"0-GlcNAcylation and Cardioprotection"

实例)： 最近，O-连接的p-N-对核蛋白、线粒体蛋白和细胞质蛋白的修饰。 乙酰氨基葡萄糖(0-GlcNAc)是应激反应和细胞存活的一种新的调节因子。 多种形式的细胞损伤，包括心脏缺血预适应(急性和长期)，导致 体内和体外模型中0-GlcNAc水平升高。在此之前提升0-GlcN酰化，或 在此之后，细胞损伤的诱导在缺血再灌注损伤模型中也具有保护作用。 如热应激、氧化应激、内质网应激、缺氧、创伤出血等。一起， 这些数据表明，0-GlcNAc是一种新的内源性心脏保护剂。然而，分子 0-GlcNAc调节蛋白质功能促进细胞存活和修复的机制 心脏保护作用尚未确定。这位研究人员的长期目标，是在分子水平上识别 水平0-GlcNAc促进细胞存活的机制。此应用程序的目标是： 1)明确0-GlcNAc在介导缺血预适应中的作用(S)。为了 描述0-GlcNAc导致心脏保护的机制，蛋白质动态 O-GlcNAc对缺血预适应的反应将被确定，并通过 导致增强的0-GlcN酰化将被定义。 2)阐明了0-GlcNAc调控的分子机制(S) 自噬导致心脏保护。为了刻画分子机制， 0-GlcNAc通过自噬保护心肌细胞我们将定义：1)0-GlcNAc在 在缺血预适应过程中诱导自噬；2)如果增强的自噬对0- GlcNAc介导的心脏保护；3)直接参与自噬的蛋白质的特性(或 调节自噬)，由0-GlcNAc修饰和调节。 总之，这些研究将描述一种新的心脏内源性防御机制，强调 开发提高心脏对缺血耐受性的替代策略的新靶点 再灌注损伤。 相关性(请参阅说明)： 糖0-GlcNAc是细胞应激反应的关键成分，它增强细胞和 组织在缺血再灌注损伤(例如，心脏病发作)中存活，但O- GlcNAc对细胞的保护作用尚不清楚。我们的目标是了解0-GlcNAc是如何促进细胞在 在分子水平上建立缺血再灌注损伤模型，从而确定新的发展靶点 以提高心脏对缺血再灌注损伤的耐受性的替代策略。

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.