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

• 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
• 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

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.

项目概要/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。 Tankou 博士在布莱根妇女医院完成了多发性硬化症博士后培训 医院。在她的研究期间，她参与了多项临床前和临床研究，调查 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中的作用 脑脊髓炎（EAE）。自从作为终身教授加入西奈山以来，她一直在进行多项研究 研究调查万古霉素对 EAE 小鼠神经炎症的影响。她的实验室的研究 揭示万古霉素是肠脑轴的有效调节剂，他们还鉴定了 50 种肠道共生体 调节 EAE 小鼠的神经炎症。该作品最近已被接受发表 Microbiome 和 Tankou 博士是通讯作者和高级作者。该应用程序基于 Tankou 博士的 初步数据支持丁酸盐产生菌在调节星形胶质细胞功能中的关键作用，并且 通过利用知识和经验，将 Tankou 博士从实习生转变为完全独立的研究者 西奈山伊坎医学院的物质资源。 Scott Russo 博士指导了成功的 学员，并将在整个培训过程中指导 Tankou 博士。 Russo 博士是一位资深的研究者 在神经精神疾病的血脑屏障通透性方面公认的领导者。咨询 委员会由神经胶质细胞研究、肠脑轴及其作用方面备受推崇的主要研究人员组成 免疫介导疾病中肠道微生物组的研究将提供额外的指导。 Tankou博士的职业生涯 发展计划是全面的，包括频繁的会议、具体的相关课程作业以及 部门支持的重点是指导早期职业调查员。她已经并将继续参加 她将在研讨会以及国内和国际会议上展示她的研究成果，建立 合作，并了解该领域的最新进展。 Tankou 博士的研究采用了尖端方法 促进了解肠道微生物群对星形胶质细胞屏障功能的作用。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及其对 中枢神经系统（CNS）炎症。 Tankou 博士的初步数据表明，丁酸盐- 产生细菌以及丁酸通过诱导星形胶质细胞claudin-4来调节星形胶质细胞屏障功能。 在第一个具体目标中，将进行实验来鉴定人类肠道来源的细菌和肠道微生物群 调节星形胶质细胞 CLDN4 表达的衍生代谢物。第二个目标将检查效果 丁酸盐对 (1) 星形细胞 CLDN4 表达、(2) 跨神经胶质细胞界限的免疫细胞运输和 (3) CNS 的影响 EAE 小鼠的炎症。伊坎医学院对 Tankou 博士的职业生涯做出了承诺 75％受保护的教职人员进行研究。她希望开发基于微生物组的创新 针对多发性硬化症中神经炎症和神经变性的方法。