CA++ SENSITIVITY STUNNED IN CARDIAC MYOCYTES

心肌细胞对 CA 的敏感性惊人

• 批准号: 2028819
• 负责人: WILLIAM P MILLER
• 金额: $ 19.2万
• 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/2028819
• 关键词: calcium flux; chemical binding; endocardium; enzyme activity; heart cell; heart contraction; heart function; molecular pathology; muscle cells; 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）： 建议是确定缺血后抑郁的分子机制， 心肌功能，并评估其功能后果的背景下， 肌原纤维收缩性的明确模型。 三个具体目标 1）研究了钙敏感性降低的机制， 等长张力 肌钙蛋白I磷酸化状态改变的作用 和/或C蛋白和肌丝蛋白降解。 的 假设收缩抑制是由于Ca 2+与 肌钙蛋白C由于一个或多个肌钙蛋白亚基的缺陷， 交叉桥诱导的Ca 2+结合，或减少的协同作用， 将测试强约束力的跨桥。 2)确定分子 跨桥分离率降低的潜在机制， 通过Vmax测量。 将测量粘弹效应以确定是否 在击晕中内部负荷增加。 Tn亚基交换 和肌球蛋白轻链2（LC 2）将决定内源性 蛋白质有助于降低Vmax。 3)调查是否 在等长时，击昏降低了过桥自行车的动力学 通过测量等长收缩力再发展的速率常数 （Ktr）。 对跨桥自行车速率的协同改变的影响 内源性Tn亚单位和LC 2在 将研究抑制的动力学。 深入了解分子 钙敏感性降低和动力学改变的机制和作用 跨桥循环对缺血后顿抑心肌收缩功能障碍的影响 将寻找心肌。