Regulation of cardiac power output in health and disease

健康和疾病状态下心脏功率输出的调节

• 批准号: 10365993
• 负责人: Michael J Greenberg
• 金额: $ 53.51万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365993
• 关键词: Actins; Address; Affect; Arrhythmia; Biochemical; Biological Assay; Biomedical Engineering; Biophysics; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cardiac Output; Cardiomyopathies; Cells; Data; Defect; Development; Dilated Cardiomyopathy; Disease; Environment; Fibrosis; Foundations; Goals; Health; Heart; Heart Diseases; Heart failure; Human; Hypertrophic Cardiomyopathy; Hypertrophy; In Vitro; Knowledge; Lead; Measures; Mechanics; Modeling; Molecular; Molecular Motors; Muscle; Muscle Cells; Mutation; Myocardial Contraction; Myosin ATPase; Output; Pathogenesis; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Phenocopy; Physiology; Population; Positioning Attribute; Production; Prognosis; Property; Proteins; Regulation; Research; Site; Structure; Sudden Death; Techniques; Testing; Thinness; Tissue Engineering; Tissues; Tropomyosin; Troponin T; Ventricular; base; cell motility; cell type; computerized tools; disease phenotype; disease-causing mutation; heart cell; heart function; induced pluripotent stem cell; inherited cardiomyopathy; insight; mathematical model; mechanotransduction; molecular scale; mutant; novel therapeutics; response; single molecule; stem cells; tool

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.

项目总结/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 心肌病、肥厚型心肌病（HCM）和扩张型心肌病（DCM）的特征在于： 心室壁组织的重塑，通常伴有纤维化和肌细胞紊乱。这些 疾病主要是由参与产生或调节功率输出的蛋白质突变引起的 心脏已经提出HCM是由分子水平上的过度收缩引起的，而DCM是由分子水平上的过度收缩引起的。 在分子水平上由收缩功能减退引起;然而，尚不清楚分子水平上的突变如何引起 导致心脏细胞和组织的收缩性和结构的改变。这项研究的目的是 更好地理解分子变化和收缩性变化之间的联系， 在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学，生物化学，细胞生物学， 和组织工程技术来测量这些组织尺度上的收缩性，然后使用 数学模型来连接这些观察。我们将研究肌钙蛋白-T的两个模型突变， 导致肥厚型心肌病或扩张型心肌病。在目的1中，我们将剖析两个心脏基因突变的分子机制， 肌钙蛋白-T、R92 Q和ERK 210，在分子水平上引起收缩过度和收缩不足， 分别在目标2中，我们将剖析这些突变对结构和收缩特性的影响 干细胞衍生的心肌细胞和工程组织。在目标3中，我们将研究这些突变是否 影响细胞和组织感知和响应机械环境的能力。这个自下而上 这种方法将使前所未有的洞察机制的心脏力量的生产，机械感应， 心脏和家族性心肌病的发病机制。