Nasal Microbiome and Host Immunity in Granulomatosis with Polyangiitis

项目总结 李医生的长期职业目标是成为一名以患者为导向的临床和 致力于改善脉管炎患者生活的翻译研究。她将在她的基础上继续发展 当前的临床流行病学技能，并获得以患者为导向的指导的关键经验 研究、使用深度测序方法，实施生物信息学和高级流行病学 方法：研究方法。通过K23奖项、拟议研究的执行和职业发展活动，Dr。 Rhee将获得在风湿学方面取得重要科学进步所需的技能和培训。 肉芽肿合并多血管炎(GPA；Wegener‘s)是一种全身性肉芽肿性血管炎，常影响 上呼吸道，并经常复发。先前的研究表明，鼻孔中的微生物 与GPA中的复发有关，但这些研究依赖于文化依赖的方法。高科技的研究进展 吞吐量测序和用于分析元基因组数据的新工具的开发现在允许 更好地理解占据我们的微生物动态群落之间的复杂关系 粘膜组织和宿主的免疫系统。我们假设患有GPA的患者有更大的生物失调 (本土微生物区系的破坏)与对照相比，更大的生物失调是相关的 与GPA的疾病活动有关，通过中性粒细胞活性(GPA中的关键致病细胞)的增加而介导。这个 具体目标是：1)比较GPA患者和对照组之间的鼻部微生物群；2) 检测GPA患者鼻部微生物组成的纵向变化 这些变化与鼻黏膜上皮基因表达谱及临床的关系 结果。更好地了解复杂的微生物与粘膜免疫系统的相互作用 GPA可以促进我们对GPA的病理生理学的了解，帮助预测未来的复发，并提供信息 新疗法的发展。这项研究的结果将应用于资金申请(R01 和其他)，对GPA中宿主与微生物的相互作用进行大规模研究。 为了成功地执行拟议的研究并发展研究宿主-微生物相互作用的事业， 风湿病，李医生和她的导师们形成了一个全面的职业发展计划， 利用她导师的专业知识和宾夕法尼亚大学丰富的资源。李博士将参与 正式教学，包括完成生物医学信息学证书课程，参与相关 研讨会和会议，并将至少75%的精力投入到研究中。由专家导师和 合作者，本申请中概述的研究和培训活动将使Rhee博士能够从 从观察型流行病学家转变为独立的以患者为中心的临床和转化型研究人员， 让她掌握更多的技能来回答有关脉管炎的重要和新问题。

PROJECT SUMMARY Dr. Rhee's long-term career goal is to become an independent investigator in patient-oriented clinical and translational research dedicated to improving the lives of patients with vasculitis. She will build upon her current skills in clinical epidemiology and gain critical experience in the conduct of prospective patient-oriented research, use of deep sequencing methods, and implementation of bioinformatics and advanced epidemiologic methods. Through the K23 award, the execution of the proposed study, and career development activities, Dr. Rhee will acquire the skills and training needed to make important scientific advances in rheumatology. Granulomatosis with polyangiitis (GPA; Wegener's) is a systemic granulomatous vasculitis which often affects the upper respiratory tract and frequently relapses. Prior studies demonstrated that microbes in the nares are associated with relapse in GPA but these studies relied on culture-dependent approaches. Advances in high- throughput sequencing and the development of new tools for analyzing metagenomic data now allow for a better understanding of the complex relationship between the dynamic community of microbes that occupy our mucosal tissues and the host's immune system. We hypothesize that patients with GPA have greater dysbiosis (disruption in indigenous microbiota) in the nares compared to controls and that greater dysbiosis is associated with disease activity in GPA, mediated by an increase in neutrophil activity (a key pathogenic cell in GPA). The Specific Aims are: 1) compare the nasal microbiome between patients with GPA versus controls, and 2) examine longitudinal changes in the nasal microbial composition of patients with GPA and the association of these changes with gene expression profiles in the nasal epithelium and clinical outcomes. A better understanding of the complex microbial interactions with the mucosal immune system in GPA can advance our understanding of the pathophysiology of GPA, help predict future relapse, and inform the development of novel therapeutics. Findings from this study will be applied to applications for funding (R01 and others) to perform large-scale studies of host-microbe interactions in GPA. In order to successfully execute the proposed study and develop a career studying host-microbe interactions in rheumatic diseases, Dr. Rhee and her mentors have formed a comprehensive career development plan which draws upon the expertise of her mentors and the rich resources available at Penn. Dr. Rhee will engage in formal didactics including completion of the Biomedical Informatics Certificate Program, participate in relevant seminars and conferences, and devote at least 75% of her effort to research. Guided by expert mentors and collaborators, the research and training activities outlined in this application will enable Dr. Rhee to grow from an observational epidemiologist into an independent patient-oriented clinical and translational researcher, equipping her with a much larger set of skills to answer important and novel questions about vasculitis.