The role of O-linked N-Acetylglucosamine Homeostasis in Pancreatic Beta-cell Development and Function

O-连接的 N-乙酰氨基葡萄糖稳态在胰腺 β 细胞发育和功能中的作用

• 批准号: 10158468
• 负责人: Emilyn Alejandro
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158468
• 关键词: Ablation; Affect; American; Apoptosis; B cell differentiation; B-Cell Development; Beta Cell; Biological; Birth; Cause of Death; Cell Maintenance; Cells; Cellular Metabolic Process; Cellular biology; Chronic Disease; Clinical Treatment; Cues; Data; Defect; Development; Diabetes Mellitus; Down-Regulation; Embryo; Endocrine; Enzymes; Functional disorder; Goals; Golgi Apparatus; Grant; Growth; Health; High Fat Diet; Homeostasis; Hormonal; Human; Individual; Insulin; Islet Cell; Lead; Life; Link; Maintenance; Mass Spectrum Analysis; Metabolic; Metabolic stress; Modeling; Modification; Molecular; Molecular Target; Mus; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; O-GlcNAc transferase; Pancreas; Pathway interactions; Patients; Phenotype; Post-Translational Protein Processing; Predisposition; Property; Proteins; Regulation; Reporting; Role; Signal Transduction; Signaling Protein; Site; Stress; Structure of beta Cell of islet; Testing; Time; United States; Wild Type Mouse; biological adaptation to stress; cell growth; early onset; endocrine pancreas development; endoplasmic reticulum stress; exhaust; genome wide association study; glucose metabolism; glycosylation; homeodomain; improved; insulin secretion; insulin signaling; islet; overexpression; pancreas development; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; progenitor; response; self-renewal; sensor; transcription factor

Type 2 diabetes (T2D) is the most common chronic disease affecting human health. Recent longitudinal and genome-wide association studies provide strong evidence that the ability of pancreatic β-cells to fulfill insulin demand through development, growth, survival, and function is a key determinant of whether an individual will develop T2D ! under various nutrient conditions. However, there are no effective clinical treatments that target β-cell growth and maintenance of their differentiated identity as insulin producing-cells. We propose that OGT (O-GlcNAc Transferase), a nutrient-sensor expressed at a very high level in β-cells, has key developmental regulatory properties and the ability to integrate signaling networks to regulate β-cell plasticity in response to insulin demand and nutrient stress. OGT is the sole enzyme adding a single O-GlcNAc post-translational modification (O-GlcNAcylation) onto proteins to orchestrate and fine-tune glucose metabolism, and β-cell growth and maintenance of identity under stress responses to nutrient changes and hormonal cues. We hypothesize that OGT tightly controls the O-GlcNAcylation state of downstream targets, including Pdx1, to promote β-cell development and function. Thus, our long-term goal is to define the mechanisms of how OGT integrates signaling networks impinging on β-cell plasticity (development and identity) to promote functional β-cells. We will test our hypothesis with the following Aims: 1. To establish the molecular mechanisms of how OGT regulates β-cell development and mass. 2. To delineate the mechanisms of how OGT regulates β-cell mass and identity under metabolic stress. The impact of this grant will show the central role of OGT in β-cell development and mass maintenance, and illustrate the translational relevance of OGT during time windows critical to metabolic health . Finally, these results will advance the field of β-cell biology and will open new horizons for therapies for patients with diabetes.

2型糖尿病（T2 D）是影响人类健康的最常见的慢性疾病。最近的纵向和全基因组关联研究提供了强有力的证据，即胰腺β细胞通过发育、生长、存活和功能满足胰岛素需求的能力是个体是否会发展为T2 D的关键决定因素！在不同的营养条件下。然而，没有靶向β细胞生长和维持其作为胰岛素产生细胞的分化身份的有效临床治疗。我们认为OGT（O-GlcNAc Transferase）是一种在β细胞中以非常高的水平表达的营养传感器，具有关键的发育调节特性和整合信号网络以调节β细胞可塑性以响应胰岛素需求和营养应激的能力。OGT是唯一一种在蛋白质上添加单个O-GlcNAc翻译后修饰（O-GlcNAc化）的酶，以协调和微调葡萄糖代谢，以及在对营养变化和激素提示的应激反应下的β细胞生长和身份维持。我们假设OGT严格控制下游靶点（包括Pdx 1）的O-GlcNAc化状态，以促进β细胞发育和功能。因此，我们的长期目标是确定OGT如何整合影响β细胞可塑性（发育和身份）的信号网络以促进功能性β细胞的机制。我们将测试我们的假设与以下目的：1.建立OGT调控β细胞发育和质量的分子机制。2.阐明代谢应激条件下OGT如何调节β细胞质量和特性的机制。这项资助的影响将显示OGT在β细胞发育和质量维持中的核心作用，并说明OGT在对代谢健康至关重要的时间窗口期间的翻译相关性。最后，这些结果将推动β细胞生物学领域的发展，并为糖尿病患者的治疗开辟新的视野。