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

本申请是重新提交的竞争继续计划项目赠款， 始于1986年。拟议中的研究是该计划在当前阶段取得进展的结果。 该项目由三个项目和两个支助核心组成，侧重于以下中心主题： 洋地黄通过心脏Na* 7 K +-ATP酶诱导的信号传导。具有专业知识的参与研究者 在膜生物化学、蛋白质化学、分子遗传学、细胞生物学和综合心血管 生理学/药理学将联合收割机进行以下研究：项目I试图 确定洋地黄诱导1A类激活的分子和细胞机制 PI 3 K/Akt通路导致心肌细胞肥大，并评估这种看似良性的肥大是否 能够对抗病理性肥大的有害作用及其后果。项目 11集中在解开的分子相互作用，构成了Na+/K+-的形成。 ATP酶/Src复合物，并评价该复合物作为启动多个ATP酶的受体。 洋地黄诱导的信号通路及其在心脏中的功能后果。项目三的重点是 洋地黄诱导的心肌细胞膜Na+/K+-ATP酶和ATP敏感性 心肌线粒体K+通道，并提出了确定分子和亚细胞 这种沟通的机制，以及由此产生的数字诱导的心脏保护， 缺血再灌注损伤核心单位的目的是提供行政支助和效率 管理实验动物和项目的其他共享资源。这些拟议 这些研究有望扩大对心脏NaVK 4 - 1的新认识的生理作用的认识。 ATP酶的活性，为缺血性心脏病的防治提供新的途径 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.