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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 |
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| 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 | |
| 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 | Principal investigator | |
|---|---|---|---|
| There are no any related projects. | |||
| Project Title: | Ac5 inhibitor treatment for heart failure | |||
| Principal Investigators (PI): |
VATNER STEPHEN F
|
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| Project Number: | 1P20HL101420-01 | |||
| Organization: | UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL | |||
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