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.

项目摘要/摘要该建议是针对四年的研究职业发展计划，重点是研究微生物组的研究对小胶质成熟和功能调节的贡献，包括经验依赖性突触修剪。候选人已经被任命为威尔·康奈尔（Weill Cornell）医学系教练医疗中心。该提案是候选人先前对小胶质细胞神经元研究的自然扩展小鼠的相互作用，突触可塑性和行为结果。它概述了候选人实现的计划他成为关键中枢神经系统过程微生物调节专家的目标，扩展候选人在二维中的培训，反映在Drs的指导中。 Conor Liston和 David Artis：1。鉴定微生物衍生的信号，这些信号改变了小胶质细胞的成熟和功能， 2。小胶质功能的改变，调节经验依赖性突触改进。提议实验和多面培训计划将以独特的技能结合授予候选人将他定位为实现贡献的身体科学家，过渡到成功的独立职业周围器官系统系统功能障碍对认知功能和情感状态的改变。微生物群的改变与小型人类的多种神经精神疾病有关相关研究和使用无菌（GF）小鼠从出生或动物开始缺乏菌群的动物研究通过抗生素治疗使急性失调的急性失调显示出多种的正常生理学缺陷中枢神经系统区域和细胞种群在经验背景下包括突触级别的变化。中间受影响的细胞群体，美国已经显示了CNS组织居民巨噬细胞称为小胶质细胞的巨噬细胞，在没有正常菌群的情况下，其他人会大大改变。鉴于小胶质细胞在调节发育中和成年小鼠大脑内突触的形成，稳定性和可塑性，它们可能代表了一个重要的渠道，微生物群衍生的信号调节正常经验 - 依赖的合成可塑性和最终的动物行为。我的提议的目的是调查角色在调节成人大脑中的小胶质细胞功能方面的微生物群。具体来说，该提案调查了如何微生物组的更改通过以下方式改变小胶质细胞 - 神经元相互作用：1。微生物组在体外改变小鼠和人类小胶质成熟和功能的分子信号； 2。测试这些代谢物在控制小胶质细胞依赖性突触改进中的作用依赖经验的可塑性。总的来说，这些实验提供了有关该作用的新颖洞察力微生物组及其在调节小胶质细胞功能中的代谢物，包括突触改进。