Regulation of cardiac power output in health and disease

项目摘要/摘要 家族性心肌病是30岁以下人群猝死的主要原因。两个密切相关的 心肌病、肥厚型心肌病(HCM)和扩张型心肌病(DCM)的特点是 室壁组织重塑，常伴有纤维化和心肌细胞紊乱。这些 疾病主要是由参与产生或调节能量输出的蛋白质突变引起的 心脏。有人认为，肥厚性心肌病是由分子水平的过度收缩引起的，而扩张性心肌病是由分子水平上的过度收缩引起的。 由分子水平上的收缩能力低下引起；然而，尚不清楚分子水平上的突变是如何 导致心脏细胞和组织的收缩能力和结构的改变。这项研究的目标是 更好地理解基于分子的变化和收缩能力变化之间的联系 细胞和组织水平上的结构。为了做到这一点，我们将利用生物物理、生化、细胞生物学、 和组织工程技术来测量这些组织规模的收缩能力，然后使用 建立数学模型来连接这些观测结果。我们将研究肌钙蛋白-T的两个模型突变 导致HCM或DCM。在目标1中，我们将剖析心脏中两个突变的分子机制。 肌钙蛋白-T、R92Q和K210，在分子水平上导致收缩过度和收缩减退， 分别进行了分析。在目标2中，我们将剖析这些突变对结构和收缩特性的影响 干细胞来源的心肌细胞和工程组织。在目标3中，我们将检查这些突变是否 影响细胞和组织对机械环境的感知和反应能力。这是自下而上 该方法将对心力产生的机制提供前所未有的见解，通过 心脏，以及家族性心肌病的发病机制。

Project Summary/Abstract Familial cardiomyopathies are the leading cause of sudden death in people under 30. Two closely related cardiomyopathies, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are characterized by remodeling of the tissue in the ventricular wall, often accompanied by fibrosis, and myocyte disarray. These diseases are primarily caused by mutation of the proteins involved in generating or regulating power output by the heart. It has been proposed that HCM is caused by hypercontractility at the molecular level while DCM is caused by hypocontractility at the molecular level; however, it is not clear how mutations at the molecular level lead to alterations in the contractility and structure of heart cells and tissues. The goal of this research is to better understand the connections between molecular-based changes and the changes in contractility and structure at the cellular and tissue levels. To do this, we will harness biophysical, biochemical, cell biological, and tissue engineering techniques to measure contractility across these scales of organization, and then use mathematical modeling to connect these observations. We will examine two model mutations in troponin-T that cause either HCM or DCM. In Aim 1, we will dissect the molecular mechanism of two mutations in cardiac troponin-T, R92Q and K210, that cause hypercontractility and hypocontractility at the molecular level, respectively. In Aim 2, we will dissect the effects of these mutations on the structural and contractile properties of stem cell derived cardiomyocytes and engineered tissues. In Aim 3, we will examine whether these mutations affect the ability of cells and tissues to sense and respond to their mechanical environment. This bottom up approach will give unprecedented insights into the mechanisms of cardiac force production, mechanosensing by the heart, and the disease pathogenesis of familial cardiomyopathies.