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：
10556325
负责人：
Yan Sanders
金额：
$ 51.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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 2023-03-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10556325
关键词：
ATAC-seq Acetylation Acetyltransferase Actins Adult Affect Apoptosis Automobile Driving Binding Binding Sites Biological Assay Bromodomain C57BL/6 Mouse CRISPR/Cas technology Cardiac Cell physiology Cells Cellular Stress Chromatin Collagen Data Disease Down-Regulation EP300 gene Elements Enhancers Enzymes Epigenetic Process Etiology Family Fibroblasts Fibrosis Gene Expression Genes Genetic Transcription Hematology Histone Acetylation Histones Kidney Knockout Mice Liver Fibrosis Lung Lung diseases Lysine Maps Mediating Methods Mus Myofibroblast NADPH Oxidase Organ Pancreas Pathogenesis Phase I/II Clinical Trial Phenotype Play Post-Translational Protein Processing Pre-Clinical Model Process Promoter Regions Proteins Pulmonary Fibrosis Reader Regulatory Element Reporting Research Resolution Role Small Interfering RNA Smooth Muscle Solid Neoplasm Testing Therapeutic Transcriptional Regulation Transforming Growth Factors Transposase Up-Regulation aged cell type chromatin immunoprecipitation chromatin modification efficacy evaluation epigenetic regulation epigenomics genome-wide histone acetyltransferase histone modification idiopathic pulmonary fibrosis improved in vivo in vivo Model inhibitor lung injury lung repair member molecular targeted therapies mortality novel novel therapeutics pharmacologic profibrotic cytokine promoter recruit repaired response therapeutic target transcription factor transcriptional 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.

项目摘要特发性肺纤维化（IPF）是一种致命的病因肺病。 IPF是以表观遗传状态改变为特征。表观遗传学的改变可能是可逆的，因此是有吸引力的治疗靶标。染色质结构重塑通过组蛋白后翻译模式控制转录响应。乙酰化组蛋白标记以及一些转录因素被溴化域（读取器）识别。 br 含有蛋白质（BRD）4是溴结构域和外部（BET）家族的成员，该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的表达。但是机制关于BRD4如何调节全基因组促纤维化反应及其与他人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，通过阻止BRD4，多个纤维化基因可以下调； BRD4的抑制会破坏P300和 H3K27AC具有纤维化基因启动子区域。我们假设BRD4会影响染色质可访问性，通过与p300相互作用的介导的纤维化基因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中纤维化反应的影响； 2。确定BRD4至P300是否介导组蛋白乙酰化以调节纤维化基因表达，3。确定肺前临床模型中BRD4抑制的体内靶向纤维化。这项研究的结果将对我们对角色的理解产生重大影响 IPF病理生物学的表观遗传调节中BRD4的of。