MECHANISMS AND THERAPY OF CIRCULATORY DISEASE

循环系统疾病的机制和治疗

• 批准号: 2211849
• 负责人: LARRY R. JONES
• 金额: $ 116.37万
• 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/2211849
• 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 关于调节主要的特定分子机制 心肌和血管肌肉的功能，包括收缩性、生长 和细胞增殖。 为此选择的统一子主题 竞争性更新是：Ca2+ 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 通过互动和协作研究，追求四个主要 总分主题下的目标： 1) 评估 在诱导或维持中选择细胞周期调节蛋白 转基因中靶向表达对心肌细胞增殖的影响 动物模型； 2) 描绘关键蛋白的调控模式 磷酸酶参与生长、细胞周期和 心脏和血管细胞的收缩功能； 3）确定 Ca2+ 在心肌收缩和细胞增殖中的作用 细胞内摄取和释放机制的具体研究； 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 Ca2+ 依赖性蛋白水解。 已立项4个项目、3个核心单元 为实现这些目标而聚集。 项目1调查 Ca2+依赖性半胱氨酸蛋白酶对血管细胞的调节 循环。 项目2探讨心肌细胞增殖机制 通过在转基因小鼠中表达突变的生长调节蛋白。 项目3分析心脏肌浆中的Ca2+转运机制 通过蛋白质的结构/功能分析， 受磷蛋白和Ca 2+ ATP酶。 项目4研究监管 心脏和血管组织共有的磷蛋白磷酸酶 调节收缩性和生长。 总的来说，该计划 项目应用蛋白质生物化学和分子生物学方法 生物学研究细胞的高度基本机制 心血管组织的调节。 转基因技术的常见用途 探索生理环境中蛋白质功能的动物模型 有望在多个层面产生新颖的观察结果，包括 生长和收缩功能。 提出的基础研究有 对心力衰竭的健康相关问题具有重要意义， 心肌的再生和血管组织生长的调节。