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:
- 金额:$ 23.25万
- 依托单位:
- 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:
- 关键词:5&apos-AMP-activated protein kinaseAffectAnimal GeneticsAnimal ModelAutophagocytosisAutophagosomeBeta CellCell physiologyChronicClinical TreatmentComplexDataDiabetes MellitusDiseaseEnzymesExcisionFRAP1 geneFailureFastingGoalsGrowth FactorHealthHomeostasisHumanHyperglycemiaImpairmentIndividualInsulinInterventionIslets of LangerhansKnockout MiceLifeLinkMitochondriaModelingMolecularMolecular TargetMusNon-Insulin-Dependent Diabetes MellitusNutrientO-GlcNAc transferaseObesityOrganellesPathologyPatientsPhenotypePhosphotransferasesPost-Translational Protein ProcessingProcessProteinsProteomicsPublic HealthRecyclingRegulationReportingResearchRiskRoleShapesSignal PathwaySignal TransductionSiteSocietiesStressStructure of beta Cell of isletTSC2 geneTestingWhole OrganismWorkblood glucose regulationdetection of nutrientdiabetes mellitus therapydiabeticfunctional disabilityglucose uptakeglycosylationimprovedin vivoin vivo Modelinnovationinsulin secretioninterdisciplinary approachisletmitochondrial dysfunctionmortalitynew therapeutic targetnovel therapeuticsoverexpressionpeptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidasepreservationpublic health relevanceresponsesensorstemtranscriptomics
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.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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
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:
$ 23.25万 - 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:
$ 23.25万 - 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:
$ 23.25万 - 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:
10158468 - 财政年份:2018
- 资助金额:
$ 23.25万 - 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:
$ 23.25万 - 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:
$ 23.25万 - 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:
$ 23.25万 - 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:
$ 23.25万 - 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:
$ 23.25万 - 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:
$ 23.25万 - 项目类别:
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