CA++ SENSITIVITY IN STUNNED CARDIAC MYOCYTES

致昏心肌细胞对 CA 的敏感性

• 批准号: 6030650
• 负责人: MATTHEW R WOLFF
• 金额: $ 20.42万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030650
• 关键词: calcium flux; cardiac myocytes; chemical binding; endocardium; enzyme activity; heart contraction; heart function; molecular pathology; muscle tension; myocardial ischemia /hypoxia; myocardium; myofibrils; phosphorylation; swine; troponin

DESCRIPTION (adapted from the applicant's abstract): The objectives of the proposal are to determine molecular mechanisms of depressed post-ischemic myocardial function and assess their functional consequences in the context of a well defined model of myofibrillar contractility. Three specific aims are proposed: 1) Investigate mechanisms of reduced Ca2+ sensitivity of isometric tension. The role of altered phosphorylation states of troponin I and/or C protein and myofilament protein degradation will be assessed. The hypothesis that depressed contraction is due to reduced Ca2+ binding to troponin C because of defects in one or more troponin subunits, disruption of cross-bridge induced Ca2+ binding, or reduced cooperative effects of strong binding cross-bridges will be tested. 2) Determine molecular mechanisms underlying the decreased rate of cross-bridge detachment as measured by Vmax. Viscoelastic effects will be measured to determine if there is an increase in internal load in stunning. Exchanges of Tn subunits and myosin light chain 2 (LC2) will determine whether changes in endogenous proteins contribute to the depression of Vmax. 3) Investigate whether stunning depresses the kinetics of cross-bridge cycling during isometric contraction by measuring the rate constant of isometric force redevelopment (Ktr). Effects on cooperative alterations in cross-bridge cycling rates will be determined, and the roles of endogenous Tn subunits and LC2 in depressed kinetics will be investigated. Insights into the molecular mechanisms and roles of decreased Ca2+ sensitivity and altered kinetics of cross-bridge cycling in contractile dysfunction of postischemic stunned myocardium will be sought.

描述(改编自申请人的摘要)： 建议确定缺血后抑郁的分子机制 在此背景下评估心肌功能及其功能后果 一个明确的肌原纤维收缩能力模型。三个具体目标 建议：1)研究钙离子敏感性降低的机制 等长张力。肌钙蛋白I磷酸化状态改变的作用 和/或C蛋白和肌丝蛋白的降解将被评估。这个 认为收缩抑制是由于钙离子结合减少所致 肌钙蛋白C因一个或多个肌钙蛋白亚基缺陷而中断 跨桥诱导的钙结合，或减少的协同效应 将测试具有较强约束性的跨桥。2)确定分子 跨桥剥离率降低的原因是 以Vmax衡量。将测量粘弹性效应以确定是否 在令人震惊的情况下，内部负荷会增加。TN亚基的交换 而肌球蛋白轻链2(Lc2)将决定内源性的变化 蛋白质参与了Vmax的降低。3)调查是否 眩晕抑制等长骑行跨桥运动的动力学 通过测量等长力再发展的速率常数进行收缩 (Ktr)。合作变更对跨桥骑行率的影响 内源TN亚基和Lc2的作用 将对抑制动力学进行研究。对分子的洞察 钙敏感性降低和钙动力学改变的机制和作用 跨桥骑行对缺血后顿抑患者收缩功能障碍的影响 将寻找心肌。