Alcohol's Impact on the Gut-Brain Axis in a Mouse Model of Multiple Sclerosis

这项建议提出了一个研究职业发展计划，重点是研究酒精的 多发性硬化症（MS）小鼠模型中神经炎症的剂量依赖性效应，实验 自身免疫性脑脊髓炎（EAE）。我目前是戴尔医疗的神经病学助理教授 UT Austin的学校这个计划是建立在我以前的性神经生物学研究基础上的 差异，神经免疫学的临床培训，并整合了生物信息学专业知识的新领域， 酒精和微生物组研究，以及基础科学神经免疫学。我将以杰出的 导师和顾问，包括Adron Harris博士（酒精研究），Hans Hofmann（生物信息学）， Sergio Baranzini（微生物组），Olaf Stuve（神经免疫学）和William Schwartz（职业指导）。 拟议的实验，教学法和指导将使我能够过渡到R01资助 神经免疫学和酒精研究交叉学科领域的医生科学家。 MS是中枢神经系统（CNS）的慢性自身免疫性脱髓鞘疾病， 导致年轻人神经系统残疾的主要后天原因。MS的病因不明。虽然 基因导致疾病风险，人们认为环境因素，如饮食和肠道 微生物群导致更大程度的风险。酒精是MS使用的常见饮食因素 患者然而，尽管其广泛使用，滥用的潜力和已知的肠道，中枢神经系统和免疫作用， 酒精在MS中的作用还不清楚。这一建议的基础是基于我的初步 PNAS出版的研究表明，适度饮酒可改善EAE， 脊髓中小胶质细胞的减少，以及肠道微生物群向调节表型的转变， 性别特异性模式，共同表明适度饮酒在EAE中具有保护作用，并可能在 女士考虑到已知的酒精的促炎作用，这些研究提出了酒精可能 高剂量与中等剂量对神经炎症的不同作用。该提案开始解决这一问题 通过评估酒精对外周和CNS免疫系统的剂量依赖性影响， 肠道微生物组具体而言，本提案的目的是（1）什么是外周和中枢免疫 EAE中驱动剂量依赖性酒精效应的细胞亚群？从酗酒的孩子到领养的孩子 小鼠在未处理小鼠中重现临床症状？和（2）哪些肠道微生物组成分是 酒精对EAE的剂量依赖性作用微生物组可以从饮酒转移 小鼠在未处理小鼠中重现临床症状？本提案的科学目标是开始 通过检查免疫系统和肠道来确定酒精在神经炎症中的剂量依赖性作用 微生物组的愿景是产生假设，为未来饮食的方向和设计提供信息 EAE和MS的研究，并扩大了MS患者可用和靶向益生菌的库。

This proposal presents a research career development program focused on the study of alcohol’s dose-dependent effects in neuroinflammation in a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). I am currently an assistant professor of neurology at Dell Medical School at UT Austin. The outlined proposal builds on my previous research in neurobiology of sex differences, clinical training in neuroimmunology and integrates new domains of expertise in bioinformatics, alcohol and microbiome research, and basic science neuroimmunology. I will be guided by outstanding mentors and advisors, including Drs. Adron Harris (alcohol research), Hans Hofmann (bioinformatics), Sergio Baranzini (microbiome), Olaf Stuve (neuroimmunology), and William Schwartz (career guidance). The proposed experiments, didactics, and mentorship will enable me to transition to an R01 funded physician scientist in the cross disciplinary field of neuroimmunology and alcohol research. MS is a chronic autoimmune demyelinating disease of the central nervous system (CNS) and the leading acquired cause of neurological disability in young adults. The cause of MS is unknown. Although genes contribute to the disease risk, it is thought that environmental factors, such as diet and the gut microbiome contribute to a larger degree of the risk. Alcohol is a common dietary factor used by MS patients. Yet, despite its widespread use, potential for abuse and known gut, CNS and immune effects, alcohol’s role in MS is not well understood. The foundation of this proposal is based on my preliminary studies, in press in PNAS, demonstrating that moderate alcohol consumption leads to EAE amelioration, decrease in microglia in the spinal cord, and a shift of gut microbiota toward a regulatory phenotype in a sex-specific pattern, that collectively suggest a protective role of moderate alcohol in EAE and potentially in MS. Given known pro-inflammatory effects of alcohol, these studies raise the question of alcohol’s possible differential effects on neuroinflammation at high vs moderate doses. This proposal begins to address this question by evaluating alcohol’s dose-dependent effects on the peripheral and CNS immune system and the gut microbiome. Specifically, the aims of this proposal are (1) What are the peripheral and CNS immune cell subsets driving dose-dependent alcohol effects in EAE? Can adoptive transfer from alcohol-consuming mice recapitulate clinical symptoms in naive mice? and (2) Which gut microbiome constituents are responsible for alcohol’s dose-dependent effects in EAE? Can microbiome transfer from alcohol-consuming mice recapitulate clinical symptoms in naive mice? The scientific objective of this proposal is to begin to define alcohol’s dose-dependent effects in neuroinflammation by examining the immune system and the gut microbiome with the vision of generating hypotheses that can inform the direction and design of future diet studies in EAE and MS and expand the repertoire of available and targeted probiotics for MS patients.