The role of Pdx1-recruited Chd4:NuRD complex in controlling mature #-cell function
Pdx1招募的Chd4:NuRD复合物在控制成熟中的作用
基本信息
- 批准号:10634693
- 负责人:
- 金额:$ 39.58万
- 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:2022-07-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqATP phosphohydrolaseAdultAffectAmericanBeta CellBindingBiochemicalBiological AssayBlood GlucoseCHD4 geneCalciumCalcium SignalingCell LineCell physiologyChIP-seqChromatinComplexDataDeacetylaseDevelopmentDiabetes MellitusDiseaseDuodenumExcisionFunctional disorderFutureG6PC2 geneGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGlucoseGlucose IntoleranceGoalsGrantHealthHealth Care CostsHigh Fat DietHomeoboxHumanHyperglycemiaImpairmentIn SituIn VitroIndividualInfluentialsInsulinInsulin ResistanceIslets of LangerhansKnockout MiceKnowledgeLigationLinkMediatingMetabolic stressMethodsMitochondriaMusNon-Insulin-Dependent Diabetes MellitusNucleosomesOrgan DonorOutcomePancreasPathogenesisPathway interactionsPatientsPeripheralPhysiologicalProductionProteinsRNARegulator GenesResearchRodentRodent ModelRoleSignal TransductionStructure of beta Cell of isletTamoxifenTestingTranscriptional Regulationblood glucose regulationchromatin remodelingconditional knockoutdiabetes mellitus therapydiabetes pathogenesisdiabetic patientdiabetogeniceconomic costendoplasmic reticulum stressgene repressiongenome-wideglucose metabolismglucose tolerancehuman tissueimpaired glucose toleranceimproved outcomein vivoin vivo Modelinsightinsulin secretionisletknock-downmouse modelnon-diabeticnovelpostnatalprogramsrecruitresponsestressortranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY
Pancreatic β-cells within the islets of Langerhans are required for glucose-stimulated insulin secretion
and glucose homeostasis. Dysfunctional β-cell activity and identity results in diabetes, a growing disease
affecting millions of Americans, thus creating an enormous fiscal and health burden. Strategies to improve
outcomes for the mounting number of diabetic patients requires understanding the complex programs that
coordinate a proper insulin release in response to changing blood glucose levels. Developing upon existing
knowledge of how islet enriched transcription factors (TFs) coordinate signals that influence gene regulatory
programs will allow us to understand how such programs are dramatically altered in islet β-cells of diabetes
patients. Pdx1, one of the most important TFs in the developing and postnatal β-cell, has been shown to recruit
a diverse set of coregulators which could potentially modulate its activity. This proposal is focused around how
Pdx1 interactions with the Nucleosome Remodeling and Deacetylase (NuRD) complex are influential to normal
β-cell function and are altered in pathophysiological conditions associated with the development of Type 2
diabetes (T2D).
The central ATPase subunit of the NuRD complex, Chd4, was found to interact with and control a subset
of Pdx1 target genes and is recruited to genes important for normal β-cell function in vitro. Preliminary studies
demonstrate that conditional removal of Chd4 from mature islet β-cells significantly impacts glucose tolerance in
vivo. This proposal will test the overall hypothesis that Pdx1-bound Chd4:NuRD complex controls chromatin
accessibility and gene expression programs important for physiological β-cell function which are compromised
during the development of diabetes. In Aim 1, we will fully characterize how β-cell dysfunction occurs due to the
absence of Chd4 in a new conditional Chd4-deleted mouse model and in Aim 2 we will uncover the mechanistic
actions of Chd4 in controlling chromatin accessibility and gene expression using unbiased genome-wide RNA-,
ATAC- and ChIP-Sequencing approaches. The influence of Chd4:NuRD on human Pdx1 and β-cell action will
be investigated. Aim 3 will evaluate how T2D associated stressors influence Pdx1:Chd4 interactions using
biochemical and in situ methods from rodent and human islets, in vivo models of T2D and primary human tissues.
Upon successful completion of this grant, we will have determined the mechanistic actions of Chd4:NuRD
on controlling Pdx1 activity and β-cell function, and defined how stressors associated with diabetes development
impact the vital Pdx1:Chd4 regulatory mechanisms. This research will identify critical targets that contribute to
the pathogenesis of T2D, which will open new avenues for diabetes research.
项目摘要
葡萄糖刺激的胰岛素分泌需要的胰岛胰岛胰岛中的胰腺β细胞是
和葡萄糖稳态。功能失调的β细胞活性和身份导致糖尿病,糖尿病,一种增长的疾病
影响数百万美国人,从而造成了巨大的财政和健康伯恩。改进的策略
糖尿病患者增加数量的结果需要了解复杂的计划
响应不断变化的血糖水平,协调适当的胰岛素释放。在现有的情况下发展
了解如何富含胰岛的转录因子(TFS)坐标信号,这些信号影响基因调节
程序将使我们能够了解糖尿病的胰岛细胞中如何改变此类程序
患者。 PDX1是发育中和产后β细胞中最重要的TF之一,已被证明是募集
一套多种多样的核心节可能会调节其活性。该提议的重点是如何
PDX1与核小体重塑和脱乙酰基酶(NURD)复合物的相互作用对正常有影响
β细胞功能,并在与2型发展有关的病理生理状况中发生了改变
糖尿病(T2D)。
发现NURD复合物CHD4的中央ATPase亚基与子集相互作用并控制
PDX1靶基因的属性,并被募集到对正常β细胞功能体外重要的基因中。初步研究
证明从成熟胰岛β细胞中有条件去除CHD4会显着影响葡萄糖耐受性
体内。该提案将检验PDX1结合CHD4的总体假设:NURD Complexch Controns Chromatin
可访问性和基因表达程序对损害的物理β细胞功能很重要
在糖尿病的发展过程中。在AIM 1中,我们将完全表征β细胞功能障碍是如何由于
在新的有条件的CHD4缺失的小鼠模型中,没有CHD4,在AIM 2中,我们将发现机械
CHD4使用无偏基因组RNA,,控制染色质的可及性和基因表达的作用
ATAC和芯片序列方法。 CHD4:NURD对人PDX1和β细胞作用的影响将
被调查。 AIM 3将评估T2D相关压力源如何影响PDX1:CHD4相互作用
来自啮齿动物和人类胰岛的生化和原位方法,T2D和原代人组织的体内模型。
成功完成这笔赠款后,我们将确定CHD4的机械行动:NURD
关于控制PDX1活性和β细胞功能,并定义了与糖尿病发展相关的压力源
影响重要的PDX1:CHD4调节机制。这项研究将确定有助于
T2D的发病机理将为糖尿病研究开辟新的途径。
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)
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Jason M Spaeth其他文献
Jason M Spaeth的其他文献
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{{ truncateString('Jason M Spaeth', 18)}}的其他基金
The Pdx1-recruited Swi/Snf chromatin remodeling complex regulates endocrine cell expansion and differentiation in vivo
Pdx1 招募的 Swi/Snf 染色质重塑复合物调节体内内分泌细胞的扩增和分化
- 批准号:
10321296 - 财政年份:2021
- 资助金额:
$ 39.58万 - 项目类别:
Islet transcription factor activation: FoxPs are required for postnatal endocrine cell proliferation while Pdx1 recruited chromatin remodeling enzymes impact pancreas size
胰岛转录因子激活:FoxPs 是出生后内分泌细胞增殖所必需的,而 Pdx1 招募的染色质重塑酶会影响胰腺大小
- 批准号:
8907572 - 财政年份:2015
- 资助金额:
$ 39.58万 - 项目类别:
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