INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA

这项合作计划项目资助（PPG）的提案侧重于哮喘中TH 2炎症的机制。统一的假设是：（i）TH 2炎症是哮喘最常见的分子表型的基础;（11）上皮细胞分泌细胞因子和趋化因子以引发和放大气道中的TH 2炎症;（111）先天辅助2型（IH 2） 细胞和CD 4 +T细胞是上皮细胞因子和趋化因子的关键细胞靶，也是气道中TH 2细胞因子的主要来源。项目1将重点关注iH 2细胞作为气道中TH 2炎症的近端调节因子的作用。该项目建议表征这些细胞的标志物，描述它们在过敏性气道反应中的作用，并与项目3中的研究人员合作，以促进对人类哮喘中iH 2细胞的理解。项目2将鉴定调节与哮喘相关的辅助性T细胞功能的miRNA，检测哮喘患者临床样本中CD 4 +T细胞和iH 2细胞中的miRNA表达模式，并表征所选miRNA的mRNA靶点和体内功能。项目3将研究先天辅助2型细胞作为TH 2高哮喘的细胞介质的作用，确定IL-33如何放大急性重度哮喘中的TH 2炎症，并探索ST 2的遗传变异如何调节哮喘中的气道TH 2炎症。这些项目将得到三个核心的支持，这三个核心将提供行政支持，获得来自特征良好的哮喘受试者和健康对照的高质量生物标本，以及专家生物统计和生物信息学支持。PPG代表了一项合作研究计划，该计划将来自UCSF气道临床研究中心（ACRC）（Fahy和Woodruff）的机制导向临床研究人员与来自UCSF桑德勒哮喘基础研究中心（SABRE）（Locksley和Ansel）的疾病导向基础免疫学家聚集在一起，这些研究人员将使用各种实验方法进行合作。包括PPG中的人体生物样本研究，该研究有望以与哮喘患者高度相关的方式促进对气道TH 2炎症的理解。

This proposal for a collaborative Program Project Grant (PPG) focuses on mechanisms of TH2 inflammation in asthma. The unifying hypotheses are: (i) TH2 inflammation underlies the most common molecular phenotypes of asthma; (11) Epithelial cells secrete cytokines and chemokines to initiate and amplify TH2 inflammation in the airway; (ill) Innate helper type 2 (IH2) cells and CD4+T cells are key cellular targets of epithelial cytokines and chemokines and principal sources of TH2 cytokines in the airway. Project 1 will focus on the role of iH2 cells as proximal regulators of TH2 inflammation in the airway. This project proposes to characterize markers for these cells, delineate their role in allergic airway responses and collaborate with investigators in Project 3 to advance understanding of iH2 cells in human asthma. Project 2 will identify the miRNAs that regulate helper T cell functions relevant to asthma, examine miRNA expression patterns in CD4+T cells and iH2 cells in clinical samples from asthmatic patients, and characterize the mRNA targets and In vivo function of select miRNAs. Project 3 will investigate the role of Innate helper type 2 cells as cellular mediators of TH2-high asthma, determine how IL-33 amplifies TH2 inflammation in acute severe asthma, and explore how genetic variation in ST2 modulates airway TH2 inflammation in asthma. These projects will be supported by three cores, which will provide administrative support, access to high quality biospecimens from well-characterized asthmatic subjects and healthy controls, and expert biostatistical and bioinformatic support. The PPG represents a collaborative program of research that brings together mechanism-oriented clinical researchers from UCSF's Airway Clinical Research Center (ACRC) (Fahy and Woodruff) with disease-oriented basic immunologists from UCSF's Sandler Asthma Basic Research Center (SABRE) (Locksley and Ansel) Together, these investigators will work collaboratively using a variety of experimental approaches. Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma.