Understanding Asthma Endotypes

计划摘要 该提案旨在更新一个成功的加州大学旧金山分校哮喘和过敏性疾病合作研究中心 致力于识别哮喘的分子表型(内型)并了解这些内型是如何 对疾病的病理生理学有贡献。这项提议建立在我们使用细胞和分子的记录之上 生物学工具、动物模型和人体研究集中在呼吸道上皮来解剖哮喘 机制，与疾病表型相关的机制，预测对现有治疗的反应，并确定 新的治疗靶点。我们中心的工作证明了这种类型的直接影响的核心重要性 2细胞因子IL-13在呼吸道上皮细胞上的表达，证实2型哮喘内型是哮喘的主要特征 大的哮喘亚组，建立了哮喘内型法预测治疗反应的能力，以及 展示了IL-13诱导的分泌细胞变化如何导致致命哮喘的粘液堵塞。最新研究 来自我们小组和其他实验室的研究表明，干扰素(干扰素)和内质网应激与其他途径有关 途径，在一些哮喘患者身上。尽管我们的中心和许多人取得了长足的进步 在其他方面，仍然迫切需要更全面地了解哮喘的发病机制，以及更多 对许多2型高哮喘或2型低哮喘患者有效的治疗方法 目前的治疗方法。该提案包括两个高度相关的项目，并共同关注 上皮细胞既是哮喘发病机制中的关键参与者，又是哮喘内分泌分型的感受器。项目 1将确定上皮细胞对IL-13敏感性升高的机制和后果，研究基础 IL-13诱导的引起呼吸道阻塞的粘液物理性质的变化，并解剖 上皮内质网应激在2型和干扰素高度型哮喘中的作用。项目2将确定临床 干扰素驱动的炎症和呼吸道上皮细胞内质网应激在哮喘中的意义 干扰素驱动的炎症和呼吸道上皮细胞内质网应激抵抗和预测不良反应 现有的哮喘治疗方法，并确定是否具有特异性抑制呼吸道上皮细胞内质网应激的新方法 治疗性的KIRA8可以改善过敏性哮喘模型的AHR、炎症和粘液产生。一家临床诊所 主题和生物素核心将招募和仔细描述患有哮喘和健康的参与者 控制并提供将在这两个项目中广泛使用的生物检疫制剂。行政核心意志 协调中心活动。通过拟议的研究，我们希望对这一机制有新的见解 哮喘内型的基础，并更好地了解如何针对在特定内型中重要的新途径。

PROGRAM SUMMARY This proposal seeks to renew a successful UCSF Asthma and Allergic Diseases Cooperative Research Center dedicated to identifying molecular phenotypes (endotypes) of asthma and understanding how these endotypes contribute to disease pathophysiology. The proposal builds on our track record of using cell and molecular biology tools, animal models, and human studies focused on the airway epithelium to dissect asthma mechanisms, relate mechanisms to disease phenotypes, predict responses to existing therapies, and identify new therapeutic targets. Work from our Center demonstrated the central importance of direct effects of the type 2 cytokine IL-13 on airway epithelial cells, identified the type 2 asthma endotype as the dominant feature in a large asthma subgroup, established the ability of asthma endotyping to predict therapeutic responses, and showed how IL-13-induced changes in secretory cells cause mucus plugging in fatal asthma. Recent studies from our group and other laboratories implicate other pathways, notably the interferon (IFN) and ER stress pathways, in some individuals with asthma. Despite the considerable progress made by our Center and many others, there is still an urgent need for a more complete understanding of asthma disease mechanisms and more effective therapies for the many individuals with type 2-high or type 2-low asthma who do not respond well to current treatments. This proposal includes two projects that are highly interrelated and share a focus on the epithelium as both a key participant in asthma pathogenesis and a useful sensor for asthma endotyping. Project 1 will determine mechanisms and consequences of heightened epithelial sensitivity to IL-13, examine the basis of IL-13-induced changes in physical properties of mucus that cause airway obstruction, and dissect the contributions of epithelial ER stress in both type 2- and IFN-high asthma. Project 2 will determine the clinical significance of interferon-driven inflammation and airway epithelial ER stress in asthma, establish whether interferon-driven inflammation and airway epithelial ER stress are resistant to and predict poor response to existing asthma therapies, and determine whether specific inhibition of airway epithelial ER stress with a novel therapeutic, KIRA8, improves AHR, inflammation and mucus production in allergic asthma models. A Clinical Subject and Biospecimen Core will recruit and carefully characterize participants with asthma and healthy controls and provide biospecimens that will be used extensively in both projects. An Administrative Core will coordinate Center activities. Through the proposed studies we expect to gain new insights into the mechanistic bases of asthma endotypes and better understand how to target novel pathways important in specific endotypes.