Modification of Troponin T to Improve Cardiac Function in Heart Failure

肌钙蛋白 T 的修饰可改善心力衰竭患者的心脏功能

基本信息

批准号：
10392565
负责人：
Jian-Ping Jin
金额：
$ 39.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-05 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392565
关键词：
ATP phosphohydrolase Adrenergic Agents Binding C-terminal Calmodulin Cardiac Cardiac Muscle Contraction Cardiovascular Diseases Chronic Clinical Clinical Treatment Complex Congestive Heart Failure Development Epitopes Exhibits Family Genes Goals Heart Heart Rate Heart failure Hypertrophic Cardiomyopathy Immunoglobulin Variable Region Ischemia Kinetics Left Link Long-Term Effects Microfilaments Modeling Modification Molecular Molecular Conformation Molecular Target Mus Mutation Myocardial Myocardial Ischemia Myocardial dysfunction Myocardium Myosin Light Chains N-terminal Organ Phase Physiologic intraventricular pressure Physiological Physiological Adaptation Plant Roots Positioning Attribute Post-Translational Protein Processing Post-Translational Regulation Protein Subunits Proteolysis Regulation Relaxation Reperfusion Therapy Repression Research Stress Striated Muscles Stroke Volume Structure Testing Thin Filament Time Transgenic Mice Translating Translations Tropomyosin Troponin Troponin C Troponin I Troponin T Ventricular Wild Type Mouse effectiveness evaluation genetic regulatory protein heart function improved in vivo mouse model novel novel strategies preservation pressure receptor response translational study

项目摘要

Project Title: Modification of Troponin T to Improve Cardiac Function in Heart Failure Project Summary Cardiac muscle contraction is regulated via the troponin complex in sarcomeric thin filaments. Troponin consists of three protein subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT). A restrictive cleavage that selectively removes the N-terminal variable region of cardiac TnT (cTnT) naturally occurs as an adaptation to myocardial energetic crisis such as ischemia or pressure overload. The N-terminal truncated cTnT (cTnT-ND) remains in the cardiac myofilaments with altered functionality to physiologically tune down left ventricular systolic velocity, which elongates the phase of rapid ejection, thereby increasing stroke volume and improving the energetic efficiency of the heart. The proposed research will characterize the mechanism by which cTnT-ND alters the kinetics of myofilament activity to allow the heart to physiologically compensate for energetic crisis, and will ultimately lay groundwork for the development of new targeted treatments for heart failure. Three Specific Aims are proposed: Aim I is to characterize how the deletion of the N-terminal variable region of cTnT restores a repressed TnI-like C-terminal conformation to result in a conditional inhibition of myofilament ATPase and contractile kinetics. Aim II is to assess the effectiveness of cTnT-ND on compensating for cardiac dysfunction and improving cardiac efficiency in heart failure mouse models with in vivo and ex vivo functional studies. Aim III is to assess the long-term effects of cTnT-ND on cardiac function, reserve and remodeling in normal and failing mouse hearts for translation to new treatments for heart failure. Significance: Heart failure is a major challenge in the management of cardiovascular diseases. While b-adrenergic blockade has proven to be clinically effective in treating chronic congestive heart failure, the long-term benefit of decreasing contractile kinetics remains incompletely understood. The restrictive deletion of the N-terminal segment of cTnT naturally occurs during myocardial ischemia and pressure overload as a posttranslational regulation to selectively tune down contractile velocity of cardiac muscle and elongate the rapid ejection phase to increase stroke volume and cardiac efficiency. This mechanism provides a novel and specifically targeted approach to sustain baseline cardiac function during energetic crisis and heart failure. Using multi-level and integrative approaches, our study will lay the groundwork for translating this molecular mechanism into a new clinical treatment for heart failure.

项目名称：修饰肌钙蛋白 T 以改善心力衰竭患者的心脏功能项目概要心肌收缩是通过肌钙蛋白细丝中的肌钙蛋白复合物调节的。由三个蛋白质亚基组成：肌钙蛋白 C (TnC)、肌钙蛋白 I (TnI) 和限制性肌钙蛋白 T (TnT)。选择性去除心脏 TnT (cTnT) N 末端可变区的裂解自然发生为对心肌能量危机（例如缺血或压力超负荷）的适应。截短的 cTnT (cTnT-ND) 保留在心肌丝中，其生理功能发生改变调低左心室收缩速度，从而延长快速射血阶段，从而增加所提出的研究将描述每搏输出量和提高心脏的能量效率。 cTnT-ND 改变肌丝活动动力学以使心脏生理上补偿能量危机，并最终为发展奠定基础提出了新的心力衰竭靶向治疗方法的三个具体目标：目的 I 是描述 cTnT N 末端可变区的删除如何恢复被抑制的 TnI 样 C 端构象导致肌丝 ATP 酶和收缩的条件性抑制动力学。目标 II 是评估 cTnT-ND 补偿心脏功能障碍的有效性和通过体内和离体功能研究提高心力衰竭小鼠模型的心脏效率。目标 III 是评估 cTnT-ND 对心脏功能、储备和重塑的长期影响正常和衰竭的小鼠心脏可转化为心力衰竭的新疗法。意义：心力衰竭是心血管疾病治疗的一个重大挑战。 b-肾上腺素能阻滞剂已被证明在临床上可有效治疗慢性充血性心力衰竭，减少收缩动力学的长期好处仍未完全了解。 cTnT N 末端片段的缺失在心肌缺血和压力期间自然发生过载作为翻译后调节，选择性地降低心肌的收缩速度，延长快速射血期以增加每搏输出量和心脏效率。提供了一种新颖且有针对性的方法来维持精力充沛期间的基线心脏功能使用多层次和综合方法，我们的研究将为危机和心力衰竭奠定基础。将这种分子机制转化为心力衰竭的新临床治疗方法。