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: 10205989
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205989
• 关键词: 8-Oxoguanine DNA Glycosylase; Actins; Acute; Adult; Air; Airway Disease; 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; Structure; 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; experimental study; histone acetyltransferase; in vivo; inhibitor/antagonist; insight; lung injury; mouse model; novel; prevent; programs; pulmonary function; respiratory; 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.

严重的下呼吸道感染（LRTI）与肺的长期降低有关 功能，这是成人慢性肺部疾病的高度显着指标。在我们当前的资金期间的工作 阐明了表观遗传共激活因子群蛋白4（BRD4）复合的核心作用 粘膜炎症反应中的NFκB/Rela。 Rela•BRD4复合物不仅激活 炎症，但也激活了TGFβ介导的纤维化程序。我们已经证明了很小的 BRD4 HAT的分子抑制可预防重复的小鼠模型中的感染，纤维化和重塑 病毒和过敏原挑战。这些发现提供了统一的机制，将先天性rela·brd4连接起来 复杂的炎症和气道重塑。在下一个资金期间，我们将测试 假设BRD4组蛋白乙酰转移酶（HAT） - 染色质重塑复合物（CRC）是一种 急性激活先天免疫反应并长期激活的表观遗传调节剂 气道重塑。我们将提出三个假设：1）NFκB/Rela激活的BRD4 HAT- CRC 将RSV感染与重塑程序链接。我们将研究Rela在激活中的作用 在主要人类小气道上皮细胞中BRD4 HAT-CRC的重新分布 （HSAECS）耗尽了BRD4，使用空气界面（ALI）培养物完成BRD4 HAT突变 由婴儿细支气管炎和病毒核（IBVC）建立。我们将测试我们的功能后果 原始观察结果是，BRD4与SWI/SNF相关的，与基质相关的肌动蛋白 - 炎症/重塑中染色质（SMARC）CRC的依赖调节剂。 2）RELA激活 上皮BRD4途径介导RSV诱导的疾病和重塑。我们将使用一个新颖的Rela 小鼠基因敲除模型，以测试RSV诱导的气管 - 支气管细胞中Rela信号传导的选择性作用 体内炎症和重塑。我们将使用BRD4CKO和小说测试BRD4沉默的效果 特定的BRD4抑制剂。我们将测量来自患有儿童的鼻咽样品中的TGFβ纤维化标记 LRTI与简单的URI和正常人。 3）RSV蛋白质修复•BRD4 HAT-CRC复合物 “素”过敏性气道重塑。在此目标中，我们将确定我们的功能后果 RSV蛋白与RELA•BRD4复合物相互作用的发现，我们将进行实验 RSV感染如何重新编程•BRD4 HAT-CRC增强（“ Prime”）过敏原诱导的肌纤维细胞 扩展和气道重塑。我们的项目与RP2的研究协同作用，以检查 在调节抗氧化基因/NRF2的调节中，并使用RP3检查8-氧气的DNA的作用 重塑重塑中的糖基化酶（OGG1）。我们的结果将确定BRD4 HAT-CRC是 炎症 - 解码化的重要目标，它们将提供原则证明以推进小分子 抑制剂减轻RSV感染在人类中的长期影响。