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.

雷帕霉素哺乳动物靶标（MTOR）过度激活和激活的STAT3水平降低在糖尿病心脏中，急性心肌梗塞后会导致更高的死亡率。基于我们引人入胜的初步数据，我们假设MTOR抑制剂雷帕霉素可以预防心肌缺血 - 重新灌注（I/R） 2型糖尿病损伤（T2D）。因此，在此应用中，我们提出了新的研究来研究用雷帕蛋白的心脏保护的机制。我们将检查雷帕霉素治疗的作用（之前缺血或再灌注期间）关于心肌梗死的大小，功能和心肌细胞的细胞死亡 I/R在T2D小鼠中。 STAT3的磷酸化将在T2D小鼠的心脏和心肌细胞中确定雷帕霉素治疗。 STAT3在雷帕霉素诱导的防御I/R伤害中的基本作用高脂饮食后，在心脏特异性STAT3缺陷小鼠中将证明心肌细胞和心肌细胞（HFD）诱导的糖尿病。由于STAT3对miR-20a进行了积极调节，我们将检查miR-17和 miR-20a是miR-17-92簇的一部分，在雷帕霉素治疗的糖尿病心脏和心肌细胞中。经过在心脏特异性miRNA-17-92群集缺陷小鼠中诱导HFD诱导T2D，我们将证明miR-17/20a在雷帕霉素诱导的心脏保护中的原因和影响。最后，我们将发展并优化基于雷帕霉素的治疗方法，以防止有意识糖尿病的再灌注损伤兔子。我们将测试雷帕霉素是否在降低梗塞大小时是否有效再灌注以及是否类似于DB/DB小鼠的信号传导机制在此是否有助于心脏保护心肌梗塞的翻译糖尿病兔模型。完成这些研究后，我们希望对雷帕霉素在糖尿病中所涉及的心脏保护作用的机制获得新的见解心肌。我们认为，雷帕霉素将代表一个有吸引力的代理商，以适用于临床环境患者急性心肌梗塞。考虑到冠状动脉疾病是死亡的主要原因在糖尿病患者中，雷帕霉素疗法可以提供一种新颖的治疗选择，可用于巨大的心脏保护公共卫生的影响。