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的目标是确定有可能成为心力衰竭治疗靶点的新型分子和途径，主题以肾上腺素能受体的信号传导机制为中心。在这个修改后的应用程序中，我们将继续这个PPG特有的梦幻般的协作环境。基于Rockman，Koch，Stamler和Lefkowitz之间已经存在的自然合作，并且在PPG期间已经开花，我们已经开发了一种识别新型β AR信号传导机制的综合方法。在过去的资助周期中，这导致了一些高影响力的出版物和β AR信号转导的新机制的鉴定。精心设计的实验组织，使每个项目的具体目标都解决了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大和心力衰竭的相关体内模型。我们提出了3个项目，每个项目都解决了肾上腺素能信号传导的一个独特方面，并将由各自领域的杰出科学家领导。 每个项目的主题是：项目1（Rockman）将研究β AR信号转导的新方面，即在G蛋白活化的情况下使用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（GRK 2）的新方面，及其在心脏信号转导和生理学中的重要作用;项目3（Stamler）将研究通过GRK的S-亚硝基化调节PAR信号传导的新模式，抑制素。我们还提出了两个科学核心，通过提供小动物专业知识，我们在实验室的发现可以在体内进行测试，以及蛋白质组学和病毒资源，这将协同增强项目发现新信号蛋白和途径的潜力，这对该计划的成功至关重要。 本修订PPG的总体目标是探索β AR信号传导的两种通用机制的相互作用，G蛋白和β-抑制蛋白的激活，以及这些如何通过各种信号传导组分的翻译后修饰（磷酸化，泛素化，S-亚硝基化）进行调节。这些结果将被用来定义新的策略来操纵这些最近发现的机制，用于治疗心力衰竭患者。