Contractile Force in Human Heart Failure

申请人（The applicant？s description verbatim）：泵的下降 人类心力衰竭的功能特征的基础是 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Ca 2+敏感性和张力降低 人类心脏衰竭的发展是人类供体心脏组织， 用作收缩力的去皮心肌细胞测量中的对照， 在器官摘取前通常都经历了肾上腺素能的强烈刺激 这可以解释为什么在以前的人体组织研究中， 具有更高钙敏感性和张力发展的心肌细胞 比捐赠的心肌细胞更好我们假设供体心肌 在器官采集时被广泛磷酸化。我们还假设 在人类心力衰竭末期， 敏感性和张力发展。我们假设， 在这种功能障碍的程度上， 心肌病与缺血性心肌病。我们有两个具体目标：目标1） 评估人供体心肌细胞在移植前和移植后的肌丝钙敏感性 去磷酸化后。目的2）评价人肌丝钙敏感性 缺血性和特发性心力衰竭组织的心肌细胞并比较结果 这些群体之间。首先，我们建议应用一种技术， 去磷酸化人供体心肌细胞。审判将首先在 大鼠心肌，这是更丰富的，复制成功已经 在其他实验室实现，并在我们自己的实验室标准化结果 实验室其次，我们将在人类CHF中进行类似的实验 心肌细胞重要性：关于分子的详细知识 对人类心力衰竭机制的研究将促进新型 旨在对抗这种致命疾病的治疗策略。

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.