Microbial Regulation of Microglial Function

小胶质细胞功能的微生物调节

• 批准号: 10677784
• 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
• 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/10677784
• 关键词: Acute; Adult; Affect; Affective; Animal Behavior; Animals; Antibiotic Therapy; Antibiotics; Asthma; Bacteria; Behavior; Biological Assay; Birth; Brain; Cells; Central Nervous System; Complement; Complement Receptor; Complex; Correlation Studies; Critical Pathways; Cues; Data; Defect; Dendritic Spines; Development; Disease; Extinction; Failure; Fright; Functional disorder; Genes; Genetic Transcription; Germ-Free; Goals; Health; Human; Impaired cognition; Impairment; In Vitro; Inflammatory Bowel Diseases; Literature; Macrophage; Macrophage-1 Antigen; Maintenance; Malignant Neoplasms; Medial; Mediating; Medical center; Medicine; Mentorship; Microbe; Microglia; Modeling; Mus; Nervous System Physiology; Neurodegenerative Disorders; 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; Synapses; Synaptic plasticity; Testing; Tissues; Training; Vertebral column; Virus Diseases; Work; behavioral outcome; body system; brain tissue; career; career development; cognitive function; conditioned fear; dysbiosis; experience; experimental study; human model; in vivo; insight; instructor; metabolomics; microbial; microbiome; microbiome alteration; microbiome research; microbiota; microbiota metabolites; neuropsychiatric disorder; normal microbiota; novel; postnatal; response; single nucleus RNA-sequencing; skills; small molecule; synaptic pruning; transcriptome; transcriptomics; two-dimensional

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.

项目总结/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。 对调节小胶质细胞成熟和功能的贡献，包括经验依赖性突触 修剪该候选人已被任命为威尔康奈尔大学医学系讲师 医学中心该提案是候选人先前对小胶质细胞-神经元研究的自然延伸 相互作用、突触可塑性和小鼠行为结果。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， 候选人在两个方面的培训，这反映在康纳利斯顿博士的指导和 大卫·阿提斯：1.鉴定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。拟议 实验和多方面的培训计划将赋予候选人独特的技能组合， 定位他过渡到一个成功的独立职业生涯作为一个物理学家，科学家研究的贡献 外周器官系统功能障碍与认知功能和情感状态改变的关系。 微生物群的改变与小规模人类中的多种神经精神疾病有关。 相关性研究和动物研究，利用无菌（GF）小鼠缺乏从出生开始的微生物群，或动物 由于抗生素治疗而呈现急性微生态失调的人已经证明了多种正常生理学的缺陷， CNS区域和细胞群，包括经验背景下的突触水平变化。之间 受影响的细胞群，CNS组织驻留巨噬细胞称为小胶质细胞已被我们证明， 另一些在没有正常微生物群的情况下被严重改变。考虑到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， 它们可能代表了一个重要的管道，通过它，微生物衍生的信号调节正常的体验， 依赖性突触可塑性和最终的动物行为。我的提案的目的是调查 调节成年人大脑中小胶质细胞功能的微生物群。具体而言，该提案探讨了如何 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.识别微生物来源的小 微生物组通过其改变小鼠和人小胶质细胞体外成熟和功能的分子信号; 2. 测试这些代谢物在调节小胶质细胞依赖性突触细化的模型中的作用， 依赖经验的可塑性总的来说，这些实验提供了新的见解的作用， 微生物组及其代谢物在调节小胶质细胞功能包括突触细化中的作用。