Epithelial innate signaling in airway inflammation and remodeling

气道炎症和重塑中的上皮先天信号传导

• 批准号: 10205986
• 负责人: Roberto P Garofalo
• 金额: $ 175.46万
• 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/10205986
• 关键词: Abbreviations; Acute; Adult; Advisory Committees; Agonist; Allergens; Antioxidants; Binding; Bromodomain; Bronchiolitis; Cells; Child; Childhood; Chromatin Remodeling Factor; Chronic; Chronic lung disease; Clinical; Complex; Couples; DNA; DNA Damage; Disease; Down-Regulation; Epigenetic Process; Epithelial; Fibrosis; Follow-Up Studies; Funding; Gene Expression; Genes; Genetic; Genome; Grant; Guanine; Hospitalization; Human; Immune signaling; Impairment; Infant; Infection; Inflammation; Inflammatory; Innate Immune Response; Institutes; Interferon Type I; Interferons; International; Knockout Mice; Life; Link; Longterm Follow-up; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung diseases; Lung infections; Measurement; Mediating; Mesenchymal; Modification; Morbidity - disease rate; Myofibroblast; NF-E2-related factor 2; Natural Immunity; Nuclear; Nucleic Acid Regulatory Sequences; OGG1 gene; Outpatients; Oxidants; Oxidative Stress; Paramyxovirus; Pathogenesis; Pathway interactions; Patients; Play; Population; Positioning Attribute; Preparation; Production; Proteins; Regulator Genes; Research Design; Research Project Grants; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Role; Sampling; Severity of illness; Shapes; Signal Transduction; Somatotype; Structure; Testing; United States; Vaccines; Viral; Virus; Virus Diseases; Visit; Wheezing; Work; adaptive immunity; aged; airway inflammation; airway remodeling; allergic airway disease; antioxidant enzyme; arm; biological adaptation to stress; cytokine; economic impact; epigenetic regulation; epithelial to mesenchymal transition; human subject; inhibitor/antagonist; innate immune mechanisms; innate immune pathways; leukemia; mouse model; novel; oxidation; oxidative damage; pathogenic virus; preclinical study; prevent; programs; promoter; pulmonary function; respiratory; response; small molecule

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.

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 人住院治疗，并产生显着的发病率和经济影响。 目前获得许可用于预防因 RSV 下呼吸道感染住院的儿童。 （LRTI）会降低肺功能，这是成人慢性肺病的重要预测因素。 我们的 P01 的竞争更新，最初由 AADCRC AI46004 资助，随后通过两个 P01 周期（2005 年 9 月 1 日至今）。我们 P01 的工作阐明了 RSV 感染产生的机制。 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 最近，我们发现了更多令人信服的证据。 支持本 P01 的中心主题——普遍存在的感染所产生的先天炎症 病毒病原体 RSV 会损害抗氧化能力，产生疾病并引发长期气道损伤 我们的项目是根据我们国际认可的项目的原创发现开发的。 领导者 (PL) 是先天性炎症、氧化应激和 DNA 损伤反应领域的专家。 包括三个主要研究项目（RP）：1）RP1（“先天炎症驱动的表观遗传调控”） 气道重塑”）将重点关注 NFκB 共激活剂（一种染色质重塑复合物 (CRC)）的作用 在 RSV 诱导的上皮重塑中，由含溴结构域蛋白 4 (BRD4) 成核 间质转化和肌成纤维细胞扩张；2) RP2（“先天免疫在 副粘病毒感染期间气道抗氧化反应的下调”）将重点关注如何 RSV 通过 NF-E2 相关因子的逐渐减少，导致由不平衡的 ROS 产生介导的疾病 因子 2 (NRF2)；和 3) RP3（“氧化剂诱导的 OGG1-DNA 复合物与气道的联系”） “炎症和重塑”）将检验 RSV 通过以下方式诱导表观遗传修饰的假设： 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 途径进行的重塑是由与我们的内部定期和持续的相互作用引导的。 和外部咨询委员会，并得到 UTMB 中心的大力机构支持的培育， 我们所有相互关联和协同的 RP 均得到行政核心的支持， 以及来自婴儿细支气管炎和病毒核心（IBVC）的人类受试者和病毒制剂。 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，该 P01 有望干扰 RSV 诱导的炎症和重塑。 将确定先天信号诱导重塑的机制并制定逆转策略 重塑和恢复过敏性气道疾病的先天免疫缺陷。