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

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，表明胰腺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。

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.