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: 10462330
• 负责人: Rennie Rhee
• 金额: $ 8.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462330
• 关键词: Affect; Bacteria; Bioinformatics; Cells; Clinical; Clinical Research; Communities; Complex; Data; Development; Development Plans; Disease; Epidemiologic Methods; Epidemiologist; Functional disorder; Funding; Future; Gene Expression; Goals; Granulomatous; High-Throughput Nucleotide Sequencing; Immune response; Immune system; Immunity; Indigenous; Lead; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Metagenomics; Methods; Microbe; Mucosal Immune System; Mucous Membrane; Nasal Epithelium; Nose; Outcome; Pathogenicity; Patients; Relapse; Research; Research Activity; Research Personnel; Resources; Rheumatism; Rheumatology; Scientific Advances and Accomplishments; Training Activity; Translational Research; Upper respiratory tract; Vasculitis; Wegener' s Granulomatosis; biomedical informatics; career; career development; certificate program; clinical epidemiology; deep sequencing; dysbiosis; experience; host-microbe interactions; improved; microbial community; microbial composition; microbiome; microbiota; microorganism; microorganism interaction; nasal microbiome; neutrophil; novel; novel therapeutics; patient oriented; patient oriented research; prospective; skills; skills training; symposium; tool; 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.

项目摘要 Rhee博士的长期职业目标是成为以患者为导向的临床和 转化研究致力于改善血管炎患者的生活。她会在她身上建立 当前的临床流行病学技能并获得了前瞻性患者的重要经验 研究，使用深度测序方法以及生物信息学和高级流行病学的实施 方法。通过K23奖，拟议的研究的执行以及职业发展活动，博士 Rhee将获得所需的技能和培训，以在风湿病学方面取得重要的科学进步。 肉芽肿性伴有多血管炎（GPA； Wegener's）是一种全身性肉芽肿性血管炎，通常会影响 上呼吸道并经常复发。先前的研究表明，鼻孔中的微生物是 与GPA复发有关，但这些研究取决于依赖培养的方法。高级进步 吞吐量测序和开发用于分析宏基因组数据的新工具现在允许 更好地了解占据我们的微生物的动态社区之间的复杂关系 粘膜组织和宿主的免疫系统。我们假设GPA患者的营养不良较大 （与对照组相比，鼻腔中的土著菌群中断），并且较大的营养不良是相关的 与GPA中的疾病活性，中性粒细胞活性的增加（GPA中的关键致病细胞）介导。这 具体目的是：1）比较患有GPA与对照的患者之间的鼻微生物组，以及2） 检查GPA患者的鼻腔微生物组成的纵向变化 这些变化与鼻上皮和临床中基因表达谱的关联 结果。更好地了解与粘膜免疫系统复杂的微生物相互作用 GPA可以提高我们对GPA病理生理学的理解，帮助预测未来的复发并告知 新型治疗学的发展。这项研究的发现将应用于资金申请（R01 和其他））对GPA中的宿主微叶相互作用进行大规模研究。 为了成功地执行拟议的研究并开发了一个职业研究主机 - 微型互动 风湿病，Rhee博士和她的导师制定了一项全面的职业发展计划 借鉴了她的导师的专业知识和宾夕法尼亚州可获得的丰富资源。 Rhee博士将参与 正式的教学学包括完成生物医学信息学证书计划，参与相关 研讨会和会议，并将至少75％的努力研究。在专家导师和 合作者，本申请中概述的研究和培训活动将使Rhee博士从 观察性流行病学家成为独立的以患者为导向的临床和翻译研究人员 为她提供更大的技能，以回答有关血管炎的重要问题。

项目成果

Long-Term Clinical and Radiographic Outcomes in Patients With Clinically Isolated Aortitis.

• DOI: 10.1002/acr2.11504
• 发表时间: 2022-12
• 期刊: ACR OPEN RHEUMATOLOGY
• 影响因子: 3.4
• 作者: Mayer, Adam;Sperry, Alexandra;Quimson, Laarni;Rhee, Rennie L.
• 通讯作者: Rhee, Rennie L.

Patient-Reported Sinonasal Symptoms and Risk of Relapse in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

患者报告的抗中性粒细胞胞质抗体相关性血管炎的鼻腔症状和复发风险。

• DOI: 10.1002/acr.25329
• 发表时间: 2024
• 期刊: Arthritis care & research
• 影响因子: 4.7
• 作者: Romich,Ellen;Banerjee,Shubhasree;Amudala,Naomi;Chou,Sherry;Li,Ruolan;Lee,Hongzhe;Cohen,Noam;Merkel,PeterA;Rhee,RennieL
• 通讯作者: Rhee,RennieL

Dynamic Changes in the Nasal Microbiome Associated With Disease Activity in Patients With Granulomatosis With Polyangiitis.

• DOI: 10.1002/art.41723
• 发表时间: 2021-09
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Rhee RL;Lu J;Bittinger K;Lee JJ;Mattei LM;Sreih AG;Chou S;Miner JJ;Cohen NA;Kelly BJ;Lee H;Grayson PC;Collman RG;Merkel PA
• 通讯作者: Merkel PA