Microbial Regulation of Microglial Function

项目摘要/摘要 这项提议是一个为期四年的研究职业发展计划，重点是微生物组的研究 对包括经验依赖突触在内的小胶质细胞成熟和功能调节的贡献 修剪。这位候选人已经被任命为威尔康奈尔大学医学系的讲师 医疗中心。这项提议是候选人之前对小胶质细胞神经元研究的自然延伸 小鼠的相互作用、突触可塑性和行为结果。它概述了候选人实现以下目标的计划 他的目标是成为关键中枢神经系统过程微生物调节方面的专家，扩展 对候选人的两个维度的培训，这体现在康纳·利斯顿博士和 David Artis：1.识别改变小胶质细胞成熟和功能的微生物来源的信号，以及 2.调节经验依赖性突触细化的小胶质细胞功能的改变。建议数 实验和多方面的培训计划将赋予应聘者独特的技能组合，将 使他成为一名研究这一贡献的内科科学家，过渡到成功的独立职业生涯 从外周器官系统功能障碍到认知功能和情感状态的改变。 微生物区系的改变与小规模人类的多种神经精神障碍有关 相关研究，以及利用出生时缺乏微生物区系的无菌(GF)小鼠或动物进行的动物研究 由于抗生素治疗而出现严重的生物失调，已显示出多发性硬化症的正常生理缺陷。 包括中枢神经系统区域和细胞群在内的突触水平变化的经验。在这些人中 在受影响的细胞群中，我们和 其他的在没有正常微生物区系的情况下会发生很大的变化。鉴于已知的小胶质细胞在 调节发育中和成年小鼠脑内突触的形成、稳定性和可塑性， 它们可能代表着一条重要的渠道，微生物区系衍生的信号通过该渠道调节正常体验- 依赖突触可塑性，并最终影响动物行为。我的建议的目标是调查 微生物区系在调节成人大脑中的小胶质功能中的作用。具体地说，该提案调查了 微生物组的变化通过以下方式改变小胶质细胞与神经元的相互作用：1.鉴定微生物来源的小分子 微生物组在体外改变小鼠和人小胶质细胞成熟和功能的分子信号； 检测这些代谢物在调节小胶质细胞依赖的突触细化中的作用 依赖经验的可塑性。总而言之，这些实验提供了对 微生物群及其代谢产物对小胶质细胞功能的调节，包括突触的细化。

Project Summary/Abstract This proposal is for a four-year research career development program, focused on the study of the microbiome’s contribution to the regulation of microglial maturation and function including experience-dependent synaptic pruning. The candidate has already been appointed an Instructor in the Department of Medicine at Weill Cornell Medical Center. The proposal is a natural extension of the candidate’s previous research into microglial-neuronal interaction, synaptic plasticity, and behavioral outcomes in mice. It outlines a plan for the candidate to achieve his goal of becoming an expert in the microbial regulation of critical central nervous system processes, extending the training of the candidate in two dimensions, which are reflected in the mentorship of Drs. Conor Liston and David Artis: 1. Identification of microbially-derived signals that alter the maturation and function of microglia, and 2. Alterations in microglial function that regulate experience-dependent synaptic refinement. The proposed experiments and multi-faceted training plan will impart the candidate with a unique combination of skills that will position him to transition into a successful independent career as a physician-scientist studying the contribution of peripheral organ system dysfunction to alterations in cognitive function and affective states. Alterations in the microbiota have been associated with multiple neuropsychiatric disorders in small-scale human correlational studies, and animal studies utilizing germ-free (GF) mice lacking a microbiota from birth, or animals rendered acutely dysbiotic by antibiotic treatment have demonstrated defects in the normal physiology of multiple CNS regions and cell populations including synapse-level changes in the context of experience. Amongst affected cell populations, the CNS tissue-resident macrophage known as microglia have been shown by us and others to be heavily altered in the absence of a normal microbiota. Given the known importance of microglia in regulating the formation, stability, and plasticity of synapses within both the developing and adult mouse brain, they likely represent an important conduit through which microbiota-derived signals regulate normal experience- dependent synaptic plasticity and ultimately animal behavior. The goal of my proposal is to investigate the role of the microbiota in modulating microglial function in the adult brain. Specifically, this proposal investigates how changes to the microbiome alter microglial-neuronal interaction by: 1. Identifying the microbially-derived small molecule signals by which the microbiome alter mouse and human microglial maturation and function in vitro; 2. Testing the role of these metabolites in regulating microglial-dependent synaptic refinement in a model of experience-dependent plasticity. Collectively, these experiments provide novel insight into the role of the microbiome and its metabolites in regulating microglial function including synaptic refinement.