Epithelial innate signaling in airway inflammation and remodeling

呼吸道合胞病毒（RSV）是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。没有一种疫苗是 目前已获许可预防RSV感染。因RSV下呼吸道感染住院的儿童 （LRTI）具有降低的肺功能，这是成人慢性肺部疾病的重要预测因素。这是一 我们的P01的竞争性更新，最初作为AADCRC AI 46004资助，随后通过两个P01 周期（2005年9月1日至今）。我们P01中的工作阐明了RSV感染产生病毒的机制。 快速的上皮氧化应激反应，触发先天信号传导并导致细胞因子分泌， 触发和形成适应性免疫。最近，我们发现了更多令人信服的证据 支持这个P01的中心主题-感染无处不在的 病毒病原体RSV损害抗氧化能力，产生疾病并引发长期气道 重塑我们的项目是从我们国际公认的项目的原始发现发展而来的。 领导者（PL）在先天性炎症，氧化应激和DNA损伤反应方面的专家。我们的更新 包括三个主要的研究项目（RP）：1）RP 1（“先天性炎症驱动的表观遗传调控”， 气道重塑”）将集中在NFκ B-共激活因子的作用，一种染色质重塑复合物（CRC） 含溴结构域蛋白4（BRD 4）在RSV诱导的上皮细胞重塑中起核心作用。 间充质转化和肌成纤维细胞扩增; 2）RP 2（“先天免疫的作用， 副粘病毒感染期间气道抗氧化反应的下调”）将关注如何 RSV通过NF-E2相关蛋白的进行性减少引起不平衡的ROS产生介导的疾病。 因子2（NRF 2）;和3）RP 3（“氧化剂诱导的OGG 1-DNA复合物与气道的连接 炎症和重塑”）将检验RSV诱导的表观遗传修饰通过 基因调控区鸟嘌呤氧化为oxoG控制急性/慢性炎症和气道 通过NFκB途径进行重构。这P01是由定期和持续的互动与我们的内部 和外部咨询委员会，并得到UTMB中心的重要机构支持， 部门和研究所。我们所有相互关联和协同作用的RP都得到了行政核心的支持， 和人类受试者以及来自婴儿细支气管炎和病毒核心（IBVC）的病毒制剂。平移 这些进展包括BRD 4抑制剂、NRF 2激动剂和OGG 1抑制剂在临床前 研究表明，有希望干扰RSV诱导的炎症和重塑。完成后，此P01 将确定先天信号诱导的重塑机制，并制定逆转的策略， 在过敏性气道疾病中重塑和恢复先天免疫缺陷。

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.