Airway inflammation and airway remodeling

描述(申请人提供)：呼吸道重塑是一个术语，适用于哮喘患者观察到的呼吸道结构变化。尽管目前的NIH指南建议维持哮喘患者正常肺功能的目标，但目前的治疗策略并未特别针对气道重塑，因为导致重塑的细胞和分子机制尚未很好地确定，因此治疗靶点也不是很清楚。因此，有必要确定气道重塑的机制，以便潜在的新疗法可以针对这些途径。此外，对这些途径的表征可能导致非侵入性血液或痰生物标记物的开发，以识别、监测，也许还包括亚组， 哮喘患者和重塑的呼吸道。加州大学圣迭戈分校的AADCRC提案将由David Broide(医学教授)指导，其中包括三个项目(Broide、Croft、Zuraw)，这些项目将研究暴露于过敏原和鼻病毒共同触发哮喘的哮喘患者的气道重塑机制。因此，将在所有三个项目中探索的总体假设是，暴露于变应原会触发过敏性哮喘患者炎症和重塑途径的表达，而暴露于鼻病毒等呼吸道病毒会加剧这些途径。将在每个项目中探索并由哮喘患者样本驱动的特定假设是，先天免疫反应(呼吸道上皮、巨噬细胞、自然辅助细胞)在启动和维持过敏性哮喘患者对环境因素的炎症和气道重塑反应中发挥重要作用。这三个相互关联的项目将集中在“先天炎症和气道重塑”(Broide，项目1)、“肿瘤坏死因子受体家族成员、炎症和重塑”(Croft，项目2)和“上皮GILZ炎症和重塑”(Zuraw，项目3)上，并得到行政核心A和“哮喘临床核心B”的支持，后者将是痰、BAL、支气管内活检的来源，以及哮喘和对照受试者的血液样本，这些血液样本由核心B的研究人员提供(加州大学圣地亚哥分校的Ramsdell、Harrell和Treslethwaite；卡尔加里大学的Proud和Leigh；以及麦吉尔大学的Hamid)。应区域金融管理局的要求，还提出了一项LOFM核心。

DESCRIPTION (provided by applicant): Airway remodeling is the term applied to the structural changes observed in the airway in asthma. Although current NIH guidelines recommend maintaining a goal of normal lung function in asthma, current therapeutic strategies do not specifically target airway remodeling as the cellular and molecular mechanisms that result in remodeling are not well defined and thus therapeutic targets are not well understood. Thus, there is an important need to identify mechanisms by which airway remodeling is mediated so that potential novel therapies could be directed at these pathways. In addition, characterization of these pathways could lead to the development of non-invasive blood or sputum biomarkers to identify, monitor, and perhaps subset, patients with asthma and remodeled airways. This UCSD AADCRC proposal will be directed by David Broide (Professor of Medicine) and include three projects (Broide, Croft, Zuraw) that will investigate mechanisms of airway remodeling in asthmatics exposed to allergen and rhinovirus common triggers of asthma. Thus, the overall hypothesis that will be explored in all three projects is that exposure to allergen triggers expression of inflammatory and remodeling pathways in allergic asthmatics that are exacerbated by exposure to respiratory viruses such as rhinovirus. The specific hypothesis that will be explored in each project and that will be driven by samples from asthmatics, is that the innate immune response (airway epithelium, macrophages, natural helper cells) play an important role in initiating and perpetuating the inflammatory and airway remodeling response to environmental triggers in allergic asthmatics. The three interrelated projects will focus on "Innate inflammation and airway remodeling" (Broide, Project 1), "TNF-R family members, inflammation and remodeling" (Croft, Project 2), and "Epithelial GILZ inflammation and remodeling" (Zuraw, Project 3) and be supported by Administrative Core A, and "Asthma Clinical Core B" which will be a source of sputum, BAL, endobronchial biopsy, and blood samples from asthma and control subjects provided by investigators in Core B (Ramsdell, Harrell, and Thistlethwaite, UCSD; Proud and Leigh, University of Calgary; and Hamid, McGill University). An lOFM Core is also proposed as requested by the RFA.