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

多发性硬化症中肠道微生物组与 B 细胞耗竭之间的相互作用

• 批准号: 10448328
• 负责人: Erin Longbrake
• 金额: $ 19.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448328
• 关键词: 16S ribosomal RNA sequencing; Adult; Affect; Autoimmunity; Award; B-Lymphocytes; Biological; Blood; Blood Circulation; CNS autoimmune disease; Cells; Central Nervous System Diseases; Clinical Course of Disease; Clinical Data; Consensus; Data; Data Analyses; Decision Making; Development; Diagnosis; Disease; Disease model; Doctor of Philosophy; Enrollment; Environmental Exposure; Environmental Risk Factor; Epidemiologist; Exhibits; Feces; Functional disorder; Funding; Future; Genetic; Genomics; Germ-Free; Glycocalyx; Goals; Gut associated lymphoid tissue; Heterogeneity; Immune; Immunoglobulin A; Immunologics; Immunology; Immunomodulators; Immunophenotyping; Immunotherapy; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal permeability; Length; Leukocyte L1 Antigen Complex; Link; Lipopolysaccharides; Longitudinal cohort; Longitudinal cohort study; Measures; Mediating; Mediator of activation protein; Medical; Mentors; Metabolic Pathway; Microbe; Monoclonal Antibodies; Monoclonal Antibody CD20; Morbidity - disease rate; Mucous Membrane; Multiple Sclerosis; Mus; Natural History; Newly Diagnosed; Onset of illness; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Play; Positioning Attribute; Predisposing Factor; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Serum; Severities; Severity of illness; Shapes; Statistical Methods; T-Lymphocyte; Taxonomy; Technology; Training; Volatile Fatty Acids; Wheelchairs; anti-CD20; authority; clinical phenotype; cohort; dietary; dietary control; disability; drug development; dysbiosis; experience; functional genomics; genomic data; gut bacteria; gut colonization; gut microbes; gut microbiome; gut microbiota; immune function; immune system function; immunoregulation; improved; individual variation; insight; inter-individual variation; metabolic profile; metabolome; metabolomics; microbial; microbiome; microbiome research; microbiota; multiple sclerosis patient; opportunistic pathogen; predictive marker; recruit; risk prediction model; small molecule; treatment response; zonulin

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.

项目总结/摘要 博士Longbrake是一名MD/PhD神经免疫学家，其长期目标是确定生物学特性。 在多发性硬化症（MS）的个体间异质性的机制。培训和指导研究 建议将使她能够发展微生物组和纵向数据统计方法的专业知识 分析.这将使她能够建立/实施风险预测模型，整合高阶遗传， 代谢组学和免疫学数据与患者的临床病程相结合，以改善医疗决策。 博士Longbrake组建了一个由导师和合作者组成的专家团队。哈弗勒博士是一个 遗传学和免疫学专家Cotsapas博士是一位生物信息学家， 基因组和临床数据。在她的顾问中，Xavier博士和Palm博士是微生物组的权威。 炎症性肠病的背景，并使用基因组和微生物组数据来模拟疾病的严重程度。 博士Waubant是一位流行病学家，他是MS微生物组研究的先驱， 纵向患者队列。在她获奖期间，朗布雷克博士将在冷泉港参加正式课程， 耶鲁大学，专注于功能基因组学和纵向数据分析的统计方法。她会得到手- 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培训。 患有MS的个体具有广泛不同的表型。有些人在几年内成为轮椅， 其他人在几十年后没有明显的残疾。此外，尽管免疫调节剂的可用性 在药物治疗中，没有生物标志物可以先验地预测哪些患者会对每种治疗做出反应。审判结果和 错误导致病态。肠道微生物群受到许多相同的环境因素的影响， 易患MS并在自身免疫性的发展中发挥未被充分认识的作用。作为 环境响应变量，直接影响免疫表型，肠道微生物组是 MS严重程度个体间变异的假定中介。 我们将对MS中的微生物组/免疫相互作用进行纵向队列研究， 诊断的患者和匹配的健康对照。我们将比较肠道微生物组， 代谢组与未治疗患者的循环血液免疫表型相比， 评估由ocrelizumab诱导的微生物群和循环免疫细胞的变化，ocrelizumab是一种高效的B- 细胞消耗免疫调节剂用于治疗MS。这项研究将有助于确定这些因素是否有助于 MS的个体间变异性。完成指导奖后，Longbrake博士将成为 只有经过培训和专业知识的MS临床研究人员才能将临床数据与微生物组并置， 代谢组学和循环免疫表型数据。她可以接触到生物样本和临床数据 来自新发MS患者的纵向队列，这将成为未来研究的基础， 将很好地定位申请资金作为一个独立的临床研究人员。