What do microglia do? Dissecting their function in CNS health and disease

小胶质细胞有什么作用？

• 批准号: 8836424
• 负责人: Mariko L. Bennett
• 金额: $ 0.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-26 至 2015-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836424
• 关键词: Ablation; Adult; Antibodies; Brain; Cells; Crush Injury; Development; Diphtheria Toxin; Disease; Embryo; Event; Gene Expression; Genetic Recombination; Goals; Health; Hematopoietic System; Immune; Immune response; Immunohistochemistry; In Situ Hybridization; Inflammation; Inflammatory Response; Injury; Integral Membrane Protein; Label; Messenger RNA; Microglia; Modeling; Mus; Myelogenous; Myeloid Cells; N-terminal; Nerve Crush; Nerve Tissue; Nervous System Trauma; Neuraxis; Optic Nerve; Pathologic; Phenotype; Physiological Processes; Process; Proteins; Reporter; Reporting; Role; Severities; Site; Synapses; Tamoxifen; Testing; Time; Tissues; Transgenic Mice; Western Blotting; base; central nervous system injury; design; hematopoietic tissue; injured; injury and repair; insight; macrophage; mouse Cre recombinase; mouse development; nervous system development; nervous system disorder; neuroprotection; new therapeutic target; novel; optic nerve regeneration; postnatal; precursor cell; prevent; repaired; research study; response to injury; therapeutic target; tissue repair; tool

DESCRIPTION (provided by applicant): What do microglia do? Microglia are myeloid-derived residents of the brain that can mount immune responses to pathologic events in the brain and periphery. Recently, we and others have identified roles for microglia in physiologic processes of the CNS, such as in synapse elimination during development. However, the inability to reliably distinguish microglia from closely related myeloid cells confounds many reports of microglial function in health and disease. Therefore, we sought out a protein marker that would allow the reliable identification, targeting, and characterization of microglia. I identified TM119 as such a marker by a screen based on our extensive cell specific gene expression arrays and confirmed with in situ hybridization. In this application, I will test the hypothesis that a subset of microglia are "alternatively activated", meaning that upon activation they limit inflammation and promote tissue repair, and that these microglia limit CNS injury. I wil then test if selective loss of microglia hinders CNS repair. In the first aim, I will characterize TM119 expression throughout development and test a TM119-based tool, a TM119/CreERT2 BAC transgenic mouse, to genetically target microglia. In the second aim, I will use this mouse to specifically prevent alternative activation of microglia and examine the effect of this on injur severity following crush injury to the optic nerve. In the final aim, I will ablate microglia using Diphtheria toxin targeted to microglia with the TM119/CreERT2 mouse to determine if they are required for CNS repair and neuroprotection. These studies have the potential to dissect and understand, for the first time, the specific contribution of microglia to CNS injury and repair.

描述（由申请人提供）：小胶质细胞做什么？小胶质细胞是大脑的髓样居民，可以对大脑和周围的病理事件进行免疫反应。最近，我们和其他人确定了小胶质细胞在中枢神经系统的生理过程中的作用，例如在发育过程中消除突触。但是，无法可靠地区分小胶质细胞和密切相关的髓样细胞会混淆许多小胶质性功能在健康和疾病中的报道。因此，我们寻找一种蛋白质标记物，该标志物将允许小胶质细胞的可靠鉴定，靶向和表征。我根据我们广泛的细胞特异性基因表达阵列将TM119通过屏幕标记为这样的标记，并通过原位杂交确认。在此应用中，我将检验以下假设：小胶质细胞的子集被“替代激活”，这意味着它们在激活后限制炎症并促进组织修复，并且这些小胶质细胞限制了CNS损伤。然后，我将测试小胶质细胞的选择性损失是否阻碍中枢神经系统修复。在第一个目标中，我将在整个开发中表征TM119的表达，并测试基于TM119的工具TM119/Creert2 BAC转基因小鼠，以靶向小胶质细胞。在第二个目标中，我将使用这只小鼠特别防止小胶质细胞的替代激活，并检查其对视神经挤压损伤后的损伤严重程度的影响。在最终目标中，我将使用 用TM119/Creert2小鼠靶向小胶质细胞的白喉毒素，以确定是否需要CNS修复和神经保护需要它们。这些研究有可能首次剖析和理解小胶质细胞对中枢神经系统损伤和修复的特定贡献。