Impact of the Gut Microbiome on Astrocyte Barrier Function

肠道微生物组对星形胶质细胞屏障功能的影响

基本信息

批准号：
10723837
负责人：
Stephanie Tankou
金额：
$ 28.22万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723837
关键词：
Address Adverse effects Advisory Committees Animal Model Astrocytes Bacteria Butyrates Cells Central Nervous System Clinical Research Collaborations Data Development Plans Disease Disease Progression Experimental Autoimmune Encephalomyelitis FDA approved Faculty Fellowship Flow Cytometry Germ-Free Goals Hospitals Household Human Immune Immune system Immunofluorescence Immunologic In Vitro Inflammation Injections International Laboratory Study Learning Measures Mediating Mentors Metagenomics Microglia Multiple Sclerosis Mus Nerve Degeneration Neuroglia Patients Penetration Pharmaceutical Preparations Pharmacotherapy Phenotype Physicians Positioning Attribute Postdoctoral Fellow Prevention therapy Principal Investigator Proteins Publications Research Research Personnel Resources Role Scientist Shotguns Sodium Butyrate Spinal Cord Structure Testing Therapeutic Tight Junctions Time Training Vancomycin Western Blotting Woman Work blood-brain barrier permeabilization brain parenchyma career career development cell motility claudin 4 experimental study gut bacteria gut microbiome gut microbiota gut-brain axis immune cell infiltrate immunoregulation in vivo innovation interest medical schools meetings microbiome microbiota microbiota metabolites mouse model multiple sclerosis patient multiple sclerosis treatment neuroinflammation neuropsychiatric disorder preclinical study reconstitution stool sample symposium tenure track trafficking

项目摘要

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.

项目摘要/摘要这提出了一项为Stephanie Tankou博士的全面的5年物理科学家职业发展计划。 Tankou博士在杨百翰和女子的多发性硬化症中完成了博士后奖学金培训医院。在奖学金年中，她参与了一些临床前和临床研究肠道微生物组在多发性硬化症（MS）及其小鼠模型实验自身免疫性中的作用脑脊髓炎（EAE）。自从加入西奈山（Mount Sinai 研究万古霉素对EAE小鼠神经炎症的影响。她的实验室研究揭示了万古霉素是肠道轴的潜在调节剂，他们还鉴定了50个肠道。调节EAE小鼠的神经炎症。这项工作最近被接受以供出版 Microbiome和Tankou博士是相应的和高级作者。该申请基于Tankou博士的初步数据支持产生丁酸酯细菌在调节星形胶质细胞功能中的关键作用，并且通过利用知识分子和西奈山的伊坎医学院的物质资源。斯科特·鲁索（Scott Russo）博士成功地指导了在整个培训中，学员并将指导Tankou博士。 Russo博士是一位既定的调查员，在神经精神疾病的背景下，公认的血脑屏障渗透性领先者。咨询由胶质细胞研究，肠脑轴和角色的备受推崇的主要研究人员组成的委员会免疫介导的疾病中的肠道微生物组将提供额外的指导。 Tankou博士的职业发展计划是全面的，包括经常会议，特定相关课程以及部门支持以心理早期职业调查人员为中心。她已经并且将继续参加 SEMIAR以及国家和国际会议，她将在那里展示自己的研究，并建立合作，了解该领域的最新进展。 Tankou博士的研究采用了尖端的方法促进对肠道微生物群在星形胶质细胞屏障功能方面的作用的理解。她建议确定调节星形胶质细胞屏障功能及其对影响的肠道微生物及其代谢物的社区及其对中枢神经系统（CNS）炎症。 Tankou博士的初步数据表明，丁酸酯 - 通过诱导星形胶质细胞Claudin-4，产生细菌和丁酸酯调节星形胶质细胞屏障功能。在第一个特定目的中，将进行实验以鉴定人类肠道衍生的细菌和肠道菌群调节星形细胞CLDN4表达的衍生代谢产物。第二个目标将检查在（1）星形胶质细胞CLDN4表达上，（2）跨胶质细胞的免疫细胞运输和（3）CNS EAE小鼠的炎症。伊坎医学院已经表现出对坦托博士的职业的承诺受到75％的保护教师职位来进行研究。她希望开发基于创新的微生物组 MS中靶向神经炎症和神经变性的方法。