CROSSBRIDGE KINETICS OF NORMAL AND FAILING HUMAN HEARTS

描述（改编自申请人的摘要）：申请人的 目的是了解改变收缩的分子基础， 心室肌衰竭 在这项研究中，申请人将 检查，在基本的生物化学和机械步骤方面， 肌动球蛋白跨桥周期，非失败和 扩张型心肌病患者的心肌功能衰竭 或二尖瓣返流。 跨桥功能的不同之处在于 最有可能是由细丝蛋白的改变引起的， 其中肌钙蛋白亚基T是主要候选者。 申请人计划 通过确定在多大程度上改变 肌钙蛋白亚基T亚型化学计量学有助于抑制 肌原纤维功能通过改变的基本步骤， 跨桥循环 具体目标是：1）测量 钙激活的皮肤心室肌条的化学机械功能 显示正常心室功能的对照组患者， 来自另外两组表现出心室功能障碍的患者， 扩张型心肌病或二尖瓣返流; 2）确定 TnT同种型的改变改变了 来自非衰竭和衰竭心脏的心肌，证明因果关系 通过同种型取代的相关性; 3）建立程度， 选取了皮层纤维性能、兴奋带、 性能和左心室性能相关。

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.