CONTROL MECHANISMS OF CARDIAC PROTEINS AND ENZYMES

心脏蛋白质和酶的控制机制

• 批准号: 2464927
• 负责人: AMIR ASKARI
• 金额: $ 79.22万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2464927
• 关键词: adenosinetriphosphatase; cardiac glycosides; heart cell; membrane transport proteins; sodium potassium exchanging ATPase

This application is for the renewal of a program project that was initiated in 1986. The proposed program is now focused on the structure- function relationships of the ion pumps that are sensitive to cardiac glycosides, and on the elucidation of mechanisms by which cardiac glycosides and intracellular calcium ion regulate the growth of cardiac cells. The participating investigators with expertise in membrane biochemistry, molecular genetics, protein chemistry, cell biology, and cardiac physiology will combine their efforts to conduct the following studies: Project I deal with NAK-ATPase which is the receptor for the positive inotropic actions of cardiac glycoside. The proposed studies are designed to reveal the structures of the ATP-sensitive occlusion pockets and their roles in the transport function of NaK-ATPase. Studies of Project II are aimed to characterize the structure of a newly discovered human HK-ATPase that is also sensitive to cardiac glycosides, and to reveal the structural bases of the ion selectivities of this and related ion transporting ATPases. Studies of Project III are based on the recent discovery that cardiac glycosides induce hypertrophy in cultured cardiac myocytes, and are aimed to define the specific signal transduction pathways that begin with the partial inhibition of NaK-ATPase and lead to Ca2+-dependent transcriptional regulations of cardiac myocyte genes. Project IV focuses on the molecular mechanisms through which intracellular Ca2+-dependent proteases (calpains) regulate the signal transduction pathways involved in the proliferative growth of fibroblasts associated with pathological cardiac hypertrophy. The proposed studies are expected to advance our knowledge of the basic mechanisms that are central to the regulation of cardiac contractility and growth in the normal and the failing hearts.

本申请是为了更新一个程序项目， 始于1986年。目前，该计划的重点是结构- 对心脏敏感的离子泵的功能关系 糖苷，并阐明机制，心脏 糖甙和细胞内钙离子调节心肌细胞生长 细胞具有膜专业知识的参与研究者 生物化学，分子遗传学，蛋白质化学，细胞生物学， 心脏生理学将结合联合收割机的努力进行以下工作 研究：项目I涉及NAK-ATP酶，这是一种受体， 强心苷的正性肌力作用。拟议的研究是 旨在揭示ATP敏感的闭塞袋的结构 以及它们在NaK-ATP酶转运功能中的作用。研究 项目二的目的是描述一个新发现的 人HK-ATP酶也对强心苷敏感， 揭示了这种和相关的离子选择性的结构基础 离子转运ATP酶。项目III的研究基于最近的 发现强心苷诱导培养心肌细胞肥大 肌细胞，并旨在定义特定的信号转导 开始与部分抑制NaK-ATP酶的途径，并导致 心肌细胞基因的钙离子依赖性转录调控。 项目四的重点是通过细胞内的分子机制， Ca 2+依赖性蛋白酶（calpains）调节信号转导 参与成纤维细胞增殖生长的途径 病理性心脏肥大预计拟议的研究将 为了增进我们对基本机制的了解， 调节正常人和老年人的心肌收缩力和生长 心脏衰竭