Severe Asthma Research Program (SARP)-Washington University

描述（由申请人提供）：本提案的总体目标是更好地了解严重哮喘气道重塑的分子基础、结构和生理后果，以及重塑如何随时间变化。在此背景下，我们建议对患有严重哮喘的成人和儿童受试者进行特征明确的队列研究，采用多学科方法，包括最先进的气道形态测量、成像和生理测量。我们将这些发现与控制良好的哮喘组、正常对照组和疾病对照组（慢性支气管炎）的结果进行对比，以确定可以提供严重哮喘特有的生物学靶点的特征。我们已经证明，上皮增生、杯状细胞化生和粘蛋白的产生是严重哮喘患者气道重塑的特征，并且上皮重塑是由于上皮增生增加和细胞死亡减少。我们认为，与控制良好的哮喘相比，严重哮喘患者有：(1)气道重塑增加，如杯状细胞化生和粘蛋白产生；（11）胸部多排CT （MDCT）显示气道厚度增加，导致超极化氦（^He） MRI显示的通气缺陷和MDCT显示的空气困住；（III）气道重塑与更严重和进行性气流阻塞相关。我们假设，我们在严重哮喘中观察到的杯状细胞化生和黏液蛋白增加是由IL-13和egfr依赖机制驱动的，该机制抑制上皮细胞凋亡，并允许IL-13将气道上皮分化为杯状细胞（Aim I）。我们进一步假设，严重哮喘中节段性气道的重塑导致远端通气缺陷和空气捕获（Aim II）。为了确定严重哮喘患者随后肺功能下降的潜在预测因素，我们假设MDCT气道壁面积（AWA%）反映的基线气道重塑可预测FEVi（皮质类固醇/支气管扩张剂后FEVi）下降（Aim III）。识别与重塑和严重哮喘相关的潜在变量将有助于识别高危个体，他们将从特定的靶向治疗中受益。该项目与SARP的共同努力将导致对严重哮喘机制基础的新见解，进一步阐明其与轻中度哮喘的区别，确定潜在的干预目标，并将提供影像学指标来客观评估新治疗方法的结果。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to better understand the molecular basis and structural and physiologic consequences of airway remodeling in severe asthma and how remodeling changes over time. In that context, we propose to study a well-characterized cohort of adult and pediatric subjects with severe asthma using a multidisciplinary approach that includes state-of-the-art morphometric, imaging, and physiologic measurements of airways. We will contrast these findings to those in groups with well- controlled asthma, normal controls, and diseased controls (chronic bronchitis) to identify features that can provide biologic targets unique to severe asthma. We have demonstrated that epithelial hyperplasia, goblet cell metaplasia and mucin production are features of airway remodeling in subjects with severe asthma, and that epithelial remodeling was due to increased epithelial proliferation and decreased cell death. We propose that individuals with severe asthma, in comparison to well controlled asthma, have: (I) increased airway remodeling as evidenced by goblet cell metaplasia and mucin production, (11) greater airway thickness by multidetector-row CT of the chest (MDCT) leading to ventilation defects demonstrated by hyperpolarized helium (^He) MRI and air trapping demonstrated by MDCT, and (III) airway remodeling associated with more severe and progressive airflow obstruction. We hypothesize that the goblet cell metaplasia and increased mucin we have observed in severe asthma are being driven by an IL-13- and EGFR-dependent mechanism that inhibits epithelial cell apoptosis and allows IL-13 differentiation of the airway epithelium into goblet cells (Aim I). We further hypothesize that this remodeling of segmental airways in severe asthma leads to distal ventilation defects and air trapping (Aim II). In an effort to define potential predictors of subsequent decline in lung function in severe asthma, we hypothesize that baseline airway remodeling as reflected by MDCT airway wall area (AWA%) is predictive of FEVi (post-corticosteroid/bronchodilator FEVi) decline (Aim III). The identification of potential variables associated with remodeling and severe asthma will help identify individuals at risk whom would benefit from specific targeted therapy. The concerted efforts of this project together with the SARP will lead to new insights on the mechanistic basis for severe asthma, further elucidate how it differs from mild-moderate asthma, identify potential targets for intervention, and will provide imaging metrics to objectively evaluate outcomes for new treatments. RELEVANCE: Understanding the molecular basis of goblet cell metaplasia and mucin production in severe asthma will provide new targets for therapy. Understanding the pathophysiologic mechanism of ventilation defects and air trapping will impact therapies such as thermoplasty and provide means of evaluating new treatments noninvasively with imaging. Finally, identification of predictors of progressive accelerated lung function decline may allow for earlier intervention in at-risk patients, leading to less severe asthma subsequently.