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.

项目概要： 2 型糖尿病 (T2D) 是全球主要的慢性公共卫生问题。 高血糖和高脂血症是 T2D 的致病因素，通过诱导胰腺 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学的展开 内质网（ER）中的蛋白质反应（UPR）导致胰岛素死亡 通过 β-细胞对蛋白质进行 O-GlcNAc 修饰（O-GlcNAc 修饰）。 OGT（O-GlcNAc 转移酶）对于许多重要的生物过程至关重要 包括线粒体功能、内质网应激反应和新陈代谢。 O-GlcNAcylation（通过删除 β 细胞中的 OGT）部分导致 T2D 和 β 细胞衰竭， 由于 ER 应激增强和高胰岛素原血症，我们追求 OGT。 通过调节线粒体的 O-GlcNAcylation 状态来调节生存和功能， O-GlcNAc 修饰蛋白的 ER-UPR、细胞质和核蛋白鉴定。 以前从未在β细胞中进行过这种研究，可能会产生新的治疗靶标 具体目标1将确定和量化蛋白质组的变化并识别。 OGT 的目标是胰岛，在 β- 中具有条件性和诱导性损失或功能获得 OGT 具体的 Aim2 将识别高胰岛素原血症的机制并确定。 β 细胞中 OGT 功能丧失和获得的小鼠胰岛线粒体功能障碍。 O-GlcNAc 蛋白的鉴定、位点定位和定量是 破译它们的功能并深入了解决定结构的因素 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。