Functional interaction of transcriptional regulators in endocrine lineage specification
内分泌谱系规范中转录调节因子的功能相互作用
基本信息
- 批准号:10577702
- 负责人:
- 金额:$ 75.47万
- 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:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqBeta CellBiophysicsC-terminalCell CycleCell Cycle ProgressionCell LineCell TherapyCell physiologyChromatinCompensationComplexConsensusDataDevelopmentDiabetes MellitusDiseaseEndocrineEnhancersEpigenetic ProcessExhibitsFailureGene Expression RegulationGenesGeneticGenetic TranscriptionGlucoseGrowthHeterozygoteHumanIn VitroInterventionIslets of LangerhansMediatingMicroscopyMolecularMolecular ConformationMusMutagenesisMutateMutationNon-Insulin-Dependent Diabetes MellitusOrgan SizeOrganogenesisPancreasPathway interactionsPhasePhenotypePhosphorylation SitePlayPost-Translational Protein ProcessingProliferatingPropertyProtein RegionProteinsPublishingRegulationResolutionRoleSiteSpecific qualifier valueStimulusStructureStructure of beta Cell of isletTechniquesTestingTherapeuticUbiquitinationWorkdesignendocrine pancreas developmentflexibilitygenome editinghomeodomainhuman embryonic stem cellhuman pluripotent stem cellin vivoinsulin promoter factor 1insulin secretionintermolecular interactionisletislet stem cellsmembermimeticsmouse modelmultiple omicsnoveloverexpressionpancreas developmentpermissivenesspostnatalprediction algorithmpreventprogenitorprogramspromoterprotein protein interactionresponsesingle nucleus RNA-sequencingsingle-cell RNA sequencingstem cell differentiationtranscription factorubiquitin-protein ligase
项目摘要
SUMMARY
Reduction in functional insulin-secreting β cells underlies the progression of all forms of diabetes, underscoring
the translational relevance of deciphering molecular pathways regulating the formation, growth, and function of
β cells. The transcriptional networks critical for the proper development, differentiation, and expansion of β cells
work through islet enhancers, super enhancers, and active promoters that form 3D hubs. The homeodomain
transcription factor Pdx1 is a critical member of the β-cell transcriptional network during development and in
postnatal β-cell function. Pdx1 is mutated in monogenic forms of human diabetes and plays critical roles in early
pancreas specification, regulation of organ size, and in β-cell formation, proliferation, and identity. Our
preliminary data reveal that developing β cells exhibit altered subnuclear localization and reduced levels of Pdx1
protein as they advance through the cell cycle. Further, ectopically elevated levels of Pdx1 prevent cell cycle
progression, suggesting that dynamic regulation of expression is required for effective β-cell expansion. We
identify an intrinsically disordered protein region (IDPR) in the Pdx1 C-terminus (aa 207-223). IDPRs, commonly
found within transcription factors, lack fixed secondary structure and are amenable to flexible conformations and
phase separation. IDPRs promote protein-protein interactions and transcriptional hub formation at super
enhancers necessary for coordinated gene regulation. We have found that the Pdx1 C-terminus mediates
interaction with the one cut homeodomain transcription factor Oc1 in multipotent pancreatic progenitor cells to
establish the endocrine gene program, with long-term impact on postnatal islet function and β-cell compensation.
We previously identified the E3 ubiquitin ligase substrate adaptor SPOP as a PDX1 C-terminus partner (via
aa224-238) that mediates ubiquitination and proteasomal degradation of PDX1. Our preliminary data suggest
that SPOP and Oc1 compete for interaction with the Pdx1 C-terminus and that Oc1 protects Pdx1 from SPOP-
mediated degradation. Notably, the C-terminus harbors several diabetes-associated human mutations, one of
which we recently found disrupts the PDX1/SPOP interaction. Thus, we hypothesize that PDX1/OC1
interactions, in part mediated by their IDPRs, regulate Pdx1 stability, cell cycle progression, and pancreatic
endocrine differentiation. This hypothesis will be tested in 3 Aims: (1) To determine the mechanisms whereby
Pdx1 and Oc1 cooperate to establish a chromatin landscape permissive for endocrine differentiation and
proliferation; (2) To define the roles of the Pdx1 and Oc1 IDPRs in protein-protein interaction and pancreas
development; and (3) To define the molecular mechanisms by which the Pdx1 C-terminal domain regulates
protein stability and function during pancreas organogenesis and endocrine differentiation. The impact of human
diabetes-associated mutations will be investigated in this context. Our studies will determine a novel and
cohesive role for unstudied structural features of the Pdx1 C-terminus in β-cell development. Results of our
studies will inform therapeutic efforts to optimize β-cell expansion for cell-based therapies.
总结
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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Maureen A Gannon其他文献
Maureen A Gannon的其他文献
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{{ truncateString('Maureen A Gannon', 18)}}的其他基金
Modulating prostaglandin E2 receptor activity to improve pancreatic islet function
调节前列腺素 E2 受体活性以改善胰岛功能
- 批准号:
10360796 - 财政年份:2022
- 资助金额:
$ 75.47万 - 项目类别:
Modulating prostaglandin E2 receptor activity to improve pancreatic islet function
调节前列腺素 E2 受体活性以改善胰岛功能
- 批准号:
10611349 - 财政年份:2022
- 资助金额:
$ 75.47万 - 项目类别:
Manipulating islet GPCR activity to promote beta cell proliferation and survival
操纵胰岛 GPCR 活性促进 β 细胞增殖和存活
- 批准号:
10453748 - 财政年份:2019
- 资助金额:
$ 75.47万 - 项目类别:
Manipulating islet GPCR activity to promote beta cell proliferation and survival
操纵胰岛 GPCR 活性促进 β 细胞增殖和存活
- 批准号:
10022326 - 财政年份:2019
- 资助金额:
$ 75.47万 - 项目类别:
Manipulating islet GPCR activity to promote beta cell proliferation and survival
操纵胰岛 GPCR 活性促进 β 细胞增殖和存活
- 批准号:
10219238 - 财政年份:2019
- 资助金额:
$ 75.47万 - 项目类别:
Pathways regulating adult pancreatic beta cell replication
调节成人胰腺β细胞复制的途径
- 批准号:
9241554 - 财政年份:2016
- 资助金额:
$ 75.47万 - 项目类别:
Formation and maturation of endocrine pancreas progenitors
内分泌胰腺祖细胞的形成和成熟
- 批准号:
9197982 - 财政年份:2015
- 资助金额:
$ 75.47万 - 项目类别:
Formation and maturation of endocrine pancreas progenitors
内分泌胰腺祖细胞的形成和成熟
- 批准号:
9056074 - 财政年份:2015
- 资助金额:
$ 75.47万 - 项目类别:
Regulation of adult pancreatic beta cell replication
成人胰腺β细胞复制的调节
- 批准号:
8140822 - 财政年份:2011
- 资助金额:
$ 75.47万 - 项目类别:
Regulation of adult pancreatic beta cell replication
成人胰腺β细胞复制的调节
- 批准号:
8244927 - 财政年份:2011
- 资助金额:
$ 75.47万 - 项目类别:
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