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

• 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
• 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

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.

项目概要（摘要） 小胶质细胞曾经被认为完全来自早期卵黄囊祖细胞，但最近的研究提出， 单核细胞衍生的小胶质细胞在正常发育中的可能性，特别是在新生儿脑损伤后， 包括中风、缺氧缺血（HI）和炎症/LPS致敏HI（LPS/HI）。然而， 单核细胞衍生的小胶质细胞在正常发育中的作用尚不清楚，单核细胞衍生的病理性小胶质细胞在正常发育中的作用尚不清楚。 小胶质细胞部分定义。更好地理解这些问题可能会摆脱机械的见解，并建议 新生儿脑损伤的潜在治疗方法。我们将在三个具体目标中处理这些问题。 目的1：利用CCR 2-Cre小鼠与R26 R-EGFP小鼠杂交，研究CCR 2-Cre小鼠与R26 R-EGFP小鼠杂交后， CCR 2+单核细胞衍生的小胶质细胞。 在目标2中，我们将使用PF-04136309（IP）抑制MCP 1/CCR 2介导的化学吸引或氯膦酸盐 脂质体（IV）消融血液传播的单核细胞，以评估其对新生儿的潜在益处 LPS/HI脑损伤。 在目标3中，我们将使用他莫昔芬给药的CCR 2-CreER; R26 R-EGFP小鼠分离单核细胞衍生的小胶质细胞。 在LPS/HI损伤的大脑中，类似细胞用于单细胞RNA-Seq，以寻找负责 延迟神经毒性和对突触网络的损害。