Novel Mechanisms and Therapies in Heart Failure

心力衰竭的新机制和疗法

• 批准号: 8077985
• 负责人: Howard A Rockman
• 金额: $ 182.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077985
• 关键词: Novel; Mechanisms; Therapies; Heart; Failure

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.

描述（由申请人提供）：我们修订后的 PPG 的目标是识别有潜力成为心力衰竭治疗靶点的新分子和途径，其主题以肾上腺素能受体的信号传导机制为中心。在此修订后的应用程序中，我们将延续 PPG 所特有的出色协作环境。基于 Rockman、Koch、Stamler 和 Lefkowitz 之间已经存在且在 PPG 期间开花结果的自然合作，我们开发了一种集成方法来识别新型 betaAR 信号传导机制。在过去的资助周期中，这导致了许多高影响力的出版物和 betaAR 信号传导新机制的确定。实验组织经过精心设计，以便每个项目的具体目标都解决使用体外和细胞培养方法的 GPCR 信号传导的基本分子机制，以及将这些基本概念转化为肥厚和心力衰竭的相关体内模型。我们提出了 3 个项目，每个项目都解决肾上腺素信号传导的一个独特方面，并且将由项目负责人指导，他们都是各自领域的杰出科学家。 每个项目的主题是： 项目 1 (Rockman) 将研究 betaAR 信号传导的新颖方面，即在没有 G 蛋白激活的情况下使用 β-arrestin 促进心肌细胞存活途径；项目 2 (Koch) 将研究 G 蛋白偶联受体激酶 2 (GRK2) 的新方面，及其在心脏信号传导和生理学中的重要作用；项目 3 (Stamler) 将通过 GRK 和 β-arrestin 的 S-亚硝基化调节来研究 PAR 信号传导的新范式。我们还提出了两个科学核心，通过提供小动物专业知识（可以在体内测试我们在实验室的发现）以及蛋白质组和病毒资源，这两个科学核心对于该计划的成功至关重要，这将协同增强项目发现新信号蛋白和途径的潜力。 修订后的 PPG 的总体目标是探索 betaAR 信号传导、G 蛋白和 β-arrestins 激活的两种通用机制之间的相互作用，以及如何通过各种信号成分的翻译后修饰（磷酸化、泛素化、S-亚硝基化）来调节这些机制。研究结果将用于定义操纵这些最近发现的心力衰竭患者治疗机制的新策略。