"0-GlcNAcylation and Cardioprotection"

“0-GlcNAc酰化和心脏保护”

• 批准号: 9067495
• 负责人: Natasha Elizabeth Zachara
• 金额: $ 30.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9067495
• 关键词: Acute; Adenosine; Autophagocytosis; Autophagosome; Cardiac; Cardiac Myocytes; Cardiotonic Agents; Cardiovascular Diseases; Cell Survival; Cells; Cellular Stress Response; Collaborations; Cytoplasmic Protein; Data; Defense Mechanisms; Development; Glycoconjugates; Goals; Heart; Heat Stress Disorders; Hemorrhage; Hypoxia; Injury; Instruction; Ischemia; Ischemic Preconditioning; Label; Lead; Link; Mass Spectrum Analysis; Mediating; Mitochondrial Proteins; Modeling; Modification; Molecular; Myocardial Infarction; Neonatal; Nuclear Proteins; Oxidative Stress; Pathway interactions; Peptides; Pharmaceutical Preparations; Process; Proteins; Rattus; Reperfusion Injury; Research Personnel; Role; Site; Tissues; Trauma; biological adaptation to stress; cell injury; conditioning; endoplasmic reticulum stress; in vitro Model; in vivo; novel; preconditioning; protein function; response; sugar

instnjctions): Recently, the modification of nuclear, mitochondrial, and cytoplasmic proteins by O-linked p-N- acetylglucosamine (0-GlcNAc) has emerged as a novel regulator of the stress response and cell survival. Numerous forms of cellular injury, including cardiac ischemic preconditioning (acute and prolonged), lead to elevated levels of 0-GlcNAc in both in vivo and in vitro models. Elevating 0-GlcNAcylation before, or immediately after, the induction of cellular injury is protective in models of ischemia reperfusion injury, as well as heat stress, oxidative stress, endoplasmic reticulum stress, hypoxia, and trauma hemorrhage. Together, these data suggest that 0-GlcNAc is a novel endogenous cardioprotective agent. However, the molecular mechanisms by which 0-GlcNAc regulates protein function leading to enhanced cell survival and cardioprotection have not been identified. The long term goal of this investigator, is to identify at a molecular level the mechanisms by which 0-GlcNAc promotes cell survival. The objective of this application is to: 1) Define the role(s) of 0-GlcNAc in mediating ischemic preconditioning. In order to characterize the mechanisms by which 0-GlcNAc leads to cardioprotection, proteins dynamically O-GlcNAc modified in response to ischemic-preconditioning will be identified and pathways that lead to enhanced 0-GlcNAcylation will be defined. 2) Elucidate the molecular mechanism(s) by which 0-GlcNAc regulates the process of autophagy leading to cardioprotection. To characterize the molecular mechanisms by which 0-GlcNAc protects cardiomyocytes via autophagy we will define: 1) the role of 0-GlcNAc in inducing autophagy during ischemic preconditioning; 2) if enhanced autophagy is critical for 0- GlcNAc mediated cardioprotection; 3) the identity of proteins involved directly in autophagy (or regulating autophagy) that are modified and regulated by 0-GlcNAc. Together, these studies will characterize a novel endogenous defense mechanism of the heart, highlighting new targets for the development of alternative strategies that enhance the hearts tolerance to ischemia reperfusion injury. RELEVANCE (See instructions): The sugar 0-GlcNAc is a key component of the cellular stress response that enhances the ability of cells and tissues to survive ischemia reperfusion injury (for example, heart attack), but the mechanisms by which O- GlcNAc protects cells are unknown. Our goal is to understand how 0-GlcNAc promotes cell survival in a model of ischemia reperfusion injury at the molecular level, thus identifying new targets for the development of alternative strategies to enhance the heart's tolerance to ischemia reperfusion injury.

Instnjctions）： 最近，通过O连接的P-N-修饰核，线粒体和细胞质蛋白 乙酰葡萄糖（0-GLCNAC）已成为应激反应和细胞存活的新调节剂。 许多形式的细胞损伤，包括心脏缺血性预处理（急性和延长），导致 体内和体外模型中的0-GLCNAC水平升高。在之前提高0-Glcnacylation或 此后，在缺血再灌注损伤模型中，细胞损伤的诱导也是保护性的 作为热应激，氧化应激，内质网应激，缺氧和创伤出血。一起， 这些数据表明0-GLCNAC是一种新型的内源性心脏保护剂。但是，分子 0-GLCNAC调节蛋白质功能的机制，导致细胞存活增强和 尚未确定心脏保护。该研究者的长期目标是在分子上识别 将0-GLCNAC促进细胞存活的机制升级。该应用程序的目的是： 1）定义0-GLCNAC在介导缺血预处理中的作用。为了 表征0-GLCNAC导致心脏保护的机制，动态蛋白质 将确定针对缺血性前提的O-GLCNAC，并确定该途径 将定义增强的0-Glcnacylation。 2）阐明0-GLCNAC调节过程的分子机制 自噬导致心脏保护。表征分子机制 0-GLCNAC通过自噬保护心肌细胞，我们将定义：1）0-GLCNAC在 在缺血性预处理期间诱导自噬； 2）如果增强自噬对于0-至关重要 GlcNAC介导的心脏保护； 3）直接参与自噬的蛋白质的身份（或 调节自噬）由0-GLCNAC修饰和调节。 这些研究一起将表征一种新型的内源性防御机制，突出显示 开发替代策略的新目标，以增强对缺血的心脏耐受性 再灌注损伤。 相关性（请参阅说明）： 糖0-GLCNAC是细胞应力反应的关键组成部分，可增强细胞和 在缺血再灌注损伤（例如心脏病发作）中生存的组织，但O-的机制 GlcNAC保护细胞是未知的。我们的目标是了解0-GLCNAC如何促进A中的细胞存活 分子水平上缺血再灌注损伤的模型，从而确定了发展的新目标 替代策略，以增强心脏对缺血再灌注损伤的耐受性。