Interactions between Gut Microbiome and B-Cell Depletion in Multiple Sclerosis

项目摘要/摘要 朗布雷特博士是一名医学博士/博士神经免疫学家，他的长期目标是确定 多发性硬化(MS)个体间异质性的机制。培训和指导性研究 提议将使她能够发展微生物组和纵向数据的统计方法方面的专业知识 分析。这将使她能够建立/实施风险预测模型，将高阶遗传、 代谢和免疫学数据与患者的临床病程相结合，以改进医疗决策。 朗布雷克博士组建了一支由导师和合作者组成的专家和忠诚的团队。哈夫勒博士是一个世界 多发性硬化症遗传学和免疫学专家。科萨帕斯博士是一位具有丰富经验的生物信息学家 基因组和临床数据。在她的顾问中，泽维尔博士和帕尔姆博士是微生物群方面的权威 并使用基因组和微生物组数据来模拟疾病的严重程度。 沃班特博士是一位流行病学家，他开创了多发性硬化症微生物群研究的先河，并创立了几个大型 纵向患者队列。在她获奖期间，Longbrake博士将在冷泉港和 耶鲁，专注于功能基因组学和纵向数据分析的统计方法。她会拿到手的- 通过与顾问和合作者合作进行微生物组和代谢组数据分析方面的培训。 多发性硬化症患者的表型差异很大。一些人在几年内被轮椅束缚住了，而 其他人几十年后没有明显的残疾。此外，尽管免疫调节剂的可用性 在药物治疗方面，没有生物标记物可以预先预测患者对每种治疗的反应。由此产生的审判和 错误会导致疾病。肠道微生物区系受到许多相同的环境因素的影响 易患多发性硬化症，在自身免疫的发展中起着被低估的作用。作为一种 直接影响免疫表型的环境响应变量，肠道微生物群是 多发性硬化症严重程度个体间差异的假定中介因子。 我们将对多发性硬化症的微生物群/免疫相互作用进行纵向队列研究，新入选40人 在这项研究中，确诊患者和匹配的健康对照。我们将比较肠道微生物群，肠道 未经治疗的患者与对照组的代谢组与循环血免疫表型的比较 评价高效B-氨基丁酸单抗诱导的微生物群和循环免疫细胞的变化 用于治疗多发性硬化症的细胞耗尽免疫调节剂这项研究将有助于确定这些因素是否起作用 在完成指导奖后，Longbrake博士将成为 只有具有将临床数据与微生物组并列的培训和专业知识的MS临床医生研究人员， 代谢组和循环免疫表型数据。她将可以获得生物制品和临床数据。 来自新发MS患者的纵向队列，这将成为未来研究的基础，她 将作为一名独立的临床医生研究员申请资金。

PROJECT SUMMARY/ABSTRACT Dr. Longbrake is an MD/PhD neuroimmunologist whose long-term goal is to determine the biological mechanisms for inter-individual heterogeneity in multiple sclerosis (MS). The training and mentored research proposed will enable her to develop expertise in statistical methods for microbiome and longitudinal data analysis. This will allow her to build/implement risk prediction models, integrating high-order genetic, metabolomic and immunologic data with patients' clinical disease course to improve medical decision making. Dr. Longbrake has assembled an expert and committed team of mentors and collaborators. Dr. Hafler is a world expert in MS genetics and immunology. Dr. Cotsapas is an bioinformatician with extensive experience integrating genomic and clinical data. Among her advisors, Dr. Xavier and Dr. Palm are authorities on the microbiome in the setting of inflammatory bowel disease and have used genomic and microbiome data to model disease severity. Dr. Waubant is an epidemiologist who pioneered the study of the microbiome in MS and founded several large longitudinal patient cohorts. During her award, Dr. Longbrake will take formal courses at Cold Spring Harbor and Yale, focusing on statistical methods for functional genomics and longitudinal data analysis. She will get hands- on training in microbiome and metabolome data analysis through working with advisors & collaborators. Individuals with MS have widely divergent phenotypes. Some become wheelchair bound within a few years while others have no apparent disability after decades. Moreover, despite the availability of immunomodulatory medications, no biomarkers predict a priori which patients will respond to each treatment. The resultant trial and error leads to morbidity. The gut microbiota are affected by many of the same environmental factors that predispose to MS and play an under-appreciated role in the development of autoimmunity. As an environmentally responsive variable that directly affects the immunophenotype, the gut microbiome is a putative mediator of inter-individual variation in MS severity. We will conduct a longitudinal cohort study of microbiome/immune interactions in MS, enrolling 40 newly diagnosed patients and matched healthy controls for this study. We will compare the gut microbiome, gut metabolome with circulating blood immunophenotypes for untreated patients compared to controls and then evaluate the changes in microbiota and circulating immune cells induced by ocrelizumab, a highly effective, B- cell depleting immunomodulator used to treat MS. This study will help determine whether these factors contribute to inter-individual variability in MS. Upon completion of the mentored award, Dr. Longbrake will be one of the only MS clinician researchers with the training and expertise to juxtapose clinical data with microbiome, metabolome and circulating immunophenotypic data. She will have access to biospecimens and clinical data from a longitudinal cohort of new-onset MS patients, which will become the substrate for future studies, and she will be well positioned to apply for funding as an independent clinician researcher.