Understanding Asthma Endotypes

了解哮喘内型

• 批准号: 10165891
• 负责人: David J Erle
• 金额: $ 288.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165891
• 关键词: Allergic Disease; Animal Model; Asthma; Biological Models; Cell Line; Cell model; Cells; Cellular biology; Clinical; Clinical Data; Communication; Disease; Ensure; Epithelial; Epithelial Cells; Extrinsic asthma; Functional disorder; Human; Human Subject Research; Immune response; Individual; Inflammation; Interferons; Interleukin-13; Knowledge; Laboratories; Lead; Longitudinal Studies; MUC5AC gene; Molecular Biology; Mucous body substance; National Institute of Allergy and Infectious Disease; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Play; Plug-in; Prediction of Response to Therapy; Predisposition; Production; Research; Research Personnel; Resistance; Role; Secretory Cell; Severities; Subgroup; Work; airway epithelium; airway inflammation; airway obstruction; asthma model; base; biological adaptation to stress; clinical development; clinically significant; common treatment; cytokine; disease phenotype; effective therapy; endoplasmic reticulum stress; human study; improved; innovation; insight; molecular phenotype; mouse model; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; physical property; pre-clinical; predicting response; programs; randomized trial; recruit; response; sensor; tool

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.

节目概要 该提案旨在更新一个成功的UCSF哮喘和过敏性疾病合作研究中心 致力于确定哮喘的分子表型（内型），并了解这些内型如何 有助于疾病的病理生理学。该提案建立在我们使用细胞和分子的记录之上 生物学工具、动物模型和人类研究集中在气道上皮上，以解剖哮喘 机制，将机制与疾病表型联系起来，预测对现有疗法的反应，并识别 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对气道上皮细胞的影响，确定2型哮喘内源性为哮喘的主要特征。 大哮喘亚组，建立了哮喘内定型预测治疗反应的能力， 显示IL-13诱导的分泌细胞变化如何导致致命性哮喘中的粘液堵塞。最近的研究 来自我们小组和其他实验室的研究暗示了其他途径，特别是干扰素（IFN）和ER应激 在某些哮喘患者中，尽管我们的中心取得了相当大的进展， 其他人，仍然迫切需要更全面地了解哮喘疾病的机制， 对于许多2型高或2型低哮喘患者， 目前的治疗。该提案包括两个高度相关的项目， 上皮细胞作为哮喘发病机制的关键参与者和哮喘内定型的有用传感器。项目 1将确定上皮细胞对IL-13的敏感性升高的机制和后果， IL-13诱导的导致气道阻塞的粘液物理性质的变化，并解剖了 上皮细胞ER应激在2型和IFN-高哮喘中的作用。项目2将确定临床 哮喘中干扰素驱动炎症和气道上皮ER应激的意义， 干扰素驱动的炎症和气道上皮ER应激抵抗并预测对 现有的哮喘疗法，并确定是否特异性抑制气道上皮ER应激与一种新的 治疗剂KIRA 8改善过敏性哮喘模型中的AHR、炎症和粘液产生。临床 受试者和生物样本中心将招募并仔细描述患有哮喘和健康的受试者 控制和提供生物标本，将广泛用于这两个项目。行政核心将 协调中心活动。通过所提出的研究，我们希望获得新的见解， 哮喘内型的基础，更好地了解如何靶向特定内型中重要的新途径。