MOLECULAR BIOLOGY AND PATHOPHYSIOLOGY OF HYPERTROPHIC CARDIOMYOPATHY

肥厚型心肌病的分子生物学和病理生理学

• 批准号: 6109269
• 负责人: NEAL DAVID EPSTEIN
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6109269
• 关键词: clinical research; disease /disorder model; gene mutation; genetic disorder; genetically modified animals; human subject; hypertrophic myocardiopathy; laboratory mouse; molecular pathology; muscle function; myocardium disorder; myosins; protein isoforms; protein structure function; stretch receptors; clinical research; disease /disorder model; gene mutation; genetic disorder; genetically modified animals; human subject; hypertrophic myocardiopathy; laboratory mouse; molecular pathology; muscle function; myocardium disorder; myosins; protein isoforms; protein structure function; stretch receptors

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease characterized by an increased left ventricular mass in the absence of another cause for hypertrophy. This disease provides a model to study the process of cardiac hypertrophy. In approximately 15% of affected families, the disease gene encodes a beta myosin heavy chain (BMHC) gene with a missense mutation. We have identified 32 distinct mutations in the BMHC gene and mapped them onto the 3D structure of the head of skeletal myosin. The mutations cluster in 4 regions, suggesting different types of interference in the actomyosin cross-bridge kinetics as a function of mutation location. We have studied the mechanical properties of extracted mutant myosins and muscle fibers expressing these myosins, to analyze the pathophysiology at a molecular level. One of the clusters of mutations led us to the discovery of mutations in the myosin light chains which cause a variant of HCM characterized by an obstruction in the middle of the left ventricle. Through a series of arguments, the association of the myosin light chain mutations with the rare subtype of HCM led us to hypothesize the importance of the "stretch-activation response" to the function of the normal heart. The stretch-activation response in Drosophila flight muscle has been previously shown to be distorted by a mutation in the "regulatory" myosin light chain (RLC), resulting in flightless flies whose wings do not beat properly. We have developed transgenic mice expressing the mutant myosin "essential" light chain (ELC), from a patient with cardiac hypertrophy. The hearts from these mice also do not beat properly. That is, there is a shift of the frequency of maximum power output to a rate beyond the physiologic range, with consequent loss of oscillatory power. We have also cloned other genes that encode additional proteins that should influence the stretch-activation response. One of these genes as well as altered RLC genes have been expressed in transgenic mice as well. Our findings suggest a novel physiologic pathway by which cardiac efficiency may be influenced. We are presently exploring this phenomenon in greater detail through the genetic and mechanical analysis of the various transgenic mice.

肥厚的心肌病（HCM）是遗传的 心脏病的特征是左心室肿块增加 在没有另一个肥大原因的情况下。这种疾病 提供了研究心脏肥大过程的模型。在 大约15％的受影响家庭，该疾病基因编码A 具有错义突变的β肌球蛋白重链（BMHC）基因。 我们已经确定了BMHC基因中的32个不同的突变和 将它们映射到骨骼肌球蛋白头部的3D结构上。 四个区域的突变簇，提示不同类型的 干扰肌动蛋白跨桥动力学的作用 突变位置。我们研究了 提取的突变体肌球蛋白和肌肉纤维表达这些 肌球蛋白，分析分子水平的病理生理学。一 突变簇使我们发现了突变 引起HCM变体的肌球蛋白光链特征 通过左心室中间的阻塞。通过一个 一系列论点，肌球蛋白轻链的关联 HCM罕见亚型的突变使我们假设 “拉伸激活响应”对功能的重要性 正常的心。果蝇的拉伸激活反应 以前已经证明飞行肌肉被A扭曲 “调节”肌球蛋白轻链（RLC）中的突变，导致 无飞的苍蝇的翅膀无法正确跳动。我们有 开发了表达突变体肌球蛋白“必需”的转基因小鼠 轻链（ELC），来自心脏肥大的患者。这 这些老鼠的心也无法正常跳动。也就是说，有一个 将最大功率输出频率转移到超出速率 生理范围，随之而来的振荡能力丧失。 我们还克隆了编码其他蛋白质的其他基因 这应该影响拉伸激活反应。其中之一 基因以及改变的RLC基因已在 也是转基因小鼠。我们的发现暗示了一种新颖的生理学 心脏效率可能受到影响的途径。我们是 目前，通过 各种转基因小鼠的遗传和机械分析。