Gene Networks promoting adipocyte cell differentiation and function
促进脂肪细胞分化和功能的基因网络
基本信息
- 批准号:10609053
- 负责人:
- 金额:$ 45.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAffectBinding SitesBiologicalBiological AssayBiological ProcessBiologyBody WeightBrown FatCCAAT-Enhancer-Binding Protein-betaCell DensityCell Differentiation processCell physiologyCellsChemicalsChromatinCollaborationsComplexDNADataData SetDetectionDevelopmentDiabetes MellitusDiseaseEnhancersExposure toFatty acid glycerol estersGene ExpressionGenerationsGenesGenetic ScreeningGenetic TranscriptionGenomicsGlucocorticoid ReceptorGoalsGrowth and Development functionHealthHealth BenefitHeart DiseasesHomeostasisHumanHyperlipidemiaHypertensionKineticsLaboratoriesMass Spectrum AnalysisMesenchymal Stem CellsMetabolic DiseasesMetabolismModificationMolecularMultipotent Stem CellsMusMutation AnalysisNormal tissue morphologyObesityObesity EpidemicOrganPPAR gammaPhysiologicalPlayPopulationProteinsProteomeProteomicsRiskRoleSignal TransductionTissue-Specific Gene ExpressionTissuesUnited StatesVisceralactivating transcription factor 4adipocyte differentiationcandidate identificationcell typecombatdiet and exerciseepigenomicsfightinggene networkgene repressiongenome-wide analysisin vivoinsightknockout animalknockout genelipid biosynthesislipid metabolismnovelparalogous geneprogramsrecruitresponsestem cell fatesubcutaneoustherapeutic targettranscription factortranslational potential
项目摘要
A major goal of this laboratory is to understand the molecular mechanisms by which TFs and epigenomic
modification control gene expression programs that regulate adipose tissue development and function.
Adipogenesis begins with an established cascade of transcription factor (TF) activity that includes collaboration
between the CCAAT/enhancer binding protein β (CEBPβ) and the glucocorticoid receptor (GR). A key goal of
the present proposal is to determine how CEBPβ and its related paralogs bridge the transcriptional programs in
multipotent stem cells and early differentiating pre-adipocytes, with a long-term objective of understanding a
comprehensive TF network promoting adipose tissue development, growth and function. Specific Aim 1
comprehensively identifies the components of active enhancers during human adipogenesis. We will
perform a state-of-the-art genomic/proteomic approach to determine the chromatin-associated proteins
promoting adipocyte differentiation. Specific Aim 2 elucidates the mechanistic actions of networked TFs
and co-regulators that control human adipogenesis and adipocyte function. Novel adipogenic roles for
protein candidates identified in Aims 1 will be examined by mutational analysis and genome-wide approaches.
As a whole, we will generate and integrate unique, orthogonal cistromic and enhancer proteomic datasets to
reveal fundamental molecular mechanisms for transcriptional regulators in native chromatin. This will elucidate
how CEBP proteins and GR perform unique biological functions, and address the more general question of
how TFs recognize, access and act at their genomic-binding sites to control tissue-specific gene expression.
Specific Aim 3 comprehensively identifies the components of active enhancers in adipose tissue. We
hypothesize that comparison of the enhancer proteomes from visceral and subcutaneous white adipose
tissues and from brown adipose tissue will reveal fundamental mechanisms controlling depot-specific gene
expression and uncover the set of transcriptional regulators controlling lipid metabolism in vivo. Our focus on
the development and function of adipose tissue is warranted given its importance in health and disease.
Indeed, adipose tissue normally benefits health, yet in excess as in obesity, it becomes a strong risk for
metabolic diseases including diabetes, hyperlipidemia, hypertension and heart disease. New insights into
adipose biology will enhance its translational potential to combat the harmful and growing epidemics of obesity
and diabetes.
该实验室的一个主要目标是了解TF和表观基因组的分子机制,
修饰控制调节脂肪组织发育和功能的基因表达程序。
脂肪生成开始于转录因子(TF)活性的既定级联反应,
CCAAT/增强子结合蛋白β(CEBPβ)与糖皮质激素受体(GR)之间。的一个关键目标
目前的建议是确定CEBPβ及其相关的旁系同源物如何桥接转录程序,
多能干细胞和早期分化的前脂肪细胞,长期目标是了解
全面的TF网络促进脂肪组织发育、生长和功能。具体目标1
全面鉴定了人脂肪形成过程中活性增强剂的组分。我们将
进行最先进的基因组/蛋白质组学方法,以确定染色质相关蛋白
促进脂肪细胞分化。具体目标2阐明了网络化TF的机制作用
以及控制人脂肪形成和脂肪细胞功能的辅助调节剂。新型脂肪形成作用
将通过突变分析和全基因组方法来检查目标1中确定的候选蛋白质。
作为一个整体,我们将生成和整合独特的,正交顺式和增强子蛋白质组数据集,
揭示了天然染色质中转录调节因子的基本分子机制。这将阐明
CEBP蛋白和GR如何执行独特的生物学功能,并解决更普遍的问题,
转录因子如何识别、进入并作用于其基因组结合位点,以控制组织特异性基因表达。
具体目标3全面鉴定了脂肪组织中活性增强剂的组分。我们
假设内脏和皮下白色脂肪增强子蛋白质组比较
组织和棕色脂肪组织的研究将揭示控制贮库特异性基因的基本机制
表达,并揭示了一套转录调节控制体内脂质代谢。我们专注于
鉴于脂肪组织在健康和疾病中的重要性,其发育和功能是有保证的。
事实上,脂肪组织通常有益于健康,但在肥胖症中过量,它会成为一种强烈的风险,
代谢疾病包括糖尿病、高脂血症、高血压和心脏病。新的见解
脂肪生物学将增强其转化潜力,以对抗有害的和日益增长的肥胖流行病。
和糖尿病
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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Patrick Seale其他文献
Patrick Seale的其他文献
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{{ truncateString('Patrick Seale', 18)}}的其他基金
Gene Networks promoting adipocyte cell differentiation and function
促进脂肪细胞分化和功能的基因网络
- 批准号:
10375459 - 财政年份:2020
- 资助金额:
$ 45.91万 - 项目类别:
Metabolic Control of Adipose Tissue Remodeling and Fibrosis
脂肪组织重塑和纤维化的代谢控制
- 批准号:
10166840 - 财政年份:2019
- 资助金额:
$ 45.91万 - 项目类别:
Metabolic Control of Adipose Tissue Remodeling and Fibrosis
脂肪组织重塑和纤维化的代谢控制
- 批准号:
10017959 - 财政年份:2019
- 资助金额:
$ 45.91万 - 项目类别:
Metabolic Control of Adipose Tissue Remodeling and Fibrosis
脂肪组织重塑和纤维化的代谢控制
- 批准号:
10418773 - 财政年份:2019
- 资助金额:
$ 45.91万 - 项目类别:
Control of adipose function through a PRDM16/Type 1 Interferon Axis
通过 PRDM16/1 型干扰素轴控制脂肪功能
- 批准号:
9706410 - 财政年份:2016
- 资助金额:
$ 45.91万 - 项目类别:
Control of adipose function through a PRDM16/Type 1 Interferon Axis
通过 PRDM16/1 型干扰素轴控制脂肪功能
- 批准号:
9339658 - 财政年份:2016
- 资助金额:
$ 45.91万 - 项目类别:
Tracing transcriptomic changes to uncover unknown roles of TZDs
追踪转录组变化以揭示 TZD 的未知作用
- 批准号:
9767118 - 财政年份:2015
- 资助金额:
$ 45.91万 - 项目类别:
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