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Cardioprotection with mTOR Inhibition

mTOR 抑制的心脏保护作用

基本信息

批准号：
9196520
负责人：
Anindita Das
金额：
$ 51.61万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196520
关键词：
Acute Acute myocardial infarction Antioxidants Apoptosis Autophagocytosis BCL2 gene Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell Death Cell physiology Clinical Congestive Heart Failure Conscious Coronary Arteriosclerosis Coronary Restenosis Data Diabetes Mellitus Diabetic mouse Dilated Cardiomyopathy Event FRAP1 gene Gene Targeting Generations Glucose Heart Heart failure High Fat Diet Human Immunosuppressive Agents Infarction Injury Insulin Resistance Investigation Ischemia Kidney Laboratories Lead Mammals Membrane Potentials Metabolic Metabolism Metals MicroRNAs Modeling Molecular Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Necrosis Non-Insulin-Dependent Diabetes Mellitus Organ Transplantation Oryctolagus cuniculus Oxidative Stress Pathogenesis Patients Peripheral arterial disease Pharmaceutical Preparations Phosphorylation Physiological Predisposition Procollagen-Proline Dioxygenase Protein-Serine-Threonine Kinases Proteins Public Health Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Reporting Risk Factors Role STAT3 gene Safety Signal Transduction Sirolimus Stents Stress Stroke Testing Therapeutic Time Translations attenuation base cell growth clinically relevant coronary angioplasty db/db mouse diabetic diabetic patient feeding glycogen synthase kinase 3 beta in vivo inhibitor/antagonist innovation insight interest mitochondrial membrane mortality myocardial infarct sizing novel novel strategies novel therapeutics outcome forecast prevent pro-apoptotic protein restenosis translational approach translational study

项目摘要

Excessive activation of the mammalian target of rapamycin (mTOR) and decreased levels of activated STAT3 in diabetic heart lead to higher mortality after acute myocardial infarction. Based on our compelling preliminary data, we hypothesize that mTOR inhibitor, rapamycin, protects against myocardial ischemia-reperfusion (I/R) injury in type 2 diabetes (T2D). Accordingly, in this application, we have proposed novel studies to investigate the mechanisms of cardioprotection with rapamcyin. We will examine the effect of rapamycin treatment (before ischemia or during reperfusion) on myocardial infarct size, function, and cardiomyocytes cell death following I/R in T2D mice. Phosphorylation of STAT3 will be determined in hearts and cardiomyocytes of T2D mice after rapamycin treatment. The essential role of STAT3 in rapamycin-induced protection against I/R injury in hearts and cardiomyocytes will be demonstrated in cardiac-specific STAT3-deficient mice following high-fat diet (HFD)-induced diabetes. Since STAT3 positively regulates miR-20a, we will examine the level of miR-17 and miR-20a, part of miR-17-92 cluster, in diabetic heart and cardiomyocytes with rapamycin treatment. By inducing T2D with the feeding of HFD in cardiac-specific miRNA-17-92 cluster-deficient mice, we will demonstrate cause and effect of miR-17/20a in rapamycin-induced cardioprotection. Finally, we will develop and optimize rapamycin-based therapeutic approach in preventing reperfusion injury in conscious diabetic rabbits. We will test whether rapamycin is effective in reducing infarct size when administered at the time of reperfusion and whether signaling mechanisms similar to db/db mice contribute to cardioprotection in this translational diabetic rabbit model of myocardial infarction. Upon completion of these studies, we expect to gain new insights into the mechanisms involved in cardioprotective effects of rapamycin in the diabetic myocardium. We believe that rapamycin would represent an attractive agent to apply to the clinical setting of acute myocardial infarction in patients. Considering that coronary artery disease is the principal cause of death in diabetic patients, rapamycin therapy may offer a novel therapeutic option for cardioprotection with enormous public health implications.

哺乳动物雷帕霉素靶蛋白（mTOR）的过度激活和STAT3激活水平的降低