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：
8997545
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/8997545
关键词：
Ablation Address Alleles Brain Brain-Derived Neurotrophic Factor Cells Cerebral cortex Cicatrix Dendritic Spines Development Excision Functional disorder Gene Targeting Genes Genetic Recombination Goals Health Immune Injury Kinetics Learning Life 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 Processes Pathology Peripheral Phagocytosis Physiological Physiological Processes Play Process Recovery Role Signal Transduction Site Solid Staging Structure Synapses Synaptic plasticity Tamoxifen Time Tissues Transgenic Mice Traumatic Brain Injury base cell motility diphtheria toxin receptor in vivo insight knockout gene macrophage motor learning nervous system disorder neural circuit neuroregulation novel novel strategies recombinase research study 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（由申请人提供）：该提案的目的是更好地了解小胶质细胞在调节生理和病理条件下大脑的结构和功能中的作用。小胶质细胞是中枢神经系统的常驻免疫细胞，并且显示出高度运动的过程，占据了非重叠领域。在生理条件下，小胶质细胞可能参与神经回路的发展和可塑性，并监测大脑的微环境是否有损伤信号。在病理条件下，小胶质细胞可能包含组织损伤，吞噬细胞的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。妨碍描述小胶质细胞精确作用的努力是缺乏在体内特异性扰动小胶质细胞功能的工具。我们最近产生了具有靶向基因插入的小鼠，允许在表达小胶质细胞和外周髓样细胞的CX3CR1中表达他莫昔芬诱导的CRE重组酶。通过利用小胶质细胞和周围髓细胞细胞的不同周转率，我们提出了一种方法，该方法将使我们首次使我们特别扰动活小鼠中的小胶质细胞功能。通过特异性消融小胶质细胞或从活小鼠中的小胶质细胞中去除脑衍生的神经营养因子（BDNF），我们将阐明小胶质细胞和小胶质细胞BDNF在突触发育中的功能以及学习依赖性突触可变性。此外，我们将揭示小胶质激活在控制神经元损伤，神经胶质疤痕形成和突触重塑后的作用。由于活化的小胶质细胞几乎涉及大脑中的所有病理状况，因此提出的鉴定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。