Cardioprotection by optimizing mTOR activity

通过优化 mTOR 活性来保护心脏

• 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
• 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

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死和压力过载引起的肥厚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复合物治疗靶点的兴趣。然而，目前还没有专门针对心肌细胞中mTORC1的药物，这突出了开发新的治疗方案的必要性。该提案将通过一种涉及内源性mTORC1抑制剂和底物PRAS40的新型分子策略来抑制mTORC1。在过去的几年里，PRAS40已经被确定为抑制癌细胞细胞生长的有力工具。PRAS40的一个独特的分子特征是抑制mTORC1，同时增加mTORC2的激活，从而通过增加AKT的激活来提高细胞存活率。适当提高PRAS40的表达，一方面可以抑制病理性生长和衰老，另一方面可以提高生存率。完成本提案的既定目标将提供心脏生物学中PRAS40的第一个全面表征。这项提议的创新是基于PRAS40在心脏环境中的首次表征和PRAS40独特的分子谱。短期目标是描述PRAS40在心脏中的关键重要性，并证明PRAS40介入方法在抑制病理性生长、延缓心脏衰老和改善胰岛素信号传导方面的有效性。具体目的是：1)PRAS40抑制病理性心脏生长和衰老，2)PRAS40改善细胞存活和胰岛素信号传导，3)PRAS40抑制mTORC1和激活mTORC2对病理性损伤具有保护作用。这些研究的意义在于确定了抑制心脏疾病中mTORC1过度激活的方法，目的是描述针对心脏中mTORC1的新治疗方法。总的来说，本提案中的研究将为调节PRAS40活性的干预方法铺平道路，以阻断病理性生长和衰老，改善AKT依赖的信号传导。