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: 9053622
• 负责人: Jian-Ping Jin
• 金额: $ 41.15万
• 依托单位: WAYNE STATE UNIVERSITY
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053622
• 关键词: Actomyosin Adenosinetriphosphatase; Adrenergic Agents; Adult; Amino Acids; Binding; Calcium-Sensing Receptors; Calpain; Cardiac; Cardiac Muscle Contraction; Cardiac Myocytes; Cardiac Output; Cardiovascular system; Cessation of life; Chronic; Cleaved cell; Clinical; Clinical Management; Collaborations; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diagnosis; Diastole; Diastolic heart failure; Economic Burden; Embryonic Heart; Excision; Failure; Foundations; Functional disorder; Goals; Healthcare; Heart; Heart Diseases; Heart failure; Homologous Gene; Investigation; Joints; Knowledge; Laboratory Research; Length; Long-Term Effects; Medical; Microfilaments; Modification; Molecular; Molecular Conformation; Morbidity - disease rate; Mus; Muscle; Muscle function; Myocardial dysfunction; Myocardium; Myofibrils; N-terminal; Performance; Phosphorylation; Phosphorylation Site; Physiological; Play; Post-Translational Protein Processing; Process; Production; Protein Isoforms; Protein Subunits; Proteolysis; Publications; Publishing; Pump; Regulation; Relaxation; Research; Research Project Grants; Role; Site; Skeletal Muscle; Skin; Solid; Stress; Stroke Volume; Structure; Sturnus vulgaris; Systole; Systolic heart failure; Testing; Thin Filament; Time; Transgenic Mice; Transgenic Organisms; Translating; Tropomyosin; Troponin; Troponin C; Troponin I; Troponin T; United States; Ventricular; Ventricular Remodeling; Vertebrates; Work; base; design; effective therapy; genetic regulatory protein; heart function; hemodynamics; improved; in vivo; molecular targeted therapies; mortality; mouse model; novel; novel therapeutic intervention; outcome forecast; overexpression; pressure; public health relevance; research study; response

 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.

 描述（通过应用提供）：心脏肌肉的收缩和/或放松导致心力衰竭，这是心血管发病率和死亡率的主要原因。肌钙蛋白I（TNI）是肌肉收缩和心脏功能的关键调节剂。我们的研究项目是研究心脏TNI（CTNI）的最近发现的翻译后修饰，其在增强心脏功能方面的作用以及在转化新治疗舒张性心力衰竭方面的潜力，这是所有心力衰竭病例的挑战临床状况，目前几乎代表了目前缺乏有效治疗。与骨骼肌中的TNI同工型相比，CTNI具有独特的N末端延伸，是一种成人心脏特异性结构，其中包含β-肾上腺素调节的蛋白激酶A（PKA）磷酸化位点。最近的研究表明，可以通过限制性蛋白水解去除CTNI的N末端扩展。这种CTNI的翻译后修饰发生在正常心脏中的低水平，在心脏适应血流动力胁迫和心力衰竭的过程中被上调。由此产生的N末端截短CTNI（CTNI-ND）仍然存在心脏肌感，并且对心脏肌肉收缩性的功能影响不可能。小鼠心脏中CTNI-ND的转基因过表达增加了松弛速度，改善心室填充并增加了中风量。 CTNI-ND对心脏功能的增强表明，这种新型翻译后修饰是无损的，可以作为一种适应性机制来补偿心力衰竭中舒张期功能障碍。为了检验这一假设，我们将表征CTNI-ND在增强心脏肌肉舒张功能及其在治疗舒张性心力衰竭中的潜在应用的功能。将追求四个具体目标：目标1是确定 CTNI-ND对修饰肌钙蛋白功能和心肌收缩的作用和机制。目的2是表征CTNI-ND在心脏坦率的反应中的功能。 AIM 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。我们以前的研究为这个新的研究项目奠定了坚实的基础。我们有大量已发表和初步数据来支持该假设并验证实验方法。 PI和合作者组成了一个具有完整专业知识的协同团队，以进行这项多层次调查。我们以前已经证明了与联合出版物的有效合作。通过全面了解CTNI-ND的功能和生产，这项研究将获得必要的知识，将新颖的分子机制转化为一种新的治疗舒张性心力衰竭的治疗方法。