Beyond the Type-2 High Endotype

超越 2 型高内型

• 批准号: 10366701
• 负责人: PRESCOTT G WOODRUFF
• 金额: $ 55.17万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366701
• 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.

程序摘要 该建议旨在续签成功的UCSF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往绩上 生物学工具，动物模型和人类研究集中于气道上皮，以剖析哮喘 机制，将机制与疾病表型相关联，预测对现有疗法的反应，并确定 新的治疗靶标。我们中心的工作表明了类型直接影响的核心重要性 在气道上皮细胞上的2个细胞因子IL-13，将2型哮喘内型确定为A中的主要特征 大型哮喘亚组确定了哮喘内型预测治疗反应的能力，并 展示了IL-13诱导的分泌细胞的变化如何导致粘液塞在致命的哮喘中。最近的研究 来自我们的小组和其他实验室牵涉到其他途径，特别是干扰素（IFN）和ER压力 在某些患有哮喘的人中。尽管我们的中心和许多 其他人，仍然需要更全面地了解哮喘疾病机制等等 对于许多2型高或2型高哮喘的人的有效疗法，他们反应不佳 当前治疗。该建议包括两个高度相互关联的项目，并分享了 上皮是哮喘发病机理的关键参与者，也是用于哮喘内型的有用传感器。项目 1将确定上皮敏感性对IL-13的敏感性的机制和后果，检查基础 IL-13诱导的粘液物理性质变化，导致气道阻塞，并剖析 2型和IFN高哮喘的上皮ER应力的贡献。项目2将确定临床 干扰素驱动的炎症和气道上皮ER应力在哮喘中的重要性，确定是否是否确定 干扰素驱动的炎症和气道上皮ER应激对 现有的哮喘疗法，并确定是否有针对气道上皮ER应力的特定抑制 Therapeutic，Kira8，改善了过敏性哮喘模型中的AHR，炎症和粘液产生。临床 受试者和生物循环核心将招募并精心表征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测量。行政核心将 协调中心活动。通过拟议的研究，我们期望获得对机械的新见解 哮喘内型的基础，并且更好地了解如何靶向特定内型重要的新型途径。