MECHANISMS AND THERAPY OF CIRCULATORY DISEASE

循环系统疾病的机制和治疗

• 批准号: 2211850
• 负责人: LARRY R. JONES
• 金额: $ 122.29万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-03-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2211850
• 关键词: calcium flux; cardiovascular disorder; myocardium; phosphorylation; vascular smooth muscle

The overall goal of this program project is to generate new knowledge concerning specific molecular mechanisms that modulate the major functions of cardiac and vascular muscle, including contractility, growth and cellular proliferation. The unifying subtheme selected for this competitive renewal is: Ca2+ and protein phosphorylation: interacting subcellular mechanisms that modulate contractile and growth properties of cardiac and vascular muscles. This group of investigators will pursue, through interactive and collaborative studies, four major objectives under the general subtheme: 1) To evaluate the role of selected cell cycle regulatory proteins in the induction or maintenance of cardiac cellular proliferation by targeted expression in transgenic animal models; 2) To delineate the mode of regulation of key protein phosphatases implicated in modulation of growth, cell cycling and contractile function of cardiac and vascular cells; 3) To determine the role of Ca2+ in cardiac muscle contraction and cellular proliferation via specific investigation of intracellular uptake and release mechanisms; and 4) To identify and characterize specific steps in the vascular cell cycle that are dependent upon irreversible protein modification via Ca2+-dependent proteolysis. Four projects and three core units have been assembled to address these objectives. Project 1 investigates Ca2+-dependent cysteine proteases in regulation of the vascular cell cycle. Project 2 explores the mechanisms of cardiomyocyte proliferation by expressing mutant growth regulatory proteins in transgenic mice. Project 3 analyzes Ca2+ transport mechanisms in cardiac sarcoplasmic reticulum via structural/functional analysis of the proteins, phospholamban and Ca 2+ ATPase. Project 4 studies the regulation of phosphoprotein phosphatases common to both cardiac and vascular tissues that modulate contractility and growth. Collectively, this Program Project applies the methodologies of protein biochemistry and molecular biology to investigate highly fundamental mechanisms of cellular regulation in cardiovascular tissues. The common use of transgenic animal models to explore protein function in a physiological milieu promises to yield novel observations at several levels including both growth and contractile function. The basic studies proposed have important implications to the health-related problems of heart failure, regeneration of cardiac muscle and modulation of vascular tissue growth.

该计划项目的总体目标是产生新知识 关于特定的分子机制，调节主要的 心脏和血管肌肉的功能，包括收缩、生长 和细胞增殖。为此选择的统一副主题 竞争性更新是：钙和蛋白质磷酸化：相互作用 调节收缩和生长特性的亚细胞机制 心脏和血管的肌肉。这组调查人员将 通过互动和合作学习，开展四大 总副主题下的目标：1)评价 选择性细胞周期调控蛋白在诱导或维持中的作用 转基因靶向表达对心肌细胞增殖的影响 动物模型；2)描述关键蛋白的调控方式 磷酸酶参与调节生长、细胞周期和 心脏和血管细胞的收缩功能；3)测定 钙离子在心肌收缩和细胞增殖中的作用 具体研究细胞内摄取和释放机制； 以及4)识别和表征血管细胞中的特定步骤 依赖于不可逆蛋白质修饰的循环 依赖于钙离子的蛋白分解。已完成四个项目和三个核心单位 为实现这些目标而聚集在一起。项目1调查 钙依赖性半胱氨酸蛋白酶在血管细胞调控中的作用 周而复始。项目2探索心肌细胞增殖的机制 通过在转基因小鼠中表达突变的生长调节蛋白。 项目3分析心肌肌浆中钙离子的转运机制 通过对蛋白质的结构/功能分析， 磷蛋白和钙-三磷酸腺苷酶。项目4研究了对 心脏和血管组织中常见的磷酸蛋白磷酸酶 调节收缩和生长的物质。总而言之，本计划 该项目应用了蛋白质生物化学和分子生物学的方法 生物学研究细胞的高度基础机制 心血管组织的调节。转基因的常用方法 在生理环境中探索蛋白质功能的动物模型 承诺在几个层面上产生新的观察结果，包括 生长和收缩功能。建议的基础研究有 对心力衰竭的健康相关问题的重要影响， 心肌再生和血管组织生长调节。