Cardioprotection by optimizing mTOR activity

通过优化 mTOR 活性来保护心脏

• 批准号: 8446101
• 负责人: MARK ALAN SUSSMAN
• 金额: $ 37.38万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446101
• 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; 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; 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; public health relevance; 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塞和压力超负荷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针对心脏中的 mTORC1 复合物进行治疗的方法的兴趣。然而，目前还没有专门针对心肌细胞中 mTORC1 的药物，这凸显了开发新治疗方案的必要性。该提案将通过一种涉及 PRAS40（一种内源性 mTORC1 抑制剂和底物）的新型分子策略来抑制 mTORC1。 PRAS40 在过去几年被认为是抑制癌细胞生长的强大工具。 PRAS40 的一个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率。明智地增强 PRAS40 表达，一方面会抑制病理生长和衰老，另一方面会提高生存率。实现该提案的既定目标将提供 PRAS40 在心脏生物学中的首次全面表征。该提案的创新基于 PRAS40 在心脏背景下的首次表征以及 PRAS40 独特的分子特征。短期目标是描绘 PRAS40 在心脏中的至关重要性，并证明 PRAS40 介入方法在抑制病理生长、减缓心脏衰老和改善胰岛素信号传导方面的有效性。具体目标是：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转导，3) PRAS40 抑制 mTORC1 和激活 mTORC2 可防止病理损伤。这些研究的意义在于确定在心脏病中抑制 mTORC1 过度激活的方法，目的是找出针对心脏中 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，以阻止病理生长和衰老并改善 AKT 依赖性信号传导。