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，重点是酒精的研究 实验性多发性硬化症(MS)小鼠神经炎症的剂量依赖效应 自身免疫性脑脊髓炎(EAE)。我目前是戴尔医疗公司的神经学助理教授 德克萨斯大学奥斯汀分校。概述的建议建立在我之前在性神经生物学方面的研究基础上 差异，神经免疫学的临床培训，并整合生物信息学的新专业领域， 酒精和微生物组研究，以及基础科学神经免疫学。我将以杰出的人为指导 导师和顾问，包括Adron Harris博士(酒精研究)、Hans Hofmann博士(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)。 建议的实验、教学和指导将使我能够过渡到R01资助的 神经免疫学和酒精研究跨学科领域的内科科学家。 MS是一种慢性自身免疫性中枢神经系统脱髓鞘疾病， 导致年轻人神经功能障碍的主要后天原因。多发性硬化症的病因不明。虽然 基因导致疾病的风险，人们认为环境因素，如饮食和肠道 微生物群在更大程度上导致了这种风险。酒精是多发性硬化症患者常见的饮食因素 病人。然而，尽管它被广泛使用，但可能被滥用，以及已知的肠道、中枢神经系统和免疫效应， 酒精在多发性硬化症中的作用还不是很清楚。这项建议的基础是我初步的 发表在《美国国家科学院院刊》上的研究表明，适量饮酒可以改善EAE， 脊髓小胶质细胞减少，肠道微生物区系向调节性表型转变 性别特有的模式，共同表明适度酒精在EAE中的保护作用，并可能在 鉴于酒精的促炎作用已知，这些研究提出了酒精可能 高剂量和中剂量对神经炎症的不同影响。这项提案开始解决这个问题。 通过评估酒精对外周和中枢免疫系统的剂量依赖性影响以及 肠道微生物群。具体地说，这项建议的目的是(1)什么是外周免疫和中枢免疫 细胞亚群在EAE中驱动剂量依赖的酒精效应？领养是否可以从饮酒中转移 小鼠在幼稚的小鼠身上会出现临床症状吗？以及(2)肠道微生物组分是什么 酒精在EAE中的剂量依赖效应？微生物群能否从饮酒中转移 小鼠在幼稚的小鼠身上会出现临床症状吗？这项提议的科学目标是开始 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效应 微生物组，其愿景是产生能够为未来饮食的方向和设计提供信息的假设 研究EAE和多发性硬化症，并扩大多发性硬化症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.