Impact of the Gut Microbiome on Astrocyte Barrier Function

项目总结/文摘

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.