved diabetes therapy pioglitazone and assess whether pain is diminished. Specific Aim 2 will test the hypothesis that methylglyoxal contributes to painful diabetic neuropathy via increasing TRPA1-dependent sensory neuron activity. TRPA1 is a protein expressed in sensory neurons that results in painful sensation upon activation. It is thought that methylglyoxal causes sustained activation of TRPA1 which is at least partially responsible for pain in type 2 diabetes. We will use behavioral assays mechanistic pharmacology and calcium imaging as a marker for sensory neuron activation to test the overall hypothesis that type 2 diabetic pain is mediated by glucose-related neurological deficits. Our long-term objective is to substantially reduce the burden of neuropathic pain in type 2 diabetes.

project_terms:
Affect;Afferent Neurons;Age;Agonist;Animals;Attenuated;Behavior;Behavioral Assay;Burn injury;Calcium;Chemosensitization;Chronic;Clinical;Data;Diabetes Mellitus;Diabetic Neuralgia;Esthesia;FDA approved;Genetic;Glucose;Goals;Health;Heating;Human;Hyperalgesia;Hyperglycemia;Hypersensitivity;Image;Insulin-Dependent Diabetes Mellitus;Knowledge;Lactoylglutathione Lyase;Lead;Learning;Longitudinal Studies;Measures;Mediating;Methods;Modeling;Mus;Neurologic;Neurons;Nociception;Non-Insulin-Dependent Diabetes Mellitus;PPAR gamma;Pain;Paresthesia;Pathology;Patients;Peptides;Peripheral;Peripheral Nerves;Peripheral nerve injury;Peroxisome Proliferator-Activated Receptors;Pharmacology;Pioglitazone;Plasma;Population;Prevalence;Prevention;Procedures;Proteins;Pyruvaldehyde;Rattus;Reporting;Rodent;Rodent Model;Sensory Process;Spinal Cord;Spinal Ganglia;Spinal cord posterior horn;Streptozocin;Testing;United States;behavioral pharmacology;cohort;diabetes mellitus therapy;diabetic;diabetic patient;diabetic rat;experience;heat stimulus;in vivo;new therapeutic target;non-diabetic;overexpression;painful neuropathy;preference;pressure;research study;response;somatosensory;spontaneous pain;type I diabetic;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Neuropathic pain is commonly associated with diabetes yet glucose management alone does not eliminate diabetic pain. Our goal is to elucidate mechanisms of peripheral neuropathic pain in type 2 diabetes. Our findings will contribute to the discovery of new therapeutic targets such as PPAR agonists and TRPA1 antagonists for the treatment and prevention of diabetic pain.


application_id: 8838850
project_number: 5R25HL084695-09
project_title: Summer Undergraduate Experiences in Biomedical Research
administering_ic: NHLBI
award_notice_date: 2015-03-12
opportunity_number: RFA-HL-12-031
application_type: 5
activity_code: R25
ic: HL
serial_number: 084695
program_official: WANG, WAYNE C
project_start_date: 2006-04-07
project_end_date: 2016-03-31
study_section: ZHL1-CSR-F(M1)
contact_pi_person_id: 1917399
contact_pi: JOSHUA, IRVING G
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The primary goal of this program is to provide minority and disadvantaged undergraduate students with an initial exposure to basic and clinical science researchers and their areas of cardiovascular interest at the University of Louisville Health Sciences Center. This program is designed to support 8 undergraduate students each summer. It is anticipated that a significant number of the undergraduate students will elect to enter into graduate research programs at either this university or others around the country as a result of the experiences in our program. Emphasis will be placed on exposing students to literature-based hypothesis generation experimental design and appropriate data analysis procedures. The students will be exposed to a biomedical research environment that emphasizes collaboration between basic and clinical science researchers and that clearly demonstrates the clinical relevance of cardiovascular research that is being conducted at this university. Based on results from our first 5 years of the program we expect that at least 25% of the graduating participants will enter into a biomedically related research program. We also expect a number of minority and disadvantaged students interested in a medical or medically related career to participate in this program. We therefore project that at least 50% of our student participants will either enter a graduate research program or medical school when they complete their undergraduate program.  (End of Abstract)

project_terms:
Animal Experimentation;Animals;Area;Basic Science;Biomedical Research;Cardiovascular system;Clinical Sciences;Collaborations;Country;Data Analyses;Development;Disadvantaged;Doctor of Philosophy;Environment;Ethics;Experimental Designs;Exposure to;Generations;Goals;Health Sciences;Investigation;Literature;Medical;Medicine;Methods;Minority;Participant;Perception;Procedures;Research;Research Personnel;Residencies;Students;Training Programs;Universities;abstracting;base;career;clinically relevant;design;experience;interest;medical schools;programs;research study;undergraduate student

public_health_relevance:
This summer program provides minority and disadvantaged undergraduate students with an initialexposure to basic and clinical science researchers and their areas of cardiovascular interest at theUniversity of Louisville Health Sciences Center. It is anticipated that significant number of theundergraduate students will elect to enter into graduate research programs at either this university orothers around the country as a results of the experiences in our program.


application_id: 8838221
project_number: 5R03HD078491-02
project_title: Biomechanical Assessment of Femur Fracture in Pediatric Falls
administering_ic: NICHD
award_notice_date: 2015-03-17
opportunity_number: PA-11-262
application_type: 5
activity_code: R03
ic: HD
serial_number: 078491
program_official: MAHOLMES, VALERIE
project_start_date: 2014-04-14
project_end_date: 2017-03-31
study_section: Function, Integration, and Rehabilitation Sciences Study Section[CHHD-K]
contact_pi_person_id: 9540778
contact_pi: THOMPSON, ANGELA KNIGHT
other_pis: BERTOCCI, GINA E.
congressional_district: 03
department: ENGINEERING (ALL TYPES)
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Child abuse is the leading cause of trauma-related fatalities in children less than four years of age. Children one year of age and younger are particularly at risk; approximately 1 out of every 48 children in this age group is a victim of abue or neglect. Cases of physical child abuse are commonly mistaken for accidental trauma. If the abuse goes unrecognized the child is at risk for further escalating injuries. An abused child returned to an unsafe home environment has up to an 80% risk for additional injury and up to a 30% risk of death. These repeat occurrences may be preventable through early detection of abuse. Fractures are early indicators of child abuse but are also a common result of accidental trauma such as household falls. Clinicians are often faced with the task of determining whether a child's injuries are the result of accidental causes or whether abuse should be suspected. Since household falls are a common false history given by caretakers to conceal abusive trauma information regarding fracture potential in short-distance falls and specifically what typeof fracture could result from different fall scenarios may aid clinicians in distinguishing abusiv from accidental injuries thus improving the accuracy of child abuse diagnoses.  The purpose of this study is to provide objective biomechanically-based information regarding femur fracture potential in short-distance falls. Three specific aims have been established to address this goal: (1) Describe femur loading (type and magnitude) associated with short-distance falls in young children (2) Describe the likelihood of femur fractures in short-distance falls (3) Develop an improved understanding of the influence of child-specific bone characteristics on fracture potential.  This study will involve three primary methodological components. First a CRABI 12-month-old anthropomorphic test device (ATD) will be modified to improve biofidelity of the lower extremities and instrumented to measure femur loads. Then fall simulations will be conducted using the improved surrogate to determine femur loading characteristics. The final component involves development of a finite element model of a 12-month-old human child's femur. Femur loads from the ATD experiments will be reproduced in the finite element model. This will provide insight into fracture potential for the combined loading scenarios measured experimentally. Additionally key parameters will be varied in the model as part of a sensitivity analysis to determine their effect on fracture potential. This will elucidate the effect of child-specific characteristics (such as bone density) on femur fracture potential. The outcomes from this study will provide an improved understanding of femur fracture potential in short-distance pediatric falls and lay the foundation for future work that will improve clinical assessments of injury and history compatibility. Additionally though this study focuses on femur fracture potential the approach used may serve as a model for future investigation of fracture potential in other bones.

project_terms:
Accidental Injury;Address;Adult;Age-Years;Alcoholism;Biomechanics;Bone Density;Cessation of life;Characteristics;Child;Child Abuse;Childhood;Childhood Injury;Clinical assessments;Computer Simulation;Consult;Cover-up;Data;Depression and Suicide;Development;Devices;Diagnosis;Drug abuse;Early Diagnosis;Early identification;Elements;Family;Femoral Fractures;Femur;Foundations;Fracture;Future;Goals;Health;Hip region structure;Home environment;Household;Injury;Investigation;Lead;Location;Lower Extremity;Measures;Mechanics;Modeling;Morbidity - disease rate;Outcome Study;Property;Publishing;Recording of previous events;Risk;Services;Stress;Testing;Trauma;Work;abuse victim;age group;base;bone;bone strength;child physical abuse;experience;falls;improved;insight;instrument;neglect;physical abuse;prevent;psychologic;research study;simulation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Clinicians are often challenged with determining whether a child's injuries are the result of accidental causes or whether abuse should be suspected. Since this decision often depends on the clinician's experience objective information about fracture potential in short-distance falls (a common excuse provided to conceal abuse) such as the location and type of fractures possible under various loading conditions will improve accuracy in child abuses diagnoses and the likelihood of earlier identification of child abuse.


application_id: 8838031
project_number: 5R01AG045775-02
project_title: Translating CD33 genetic mechanism into a novel Alzheimers therapeutic
administering_ic: NIA
award_notice_date: 2015-03-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AG
serial_number: 045775
program_official: REFOLO, LORENZO
project_start_date: 2014-04-15
project_end_date: 2018-03-31
study_section: Cellular and Molecular Biology of Neurodegeneration Study Section[CMND]
contact_pi_person_id: 1859637
contact_pi: ESTUS, STEVEN
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 overarching theme of this proposal is that polymorphisms identified by recent Alzheimer's disease (AD) genome wide association studies biologically define rate-limiting steps in AD pathways. Hence elucidating their mechanism of action will identify robust pharmacologic targets. Notably a SNP with modest molecular actions may reduce AD risk by 10% but a drug that acts strongly at the same target may have a large effect on AD risk. This proposal will elucidate the mechanism of action of rs3865444 (rs444) an AD-associated SNP in CD33 and translate this mechanism into a proof of concept AD treatment. In our highly compelling preliminary results we associate the AD-protective minor allele of rs444 with (i) a robust increase in the proportion of CD33 lacking exon 2 (D2-CD33) which appears critical to CD33 function. Large pharma have developed humanized monoclonal antibodies against CD33 for acute myeloid leukemia (AML); these antibodies and their derivatives have potential AD relevance as CD33 antagonists. This leads to our global hypothesis: Reduced CD33 function decreases AD risk whether CD33 inhibition is due to genetics or pharmacologic agents. To test our hypothesis we will (i) Elucidate the mechanism underlying the CD33 AD SNP (ii) Compare CD33 and D2- CD33 function especially relative to AD pathogenic mechanisms and (iii) Translate CD33 genetics into a novel AD therapeutic mimic. Overall this focused proposal will develop our compelling mechanistic genetic results elucidate the differences in D2-CD33 and CD33 function and begin to translate these changes into an AD-preventive agent. In work beyond the scope of this focused proposal we anticipate that these therapeutic agents will be tested in "AD" murine models that are transgenic for human CD33 and eventually humans.

project_terms:
Alleles;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's Disease Pathway;Alzheimer's disease risk;Antibodies;Apolipoprotein E;Apoptotic;Asses;Binding (Molecular Function);Brain;Critical Pathways;Exons;Fab Immunoglobulins;Family member;Foundations;Future;Genes;Genetic;Genetic Polymorphism;Genotype;Goals;Half-Life;Health;Human;Immunoglobulins;In Vitro;Individual;Lectin;Length;Leukemia Myelocytic Acute;Ligands;Mediator of activation protein;Messenger RNA;Microglia;Minor;Molecular;Mus;Mutate;NR0B2 gene;Neurons;Odds Ratio;PTPN11 gene;Phagocytosis;Pharmaceutical Preparations;Preventive;Process;Production;Protein Isoforms;Proteins;RNA Splicing;Relative (related person);Reporting;Sialic Acids;Signal Transduction;Single Nucleotide Polymorphism;Staging;Testing;Therapeutic;Therapeutic Agents;Transgenic Model;Translating;Work;cohort;cytokine;genome wide association study;humanized monoclonal antibodies;in vivo;inhibitor/antagonist;novel;novel therapeutics;pre-clinical;public health medicine (field);receptor;sulfated glycoprotein 2;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The significance of this proposal to public health is that we will identify the mechanism whereby a genetic factor modulates the risk of Alzheimer's disease. We will then perform studies to identify agents that target this mechanism as proof-of-concept pre- clinical Alzheimer's disease prevention studies.


application_id: 8837638
project_number: 5R01ES019217-05
project_title: Endothelial Progenitor Cells and Particulate Air Pollution
administering_ic: NIEHS
award_notice_date: 2015-04-23
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 019217
program_official: SCHUG, THADDEUS
project_start_date: 2011-09-23
project_end_date: 2017-10-31
study_section: Special Emphasis Panel[ZRG1-CVRS-C(02)M]
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: BHATNAGAR, ARUNI ;POPE, ARDEN
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): Multiple epidemiological and experimental studies report that acute or chronic exposure to air pollution is associated with adverse cardiovascular events including myocardial ischemia stroke arrhythmias heart failure sudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fine and ultrafine particulate matter (PM) fractions which are generated directly from the combustion of fossil fuels and are found in automobile exhaust wood or coal smoke and industrial emission from smelters paper or steel mills or cement plants. A common feature of PM-associated cardiovascular disorders is the establishment and maintenance of a dysfunctional endothelium. Because endothelial dysfunction is an early symptom of cardiovascular disease and an important factor in acute thrombotic complications of atherosclerosis such as stable and unstable angina myocardial infarction and ischemic stroke it could be a key mediator of the cardiovascular toxicity associated with PM exposure. The adult endothelium is a differentiated cell layer that provides a non-thrombotic interface between parenchymal cells and peripheral blood. Damages due to normal "wear-and-tear" in this layer are repaired by the mobilization and homing of bone-marrow resident pluripotent cells or endothelial progenitor cells (EPCs) which also promote angiogenesis and wound healing. We have recently identified a negative correlation between PM exposure and circulating EPC level. Here we hypothesize that defects in EPC mobilization or function are a consequence of PM-induced systemic inflammation induced by oxidative stress. We will test this hypothesis in three aims. First we will examine PM-induced changes in EPC populations in the peripheral blood and bone marrow of mice exposed to concentrated ambient air particles (CAPS) or filtered air. We will determine the time course of these effects whether there is a mobilization defect per se whether specific populations and locations of EPC are affected and whether this response is selective to EPCs or other stem cells such as the hematopoietic stem cells and mesenchymal stem cells are affected as well. In addition we will measure circulating levels of EPC-derived microparticles to test whether exposure to PM increases EPC activation or cell death. The second aim is to delineate the mechanisms by which PM exposure affects EPC function. For this we will assess how exposure to CAPs affects the ability of EPCs to grow differentiate migrate and promote wound healing. We will examine whether these changes in EPC are accompanied by an increase in systemic inflammation and oxidative stress and whether antioxidant interventions or strategies to increase NO availability would prevent PM-induced deficits in EPC number and function. Finally Aim 3 is to examine whether PM-induced changes in human peripheral blood EPC number and function are accompanied by an increase in systemic inflammation oxidative stress and microparticle or miRNA biomarkers and whether anti-oxidant intervention could reverse such changes. Successful completion of this project will provide novel insights into the cardiovascular toxicity of PM and how it affects the abundance and the reparative capacity of stem cells. Findings of this project could also form the basis for the development of new biomarkers of PM exposure or new strategies to mitigate PM toxicity.

project_terms:
Acetylcholine;Acute;Admission activity;Adult;Affect;Air;Air Pollution;Animals;Antioxidants;Aorta;Arrhythmia;Atherosclerosis;Automobile Exhaust;Biological Markers;Blood Cells;Blood Pressure;Blood Vessels;Bone Marrow;Breathing;Cardiotoxicity;Cardiovascular Diseases;Cardiovascular Pathology;Cardiovascular system;Cell Count;Cell Death;Cell Survival;Cell physiology;Cells;Cessation of life;Chronic;Coagulation Process;Coal;Defect;Deposition;Development;Endothelium;Epidemiologic Studies;Event;Exposure to;Flow Cytometry;Fossil Fuels;Free Radicals;Generations;Goals;Heart Arrest;Heart failure;Hematopoietic;Hematopoietic stem cells;Homing;Hospitals;Human;Inflammation;Inflammatory Response;Injury;Intervention;Ischemic Stroke;Lead;Location;Maintenance;Measures;Mediator of activation protein;Mesenchymal Stem Cells;MicroRNAs;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Oxidation-Reduction;Oxidative Stress;Paper;Particulate;Particulate Matter;Plants;Plasma;Population;Reaction;Relaxation;Reporting;Risk;Smoke;Steel;Stem cells;Symptoms;Testing;Thrombosis;Time;Toxic effect;Ultrafine;Unstable angina;Wood material;Wound Healing;air filter;angiogenesis;atherogenesis;base;cardiovascular disorder risk;cardiovascular health;cardiovascular risk factor;cell growth;endothelial dysfunction;human tissue;insight;novel;particle;peripheral blood;prevent;repaired;research study;response;stroke;tissue repair;young adult

public_health_relevance:
Exposure to particulate matter (PM) air pollution is strongly correlated with the initiation and progression of atherosclerosis increased thrombosis myocardial infarction and stroke. These cardiovascular pathologies are characterized by a dysfunctional endothelium and its inefficient repair by pluripotent cells or endothelial progenitor cells (EPCs). Thus in this proposal we test the hypothesis that the cardiotoxicity resulting from PM exposure is a consequence of PM-induced deficits in EPC number or function.


application_id: 8837170
project_number: 1R01HL123927-01A1
project_title: Crosstalk between membrane traffic proteins and integrin activation
administering_ic: NHLBI
award_notice_date: 2014-09-24
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: HL
serial_number: 123927
suffix: A1
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
project_abstract:
DESCRIPTION (provided by applicant): Crosstalk between membrane traffic proteins and integrin activation DESCRIPTION (provided by applicant): Platelets are central to hemostasis because they respond to vascular damage and secrete a variety of granule cargo molecules which are critical to thrombosis and its sequellae. Platelet secretion is a multistep process involving centralization of cytoplasmic organelles that provides a contractile force membrane fusion controlled by membrane traffic proteins and release of granule contents. The platelet integrin IIb3 interacts with adhesive ligands such as fibrinogen and fibrin and mediates platelet adhesion and aggregation and thus plays a critical role in the development of thrombotic diseases such as heart attack and stroke. The overall goal of this proposal is to establish a link between the membrane traffic proteins and integrins that involve the two key events to platelet function platelet cargo release and integrin activation. VPS33B is a member of the Sec1/Munc18 protein family that has multiple roles in exocytosis. VPS33B is defective in patients with arthrogryposis renal dysfunction cholestasis (ARC) syndrome. Platelets from these patients lack  granules. In an attempt to define the roles of  granules in platelet functio and thrombosis we produced a mouse model of  granule deficiency in which VPS33B was deleted only in megakaryocytes and platelets. In Specific Aim 1 we will determine the roles of VPS33B in IIb3 dependent endocytosis and IIb3 outside-in signaling.  granule contents vWF and fibrinogen are significantly reduced in the platelets lacking VPS33B. Surprisingly VPS33B-/- platelets fail to retract a clot and are defective in spreading on fibrinogen. Using the CHO recombinant IIb3activation model we showed that overexpression of VPS33B markedly potentiates cell spreading on fibrinogen and actin polymerization. Thus we hypothesize that in platelets there exists a crosstalk between the membrane traffic proteins and integrin activation and that VPS33B is a key contributor to IIb3 outside-in signaling. This hypothesis will be tested using the platelet- specific VPS33B conditional knockout mice and other VPS33B knockout mice such as whole-body knockout mice and a Chinese Hamster Ovary (CHO) integrin activation model. Our preliminary data demonstrated that VPS33B co-localizes with IIb3 as detected by confocal microscopy and forms a complex with IIb3 as detected by co-immunoprecipitation. In Specific Aim 2 we will use multiple approaches to characterize the binding determinants in VPS33B and the cytoplasmic domains for each other. In Specific Aim 3 we will identify the molecular mechanisms of VPS33B-dependent IIb3 outside-in signaling. Completion of these studies will not only identify a novel IIb3 binding partner that plays an important role in IIb3 outside-in signaling but also for the first time establish a lin between membrane traffic proteins and integrin activation in platelets.

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

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Blood platelets are essential for acute thrombotic events such as heart attacks and strokes and also contribute to local and systemic inflammation. This research project seeks to understand how the membrane traffic proteins such as VPS33B regulate platelet integrin activation and thrombosis. Completion of the work will provide new insights into pathways that could be targeted to prevent and treat arterial thrombosis a leading cause of death in the United States.


application_id: 8836996
project_number: 5R33DA035641-03
project_title: Buprenorphine Treatment and Health Reform: Availability Utilization and Quality
administering_ic: NIDA
award_notice_date: 2015-05-01
opportunity_number: RFA-DA-13-001
application_type: 5
activity_code: R33
ic: DA
serial_number: 035641
program_official: DUFFY, SARAH Q
project_start_date: 2013-05-01
project_end_date: 2018-04-30
study_section: NSS
contact_pi_person_id: 8146786
contact_pi: KNUDSEN, HANNAH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Although its implementation is likely to vary across states due to the recent Supreme Court decision passage of the Affordable Care Act (ACA) is expected to dramatically impact the delivery of substance use disorder (SUD) treatment through changes to treatment financing and greater integration of mainstream health care and SUD treatment. The evolving system of buprenorphine treatment for opioid use disorders (OUDs) is a prime example of integration. While this system has grown substantially in the past decade research is limited regarding how physicians are implementing this lifesaving treatment and whether they are delivering HIVrelated services. It is unknown how the ACA will impact the delivery of buprenorphine treatment. The proposed study seeks 1 year of R21 support to establish study feasibility and 4 years of R33 support to conduct a longitudinal study of buprenorphine implementation that integrates multi-level data on state-level variations in ACA implementation with longitudinal surveys of buprenorphine-prescribing physicians. The primary aim of the R21 phase is to determine the feasibility of conducting a longitudinal study that integrates physician-level and state-level data collection through research procedures linked to 4 milestones encompassing the construction of the physician sample survey development through qualitative and cognitive interviews and generation of a protocol for longitudinal collection of state-level data on ACA implementation. The three specific aims of the proposed R33 study are: (1) To estimate cross-sectional and longitudinal models of buprenorphine utilization as well as the implementation of high-quality clinical practice behaviors (CPBs) and HIV-related services in buprenorphine treatment in the context of states implementation of the ACA; (2) To examine the relative importance of patient payment source (e.g. Medicaid private insurance or out-of-pocket) and other patient characteristics on physician decision-making during buprenorphine treatment; and (3) To model the state-level associations between the implementation of the ACA and two state-level outcomes: utilization of buprenorphine within Medicaid and the number of physicians holding the X-license for prescribing buprenorphine. These aims will be accomplished through ongoing collection of policy and administrative data at the state-level with 4 annual surveys of a nationally representative sample of 1200 physicians who hold the X-license to prescribe buprenorphine. This longitudinal survey design will support fielding four unique conjoint analyses each addressing a key domain of physician decision-making while also collecting data on CPBs over time. Data analysis will include cross-sectional multivariate models of decision-making and multi-level longitudinal analyses of CPB adoption and implementation to test theory-driven hypotheses. By measuring the quality availability and utilization of buprenorphine treatment in the US this research may identify treatment gaps for which interventions may be developed to improve treatment quality for OUDs while contributing to scientific knowledge regarding the impact of the ACA on US treatment services.

project_terms:
Address;Adoption;Behavior;Buprenorphine;Caring;Characteristics;Clinical;Cognitive;Collection;Data;Data Analyses;Data Collection;Decision Making;Development;Disease;District of Columbia;Drug Utilization;Feasibility Studies;Future;Generations;Growth;Guidelines;HIV;HIV risk;Health;Health Care Reform;Healthcare;Individual;Insurance;Intervention;Interview;Knowledge;Licensing;Link;Longitudinal Studies;Longitudinal Surveys;Mainstreaming (Education);Measurement;Measures;Medicaid;Methodology;Modeling;Monitor;Opiate Addiction;Opioid;Outcome;Patient Selection;Patients;Persons;Pharmaceutical Preparations;Phase;Physicians;Policies;Procedures;Protocols documentation;Quality of Care;Relative (related person);Research;Sampling;Services;Source;Statutes and Laws;Substance Use Disorder;Supreme Court Decisions;Surveys;System;Technology;Testing;Time;Variant;base;clinical care;clinical decision-making;clinical practice;court;design;improved;innovation;longitudinal design;medical specialties;payment;theories

public_health_relevance:
This research will provide significant information about the implementation of buprenorphine for the treatment of opioid dependence by physicians in the context of the Affordable Care Act including clinical decisionmaking and treatment quality. Measuring the quality of buprenorphine treatment may identify important targets for future interventions to improve the quality of care received by opioid-dependent patients while providing vital information regarding how health care reform is impacting this sector of the US treatment system.


application_id: 8836910
project_number: 5R01DE012505-18
project_title: Molecular Aspects of Oral Plaque Formation
administering_ic: NIDCR
award_notice_date: 2015-03-30
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 012505
program_official: LUNSFORD, DWAYNE
project_start_date: 1998-09-01
project_end_date: 2016-04-30
study_section: Special Emphasis Panel[ZRG1-MOSS-B(02)M]
contact_pi_person_id: 7355414
contact_pi: LAMONT, RICHARD J
other_pis: DEMUTH, DONALD R
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): Periodontal disease one of the most common infections of humans has a polymicrobial etiology whereby groups of microorganisms exhibit synergistic pathogenicity. As a model system for the study of polymicrobial synergy we are investigating P. gingivalis-S. gordonii interactions. S. gordonii an early colonizer of the plaque
biofilm provides an attachment substratum for the more pathogenic later colonizer P. gingivalis. Contact dependent signaling and metabolite perception initiate further accumulation of P. gingivalis and the development of a dual species community. Interspecies coadhesion is mediated by the short fimbriae (comprised of the Mfa1 structural subunit) of P. gingivalis that engage the Ssp surface proteins of S. gordonii. Within SspB several amino acid motifs within a region spanning residues 1167-1193 (designated BAR) dictate binding activity and specificity. Development and later constraint of community development depends on the balance of tyrosine phosphorylation (through the kinase Ptk1) and dephosphorylation (through the phosphatase Ltp1) within P. gingivalis which controls expression of community effectors such as Mfa1 and LuxS. This tyrosine (de)phosphorylation dependent signal transduction pathway also converges on the expression genes encoding proteases and a dual species community of P. gingivalis and S. gordonii is more pathogenic compared to either species alone in a murine alveolar bone loss model. The objectives of this study are to: i) characterize the structural and functional motifs of Mfa1 that interact with the BAR domain of SspB; ii) define the role of the P. gingivalis tyrosine kinase Ptk1 in regulatory networks that control heterotypic community development with S. gordonii; and iii) determine the responses of P. gingivalis to the streptococcal metabolite 4-aminobenzoate (pABA) that regulate community development and pathogenic potential. Successful completion of these objectives will provide novel structure and function information on the P. gingivalis Mfa1 fimbrial adhesin. In addition we will unravel the interplay between tyrosine kinase (Ptk1) and phosphatase (Ltp1) activities in the signal transduction events that regulate community development. We will also generate novel information regarding metabolite sensing and its role in both community development and pathogenic potential. Our broad long-term goal is to translate this fundamental mechanistic information into the identification of novel targets for therapeutic intervention directed toward pathogenic community inhibition. As single target intervention can have limited utility and has yet to yield any significant advances in periodontal therapeutic options interference with multiple components of pathogenic community development including adhesive and maturation events may have a greater likelihood of success.

project_terms:
Adherence (attribute);Adhesives;Affect;Alveolar Bone Loss;Amino Acid Motifs;Bacteria;Bacterial Infections;Bacteroides;Binding (Molecular Function);Biochemical;Biological Models;Catalytic Domain;Cell Communication;Cells;Communication;Communities;Community Developments;Complex;Coupled;Development;Disease;Disease Progression;Equilibrium;Etiology;Event;Exhibits;FeBABE;Fimbrial Adhesins;Gene Expression;Gene Expression Regulation;Genes;Goals;Human;Infection;Intercept;Intervention;Maps;Mediating;Membrane Proteins;Metabolic;Microbial Biofilms;Modeling;Molecular;Molecular Models;Mono-S;Mus;Oral;Oral cavity;Organism;Pathogenesis;Pathogenicity;Peptide Hydrolases;Perception;Periodontal Diseases;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Porphyromonas gingivalis;Process;Production;Protease Gene;Protein Dephosphorylation;Protein S;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;Regulation;Role;Severities;Signal Transduction;Signal Transduction Pathway;Specificity;Streptococcus gordonii;Structure;Surface;System;Testing;Therapeutic;Therapeutic Intervention;Tooth structure;Toothpaste;Translating;Tyrosine;Tyrosine Phosphorylation;Virulence;base;bone loss;fimbria;microbial;microbial community;microorganism;microorganism culture;molecular modeling;mutant;novel;oral plaque;pathogen;prevent;protein metabolite;public health relevance;response;success;yeast two hybrid system

public_health_relevance:
Information that will be obtained from this study has the potential to be translated into the development of toothpastes or mouthrinses that can prevent disease causing organisms from accumulating on the teeth. These would reduce the ability of disease causing bacteria to persist in the mouth and consequently prevent or reduce the severity of gum disease.


application_id: 8836396
project_number: 5R01CA125454-08
project_title: Regulation of Snail in breast cancer progression and metastasis
administering_ic: NCI
award_notice_date: 2015-06-03
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 125454
program_official: AULT, GRACE S
project_start_date: 2007-09-13
project_end_date: 2016-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7042357
contact_pi: ZHOU, BINHUA P
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):  Basal-like breast cancer (BLBC) exhibits an aggressive clinical history with development of recurrence distant metastasis shorter survival and usually occurs in young women. BLBC intrinsically possesses many epithelial-mesenchymal transition (EMT) characteristics and cancer stem cell (CSC)-like features suggesting that activation of EMT program generates high-grade invasive cells with CSC-like traits in BLBC. Our long-term goal is to discover the intrinsic factors within tumor cells and the extrinsic signals from tumor microenvironments that regulate EMT and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last several years we have systematically studied the role of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our study clearly indicates that Snail is one of the key intrinsic factors within tumor cells responsible for EMT; our study also implies that the inflammatory tumor microenvironment provides an extrinsic signal for EMT. However how the extrinsic tumor milieu of BLBC is initiated and built up despite its paramount importance remains unaddressed. Recently we found that expression of the X-box binding protein (XBP1) was significantly reduced in BLBC from human breast tumor samples and mouse breast cancer tissues. Snail suppressed XBP1 expression and resulted in a significant upregulation of CCL2 a major chemokine for tumor associated macrophages (TAMs) and lymphocytes. XBP1 is a key molecule in the most conserved "unfolded-protein response" (UPR) signaling pathway that cells use to cope with environmental and cellular stresses in endoplasmic reticulum (ER). Loss of XBP1 results in "unresolved ER stress" which signals endogenous cellular injury triggering leukocyte infiltration and a significant boost of inflammatory responses in target tissues. We hypothesize that the loss of XBP1 by Snail-mediated repression ignites an "inside out" signal for recruiting TAMs and lymphocytes which establish an inflammatory/wound stroma to further boost EMT and cultivate CSC-like traits in BLBC by providing additional cytokines and growth factors. The objective of this proposal is to characterize the repression of XBP1 by Snail and explore therapeutic interventions that will disrupt this vicious cycle and thereby restore ER homeostasis using a newly developed specific Snail inhibitor. Guided by strong preliminary data we will test this hypothesis by pursuing three specific aims: (1) to determine the molecular mechanisms responsible for Snail-mediated XBP1 repression in BLBC; (2) to delineate why loss of XBP1 enhances inflammation in BLBC; and (3) to elucidate the functional roles of XBP1 in vivo. Our proposal is innovative and significant because it will not only open a new paradigm that significantly affects our views on the co- evolvement of tumor cells and their microenvironments in breast cancer progression and metastasis but will also lay groundwork for developing new therapeutic strategies against this disease.

project_terms:
Address;Affect;BRCA1 gene;Binding Proteins;Boxing;Brain;Breast;Breast Cancer Cell;CCL2 gene;Caenorhabditis elegans;Cancer cell line;Cancer stem cell;Cells;Cellular Stress;Characteristics;Chromatin;Clinical;Complex;Data;Development;Disease;Distant Metastasis;Down-Regulation;E-Cadherin;Endoplasmic Reticulum;Environment;Enzymes;Epithelial;Exhibits;Fostering;Gene Silencing;Glycogen Synthase Kinase 3;Goals;Growth Factor;Homeostasis;Human;IL8 gene;Immune;Infiltration;Inflammation;Inflammatory;Inflammatory Bowel Diseases;Inflammatory Response;Interleukin-6;Intervention;Intestines;Intrinsic factor;Knowledge;Leukocytes;Location;Lung;Lymphocyte;Malignant Neoplasms;Mammary Neoplasms;Mediating;Medical Oncologist;Mesenchymal;Molecular;Mus;Mutation;Neoplasm Metastasis;Outcome;Pathologist;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Play;Promotor (Genetics);Proteins;Reagent;Recording of previous events;Recruitment Activity;Recurrence;Regulation;Repression;Research;Role;Sampling;Signal Pathway;Signal Transduction;Site;Snails;Stromal Neoplasm;Testing;Therapeutic Intervention;Tissues;Up-Regulation (Physiology);cancer therapy;cell injury;chemokine;chromatin modification;coping;cytokine;endoplasmic reticulum stress;epithelial to mesenchymal transition;gene repression;genome wide association study;in vivo;inhibitor/antagonist;innovation;insight;macrophage;malignant breast neoplasm;multidisciplinary;neoplastic cell;novel;novel therapeutics;outcome forecast;paracrine;prevent;programs;public health medicine (field);public health relevance;research study;response;success;targeted treatment;trait;tumor;tumor microenvironment;tumor progression;ubiquitin isopeptidase;ubiquitin-protein ligase;wound;young woman

public_health_relevance:
Our proposal is innovative since we will have a significant impact to public health through its potential to influence cancer treatment. The knowledge gained will expand our understanding of the co-evolvement between tumor cells and their microenvironments in tumor progression and metastasis. When successfully completed these studies will provide insights for the development of novel interventions to prevent and treat metastatic basal-like breast cancer.


application_id: 8836250
project_number: 1F31NS087878-01A1
project_title: The role of microglia in acute pathology of repeated concussion and CTE development
administering_ic: NINDS
award_notice_date: 2014-09-16
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: NS
serial_number: 087878
suffix: A1
program_official: BELLGOWAN, PATRICK S F
project_start_date: 2014-09-22
project_end_date: 2016-09-21
study_section: Special Emphasis Panel[ZRG1 F01-F (20)]
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
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;Behavior;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;astrogliosis;behavior test;catalyst;combat;cytokine;cytotoxic;early onset;high risk;hyperphosphorylated tau;in vivo;injured;innovation;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: 8835777
project_number: 1F30ES025099-01
project_title: Xenobiotic Receptors Modulate PCB-induced Steatohepatitis
administering_ic: NIEHS
award_notice_date: 2015-04-02
opportunity_number: PA-14-150
application_type: 1
activity_code: F30
ic: ES
serial_number: 025099
program_official: HEINDEL, JERROLD
project_start_date: 2015-04-15
project_end_date: 2020-04-14
study_section: Special Emphasis Panel[ZRG1 F06-S (20)]
contact_pi_person_id: 12058438
contact_pi: CLAIR, HEATHER B
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): Non-alcoholic fatty liver disease (NAFLD) is intimately associated with obesity diabetes and the metabolic syndrome. Traditionally NAFLD has been associated with caloric excess on a susceptible genetic background however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of steatosis and steatohepatitis particularly in
the context of hypercaloric diet coexposure. Our proposed study uses exposure parameters informed by our recent analysis of serum samples from a previously-described cohort of individuals residing in Anniston AL who were exposed to high levels of PCB-containing waste. Although many of these individuals have serum levels of PCBs above that found in the general population of the US their exposures remain well below the levels implicated in acute liver injury. Nevertheless these individuals have significantly elevated biomarkers of liver injury as well as elevated inflammatory cytokines elevated prevalence of diabetes and increased BMI when compared to an unexposed population. A frustrating finding of previous toxicity studies has been the very different pathological response of mice and humans to such subacute chronic and environmentally relevant PCB exposures. Our preliminary data in a mouse model of subacute PCB exposure shows paradoxical elevations of liver injury biomarkers fatty change and inflammatory cytokines at lower exposure vs. higher exposure to a PCB mixture (20mg Aroclor 1260/kg body weight vs. 200mg/kg body weight Aroclor 1260). In two knockout mouse models that lack the constitutive androstane receptor (CAR) or the pregnane and xenobiotic receptor (PXR) our laboratory has found differential transcription of the gene targets of these receptors in response to Aroclor 1260 and high-fat diet exposure. These patterns of pathological and phenotypic responses are consistent with a transcription-factor based mechanism of PCB toxicity. The differences in disease endpoints may therefore be due to differences in ligand specificity and target gene cohort between the human and mouse forms of these receptors. We therefore propose to expand our investigation of receptor-based mechanisms of PCB toxicity with the use of a novel triple-transgenic mouse model expressing human forms of AhR PXR and CAR. We hypothesize that using both an acute-exposure primary hepatocyte culture and a whole animal chronic exposure model we will find that differences in the structure and function of these receptors will drive a differential transcriptioal response to PCBs and ultimately differences in PCB-associated disease endpoints.

project_terms:
AHR gene;Acute;Address;Adolescent;Adult;Affect;Affinity;Animals;Aryl Hydrocarbon Receptor;Biological Markers;Body Weight;Cessation of life;Chemicals;Chronic;Comorbidity;Complex;Computer Simulation;Data;Diabetes Mellitus;Diet;Disease;Dose;Energy Intake;Environmental Exposure;Enzymes;Etiology;Exposure to;Fatty Change;Fatty Liver;Fatty acid glycerol esters;Gene Expression;Gene Expression Profile;Gene Targeting;General Population;Genes;Genetic;Genetic Transcription;Hepatic;Hepatocyte;Human;Individual;Inflammation;Inflammatory;Insulin Resistance;Investigation;Knockout Mice;Laboratories;Ligands;Lipids;Liver Cirrhosis;Liver diseases;Mediating;Metabolic Diseases;Metabolic syndrome;Metabolism;Microarray Analysis;Modeling;Molecular Weight;Mus;NHANES;Nutritional;Obesity;Odds Ratio;Overweight;Participant;Pathologic;Pathway interactions;Pattern;Pharmaceutical Preparations;Pollution;Polychlorinated Biphenyls;Population;Pregnanes;Prevalence;Primary carcinoma of the liver cells;Receptor Activation;Research;Risk;Role;Sampling;Serum;Specificity;Steatohepatitis;Testing;Toxic Environmental Substances;Toxic effect;Transcript;Transgenic Mice;Transplantation;Wild Type Mouse;Xenobiotics;acute liver injury;base;carbohydrate metabolism;cardiovascular risk factor;cohort;constitutive androstane receptor;cytokine;design;exposed human population;feeding;human AHR protein;improved;liver injury;mRNA Expression;mouse model;non-alcoholic fatty liver;nonalcoholic steatohepatitis;novel;pollutant;population based;public health relevance;receptor;receptor structure function;response;transcription factor;transcriptomics;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Traditionally non-alcoholic fatty liver disease has been associated with high caloric intake however recent studies from our laboratory and others have pointed out a role for environmental toxicants including polychlorinated biphenyls (PCBs) in the etiology of fatty liver and liver disease. This application studies the connection of pollution and
liver disease.


application_id: 8835696
project_number: 3R21NS080091-02S1
project_title: Novel transgenic mice for tracing and electrophysiology of stressed neurons
administering_ic: NINDS
award_notice_date: 2014-04-10
opportunity_number: PA-11-261
application_type: 3
activity_code: R21
ic: NS
serial_number: 080091
suffix: S1
program_official: JAKEMAN, LYN B
project_start_date: 2012-07-01
project_end_date: 2016-06-30
study_section: Molecular Neurogenetics Study Section[MNG]
contact_pi_person_id: 9011081
contact_pi: PETRUSKA, JEFFREY C
other_pis: HAI, TSONWIN
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Numerous neurological diseases and pathologies include or are hypothesized to include cellular injury and/or stress as part of the mechanism. Experimental approaches to examine these mechanisms or even determine if they are indeed at play in certain conditions are generally limited. They include post-mortem analyses of known stress-response genes/molecules in vivo pharmacological manipulations which are often systemic or functional assessments/manipulations which often cannot separate stressed from non-stressed neurons. Ideally it would be possible to determine a priori on a cell-by-cell basiswhich neurons in a mixed population were exhibiting a cell-stress response. Further since some stress responses or at least some components of the stress response are only transiently expressed even though the overall stress responses may have a cumulative effect on the cell it would be highly useful to have an a priori indication of which neurons had exhibited a stress response at some point in the past. It would also be highly useful to be able to selectively assess the cellular and inter-cellular functionality of the stressed neurons. To these ends we propose to generate new functional-reporter transgenic mouse lines which will incorporate these characteristics. The reporters will be driven by the promoter region of Activating Transcription Factor 3 (ATF3) a "hub" protein involved in a variety of cellular stress responses. Generation of the mice will be via BAC-transgenes in order to preserve function of the native ATF3 alleles which are necessary for certain cellular processes. The BAC transgene with the ATF3 locus will drive production of the light-gated ion channel channelrhodopsin-2 (ChR2) fused to a fluorescent protein. One model will have the reporters produced in an analogue fashion (i.e. to reflect native ATF3 expression). A second model will use an inducible Cre-recombinase system to permanently "switch-on" reporter production thus allowing at any later time identification ofneurons that previously expressed a stress response. These functional-reporter models will allow offline anatomical assessments FACS or laser-capture separations fate-tracing of previously-stressed neurons and in vivo or in vitro functional assessments specifically of stressed neurons (i.e. those expressing ChR2).

project_terms:
Acute;Address;Affect;Afferent Neurons;Alleles;Basic Science;Behavior assessment;Biochemical Genetics;Brain Concussion;Breeding;Cell physiology;Cells;Cellular Stress;Cellular Stress Response;Characteristics;Chimeric Proteins;Chronic;Core Facility;Demyelinations;Disease;Electrophysiology (science);Event;Exhibits;Gated Ion Channel;Gene Expression;Generations;Genes;Genetic;Goals;Hand;Health;Image;In Vitro;Individual;Injection of therapeutic agent;Injury;Ischemia;Knockout Mice;Label;Lasers;Life;Light;Long-Term Effects;Microscopy;Modeling;Motor Neurons;Mus;Nerve Crush;Neurologic;Neurons;Nuclear;Operative Surgical Procedures;Optics;Pain;Pathology;Peripheral Nervous System;Physiological;Play;Population;Process;Production;Promoter Regions (Genetics);Proteins;Reporter;Research;Signal Transduction;Stress;Synapses;System;Tamoxifen;Time;Tissues;Transgenes;Transgenic Mice;Transgenic Organisms;Trauma;Venus (Planet);activating transcription factor 3;analog;base;biological adaptation to stress;cell injury;chemotherapeutic agent;chronic pain;in vivo;injured;innovation;light gated;mouse model;nervous system disorder;neurological pathology;novel;optogenetics;recombinase;response;response to injury;stressor;tissue fixing;tool

public_health_relevance:
This project is intended to generate research tools specifically 2 new lines of transgenic mice that will produce functional and anatomical reporters in response to cellular stress. These lines would significantly enhance basic science approaches to understand neurological processes and conditions that have a cellular injury and/or stress component. They would provide capabilities that are currently either highly limited or entirely lacking.


application_id: 8835226
project_number: 1F32NS087833-01A1
project_title: Assessing interactions between cerebrovascular and tau pathologies
administering_ic: NINDS
award_notice_date: 2014-09-11
opportunity_number: PA-14-149
application_type: 1
activity_code: F32
ic: NS
serial_number: 087833
suffix: A1
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-09-22
project_end_date: 2014-12-31
study_section: Special Emphasis Panel[ZRG1 F01-F (20)]
contact_pi_person_id: 11740087
contact_pi: BROTHERS, HOLLY
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
project_abstract:
DESCRIPTION (provided by applicant): Dementia is a loss of cognitive function that is extremely costly to individuals and society. Dementia is not defined by a single cause or pathology and is most often attributed to Alzheimer's disease (AD ~70%) and vascular dementia (VaD ~17%) yet a considerable number of dementia cases (20-50%) share aspects of both. The broad objective of this proposal is to improve characterization of the commonalities and differences between these forms of dementia. Better understanding can improve diagnosis of dementias within this spectrum interpretation of clinical results confounded by co-morbidity and direction of therapeutic approaches.  In order to better understand the overlap and differences between dementias within the spectrum between AD and VaD this proposal focuses on two factors often shared between AD and VaD hyperhomocysteinemia (HHcy) and tau pathology. HHcy is a risk factor for cardiovascular disease and related VaD but is also frequently present in AD and other dementias. HHcy may play a causal role in the development of dementia. Tau pathology is a hallmark of AD but is also present in a range of neurodegenerative diseases including VaD and may be promoted by HHcy. The focused objectives of this proposal are to understand the interactions between cerebrovascular and tau pathologies identify mechanism by which HHcy may promote tau pathology and to address interventional approaches that may be useful in dementia patients with HHcy.  In order to address these objectives this proposal will utilize a model of diet-induced chronic HHcy developed by our lab and a recently developed transgenic mouse that expresses a suppressible human tau transgene. Aim 1 will evaluate the interactions between HHcy and tau particularly the effects on cognitive deficit and address dietary reversal of HHcy and pharmacological suppression of tau pathology as therapeutic approaches. Aim 2 will determine if changes in the metabolic pathway of homocysteine are likely pathway for an HHcy-induced increase in tau pathology. HHcy-induced vascular pathology (microhemorrhage) tau pathology (oligomers hyperphosphorylated species and neurofibrillary tangles) cognitive impairment (spatial memory) and enzymes/metabolites of homocysteine metabolism will be evaluated. These aims investigate separate aspects of the relationship between HHcy tau and cognitive impairment. Each aim will offer valuable information to determine the usefulness of intervention strategies to reduce HHcy and tau pathology in the substantial subset of dementia patients with comorbid HHcy.  Finally these studies provide the opportunity to broaden my repertoire of technical skills and develop intellectually under the mentorship of my sponsor and mentoring committee. In particular I will learn: magnetic resonance imaging in mice use of transgenic mice assessment of tau and vascular pathology and how to address a need with the development of a novel model. These aims are designed to support my gradual progression toward autonomy and will provide the foundation for independent research.

project_terms:
Address;Age-Months;Alzheimer's Disease;Amino Acids;Attenuated;Behavioral;Biochemical;Blood Vessels;Cardiovascular Diseases;Cerebrovascular Disorders;Chronic;Clinical;Clinical Treatment;Cognitive;Cognitive deficits;Comorbidity;Data;Dementia;Development;Diagnosis;Diet;Enzymes;Foundations;Goals;Homocysteine;Homocystine;Human;Hyperhomocysteinemia;Impaired cognition;Individual;Intervention;Lead;Learning;Lithium;Magnetic Resonance Imaging;Measures;Memory;Memory impairment;Mentors;Mentorship;Metabolic Pathway;Metabolism;Methylation;Modeling;Mus;Nerve Degeneration;Neurodegenerative Disorders;Neurofibrillary Tangles;Outcome;Outcome Measure;Pathology;Pathway interactions;Patients;Pharmacological Treatment;Phosphoric Monoester Hydrolases;Phosphorylation;Play;Process;Relative (related person);Research;Risk Factors;Role;S-Adenosylhomocysteine;S-Adenosylmethionine;Societies;Testing;Therapeutic;Time;Transgenes;Transgenic Mice;Transgenic Organisms;Vascular Dementia;cardiovascular risk factor;cerebrovascular;cognitive function;design;improved;innovation;mixed dementia;mouse model;novel;public health relevance;skills;tau Proteins;tau phosphorylation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Dementia has no single cause or pathology and varies across a wide spectrum which includes Alzheimer's disease and vascular dementia. This proposal is designed to better understand the interaction between a cardiovascular risk factor (high homocysteine) and hallmark pathology of Alzheimer's (tau) common to both types of dementia. When understanding of this relationship is improved we will be better able to diagnose different dementias interpret clinical results and direct therapeutic approaches.


application_id: 8835204
project_number: 3R01NS073584-04S1
project_title: ER stress and oligodendrocyte survival after spinal cord injury
administering_ic: NINDS
award_notice_date: 2014-04-10
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: NS
serial_number: 073584
suffix: S1
program_official: JAKEMAN, LYN B
project_start_date: 2011-02-01
project_end_date: 2016-01-31
study_section: Acute Neural Injury and Epilepsy Study Section[ANIE]
contact_pi_person_id: 1895692
contact_pi: WHITTEMORE, SCOTT R
other_pis: HETMAN, MICHAL
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
project_abstract:
DESCRIPTION (provided by applicant): The endoplasmic reticulum (ER) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia inflammation trauma excitotoxicity and oxidative damage. The ERSR is initially protective but if malfolded proteins cannot be cleared apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK IRE1/XBP-1 and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI. In Aim 1 we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents constitutive and conditional null mice as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions.

project_terms:
Acute;Address;Apoptosis;Apoptotic;Cell Culture Techniques;Cell Death;Cell Survival;Cells;Cellular Stress;Cessation of life;Chemicals;Chemosensitization;Chronic;Coculture Techniques;Commit;Cytoplasm;Cytoprotection;Data;Defense Mechanisms;Disease;Endoplasmic Reticulum;Family;Functional disorder;Genes;Genetic;Grant;Hand;Health;Hypoxia;In Vitro;Inflammation;Injury;Knockout Mice;Locomotor Recovery;Mediating;Mediator of activation protein;Membrane Proteins;Methods;Modeling;Molecular Chaperones;Mus;Neurons;Oligodendroglia;Organelles;Pathology;Pathway interactions;Patients;Phosphorylation;Protein Dephosphorylation;Proteins;Recovery of Function;Role;Signal Transduction;Small Interfering RNA;Spinal Cord;Spinal Ganglia;Spinal cord injury;TNFRSF10B gene;Translational Repression;Translations;Trauma;Traumatic CNS injury;Tunicamycin;Up-Regulation (Physiology);arm;biological adaptation to stress;cytotoxic;effective therapy;endoplasmic reticulum stress;excitotoxicity;improved;in vitro Assay;in vivo;inhibitor/antagonist;insight;loss of function;nervous system disorder;new therapeutic target;novel;oligodendrocyte precursor;oxidative damage;precursor cell;protective effect;research study;response;secretory protein;tauroursodeoxycholic acid;therapeutic target;transcription factor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present there is no effective treatment either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response a cellular defense mechanism induced in every spinal cord cell after SCI in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.


application_id: 8835108
project_number: 5R21DK100258-02
project_title: Dietary fat lipoproteins and lipopolysaccharide: role in insulin resistance
administering_ic: NIDDK
award_notice_date: 2015-03-30
opportunity_number: PA-12-157
application_type: 5
activity_code: R21
ic: DK
serial_number: 100258
program_official: ABRAHAM, KRISTIN M
project_start_date: 2014-04-15
project_end_date: 2017-09-30
study_section: Special Emphasis Panel[ZRG1-EMNR-P(03)S]
contact_pi_person_id: 6773599
contact_pi: KERN, PHILIP A
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Obesity is associated with insulin resistance and chronic inflammation in adipose tissue muscle and liver and the mechanisms underlying this inflammation is not well understood. Endotoxin (lipopolysaccharide LPS) is carried on gut-derived lipoproteins (chylomicrons) and provides a link between dietary fat and inflammation. During chylomicrons assembly LPS and LPS binding protein (LBP) are attached to the particle. Plasma LPS in the chylomicron fraction transiently increases following a fatty meal. Chylomicron triglyceride is cleared from plasma by adipose and muscle lipoprotein lipase (LpL); remnant lipoproteins are then cleared by the liver. Strong associations between insulin resistance/diabetes and plasma LPS have been found. Further links between gut bacteria and insulin resistance are illustrated by many experiments in germ-free mice or in mice with microbiota transplants which show changes in diet-induced obesity and insulin resistance. We hypothesize that the LPS on chylomicrons is delivered to adipose tissue muscle and liver during chylomicron TG lipolysis and the released LPS initiates a low-grade inflammatory reaction in these tissues that contributes to tissue inflammation and insulin resistance. A slow process of chylomicron lipolysis with persistent remnant lipoproteinemia may be associated with high exposure to LPS and consequent tissue inflammation. There is already an extensive literature in rodents demonstrating alterations in obesity inflammation and insulin resistance with various immune modulations or manipulations of microbiota. These questions have not been well tested in humans. This study is intended to determine whether alteration of gut microbiota can impact human lipoprotein associated LPS and insulin resistance. Specific Aim 1. We will determine whether an alteration in the gut microbiota achieved with rifaximin will decrease circulating LPS. We will measure plasma LPS both in the fasting state and after a lipid-rich meal in obese MetS subjects. The subjects will then be treated with the antibiotic rifaximin for 8 weeks to substantially reduce gut bacteria which can be detected by current techniques. Specific Aim 2. We will determine whether a change in the gut microbiota from rifaximin treatment will decrease adipose inflammation and improve insulin resistance. Subjects will undergo a baseline fat biopsy and a euglycemic clamp to measure peripheral and hepatic insulin sensitivity. They will then be treated with rifaximin and the insulin sensitivity testing ad biopsies will be repeated to determine if disruption of the microbiota reduces tissue inflammation and improves insulin sensitivity.

project_terms:
Abbreviations;Adipose tissue;Aftercare;Antibiotic Therapy;Antibiotics;Area Under Curve;Bacteria;Binding (Molecular Function);Biopsy;Chronic;Chylomicrons;Diabetes Mellitus;Diet;Dietary Fats;Endotoxins;Euglycemic Clamping;Exposure to;Extracellular Matrix;Fasting;Fatty acid glycerol esters;Germ-Free;Glucose Clamp;Health;Hepatic;Human;Immune system;Inflammation;Inflammatory;Infusion procedures;Insulin;Insulin Resistance;Intervention;Limulus;Link;Lipids;Lipolysis;Lipopolysaccharides;Lipoproteins;Literature;Liver;Measures;Metabolic syndrome;Methods;Mus;Muscle;Nonesterified Fatty Acids;OGTT;Obesity;Peripheral;Plasma;Play;Process;Reaction;Research;Rodent;Role;Safety;Serum amyloid A protein;Techniques;Testing;Tissues;Transplantation;Triglycerides;bacterial resistance;gut microbiota;immunoregulation;improved;insulin sensitivity;lipopolysaccharide-binding protein;lipoprotein lipase;particle;research study;rifaximin

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity is closely linked with insulin resistance and diabetes and current research suggests that inflammation of fat plays a causal role in insulin resistance. Dietary fat causes an increase in plasma lipopolysaccharide which circulates bound to lipoproteins and we hypothesize that the LPS is transported to tissues and is responsible for much of the tissue inflammation associated with insulin resistance.


application_id: 8834521
project_number: 1R43DK104625-01
project_title: A new biomarker for diabetic foot ulcers
administering_ic: NIDDK
award_notice_date: 2015-02-09
opportunity_number: PA-14-058
application_type: 1
activity_code: R43
ic: DK
serial_number: 104625
program_official: ARREAZA-RUBIN, GUILLERMO
project_start_date: 2015-02-09
project_end_date: 2016-08-08
study_section: Special Emphasis Panel[ZRG1 SBIB-Q (11)]
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 submitted in response to the new NIDDK announcement (PA-14- 058) calling for development of methodologies or biomarkers to help understand the pathophysiology of T1D type 1 diabetes (T1D) complications. An estimated 15-25% of the 25.8 million diabetic patients in this country will develop diabetic foot ulcers (DFU) at some point in their lives. DFU is the leading cause of non-traumatic lower-extremity amputations caused by non-healing wounds. Despite thousands of dressing products developed to treat chronic wounds none has proven effective for DFU. As stated in the RFA a significant obstacle for progress in developing drugs for diabetic complications is the paucity of biomarkers and surrogate endpoints for measuring the initiation progression and response to treatments of diabetic complications.  Although many factors are involved in non-healing DFU tissue ischemia is known to be a major factor contributing to poor wound healing. Ischemia may not be the initiating factor for DFU because most ulcers start from a combination of neuropathy pressure loading and/or trauma. However tissue ischemia is the main cause that hinders healing. Providing oxygen to chronic ulcers has not obtained stable results. This is because oxygen is only one of the ingredients required for HEP production.  The specific aim of this phase I proposal is to explore the possibility of using high- energy phosphate (HEP) contents as a biomarker to predict the progression and recurrence of diabetic ulcers. We plan to use a diabetic animal wound model with and without ischemia to test the changes of HEP in these wounds along with the expression of several key factors known to be critical to wound healing such as vascular endothelial growth factors cytokines macrophages collagens and angiogenesis and correlated them to obtain a preliminary picture of the relationship between these factors and the haling of diabetic wounds. The result may provide a preliminary indication whether the change of HEP content alone or along with other key factors will be better used to predict the likelihood of healing. This is a difficult job but we already have a proof-of-concept.

project_terms:
Amputation;Animals;Biological Markers;Chronic;Collagen;Complications of Diabetes Mellitus;Country;Development;Diabetic Foot Ulcer;Diabetic ulcer;Diabetic wound;Functional disorder;Goals;Growth Factor;Healed;Human;Insulin-Dependent Diabetes Mellitus;Ischemia;Lower Extremity;Measures;Methodology;Modeling;National Institute of Diabetes and Digestive and Kidney Diseases;Neuropathy;Occupations;Oxygen;Pharmaceutical Preparations;Phase;Production;Recurrence;Research;Sterile coverings;Supplementation;Surrogate Endpoint;Testing;Tissues;Trauma;Ulcer;Up-Regulation (Physiology);Vascular Endothelial Growth Factors;Wound Healing;angiogenesis;cost;cytokine;diabetic;diabetic patient;healing;inorganic phosphate;macrophage;pressure;public health relevance;response;wound

public_health_relevance:
PUBLIC HEALTH RELEVANCE: A significant obstacle for progress in developing drugs for diabetic complications is the paucity of biomarkers and surrogate endpoints to measure the initiation progress and response to treatments for diabetic foot ulcers despite decades of research. We have found that tissue high-energy phosphate contents are severely reduced in human diabetic wounds and supplementation of high-energy phosphate to diabetic wounds in animals resulted in enhanced healing along with up regulation of growth factors cytokines angiogenesis and macrophage accumulation and proliferation. This phase I proposal will explore the possibility of using tissue high-energy phosphate as a biomarker to predict the likelihood of healing along with the expression of growth factors cytokines macrophages and angiogenesis. Our goal is to develop a biomarker which is low cost easy to use and accurate for diabetic foot ulcers.


application_id: 8834428
project_number: 1F31HL126403-01
project_title: Bringing Advanced Heart MRI to Pediatric Clinics Using an Interactive Videogame
administering_ic: NHLBI
award_notice_date: 2015-04-15
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: HL
serial_number: 126403
program_official: MEADOWS, TAWANNA
project_start_date: 2015-04-20
project_end_date: 2018-04-19
study_section: Special Emphasis Panel[ZRG1 F15-P (20)]
contact_pi_person_id: 12104869
contact_pi: HAMLET, SEAN MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Congenital heart disease (CHD) affects roughly 2 million people in the US and remains responsible for twice as many years of life lost as all of childhood cancer combined. Cardiac magnetic resonance (CMR) imaging has become the gold standard technique that clinicians use to monitor cardiovascular function in patients over time. Advanced CMR techniques offer incredible potential for improving our ability to diagnose and treat patients with CHD but currently require long acquisition times that limit their feasibility n the clinic. Our overall goal is to make these advanced CMR techniques clinically feasible through dramatically reducing the time required to acquire the image data. We propose a new CMR system which we call videogame interface for diaphragm location (VIDLoc) that can reduce acquisition times by 50%. VIDLoc works by advising children how to alter their breathing patterns in real-time during CMR in order to dramatically reduce the total time required to acquire CMR data. Because the heart moves up and down on the diaphragm as children breathe imaging can only be performed when the diaphragm is within a narrow region called the "acceptance window". Since children breathe very erratically the amount of time they spend in the acceptance window is often as low as 20% (thus imaging can only be performed 1/5th of the time). VIDLoc overcomes this by imaging the child's diaphragm location in real-time and using this to generate a videogame showing a car on a road. The car's location relative to the road represents the diaphragm location relative to the acceptance window. VIDLoc will provide instructions to children to guide their diaphragm (or car) to be within the acceptance window (or road) where the heart can be imaged. We hypothesize that using VIDLoc will increase the amount of time spent in the acceptance window and therefore dramatically reduce CMR acquisition times. This will make advanced CMR techniques clinically feasible in patients with CHD. We will first optimize VIDLoc by adding extra features such as text and voice feedback of breathing instructions which will be tested by children with CHD to determine each feature's effectiveness. Then we will test VIDLoc against conventional free breathing for acquisition time and quality of data derived. Twenty children with CHD will undergo an advanced CMR technique to image three-dimensional cardiac motion. Lastly we will quantify the acquisition time and quality of data derived from VIDLoc with and without pre-CMR training in a simulator. A simulated version of the VIDLoc system outside of the scanner will use a sensor to quantify chest wall excursion as a proxy for diaphragm location. Twenty children with CHD will be randomized to undergo advanced CMR using VIDLoc with or without pre-CMR training in the simulator. Acquisition times and image quality will be used to determine the efficacy of pre-CMR training. The overall goal of this proposal is to use VIDLoc to reduce CMR acquisition time so that we can start using advanced CMR techniques in the clinic to ultimately improve the lives of patients with congenital heart disease.

project_terms:
Adult;Affect;Automobile Driving;Benchmarking;Blood;Breathing;Cardiac;Cardiovascular Physiology;Chest wall structure;Child;Childhood;Clinic;Clinical;Congenital Heart Defects;Data;Data Quality;Decision Making;Diagnosis;Diaphragm (Anatomy);Effectiveness;Feedback;Figs - dietary;Future;Goals;Gold;Heart;Heart Diseases;Image;Imaging Techniques;Imaging technology;Instruction;Ionizing radiation;Location;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Childhood Neoplasm;Measures;Monitor;Mortality Vital Statistics;Motion;Operative Surgical Procedures;Patients;Pattern;Positioning Attribute;Proxy;Randomized;Relative (related person);Reproducibility;Role;Scanning;System;Techniques;Testing;Text;Time;Training;Voice;Work;base;congenital heart disorder;heart function;heart imaging;heart motion;improved;public health relevance;repaired;sensor;time use;years of life lost

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Advanced imaging techniques for quantifying heart function in children born with heart defects require long imaging times that reduce their clinical feasibility.
This project's interactive videogame system has the ability to reduce the imaging times required to perform advanced heart imaging by over 50%. The overall goal of this project is to use this imaging technology to improve our understanding of heart function in order to guide appropriate treatments in children and in the future adults with heart disease.


application_id: 8834106
project_number: 1F32HL126300-01
project_title: Prevention of heart failure and remodeling through calcium channel modulation
administering_ic: NHLBI
award_notice_date: 2014-12-01
opportunity_number: PA-14-149
application_type: 1
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)]
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;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;Outcome;Paper;Pathway interactions;Patients;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;adrenergic;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;public health relevance;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: 8833900
project_number: 1R43CA192850-01
project_title: Large Volume Intratumoral Injection Device for Therapeutic Liver Infusions
administering_ic: NCI
award_notice_date: 2015-05-14
opportunity_number: PA-14-071
application_type: 1
activity_code: R43
ic: CA
serial_number: 192850
program_official: NARAYANAN, DEEPA
project_start_date: 2015-05-14
project_end_date: 2017-10-31
study_section: Special Emphasis Panel[ZRG1 OTC-T (12)]
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: 2015-05-14
budget_end_date: 2017-10-31
project_abstract:
DESCRIPTION (provided by applicant): The objective of this proposal is to demonstrate the feasibility of an innovative injection device (proposed product) to improve upon intratumoral delivery of liver therapeutics as compared to standard injection needles currently used. Hepatocelluar carcinoma (HCC) will become an increasing burden on economic resources in the coming years as the prevalence of cirrhosis due to multiple disease processes in the general population increases. Transplant and surgical treatment are well established and have provided satisfactory overall survival for eligible patients however only a small minority of HCC patients are eligible for these therapies. Therefore considerable efforts have been directed toward developing alternative minimally invasive treatments. HCC therapeutic delivery by direct injection has the potential to significantly reduce the expense and morbidity of current therapeutics or those in development. Though direct injection is a seemingly straightforward approach to the problem limited ability to inject tumors greater than 3cm in diameter and uneven distribution of the therapeutic after injection are significant drawbacks to direct injectin. In contrast to conventional injection needles the proposed injection device is porous along the entire length of the targeted anatomy; therefore the surface area of tissue in contact with infusate is considerably increased. Hypothesis: Improved infusate delivery will lead to a larger area and more uniform distribution of infusate within the tumor tissue and lend itself to enhanced therapeutic direct intratumoral injection protocols for various chemoablative and anti- neoplastic infusates. Preliminary Data: We have demonstrated that porous injection devices have significantly improved in vivo distribution of ethanol within normal canine prostates and other studies have demonstrated the unique performance benefits of applicant's porous injection device. Specific Aim: This project entails preclinical testing of the porous injection device for eventual application to human patients with intrahepatic tumors. Aim 1. Demonstrate that the porous injection device provides broader distribution of an infusate compared to a standard needle. Task 1 - Transfer of VX-2 Cells and growth of tumor in rabbit for tumor implant tissue. Task 2 - Determine the preferred flow rate for infusate into the VX-2 tumor in rabbit liver Task 3 - Comparison of concentration and distribution of infusate components after infusion into VX-2 tumor with porous device and standard needle. Milestone: The porous injection device will show 50% greater distribution as compared to needle injection.

project_terms:
Ablation;Anatomy;Animal Model;Animals;Area;Caliber;Canis familiaris;Carcinoma;Catheters;Chemicals;Chemoembolization;Cirrhosis;Clinical;Cytotoxic agent;Data;Development;Devices;Diagnosis;Disease;Doxorubicin;Drug Delivery Systems;Drug resistance;Economics;Encapsulated;Ensure;Ethanol;Fiber;Gadopentetate Dimeglumine;General Population;Hepatitis C;Human;Implant;Incidence;Infusion procedures;Injection of therapeutic agent;Lead;Length;Link;Liver;Liver neoplasms;Malignant neoplasm of liver;Methodology;Minority;Modeling;Morbidity - disease rate;Needles;New Zealand;Operative Surgical Procedures;Oryctolagus cuniculus;Partial Hepatectomy;Patients;Penetration;Performance;Phase;Preclinical Testing;Prevalence;Primary carcinoma of the liver cells;Process;Prostate;Protocols documentation;Radioembolization;Recurrence;Regulatory Pathway;Research;Resources;Solid Neoplasm;Surface;Survival Rate;System;Technology;Therapeutic;Therapeutic Agents;Tissues;Transplantation;Treatment Efficacy;Tumor Pathology;Tumor Tissue;United States;cancer cell;cell growth;chemotherapeutic agent;commercialization;contrast imaging;cytotoxic;drug distribution;improved;in vivo;innovation;interest;intrahepatic;liver transplantation;minimally invasive;neoplastic;novel;public health relevance;standard of care;treatment planning;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Effective drug delivery of therapeutic agents directly into avascular regions of solid tumors is challenging with current clinical methodologies. The Applicants have developed novel porous hollow fiber catheters which have the potential to demonstrate more uniform and better distribution of an infusate into solid tumor tissue than standard of care needles. In this project animal studies will be conducted to compare the PHFC to standard needle for infusate delivery into a liver cancer animal model.


application_id: 8833528
project_number: 2R44AI102326-02
project_title: Enhanced baculovirus vectors with higher titers and increased genome stability
administering_ic: NIAID
award_notice_date: 2014-12-01
opportunity_number: PA-14-071
application_type: 2
activity_code: R44
ic: AI
serial_number: 102326
program_official: CHALLBERG, MARK D
project_start_date: 2013-01-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1 IMST-K (14)]
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 the
fact 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 an
improved 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. Many
BEVS 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;Heavy Metals;Infection;Insect Viruses;Insecta;Link;Maintenance;Mammalian Cell;Marketing;Methods;Modification;Mutation;Phase;Phenotype;Process;Production;Promotor (Genetics);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;protein expression;protein function;protein structure function;public health relevance;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: 8833473
project_number: 2R44OD018231-02A1
project_title: A non-surgical embryo transfer device for producing gene modified rats
administering_ic: OD
award_notice_date: 2015-08-18
opportunity_number: PA-14-071
application_type: 2
activity_code: R44
ic: OD
serial_number: 018231
suffix: A1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2010-07-15
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1 EMNR-S (10)]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): ParaTechs Corporation develops innovative technologies for biomedical research while seeking to improve animal welfare for laboratory animals. One of ParaTechs' major goals is to further the guiding principles of ethical animal use by 'reducing replacing and refining' the use of animals in research according to the guidelines of Russell and Burch's 3Rs of animal research. ParaTechs already has brought to market a non-surgical embryo transfer device (NSETTM) for mice which replaces surgical embryo transfers with a non-surgical method that has been proven to cause less stress in research animals. The goal of this project is to develop a device and a research protocol for nonsurgical embryo transfer in rats. The device and protocol is to be rapid easy to use cost effective and efficien for embryo transfer. Poof of principle for the project was established during Phase I where multiple prototypes of a rat NSET device were designed manufactured and tested. Rat embryos were transferred and viable rat pups were obtained demonstrating the first successful nonsurgical embryo transfer in rats. The goal of Phase II is to further establish the parameters of
rat NSET technology and to develop the device for commercialization to the biomedical research community. Four objectives are proposed to achieve this goal. First we will determine the efficiency of non-surgical embryo transfer relative to surgical embryo transfer in Sprague-Dawley and Fischer 344 rats for both morula and blastocyst stage embryos. This study will have broad applications for transfer of cryopreserved embryos and for transfer of genetically modified embryos after introduction of embryonic stem cells. Second we will transfer in vitro cultured embryos using the rNSET and compared efficiency to surgical embryo transfer techniques. This aim will address successful transfer of rat embryos that may be modified very early in development; for example after pronuclear injection for the purpose of genetic modification. Third we will test the use of the rat NSET for artificial insemination as an alternative to surgical techniques. This aim will support the use of the device as an alternative t surgical artificial insemination and as a possible alternative to in vitro fertilization. Fourth w will assess the level of stress reduction of the NSET procedure compared to surgical embryo transfer. These aims are consistent with ParaTechs' overall goal to improve animal welfare and support more effective and humane use of animal models in biomedical research.

project_terms:
Address;Adopted;Animal Experimentation;Animal Model;Animal Welfare;Animals;Artificial Insemination;Assisted Reproductive Techniques;Award;Behavior;Biological Markers;Biomedical Research;Birth;Businesses;Cardiovascular Diseases;Categories;Cell Culture Techniques;Collaborations;Communities;Data;Development;Device Designs;Devices;Distress;Embryo;Embryo Transfer;Ethics;Female;Fertilization in Vitro;Funding;Gene-Modified;Genetic;Goals;Guidelines;Implant;In Vitro;Individual;Injection of therapeutic agent;Institution;Knock-out;Laboratories;Laboratory Animals;Laboratory Rat;Laboratory Research;Lead;Letters;Life;Maintenance;Marketing;Measures;Methods;Modeling;Modification;Morals;Morula;Mus;Operative Surgical Procedures;Outcome;Pain;Painless;Pharmaceutical Preparations;Phase;Physiology;Procedures;Protocols documentation;Rat Strains;Rattus;Relative (related person);Research;Research Personnel;Resources;Rivers;Services;Societies;Staging;Stress;Techniques;Technology;Testing;Tissue Sample;Toxicology;Transgenic Organisms;blastocyst;commercialization;cost;cost effective;design;embryo culture;embryonic stem cell;genetic manipulation;human disease;human tissue;improved;innovative technologies;meetings;method development;mouse model;prototype;public health relevance;pup;sperm cell;tissue culture

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The ability to genetically modify the laboratory rat is producing increasingly valuable and unique strains to investigate human disease. Currently this technology is dependent on implanting embryos in female rats by surgical means. ParaTechs proposes to develop and commercialize a unique device and technology for fast simple and painless nonsurgical embryo transfer (NSET) in rats which will support the Office of Laboratory Animal Welfare (OLAW) objectives of reducing pain and distress for laboratory animals because it will provide an alternative to surgical methods for assisted reproductive techniques.


application_id: 8833310
project_number: 5R21HD079256-02
project_title: NMDA modulation of diabetes-induced glutamate synaptic plasticity
administering_ic: NICHD
award_notice_date: 2015-03-13
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: HD
serial_number: 079256
program_official: GRAVE, GILMAN D
project_start_date: 2014-04-10
project_end_date: 2017-03-31
study_section: Special Emphasis Panel[ZRG1-IFCN-Z(02)M]
contact_pi_person_id: 1911523
contact_pi: SMITH, BRET N
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):  Diabetes mellitus is a major health concern affecting nearly 26 million people in the United States. Serious complications result from diabetes including heart disease stroke hypertension blindness nervous system damage and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control including control of blood glucose homeostasis. Experiments utilize a model of type 1 diabetes but findings will more broadly apply to other forms of diabetes since autonomic dysfunction increases the risk of developing type 2 diabetes. Preautonomic neurons of the dorsal vagal complex which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV) are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes leading to autonomic dysregulation including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that glutamate release in the DMV is persistently enhanced in a model of type 1 diabetes in a manner consistent with development of a possible compensatory response to prolonged hyperglycemia that suggests homeostatic plasticity that mitigates against the decreased vagal output seen in diabetes. In addition NMDA receptor modulation has a relatively larger effect on glutamate release in diabetic mice versus controls. This exploratory proposal aims to determine the causes and underlying features of the recently-discovered diabetes-induced enhancement of tonic excitatory drive to DMV neurons. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to NMDA receptor sensitivity changes associated with diabetes development in the streptozotocin-treated mouse a model of type 1 diabetes. Aim 1 will determine if recently-identified NMDA receptors located on presynaptic terminals contacting DMV cells are upregulated in diabetes. Aim 2 will determine if postsynaptic NMDA receptors on the somadendritic portion of identified glutamatergic NTS neurons that project to the DMV are upregulated in diabetes. The sensitivity of these changes to glucose and insulin will also be identified. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint based on modulating specific neural functions in the brainstem to eventually address diabetes-related autonomic dysregulation in patients.

project_terms:
Abdomen;Accounting;Address;Affect;Animal Model;Area;Autonomic Dysfunction;Blindness;Blood Glucose;Brain;Brain Diseases;Brain Stem;Cell Nucleus;Cells;Chronic;Complex;Data;Development;Diabetes Mellitus;Diabetic mouse;Disease;Dorsal;Equilibrium;Functional disorder;Future;Gastrointestinal tract structure;Glucose;Glutamates;Goals;Health;Heart Diseases;Hepatic;Homeostasis;Human;Hyperglycemia;Hypertension;Insulin;Insulin-Dependent Diabetes Mellitus;Knowledge;Liver;Mediating;Metabolic Control;Modeling;Modification;Motor Neurons;Motor output;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Nervous System Trauma;Neurons;Neurophysiology - biologic function;Non-Insulin-Dependent Diabetes Mellitus;Nucleus solitarius;Organ;Output;Pancreas;Pathology;Patients;Peripheral;Play;Presynaptic Terminals;Receptor Activation;Regulation;Relative (related person);Risk;Role;Slice;Staging;Stomach;Streptozocin;Symptoms;Synapses;Synaptic plasticity;System;Testing;Tissues;United States;Vagus nerve structure;Viscera;Whole Blood;base;blood glucose regulation;cell body (neuron);cell motility;diabetes mellitus therapy;diabetic;dorsal motor nucleus;gastrointestinal;glucose metabolism;glucose production;neural circuit;postsynaptic;presynaptic;receptor;receptor function;receptor sensitivity;research study;response;stroke

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Preganglionic parasympathetic neurons in the vagal complex innervate the abdominal organs and critically regulate whole blood glucose metabolism. These neurons are sensitive to elevated glucose and undergo long- lasting changes in synaptic excitability in an animal model of diabetes. The proposed exploratory experiments will examine mechanisms underlying diabetes-associated synaptic changes in the vagal complex that may represent a compensatory response to chronic hyperglycemia with the eventual goal of informing future studies aimed at treating pathologies underlying diabetic hyperglycemia.


application_id: 8832046
project_number: 1R43NS084701-01A1
project_title: Catheter for Large Volume Intraparenchymal Brain Therapies
administering_ic: NINDS
award_notice_date: 2014-09-25
opportunity_number: PA-14-071
application_type: 1
activity_code: R43
ic: NS
serial_number: 084701
suffix: A1
program_official: FERTIG, STEPHANIE
project_start_date: 2014-09-30
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1 ETTN-C (10)]
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: 2014-09-30
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;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;design;gene therapy;human study;improved;in vivo;innovation;meetings;novel;prototype;public health relevance;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: 8831674
project_number: 5P42ES007380-18
project_title: Chloro-Organic Degradation by Polymer Membrane Immobilized Iron-Based Particle Sy
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7485
contact_pi_person_id: 8534525
contact_pi: BHATTACHARYYA, DIBAKAR
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: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Adsorption;Aftercare;Attention;Benign;Biological Sciences;Carbon;Chemicals;Chemistry;Chlorine;Collaborations;Development;Diffusion;Drug Metabolic Detoxication;Engineering;Environment;Environmental Health;Free Radicals;Funding;Generations;Health;Heating;High temperature of physical object;Human;Hydrogen Peroxide;Hydroxyl Radical;Individual;Inflammatory;Iron;Kentucky;Knowledge;Laboratories;Laboratory Research;Lead;Ligands;Manufacturer Name;Medical;Membrane;Metals;Methods;Modeling;Mono-S;Nature;Outcome Study;Palladium;Pathway interactions;Phase;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Production;Reaction;Relative (related person);Research;Risk;Risk Management;Science;Scientist;Site;Soil;Solutions;Solvents;Source;Structure;Superfund;System;Techniques;Technology;Temperature;Testing;Toxic effect;Toxicity Tests;Translational Research;Trichloroethylene;United States Environmental Protection Agency;Vinyl Chloride;Water;Work;base;chemical stability;cost effective;dechlorination;demineralization;design;drinking;drinking water;global environment;hazard;hydrodynamic flow;innovation;iron oxide;metal oxide;microbial;nanoparticle;nanoscale;nanosized;nanostructured;novel;nutrition;oxidation;particle;pollutant;prevent;public health medicine (field);remediation;scaffold;sensor;superfund chemical;superfund site;treatment strategy


application_id: 8831673
project_number: 5P42ES007380-18
project_title: Biomimetic Magnetic Nanocomposites as a Platform Technology for the Capture and S
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7484
contact_pi_person_id: 8239234
contact_pi: HILT, JAMES ZACH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Affinity;Antibodies;Binding (Molecular Function);Binding Proteins;Biodistribution;Biological;Biomimetics;Chemistry;Coupled;Detection;Dioxins;Engineering;Environment;Environmental Health;Environmental Pollution;Excision;Flavonoids;Fluorescence;Goals;Health;Human;Kentucky;Light;Magnetic nanoparticles;Magnetism;Mass Fragmentography;Membrane Microdomains;Methods;Milk;Molecular;Plants;Poisons;Polychlorinated Biphenyls;Polymers;Process;Production;Property;Proteins;Relative (related person);Reporting;Research;Resources;Risk;Route;Sampling;Sensitivity and Specificity;Soil;Solubility;Solutions;Specificity;Superfund;Surface;System;Techniques;Technology;Testing;Thick;Time;Toxic effect;Tryptophan;Tyrosine;Universities;Work;aqueous;base;bisphenol A;chemical stability;design;disorder prevention;evidence base;exposed human population;fundamental research;global environment;imprint;nanocomposite;nanomaterials;nanoscale;novel;novel strategies;nutrition;pi bond;pollutant;polymerization;polyphenol;rapid detection;remediation;screening;superfund chemical;superfund site;tool


application_id: 8831672
project_number: 5P42ES007380-18
project_title: Polychlorinated Biphenyls Nutrition and Diabetes - Project 3
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7483
contact_pi_person_id: 1857999
contact_pi: CASSIS, LISA A
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: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Acute;Adipocytes;Adipose tissue;Affect;Antioxidants;Aryl Hydrocarbon Receptor;Body Burden;Body Weight decreased;Community Health;Consumption;Data;Development;Diabetes Mellitus;Diabetic Diet;Diet;Dioxins;Environmental Exposure;Exhibits;Exposure to;Fatty acid glycerol esters;Female;Glucose;Health Surveys;Impairment;Insulin;Insulin Resistance;Intervention;Laboratories;Link;Lipids;Mediating;Mus;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Odds Ratio;Overweight;Oxidative Stress;Plasma;Polychlorinated Biphenyls;Population;Research;Resveratrol;Risk;Role;Serum;Testing;Therapeutic;Toxic Environmental Substances;Toxic effect;Tumor Necrosis Factor-alpha;Weight;Work;World Health Organization;aryl hydrocarbon receptor ligand;blood glucose regulation;clinically significant;cytokine;experience;feeding;glucose tolerance;glucose uptake;impaired glucose tolerance;improved;insulin signaling;insulin tolerance;lipophilicity;male;nutrition;pollutant;polyphenol;prevent;superfund chemical


application_id: 8831671
project_number: 5P42ES007380-18
project_title: Postnatal Complications of Perinatal Polychlorinated Biphenyl Exposure - Project
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7482
contact_pi_person_id: 10180341
contact_pi: PEARSON, KEVIN JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Adipose tissue;Adult;Adult Children;Aryl Hydrocarbon Receptor;Attenuated;Beta Cell;Biochemical;Body Composition;Breast;Child;Chlorinated Hydrocarbons;Data;Development;Diabetes Mellitus;Diet;Discipline of Nursing;Disease;Dose;Environment;Environmental Health;Environmental Pollutants;Environmental Pollution;Epidemic;Erythroid;Euglycemic Clamping;Exercise;Exposure to;Fatty acid glycerol esters;Female;Fostering;Functional disorder;Funding;Gender;Glucose Clamp;Glucose Intolerance;Goals;Gold;Health;Human Milk;Impairment;Inflammation;Inflammatory;Insulin;Insulin Resistance;Intervention;Laboratories;Life;Life Cycle Stages;Lipids;Long-Term Effects;Measures;Messenger RNA;Metabolism;Methods;Molecular;Mus;Neonatal;Nuclear;Obesity;Outcome;Oxidative Stress;Paper;Partner in relationship;Perinatal;Perinatal Exposure;Placenta;Play;Polychlorinated Biphenyls;Predisposition;Pregnancy;Prevalence;Principal Investigator;Relative (related person);Research;Risk;Role;Running;Serum;Solutions;Source;Staging;Techniques;Testing;Time;Tissues;Toxic effect;Toxin;United States;Weaning;Work;base;blood glucose regulation;chemical stability;cost effective;critical period;cytokine;exposed human population;fasting glucose;feeding;fetal;glucose tolerance;impaired glucose tolerance;improved;in utero;in vivo Model;innovation;insight;insulin sensitivity;insulin signaling;lifestyle intervention;liver inflammation;mouse model;novel;nutrition;offspring;pollutant;postnatal;pregnant;prenatal;prenatal exposure;programs;public health medicine (field);sedentary;superfund chemical;trait;trend


application_id: 8831670
project_number: 5P42ES007380-18
project_title: Superfund Chemicals Nutrition and Endothelial Cell Dysfunction - Project 1
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7481
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Affect;Agonist;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Arterial Fatty Streak;Aryl Hydrocarbon Receptor;Atherosclerosis;Biological Assay;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Catechin;Cause of Death;Caveolae;Cells;Chemicals;Chronic;Complement;Data;Development;Diet;Dietary Fats;Dietary Intervention;Dietary Polyphenol;Disease;Ecology;Endocrine disruption;Endothelial Cells;Endothelium;Environment;Environmental Health;Environmental Pollutants;Epigallocatechin Gallate;Erythroid;Event;Exposure to;Flavonoids;Foundations;Functional disorder;Genes;Green tea (dietary);Hazardous Waste Sites;Health;Health Food;Heme Oxygenase (Decyclizing);Human;Hypertriglyceridemia;In Vitro;Inflammation;Inflammatory;Investigation;Kentucky;Knockout Mice;Link;Lipids;Measures;Mediating;Membrane;Methodology;Modeling;Nuclear;Nutritional;Nutritional status;Omega-3 Fatty Acids;Omega-6 Fatty Acids;Oxidation-Reduction;Plants;Play;Poisons;Polychlorinated Biphenyls;Preventive;Process;Proteins;Regulation;Relative (related person);Research;Risk;Risk Assessment;Risk Factors;Role;Severities;Signal Pathway;Signal Transduction;Small Interfering RNA;Solutions;Structural Protein;Superfund;Technology;Testing;Time;Toxic effect;United States;Universities;Vascular Diseases;Vascular Endothelial Cell;Work;bioactive food component;caveolin 1;chemical stability;design;disorder risk;exposed human population;genetic manipulation;global environment;in vivo;mouse model;novel;nutrition;organic contaminant;pollutant;polyphenol;prevent;programs;protective effect;public health medicine (field);remediation;response;stressor;superfund chemical;superfund site;toxicant;trafficking;vascular inflammation


application_id: 8831669
project_number: 5P42ES007380-18
project_title: Training Core - Core E
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7480
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Affect;Clinical Sciences;Communication;Communities;Complex;Detection;Development;Dimensions;Discipline;Ecology;Educational aspects;Educational workshop;Environment;Environmental Health;Ethics;Fostering;Foundations;Future;Generations;Goals;Grant;Health;Human;Individual;Institution;Interdisciplinary Study;Internships;Intervention;Kentucky;Knowledge;Leadership;Life;Link;Measures;Medical Ethics;Mentors;Methods;Mission;Policies;Problem Solving;Public Health Education;Qualifying;Recruitment Activity;Research;Research Personnel;Research Training;Science;Scientific Advances and Accomplishments;Series;Signal Recognition Particle;Solid;Solutions;Students;Superfund;Targeted Research;Toxic effect;Toxicology;Training;Training Activity;Training Programs;Translational Research;Translations;Underrepresented Minority;Universities;Writing;base;biomedical scientist;career;career development;college;graduate student;health knowledge;improved;interdisciplinary collaboration;meetings;nutrition;outreach;pollutant;programs;public health medicine (field);remediation;responsible research conduct;skills;skills training;social;socioeconomics;success;superfund chemical;superfund site;symposium;tool;web page


application_id: 8831668
project_number: 5P42ES007380-18
project_title: Community Engagement Core - Core D
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7479
contact_pi_person_id: 8535399
contact_pi: GAETKE, LISA 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: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Affect;Appalachian Region;Area;Attitude;Chronic Disease;Collaborations;Communication;Communities;Community Actions;Community Services;County;Diet;Dietitian;Environmental Health;Environmental Pollutants;Evaluation;Exposure to;Family;Feedback;Food;Fostering;Funding;Hazardous Waste Sites;Health;Health Professional;Health Status;Health behavior;Human Resources;Individual;Kentucky;Knowledge;Life Style;Location;Methods;Nurses;Nutritional;Outcome;Outcome Measure;Outcomes Research;Physicians;Poisons;Population;Prevalence;Process;Recommendation;Research;Research Personnel;Resources;Risk;Services;Site;Superfund;Toxic effect;Translating;Trust;United States Environmental Protection Agency;Work;base;design;disease registry;empowered;evidence base;health knowledge;improved;interest;meetings;nutrition;programs;public health medicine (field);response;superfund chemical


application_id: 8831667
project_number: 5P42ES007380-18
project_title: Research Translation Core - Core C
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7478
contact_pi_person_id: 8535916
contact_pi: ORMSBEE, LINDELL E
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: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Advisory Committees;Appalachian Region;Area;Behavior Therapy;Chemicals;Clinical Sciences;Collaborations;Communication;Communities;County;Decision Making;Department of Energy;Diffusion;Documentation;Educational workshop;Electronics;Engineering;Ensure;Environment;Environment and Public Health;Environmental Health;Event;Exercise;Exposure to;Family health status;Fostering;Future;Goals;Health;Home environment;Housing;Human Resources;Information Dissemination;Interdisciplinary Study;Kentucky;Laboratory Research;Lead;Leadership;Maintenance;Medicine;Mentors;Mentorship;National Institute of Environmental Health Sciences;Outcome;Outcomes Research;Output;Pharmacology and Toxicology;Physiological;Plants;Poisons;Polychlorinated Biphenyls;Positioning Attribute;Printing;Process;Productivity;Program Development;Public Health Practice;Public Policy;Reporting;Research;Research Activity;Research Infrastructure;Research Institute;Research Project Grants;Research Support;Resources;Risk;Risk Management;Role;Scientist;Series;Services;Site;Solutions;Superfund;Targeted Research;Technology;Toxic effect;Training;Translating;Translational Research;Translations;Trichloroethylene;United States Environmental Protection Agency;Universities;Water;Work;base;cardiovascular pharmacology;disease registry;experience;health science research;implementation science;innovation;meetings;nano;new technology;nutrition;pollutant;practice-based research network;programs;public health medicine (field);success;superfund chemical;web site


application_id: 8831666
project_number: 5P42ES007380-18
project_title: Research Support Core - Core B
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7477
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Advanced Development;Animal Model;Animals;Area;Basic Science;Bioinformatics;Biological Markers;Biology;Biomedical Research;Biometry;Calibration;Cardiovascular Diseases;Cell model;Cells;Center for Translational Science Activities;Clinical;Clinical Research;Cultured Cells;Data;Data Analyses;Data Base Management;Data Set;Detection;Development;Dose;Drug Metabolic Detoxication;Ecology;Ensure;Experimental Designs;Funding;Gene Expression Profiling;Generations;Health Hazards;Health Services Research;High Pressure Liquid Chromatography;Individual;Inflammation;Informatics;Intervention;Investments;Kentucky;Laboratories;Life Style;Mass Fragmentography;Mass Spectrum Analysis;Mediator of activation protein;Metabolic;Metabolic Diseases;Methods;Monitor;Nutritional;Nutritional Study;Nutritional Toxin;Outcome;Oxidation-Reduction;Oxidative Stress;Pathway interactions;Polychlorinated Biphenyls;Productivity;Proteomics;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resources;Services;Superfund;Suspension substance;Suspensions;Systems Biology;Technology;Toxic effect;Toxin;Training;Universities;Validation;base;case control;computer infrastructure;data acquisition;data management;design;diphenyl;exposed human population;instrumentation;metabolomics;nutrition;programs;public health medicine (field);remediation;research study;sensor;sharing data;small molecule;superfund chemical


application_id: 8831665
project_number: 5P42ES007380-18
project_title: Administrative Core - Core A
administering_ic: NIEHS
award_notice_date: 2015-04-03
opportunity_number: RFA-ES-13-001
application_type: 5
activity_code: P42
ic: ES
serial_number: 007380
study_section: ZES1-LKB-K
subproject_number: 7476
contact_pi_person_id: 1897514
contact_pi: HENNIG, BERNHARD
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2016-03-31
project_terms:
Address;Advisory Committees;Area;Benign;Chemicals;Collaborations;Communication;Communities;Discipline;Documentation;Ecology;Educational workshop;Engineering;Ensure;Environment;Environmental Health;Environmental Pollution;Event;Exercise;Exposure to;Federal Government;Fostering;Future;Goals;Health;Housing;Human Resources;Individual;Inflammatory;Information Centers;Interdisciplinary Study;Kentucky;Leadership;Life Style;Maintenance;Medicine;Mentors;Mentorship;Modeling;National Institute of Environmental Health Sciences;Outcome;Output;Pharmacology and Toxicology;Physiological;Polychlorinated Biphenyls;Positioning Attribute;Private Sector;Process;Productivity;Program Development;Reporting;Research;Research Activity;Research Infrastructure;Research Project Grants;Research Support;Research Training;Resources;Risk;Role;Science;Scientist;Solutions;Superfund;Targeted Research;Technology;Toxic effect;Training;Translational Research;Translations;Universities;base;cardiovascular pharmacology;experience;health science research;innovation;meetings;nano;nutrition;pollutant;programs;public health medicine (field);remediation;superfund chemical;superfund site;training project


application_id: 8831603
project_number: 5R01CA109136-09
project_title: Novel Mechanisms of Carcinoma Cell Migration
administering_ic: NCI
award_notice_date: 2015-03-09
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 109136
program_official: WOODHOUSE, ELIZABETH
project_start_date: 2006-03-09
project_end_date: 2016-03-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1947523
contact_pi: O'CONNOR, KATHLEEN L.
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Tumor invasion and metastasis still claim the majority of cancer patients' lives. Although great strides have been made in cancer detection and prevention the need for a more effective treatment for cancer metastasis remains a central problem. Notably molecules that control spatial signaling for cell polarization and directed migration contribute to the lethality of cancer through their ability to improve the efficiency of he first steps of metastasis. RhoA contributes to cell polarization during directed cell motility yethow RhoA is spatially controlled remains unclear. We propose that integrin signaling through cAMP/PKA is instrumental for spatial signaling of RhoA and cell polarization. Importantly our previous work has shown that ?1 integrins control the generation of PKA activity gradients at the leading edge of migrating carcinoma cells where it controls RhoA function. We provide compelling evidence that these PKA activity gradients exist in breast carcinoma patient samples and in three-dimensional breast carcinoma cultures which attest to the significance of these gradients in human breast cancer. Integrin??6?4 is upregulated in advanced breast cancers where it is most closely associated with basal-like breast cancers. Importantly integrin ??6?4 promotes the activation of RhoA by a mechanism that we propose reverses the effect of PKA. Therefore we suggest that the counter-opposing modes of regulation these integrins have on RhoA permit efficient compartmentalization of RhoA that facilitates breast carcinoma motility invasion and metastasis. Accordingly the central hypothesis of this application is that cooperative signaling between ?1 integrins and integrin ?6?4 facilitates the spatial distribution of RhoA activity to promote lamellae formation and directed migration. The long-term goal of our group is to determine how integrins contribute to tumor invasion so that they may be eventually targeted appropriately for therapeutic intervention with special emphasis on integrin ?6?4. We will test our central hypothesis and achieve our long- term goal through the completion of the following aims: 1) Define the macromolecular complex that couples ?1 integrins to PKA activation thereby limiting RhoA activity at the leading edge 2) Determine how integrin ?6?4 leads to the activation of RhoA and 3) Elucidate how RhoA function is altered to promote lamellae formation. We are uniquely suited to perform these studies due to our strong collaborations; our well-characterized models of ?6?4 integrin- and RhoA-dependent invasion and migration; our expertise in integrin biology and Rho signaling and our solid preliminary data supporting this project. The results obtained from this study will be important as they will go int mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization lamellae formation directed cell migration and finally invasion. Ultimately our study will be significant as it will generate a firmer understanding of signaling pathways that govern leading edge dynamics that will produce successful methods to therapeutically target the early steps in metastasis.

project_terms:
A kinase anchoring protein;Adenylate Cyclase;Adhesions;Binding (Molecular Function);Biochemical;Biology;Breast Carcinoma;Cancer Biology;Cancer Detection;Cancer Patient;Carcinoma;Cells;Collaborations;Complex;Consensus;Couples;Coupling;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;Equilibrium;Generations;Goals;Growth;Growth Factor Receptors;Guanine;Guanine Nucleotide Exchange Factors;Human;Imaging Techniques;Integrins;Invaded;Joints;Macromolecular Complexes;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Methods;Modeling;Molecular;Monomeric GTP-Binding Proteins;Morphology;Neoplasm Metastasis;Operative Surgical Procedures;Output;Pathology;Patients;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphorylation Site;Positioning Attribute;Process;Production;Protein Serine/Threonine Phosphatase;Regulation;Research;Sampling;Signal Pathway;Signal Transduction;Solid;Spatial Distribution;Stress Fibers;Study models;Testing;Therapeutic Intervention;Tumor Cell Invasion;Validation;Work;cancer prevention;cell motility;cellular imaging;effective therapy;improved;in vivo;inorganic phosphate;insight;malignant breast neoplasm;migration;novel;receptor;rho;rhotekin;tissue-factor-pathway inhibitor 2;tumor;tumor progression

public_health_relevance:
Understanding how integrins signal continues to have a sustained impact on our understanding of cancer biology. Notably integrins contribute to the most deadly aspects of cancer progression including tumor invasion and metastasis; yet how they contribute to these processes remains poorly understood. Here we will go into mechanistic depth regarding how integrins coordinate spatial signaling to achieve polarization lamellae formation directed cell migration and ultimately invasion. By understanding leading edge dynamics of invading cells better methods of therapeutically targeting the early steps in metastasis will be achievable.


application_id: 8830952
project_number: 5R01CA186661-02
project_title: Small molecule targeting of MIF as a novel melanoma therapeutic
administering_ic: NCI
award_notice_date: 2015-03-10
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 186661
program_official: ALLEY, MICHAEL C
project_start_date: 2014-04-03
project_end_date: 2019-03-31
study_section: Drug Discovery and Molecular Pharmacology Study Section[DMP]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
5'-AMP-activated protein kinase;American;Antibody Therapy;Attenuated;Binding (Molecular Function);Biological Availability;Cancer Center;Cancer Patient;Cells;Chemotherapy-Oncologic Procedure;Chimeric Proteins;Chronic;Clinical;Clinical Trials;Denileukin Diftitox;Diagnosis;Disease Progression;Drug Targeting;Effector Cell;Exhibits;Future;Gene Expression;Goals;Growth;Health;IL2 gene;IL2RA gene;Immune;Immune response;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;In Vitro;In complete remission;In-Migration;Individual;Inhibitory Concentration 50;Invaded;Lead;Lesion;Lifetime Risk;Ligands;Lung;Malignant Neoplasms;Mediator of activation protein;Metastatic Melanoma;Migration Inhibitory Factor;Modality;Molecular Profiling;Mus;Myelogenous;Natural immunosuppression;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Phenotype;Population;Process;Proteins;Quantitative Structure-Activity Relationship;Regulatory T-Lymphocyte;Resistance;Role;Signal Pathway;Skin Cancer;Solid;Solid Neoplasm;Specificity;Staging;Suppressor-Effector T-Lymphocytes;Survival Rate;Testing;Therapeutic;Toxic effect;Tumor-Derived;United States;analog;angiogenesis;base;cancer cell;cell motility;clinical efficacy;combinatorial;cytokine;design;improved;in vivo;inhibitor/antagonist;insight;macrophage;melanoma;monocyte;mouse model;multicatalytic endopeptidase complex;neovascularization;novel;novel therapeutics;partial response;phenylpyruvate tautomerase;prevent;receptor;scaffold;small molecule;subcutaneous;therapeutic target;therapy resistant;tumor;tumor microenvironment;tumorigenic


application_id: 8830854
project_number: 5R01CA175105-03
project_title: Targeting Translation Dependence in Colorectal Cancer Progression
administering_ic: NCI
award_notice_date: 2015-02-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 175105
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2013-04-01
project_end_date: 2016-03-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 10534129
contact_pi: SHE, QING-BAI
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):  Mutational activation of the RAS/RAF/MEK/ERK and PI3K/AKT pathways is associated with colorectal cancer (CRC) progression and metastasis. Several small molecularly-targeted PI3K AKT RAF and MEK inhibitors have been tested in the clinic for the treatment of CRC but have shown only limited activity as a single agent. We have recently discovered that inhibition of both the ERK and AKT pathways exhibits potent synergistic anti-CRC effects both in vitro and in vivo by effectively inhibiting eIF4E-initiated cap-dependent translation. Our overarching hypothesis is that the activation of cap-dependent translation by cooperative ERK and AKT signaling can selectively upregulate key oncoproteins that confer CRC progression and metastasis. By characterizing the molecular details of the activation of cap-dependent translation by cooperative ERK and AKT signaling we aim to understand the molecular mechanisms underlying translational activation for CRC metastatic progression and to explore the therapeutic applications of targeting translational regulation for CRC treatment. Our Specific Aims are: Aim 1. Determine the biologic and therapeutic consequences of translational activation by cooperative ERK and AKT signaling in CRC. We will determine 1) the extent to which the mTOR kinase integrates the function of ERK and AKT signaling in translational regulation of CRC cell growth and motility; 2) how mTOR inhibition-induced feedback activation of ERK and AKT deregulates cap-dependent translation and causes mTOR-independence; and 3) the molecular basis of metastatic progression-modulated translational activity using our well-established orthotopic metastastic model of CRC. Aim 2. Characterize the molecular mechanism of translational activation by cooperative ERK and AKT signaling for CRC progression and metastasis. We demonstrate that survivin is a key translational target of the ERK and AKT pathways. We will explore the possible mechanism by which the translationally-regulated survivin acts as an important growth/metastasis-promoting effector of these pathways. We will use combined polysome profiling and proteomic approaches to systematically identify other mRNAs that are selectively recruited to polysomes and translated by cooperative ERK and AKT signaling and characterize in detail the functional importance of these genes in CRC progression and metastasis. Aim 3. Evaluate the in vivo utility of combined inhibition of the MEK/ERK and AKT/mTOR pathways and targeting the convergence of their signals on translation initiation for enhancing CRC therapy. We will use both the mouse orthotopic model of CRC and the patient tumor-derived xenograft model to determine the effectiveness of MEK AKT and mTOR inhibitors alone and in combination and to characterize the ability of the translation initiation inhibitor 4EGI-1 to prevent tumor progressio and metastasis. The expression and modulation of eIF4E 4E-BP1 and survivin and their correlation with the mutational activation status of ERK and AKT pathways will also be characterized in response to the targeted therapies and in clinical specimens.

project_terms:
Address;Animal Model;Biochemical;Biological Markers;Biology;Biometry;Cancer Cell Growth;Clinic;Clinical;Colonic Neoplasms;Colorectal Cancer;Data;Dependence;Drug Targeting;Effectiveness;Exhibits;Feedback;Genes;Goals;Growth;Human;In Vitro;Knowledge;MEK inhibition;MEKs;Messenger RNA;Modeling;Molecular;Mus;Mutation;Neoplasm Metastasis;Oncogene Proteins;Operative Surgical Procedures;PI3K/AKT;PTEN gene;Pathogenesis;Pathology;Pathway interactions;Patients;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Polyribosomes;Proteomics;Proto-Oncogene Proteins c-akt;Recruitment Activity;Research Infrastructure;Resistance;Role;Signal Pathway;Signal Transduction;Solid;Specimen;Techniques;Testing;Therapeutic;Translating;Translation Initiation;Translational Activation;Translational Regulation;Translational Repression;Translations;Tumor-Derived;Tyrosine Kinase Receptor Inhibition;Xenograft Model;base;cancer therapy;cell motility;clinically relevant;colon cancer cell line;colon cancer patients;human FRAP1 protein;in vivo;inhibitor/antagonist;insight;interdisciplinary collaboration;mTOR Inhibitor;mTOR inhibition;metastatic colorectal;novel;pre-clinical;prevent;public health relevance;response;survivin;targeted treatment;therapeutic target;tumor;tumor growth;tumor progression;tumorigenesis

public_health_relevance:
The great majority of patients with metastatic colorectal cancer (CRC) is unresponsive to currently known therapy. This proposal aims to lay the groundwork for understanding the molecular mechanisms involved in the translational control of metastatic progression and treatment of CRC and is therefore of clinical relevance in itself since new therapy for metastatic CRC is urgently needed. The overarching high impact of this proposal lies in the proof-of-concept that will be established for discovery of novel biomarkers and therapeutic targets for CRC.


application_id: 8829674
project_number: 5R01DE017680-08
project_title: Role of GSK3 in host inflammation
administering_ic: NIDCR
award_notice_date: 2015-02-02
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: DE
serial_number: 017680
program_official: CHANDER, PREETHI
project_start_date: 2007-04-25
project_end_date: 2016-02-29
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 7338645
contact_pi: SCOTT, DAVID A
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):  The overall goal of this project is to elucidate interacting endogenous anti-inflammatory pathways that can be harnessed to suppress an over-exuberant host response to periodontal bacteria and other pathogens. Bacteria are initially recognized by Toll-like receptors (TLRs) and other pathogen recognition receptors expressed on innate cells. TLR interaction with microbe-specific molecular patterns induces the innate production of pro- inflammatory cytokines which direct the intensity and direction of the immune response leads to recruitment of leukocytes to the site of infection and the production of an arsenal of anti-bacterial molecules many of which have the potential to cause the collateral tissue damage that defines destructive inflammatory diseases. There are at least three endogenous anti-inflammatory pathways. The first life cycle of DE017680 focused on the in vitro elucidation of the PI3K/ AKT anti-inflammatory pathway the key role of GSK3b in this signaling cascade and the mechanisms by which this pathway regulates the expression of IFNb IL-1Ra IL-10 in innate cells in addition to controlling T cell development and proliferation. In addition o the PI3K/ AKT cascade this renewal will also consider the a7 nicotinic acetylcholine receptor-dependent cholinergic and the Wnt3a anti- inflammatory pathways. Crosstalk between these three pathways will be elucidated with particular attention paid to the pivotal role of the centra inflammatory mediator GSK3b in pathway convergence. While each pathway is efficacious in its own right therapeutic interventions that maximize the anti-inflammatory potential of convergent signaling events are likely to be particularly potent. To this end anti-inflammatory signaling events will be exploited using murine models of inflammation (sub-cutaneous chamber) and periodontitis (alveolar bone loss). Therefore this project will lay the groundwork for the development of novel approaches to the treatment of periodontitis and other inflammatory diseases and identify therapeutic targets that should be readily translatable.

project_terms:
Alveolar Bone Loss;Amplifiers;Anti-Bacterial Agents;Anti-Inflammatory Agents;Anti-inflammatory;Attention;Bacteria;Bacterial Infections;Cardiovascular system;Cells;Cessation of life;Chronic;Communicable Diseases;Complex;Cutaneous;Data;Dental Plaque;Development;Disease;Disease Progression;Event;Glycogen Synthase Kinases;Goals;Health Care Costs;Host Defense;Human;Immune;Immune response;Immune system;In Vitro;Infection;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Interferon-beta;Interleukin-10;Invaded;Lead;Leukocytes;Life Cycle Stages;Lung diseases;Matrix Metalloproteinases;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Nature;Nicotinic Receptors;PI3K/AKT;Pathology;Pathway interactions;Pattern;Pattern recognition receptor;Periodontal Diseases;Periodontitis;Pharmacologic Substance;Play;Porphyromonas gingivalis;Production;Regulation;Role;Seminal;Signal Pathway;Signal Transduction;Site;T-Cell Development;TLR2 gene;TLR4 gene;Testing;Therapeutic;Therapeutic Intervention;Tissues;Toll-like receptors;adaptive immunity;anakinra;cholinergic;controlled release;cytokine;driving force;in vivo;microbial;novel;novel strategies;oral pathogen;pathogen;pathogenic bacteria;public health relevance;receptor;response;therapeutic target;tool

public_health_relevance:
It is the host response to dental plaque that leads to the development of periodontitis one of the most common infectious diseases in humans that consumes   >$14 billion dollars in health costs in the U.S. per annum. We will identify overlapping events between several endogenous mechanisms of inflammatory suppression (the PI3K/AKT/GSK3b; cholinergic; and Wnt3a anti-inflammatory pathways); elucidate specific mechanisms that suppress pro-inflammatory cytokine production in response to bacterial infection; determine anti-inflammatory events that control the release of tissue degrading matrix metalloproteinases; and establish if we can exploit these anti-inflammatory pathways to reduce inflammation and periodontal disease progression in murine models. These data will identify novel potential therapeutic approaches to the control of destructive inflammation.


application_id: 8829373
project_number: 1R43AI112048-01A1
administering_ic: NIAID
award_notice_date: 2014-12-10
opportunity_number: PA-14-071
application_type: 1
activity_code: R43
ic: AI
serial_number: 112048
suffix: A1
program_official: COSTERO-SAINT DENIS, ADRIANA
project_start_date: 2014-12-15
project_end_date: 2017-02-16
study_section: Special Emphasis Panel[ZRG1 IDM-U (10)]
contact_pi_person_id: 10420394
contact_pi: BRELSFOARD, COREY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 780816091
primary_uei: F873ZJEX7615
duns_number: 780816091
uei: F873ZJEX7615
fips: US
organization_id: 10027931
organization_name: MOSQUITOMATE, INC.
organization_city: Lexington
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40502
organization_country: UNITED STATES
arra_indicator: N
project_title:
Feasibility assessment of a novel tool for mosquito vector control: Auto-Dissemination Augmented by Males (ADAM)

project_abstract:
DESCRIPTION (provided by applicant): Vector control remains the only means to combat many important mosquito-borne pathogens including the viruses responsible for West Nile Dengue and Chikungunya. A key deficiency of existing vector control methods is the inability to affect cryptic breeding sites which provide refugia to immature mosquitoes and allow for the rapid recovery of mosquito populations following conventional control efforts. The self-delivering method known as 'auto-dissemination' promises to address this deficiency by using mosquitoes as the vehicle to deliver powerful larvicides to cryptic breeding sites. However current auto-dissemination methods rely upon the indigenous mosquito population to become contaminated at a device that is attractive to mosquitoes and then to transmit the larvicide as they encounter breeding sites; thus models predict that a robust mosquito population is required for the method to work effectively i.e. without mosquitoes to act as vehicles the larvicide will not leave the introduced/attractive device. The auto-dissemination approach is based on an active ingredient classified as a 'reduced risk pesticide' by the US EPA. It is potent: 1/1000th of the dry weight o a mosquito adult is adequate to treat a 200ml breeding site and there is no resistance in mosquitoes. A novel paradigm shift to the auto-dissemination approach is employing as the larvicide vehicle: mass- produced larvicide-treated adult male mosquitoes which do not bite or transmit disease. We refer to this approach as "Auto-Dissemination Augmented by Males" (ADAM). By no longer relying on the indigenous mosquito population the ADAM approach can be used as a preventative tool i.e. treating cryptic sites in advance of the normal population increase (e.g. in early spring). Furthermore using the ADAM approach the number of introduced larvicide treated males can be sustained despite a reduced indigenous population. Preliminary data from laboratory tests show that males in the ADAM approach can (1) contaminate females with dosages that are subsequently lethal to larvae ('Sexually Transmitted Larvicide') and (2) directly deliver larvicide to breeding sites. The outcome of a small field tria demonstrates that introduced oviposition sites experienced significant larval mortality relative to
control sites up to 150m from a release site that received ADAM male introductions at a rate of 4500/week over four weeks. Methods for the mass manufacturing of adult male mosquitoes are previously developed as part of an ongoing Wolbachia-biopesticide project at MosquitoMate. In the proposed work (Aims 1-3) we will examine the feasibility of the ADAM approach against Culex pipiens Aedes aegypti and Ae. albopictus first in laboratory trials and subsequently under field conditions. In Aim 4 we will prepare for a pre-registration meeting with the US EPA toward obtaining an Experimental Use Permit required for large-scale Phase 2 trials.

project_terms:
Address;Adult;Aedes (genus);Affect;Animals;Area;Attention;Behavior;Bite;Blood;Breeding;Businesses;Chikungunya virus;Culex pipiens;Culicidae;Data;Dengue;Dengue Virus;Devices;Disease;Dose;Face;Female;Goals;Human;Indigenous;Insecta;Insecticides;Investments;Killings;Laboratories;Larva;Lead;Left;Measures;Methods;Modeling;Mortality Vital Statistics;Mosquito-borne infectious disease;Names;Native-Born;Outcome;Oviposition;Partner in relationship;Pesticides;Phase;Phase II Clinical Trials;Plant Leaves;Population;Preparation;Production;Recovery;Relative (related person);Resistance;Risk;Site;Sterility;Techniques;Testing;Trees;Virus;Water;Weight;West Nile virus;Wolbachia;Work;base;chikungunya;combat;commercialization;dosage;experience;feeding;male;mathematical model;meetings;milliliter;novel;pathogen;public health relevance;research study;success;tool;vector;vector control;vector mosquito;wasting

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Vector control remains the only means to combat many mosquito borne diseases including those caused by West Nile Dengue Chikungunya viruses and other pathogens. A critical existing gap in vector control is the inability to affect the immature proportion of the mosquito population that remains hidden/protected within cryptic breeding sites and inaccessible to conventional control tools. The proposed work will test the feasibility of a novel 'self-delivering' approach which will employ manufactured adult male mosquitoes as the vehicle for treating cryptic sites with a potent larvicide.


application_id: 8829142
project_number: 5R21AI109529-02
project_title: Mechanism of inhibition of RNA virus replication by host WW-domain proteins
administering_ic: NIAID
award_notice_date: 2015-03-18
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: AI
serial_number: 109529
program_official: PARK, EUN-CHUNG
project_start_date: 2014-04-01
project_end_date: 2017-03-31
study_section: Virology - A Study Section[VIRA]
contact_pi_person_id: 7353039
contact_pi: NAGY, PETER
other_pis: Not Applicable
congressional_district: 06
department: OTHER BASIC 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): Recent genome-wide screens with multiple viruses have identified several host proteins which inhibit RNA virus accumulation and act as restriction factors against viruses. Unfortunately the restriction functions of these host factors are not yetdefined for important human viruses. Among the identified inhibitory host proteins are the family of WW-domain proteins which are effective against several viruses. WW-domain proteins are abundant proteins participating in protein interactions and they are involved in several diseases such as human cancers inherited diseases and viral infections. Progress in our understanding of the mechanisms of host factors is slow due to functional redundancy or lack of knowledge about their functions. However easily tractable virus - host systems such as Tomato bushy stunt virus (TBSV) and yeast as a model host can contribute to our understanding of the functions of these host proteins. This project will likely advance our understanding of the role ofhost WW-domain proteins in virus-host interactions. This advance could immensely help other scientists working with less tractable but devastating viral pathogens for which similar studies are currently not yet feasible. The following are the major strengths of the proposal: (i) Host restriction factors have clear negative impact on viruses. (ii) The restriction function of WW-domain proteins will be explored against tombusviruses and insect nodaviruses. (iii) The combination of yeast and authentic cell-free assay developed by the PI is currently the most potent for studying the mechanism of host factors involvement in viral RNA replication and viral pathogenesis. (iv) The research holds promise of benefiting society by leading to groundbreaking results in the area of virus replication host-virus interactions and the viral pathogenesis.

project_terms:
Affect;Animals;Antiviral Agents;Area;Biochemical;Biological Assay;Cataloging;Catalogs;Cells;Dengue Virus;Development;Disease;Evolution;Flavivirus;Genes;Health;Hepatitis C virus;Human;Human Virus;Inherited;Insecta;Integration Host Factors;Knowledge;Lead;Malignant Neoplasms;Modeling;Pathology;Pestivirus;Plants;Play;Protein Family;Proteins;Proteomics;RNA Viruses;RNA replication;Research;Role;Scientist;Societies;System;Tertiary Protein Structure;Tombusvirus;Viral;Viral Pathogenesis;Virus;Virus Diseases;Virus Replication;West Nile virus;Work;Yeast Model System;Yeasts;base;genome-wide analysis;high throughput screening;insight;novel;novel strategies;pathogen;protein protein interaction;replicase;tomato bushy stunt virus;viral RNA;virus host interaction;yeast genetics

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Viruses which are important and emerging human animal and plant pathogens are greatly affected by host restriction factors. We find in high throughput screens that inactivation of selected host WW-domain proteins facilitated robust RNA virus replication. The proposed work will explore the inhibitory roles of host WW-domain proteins in virus infection that could facilitate the development of novel antiviral approaches.


application_id: 8829123
project_number: 5R44AG044157-03
project_title: Circulating Blood-Based Diagnostic for Mild Cognitive Impaired Victims
administering_ic: NIA
award_notice_date: 2015-02-13
opportunity_number: PA-12-088
application_type: 5
activity_code: R44
ic: AG
serial_number: 044157
program_official: HSIAO, JOHN
project_start_date: 2014-04-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1-ETTN-M(11)B]
contact_pi_person_id: 1860379
contact_pi: WANG, EUGENIA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 805479370
primary_uei: KPMEKJJTDUS5
duns_number: 805479370
uei: KPMEKJJTDUS5
fips: US
organization_id: 10020610
organization_name: ADVANCED GENOMIC TECHNOLOGY, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402416052
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This project aims to generate blood tests for: 1. mild cognitive impairment (MCI) and 2. conversion risk from MCI to full-blown Alzheimer's disease (AD). We have reported that systemic footprints increases in key micro- RNA (miR) levels are identifiable in AD blood samples; here we suggest that this is also true for MCI the pre- AD phase. Our recent results suggest two stages of cognitive decline continuum: Stage 1 for key microRNAs increased from circulating blood of normal elderly controls (NEC) to that of MCI patients but not further to AD; and Stage 2 for specific circulating blood microRNA increases from MCI to AD. This led us to suggest our mo- del: Stage 1 circulating microRNAs as MCI-specific biomarkers and Stage 2 circulating microRNAs as biomark- ers for conversion of MCI to AD. Prototypes of these biomarkers are: Stage 1 miR-181b increases from NEC to MCI levels but not further in AD plasma samples; Stage 2 increased miR-34a & miR-34c levels observed only from MCI to AD but not from NEC to MCI plasma. These results suggest that the MCI cognitive decline may start with increased Stage 1 microRNAs' expression then Stage 2 increases add insult to injury; the for- mer being MCI-specific biomarkers and the latter specificfor AD and/or converter patients. Our goal is then to establish two sets of stage-specific biomarkers based on: a. highly reproducible data for identified blood micro- RNAs; b. training datasets for next-stage development for FDA approval; and c. validated specificity for de- mentia due to AD in contrast to other types of dementia. Toward this end Phase I will study 30 archived sam- ples each of MCI NEC and AD blood to attain: Aim 1 establishing the reproducibility of our protocol for opti- mal blood microRNA assays and identifying lead microRNAs' origins by determining concordance and/or dis- cordance among the above three microRNAs' increases in three circulating blood compartments: peripheral blood mononuclear cells (PBMC) plasma/serum and its derivative exosomes; and Aim 2 identifying other members of four lead array-profiled and PCR-validated microRNA families: miR-34 -181 200 & Let-7 to expand our pool of candidate Stage 1 and Stage 2 biomarkers. In Phase II Aim 1 expands to a larger cohort of 200 MCI patients' samples to establish a Stage 1 biomarker training dataset tracing 21 microRNAs of these 4 families; Aim 2 establishes a repertoire of Stage 2 biomarkers in archived specimens from 22 MCI subjects in our study 12 of whom have converted to AD within the past decade by comparing freshly collected with archived blood samples from converters versus non-converters by qPCR assays of the 21 listed miRNAs and array profiling to identify additional novel ones; and Aim 3 establishes the identified biomarkers as specific for AD in contrast with non-AD dementias i.e. Frontotemporal (FTD) Lewy body (LBD) and Parkinson's disease (PD) with dementia (PDD). Success of this project will provide blood miRNA-based diagnostics for MCI and predict conversion from MCI to AD unprecedented tests to monitor disease onset progression and drug efficacy for novel therapies to retard the decline of MCI to bona fide AD.

project_terms:
Alzheimer's Disease;Archives;Biological Assay;Biological Markers;Bipolar Disorder;Blood;Blood Tests;Blood specimen;Boxing;Brain;Cancer Diagnostics;Cardiovascular Diseases;Cells;Central Nervous System Diseases;Cerebrospinal Fluid;Clinical;Cognitive;Companions;Comparative Study;Data;Data Quality;Data Set;Dementia;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Elderly;Family;Frontotemporal Dementia;Funding;Genomics;Goals;Grant;Health;Healthcare;Healthcare Systems;Huntington Disease;Image;Impaired cognition;Individual;Injury;Lead;Lewy Bodies;Lewy Body Dementia;Magnetic Resonance Imaging;Measurable;Measurement;Messenger RNA;MicroRNAs;Mind;Mission;Monitor;Nature;Nerve Degeneration;Onset of illness;Parkinson Disease;Parkinson's Dementia;Pathogenesis;Patients;Peripheral Blood Mononuclear Cell;Phase;Plasma;Population;Pregnancy Trimesters;Proteins;Protocols documentation;Reporting;Reproducibility;Risk;Risk Assessment;Sampling;Small Business Innovation Research Grant;Specificity;Specimen;Staging;Technology;Testing;Training;Validation;Work;aging population;base;circulating microRNA;cohort;commercialization;cost effective;drug efficacy;indexing;member;mental state;mild cognitive impairment;neuropsychological;novel;outcome forecast;prototype;success;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Like Alzheimer's disease (AD) health care mild cognitive impairment (MCI) due to AD suffers from the lack of a noninvasive blood test which is a major roadblock to MCI diagnosis; in its absence the disease is largely de- fined by neuropsychological assessment and costly MRI imaging and secondarily by identified cerebrospinal fluid biomarkers a less ideal approach due to its invasive nature. This project aims to generate cost-effective noninvasive blood tests for serial diagnosis and staging of MCI and its conversion to full-blown AD based on unique biomarkers microRNA expressions whose levels in circulating blood are 'footprints' of disease patho- genesis reflecting cognitive declin in brain. Quantitative metrics of circulating key microRNAs may serve as numerical indices for diagnosis of MCI and prognosis of conversion to AD as well as objective drug efficacy measurements for novel therapies to retard the further decline of these victims from developing full-blown Alzheimer's disease and thus halting the tidal wave of a fast-increasing aging population suffering this devastating mind-robbing peril.


application_id: 8828764
project_number: 5R01HL107319-04
project_title: Mechanisms of thoracic aortic aneurysms
administering_ic: NHLBI
award_notice_date: 2015-03-31
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 107319
program_official: TOLUNAY, ESER
project_start_date: 2012-04-01
project_end_date: 2017-12-31
study_section: Special Emphasis Panel[ZRG1-VH-B(02)]
contact_pi_person_id: 8378256
contact_pi: DAUGHERTY, ALAN
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Thoracic aortic aneurysms (TAAs) most commonly develop in the ascending region in an asymptomatic manner. Frequently the first indication of its presence is rupture that commonly leads to death. TAAs are the life-threatening consequence in patients afflicted with a broad range of genetically determined diseases; one of the most common being Marfan's disease. The only current therapeutic strategy for individuals diagnosed with TAAs is surgical options. Consequently there is a pressing need for mechanistic insight into TAAs to develop effective therapeutics.  We have recently demonstrated that AngII infusion also leads to TAAs that are localized to the ascending aorta. AngII-induced TAAs are attenuated by CC Chemokine receptor 2 (CCR2) deficiency. This infers a role for monocyte chemoattractant protein-1 (MCP-1) in TAAs although CCR2 also interacts with other chemokines. We have recently demonstrated that endothelial-specific deficiency of AT1a receptors imparts a similar degree of attenuation of AngII-induced TAAs as whole body CCR2 deficiency. These two observations could potentially be associated via a paracrine mechanism by which AngII stimulates MCP-1 release the ligand that determines the major effects of CCR2 stimulation. The AngII-induced TAAs are characterized by profound medial macrophage accumulation that is predominantly on the adventitial aspect. On the basis of this briefly described background we are proposing to test the central hypothesis that the MCP-1-CCR2 axis promotes AngII-induced TAAs localized to the ascending region through an endothelial-mediated mechanism of macrophage recruitment from the adventitia via aortic region- specific effects. To test this hypothesis the following specific aims will be addressed: Aim 1. Determine the role of the MCP-1-CCR2 axis in development of AngII-induced TAAs. A. Does whole body deficiency of either MCP-1 or CCR2 promote equivalent reductions in AngII-induced TAAs that are persistent and associated with reduced medial macrophage accumulation? B. Is the source of MCP-1 in promoting TAAs due to AngII releasing this chemokine directly from endothelial or indirectly via specific SMC populations? Aim 2. Determine the origin of medial macrophages accumulating in ascending aortas during development of AngII-induced TAAs. A. What is the sequence of leukocytic infiltration in the development of AngII-induced TAAs and does this correlate to the expression of MCP-1 and CCR2? B. Are macrophages that accumulate in media and adventitia of ascending aortas during AngII infusion derived from blood or tissue origin? C. Is leukocyte accumulation in human ascending aortic aneurysmal tissue associated with MCP-1 and CCR2 expression?

project_terms:
Abdominal Aortic Aneurysm;Address;Affect;Angiotensin II;Anterior;Aorta;Area;Attenuated;Blood;CC chemokine receptor 2;CCL2 gene;Cardiac;Cells;Cessation of life;Characteristics;Complex;Defect;Development;Diagnosis;Disease;Embryo;Endothelial Cells;Fibroblasts;Growth;Health;Heart;Human;Individual;Infiltration;Infusion procedures;Leukocytes;Life;Ligands;Literature;Medial;Mediating;Mediator of activation protein;Medical;Monocyte Chemoattractant Protein-1;Mus;Neural Crest;Operative Surgical Procedures;Pathology;Patients;Pericytes;Population;Research;Role;Rupture;Ruptured Abdominal Aortic Aneurysm;Smooth Muscle Myocytes;Source;Specificity;Structure;Surface;Testing;Therapeutic;Thoracic Aortic Aneurysm;Thoracic aorta;Tissues;Tunica Adventitia;Ulcer;abdominal aorta;ascending aorta;attenuation;base;cell type;chemokine;insight;macrophage;neutralizing antibody;paracrine;public health medicine (field);receptor

public_health_relevance:
Aortic aneurysmal diseases have devastating health consequences and are increasingly more common. Despite the large impact on public health there is a relatively paucity of investigative efforts on these diseases. Consequently there are no defined medical options developed to provide an alternative to surgical intervention. Further research in aortic aneurysmal diseases is a public health imperative.


application_id: 8828616
project_number: 5R21CA179283-02
project_title: Regulation of Par-4 Secretion in Normal Cells for Paracrine Action in Tumor Cells
administering_ic: NCI
award_notice_date: 2015-03-09
opportunity_number: PAR-13-146
application_type: 5
activity_code: R21
ic: CA
serial_number: 179283
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2014-04-01
project_end_date: 2018-03-31
study_section: ZCA1-RPRB-O(J1)
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Lung cancer is a leading cause of cancer death in men and women in the United States. Mutations leading to activation of the Ras oncogenes and inactivation of the p53 tumor suppressor gene are two of the most common alterations in lung cancer. As the tumor growth inhibitory action of chemotherapy and radiation therapy generally requires wild-type p53 function lung tumors with p53 mutations or deletions develop resistance to therapy resulting in ultimate death of the patients. Moreover oncogenic Ras activation and p53 inactivation results in elevated NF-kB activity that contributes to cell survival and therapeutic resistance. Tumor growth is regulated by a complex network of interactions between normal cells and cancer cells. In addition to local interactions tumor growth may be influenced by growth-promoting and growth-inhibiting factors produced systemically by the host. Accordingly cancer therapeutics can be aptly utilized to regulate the systemic environment in order to directly target aberrant growth. Understanding the mechanisms associated with systemic secretion of pro-apoptotic proteins by normal cells and their effect on tumor epithelial cells is a critical facet of such investigations. A majority of the cells throughout the body of lug cancer patients are normal and have wild type p53 status. This proposal will explore whether p53 activation in normal cells triggers paracrine cell death in p53-deficient lung tumors. As p53 activation only partially inhibits NF-kB activity our Preliminary Studies used co-parallel activation of p53 and inhibition of NF-kB in normal cells to identify secreted protein(s) that can cause a paracrine apoptotic effect in p53-deficient lung cancer cells. Based on our findings we hypothesize that p53 regulates the secretion of the pro-apoptotic tumor suppressor protein Par-4 from normal cells for paracrine effect in cancer cells and that maximum induction of Par-4 protein by p53 activation and NF-kB inhibition from normal cells should effectively induce apoptosis in p53-deficient lung tumors in mice. The proposed study will explore the feasibility of this novel area of investigation by pursuing two Specific Aims. (Aim 1) Determine the mechanism by which p53 activation in normal cells induces tumor cell apoptosis. We will study the kinetics and mechanism of Par-4 secretion induced by p53 in diverse normal cell types leading to apoptosis of p53-deficient lung cancer cells. (Aim 2) Determine the paracrine effect of Par-4 secretion which is induced by p53 activation in normal cells on p53-deficient lung tumors. After concomitant activation of p53 and inhibition of NF-kB activity we will test the kinetics of systemic elevation of Par-4 protein and its effect on apoptosis and regression of lung tumors in K-rasLSL-G12Dp53Fl/Fl mice. Moreover mechanistic studies will be undertaken to gain deeper insights into the functional role of Par-4 in the paracrine action on these tumors in mice. Collectively these studies will uncover the feasibility and mechanism of the paracrine effects of p53 activation in normal cells for apoptosis and regression of p53-deficient lung cancer. As p53 is mutated in diverse cancers the findings of this study will have broad translational implications.

project_terms:
Apoptosis;Apoptotic;Area;B-Lymphocytes;Binding (Molecular Function);Binding Sites;Blood Cells;Breeding;Cancer Etiology;Cancer Patient;Cancer cell line;Cell Culture Techniques;Cell Death;Cell Survival;Cell surface;Cells;Cessation of life;Complex;Conditioned Culture Media;Consensus;Coupled;Cytokine Activation;Data;Endothelial Cells;Environment;Epithelial Cells;Fibroblasts;GRP78;Growth;Health;Human;Investigation;Kinetics;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Molecular;Mus;Mutate;Mutation;NF-kappa B;Normal Cell;Oncogenic;PAWR gene;PAWR protein;Pathway interactions;Patients;Protein Secretion;Protein p53;Proteins;Radiation therapy;Regulation;Relative (related person);Resistance development;Role;Serum;TP53 gene;Testing;Therapeutic;Therapeutic Agents;Tumor Suppressor Genes;Tumor Suppressor Proteins;United States;Woman;base;cancer cell;cancer diagnosis;cell type;chemotherapy;functional status;human MDM2 protein;in vivo;inhibitor/antagonist;insight;men;mouse model;neoplastic cell;novel;paracrine;pro-apoptotic protein;ras Genes;ras Oncogene;receptor;response;secretory protein;small molecule;therapy resistant;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  The proposed studies will examine the paracrine effect of co-parallel activation of p53 and inhibition of NF-kB in normal cells on p53-deficient lung cancer cel lines and tumors. Both cell culture and mouse models will be used to determine the mechanism of tumor suppressor Par-4 protein secretion by normal cells. The findings will validate the role ofPar-4 in mediating the paracrine tumor suppressor effect of p53.


application_id: 8828205
project_number: 5R21ES022745-02
project_title: Mechanisms of atherogenic effects of bisphenol A
administering_ic: NIEHS
award_notice_date: 2015-03-27
opportunity_number: PA-11-261
application_type: 5
activity_code: R21
ic: ES
serial_number: 022745
program_official: SCHUG, THADDEUS
project_start_date: 2014-04-01
project_end_date: 2017-09-30
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This is an R21 application intended to investigate the mechanisms of atherogenic effects of bisphenol A (BPA). BPA is a base chemical used extensively in polycarbonate plastics in many consumer products and human exposure to BPA is ubiquitous. Higher BPA exposure has recently been associated with an increased risk of cardiovascular disease (CVD) in multiple human population-based studies. However the mechanisms responsible for these associations remain unknown. Many environmental chemicals can activate the xenobiotic receptor pregnane X receptor (PXR) which in turn acts as a xenobiotic sensor to regulate xenobiotic metabolism and exhibits considerable differences in its pharmacology across species. Very recently we revealed PXR's pro-atherogenic effects in animal models and found that chronic activation of mouse PXR increases atherosclerosis in atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice. We also demonstrated that BPA is a potent activator of human but not mouse PXR consequently the choice of animal model is paramount in predicting the human risk assessment of BPA. Therefore we generated novel PXR- humanized ApoE-/- mice (huPXR.ApoE-/- i.e. ApoE knockout mice with the human PXR transgene in place of mouse PXR) that can respond to human PXR ligands. Our central hypothesis is that chronic activation of PXR by exposure to BPA promotes foam cell formation and increases atherosclerotic lesion formation in PXR- humanized mice thereby increasing the risk of CVD in exposed individuals. Two specific aims are proposed to test this hypothesis: 1) Does chronic exposure to BPA at doses relevant to human exposure increase atherosclerosis in PXR-humanized ApoE-/- mice? 2) What molecular pathway does BPA act through to influence atherogenesis? The proposed studies are the first to investigate the effects of BPA exposure on atherosclerosis in a suitable animal model and to explore the precise molecular mechanisms by which BPA induces CVD at the molecular level.

project_terms:
Address;Adverse effects;Affect;Agonist;Animal Model;Animals;ApoE knockout mouse;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological;Biological Monitoring;Bone Marrow Transplantation;CD36 gene;Cardiovascular Diseases;Chemicals;Chronic;Development;Dietary Steroid;Dose;Environment;Etiology;Exhibits;Exposure to;Foam Cells;Future;Genes;Goals;Health;Hormones;Human;Individual;Ligands;Link;Lipids;Mediating;Molecular;Mus;Nuclear Receptors;Pathway interactions;Pharmacologic Substance;Pharmacology;Pilot Projects;Play;Population;Production;Receptor Activation;Risk;Risk Assessment;Role;Specificity;Testing;Transgenes;Transgenic Mice;Uncertainty;Variant;Xenobiotic Metabolism;Xenobiotics;atherogenesis;base;bisphenol A;blood lipid;cardiovascular disorder risk;consumer product;environmental chemical;exposed human population;gene environment interaction;human population study;in vivo;leukocyte activation;macrophage;novel;polycarbonate plastic;population based;pregnane X receptor;receptor;scavenger receptor;sensor;species difference

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The roles of environmental chemicals in the etiology of CVD are poorly understood. Although exposure to environmental chemicals such as bisphenol A (BPA) is suspected to increase the risk of CVD the lack of evidence in suitable animal models has hampered progress. We will now remedy this impasse by employing unique "humanized" transgenic mice that will enable us to study the biological mechanisms by which environmental chemicals induce CVD.


application_id: 8827947
project_number: 3R01DC007176-10S1
project_title: Neurotrophin regulation of taste system development
administering_ic: NIDCD
award_notice_date: 2014-05-09
opportunity_number: PA-12-149
application_type: 3
activity_code: R01
ic: DC
serial_number: 007176
suffix: S1
program_official: SULLIVAN, SUSAN L
project_start_date: 2005-03-01
project_end_date: 2016-05-31
study_section: Special Emphasis Panel[ZRG1(03)-M]
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
project_abstract:
DESCRIPTION (provided by applicant): During development gustatory innervation is a tightly regulated process in which specific numbers of primary taste afferents project to discrete regions of the oral cavity. Brain-derived neurotrophic factor (BDNF) regulates both the number and location of gustatory innervation during embryonic development. Our current research is designed to determine if and/or how these connections are important for central gustatory development or taste function and whether BDNF regulates development of the postnatal taste system. The proposed studies combine cell counting tract tracing immunohistochemistry electrophysiology and behavioral testing in conditional and inducible transgenic mice to: 1) determine if BDNF influences postnatal changes in geniculate ganglion and taste bud development 2) determine if embryonic or postnatal BDNF is important for central terminal field organization and 3) determine if embryonic or postnatal BDNF is important for adult gustatory function. Together these studies test the hypotheses that: 1) embryonic BDNF determines the number of neurons innervating a taste bud and taste buds increase in size to meet that number postnatally. 2) CNS terminal field formation is regulated by BDNF and the specificity of peripheral connections. 3) Gustatory sensitivity is reduced but that the taste system still functions despite wide-scale reorganization. These studies will determine how early peripheral innervation patterns influence continued development and function of the taste system. In addition we will determine whether BDNF is required for postnatal gustatory development. Because these experiments examine how neurotrophin regulation of sensory innervation influences continued development and adult function this project has important implications for the potential therapeutic use of these powerful signaling molecules in re-establishing gustatory function following neuronal impairment.

project_terms:
Adult;Attention;Birth;Brain-Derived Neurotrophic Factor;Cell Count;Chemicals;Development;Electrophysiology (science);Embryo;Embryonic Development;Epithelium;Excision;Goals;Health;Homeostasis;Immunohistochemistry;Impairment;Individual;Lead;Location;Mus;National Institute on Deafness and Other Communication Disorders;Nerve;Neurons;Oral cavity;Pattern;Peripheral;Peripheral Nervous System Diseases;Persons;Physiological;Process;Quality of life;Recovery;Regulation;Research;Sensory;Signaling Molecule;Specificity;Stimulus;Structure of geniculate ganglion;System;Systems Development;Taste Buds;Taste Disorders;Taste Perception;Testing;Therapeutic;Therapeutic Uses;Tongue;Transgenic Mice;Visit;behavior test;chorda tympani;critical period;design;meetings;nerve supply;neurotrophic factor;overexpression;postnatal;preference;research study;response

public_health_relevance:
Taste disorders can have detrimental effects on a person's health and quality of life. According to NIDCD more than 200000 people visit a doctor each year for problems with their chemical senses including taste. The underlying mechanism of many gustatory disruptions is not well understood. As a result much emphasis has been placed on a basic understanding of the taste bud. However the neurons innervating taste buds receive little attention and are also required for normal gustatory function. Some adult gustatory disruptions may result from an alteration in factor(s) regulating gustatory system innervation both during development and as a part of normal adult homeostasis. Peripheral neuropathies are relatively common and frequently accompany other illnesses. A basic understanding of the factors that are required to promote innervation during development and possibly maintain it in adulthood may lead to therapeutic approaches that allow taste recovery following its loss.


application_id: 8827793
project_number: 5R01GM077422-07
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2015-03-24
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: GM
serial_number: 077422
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2017-08-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: TRENT, JOHN O
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):  DNA remains an underrepresented target for small molecule therapeutic agents. There is mounting evidence to indicate that non-B DNA structures play prominent roles in gene expression and in the function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the development of new therapeutic agents. The use of small molecules in such an antigene strategy is promising for many reasons. Targeting the gene before its amplification to produce multiple mRNA and protein molecules is advantageous because there are fewer targets to hit. In addition is easier to manipulate small molecules (rather than therapeutic DNA or RNA molecules) chemically to optimize binding and pharmacological properties. We seek renewal for our innovative and highly productive program to develop an integrated virtual and actual screening platform for the discovery of new lead compounds that bind selectively to unique DNA structures of biological significance. Progress during the initial funding period was outstanding and we achieved most of the specific aims proposed in our initial proposal. We have discovered several compounds that bind selectively to particular quadruplex structures a target of intense current interest. We propose studies that will continue to develop and optimize the integrated screening platform. During the next funding period we will focus on the discovery of lead compounds that bind selectively to biologically important quadruplex and DNA-RNA hybrid structures. In order to do this we will develop structural models for complex quadruplex structures using a novel approach that integrates molecular dynamics simulations with rigorous experimental validation. We will characterize the biophysical and functional properties of the novel quadruplex binders we have discovered during the initial funding period. Specific aims include: 1. Development and refinement of the virtual screening platform. 2. Development of higher-throughput assays for ligand binding. 3. Discovery of lead compounds that bind to functionally important nucleic acid structures. 4. Biophysical and biological characterization of novel G-quadruplex binding agents discovered during the initial funding period. The proposed studies will deliver an improved integrated platform for the discovery of novel lead compounds and a thorough characterization of several newly-discovered quadruplex binders with unique chemical scaffolds.

project_terms:
Active Sites;Antineoplastic Agents;Area;Beryllium;Binding (Molecular Function);Biological;Biological Assay;Chemicals;Complex;Computer Simulation;DNA;DNA Structure;Detection;Development;Dialysis procedure;Drug Targeting;Elements;Fluorescence;Fluorescence Resonance Energy Transfer;Funding;G-Quartets;Gene Expression;Gene Targeting;Genome;Hybrids;Indium;Intercalating Agents;Label;Laboratories;Lead;Libraries;Ligand Binding;Ligands;Measures;Messenger RNA;Methods;Modeling;Nucleic Acid Binding;Nucleic Acids;Oncogenes;Pharmaceutical Preparations;Play;Promotor (Genetics);Property;Proteins;RNA;RNA-Directed DNA Polymerase;Role;Specificity;Structural Models;Structure;Telomerase;Telomere Maintenance;Temperature;Therapeutic Agents;Validation;Work;antigene;c-myc Genes;cancer cell;high throughput screening;improved;innovation;interest;melting;molecular dynamics;novel;novel strategies;novel therapeutics;nucleic acid structure;overexpression;programs;quadruplex DNA;receptor;scaffold;screening;small molecule;telomere;therapeutic DNA;therapeutic RNA;virtual

public_health_relevance:
This project will develop an integrated computational and experimental screening platform for the discovery of new drugs that target specific structures of functional importance within the genome. The initial funding period for this project was successful and productive and we will continue our efforts. Several novel lead compounds were discovered that bind to functionally important quadruplex structures. We will characterize the biophysical and biological properties of these novel agents.


application_id: 8827769
project_number: 5R01ES017244-05
project_title: Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside
administering_ic: NIEHS
award_notice_date: 2015-03-25
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 017244
program_official: REINLIB, LESLIE J
project_start_date: 2011-08-01
project_end_date: 2017-03-31
study_section: Special Emphasis Panel[ZRG1-OTC-N(03)M]
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): Epidemiological clinical and laboratory studies have implicated that ultraviolet radiation (UV) is a complete environmental carcinogen and that repeated exposures can lead to the development of melanoma and nonmelanoma skin cancers. In addition to sunscreens chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our in vitro and in vivo studies on cyanidin-3-glucoside (C3G) a compound found in blackberries and other foods show that this compound is able to inhibit NF-:B AP-1 COX2 and TNF1 activation/expression neoplastic transformation cancer cell migration and invasion and induction of apoptosis in HL60 cells. C3G also functions as an antioxidant by inhibiting the generation of reactive oxygen species and inducing antioxidant-regulative transcription factors. These preliminary studies indicate that C3G may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that C3G functions as an antioxidant and inhibits oxidative stress activation of transcription factors and inflammatory signaling proteins leading to protection against UVB-induced carcinogenesis. Specific Aim 1. In vitro and in vivo investigation of antioxidant properties of C3G. Electron spin resonance (ESR) spin trapping will be used to determine the reaction rates of C3G toward hydroxyl (7OH) and superoxide (O27-) radicals using Fenton reaction (Fe(II) + H2O2) and xanthine/xanthine oxidase as sources of these free radicals in a non-cellular system and to investigate antioxidant activities against UVB-induced 7OH and O27- radicals in a cellular system. Low frequency (in vivo) ESR will be also used to study antioxidant activities of C3G against UVB-generated O27- and 7OH radicals in the skin of SKH-1 hairless mice. Specific Aim 2. In vivo investigation of the effects of C3G on UVB-induced oxidative stress and activation of oxidative stress sensitive transcription factors. We will investigate the effects of C3G on UVB-induced lipid peroxidation protein oxidation and oxidative DNA damage in KSH mice. We will also study the effects of C3G on UVB-induced activation of activation protein (AP)-1 nuclear factor (NF)-:B and nuclear factor of activated T cells (NAFT) in transgenic mice. Specific Aim 3. Investigate the effects of C3G on UVB-induced inflammatory mediators. These inflammatory mediators include infiltrating leukocytes and myeloperoxidase (MPO) COX-2 PGE2 and several pro-inflammatory cytokines TNF-1 IL-2 and IL-6. Specific Aim 4. Investigation of the effects of C3G on UVB-induced tumorigenesis and early biomarkers. These markers include changes in thymine-positive cells proliferative cell nuclear antigen terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and apoptotic cells together with a change in p53 and p21/cip1- positive cell population in epidermis. These studies will provide a mechanistic rationale for an early on C3G efficacy in skin cancer prevention.

project_terms:
Acetates;Animal Model;Anthocyanins;Anthracenes;Antioxidants;Apoptosis;Apoptotic;Berry;Biological Markers;Cabbage - dietary;Cells;Chemicals;Chemoprevention;Chemopreventive Agent;Chronic;Chronic Disease;Clinical Research;Complement Factor B;Consumption;DNA Nucleotidylexotransferase;Development;Diet;Dinoprostone;EGF gene;Electron Spin Resonance Spectroscopy;Environmental Carcinogens;Enzymes;Epidemiologic Studies;Epidermis;Epigallocatechin Gallate;Exhibits;Family;Food;Free Radicals;Frequencies (time pattern);Generations;Glucosides;Grapes;Green tea (dietary);Growth Factor;HL-60 Cells;Health;Human;Hydrogen Peroxide;Hydroxyl Radical;In Vitro;Inbred HRS Mice;Incidence;Individual;Induction of Apoptosis;Inflammation;Inflammation Mediators;Inflammatory;Interleukin-2;Interleukin-6;Investigation;Label;Laboratories;Laboratory Study;Lead;Leukocytes;Link;Lipid Peroxidation;MAP Kinase Gene;Malignant Neoplasms;Mediating;Mediator of activation protein;Methods;Micronutrients;Milk Thistle;Minerals;Mus;Neoplastic Cell Transformation;Non-Malignant;Nuclear;Nuclear Antigens;Oxidative Stress;PTGS2 gene;Peroxidases;Phytochemical;Pigments;Plants;Population;Prevention;Preventive;Property;Prostaglandins;Proteins;Reaction;Reactive Oxygen Species;Signal Pathway;Signaling Protein;Skin;Skin Cancer;Skin Carcinoma;Source;Spin Trapping;Stimulus;Sunlight;Sunscreening Agents;Superoxides;System;TNF gene;Therapeutic;Thymine;Topical application;Transgenic Mice;Tumor Necrosis Factor-alpha;UVB carcinogenesis;UVB induced;Ultraviolet B Radiation;Ultraviolet Rays;Vitamins;Xanthine Oxidase;Xanthines;ascorbate;base;cancer cell;carcinogenesis;cell motility;cell transformation;chemotherapeutic agent;cyclooxygenase 2;cytokine;fruits and vegetables;high risk;in vivo;melanoma;member;nuclear factors of activated T-cells;oxidation;oxidative DNA damage;prevent;protein activation;public health medicine (field);reaction rate;silibinin;skin cancer prevention;transcription factor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The incidence of UV-induced skin cancer is a major public health concern. Present study attempts to identify cyanidin-3-glucoside a plant-derived compound as a mechanism-based preventive agent against UV-induced skin cancers.


application_id: 8826389
project_number: 1S10OD020106-01
project_title: Ultra Performance Liquid Chromatography High Resolution High Mass Accuracy Mass Spectrometer
administering_ic: OD
award_notice_date: 2015-02-25
opportunity_number: PAR-14-073
application_type: 1
activity_code: S10
ic: OD
serial_number: 020106
program_official: CHEN, YONG
project_start_date: 2015-02-27
project_end_date: 2016-02-26
study_section: Special Emphasis Panel[ZRG1 BCMB-D (30)]
contact_pi_person_id: 8487327
contact_pi: ZHANG, XIANG
other_pis: Not Applicable
congressional_district: 03
department: CHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal requests funds for acquisition and continuing operation of a two-dimensional ultra performance liquid chromatography coupled with a high resolution and high accuracy mass spectrometer with tandem MS/MS capability (2DLC-MS/MS) for metabolomics. This instrument will be located in the Shumaker Research Building (room 335) at the Center for Regulatory Environmental and Analytical Metabolomics (CREAM) as a part of integrated metabolomics platforms to support the basic translational and clinical research at the University of Louisville. The proposed instrument will complement and gradually replace our use of the existing hybrid quadrupole linear ion-trap and Fourier transform ion cyclotron resonance mass spectrometry (LTQ- FTICR-MS) instrument. This LTQ-FTICR-MS has been formally designated as in "retired status" by the manufacturer as of January 2014 and the manufacturer will now only provide preventive maintenance. We are under risk at any moment of losing the capability of conducting high resolution high accuracy mass spectrometry-based metabolomics analyses at the CREAM Center. The Specific Aims of this proposal are provision of the following for the University of Louisville biomedical research community: Specific Aim 1: For the established Major Users (78% allotment of time): Provision of increased capacity for identification and quantification of metabolites with complementary analyses of spatial and temporal flux through metabolic pathways. Specific Aim 2: For appropriate Research Centers & Institutes less frequent (<100 samples / year) Users and prospective Users of mass spectrometry (17% allotment of time): Vigorous promotion of the use of high accuracy and high resolution mass spectrometry in biomedical research with an education program for research and scientific career development.

project_terms:
Basic Science;Biomedical Research;Clinical Research;Communities;Complement;Coupled;Educational aspects;Fourier transform ion cyclotron resonance;Funding;High Pressure Liquid Chromatography;Hybrids;Institutes;Ions;Liquid Chromatography;Maintenance;Manufacturer Name;Mass Spectrum Analysis;Metabolic Pathway;Performance;Preventive;Request for Proposals;Research;Resolution;Risk;Sampling;Time;Translational Research;Universities;base;career development;instrument;mass spectrometer;metabolomics;operation;programs;prospective;two-dimensional

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This proposal requests funds for purchase of a LC-MS system that couples an ultra performance liquid chromatography with a high resolution and high accuracy mass spectrometer with tandem MS/MS capability (2DLC-MS/MS). The 2DLC-MS/MS instrument will be located at the CREAM Center as a part of integrated analytical platforms to provide metabolomics service for the biomedical research community at the University of Louisville.


application_id: 8826166
project_number: 5R01HL112788-03
project_title: BIOACTIVE LIPIDS IN STEM CELL HOMING AND MOBILIZATION
administering_ic: NHLBI
award_notice_date: 2015-03-31
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: HL
serial_number: 112788
program_official: YANG, YU-CHUNG
project_start_date: 2013-06-01
project_end_date: 2016-03-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
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): A tug-of-war concept has been proposed to explain how a chemotactic stromal derived factor-1 (SDF-1) gradient between bone marrow (BM) and peripheral blood (PB) determines whether cells will be released and mobilized from BM into PB or home back from PB to the BM microenvironment. This concept however needs reappraisal because plasma SDF-1 levels do not consistently correlate with mobilization of hematopoietic stem/progenitor cells (HSPCs). At the same time it is becoming clear that SDF-1 does not play an exclusive role in the homing of HSPCs into BM implying the existence of additional factors. New data from our laboratory and supported by recent observations from other researchers identify a potentially important role for the bioactive sphingolipids sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) in trafficking of HSPCs. S1P and C1P are i) strong chemoattractants for HSPCs ii) resistant to proteolytic enzymes and iii) exhibit markedly increased levels in PB during mobilization and in BM after myeloablative conditioning for transplantation. Based on these data we propose three interrelated aims to reappraise the role of SDF-1 in stem cell trafficking and address our central hypothesis that the bioactive lipids S1P and C1P play an important and presently unappreciated role in homing and mobilization of HSPCs. In addition to clinical studies our approach will exploit small molecule- and genetics-based strategies in mouse models. Specific Aim 1. Bioactive lipids S1P and C1P as executors of HSPC mobilization. Our recently published data support a pivotal role for the S1P- S1P receptor type 1 (S1P1) axis in egress of HSPCs from BM into PB. We will investigate the impact of mobilization on the distribution of S1P between blood compartments and determine whether the level of S1P in PB correlates with mobilization efficacy in patients. In parallel we will address the role of C1P and investigate whether one or both bioactive lipids (which are stored in circulating red blood cells) are responsible for mobilization of HSPCs in patients with hemolytic syndromes. Finally we will mechanistically define which mobilization steps are promoted by S1P and C1P. Specific Aim 2. Bioactive lipids as a novel homing factors for HSPCs. Myeloablative conditioning for transplantation induces a proteolytic microenvironment in BM leading to a decrease in chemotactically active SDF-1. We have found that BM levels of S1P and C1P are increased during conditioning and that antagonism of S1P1 impairs engraftment of HSPCs. Since these lipids are strong HSPC chemoattractants for HSPCs we will focus on their potential role in homing of HSPCs and elucidate the molecular and cellular basis for this phenomenon. Specific Aim 3. Develop strategies to improve mobilization and homing of hematopoietic stem cells by modulating S1P and C1P signaling. Based on our preliminary data we propose to develop new strategies that will improve both mobilization and homing of HSPCs. These strategies will be tested first in mice and subsequently validated in chimeric human HSPCs/immunodeficient mouse xenotransplant models.

project_terms:
AMD3100;Address;Adult;Affect;Back;Blood;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell surface;Cells;Chemotactic Factors;Clinical Research;Complement Activation;Data;Development;Engraftment;Erythrocytes;Exhibits;Fetal Liver;Fibroblasts;Genetic;Growth Factor;Health;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;Home environment;Homing;Human;Immunodeficient Mouse;Injection of therapeutic agent;Integrin alpha4beta1;Integrins;Laboratories;Life;Ligands;Lipids;Mediating;Modeling;Molecular;Mus;Osteoblasts;Patients;Peptide Hydrolases;Plasma;Play;Process;Publishing;Refractory;Research Personnel;Resistance;Role;Signal Transduction;Sphingolipids;Sphingosine-1-Phosphate Receptor;Stem cell transplant;Stem cells;Syndrome;Testing;Time;Transplantation Conditioning;Vascular Cell Adhesion Molecule-1;War;base;ceramide 1-phosphate;conditioning;improved;knock-down;mouse model;novel;peripheral blood;receptor;reconstitution;small molecule;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With new data from our laboratory we have identified an important potential role for bioactive sphingolipids in trafficking of HSPCs. Bioactive sphingolipids are i) strong chemoattractants for HSPCs ii) resistant to proteolytic enzymes and iii) markedly increased in level in PB during mobilization and in BM after myeloablative conditioning for transplantation. Based on these findings we propose three interrelated aims to reappraise the role of SDF-1 in stem cell trafficking and address our central hypothesis that the bioactive lipids play an important and presently unappreciated role in homing and mobilization of HSPCs.


application_id: 8825991
project_number: 5R01AG027297-09
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2015-04-08
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 027297
program_official: WISE, BRADLEY C
project_start_date: 2006-09-01
project_end_date: 2016-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
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): The experiments in this project use innovative gene delivery techniques and a multipronged approach to assess the fundamental role of astrocyte activation in neurologic function in an intact mouse model of Alzheimer's disease (AD). Studies use adeno-associated virus vectors (AAV) bearing the astrocyte-specific promoter Gfa2 to target the protein phosphatase calcineurin (CN) and NFAT transcription factors in astrocytes of wild-type and APP/PS1 mice. AAV-Gfa2 vectors are bilaterally delivered to the hippocampus at different ages/disease stages and mice are assessed on different AD biomarkers. In Aim 1 cognitive status is assessed using the active avoidance task while synaptic function is evaluated using hippocampal slice electrophysiology and Western blot measures of synaptic proteins. In Aim 2 hippocampal glutamate regulation is investigated using ceramic enzyme-based microelectrode arrays and measures of glutamate transporter levels. In Aim 3 levels of glial activation and neuroinflammation are determined with immunohistochemical (IHC) analyses and assessment of cytokine levels using Multiplex ELISAs. In Aim 4 IHC is used to determine the extent of A? deposition while ELISAs are used to quantify levels of A?40 and A?42 in soluble and insoluble hippocampal tissue fractions and Westerns used to assess BACE protein expression. AAV-Gfa2 vectors encode either potent inhibitors or activators of CN/NFAT signaling and therefore will determine the necessity and sufficiency of this astrocytic pathway in driving and/or maintaining neurologic dysfunction in AD mice. These studies provide a highly novel approach to the study of activated astrocytes and could have a major impact on the development of treatment strategies for AD and other neurodegenerative conditions.

project_terms:
APP-PS1;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Animals;Astrocytes;Automobile Driving;Avoidance Learning;Behavior;Behavioral;Biochemical Process;Biological Assay;Biological Markers;Brain;Brain Diseases;Calcineurin;Cells;Ceramics;Cognitive;Data;Dependence;Dependovirus;Deposition;Development;Disease;Electrodes;Electrophysiology (science);Enzyme-Linked Immunosorbent Assay;Enzymes;Funding;Gene Delivery;Glial Fibrillary Acidic Protein;Glutamate Receptor;Glutamate Transporter;Glutamates;Hippocampus (Brain);Human;Hypertrophy;Impaired cognition;Implant;In Vitro;Inflammatory;Ipsilateral;Label;Measurement;Measures;Methods;Microelectrodes;Microglia;Mus;NFAT Pathway;Nerve Degeneration;Nervous System Physiology;Neurodegenerative Disorders;Neurologic Dysfunctions;Outcome Measure;Pathologic;Pathology;Pathway interactions;Phenotype;Process;Production;Promotor (Genetics);Protein phosphatase;Proteins;Reaction;Regulation;Resolution;Rodent Model;Role;Signal Transduction;Slice;Staging;Synapses;Synaptic plasticity;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Mice;Transgenic Organisms;Western Blotting;Wild Type Mouse;adeno-associated viral vector;aging brain;amyloid pathology;astrogliosis;base;beta-site APP cleaving enzyme 1;cytokine;functional outcomes;glutamatergic signaling;improved;in vivo;inhibitor/antagonist;innovation;interest;mouse model;multi-electrode arrays;neuroinflammation;neuropathology;neuroprotection;novel strategies;prevent;protein expression;relating to nervous system;research study;response;signal processing;synaptic function;transcription factor;treatment strategy;vector

public_health_relevance:
Increasing evidence implicates activated astrocytes in a variety of neurodegenerative conditions including Alzheimer's disease (AD). However these cells are difficult to target selectively with therapeutics. In this project we use cutting-edge adeno associated virus vectors to selectively prevent astrocyte activation and improve neurologic function in intact AD model mice. This approach could emerge as a new treatment strategy for AD and other neurodegenerative disorders.


application_id: 8825987
project_number: 5R37AG004542-26
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2015-04-08
opportunity_number: PA-10-067
application_type: 5
activity_code: R37
ic: AG
serial_number: 004542
program_official: WISE, BRADLEY C
project_start_date: 1998-01-01
project_end_date: 2016-03-31
study_section: Neurobiology of Learning and Memory Study Section[LAM]
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
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):  This is the resubmission of a renewal application for a longstanding project on dysregulation of calcium (Ca2+)-related processes in hippocampal neurons during aging and the consequences for altered neuronal function/vulnerability. The project initially derived from the finding that the Ca2+-dependent slow afterhyperpolarization (sAHP) that follows a burst of action potentials in hippocampal pyramidal neurons is larger in aged than in young-adult animals. Importantly larger sAHPs are correlated with reduced neuronal excitability and impaired learning and memory. Conversely smaller sAHPs are found in animals that learn a task. Since then we and others have determined that Ca2+ action potentials Ca2+ transients and L-type Ca2+ currents also are increased in aged neurons. These results led to a Ca2+ dysregulation hypothesis of brain aging in which increased activity of L-channels plays a key initiating role and the resulting larger sAHP reduces neuronal excitability. It also has become apparent that enhanced Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs) modulates the magnitude of aging-related Ca2+ transients and sAHPs in pyramidal neurons. The major objective of this project is to fundamentally advance our understanding of the underlying molecular mechanisms of Ca2+ dysregulation that lead to unhealthy brain aging. Based on our new intriguing results we have formulated a novel working hypothesis of age-related Ca2+ dysregulation that suggests that downregulation of immunophilins particularly FK-506 binding protein 1b and/or 1a (FKBP1b/1a) leads to a cascade of RyR destabilization greater CICR and larger sAHPs. The resulting effect is impaired neuronal excitability and behavioral plasticity. These studies will manipulate hippocampal expression/function of FKBP1b/1a and other proteins in the FKBP- Ca2+ regulatory pathway in vivo using microinjection of viral vectors. Multiple outcomes will be assessed in the same animals using a multidisciplinary approach comprising extensive behavioral testing state-of-the-art intracellular electrophysiology with concomitant Ca2+ imaging immunohistochemistry and gene microarray analysis. These studies should substantially elucidate aging changes that depend on Ca2+ dysregulation and should clearly test the role of FKBPs in Ca2+ dysregulation and hippocampal function during aging. Chronic intervention studies are proposed that could have direct translational relevance and lead directly to novel preventative and therapeutic treatments against aging-related decline of brain function. Given the dramatic increase in the aging population it is becoming increasingly important to identify and develop such therapies to maintain cognitive function in the elderly.

project_terms:
Action Potentials;Affect;Age-Years;Aging;Alzheimer's Disease;Animals;Base of the Brain;Behavior;Behavioral;Binding (Molecular Function);Binding Proteins;Biological Markers;Brain;Brain-Derived Neurotrophic Factor;Calcium;Chronic;Control Animal;Data;Disinhibition;Down-Regulation;Elderly;Electrophysiology (science);Exposure to;Fostering;Genes;Genomics;Goals;Health;Healthcare Systems;Heart failure;Hippocampus (Brain);Image;Immunohistochemistry;Immunophilins;Impaired cognition;Intervention;Intervention Studies;Lead;Learning;Maze Learning;Mediating;Memory;Methods;Microarray Analysis;Microinjections;Modeling;Molecular;Muscle Cells;Neurons;Open Reading Frames;Outcome;Outcome Measure;Pathway interactions;Pattern;Pharmaceutical Preparations;Play;Population;Process;Progress Reports;Protein Isoforms;Proteins;Protocols documentation;Quality of life;RNA;Rattus;Regulation;Regulatory Pathway;Role;RyR2;Ryanodine Receptors;Severities;Sirolimus;Slice;Small Interfering RNA;Structure;Synapses;Tacrolimus Binding Proteins;Techniques;Testing;Therapeutic;United States;Up-Regulation (Physiology);Viral Vector;Work;adeno-associated viral vector;age related;aged;aging brain;aging hippocampus;aging population;base;behavior test;cognitive function;gene therapy;hippocampal pyramidal neuron;human FRAP1 protein;in vivo;innovation;interdisciplinary approach;knock-down;mTOR protein;mature animal;neuronal excitability;novel;overexpression;prevent;protein expression;response;vector;voltage;young adult

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   The aging population of the United States is projected to increase at a dramatic rate with numbers that will undoubtedly impact our healthcare system (20% of the population will be >65 years of age by the year 2030). Cognitive decline frequently accompanies aging and depending on the severity can significantly affect quality of life. Our results indicate that a specific pathway (FKBP-Ca2+) that plays a major role in cardiac failure may also play a critical role in brain aging and cognitive decline; thus the goal of this project is to use gene therapy techniques to determine whether such interventions can prevent or slow the onset of age-related brain decline. The outcomes may have substantial therapeutic implications.


application_id: 8825443
project_number: 5R01CA149438-05
project_title: Activation of Cyclin-Dependent Kinases by Fructose-26-Bisphosphate
administering_ic: NCI
award_notice_date: 2015-02-27
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 149438
program_official: SPALHOLZ, BARBARA A
project_start_date: 2011-04-01
project_end_date: 2017-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) phosphorylate fructose-6-phosphate (F6P) to fructose-26-bisphosphate (F26BP) which is an allosteric activator of 6-phosphofructo-1-kinase a rate-limiting enzyme in the glycolytic pathway. Although there are four PFKFB enzymes PFKFB3 and PFKFB4 are of particular interest since these enzymes have been found to be activated in human cancers to be increased by hypoxic exposure via HIF-1? and in the case of PFKFB3 to be required for the growth of Ras-transformed tumors. In order to better understand the relative contributions of PFKFB2-4 to glycolysis we examined the subcellular localization of these enzymes and were surprised to find that whereas PFKFB2 and PFKFB4 localized to the cytoplasm (the site of glycolysis) PFKFB3 localized to the nucleus. We then over-expressed PFKFB3 in HeLa cells and observed no change in glucose uptake but rather an increase in proliferation. Eukaryotic cell division is controlled by cyclin dependent kinases (CDKs) that bind to regulatory cyclins and phosphorylate hundreds of substrates that control DNA replication transcription and mitosis. We found that over-expression of PFKFB3 stimulated CDK1 activity in HeLa cells and that purified F26BP stimulated recombinant monomeric CDK1 in vitro. We then confirmed the requirement of CDK1 for the pro-proliferative effects of PFKFB3 by demonstrating that CDK1 siRNA but not CDK2 CDK4 or CDK6 siRNA reversed the increased proliferation caused by over-expression of PFKFB3. Importantly transfection of HeLa cells with PFKFB3-specific siRNA decreased endogenous PFKFB3 which in turn reduced CDK1 activity increased p27 expression suppressed G1/S transition induced apoptosis but had no impact on glucose uptake. These data support a distinct role for PFKFB3 in the regulation of cell cycle progression and apoptosis and not glucose metabolism. We propose to test the hypothesis that nuclear F26BP generated by PFKFB3 activates CDKs and promotes cell cycle progression. We anticipate that nuclear F26BP may serve unique roles in regulating CDK1 and other CDKs and that inhibition of PFKFB3 will suppress CDK activities without significantly affecting glucose metabolism in transformed but not in normal cells.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;Affect;Amino Acids;Apoptosis;Binding (Molecular Function);CDC2 Protein Kinase;CDK2 gene;CDK4 gene;Cancer cell line;Cell Cycle;Cell Cycle Progression;Cell Cycle Regulation;Cell Nucleus;Cell division;Cells;Cyclin-Dependent Kinases;Cyclins;Cytoplasm;Cytostatics;DNA biosynthesis;Data;Enzymes;Epithelial;Epithelial Cells;Eukaryotic Cell;Family;Family member;Fructose;G1/S Transition;Genes;Genetic Transcription;Genomics;Glycolysis;Growth;Health;Hela Cells;Hematopoietic;Human;Human Development;Hypoxia;In Vitro;Liver;Malignant Neoplasms;Mitosis;Molecular Target;Mus;Mutation;Normal Cell;Normal tissue morphology;Nuclear;Oncogenes;Pathway interactions;Phosphoric Monoester Hydrolases;Phosphotransferases;Protein p53;Recombinants;Regulation;Relative (related person);Research;Role;Signal Pathway;Site;Small Interfering RNA;Testing;Tissues;Transfection;Transformed Cell Line;Transgenic Organisms;base;cancer cell;chemotherapeutic agent;clinically significant;fructose-6-phosphate;glucose metabolism;glucose uptake;in vitro activity;interest;mutant;neoplastic;novel;receptor;screening;small molecule;tumor;tumor growth;tumor progression;virtual

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application may enable the identification of a novel molecular target - the CDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression. This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplastic agents.


application_id: 8825180
project_number: 2R01CA133429-08
project_title: The Role of PHLPP in Colon Cancer
administering_ic: NCI
award_notice_date: 2014-12-05
opportunity_number: PA-13-302
application_type: 2
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;Family;Genetic;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;human FRAP1 protein;improved;in vivo;insight;leucine-rich repeat protein;lipid biosynthesis;lipid metabolism;mTOR Inhibitor;macromolecule;metabolomics;mouse model;novel;outcome forecast;public health relevance;research study;stable isotope;success;treatment strategy;tumor metabolism;tumor progression;tumorigenesis


application_id: 8824618
project_number: 1R34DA038869-01
project_title: A Feasibility Trial for Inhibitory-Control Training to Reduce Cocaine Use
administering_ic: NIDA
award_notice_date: 2015-03-09
opportunity_number: PA-13-078
application_type: 1
activity_code: R34
ic: DA
serial_number: 038869
program_official: AKLIN, WILL
project_start_date: 2015-03-15
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
contact_pi_person_id: 1888410
contact_pi: RUSH, CRAIG R
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Cocaine abuse is an unrelenting public-health concern. Behavioral therapies are considered the "standard of care" for reducing cocaine use and preventing relapse. However even with intense behavioral interventions rates of relapse to cocaine use are discouragingly high (i.e. 60-95% of patients return to drug use). Novel strategies are urgently needed to improve treatment outcomes for cocaine-use disorders. The overarching goal of this project is to assess the feasibility acceptability and initial efficacy o an innovative cocaine-based inhibitory-control training procedure. This goal will be accomplished through the conduct of a Stage I pilot trial. Cocaine-dependent participants will be enrolled and randomized to receive inhibitory-control training to cocaine or neutral images (N=20/condition). This proposed intervention cocaine- based inhibitory-control training will be delivered using an innovative computer program which teaches cocaine abusers to inhibit a pre-potent response to cocaine or neutral cues. The primary hypothesis is the proposed procedures are feasible and acceptable to the participants. Feasibility will be assessed by determining time needed to enroll the target sample; adaptive randomization outcomes; maintenance of blind for blinded study personnel; participant attendance completion and adherence to study procedures. Acceptability will be determined using a Treatment Acceptability Questionnaire. The secondary hypothesis is that participants receiving cocaine-based inhibitory-control training will reduce their drug use to
a greater extent than their counterparts in the neutral-image condition. Reduced cocaine use will be demonstrated by fewer positive-urine samples using qualitative urinalysis and a reduction in levels of benzoylecgonine as determined by quantitative urinalysis (i.e. ELISA). The third hypothesis is that participants receiving cocaine-based inhibitory-control training will show improved inhibitory control and neurocognitive functioning relative to their counterparts in the neutral-image condition. Improved inhibitory control impulsivity and cognitive functioning will be
demonstrated using a battery of clinical instruments and laboratory tasks. The proposed research is highly innovative in that it will provide critical information regarding the feasibilit acceptability initial efficacy of cocaine-based inhibitory-control training to reduce drug use and
improve inhibitory control and neurocognitive functioning in cocaine-dependent participants. Cocaine-based inhibitory- control training is also easy to administer (i.e. 15 minutes) inexpensive need not be administered by a clinician and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence thereby quickly impacting clinical research and practice. The cocaine-based inhibitory-control training program could also be converted to a smart-phone for administration outside the clinic. Administering training outside of the clinic would allow patients to receive more frequent booster sessions further improving sustained abstinence by allowing them to be exposed to therapy as needed.

project_terms:
Abstinence;Address;Adherence (attribute);Alcoholic beverage heavy drinker;Alcohols;Behavior Therapy;Behavioral;Blinded;Cellular Phone;Clinic;Clinical;Clinical Research;Cocaine;Cocaine Abuse;Cocaine Dependences;Computer Programs and Programming;Cues;Development;Disease;Double-Blind Method;Drug usage;Ecology;Educational process of instructing;Employee Strikes;Enrollment;Enzyme-Linked Immunosorbent Assay;Future;Gambling;Goals;Human Resources;Image;Impulsivity;Intervention;Intervention Studies;Iowa;Laboratories;Maintenance;Modification;NIH Program Announcements;Neurocognitive;Outcome;Participant;Patients;Procedures;Questionnaires;Randomized;Relapse;Relative (related person);Research;Risk;Sampling;Signal Transduction;Staging;Testing;Time;Training;Training Programs;Treatment outcome;Urinalysis;Urine;attentional bias;base;benzoylecgonine;blind;clinical practice;cocaine use;cognitive function;community based treatment;discounting;drinking;efficacy trial;improved;innovation;instrument;novel strategies;pilot trial;prevent;programs;public health medicine (field);public health relevance;response;standard of care;therapy development;trial design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The research proposed in this application will demonstrate the feasibility acceptability and initial efficacy of an innovative cocaine-based inhibitory-contol training procedure for cocaine-use disorders. A Stage I double blind pilot trial will be conducted. The proposed research is innovative because cocaine-based inhibitory- control training is easy to administer (i.e. requires about 15 minutes) inexpensive need not be administered by a clinician and could easily be incorporated into current behavioral or community-based treatment approaches to enhance sustained abstinence.


application_id: 8824551
project_number: 5R01HL104103-05
project_title: Homocysteine & Angiotensin II in Renovascular Remodeling
administering_ic: NHLBI
award_notice_date: 2015-03-20
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 104103
program_official: OH, YOUNGSUK
project_start_date: 2011-05-01
project_end_date: 2017-03-31
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 9501257
contact_pi: SEN, UTPAL
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although it is not clear whether hyperhomocysteinemia (HHcy) an elevated plasma homocysteine (Hcy) level causes hypertension recent clinical data suggest an association between systolic hypertension and HHcy. Both angiotensin II (Ang II) and Hcy decrease blood flow; however the role of Hcy in Ang II mediated decrease in blood flow and vascular density is unclear. Interestingly preliminary studies of this proposal suggest that Ang II increases plasma Hcy level in mice. Treatment of Ang II animals with folic acid (FA) decreases plasma Hcy and mitigates hypertension. Based on our preliminary studies in this proposal we hypothesize that HHcy decreases blood flow in part by decreasing vascular density increasing oxidative pro-inflammatory pro-fibrotic and anti-angiogenic factors in Ang II mediated renovascular remodeling. FA treatment through Hcy clearance mechanism reduces plasma Hcy level that mitigates renal remodeling. The hypothesis will be tested by following their specific aims: (1) To determine whether the Hcy contributes to Ang II hypertension in part by inducing oxidative stress (Nox2 gp47phox Nox4 and mtROS) exacerbating renal inflammation by inducing MCP-1 MIP-2 ICAM-1 VCAM-1 and if FA ameliorates these changes; (2) To determine whether the Hcy instigates Ang II hypertension and renovascular fibrosis in part by inducing collagen IV MMP-2 -9 -13; TIMP-1-2 -3 -4; and if FA mitigates this renovascular fibrosis; and (3) To determine whether the Hcy promotes Ang II hypertension and decreases renovascular blood flow in part by unbalancing of angiogenic (VEGF) and anti-angiogenic factors (angiostatin and endostatin) and if FA increases vascular density and blood flow. WT (C57BL/6J) mouse genetic mouse model of HHcy (CBS) and mouse deficient with angiotensin receptor I (AT1R-/-) will be used in this study. In WT and CBS mice hypertension will be created by infusing Ang II (1000 ng/kg/min for 4 weeks) through alzet mini pump. Control animals will receive only vehicle. In a separate group of animals FA (0.015g/L in drinking water) will be introduced after 2 weeks of Ang II infusion and will be continued until the end of experiments (total 2 weeks). Appropriate FA controls will be used. AT1R-/- mice will be treated with or without Hcy (1.8 g/L for 4 weeks) to determine whether the effect of HHcy is AT1R dependent. Ambulatory blood pressure will be measured by DSI radiotelemetry (model TA11PA- C10). Plasma Hcy will be measured by HPLC. Vascular density will be measured by in vivo soft-tissue Barium sulfate-contrast X-ray angiography and renal cortical blood flow by moorFLPI full-filled laser perfusion imager. Renal function will be determined by measuring glomerular filtration rate (GFR). Histological kidney sections will be used to detect ROS collagen mesangial widening and podocyte injury. Plasma MCP-1 MIP-2 VCAM- 1 and ICAM-1 will be measured by ELISA. Tissue collagen MMPs TIMPs Nox2 p47phox Nox4 ICAM-1 VCAM-1 protein expressions will be measured by Western blot and immunostaining. MMPs activities will be measured by in gel zymography TIMPs activity by reverse zymography and mRNA abundance by Q-PCR. In addition to confirming the preliminary studies the scope of the research will be extended to understand the implications of FA treatment in Ang II-induced hypertension to modulate pro-inflammatory pro-fibrotic and anti- angiogenic factors. The results of this study will increase our understanding of role of Hcy in Ang II hypertension and renovascular remodeling. Additionally the research outcome will provide the missing information of HHcy as a potential risk factor of renovascular fibrosis which exacerbates hypertension and will lead to develop or modify current therapeutic strategies of renovascular disease.

project_terms:
3-Mercaptopyruvate sulfurtransferase;Angiogenic Factor;Angiography;Angiostatins;Angiotensin II;Angiotensin Receptor;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Attenuated;Barium;Barium Sulfate;Basement membrane;Blood Pressure;Blood Vessels;Blood flow;C10;CCL2 gene;Clinical Data;Collagen;Collagen Type IV;Control Animal;Cystathionine;Disease;Endostatins;Enzyme-Linked Immunosorbent Assay;Enzymes;Equilibrium;Extracellular Matrix;Extracellular Matrix Proteins;Fibrosis;Folic Acid;Functional disorder;Gel;Gelatinase A;Genetic;Glomerular Capillary;Glomerular Filtration Rate;Goals;Health;High Pressure Liquid Chromatography;Histology;Homocysteine;Homocystine;Hyperhomocysteinemia;Hypertension;Individual;Inflammation;Inflammatory;Infusion procedures;Injury;Intercellular adhesion molecule 1;Kidney;Lasers;Lead;Link;Lyase;MTHFR gene;Matrix Metalloproteinases;Measures;Mediating;Messenger RNA;Metabolism;Methylenetetrahydrofolate reductase (NADPH);Mitochondria;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;NADP;Outcomes Research;Oxidases;Oxidative Stress;Pathogenesis;Patients;Perfusion;Plasma;Pump;Reactive Oxygen Species;Renal Blood Flow;Renal function;Renovascular Hypertension;Research;Reverse Transcriptase Polymerase Chain Reaction;Risk;Risk Factors;Roentgen Rays;Role;Sclerosis;Stress;Testing;Therapeutic;Tissue Inhibitor of Metalloproteinase-1;Tissue Inhibitor of Metalloproteinases;Tissues;Vascular Cell Adhesion Molecule-1;Vascular Endothelial Growth Factors;Western Blotting;base;bevacizumab;density;drinking water;glomerulosclerosis;in vivo;inhibitor/antagonist;kidney vascular structure;mouse model;oxidation;podocyte;protein expression;research study;soft tissue;systolic hypertension

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Angiotensin II (Ang II) is a main player in the pathogenesis of hypertensive renovascular disease. Elevated level of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) is frequently observed in patients with renal dysfunction. Although it is not well known whether HHcy induces blood pressure; recent clinical data suggest elevation of plasma Hcy level in essential hypertensive patients. The preliminary studies of this proposal suggested that in Ang II-induced hypertensive mouse model an elevated plasma level of Hcy was also observed. Hcy is a known risk factor of cardio-renovascular disease however the role of Hcy in hypertensive individuals in the progression of renovascular remodeling and glomerulosclerosis is unclear. Folic acid (FA) reduces plasma Hcy level and therefore modulates risks of cardio-renovascular disease caused by HHcy. Herein this study proposes to investigate the role of Ang II hypertension in inducing HHcy and whether this HHcy aggravates hypertensive renovascular remodeling by triggering oxidative pro-inflammatory and pro- fibrotic factors. The contribution of Hcy in reducing vascular density and blood flow by decreasing angiogenic and increasing anti-angiogenic factors will also be investigated through FA treatment. To delineate these issues inflammatory molecules such as MCP-1 MIP-2 ICAM-1 and VCAM-1 will be measured in Ang II- induced hypertensive mouse model. The matrix metalloproteinase-2 -9 & -13 and their tissue inhibitors TIMP- 1 -2 -3 & -4 as well as extracellular matrix protein collagen will be measured in hypertensive mice. The angiogenic factor VEGF and anti-angiogenic factors angiostatin and endostatin will also be measured. The contribution of HHcy in AngII-induced glomerulovascular remodeling and glomerulosclerosis will be determined through FA treatment. This is a pure elegant and mechanistic study to investigate the potential role of HHcy in Ang II-induced glomerular extracellular matrix remodeling and sclerosis. The research outcome of this proposal will lead us to better understand the hypertensive renovascular disease and the findings of this study will open new avenues for therapeutic strategies of hypertensive renovascular disease.


application_id: 8824514
project_number: 5T35DK072923-10
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2015-04-01
opportunity_number: PA-08-227
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: CASTLE, ARTHUR
project_start_date: 2006-05-01
project_end_date: 2016-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
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
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This is a competing renewal of NIH 5 T35 DK072923 which was originally funded for five years with 6 students supported/year. The principal objectives of the Summer Endocrine Research Training Program are to provide research experience for medical students and to stimulate interest among medical students in becoming clinical research scientists. Trainees engage in research activities with faculty members and participate in projects that are germane to the field of endocrinology and the health concerns of this country. Over the past 3 years we have trained 18 second year medical students who participated in our "Summer Endocrine Research Training Program" research programs in Endocrinology Metabolism and Diabetes at University of Louisville School of Medicine and as this application is submitted 6 new second year medical students will begin their summer research in this program. Approximately 25% of our trainees are members of minority populations and 1/3rd of trainees are female. Our program includes didactic instruction ("Summer Endocrine Research Training Seminar Series" and "Bench-to-Bedside: Introduction to Clinical Research") as well as a hands-on-research experience under the direction of a team of experienced basic and clinical research scientists centered on a core of NIDDK-funded investigators and collaborating faculty. Trainees also attend Endocrine-specific seminars and journal clubs in basic and clinical research. The present application addressses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The T35 competing renewal funding will provide stipends for a 10-week summer program for 8-10 second year medical students. Our current T35 grant funds 6 students/year. Given the increase in training faculty mentors and NIDDK-funded research at the University of Louisville School of Medicine documented within the text we request funds to increase to 8 students/year in years 6 and 7 (Yr. one and two of the next funding period) 9 in years 8 and 9 (Yr. three and four of the next funding period and 10 in year 10 (Yr. five of the next funding period).

project_terms:
Basic Science;Clinical;Clinical Research;Country;Diabetes Mellitus;Endocrine;Endocrinology;Environment;Faculty;Female;Funding;Grant;Health;Instruction;Journals;Medical Students;Mentors;Minority;National Institute of Diabetes and Digestive and Kidney Diseases;Population;Research;Research Activity;Research Personnel;Research Training;Scientist;Series;Structure;Students;Teacher Professional Development;Text;Training;Training Programs;United States National Institutes of Health;Universities;base;bench to bedside;experience;interest;medical schools;member;programs;skills

public_health_relevance:
This competing renewal T35 application directly addresses the NIH's goal of ensuring that a diverse pool of highly trained scientists are available in the field of Endocrinology to address the Nation's biomedical and clinical research needs.


application_id: 8824160
project_number: 1R21HD080035-01A1
project_title: Preventing hyperphagia in Prader Willi syndrome using an oligonucleotide
administering_ic: NICHD
award_notice_date: 2014-09-22
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: HD
serial_number: 080035
suffix: A1
program_official: KING, TRACY
project_start_date: 2014-09-23
project_end_date: 2016-08-31
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
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;Functional RNA;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;Receptor Serotonin 5-HT2C;Safety;Satiation;Serotonin;Signal Transduction;Site;Small Nucleolar RNA;Structure;Structure of nucleus infundibularis hypothalami;System;Techniques;Testing;Therapeutic;Time;Toxic effect;United States;Work;base;ghrelin;innovation;insight;mRNA Precursor;nervous system disorder;non-genetic;prevent;public health relevance;receptor;response;tool;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.


