Contractile Force in Human Heart Failure

描述(申请人？S逐字描述)：泵的衰落 人类心力衰竭的功能特征在其基础上是抑郁 肌细胞功能。潜在的细胞机制尚不清楚。一个问题 试图证明肌丝对钙的敏感性和张力降低 人类心力衰竭的发展是人类捐献的心脏组织，这是 用作去皮心肌细胞收缩力测量的对照， 通常在器官采集前经历巨大的肾上腺素能刺激。 这可能解释了为什么在以前对人体组织的研究中，它是CHF 具有更强的钙敏感性和张力发育的心肌细胞 而不是供体心肌细胞。我们假设捐赠者的人体心肌是 在器官采集时被广泛的磷酸化。我们还假设 在终末期人类心力衰竭中，钙含量下降 敏感度和张力的发展。我们假设也可能存在差异 在比较特发性扩张症时这种功能障碍的程度 心肌病与缺血性心肌病。我们有两个具体目标：目标1) 人供体心肌细胞对肌丝钙敏感性的测定 去磷酸化后。目的2)评价人体肌丝钙敏感性 缺血性和特发性心力衰竭组织的心肌细胞及其结果比较 在这些群体之间。首先，我们建议应用一种技术 使人类供体心肌细胞去磷酸化。试验将首先在#年进行 更丰富的大鼠心肌，已经复制成功 在其他实验室取得成果，并在我们自己的实验室实现结果标准化 实验室。其次，我们将在人类充血性心力衰竭中进行类似的实验 心肌细胞。意义：关于分子的详细知识 人类心力衰竭的机制将推动小说的发展 旨在与这种致命疾病作斗争的治疗策略。

DESCRIPTION (the applicant?s description verbatim): The decline in pump function characteristic of human heart failure has at its basis a depression of myocyte function. The underlying cellular mechanisms are unknown. A problem with trying to demonstrate decreased myofilament Ca2+ sensitivity and tension development in human heart failure is that human donor heart tissue, which is used as the control in skinned cardiocyte measurements of contractile force, has usually undergone tremendous adrenergic stimulation prior to organ harvest. This may explain why in previous studies on human tissue it has been the CHF cardiocytes that has had greater calcium sensitivity and tension development than donor cardiocytes. We hypothesize that donor human myocardium is extensively phosphorylated at the time of organ harvest. We also hypothesize that in end-stage human heart failure, there is a decrease in calcium sensitivity and tension development. We hypothesize distinctions may also exist in the degree of this dysfunction when comparing idiopathic dilated cardiomyopathy vs. ischemic cardiomyopathy. We have two specific aims: Aim 1) Assess myofilament calcium sensitivity of human donor cardiocytes before and after dephosphorylation. Aim 2) Assess myofilament calcium sensitivity of human cardiocytes of ischemic and idiopathic heart failure tissue and compare results between these groups. First, we propose to apply a technique of dephosphorylating human donor cardiocytes. Trials will first be conducted in rat myocardium, which is more abundant, to duplicate the success already achieved in other laboratories and to standardize results in our own laboratory. Second, we will conduct similar experiments in human CHF cardiocytes. Significance: Detailed knowledge regarding the molecular mechanisms of human heart failure will promote the development of novel treatment strategies aimed to combat this lethal disease.