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.

 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.