Novel Mechanisms and Therapies in Heart Failure

心力衰竭的新机制和疗法

• 批准号: 8323340
• 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/8323340
• 关键词: Address; Adrenergic Agents; Adrenergic Receptor; Animals; Arrestins; Beta-Adrenergic Receptor Kinase 1; Cardiac Myocytes; Cell Culture Techniques; Cell Survival; Collaborations; Environment; Flowers; Funding; G Protein-Coupled Receptor Signaling; GRK; GTP-Binding Proteins; Goals; Heart; Heart failure; Hypertrophy; In Vitro; Methods; Molecular; Pathway interactions; Patients; Phosphorylation; Physiology; Post-Translational Protein Processing; Proteomics; Publications; Regulation; Resources; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Testing; Translations; Ubiquitination; Viral; adrenergic; base; beta-arrestin; in vivo; in vivo Model; novel; novel strategies; programs; protein activation; success; therapeutic target

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的目标是确定新的分子和途径，这些分子和途径有潜力成为治疗心力衰竭的治疗靶点，主题集中在肾上腺素能受体的信号机制。在这个修改后的应用程序中，我们将继续这个PPG所特有的奇妙的协作环境。基于Rockman， Koch， Stamler和Lefkowitz之间的自然合作，并在PPG期间开花结果，我们开发了一种识别新型β - aar信号机制的综合方法。在过去的资助周期中，这导致了许多高影响力的出版物和β - α信号传导新机制的确定。实验组织精心设计，使每个项目的具体目标都涉及GPCR信号的基本分子机制，使用体外和细胞培养方法，并将这些基本概念转化为相关的肥大和心力衰竭的体内模型。我们提出了3个项目，每个项目都涉及肾上腺素能信号的一个独特方面，并将由项目负责人指导，他们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β - aar信号的新方面，在缺乏G蛋白激活的情况下，使用β -抑制素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中的重要作用；项目3 （Stamler）将研究通过GRK的s -亚硝基化和-阻滞蛋白调控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，我们在实验台上的发现可以在体内进行测试，以及蛋白质组学和病毒资源，这将协同提高项目发现新信号蛋白和途径的潜力，这对项目的成功是不可或缺的。