Novel Mechanisms and Therapies in Heart Failure

描述(申请人提供)：我们修订的PPG的目标是识别有潜力成为治疗心力衰竭治疗靶点的新分子和途径，主题集中在肾上腺素能受体的信号机制上。在这个修订后的应用程序中，我们将继续这个PPG所特有的出色的协作环境。基于Rockman、Koch、Stamler和Lefkowitz之间已经存在并在PPG期间开花结果的自然合作，我们开发了一种综合方法来识别新的BetaAR信号机制。在过去的供资周期中，这导致了一些影响很大的出版物，并确定了BetaAR信号的新机制。实验组织是精心设计的，每个项目的具体目标都涉及使用体外和细胞培养方法的GPCR信号的基本分子机制，以及将这些基本概念转化为相关的体内肥厚和心力衰竭模型。我们提出了三个项目，每个项目都解决了肾上腺素能信号的一个独特方面，并将由各自领域的杰出科学家的项目负责人指导。每个项目的主题是：项目1(Rockman)将研究在没有G蛋白激活的情况下使用β-arrestin促进心肌细胞生存的β-AR信号的新方面；项目2(Koch)将研究G蛋白偶联受体激酶-2(GRK2)的新方面，及其在心脏信号和生理中的重要作用；项目3(Stamler)将研究通过S调节PAR信号的新范式-GRK和β-arrestin的硝基化。我们还提出了两个对该计划的成功不可或缺的科学核心，既提供了小动物专业知识(我们在实验台上的发现可以在体内进行测试)，也提供了蛋白质组和病毒资源，将协同增强项目发现新信号蛋白和通路的潜力。 这一修订的PPG的总体目标是探索两种普遍的信号机制之间的相互作用，即激活G蛋白和β-拦阻蛋白，以及这些机制如何受到各种信号成分的翻译后修饰(磷酸化、泛素化、S亚硝化)的调节。这些结果将被用来定义操纵这些最近发现的治疗心力衰竭患者的机制的新策略。

DESCRIPTION (provided by applicant): The goal of our revised PPG is to identify novel molecules and pathways that have the potential to become therapeutic targets in the treatment of heart failure with a theme centered on signaling mechanisms of adrenergic receptors. In this revised application, we will continue the fantastic collaborative environment that has characterized this PPG. Based on natural collaborations that were already in place between Rockman, Koch, Stamler and Lefkowitz, and which have flowered during the PPG, we have developed an integrated approach to identifying novel betaAR signaling mechanisms. Over the past funding cycle, this has led to a number of high impact publications and the identification of novel mechanisms of betaAR signaling. The experimental organization is crafted so that the specific aims for each project address both basic molecular mechanisms of GPCR signaling using in vitro and cell culture methods, and the translation of these fundamental concepts into relevant in vivo models of hypertrophy and heart failure. We propose 3 projects that each addresses a unique aspect of adrenergic signaling and which will be directed by project leaders that are distinguished scientists in their field. The themes for each project are: Project 1 (Rockman) will study novel aspects of betaAR signaling that uses beta-arrestin to promote cardiomyocyte cell survival pathways in the absence of G protein activation; Project 2 (Koch) will study novel aspects of the G protein-coupled receptor kinase-2(GRK2), and its important roles in the signaling and physiology of the heart; Project 3 (Stamler) will study a newparadigm for PAR signaling through regulation by S-nitrosylation of GRK and ?-arrestin. We also propose two scientific cores that are integral to the success of the program by providing both small animal expertise, where our discoveries at the bench can be tested in vivo, and proteomic and viral resources that will synergistically enhance the projects potential to discover new signaling proteins and pathways. The overall goal of this revised PPG is to explore the interplay of two universal mechanisms for signaling by betaARs, activation of G proteins and beta-arrestins, and how these are regulated by post-translational modifications (phosphorylation, ubiquitination, S-nitrosylation) of various signaling components. The results will be used to define novel strategies for manipulation of these recently discovered mechanisms for the therapy of patients with heart failure.