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.

项目标题：肌钙蛋白T的修饰以改善心力衰竭的心脏功能项目摘要心脏肌肉收缩通过肌瘤薄细丝中的肌钙蛋白复合物调节。肌钙蛋白由三个蛋白质亚基组成：肌钙蛋白C（TNC），肌钙蛋白I（TNI）和肌钙蛋白T（TNT）。限制性有选择地去除心脏TNT（CTNT）的N末端变量区域的切割自然发生适应心肌能量危机，例如缺血或压力超负荷。 N末端截短的CTNT（CTNT-ND）保留在功能上改变的心脏肌膜中调低左心室收缩速度，该速度拉长了快速弹出的相位，从而增加中风量并提高心脏的能量效率。拟议的研究将表征 CTNT-ND改变肌丝活动的动力学的机制使心脏得以实现在生理上弥补能源危机，并最终为发展奠定基础新的针对心力衰竭的目标治疗方法。提出了三个具体目标：目的我是表征CTNT的N末端变量区域的删除如何恢复被压抑的 TNI样的C末端构象会导致肌丝ATPase和收缩的条件抑制动力学。 AIM II是评估CTNT-ND在补偿心脏功能障碍和通过体内和体内功能研究提高心力衰竭小鼠模型的心力衰竭心脏效率。 AIM III是评估CTNT-ND对心脏功能，保留和重塑的长期影响鼠标心脏正常和失败的心脏转化为心力衰竭的新疗法。意义：心力衰竭是心血管疾病管理的主要挑战。尽管事实证明，b-肾上腺素能阻断在治疗慢性充血性心力衰竭方面具有临床有效减少收缩动力学的长期益处仍然没有完全理解。限制性 CTNT的N末端段的缺失自然发生在心肌缺血和压力期间超负荷作为翻译后调节，以选择性调整心脏肌肉的收缩速度和延长快速弹出阶段以增加中风量和心脏效率。这种机制提供了一种新颖且特别针对的方法来维持能量期间基线心脏功能危机和心力衰竭。使用多层和集成的方法，我们的研究将为将这种分子机制转化为心力衰竭的新临床治疗方法。