Bromodomain-containing Protein 4 in Profibrotic Gene Expression and Lung Fibrosis
含溴结构域蛋白 4 在促纤维化基因表达和肺纤维化中的作用
基本信息
- 批准号:10318204
- 负责人:
- 金额:$ 52.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAcetylationAcetyltransferaseAdultAffectApoptosisAutomobile DrivingBindingBinding SitesBiological AssayBromodomainC57BL/6 MouseCRISPR/Cas technologyCardiacCell physiologyCellsCellular StressChromatinCollagenDataDiseaseDown-RegulationEP300 geneElementsEnhancersEnzymesEpigenetic ProcessEtiologyFamilyFibroblastsFibrosisGene ExpressionGenesGenetic TranscriptionHematologyHistone AcetylationHistonesKidneyKnockout MiceLiver FibrosisLungLung diseasesLysineMediatingMethodsMusMyofibroblastNADPH OxidaseOrganPancreasPathogenesisPharmacologyPhase I/II Clinical TrialPhenotypePlayPost-Translational Protein ProcessingPre-Clinical ModelProcessPromoter RegionsProteinsPulmonary FibrosisReaderRegulatory ElementReportingResearchResolutionRoleSmall Interfering RNASmooth Muscle Actin Staining MethodSolid NeoplasmTestingTherapeuticTranscriptional RegulationTransforming Growth FactorsTransposaseUp-Regulationagedcell typechromatin immunoprecipitationchromatin modificationefficacy evaluationepigenetic regulationepigenomicsgenome-widehistone acetyltransferasehistone modificationidiopathic pulmonary fibrosisimprovedin vivoin vivo Modelinhibitorinjury and repairlung injurymembermolecular targeted therapiesmortalitynovelnovel therapeuticsprofibrotic cytokinepromoterrecruitrepairedresponsetherapeutic targettranscription factortranscriptional reprogramming
项目摘要
PROJECT SUMMARY
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder of unknown etiology. IPF is
characterized by altered epigenetic state. Epigenetic alterations are potentially reversible, thus
are attractive therapeutic targets. Chromatin structural remodeling through histone post-
translational-modifications control transcriptional responses. Acetylated histone marks as well as
some transcriptional factors are recognized by bromodomains (readers). Bromodomain-
containing protein (Brd) 4 is a member of the bromodomain and extraterminal (BET) family, which
binds to cell type-specific enhancers and promoters. Brd4 has been reported to be essential for
enhancer-mediated pro-fibrotic genes expression in many organ fibrosis. However mechanisms
of how Brd4 regulates genome-wide pro-fibrotic responses and its interaction with other his
acetyltransferase, such as p300, is not clear. Fibrotic responses involve many cellular processes,
including epigenetic alterations. Our preliminary data show that by blocking Brd4, multiple
profibrotic genes can be downregulated; inhibition of Brd4 can disrupt the association of p300 and
H3K27ac with profibrotic genes promoter region. We hypothesis that Brd4 affects chromatin
accessibility, mediates the up-regulation of profibrotic genes through interaction with p300 by
acetylating active enhancer mark H3K27ac during lung injury and repair process. Our aims are:
1. Determine the effects of Brd4 inhibition on profibrotic responses in lung fibroblasts; 2.
Determine if Brd4 through p300 mediates histone acetylation to regulate profibrotic genes
expression, 3. Determine the in vivo targeting of Brd4 inhibition in pre-clinical models of lung
fibrosis. Results from this research will make a significant impact on our understanding of the role
of Brd4 in epigenetic regulation in the pathobiology of IPF.
项目概要
特发性肺纤维化(IPF)是一种病因不明的致命性肺部疾病。特发性肺纤维化是
其特征是表观遗传状态改变。表观遗传改变可能是可逆的,因此
是有吸引力的治疗靶点。通过组蛋白后染色质结构重塑
翻译修饰控制转录反应。乙酰化组蛋白标记以及
一些转录因子被溴结构域(读取器)识别。溴结构域-
含有蛋白 (Brd) 4 是溴结构域和外部末端 (BET) 家族的成员,
与细胞类型特异性增强子和启动子结合。据报道,Brd4 对于
增强子介导的促纤维化基因在许多器官纤维化中表达。然而机制
Brd4 如何调节全基因组促纤维化反应及其与其他蛋白的相互作用
乙酰转移酶,例如p300,尚不清楚。纤维化反应涉及许多细胞过程,
包括表观遗传改变。我们的初步数据表明,通过阻断 Brd4,多个
促纤维化基因可以被下调;抑制 Brd4 可以破坏 p300 和
H3K27ac 具有促纤维化基因启动子区域。我们假设 Brd4 影响染色质
可及性,通过与 p300 相互作用介导促纤维化基因的上调
在肺损伤和修复过程中乙酰化活性增强子标记H3K27ac。我们的目标是:
1.确定Brd4抑制对肺成纤维细胞促纤维化反应的影响; 2.
确定 Brd4 通过 p300 是否介导组蛋白乙酰化来调节促纤维化基因
表达,3. 确定临床前肺模型中 Brd4 抑制的体内靶向
纤维化。这项研究的结果将对我们对该角色的理解产生重大影响
Brd4 在 IPF 病理学表观遗传调控中的作用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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{{ truncateString('Yan Sanders', 18)}}的其他基金
Bromodomain-containing Protein 4 in Profibrotic Gene Expression and Lung Fibrosis
含溴结构域蛋白 4 在促纤维化基因表达和肺纤维化中的作用
- 批准号:
10556325 - 财政年份:2021
- 资助金额:
$ 52.62万 - 项目类别:
Histone H4 Lysine16 Acetylation in Aging and Lung Fibrosis
衰老和肺纤维化中的组蛋白 H4 赖氨酸 16 乙酰化
- 批准号:
9275907 - 财政年份:2016
- 资助金额:
$ 52.62万 - 项目类别:
Epigenetic Alterations in IPF Fibroblastic Foci
IPF 成纤维细胞灶的表观遗传改变
- 批准号:
7837607 - 财政年份:2009
- 资助金额:
$ 52.62万 - 项目类别:
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