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.

项目摘要 特发性肺纤维化（IPF）是一种病因不明的致死性肺部疾病。IPF是 以改变的表观遗传状态为特征。表观遗传改变是潜在可逆的，因此， 是有吸引力的治疗靶点。染色质结构重塑通过组蛋白后- 功能性修饰控制转录反应。乙酰化组蛋白标记以及 某些转录因子被溴结构域（bromodomains）识别（阅读器）。溴结构域- 含有蛋白质（Brd）4是溴结构域和末端外（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，Brd 4对以下方面至关重要： 增强子介导的促纤维化基因在许多器官纤维化中的表达。然而，机制 Brd 4如何调节全基因组促纤维化反应及其与其他组织的相互作用 乙酰转移酶，如p300，是不清楚的。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显示，通过阻断Brd 4， 促纤维化基因可以下调; Brd 4的抑制可以破坏p300和 具有促纤维化基因启动子区的H3 K27 ac。我们假设Brd 4影响染色质 可及性，通过与p300的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H3 K27 ac。我们的目标是： 1.确定Brd 4抑制对肺成纤维细胞中促纤维化反应的影响; 2. 确定Brd 4是否通过p300介导组蛋白乙酰化以调节促纤维化基因 表达式，3.确定Brd 4抑制在肺的临床前模型中的体内靶向 纤维化这项研究的结果将对我们理解这一角色产生重大影响。 Brd 4在IPF病理生物学表观遗传调控中的作用。