Impact of the Gut Microbiome on Astrocyte Barrier Function

项目摘要/摘要 这为斯蒂芬妮·谭库博士提出了一个全面的5年内科科学家职业发展计划。 Tankou博士完成了她在Brigham和女性医院接受的多发性硬化症博士后培训 医院。在她担任研究员期间，她参与了几项临床前和临床研究 肠道微生物群在多发性硬化及其小鼠实验性自身免疫中的作用 脑脊髓炎(EAE)。自从加入西奈山担任终身教职教师以来，她已经进行了几次 研究万古霉素对EAE小鼠神经炎症的影响。来自她实验室的研究 他们发现，万古霉素是肠道-脑轴的有效调节剂，他们还确定了50个肠道共生体 调节EAE小鼠神经炎症的药物。这项工作最近已被接受，将在 微生物组，谭口博士是相应的资深作者。该应用程序建立在Tankou博士的 初步数据支持丁酸产生菌在调节星形胶质细胞功能中的关键作用 将Tankou博士从实习生转变为完全独立的研究员，通过利用智力和 西奈山伊坎医学院的物质资源。斯科特·鲁索博士指导了成功的 他将指导坦库博士完成整个培训过程。鲁索博士是一位知名的研究人员 在神经精神疾病方面的血脑屏障通透性方面公认的领导者。忠告 由在神经胶质细胞研究、肠-脑轴及其作用方面备受推崇的首席研究员组成的委员会 对肠道微生物群在免疫介导性疾病中的研究将提供额外的指导。谭口博士的职业生涯 发展计划是全面的，包括频繁的会议、具体的相关课程和 部门支持集中在指导早期职业调查人员。她已经并将继续参加 研讨会以及国内和国际会议，在那里她将展示她的研究，建立 合作，并了解该领域的最新进展。Tankou博士的研究利用了尖端方法 进一步了解肠道微生物区系在星形胶质细胞屏障功能中的作用。她建议找出 调节星形胶质细胞屏障功能的肠道微生物及其代谢产物群落及其对 中枢神经系统(CNS)炎症。谭口博士的初步数据表明，丁酸盐- 产生菌和丁酸盐通过诱导星形细胞claudin-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区系 调节星形细胞CLDN4表达的衍生代谢物。第二个目标将检查以下方面的影响 丁酸对(1)星形胶质细胞CLDN4表达，(2)免疫细胞跨越胶质细胞界限和(3)中枢神经系统的影响 EAE小鼠的炎症反应。伊坎医学院表现出了对坦库博士职业生涯的承诺 拥有75%受保护的教职员工职位进行研究。她希望开发基于微生物组的创新技术 针对多发性硬化患者神经炎症和神经变性的治疗方法

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.