The impact of the gut microbiome on rheumatoid arthritis treatment

项目总结/摘要 这个为期5年的K 08培训计划旨在推动Renuka Nayak，医学博士，哲学博士、 为她作为一名学术物理学家和科学家的独立研究生涯做好准备。这 一项多学科的提案质疑人类肠道微生物组在治疗类风湿性关节炎中的作用 关节炎（RA）与甲氨蝶呤（MTX）。在颁奖结束时，纳亚克博士将是一个独立的 领导多学科研究实验室的研究员，将为 了解肠道微生物组在风湿性疾病个性化治疗中的作用。博士 Nayak将通过她的主要导师Peter Turnbaugh博士， 营养和药理学微生物组研究的领导者; Katie Pollard博士，全球知名 具有大规模基因组和微生物组研究专业知识的统计学家; Lindsey Criswell，医学博士，一个 自身免疫性疾病患者基因组研究的国际领导者;和玛丽中村，医学博士，一 世界公认的骨生物学和骨免疫学的领导者。纳亚克博士和她的导师们开发了一种 正式的培训计划，包括教学法、研讨会、讲习班和实验研究，这将推动她 实现她的职业目标。加州大学弗朗西斯科分校的广泛资源， 生物医学校园与世界专家和医生，科学家，以及深刻的承诺和支持 她的部门和部门的领导将促进Nayak博士的独立之路和她的长期目标， 通过个体化用药促进风湿病患者的护理。 RA是一种炎症性关节炎，除非提供有效的治疗，否则会导致不可逆的损伤 快口服MTX是类风湿关节炎的一线治疗，但对50-70%的患者无效;临床医生目前采用 一种“试错法”的治疗方法虽然许多人研究了遗传或环境因素 预测反应，没有人研究肠道微生物组的作用。纳亚克博士的研究表明 人类肠道细菌代谢MTX，来自健康个体的粪便微生物组在其代谢过程中存在差异。 代谢MTX的能力此外，她的合作者的工作表明，基线，治疗前 微生物组与RA患者的MTX反应相关。这些观察促使纳亚克博士测试 MTX的肠道细菌代谢干扰RA治疗的假设。她将调查 （1）确定基准作用的机制 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， 和（3）建立体内模型以测试微生物组代谢MTX的相关性。拟议 这些研究将深入了解微生物组影响治疗的机制， 风湿病定义这些机制将推进我们对微生物组作用的认识 在精准医疗方面。

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.