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，造成75,000 – 每年125,000次住院，并产生明显的发病率和经济影响。没有疫苗 目前已获得预防RSV感染的许可。儿童因RSV下呼吸道感染而住院 （LRTI）的肺功能降低，这是成年慢性肺部疾病的重要预测指标。这是一个 为我们的P01竞争，最初以AADCRC AI46004资助，然后通过两个P01资助 循环（9/1/2005-tresent）。我们的P01的工作具有阐明RSV感染的机制 快速上皮氧化应激反应，引发先天信号传导并导致细胞因子分泌 触发和形状适应性免疫学。最近，我们开发了其他令人信服的证据 支持该P01的中心主题 - 与无处不在的感染产生的先天注射 病毒病原体RSV损害抗氧化能力，产生疾病并触发长期气道 重塑。我们的项目是从我们国际认可的项目的原始发现开发的 领导者（PLS）先天注射，氧化应激和DNA损伤反应方面的专家。我们的续约 包括三个主要的研究项目（RPS）：1）RP1（“先天注射驱动的表观遗传调节 气道重塑”）将重点关注NFκB-激活因子（染色质重塑络合物（CRC））的作用。 用含溴二域的蛋白4（BRD4）在RSV诱导的重塑中通过上皮 - 间充质转变和肌纤维细胞膨胀； 2）RP2（“先天免疫的作用 在帕托马病毒感染期间气道抗氧化剂反应的下调”将重点介绍 RSV导致由ROS产生不平衡的ROS产生介导的疾病，通过NF-E2相关的逐步降低 因子2（NRF2）; 3）RP3（氧化物诱导的OGG1-DNA复合物与气道的连锁 炎症和重塑”）将检验以下假设，即RSV诱导的表观遗传修饰通过 基因调节区域中鸟嘌呤对OXOG的氧化控制急性/慢性注射和气道 通过NFκB途径进行重塑。该P01的指导是与我们的内部持续互动的指导 和外部咨询委员会，并受到UTMB中心的大量机构支持的护理， 部门和机构。我们所有相互关联和协同的RP都由行政核心支持， 来自婴儿支气管炎和病毒核心（IBVC）的人类受试者和病毒制剂。翻译 进步包括BRD4抑制剂，NRF2激动剂和OGG1抑制剂的应用 研究表明，有望干扰RSV诱导的注射和重塑。完成后，此P01 将确定先天信号引起的重塑和开发逆转策略的机制 过敏性气道疾病中的重塑和恢复有缺陷的先天免疫力。