权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：改良肌钙蛋白T改善心力衰竭患者心功能