Impact of the Gut Microbiome on Astrocyte Barrier Function

项目总结/摘要 这为Stephanie Tankou博士提出了一个全面的5年医师科学家职业发展计划。 博士Tankou完成了她在布里格姆和妇女的多发性硬化症博士后奖学金培训 医院在研究期间，她参与了几项临床前和临床研究， 肠道微生物组在多发性硬化（MS）及其小鼠模型实验性自身免疫中的作用 脑脊髓炎（EAE）。自从加入西奈山作为终身教职，她一直在进行几个 研究万古霉素对EAE小鼠神经炎症的影响。她实验室的研究 发现万古霉素是肠-脑轴的有效调节剂， 调节EAE小鼠的神经炎症。这项工作最近已被接受出版， Microbiome和Tankou博士是通讯和资深作者。该应用程序建立在Tankou博士的 初步数据支持丁酸生产细菌在调节星形胶质细胞功能中的关键作用， 通过利用知识和经验， 西奈山伊坎医学院的物质资源。斯科特·罗素博士成功地指导了 她将在培训期间指导Tankou博士。鲁索医生是一位知名的调查员， 在神经精神疾病的背景下，血脑屏障通透性的公认领导者。一个咨询 委员会由在神经胶质细胞研究、肠-脑轴和 肠道微生物组在免疫介导疾病中的作用将提供额外的指导。Tankou博士的职业生涯 发展计划是全面的，包括经常会议，具体的相关课程， 部门支持以指导早期职业调查员为中心。她已经并将继续出席 研讨会以及国家和国际会议，她将提出她的研究，建立 合作，并了解该领域的最新进展。Tankou博士的研究采用了最先进的方法 以促进对肠道微生物群对星形胶质细胞屏障功能的作用的理解。她建议确定 调节星形胶质细胞屏障功能的肠道微生物群落及其代谢物， 中枢神经系统（CNS）炎症。Tankou博士的初步数据表明丁酸盐- 产生细菌以及丁酸盐通过诱导星形胶质细胞紧密连接蛋白-4调节星形胶质细胞屏障功能。 在第一个具体目标中，将进行实验以鉴定人类肠道来源的细菌和肠道微生物群 衍生的代谢物，其调节星形胶质细胞CLDN 4表达。第二个目标将检查 丁酸对（1）星形胶质细胞CLDN 4表达、（2）免疫细胞跨胶质界膜运输和（3）CNS EAE小鼠的炎症。伊坎医学院已经证明了对Tankou博士职业生涯的承诺 有75%的教师职位受保护来进行研究她希望开发基于微生物组的创新 针对多发性硬化症神经炎症和神经变性的方法。

Project Summary/Abstract This proposes a comprehensive 5-year physician scientist career development plan for Dr. Stephanie Tankou. Dr. Tankou completed her postdoctoral fellowship training in Multiple Sclerosis at the Brigham and Women’s Hospital. During her fellowship years, she was involved in several preclinical and clinical studies investigating the role of the gut microbiome in multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE). Since joining Mount Sinai as a tenure track faculty, she has been conducting several studies to investigate the effect of vancomycin on neuroinflammation in EAE mice. Studies from her laboratory revealed that vancomycin is a potent modulator of the gut-brain axis and they also identified 50 gut commensals that regulate neuroinflammation in EAE mice. This work has been recently accepted for publication in Microbiome and Dr. Tankou is the corresponding and senior author. The application builds on Dr. Tankou’s preliminary data supporting a key role for butyrate-producing bacteria in regulating astrocyte function and is structured to transition Dr. Tankou from trainee to fully independent investigator by leveraging intellectual and material resources at the Icahn School of Medicine at Mount Sinai. Dr. Scott Russo has mentored successful trainees and will guide Dr. Tankou throughout her training. Dr. Russo is an established investigator and recognized leader in blood brain barrier permeability in the context of neuropsychiatric diseases. An advisory committee composed of highly regarded principal investigators in glial cell research, gut-brain axis and the role of the gut microbiome in immune mediated diseases will provide additional guidance. Dr. Tankou’s career development plan is comprehensive, including frequent meetings, specific relevant coursework, and departmental support centered on mentoring early career investigators. She has and will continue to attend seminars as well as national and international conferences where she will present her research, establish collaborations, and learn of recent advances in the field. Dr. Tankou’s research utilizes cutting-edge approaches to advance understanding of the role of the gut microbiota on astrocyte barrier function. She proposes to identify communities of gut microbes and their metabolites that regulate astrocyte barrier function and their impact on central nervous system (CNS) inflammation. Dr. Tankou preliminary data have demonstrated that butyrate- producing bacteria as well as butyrate modulate astrocyte barrier function via induction of astrocytic claudin-4. In the first specific aim, experiments will be conducted to identify human gut derived bacteria and gut microbiota derived metabolites that modulate astrocytic CLDN4 expression. The second aim will examine the effect of butyrate on (1) astrocytic CLDN4 expression, (2) immune cell trafficking across the glia limitans and (3) CNS inflammation in EAE mice. The Icahn School of Medicine has demonstrated commitment to Dr. Tankou’s career with a 75% protected faculty position to conduct research. She hopes to develop innovative microbiome-based approaches to target neuroinflammation and neurodegeneration in MS.