The epithelial NFkB-BRD4 pathway in airway inflammation and remodeling

上皮 NFkB-BRD4 通路在气道炎症和重塑中的作用

• 批准号: 10450721
• 负责人: Allan R. Brasier
• 金额: $ 45.95万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450721
• 关键词: 8-Oxoguanine DNA Glycosylase; Actins; Acute; Adult; Air; Allergens; Allergic; Antioxidants; Attenuated; Bromodomain; Bronchiolitis; Cells; Child; Chromatin; Chromatin Remodeling Factor; Chronic; Chronic lung disease; Collaborations; Collagen; Complement; Complex; DNA glycosylase; Deposition; Disease; Epigenetic Process; Epithelial; Epithelial Cells; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Fibrosis; Funding; Genes; Goals; Guanine; Histones; Human; IRF1 gene; Immunologics; In Vitro; Infant; Inflammation; Inflammatory Response; Innate Immune Response; Interferons; Knock-out; Knockout Mice; Link; Liquid substance; Long-Term Effects; Longterm Follow-up; Lower Respiratory Tract Infection; Lung; Measures; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Mucous Membrane; Mus; Mutation; Myofibroblast; OGG1 gene; Pathway interactions; Pattern recognition receptor; Population; Production; Proteins; Regulation; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Respiratory syncytial virus RSV proteins; Risk; Role; Sampling; Signal Transduction; Survivors; System; Tamoxifen; Testing; Transcription Elongation; Transferase; Transforming Growth Factor beta; Transitional Epithelium; Tretinoin; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; Work; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; chromatin remodeling; chronic respiratory disease; experimental study; histone acetyltransferase; in vivo; inhibitor; insight; lung injury; mouse model; novel; prevent; programs; pulmonary function; response; small molecule; small molecule inhibitor

Severe lower respiratory tract infections (LRTIs) are associated with long-term reductions in pulmonary function, a highly significant indicator of chronic lung disease in adults. Work in our current funding period has elucidated the central role of the epigenetic coactivator bromodomain-containing protein 4 (BRD4) complexed with NFκB/RelA in mucosal inflammatory responses. Not only does the RelA•BRD4 complex activate inflammation, but it also activates the TGFβ-mediated fibrotic program. We have demonstrated that small- molecule inhibition of BRD4 HAT prevents inflammation, fibrosis, and remodeling in mouse models of repetitive viral and allergen challenges. These findings provide the unifying mechanism linking the innate RelA·BRD4 complex with inflammation and airway remodeling. During the next funding period, we will test the hypothesis that the BRD4 histone acetyl transferase (HAT)-chromatin remodeling complex (CRC) is an epigenetic regulator that acutely activates the innate immune response and chronically activates airway remodeling. We will pursue three hypotheses that: 1) The NFκB/RelA-activated BRD4 HAT- CRC links RSV infection with the remodeling program. We will examine the role of RelA in activation and redistribution of the BRD4 HAT-CRC in fibrotic gene programs in primary human small airway epithelial cells (hSAECs) depleted of BRD4, complemented with BRD4 HAT mutations using air-liquid interface (ALI) cultures established by the Infant Bronchiolitis and Viral Core (IBVC). We will test the functional consequences of our original observations that BRD4 is in a dynamic complex with the SWI/SNF-related, Matrix-associated, Actin- dependent Regulator of Chromatin (SMARC) CRC in inflammation/remodeling. 2) RelA activates the epithelial BRD4 pathway to mediate RSV-induced disease and remodeling. We will use a novel RelA mouse knockout model to test the selective role of RelA signaling by tracheo-bronchiolar cells in RSV-induced inflammation and remodeling in vivo. We will test the effect of BRD4 silencing using BRD4CKO and a novel specific BRD4 inhibitor. We will measure TGFβ fibrotic markers in nasopharyngeal samples from children with LRTI vs uncomplicated URI and normals. 3) RSV proteins restructure the RelA•BRD4 HAT-CRC complex to “prime” allergic airway remodeling. In this aim, we will determine the functional consequences of our findings that RSV proteins interact with the RelA•BRD4 complex, and we will conduct experiments elucidating how RSV infection reprograms the RelA•BRD4 HAT-CRC to enhance (“prime”) allergen-induced myofibroblast expansion and airway remodeling. Our project is synergistic with the studies in RP2 to examine the role of RelA in the regulation of antioxidant genes/NRF2, and with RP3 to examine the role of 8-oxoguanine DNA glycosylase (OGG1) in RelA-activated remodeling. Our results will identify the BRD4 HAT-CRC as an important target in inflammation-remodeling, and they will provide proof-of-principle to advance small-molecule inhibitors to attenuate the long-term effects of RSV infections in humans.

严重下呼吸道感染 (LRTI) 与肺部感染的长期减少有关。 功能是成人慢性肺病的一个非常重要的指标，在​​我们当前资助期间的工作已经取得了进展。 阐明了表观遗传共激活剂含溴结构域蛋白 4 (BRD4) 复合物的核心作用 NFκB/RelA 在粘膜炎症反应中的作用不仅激活RelA·BRD4 复合物。 炎症，但它也会激活 TGFβ 介导的纤维化程序。 BRD4 HAT 的分子抑制可预防重复性小鼠模型中的炎症、纤维化和重塑 这些发现提供了连接先天 RelA·BRD4 的统一机制。 在下一个资助期间，我们将测试炎症和气道重塑的复杂性。 假设 BRD4 组蛋白乙酰转移酶 (HAT)-染色质重塑复合物 (CRC) 是一种 表观遗传调节剂可急性激活先天免疫反应并长期激活 我们将追求三个假设：1) NFκB/RelA 激活的 BRD4 HAT-CRC 将 RSV 感染与重塑程序联系起来 我们将研究 RelA 在激活和重塑过程中的作用。 BRD4 HAT-CRC 在原代人小气道上皮细胞纤维化基因程序中的重新分布 (hSAEC) 耗尽 BRD4，并使用气液界面 (ALI) 培养物补充 BRD4 HAT 突变 由婴儿细支气管炎和病毒核心 (IBVC) 建立的我们将测试我们的功能后果。 最初观察到 BRD4 与 SWI/SNF 相关、基质相关、肌动蛋白处于动态复合体中 炎症/重塑中染色质依赖性调节因子 (SMARC) CRC 2) RelA 激活 上皮 BRD4 通路介导 RSV 诱导的疾病和重塑 我们将使用一种新型 RelA。 小鼠敲除模型测试气管细支气管细胞 RelA 信号传导在 RSV 诱导中的选择性作用 我们将使用 BRD4CKO 和一种新型药物来测试 BRD4 沉默的效果。 我们将测量患有以下疾病的儿童鼻咽样本中的 TGFβ 纤维化标志物。 LRTI 与简单的 URI 和正常 3) RSV 蛋白重组 RelA•BRD4 HAT-CRC 复合物。 为了“启动”过敏性气道重塑，我们将确定我们的功能后果。 发现RSV蛋白与RelA•BRD4复合物相互作用，我们将进行实验阐明 RSV 感染如何重新编程 RelA•BRD4 HAT-CRC 以增强（“启动”）过敏原诱导的肌成纤维细胞 我们的项目与 RP2 中的研究具有协同作用，以检验 RP2 的作用。 RelA 在抗氧化基因/NRF2 的调节中，并与 RP3 一起检查 8-氧鸟嘌呤 DNA 的作用 RelA 激活的重构中的糖基化酶 (OGG1) 我们的结果将鉴定 BRD4 HAT-CRC 作为一个 炎症重塑的重要目标，它们将为推进小分子提供原理验证 抑制剂可减轻 RSV 感染对人类的长期影响。