Nasal Microbiome and Host Immunity in Granulomatosis with Polyangiitis

项目摘要 博士李承晚的长期职业目标是成为一名独立的研究者，在以病人为导向的临床和 致力于改善血管炎患者生活的转化研究。她会在她的基础上 目前的临床流行病学技能，并在前瞻性的以病人为导向的行为中获得重要的经验 研究，深度测序方法的使用，以及生物信息学和先进流行病学的实施 方法.通过K23奖，执行拟议的研究，和职业发展活动，博士。 李承晚将获得在流变学方面取得重要科学进展所需的技能和培训。 肉芽肿病伴多血管炎（GPA;韦格纳氏）是一种全身性肉芽肿性血管炎， 上呼吸道感染，经常复发。先前的研究表明，鼻孔中的微生物 与GPA复发相关，但这些研究依赖于文化依赖性方法。在高- 通量测序和用于分析宏基因组数据的新工具的开发现在允许 更好地了解占据我们身体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GPA患者有更大的生态失调 与对照组相比，在鼻孔中存在（固有微生物群的破坏），并且与更大的生态失调相关 与GPA中的疾病活动有关，由中性粒细胞活性（GPA中的关键致病细胞）增加介导。的 具体目的是：1）比较GPA患者与对照组之间的鼻微生物组，以及2） 检查GPA患者鼻腔微生物组成的纵向变化， 这些变化与鼻上皮和临床中的基因表达谱的关联 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病理生理学的理解，帮助预测未来的复发，并为我们提供信息。 新疗法的发展。这项研究的结果将应用于资助申请（R 01 和其他人）进行大规模的研究宿主微生物的相互作用在GPA。 为了成功地执行拟议的研究，并发展研究宿主-微生物相互作用的职业生涯， 风湿性疾病，李博士和她的导师已经形成了一个全面的职业发展计划， 利用她的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 正式的教学，包括完成生物医学信息学证书课程，参加相关的 她经常参加研讨会和会议，并将至少75%的精力用于研究。由专家导师指导， 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 从一名观察性流行病学家转变为一名独立的、以患者为导向的临床和转化研究者， 使她具备了更多的技能来回答有关血管炎的重要和新颖的问题。

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.