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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

基本信息

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
项目类别：
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

项目摘要

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（T2D）是影响人类健康的最常见慢性疾病。最近的纵向和全基因组关联研究提供了强有力的证据，表明胰腺 β 细胞通过发育、生长、生存和功能满足胰岛素需求的能力是个体是否会患上 T2D 的关键决定因素！在各种营养条件下。然而，目前还没有针对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方法。我们认为，OGT（O-GlcNAc 转移酶）是一种在 β 细胞中高水平表达的营养传感器，具有关键的发育调节特性，并且能够整合信号网络来调节 β 细胞可塑性，以响应胰岛素需求和营养应激。 OGT 是唯一一种在蛋白质上添加单个 O-GlcNAc 翻译后修饰 (O-GlcNAcylation) 的酶，以协调和微调葡萄糖代谢、β 细胞生长以及在营养变化和激素提示的应激反应下维持身份。我们假设 OGT 严格控制下游靶标（包括 Pdx1）的 O-GlcNAcylation 状态，以促进 β 细胞的发育和功能。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。我们将通过以下目标来检验我们的假设： 1. 建立 OGT 如何调节 β 细胞发育和质量的分子机制。 2. 阐明OGT在代谢应激下如何调节β细胞质量和身份的机制。这笔资助的影响将显示 OGT 在 β 细胞发育和大规模维持中的核心作用，并说明 OGT 在对代谢健康至关重要的时间窗口内的转化相关性。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。