Ac5 inhibitor treatment for heart failure

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Project Title: Ac5 inhibitor treatment for heart failure
Principal Investigators (PI): VATNER STEPHEN F
Project Number: 1P20HL101420-01
Organization: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
 
Project Description:
Congestive heart failure (HF) in the U.S is the leading cause of death, and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy post myocardial infarction (Ml) is extremely important, and the development of a new class of medicine that prevents the progression of HF would have a large market opportunity, representing a significant clinical advance. Additionally, most of these patients have elevated blood lipids and many have impaired glucose metabolism and are either diabetic or pre-diabetic. Therefore, a HF drug which can exert a favorable effect on diabetes control will have a unique niche in the HF market. The goal of this grant proposal is to demonstrate the efficacy of a new class of HF drugs, with a mechanism of inhibition of type 5 adenylyl cyclase (ACS), to improve the adverse effects of remodeling following chronic Ml and to simultaneously improve disorders of glucose metabolism,. This proposal is based on our prior work in a mouse model with disruption of the ACS gene, i.e., ACS knockout mice (ACS KO), and based on the utilization of a specific pharmacological ACS inhibitor. ACS KO mice have prolonged lifespan and are protected from the cardiomyopathy of aging. They are also protected against the development of HF induced by either chronic pressure overload, or by excessive sympathetic stimulation. Another unique feature of the ACS KO mouse model is its ability to increase coronary reserve, which should be particularly useful in preventing the development of HF. Importantly for this proposal these mice eat more than wild type, but weigh less, which points to a favorable metabolic profile, confirmed by our preliminary data using a specific pharmacological ACS inhibitor. In our preliminary screening for ACS inhibitors, adenine 9-?-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(r)), which was used in the clinic for a different indication, i.e., treating viral infections, showed potent and selective inhibition of ACS. Furthermore, our preliminary data demonstrate that the pharmacological AC 5 inhibitor protects against HF following chronic Ml and also protects against development of hyperglycemia induced by a high-fat diet in mice, suggesting that inhibition of ACS improves glucose metabolism in addition to its salutary effects in protecting against HF. Accordingly, in this preclinical study, we will examine the effects of AraAde on post-MI HF with or without impaired glucose metabolism. In addition we will examine the efficacy of this drug in the best pre-clinical model for HF, the chronically instrumented, conscious monkey post-MI. RELEVANCE (See instructions): Almost 5.5 million patients are diagnosed with congestive heart failure in the U.S and the major cause of HF is myocardial ischemic disease. However, no effective therapy has been established to treat congestive HF. The current investigation is aimed at generating a new class of medicine that will prevent progression of HF. Due to the large number of patients with this condition, this may have a significant impact on public health.
 
Project Terms:
1H-Purin-6-amine 3,5 cyclic AMP synthetase 9-Beta-D-arabinofuranosyl-9H-purine-6-amine Monohydrate 9-Beta-D-arabinofuranosyladenine Monohydrate 9-beta-Arabinofuranosyladenine 9-beta-D-Arabinofuranosyladenine 9H-Purin-6-amine, 9-beta-D-arabinofuranosyl- AC5 enzyme ATP pyrophosphate-lyase (cyclizing) Adenine Adenine Arabinoside Adenyl Cyclase Adenylate Cyclase Adenylyl Cyclase Adverse effects Aging Applications Grants Ara-A Arabinofuranosyladenine Arabinosyladenine Arasena-A Cardiac Failure Congestive Cardiac infarction Cardiomyopathies Cause of Death Chronic Clinic Clinical Congestive Heart Failure Conscious Consciousness Coronary Data Development Diagnosis Diet Disease Disorder Drugs Eating Fats Fatty acid glycerol esters Food Intake Genes Glucose Metabolic Disorders Glucose Metabolism Disorders Goals Grant Proposals Grants, Applications Heart Decompensation Heart Failure, Congestive Heart failure Hyperglycemia Instruction Investigation Knockout Mice Length of Life Longevity Mammals, Mice Marketing Medication Medicine Metabolic Mice Mice, Knock-out Mice, Knockout Monkeys Murine Mus Mycocardium Disease Myocardial Myocardial Diseases Myocardial Disorder Myocardial Infarct Myocardial Infarction Myocardiopathies Null Mouse Patients Pharmaceutic Preparations Pharmaceutical Preparations Pre-Clinical Model Preclinical Models Pressure Pressure- physical agent Public Health Science of Medicine Screening procedure Senescence Spongoadenosine Treatment Side Effects Vidarabine Vira A ViraA Viral Diseases Virus Diseases Vitamin B4 Work adenylcyclase adenylyl cyclase type 5 adenylyl cyclase type V alpha-Ara A alpha-D-Arabinofuranosyladenine base beta-Ara A blood lipid cardiac failure cardiac infarct coronary attack coronary infarct coronary infarction diabetes control diabetic disease/disorder drug efficacy drug/agent effective therapy glucose metabolism heart attack heart infarct heart infarction hyperglycemic improved inhibitor inhibitor/antagonist instrument life span lifespan mouse model myocardium disorder preclinical study pressure prevent preventing public health medicine (field) screening screenings senescent side effect therapy adverse effect treatment adverse effect viral infection virus infection
Project Title: Ac5 inhibitor treatment for heart failure
Principal Investigators (PI): VATNER STEPHEN F
Project Number: 1P20HL101420-01
Organization: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
 
Project Categories:
Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases
 
Other Information:
Fiscal Year: 2010
Project Start Date: 1 April 2010
Project End Date: 31 March 2012
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $779,111
Total Cost: $779,111
Year Funding Organization Total Funding, $
2010 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $779,111
Project Title: Ac5 inhibitor treatment for heart failure
Principal Investigators (PI): VATNER STEPHEN F
Project Number: 1P20HL101420-01
Organization: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Ac5 inhibitor treatment for heart failure
Principal Investigators (PI): VATNER STEPHEN F
Project Number: 1P20HL101420-01
Organization: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
 
Project number Project title Organization FY Funding Organization FY Total Cost
5R01HL102472-02Intrinsic Vascular Smooth Muscle Cell StiffnessUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2013NATIONAL HEART
$453,532
5R01HL093481-04Adenylyl cyclase isoforms in hypertrophy and heart failureUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2012NATIONAL HEART
$469,235
5R01HL106511-02Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KOUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2012NATIONAL HEART
$453,345
5T32HL069752-09Integrative mechanisms in Cardiovascular DiseaseUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2012NATIONAL HEART
$209,834
5R01HL033107-27Cardiovascular Control in Normal and Disease StatesUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2011NATIONAL HEART
$670,274
1R01HL106511-01A1Skeletal Muscle Basis for Improved Exercise Endurance in AC5 KOUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2011NATIONAL HEART
$468,800
5P01AG027211-05Longevity and Stress ResistanceUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2011NATIONAL INSTITUTE ON AGING
$2,037,769
5P20HL101420-02AC5 Inhibitor Treatment for Heart FailureUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2011NATIONAL HEART
$779,111
5R01HL093481-03Adenylyl cyclase isoforms in hypertrophy and heart failureUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2011NATIONAL HEART
$468,924
5T32HL069752-08Integrative mechanisms in Cardiovascular DiseaseUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2011NATIONAL HEART
$170,402
5P01HL069020-10-6Molecular Mechanisms in Chronically Stunned MyocardiumUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL HEART
$342,976
5P01AG027211-04Longevity and Stress ResistanceUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL INSTITUTE ON AGING
$2,054,477
1R01HL102472-01Intrinsic Vascular Smooth Muscle Cell StiffnessUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL HEART
$491,296
1P20HL101420-01AC5 Inhibitor Treatment for Heart FailureUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL HEART
$779,111
5T32HL069752-07Integrative mechanisms in Cardiovascular DiseaseUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL HEART
$271,048
5R01HL093481-02Adenylyl cyclase isoforms in hypertrophy and heart failureUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL HEART
$473,661
5R01HL033107-26Cardiovascular Control in Normal and Disease StatesUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2010NATIONAL HEART
$737,225
5P01AG027211-03Longevity and Stress ResistanceUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2009NATIONAL INSTITUTE ON AGING
$2,182,671
5P01HL069020-09-6Molecular Mechanisms in Chronically Stunned MyocardiumUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2009NATIONAL HEART
$335,213
5R01HL033107-25Cardiovascular Control in Normal and Disease StatesUNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL2009NATIONAL HEART
$752,274
Project Title: Ac5 inhibitor treatment for heart failure
Principal Investigators (PI): VATNER STEPHEN F
Project Number: 1P20HL101420-01
Organization: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
 
Project number Project title Principal investigator
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Project Title: Ac5 inhibitor treatment for heart failure
Principal Investigators (PI): VATNER STEPHEN F
Project Number: 1P20HL101420-01
Organization: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
 
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