Nasal Microbiome and Host Immunity in Granulomatosis with Polyangiitis

肉芽肿性多血管炎的鼻微生物组和宿主免疫

• 批准号: 9295328
• 负责人: Rennie Rhee
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-03 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295328
• 关键词: Affect; Antibiotics; Autoimmune Diseases; Autoimmunity; Bacteria; Bioinformatics; Cells; Chronic; Clinical; Clinical Research; Communities; Complex; Cotrimoxazole; Data; Development; Development Plans; Disease; Epidemiologic Methods; Epidemiologist; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Goals; Granulomatous; High-Throughput Nucleotide Sequencing; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Indigenous; Inflammation; Inflammatory Bowel Diseases; Innovative Therapy; Knowledge; Lead; Link; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Metagenomics; Methods; Microbe; Microscopic polyangiitis; Molecular Profiling; Mucosal Immune Responses; Mucous Membrane; Nasal Epithelium; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Immunity; Nose; Organism; Outcome; Pathogenicity; Patients; Pennsylvania; Physiology; Prevalence; Randomized Controlled Trials; Recording of previous events; Relapse; Research; Research Activity; Research Infrastructure; Research Personnel; Resources; Respiratory System; Respiratory tract structure; Rheumatism; Rheumatoid Arthritis; Rheumatology; Risk; Scientific Advances and Accomplishments; Staphylococcus aureus; Symbiosis; Training; Training Activity; Translational Research; United States National Institutes of Health; Universities; Up-Regulation; Upper respiratory tract; Vasculitis; Wegener' s Granulomatosis; Work; antimicrobial; biomedical informatics; career; career development; certificate program; clinical epidemiology; deep sequencing; experience; high risk; host-microbe interactions; improved; metagenome; microbial; microbial community; microbiome; microbiota; microorganism; microorganism interaction; multidisciplinary; neutrophil; novel; novel therapeutics; patient oriented; patient oriented research; programs; prospective; relapse risk; respiratory; rhinosinusitis; skills; skills training; symposium; tool; transcriptome; translational scientist

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.

项目概要 Rhee 博士的长期职业目标是成为以患者为导向的临床和医学领域的独立研究者。 致力于改善血管炎患者生活的转化研究。她将在她的基础上再接再厉 现有的临床流行病学技能，并在开展以患者为导向的前瞻性研究方面获得重要经验 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、拟议研究的执行和职业发展活动，博士。 李将获得在风湿病学方面取得重要科学进步所需的技能和培训。 肉芽肿性多血管炎（GPA；韦格纳氏）是一种全身性肉芽肿性血管炎，常影响 上呼吸道感染，且经常复发。先前的研究表明，鼻腔中的微生物 与 GPA 复发相关，但这些研究依赖于文化依赖性方法。高技术方面的进展 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 GPA 患者存在更大的菌群失调 与对照组相比，鼻孔中的（本土微生物群受到破坏）以及更大的菌群失调相关 GPA 中的疾病活动，由中性粒细胞活性（GPA 中的关键致病细胞）的增加介导。这 具体目标是：1) 比较 GPA 患者与对照组之间的鼻腔微生物组，2) 检查 GPA 患者鼻腔微生物组成的纵向变化 这些变化与鼻上皮基因表达谱和临床的关联 结果。更好地了解微生物与粘膜免疫系统的复杂相互作用 GPA 可以增进我们对 GPA 病理生理学的理解，帮助预测未来的复发，并提供信息 新疗法的开发。这项研究的结果将应用于资助申请（R01 等）对 GPA 中的宿主-微生物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-微生物相互作用的职业 针对风湿性疾病，Rhee 博士和她的导师们制定了全面的职业发展计划， 借鉴了导师的专业知识和宾夕法尼亚大学的丰富资源。李博士将从事 正式教学，包括完成生物医学信息学证书课程、参加相关课程 研讨会和会议，并将至少 75% 的精力用于研究。由专家导师指导和 合作者，本申请中概述的研究和培训活动将使李博士能够从 观察流行病学家转变为独立的以患者为导向的临床和转化研究员， 为她提供了更多的技能来回答有关血管炎的重要而新颖的问题。