O-linked-N-acetylglucosamine Post-translational Modification in Pancreatic Beta-cells Regulating ER Stress and Mitochondrial Function

项目摘要： 2型糖尿病（T2 D）是全球主要的公共卫生问题。慢性 高血糖和高脂血症是T2 D的致病因素， β细胞衰竭。导致β细胞衰竭的两种机制包括线粒体 蛋白质质量控制系统的功能障碍和破坏以及病理性的非折叠 内质网（ER）中的蛋白质反应（UPR）导致胰岛素死亡- 产生β细胞。O-GlcNAc修饰（O-GlcNAc酰化） 酶OGT（O-GlcNAc转移酶）在许多重要的生物过程中是至关重要的 包括线粒体功能、内质网应激反应和代谢。全局约简 O-GlcNAc化（通过删除β细胞中的OGT）导致T2 D和β细胞衰竭，部分地， 由于增强的内质网应激和高胰岛素原血症。我们假设OGT 通过调节线粒体的O-GlcNAc化状态来调节存活和功能， ER-UPR、胞质和核蛋白。O-GlcNAc修饰的蛋白质的鉴定 在β-细胞中以前没有做过，可能会导致新的治疗目标， 糖尿病特异性Aim 1将确定和量化蛋白质组的变化， 胰岛中的OGT靶向β-葡萄糖受体中的条件性和诱导性功能丧失或获得OGT 细胞特异性Aim 2将确定高胰岛素原血症的机制， 小鼠胰岛中的线粒体功能障碍，β细胞中的功能丧失和获得OGT。 O-GlcNAc蛋白的鉴定、位点定位和定量是研究O-GlcNAc蛋白的先决条件。 破译它们的功能，并深入了解决定结构的因素， 函数关系从长远来看，该项目将确定潜在的新药理学 目标是改善β细胞质量和功能。

Project Summary: Type 2 diabetes (T2D) is a major public health concern worldwide. Chronic hyperglycemia and hyperlipidemia are causative factors for T2D by inducing pancreatic β-cell failure. Two of the mechanisms causing β-cell failure include mitochondrial dysfunction and disruption of protein quality control systems and pathological unfolded protein response (UPR) in the Endoplasmic Reticulum (ER) leading to death of insulin- producing β-cells. O-GlcNAc modification (O-GlcNAcylation) onto proteins by the enzyme OGT (O-GlcNAc Transferase) is crucial for many important biological processes including mitochondrial function, ER stress response and metabolism. Global reduction of O-GlcNAcylation (by deleting OGT in β-cells) causes T2D and β-cell failure, in part, due to enhanced ER stress and hyperproinsulinemia. We hypothesize that OGT regulates survival and function by regulating the O-GlcNAcylation state of mitochondrial, ER-UPR, cytoplasmic, and nuclear proteins. Identification of O-GlcNAc modified proteins in β-cells have not been done before and may lead to new targets for treatment for diabetes. Specific Aim1 will determine and quantify changes in proteome and to identify OGT targets in islets with conditional and inducible loss or gain-of-function OGT in β- cells. Specific Aim2 will identify the mechanisms of hyperproinsulinemia and determine mitochondrial dysfunction in islets of mice with loss and gain-of-function OGT in β-cells. Identification, site mapping, and quantification of O-GlcNAc proteins are a prerequisite to decipher their functions and to gain insights in the factors that determine structure- function relationship. In long term, this project will identify potential new pharmacological targets to improve β-cell mass and function.