The impact of the gut microbiome on rheumatoid arthritis treatment

肠道微生物组对类风湿关节炎治疗的影响

• 批准号: 10229456
• 负责人: Renuka Rajendra Nayak
• 金额: $ 17.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229456
• 关键词: 16S ribosomal RNA sequencing; Affect; American; Autoimmune Diseases; Award; Bacteria; Bacteroidetes; Biology; Blood; California; Cardiac; Caring; Clinical; Communities; Data; Digoxin; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Environmental Risk Factor; Enzymes; Exhibits; Feces; Firmicutes; Gastrointestinal tract structure; Gene Expression Profiling; Genes; Genetic; Genome; Genomics; Gnotobiotic; Goals; Human; Human Microbiome; Immunology; In Vitro; Individual; Inflammation; Inflammatory Arthritis; Interdisciplinary Study; International; Knowledge; Measures; Mentors; Metabolism; Methotrexate; Microbiology; Mus; Mutagenesis; Oral; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physicians; Reaction; Research; Research Personnel; Resources; Rheumatism; Rheumatoid Arthritis; Rheumatology; Role; Sampling; San Francisco; Scientist; Testing; Training; Training Programs; Translating; Universities; Variant; Work; bacterial genetics; bacterial metabolism; base; bone; career; clinical predictors; cohort; design; drug metabolism; druggable target; effective therapy; epigenomics; experience; experimental study; fecal microbiome; gut bacteria; gut microbes; gut microbiome; humanized mouse; improved; in vivo; in vivo Model; innovation; insight; microbial; microbiome; microbiome composition; microbiome research; mouse model; multidisciplinary; nutrition; personalized care; personalized medicine; precision medicine; predicting response; predictive tools; response; transcriptome sequencing; treatment response

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.

项目概要/摘要 这个为期 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医师科学家的独立研究生涯做好准备。 多学科提案质疑人类肠道微生物组在类风湿治疗中的作用 获奖后，Nayak 博士将成为一名独立人士。 领导一个多学科研究实验室的研究员将为该领域做出重大贡献 了解肠道微生物组在风湿性疾病个性化治疗中的作用。 Nayak 将通过以下人员的综合指导获得专业知识： 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导者；Katie Pollard 博士，世界知名人士 Lindsey Criswell 医学博士，具有大规模基因组和微生物组研究专业知识的统计学家； 自身免疫性疾病患者基因组研究的国际领导者；Mary Nakamura，医学博士， 世界公认的骨生物学和骨免疫学领域的领导者 Nayak 博士和她的导师开发了一种方法。 正式的培训计划包括教学、研讨会、讲习班和实验研究，这将推动她 她的职业目标完全是为了获得加州大学旧金山分校的丰富资源。 拥有世界专家和医师科学家的生物医学园区，以及坚定的承诺和支持 她的部门和部门的领导将促进 Nayak 博士走向独立之路以及她的长期目标： 通过个性化医疗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，否则会导致不可逆转的损害 口服 MTX 是治疗 RA 的一线疗法，但对 50-70% 的患者无效； 尽管许多人研究了遗传因素或环境因素，但仍采用“反复试验”的治疗方法。 预测反应，但纳亚克博士的研究已经证明，没有人检查过肠道微生物组的作用。 人类肠道细菌代谢 MTX，并且健康个体的粪便微生物组在其 此外，她的合作者的工作表明，基线、治疗前的代谢能力。 这些观察结果促使 Nayak 博士进行测试。 MTX 的肠道细菌代谢会干扰 RA 治疗的假设她将进行研究。 遵循独立且互补的目标：（1）定义基线的作用机制 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)建立体内模型来测试微生物组对MTX代谢的相关性。 研究将深入了解微生物组影响治疗的机制 定义这些机制将增进我们对微生物组作用的了解。 在精准医学领域。