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）：我们修订的PPG的目的是识别具有新的分子和途径，这些分子和途径有可能成为治疗心力衰竭的治疗靶标的主题，其主题为肾上腺素能受体的信号机制。在此修订后的应用程序中，我们将继续以该PPG为特征的奇妙协作环境。基于Rockman，Koch，Stamler和Lefkowitz之间已经进行的自然合作，并且在PPG期间开花，我们开发了一种综合方法来识别新型的Betaar信号传导机制。在过去的融资周期中，这导致了许多高影响出版物以及对Betaar信号的新机制的识别。制定了实验组织，以便使用体外和细胞培养方法来解决每个项目的具体目标，以解决GPCR信号传导的基本分子机制，并将这些基本概念转化为相关的体内肥大和心力衰竭模型。我们提出了3个项目，每个项目都解决了肾上腺素能信号的独特方面，并将由项目领导者指导，这些项目领导者是其领域的杰出科学家。 每个项目的主题是：项目1（Rockman）将研究Betaar信号传导的新方面，该方面使用Beta-arrestin在没有G蛋白激活的情况下促进心肌细胞的存活途径；项目2（Koch）将研究​​G蛋白偶联受体激酶-2（GRK2）的新颖方面，及其在心脏的信号传导和生理学中的重要作用；项目3（Stamler）将通过通过S-亚硝基化和？arrestin调节来研究用于PAR信号传导的新paradigm。我们还提出了两个科学核心，它们通过提供小型动物专业知识，是该计划成功的重要性，在该方面我们可以在板凳上的发现进行体内测试，以及蛋白质组学和病毒资源，这些资源将协同增强潜在的项目，以发现新的信号蛋白和途径。 该修订后的PPG的总体目标是探索βARS信号传导的两种通用机制，G蛋白和β-arre依的激活，以及如何通过过翻译后修改（磷酸化，泛素化，泛素化，S-硝基化）来调节各种信号传导成分的各种信号成分。结果将用于定义操纵这些最近发现的心力衰竭患者治疗的新策略。