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CONTRACTILE FORCE AND CALCIUM HANDLING IN HEART FAILURE

心力衰竭时的收缩力和钙处理

基本信息

批准号：
2668721
负责人：
Pieter P. de TOMBE
金额：
$ 7.45万
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：
1996
资助国家：
美国
起止时间：
1996-06-01 至 1999-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2668721
关键词：
calcium flux congestive heart failure disease /disorder model fluorescent dye /probe heart contraction heart dimension /size heart function laboratory rat protein biosynthesis protein isoforms sarcomeres

项目摘要

Congestive heart failure (CHF) is associated with impaired myocardial cell function. Alterations in the content and isoform distribution of contractile proteins and key proteins involved in calcium handling have been found in CHF. Thus, decreased force development in CHF may result from altered calcium handling or from reduced contractile protein function. Conflicting results regarding calcium handling in CHF have been obtained, which may be due to uncertainties with the methods used to measure intracellular calcium. Likewise, whether contractile protein function is impaired in CHF is also uncertain because sarcomere length was not measured and controlled. Thus, the relationship between alterations in protein synthesis and impaired myocardial cell function in CHF is still uncertain. Accurate knowledge regarding the cellular processes that participate in the development of CHF is critical to the development of innovative strategies aimed to combat CHF. The overall goal of the present research proposal is to determine the mechanism of reduced myocardial force development in an experimental animal model of CHF. The experimental animal model that we will use is CHF in rats, induced by left ventricular myocardial infarction. The right ventricles of these small rodents can provide trabeculae that are sufficiently thin and homogenous to allow i) state of art mechanical studies at the level of the sarcomere, and ii) accurate calibrated measurements of intracellular calcium. Preliminary data, using this model, indicate depressed function of isolated right ventricular trabeculae at end-stage CHF. Specifically we will test the hypothesis that reduced myocardial force development during the development of CHF is caused by: 1) Reduced intracellular calcium concentration during systole. Intracellular calcium will be measured directly in trabeculae by fluorescence calcium probe. To obtain unambiguous data, in-vivo calibration will be obtained by using the free salt of Indo-1, introduced into the cytolol by a recently developed technique. 2) Reduced maximum force development or calcium responsiveness of the contractile apparatus. Force development will be measured in permeabilized trabeculae as function of free calcium. Laser diffraction techniques will be used to accurately measure and control sarcomere length such that accurate and unambiguous data are obtained.

充血性心力衰竭（CHF）与心肌细胞受损有关功能含量和异构体分布的改变收缩蛋白质和参与钙处理的关键蛋白质在CHF中发现。因此，CHF中的力发展减少可能导致由于钙处理改变或收缩蛋白减少功能关于CHF中钙处理的验证结果已被这可能是由于所用方法的不确定性，测量细胞内钙。同样，收缩蛋白功能受损的CHF也是不确定的，因为肌节长度不受测量和控制。因此，改变之间的关系 CHF中蛋白质合成和受损的心肌细胞功能仍然是不确定关于细胞过程的准确知识，参与CHF的发展对发展至关重要创新战略，旨在打击CHF。当前的总体目标研究建议是确定心肌细胞减少的机制，在CHF实验动物模型中的力发展。的我们将使用的实验动物模型是大鼠CHF，心室心肌梗塞这些小的右心室啮齿类动物可以提供足够薄和均匀的骨小梁为了允许i）肌节水平的现有技术的机械研究，和ii）细胞内钙的精确校准测量。使用该模型的初步数据表明，在终末期CHF时孤立的右心室小梁。另外还将检验这一假设，即减少心肌力量的发展， CHF的发展是由以下原因引起的： 1)收缩期细胞内钙浓度降低。细胞内钙将直接在小梁中测量，荧光钙探针为了获得明确的体内数据将通过使用引入的Indo-1的游离盐来获得校准注入细胞醇中。 2)最大力发展或钙反应性降低，收缩器将在透化的小梁作为游离钙的函数。激光衍射技术将用于精确测量和控制肌节长度，获得了准确和明确的数据。