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.

项目摘要 /摘要 这项为期5年的K08培训计划旨在推进Renuka Nayak，M.D。，博士学位， 目的是为她作为学术生理科学家的独立研究事业做好准备。这 多学科建议询问人肠道微生物组在类风湿病中的作用 关节炎（RA），方法二邻苯二甲酸盐（MTX）。奖项结束时，纳亚克博士将是一个独立的 研究人员领导了一个多学科研究实验室，该实验室将为 了解肠道微生物组在风湿性疾病的个性化治疗中的作用。博士 Nayak将通过：她的主要导师，Peter Turnbaugh，Ph.D。 营养和药理学微生物组研究的领导者；凯蒂·波拉德（Katie Pollard）博士，世界知名的 Lindsey Criswell，医学博士 自身免疫性疾病患者基因组研究的国际领导者；和Mary Nakamura，医学博士 世界认可的骨骼生物学和骨免疫学领导者。 Nayak博士和她的导师已经开发了 与教学，半手，研讨会和实验研究的正式培训计划，这些研究将推动她 朝着她的职业目标。加利福尼亚大学旧金山分校的广泛资源，完全是 与世界专家和身体科学家的生物医学校园以及深厚的承诺和支持 她的部门和部门将支持纳亚克博士的独立之途径，以及她的长期目标 通过个性化医学来改善风湿病患者的护理。 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害 迅速地。口服MTX是RA的一线治疗，但在50-70％的患者中无效；临床医生目前雇用 一种“反复试验”治疗方法。尽管许多人都有遗传学或环境因素 预测反应，没有人检查了肠道微生物组的作用。 Nayak博士的研究证明了 人类的肠道细菌代谢MTX，而来自健康个体的粪便微生物组在其中有所不同 能够代谢MTX。此外，她的合作者的工作表明基线，预处理 RA患者中的微生物组与MTX反应有关。这些观察激励了Nayak博士进行测试 MTX干扰RA治疗的肠道细菌代谢的假设。她将调查 遵循独立和完整的目标：（1）定义基线作用的机制 临床MTX反应中的微生物组，（2）阐明MTX治疗对细菌药物代谢的影响， （3）建立一个体内模型，以测试微生物组MTX代谢的相关性。提议 研究将洞悉微生物组影响处理的机制 风湿病。定义这些机制将提高我们对微生物组作用的了解 精密医学。