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:
- 金额:$ 38.5万
- 依托单位:
- 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:
- 关键词:AblationAffectAmericanApoptosisB cell differentiationB-Cell DevelopmentBeta CellBiologicalBirthCause of DeathCell MaintenanceCellsCellular Metabolic ProcessCellular biologyChronic DiseaseClinical TreatmentCuesDataDefectDevelopmentDiabetes MellitusDown-RegulationEmbryoEndocrineEnzymesFunctional disorderGoalsGolgi ApparatusGrantGrowthHealthHigh Fat DietHomeostasisHormonalHumanIndividualInsulinIslet CellLeadLifeLinkMaintenanceMass Spectrum AnalysisMetabolicMetabolic stressModelingModificationMolecularMolecular TargetMusMutateMutationNon-Insulin-Dependent Diabetes MellitusNutrientO-GlcNAc transferasePancreasPathway interactionsPatientsPhenotypePost-Translational Protein ProcessingPredispositionPropertyProteinsRegulationReportingRoleSignal TransductionSignaling ProteinSiteStressStructure of beta Cell of isletTestingTimeUnited StatesWild Type Mousebiological adaptation to stresscell growthearly onsetendocrine pancreas developmentendoplasmic reticulum stressexhaustgenome wide association studyglucose metabolismglycosylationhomeodomainimprovedinsulin secretioninsulin signalingisletoverexpressionpancreas developmentpeptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidaseprogenitorresponseself-renewalsensortranscription 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(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。
项目成果
期刊论文数量(0)
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Emilyn Alejandro其他文献
Emilyn Alejandro的其他文献
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{{ truncateString('Emilyn Alejandro', 18)}}的其他基金
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 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health
胎盘胰岛素信号传导和 mTOR 营养感应编程对后代代谢健康的影响
- 批准号:
10679756 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health
胎盘胰岛素信号传导和 mTOR 营养感应编程对后代代谢健康的影响
- 批准号:
10625938 - 财政年份:2022
- 资助金额:
$ 38.5万 - 项目类别:
Innate Immune Complement System and Developmental Programming of Functional β Cell Mass
先天免疫补体系统和功能性β细胞群的发育编程
- 批准号:
10194574 - 财政年份:2020
- 资助金额:
$ 38.5万 - 项目类别:
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:
10406255 - 财政年份:2018
- 资助金额:
$ 38.5万 - 项目类别:
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:
9922900 - 财政年份:2018
- 资助金额:
$ 38.5万 - 项目类别:
O-linked-N-acetylglucosamine Post-translational Modification in Pancreatic Beta-cells Regulating ER Stress and Mitochondrial Function
胰腺β细胞中的O-连接-N-乙酰氨基葡萄糖翻译后修饰调节内质网应激和线粒体功能
- 批准号:
9387765 - 财政年份:2017
- 资助金额:
$ 38.5万 - 项目类别:
Mechanisms of Developmental Programing of beta-cell Susceptibility to Glucolipotoxicity
β细胞对糖脂毒性敏感性的发育规划机制
- 批准号:
9285779 - 财政年份:2014
- 资助金额:
$ 38.5万 - 项目类别:
Mechanisms of Developmental Programing of beta-cell Susceptibility to Glucolipotoxicity
β细胞对糖脂毒性敏感性的发育规划机制
- 批准号:
8804376 - 财政年份:2014
- 资助金额:
$ 38.5万 - 项目类别:
Mechanisms of Developmental Programing of beta-cell Susceptibility to Glucolipotoxicity
β细胞对糖脂毒性敏感性的发育规划机制
- 批准号:
9176214 - 财政年份:2014
- 资助金额:
$ 38.5万 - 项目类别:
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