Cardiac Na+/K+-ATPase: Digitalis-Induced Signaling through P13K/Akt Pathway

此申请是为竞争延续的计划项目赠款重新提交的申请 发起于1986年。拟议的研究是该计划在当前阶段进展的产物 供资期间，由三个项目和两个支助核心组成，重点是 洋地黄通过心肌Na*7K-ATPase诱导信号传导。有专业知识的参与调查人员 膜生物化学、蛋白质化学、分子遗传学、细胞生物学和综合心血管 生理学/药理学将结合他们的努力进行以下研究：项目I试图 确定洋地黄诱导A类分子活化的分子和细胞机制 PI3K/Akt通路导致心肌细胞肥大，并评估这种看似良性的肥大 能够对抗病理性肥厚及其后果的有害影响。项目 11集中于解开构成Na/K-形成的分子相互作用。 ATPase/Src复合体，以及该复合体作为多聚体启动受体的评价 洋地黄诱导的信号通路及其在心脏中的功能后果。项目III的重点是 洋地黄诱导心肌细胞膜Na/K-ATPase和ATP敏感性之间的通讯 K通道，并建议确定分子和亚细胞 这种交流的机制，以及由此产生的洋地黄诱导的心脏保护 缺血再灌注损伤。核心单位旨在提供行政支持和高效 管理实验动物和其他共享资源的计划。这些建议 预计研究将扩大关于心脏NaVK4-新认识的生理作用的知识。 ATPase的表达，为防治缺血性心脏病的新途径提供依据 疾病和心力衰竭。

This application is the resubmission for the competing continuation of a program project grant that was initiated in 1986. The proposed research is the outgrowth of the program's progress during the current funding period, and consists of three projects and two supporting cores, focused on the central theme of digitalis-induced signaling through the cardiac Na*7K+-ATPase. The participating investigators with expertise in membrane biochemistry, protein chemistry, molecular genetics, cell biology, and integrative cardiovascular physiology/ pharmacology will combine their efforts to conduct the following studies: Project I attempts to determine the molecular and cellular mechanisms by which the digitalis-induced activation of class 1A PI3K/Akt pathway leads to cardiac myocyte hypertrophy, and to assess if this seemingly benign hypertrophy is capable of antagonizing the deleterious effects of pathological hypertrophy and its consequences. Project 11 concentrates on the unraveling of the molecular interactions that constitute the formation of the Na+/K+- ATPase/Src complex, and on the evaluation of this complex as the receptor for the initiation of the multiple digitalis-induced signaling pathways and their functional consequences in the heart. Project III focuses on the established digitalis-induced communication between cardiac sarcolemmal Na+/K+-ATPase and ATPsensitive K+ channels of cardiac mitochondria, and proposes to determine the molecular and subcellular mechanisms of this communication, and the resulting digitalis-induced protection of the heart against ischemia-reperfusion injury. The core units are designed to provide administrative support and efficient management of the experimental animals and other shared resources of the program. These proposed studies are expected to expand knowledge on the newly appreciated physiological roles of cardiac NaVK4- ATPase, and to provide the bases for novel approaches to the prevention and treatment of ischemic heart disease and heart failure.