Monocyte-Derived Microglia in Development and after Neonatal Brain Injury

发育中和新生儿脑损伤后的单核细胞衍生的小胶质细胞

基本信息

批准号：
10593385
负责人：
Chia-Yi Kuan
金额：
$ 24.23万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593385
关键词：
ARHGEF5 gene Ablation Acute Bacterial Artificial Chromosomes Behavior Biological Availability Birth Brain Brain Hypoxia-Ischemia Brain Injuries CCL2 gene Cells Chronic Clinical Clinical Management Clinical Trials Data Development Dichloromethylene Diphosphonate Disease Disease associated microglia Dose Generations Genes Growth Heterogeneity Heterozygote Histologic Histology Hypoxic-Ischemic Brain Injury Impairment Inflammation Injections Injury Intravenous Invaded Label Lipopolysaccharides Liposomes Location Macrophage Maps Mediating Methods Microglia Modeling Mus NADPH Oxidase Neonatal Neonatal Brain Injury Nerve Degeneration Oral Outcome Pathologic Perinatal Brain Injury Role Source Stroke Structure of choroid plexus Synapses TREM2 gene Tamoxifen Testing Therapeutic Effect Toxin Transgenic Mice Yolk Sac behavioral outcome cell type cognitive function cytokine developmental disease hypoxic ischemic injury immune cell infiltrate improved inhibitor insight monocyte mouse model neonatal hypoxic-ischemic brain injury neonatal injury neonatal period neural network neurodevelopment neuron loss neurotoxicity new therapeutic target novel prenatal progenitor public health relevance single-cell RNA sequencing transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY (Abstract) Microglia were once thought derived exclusively from the early yolk sac progenitors, but recent studies raised the possibility of monocyte-derived microglia in normal development and particularly after neonatal brain injury, including stroke, hypoxia-ischemia (HI), and inflammation/LPS-sensitized HI (LPS/HI). However, the extent of monocyte-derived microglia in normal development is unknown, and the roles of monocyte-derived pathologic microglia partially defined. Better understanding of these issues may shed mechanistic insights and suggest potential treatments of neonatal brain injury. We will address these issues in three specific aims. In Aim 1, we will use CCR2-Cre mice crossed with R26R-EGFP mice to determine the extent and distributions of CCR2+ monocyte-derived microglia in the brain. In Aim 2, we will use PF-04136309 (IP) to inhibit the MCP1/CCR2-mediated chemoattraction or clodronate liposomes (IV) to ablate the blood-borne monocytes to assess their potential benefits against the neonatal LPS/HI brain injury. In Aim 3, we will use tamoxifen-dosed CCR2-CreER; R26R-EGFP mice to isolate monocyte-derived microglia- like cells in LPS/HI-injured brains for single-cell RNA-Seq to search for the potential effectors responsible for delayed neurotoxicity and damage to the synaptic network.

项目摘要（摘要）曾经认为，小胶质细胞仅来自早期的蛋黄囊祖细胞，但最近提出的研究提出了单核细胞衍生的小胶质细胞在正常发育中，尤其是在新生儿脑损伤之后的可能性，包括中风，缺氧 - 缺血（HI）和炎症/LPS敏化HI（LPS/HI）。但是，单核细胞衍生的小胶质细胞在正常发育中尚不清楚，并且单核细胞衍生的病理作用小胶质细胞部分定义。更好地理解这些问题可能会提供机械见解并提出建议新生儿脑损伤的潜在治疗方法。我们将以三个具体目标解决这些问题。在AIM 1中，我们将使用与R26R-EGFP小鼠交叉的CCR2-CRE小鼠来确定程度和分布 CCR2+单核细胞衍生的小胶质细胞的大脑。在AIM 2中，我们将使用PF-04136309（IP）抑制MCP1/CCR2介导的趋化或克隆酸盐脂质体（IV）消除血液传播单核细胞，以评估其对新生儿的潜在益处 LPS/HI脑损伤。在AIM 3中，我们将使用他莫昔芬剂量的CCR2-Creer； R26R-EGFP小鼠分离单核细胞衍生的小胶质细胞像单细胞RNA-seq中的LPS/Hi损伤大脑中的细胞一样，以寻找负责的潜在效应子神经毒性延迟对突触网络的损害。