Regulation of Troponin I in Cardiac Adaptation & Failure

肌钙蛋白 I 在心脏适应中的调节

• 批准号: 10349218
• 负责人: Jian-Ping Jin
• 金额: $ 14.04万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349218
• 关键词: Regulation; Troponin; Cardiac; Adaptation; Failure

Project Summary (Project Title: Regulation of Troponin I in Cardiac Adaptation & Failure) Impaired contraction and/or relaxation of cardiac muscle causes heart failure, a leading cause of cardiovascular morbidity and mortality. Troponin I (TnI) is a key regulator of muscle contractility and heart function. Our research project is to study a recently discovered posttranslational modification of cardiac TnI (cTnI) for its role in enhancing cardiac function and the potential in translational development of new treatment for diastolic heart failure, a challenging clinical condition that represents nearly half of all heart failure cases and currently lacks effective treatment. Comparing to the TnI isoforms in skeletal muscle, cTnI has a unique N-terminal extension that is an adult heart-specific structure containing β-adrenergic regulated protein kinase A (PKA) phosphorylation sites. Recent studies demonstrated that the N-terminal extension of cTnI can be removed by restrictive proteolysis. This posttranslational modification of cTnI occurs at low levels in normal hearts, and is up- regulated during cardiac adaptations to hemodynamic stresses and heart failure. The resultant N-terminal truncated cTnI (cTnI-ND) remains in cardiac myofilaments and imposes functional effects on the contractility of cardiac muscle. Transgenic over-expression of cTnI-ND in mouse hearts increases relaxation velocity, improves ventricular filling, and increases stroke volume. The enhancement of cardiac function by cTnI-ND suggests that this novel posttranslational modification is non-destructive and may serve as an adaptive mechanism to compensate for diastolic dysfunction in heart failure. To test this hypothesis, we shall characterize the function of cTnI-ND in enhancing the diastolic function of cardiac muscle and its potential application in the treatment of diastolic heart failure. Four Specific Aims will be pursued: Aim 1 is to determine the effects and mechanisms of cTnI-ND on modifying troponin function and cardiac muscle contractility. Aim 2 is to characterize the function of cTnI-ND in Frank-Starling response of the heart. Aim 3 is to investigate the production of cTnI-ND in cardiac muscle. Aim 4 is to understand the long-term effects of cTnI-ND on cardiac function and adaptation. Our previous studies have laid a solid foundation for this new research project. We have substantial amounts of published and preliminary data to support the hypothesis and validate the experimental approaches. The PI and collaborators have formed a synergistic team with complementary expertise to carry out this multi-level investigation. We have previously demonstrated effective collaborations with joint publications. By comprehensively understanding the function and production of cTnI-ND, this study will gain the necessary knowledge for translating a novel molecular mechanism into a new therapeutic approach for the treatment of diastolic heart failure.

项目概述(项目名称：肌钙蛋白I在心脏适应和衰竭中的调节) 心肌收缩和/或松弛受损会导致心力衰竭，这是 心血管发病率和死亡率。肌钙蛋白I(TnI)是肌肉收缩和心脏的关键调节因子 功能。我们的研究项目是研究最近发现的心脏TnI的翻译后修饰 (CTnI)在增强心功能方面的作用和在新的翻译开发中的潜力 舒张性心力衰竭的治疗，这是一种具有挑战性的临床状况，占所有心脏的近一半 失败的病例，目前缺乏有效的治疗。 与骨骼肌中的TnI亚型相比，cTnI有一个独特的N末端延伸，即 含有β-肾上腺素能调节的蛋白激酶A磷酸化的成人心脏特异结构 网站。最近的研究表明，cTnI的N端延伸可以通过限制性的方法去除 蛋白质分解。这种cTnI的翻译后修饰在正常心脏中低水平发生，并在- 在心脏适应血流动力学应激和心力衰竭的过程中进行调节。合成的N-末端 截短型cTnI(cTnI-ND)残留在心肌纤维中，对心肌收缩功能有影响 对心肌的影响。转基因cTnI-ND在小鼠心脏中的过表达提高了松弛速度， 改善脑室充盈，增加每搏量。肌钙蛋白I-ND对心功能的增强作用 提示这种新的翻译后修饰是非破坏性的，可以作为一种适应性 心力衰竭时舒张期功能障碍的补偿机制。 为了验证这一假设，我们将表征cTnI-ND在增强舒张压方面的功能。 心肌功能及其在舒张性心力衰竭治疗中的潜在应用。四 具体目标将会落实： 目的1确定cTnI-ND对肌钙蛋白功能的影响及其机制。 心肌收缩能力。 目的2研究cTnI-ND在心脏Frank-Starling反应中的作用。 目的3研究心肌中cTnI-ND的产生。 目的4了解cTnI-ND对心脏功能和适应性的长期影响。 我们之前的研究为这一新的研究项目奠定了坚实的基础。我们有大量的 支持假设和验证实验的已发表数据和初步数据的数量 接近了。PI和合作者组成了一个具有互补专业知识的协同团队，以 开展这项多层次的调查。我们之前已经展示了与联合 出版物。通过全面了解cTnI-ND的功能和产物，本研究将获得 将一种新的分子机制转化为新的治疗方法所必需的知识 舒张性心力衰竭的治疗。