# projects

application_id: 9863997
project_number: 5I01BX003405-04
project_title: mitoNEET as a therapeutic target for TBI
administering_ic: VA
award_notice_date: 2020-09-17
opportunity_number: BX-16-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 003405
project_start_date: 2017-01-01
project_end_date: 2020-12-31
study_section: Neurobiology C[NURC]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-01
project_abstract:
Accumulating clinical evidence as well as experience in contemporary military operations suggests thattraumatic brain injury (TBI) is the signature injury of this war making our troops a high-risk population for TBI.Among the 327388 OEF/OIF veterans using VA services in 2009 6.7% were diagnosed with TBI of which 73%of those were diagnosed with posttraumatic stress disorder (PTSD). However to date there is no approvedtreatment for TBI in part due to an incomplete understanding of the pathobiology underlying TBI. Thereforeprogress in this area of research is desperately needed. Recently we have shown that pioglitazone isneuroprotective following TBI and that its mechanism of action may be directly related to its interactions with themitochondrial protein mitoNEET. Consistent with these ideas our preliminary results indicate pioglitazone is notprotective in mitoNEET knockout animals and that treatment with a specific mitoNEET ligand (NL1) isneuroprotective following TBI. The proposed experiments are designed to elucidate the mechanism(s) bywhich pioglitazone confers neuroprotection following TBI by testing the novel hypothesis thatpioglitazone via mitoNEET interaction directly ameliorates mitochondrial dysfunction. To test thishypothesis we propose three specific aims that include the use of multiple innovative tools and techniques thatwe have in hand specifically the use of mitoNEET null transgenic mice a novel mitoNEET ligand (NL-1) andantagonist (NL-3). In Specific Aim 1 we will determine the optimal dosage and therapeutic window ofopportunity for pioglitazone to maintain mitochondrial homeostasis post-injury. These measurements will for thefirst time measure mitochondrial dysfunction from synaptic and nonsynaptic mitochondria in the injury core andpenumbra from a single animal. In Specific Aim 2 will measure the degree of cortical sparing and behaviorimprovements that are mediated through pioglitazone treatment after TBI using the optimal dosage determinedin Specific Aim 1. In this aim we will use T2 weighted and DTI MRI to longitudinally assess changes in corticaland hippocampal morphology at -3 3 7 14 28 and 168 days post-injury followed by unbiased stereology at168 days post-injury. Additionally we will measure acute motor serial cognitive functional testing and aggressivebehavioral function and fear conditioning (chronic measurements of PTSD) to assess the degree of functionalrecovery as a result of treatment. Specific Aim 3 will determine the mechanism by which pioglitazone affordsneuroprotection by testing the hypothesis that pioglitazone's therapeutic effect is mediated through interactionswith mitoNEET. This aim will employ the use of transgenic mitoNEET null mice in tandem with a novel mitoNEETspecific ligand (NL-1) and mitoNEET antagonist (NL-3). Mitochondrial bioenergetics will be measured at 24 hoursand behavioral outcome and tissue sparing will be measured following TBI. The results of these studies will notonly shed light on the fundamental processes involved in TBI neuropathology they also move forward therepurposing of an FDA compound for the treatment of TBI and the proposed experiments may pinpoint potentialnovel targets for the treatment of TBI and perhaps other neuronal injuries.

project_terms:
Acute;Adult;Aftercare;Animals;Area;Behavior;Behavioral;Bioenergetics;Brain Injuries;Chronic;Clinical;Cognitive;Coupled;Data;Diagnosis;Dose;FDA approved;Hand;Hippocampus (Brain);Homeostasis;Hour;Injury;Knock-out;Knockout Mice;Ligands;Light;Link;Magnetic Resonance Imaging;Measurement;Measures;Mediating;Military Personnel;Mitochondria;Mitochondrial Proteins;Modeling;Molecular Target;Morphology;Motor;Mus;Neuronal Injury;Neurons;Outcome;Pathway interactions;Patients;Peroxisome Proliferator-Activated Receptors;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Publishing;Reactive Oxygen Species;Recovery of Function;Research;Respiration;Scanning;Services;Site;Synapses;TBI treatment;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Transgenic Mice;Transgenic Organisms;Translating;Traumatic Brain Injury;Veterans;War;Work;base;behavior measurement;behavioral outcome;brain dysfunction;conditioned fear;controlled cortical impact;cost;design;dosage;experience;experimental study;functional outcomes;high risk population;improved;innovation;knockout animal;male;mitochondrial dysfunction;neuropathology;neuroprotection;novel;operation;primary endpoint;receptor binding;response;secondary endpoint;severe injury;therapeutic target;tool

public_health_relevance:
Clinical evidence coupled with experience in contemporary military arenas clearly indicates that traumatic braininjury (TBI) is becoming a signature injury of war which makes our troops a high-risk population. In fact 6.7% ofOEF/OIF veterans in 2009 were diagnosed with TBI and 73% of those were diagnosed with posttraumatic stressdisorder (PTSD). At present there is no approved treatment for TBI due to an incomplete understanding of theunderlying pathobiology. This proposal examines the potential of targeting the novel mitochondrial proteinmitoNEET and to push forward the repurposing of pioglitazone to limit the brain damage and dysfunction resultingfrom TBI.


application_id: 9858243
project_number: 5I01CX001550-08
project_title: Lysophosphatidic acid and cardiovascular disease risk
administering_ic: VA
award_notice_date: 2020-10-27
opportunity_number: CX-16-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001550
project_start_date: 2013-01-01
project_end_date: 2020-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-01
project_abstract:
Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovasculardisease risk is caused by environmental and heritable factors. The broad goal of our research is to understandhow these factors interact to determine overall disease risk. In current funding period of this award we studiedhow heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate withheritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of thegene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results inaccelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an atherosclerosissuppressor gene and that heritable variants that decrease expression of the gene promote heart disease risk.LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipidmediators. One of these LPP3 substrates lysophosphatidic acid (LPA) acts on multiple blood and vascularcells to promote inflammation and cardiovascular disease progression. In mice genetic or pharmacologicaltargeting of LPA modulates atherosclerosis. In our mouse studies LPP3 deficiency was associated withincreased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesisthat dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 oncardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. Inpreliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. Thisdiet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestinefrom dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low densitylipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is asecreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources ofcirculating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also anintermediate in the synthesis of triglycerides by the intestine and liver so since this process is coupled to thegeneration of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo. The firstaim of this proposal will test these competing hypotheses directly by using stable isotope tracers and massspectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studieswill allow us to use genetic and pharmacological approaches to selectively manipulate ATX LPP3 and theformation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signalingresponses in blood and vascular cell types that underlie the initiation and progression of cardiovasculardisease by promoting permeability of vascular endothelium phenotypic modulation and proliferation/migrationof vascular smooth muscle cells and the classical macrophage foam cell response. The second aim of theproposal will test the hypothesis that the LPA content of these lipoproteins is a determinant of these responses.LPA is present in atherosclerotic blood vessels and release of LPA may contribute to platelet activation andthrombosis during plaque rupture. The final aim of this proposal will use state of the art mass spectrometrybased imaging to test the hypothesis that atheroma associated LPA accumulates progressively as a result oflipoprotein extravasation during the development of atherosclerosis. Together these studies will build on theresearch accomplished during the present funding period by providing important new information about theimpact of diet on a bioactive lipid signaling pathway that is now strongly implicated in heritable cardiovasculardisease risk. This research could inform strategies to mitigate cardiovascular disease risk through dietaryinterventions that decrease atherogenic lipoprotein associated LPA and will further underscore the value ofpharmacological targeting of LPA metabolism and signaling to mitigate cardiovascular disease risk.

project_terms:
Adipose tissue;Apolipoproteins B;Arterial Fatty Streak;Atherosclerosis;Attention;Award;Biological Markers;Blood;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Caring;Cell membrane;Cell surface;Cells;Cholesterol;Chylomicrons;Coronary Arteriosclerosis;Coronary artery;Coupled;Data;Development;Diabetes Mellitus;Diagnosis;Diet;Dietary Fats;Dietary Intervention;Dietary Phospholipid;Disease;Disease Progression;Endothelium;Enterocytes;Environmental Risk Factor;Enzymes;Extravasation;Family;Fasting;Fatty acid glycerol esters;Foam Cells;Funding;Gene Expression;General Population;Generations;Genes;Genetic;Goals;Heart;Heart Diseases;Hepatic;Heritability;Human;Image;In Vitro;Incidence;Individual;Inflammation;Ingestion;Inherited;Intestines;Introns;Investigation;Lead;Life Style;Link;Lipids;Lipoproteins;Liver;Low-Density Lipoproteins;Lysophospholipase;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Metabolic;Metabolism;Methods;Mus;Myocardial Infarction;Myocardial Ischemia;Obesity;Overweight;Oxides;Pathologic;Permeability;Pharmacology;Phenotype;Phospholipids;Plasma;Platelet Activation;Prevention;Process;Protein Dephosphorylation;Recording of previous events;Research;Risk Factors;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Suppressor Genes;Testing;Thrombosis;Tissues;Tracer;Triglycerides;Unhealthy Diet;United States;Variant;Vascular Smooth Muscle;Very low density lipoprotein;Veterans;Weight maintenance regimen;Woman;base;cardiovascular disorder risk;cell motility;cell type;dietary;disorder risk;feeding;heart disease risk;insight;lipid mediator;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;men;monocyte;mortality;mouse model;novel therapeutics;nutrition;obese person;oxidized low density lipoprotein;particle;prevent;protective effect;recruit;response;stable isotope;vascular endothelium permeability;vascular inflammation;vascular smooth muscle cell migration

public_health_relevance:
Veterans have a higher incidence of heart disease than the general population. Heart disease risk is causedby inherited (ie family history) and environmental factors. The most powerful environmental determinant ofcardiovascular disease risk is the diet. Unhealthy diets promote obesity and dramatically increasecardiovascular disease risk in men and women because obese individuals and particularly those with diabeteshave persistently high levels of bad lipids in their blood called low density lipoproteins. These are formeddirectly from fats and lipids that are ingested in the diet and can also be produced by the liver. Accumulation ofthese bad lipids in the walls of blood vessels in the heart causes angina and heart attacks. We have identifieda particular component of these bad lipids that can increase these heart disease processes and may be a linkbetween heritable and diet dependent heart disease risk. We will study where this particular bad lipid comesfrom in the body. Our studies might lead to new ways to prevent diagnose or treat heart disease in Veterans.


application_id: 9832131
project_number: 5I01BX001721-06
project_title: Thiamine deficiency and alcohol-induced neurodegeneration
administering_ic: VA
award_notice_date: 2020-01-07
opportunity_number: BX-18-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001721
project_start_date: 2013-10-01
project_end_date: 2022-12-31
study_section: ZRD1-NURA-F(01)1
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2020-01-01
project_abstract:
Alcohol abuse causes many long-lasting health consequences; one of which is impaired cognitivefunctioning known as alcohol-associated dementia (AAD). AAD is caused by the morphologicalneurophysiological and biochemical changes in the brain. The most devastating feature of brain damagefollowing chronic alcohol abuse is neurodegeneration. Alcohol abuse is frequently associated with thedeficiency of thiamine (vitamin B1). Besides alcohol exposure other factors such as genetic backgroundaging or nutritional status also contribute to thiamine deficiency (TD). The relationship between TD andalcohol-induced neurodegeneration remains unclear. Our studies indicate that TD exacerbated alcohol-inducedneurodegeneration. Alcohol exposure caused significant endoplasmic reticulum ER stress in the brain. Wehypothesize that TD causes a deficiency in unfolded protein response (UPR) which function as a protectiveresponse to alleviate ER stress-induced damage. MANF is an evolutionarily conserved neurotrophic factor andan important UPR component. We further hypothesize that MANF is a key protein that maintains ERhomeostasis and TD-induced deficiency in MANF makes neurons more susceptible to alcohol-induced ERstress and neurodegeneration. In this proposal we will first investigate the effect of TD on MANF expression.We will then determine the role of MANF in alcohol-induced ER stress and neurodegeneration. Finally we willdetermine whether manipulation of MANF expression in the brain can alter TD/alcohol-induced behavioraldeficits. As a unit the proposal will investigate the mechanisms of how TD exacerbates alcohol-inducedneurodegeneration and establish a protective role of MANF in alcohol-induced neurodegeneration. It will notonly provide a novel insight into the interaction between TD and alcohol exposure in the context of AAD butalso identify potential therapeutic targets for the treatment of AAD.

project_terms:
Accounting;Address;Adult;Affect;Age of Onset;Aging;Alcohol abuse;Alcoholism;Alcohols;Animals;Astrocytes;Attenuated;Behavioral;Biochemical;Blood Circulation;Brain;Brain Injuries;Cell physiology;Chronic;Clinical;Cognitive deficits;Data;Dementia;Diet;Down-Regulation;Endoplasmic Reticulum;Enzymes;Etiology;Experimental Models;Genetic;Health;Homeostasis;Human;Impaired cognition;Impairment;In Vitro;Injections;Knock-out;Knockout Mice;Learning;Memory;Metabolic;Modeling;Morphology;Motor;Mus;Nerve Degeneration;Neuraxis;Neurocognitive Deficit;Neurons;Neuroprotective Agents;Nutritional status;Oral;Oxidative Stress;Play;Population;Process;Proteins;Purkinje Cells;Research;Role;Symptoms;Thiamine;Thiamine Deficiency;Tissues;Veterans;Wernicke-Korsakoff Syndrome;absorption;alcohol abuse therapy;alcohol effect;alcohol exposure;alcohol response;alcohol use disorder;cofactor;cognitive function;endoplasmic reticulum stress;glucose metabolism;in vivo;insight;motor deficit;mouse model;neurophysiology;neurotrophic factor;novel;problem drinker;response;restoration;synergism;therapeutic target

public_health_relevance:
Alcohol abuse is a serious health problem among veterans. Chronic alcohol abuse causes brain damageand thiamine (vitamin B1) deficiency (TD). This proposal will investigate how TD and alcohol exposure interactto induce neurodegeneration in the central nervous system. We will also identify neurotrophic factors that canoffer protection and explore potential neuroprotective strategy to ameliorate alcohol-induced brain damage.


application_id: 9815441
project_number: 5I01BX003877-03
project_title: Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis
administering_ic: VA
award_notice_date: 2019-10-24
opportunity_number: BX-16-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003877
project_start_date: 2017-10-01
project_end_date: 2021-09-30
study_section: Hematology[HEMA]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-10-01
project_abstract:
World-wide spurious thrombosis accounts for 1 of 4 non-communicable disease deaths.Cardiovascular disease is a leading killer of aging US veterans and is the major cause of death in olderfemale veterans. Understanding how to modulate thrombosis will significantly aide the VA's mission toimprove veterans' health. Normally platelets respond to vascular damage and secrete granule cargothat are essential for recruiting more platelets and for generating a thrombus. This releasate promotesnormal sequelae but can also contribute to occlusive pathologies such as strokes and heart attacks. Inplatelets VAMPs SNAP-23 and Syntaxin-11 form a membrane-spanning complex that mediatesexocytosis. Formation of this complex requires a host of SNARE-regulators e.g. Munc18bSTXBP5/tomosyn-1 and granuphilin/SLP4; however the mechanisms by which these proteins controlthe complexity of the platelet release reaction (its rate extent and content) is uncertain. Platelets arealso capable of other cellular processes (i.e. RNA splicing translation glycosylation autophagy);however their effects on platelet function are still unknown. Our data suggest that endocytosis affectsthrombus growth by modulating platelet spreading and platelet-platelet contacts. Our goal is tomanipulate the membrane trafficking in platelets both endocytosis and exocytosis in order tomodulate occlusive thrombosis with only modest effects on hemostasis. To reach this goal wemust probe the molecular mechanisms of exocytosis. Our specific focus will be on Syntaxin-11regulators. We will also use an endocytosis defective mouse strain to define the roles of endocytosis inthrombosis and hemostasis. Two aims are proposed: 1) Define the network of protein-proteininteractions that affect Syntaxin-11-mediated membrane fusion and granule cargo release; and2) Determine the roles of platelet endocytosis in hemostasis. To complete these aims we willemploy biochemical assays to define the interactions between the SNARE regulators and in vitro andin vivo functional assays using transgenic mice to define the roles of the specific Syntaxin-11regulators and of endocytosis in thrombosis and hemostasis. Our results will expand the understandingof the molecular requirements and the sequence of protein-protein interactions controlling plateletexocytosis. We will also expand the mechanistic understanding of what cellular processes platelets canperform (i.e. endocytosis) and why they are important. Our results will be significant to the field sincethey will provide the needed mechanistic insights to identify potential targets for therapeutic interventionand to evaluate the relevance of the increasing volume of gene/risk associations that are guiding patienttreatment strategies. This will enhance the anti-thrombotic treatment options available for the care ofaging veterans.

project_terms:
Acute;Address;Adhesions;Affect;Age;Aging;Amino Acid Sequence;Autophagocytosis;Biochemical;Biological Assay;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Caring;Carotid Artery Injuries;Cause of Death;Cell physiology;Cellular biology;Cessation of life;Clot retraction;Coagulation Process;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Disease;Endocytosis;Equilibrium;Event;Exocytosis;Female;Fibrinogen;Gene Deletion;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Hemorrhage;Hemostatic function;Hyperactive behavior;In Vitro;Infarction;Integrins;Knock-out;Knockout Mice;Knowledge;Mediating;Membrane;Membrane Fusion;Mission;Modeling;Molecular;Molecular Chaperones;Molecular Probes;Morbidity - disease rate;Mouse Strains;Mus;Myocardial Infarction;Pathology;Patients;Physicians;Population;Precision Medicine Initiative;Process;Protein Biochemistry;Proteins;Publishing;RNA Splicing;Reaction;Risk;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Sampling;Stroke;Tail;Therapeutic Intervention;Thrombosis;Thrombus;Transgenic Mice;Translations;Veterans;Work;base;clinically significant;experimental study;familial hemophagocytic lymphohistiocytosis;genome wide association study;glycosylation;granuphilin;health management;improved;in vitro Assay;in vivo;insight;male;mortality;platelet function;protein protein interaction;recruit;response;restenosis;risk variant;synaptotagmin;syntaxin;syntaxin 11;syntaxin A;syntaxin-2;target SNARE proteins;targeted treatment;therapeutic target;trafficking;treatment strategy;vesicular SNARE proteins

public_health_relevance:
Relevance of the Project to Veterans' Health: Worldwide thrombotic events e.g. strokes and heart attacksaccount for 1 of 4 deaths not caused by communicable diseases. Thrombotic events are major killers of agingveterans especially female veterans. Platelets are essential for clot formation but targeting them to controlthrombosis requires a greater understanding of how platelet work. In this proposal we look at two aspects ofplatelet cell biology exocytosis and endocytosis to determine how and why platelets both release clottingcomponents and take them up them during clot formation. Our experiments will generate the critical mechanisticinsights needed to effectively control platelet function and thus limit thrombosis in aging veterans.


application_id: 9815365
project_number: 5I01BX004252-02
project_title: CD47 as a therapeutic target for obesity
administering_ic: VA
award_notice_date: 2019-10-24
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 004252
project_start_date: 2018-10-01
project_end_date: 2022-09-30
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-10-01
project_terms:
Adipocytes;Adipose tissue;Animal Model;Animals;Antisense Oligonucleotides;Attenuated;Body Weight;Body fat;Body mass index;Brown Fat;CD47 gene;Carnitine Palmitoyltransferase I;Cell Line;Cell membrane;Cell physiology;Cells;Complex;Cyclic AMP;Cyclic GMP;Data;Development;Diet;Eating;Energy Intake;Energy Metabolism;Exhibits;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Genes;Genotype;High Fat Diet;Homeostasis;Human Genome;In Vitro;Insulin Resistance;Investigation;Knockout Mice;Liver diseases;Mediating;Metabolic;Mitochondria;Modeling;Molecular;Mus;Nerve;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Obesity Epidemic;Resistance;Respiration;Risk Factors;Rodent;Rodent Model;Role;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;System;Testing;Therapeutic;Thermogenesis;Tissues;Wild Type Mouse;Work;base;blood glucose regulation;clinically significant;combat;comorbidity;genome-wide analysis;human subject;immune function;improved;in vivo;knock-down;lipid biosynthesis;lipid metabolism;mouse model;novel;novel therapeutics;obesity development;obesity genetics;obesity treatment;oxidation;prevent;receptor;therapeutic target;tool


application_id: 9814692
project_number: 5I01BX002996-04
project_title: Dietary Fat and Alcoholic Liver Disease
administering_ic: VA
award_notice_date: 2019-10-23
opportunity_number: BX-15-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002996
project_start_date: 2016-10-01
project_end_date: 2022-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-10-01
project_abstract:
DESCRIPTION (provided by applicant):      Alcohol abuse exacts a major toll on health and health costs in Veterans. Indeed even though there is an "epidemic" of hepatitis C in the U.S. alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in the oxidation of LA in an animal model of ALD. These findings led us to postulate that specific oxidized LA metabolites (OXLAMs) play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms for stressor-induced pathogenesis and which upon activation trigger the release of highly pro- inflammatory cytokines interleukin-1 (IL-1)and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator of inflammation andthus serves as a potential therapeutic target for treating hepatic inflammation in ALD. We propose that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two major mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction endoplasmic reticulum stress (ER stress) and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1 release. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD. Our research will be achieved through 3 specific aims: Aim 1. Evaluate whether OXLAMs exacerbate EtOH-mediated liver injury via induction of mitochondrial dysfunction ER stress and hepatocyte cell death in an animal model of ALD; Aim 2. Determine whether OXLAMs contribute to an EtOH-induced hepatic pro-inflammatory response via OXLAM-TRPV1-mediated inflammasome activation and subsequent increase in IL- release in an animal model of ALD. Aim 3. Explore the role of OXLAMs in monocytes/macrophages inflammasome activation in Alcoholic Hepatitis in Veterans.

project_terms:
Ablation;Address;Affect;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Blood;Breast;Cations;Cell Death;Cessation of life;Chronic;Cirrhosis;Clinical;Colon;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Epidemic;Ethanol;Etiology;Experimental Animal Model;FDA approved;Fatty Liver;Genetic;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis C;Hepatocyte;Hepatotoxicity;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1 beta;Interleukin-18;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Link;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Oxides;Pathogenesis;Patients;Permeability;Pharmacology;Play;Population;Prostate;Publishing;Research;Role;Signal Transduction;Steatohepatitis;Time;Translating;United States Department of Veterans Affairs;Unsaturated Fats;Up-Regulation;Vanilloid;Veterans;Whole Blood;base;cancer type;cytokine;endoplasmic reticulum stress;human study;in vitro testing;in vivo;intestinal injury;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;new therapeutic target;nonalcoholic steatohepatitis;novel;octadecadienoic acid;outcome forecast;oxidation;peripheral blood;public health relevance;receptor;stressor;therapeutic target;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:      Alcohol abuse exacts a major toll on health and health costs in Veterans. Even though there is an "epidemic" of hepatitis C in the U.S. and the Veterans Administration alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. The proposed studies will help to better understand the molecular mechanisms of alcohol-induced liver and intestinal injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD.


application_id: 9812847
project_number: 5I01CX001353-04
project_title: The role of Axin2+ stem cells in ulcer healing during colitis.
administering_ic: VA
award_notice_date: 2019-10-11
opportunity_number: CX-15-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001353
project_start_date: 2016-10-01
project_end_date: 2021-12-31
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-10-01
project_abstract:
DESCRIPTION (provided by applicant):      A major cause of colon removal surgery in veterans with inflammatory bowel disease (IBD) is a failure of medically-induced mucosal healing. Mucosal healing is a reliable clinical marker of recovery after IBD therapy as it is associated with durable clinical remission. Despite the importance of mucosal repair we continue to have a poor understanding of many of the cellular and molecular elements that mediate ulcer healing. The current proposal focuses on the role of colonic (epithelial) stem cells (CSC) in ulcer healing during colitis. Wnt/-catenin signaling in stem cells promotes cell proliferation as well as self-renewal both essential functions needed for ulcer healing and restitution of the mucosal barrier. A central tenant of this proposal is the hypothesis that Wnt/-catenin signaling plays an integral role in mucosal repair in IBD and that steroids delay ulcer healing my impairing Wnt/-catenin signaling. In mucosal ulceration as seen in IBD there is replacement of surface mucosa with granulation tissue that is re-epithelialized with new crypt structures. We suspect that active Wnt signaling is required for several steps through this sequence of events from stage 1) generation of an intestinal epithelial cell (IEC) monolayer to stage 2) formation of epithelial invaginations to stage 3) formation of crypt islands on ulcer surfaces and finally stage 4) regeneration of mature crypts (Fig 3). Biochemical data from our lab indicate Wnt/-catenin signaling is increased during ulcer healing in colitis in mice and IBD patients. In studies to interrogate the role of Wnt signaling in ulcer healing we discovered that IEC expressing mRNA for the Wnt target gene Axin2 expand in ulcer margins on ulcer surfaces and within newly-formed crypt structures in the middle of ulcers. Studies using a novel Axin2 reporter mouse model indicate that Axin2+ IEC are pluripotent and capable of growing colonoid structures in vitro from a single cell. Together the preliminary data suggest that Axin2+ IEC represent a novel ISC population that forms new crypt structures during ulcer healing. In Aim 1 Axin2lacZ/+ and Axin2 CreERT2/+; R26RmTmG/+ mice will be used to study ulcer-associated Axin2+ IEC localization and gene expression profiles of this new stem cell population as well as perform lineage tracing during ulcer healing in DSS colitis. In Aim 2 we will examine ulcer healing in mice treated with steroids. New studies will utilize Axin2-specific expression of stabilized -catenin to examine its role in ulcer healin during steroid therapy. Aim 3 studies will interrogate the role of Axin2+ IEC in human IBD and will analyze the mechanisms by which steroids impair ulcer healing. The goal of these studies will be to determine if untreated UC patients exhibit increased Axin2 expression Wnt signaling and stem cell gene expression in areas of ulcer healing (Aim 3A) and determine whether steroid therapy reduces levels of Axin2 expression and stem cell activation in areas of delayed ulcer healing in a prospective trial of UC patients treated with steroids for a colitis flare (Aim 3B). Together the studies proposed will provide valuable insights into the molecular mechanisms that govern ulcer healing in colitis. The goal is to determine areas where therapeutic targets can be designed to safely accelerate ulcer healing and reverse the negative impact of steroids on mucosal repair in colitis.

project_terms:
AXIN2 gene;Area;Biochemical;Cell Proliferation;Cells;Clinical Markers;Colitis;Colon;Data;Disease;Elements;Epithelial;Epithelial Cells;Epithelium;Event;Excision;Exhibits;Expression Profiling;Failure;Flare;Gene Expression;General Population;Generations;Goals;Granulation Tissue;Hospitalization;Human;Impairment;In Vitro;Incidence;Inflammatory Bowel Diseases;Intestines;Island;Lasers;Mediating;Medical;Messenger RNA;Microscopy;Molecular;Mucous Membrane;Mus;Natural regeneration;Operative Surgical Procedures;Oral;Patients;Play;Population;Prevalence;Recovery;Refractory;Reporter;Role;Signal Transduction;Steroid therapy;Steroids;Structure;Surface;Symptoms;Ulcer;Ulcerative Colitis;Veterans;WNT Signaling Pathway;Work;beta catenin;cell type;clinical remission;colon cancer risk;design;disability;epithelial stem cell;healing;improved;insight;intestinal epithelium;monolayer;mouse model;novel;prevent;prospective;public health relevance;repaired;self-renewal;stem cell population;stem cells;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:      The incidence and prevalence of ulcerative colitis (UC) is higher among veterans than in the general population and the prevalence of UC increased 2-fold to 3-fold among veterans between 1998 and 2009. Lifelong effects of this disease include expensive medical treatments hospitalization surgery disability and increased risk of colon cancer. For many patients oral steroids are the first-line treatment for UC. Although steroids are effective in reducing overt symptoms studies have shown that approximately half of all patients are refractory to steroid treatment with limited ulcer healing. We have identified a new type of intestinal stem cell that i involved in healing ulcers. The goal of this project is to identify which types of cells are involvd in ulcer healing and to understand how the activity of those cells is regulated. Additionally we propose to investigate how steroids influence stem cell activity and limit ulcer healing. Completion of this work will lead to new understanding of how to improve medical treatment of colitis and prevent surgery in veterans.


application_id: 9795013
project_number: 1IS1BX004791-01
project_title: ShEEP Request For Gas Chromatograph Mass Spectrometer
administering_ic: VA
award_notice_date: 2019-04-01
opportunity_number: BX-18-015
application_type: 1
activity_code: IS1
ic: BX
serial_number: 004791
project_start_date: 2019-01-01
project_end_date: 2019-09-30
study_section: Special Emphasis Panel[ZRD1 SPLJ-C (01)]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-01-01
project_abstract:
The purpose of this application is to request funds for acquisition of an integrated gas chromatography massspectrometer system (GC MS) with an electron capture detector and a workstation computer with dedicatedsoftware for instrument control data acquisition and analysis. The instrument system requested comprises anAgilent Intuvio 9000 gas chromatograph with an Agilent 7693A auto injector an air cooled multimode inlet(enables split/splitless and large volume injections) and an Agilent micro electron capture detector with asplitter chip. The system is interfaced with an Agilent 5977B single quadrupole mass spectrometer with a HighEfficiency Electron Impact ionization source and an oil free scroll roughing pump. The system includes aWorkstation Computer with Agilent Mass Hunter software for instrument control and data analysis with the2017 NIST library of 307000 spectra for 267000 compounds and retention indices for 87000 compounds.This instrument system will be primarily used by 4 VA funded researchers (Major Users) for research in areasthat include lipid metabolism and signaling in cardiovascular disease the effects of diet and environmentalchemicals on human health regulation of blood clotting treatment of muscle weakness in hospitalizedpatients management and treatment of patients with ulcerative colitis breast cancer and blast induced brainand retinal injuries. These are hematic areas of notable strength at the Lexington VA Medical Center andrepresent areas of medical research that are particularly relevant to Veterans. The instrument will be overseenand operated by highly experienced analytical chemists who will work together with the Major Users to ensurethe requested instrument system is used efficiently to generate high quality reliable data to support their VAfunded research projects. Administrative mechanisms are in place to control and monitor access to theinstrument system. A business plan will be enacted to ensure sustainability of the instrument system so thatthe investment requested from this funding program will be repaid with a high level of research productivity.

project_terms:
15 year old;Address;Agreement;Air;Area;Blood coagulation;Brain;Brain Injuries;Businesses;Cardiovascular Diseases;Clinical;Computer Workstations;Computer software;Contract Services;Cost Measures;Data;Data Analyses;Development;Diet;Digestive System Disorders;Doctor of Philosophy;Electrons;Ensure;Fee-for-Service Plans;Focus Groups;Funding;Gas Chromatography;Gases;Health;Healthcare Systems;Heart Diseases;Human;Human Resources;Individual;Injections;Injury;Institutional Review Boards;Investments;Kentucky;Knowledge;Libraries;Maintenance;Mass Spectrum Analysis;Measures;Medical Research;Medical center;Medicine;Methods;Monitor;Muscle Weakness;Neurodegenerative Disorders;Oils;Patients;Peer Review;Play;Process;Productivity;Publications;Pump;Recovery;Regulation;Research;Research Personnel;Research Project Grants;Research Support;Retinal;Role;Sampling;Scientist;Sepsis;Services;Sheep;Signal Transduction;Solvents;Source;Speed;System;Technical Expertise;Training;Traumatic Brain Injury;Ulcerative Colitis;Universities;Validation;Veterans;Work;assay development;beneficiary;college;cost;data acquisition;detector;environmental chemical;equipment acquisition;experience;flexibility;human disease;improved;indexing;instrument;instrumentation;ionization;lipid metabolism;malignant breast neoplasm;mass spectrometer;member;operation;programs;research and development

public_health_relevance:
Natural and manmade molecules play critical roles in human disease processes. Detecting measuring andidentifying these molecules requires sophisticated instrumentation. The purpose of this application is torequest funds to purchase an instrument system that will be used to identify and measure molecules that areimportant for research to understand heart and digestive diseases muscle weakness and traumatic braininjury which are of high relevance to Veterans Healthcare System beneficiaries.


application_id: 9766444
project_number: 1I01BX004639-01
project_title: HDL as a therapeutic target for sepsis
administering_ic: VA
award_notice_date: 2019-10-21
opportunity_number: BX-18-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 004639
project_start_date: 2019-10-01
project_end_date: 2023-09-30
study_section: Special Emphasis Panel[ZRD1 SURG-P (01)]
contact_pi_person_id: 8132330
contact_pi: LI, XIANG-AN
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-10-01
project_terms:
Animals;Bacteria;Biological;Biology;Blood;Cessation of life;Clinical;Clinical Data;Clinical Trials;Coagulation Process;Data;Disease;Dose;Drops;Drug Kinetics;Effector Cell;Endogenous Factors;Endothelial Cells;Endotoxins;Frequencies;Future;Generations;Grant;Health;High Density Lipoprotein therapy;High Density Lipoproteins;Hospitals;Immune;Immune response;Immunity;In Vitro;Infection;Inflammatory;Inflammatory Response;Investigational Drugs;Knockout Mice;Knowledge;Lead;Mediating;Modeling;Mus;Operative Surgical Procedures;Pathogenesis;Pathway interactions;Patients;Play;Positioning Attribute;Postoperative Period;Property;Public Health;Regimen;Reporting;Risk;Risk Factors;Role;Sepsis;Signal Transduction;Testing;Therapeutic;Toxic effect;Treatment Protocols;Vascular Endothelial Cell;Veterans;base;cecal ligation puncture;cell injury;clinical translation;drug development;effective therapy;endothelial dysfunction;experience;improved;in vivo;innovation;macrophage;mortality;neutrophil;novel;novel strategies;organ injury;outcome forecast;overexpression;pre-clinical;protective effect;reconstitution;response;septic;septic patients;success;targeted treatment;therapeutic target;tool;treatment optimization


application_id: 9733695
project_number: 5I01CX001614-02
project_title: Systems biology approach to the management of chronic kidney disease-mineral bone disorder
administering_ic: VA
award_notice_date: 2019-05-23
opportunity_number: CX-17-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001614
project_start_date: 2018-07-01
project_end_date: 2022-06-30
study_section: Endocrinology B[ENDB]
contact_pi_person_id: 2262379
contact_pi: LEDERER, ELEANOR D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-07-01
project_abstract:
Veterans are at an increased risk of kidney disease compared to the non-Veteran US population.Cardiovascular and bone disease are two major causes of death in Veterans with end stage renal disease(ESRD) resulting from abnormal mineral metabolism. Specifically Mineral and Bone Disorder (MBD) is auniversal complication of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD). Themultifactorial nature of MBD in the Veteran ESRD population makes the effective management of thiscondition complex. Proper management entails the maintenance of serum calcium phosphorus and intactPTH levels within guidelines established and refined by international working groups using dietary counselingphosphate binders active vitamin D analogues calcium sensing receptor agonists and parathyroidectomy.Achievement of the target goals for each parameter in every patient has been elusive though studies havedemonstrated that attainment of the desired guideline goals for all three parameters is associated with lowercardiovascular risk. The hypothesis to be tested is that the success rate in achievement of the guidelines forMBD management can be improved and better informed by systems biology modeling of mineral metabolismand development of a personalized algorithm for prescription of each of the current therapies. The broad-basedlong term goal of this research endeavor is to address critical technological barriers to the progress ofpersonalized MBD management thus improving cardiovascular and bone outcomes in Veteran patients.Preliminary work in this area has demonstrated the feasibility of the systems biology modeling approach to theachievement of established clinical guidelines. Current care of these Veteran Patients is based in a trial anderror approach. Ideally dosing of multiple agents for MDB should be guided by individual response to each ofthese agents. To address the challenges outlined above a systems biology approach to modeling the complexdisorder MBD with be utilized. The hypothesis is that advanced computational techniques can beused to optimally guide dosing of the agents used in MBD. The plan to accomplish this objective areoutlined in these five specific aims: 1. Development of a QSP-SB model for metabolic bone disorder. 2. Development of a drug dosing and hemodialysis model 3. Development of a database of clinically derived data obtained from CPRS. 4. Development of a dosing algorithm and a clinical tool used for CKD-MBDmanagement. 5. Testing of the developed MBD-CKD dosing algorithm and tool in in-center hemodialysis patients.A broad inclusive population of Veterans will be studied to develop these novel dosing algorithms. Improvedindividualized control of calcium phosphorus and PTH has been shown to improve cardiovascular mortalitywhen recommended concentrations are achieved. These tools will result in an advance in the dosing of drugsfor chronic conditions that will be applicable to areas other than bone disease and an improvement in thehealth of each individual Veteran with kidney disease.

project_terms:
Achievement;Address;Adult;Agonist;Algorithmic Software;Algorithms;Anemia;Area;Biological Models;Bone Diseases;Calcium;Calcium-Sensing Receptors;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Chronic;Chronic Kidney Failure;Clinical;Clinical Decision Support Systems;Clinical Practice Guideline;Comorbidity;Complex;Complication;Computational Technique;Computerized Medical Record;Computers;Consensus;Counseling;Data;Development;Dialysis procedure;Diet;Disease;Disease Management;Dose;Drug usage;End stage renal failure;Equation;Evaluation;Funding;Goals;Guidelines;Health;Hemodialysis;Hypertension;Immunosuppression;Individual;International;Kidney Diseases;Literature;Maintenance;Medical;Metabolic Bone Diseases;Metabolic Pathway;Metabolism;Minerals;Minority;Modeling;Monitor;Morbidity - disease rate;Nature;Osteoporosis;Outcome;Parathyroidectomy;Patients;Pharmaceutical Preparations;Pharmacology;Phosphorus;Plant Roots;Population;Publishing;Regulation;Renal function;Research;Risk;Series;Serum;System;Systems Biology;Techniques;Testing;Therapeutic;Translating;United States National Institutes of Health;Veterans;Vitamin D;Vitamin D Analog;Work;base;bone;bone turnover;calcification;cardiovascular risk factor;clinical database;clinical practice;computerized tools;cost;cost effective;dose information;first-in-human;glycemic control;improved;individual response;individualized medicine;inorganic phosphate;mimetics;mortality;named group;novel;novel strategies;patient response;personalized approach;personalized medicine;pharmacometrics;success;tool;working group

public_health_relevance:
Veterans with End-Stage Renal Disease (ESRD) require chronic dialysis to replace lostkidney function at a cost of $89000 per patient annually. The VA is responsible for dialysisof over 16000 Veterans nationwide. Cardiovascular disease is the primary morbiditydirectly related to abnormal mineral metabolism (MBD). Although achievement of theguideline established goals for serum calcium phosphorus and intact PTH is associatedwith greater survival only a minority of patients 10-20% are able to accomplish this on aconsistent basis at least in part due to the complex array of interacting therapies to treatthis disorder. Developing and implementing a modeling system to deliver personalized andindividualized therapy for MBD would decrease cardiovascular death for Veterans withESRD as well as the general ESRD population.


application_id: 9678201
project_number: 5IK6BX004199-02
project_title: BLR&D Research Career Scientist Award application
administering_ic: VA
award_notice_date: 2019-03-21
opportunity_number: BX-17-022
application_type: 5
activity_code: IK6
ic: BX
serial_number: 004199
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Research Career Scientist[RCSR]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Alcoholic liver damage;Antibodies;Award;Biological;Biological Markers;Biology;Brain;Brain Injuries;Brain Neoplasms;Breast Cancer Cell;Broccoli - dietary;Cancer Patient;Caring;Cell Communication;Cell Differentiation Inhibition;Cell Differentiation process;Cells;Cessation of life;Chronic;Clinical;Clinical Management;Colitis;Colon;Colonic Neoplasms;Colorectal;Communication;Curcumin;Cutaneous Melanoma;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Dinoprostone;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Explosion;Failure;Folic Acid;Food;Foundations;Funding;Gene Expression;Ginger;Goals;Grapefruit;Grapes;Health Status;Hepatocyte;Hepatology;High Fat Diet;Homeostasis;Homing;Human;Immunosuppression;Immunosuppressive Agents;Immunotherapy;Inflammation;Inflammatory;Insulin Resistance;International;Intestines;Journals;Kidney;Light;Link;Lipids;Liver;Long-Term Effects;Lung;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Mammary Neoplasms;Manuscripts;Mediating;Medical;Methods;MicroRNAs;Microglia;Molecular;Mucous body substance;Mus;Myelogenous;Myeloid-derived suppressor cells;NK Cell Activation;Names;Nature;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncogenes;Oncogenic;Oncoproteins;Overweight;Patients;Pharmaceutical Preparations;Physiological;Plants;Play;Population;Prostate;Publishing;RNA;Radiation therapy;Research;Resistance;Risk;Role;Scientist;Signal Transduction;Site;Small Interfering RNA;Sorting - Cell Movement;Specificity;Stem cells;T-Lymphocyte;Therapeutic;Therapeutic Agents;Tissues;Traumatic Brain Injury;Tumor Promotion;Tumor Suppressor Proteins;Tumor-Derived;Vesicle;Veterans;WNT Signaling Pathway;War;Work;alcohol prevention;anergy;anticancer research;base;beta catenin;cancer cell;cancer diagnosis;cancer immunotherapy;cancer prevention;cancer therapy;cancer type;career;cell type;chemokine;chemokine receptor;cytokine;exosome;expression vector;extracellular;folate-binding protein;improved;in vivo;interspecies communication;intestinal homeostasis;liver development;liver inflammation;liver injury;macrophage;major vault protein;member;microvesicles;mild traumatic brain injury;mortality;mouse model;nanoparticle;nanovector;nanovesicle;neoplastic cell;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;patient population;pressure;prevent;side effect;sound;targeted delivery;therapeutic development;therapeutic miRNA;translational study;treatment strategy;tumor;tumor progression


application_id: 9678185
project_number: 5I01BX003274-02
project_title: The Vagus Nerve in Lung Disease
administering_ic: VA
award_notice_date: 2019-03-21
opportunity_number: BX-17-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 003274
project_start_date: 2018-04-01
project_end_date: 2022-03-31
study_section: Respiration[PULM]
contact_pi_person_id: 2084836
contact_pi: YU, JERRY (JUN)
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
project_terms:
Acetylcholine;Address;Adoptive Cell Transfers;Adult Respiratory Distress Syndrome;Agonist;Asthma;Attenuated;Biochemical;Biochemistry;Biological;Biosensor;Brain;Bronchoalveolar Lavage;Cell Count;Cells;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Cicatrix;Collagen;Complex;Cytology;Data;Deposition;Development;Disease;Dyspnea;Endothelial Cells;Epithelial Cells;Fibroblasts;Fibrosis;Gases;Gene Expression;Genes;Growth Factor;Histology;Hospitals;Immune response;Inflammatory;Injury;Lead;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mammals;Mediating;Mediator of activation protein;Molecular;Mucous Membrane;Mus;Myofibroblast;Nerve;Nerve Block;Neural Pathways;Neuraxis;Neuroendocrine Cell;Neuroepithelial Bodies;Neuroimmune;Neurosecretory Systems;Outcome;Pathogenesis;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacology;Phase;Physiology;Plasma;Play;Population;Process;Pulmonary Fibrosis;Research;Role;Sensory Receptors;Severities;Stem cells;System;Techniques;Testing;Transforming Growth Factor beta;Vagotomy;Vagus nerve structure;Veterans;chemical release;cytokine;effective therapy;fibrogenesis;improved;indium-bleomycin;lung development;lung injury;lung repair;mouse model;neuromechanism;novel;novel strategies;patient population;protein expression;receptor;recruit;sensor;vagus nerve stimulation


application_id: 9663270
project_number: 5I01RX002316-03
project_title: Force Feedback Redistribution & Eccentric-Focused Rehab post-SCI
administering_ic: VA
award_notice_date: 2019-04-01
opportunity_number: RX-16-012
application_type: 5
activity_code: I01
ic: RX
serial_number: 002316
project_start_date: 2017-04-01
project_end_date: 2021-03-31
study_section: Spinal Cord Injury/Disorders & Neuropathic Pain[RRDA]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-04-01
project_terms:
Address;Adult;Animal Model;Animals;Behavior;Bilateral;Characteristics;Chest;Chronic;Cicatrix;Data;Data Collection;Databases;Decerebrate State;Development;Disease;Distal;Dorsal;Experimental Designs;Extensor;Feedback;Felis catus;Gait;Goals;Golgi Tendon Organs;Health;Histology;Human;Injury;Joints;Knowledge;Laboratories;Lateral;Leg;Lesion;Limb structure;Link;Locomotion;Locomotor training;Maps;Mediating;Mission;Modeling;Motor;Motor Skills;Movement;Muscle;Normal Statistical Distribution;Pathway interactions;Performance;Phase;Physical Rehabilitation;Preparation;Procedures;Production;Productivity;Quality of life;Ramp;Recovery;Reflex action;Rehabilitation therapy;Research;Research Proposals;Specificity;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Stains;System;Testing;Thoracic spinal cord structure;Time;Tissues;Training;Veterans;Walking;Weight;Work;base;care systems;design;evidence base;experimental study;gait examination;gait rehabilitation;improved;injured;innovation;insight;kinematics;locomotor tasks;motor control;motor disorder;motor recovery;motor rehabilitation;nervous system disorder;novel;receptor;rehabilitation strategy;relating to nervous system;response;translational model;treadmill


application_id: 9638507
project_number: 5I01CX001550-07
project_title: Lysophosphatidic acid and cardiovascular disease risk
administering_ic: VA
award_notice_date: 2019-01-31
opportunity_number: CX-16-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001550
project_start_date: 2013-01-01
project_end_date: 2020-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-01-01
project_abstract:
Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovasculardisease risk is caused by environmental and heritable factors. The broad goal of our research is to understandhow these factors interact to determine overall disease risk. In current funding period of this award we studiedhow heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate withheritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of thegene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results inaccelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an atherosclerosissuppressor gene and that heritable variants that decrease expression of the gene promote heart disease risk.LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipidmediators. One of these LPP3 substrates lysophosphatidic acid (LPA) acts on multiple blood and vascularcells to promote inflammation and cardiovascular disease progression. In mice genetic or pharmacologicaltargeting of LPA modulates atherosclerosis. In our mouse studies LPP3 deficiency was associated withincreased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesisthat dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 oncardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. Inpreliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. Thisdiet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestinefrom dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low densitylipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is asecreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources ofcirculating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also anintermediate in the synthesis of triglycerides by the intestine and liver so since this process is coupled to thegeneration of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo. The firstaim of this proposal will test these competing hypotheses directly by using stable isotope tracers and massspectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studieswill allow us to use genetic and pharmacological approaches to selectively manipulate ATX LPP3 and theformation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signalingresponses in blood and vascular cell types that underlie the initiation and progression of cardiovasculardisease by promoting permeability of vascular endothelium phenotypic modulation and proliferation/migrationof vascular smooth muscle cells and the classical macrophage foam cell response. The second aim of theproposal will test the hypothesis that the LPA content of these lipoproteins is a determinant of these responses.LPA is present in atherosclerotic blood vessels and release of LPA may contribute to platelet activation andthrombosis during plaque rupture. The final aim of this proposal will use state of the art mass spectrometrybased imaging to test the hypothesis that atheroma associated LPA accumulates progressively as a result oflipoprotein extravasation during the development of atherosclerosis. Together these studies will build on theresearch accomplished during the present funding period by providing important new information about theimpact of diet on a bioactive lipid signaling pathway that is now strongly implicated in heritable cardiovasculardisease risk. This research could inform strategies to mitigate cardiovascular disease risk through dietaryinterventions that decrease atherogenic lipoprotein associated LPA and will further underscore the value ofpharmacological targeting of LPA metabolism and signaling to mitigate cardiovascular disease risk.

project_terms:
Adipose tissue;Apolipoproteins B;Arterial Fatty Streak;Atherosclerosis;Attention;Award;Biological Markers;Blood;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Caring;Cell membrane;Cell surface;Cells;Cholesterol;Chylomicrons;Coronary Arteriosclerosis;Coronary artery;Coupled;Data;Development;Diabetes Mellitus;Diagnosis;Diet;Dietary Fats;Dietary Intervention;Dietary Phospholipid;Disease;Disease Progression;Endothelium;Enterocytes;Environmental Risk Factor;Enzymes;Extravasation;Family;Fasting;Fatty acid glycerol esters;Foam Cells;Funding;Gene Expression;General Population;Generations;Genes;Genetic;Goals;Heart;Heart Diseases;Hepatic;Heritability;Human;Image;In Vitro;Incidence;Individual;Inflammation;Ingestion;Inherited;Intestines;Introns;Investigation;Lead;Life Style;Link;Lipids;Lipoproteins;Liver;Low-Density Lipoproteins;Lysophospholipase;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Metabolic;Metabolism;Methods;Mus;Myocardial Infarction;Myocardial Ischemia;Obesity;Overweight;Oxides;Pathologic;Permeability;Pharmacology;Phenotype;Phospholipids;Plasma;Platelet Activation;Prevention;Process;Protein Dephosphorylation;Recording of previous events;Research;Risk Factors;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Suppressor Genes;Testing;Thrombosis;Tissues;Tracer;Triglycerides;Unhealthy Diet;United States;Variant;Vascular Smooth Muscle;Very low density lipoprotein;Veterans;Weight maintenance regimen;Woman;base;cardiovascular disorder risk;cell motility;cell type;disorder risk;feeding;heart disease risk;insight;lipid mediator;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;men;monocyte;mortality;mouse model;novel therapeutics;nutrition;oxidized low density lipoprotein;particle;prevent;protective effect;recruit;response;stable isotope;vascular endothelium permeability;vascular inflammation;vascular smooth muscle cell migration

public_health_relevance:
Veterans have a higher incidence of heart disease than the general population. Heart disease risk is causedby inherited (ie family history) and environmental factors. The most powerful environmental determinant ofcardiovascular disease risk is the diet. Unhealthy diets promote obesity and dramatically increasecardiovascular disease risk in men and women because obese individuals and particularly those with diabeteshave persistently high levels of bad lipids in their blood called low density lipoproteins. These are formeddirectly from fats and lipids that are ingested in the diet and can also be produced by the liver. Accumulation ofthese bad lipids in the walls of blood vessels in the heart causes angina and heart attacks. We have identifieda particular component of these bad lipids that can increase these heart disease processes and may be a linkbetween heritable and diet dependent heart disease risk. We will study where this particular bad lipid comesfrom in the body. Our studies might lead to new ways to prevent diagnose or treat heart disease in Veterans.


application_id: 9636507
project_number: 5I01BX003405-03
project_title: mitoNEET as a therapeutic target for TBI
administering_ic: VA
award_notice_date: 2019-02-05
opportunity_number: BX-16-003
application_type: 5
activity_code: I01
ic: BX
serial_number: 003405
project_start_date: 2017-01-01
project_end_date: 2020-12-31
study_section: Neurobiology C[NURC]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2019-01-01
project_abstract:
Accumulating clinical evidence as well as experience in contemporary military operations suggests thattraumatic brain injury (TBI) is the signature injury of this war making our troops a high-risk population for TBI.Among the 327388 OEF/OIF veterans using VA services in 2009 6.7% were diagnosed with TBI of which 73%of those were diagnosed with posttraumatic stress disorder (PTSD). However to date there is no approvedtreatment for TBI in part due to an incomplete understanding of the pathobiology underlying TBI. Thereforeprogress in this area of research is desperately needed. Recently we have shown that pioglitazone isneuroprotective following TBI and that its mechanism of action may be directly related to its interactions with themitochondrial protein mitoNEET. Consistent with these ideas our preliminary results indicate pioglitazone is notprotective in mitoNEET knockout animals and that treatment with a specific mitoNEET ligand (NL1) isneuroprotective following TBI. The proposed experiments are designed to elucidate the mechanism(s) bywhich pioglitazone confers neuroprotection following TBI by testing the novel hypothesis thatpioglitazone via mitoNEET interaction directly ameliorates mitochondrial dysfunction. To test thishypothesis we propose three specific aims that include the use of multiple innovative tools and techniques thatwe have in hand specifically the use of mitoNEET null transgenic mice a novel mitoNEET ligand (NL-1) andantagonist (NL-3). In Specific Aim 1 we will determine the optimal dosage and therapeutic window ofopportunity for pioglitazone to maintain mitochondrial homeostasis post-injury. These measurements will for thefirst time measure mitochondrial dysfunction from synaptic and nonsynaptic mitochondria in the injury core andpenumbra from a single animal. In Specific Aim 2 will measure the degree of cortical sparing and behaviorimprovements that are mediated through pioglitazone treatment after TBI using the optimal dosage determinedin Specific Aim 1. In this aim we will use T2 weighted and DTI MRI to longitudinally assess changes in corticaland hippocampal morphology at -3 3 7 14 28 and 168 days post-injury followed by unbiased stereology at168 days post-injury. Additionally we will measure acute motor serial cognitive functional testing and aggressivebehavioral function and fear conditioning (chronic measurements of PTSD) to assess the degree of functionalrecovery as a result of treatment. Specific Aim 3 will determine the mechanism by which pioglitazone affordsneuroprotection by testing the hypothesis that pioglitazone's therapeutic effect is mediated through interactionswith mitoNEET. This aim will employ the use of transgenic mitoNEET null mice in tandem with a novel mitoNEETspecific ligand (NL-1) and mitoNEET antagonist (NL-3). Mitochondrial bioenergetics will be measured at 24 hoursand behavioral outcome and tissue sparing will be measured following TBI. The results of these studies will notonly shed light on the fundamental processes involved in TBI neuropathology they also move forward therepurposing of an FDA compound for the treatment of TBI and the proposed experiments may pinpoint potentialnovel targets for the treatment of TBI and perhaps other neuronal injuries.

project_terms:
Acute;Adult;Aftercare;Animals;Area;Behavior;Behavioral;Bioenergetics;Brain Injuries;Chronic;Clinical;Cognitive;Coupled;Data;Diagnosis;Dose;FDA approved;Hand;Hippocampus (Brain);Homeostasis;Hour;Injury;Knock-out;Knockout Mice;Ligands;Light;Link;Magnetic Resonance Imaging;Measurement;Measures;Mediating;Military Personnel;Mitochondria;Mitochondrial Proteins;Modeling;Molecular Target;Morphology;Motor;Mus;Neuronal Injury;Neurons;Outcome;Pathway interactions;Patients;Peroxisome Proliferator-Activated Receptors;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Publishing;Reactive Oxygen Species;Recovery of Function;Research;Respiration;Scanning;Services;Site;Synapses;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Transgenic Mice;Transgenic Organisms;Translating;Traumatic Brain Injury;Veterans;War;Work;base;behavior measurement;behavioral outcome;brain dysfunction;conditioned fear;controlled cortical impact;cost;design;dosage;experience;experimental study;functional outcomes;high risk population;improved;innovation;knockout animal;male;mitochondrial dysfunction;neuropathology;neuroprotection;novel;operation;primary endpoint;receptor binding;response;secondary endpoint;therapeutic target;tool

public_health_relevance:
Clinical evidence coupled with experience in contemporary military arenas clearly indicates that traumatic braininjury (TBI) is becoming a signature injury of war which makes our troops a high-risk population. In fact 6.7% ofOEF/OIF veterans in 2009 were diagnosed with TBI and 73% of those were diagnosed with posttraumatic stressdisorder (PTSD). At present there is no approved treatment for TBI due to an incomplete understanding of theunderlying pathobiology. This proposal examines the potential of targeting the novel mitochondrial proteinmitoNEET and to push forward the repurposing of pioglitazone to limit the brain damage and dysfunction resultingfrom TBI.


application_id: 9605233
project_number: 5I01BX002996-03
project_title: Dietary Fat and Alcoholic Liver Disease
administering_ic: VA
award_notice_date: 2018-10-30
opportunity_number: BX-15-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002996
project_start_date: 2016-10-01
project_end_date: 2020-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-10-01
project_abstract:
DESCRIPTION (provided by applicant):      Alcohol abuse exacts a major toll on health and health costs in Veterans. Indeed even though there is an "epidemic" of hepatitis C in the U.S. alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in the oxidation of LA in an animal model of ALD. These findings led us to postulate that specific oxidized LA metabolites (OXLAMs) play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms for stressor-induced pathogenesis and which upon activation trigger the release of highly pro- inflammatory cytokines interleukin-1 (IL-1)and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator of inflammation andthus serves as a potential therapeutic target for treating hepatic inflammation in ALD. We propose that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two major mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction endoplasmic reticulum stress (ER stress) and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1 release. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD. Our research will be achieved through 3 specific aims: Aim 1. Evaluate whether OXLAMs exacerbate EtOH-mediated liver injury via induction of mitochondrial dysfunction ER stress and hepatocyte cell death in an animal model of ALD; Aim 2. Determine whether OXLAMs contribute to an EtOH-induced hepatic pro-inflammatory response via OXLAM-TRPV1-mediated inflammasome activation and subsequent increase in IL- release in an animal model of ALD. Aim 3. Explore the role of OXLAMs in monocytes/macrophages inflammasome activation in Alcoholic Hepatitis in Veterans.

project_terms:
Ablation;Address;Affect;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Blood;Breast;Cations;Cell Death;Cessation of life;Chronic;Cirrhosis;Clinical;Colon;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Epidemic;Ethanol;Etiology;Experimental Animal Model;FDA approved;Fatty Liver;Genetic;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis C;Hepatocyte;Hepatotoxicity;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Link;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Oxides;Pathogenesis;Patients;Permeability;Pharmacology;Play;Population;Prostate;Publishing;Research;Role;Signal Transduction;Steatohepatitis;Time;Translating;United States Department of Veterans Affairs;Unsaturated Fats;Up-Regulation;Vanilloid;Veterans;Whole Blood;base;cancer type;cytokine;endoplasmic reticulum stress;human study;in vitro testing;in vivo;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;new therapeutic target;nonalcoholic steatohepatitis;novel;octadecadienoic acid;outcome forecast;oxidation;peripheral blood;public health relevance;receptor;stressor;therapeutic target;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:      Alcohol abuse exacts a major toll on health and health costs in Veterans. Even though there is an "epidemic" of hepatitis C in the U.S. and the Veterans Administration alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. The proposed studies will help to better understand the molecular mechanisms of alcohol-induced liver and intestinal injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD.


application_id: 9605204
project_number: 5I01BX002149-04
project_title: FUS Protein Homeostasis in ALS
administering_ic: VA
award_notice_date: 2018-10-30
opportunity_number: BX-14-004
application_type: 5
activity_code: I01
ic: BX
serial_number: 002149
project_start_date: 2015-10-01
project_end_date: 2019-09-30
study_section: Neurobiology E[NURE]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease with no effective treatment. ALS is connected with military service and veterans are at a higher risk of contracting this debilitating disease. Mutations in several genes have been discovered to cause a subset of familial ALS including copper- zinc superoxide dismutase (SOD1) fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43). Studying familial ALS using the well-defined genetic models will provide critical insights into the disease pathology as well as novel targets for future therapeutic development.  This project is focused on the RNA binding protein FUS that has been implicated in both familial and sporadic ALS. Since FUS mutations were found in a subset of familial ALS patients in 2009 mislocalization of mutant FUS in the cytoplasm has been considered a hallmark of this subset (Type 6) of ALS. However protein inclusions containing wild-type FUS have been reported in multiple forms of familial and sporadic ALS suggesting that FUS plays an important role in a larger portion of ALS beyond the Type 6 familial ALS. Protein inclusions can be caused by protein over-production inefficient protein degradation protein mislocalization or a combination of these defects. However the regulation of FUS protein expression and degradation remains poorly understood. We have published that it is critical to maintain proper levels of FUS inside the nucleus and that either elevated or reduced levels of FUS causes similar degenerative phenotypes in Drosophila models. Thus we propose that maintaining appropriate FUS protein homeostasis is critical to attenuate FUS toxicity and motor neuron dysfunction. Since little is known about how FUS gene transcription and protein turnover are regulated discoveries in this project will fill this knowledge gap and advance the field significantly.  The specific hypotheses to be tested are: FUS gene transcription is regulated by the Jak/Stat signaling cascade (Aim 1) while FUS degradation is largely mediated by the ubiquitin-proteasome system (Aim 2). Moreover we will test the hypothesis that FUS ubiquitination regulates its RNA binding and subcellular localization (Aim 3). We have carried out preliminary studies to show that the transcription of FUS is indeed controlled by Jak/Stat signaling and that Jak/Stat signaling attenuates FUS toxicity in Drosophila models. We also show that the degradation of FUS is mediated by the ubiquitin-proteasome system and that FUS ubiquitination is regulated by a specific E3 ligase named FBXW7. Moreover a dominant negative mutant FBXW7 decreased FUS ubiquitination delayed FUS degradation and changed FUS subcellular localization. Therefore each of these three specific hypotheses is supported by our preliminary results. These inter-related pathways play a critical role in regulating FUS function and alterations in any of them will likely contribute to the pathogenesis of ALS. The results from this study will help understand how to target FUS in motor neurons providing a new avenue to attenuate FUS toxicity in future therapeutic developments.  The proposal is constructed based on a number of novel observations which leads to a novel hypothesis that that FUS protein biosynthesis and turnover can be modulated to attenuate FUS toxicity in ALS. An array of techniques will be employed to test the hypothesis in a combination of in vitro and in vivo models. The results from the proposed studies should yield potential new targets that can be translated into novel treatments for veteran and other ALS patients.

project_terms:
Amyotrophic Lateral Sclerosis;Anabolism;Attenuated;Cell Nucleus;Cells;Cessation of life;Complex;Contracts;Cultured Cells;Cytoplasm;DNA Sequence Alteration;Defect;Diagnosis;Disease;Dominant-Negative Mutation;Drosophila genus;FBXW7 gene;Familial Amyotrophic Lateral Sclerosis;Foundations;Functional disorder;Future;Gene Proteins;Genes;Genetic;Genetic Models;Genetic Transcription;Health;Healthcare;In Vitro;Incidence;Knowledge;Ligands;Mass Spectrum Analysis;Mediating;Military Personnel;Modeling;Molecular;Motor Neurons;Mutation;Names;Neurodegenerative Disorders;Pathogenesis;Pathology;Pathway interactions;Patients;Phenotype;Play;Polyubiquitination;Production;Protein Biosynthesis;Proteins;Publishing;RNA Binding;RNA Interference;RNA-Binding Proteins;Rattus;Regulation;Reporting;Research;Role;Services;Signal Transduction;Site;System;Techniques;Testing;Toxic effect;Transgenic Organisms;Translating;Ubiquitin;Ubiquitination;Veterans;base;care costs;copper zinc superoxide dismutase;cost;disability;effective therapy;fly;high risk;improved;in vivo;in vivo Model;innovation;insight;multicatalytic endopeptidase complex;mutant;neurodegenerative phenotype;neuron loss;neurotoxicity;novel;overexpression;programs;protein TDP-43;protein degradation;protein expression;proteostasis;public health relevance;sarcoma;therapeutic development;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease and currently there is no cure. Veterans are at a higher risk of being inflicted with the disorder so that ALS has been listed as a disease entitled to presumptive service connection. All veterans diagnosed with ALS have received full disability lifetime health and death benefits since 2009 costing VA an estimated $505 million over 10 years.  Mutations in the gene encoding Fused in Sarcoma (FUS) have been recently reported to cause a subset of familial ALS. This project is to use the well-defined genetic model to understand the mechanisms regulating the biosynthesis degradation and subcellular localization of FUS. The results from studying the mutant FUS mediated familial ALS will provide critical insights into the pathology of all types of ALS. Our project will likely identify novel targets for future therapeutic developments thus improving the healthcare of veterans who have higher incidence of contracting ALS and reducing the cost of caring for these veterans.


application_id: 9604743
project_number: 5I01CX001353-03
project_title: The role of Axin2+ stem cells in ulcer healing during colitis.
administering_ic: VA
award_notice_date: 2018-10-25
opportunity_number: CX-15-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001353
project_start_date: 2016-10-01
project_end_date: 2020-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-10-01
project_abstract:
DESCRIPTION (provided by applicant):      A major cause of colon removal surgery in veterans with inflammatory bowel disease (IBD) is a failure of medically-induced mucosal healing. Mucosal healing is a reliable clinical marker of recovery after IBD therapy as it is associated with durable clinical remission. Despite the importance of mucosal repair we continue to have a poor understanding of many of the cellular and molecular elements that mediate ulcer healing. The current proposal focuses on the role of colonic (epithelial) stem cells (CSC) in ulcer healing during colitis. Wnt/-catenin signaling in stem cells promotes cell proliferation as well as self-renewal both essential functions needed for ulcer healing and restitution of the mucosal barrier. A central tenant of this proposal is the hypothesis that Wnt/-catenin signaling plays an integral role in mucosal repair in IBD and that steroids delay ulcer healing my impairing Wnt/-catenin signaling. In mucosal ulceration as seen in IBD there is replacement of surface mucosa with granulation tissue that is re-epithelialized with new crypt structures. We suspect that active Wnt signaling is required for several steps through this sequence of events from stage 1) generation of an intestinal epithelial cell (IEC) monolayer to stage 2) formation of epithelial invaginations to stage 3) formation of crypt islands on ulcer surfaces and finally stage 4) regeneration of mature crypts (Fig 3). Biochemical data from our lab indicate Wnt/-catenin signaling is increased during ulcer healing in colitis in mice and IBD patients. In studies to interrogate the role of Wnt signaling in ulcer healing we discovered that IEC expressing mRNA for the Wnt target gene Axin2 expand in ulcer margins on ulcer surfaces and within newly-formed crypt structures in the middle of ulcers. Studies using a novel Axin2 reporter mouse model indicate that Axin2+ IEC are pluripotent and capable of growing colonoid structures in vitro from a single cell. Together the preliminary data suggest that Axin2+ IEC represent a novel ISC population that forms new crypt structures during ulcer healing. In Aim 1 Axin2lacZ/+ and Axin2 CreERT2/+; R26RmTmG/+ mice will be used to study ulcer-associated Axin2+ IEC localization and gene expression profiles of this new stem cell population as well as perform lineage tracing during ulcer healing in DSS colitis. In Aim 2 we will examine ulcer healing in mice treated with steroids. New studies will utilize Axin2-specific expression of stabilized -catenin to examine its role in ulcer healin during steroid therapy. Aim 3 studies will interrogate the role of Axin2+ IEC in human IBD and will analyze the mechanisms by which steroids impair ulcer healing. The goal of these studies will be to determine if untreated UC patients exhibit increased Axin2 expression Wnt signaling and stem cell gene expression in areas of ulcer healing (Aim 3A) and determine whether steroid therapy reduces levels of Axin2 expression and stem cell activation in areas of delayed ulcer healing in a prospective trial of UC patients treated with steroids for a colitis flare (Aim 3B). Together the studies proposed will provide valuable insights into the molecular mechanisms that govern ulcer healing in colitis. The goal is to determine areas where therapeutic targets can be designed to safely accelerate ulcer healing and reverse the negative impact of steroids on mucosal repair in colitis.

project_terms:
AXIN2 gene;Area;Biochemical;Cell Proliferation;Cells;Clinical Markers;Colitis;Colon;Data;Disease;Elements;Epithelial;Epithelial Cells;Event;Excision;Exhibits;Expression Profiling;Failure;Flare;Gene Expression;General Population;Generations;Goals;Granulation Tissue;Hospitalization;Human;Impairment;In Vitro;Incidence;Inflammatory Bowel Diseases;Intestines;Island;Lasers;Mediating;Medical;Messenger RNA;Microscopy;Molecular;Mucous Membrane;Mus;Natural regeneration;Operative Surgical Procedures;Oral;Patients;Play;Population;Prevalence;Recovery;Refractory;Reporter;Role;Signal Transduction;Stem cells;Steroid therapy;Steroids;Structure;Surface;Symptoms;Ulcer;Ulcerative Colitis;Veterans;WNT Signaling Pathway;Work;beta catenin;cell type;clinical remission;colon cancer risk;design;disability;healing;improved;insight;monolayer;mouse model;novel;prevent;prospective;public health relevance;repaired;self-renewal;stem cell population;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:      The incidence and prevalence of ulcerative colitis (UC) is higher among veterans than in the general population and the prevalence of UC increased 2-fold to 3-fold among veterans between 1998 and 2009. Lifelong effects of this disease include expensive medical treatments hospitalization surgery disability and increased risk of colon cancer. For many patients oral steroids are the first-line treatment for UC. Although steroids are effective in reducing overt symptoms studies have shown that approximately half of all patients are refractory to steroid treatment with limited ulcer healing. We have identified a new type of intestinal stem cell that i involved in healing ulcers. The goal of this project is to identify which types of cells are involvd in ulcer healing and to understand how the activity of those cells is regulated. Additionally we propose to investigate how steroids influence stem cell activity and limit ulcer healing. Completion of this work will lead to new understanding of how to improve medical treatment of colitis and prevent surgery in veterans.


application_id: 9564288
project_number: 1I01CX001614-01A2
project_title: Systems biology approach to the management of chronic kidney disease-mineral bone disorder
administering_ic: VA
award_notice_date: 2018-06-27
opportunity_number: CX-17-001
application_type: 1
activity_code: I01
ic: CX
serial_number: 001614
suffix: A2
project_start_date: 2018-07-01
project_end_date: 2022-06-30
study_section: Endocrinology B[ENDB]
contact_pi_person_id: 2262379
contact_pi: LEDERER, ELEANOR D
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Veterans are at an increased risk of kidney disease compared to the non-Veteran US population.Cardiovascular and bone disease are two major causes of death in Veterans with end stage renal disease(ESRD) resulting from abnormal mineral metabolism. Specifically Mineral and Bone Disorder (MBD) is auniversal complication of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD). Themultifactorial nature of MBD in the Veteran ESRD population makes the effective management of thiscondition complex. Proper management entails the maintenance of serum calcium phosphorus and intactPTH levels within guidelines established and refined by international working groups using dietary counselingphosphate binders active vitamin D analogues calcium sensing receptor agonists and parathyroidectomy.Achievement of the target goals for each parameter in every patient has been elusive though studies havedemonstrated that attainment of the desired guideline goals for all three parameters is associated with lowercardiovascular risk. The hypothesis to be tested is that the success rate in achievement of the guidelines forMBD management can be improved and better informed by systems biology modeling of mineral metabolismand development of a personalized algorithm for prescription of each of the current therapies. The broad-basedlong term goal of this research endeavor is to address critical technological barriers to the progress ofpersonalized MBD management thus improving cardiovascular and bone outcomes in Veteran patients.Preliminary work in this area has demonstrated the feasibility of the systems biology modeling approach to theachievement of established clinical guidelines. Current care of these Veteran Patients is based in a trial anderror approach. Ideally dosing of multiple agents for MDB should be guided by individual response to each ofthese agents. To address the challenges outlined above a systems biology approach to modeling the complexdisorder MBD with be utilized. The hypothesis is that advanced computational techniques can beused to optimally guide dosing of the agents used in MBD. The plan to accomplish this objective areoutlined in these five specific aims: 1. Development of a QSP-SB model for metabolic bone disorder. 2. Development of a drug dosing and hemodialysis model 3. Development of a database of clinically derived data obtained from CPRS. 4. Development of a dosing algorithm and a clinical tool used for CKD-MBDmanagement. 5. Testing of the developed MBD-CKD dosing algorithm and tool in in-center hemodialysis patients.A broad inclusive population of Veterans will be studied to develop these novel dosing algorithms. Improvedindividualized control of calcium phosphorus and PTH has been shown to improve cardiovascular mortalitywhen recommended concentrations are achieved. These tools will result in an advance in the dosing of drugsfor chronic conditions that will be applicable to areas other than bone disease and an improvement in thehealth of each individual Veteran with kidney disease.

project_terms:
Achievement;Address;Adult;Agonist;Algorithmic Software;Algorithms;Anemia;Area;Biological Models;Bone Diseases;Calcium;Calcium-Sensing Receptors;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Chronic;Chronic Kidney Failure;Clinical;Clinical Decision Support Systems;Clinical Practice Guideline;Comorbidity;Complex;Complication;Computational Technique;Computerized Medical Record;Computers;Consensus;Counseling;Data;Databases;Development;Dialysis procedure;Diet;Disease;Disease Management;Dose;Drug usage;End stage renal failure;Equation;Evaluation;Funding;Goals;Guidelines;Health;Hemodialysis;Hypertension;Immunosuppression;Individual;International;Kidney Diseases;Literature;Maintenance;Medical;Metabolic Bone Diseases;Metabolic Pathway;Metabolism;Minerals;Minority;Modeling;Monitor;Morbidity - disease rate;Nature;Osteoporosis;Outcome;Parathyroidectomy;Patients;Pharmaceutical Preparations;Pharmacology;Phosphorus;Plant Roots;Population;Publishing;Regulation;Renal function;Research;Risk;Series;Serum;System;Systems Biology;Techniques;Testing;Therapeutic;Translating;United States National Institutes of Health;Veterans;Vitamin D;Vitamin D Analog;Work;base;bone;bone turnover;calcification;cardiovascular risk factor;clinical practice;computerized tools;cost;cost effective;first-in-human;glycemic control;improved;individual response;individualized medicine;inorganic phosphate;mimetics;mortality;named group;novel;novel strategies;patient response;personalized approach;personalized medicine;success;tool;working group

public_health_relevance:
Veterans with End-Stage Renal Disease (ESRD) require chronic dialysis to replace lostkidney function at a cost of $89000 per patient annually. The VA is responsible for dialysisof over 16000 Veterans nationwide. Cardiovascular disease is the primary morbiditydirectly related to abnormal mineral metabolism (MBD). Although achievement of theguideline established goals for serum calcium phosphorus and intact PTH is associatedwith greater survival only a minority of patients 10-20% are able to accomplish this on aconsistent basis at least in part due to the complex array of interacting therapies to treatthis disorder. Developing and implementing a modeling system to deliver personalized andindividualized therapy for MBD would decrease cardiovascular death for Veterans withESRD as well as the general ESRD population.


application_id: 9555466
project_number: 1I01BX004252-01
project_title: CD47 as a therapeutic target for obesity
administering_ic: VA
award_notice_date: 2018-10-30
opportunity_number: BX-17-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 004252
project_start_date: 2018-10-01
project_end_date: 2022-09-30
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-10-01
project_terms:
Adipocytes;Adipose tissue;Animal Model;Animals;Antisense Oligonucleotides;Attenuated;Body Weight;Body fat;Body mass index;Brown Fat;CD47 gene;Carnitine Palmitoyltransferase I;Cell Line;Cell membrane;Cell physiology;Cells;Comorbidity;Complex;Cyclic AMP;Cyclic GMP;Data;Development;Diet;Eating;Energy Intake;Energy Metabolism;Exhibits;Fatty Liver;Fatty acid glycerol esters;Functional disorder;Genes;Genotype;High Fat Diet;Homeostasis;Human Genome;In Vitro;Insulin Resistance;Investigation;Knockout Mice;Liver diseases;Mediating;Metabolic;Mitochondria;Modeling;Molecular;Mus;Nerve;Non-Insulin-Dependent Diabetes Mellitus;Obese Mice;Obesity;Obesity Epidemic;Resistance;Respiration;Risk Factors;Rodent;Rodent Model;Role;Signal Pathway;Signal Transduction;Single Nucleotide Polymorphism;System;Testing;Therapeutic;Thermogenesis;Tissues;Wild Type Mouse;Work;base;blood glucose regulation;clinically significant;combat;genome-wide analysis;human subject;immune function;improved;in vivo;knock-down;lipid biosynthesis;lipid metabolism;mouse model;novel;novel therapeutics;obesity development;obesity genetics;obesity treatment;oxidation;prevent;receptor;therapeutic target;tool


application_id: 9543881
project_number: 1IK6BX004199-01
project_title: BLR&D Research Career Scientist Award application
administering_ic: VA
award_notice_date: 2018-04-03
opportunity_number: BX-17-022
application_type: 1
activity_code: IK6
ic: BX
serial_number: 004199
project_start_date: 2018-04-01
project_end_date: 2023-03-31
study_section: Research Career Scientist[RCSR]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-04-01
project_terms:
5'-AMP-activated protein kinase;Adipose tissue;Adverse effects;Alcoholic liver damage;Antibodies;Award;Biological;Biological Markers;Biology;Blast Cell;Brain;Brain Injuries;Brain Neoplasms;Breast Cancer Cell;Broccoli - dietary;Cancer Patient;Caring;Cell Communication;Cell Differentiation Inhibition;Cell Differentiation process;Cells;Cessation of life;Chronic;Clinical;Clinical Management;Colitis;Colon;Colonic Neoplasms;Colorectal;Communication;Curcumin;Cutaneous Melanoma;DNA;Data;Dendritic Cells;Development;Diabetes Mellitus;Dinoprostone;Disease;Disease Progression;Drug Targeting;Edible Plants;Encephalitis;Explosion;Failure;Folic Acid;Food;Foundations;Funding;Gene Expression;Ginger;Goals;Grapefruit;Grapes;Health Status;Hepatocyte;Hepatology;High Fat Diet;Homeostasis;Homing;Human;Immunosuppression;Immunosuppressive Agents;Immunotherapy;Inflammation;Inflammatory;Insulin Resistance;International;Intestines;Journals;Kidney;Light;Link;Lipids;Liver;Long-Term Effects;Lung;Macrophage Activation;Malignant Neoplasms;Malignant neoplasm of urinary bladder;Mammalian Cell;Mammary Neoplasms;Manuscripts;Mediating;Medical;Methods;MicroRNAs;Microglia;Molecular;Mucous body substance;Mus;Myelogenous;Myeloid-derived suppressor cells;NK Cell Activation;Names;Nature;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oncogenes;Oncogenic;Oncoproteins;Overweight;Patients;Pharmaceutical Preparations;Physiological;Plants;Play;Population;Prostate;Publishing;Radiation therapy;Research;Resistance;Risk;Role;Scientist;Signal Transduction;Site;Small Interfering RNA;Sorting - Cell Movement;Specificity;Stem cells;T-Lymphocyte;Therapeutic;Therapeutic Agents;Tissues;Traumatic Brain Injury;Tumor Promotion;Tumor Suppressor Proteins;Tumor-Derived;Vesicle;Veterans;WNT Signaling Pathway;War;Work;alcohol prevention;anergy;anticancer research;base;beta catenin;cancer cell;cancer diagnosis;cancer immunotherapy;cancer prevention;cancer therapy;cancer type;career;cell type;chemokine;chemokine receptor;cytokine;exosome;expression vector;extracellular;folate-binding protein;improved;in vivo;interspecies communication;intestinal homeostasis;liver development;liver inflammation;liver injury;macrophage;major vault protein;member;microvesicles;mild traumatic brain injury;mortality;mouse model;nanoparticle;nanovector;nanovesicle;neoplastic cell;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;patient population;pressure;prevent;sound;targeted delivery;therapeutic development;therapeutic miRNA;translational study;treatment strategy;tumor;tumor progression


application_id: 9519703
project_number: 5I01BX002769-04
project_title: Adipose autotaxin: a novel link between obesity and cardiovascular disease
administering_ic: VA
award_notice_date: 2018-01-30
opportunity_number: BX-14-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002769
project_start_date: 2015-01-01
project_end_date: 2019-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
project_abstract:
DESCRIPTION (provided by applicant):       Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular biologically active lysophosphatidic acid (LPA) a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.

project_terms:
Acute;Address;Adipocytes;Adipose tissue;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Biological;Biological Models;Blood;Blood Vessels;Body mass index;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Chronic;Coronary Arteriosclerosis;Data;Development;Diabetes Mellitus;Disease;Dyslipidemias;Enzymes;Exhibits;Experimental Models;Fatty acid glycerol esters;G-Protein-Coupled Receptors;Gap Junctions;Genetic;Genetic Polymorphism;Goals;Grant;Health;Healthcare;Healthcare Systems;Height;Human;Hypertension;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Insulin Resistance;Link;Lipids;Liquid substance;Lysophospholipase;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Medical Care Costs;Medical center;Mus;Myocardial Infarction;Obese Mice;Obesity;Obesity associated cardiovascular disease;Overweight;Permeability;Pharmacology;Phosphoric Monoester Hydrolases;Physiological;Plasma;Play;Positioning Attribute;Prevention;Production;Reagent;Recombinants;Reporting;Research;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Source;Stroke;System;Testing;United States;Vascular Diseases;Veterans;atherothrombosis;base;cardiovascular disorder risk;cardiovascular risk factor;disability;disorder risk;extracellular;feeding;inhibitor/antagonist;innovation;inorganic phosphate;lipid metabolism;lysophosphatidic acid;macrophage;migration;monocyte;mouse model;novel;novel strategies;prevent;preventable death;programs;public health relevance;response to injury;small molecule;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Obesity is a significant health care problem among veterans receiving care at VA Medical Centers. A comprehensive analysis of nearly 2 million veterans in 2000 indicated that ~68% were overweight and ~37% were obese. Obesity is an established risk factor for cardiovascular disease. In addition to contributing to traditional risk factors obesity is also characterized by  chronic inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Recent evidence focuses attention on the autotaxin - lysophosphatidic acid - lipid phosphate phosphates signaling nexus as a predictor of coronary artery disease that may be linked to obesity in that adipocytes serve as a major contributor of autotaxin levels. The goal of the current study is to identify the role of the adipose-derived autotaxin and the LPA signaling nexus in the development of atherosclerosis. Our results may suggest innovative targets to prevent and treat the cardiovascular complications of obesity in humans.


application_id: 9519669
project_number: 5I01BX002132-04
project_title: Respiratory Muscle Weakness
administering_ic: VA
award_notice_date: 2018-01-30
opportunity_number: BX-14-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002132
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Respiration[PULM]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
project_abstract:
DESCRIPTION (provided by applicant):       Recent studies indicate that the diaphragm becomes profoundly weak in critically ill patients. Diaphragm weakness in turn increases the duration of mechanical ventilation increases patient mortality and is a major contributor to the high cost of taking care of critically ill mechanically ventilated patients in the VA health care system. Our own work indicates that infections are a major cause of the development of severe diaphragm weakness in critically ill patients. It is also known that infections elicit increases in diaphragm free radical generation and that heightened free radical generation contributes to the development of weakness. The precise mechanism(s) by which infections activate free radical generation in skeletal muscle are not known however. Moreover currently there is no pharmacological treatment to prevent or reverse infection induced diaphragm weakness in critically ill patients. The purpose of the present project is to discover the mechanisms by which infections increase diaphragm free generation and to employ this mechanistic information to define novel translatable pharmacological treatments that can be used to prevent and reverse diaphragm weakness in critically patients.  Our central hypothesis is that infection induced diaphragm dysfunction is primarily a consequence of the sequential activation of neutral sphingomyelinase 2 cytosolic phospholipase A2 (cPLA2) mitochondrial free radical generation and proteolytic pathways (e.g. calpain). The planned studies will test this hypothesis and use this information to define new therapies that can be quickly translated into clinical usage.  Aim 1 experiments will delineate thespecific mechanism(s) by which infections induce heightened free radical generation in skeletal muscle. Experiment 1.1 will test the hypothesis that infections first activate neutral sphingomyelinase 2 in skeletal muscle. Experiment 1.2 will test the hypothesis that infection induced activation of neutral sphingomyelinase 2 subsequently activates skeletal muscle cPLA2 which in turn induces an increase in mitochondrial free radical production.  Aim 2 experiments will determine the specific skeletal muscle proteolytic pathways activated (Experiment 2.1) and cellular proteins degraded (Experiment 2.2) as a consequence of infection induced activation of cPLA2 and mitochondrial free radical generation.  Aim 3 experiments will determine if novel pharmacological agents which block cPLA2 activation and mitochondrial free radical generation prevent loss of diaphragm function in the cecal ligation perforation animal model of sepsis. We will study an agent which blocks activation of cPLA2 (taurine) in Experiment 3.1 a direct cPLA2 inhibitor (CDIBA) in Experiment 3.2 and an inhibitor of mitochondrial free radical generation (SS31) in Experiment 3.3.

project_terms:
Adrenal Cortex Hormones;Animal Model;Animals;Biophysical Process;Calpain;Caspase;Cecum;Clinical;Contractile Proteins;Critical Care;Critical Illness;Cytosolic Phospholipase A2;Development;Free Radicals;Functional disorder;Generations;Goals;Healthcare Systems;Human;Hyperglycemia;Infection;Interferons;Interleukin-1;Ligation;Mechanical Ventilators;Mechanical ventilation;Mechanics;Mediating;Mitochondria;Muscle;Muscle Weakness;Muscle function;Myosin Heavy Chains;Pathway interactions;Patients;Perforation;Pharmacological Treatment;Pharmacology;Production;Proteins;Proteolysis;Respiration;Respiratory Diaphragm;Respiratory Failure;Respiratory Muscles;Risk Factors;Sepsis;Skeletal Muscle;Spectrin;Sphingomyelinase;TNF gene;Talin;Taurine;Testing;Translating;Weaning;Work;base;cost;cytokine;disability;experimental study;improved;inhibitor/antagonist;mortality;multicatalytic endopeptidase complex;muscle strength;novel;novel therapeutics;patient population;prevent;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       The long term goal of this proposal is to identify treatments to prevent weakness in critically illpatients. The novel pharmacological agents that will be tested in Aim 3 studies of the current proposal were found to approximately double diaphragm strength in an animal model of infection. If these same agents can produce comparable effects on diaphragm strength in humans then administration of these therapies to critically ill VA MICU patients should reduce the duration of mechanical ventilation by more than 60%. A therapy with this large of an impact should cut VA MICU costs by as much as $850 Million dollars per year and save 2400 lives per year. As a result if the present work leads to the discovery of a new treatment for diaphragm weakness in MICU patients this discovery has the potential to markedly reduce VA MICU costs save thousands of lives and reduce long term disability by improving skeletal muscle strength.


application_id: 9501671
project_number: 5I01BX000216-08
project_title: Nicotine and nicotinic receptors in lung transitional remodeling
administering_ic: VA
award_notice_date: 2017-11-23
opportunity_number: BX-13-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 000216
project_start_date: 2009-04-01
project_end_date: 2018-09-30
study_section: Respiration[PULM]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Tobacco and alcohol are the two most used and abused drugs in the world. Together they are responsible for millions of deaths each year worldwide. Despite the enormous amount of research carried out to understand how these agents affect the lung new information leading to significant advances at the clinic has been disappointing. Because of the high prevalence of tobacco and alcohol exposure in veterans the Roman lab is exploring the mechanisms by which these agents affect the lung. Our research revealed that both alcohol and nicotine an alkaloid present in tobacco promote alterations in lung matrix composition that we have termed 'transitional' remodeling a process characterized by subtle alterations in the relatively composition of the lung extracellular matrix. Although the exact mechanisms linking these events to lung disease remain incompletely understood we believe that transitional remodeling renders the host susceptible to lung disease and this belief is supported by published research performed both in vitro and in vivo. Considering the above we set out to identify the cellular/molecular mechanisms responsible for these events. Using cultured primary lung fibroblasts we found that nicotine induces cellular proliferation and matrix expression through the activation of specific 7 nicotinic acetylcholine receptors (7 nAChRs). The importance of these receptors was confirmed in vivo showing that prenatal exposure to nicotine affects lung development and induces airway thickening and hyperreactivity in wildtype animals but not in 7 nAChR knockout mice. Using the same culture model we discovered that alcohol acts on lung fibroblasts via another set of nAChRs 4 nAChRs. In rodent lungs the expression of these receptors is increased by chronic alcohol exposure which in turn predisposes to acute lung injury. This work suggests that the cholinergic system plays an important role in lung homeostasis and response to injury and points to nAChRs as potential targets for intervention. More recently we found that nAChRs are activated through both ligand-dependent and -independent pathways. Specifically while nicotine acts on 7 nAChRs in a traditional ligand-dependent fashion alcohol works at least in part through induction of a particular form of oxidant stress (oxidation of the cysteine/cystine redox potential or Eh Cys/CySS) which together with cysteine residues strategically located on the subunits of certain nAChR pentamers activates nAChR signaling via ligand-independent mechanisms of action. Importantly we have generated preliminary data to suggest that susceptibility to injury in aging might activate nAChRs through similar pathways thereby promoting transitional remodeling and increased susceptibility to lung injury. Considering the above we propose that aging (as observed for nicotine and ethanol exposure) is associated with lung transitional remodeling via distinct nAChRs. nAChRs can be activated via ligand-dependent and -independent pathways the latter triggered by oxidant stress induced by oxidation of the Eh Cys/CySS. Specifically oxidant stress affects cysteines strategically located in the  subunits of nAChRs which in turn triggers signal transduction and promotes lung transitional remodeling and increase susceptibility to disrepair after lung injury. To test this hypothesis we propose experiments designed to: Aim 1. Investigate the role of specific subunit cysteines in nAChR activation in lung cells and in vivo. Aim 2. Determine the role of oxidant stress especially oxidation of the Eh Cys/CySS in nAChR activation both in vitro and in vivo. Aim 3. Examine the role of nAChR activation in lung disease related to aging and how this is affected by tobacco and alcohol exposure.

project_terms:
Acute Lung Injury;Adult;Affect;Aging;Alcohol abuse;Alcohols;Alkaloids;Animal Model;Animals;Architecture;Belief;Cell Proliferation;Cells;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Clinic;Cultured Cells;Cysteine;Cystine;Cytoskeleton;Data;Development;Disease;Endotoxemia;Ethanol;Event;Extracellular Matrix;Fibroblasts;Fibronectins;Funding;Glycoproteins;High Prevalence;Homeostasis;In Vitro;Incidence;Individual;Infection;Injury;Intervention;Knockout Mice;Ligands;Link;Lung;Lung diseases;Malignant neoplasm of lung;Modeling;Molecular;Morphogenesis;Nicotine;Nicotinic Receptors;Obstructive Lung Diseases;Organ;Oxidation-Reduction;Pathway interactions;Play;Predisposition;Process;Publishing;Receptor Activation;Receptor Cell;Receptor Signaling;Reporting;Research;Risk;Rodent;Role;Secure;Signal Transduction;System;Testing;Tissues;Tobacco;United States National Institutes of Health;Veterans;Work;airway hyperresponsiveness;alcohol effect;alcohol exposure;cholinergic;design;drug of abuse;experimental study;in vivo;lung development;lung injury;nicotine exposure;oxidant stress;oxidation;prenatal exposure;public health relevance;receptor;receptor expression;response;response to injury;tobacco abuse;tobacco exposure

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Aging and tobacco and alcohol abuse are important problems worldwide and many disorders observed in veterans are associated with these states. This work will study how aging affects lung cells in an attempt to identify potential targets for intervention and determine how tobacco and alcohol exposure influence these events. Specifically the research will focus on a special kind of cell receptors termed nicotinic acetylcholine receptors (nAChRs). Studies will be performed in cultured cells as well as in animal models to study the role of these receptors in aging and in tobacco- and alcohol-related lung disease.


application_id: 9487115
project_number: 5I01BX002141-04
project_title: iPLA2 as a Target in Vascular Inflammation Neointima Formation and Restenosis
administering_ic: VA
award_notice_date: 2017-11-23
opportunity_number: BX-13-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002141
project_start_date: 2014-10-01
project_end_date: 2018-09-30
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-10-01
project_abstract:
DESCRIPTION (provided by applicant):        Coronary heart disease is the single leading cause of death among men and women in the United States. Coronary revascularization including coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) is the most common modality in patients with coronary diseases. However it is also among the most costly and is often associated with a high incidence of restenosis. Although the rate of restenosis is significantly reduced with the useof bare-metal stent (BMS) and particularly with drug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stent thrombosis with DES have been encountered as significant limitations to the long-term efficacy of coronary revascularization. With a long-term goal of identifying novel therapeutic targets for coronary heart disease the current application specifically investigates a potentially critical role of calcium independent phospholipase A2b (iPLA2b) in vascular inflammation re-endothelialization and neointima formation in a mouse femoral artery wire injury model. iPLA2b is a member of the phospholipase A2 superfamily that acts on phospholipids to produce a free fatty acid and a lysophospholipid. iPLA2b is expressed in vascular smooth muscle cells (VSMC) and is implicated in many human diseases. Whereas little is known about the role of other PLA2 in vascular injury-induced neointima formation substantial evidence including pharmacological inhibition antisense oligonucleotide down- rgulation genetic deletion and smooth muscle-specific overexpression consistently demonstrated that iPLA2b plays a critical role in vascular inflammation and neointima formation in a mouse carotid artery ligation model. To investigate whether targeting smooth muscle-specific iPLA2b is sufficient to reduce vascular inflammation and neointima formation a femoral artery injury model that better mimics PCI was established a novel tamoxifen-inducible smooth muscle-specific iPLA2b knockout mouse model (SM-iPLA2b-iKO) was developed and the current proposal hypothesizes that activation of iPLA2b in VSMC by vascular injury plays a key role in wire injury-induced vascular inflammation re-endothelialization and neointima formation thereby significantly contributing to the development of restenosis after coronary revascularization. Three Specific Aims are:  1) To test the hypothesis that smooth muscle-specific iPLA2b plays a critical role in the initiation of vascular inflammation re-endothelialization and neointima formation; 2) To determine the molecular mechanism that underlies wire injury-induced iPLA2b activation vascular inflammation and neointima formation; 3) To investigate whether post-wire injury molecular and genetic targeting iPLA2b has an effect on the progression of re-endothelialization vascular inflammation and neointima formation. To achieve this goal a well established and most physiological relevant femoral artery wire injury model will be used in combination with several novel and established genetic animal models (SM- iPLA2b-iKO SM-HIF-1a-iKO and SM-iPLA2b-Tg/12/15-LO) to selectively inhibit or activate iPLA2b HIF-1a and 12/15-LO before and after wire injury. Injured and non-injured femoral arteries will be isolated and then subjected to molecular immunohistological and biochemical studies to determine the role of iPLA2b in vascular inflammation and neointima formation. Results from the proposed studies may modify the current paradigm that the initiation and early progression of vascular inflammation are largely attributed to coordinated interactions among monocytes/macrophages leukocytes and endothelial cells by providing the first direct experimental evidence that VSMC also play a critical role in these early key events. Importantly results from the proposed studies will elucidate specific mechanisms that could lead to the identification of iPLA2b as a novel potential therapeutic target for the prevention and treatment of vascular inflammation re- endothelialization neointima formation and restenosis.

project_terms:
Adopted;Animal Genetics;Animal Model;Antisense Oligonucleotides;Arachidonate 15-Lipoxygenase;Biochemical;Blood;Blood Vessels;Calcium;Carotid Arteries;Cause of Death;Cessation of life;Chest Pain;Congestive Heart Failure;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Development;Endothelial Cells;Enzymes;Event;Gel;Genetic;Goals;Healthcare Systems;Heart;Hospitalization;Hypoxia;Incidence;Injury;Knockout Mice;Lead;Leukocytes;Ligation;Lipids;Lysophospholipids;Mediating;Metals;Modality;Modeling;Molecular;Molecular Genetics;Mus;Myocardial Infarction;Myocardial Ischemia;Nonesterified Fatty Acids;Oxygen;Patients;Pharmaceutical Preparations;Pharmacology;Phospholipase;Phospholipase A2;Phospholipids;Physiological;Play;Pluronics;Prevention;Risk;Role;Scheme;Smooth Muscle;Smooth Muscle Myocytes;Stents;Tamoxifen;Testing;Therapeutic Effect;United States;Vascular Smooth Muscle;Woman;cost;femoral artery;genetic approach;human disease;injured;macrophage;member;men;monocyte;mouse model;neointima formation;new therapeutic target;novel;overexpression;percutaneous coronary intervention;prevent;public health relevance;restenosis;stent thrombosis;therapeutic target;vascular inflammation;vascular smooth muscle cell proliferation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:        Coronary heart disease also called ischemic heart disease is the result of narrowed or clogged coronary arteries that cannot carry sufficient amounts of blood and oxygen to the heart which can result in angina (chest pain) heart attack and death. Coronary heart disease is a common cause of congestive heart failure remains the leading cause of death among men and women in the United States and is also one of the most frequent indications for hospitalization within the VA healthcare system. Coronary revascularization has been adopted worldwide and is the most common modality in patients with coronary diseases in the United States including VA healthcare system. However it is most costly and is associated with a high incidence of restenosis (repeat narrowing of a coronary artery). The proposed studies specifically investigate the role of iPLA2b (an enzyme that produce bioactive lipids) in restenosis. If aims of the application are achieved it will provide evidence that could be used to develop new drugs that target iPLA2b to effectively prevent and reduce restenosis.


application_id: 9415985
project_number: 5I01CX001550-06
project_title: Lysophosphatidic acid and cardiovascular disease risk
administering_ic: VA
award_notice_date: 2018-02-02
opportunity_number: CX-16-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001550
project_start_date: 2013-01-01
project_end_date: 2020-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2018-01-01
project_abstract:
Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovasculardisease risk is caused by environmental and heritable factors. The broad goal of our research is to understandhow these factors interact to determine overall disease risk. In current funding period of this award we studiedhow heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate withheritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of thegene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results inaccelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an atherosclerosissuppressor gene and that heritable variants that decrease expression of the gene promote heart disease risk.LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipidmediators. One of these LPP3 substrates lysophosphatidic acid (LPA) acts on multiple blood and vascularcells to promote inflammation and cardiovascular disease progression. In mice genetic or pharmacologicaltargeting of LPA modulates atherosclerosis. In our mouse studies LPP3 deficiency was associated withincreased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesisthat dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 oncardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. Inpreliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. Thisdiet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestinefrom dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low densitylipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is asecreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources ofcirculating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also anintermediate in the synthesis of triglycerides by the intestine and liver so since this process is coupled to thegeneration of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo. The firstaim of this proposal will test these competing hypotheses directly by using stable isotope tracers and massspectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studieswill allow us to use genetic and pharmacological approaches to selectively manipulate ATX LPP3 and theformation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signalingresponses in blood and vascular cell types that underlie the initiation and progression of cardiovasculardisease by promoting permeability of vascular endothelium phenotypic modulation and proliferation/migrationof vascular smooth muscle cells and the classical macrophage foam cell response. The second aim of theproposal will test the hypothesis that the LPA content of these lipoproteins is a determinant of these responses.LPA is present in atherosclerotic blood vessels and release of LPA may contribute to platelet activation andthrombosis during plaque rupture. The final aim of this proposal will use state of the art mass spectrometrybased imaging to test the hypothesis that atheroma associated LPA accumulates progressively as a result oflipoprotein extravasation during the development of atherosclerosis. Together these studies will build on theresearch accomplished during the present funding period by providing important new information about theimpact of diet on a bioactive lipid signaling pathway that is now strongly implicated in heritable cardiovasculardisease risk. This research could inform strategies to mitigate cardiovascular disease risk through dietaryinterventions that decrease atherogenic lipoprotein associated LPA and will further underscore the value ofpharmacological targeting of LPA metabolism and signaling to mitigate cardiovascular disease risk.

project_terms:
Adipose tissue;Apolipoproteins B;Arterial Fatty Streak;Atherosclerosis;Attention;Award;Biological Markers;Blood;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Caring;Cell membrane;Cell surface;Cells;Cholesterol;Chylomicrons;Coronary Arteriosclerosis;Coronary artery;Coupled;Data;Development;Diabetes Mellitus;Diagnosis;Diet;Dietary Fats;Dietary Intervention;Dietary Phospholipid;Disease;Disease Progression;Enterocytes;Environmental Risk Factor;Enzymes;Extravasation;Family;Fasting;Fatty acid glycerol esters;Foam Cells;Funding;Gene Expression;General Population;Generations;Genes;Genetic;Goals;Heart;Heart Diseases;Hepatic;Heritability;Human;Image;In Vitro;Incidence;Individual;Inflammation;Inherited;Intestines;Introns;Investigation;Lead;Life Style;Link;Lipids;Lipoproteins;Liver;Low-Density Lipoproteins;Lysophospholipase;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Metabolic;Metabolism;Methods;Mus;Myocardial Infarction;Myocardial Ischemia;Obesity;Overweight;Oxides;Pathologic;Permeability;Pharmacology;Phenotype;Phospholipids;Plasma;Platelet Activation;Prevention;Process;Protein Dephosphorylation;Recording of previous events;Research;Risk Factors;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Suppressor Genes;Testing;Thrombosis;Tissues;Tracer;Triglycerides;Unhealthy Diet;United States;Variant;Vascular Smooth Muscle;Very low density lipoprotein;Veterans;Weight maintenance regimen;Woman;base;cardiovascular disorder risk;cell motility;cell type;disorder risk;feeding;heart disease risk;insight;lipid mediator;lipid phosphate phosphatase;lysophosphatidic acid;macrophage;men;monocyte;mortality;mouse model;novel therapeutics;nutrition;oxidized low density lipoprotein;particle;prevent;protective effect;recruit;response;stable isotope;vascular endothelium permeability;vascular inflammation;vascular smooth muscle cell migration

public_health_relevance:
Veterans have a higher incidence of heart disease than the general population. Heart disease risk is causedby inherited (ie family history) and environmental factors. The most powerful environmental determinant ofcardiovascular disease risk is the diet. Unhealthy diets promote obesity and dramatically increasecardiovascular disease risk in men and women because obese individuals and particularly those with diabeteshave persistently high levels of bad lipids in their blood called low density lipoproteins. These are formeddirectly from fats and lipids that are ingested in the diet and can also be produced by the liver. Accumulation ofthese bad lipids in the walls of blood vessels in the heart causes angina and heart attacks. We have identifieda particular component of these bad lipids that can increase these heart disease processes and may be a linkbetween heritable and diet dependent heart disease risk. We will study where this particular bad lipid comesfrom in the body. Our studies might lead to new ways to prevent diagnose or treat heart disease in Veterans.


application_id: 9378725
project_number: 5I01CX001353-02
project_title: The role of Axin2+ stem cells in ulcer healing during colitis.
administering_ic: VA
award_notice_date: 2017-11-22
opportunity_number: CX-15-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 001353
project_start_date: 2016-10-01
project_end_date: 2020-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-10-01
project_abstract:
DESCRIPTION (provided by applicant):   
   
A major cause of colon removal surgery in veterans with inflammatory bowel disease (IBD) is a failure of medically-induced mucosal healing. Mucosal healing is a reliable clinical marker of recovery after IBD therapy as it is associated with durable clinical remission. Despite the importance of mucosal repair we continue to have a poor understanding of many of the cellular and molecular elements that mediate ulcer healing. The current proposal focuses on the role of colonic (epithelial) stem cells (CSC) in ulcer healing during colitis. Wnt/-catenin signaling in stem cells promotes cell proliferation as well as self-renewal both essential functions needed for ulcer healing and restitution of the mucosal barrier. A central tenant of this proposal is the hypothesis that Wnt/-catenin signaling plays an integral role in mucosal repair in IBD and that steroids delay ulcer healing my impairing Wnt/-catenin signaling. In mucosal ulceration as seen in IBD there is replacement of surface mucosa with granulation tissue that is re-epithelialized with new crypt structures. We suspect that active Wnt signaling is required for several steps through this sequence of events from stage 1) generation of an intestinal epithelial cell (IEC) monolayer to stage 2) formation of epithelial invaginations to stage 3) formation of crypt islands on ulcer surfaces and finally stage 4) regeneration of mature crypts (Fig 3). Biochemical data from our lab indicate Wnt/-catenin signaling is increased during ulcer healing in colitis in mice and IBD patients. In studies to interrogate the role of Wnt signaling in ulcer healing we discovered that IEC expressing mRNA for the Wnt target gene Axin2 expand in ulcer margins on ulcer surfaces and within newly-formed crypt structures in the middle of ulcers. Studies using a novel Axin2 reporter mouse model indicate that Axin2+ IEC are pluripotent and capable of growing colonoid structures in vitro from a single cell. Together the preliminary data suggest that Axin2+ IEC represent a novel ISC population that forms new crypt structures during ulcer healing. In Aim 1 Axin2lacZ/+ and Axin2 CreERT2/+; R26RmTmG/+ mice will be used to study ulcer-associated Axin2+ IEC localization and gene expression profiles of this new stem cell population as well as perform lineage tracing during ulcer healing in DSS colitis. In Aim 2 we will examine ulcer healing in mice treated with steroids. New studies will utilize Axin2-specific expression of stabilized -catenin to examine its role in ulcer healin during steroid therapy. Aim 3 studies will interrogate the role of Axin2+ IEC in human IBD and will analyze the mechanisms by which steroids impair ulcer healing. The goal of these studies will be to determine if untreated UC patients exhibit increased Axin2 expression Wnt signaling and stem cell gene expression in areas of ulcer healing (Aim 3A) and determine whether steroid therapy reduces levels of Axin2 expression and stem cell activation in areas of delayed ulcer healing in a prospective trial of UC patients treated with steroids for a colitis flare (Aim 3B). Together the studies proposed will provide valuable insights into the molecular mechanisms that govern ulcer healing in colitis. The goal is to determine areas where therapeutic targets can be designed to safely accelerate ulcer healing and reverse the negative impact of steroids on mucosal repair in colitis.

project_terms:
AXIN2 gene;Area;Biochemical;Cell Proliferation;Cells;Clinical Markers;Colitis;Colon;Data;Disease;Elements;Epithelial;Epithelial Cells;Event;Excision;Exhibits;Expression Profiling;Failure;Flare;Gene Expression;Gene Targeting;General Population;Generations;Goals;Granulation Tissue;Hospitalization;Human;Impairment;In Vitro;Incidence;Inflammatory Bowel Diseases;Intestines;Island;Lasers;Mediating;Medical;Messenger RNA;Microscopy;Molecular;Mucous Membrane;Mus;Natural regeneration;Operative Surgical Procedures;Oral;Patients;Play;Population;Prevalence;Recovery;Refractory;Reporter;Role;Signal Transduction;Stem cells;Steroid therapy;Steroids;Structure;Surface;Symptoms;Ulcer;Ulcerative Colitis;Veterans;WNT Signaling Pathway;Work;beta catenin;cell type;clinical remission;colon cancer risk;design;disability;healing;improved;insight;monolayer;mouse model;novel;prevent;prospective;public health relevance;repaired;self-renewal;stem cell population;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   
   
The incidence and prevalence of ulcerative colitis (UC) is higher among veterans than in the general population and the prevalence of UC increased 2-fold to 3-fold among veterans between 1998 and 2009. Lifelong effects of this disease include expensive medical treatments hospitalization surgery disability and increased risk of colon cancer. For many patients oral steroids are the first-line treatment for UC. Although steroids are effective in reducing overt symptoms studies have shown that approximately half of all patients are refractory to steroid treatment with limited ulcer healing. We have identified a new type of intestinal stem cell that i involved in healing ulcers. The goal of this project is to identify which types of cells are involvd in ulcer healing and to understand how the activity of those cells is regulated. Additionally we propose to investigate how steroids influence stem cell activity and limit ulcer healing. Completion of this work will lead to new understanding of how to improve medical treatment of colitis and prevent surgery in veterans.


application_id: 9378385
project_number: 5I01BX002996-02
project_title: Dietary Fat and Alcoholic Liver Disease
administering_ic: VA
award_notice_date: 2017-11-27
opportunity_number: BX-15-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002996
project_start_date: 2016-10-01
project_end_date: 2020-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-10-01
project_abstract:
DESCRIPTION (provided by applicant):   
   
Alcohol abuse exacts a major toll on health and health costs in Veterans. Indeed even though there is an "epidemic" of hepatitis C in the U.S. alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in the oxidation of LA in an animal model of ALD. These findings led us to postulate that specific oxidized LA metabolites (OXLAMs) play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms for stressor-induced pathogenesis and which upon activation trigger the release of highly pro- inflammatory cytokines interleukin-1 (IL-1)
and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator of inflammation and
thus serves as a potential therapeutic target for treating hepatic inflammation in ALD. We propose that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two major mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction endoplasmic reticulum stress (ER stress) and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1 release. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD. Our research will be achieved through 3 specific aims: Aim 1. Evaluate whether OXLAMs exacerbate EtOH-mediated liver injury via induction of mitochondrial dysfunction ER stress and hepatocyte cell death in an animal model of ALD; Aim 2. Determine whether OXLAMs contribute to an EtOH-induced hepatic pro-inflammatory response via OXLAM-TRPV1-mediated inflammasome activation and subsequent increase in IL- release in an animal model of ALD. Aim 3. Explore the role of OXLAMs in monocytes/macrophages inflammasome activation in Alcoholic Hepatitis in Veterans.

project_terms:
Ablation;Address;Affect;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Blood;Breast;Cations;Cell Death;Cessation of life;Chronic;Cirrhosis;Clinical;Colon;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Epidemic;Etiology;Experimental Animal Model;FDA approved;Fatty Liver;Genetic;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis C;Hepatocyte;Hepatotoxicity;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Link;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Oxides;Pathogenesis;Patients;Permeability;Pharmacology;Play;Population;Prostate;Publishing;Research;Role;Signal Transduction;Steatohepatitis;Time;Translating;United States Department of Veterans Affairs;Unsaturated Fats;Up-Regulation;Vanilloid;Veterans;Whole Blood;base;cancer type;cytokine;endoplasmic reticulum stress;human study;in vitro testing;in vivo;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;new therapeutic target;nonalcoholic steatohepatitis;novel;octadecadienoic acid;outcome forecast;oxidation;peripheral blood;public health relevance;receptor;stressor;therapeutic target;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   
   
Alcohol abuse exacts a major toll on health and health costs in Veterans. Even though there is an "epidemic" of hepatitis C in the U.S. and the Veterans Administration alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. The proposed studies will help to better understand the molecular mechanisms of alcohol-induced liver and intestinal injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD.


application_id: 9348828
project_number: 1I01BX003877-01
project_title: Targeting Platelet Endocytosis and Exocytosis to Control Thrombosis
administering_ic: VA
award_notice_date: 2017-10-25
opportunity_number: BX-16-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 003877
project_start_date: 2017-10-01
project_end_date: 2021-09-30
study_section: Hematology[HEMA]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-10-01
project_terms:
Acute;Address;Adhesions;Affect;Age;Aging;Amino Acid Sequence;Autophagocytosis;Biochemical;Biological Assay;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Caring;Carotid Artery Injuries;Cause of Death;Cell physiology;Cellular biology;Cessation of life;Clot retraction;Coagulation Process;Communicable Diseases;Complex;Cytoplasmic Granules;Data;Disease;Endocytosis;Equilibrium;Event;Exocytosis;Female;Fibrinogen;Gene Deletion;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Health;Hemorrhage;Hemostatic function;Hyperactive behavior;In Vitro;Infarction;Integrins;Knock-out;Knockout Mice;Knowledge;Mediating;Membrane;Membrane Fusion;Mission;Modeling;Molecular;Molecular Chaperones;Molecular Probes;Morbidity - disease rate;Mouse Strains;Mus;Myocardial Infarction;Pathology;Patients;Physicians;Population;Precision Medicine Initiative;Process;Protein Biochemistry;Proteins;Publishing;RNA Splicing;Reaction;Risk;Risk Factors;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Sampling;Stroke;Tail;Therapeutic Intervention;Thrombosis;Thrombus;Transgenic Mice;Translations;Veterans;Work;base;clinically significant;experimental study;familial hemophagocytic lymphohistiocytosis;genome wide association study;glycosylation;granuphilin;health management;improved;in vitro Assay;in vivo;insight;male;mortality;protein protein interaction;recruit;response;restenosis;risk variant;synaptotagmin;syntaxin;syntaxin 11;syntaxin A;syntaxin-2;target SNARE proteins;targeted treatment;therapeutic target;trafficking;treatment strategy;vesicular SNARE proteins


application_id: 9336848
project_number: 5I01CX000975-04
project_title: The association of SAA with apoB lipoproteins affects cardiovascular risk
administering_ic: VA
award_notice_date: 2017-08-28
opportunity_number: CX-13-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 000975
project_start_date: 2014-04-01
project_end_date: 2018-03-31
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-04-01
project_abstract:
DESCRIPTION (provided by applicant):        Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations and is a major health issue in Veterans. Despite numerous pharmacological agents targeting CVD risk factors the identification of individuals at high risk remains incomplete. Further there is still a need to identify new targets for therapy. SAA is an acute phase reactant that is significantly and persistently elevated in chronic inflammatory conditions such as diabetes metabolic syndrome (MetS) or rheumatoid arthritis which are all associated with increased rates of CVD. SAA has been found to be predictive of CVD events. Furthermore we and others have recently shown in murine models that increased SAA is directly pro-atherogenic. As described in the Response to Retention hypothesis of atherosclerosis the sub-endothelial retention of atherogenic lipoproteins by vascular wall proteoglycans initiates atherosclerosis. Although in the healthy state SAA is exclusively associated with HDL we and others have previously reported SAA in association with apoB-containing lipoproteins in murine models of diabetes and/or obesity and we recently confirmed this observation in human studies. In preliminary studies we demonstrate increased association of SAA with apoB- containing lipoproteins in insulin resistant states which may be due to the delayed lipoprotein clearance seen with insulin resistance. In new preliminary studies we demonstrate that SAA can shift from HDL to apoB-containing lipoproteins. SAA itself has proteoglycan binding properties and our preliminary data demonstrates that the presence of SAA on apoB-lipoproteins enhances their retention. The central hypothesis of this grant is that the shift of SAA from HDL to apoB-containing lipoproteins is pro-atherogenic. We propose that the presence of SAA on apoB- containing lipoproteins in insulin resistant conditions such as MetS and diabetes contributes to the increased atherosclerosis and CVD observed in these populations. Using in vitro in vivo and clinical studies the results of this proposal will identify that SAA augments the atherogenicity of apoB lipoproteins and thus may identify SAA as a target for therapeutic intervention.

project_terms:
Acute-Phase Proteins;Affect;Affinity;Apolipoproteins B;Atherosclerosis;Binding;Biological Markers;Blood Vessels;Cardiovascular Diseases;Cause of Death;Chronic;Clinical Research;Data;Developed Countries;Developing Countries;Development;Diabetes Mellitus;Dyslipidemias;Event;Fatty acid glycerol esters;Grant;Health;High Density Lipoproteins;Human;In Vitro;Individual;Inflammatory;Injectable;Insulin Resistance;Lipase;Lipids;Lipoproteins;Literature;Low-Density Lipoproteins;Metabolic syndrome;Morbidity - disease rate;Mus;Obesity;Outcome;Pharmacology;Population;Property;Proteins;Proteoglycan;Publishing;Reporting;Rheumatoid Arthritis;Risk;Risk Factors;Role;Sampling;Serum amyloid A protein;Testing;Therapeutic Intervention;Time;Very low density lipoprotein;Veterans;base;cardiovascular disorder risk;cardiovascular risk factor;high risk;in vivo;inflammatory marker;insulin sensitivity;intravenous glucose tolerance test;mortality;mouse model;new therapeutic target;novel;overexpression;particle;public health relevance;response;targeted agent;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:        Cardiovascular disease is the leading cause of death in developed nations and is a major health issue in Veterans. The inflammatory marker Serum Amyloid A (SAA) has been found to predict cardiovascular disease. This proposal is testing the concept that beyond predicting cardiovascular disease SAA may cause cardiovascular disease. The results of this proposal may identify SAA as a new target of risk reducing therapy.


application_id: 9294667
project_number: 1I01RX002316-01A1
project_title: Force Feedback Redistribution & Eccentric-Focused Rehab post-SCI
administering_ic: VA
award_notice_date: 2017-04-06
opportunity_number: RX-16-012
application_type: 1
activity_code: I01
ic: RX
serial_number: 002316
suffix: A1
project_start_date: 2017-04-01
project_end_date: 2021-03-31
study_section: Spinal Cord Injury/Disorders & Neuropathic Pain[RRDA]
contact_pi_person_id: 1904515
contact_pi: HOWLAND, DENA R.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adult;Animal Model;Animals;Behavior;Bilateral;Characteristics;Chest;Chronic;Cicatrix;Data;Data Collection;Databases;Decerebrate State;Development;Disease;Distal;Dorsal;Experimental Designs;Extensor;Feedback;Felis catus;Gait;Goals;Golgi Tendon Organs;Health;Histology;Human;Injury;Joints;Knowledge;Laboratories;Lateral;Leg;Lesion;Limb structure;Link;Locomotion;Locomotor training;Maps;Mediating;Mission;Modeling;Motor;Motor Skills;Movement;Muscle;Normal Statistical Distribution;Pathway interactions;Performance;Phase;Physical Rehabilitation;Preparation;Procedures;Production;Productivity;Quality of life;Ramp;Recovery;Reflex action;Rehabilitation therapy;Research;Research Proposals;Specificity;Spinal;Spinal Cord;Spinal Cord Lesions;Spinal cord injury;Staining method;Stains;System;Testing;Thoracic spinal cord structure;Time;Tissues;Training;Veterans;Walking;Weight;Work;base;care systems;design;evidence base;experimental study;gait examination;gait rehabilitation;improved;injured;innovation;insight;kinematics;locomotor tasks;motor control;motor disorder;motor recovery;motor rehabilitation;nervous system disorder;novel;receptor;rehabilitation strategy;relating to nervous system;response;treadmill


application_id: 9280845
project_number: 5I01BX002769-03
project_title: Adipose autotaxin: a novel link between obesity and cardiovascular disease
administering_ic: VA
award_notice_date: 2017-06-30
opportunity_number: BX-14-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002769
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-01-01
project_abstract:
DESCRIPTION (provided by applicant):       Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular biologically active lysophosphatidic acid (LPA) a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.

project_terms:
Acute;Address;Adipocytes;Adipose tissue;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Biological;Biological Models;Blood;Blood Vessels;Body mass index;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Chronic;Coronary Arteriosclerosis;Data;Development;Diabetes Mellitus;Disease;Dyslipidemias;Enzymes;Exhibits;Experimental Models;Fatty acid glycerol esters;G-Protein-Coupled Receptors;Gap Junctions;Genetic;Genetic Polymorphism;Goals;Grant;Health;Healthcare;Healthcare Systems;Height;Human;Hypertension;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Insulin Resistance;Link;Lipids;Liquid substance;Lysophospholipase;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Medical;Medical center;Mus;Myocardial Infarction;Obese Mice;Obesity;Obesity associated cardiovascular disease;Overweight;Permeability;Pharmacology;Phosphoric Monoester Hydrolases;Physiological;Plasma;Play;Positioning Attribute;Prevention;Production;Reagent;Recombinants;Reporting;Research;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Source;System;Testing;United States;Vascular Diseases;Veterans;atherothrombosis;base;cardiovascular disorder risk;cardiovascular risk factor;cost;disability;disorder risk;extracellular;feeding;inhibitor/antagonist;innovation;inorganic phosphate;lipid metabolism;lysophosphatidic acid;macrophage;migration;monocyte;mouse model;novel;novel strategies;prevent;programs;public health relevance;response to injury;small molecule;stroke;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Obesity is a significant health care problem among veterans receiving care at VA Medical Centers. A comprehensive analysis of nearly 2 million veterans in 2000 indicated that ~68% were overweight and ~37% were obese. Obesity is an established risk factor for cardiovascular disease. In addition to contributing to traditional risk factors obesity is also characterized by  chronic inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Recent evidence focuses attention on the autotaxin - lysophosphatidic acid - lipid phosphate phosphates signaling nexus as a predictor of coronary artery disease that may be linked to obesity in that adipocytes serve as a major contributor of autotaxin levels. The goal of the current study is to identify the role of the adipose-derived autotaxin and the LPA signaling nexus in the development of atherosclerosis. Our results may suggest innovative targets to prevent and treat the cardiovascular complications of obesity in humans.


application_id: 9280803
project_number: 5I01BX002132-03
project_title: Respiratory Muscle Weakness
administering_ic: VA
award_notice_date: 2017-06-30
opportunity_number: BX-14-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002132
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Respiration[PULM]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-01-01
project_abstract:
DESCRIPTION (provided by applicant):       Recent studies indicate that the diaphragm becomes profoundly weak in critically ill patients. Diaphragm weakness in turn increases the duration of mechanical ventilation increases patient mortality and is a major contributor to the high cost of taking care of critically ill mechanically ventilated patients in the VA health care system. Our own work indicates that infections are a major cause of the development of severe diaphragm weakness in critically ill patients. It is also known that infections elicit increases in diaphragm free radical generation and that heightened free radical generation contributes to the development of weakness. The precise mechanism(s) by which infections activate free radical generation in skeletal muscle are not known however. Moreover currently there is no pharmacological treatment to prevent or reverse infection induced diaphragm weakness in critically ill patients. The purpose of the present project is to discover the mechanisms by which infections increase diaphragm free generation and to employ this mechanistic information to define novel translatable pharmacological treatments that can be used to prevent and reverse diaphragm weakness in critically patients.  Our central hypothesis is that infection induced diaphragm dysfunction is primarily a consequence of the sequential activation of neutral sphingomyelinase 2 cytosolic phospholipase A2 (cPLA2) mitochondrial free radical generation and proteolytic pathways (e.g. calpain). The planned studies will test this hypothesis and use this information to define new therapies that can be quickly translated into clinical usage.  Aim 1 experiments will delineate thespecific mechanism(s) by which infections induce heightened free radical generation in skeletal muscle. Experiment 1.1 will test the hypothesis that infections first activate neutral sphingomyelinase 2 in skeletal muscle. Experiment 1.2 will test the hypothesis that infection induced activation of neutral sphingomyelinase 2 subsequently activates skeletal muscle cPLA2 which in turn induces an increase in mitochondrial free radical production.  Aim 2 experiments will determine the specific skeletal muscle proteolytic pathways activated (Experiment 2.1) and cellular proteins degraded (Experiment 2.2) as a consequence of infection induced activation of cPLA2 and mitochondrial free radical generation.  Aim 3 experiments will determine if novel pharmacological agents which block cPLA2 activation and mitochondrial free radical generation prevent loss of diaphragm function in the cecal ligation perforation animal model of sepsis. We will study an agent which blocks activation of cPLA2 (taurine) in Experiment 3.1 a direct cPLA2 inhibitor (CDIBA) in Experiment 3.2 and an inhibitor of mitochondrial free radical generation (SS31) in Experiment 3.3.

project_terms:
Adrenal Cortex Hormones;Animal Model;Animals;Biophysical Process;Calpain;Caspase;Clinical;Contractile Proteins;Critical Care;Critical Illness;Cytosolic Phospholipase A2;Development;Free Radicals;Functional disorder;Generations;Goals;Healthcare Systems;Human;Hyperglycemia;Infection;Interferons;Interleukin-1;Ligation;Mechanical Ventilators;Mechanical ventilation;Mechanics;Mediating;Mitochondria;Muscle;Muscle Weakness;Muscle function;Myosin Heavy Chains;Pathway interactions;Patients;Perforation;Pharmacological Treatment;Pharmacology;Production;Proteins;Proteolysis;Respiration;Respiratory Diaphragm;Respiratory Failure;Respiratory Muscles;Risk Factors;Sepsis;Skeletal Muscle;Spectrin;Sphingomyelinase;TNF gene;Talin;Taurine;Testing;Translating;Weaning;Work;base;cost;cytokine;disability;experimental study;improved;inhibitor/antagonist;mortality;multicatalytic endopeptidase complex;muscle strength;novel;novel therapeutics;patient population;prevent;public health relevance

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       The long term goal of this proposal is to identify treatments to prevent weakness in critically illpatients. The novel pharmacological agents that will be tested in Aim 3 studies of the current proposal were found to approximately double diaphragm strength in an animal model of infection. If these same agents can produce comparable effects on diaphragm strength in humans then administration of these therapies to critically ill VA MICU patients should reduce the duration of mechanical ventilation by more than 60%. A therapy with this large of an impact should cut VA MICU costs by as much as $850 Million dollars per year and save 2400 lives per year. As a result if the present work leads to the discovery of a new treatment for diaphragm weakness in MICU patients this discovery has the potential to markedly reduce VA MICU costs save thousands of lives and reduce long term disability by improving skeletal muscle strength.


application_id: 9278079
project_number: 5I01CX000773-04
project_title: HDL Remodeling in Metabolic Syndrome
administering_ic: VA
award_notice_date: 2017-06-20
opportunity_number: CX-13-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 000773
project_start_date: 2014-01-01
project_end_date: 2017-12-31
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-01-01
project_abstract:
DESCRIPTION (provided by applicant):       With a prevalence of 30-50% and clear association with increased cardiovascular disease (CVD) Metabolic Syndrome (MetS) is emerging as a major public health problem. MetS is characterized by elevated markers of inflammation hypertriglyceridemia and low levels of high density lipoprotein (HDL). This proposal aims to understand how HDL metabolism and function are altered in MetS. In MetS increases in triglyceride-rich lipoproteins (TGRL) in combination with increased activity of cholesterol ester transfer protein (CETP) leads to TG enrichment of HDL. Although there is evidence that TG enrichment per se may destabilize the particle to promote release of apoA-I it is likely that HDL remodeling factors in the circulation act on TG-enriched HDL to amplify apoA-I release and catabolism. Based on our preliminary data we propose that circulating phospholipases (endothelial lipase Group IIA secretory phospholipase A2) contribute significantly to HDL remodeling in MetS by liberating lipid-poor apoA-I from TG-enriched HDL. Once released from remodeled HDL lipid-poor apoA-I has three potential fates: it may serve as an acceptor for cellular cholesterol efflux associate with circulating HDL or be cleared from the circulation due to a failure to undergo re-lipidation. Emerging evidence indicates that not all lipid-poor apoA-I species are capable of acquiring additional lipid and are thus susceptible to rapid catabolism. We propose that HDL lowering in MetS is due not only to enhanced HDL remodeling to amplify the release of lipid-poor apoA-I but is also due to the increased production of "dysfunctional" lipid-poor species that are inherently susceptible to catabolism. The HDL receptor SR-BI plays a key role in HDL metabolism by mediating the selective uptake of CE from the core of HDL particles into cells. We have shown that SR-BI processing of HDL from healthy subjects generates at least 3 distinct lipid-depleted HDL "remnants" that differ in composition and subsequent metabolism. We propose that as SR-BI depletes the core of TG-enriched MetS HDL the propensity of such particles to remodel leads to enhanced released of lipid-poor apoA-I. The central hypothesis of this proposal is that TG enrichment of HDL in MetS predisposes the particle to remodeling by intravascular factors and alters its processing by SR-BI leading to the generation of lipid-poor species that are susceptible to catabolism. Specific Objective 1: Test the hypothesis that enhanced remodeling of HDL in hypertriglyceridemic MetS subjects leads to generation of lipid-poor apoA-I. The goal is to identify specific features of MetS HDL and/or MetS plasma that predict susceptibility to remodeling. We will also determine whether fibrate-induced TG lowering in MetS subjects leads to altered HDL remodeling. Specific Objective 2: Test the hypothesis that enhanced remodeling of TG-enriched HDL leads to alterations in subsequent HDL metabolism. Specific Objective 3: Test the hypothesis that TG enrichment alters SR-BI metabolism of HDL. Results from this project will provide new insights into mechanisms underlying reduced HDL in MetS a prevalent condition in the Veteran population that significantly increases the risk of developing CVD. Findings from this project have the potential to define novel biological correlates of accelerated apoA-I catabolism in MetS and to identify MetS subjects most likely to benefit from TG lowering/HDL raising interventions.

project_terms:
Affinity;Apolipoprotein A-I;Biological;Blood;Blood Circulation;Cardiovascular Diseases;Catabolism;Cells;Cholesterol;Cholesterol Ester Transfer Proteins;Chronic;Clinical Management;Complex;Data;Disease;Epidemic;Failure;Fibrates;Generations;Goals;Heart Diseases;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Human;Hypertriglyceridemia;Incidence;Individual;Inflammation;Intervention;LIPG gene;Lipase;Lipids;Lipoproteins;Mediating;Metabolic Control;Metabolic syndrome;Metabolism;Outcome;Patients;Phospholipase;Phospholipase A2;Phospholipid Transfer Proteins;Plasma;Play;Population;Predisposition;Prevalence;Production;Public Health;Research;Risk;Risk Factors;SR-BI receptor;Testing;Triglycerides;United States;Veterans;base;diabetes risk;hepatic lipase;high density lipoprotein receptor;inflammatory marker;insight;novel;particle;public health relevance;stroke;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       The metabolic syndrome (MetS) is a complex disorder that increases the risk for diabetes heart disease and stroke. The incidence of MetS has reached epidemic proportions in the United States including the Veteran population. A common feature of MetS is low HDL cholesterol (HDL-C) which is recognized as a major risk factor for heart disease and stroke. Previous research indicates that HDL in individuals with MetS is more rapidly cleared from the blood compared to people without MetS. This proposal seeks to understand why HDL in MetS subjects is more susceptible to clearance. Results from these studies may identify new strategies for the clinical management of individuals with MetS.


application_id: 9275392
project_number: 5I01BX002141-03
project_title: iPLA2 as a Target in Vascular Inflammation Neointima Formation and Restenosis
administering_ic: VA
award_notice_date: 2017-05-19
opportunity_number: BX-13-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002141
project_start_date: 2014-10-01
project_end_date: 2018-09-30
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-10-01
project_abstract:
DESCRIPTION (provided by applicant):        Coronary heart disease is the single leading cause of death among men and women in the United States. Coronary revascularization including coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) is the most common modality in patients with coronary diseases. However it is also among the most costly and is often associated with a high incidence of restenosis. Although the rate of restenosis is significantly reduced with the useof bare-metal stent (BMS) and particularly with drug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stent thrombosis with DES have been encountered as significant limitations to the long-term efficacy of coronary revascularization. With a long-term goal of identifying novel therapeutic targets for coronary heart disease the current application specifically investigates a potentially critical role of calcium independent phospholipase A2b (iPLA2b) in vascular inflammation re-endothelialization and neointima formation in a mouse femoral artery wire injury model. iPLA2b is a member of the phospholipase A2 superfamily that acts on phospholipids to produce a free fatty acid and a lysophospholipid. iPLA2b is expressed in vascular smooth muscle cells (VSMC) and is implicated in many human diseases. Whereas little is known about the role of other PLA2 in vascular injury-induced neointima formation substantial evidence including pharmacological inhibition antisense oligonucleotide down- rgulation genetic deletion and smooth muscle-specific overexpression consistently demonstrated that iPLA2b plays a critical role in vascular inflammation and neointima formation in a mouse carotid artery ligation model. To investigate whether targeting smooth muscle-specific iPLA2b is sufficient to reduce vascular inflammation and neointima formation a femoral artery injury model that better mimics PCI was established a novel tamoxifen-inducible smooth muscle-specific iPLA2b knockout mouse model (SM-iPLA2b-iKO) was developed and the current proposal hypothesizes that activation of iPLA2b in VSMC by vascular injury plays a key role in wire injury-induced vascular inflammation re-endothelialization and neointima formation thereby significantly contributing to the development of restenosis after coronary revascularization. Three Specific Aims are:  1) To test the hypothesis that smooth muscle-specific iPLA2b plays a critical role in the initiation of vascular inflammation re-endothelialization and neointima formation; 2) To determine the molecular mechanism that underlies wire injury-induced iPLA2b activation vascular inflammation and neointima formation; 3) To investigate whether post-wire injury molecular and genetic targeting iPLA2b has an effect on the progression of re-endothelialization vascular inflammation and neointima formation. To achieve this goal a well established and most physiological relevant femoral artery wire injury model will be used in combination with several novel and established genetic animal models (SM- iPLA2b-iKO SM-HIF-1a-iKO and SM-iPLA2b-Tg/12/15-LO) to selectively inhibit or activate iPLA2b HIF-1a and 12/15-LO before and after wire injury. Injured and non-injured femoral arteries will be isolated and then subjected to molecular immunohistological and biochemical studies to determine the role of iPLA2b in vascular inflammation and neointima formation. Results from the proposed studies may modify the current paradigm that the initiation and early progression of vascular inflammation are largely attributed to coordinated interactions among monocytes/macrophages leukocytes and endothelial cells by providing the first direct experimental evidence that VSMC also play a critical role in these early key events. Importantly results from the proposed studies will elucidate specific mechanisms that could lead to the identification of iPLA2b as a novel potential therapeutic target for the prevention and treatment of vascular inflammation re- endothelialization neointima formation and restenosis.

project_terms:
Adopted;Animal Genetics;Animal Model;Antisense Oligonucleotides;Arachidonate 15-Lipoxygenase;Biochemical;Blood;Blood Vessels;Calcium;Carotid Arteries;Cause of Death;Cessation of life;Chest Pain;Congestive Heart Failure;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Development;Endothelial Cells;Enzymes;Event;Gel;Genetic;Goals;Healthcare Systems;Heart;Hospitalization;Hypoxia;Incidence;Injury;Knockout Mice;Lead;Leukocytes;Ligation;Lipids;Lysophospholipids;Mediating;Metals;Modality;Modeling;Molecular;Molecular Genetics;Mus;Muscle Cells;Myocardial Infarction;Myocardial Ischemia;Nonesterified Fatty Acids;Oxygen;Patients;Pharmaceutical Preparations;Pharmacology;Phospholipase;Phospholipase A2;Phospholipids;Physiological;Play;Pluronics;Prevention;Risk;Role;Scheme;Smooth Muscle;Stents;Tamoxifen;Testing;Therapeutic Effect;United States;Vascular Smooth Muscle;Woman;cost;femoral artery;genetic approach;human disease;injured;macrophage;member;men;monocyte;mouse model;neointima formation;new therapeutic target;novel;overexpression;percutaneous coronary intervention;prevent;public health relevance;restenosis;stent thrombosis;therapeutic target;vascular inflammation;vascular smooth muscle cell proliferation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:        Coronary heart disease also called ischemic heart disease is the result of narrowed or clogged coronary arteries that cannot carry sufficient amounts of blood and oxygen to the heart which can result in angina (chest pain) heart attack and death. Coronary heart disease is a common cause of congestive heart failure remains the leading cause of death among men and women in the United States and is also one of the most frequent indications for hospitalization within the VA healthcare system. Coronary revascularization has been adopted worldwide and is the most common modality in patients with coronary diseases in the United States including VA healthcare system. However it is most costly and is associated with a high incidence of restenosis (repeat narrowing of a coronary artery). The proposed studies specifically investigate the role of iPLA2b (an enzyme that produce bioactive lipids) in restenosis. If aims of the application are achieved it will provide evidence that could be used to develop new drugs that target iPLA2b to effectively prevent and reduce restenosis.


application_id: 9275367
project_number: 5I01BX001721-04
project_title: Thiamine deficiency and alcohol-induced neurodegeneration
administering_ic: VA
award_notice_date: 2017-05-19
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001721
project_start_date: 2013-10-01
project_end_date: 2017-09-30
study_section: Neurobiology A[NURA]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health social and economic impact. Chronic alcohol abuse induces dementia which is associated with morphological neurophysiological and biochemical changes in the central nervous system (CNS). The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. The underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). Thiamine deficiency (TD) can damage the CNS. TD in humans may results from chronic alcohol exposure genetic background aging or nutritional status. The relationship between thiamine status and neuron susceptibility to alcohol- induced neurodegeneration however remains unclear. Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles. It provides the cells with an alternative source of intracellular building blocks and energy thereby enhancing cell survival during nutrient deficiency or stress conditions. We hypothesize that TD may inhibit the autophagic pathways and impair this cellular self-protection mechanism. As a result neurons are more susceptible to alcohol- induced neurodegeneration after chronic TD. Three specific aims are proposed to test this hypothesis. We will first investigate whether the status of thiamine content determines neuron susceptibility to alcohol-induced neurodegeneration. We will next characterize the effect TD/alcohol on autophagy in the brain. Finally we will determine the role of autophagy in alcohol/TD interaction and alcohol-induced neurodegeneration. As a unit the proposal will elucidate the relationship between TD and neuron susceptibility to alcohol neurotoxicity and provide a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.

project_terms:
Accounting;Adult;Affect;Aging;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic beverage heavy drinker;Alcohols;Animals;Autophagocytosis;Biochemical;Brain;Brain Injuries;Brain region;C57BL/6 Mouse;Cell Survival;Cell physiology;Cells;Cerebellum;Chronic;Data;Dementia;Disease;Enzymes;Etiology;Experimental Models;Genetic;Health;Human;Impaired cognition;Impairment;Medial;Metabolic;Morphology;Nerve Degeneration;Neuraxis;Neurons;Neuropathy;Nutrient;Nutritional status;Organelles;Pathway interactions;Play;Predisposition;Role;Social Impacts;Source;Stress;Testing;Thalamic structure;Thiamine;Thiamine Deficiency;Veterans;Wernicke-Korsakoff Syndrome;alcohol exposure;alcohol response;brain abnormalities;chronic alcohol ingestion;cofactor;cognitive function;combat;economic impact;frontal lobe;glucose metabolism;insight;macromolecule;neurophysiology;neurotoxicity;novel;problem drinker;public health relevance;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:        An estimated 7.5 percent of veterans are heavy drinkers and alcohol abuse is on the rise among combat veterans. Chronic alcohol abuse causes dementia and the most devastating feature of brain damage following chronic alcohol exposure is neurodegeneration. However the underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). This proposal will determine how thiamine deficiency (TD) and alcohol exposure interact and cause neurodegeneration in the central nervous system providing a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.


application_id: 9275300
project_number: 5I01BX000216-07
project_title: Nicotine and nicotinic receptors in lung transitional remodeling
administering_ic: VA
award_notice_date: 2017-06-06
opportunity_number: BX-13-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 000216
project_start_date: 2009-04-01
project_end_date: 2018-09-30
study_section: Respiration[PULM]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Tobacco and alcohol are the two most used and abused drugs in the world. Together they are responsible for millions of deaths each year worldwide. Despite the enormous amount of research carried out to understand how these agents affect the lung new information leading to significant advances at the clinic has been disappointing. Because of the high prevalence of tobacco and alcohol exposure in veterans the Roman lab is exploring the mechanisms by which these agents affect the lung. Our research revealed that both alcohol and nicotine an alkaloid present in tobacco promote alterations in lung matrix composition that we have termed 'transitional' remodeling a process characterized by subtle alterations in the relatively composition of the lung extracellular matrix. Although the exact mechanisms linking these events to lung disease remain incompletely understood we believe that transitional remodeling renders the host susceptible to lung disease and this belief is supported by published research performed both in vitro and in vivo. Considering the above we set out to identify the cellular/molecular mechanisms responsible for these events. Using cultured primary lung fibroblasts we found that nicotine induces cellular proliferation and matrix expression through the activation of specific 7 nicotinic acetylcholine receptors (7 nAChRs). The importance of these receptors was confirmed in vivo showing that prenatal exposure to nicotine affects lung development and induces airway thickening and hyperreactivity in wildtype animals but not in 7 nAChR knockout mice. Using the same culture model we discovered that alcohol acts on lung fibroblasts via another set of nAChRs 4 nAChRs. In rodent lungs the expression of these receptors is increased by chronic alcohol exposure which in turn predisposes to acute lung injury. This work suggests that the cholinergic system plays an important role in lung homeostasis and response to injury and points to nAChRs as potential targets for intervention. More recently we found that nAChRs are activated through both ligand-dependent and -independent pathways. Specifically while nicotine acts on 7 nAChRs in a traditional ligand-dependent fashion alcohol works at least in part through induction of a particular form of oxidant stress (oxidation of the cysteine/cystine redox potential or Eh Cys/CySS) which together with cysteine residues strategically located on the subunits of certain nAChR pentamers activates nAChR signaling via ligand-independent mechanisms of action. Importantly we have generated preliminary data to suggest that susceptibility to injury in aging might activate nAChRs through similar pathways thereby promoting transitional remodeling and increased susceptibility to lung injury. Considering the above we propose that aging (as observed for nicotine and ethanol exposure) is associated with lung transitional remodeling via distinct nAChRs. nAChRs can be activated via ligand-dependent and -independent pathways the latter triggered by oxidant stress induced by oxidation of the Eh Cys/CySS. Specifically oxidant stress affects cysteines strategically located in the  subunits of nAChRs which in turn triggers signal transduction and promotes lung transitional remodeling and increase susceptibility to disrepair after lung injury. To test this hypothesis we propose experiments designed to: Aim 1. Investigate the role of specific subunit cysteines in nAChR activation in lung cells and in vivo. Aim 2. Determine the role of oxidant stress especially oxidation of the Eh Cys/CySS in nAChR activation both in vitro and in vivo. Aim 3. Examine the role of nAChR activation in lung disease related to aging and how this is affected by tobacco and alcohol exposure.

project_terms:
Acute Lung Injury;Adult;Affect;Aging;Alcohol abuse;Alcohols;Alkaloids;Animal Model;Animals;Architecture;Belief;Cell Proliferation;Cells;Cessation of life;Cholinergic Receptors;Chronic;Chronic Obstructive Airway Disease;Clinic;Cultured Cells;Cysteine;Cystine;Cytoskeleton;Data;Development;Disease;Endotoxemia;Ethanol;Event;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Funding;Glycoproteins;High Prevalence;Homeostasis;In Vitro;Incidence;Individual;Infection;Injury;Intervention;Knockout Mice;Ligands;Link;Lung;Lung diseases;Malignant neoplasm of lung;Modeling;Molecular;Morphogenesis;Nicotine;Nicotinic Receptors;Obstructive Lung Diseases;Organ;Oxidation-Reduction;Pathway interactions;Play;Predisposition;Process;Publishing;Receptor Activation;Receptor Cell;Receptor Signaling;Reporting;Research;Risk;Rodent;Role;Secure;Signal Transduction;System;Testing;Tissues;Tobacco;United States National Institutes of Health;Veterans;Work;airway hyperresponsiveness;alcohol effect;alcohol exposure;cholinergic;design;drug of abuse;experimental study;in vivo;lung development;lung injury;oxidant stress;oxidation;prenatal exposure;public health relevance;receptor;receptor expression;response;response to injury;tobacco abuse;tobacco exposure

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Aging and tobacco and alcohol abuse are important problems worldwide and many disorders observed in veterans are associated with these states. This work will study how aging affects lung cells in an attempt to identify potential targets for intervention and determine how tobacco and alcohol exposure influence these events. Specifically the research will focus on a special kind of cell receptors termed nicotinic acetylcholine receptors (nAChRs). Studies will be performed in cultured cells as well as in animal models to study the role of these receptors in aging and in tobacco- and alcohol-related lung disease.


application_id: 9240940
project_number: 1I01BX003405-01A1
project_title: mitoNEET as a therapeutic target for TBI
administering_ic: VA
award_notice_date: 2016-12-08
opportunity_number: BX-16-003
application_type: 1
activity_code: I01
ic: BX
serial_number: 003405
suffix: A1
project_start_date: 2017-01-01
project_end_date: 2020-12-31
study_section: Neurobiology C[NURC]
contact_pi_person_id: 8536013
contact_pi: SULLIVAN, PATRICK G
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Acute;Adult;Aftercare;Animals;Area;Behavior;Behavioral;Bioenergetics;Brain Injuries;Chronic;Clinical;Cognitive;Coupled;Data;Diagnosis;Dose;FDA approved;Hand;Hippocampus (Brain);Homeostasis;Hour;Injury;Knock-out;Knockout Mice;Ligands;Light;Link;Magnetic Resonance Imaging;Measurement;Measures;Mediating;Military Personnel;Mitochondria;Mitochondrial Proteins;Modeling;Molecular Target;Morphology;Motor;Mus;Neuronal Injury;Neurons;Outcome;Pathway interactions;Patients;Peroxisome Proliferator-Activated Receptors;Pioglitazone;Post-Traumatic Stress Disorders;Process;Production;Publishing;Reactive Oxygen Species;Recovery of Function;Research;Respiration;Scanning;Services;Site;Synapses;Techniques;Testing;Therapeutic;Therapeutic Effect;Time;Tissues;Transgenic Mice;Transgenic Organisms;Translating;Traumatic Brain Injury;Veterans;War;Work;base;behavior measurement;behavioral outcome;brain dysfunction;conditioned fear;controlled cortical impact;cost;design;dosage;experience;experimental study;functional outcomes;high risk population;improved;innovation;knockout animal;male;mitochondrial dysfunction;neuropathology;neuroprotection;novel;operation;receptor binding;response;therapeutic target;tool


application_id: 9240811
project_number: 2I01CX001550-05
project_title: Lysophosphatidic acid and cardiovascular disease risk
administering_ic: VA
award_notice_date: 2017-01-23
opportunity_number: CX-16-001
application_type: 2
activity_code: I01
ic: CX
serial_number: 001550
project_start_date: 2013-01-01
project_end_date: 2020-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2017-01-01
project_terms:
Adipose tissue;Alpha Cell;Apolipoproteins B;Arterial Fatty Streak;Atherosclerosis;Attention;Award;Biological Markers;Blood;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Caring;Cell membrane;Cell surface;Cells;Cholesterol;Chylomicrons;Coronary Arteriosclerosis;Coronary artery;Coupled;Data;Development;Diabetes Mellitus;Diagnosis;Diet;Dietary Fats;Dietary Intervention;Dietary Phospholipid;Disease;Disease Progression;Environmental Risk Factor;Enzymes;Extravasation;Fasting;Fatty acid glycerol esters;Foam Cells;Funding;Gene Expression;General Population;Generations;Genes;Genetic;Goals;Heart;Heart Diseases;Hepatic;Heritability;Human;Image;In Vitro;Incidence;Individual;Inflammation;Inherited;Intestines;Introns;Investigation;Lead;Life Style;Link;Lipids;Lipoproteins;Liver;Low-Density Lipoproteins;Lysophospholipase;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Metabolic;Metabolism;Methods;Mus;Muscle Cells;Myocardial Infarction;Myocardial Ischemia;Obesity;Overweight;Oxides;Pathologic;Permeability;Pharmacology;Phenotype;Phospholipids;Plasma;Platelet Activation;Prevention;Process;Protein Dephosphorylation;Recruitment Activity;Research;Risk Factors;Rupture;Signal Pathway;Signal Transduction;Smooth Muscle Myocytes;Source;Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization;Suppressor Genes;Testing;Thrombosis;Tissues;Tracer;Triglycerides;United States;Variant;Vascular Smooth Muscle;Very low density lipoprotein;Veterans;Weight;Woman;base;cardiovascular disorder risk;cell motility;cell type;disorder risk;feeding;heart disease risk;insight;lipid mediator;lipid phosphate phosphatase;low density lipoprotein inhibitor;lysophosphatidic acid;macrophage;men;monocyte;mortality;mouse model;novel therapeutics;nutrition;oxidized low density lipoprotein;particle;prevent;protective effect;response;stable isotope;vascular endothelium permeability;vascular inflammation;vascular smooth muscle cell migration


application_id: 9211962
project_number: 1IS1BX003561-01
project_title: Q-Exative hybrid mass spectrometer for proteomic services
administering_ic: VA
award_notice_date: 2016-09-19
opportunity_number: BX-16-015
application_type: 1
activity_code: IS1
ic: BX
serial_number: 003561
project_start_date: 2016-05-01
project_end_date: 2016-09-30
study_section: Special Initiatives - Shared Equipment (ShEEP/LAMb)[SPLJ]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-05-01
project_abstract:
The Lexington VA Medical Center requests funds to acquire a Thermo Scientific Q-ExactivePlus hybrid mass spectrometer with a nano-electrospray ionization source and an UltiMate 3000RSLC nano HPLC as an integrated nano-LC-MS/MS system. The goal of this application is to provideadvanced mass spectrometry capabilities to meet the proteomics needs of 7 highly productive VA-funded investigators at the Lexington VA Medical Center. The Q Exactive hybrid mass spectrometeroffers a combination of a quadrupole and an advanced and high precision electrostatic ion trap(Orbitrap) mass analyzers. In comparison to the existing mass spectrometers for protein and peptideanalysis this hybrid instrument simultaneously provides high sensitivity (attomoles) high spectrumrepetition rates high mass resolution (140000 HWFM) and high mass accuracy (< 3ppm with eternalcalibration and < 1ppm with internal calibration). Moreover it provides a versatile system capable ofcarrying out both qualitative and quantitative proteomic workflows. This equipment is essential tothese ongoing research programs and to stimulating and enabling new collaborative researchinitiatives on protein identification posttranslational modification characterization and functionalproteomics. Currently there is no proteomic instrument at the Lexington VA Medical Center. Thepurchase of the instrument is critical to the continuing expansion and enhancement of the proteomicsresearch program in human disease at VA. As described in this application 7 VA-funded (major users)and 3 NIH/NSF-funded (minor users) investigators have specific needs for this mass spectrometer.The research projects to be supported by this instrument address critically important healthchallenges faced by Veterans spanning major disease areas such as neurological disorderscardiovascular diseases metabolic syndrome respiratory disease chronic pain and alcohol abuse.The PI has over 15 years experience in the area of biological mass spectrometry and proteomics. AnAdvisory Committee with both VA and University investigators is assembled for overall guidance forthe usage of the shared instrument. The requested instrument will have a major and long term impacton research capabilities at the Lexington VA Medical Center.

project_terms:
Address;Advisory Committees;Alcohol abuse;Area;Biological;Calibration;Cardiovascular Diseases;Computer software;Computers;Data Analyses;Disease;Electrospray Ionization;Electrostatics;Equipment;Funding;Goals;Health;High Pressure Liquid Chromatography;Hybrids;Ions;Lung diseases;Mass Spectrum Analysis;Measurement;Medical center;Metabolic syndrome;Minor;Peptides;Post-Translational Protein Processing;Program Evaluation;Proteins;Proteome;Proteomics;Research;Research Personnel;Research Project Grants;Resolution;Running;Services;Source;System;United States National Institutes of Health;Universities;Veterans;chronic pain;data acquisition;equipment acquisition;experience;human disease;instrument;mass analyzer;mass spectrometer;meetings;nano;nano-electrospray;nervous system disorder;programs;tandem mass spectrometry

public_health_relevance:
This Shared Equipment Evaluation Program (ShEEP) application is to request an integratedLC-MS/MS system to provide proteomic analysis for investigators at the Lexington VA Medical Center.The research projects to be supported by this instrument address critically important healthchallenges faced by Veterans spanning major disease areas such as neurological disorderscardiovascular diseases metabolic syndrome respiratory disease chronic pain and alcohol abuse.The requested instrument will have a major and long term impact on research capabilities at theLexington VA Medical Center.


application_id: 9206075
project_number: 5I01BX002149-02
project_title: FUS Protein Homeostasis in ALS
administering_ic: VA
award_notice_date: 2017-05-19
opportunity_number: BX-14-004
application_type: 5
activity_code: I01
ic: BX
serial_number: 002149
project_start_date: 2015-10-01
project_end_date: 2019-09-30
study_section: Neurobiology E[NURE]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-10-01
project_abstract:
DESCRIPTION (provided by applicant):    
   
Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease with no effective treatment. ALS is connected with military service and veterans are at a higher risk of contracting this debilitating disease. Mutations in several genes have been discovered to cause a subset of familial ALS including copper- zinc superoxide dismutase (SOD1) fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43). Studying familial ALS using the well-defined genetic models will provide critical insights into the disease pathology as well as novel targets for future therapeutic development.  This project is focused on the RNA binding protein FUS that has been implicated in both familial and sporadic ALS. Since FUS mutations were found in a subset of familial ALS patients in 2009 mislocalization of mutant FUS in the cytoplasm has been considered a hallmark of this subset (Type 6) of ALS. However protein inclusions containing wild-type FUS have been reported in multiple forms of familial and sporadic ALS suggesting that FUS plays an important role in a larger portion of ALS beyond the Type 6 familial ALS. Protein inclusions can be caused by protein over-production inefficient protein degradation protein mislocalization or a combination of these defects. However the regulation of FUS protein expression and degradation remains poorly understood. We have published that it is critical to maintain proper levels of FUS inside the nucleus and that either elevated or reduced levels of FUS causes similar degenerative phenotypes in Drosophila models. Thus we propose that maintaining appropriate FUS protein homeostasis is critical to attenuate FUS toxicity and motor neuron dysfunction. Since little is known about how FUS gene transcription and protein turnover are regulated discoveries in this project will fill this knowledge gap and advance the field significantly.  The specific hypotheses to be tested are: FUS gene transcription is regulated by the Jak/Stat signaling cascade (Aim 1) while FUS degradation is largely mediated by the ubiquitin-proteasome system (Aim 2). Moreover we will test the hypothesis that FUS ubiquitination regulates its RNA binding and subcellular localization (Aim 3). We have carried out preliminary studies to show that the transcription of FUS is indeed controlled by Jak/Stat signaling and that Jak/Stat signaling attenuates FUS toxicity in Drosophila models. We also show that the degradation of FUS is mediated by the ubiquitin-proteasome system and that FUS ubiquitination is regulated by a specific E3 ligase named FBXW7. Moreover a dominant negative mutant FBXW7 decreased FUS ubiquitination delayed FUS degradation and changed FUS subcellular localization. Therefore each of these three specific hypotheses is supported by our preliminary results. These inter-related pathways play a critical role in regulating FUS function and alterations in any of them will likely contribute to the pathogenesis of ALS. The results from this study will help understand how to target FUS in motor neurons providing a new avenue to attenuate FUS toxicity in future therapeutic developments.  The proposal is constructed based on a number of novel observations which leads to a novel hypothesis that that FUS protein biosynthesis and turnover can be modulated to attenuate FUS toxicity in ALS. An array of techniques will be employed to test the hypothesis in a combination of in vitro and in vivo models. The results from the proposed studies should yield potential new targets that can be translated into novel treatments for veteran and other ALS patients.

project_terms:
Amyotrophic Lateral Sclerosis;Anabolism;Attenuated;Caring;Cell Nucleus;Cells;Cessation of life;Complex;Contracts;Cultured Cells;Cytoplasm;DNA Sequence Alteration;Defect;Diagnosis;Disease;Dominant-Negative Mutation;Drosophila genus;FBXW7 gene;Familial Amyotrophic Lateral Sclerosis;Foundations;Functional disorder;Future;Gene Proteins;Genes;Genetic;Genetic Models;Genetic Transcription;Health;Healthcare;In Vitro;Incidence;Knowledge;Ligands;Mass Spectrum Analysis;Mediating;Military Personnel;Modeling;Molecular;Motor Neurons;Mutation;Names;Neurodegenerative Disorders;Pathogenesis;Pathology;Pathway interactions;Patients;Phenotype;Play;Polyubiquitination;Production;Protein Biosynthesis;Proteins;Publishing;RNA Binding;RNA Interference;RNA-Binding Proteins;Rattus;Regulation;Reporting;Research;Role;Services;Signal Transduction;Site;System;Techniques;Testing;Toxic effect;Transgenic Organisms;Translating;Ubiquitin;Ubiquitination;Veterans;base;copper zinc superoxide dismutase;cost;disability;effective therapy;fly;high risk;improved;in vivo;in vivo Model;innovation;insight;multicatalytic endopeptidase complex;mutant;neurodegenerative phenotype;neuron loss;neurotoxicity;novel;overexpression;programs;protein TDP-43;protein degradation;protein expression;proteostasis;public health relevance;sarcoma;therapeutic development;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
   
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease and currently there is no cure. Veterans are at a higher risk of being inflicted with the disorder so that ALS has been listed as a disease entitled to presumptive service connection. All veterans diagnosed with ALS have received full disability lifetime health and death benefits since 2009 costing VA an estimated $505 million over 10 years.  Mutations in the gene encoding Fused in Sarcoma (FUS) have been recently reported to cause a subset of familial ALS. This project is to use the well-defined genetic model to understand the mechanisms regulating the biosynthesis degradation and subcellular localization of FUS. The results from studying the mutant FUS mediated familial ALS will provide critical insights into the pathology of all types of ALS. Our project will likely identify novel targets for future therapeutic developments thus improving the healthcare of veterans who have higher incidence of contracting ALS and reducing the cost of caring for these veterans.


application_id: 9143207
project_number: 1I01BX002996-01A2
project_title: Dietary Fat and Alcoholic Liver Disease
administering_ic: VA
award_notice_date: 2016-10-26
opportunity_number: BX-15-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 002996
suffix: A2
project_start_date: 2016-10-01
project_end_date: 2020-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1902075
contact_pi: MCCLAIN, CRAIG J.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
   
Alcohol abuse exacts a major toll on health and health costs in Veterans. Indeed even though there is an "epidemic" of hepatitis C in the U.S. alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat specifically rich in linoleic acid (LA) exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO) a key enzyme involved in the oxidation of LA in an animal model of ALD. These findings led us to postulate that specific oxidized LA metabolites (OXLAMs) play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1) a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation which are key signaling platforms for stressor-induced pathogenesis and which upon activation trigger the release of highly pro- inflammatory cytokines interleukin-1 (IL-1)
and interleukin-18 (IL-18). IL-1 release is thought to be a critical mediator of inflammation and
thus serves as a potential therapeutic target for treating hepatic inflammation in ALD. We propose that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two major mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction endoplasmic reticulum stress (ER stress) and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1 release. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD. Our research will be achieved through 3 specific aims: Aim 1. Evaluate whether OXLAMs exacerbate EtOH-mediated liver injury via induction of mitochondrial dysfunction ER stress and hepatocyte cell death in an animal model of ALD; Aim 2. Determine whether OXLAMs contribute to an EtOH-induced hepatic pro-inflammatory response via OXLAM-TRPV1-mediated inflammasome activation and subsequent increase in IL- release in an animal model of ALD. Aim 3. Explore the role of OXLAMs in monocytes/macrophages inflammasome activation in Alcoholic Hepatitis in Veterans.

project_terms:
Ablation;Address;Affect;Alcohol abuse;Alcoholic Hepatitis;Alcoholic Liver Diseases;Alcoholic beverage heavy drinker;Alcohols;Animal Model;Animals;Arachidonate 15-Lipoxygenase;Attenuated;Blood;Breast;Cations;Cell Death;Cessation of life;Chronic;Cirrhosis;Clinical;Colon;Data;Development;Diet;Dietary Fats;Dietary Intervention;Enzymes;Epidemic;Etiology;Experimental Animal Model;FDA approved;Fatty Liver;Genetic;Health;Health Care Costs;Heavy Drinking;Hepatic;Hepatitis C;Hepatocyte;Hepatotoxicity;Human;In Vitro;Inflammasome;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Interleukin-1 beta;Interleukin-18;Intestines;Knockout Mice;Kupffer Cells;Laboratories;Lead;Ligands;Link;Linoleic Acids;Liver;Mediating;Molecular;Morbidity - disease rate;Oxides;Pathogenesis;Patients;Permeability;Pharmacology;Play;Population;Prostate;Publishing;Research;Role;Signal Transduction;Steatohepatitis;Time;Translating;United States Department of Veterans Affairs;Unsaturated Fats;Up-Regulation;Vanilloid;Veterans;Whole Blood;base;cancer type;cytokine;endoplasmic reticulum stress;human study;in vitro testing;in vivo;liver inflammation;liver injury;macrophage;mitochondrial dysfunction;monocyte;mortality;new therapeutic target;nonalcoholic steatohepatitis;novel;octadecadienoic acid;outcome forecast;oxidation;peripheral blood;public health relevance;receptor;stressor;therapeutic target;toxicant

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   
   
Alcohol abuse exacts a major toll on health and health costs in Veterans. Even though there is an "epidemic" of hepatitis C in the U.S. and the Veterans Administration alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time with most of those deaths occurring in the first few months. Thus the prognosis for this stage of ALD is worse than many common types of cancer such as breast prostate and colon. Unfortunately there is no FDA-approved therapy for any stage of ALD and this makes the need for this proposed research even more compelling. The proposed studies will help to better understand the molecular mechanisms of alcohol-induced liver and intestinal injury including alcohol-diet interactions which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD as well as help to explain why only some heavy drinkers develop clinically important ALD.


application_id: 9138122
project_number: 1I01CX001353-01A1
project_title: The role of Axin2+ stem cells in ulcer healing during colitis.
administering_ic: VA
award_notice_date: 2016-10-27
opportunity_number: CX-15-001
application_type: 1
activity_code: I01
ic: CX
serial_number: 001353
suffix: A1
project_start_date: 2016-10-01
project_end_date: 2020-09-30
study_section: Gastroenterology[GAST]
contact_pi_person_id: 1883566
contact_pi: BARRETT, TERRENCE A.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   
   
A major cause of colon removal surgery in veterans with inflammatory bowel disease (IBD) is a failure of medically-induced mucosal healing. Mucosal healing is a reliable clinical marker of recovery after IBD therapy as it is associated with durable clinical remission. Despite the importance of mucosal repair we continue to have a poor understanding of many of the cellular and molecular elements that mediate ulcer healing. The current proposal focuses on the role of colonic (epithelial) stem cells (CSC) in ulcer healing during colitis. Wnt/-catenin signaling in stem cells promotes cell proliferation as well as self-renewal both essential functions needed for ulcer healing and restitution of the mucosal barrier. A central tenant of this proposal is the hypothesis that Wnt/-catenin signaling plays an integral role in mucosal repair in IBD and that steroids delay ulcer healing my impairing Wnt/-catenin signaling. In mucosal ulceration as seen in IBD there is replacement of surface mucosa with granulation tissue that is re-epithelialized with new crypt structures. We suspect that active Wnt signaling is required for several steps through this sequence of events from stage 1) generation of an intestinal epithelial cell (IEC) monolayer to stage 2) formation of epithelial invaginations to stage 3) formation of crypt islands on ulcer surfaces and finally stage 4) regeneration of mature crypts (Fig 3). Biochemical data from our lab indicate Wnt/-catenin signaling is increased during ulcer healing in colitis in mice and IBD patients. In studies to interrogate the role of Wnt signaling in ulcer healing we discovered that IEC expressing mRNA for the Wnt target gene Axin2 expand in ulcer margins on ulcer surfaces and within newly-formed crypt structures in the middle of ulcers. Studies using a novel Axin2 reporter mouse model indicate that Axin2+ IEC are pluripotent and capable of growing colonoid structures in vitro from a single cell. Together the preliminary data suggest that Axin2+ IEC represent a novel ISC population that forms new crypt structures during ulcer healing. In Aim 1 Axin2lacZ/+ and Axin2 CreERT2/+; R26RmTmG/+ mice will be used to study ulcer-associated Axin2+ IEC localization and gene expression profiles of this new stem cell population as well as perform lineage tracing during ulcer healing in DSS colitis. In Aim 2 we will examine ulcer healing in mice treated with steroids. New studies will utilize Axin2-specific expression of stabilized -catenin to examine its role in ulcer healin during steroid therapy. Aim 3 studies will interrogate the role of Axin2+ IEC in human IBD and will analyze the mechanisms by which steroids impair ulcer healing. The goal of these studies will be to determine if untreated UC patients exhibit increased Axin2 expression Wnt signaling and stem cell gene expression in areas of ulcer healing (Aim 3A) and determine whether steroid therapy reduces levels of Axin2 expression and stem cell activation in areas of delayed ulcer healing in a prospective trial of UC patients treated with steroids for a colitis flare (Aim 3B). Together the studies proposed will provide valuable insights into the molecular mechanisms that govern ulcer healing in colitis. The goal is to determine areas where therapeutic targets can be designed to safely accelerate ulcer healing and reverse the negative impact of steroids on mucosal repair in colitis.

project_terms:
AXIN2 gene;Area;Biochemical;Cell Proliferation;Cells;Clinical Markers;Colitis;Colon;Colon Carcinoma;Data;Disease;Elements;Epithelial;Epithelial Cells;Event;Excision;Exhibits;Failure;Flare;Gene Expression;Gene Targeting;General Population;Generations;Goals;Granulation Tissue;Hospitalization;Human;Impairment;In Vitro;Incidence;Inflammatory Bowel Diseases;Intestines;Island;Lasers;Mediating;Medical;Messenger RNA;Microscopy;Molecular;Molecular Profiling;Mucous Membrane;Mus;Natural regeneration;Operative Surgical Procedures;Oral;Patients;Play;Population;Prevalence;Recovery;Refractory;Reporter;Risk;Role;Signal Transduction;Stem cells;Steroid therapy;Steroids;Structure;Surface;Symptoms;Ulcer;Ulcerative Colitis;Veterans;WNT Signaling Pathway;Work;beta catenin;cell type;clinical remission;design;disability;healing;improved;insight;monolayer;mouse model;novel;prevent;prospective;public health relevance;repaired;self-renewal;stem cell population;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   
   
The incidence and prevalence of ulcerative colitis (UC) is higher among veterans than in the general population and the prevalence of UC increased 2-fold to 3-fold among veterans between 1998 and 2009. Lifelong effects of this disease include expensive medical treatments hospitalization surgery disability and increased risk of colon cancer. For many patients oral steroids are the first-line treatment for UC. Although steroids are effective in reducing overt symptoms studies have shown that approximately half of all patients are refractory to steroid treatment with limited ulcer healing. We have identified a new type of intestinal stem cell that i involved in healing ulcers. The goal of this project is to identify which types of cells are involvd in ulcer healing and to understand how the activity of those cells is regulated. Additionally we propose to investigate how steroids influence stem cell activity and limit ulcer healing. Completion of this work will lead to new understanding of how to improve medical treatment of colitis and prevent surgery in veterans.


application_id: 9031396
project_number: 1I01BX002695-01A2
project_title: Peripheral and Central Pain Generators of Chronic Trigeminal Neuropathic Pain
administering_ic: VA
award_notice_date: 2016-01-26
opportunity_number: BX-15-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 002695
suffix: A2
project_start_date: 2016-01-01
project_end_date: 2019-12-31
study_section: Neurobiology B[NURB]
contact_pi_person_id: 6346300
contact_pi: WESTLUND-HIGH, KARIN N.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):     
   
ABSTRACT Persisting dysfunctional neuroplasticity in peripheral nerves as well as in the brain exert powerful influences on the pain experience. For example facial trauma suffered by military personnel may heal yet months later progress to a chronic neuropathic pain state. A facial laceration trigeminal nerve trauma model (CCI-ION) is utilized in our pursuit of mechanistic support for repurposing a noradrenergic (NA) therapeutic currently in use for treatment of post-traumatic stress disorder (PTSD) in active duty and Veteran military personnel to reduce chronic pain. The proposed studies address novel hypotheses to explore mechanistic changes that cause overactivation of NA neurons in the nucleus locus coeruleus (LC) neurons that modulate pain and their dysfunctional NA receptor signaling in two targeted brain regions. Our Preliminary Data support our overall hypothesis that neuroplastic changes in the pain network and related limbic structures modulate a shift to chronic pain. This also causes anxiety and depression related behavioral measures in our preclinical model. Our studies are unique in that we test through an extended time course compared to studies using acute injuries to provide more clinically relevant information. We have discovered that switch from pain inhibition to facilitatio occurs through paradoxical ongoing dysregulation of NA LC neurons (Aim 1) that can be reversed pharmacologically (Aim 2). Long-term block of NA1 receptor facilitation is proposed as therapy for chronic pain behaviors overactivation and maladaptive neuropathology (Aim 3). Aim 1 tests the hypothesis that chronic trigeminal neuropathic pain facilitates central sensitization by overactivation and dysregulation of LC NA neurons producing a functional shift from pain inhibition to facilitation. Maladaptive signaling mechanisms have been identified during chronic pain. Biomarker changes indicate overactivation of the LC an important NA modulator of pain processing. Removal of LC NA influence with intracerebroventricular or trigeminal dorsal horn (spVc) microinjections of neurotoxic saporin conjugated dopamine-beta-hydroxylase antibodies specifically ablates NA neurons reducing mechanical hypersensitivity. Aim 2 tests the hypothesis that trigeminal nerve injury shifts NA2 receptor mediated inhibition to NA1 receptor mediated facilitation of chronic pain assisted by GABA dysregulation. Pharmacological findings indicate that during chronic pain GABA disinhibition occurs. Thus in chronic pain ligand-gated GABAA receptor chloride signaling becomes excitatory instead of inhibitory. Injury-induced long-term neuronal excitation causes intracellular chloride accumulation and equilibrium potential shift. Concomitant dysfunctional shift from NA2 receptor inhibition to NA1 receptor facilitation results in the medial prefrontal limbic cortex (mPFC) and
spVc targeted by the NA LC neurons. Aim 3 tests the hypothesis that long-term treatment with prazosin will reduce the effects of dysregulated NA LC signaling. Efficacy of long-term treatment with orally dosed prazosin a clinically used NA receptor antagonist will be tested in the chronic
facial laceration and nerve injury model. Attenuation is anticipated of hypersensitivity anxiety depression and cognition related measures based on its efficacy for the treatment of Veterans with PTSD. Chronic pain induced histopathological changes i.e. biomarker expression of cellular overactivation cortical neuronal death and glial scar formation are expected to be improved by long-term treatment with prazosin.  The long term goal of the proposed studies is greater understanding of pain generators and neuroplastic changes precipitating dysfunctional neuronal signaling that produce chronic pain. Completion of the studies will provide scientific justification for "repurposing" FDA approved noradrenergic therapies that (1) have potential to decrease chronic neuropathic pain and (2) will move quickly through regulatory approvals. This would improve quality of life return to work rates for Veterans and decrease costs for the VA system.

project_terms:
Acute;Acute Pain;Address;Animals;Anterior;Antibodies;Anxiety;Attenuated;Behavioral;Behavioral Assay;Biological Assay;Biological Markers;Blast Cell;Brain;Brain Injuries;Brain region;Cell Nucleus;Chloride Ion;Chlorides;Chronic;Cicatrix;Cognition;Cognitive;Craniocerebral Trauma;Data;Disinhibition;Dopamine-beta-monooxygenase;Dose;Effectiveness;Equilibrium;Excision;Explosion;FDA approved;Face;Facial Injuries;Functional Magnetic Resonance Imaging;Functional disorder;Goals;Head;Healed;Healthcare Systems;Hippocampus (Brain);Hypersensitivity;Immunohistochemistry;Incidence;Injury;Laceration;Lesion;Ligands;Measures;Mechanics;Medial;Mediating;Mental Depression;Microinjections;Military Personnel;Modeling;Monitor;Neuronal Plasticity;Neurons;Pain;Patients;Peripheral Nerves;Pharmaceutical Preparations;Pharmacological Treatment;Post-Traumatic Stress Disorders;Prazosin;Pre-Clinical Model;Prefrontal Cortex;Process;Prosencephalon;Quality of life;Receptor Inhibition;Receptor Signaling;Role;Signal Transduction;Sleep disturbances;Staining method;Stains;Structure;Symptoms;System;Testing;Therapeutic;Time;Trauma;Treatment Efficacy;Trigeminal System;Trigeminal nerve structure;Ventricular;Veterans;Work;attenuation;base;behavior measurement;central pain;central sensitization;chloride-cotransporter potassium;chronic neuropathic pain;chronic pain;cingulate cortex;clinically relevant;cohort;combat;comparison group;constriction;cost;dorsal horn;drinking water;experience;follow-up;gamma-Aminobutyric Acid;healing;improved;in vivo;locus ceruleus structure;nerve injury;nerve supply;neuron loss;neuropathology;neurotoxic;neurotransmission;noradrenergic;novel;pain behavior;pain inhibition;painful neuropathy;peripheral pain;pre-clinical;public health relevance;receptor

public_health_relevance:
PUBLIC HEALTH RELEVANCE:   
   
NARRATIVE Head laceration and chronic nerve injury pain are chief complaints of approximately 772000 of the 2.5 million military personnel deployed since 2001 that have sought out the VA health care system. We have identified two dysregulated signaling mechanisms that occur only after chronic pain is established. The dysregulated mechanisms involve a major neuronal group in the brain with connections to pain processing regions. This neuronal group which normally reduces pain begins to facilitate pain and damages brain neurons. The proposed studies will provide better rationale for the beneficial effects of noradrenergic drugs for pain in addition to their current use for PTSD and sleep disturbance suffered by many Veterans after face and head injuries associated with blast explosions and other combat incidences.


application_id: 9002769
project_number: 5I01BX002132-02
project_title: Respiratory Muscle Weakness
administering_ic: VA
award_notice_date: 2016-05-26
opportunity_number: BX-14-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002132
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Respiration[PULM]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-01-01
project_abstract:
DESCRIPTION (provided by applicant):       Recent studies indicate that the diaphragm becomes profoundly weak in critically ill patients. Diaphragm weakness in turn increases the duration of mechanical ventilation increases patient mortality and is a major contributor to the high cost of taking care of critically ill mechanically ventilated patients in the VA health care system. Our own work indicates that infections are a major cause of the development of severe diaphragm weakness in critically ill patients. It is also known that infections elicit increases in diaphragm free radical generation and that heightened free radical generation contributes to the development of weakness. The precise mechanism(s) by which infections activate free radical generation in skeletal muscle are not known however. Moreover currently there is no pharmacological treatment to prevent or reverse infection induced diaphragm weakness in critically ill patients. The purpose of the present project is to discover the mechanisms by which infections increase diaphragm free generation and to employ this mechanistic information to define novel translatable pharmacological treatments that can be used to prevent and reverse diaphragm weakness in critically patients.  Our central hypothesis is that infection induced diaphragm dysfunction is primarily a consequence of the sequential activation of neutral sphingomyelinase 2 cytosolic phospholipase A2 (cPLA2) mitochondrial free radical generation and proteolytic pathways (e.g. calpain). The planned studies will test this hypothesis and use this information to define new therapies that can be quickly translated into clinical usage.  Aim 1 experiments will delineate thespecific mechanism(s) by which infections induce heightened free radical generation in skeletal muscle. Experiment 1.1 will test the hypothesis that infections first activate neutral sphingomyelinase 2 in skeletal muscle. Experiment 1.2 will test the hypothesis that infection induced activation of neutral sphingomyelinase 2 subsequently activates skeletal muscle cPLA2 which in turn induces an increase in mitochondrial free radical production.  Aim 2 experiments will determine the specific skeletal muscle proteolytic pathways activated (Experiment 2.1) and cellular proteins degraded (Experiment 2.2) as a consequence of infection induced activation of cPLA2 and mitochondrial free radical generation.  Aim 3 experiments will determine if novel pharmacological agents which block cPLA2 activation and mitochondrial free radical generation prevent loss of diaphragm function in the cecal ligation perforation animal model of sepsis. We will study an agent which blocks activation of cPLA2 (taurine) in Experiment 3.1 a direct cPLA2 inhibitor (CDIBA) in Experiment 3.2 and an inhibitor of mitochondrial free radical generation (SS31) in Experiment 3.3.

project_terms:
Adrenal Cortex Hormones;Animal Model;Animals;Biophysical Process;Calpain;Caring;Caspase;Clinical;Contractile Proteins;Critical Illness;Cytosolic Phospholipase A2;Development;Free Radicals;Functional disorder;Generations;Goals;Health;Healthcare Systems;Human;Hyperglycemia;Infection;Interferons;Interleukin-1;Ligation;Mechanical Ventilators;Mechanical ventilation;Mediating;Mitochondria;Muscle;Muscle Weakness;Muscle function;Myosin Heavy Chains;Pathway interactions;Patients;Perforation;Pharmacological Treatment;Production;Proteins;Proteolysis;Respiration;Respiratory Diaphragm;Respiratory Failure;Respiratory Muscles;Risk Factors;Sepsis;Skeletal Muscle;Spectrin;Sphingomyelinase;TNF gene;Talin;Taurine;Testing;Translating;Weaning;Work;base;cost;cytokine;disability;improved;inhibitor/antagonist;mortality;multicatalytic endopeptidase complex;muscle strength;novel;novel therapeutics;patient population;phospholipase A2 inhibitor;prevent;research study

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       The long term goal of this proposal is to identify treatments to prevent weakness in critically illpatients. The novel pharmacological agents that will be tested in Aim 3 studies of the current proposal were found to approximately double diaphragm strength in an animal model of infection. If these same agents can produce comparable effects on diaphragm strength in humans then administration of these therapies to critically ill VA MICU patients should reduce the duration of mechanical ventilation by more than 60%. A therapy with this large of an impact should cut VA MICU costs by as much as $850 Million dollars per year and save 2400 lives per year. As a result if the present work leads to the discovery of a new treatment for diaphragm weakness in MICU patients this discovery has the potential to markedly reduce VA MICU costs save thousands of lives and reduce long term disability by improving skeletal muscle strength.


application_id: 8994168
project_number: 5I01BX002769-02
project_title: Adipose autotaxin: a novel link between obesity and cardiovascular disease
administering_ic: VA
award_notice_date: 2016-05-26
opportunity_number: BX-14-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002769
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-01-01
project_abstract:
DESCRIPTION (provided by applicant):       Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular biologically active lysophosphatidic acid (LPA) a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.

project_terms:
Acute;Address;Adipocytes;Adipose tissue;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Biological Models;Blood;Blood Vessels;Body mass index;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Chronic;Coronary Arteriosclerosis;Data;Development;Diabetes Mellitus;Disease;Dyslipidemias;Enzymes;Exhibits;Experimental Models;Fatty acid glycerol esters;G-Protein-Coupled Receptors;Gap Junctions;Genetic;Genetic Polymorphism;Goals;Grant;Health;Healthcare;Healthcare Systems;Human;Hypertension;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Insulin Resistance;Link;Lipids;Liquid substance;Lysophospholipase;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Medical;Medical center;Mus;Myocardial Infarction;Obese Mice;Obesity;Obesity associated cardiovascular disease;Overweight;Permeability;Phosphoric Monoester Hydrolases;Plasma;Play;Positioning Attribute;Prevention;Production;Reagent;Recombinants;Reporting;Research;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Source;System;Testing;United States;Vascular Diseases;Veterans;Work;atherothrombosis;base;cardiovascular disorder risk;cost;disability;disorder risk;extracellular;feeding;inhibitor/antagonist;innovation;inorganic phosphate;lipid metabolism;lysophosphatidic acid;macrophage;migration;monocyte;mouse model;novel;novel strategies;prevent;programs;response to injury;small molecule;stroke;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Obesity is a significant health care problem among veterans receiving care at VA Medical Centers. A comprehensive analysis of nearly 2 million veterans in 2000 indicated that ~68% were overweight and ~37% were obese. Obesity is an established risk factor for cardiovascular disease. In addition to contributing to traditional risk factors obesity is also characterized by  chronic inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Recent evidence focuses attention on the autotaxin - lysophosphatidic acid - lipid phosphate phosphates signaling nexus as a predictor of coronary artery disease that may be linked to obesity in that adipocytes serve as a major contributor of autotaxin levels. The goal of the current study is to identify the role of the adipose-derived autotaxin and the LPA signaling nexus in the development of atherosclerosis. Our results may suggest innovative targets to prevent and treat the cardiovascular complications of obesity in humans.


application_id: 8971984
project_number: 5I01BX001984-04
project_title: Association of a common variant of the PPAP2B gene with cardiovascular disease.
administering_ic: VA
award_notice_date: 2016-05-25
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001984
project_start_date: 2013-01-01
project_end_date: 2016-12-31
study_section: Cellular and Molecular Medicine[CAMM]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-01-01
project_abstract:
DESCRIPTION (provided by applicant):      Ischemic heart disease caused by atherosclerosis of the coronary arteries remains the most frequent cause of mortality among Veterans despite extensive investigation into its pathobiology the identification of many risk factors and development of new therapeutic strategies. The hallmark features of endothelial damage lipid deposition smooth muscle cell proliferation and vascular inflammation contribute to the development and complications of atherosclerosis. The bioactive lysophospholipids sphingosphine-1-phosphate (S1P) and lysophosphatidic acid (LPA) act on cell surface receptors expressed by many vascular cells. These lipids are positioned to serve as mediators of the cellular events contributing to atherosclerosis and their role is supported by emerging evidence from experimental models. The lipid phosphate phosphatase 3 (encoded by the PPAP2B gene) is a cell surface integral membrane protein that regulates the bioavailability of S1P and LPA by catalyzing their dephosphorylation to generate lipid products that are not receptor active. Analysis of data from a series of genome-wide association studies (GWAS) focuses attention on a striking association between a single nucleotide polymorphism (SNP) in the PPAP2B locus and coronary artery disease. This rs17114036 SNP lies in an intronic non-coding region of the gene that could affect gene expression. How genetic variation in PPAP2B confers risk of coronary artery disease is unknown in large part because of a lack of understanding of LPP3 function in vascular cells. In this application we present evidence that vascular cell LPP3 serves as an intrinsic negative regulator of vascular inflammation suppresses smooth muscle cell proliferation and promotes endothelial barrier function. These protective effects of LPP3 suggest that PPAP2B polymorphisms associated with reduced gene expression could aggravate cellular events underlying atherosclerosis and increase the likelihood of myocardial infarction.  The broad long-term goal of this research project is to explain how human genetic variation at the PPAP2B locus alters the risk of myocardial infarction and apply that knowledge to improve the diagnosis and therapy of ischemic heart disease. We have assembled a team of experts whose knowledge spans all aspects of the proposed research to position ourselves to validate the function of the PPAP2B locus in atherosclerosis. In this proposal we will test our central hypothesis which is that the minor allele of rs17114036 in PPAP2B reduces gene expression and that lower levels of LPP3 promote atherosclerosis. We will apply unique tools that we have developed to study LPP3 and our considerable expertise to test our central hypothesis. Firstly we will identify the mechanism by which in the rs17114036 SNP in PPAP2B affects LPP3 expression and activity. We predict that rs17114036 affects a U1 splisome binding site and thereby reduces gene expression.  We will test this working hypothesis by determining if the minor allele of rs17114036 associates with altered  LPP3 transcript and protein levels in white blood cells and arterial tissue and by examining the consequences of the polymorphism on RNA splicing and stability. Secondly we will establish a mechanistic role for LPP3 in experimental atherosclerosis. Based on our Preliminary Studies of vascular pathology in mice with tissue-specific defects in smooth muscle and endothelial LPP3 the working hypothesis of this section is that LPP3 protects against vascular inflammation and that reduced expression will therefore accelerate atherosclerosis.  We will test this working hypothesis by determining the consequences of vascular tissue specific deficiency of LPP3 on the development of atherosclerosis in mice.  The experiments proposed in this application are an important step in functionally validating a common genetic variant in PPAP2B as a cardiovascular risk predictor in humans. Establishing PPAP2B its product LPP3 and the lipid substrates of this enzyme as risk predictors and mediators of CAD promises to identify important and innovative targets for the development of new biomarkers and/or therapeutics.

project_terms:
Accounting;Address;Admission activity;Affect;Alleles;Atherosclerosis;Attention;Binding Sites;Biological Availability;Biological Markers;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cell Proliferation;Cell Surface Receptors;Cell surface;Cells;Cholesterol;Clinical;Congestive Heart Failure;Coronary Arteriosclerosis;Coronary artery;Data Analyses;Defect;Deposition;Development;Diabetes Mellitus;Diagnosis;Disease;Disease susceptibility;Employee Strikes;Enzymes;Event;Experimental Models;Family;Frequencies;Gene Expression;Genes;Genetic Polymorphism;Genetic screening method;Genotype;Goals;Health;Healthcare;Hospitals;Human;Human Genetics;Hypertension;Integral Membrane Protein;Investigation;Knowledge;LDL Cholesterol Lipoproteins;Lead;Leukocytes;Lipids;Lysophospholipids;Mediator of activation protein;Membrane;Messenger RNA;Minor;Mus;Mutation;Myocardial Infarction;Myocardial Ischemia;Nuclear;Pathology;Plasma;Positioning Attribute;Predisposition;Prevention;Process;Protein Dephosphorylation;Proteins;RNA Splicing;RNA Stability;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Ribonucleoproteins;Risk;Risk Factors;Role;Sampling;Series;Single Nucleotide Polymorphism;Smooth Muscle;Smooth Muscle Myocytes;Specific qualifier value;Susceptibility Gene;Testing;Therapeutic;Tissues;Transcript;Translating;United States;Untranslated RNA;Validation;Variant;Variation (Genetics);Vascular Endothelial Cell;Vascular Smooth Muscle;Veterans;Work;base;cardiovascular disorder risk;cardiovascular risk factor;disorder risk;enzyme activity;enzyme substrate;gene product;genetic variant;genome wide association study;improved;innovation;inorganic phosphate;inter-individual variation;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;mortality;novel strategies;novel therapeutic intervention;novel therapeutics;protective effect;receptor;research study;tool;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Cardiovascular diseases are one of the most prevalent health problems among Veterans resulting in over 25000 admissions to VA hospitals annually. Family history is well established to provide a strong clinical indicator of cardiovascular disease risk but until very recently in al but a few cases the genes involved were not known. A new approach called "genome wide association" has been used to identify common genetic variants that predict cardiovascular disease risk without obvious association with established cardiovascular disease risk factors such as elevated plasma cholesterol levels and increased blood pressure. The goal of this project is to determine why a common variant in a gene called PPAP2B is associated with significantly elevated cardiovascular disease risk. Completion of the work could lead to validation of this variant as a genetic test for cardiovascular disease susceptibility and the development of new therapies for treatment and prevention of cardiovascular to enable improved and more efficient healthcare for Veterans.


application_id: 8967203
project_number: 5I01CX000975-03
project_title: The association of SAA with apoB lipoproteins affects cardiovascular risk
administering_ic: VA
award_notice_date: 2016-08-24
opportunity_number: CX-13-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 000975
project_start_date: 2014-04-01
project_end_date: 2018-03-31
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-01
project_abstract:
DESCRIPTION (provided by applicant):        Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations and is a major health issue in Veterans. Despite numerous pharmacological agents targeting CVD risk factors the identification of individuals at high risk remains incomplete. Further there is still a need to identify new targets for therapy. SAA is an acute phase reactant that is significantly and persistently elevated in chronic inflammatory conditions such as diabetes metabolic syndrome (MetS) or rheumatoid arthritis which are all associated with increased rates of CVD. SAA has been found to be predictive of CVD events. Furthermore we and others have recently shown in murine models that increased SAA is directly pro-atherogenic. As described in the Response to Retention hypothesis of atherosclerosis the sub-endothelial retention of atherogenic lipoproteins by vascular wall proteoglycans initiates atherosclerosis. Although in the healthy state SAA is exclusively associated with HDL we and others have previously reported SAA in association with apoB-containing lipoproteins in murine models of diabetes and/or obesity and we recently confirmed this observation in human studies. In preliminary studies we demonstrate increased association of SAA with apoB- containing lipoproteins in insulin resistant states which may be due to the delayed lipoprotein clearance seen with insulin resistance. In new preliminary studies we demonstrate that SAA can shift from HDL to apoB-containing lipoproteins. SAA itself has proteoglycan binding properties and our preliminary data demonstrates that the presence of SAA on apoB-lipoproteins enhances their retention. The central hypothesis of this grant is that the shift of SAA from HDL to apoB-containing lipoproteins is pro-atherogenic. We propose that the presence of SAA on apoB- containing lipoproteins in insulin resistant conditions such as MetS and diabetes contributes to the increased atherosclerosis and CVD observed in these populations. Using in vitro in vivo and clinical studies the results of this proposal will identify that SAA augments the atherogenicity of apoB lipoproteins and thus may identify SAA as a target for therapeutic intervention.

project_terms:
Acute-Phase Proteins;Affect;Affinity;Apolipoproteins B;Atherosclerosis;Binding;Biological Markers;Blood Vessels;Cardiovascular Diseases;Cause of Death;Chronic;Clinical Research;Data;Developed Countries;Development;Diabetes Mellitus;Dyslipidemias;Event;Fatty acid glycerol esters;Grant;Health;High Density Lipoproteins;Human;In Vitro;Individual;Inflammatory;Insulin Resistance;Lipase;Lipids;Lipoproteins;Literature;Low-Density Lipoproteins;Metabolic syndrome;Morbidity - disease rate;Mus;Obesity;Outcome;Population;Property;Proteins;Proteoglycan;Publishing;Reporting;Rheumatoid Arthritis;Risk;Risk Factors;Role;Sampling;Serum amyloid A protein;Testing;Therapeutic Intervention;Time;Vascular remodeling;Very low density lipoprotein;Veterans;base;cardiovascular disorder risk;cardiovascular risk factor;drinking;high risk;in vivo;inflammatory marker;insulin sensitivity;intravenous glucose tolerance test;mortality;mouse model;new therapeutic target;novel;overexpression;particle;response;targeted agent;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:        Cardiovascular disease is the leading cause of death in developed nations and is a major health issue in Veterans. The inflammatory marker Serum Amyloid A (SAA) has been found to predict cardiovascular disease. This proposal is testing the concept that beyond predicting cardiovascular disease SAA may cause cardiovascular disease. The results of this proposal may identify SAA as a new target of risk reducing therapy.


application_id: 8967170
project_number: 5I01CX000773-03
project_title: HDL Remodeling in Metabolic Syndrome
administering_ic: VA
award_notice_date: 2016-05-24
opportunity_number: CX-13-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 000773
project_start_date: 2014-01-01
project_end_date: 2017-12-31
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-01-01
project_abstract:
DESCRIPTION (provided by applicant):       With a prevalence of 30-50% and clear association with increased cardiovascular disease (CVD) Metabolic Syndrome (MetS) is emerging as a major public health problem. MetS is characterized by elevated markers of inflammation hypertriglyceridemia and low levels of high density lipoprotein (HDL). This proposal aims to understand how HDL metabolism and function are altered in MetS. In MetS increases in triglyceride-rich lipoproteins (TGRL) in combination with increased activity of cholesterol ester transfer protein (CETP) leads to TG enrichment of HDL. Although there is evidence that TG enrichment per se may destabilize the particle to promote release of apoA-I it is likely that HDL remodeling factors in the circulation act on TG-enriched HDL to amplify apoA-I release and catabolism. Based on our preliminary data we propose that circulating phospholipases (endothelial lipase Group IIA secretory phospholipase A2) contribute significantly to HDL remodeling in MetS by liberating lipid-poor apoA-I from TG-enriched HDL. Once released from remodeled HDL lipid-poor apoA-I has three potential fates: it may serve as an acceptor for cellular cholesterol efflux associate with circulating HDL or be cleared from the circulation due to a failure to undergo re-lipidation. Emerging evidence indicates that not all lipid-poor apoA-I species are capable of acquiring additional lipid and are thus susceptible to rapid catabolism. We propose that HDL lowering in MetS is due not only to enhanced HDL remodeling to amplify the release of lipid-poor apoA-I but is also due to the increased production of "dysfunctional" lipid-poor species that are inherently susceptible to catabolism. The HDL receptor SR-BI plays a key role in HDL metabolism by mediating the selective uptake of CE from the core of HDL particles into cells. We have shown that SR-BI processing of HDL from healthy subjects generates at least 3 distinct lipid-depleted HDL "remnants" that differ in composition and subsequent metabolism. We propose that as SR-BI depletes the core of TG-enriched MetS HDL the propensity of such particles to remodel leads to enhanced released of lipid-poor apoA-I. The central hypothesis of this proposal is that TG enrichment of HDL in MetS predisposes the particle to remodeling by intravascular factors and alters its processing by SR-BI leading to the generation of lipid-poor species that are susceptible to catabolism. Specific Objective 1: Test the hypothesis that enhanced remodeling of HDL in hypertriglyceridemic MetS subjects leads to generation of lipid-poor apoA-I. The goal is to identify specific features of MetS HDL and/or MetS plasma that predict susceptibility to remodeling. We will also determine whether fibrate-induced TG lowering in MetS subjects leads to altered HDL remodeling. Specific Objective 2: Test the hypothesis that enhanced remodeling of TG-enriched HDL leads to alterations in subsequent HDL metabolism. Specific Objective 3: Test the hypothesis that TG enrichment alters SR-BI metabolism of HDL. Results from this project will provide new insights into mechanisms underlying reduced HDL in MetS a prevalent condition in the Veteran population that significantly increases the risk of developing CVD. Findings from this project have the potential to define novel biological correlates of accelerated apoA-I catabolism in MetS and to identify MetS subjects most likely to benefit from TG lowering/HDL raising interventions.

project_terms:
Affinity;Apolipoprotein A-I;Biological;Blood;Blood Circulation;Cardiovascular Diseases;Catabolism;Cells;Cholesterol;Cholesterol Ester Transfer Proteins;Chronic;Clinical Management;Complex;Data;Disease;Epidemic;Failure;Fibrates;Generations;Goals;Health;Heart Diseases;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Human;Hypertriglyceridemia;Incidence;Individual;Inflammation;Intervention;LIPG gene;Lipase;Lipids;Lipoproteins;Mediating;Metabolic syndrome;Metabolism;Outcome;Patients;Phospholipase;Phospholipase A2;Phospholipid Transfer Proteins;Plasma;Play;Population;Predisposition;Prevalence;Process;Production;Public Health;Research;Risk;Risk Factors;Testing;Triglycerides;United States;Veterans;base;diabetes risk;hepatic lipase;high density lipoprotein receptor;inflammatory marker;insight;novel;particle;stroke;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       The metabolic syndrome (MetS) is a complex disorder that increases the risk for diabetes heart disease and stroke. The incidence of MetS has reached epidemic proportions in the United States including the Veteran population. A common feature of MetS is low HDL cholesterol (HDL-C) which is recognized as a major risk factor for heart disease and stroke. Previous research indicates that HDL in individuals with MetS is more rapidly cleared from the blood compared to people without MetS. This proposal seeks to understand why HDL in MetS subjects is more susceptible to clearance. Results from these studies may identify new strategies for the clinical management of individuals with MetS.


application_id: 8967092
project_number: 5I01BX002141-02
project_title: iPLA2 as a Target in Vascular Inflammation Neointima Formation and Restenosis
administering_ic: VA
award_notice_date: 2016-05-18
opportunity_number: BX-13-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 002141
project_start_date: 2014-10-01
project_end_date: 2018-09-30
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-10-01
project_abstract:
DESCRIPTION (provided by applicant):     
   
Coronary heart disease is the single leading cause of death among men and women in the United States. Coronary revascularization including coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) is the most common modality in patients with coronary diseases. However it is also among the most costly and is often associated with a high incidence of restenosis. Although the rate of restenosis is significantly reduced with the use
of bare-metal stent (BMS) and particularly with drug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stent thrombosis with DES have been encountered as significant limitations to the long-term efficacy of coronary revascularization. With a long-term goal of identifying novel therapeutic targets for coronary heart disease the current application specifically investigates a potentially critical role of calcium independent phospholipase A2b (iPLA2b) in vascular inflammation re-endothelialization and neointima formation in a mouse femoral artery wire injury model. iPLA2b is a member of the phospholipase A2 superfamily that acts on phospholipids to produce a free fatty acid and a lysophospholipid. iPLA2b is expressed in vascular smooth muscle cells (VSMC) and is implicated in many human diseases. Whereas little is known about the role of other PLA2 in vascular injury-induced neointima formation substantial evidence including pharmacological inhibition antisense oligonucleotide down- rgulation genetic deletion and smooth muscle-specific overexpression consistently demonstrated that iPLA2b plays a critical role in vascular inflammation and neointima formation in a mouse carotid artery ligation model. To investigate whether targeting smooth muscle-specific iPLA2b is sufficient to reduce vascular inflammation and neointima formation a femoral artery injury model that better mimics PCI was established a novel tamoxifen-inducible smooth muscle-specific iPLA2b knockout mouse model (SM-iPLA2b-iKO) was developed and the current proposal hypothesizes that activation of iPLA2b in VSMC by vascular injury plays a key role in wire injury-induced vascular inflammation re-endothelialization and neointima formation thereby significantly contributing to the development of restenosis after coronary revascularization. Three Specific Aims are:  1) To test the hypothesis that smooth muscle-specific iPLA2b plays a critical role in the initiation of vascular inflammation re-endothelialization and neointima formation; 2) To determine the molecular mechanism that underlies wire injury-induced iPLA2b activation vascular inflammation and neointima formation; 3) To investigate whether post-wire injury molecular and genetic targeting iPLA2b has an effect on the progression of re-endothelialization vascular inflammation and neointima formation. To achieve this goal a well established and most physiological relevant femoral artery wire injury model will be used in combination with several novel and established genetic animal models (SM- iPLA2b-iKO SM-HIF-1a-iKO and SM-iPLA2b-Tg/12/15-LO) to selectively inhibit or activate iPLA2b HIF-1a and 12/15-LO before and after wire injury. Injured and non-injured femoral arteries will be isolated and then subjected to molecular immunohistological and biochemical studies to determine the role of iPLA2b in vascular inflammation and neointima formation. Results from the proposed studies may modify the current paradigm that the initiation and early progression of vascular inflammation are largely attributed to coordinated interactions among monocytes/macrophages leukocytes and endothelial cells by providing the first direct experimental evidence that VSMC also play a critical role in these early key events. Importantly results from the proposed studies will elucidate specific mechanisms that could lead to the identification of iPLA2b as a novel potential therapeutic target for the prevention and treatment of vascular inflammation re- endothelialization neointima formation and restenosis.

project_terms:
Adopted;Animal Model;Antisense Oligonucleotides;Arachidonate 15-Lipoxygenase;Biochemical;Blood;Blood Vessels;Calcium;Carotid Arteries;Cause of Death;Cessation of life;Chest Pain;Congestive Heart Failure;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Development;Endothelial Cells;Enzymes;Event;Gel;Genetic;Goals;Healthcare Systems;Heart;Hospitalization;Hypoxia;Incidence;Injury;Knockout Mice;Lead;Leukocytes;Ligation;Lipids;Lysophospholipids;Mediating;Metals;Modality;Modeling;Molecular;Molecular Genetics;Mus;Myocardial Infarction;Myocardial Ischemia;Nonesterified Fatty Acids;Oxygen;Patients;Pharmaceutical Preparations;Phospholipase;Phospholipase A2;Phospholipids;Physiological;Play;Pluronics;Prevention;Risk;Role;Scheme;Smooth Muscle;Smooth Muscle Myocytes;Stents;Tamoxifen;Testing;Therapeutic Effect;United States;Vascular Smooth Muscle;Woman;femoral artery;genetic approach;human disease;injured;macrophage;member;men;monocyte;mouse model;neointima formation;new therapeutic target;novel;overexpression;percutaneous coronary intervention;prevent;public health relevance;restenosis;stent thrombosis;therapeutic target;vascular inflammation;vascular smooth muscle cell proliferation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:     
   
Coronary heart disease also called ischemic heart disease is the result of narrowed or clogged coronary arteries that cannot carry sufficient amounts of blood and oxygen to the heart which can result in angina (chest pain) heart attack and death. Coronary heart disease is a common cause of congestive heart failure remains the leading cause of death among men and women in the United States and is also one of the most frequent indications for hospitalization within the VA healthcare system. Coronary revascularization has been adopted worldwide and is the most common modality in patients with coronary diseases in the United States including VA healthcare system. However it is most costly and is associated with a high incidence of restenosis (repeat narrowing of a coronary artery). The proposed studies specifically investigate the role of iPLA2b (an enzyme that produce bioactive lipids) in restenosis. If aims of the application are achieved it will provide evidence that could be used to develop new drugs that target iPLA2b to effectively prevent and reduce restenosis.


application_id: 8966631
project_number: 5I01BX001721-03
project_title: Thiamine deficiency and alcohol-induced neurodegeneration
administering_ic: VA
award_notice_date: 2016-05-18
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001721
project_start_date: 2013-10-01
project_end_date: 2017-09-30
study_section: Neurobiology A[NURA]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health social and economic impact. Chronic alcohol abuse induces dementia which is associated with morphological neurophysiological and biochemical changes in the central nervous system (CNS). The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. The underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). Thiamine deficiency (TD) can damage the CNS. TD in humans may results from chronic alcohol exposure genetic background aging or nutritional status. The relationship between thiamine status and neuron susceptibility to alcohol- induced neurodegeneration however remains unclear. Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles. It provides the cells with an alternative source of intracellular building blocks and energy thereby enhancing cell survival during nutrient deficiency or stress conditions. We hypothesize that TD may inhibit the autophagic pathways and impair this cellular self-protection mechanism. As a result neurons are more susceptible to alcohol- induced neurodegeneration after chronic TD. Three specific aims are proposed to test this hypothesis. We will first investigate whether the status of thiamine content determines neuron susceptibility to alcohol-induced neurodegeneration. We will next characterize the effect TD/alcohol on autophagy in the brain. Finally we will determine the role of autophagy in alcohol/TD interaction and alcohol-induced neurodegeneration. As a unit the proposal will elucidate the relationship between TD and neuron susceptibility to alcohol neurotoxicity and provide a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.

project_terms:
Accounting;Adult;Affect;Aging;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic beverage heavy drinker;Alcohols;Animals;Autophagocytosis;Biochemical;Brain;Brain Injuries;Brain region;C57BL/6 Mouse;Cell Survival;Cell physiology;Cells;Cerebellum;Chronic;Data;Dementia;Disease;Enzymes;Etiology;Experimental Models;Genetic;Health;Human;Medial;Metabolic;Nerve Degeneration;Neuraxis;Neurons;Neuropathy;Nutrient;Nutritional status;Organelles;Pathway interactions;Play;Predisposition;Role;Social Impacts;Source;Stress;Testing;Thalamic structure;Thiamine;Thiamine Deficiency;Veterans;Wernicke-Korsakoff Syndrome;alcohol exposure;alcohol response;brain abnormalities;chronic alcohol ingestion;cofactor;cognitive function;combat;economic impact;frontal lobe;glucose metabolism;insight;macromolecule;neurophysiology;neurotoxicity;novel;problem drinker;response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:        An estimated 7.5 percent of veterans are heavy drinkers and alcohol abuse is on the rise among combat veterans. Chronic alcohol abuse causes dementia and the most devastating feature of brain damage following chronic alcohol exposure is neurodegeneration. However the underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). This proposal will determine how thiamine deficiency (TD) and alcohol exposure interact and cause neurodegeneration in the central nervous system providing a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.


application_id: 8966536
project_number: 5I01BX000216-06
project_title: Nicotine and nicotinic receptors in lung transitional remodeling
administering_ic: VA
award_notice_date: 2016-05-18
opportunity_number: BX-13-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 000216
project_start_date: 2009-04-01
project_end_date: 2018-09-30
study_section: Respiration[PULM]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Tobacco and alcohol are the two most used and abused drugs in the world. Together they are responsible for millions of deaths each year worldwide. Despite the enormous amount of research carried out to understand how these agents affect the lung new information leading to significant advances at the clinic has been disappointing. Because of the high prevalence of tobacco and alcohol exposure in veterans the Roman lab is exploring the mechanisms by which these agents affect the lung. Our research revealed that both alcohol and nicotine an alkaloid present in tobacco promote alterations in lung matrix composition that we have termed 'transitional' remodeling a process characterized by subtle alterations in the relatively composition of the lung extracellular matrix. Although the exact mechanisms linking these events to lung disease remain incompletely understood we believe that transitional remodeling renders the host susceptible to lung disease and this belief is supported by published research performed both in vitro and in vivo. Considering the above we set out to identify the cellular/molecular mechanisms responsible for these events. Using cultured primary lung fibroblasts we found that nicotine induces cellular proliferation and matrix expression through the activation of specific 7 nicotinic acetylcholine receptors (7 nAChRs). The importance of these receptors was confirmed in vivo showing that prenatal exposure to nicotine affects lung development and induces airway thickening and hyperreactivity in wildtype animals but not in 7 nAChR knockout mice. Using the same culture model we discovered that alcohol acts on lung fibroblasts via another set of nAChRs 4 nAChRs. In rodent lungs the expression of these receptors is increased by chronic alcohol exposure which in turn predisposes to acute lung injury. This work suggests that the cholinergic system plays an important role in lung homeostasis and response to injury and points to nAChRs as potential targets for intervention. More recently we found that nAChRs are activated through both ligand-dependent and -independent pathways. Specifically while nicotine acts on 7 nAChRs in a traditional ligand-dependent fashion alcohol works at least in part through induction of a particular form of oxidant stress (oxidation of the cysteine/cystine redox potential or Eh Cys/CySS) which together with cysteine residues strategically located on the subunits of certain nAChR pentamers activates nAChR signaling via ligand-independent mechanisms of action. Importantly we have generated preliminary data to suggest that susceptibility to injury in aging might activate nAChRs through similar pathways thereby promoting transitional remodeling and increased susceptibility to lung injury. Considering the above we propose that aging (as observed for nicotine and ethanol exposure) is associated with lung transitional remodeling via distinct nAChRs. nAChRs can be activated via ligand-dependent and -independent pathways the latter triggered by oxidant stress induced by oxidation of the Eh Cys/CySS. Specifically oxidant stress affects cysteines strategically located in the  subunits of nAChRs which in turn triggers signal transduction and promotes lung transitional remodeling and increase susceptibility to disrepair after lung injury. To test this hypothesis we propose experiments designed to: Aim 1. Investigate the role of specific subunit cysteines in nAChR activation in lung cells and in vivo. Aim 2. Determine the role of oxidant stress especially oxidation of the Eh Cys/CySS in nAChR activation both in vitro and in vivo. Aim 3. Examine the role of nAChR activation in lung disease related to aging and how this is affected by tobacco and alcohol exposure.

project_terms:
Acute Lung Injury;Adult;Affect;Aging;Alcohol abuse;Alcohols;Alkaloids;Animal Model;Animals;Architecture;Belief;Cell Proliferation;Cells;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Clinic;Cultured Cells;Cysteine;Cystine;Cytoskeleton;Data;Development;Disease;Endotoxemia;Ethanol;Event;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Funding;Glycoproteins;Health;High Prevalence;Homeostasis;In Vitro;Incidence;Individual;Infection;Injury;Intervention;Knockout Mice;Ligands;Link;Lung;Lung diseases;Malignant neoplasm of lung;Modeling;Molecular;Morphogenesis;Nicotine;Nicotinic Receptors;Obstructive Lung Diseases;Organ;Oxidation-Reduction;Pathway interactions;Play;Predisposition;Process;Publishing;Receptor Cell;Reporting;Research;Risk;Rodent;Role;Secure;Signal Transduction;System;Testing;Tissues;Tobacco;United States National Institutes of Health;Veterans;Work;airway hyperresponsiveness;alcohol effect;alcohol exposure;cholinergic;design;drug of abuse;in vivo;lung development;lung injury;oxidant stress;oxidation;prenatal exposure;receptor;receptor expression;research study;response;response to injury;tobacco abuse;tobacco exposure

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Aging and tobacco and alcohol abuse are important problems worldwide and many disorders observed in veterans are associated with these states. This work will study how aging affects lung cells in an attempt to identify potential targets for intervention and determine how tobacco and alcohol exposure influence these events. Specifically the research will focus on a special kind of cell receptors termed nicotinic acetylcholine receptors (nAChRs). Studies will be performed in cultured cells as well as in animal models to study the role of these receptors in aging and in tobacco- and alcohol-related lung disease.


application_id: 8963457
project_number: 5I01BX001838-04
project_title: Mechanism of Neutrophil Activation
administering_ic: VA
award_notice_date: 2016-05-18
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001838
project_start_date: 2012-10-01
project_end_date: 2016-09-30
study_section: Immunology and Dermatology A[IMMA]
contact_pi_person_id: 1886516
contact_pi: MCLEISH, KENNETH R
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Neutrophils are a critical component of both the innate and adaptive immune responses that control microbial invasion. Priming is an intermediate step by which resting neutrophils enhance their production of reactive oxygen intermediates (ROI) upon activation and priming is necessary for optimal microbial killing. Although priming greatly enhances neutrophil bactericidal capability primed neutrophils are also more dangerous to normal cells. Primed neutrophils participate in a number of diseases prominent in the aging Veteran population including ANCA-associated vasculitis ischemia- reperfusion injury acute respiratory distress syndrome rheumatoid arthritis peridontitis atherosclerosis and acute inflammatory liver injury. Thus manipulation of neutrophil priming is a potential therapeutic strategy for pharmacological intervention to restrain inflammation. Recent studies identified granule exocytosis and enhanced translocation of cytosolic components of the NADPH oxidase to the plasma membrane as possible mechanisms of neutrophil priming. However many gaps in knowledge remain. The relative contribution of each of those events to priming has not been examined and whether both are necessary or sufficient for priming is unknown. The molecular events by which granule exocytosis contributes to priming and the molecular events that control enhanced translocation of cytosolic NADPH oxidase components are incompletely understood. Finally the ability to manipulate neutrophil priming in vivo has not been established. The McLeish laboratory is in a unique position to address each of these gaps based on our extensive experience examining signal transduction pathways our application of biochemical genetic and proteomic approaches to understand neutrophil biology and our recent development of novel reagents that inhibit exocytosis in vitro and in vivo. The current proposal will address the central hypothesis that neutrophil priming results from the convergence of signal transduction pathways into two responses an exocytose-dependent increase in plasma membrane expression of membrane components of NADPH oxidase and prolyl isomerase-dependent conformational changes in cytosolic components of NADPH oxidase. The following four specific objectives will be accomplished.  Specific Objective 1 will test the working hypothesis that exocytosis of secretory vesicles and gelatinase granules results in increased plasma membrane expression of p91phox and p22phox which is necessary but not sufficient for priming. Specific Objective 2 will test the working hypothesis that activation of the prolyl isomerase Pin1 contributes to priming of human neutrophils by multiple mechanisms including enhanced p47phox translocation and increased granule exocytosis. Specific Objective 3 will test the working hypothesis that p38 MAPK phosphorylates multiple proteins that mediate events necessary for priming including exocytosis and Pin1 activation. Specific Objective 4 will test theworking hypothesis that neutrophil priming is a necessary component for neutrophil participation in inflammatory diseases and represents a viable therapeutic strategy using an animal model of acute lung injury (ALI). The proposed work is expected to establish the molecular basis for neutrophil priming. The impact of the project is that molecular targets identified will permit therapeutic manipulation of neutrophil priming in inflammatory diseases. Thus new approaches to treating Veteran patients with a number of acute and chronic inflammatory diseases are anticipated.

project_terms:
Acute;Acute Lung Injury;Address;Adult Respiratory Distress Syndrome;Affect;Aging;Animal Model;Antineutrophil Cytoplasmic Antibodies;Arteriosclerotic Cardiovascular Disease;Atherosclerosis;Bacteria;Biochemical Genetics;Biology;Blood Vessels;Cell membrane;Chemicals;Chronic;Cytoplasmic Granules;Data;Development;Disease;Event;Exocytosis;Exposure to;Gelatinases;Goals;Health;Human;In Vitro;Infection;Infection Control;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Arthritis;Injury;Intervention;Invaded;Killings;Knowledge;Laboratories;Lead;Leukocytes;MAP Kinase Gene;MAPK14 gene;Mediating;Membrane;Molecular;Molecular Target;NADPH Oxidase;Neutrophil Activation;Normal Cell;Oxidases;Patients;Peptidylprolyl Isomerase;Phosphorylation;Play;Poisons;Population;Positioning Attribute;Process;Production;Proteins;Proteomics;Reagent;Reperfusion Injury;Reporting;Rest;Rheumatoid Arthritis;Role;Secretory Vesicles;Signal Transduction Pathway;Testing;Therapeutic;Tissues;Toxin;Vasculitis;Veterans;Work;acute liver injury;adaptive immunity;bactericide;base;experience;extracellular;human disease;in vivo;liver injury;microbial;neutrophil;novel;novel strategies;reactive oxygen intermediate;response;sound;therapeutic target;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       White blood cells (WBCs) protect against infection by producing toxic chemicals that kill invading bacteria. The production of those toxin chemicals is enhanced by prior exposure to a variety of mediators of inflammation by a process termed priming. Although WBC priming plays a critical role in the control of infection priming is a two-edged sword that also reduces the ability of WBCs to co-exist with normal cells. Primed WBCs produce tissue injury in a number of diseases that affect our Veteran patients. The events that lead to priming are not known and inhibition of priming has not been used to treat those diseases. The current proposal will define the mechanisms by which WBCs become primed and will establish priming is a therapeutic target in inflammatory diseases. Accomplishing those goals will provide new treatments for Veteran patients with a number of acute and chronic inflammatory diseases.


application_id: 8947613
project_number: 1IS1BX003153-01
administering_ic: VA
award_notice_date: 2015-08-07
opportunity_number: BX-14-015
application_type: 1
activity_code: IS1
ic: BX
serial_number: 003153
project_start_date: 2015-04-01
project_end_date: 2015-09-30
study_section: Special Initiatives - Shared Equipment (ShEEP/LAMb)[SPLJ]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
budget_end_date: 2015-09-30
project_title:
Acquisition of an HPLC Electrospray/chemical ionization triple quadrupole linear ion trap mass spectrometer system.

project_abstract:
DESCRIPTION (provided by applicant):    
The purpose of this application is to request funds for acquisition of an integrated instrument system comprising an AB Sciex 6500 triple quadrupole linear ion trap mass spectrometer with an electrospray and atmospheric pressure chemical ionization source a Parker Balston Tri Gas Generator and a Shimadzu dual pump HPLC system with autosampler column oven and controller. This instrument system enables highly specific detection structural identification and
quantitation of naturally occurring and synthetic molecules in complex biological samples. The instrument will be used by VA funded Major Users at the Lexington VA Medical Center who share an interest in understanding how being obese or overweight increases the risk of cardiovascular disease. The investigators participating in this proposal are investigating the concept that diet- dependent obesity and consequent hyperlipidemia result in changes in the lipid composition of circulating plasma components to initiate mechanisms that promote cardiovascular disease risk. The requested instrument system is required to complete the aims of VA sponsored research that tests specific hypotheses about how diets high in fats and carbohydrates lead to the formation of cardiovascular disease promoting lipids and lipid metabolites. Other minor users who will benefit from the instrument are studying the role of bioactive lipids as mediators of stem cell mobilization and homing after a heart attack and as potential markers and therapeutic targets for diagnosis and treatment of Traumatic Brain Injury. All of these conditions are of high relevance to Veterans Health. In particular Obesity and associated chronic health conditions cause significant morbidity and negatively impact military readiness. Sixty-one to 83% of Department of Defense healthcare beneficiaries and 78% of Veterans are overweight or obese. Treatment of diseases associated with overweight and obesity is consistent with the priorities of the leadership of the Department of Veterans Affairs t promote personalized proactive Veteran-driven care. Obesity is associated with known risk factors for cardiovascular disease including high blood pressure elevated plasma triglycerides and cholesterol alterations in the balance between HDL-associated "good cholesterol" and LDL-associated "bad cholesterol" and diabetes. However obesity predicts cardiovascular disease risk even when these co-morbid conditions are not present. Dietary restriction and exercise programs such as the VHA "Move" program can accomplish significant weight loss in Veterans but the majority of obese dieters fail to maintain their reduced weight. Given these challenges a better understanding of the link between diet and cardiovascular disease risk that will result from completion of these studies might lead to improvements in healthful nutrition for obese or overweight veterans or identify targets for pharmacological intervention to mitigate cardiovascular disease risk associated with obesity in Veterans and active duty military personnel. The requested instrument is essential for completion of our research in this important area.

project_terms:
Area;Atmospheric Pressure;Award;Biological;Body Weight decreased;Carbohydrates;Cardiovascular Diseases;Caring;Cells;Chemicals;Cholesterol;Chronic;Collection;Complex;Contract Services;Contracts;Core Facility;Data;Department of Defense;Detection;Diabetes Mellitus;Diagnosis;Diet;Disease;Doctor of Philosophy;Ensure;Equilibrium;Exercise;Fatty acid glycerol esters;Fee-for-Service Plans;Focus Groups;Funding;Gases;Health;Healthcare;Heart Diseases;Hematopoietic Stem Cell Mobilization;High Density Lipoproteins;High Pressure Liquid Chromatography;Homing;Human Resources;Hybrids;Hyperlipidemia;Hypertension;Individual;Intervention;Investments;Ions;Kentucky;LDL Cholesterol Lipoproteins;Lead;Leadership;Link;Lipids;Maintenance;Mass Spectrum Analysis;Measurement;Measures;Mediator of activation protein;Medical center;Medicine;Military Personnel;Minor;Molecular;Monitor;Morbidity - disease rate;Myocardial Infarction;Obesity;Overweight;Peer Review;Phospholipids;Plasma;Play;Process;Publications;Pump;Readiness;Reproducibility;Research;Research Personnel;Research Support;Resolution;Risk;Risk Factors;Role;Running;Sampling;Schedule;Scientist;Services;Signal Transduction;Solvents;Source;Speed (motion);System;Technical Expertise;Testing;Time;Training;Traumatic Brain Injury;Triglycerides;United States National Institutes of Health;Universities;Veterans;Weight;Work;assay development;base;beneficiary;cardiovascular disorder risk;college;cost;dietary restriction;experience;flexibility;human disease;improved;instrument;instrumentation;interest;ionization;lipid metabolism;mass spectrometer;member;method development;molecular mass;nutrition;operation;programs;public health relevance;research and development;research study;therapeutic target;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
Natural and manmade molecules play critical roles in human disease processes. Detecting measuring and identifying these molecules requires sophisticated instrumentation. The purpose of this application is to request funds to purchase an instrument that will be used to identify and
measure molecules that are important for research to understand how being obese or overweight increases the risk of developing heart disease which is of particular relevance to Veterans and Department of Defense healthcare beneficiaries.


application_id: 8922484
project_number: 1I01BX002149-01A2
project_title: FUS Protein Homeostasis in ALS
administering_ic: VA
award_notice_date: 2016-01-13
opportunity_number: BX-14-004
application_type: 1
activity_code: I01
ic: BX
serial_number: 002149
suffix: A2
project_start_date: 2015-10-01
project_end_date: 2019-09-30
study_section: Neurobiology E[NURE]
contact_pi_person_id: 7875249
contact_pi: ZHU, HAINING
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    
   
Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease with no effective treatment. ALS is connected with military service and veterans are at a higher risk of contracting this debilitating disease. Mutations in several genes have been discovered to cause a subset of familial ALS including copper- zinc superoxide dismutase (SOD1) fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43). Studying familial ALS using the well-defined genetic models will provide critical insights into the disease pathology as well as novel targets for future therapeutic development.  This project is focused on the RNA binding protein FUS that has been implicated in both familial and sporadic ALS. Since FUS mutations were found in a subset of familial ALS patients in 2009 mislocalization of mutant FUS in the cytoplasm has been considered a hallmark of this subset (Type 6) of ALS. However protein inclusions containing wild-type FUS have been reported in multiple forms of familial and sporadic ALS suggesting that FUS plays an important role in a larger portion of ALS beyond the Type 6 familial ALS. Protein inclusions can be caused by protein over-production inefficient protein degradation protein mislocalization or a combination of these defects. However the regulation of FUS protein expression and degradation remains poorly understood. We have published that it is critical to maintain proper levels of FUS inside the nucleus and that either elevated or reduced levels of FUS causes similar degenerative phenotypes in Drosophila models. Thus we propose that maintaining appropriate FUS protein homeostasis is critical to attenuate FUS toxicity and motor neuron dysfunction. Since little is known about how FUS gene transcription and protein turnover are regulated discoveries in this project will fill this knowledge gap and advance the field significantly.  The specific hypotheses to be tested are: FUS gene transcription is regulated by the Jak/Stat signaling cascade (Aim 1) while FUS degradation is largely mediated by the ubiquitin-proteasome system (Aim 2). Moreover we will test the hypothesis that FUS ubiquitination regulates its RNA binding and subcellular localization (Aim 3). We have carried out preliminary studies to show that the transcription of FUS is indeed controlled by Jak/Stat signaling and that Jak/Stat signaling attenuates FUS toxicity in Drosophila models. We also show that the degradation of FUS is mediated by the ubiquitin-proteasome system and that FUS ubiquitination is regulated by a specific E3 ligase named FBXW7. Moreover a dominant negative mutant FBXW7 decreased FUS ubiquitination delayed FUS degradation and changed FUS subcellular localization. Therefore each of these three specific hypotheses is supported by our preliminary results. These inter-related pathways play a critical role in regulating FUS function and alterations in any of them will likely contribute to the pathogenesis of ALS. The results from this study will help understand how to target FUS in motor neurons providing a new avenue to attenuate FUS toxicity in future therapeutic developments.  The proposal is constructed based on a number of novel observations which leads to a novel hypothesis that that FUS protein biosynthesis and turnover can be modulated to attenuate FUS toxicity in ALS. An array of techniques will be employed to test the hypothesis in a combination of in vitro and in vivo models. The results from the proposed studies should yield potential new targets that can be translated into novel treatments for veteran and other ALS patients.

project_terms:
Amyotrophic Lateral Sclerosis;Anabolism;Attenuated;Caring;Cell Nucleus;Cells;Cessation of life;Complex;Contracts;Cultured Cells;Cytoplasm;DNA Sequence Alteration;DNA-Binding Proteins;Defect;Diagnosis;Disease;Dominant-Negative Mutation;Drosophila genus;FBXW7 gene;Familial Amyotrophic Lateral Sclerosis;Foundations;Functional disorder;Future;Gene Proteins;Genes;Genetic;Genetic Models;Genetic Transcription;Health;Healthcare;Homeostasis;In Vitro;Incidence;Knowledge;Ligands;Mass Spectrum Analysis;Mediating;Military Personnel;Modeling;Molecular;Motor Neurons;Mutation;Names;Neurodegenerative Disorders;Pathogenesis;Pathology;Pathway interactions;Patients;Phenotype;Play;Production;Protein Biosynthesis;Proteins;Publishing;RNA Binding;RNA Interference;RNA-Binding Proteins;Rattus;Regulation;Reporting;Research;Role;Services;Signal Transduction;Site;System;Techniques;Testing;Toxic effect;Transgenic Organisms;Translating;Ubiquitin;Ubiquitination;Veterans;base;copper zinc superoxide dismutase;cost;disability;effective therapy;fly;high risk;improved;in vivo;in vivo Model;innovation;insight;multicatalytic endopeptidase complex;mutant;neurodegenerative phenotype;neuron loss;neurotoxicity;novel;overexpression;programs;protein degradation;protein expression;public health relevance;sarcoma;therapeutic development;ubiquitin-protein ligase

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
   
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease and currently there is no cure. Veterans are at a higher risk of being inflicted with the disorder so that ALS has been listed as a disease entitled to presumptive service connection. All veterans diagnosed with ALS have received full disability lifetime health and death benefits since 2009 costing VA an estimated $505 million over 10 years.  Mutations in the gene encoding Fused in Sarcoma (FUS) have been recently reported to cause a subset of familial ALS. This project is to use the well-defined genetic model to understand the mechanisms regulating the biosynthesis degradation and subcellular localization of FUS. The results from studying the mutant FUS mediated familial ALS will provide critical insights into the pathology of all types of ALS. Our project will likely identify novel targets for future therapeutic developments thus improving the healthcare of veterans who have higher incidence of contracting ALS and reducing the cost of caring for these veterans.


application_id: 8916636
project_number: 5I01RX000338-04
project_title: TBI epileptogenesis: pathologic hippocampal L-glut synaptic plasticity
administering_ic: VA
award_notice_date: 2014-09-11
opportunity_number: RX-10-005
application_type: 5
activity_code: I01
ic: RX
serial_number: 000338
project_start_date: 2010-10-01
project_end_date: 2014-09-30
study_section: Brain Health and Injury[RRD1]
contact_pi_person_id: 9405862
contact_pi: SLEVIN, JOHN T.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-10-01
project_abstract:
DESCRIPTION (provided by applicant):     Project Summary The molecular mechanism that underlies evolution to post-traumatic epilepsy (PTE) in individuals with traumatic brain injury (TBI) is unknown. It has been suggested that the development of PTE following TBI is the combined result of kindling epileptogenesis during the early stages of recovery and triggering by residual irritation from damaged neural tissue. Glutamate the major excitatory neurotransmitter (NT) in the central nervous system must be tightly regulated to allow for proper neuronal signaling without creating excessive excitation. TBI produces an increase in glutamate release into the extracellular space and a concurrent decrease in the ability of excitatory amino acid transporters to reuptake glutamate that may lead to its accumulation propagating secondary damage cascades and producing aberrant neuronal signaling. We suggest that the enhanced hippocampal glutamate levels seen post-TBI are in part due to changes of the neurosecretory machinery and SNARE regulators and/or re-sequestration process. Left unchecked these changes become drivers of post-TBI epileptogenesis leading to PTE. The hypothesis that pathologic adaptation of inherent hippocampal glutamatergic synaptic plasticity promotes post-TBI epileptogenesis will be tested through three specific aims in animals (and appropriate controls) that have been administered a lateral fluid percussion injury (LFPI) and then monitored by telemetry until electroencephalographic (EEG) evidence of epileptiform activity: (1) Measure of tonic glutamate levels and evoked glutamateamate release in the hippocampal formation of epileptic and non-epileptic animals after moderate LFPI through use of a novel microarray electrode system. In tissue from hippocampal formation of these same animals we will use Western blotting techniques to quantify (2) components of the neurotransmitter release process and (3) certain glutamate transporters. Investigation of this putative relationship between aberrant glutamate neuronal exocytosis/resequestration and PTE will provide insight into potential mechanisms by which glutamate neurotransmission is regulated and into the molecular events of epileptogenesis as well as provide potential foci for therapeutic intervention. The long-term goal of this project is to restore to normal aberrant mechanisms associated with TBI-associated epileptogenesis. There are indications from animal studies that several newer FDA-approved and actively used antiepileptic drugs e.g. levetiracetam and lacosamide may also act as antiepileptogenic agents through effect on glutamate neurotransmission. Such agents would be appropriate compounds for further mechanistic evaluation in animals and clinical studies in PTE patients if the studies proposed here suggest that chronic dysregulation of glutamatergic release is associated with epileptogenesis. Pretransfection with a recently developed adeno-associated virus for the GLT-1 transporter to enhance glutamate reuptake currently under investigation by one of us may provide yet another novel approach to target a specific mechanism involved in glutamate regulation should these studies confirm a glutamate transporter abnormality is associated with development of PTE.

project_terms:
Acute;Affect;Afghanistan;Amino Acid Transporter;Amygdaloid structure;Animal Model;Animals;Antiepileptic Agents;Antiepileptogenic;Behavior;Chronic;Clinical Research;Dependovirus;Development;Electrodes;Enzymes;Epilepsy;Epileptogenesis;Evaluation;Event;Evolution;Excitatory Amino Acids;Exocytosis;Extracellular Space;FDA approved;Glutamate Transporter;Glutamates;Goals;Healthcare Systems;Hippocampal Formation;Hippocampus (Brain);Human;Individual;Injury;Investigation;Iraq;Kindling (Neurology);Label;Lateral;Lead;Left;Levetiracetam;Life;Measures;Microelectrodes;Military Personnel;Modeling;Molecular;Molecular Target;Monitor;Morbidity - disease rate;Mortality Vital Statistics;Neuraxis;Neurons;Neurotransmitters;Pathologic;Patients;Population;Post-Traumatic Epilepsy;Probability;Process;Recovery;Regulation;Research;Residual state;Risk Factors;SNAP receptor;Signal Transduction;Site;Soldier;Staging;Survivors;Synapses;Synaptic plasticity;System;Techniques;Telemetry;Testing;Therapeutic;Therapeutic Intervention;Tissues;Traumatic Brain Injury;United States;United States Department of Veterans Affairs;Veterans;Western Blotting;base;combat;dentate gyrus;economic cost;fluid percussion injury;insight;irritation;neurotransmission;neurotransmitter release;neurotransmitter reuptake;novel;novel strategies;presynaptic;relating to nervous system;reuptake;therapeutic target;uptake

public_health_relevance:
In addition to affecting civilian populations traumatic brain injury (TBI) has been labeled the signature injury of the current combat in Iraq and Afghanistan. TBI is a leading cause of morbidity and mortality in the United States and is a risk factor for post-traumatic epilepsy (PTE). Examining TBI-induced dysregulation of glutamate neurotransmitter release and reuptake the specific aims of this proposal may reveal important mechanisms identify potential therapeutic targets and pinpoint the therapeutic window to eliminate or reduce the probability of developing PTE. Recognition of molecular targets for new therapies that would extinguish TBI- induced epileptogenesis would alleviate the human suffering of civilians soldiers and veterans as they return to civilian life as well as diminish the concomitant long-term economic costs of epilepsy to the US health care system the military and the Veterans Administration.


application_id: 8822730
project_number: 5I01CX000975-02
project_title: The association of SAA with apoB lipoproteins affects cardiovascular risk
administering_ic: VA
award_notice_date: 2014-11-11
opportunity_number: CX-13-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 000975
project_start_date: 2014-04-01
project_end_date: 2018-03-31
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-04-01
project_abstract:
DESCRIPTION (provided by applicant):     
   
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations and is a major health issue in Veterans. Despite numerous pharmacological agents targeting CVD risk factors the identification of individuals at high risk remains incomplete. Further there is still a need to identify new targets for therapy. SAA is an acute phase reactant that is significantly and persistently elevated in chronic inflammatory conditions such as diabetes metabolic syndrome (MetS) or rheumatoid arthritis which are all associated with increased rates of CVD. SAA has been found to be predictive of CVD events. Furthermore we and others have recently shown in murine models that increased SAA is directly pro-atherogenic. As described in the Response to Retention hypothesis of atherosclerosis the sub-endothelial retention of atherogenic lipoproteins by vascular wall proteoglycans initiates atherosclerosis. Although in the healthy state SAA is exclusively associated with HDL we and others have previously reported SAA in association with apoB-containing lipoproteins in murine models of diabetes and/or obesity and we recently confirmed this observation in human studies. In preliminary studies we demonstrate increased association of SAA with apoB- containing lipoproteins in insulin resistant states which may be due to the delayed lipoprotein clearance seen with insulin resistance. In new preliminary studies we demonstrate that SAA can shift from HDL to apoB-containing lipoproteins. SAA itself has proteoglycan binding properties and our preliminary data demonstrates that the presence of SAA on apoB-lipoproteins enhances their retention. The central hypothesis of this grant is that the shift of SAA from HDL to apoB-containing lipoproteins is pro-atherogenic. We propose that the presence of SAA on apoB- containing lipoproteins in insulin resistant conditions such as MetS and diabetes contributes to the increased atherosclerosis and CVD observed in these populations. Using in vitro in vivo and clinical studies the results of this proposal will identify that SAA augments the atherogenicity of apoB lipoproteins and thus may identify SAA as a target for therapeutic intervention.

project_terms:
Acute-Phase Proteins;Affect;Affinity;Apolipoproteins B;Atherosclerosis;Binding (Molecular Function);Biological Markers;Blood Vessels;Cardiovascular Diseases;Cause of Death;Chronic;Clinical Research;Data;Developed Countries;Development;Diabetes Mellitus;Dyslipidemias;Event;Fatty acid glycerol esters;Grant;Health;High Density Lipoproteins;Human;In Vitro;Individual;Inflammatory;Insulin Resistance;Lipase;Lipids;Lipoproteins;Literature;Low-Density Lipoproteins;Metabolic syndrome;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Obesity;Outcome;Population;Property;Proteins;Proteoglycan;Publishing;Relative (related person);Reporting;Rheumatoid Arthritis;Risk;Risk Factors;Role;Sampling;Serum amyloid A protein;Testing;Therapeutic Intervention;Time;Vascular remodeling;Very low density lipoprotein;Veterans;base;cardiovascular disorder risk;cardiovascular risk factor;drinking;high risk;in vivo;inflammatory marker;insulin sensitivity;intravenous glucose tolerance test;novel;particle;public health relevance;response;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:     
   
Cardiovascular disease is the leading cause of death in developed nations and is a major health issue in Veterans. The inflammatory marker Serum Amyloid A (SAA) has been found to predict cardiovascular disease. This proposal is testing the concept that beyond predicting cardiovascular disease SAA may cause cardiovascular disease. The results of this proposal may identify SAA as a new target of risk reducing therapy.


application_id: 8820510
project_number: 1I01BX002769-01
project_title: Adipose autotaxin: a novel link between obesity and cardiovascular disease
administering_ic: VA
award_notice_date: 2015-01-09
opportunity_number: BX-14-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 002769
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Cardiovascular Studies B[CARB]
contact_pi_person_id: 1932626
contact_pi: SMYTH, SUSAN S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-01-01
project_abstract:
DESCRIPTION (provided by applicant):    
   
Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. The medical costs associated with obesity strain the VA health care system. Obesity is an established risk factor for cardiovascular disease (CVD) and stroke and the cardiovascular complications of obesity are a leading cause of potentially preventable death in Veterans. In addition to contributing to traditional CVD risk factors obesity is also characterized by a chronic sub-acute inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Inflamed adipose tissue may uniquely contribute to systemic inflammatory mediators that promote the development of atherosclerosis. A better understanding of the role of adipose tissue in generating inflammatory mediators will ultimately result in identification of novel strategies to prevent and treat associated CVD. Recent evidence and our own findings indicate that adipose tissue contributes to systemic levels of the secreted lysophospholipase D autotaxin (ATX). ATX is responsible for production of extracellular biologically active lysophosphatidic acid (LPA) a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids that is positioned to play a role in human health and disease. Based on observations that ATX expression increases with adiposity and demonstrated effects of ATX and LPA on monocyte migration and endothelial permeability we propose the central hypothesis that signaling pathways regulated by ATX contribute to obesity associated inflammation and the development of atherosclerosis. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in two specific aims. In Aim One we will identify the role of adipose derived ATX in local and systemic inflammation. In Aim Two we will identify the role of adipose-derived ATX in the development of atherosclerosis. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling namely role of adipose-derived ATX in biologic signaling mediated by LPA and its role in atherosclerosis These results will be significant because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of the cardiovascular complications of obesity in humans.

project_terms:
Acute;Address;Adipocytes;Adipose tissue;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Attention;Biological Models;Blood;Blood Vessels;Body mass index;Cardiovascular Diseases;Cardiovascular system;Caring;Cause of Death;Cessation of life;Chronic;Coronary Arteriosclerosis;Data;Development;Diabetes Mellitus;Disease;Dyslipidemias;Enzymes;Exhibits;Experimental Models;Fatty acid glycerol esters;G-Protein-Coupled Receptors;Gap Junctions;Genetic;Genetic Polymorphism;Goals;Grant;Health;Healthcare;Healthcare Systems;Human;Hypertension;Infiltration;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Insulin Resistance;Link;Lipids;Liquid substance;Lysophospholipids;Mass Spectrum Analysis;Mediating;Mediator of activation protein;Medical;Medical center;Mus;Myocardial Infarction;Obese Mice;Obesity;Obesity associated cardiovascular disease;Overweight;Permeability;Phosphoric Monoester Hydrolases;Plasma;Play;Positioning Attribute;Prevention;Production;Reagent;Recombinants;Reporting;Research;Risk;Risk Factors;Role;Signal Pathway;Signal Transduction;Source;System;Testing;United States;Vascular Diseases;Veterans;Work;alkylglycerophosphoethanolamine phosphodiesterase;atherothrombosis;base;cardiovascular disorder risk;cost;disability;disorder risk;extracellular;feeding;inhibitor/antagonist;innovation;inorganic phosphate;lipid metabolism;lysophosphatidic acid;macrophage;migration;monocyte;mouse model;novel;novel strategies;prevent;programs;public health relevance;response to injury;small molecule;stroke;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
   
Obesity is a significant health care problem among veterans receiving care at VA Medical Centers. A comprehensive analysis of nearly 2 million veterans in 2000 indicated that ~68% were overweight and ~37% were obese. Obesity is an established risk factor for cardiovascular disease. In addition to contributing to traditional risk factors obesity is also characterized by  chronic inflammatory state with macrophage infiltration in fat and the production of inflammatory mediators by adipose tissue. Recent evidence focuses attention on the autotaxin - lysophosphatidic acid - lipid phosphate phosphates signaling nexus as a predictor of coronary artery disease that may be linked to obesity in that adipocytes serve as a major contributor of autotaxin levels. The goal of the current study is to identify the role of the adipose-derived autotaxin and the LPA signaling nexus in the development of atherosclerosis. Our results may suggest innovative targets to prevent and treat the cardiovascular complications of obesity in humans.


application_id: 8820169
project_number: 1I01BX002132-01A2
project_title: Respiratory Muscle Weakness
administering_ic: VA
award_notice_date: 2015-01-30
opportunity_number: BX-14-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 002132
suffix: A2
project_start_date: 2015-01-01
project_end_date: 2018-12-31
study_section: Respiration[PULM]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD S.
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    
   
Recent studies indicate that the diaphragm becomes profoundly weak in critically ill patients. Diaphragm weakness in turn increases the duration of mechanical ventilation increases patient mortality and is a major contributor to the high cost of taking care of critically ill mechanically ventilated patients in the VA health care system. Our own work indicates that infections are a major cause of the development of severe diaphragm weakness in critically ill patients. It is also known that infections elicit increases in diaphragm free radical generation and that heightened free radical generation contributes to the development of weakness. The precise mechanism(s) by which infections activate free radical generation in skeletal muscle are not known however. Moreover currently there is no pharmacological treatment to prevent or reverse infection induced diaphragm weakness in critically ill patients. The purpose of the present project is to discover the mechanisms by which infections increase diaphragm free generation and to employ this mechanistic information to define novel translatable pharmacological treatments that can be used to prevent and reverse diaphragm weakness in critically patients.  Our central hypothesis is that infection induced diaphragm dysfunction is primarily a consequence of the sequential activation of neutral sphingomyelinase 2 cytosolic phospholipase A2 (cPLA2) mitochondrial free radical generation and proteolytic pathways (e.g. calpain). The planned studies will test this hypothesis and use this information to define new therapies that can be quickly translated into clinical usage.  Aim 1 experiments will delineate the
specific mechanism(s) by which infections induce heightened free radical generation in skeletal muscle. Experiment 1.1 will test the hypothesis that infections first activate neutral sphingomyelinase 2 in skeletal muscle. Experiment 1.2 will test the hypothesis that infection induced activation of neutral sphingomyelinase 2 subsequently activates skeletal muscle cPLA2 which in turn induces an increase in mitochondrial free radical production.  Aim 2 experiments will determine the specific skeletal muscle proteolytic pathways activated (Experiment 2.1) and cellular proteins degraded (Experiment 2.2) as a consequence of infection induced activation of cPLA2 and mitochondrial free radical generation.  Aim 3 experiments will determine if novel pharmacological agents which block cPLA2 activation and mitochondrial free radical generation prevent loss of diaphragm function in the cecal ligation perforation animal model of sepsis. We will study an agent which blocks activation of cPLA2 (taurine) in Experiment 3.1 a direct cPLA2 inhibitor (CDIBA) in Experiment 3.2 and an inhibitor of mitochondrial free radical generation (SS31) in Experiment 3.3.

project_terms:
Adrenal Cortex Hormones;Animal Model;Animals;Biophysical Process;Calpain;Caring;Clinical;Contractile Proteins;Critical Illness;Cytosolic Phospholipase A2;Development;Diaphragm (Anatomy);Free Radicals;Functional disorder;Generations;Goals;Healthcare Systems;Human;Hyperglycemia;Infection;Interferons;Interleukin-1;Ligation;Mechanical Ventilators;Mechanical ventilation;Mediating;Mitochondria;Mortality Vital Statistics;Muscle;Muscle Weakness;Muscle function;Myosin Heavy Chains;Pathway interactions;Patients;Perforation;Pharmacological Treatment;Production;Proteins;Proteolysis;Respiration;Respiratory Failure;Respiratory Muscles;Risk Factors;Sepsis;Skeletal muscle structure;Spectrin;Sphingomyelinase;TNF gene;Talin;Taurine;Testing;Translating;Weaning;Work;base;caspase;cost;cytokine;disability;improved;inhibitor/antagonist;multicatalytic endopeptidase complex;muscle strength;novel;patient population;phospholipase A2 inhibitor;prevent;public health relevance;research study

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
   
The long term goal of this proposal is to identify treatments to prevent weakness in critically ill
patients. The novel pharmacological agents that will be tested in Aim 3 studies of the current proposal were found to approximately double diaphragm strength in an animal model of infection. If these same agents can produce comparable effects on diaphragm strength in humans then administration of these therapies to critically ill VA MICU patients should reduce the duration of mechanical ventilation by more than 60%. A therapy with this large of an impact should cut VA MICU costs by as much as $850 Million dollars per year and save 2400 lives per year. As a result if the present work leads to the discovery of a new treatment for diaphragm weakness in MICU patients this discovery has the potential to markedly reduce VA MICU costs save thousands of lives and reduce long term disability by improving skeletal muscle strength.


application_id: 8811836
project_number: 5I01CX000773-02
project_title: HDL Remodeling in Metabolic Syndrome
administering_ic: VA
award_notice_date: 2014-11-11
opportunity_number: CX-13-001
application_type: 5
activity_code: I01
ic: CX
serial_number: 000773
project_start_date: 2014-01-01
project_end_date: 2017-12-31
study_section: Endocriniology A[ENDA]
contact_pi_person_id: 7875305
contact_pi: WEBB, NANCY R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-01-01
project_abstract:
With a prevalence of 30-50% and clear association with increased cardiovascular disease (CVD) MetabolicSyndrome (MetS) is emerging as a major public health problem. MetS is characterized by elevated markers ofinflammation hypertriglyceridemia and low levels of high density lipoprotein (HDL). This proposal aims tounderstand how HDL metabolism and function are altered in MetS. In MetS increases in triglyceride-richlipoproteins (TGRL) in combination with increased activity of cholesterol ester transfer protein (CETP) leads toTG enrichment of HDL. Although there is evidence that TG enrichment per se may destabilize the particle topromote release of apoA-I it is likely that HDL remodeling factors in the circulation act on TG-enriched HDL toamplify apoA-I release and catabolism. Based on our preliminary data we propose that circulatingphospholipases (endothelial lipase Group IIA secretory phospholipase A2) contribute significantly to HDLremodeling in MetS by liberating lipid-poor apoA-I from TG-enriched HDL. Once released from remodeled HDLlipid-poor apoA-I has three potential fates: it may serve as an acceptor for cellular cholesterol efflux associatewith circulating HDL or be cleared from the circulation due to a failure to undergo re-lipidation. Emergingevidence indicates that not all lipid-poor apoA-I species are capable of acquiring additional lipid and are thussusceptible to rapid catabolism. We propose that HDL lowering in MetS is due not only to enhanced HDLremodeling to amplify the release of lipid-poor apoA-I but is also due to the increased production of"dysfunctional" lipid-poor species that are inherently susceptible to catabolism. The HDL receptor SR-BI playsa key role in HDL metabolism by mediating the selective uptake of CE from the core of HDL particles into cells.We have shown that SR-BI processing of HDL from healthy subjects generates at least 3 distinct lipid-depletedHDL "remnants" that differ in composition and subsequent metabolism. We propose that as SR-BI depletes thecore of TG-enriched MetS HDL the propensity of such particles to remodel leads to enhanced released oflipid-poor apoA-I. The central hypothesis of this proposal is that TG enrichment of HDL in MetS predisposesthe particle to remodeling by intravascular factors and alters its processing by SR-BI leading to the generationof lipid-poor species that are susceptible to catabolism. Specific Objective 1: Test the hypothesis thatenhanced remodeling of HDL in hypertriglyceridemic MetS subjects leads to generation of lipid-poor apoA-I.The goal is to identify specific features of MetS HDL and/or MetS plasma that predict susceptibility toremodeling. We will also determine whether fibrate-induced TG lowering in MetS subjects leads to altered HDLremodeling. Specific Objective 2: Test the hypothesis that enhanced remodeling of TG-enriched HDL leads toalterations in subsequent HDL metabolism. Specific Objective 3: Test the hypothesis that TG enrichment altersSR-BI metabolism of HDL. Results from this project will provide new insights into mechanisms underlyingreduced HDL in MetS a prevalent condition in the Veteran population that significantly increases the risk ofdeveloping CVD. Findings from this project have the potential to define novel biological correlates ofaccelerated apoA-I catabolism in MetS and to identify MetS subjects most likely to benefit from TGlowering/HDL raising interventions.

project_terms:
Affinity;Apolipoprotein A-I;Biological;Blood;Blood Circulation;Cardiovascular Diseases;Catabolism;Cells;Cholesterol;Cholesterol Ester Transfer Proteins;Chronic;Clinical Management;Complex;Data;Disease;Epidemic;Failure (biologic function);Fibrates;Generations;Goals;Health;Heart Diseases;High Density Lipoprotein Cholesterol;High Density Lipoproteins;Human;Hypertriglyceridemia;Incidence;Individual;Inflammation;Intervention;Lipase;Lipids;Lipoproteins;Mediating;Metabolic syndrome;Metabolism;Outcome;Patients;Phospholipase;Phospholipase A2;Phospholipid Transfer Proteins;Plasma;Play;Population;Predisposition;Prevalence;Process;Production;Research;Risk;Risk Factors;Testing;Triglycerides;United States;Veterans;base;diabetes risk;hepatic lipase;high density lipoprotein receptor;inflammatory marker;insight;novel;particle;public health medicine (field);stroke;uptake

public_health_relevance:
The metabolic syndrome (MetS) is a complex disorder that increases the risk for diabetes heartdisease and stroke. The incidence of MetS has reached epidemic proportions in the United Statesincluding the Veteran population. A common feature of MetS is low HDL cholesterol (HDL-C) which isrecognized as a major risk factor for heart disease and stroke. Previous research indicates that HDL inindividuals with MetS is more rapidly cleared from the blood compared to people without MetS. Thisproposal seeks to understand why HDL in MetS subjects is more susceptible to clearance. Results fromthese studies may identify new strategies for the clinical management of individuals with MetS.


application_id: 8774196
project_number: 5I01BX001984-03
project_title: Association of a common variant of the PPAP2B gene with cardiovascular disease.
administering_ic: VA
award_notice_date: 2014-11-19
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001984
project_start_date: 2013-01-01
project_end_date: 2016-12-31
study_section: Cellular and Molecular Medicine[CAMM]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-01-01
project_abstract:
DESCRIPTION (provided by applicant):      Ischemic heart disease caused by atherosclerosis of the coronary arteries remains the most frequent cause of mortality among Veterans despite extensive investigation into its pathobiology the identification of many risk factors and development of new therapeutic strategies. The hallmark features of endothelial damage lipid deposition smooth muscle cell proliferation and vascular inflammation contribute to the development and complications of atherosclerosis. The bioactive lysophospholipids sphingosphine-1-phosphate (S1P) and lysophosphatidic acid (LPA) act on cell surface receptors expressed by many vascular cells. These lipids are positioned to serve as mediators of the cellular events contributing to atherosclerosis and their role is supported by emerging evidence from experimental models. The lipid phosphate phosphatase 3 (encoded by the PPAP2B gene) is a cell surface integral membrane protein that regulates the bioavailability of S1P and LPA by catalyzing their dephosphorylation to generate lipid products that are not receptor active. Analysis of data from a series of genome-wide association studies (GWAS) focuses attention on a striking association between a single nucleotide polymorphism (SNP) in the PPAP2B locus and coronary artery disease. This rs17114036 SNP lies in an intronic non-coding region of the gene that could affect gene expression. How genetic variation in PPAP2B confers risk of coronary artery disease is unknown in large part because of a lack of understanding of LPP3 function in vascular cells. In this application we present evidence that vascular cell LPP3 serves as an intrinsic negative regulator of vascular inflammation suppresses smooth muscle cell proliferation and promotes endothelial barrier function. These protective effects of LPP3 suggest that PPAP2B polymorphisms associated with reduced gene expression could aggravate cellular events underlying atherosclerosis and increase the likelihood of myocardial infarction.  The broad long-term goal of this research project is to explain how human genetic variation at the PPAP2B locus alters the risk of myocardial infarction and apply that knowledge to improve the diagnosis and therapy of ischemic heart disease. We have assembled a team of experts whose knowledge spans all aspects of the proposed research to position ourselves to validate the function of the PPAP2B locus in atherosclerosis. In this proposal we will test our central hypothesis which is that the minor allele of rs17114036 in PPAP2B reduces gene expression and that lower levels of LPP3 promote atherosclerosis. We will apply unique tools that we have developed to study LPP3 and our considerable expertise to test our central hypothesis. Firstly we will identify the mechanism by which in the rs17114036 SNP in PPAP2B affects LPP3 expression and activity. We predict that rs17114036 affects a U1 splisome binding site and thereby reduces gene expression.  We will test this working hypothesis by determining if the minor allele of rs17114036 associates with altered  LPP3 transcript and protein levels in white blood cells and arterial tissue and by examining the consequences of the polymorphism on RNA splicing and stability. Secondly we will establish a mechanistic role for LPP3 in experimental atherosclerosis. Based on our Preliminary Studies of vascular pathology in mice with tissue-specific defects in smooth muscle and endothelial LPP3 the working hypothesis of this section is that LPP3 protects against vascular inflammation and that reduced expression will therefore accelerate atherosclerosis.  We will test this working hypothesis by determining the consequences of vascular tissue specific deficiency of LPP3 on the development of atherosclerosis in mice.  The experiments proposed in this application are an important step in functionally validating a common genetic variant in PPAP2B as a cardiovascular risk predictor in humans. Establishing PPAP2B its product LPP3 and the lipid substrates of this enzyme as risk predictors and mediators of CAD promises to identify important and innovative targets for the development of new biomarkers and/or therapeutics.

project_terms:
Accounting;Address;Admission activity;Affect;Alleles;Atherosclerosis;Attention;Binding Sites;Biological Availability;Biological Markers;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cell Proliferation;Cell Surface Receptors;Cell surface;Cells;Cholesterol;Clinical;Congestive Heart Failure;Coronary Arteriosclerosis;Coronary artery;Data Analyses;Defect;Deposition;Development;Diabetes Mellitus;Diagnosis;Disease;Disease susceptibility;Employee Strikes;Enzymes;Event;Experimental Models;Family;Frequencies (time pattern);Gene Expression;Genes;Genetic Polymorphism;Genetic screening method;Genotype;Goals;Health;Healthcare;Hospitals;Human;Human Genetics;Hypertension;Individual;Integral Membrane Protein;Investigation;Knowledge;LDL Cholesterol Lipoproteins;Lead;Leukocytes;Lipids;Lysophospholipids;Mediator of activation protein;Membrane;Messenger RNA;Minor;Mortality Vital Statistics;Mus;Muscle Smooth Vascular;Mutation;Myocardial Infarction;Myocardial Ischemia;Nuclear;Pathology;Plasma;Positioning Attribute;Predisposition;Prevention;Process;Protein Dephosphorylation;Proteins;RNA Splicing;RNA Stability;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Ribonucleoproteins;Risk;Risk Factors;Role;Sampling;Series;Single Nucleotide Polymorphism;Smooth Muscle Myocytes;Smooth muscle (tissue);Specific qualifier value;Testing;Therapeutic;Tissues;Transcript;Translating;United States;Untranslated RNA;Validation;Variant;Variation (Genetics);Vascular Endothelial Cell;Veterans;Work;base;cardiovascular disorder risk;cardiovascular risk factor;disorder risk;enzyme activity;enzyme substrate;genetic variant;genome wide association study;improved;innovation;inorganic phosphate;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;novel strategies;novel therapeutics;protective effect;receptor;research study;tool;vascular inflammation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       Cardiovascular diseases are one of the most prevalent health problems among Veterans resulting in over 25000 admissions to VA hospitals annually. Family history is well established to provide a strong clinical indicator of cardiovascular disease risk but until very recently in al but a few cases the genes involved were not known. A new approach called "genome wide association" has been used to identify common genetic variants that predict cardiovascular disease risk without obvious association with established cardiovascular disease risk factors such as elevated plasma cholesterol levels and increased blood pressure. The goal of this project is to determine why a common variant in a gene called PPAP2B is associated with significantly elevated cardiovascular disease risk. Completion of the work could lead to validation of this variant as a genetic test for cardiovascular disease susceptibility and the development of new therapies for treatment and prevention of cardiovascular to enable improved and more efficient healthcare for Veterans.


application_id: 8762444
project_number: 5I01BX001838-03
project_title: Mechanism of Neutrophil Activation
administering_ic: VA
award_notice_date: 2014-11-05
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001838
project_start_date: 2012-10-01
project_end_date: 2016-09-30
study_section: Immunology and Dermatology A[IMMA]
contact_pi_person_id: 1886516
contact_pi: MCLEISH, KENNETH R
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Neutrophils are a critical component of both the innate and adaptive immune responses that control microbial invasion. Priming is an intermediate step by which resting neutrophils enhance their production of reactive oxygen intermediates (ROI) upon activation and priming is necessary for optimal microbial killing. Although priming greatly enhances neutrophil bactericidal capability primed neutrophils are also more dangerous to normal cells. Primed neutrophils participate in a number of diseases prominent in the aging Veteran population including ANCA-associated vasculitis ischemia- reperfusion injury acute respiratory distress syndrome rheumatoid arthritis peridontitis atherosclerosis and acute inflammatory liver injury. Thus manipulation of neutrophil priming is a potential therapeutic strategy for pharmacological intervention to restrain inflammation. Recent studies identified granule exocytosis and enhanced translocation of cytosolic components of the NADPH oxidase to the plasma membrane as possible mechanisms of neutrophil priming. However many gaps in knowledge remain. The relative contribution of each of those events to priming has not been examined and whether both are necessary or sufficient for priming is unknown. The molecular events by which granule exocytosis contributes to priming and the molecular events that control enhanced translocation of cytosolic NADPH oxidase components are incompletely understood. Finally the ability to manipulate neutrophil priming in vivo has not been established. The McLeish laboratory is in a unique position to address each of these gaps based on our extensive experience examining signal transduction pathways our application of biochemical genetic and proteomic approaches to understand neutrophil biology and our recent development of novel reagents that inhibit exocytosis in vitro and in vivo. The current proposal will address the central hypothesis that neutrophil priming results from the convergence of signal transduction pathways into two responses an exocytose-dependent increase in plasma membrane expression of membrane components of NADPH oxidase and prolyl isomerase-dependent conformational changes in cytosolic components of NADPH oxidase. The following four specific objectives will be accomplished.  Specific Objective 1 will test the working hypothesis that exocytosis of secretory vesicles and gelatinase granules results in increased plasma membrane expression of p91phox and p22phox which is necessary but not sufficient for priming. Specific Objective 2 will test the working hypothesis that activation of the prolyl isomerase Pin1 contributes to priming of human neutrophils by multiple mechanisms including enhanced p47phox translocation and increased granule exocytosis. Specific Objective 3 will test the working hypothesis that p38 MAPK phosphorylates multiple proteins that mediate events necessary for priming including exocytosis and Pin1 activation. Specific Objective 4 will test theworking hypothesis that neutrophil priming is a necessary component for neutrophil participation in inflammatory diseases and represents a viable therapeutic strategy using an animal model of acute lung injury (ALI). The proposed work is expected to establish the molecular basis for neutrophil priming. The impact of the project is that molecular targets identified will permit therapeutic manipulation of neutrophil priming in inflammatory diseases. Thus new approaches to treating Veteran patients with a number of acute and chronic inflammatory diseases are anticipated.

project_terms:
Acute;Address;Adult Respiratory Distress Syndrome;Affect;Aging;Animal Model;Antineutrophil Cytoplasmic Antibodies;Arteriosclerotic Cardiovascular Disease;Atherosclerosis;Bacteria;Biochemical Genetics;Biology;Cell membrane;Chemicals;Chronic;Cytoplasmic Granules;Data;Development;Disease;Event;Exocytosis;Exposure to;Gelatinases;Goals;Health;Human;In Vitro;Infection;Infection Control;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Arthritis;Injury;Intervention;Invaded;Killings;Knowledge;Laboratories;Lead;Leukocytes;Lung Injury Acute;MAP Kinase Gene;MAPK14 gene;Mediating;Membrane;Molecular;Molecular Target;NADPH Oxidase;Neutrophil Activation;Normal Cell;Oxidases;Patients;Peptidylprolyl Isomerase;Phosphorylation;Play;Poisons;Population;Positioning Attribute;Process;Production;Proteins;Proteomics;Reagent;Relative (related person);Reperfusion Injury;Reporting;Rest;Rheumatoid Arthritis;Role;Secretory Vesicles;Signal Transduction Pathway;Testing;Therapeutic;Tissues;Toxin;Vasculitis;Veterans;Work;acute liver injury;adaptive immunity;bactericide;base;experience;extracellular;human CYBA protein;human disease;in vivo;liver injury;lung vascular injury;microbial;neutrophil;novel;novel strategies;reactive oxygen intermediate;response;sound;therapeutic target;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE:       White blood cells (WBCs) protect against infection by producing toxic chemicals that kill invading bacteria. The production of those toxin chemicals is enhanced by prior exposure to a variety of mediators of inflammation by a process termed priming. Although WBC priming plays a critical role in the control of infection priming is a two-edged sword that also reduces the ability of WBCs to co-exist with normal cells. Primed WBCs produce tissue injury in a number of diseases that affect our Veteran patients. The events that lead to priming are not known and inhibition of priming has not been used to treat those diseases. The current proposal will define the mechanisms by which WBCs become primed and will establish priming is a therapeutic target in inflammatory diseases. Accomplishing those goals will provide new treatments for Veteran patients with a number of acute and chronic inflammatory diseases.


application_id: 8762233
project_number: 5I01BX001721-02
project_title: Thiamine deficiency and alcohol-induced neurodegeneration
administering_ic: VA
award_notice_date: 2014-11-10
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001721
project_start_date: 2013-10-01
project_end_date: 2017-09-30
study_section: Neurobiology A[NURA]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-10-01
project_abstract:
DESCRIPTION (provided by applicant):    
   
Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health social and economic impact. Chronic alcohol abuse induces dementia which is associated with morphological neurophysiological and biochemical changes in the central nervous system (CNS). The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. The underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). Thiamine deficiency (TD) can damage the CNS. TD in humans may results from chronic alcohol exposure genetic background aging or nutritional status. The relationship between thiamine status and neuron susceptibility to alcohol- induced neurodegeneration however remains unclear. Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles. It provides the cells with an alternative source of intracellular building blocks and energy thereby enhancing cell survival during nutrient deficiency or stress conditions. We hypothesize that TD may inhibit the autophagic pathways and impair this cellular self-protection mechanism. As a result neurons are more susceptible to alcohol- induced neurodegeneration after chronic TD. Three specific aims are proposed to test this hypothesis. We will first investigate whether the status of thiamine content determines neuron susceptibility to alcohol-induced neurodegeneration. We will next characterize the effect TD/alcohol on autophagy in the brain. Finally we will determine the role of autophagy in alcohol/TD interaction and alcohol-induced neurodegeneration. As a unit the proposal will elucidate the relationship between TD and neuron susceptibility to alcohol neurotoxicity and provide a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.

project_terms:
Accounting;Adult;Affect;Aging;Alcohol abuse;Alcohol consumption;Alcohol dependence;Alcoholic beverage heavy drinker;Alcohols;Animals;Autophagocytosis;Biochemical;Brain;Brain Injuries;Brain region;C57BL/6 Mouse;Cell Survival;Cell physiology;Cells;Cerebellum;Chronic;Data;Dementia;Disease;Enzymes;Etiology;Experimental Models;Genetic;Health;Human;Medial;Metabolic;Nerve Degeneration;Neuraxis;Neurons;Neuropathy;Nutrient;Nutritional status;Organelles;Pathway interactions;Play;Predisposition;Role;Social Impacts;Source;Stress;Testing;Thalamic structure;Thiamine;Thiamine Deficiency;Veterans;Wernicke-Korsakoff Syndrome;alcohol exposure;alcohol response;chronic alcohol ingestion;cofactor;cognitive function;combat;economic impact;frontal lobe;glucose metabolism;insight;macromolecule;neurophysiology;neurotoxicity;novel;problem drinker;public health relevance;response

public_health_relevance:
An estimated 7.5 percent of veterans are heavy drinkers and alcohol abuse is on the rise among combat veterans. Chronic alcohol abuse causes dementia and the most devastating feature of brain damage following chronic alcohol exposure is neurodegeneration. However the underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). This proposal will determine how thiamine deficiency (TD) and alcohol exposure interact and cause neurodegeneration in the central nervous system providing a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.


application_id: 8735744
project_number: 1I01CX000975-01A1
project_title: The association of SAA with apoB lipoproteins affects cardiovascular risk
administering_ic: VA
award_notice_date: 2014-03-13
opportunity_number: CX-13-001
application_type: 1
activity_code: I01
ic: CX
serial_number: 000975
suffix: A1
project_start_date: 2014-04-01
project_end_date: 2018-03-31
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 3123430
contact_pi: TANNOCK, LISA R
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):     
   
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations and is a major health issue in Veterans. Despite numerous pharmacological agents targeting CVD risk factors the identification of individuals at high risk remains incomplete. Further there is still a need to identify new targets for therapy. SAA is an acute phase reactant that is significantly and persistently elevated in chronic inflammatory conditions such as diabetes metabolic syndrome (MetS) or rheumatoid arthritis which are all associated with increased rates of CVD. SAA has been found to be predictive of CVD events. Furthermore we and others have recently shown in murine models that increased SAA is directly pro-atherogenic. As described in the Response to Retention hypothesis of atherosclerosis the sub-endothelial retention of atherogenic lipoproteins by vascular wall proteoglycans initiates atherosclerosis. Although in the healthy state SAA is exclusively associated with HDL we and others have previously reported SAA in association with apoB-containing lipoproteins in murine models of diabetes and/or obesity and we recently confirmed this observation in human studies. In preliminary studies we demonstrate increased association of SAA with apoB- containing lipoproteins in insulin resistant states which may be due to the delayed lipoprotein clearance seen with insulin resistance. In new preliminary studies we demonstrate that SAA can shift from HDL to apoB-containing lipoproteins. SAA itself has proteoglycan binding properties and our preliminary data demonstrates that the presence of SAA on apoB-lipoproteins enhances their retention. The central hypothesis of this grant is that the shift of SAA from HDL to apoB-containing lipoproteins is pro-atherogenic. We propose that the presence of SAA on apoB- containing lipoproteins in insulin resistant conditions such as MetS and diabetes contributes to the increased atherosclerosis and CVD observed in these populations. Using in vitro in vivo and clinical studies the results of this proposal will identify that SAA augments the atherogenicity of apoB lipoproteins and thus may identify SAA as a target for therapeutic intervention.

project_terms:
Acute-Phase Proteins;Affect;Affinity;Apolipoproteins B;Atherosclerosis;Binding (Molecular Function);Biological Markers;Blood Vessels;Cardiovascular Diseases;Cause of Death;Chronic;Clinical Research;Data;Developed Countries;Development;Diabetes Mellitus;Dyslipidemias;Event;Fatty acid glycerol esters;Grant;Health;High Density Lipoproteins;Human;In Vitro;Individual;Inflammatory;Insulin Resistance;Lipase;Lipids;Lipoproteins;Literature;Low-Density Lipoproteins;Metabolic syndrome;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Obesity;Outcome;Population;Property;Proteins;Proteoglycan;Publishing;Relative (related person);Reporting;Rheumatoid Arthritis;Risk;Risk Factors;Role;Sampling;Serum amyloid A protein;Testing;Therapeutic Intervention;Time;Vascular remodeling;Very low density lipoprotein;Veterans;base;cardiovascular disorder risk;cardiovascular risk factor;drinking;high risk;in vivo;inflammatory marker;insulin sensitivity;intravenous glucose tolerance test;novel;particle;public health relevance;response;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE:     
   
Cardiovascular disease is the leading cause of death in developed nations and is a major health issue in Veterans. The inflammatory marker Serum Amyloid A (SAA) has been found to predict cardiovascular disease. This proposal is testing the concept that beyond predicting cardiovascular disease SAA may cause cardiovascular disease. The results of this proposal may identify SAA as a new target of risk reducing therapy.


application_id: 8734795
project_number: 2I01BX000216-05A1
project_title: Nicotine and nicotinic receptors in lung transitional remodeling
administering_ic: VA
award_notice_date: 2014-11-07
opportunity_number: BX-13-001
application_type: 2
activity_code: I01
ic: BX
serial_number: 000216
suffix: A1
project_start_date: 2009-04-01
project_end_date: 2018-09-30
study_section: Respiration[PULM]
contact_pi_person_id: 1876531
contact_pi: ROMAN, JESSE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):    
   
Tobacco and alcohol are the two most used and abused drugs in the world. Together they are responsible for millions of deaths each year worldwide. Despite the enormous amount of research carried out to understand how these agents affect the lung new information leading to significant advances at the clinic has been disappointing. Because of the high prevalence of tobacco and alcohol exposure in veterans the Roman lab is exploring the mechanisms by which these agents affect the lung. Our research revealed that both alcohol and nicotine an alkaloid present in tobacco promote alterations in lung matrix composition that we have termed 'transitional' remodeling a process characterized by subtle alterations in the relatively composition of the lung extracellular matrix. Although the exact mechanisms linking these events to lung disease remain incompletely understood we believe that transitional remodeling renders the host susceptible to lung disease and this belief is supported by published research performed both in vitro and in vivo. Considering the above we set out to identify the cellular/molecular mechanisms responsible for these events. Using cultured primary lung fibroblasts we found that nicotine induces cellular proliferation and matrix expression through the activation of specific 7 nicotinic acetylcholine receptors (7 nAChRs). The importance of these receptors was confirmed in vivo showing that prenatal exposure to nicotine affects lung development and induces airway thickening and hyperreactivity in wildtype animals but not in 7 nAChR knockout mice. Using the same culture model we discovered that alcohol acts on lung fibroblasts via another set of nAChRs 4 nAChRs. In rodent lungs the expression of these receptors is increased by chronic alcohol exposure which in turn predisposes to acute lung injury. This work suggests that the cholinergic system plays an important role in lung homeostasis and response to injury and points to nAChRs as potential targets for intervention. More recently we found that nAChRs are activated through both ligand-dependent and -independent pathways. Specifically while nicotine acts on 7 nAChRs in a traditional ligand-dependent fashion alcohol works at least in part through induction of a particular form of oxidant stress (oxidation of the cysteine/cystine redox potential or Eh Cys/CySS) which together with cysteine residues strategically located on the subunits of certain nAChR pentamers activates nAChR signaling via ligand-independent mechanisms of action. Importantly we have generated preliminary data to suggest that susceptibility to injury in aging might activate nAChRs through similar pathways thereby promoting transitional remodeling and increased susceptibility to lung injury. Considering the above we propose that aging (as observed for nicotine and ethanol exposure) is associated with lung transitional remodeling via distinct nAChRs. nAChRs can be activated via ligand-dependent and -independent pathways the latter triggered by oxidant stress induced by oxidation of the Eh Cys/CySS. Specifically oxidant stress affects cysteines strategically located in the  subunits of nAChRs which in turn triggers signal transduction and promotes lung transitional remodeling and increase susceptibility to disrepair after lung injury. To test this hypothesis we propose experiments designed to: Aim 1. Investigate the role of specific subunit cysteines in nAChR activation in lung cells and in vivo. Aim 2. Determine the role of oxidant stress especially oxidation of the Eh Cys/CySS in nAChR activation both in vitro and in vivo. Aim 3. Examine the role of nAChR activation in lung disease related to aging and how this is affected by tobacco and alcohol exposure.

project_terms:
Adult;Affect;Aging;Alcohol abuse;Alcohols;Alkaloids;Animal Model;Animals;Architecture;Belief;Cell Proliferation;Cells;Cessation of life;Chronic;Chronic Obstructive Airway Disease;Clinic;Cultured Cells;Cysteine;Cystine;Cytoskeleton;Data;Development;Disease;Endotoxemia;Ethanol;Event;Exposure to;Extracellular Matrix;Fibroblasts;Fibronectins;Funding;Glycoproteins;High Prevalence;Homeostasis;In Vitro;Incidence;Individual;Infection;Injury;Intervention;Knockout Mice;Ligands;Link;Lung;Lung Injury Acute;Lung diseases;Malignant neoplasm of lung;Modeling;Molecular;Morphogenesis;Nicotine;Nicotinic Receptors;Obstructive Lung Diseases;Organ;Oxidation-Reduction;Pathway interactions;Play;Predisposition;Process;Publishing;Receptor Cell;Reporting;Research;Risk;Rodent;Role;Secure;Signal Transduction;System;Testing;Tissues;Tobacco;United States National Institutes of Health;Veterans;Work;airway hyperresponsiveness;alcohol effect;alcohol exposure;cholinergic;design;drug of abuse;in vivo;lung development;lung injury;oxidant stress;oxidation;prenatal exposure;public health relevance;receptor;receptor expression;research study;response;response to injury;tobacco abuse;tobacco exposure

public_health_relevance:
PUBLIC HEALTH RELEVANCE:    
   
Aging and tobacco and alcohol abuse are important problems worldwide and many disorders observed in veterans are associated with these states. This work will study how aging affects lung cells in an attempt to identify potential targets for intervention and determine how tobacco and alcohol exposure influence these events. Specifically the research will focus on a special kind of cell receptors termed nicotinic acetylcholine receptors (nAChRs). Studies will be performed in cultured cells as well as in animal models to study the role of these receptors in aging and in tobacco- and alcohol-related lung disease.


application_id: 8733269
project_number: 1I01BX002141-01A1
project_title: iPLA2 as a Target in Vascular Inflammation Neointima Formation and Restenosis
administering_ic: VA
award_notice_date: 2014-11-07
opportunity_number: BX-13-001
application_type: 1
activity_code: I01
ic: BX
serial_number: 002141
suffix: A1
project_start_date: 2014-10-01
project_end_date: 2018-09-30
study_section: Cardiovascular Studies A[CARA]
contact_pi_person_id: 8664760
contact_pi: GUO, ZHENHENG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):     
   
Coronary heart disease is the single leading cause of death among men and women in the United States. Coronary revascularization including coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) is the most common modality in patients with coronary diseases. However it is also among the most costly and is often associated with a high incidence of restenosis. Although the rate of restenosis is significantly reduced with the use
of bare-metal stent (BMS) and particularly with drug-eluting stent (DES) a persistently high rate of restenosis after BMS and an increased risk of in-stent thrombosis with DES have been encountered as significant limitations to the long-term efficacy of coronary revascularization. With a long-term goal of identifying novel therapeutic targets for coronary heart disease the current application specifically investigates a potentially critical role of calcium independent phospholipase A2b (iPLA2b) in vascular inflammation re-endothelialization and neointima formation in a mouse femoral artery wire injury model. iPLA2b is a member of the phospholipase A2 superfamily that acts on phospholipids to produce a free fatty acid and a lysophospholipid. iPLA2b is expressed in vascular smooth muscle cells (VSMC) and is implicated in many human diseases. Whereas little is known about the role of other PLA2 in vascular injury-induced neointima formation substantial evidence including pharmacological inhibition antisense oligonucleotide down- rgulation genetic deletion and smooth muscle-specific overexpression consistently demonstrated that iPLA2b plays a critical role in vascular inflammation and neointima formation in a mouse carotid artery ligation model. To investigate whether targeting smooth muscle-specific iPLA2b is sufficient to reduce vascular inflammation and neointima formation a femoral artery injury model that better mimics PCI was established a novel tamoxifen-inducible smooth muscle-specific iPLA2b knockout mouse model (SM-iPLA2b-iKO) was developed and the current proposal hypothesizes that activation of iPLA2b in VSMC by vascular injury plays a key role in wire injury-induced vascular inflammation re-endothelialization and neointima formation thereby significantly contributing to the development of restenosis after coronary revascularization. Three Specific Aims are:  1) To test the hypothesis that smooth muscle-specific iPLA2b plays a critical role in the initiation of vascular inflammation re-endothelialization and neointima formation; 2) To determine the molecular mechanism that underlies wire injury-induced iPLA2b activation vascular inflammation and neointima formation; 3) To investigate whether post-wire injury molecular and genetic targeting iPLA2b has an effect on the progression of re-endothelialization vascular inflammation and neointima formation. To achieve this goal a well established and most physiological relevant femoral artery wire injury model will be used in combination with several novel and established genetic animal models (SM- iPLA2b-iKO SM-HIF-1a-iKO and SM-iPLA2b-Tg/12/15-LO) to selectively inhibit or activate iPLA2b HIF-1a and 12/15-LO before and after wire injury. Injured and non-injured femoral arteries will be isolated and then subjected to molecular immunohistological and biochemical studies to determine the role of iPLA2b in vascular inflammation and neointima formation. Results from the proposed studies may modify the current paradigm that the initiation and early progression of vascular inflammation are largely attributed to coordinated interactions among monocytes/macrophages leukocytes and endothelial cells by providing the first direct experimental evidence that VSMC also play a critical role in these early key events. Importantly results from the proposed studies will elucidate specific mechanisms that could lead to the identification of iPLA2b as a novel potential therapeutic target for the prevention and treatment of vascular inflammation re- endothelialization neointima formation and restenosis.

project_terms:
Adopted;Animal Model;Antisense Oligonucleotides;Arachidonate 15-Lipoxygenase;Biochemical;Blood;Blood Vessels;Calcium;Carotid Arteries;Cause of Death;Cessation of life;Chest Pain;Congestive Heart Failure;Coronary;Coronary Artery Bypass;Coronary artery;Coronary heart disease;Development;Drug Targeting;Endothelial Cells;Enzymes;Event;Gel;Genetic;Goals;Healthcare Systems;Heart;Hospitalization;Hypoxia;Incidence;Injury;Knockout Mice;Lead;Leukocytes;Ligation;Lipids;Lysophospholipids;Mediating;Metals;Modality;Modeling;Molecular;Molecular Genetics;Mus;Myocardial Infarction;Myocardial Ischemia;Nonesterified Fatty Acids;Oxygen;Patients;Pharmaceutical Preparations;Phospholipase;Phospholipase A2;Phospholipids;Physiological;Play;Pluronics;Prevention;Risk;Role;Scheme;Smooth Muscle Myocytes;Smooth muscle (tissue);Stents;Tamoxifen;Testing;Therapeutic Effect;United States;Woman;femoral artery;genetic approach;human disease;injured;macrophage;member;men;monocyte;mouse model;neointima formation;new therapeutic target;novel;overexpression;percutaneous coronary intervention;prevent;public health relevance;restenosis;stent thrombosis;therapeutic target;vascular inflammation;vascular smooth muscle cell proliferation

public_health_relevance:
PUBLIC HEALTH RELEVANCE:     
   
Coronary heart disease also called ischemic heart disease is the result of narrowed or clogged coronary arteries that cannot carry sufficient amounts of blood and oxygen to the heart which can result in angina (chest pain) heart attack and death. Coronary heart disease is a common cause of congestive heart failure remains the leading cause of death among men and women in the United States and is also one of the most frequent indications for hospitalization within the VA healthcare system. Coronary revascularization has been adopted worldwide and is the most common modality in patients with coronary diseases in the United States including VA healthcare system. However it is most costly and is associated with a high incidence of restenosis (repeat narrowing of a coronary artery). The proposed studies specifically investigate the role of iPLA2b (an enzyme that produce bioactive lipids) in restenosis. If aims of the application are achieved it will provide evidence that could be used to develop new drugs that target iPLA2b to effectively prevent and reduce restenosis.


application_id: 8698258
project_number: 5I01BX001204-04
project_title: Renoprotective effect of increased PKG activity in diabetic nephropathy
administering_ic: VA
award_notice_date: 2014-01-29
opportunity_number: BX-10-006
application_type: 5
activity_code: I01
ic: BX
serial_number: 001204
project_start_date: 2011-07-01
project_end_date: 2015-06-30
study_section: Nephrology[NEPH]
contact_pi_person_id: 7837422
contact_pi: WANG, SHUXIA
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-07-01
project_abstract:
DESCRIPTION (provided by applicant):     Diabetic nephropathy is the single most common cause of end-stage renal failure and is highly prevalent in both type 1 and type 2 diabetics. Hyperglycemia has been suggested to play a critical role in the pathogenesis of diabetic nephropathy. Transforming growth factor-2 (TGF-2) is a major effector leading to renal fibrosis in response to hyperglycemia. TGF-2 is expressed as a biologically inactive form and must be converted to its active form to elicit fibrogenic effects. Thrombospondin1 (TSP1) has been identified as the molecular regulator of TGF-2 activation under diabetic conditions. TSP1-mediated TGF-2 activation is involved in the development of experimental diabetic nephropathy and also plays a role in human diabetic nephropathy. Preliminary data demonstrate a novel inhibitory effect of cGMP-dependent protein kinase (PKG) on glucose-induced TSP1 expression and TSP1-mediated TGF-2 activation in mesangial cells suggesting a therapeutic potential of PKG in diabetic nephropathy. The proposed studies will test whether genetically or pharmacologically increased PKG activity prevents the development of diabetic nephropathy through inhibition of TSP1-mediated TGF-2 activation in different diabetic mouse models. Specific Aim 1 will determine the mechanisms by which high glucose down-regulates PKG activity in kidney cells in vitro and its role in glucose-induced TSP1 expression TGF-2 levels/activity and extracellular matrix (ECM) production. Specific Aim 2 will determine whether increased PKG activity prevents the development of diabetic nephropathy in vivo. These studies will establish the significance of PKG in the development of diabetic nephropathy. Importantly utilization of sildenafil (an inhibitor of cGMP specific phosphodiesterase 5) to increase PKG activity in the proposed studies is translational and relevant to human therapy. Sildenafil is a drug used to treat erectile dysfunction (ED another diabetic complication in male patients) and pulmonary arterial hypertension (PAH) in clinic. The current proposed studies will test a novel potential application of sildenafil in the treatment of diabetic nephropathy in different diabetic mouse models. Therefore these studies have significant clinical relevance and will lead to the development of novel therapies to attenuate/treat diabetic nephropathy a major complication of diabetes.

project_terms:
Affect;Albuminuria;Attenuated;Clinic;Complication;Complications of Diabetes Mellitus;Cyclic GMP;Cyclic GMP-Dependent Protein Kinases;Data;Deposition;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Dialysis procedure;Down-Regulation;Drug usage;End stage renal failure;Erectile dysfunction;Extracellular Matrix;Fibrosis;Gene Expression;Genetic;Glucose;Growth Factor;Health Expenditures;Healthcare;Healthcare Systems;High Prevalence;Human;Hyperglycemia;In Vitro;Injury;Kidney;Kidney Diseases;Kidney Transplantation;Lead;Link;Mediating;Mediator of activation protein;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Pathogenesis;Patients;Play;Population;Production;Protein Kinase;Proteins;Quality of life;Role;Signal Transduction;Testing;Therapeutic;Transforming Growth Factor beta;Transforming Growth Factors;Transgenic Mice;Translating;Up-Regulation (Physiology);Veterans;Work;clinically relevant;diabetic;glomerular basement membrane;glomerulosclerosis;improved;in vivo;inhibitor/antagonist;kidney cell;male;mesangial cell;mouse model;novel;novel therapeutic intervention;novel therapeutics;phosphodiesterase V;prevent;pulmonary arterial hypertension;response;sildenafil;success

public_health_relevance:
More than 20% of veterans or one million veterans who use VA health care system are affected by diabetes. Veterans also have very high prevalence of diabetic complications including nephropathy. Nephropathy is a major complication of diabetes which leads to considerable morbidity and mortality. Despite current improved treatments significant numbers of patients with albuminuria progress to end stage renal disease which requires dialysis or kidney transplantation. This proposal aims at defining the novel roles for PKG a cGMP- dependent protein kinase in the development of diabetic nephropathy and testing the novel therapeutic potential of genetically or pharmacologically increased PKG activity in attenuating diabetic nephropathy in different mouse models of diabetes. The success of this proposal will benefit the veterans' health care: improving the quality of life of veterans and reducing the health care expenditures in the VA health care system.


application_id: 8696800
project_number: 5I01BX000962-04
project_title: Exosomal TRAF2-CSN5 complex mediated inflammation promotes tumor growth
administering_ic: VA
award_notice_date: 2014-01-28
opportunity_number: BX-10-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 000962
project_start_date: 2011-04-01
project_end_date: 2015-03-31
study_section: Immunology and Dermatology A[IMMA]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-04-01
project_abstract:
DESCRIPTION (provided by applicant):     The overall goal of this proposal is to elucidate the mechanisms by which lung tumor exosomes promote an inflammatory response namely the activation of macrophages and promote the progression and growth of lung tumors. Our preliminary data indicate that pretreatment of A/J mice with exosomes produced by TC-1 lung tumor cells or exosomes isolated from the lung tissue of A/J mice that have been pretreated with the carcinogen urethane results in more rapid tumor growth and earlier progression of lung carcinomas. Urethane treatment results in the recruitment of the activated form of TRAF2 to the exosomes and the exosomes with activated TRAF2 are taken up by the bone marrow-derived precursors of macrophages leading to their maturation and subsequent migration to the lung. The recruitment of the activated TRAF2 to the exosomes requires degradation of the inflammation suppressor protein CYLD in the tumor cells; moreover TRAF2 can mediate ubiquination of CYLD thereby promoting its degradation. The results of siRNA TRAF2 knockout indicated however that TRAF2 is required but is not sufficient for ubiquitination of CYLD. We have now identified two exosomal proteins that interact with TRAF2 Itch and CSN5 which have the potential to enhance the ubiquitination of CYLD in lung tumor cells. Our recent data indicating that CYLD is not packed in exosomes isolated from the peripheral blood of lung cancer patients although it is present in exosomes from healthy volunteers indicate the potential clinical relevance of this model that directly links the effects of a carcinogen with an inflammatory response and promotion of tumor development. We propose to: (1) Confirm the role of lung tumor exosomal TRAF2 in the promotion of urethane-induced lung carcinomas by determining whether knockout of TRAF2 in TC-1 lung tumor cells is sufficient for (i) inhibition of macrophage differentiation and (ii) prevention of lung tumor exosome-mediated enhancement of urethane induced lung cancer. (2) Determine if other exosomal proteins that interact with CYLD participate in the ubiquitination of CYLD in TC-1 tumor cells and determine if the elimination of these proteins stabilizes exosomal CYLD and suppresses exosomal TRAF2 activation resulting in the inhibition of macrophage activation and prevention of tumor growth. (3) Determine if macrophages pulsed with lung tumor exosomes isolated from lung cancer patients promote lung tumor growth in a NOD-SCID mouse model. The data generated should permit the development of a highly innovative model of the cellular and molecular basis for exosome-mediated chronic inflammation and promotion of tumor growth and indicate novel preventive and therapeutic strategies.

project_terms:
A/J Mouse;Acceleration;Anti-Inflammatory Agents;Bone Marrow;Bone Marrow Cells;Cancer Patient;Carcinogens;Cell model;Cells;Chronic;Complex;Curcumin;Data;Development;Epithelial;Epithelial Cells;Goals;Growth;Human;IL8 gene;ITGAM gene;Inflammation;Inflammatory Response;Interleukin-6;Knock-out;Lead;Link;Lung;Lung Neoplasms;Macrophage Activation;Malignant neoplasm of lung;Mediating;Membrane;Modeling;Molecular;Mus;Myelogenous;Myeloid Cells;NOD/SCID mouse;Physiologic pulse;Play;Prevention;Preventive;Production;Property;Proteins;Research;Role;SCID Mice;Small Interfering RNA;Structure of parenchyma of lung;TRAF2 gene;Testing;Therapeutic;Tissues;Tumor Necrosis Factor-alpha;Tumor Promotion;Tumor Tissue;Tumor-Derived;Ubiquitination;Urethane;Vascular Endothelial Growth Factors;Vesicle;base;cancer cell;cell growth;clinically relevant;healthy volunteer;human TNF protein;in vivo;innovation;lung Carcinoma;macrophage;migration;mouse model;neoplastic cell;novel;peripheral blood;precursor cell;tumor;tumor growth;ubiquilin

public_health_relevance:
The proposed research is highly relevant to characterizing the association of lung tumor exosomes mediated inflammatory responses and lung tumor growth in that it is focused on characterizing the molecular mechanisms underlying the ability of tumor exosomes to both activate macrophages and promote tumor growth. The central hypothesis is that exosomes produced by lung tumor cells or lung tumor tissue are taken up by bone marrow myeloid precursor cells. These cells further differentiate into macrophages and migrate into the lung promote the progression of urethane- induced lung cancer.


application_id: 8629526
project_number: 5I01BX001984-02
project_title: Association of a common variant of the PPAP2B gene with cardiovascular disease.
administering_ic: VA
award_notice_date: 2013-11-20
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001984
project_start_date: 2013-01-01
project_end_date: 2016-12-31
study_section: Cellular and Molecular Medicine[CAMM]
contact_pi_person_id: 1879477
contact_pi: MORRIS, ANDREW J
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 018766373
primary_uei: QGWRFBMD3XT5
duns_number: 018766373
uei: QGWRFBMD3XT5
fips: US
organization_id: 481036
organization_name: VA MEDICAL CENTER - LEXINGTON, KY
organization_city: LEXINGTON
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 405022235
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2014-01-01
project_abstract:
DESCRIPTION (provided by applicant):      Ischemic heart disease caused by atherosclerosis of the coronary arteries remains the most frequent cause of mortality among Veterans despite extensive investigation into its pathobiology the identification of many risk factors and development of new therapeutic strategies. The hallmark features of endothelial damage lipid deposition smooth muscle cell proliferation and vascular inflammation contribute to the development and complications of atherosclerosis. The bioactive lysophospholipids sphingosphine-1-phosphate (S1P) and lysophosphatidic acid (LPA) act on cell surface receptors expressed by many vascular cells. These lipids are positioned to serve as mediators of the cellular events contributing to atherosclerosis and their role is supported by emerging evidence from experimental models. The lipid phosphate phosphatase 3 (encoded by the PPAP2B gene) is a cell surface integral membrane protein that regulates the bioavailability of S1P and LPA by catalyzing their dephosphorylation to generate lipid products that are not receptor active. Analysis of data from a series of genome-wide association studies (GWAS) focuses attention on a striking association between a single nucleotide polymorphism (SNP) in the PPAP2B locus and coronary artery disease. This rs17114036 SNP lies in an intronic non-coding region of the gene that could affect gene expression. How genetic variation in PPAP2B confers risk of coronary artery disease is unknown in large part because of a lack of understanding of LPP3 function in vascular cells. In this application we present evidence that vascular cell LPP3 serves as an intrinsic negative regulator of vascular inflammation suppresses smooth muscle cell proliferation and promotes endothelial barrier function. These protective effects of LPP3 suggest that PPAP2B polymorphisms associated with reduced gene expression could aggravate cellular events underlying atherosclerosis and increase the likelihood of myocardial infarction.  The broad long-term goal of this research project is to explain how human genetic variation at the PPAP2B locus alters the risk of myocardial infarction and apply that knowledge to improve the diagnosis and therapy of ischemic heart disease. We have assembled a team of experts whose knowledge spans all aspects of the proposed research to position ourselves to validate the function of the PPAP2B locus in atherosclerosis. In this proposal we will test our central hypothesis which is that the minor allele of rs17114036 in PPAP2B reduces gene expression and that lower levels of LPP3 promote atherosclerosis. We will apply unique tools that we have developed to study LPP3 and our considerable expertise to test our central hypothesis. Firstly we will identify the mechanism by which in the rs17114036 SNP in PPAP2B affects LPP3 expression and activity. We predict that rs17114036 affects a U1 splisome binding site and thereby reduces gene expression.  We will test this working hypothesis by determining if the minor allele of rs17114036 associates with altered  LPP3 transcript and protein levels in white blood cells and arterial tissue and by examining the consequences of the polymorphism on RNA splicing and stability. Secondly we will establish a mechanistic role for LPP3 in experimental atherosclerosis. Based on our Preliminary Studies of vascular pathology in mice with tissue-specific defects in smooth muscle and endothelial LPP3 the working hypothesis of this section is that LPP3 protects against vascular inflammation and that reduced expression will therefore accelerate atherosclerosis.  We will test this working hypothesis by determining the consequences of vascular tissue specific deficiency of LPP3 on the development of atherosclerosis in mice.  The experiments proposed in this application are an important step in functionally validating a common genetic variant in PPAP2B as a cardiovascular risk predictor in humans. Establishing PPAP2B its product LPP3 and the lipid substrates of this enzyme as risk predictors and mediators of CAD promises to identify important and innovative targets for the development of new biomarkers and/or therapeutics.

project_terms:
Accounting;Address;Admission activity;Affect;Alleles;Atherosclerosis;Attention;Binding Sites;Biological Availability;Biological Markers;Blood Pressure;Blood Vessels;Cardiovascular Diseases;Cardiovascular system;Cell Proliferation;Cell Surface Receptors;Cell surface;Cells;Cholesterol;Clinical;Congestive Heart Failure;Coronary Arteriosclerosis;Coronary artery;Data Analyses;Defect;Deposition;Development;Diabetes Mellitus;Diagnosis;Disease;Disease susceptibility;Employee Strikes;Enzymes;Event;Experimental Models;Family;Frequencies (time pattern);Functional RNA;Gene Expression;Genes;Genetic Polymorphism;Genetic screening method;Genotype;Goals;Health;Healthcare;Hospitals;Human;Human Genetics;Hypertension;Individual;Integral Membrane Protein;Investigation;Knowledge;LDL Cholesterol Lipoproteins;Lead;Leukocytes;Lipids;Lysophospholipids;Mediator of activation protein;Membrane;Messenger RNA;Minor;Mortality Vital Statistics;Mus;Muscle Smooth Vascular;Mutation;Myocardial Infarction;Myocardial Ischemia;Nuclear;Pathology;Plasma;Positioning Attribute;Predisposition;Prevention;Process;Protein Dephosphorylation;Proteins;RNA Splicing;RNA Stability;Reagent;Recording of previous events;Research;Research Project Grants;Resolution;Ribonucleoproteins;Risk;Risk Factors;Role;Sampling;Series;Single Nucleotide Polymorphism;Smooth Muscle Myocytes;Smooth muscle (tissue);Specific qualifier value;Testing;Therapeutic;Tissues;Transcript;Translating;United States;Validation;Variant;Variation (Genetics);Vascular Endothelial Cell;Veterans;Work;base;cardiovascular disorder risk;cardiovascular risk factor;disorder risk;enzyme activity;enzyme substrate;genetic variant;genome wide association study;improved;innovation;inorganic phosphate;lipid metabolism;lipid phosphate phosphatase;lysophosphatidic acid;novel strategies;novel therapeutics;protective effect;public health relevance;receptor;research study;tool;vascular inflammation

public_health_relevance:
Cardiovascular diseases are one of the most prevalent health problems among Veterans resulting in over 25000 admissions to VA hospitals annually. Family history is well established to provide a strong clinical indicator of cardiovascular disease risk but until very recently in al but a few cases the genes involved were not known. A new approach called "genome wide association" has been used to identify common genetic variants that predict cardiovascular disease risk without obvious association with established cardiovascular disease risk factors such as elevated plasma cholesterol levels and increased blood pressure. The goal of this project is to determine why a common variant in a gene called PPAP2B is associated with significantly elevated cardiovascular disease risk. Completion of the work could lead to validation of this variant as a genetic test for cardiovascular disease susceptibility and the development of new therapies for treatment and prevention of cardiovascular to enable improved and more efficient healthcare for Veterans.


application_id: 8621979
project_number: 5I01BX001838-02
project_title: Mechanism of Neutrophil Activation
administering_ic: VA
award_notice_date: 2013-11-06
opportunity_number: BX-12-001
application_type: 5
activity_code: I01
ic: BX
serial_number: 001838
project_start_date: 2012-10-01
project_end_date: 2016-09-30
study_section: Immunology and Dermatology A[IMMA]
contact_pi_person_id: 1886516
contact_pi: MCLEISH, KENNETH R
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 086765245
primary_uei: GXE7VBBR38K8
duns_number: 086765245
uei: GXE7VBBR38K8
fips: US
organization_id: 481037
organization_name: LOUISVILLE VA MEDICAL MEDICAL CENTER
organization_city: LOUISVILLE
organization_state: KY
organization_type: Independent Hospitals
organization_zip: 402061433
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-10-01
project_abstract:
DESCRIPTION (provided by applicant):       Neutrophils are a critical component of both the innate and adaptive immune responses that control microbial invasion. Priming is an intermediate step by which resting neutrophils enhance their production of reactive oxygen intermediates (ROI) upon activation and priming is necessary for optimal microbial killing. Although priming greatly enhances neutrophil bactericidal capability primed neutrophils are also more dangerous to normal cells. Primed neutrophils participate in a number of diseases prominent in the aging Veteran population including ANCA-associated vasculitis ischemia- reperfusion injury acute respiratory distress syndrome rheumatoid arthritis peridontitis atherosclerosis and acute inflammatory liver injury. Thus manipulation of neutrophil priming is a potential therapeutic strategy for pharmacological intervention to restrain inflammation. Recent studies identified granule exocytosis and enhanced translocation of cytosolic components of the NADPH oxidase to the plasma membrane as possible mechanisms of neutrophil priming. However many gaps in knowledge remain. The relative contribution of each of those events to priming has not been examined and whether both are necessary or sufficient for priming is unknown. The molecular events by which granule exocytosis contributes to priming and the molecular events that control enhanced translocation of cytosolic NADPH oxidase components are incompletely understood. Finally the ability to manipulate neutrophil priming in vivo has not been established. The McLeish laboratory is in a unique position to address each of these gaps based on our extensive experience examining signal transduction pathways our application of biochemical genetic and proteomic approaches to understand neutrophil biology and our recent development of novel reagents that inhibit exocytosis in vitro and in vivo. The current proposal will address the central hypothesis that neutrophil priming results from the convergence of signal transduction pathways into two responses an exocytose-dependent increase in plasma membrane expression of membrane components of NADPH oxidase and prolyl isomerase-dependent conformational changes in cytosolic components of NADPH oxidase. The following four specific objectives will be accomplished.  Specific Objective 1 will test the working hypothesis that exocytosis of secretory vesicles and gelatinase granules results in increased plasma membrane expression of p91phox and p22phox which is necessary but not sufficient for priming. Specific Objective 2 will test the working hypothesis that activation of the prolyl isomerase Pin1 contributes to priming of human neutrophils by multiple mechanisms including enhanced p47phox translocation and increased granule exocytosis. Specific Objective 3 will test the working hypothesis that p38 MAPK phosphorylates multiple proteins that mediate events necessary for priming including exocytosis and Pin1 activation. Specific Objective 4 will test theworking hypothesis that neutrophil priming is a necessary component for neutrophil participation in inflammatory diseases and represents a viable therapeutic strategy using an animal model of acute lung injury (ALI). The proposed work is expected to establish the molecular basis for neutrophil priming. The impact of the project is that molecular targets identified will permit therapeutic manipulation of neutrophil priming in inflammatory diseases. Thus new approaches to treating Veteran patients with a number of acute and chronic inflammatory diseases are anticipated.

project_terms:
Acute;Address;Adult Respiratory Distress Syndrome;Affect;Aging;Animal Model;Antineutrophil Cytoplasmic Antibodies;Arteriosclerotic Cardiovascular Disease;Atherosclerosis;Bacteria;Biochemical Genetics;Biology;Cell membrane;Chemicals;Chronic;Cytoplasmic Granules;Data;Development;Disease;Event;Exocytosis;Exposure to;Gelatinases;Goals;Human;Immune response;In Vitro;Infection;Infection Control;Inflammation;Inflammation Mediators;Inflammatory;Injury;Intervention;Invaded;Killings;Knowledge;Laboratories;Lead;Leukocytes;Lung Injury Acute;MAP Kinase Gene;MAPK14 gene;Mediating;Membrane;Molecular;Molecular Target;NADPH Oxidase;Neutrophil Activation;Normal Cell;Oxidases;Patients;Peptidylprolyl Isomerase;Phosphorylation;Play;Poisons;Population;Positioning Attribute;Process;Production;Proteins;Proteomics;Reagent;Relative (related person);Reperfusion Injury;Reporting;Rest;Rheumatoid Arthritis;Role;Secretory Vesicles;Signal Transduction Pathway;Testing;Therapeutic;Tissues;Toxin;Vasculitis;Veterans;Work;acute liver injury;bactericide;base;experience;extracellular;human CYBA protein;human disease;in vivo;liver injury;lung vascular injury;microbial;neutrophil;novel;novel strategies;public health relevance;reactive oxygen intermediate;response;sound;therapeutic target;tool

public_health_relevance:
White blood cells (WBCs) protect against infection by producing toxic chemicals that kill invading bacteria. The production of those toxin chemicals is enhanced by prior exposure to a variety of mediators of inflammation by a process termed priming. Although WBC priming plays a critical role in the control of infection priming is a two-edged sword that also reduces the ability of WBCs to co-exist with normal cells. Primed WBCs produce tissue injury in a number of diseases that affect our Veteran patients. The events that lead to priming are not known and inhibition of priming has not been used to treat those diseases. The current proposal will define the mechanisms by which WBCs become primed and will establish priming is a therapeutic target in inflammatory diseases. Accomplishing those goals will provide new treatments for Veteran patients with a number of acute and chronic inflammatory diseases.


