Mentoring patient-oriented researchers in inflammatory airway disease

摘要 这项研究的总体目标是确定人类先天淋巴细胞的新方面， 细胞（ILC）生物学在气道疾病中使用以患者为导向的研究（POR），并通过指导初级 临床研究者。候选人在多个层面上都有很好的指导记录，包括 多个专业的临床研究者。指导计划包括招募和培训研究员 以及加州大学圣地亚哥分校内三个学科（过敏、耳鼻喉科和肺科）的教员调查员 哮喘和鼻窦疾病中心卓越中心，以促进初级研究人员的职业生涯 并执行出色的POR。目前，我们对国际法委员会作用的理解存在很大差距 在全世界引起显著发病率人类鼻窦疾病和哮喘中。ILC分为 它们分泌的细胞因子类型和分泌Th2细胞因子的ILC2已经显示出促进 动物模型中的气道炎症。重要的是，最近的研究表明，ILC2在 来自患有哮喘和慢性鼻窦炎（CRS）的患者的样品。我们组是第一个 ILC2在含有嗜酸性粒细胞的CRS鼻息肉亚组中增加， 阿司匹林急性呼吸道疾病患者阿司匹林激发后鼻内聚集 （AERD）. AERD患者有严重的鼻窦疾病伴鼻息肉，中度至重度哮喘， 对阿司匹林和类似化合物的呼吸反应。在目前的提案中，我们将测试假设 通过使用尖端技术（单细胞RNA-seq），我们将能够识别特定的 根据组织和血液ILC亚组组成，CRS和哮喘患者的亚组或"内在型"。 我们还证实，在AERD、哮喘和CRS患者中，2型炎症的生物阻断剂将 减少ILC2向气道的募集。至关重要的是，该奖项将为窦内POR提供保护时间 疾病和哮喘，并允许下一代POR研究人员的杰出导师。

Abstract The overall goal of the proposed research is to identify novel aspects of human innate lymphoid cell (ILC) biology in airway diseases using patient-oriented research (POR) and through mentoring junior clinical investigators. The candidate has a strong record of mentoring individuals at many levels including clinical investigators in multiple specialties. The mentoring plan includes recruitment and training of fellow and faculty investigators from three disciplines (allergy, otolaryngology, and pulmonary) within the UCSD Center for Asthma and Sinus Disease center of excellence to foster the careers of junior investigators and perform outstanding POR. There are currently large gaps in our understanding of the roles of ILCs in human sinus disease and asthma which cause significant morbidity worldwide. ILCs are divided by the types of cytokines they secrete and ILC2s that secrete Th2 cytokines have been shown to promote airway inflammation in animal models. Importantly, recent work has shown that ILC2s are increased in samples from patients with asthma and chronic rhinosinusitis (CRS). Our group was the first to show that ILC2s are increased in a subgroup of nasal polyps in CRS that contain eosinophils and are also recruited to the nose after aspirin challenge in patients with aspirin-exacerbated respiratory disease (AERD). AERD patients have severe sinus disease with nasal polyps, moderate to severe asthma, and respiratory reactions to aspirin and similar compounds. In the current proposal, we will test the hypothesis that through the use of cutting-edge technology (single cell RNA-seq) we will be able to identify specific subgroups or “endotypes” of patients with CRS and asthma by tissue and blood ILC subset composition. We also posit that biologic blockade of type 2 inflammation in AERD, asthma and CRS patients will reduce ILC2 recruitment to the airway. Critically, this award will provide protected time for POR in sinus disease and asthma and allow for outstanding mentorship of the next generations of POR investigators.