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.

项目摘要（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/或舒张受损会导致心力衰竭，这是心力衰竭的主要原因 肌钙蛋白 I (TnI) 是肌肉收缩力和心脏的关键调节因子。 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) 因其在增强心脏功能方面的作用以及新药物转化开发的潜力 舒张性心力衰竭的治疗，这是一种具有挑战性的临床病症，占所有心脏疾病的近一半 失败案例较多，目前缺乏有效的治疗方法。 与骨骼肌中的 TnI 亚型相比，cTnI 具有独特的 N 末端延伸， 成人心脏特异性结构，含有 β-肾上腺素能调节蛋白激酶 A (PKA) 磷酸化 最近的研究表明，cTnI 的 N 端延伸可以通过限制性去除。 cTnI 的这种翻译后修饰在正常心脏中以低水平发生，并且是上调的。 在心脏适应血流动力学应激和心力衰竭过程中受到调节。 截短的 cTnI (cTnI-ND) 保留在心肌丝中并对收缩力产生功能影响 小鼠心脏中 cTnI-ND 的转基因过度表达增加了舒张速度， 改善心室充盈，增加每搏输出量 cTnI-ND 增强心脏功能。 表明这种新颖的翻译后修饰是非破坏性的，并且可以作为一种适应性 心力衰竭舒张功能障碍的代偿机制。 为了检验这一假设，我们将描述 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4 将追求的具体目标： 目标 1 是确定 cTnI-ND 对改变肌钙蛋白功能的影响和机制，以及 心肌收缩力。 目标 2 是表征 cTnI-ND 在心脏 Frank-Starling 反应中的功能。 目标 3 是研究心肌中 cTnI-ND 的产生。 目标 4 是了解 cTnI-ND 对心脏功能和适应的长期影响。 我们之前的研究为这个新的研究项目奠定了坚实的基础。 大量已发表的数据和初步数据来支持假设并验证实验 PI 和合作者组成了一个具有互补专业知识的协同团队。 我们之前已经与联合开展了这一多层次的调查。 通过全面了解 cTnI-ND 的功能和产生，本研究将获得成果。 将新的分子机制转化为新的治疗方法的必要知识 舒张性心力衰竭的治疗。