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

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

项目概要/摘要 O-GlcNAc 转移酶 (OGT) 是一种在胰腺 β 细胞中高度表达的营养和应激传感器蛋白。该酶专门催化目标胞浆蛋白和核酸蛋白的翻译后糖基化（O- β细胞 OGT 基因敲除小鼠出现严重的糖尿病表型，表明 OGT 在糖尿病中发挥着至关重要的作用。这项研究的长期目标是了解其机制。蛋白质 O-GlcNAc 基化影响 β 细胞的健康和功能，mTORC1 和 AMPK 信号传导。尽管我们在包括 2 型糖尿病在内的许多疾病中都出现了失调。通过研究营养传感器蛋白 mTORC1、AMPK 和 OGT 来了解它们的作用独立地，它们在体内如何相互影响在很大程度上是未知的。我们过去六年的研究工作揭示了这一点。 OGT 通过其感知营养水平和协调一致的能力来促进最佳 β 细胞健康在当前的提案中，我们将通过细胞反应来维持β细胞质量并引起足够的胰岛素释放。检验 OGT 引发与 mTORC1 和 AMPK 及其下游串扰的主要假设靶向 ULK，负向调节自噬以维持 β 细胞质量和功能稳态。与 β 细胞自噬失调和改善自噬稳态的干预措施有关可能有益于减少糖脂毒性引起的胰岛功能损伤。创新的体内模型，增加或减少 OGT、mTORC1、AMPK 和 ULK 的功能，以测试这些营养传感器蛋白之间的串扰调节自噬依赖性β细胞功能具体目标 1：描述 OGT 的分子机制。调节 β 细胞中的 mTORC1 信号传导具体目标 2：描述 OGT 对 β 细胞自噬的作用。这项新提议具有创新性，因为目前还没有将 OGT 和 mTORC1 联系起来的研究。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 A。更好地了解主要营养和压力传感器 OGT、mTOR 和 AMPK 信号传导对于优化 β 细胞健康至关重要，我们的结果将揭示 OGT 作为细胞因子的核心功能。 β细胞营养信号通路的主要协调者，可能是β细胞保存的有价值的目标，为治疗糖尿病患者提供新的治疗模式。