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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

基本信息

批准号：
10659196
负责人：
Erin Longbrake
金额：
$ 19.6万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10659196
关键词：
16S ribosomal RNA sequencing Adult Affect Authorization documentation Autoimmunity Award B-Lymphocytes Binding Biological Blood CNS autoimmune disease Cells Central Nervous System Diseases Circulation Clinical Course of Disease Clinical Data Consensus Data Data Analyses Decision Making Development Diagnosis Disease Disease model Doctor of Philosophy Enrollment Environment 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 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 Predisposition 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 comparison control 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 modulating agents 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

项目摘要

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.

项目概要/摘要 Longbrake 博士是一位医学博士/博士神经免疫学家，其长期目标是确定生物学多发性硬化症（MS）个体间异质性的机制。培训和指导研究提议将使她能够发展微生物组和纵向数据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，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。 Longbrake 博士组建了一支由导师和合作者组成的专家和忠诚团队。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。 Cotsapas 博士是一位生物信息学家，拥有丰富的整合经验基因组和临床数据。在她的顾问中，Xavier 博士和 Palm 博士是微生物组方面的权威。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。 Waubant 博士是一位流行病学家，他开创了多发性硬化症微生物组研究的先河，并创立了多个大型研究机构。纵向患者队列。在获奖期间，朗布雷克博士将在冷泉港参加正式课程，并耶鲁大学，专注于功能基因组学和纵向数据分析的统计方法。她会伸手—— 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。多发性硬化症患者的表型差异很大。有些人在几年内就必须坐轮椅，而其他人几十年后没有明显的残疾。此外，尽管有免疫调节剂药物治疗中，没有生物标志物可以先验地预测哪些患者会对每种治疗产生反应。由此产生的试验和错误会导致发病。肠道微生物群受到许多与肠道菌群相同的环境因素的影响。易患多发性硬化症，并在自身免疫的发展中发挥着未被充分认识的作用。作为一个直接影响免疫表型的环境响应变量，肠道微生物组是 MS 严重程度个体间差异的假定中介因素。我们将开展一项关于多发性硬化症中微生物组/免疫相互作用的纵向队列研究，新招募了 40 名本研究中诊断出的患者和匹配的健康对照。我们将比较肠道微生物组、肠道与对照组相比，未治疗患者的循环血液免疫表型代谢组，然后评估 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- 用于治疗多发性硬化症的细胞消耗免疫调节剂。这项研究将有助于确定这些因素是否有助于 MS 的个体差异。完成指导奖后，Longbrake 博士将成为其中一位只有经过培训和专业知识的多发性硬化症临床研究人员才能将临床数据与微生物组并列，代谢组和循环免疫表型数据。她将有权访问生物样本和临床数据来自新发多发性硬化症患者的纵向队列，这将成为未来研究的基础，她将有能力作为独立临床研究员申请资金。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Manifestations and impact of the COVID-19 pandemic in neuroinflammatory diseases.

19009年大流行在神经炎症性疾病中的表现和影响。

DOI：
10.1002/acn3.51314
发表时间：
2021-04
期刊：
Annals of clinical and translational neurology
影响因子：
5.3
作者：
Levin SN;Venkatesh S;Nelson KE;Li Y;Aguerre I;Zhu W;Masown K;Rimmer KT;Diaconu CI;Onomichi KB;Leavitt VM;Levine LL;Strauss-Farber R;Vargas WS;Banwell B;Bar-Or A;Berger JR;Goodman AD;Longbrake EE;Oh J;Weinstock-Guttman B;Thakur KT;Edwards KR;Riley CS;Xia Z;De Jager PL;Multiple Sclerosis Resilience to COVID-19 (MSReCOV) Collaborative
通讯作者：
Multiple Sclerosis Resilience to COVID-19 (MSReCOV) Collaborative

High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing-Remitting Multiple Sclerosis.

DOI：
10.1007/s40263-022-00965-7
发表时间：
2022-12
期刊：
CNS drugs
影响因子：
6
作者：
通讯作者：

Outcomes and future directions for neuroimmunology/multiple sclerosis fellowship training: Survey of recent trainees.

DOI：
10.1016/j.msard.2020.102296
发表时间：
2020-09
期刊：
Multiple sclerosis and related disorders
影响因子：
4
作者：
Hua LH;Obeidat AZ;Longbrake EE
通讯作者：
Longbrake EE

23Na imaging: Worth its salt for understanding multiple sclerosis.

23Na 成像：对于了解多发性硬化症是值得的。

DOI：
10.1073/pnas.2110799118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Longbrake,ErinE;Hafler,DavidA
通讯作者：
Hafler,DavidA

Neuroinflammation Associated With Tumor Necrosis Factor-α Inhibitor Exposure.

与肿瘤坏死因子-α 抑制剂暴露相关的神经炎症。