The impact of the gut microbiome on rheumatoid arthritis treatment

项目摘要/摘要 这项为期5年的K08培训计划旨在促进Renuka Nayak，医学博士，博士， 目标是为她作为一名学术内科科学家的独立研究生涯做好准备。这 多学科提案质疑人类肠道微生物群在类风湿治疗中的作用 使用甲氨蝶呤(MTX)的关节炎(RA)。在颁奖结束时，纳亚克博士将成为一名独立的 领导一个多学科研究实验室的调查员将对 了解肠道微生物群在风湿病个体化治疗中的作用。Dr。 Nayak将通过她的主要导师Peter Turnbaugh博士、 营养学和药理学微生物组研究的领先者；世界知名的 具有大规模基因组和微生物组研究专长的统计学家；林赛·克里斯韦尔，医学博士和 自身免疫性疾病患者基因组研究的国际领先者；玛丽·中村医学博士 世界公认的骨生物学和骨免疫学领先者。纳亚克博士和她的导师开发了一种 正式的培训计划，包括教学、研讨会、研讨会和实验研究，这将推动她 朝着她的职业目标前进。加州大学旧金山分校的广泛资源，完全是 生物医学园区，有世界专家和内科科学家，以及深切的承诺和支持 她的部门和司将促进纳亚克博士的独立之路和她的长期目标 通过个性化用药推进风湿病患者的护理。 类风湿关节炎是一种炎性关节炎，除非提供有效的治疗，否则会造成不可逆转的损害。 快点。口服MTX是RA的一线治疗方法，但对50%-70%的患者无效；临床医生目前雇用 一种“试错”的治疗方法。虽然许多人研究了遗传因素或环境因素 预测反应，没有人研究肠道微生物组的作用。纳亚克博士的研究证明 人类肠道细菌代谢甲氨蝶呤，而健康人的粪便微生物群在其 代谢甲氨蝶呤的能力。此外，她的合作者的研究表明，基线、治疗前 微生物群与类风湿关节炎患者的MTX反应有关。这些观察结果促使纳亚克博士对 甲氨蝶呤肠道细菌代谢干扰RA治疗的假说。她将调查 以下是独立和相辅相成的目标：(1)确定基线作用的机制 微生物组在临床MTX反应中的作用，(2)阐明MTX治疗对细菌药物代谢的影响， (3)建立体内模型，通过微生物组检测MTX代谢的相关性。建议数 研究将提供对微生物群影响治疗的机制的洞察 风湿病。定义这些机制将促进我们对微生物组作用的了解 在精准医学领域。

PROJECT SUMMARY / ABSTRACT This 5-year K08 training program is designed to advance the career of Renuka Nayak, M.D., Ph.D., with the goal of preparing her for an independent research career as an academic physician-scientist. This multidisciplinary proposal interrogates the role of the human gut microbiome in the treatment of rheumatoid arthritis (RA) with methotrexate (MTX). At the conclusion of the award, Dr. Nayak will be an independent investigator leading a multidisciplinary research lab that will make substantial contributions to the understanding of the role of the gut microbiome in the personalized treatment of rheumatic diseases. Dr. Nayak will gain this expertise through the combined guidance of: her primary mentor, Peter Turnbaugh, Ph.D., a leader in microbiome studies in nutrition and pharmacology; Katie Pollard, Ph.D., a world-renowned statistician with expertise in large scale genomic and microbiome studies; Lindsey Criswell, M.D., an international leader in genomic studies in patients with autoimmune disease; and Mary Nakamura, M.D., a world-recognized leader in bone biology and bone immunology. Dr. Nayak and her mentors have developed a formal training plan with didactics, seminars, workshops, and experimental research that will propel her towards her career goals. The extensive resources at the University of California, San Francisco, an entirely biomedical campus with world experts and physician-scientists, as well as the deep commitment and support of her Department and Division will facilitate Dr. Nayak's pathway to independence and her long-term goals to advance the care of rheumatology patients through personalized medicine. RA is an inflammatory arthritis resulting in irreversible damage unless effective therapy is provided quickly. Oral MTX is first-line therapy for RA, but is ineffective in 50-70% of patients; clinicians currently employ a “trial and error” approach to treatment. While many have studied whether genetics or environmental factors predict response, none have examined the role of the gut microbiome. Dr. Nayak's research has demonstrated that human gut bacteria metabolize MTX, and that fecal microbiomes from healthy individuals vary in their ability to metabolize MTX. Additionally, work from her collaborators suggests that the baseline, pre-treatment microbiome is associated with MTX response in RA patients. These observations motivate Dr. Nayak to test the hypothesis that gut bacterial metabolism of MTX interferes with RA treatment. She will investigate the following independent and complementary aims: (1) define a mechanism for the role of the baseline microbiome in clinical MTX response, (2) elucidate the effects of MTX treatment on bacterial drug metabolism, and (3) establish an in vivo model to test the relevance of MTX metabolism by the microbiome. The proposed studies will provide insight into the mechanisms by which the microbiome affects the treatment of rheumatologic disease. Defining these mechanisms will advance our knowledge of the role of the microbiome in precision medicine.