Cardioprotection by optimizing mTOR activity

通过优化 mTOR 活性来保护心脏

基本信息

批准号：
8792404
负责人：
MARK ALAN SUSSMAN
金额：
$ 36.81万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792404
关键词：
Aging Anabolism Apoptosis Biology Cardiac Cardiac Myocytes Cell Cycle Progression Cell Death Cell Size Cell Survival Cessation of life Characteristics Complex Coronary Cytoskeletal Modeling Development Diastolic heart failure Disease Elements Equilibrium Feedback Functional disorder Genes Goals Growth Growth Factor Health Healthcare Systems Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Hypertrophy Impairment Insulin Receptor Insulin Resistance Link Longevity Malignant Neoplasms Mediating Metabolic Diseases Metabolism Molecular Molecular Profiling Mus Myocardial Myocardial Infarction Myocardial dysfunction Myocardium Nuclear Nutrient Organism Performance Pharmaceutical Preparations Phosphorylation Proline Proteins Proto-Oncogene Proteins c-akt Public Health Regulation Regulatory Element Repression Resistance Services Signal Transduction Sirolimus Source Stents Structure Techniques Therapeutic Therapeutic Effect Tissues Translations United States age related aged base cancer cell cell growth clinical application desensitization fetal gene therapy hemodynamics implantation improved in vivo inhibitor/antagonist innovation insulin signaling interest mTOR protein mortality novel novel therapeutics overexpression premature pressure prevent programs response restenosis senescence stressor therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Activation of the mTORC1 complex is a critical step in the progression of cardiac disease after myocardial infarction and pressure overload induced hypertrophy. This fact has spurred interest for ways to therapeutic target the mTORC1 complex in the heart. However, no drugs are currently available that specifically target mTORC1 in cardiomyocytes highlighting the need for the development of new therapeutic regimes. This proposal will inhibit mTORC1 through a novel molecular strategy involving PRAS40, an endogenous mTORC1 inhibitor and substrate. PRAS40 has been identified in the last years as a powerful tool to inhibit cellular growth in cancer cells. A unique molecular feature of PRAS40 is to inhibit mTORC1 and simultaneously increase mTORC2 activation, which increase cellular survival via increased AKT activation. Judicious enhancement of PRAS40 expression will inhibit pathological growth and senescence on the one hand and improve survival on the other hand. Accomplishing the stated aims of this proposal will provide a first comprehensive characterization of PRAS40 in cardiac biology. The innovation of this proposal is based on the first characterization of PRAS40 in the cardiac context and the unique molecular profile of PRAS40. The short- term goal is to delineate the critical importance of PRAS40 in the heart and demonstrate the efficiency of PRAS40 interventional approaches to inhibit pathological growth, blunt cardiac senescence and improve insulin signaling. Specific aims are: 1) Pathological cardiac growth and senescence are inhibited by PRAS40, 2) cell survival and insulin signaling are improved by PRAS40 and 3) that mTORC1 inhibition together with mTORC2 activation by PRAS40 is protective against pathological damage. The significance of these studies is to define ways to blunt hyperactivation of mTORC1 in cardiac diseases with the goal to delineate new therapeutic ways to target mTORC1 in the heart. Collectively, the studies in this proposal will pave the way for interventional approaches to regulate PRAS40 activity in service to block pathological growth and senescence and improving AKT dependent signaling.

描述（由申请人提供）：MTORC1复合物的激活是心肌梗塞和压力超负荷诱导肥大后心脏病进展的关键步骤。这一事实激发了人们对心脏中MTORC1复合物的治疗方法的兴趣。但是，目前尚无专门针对MTORC1在心肌细胞中的药物，强调了开发新的治疗方案的需求。该建议将通过涉及内源性MTORC1抑制剂和底物的新型分子策略来抑制MTORC1。在过去几年中，PRAS40已被确定为抑制癌细胞细胞生长的强大工具。 PRAS40的独特分子特征是抑制MTORC1并同时增加MTORC2激活，从而通过增加AKT激活来增加细胞存活。 PRAS40表达的明智增强将一方面抑制病理生长和衰老，另一方面提高生存率。完成该提案的既定目标将提供对心脏生物学中PRAS40的首次全面特征。该提案的创新基于心脏环境中PRAS40的首次表征和PRAS40的独特分子曲线。短期目标是描述PRAS40在心脏中的重要重要性，并证明PRAS40介入方法的效率以抑制病理生长，钝心脏衰老和改善胰岛素信号传导。具体目的是：1）PRAS40，2）PRAS40和3）细胞存活和胰岛素信号传导抑制了病理心脏生长和衰老。这些研究的重要性是定义方法在心脏病中钝化MTORC1的过度激活的方法，目的是描述新的治疗方法，以靶向MTORC1心脏中的MTORC1。总的来说，该提案中的研究将为调节服务中的PRAS40活性以阻止病理生长和衰老并改善依赖AKT的信号传导铺平道路。