Microbial Regulation of Microglial Function

小胶质细胞功能的微生物调节

基本信息

批准号：
10507543
负责人：
Christopher Neal Parkhurst
金额：
$ 19.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-05 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10507543
关键词：
Acute Adult Affect Affective Animal Behavior Animals Antibiotic Therapy Antibiotics Bacteria Behavior Birth Brain Cell Nucleus Cells Complement Complement Receptor Complex Correlation Studies Critical Pathways Cues Data Defect Dendritic Spines Development Disease Extinction (Psychology)Failure Fright Functional disorder Genes Genetic Transcription Germ-Free Goals Health Human Impaired cognition Impairment In Vitro Inflammatory Bowel Diseases Literature Macrophage-1 Antigen Maintenance Malignant Neoplasms Medial Mediating Medical center Medicine Mentorship Microbe Microglia Modeling Mus Nerve Degeneration Nervous System Physiology Neuraxis Neurons Organism Pathology Peripheral Peripheral Blood Mononuclear Cell Phagocytosis Phenotype Physicians Physiology Population Positioning Attribute Prefrontal Cortex Process Program Development Proteins Publishing Regulation Research Research Proposals Role Scientist Signal Transduction Signaling Molecule Small Nuclear RNA Synapses Synaptic plasticity Testing Tissues Training Vertebral column Viral Work base behavioral outcome body system brain tissue career career development cognitive function conditioned fear dysbiosis experience experimental study human model in vivo insight instructor macrophage metabolomics microbial microbiome microbiome alteration microbiome research microbiota microbiota metabolites neuropsychiatric disorder neuropsychiatry normal microbiota novel programs response skills small molecule synaptic pruning transcriptome transcriptome sequencing transcriptomics two-dimensional

项目摘要

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.

项目概要/摘要该提案是一项为期四年的研究职业发展计划，重点是微生物组的研究对小胶质细胞成熟和功能调节的贡献，包括经验依赖性突触该候选人已被任命为威尔康奈尔大学医学系讲师。该提案是候选人之前对小胶质细胞神经元研究的自然延伸。它概述了候选人要实现的计划。他的目标是成为关键中枢神经系统过程的微生物调节专家，扩展对候选人的培训有两个维度，这反映在康纳·利斯顿博士和博士的指导中。 David Artis：1. 鉴定改变小胶质细胞成熟和功能的微生物衍生信号，以及 2. 小胶质细胞功能的改变调节经验依赖性突触细化。实验和多方面的培训计划将赋予候选人独特的技能组合，使他能够过渡到成功的独立职业生涯，成为一名研究贡献的医生科学家周围器官系统功能障碍导致认知功能和情感状态的改变。微生物群的改变与小规模人类的多种神经精神疾病有关相关研究以及利用出生时缺乏微生物群的无菌 (GF) 小鼠或动物进行的动物研究抗生素治疗造成的严重生态失调已证明多种正常生理机能存在缺陷中枢神经系统区域和细胞群，包括经验背景下的突触水平变化。我们已经证明，在受影响的细胞群中，存在中枢神经系统组织的巨噬细胞（称为小胶质细胞）鉴于小胶质细胞在正常微生物群缺失的情况下的已知重要性，其他一些可能会发生严重改变。调节发育中和成年小鼠大脑中突触的形成、稳定性和可塑性，它们可能代表了微生物群衍生信号调节正常体验的重要渠道—— 我的建议的目标是研究突触可塑性和最终的动物行为的作用。具体来说，该提案研究了微生物群如何调节成人大脑中的小胶质细胞功能。微生物组的变化通过以下方式改变小胶质细胞-神经元相互作用： 1. 识别微生物衍生的小胶质细胞 2. 微生物组在体外改变小鼠和人类小胶质细胞成熟和功能的分子信号；在模型中测试这些代谢物在调节小胶质细胞依赖性突触细化中的作用总的来说，这些实验提供了对经验依赖性可塑性的新见解。微生物组及其代谢物调节小胶质细胞功能，包括突触细化。