In vivo studies of microglial functions in brain plasticity and pathology

小胶质细胞在脑可塑性和病理学中的功能的体内研究

基本信息

批准号：
9223747
负责人：
WENBIAO GAN
金额：
$ 37.08万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9223747
关键词：
Ablation Address Alleles Brain Brain-Derived Neurotrophic Factor Cells Cerebral cortex Cicatrix Dendritic Spines Development Enterobacteria phage P1 Cre recombinase Excision Functional disorder Gene Targeting Genes Genetic Recombination Goals Immune Injury Kinetics Learning Link LoxP-flanked allele Memory Memory impairment Microglia Microscopy Modification Molecular Monitor Motor Cortex Mus Myeloid Cells Natural regeneration Nerve Regeneration Neuraxis Neuronal Injury Neuronal Plasticity Neurons Pathologic Pathologic Processes Pathology Peripheral Physiological Physiological Processes Play Process Recovery Role Signal Transduction Site Solid Structure Synapses Synaptic plasticity Tamoxifen Time Tissues Transgenic Mice Traumatic Brain Injury cell motility diphtheria toxin receptor experimental study in vivo insight knockout gene macrophage motor learning nervous system disorder neural circuit novel novel strategies public health relevance relating to nervous system response tool two-photon

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to better understand the role of microglia in regulating the structure and function of the brain under physiological and pathological conditions. Microglia are the resident immune cells of the central nervous system and display highly motile processes occupying a non- overlapping territory. Under physiological conditions, microglia may participate in the development and plasticity of neural circuits and monitor the brain's microenvironment for damage signals. Under pathological conditions, microglia may contain tissue damage, phagocytose cellular debris, and promote neuronal plasticity. Although microglia have been implicated in many physiological and pathological processes, their functions in the central nervous system remains elusive. Hampering efforts to delineate the precise role of microglia is the lack of tools to specifically perturb microglial function in vivo. We have recently generated mice with a targeted gene insertion allowing for the expression of tamoxifen-inducible Cre recombinase in CX3CR1 expressing microglial cells and peripheral myeloid cells. By taking advantage of different turnover rates of microglia and peripheral myeloid cells, we propose to establish an approach that will allow us, for the first time, to specifically perturb microglial functions in the living mice. By specifically ablating microglia or removing brain- derived neurotrophic factor (BDNF) from microglia in the living mice, we will elucidate the functions of microglia and microglial BDNF in synapse development and learning-dependent synaptic plasticity. In addition, we will reveal the role of microglial activation in controlling neuronal damage, glial scar formation and synaptic remodeling after traumatic brain injury. As activated microglia are involved in almost every pathological condition in the brain, the proposed studies of identifying precise functions of microglia will provide important insights for the understanding and treatment of many neurological diseases.

描述（申请人提供）：本提案的目的是更好地了解小胶质细胞在生理和病理条件下调节大脑结构和功能的作用。小胶质细胞是中枢神经系统的常驻免疫细胞，并表现出占据非重叠区域的高度活动的过程。在生理条件下，小胶质细胞可能参与神经回路的发育和可塑性，并监测大脑微环境的损伤信号。在病理条件下，小胶质细胞可能含有组织损伤、吞噬细胞碎片并促进神经元可塑性。尽管小胶质细胞与许多生理和病理过程有关，但它们在中枢神经系统中的功能仍然难以捉摸。由于缺乏专门干扰体内小胶质细胞功能的工具，阻碍了描述小胶质细胞精确作用的努力。我们最近培育了带有靶向基因插入的小鼠，允许在表达 CX3CR1 的小胶质细胞和外周骨髓细胞中表达他莫昔芬诱导型 Cre 重组酶。通过利用小胶质细胞和外周骨髓细胞的不同周转率，我们建议建立一种方法，使我们能够首次特异性地干扰活体小鼠的小胶质细胞功能。通过特异性消融小胶质细胞或去除活体小鼠小胶质细胞中的脑源性神经营养因子（BDNF），我们将阐明小胶质细胞和小胶质细胞 BDNF 在突触发育和学习依赖性突触可塑性中的功能。此外，我们还将揭示小胶质细胞激活在控制脑外伤后神经元损伤、胶质疤痕形成和突触重塑中的作用。由于激活的小胶质细胞几乎涉及大脑的所有病理状况，因此所提出的识别小胶质细胞精确功能的研究将为理解和治疗许多神经系统疾病提供重要的见解。