Beta cell Notch activity in Type 2 Diabetes
2 型糖尿病中的 Beta 细胞 Notch 活性
基本信息
- 批准号:10592434
- 负责人:
- 金额:$ 56.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAcetyltransferaseActivities of Daily LivingAddressAdultAffectAgingAntibodiesArchitectureBeta CellBiologicalCell Differentiation processCellsCellular biologyChromatinClinicalDataDecision MakingDefectDevelopmentEmbryoFunctional disorderGene ExpressionGeneticGenetic TranscriptionGlucoseGlucose IntoleranceGoalsHeterogeneityHigh Fat DietHumanHyperglycemiaImpairmentInsulinInsulin ResistanceIslets of LangerhansKnock-outKnockout MiceLigandsLysineMediatingMetabolic DiseasesMethodsModelingMolecularMusNon-Insulin-Dependent Diabetes MellitusObese MiceObesityOrganismPancreasPathologyPathway interactionsPatientsPost-Translational Protein ProcessingPregnancyProtein FamilyProteinsPublishingRoleSignal PathwaySignal TransductionTestingTherapeuticThinnessTissuesTransactivationTransgenic OrganismsWorkcell stromadb/db mousediabetes mellitus therapydirect patient careeuglycemiaexpectationfeedingfunctional adaptationgain of functionglucose toleranceimprovedinhibitorinsulin secretionisletknock-downleptin receptorliquid chromatography mass spectrometryloss of functionmutantnotch proteinnovelnovel therapeuticspostnatal humanreceptorresponsesingle-cell RNA sequencingstressortranscription factortranscriptome sequencing
项目摘要
Project Abstract
β cell mass and function adapts to the insulin requirements of the organism to maintain euglycemia across a
wide range of pathophysiology, such as insulin resistance induced by obesity, pregnancy or aging. Although
molecular mechanisms that enable β cell adaptation to these stressors are not yet fully understood, insufficient
functional adaptation becomes clinically apparent with the onset of Type 2 Diabetes (T2D). With the continued
increase in obesity, novel therapeutically-tractable pathways that regulate β cell adaptation are sought to
reverse β cell dysfunction in T2D.
Notch is a highly conserved family of proteins critical for cell fate decision-making; in the developing endocrine
pancreas, Notch signaling regulates β cell differentiation, but less is known about Notch action in mature
tissue. We have recently shown that Notch signaling is present at low levels in fully developed β cells, but
increased in islets cultured in high glucose or isolated from obese mice. Persistent β cell Notch signaling
appears detrimental to function, as we observed improved glucose tolerance with genetic inhibition of β cell
Notch action. Conversely, forced Notch activation impaired glucose-stimulated insulin secretion (GSIS) in
isolated mouse or human islets, and induced glucose intolerance in β cell-specific Notch gain-of-function mice.
In Aim 1, we investigate mechanism of increased β cell Notch activity, leveraging data showing that β cell
expression of the Notch ligand, Jagged1, tracks with Notch activity. We test whether β cell Jagged1 is
necessary and sufficient for the maladaptive β cell Notch response in obesity. In Aim 2, we address
mechanism of Notch-induced GSIS defects. In key preliminary data, we found that Notch induces degradation
of MafA, a key regulator of β cell maturity disrupted in T2D. We also observe novel MafA acetylations, blocked
by Notch activity. We now study whether MafA stability and activity is dependent on acetylations, and elucidate
the molecular machinery underlying these post-translational modifications. We also test whether Notch impacts
stability and acetylation of the closely related transcription factor, MafB. Finally, in Aim 3, we test implications
of our identified NOTCH-MAFA/B axis in human β cell transcriptional and function response to glucose, as well
as effects on β cell heterogeneity in human islets. Achieving the goals of this application will determine
upstream signals for Notch activation, downstream effectors of Notch-induced β cell dysfunction, and
potentially develop novel therapeutic directions for the care of patients with T2D.
项目摘要
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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Utpal Pajvani其他文献
Utpal Pajvani的其他文献
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{{ truncateString('Utpal Pajvani', 18)}}的其他基金
Jagged-Notch signaling in NASH/fibrosis
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- 批准号:
10744371 - 财政年份:2019
- 资助金额:
$ 56.53万 - 项目类别:
Jagged-Notch signaling in NASH/fibrosis
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- 批准号:
10338130 - 财政年份:2019
- 资助金额:
$ 56.53万 - 项目类别:
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