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: 10318204
• 负责人: Yan Sanders
• 金额: $ 52.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10318204
• 关键词: ATAC-seq; Acetylation; Acetyltransferase; 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; Mediating; Methods; Mus; Myofibroblast; NADPH Oxidase; Organ; Pancreas; Pathogenesis; Pharmacology; 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 Actin Staining Method; 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; injury and repair; lung injury; member; molecular targeted therapies; mortality; novel; novel therapeutics; profibrotic cytokine; promoter; recruit; repaired; response; therapeutic target; transcription factor; transcriptional reprogramming

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。