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

胰腺β细胞中的O-连接-N-乙酰氨基葡萄糖翻译后修饰调节内质网应激和线粒体功能

• 批准号: 9387765
• 负责人: Emilyn Alejandro
• 金额: $ 19.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387765
• 关键词: Address; Affect; Alleles; Antibodies; Apoptosis; Apoptotic; Beta Cell; Biological Process; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic; Chronic Disease; Crista ampullaris; Cytoplasmic Protein; Data; Diabetes Mellitus; Diabetic mouse; Disease; Endoplasmic Reticulum; Enzymes; Failure; Fluorescence; Functional disorder; Goals; Grant; Health; Heat shock proteins; Human; Hyperglycemia; Hyperlipidemia; Insulin; Lead; Link; Mature B-Lymphocyte; Mediating; Metabolism; Mitochondria; Mitochondrial Proteins; Modification; Molecular; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Proteins; Nutrient; O-GlcNAc transferase; Oxygen Consumption; Pathogenesis; Pathologic; Pharmacology; Phosphorylation; Post-Translational Protein Processing; Predisposition; Process; Proinsulin; Proteins; Proteome; Proteomics; Public Health; Publishing; Quality Control; Regulation; Research; Role; Serine; Signal Transduction; Site; Stress; Structure; Structure of beta Cell of islet; Structure-Activity Relationship; System; Testing; Therapeutic; Threonine; Translation Initiation; base; biological adaptation to stress; carboxypeptidase H; design; diabetogenic; effective therapy; endoplasmic reticulum stress; experimental study; gain of function; improved; insight; islet; mitochondrial dysfunction; new therapeutic target; novel; overexpression; pancreas development; partial recovery; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; response; sensor; transcription factor; transcription factor CHOP

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.

项目总结： 2型糖尿病(T2D)是世界范围内一个主要的公共卫生问题。慢性 高血糖、高脂血症是胰腺T2D的致病因素 β-单元故障。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展开 内质网中的蛋白质反应(UPR)导致胰岛素死亡。 产生β细胞。蛋白质的O-GlcNAc修饰(O-GlcN酰化) 酶OGT(O-GlcNAc Transferase)在许多重要的生物学过程中起着至关重要的作用 包括线粒体功能、内质网应激反应和代谢。全球减排 O-GlcN酰化(通过在β细胞中删除OGT)导致T2D和β细胞失效，部分地， 由于内质网应激增强和高胰岛素血症。我们假设OGT 通过调节线粒体的O-GlcN酰化状态来调节生存和功能， ER-UPR、细胞质和核蛋白。O-GlcNAc修饰蛋白的鉴定 在β中-细胞以前没有做过，可能会导致治疗的新靶点 糖尿病。特定的Aim1将确定和量化蛋白质组的变化并鉴定 β中有条件的和可诱导的OGT功能丧失或功能增益的胰岛靶 细胞。特异性AIM2将确定高胰岛素血症的机制并确定 β-细胞中OGT功能丧失和功能恢复的小鼠胰岛线粒体功能障碍。 鉴定、定位和定量O-GlcNAc蛋白是 破译它们的功能，洞察决定结构的因素-- 函数关系。从长远来看，该项目将确定潜在的新药理作用 目标是提高β-细胞的质量和功能。