Epithelial innate signaling in airway inflammation and remodeling

呼吸道合胞病毒(RSV)是导致儿童呼吸道疾病的主要原因，导致75,000- 每年有125,000人住院，并产生重大的发病率和经济影响。没有疫苗是 目前获得了预防呼吸道合胞病毒感染的许可。儿童因呼吸道合胞病毒下呼吸道感染住院 (LRTI)会降低肺功能，这是成人慢性肺部疾病的重要预测因素。这是一个 竞争更新我们的P01，最初作为AADCRC AI46004资助，随后通过两个P01 周期(2005年9月1日至今)。我们在P01中的工作阐明了RSV感染产生 快速的上皮细胞氧化应激反应，触发先天信号并导致细胞因子分泌，从而 触发和塑造适应性免疫。最近，我们发现了更多令人信服的证据 支持这篇P01的中心主题--由感染无处不在的 病毒病原体RSV削弱抗氧化能力，引发疾病并触发长期呼吸道 改建。我们的项目是由我们的国际公认的项目从原始发现发展而来的 先天炎症、氧化应激和DNA损伤反应方面的专家。我们的更新 包括三个主要研究项目(RP)：1)RP1(“先天炎症的表观遗传调控 将重点关注核因子κB共激活因子的作用，它是一种染色质重塑复合体 在呼吸道合胞病毒诱导的重塑中，含溴结构域蛋白4(BRD4)通过上皮细胞 间充质转化和肌成纤维细胞的扩张；2)RP2(“先天免疫在 副粘病毒感染期间呼吸道抗氧化反应的下调“)将集中于如何 呼吸道合胞病毒通过核因子-E2相关的进行性减少导致ROS产生失衡而导致疾病 因子2(NRF2)；和3)RP3(“氧化剂诱导的OGG1-DNA复合体与呼吸道的连接 炎症和重塑“)将检验这一假说：RSV通过 基因调控区鸟嘌呤氧化为oxoG控制急/慢性炎症和呼吸道 通过核因子κB途径进行重塑。本P01以与我们的内部定期和持续的互动为指导 和外部咨询委员会，并得到UTMB中心的重大机构支持， 系和研究所。我们所有相互关联和协同的RPS都有一个管理核心来支持， 以及来自婴儿毛细支气管炎和病毒核心(IBVC)的受试者和病毒制剂。翻译 进展包括BRD4抑制剂、NRF2激动剂和OGG1抑制剂在临床前的应用 研究表明，干预RSV诱导的炎症和重塑是有希望的。完成后，本P01 将识别先天信号诱导重塑的机制，并开发逆转策略 过敏性呼吸道疾病中先天免疫缺陷的重建和恢复。

Respiratory Syncytial Virus (RSV) is a leading cause of childhood respiratory disease, responsible for 75,000– 125,000 hospitalizations annually and producing significant morbidity and economic impact. No vaccine is currently licensed to prevent RSV infections. Children hospitalized for RSV lower respiratory tract infections (LRTIs) have reduced pulmonary function, a significant predictor of adult chronic lung disease. This is a competing renewal for our P01, originally funded as AADCRC AI46004 and subsequently through two P01 cycles (9/1/2005-present). Work in our P01 has elucidated mechanisms by which RSV infection produces a rapid epithelial oxidative stress response, triggering innate signaling and resulting in cytokine secretion that triggers and shapes adaptive immunity. More recently, we have developed additional compelling evidence supporting the central theme of this P01 – that innate inflammation produced by infection with the ubiquitous viral pathogen RSV impairs antioxidant capacity, producing disease and triggering long-term airway remodeling. Our projects are developed from original discoveries by our internationally recognized project leaders (PLs) expert in innate inflammation, oxidative stress, and the DNA damage response. Our renewal includes three major research projects (RPs): 1) RP1 (“Epigenetic regulation of innate inflammation-driven airway remodeling”) will focus on the role of the NFκB-coactivator, a chromatin remodeling complex (CRC) nucleated by bromodomain-containing protein 4 (BRD4) in RSV-induced remodeling via epithelial- mesenchymal transition and myofibroblast expansion; 2) RP2 (“The role of innate immunity in downregulation of the airway antioxidant response during paramyxovirus infection”) will focus on how RSV causes disease mediated by unbalanced ROS production via a progressive decrease in NF-E2-related factor 2 (NRF2); and 3) RP3 (“Linkage of the oxidant induced OGG1-DNA complex to airway inflammation and remodeling”) will test the hypothesis that RSV-induced epigenetic modification via oxidation of guanine to oxoG in gene regulatory regions controls acute/chronic inflammation and airway remodeling via the NFκB pathway. This P01 is guided by regular and sustained interactions with our Internal and External Advisory Committees and is nurtured by significant institutional support from UTMB Centers, Departments, and Institutes. All our inter-related and synergistic RPs are supported by an Administrative Core, and human subjects and viral preparations from the Infant Bronchiolitis and Viral Core (IBVC). Translational advances include applications of BRD4 inhibitors, NRF2 agonists, and OGG1 inhibitors that in preclinical studies show promise to interfere with RSV-induced inflammation and remodeling. Upon completion, this P01 will have identified mechanisms of innate signaling-induced remodeling and developed strategies for reversing remodeling and restoring defective innate immunity in allergic airway diseases.