CROSSBRIDGE KINETICS OF NORMAL AND FAILING HUMAN HEARTS

描述(改编自申请人的摘要)：申请人的 目的是了解心脏收缩改变的分子基础。 人体心室肌功能衰竭。在这项研究中，申请人将 根据基本的生物化学和机械步骤来检查 肌动球蛋白交叉桥周期，非失败与非失败的区别 扩张型心肌病患者的心肌功能衰竭 或者二尖瓣返流。交叉桥功能的不同之处在于 最有可能的原因是细丝蛋白的变化， 哪个肌钙蛋白亚基T是首选候选者。申请人计划 通过确定变化的程度来直接检查这种可能性 在肌钙蛋白亚基T亚基中，化学计量学与抑郁症有关 肌原纤维功能通过改变的基本步骤 跨桥自行车。具体目标是：1)测量 钙激活皮肤心肌条的化学机械性能 对照组患者表现为正常的心功能和 来自另外两组表现为心功能不全的患者 扩张型心肌病或二尖瓣返流；2)确定程度 TnT异构体变化对动力学常数的影响(S) 来自非衰竭和衰竭心脏的心肌，证明了因果关系 通过异构体替换的相关性；3)建立的程度 哪些选择的结皮纤维性能指标、可兴奋条带 表现和左心室表现相关。

DESCRIPTION (adapted from the applicant's abstract): The applicant's objective is to understand the molecular basis of altered contraction of failing human ventricular muscle. In this study the applicant will examine, in terms of the elementary biochemical and mechanical steps of the actomyosin crossbridge cycle, the differences between non-failing and failing myocardial performance in patients with dilated cardiomyopathy or mitral regurgitation. The differences in crossbridge function are most likely caused by alterations in the thin filament proteins, of which troponin subunit T is a prime candidate. The applicant plans to examine this possibility directly by determining to what extent changes in troponin subunit T isoform stoichiometry contribute to depressed myofibrillar function via alterations in the elementary steps of the crossbridge cycle. The specific aims are to: 1) measure the chemomechanical function of Ca-activated skinned ventricular strips from a control group of patients exhibiting normal ventricular function and from two other groups exhibiting ventricular dysfunction associated with dilated cardiomyopathy or mitral regurgitation; 2) establish the extent to which TnT isoform alterations change the kinetic constant(s) in myocardium from non-failing and failing hearts, demonstrating causality of correlations by isoform substitutions; 3) establish the extent to which selected indices of skinned fiber performance, excitable strip performance, and left ventricular performance correlate.