Regulation of Troponin I in Cardiac Adaptation & Failure

 描述(由申请人提供)：心肌收缩和/或松弛受损导致心力衰竭，这是心血管疾病和死亡的主要原因。肌钙蛋白I(TnI)是肌肉收缩和心脏功能的关键调节因子。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)在增强心功能方面的作用以及在舒张性心力衰竭新治疗方法的翻译开发中的潜力。舒张性心力衰竭是一种具有挑战性的临床疾病，占所有心力衰竭病例的近一半，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，这是一个成人心脏特有的结构，含有β肾上腺素能调节的蛋白激酶A的磷酸化位点。最近的研究表明，cTnI的N端延伸可以通过限制性蛋白水解法去除。这种cTnI的翻译后修饰在正常心脏中水平较低，在心脏对血流动力学应激和心力衰竭的适应过程中上调。由此产生的N-末端截短型cTnI(cTnI-ND)残留在心肌纤维中，对心肌的收缩功能产生影响。在小鼠心脏中过表达cTnI-ND可以提高松弛速度，改善心脏充盈，增加每搏输出量。CTnI-ND对心功能的增强表明，这种新的翻译后修饰是非破坏性的，可能作为一种适应性机制来补偿心力衰竭时的舒张期功能障碍。为了验证这一假设，我们将表征cTnI-ND在增强心肌舒张性功能方面的作用及其在治疗舒张性心力衰竭中的潜在应用。将追求四个具体目标：目标1是确定 肌钙蛋白I-ND改善肌钙蛋白功能和心肌收缩能力的作用及其机制目的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。我们有大量已发表的和初步的数据来支持这一假设并验证实验方法。PI和合作者组成了一个具有互补专业知识的协同小组，以开展这项多层次的调查。我们以前已经展示了与联合出版物的有效合作。通过全面了解cTnI-ND的功能和产生，本研究将为将新的分子机制转化为治疗舒张性心力衰竭的新途径提供必要的知识。

 DESCRIPTION (provided by applicant): 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 functionof 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.