Nutrient-sensor O-GlcNAc Transferase Regulation of Autophagy in Homeostatis of Pancreatic Beta-cell Mass and Function

营养传感器 O-GlcNAc 转移酶对胰腺 β 细胞质量和功能稳态中自噬的调节

• 批准号: 10907874
• 负责人: Emilyn Alejandro
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10907874
• 关键词: 5' -AMP-activated protein kinase; Affect; Animal Genetics; Animal Model; Autophagocytosis; Autophagosome; Beta Cell; Cell physiology; Chronic; Clinical Treatment; Complex; Data; Diabetes Mellitus; Disease; Enzymes; Excision; FRAP1 gene; Failure; Fasting; Goals; Growth Factor; Health; Homeostasis; Human; Hyperglycemia; Impairment; Individual; Insulin; Intervention; Islets of Langerhans; Knockout Mice; Life; Link; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; O-GlcNAc transferase; Obesity; Organelles; Pathology; Patients; Phenotype; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Proteomics; Public Health; Recycling; Regulation; Reporting; Research; Risk; Role; Shapes; Signal Pathway; Signal Transduction; Site; Societies; Stress; Structure of beta Cell of islet; TSC2 gene; Testing; Whole Organism; Work; blood glucose regulation; detection of nutrient; diabetes mellitus therapy; diabetic; functional disability; glucose uptake; glycosylation; improved; in vivo; in vivo Model; innovation; insulin secretion; interdisciplinary approach; islet; mitochondrial dysfunction; mortality; new therapeutic target; novel therapeutics; overexpression; peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase; preservation; public health relevance; response; sensor; stem; transcriptomics

PROJECT SUMMARY/ABSTRACT O-GlcNAc transferase (OGT) is a nutrient and stress sensor protein highly expressed in pancreatic β-cells. This enzyme exclusively catalyzes the post-translational glycosylation of target cytosolic and nucleic proteins (O- GlcNAcylation). β-cell OGT knockout mice develop severe diabetic phenotype, suggesting that OGT is crucial in shaping glucose homeostasis. The long-term goal of this research is to understand the mechanisms of how protein O-GlcNAcylation shape β-cell health and function. O-GlcNAcylation, mTORC1 and AMPK signaling are dysregulated in many diseases including Type 2 diabetes. Although we have made advancements in our understanding of the roles of nutrient sensor proteins mTORC1, AMPK, and OGT by studying them independently, how they crosstalk in vivo is largely unknown. Our research work for the past six years reveal that OGT promotes optimal β-cell health through its ability to sense nutrient levels and orchestrate a cohesive cellular response to maintain β-cell mass and elicit sufficient insulin release. In this current proposal, we will test the main hypothesis that OGT elicits crosstalk with mTORC1 and AMPK, and their downstream target ULK, to negatively regulate autophagy to maintain β-cell mass and function homeostasis. Diabetes is associated with dysregulated autophagy in β-cells and interventions ameliorating autophagy homeostasis could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity. We will leverage innovative in vivo models with increased or reduced function of OGT, mTORC1, AMPK, and ULK to test the crosstalk among these nutrient-sensor proteins regulating autophagy-dependent β-cell function and mitochondrial homeostasis. Specific Aim 1: To delineate molecular mechanisms through which OGT regulates mTORC1 signaling in β-cells. Specific Aim 2: To delineate the role of OGT on autophagy in β- cells. This new proposal is innovative because there are currently no studies linking OGT and mTORC1 crosstalk in pancreatic islets and their regulation of autophagy-dependent β-cell mass and insulin secretion. A greater understanding of the complex interactions between major nutrient and stress sensors OGT, mTOR and AMPK signaling is critical in optimizing β-cell health. Our results will reveal the central function of OGT as a master orchestrator of nutrient signaling pathways in β-cells that may be valuable targets for β-cells preservation, providing new therapeutic models for treating patients with diabetes.

项目总结/摘要 O-GlcNAc转移酶（OGT）是在胰腺β细胞中高度表达的营养和应激传感器蛋白。这 酶专门催化靶细胞溶质和核蛋白（O-）的翻译后糖基化。 GlcNAc酰化）。β-细胞OGT敲除小鼠发展为严重的糖尿病表型，表明OGT在糖尿病中至关重要。 形成葡萄糖稳态。这项研究的长期目标是了解 蛋白质O-GlcNAc化塑造β细胞的健康和功能。O-GlcNAc化、mTORC 1和AMPK信号传导是 在包括2型糖尿病在内的许多疾病中失调。尽管我们在我们的研究领域取得了进展， 通过研究了解营养传感蛋白mTORC 1、AMPK和OGT的作用 独立地，它们如何在体内串扰在很大程度上是未知的。我们过去六年的研究工作显示， OGT通过其感知营养水平和协调凝聚力的能力促进最佳β细胞健康， 细胞应答以维持β细胞质量并引起足够的胰岛素释放。在目前的提案中，我们将 测试OGT消除与mTORC 1和AMPK及其下游的串扰的主要假设 靶向ULK，负调节自噬以维持β细胞质量和功能稳态。糖尿病 与β细胞中失调的自噬和改善自噬稳态的干预有关 可能有益于减少由糖脂毒性引起的胰岛功能损伤。我们将利用 OGT、mTORC 1、AMPK和ULK功能增加或减少的创新体内模型，以测试 这些调节自噬依赖性β细胞功能的营养传感器蛋白之间的串扰， 线粒体内稳态具体目标1：阐明OGT的分子机制， 调节β细胞中的mTORC 1信号传导。具体目标2：阐明OGT在β-肾上腺素细胞自噬中的作用。 细胞这一新提议是创新的，因为目前还没有研究将OGT和mTORC 1联系起来 胰岛中的串扰及其对自噬依赖性β细胞质量和胰岛素分泌的调节。一 更好地了解主要营养和压力传感器OGT，mTOR和 AMPK信号传导在优化β细胞健康方面至关重要。我们的研究结果将揭示OGT的核心功能， β细胞中营养信号传导途径的主要协调者，其可能是β细胞保存的有价值的靶点， 为治疗糖尿病患者提供了新的治疗模式。