Genetic Control of Microglia and Neural Macrophages

摘要 这个项目将利用斑马鱼遗传学的力量来发现新的基因，这些基因对于 小胶质细胞和神经巨噬细胞的发育、迁移和激活。小胶质细胞具有很强的运动性， 中枢神经系统(CNS)内的吞噬神经胶质细胞，破坏病原体并清除碎片，如 凋亡的细胞和受损的轴突。巨噬细胞在周围神经中发挥着类似的功能。在疾病或 损伤后，小胶质细胞和巨噬细胞的不适当激活可能会对神经系统造成损害。 例如，在多发性硬化症(MS)和其他中枢神经系统疾病中，激活的小胶质细胞释放细胞毒 损害有髓鞘轴突的因素。同样，激活的巨噬细胞损害糖尿病患者的有髓轴突 周围神经病。尽管小胶质细胞和巨噬细胞在健康和疾病中的重要性 神经系统的发育、迁移和发育的认识存在着根本性的差距 这些细胞的激活。因此，对小胶质细胞功能的调节机制和 神经巨噬细胞将为神经疾病的病理生理学提供重要的见解 系统，包括多发性硬化症、周围神经病和许多其他疾病。此外，这些研究将提出新的 找到预防和修复神经系统损伤的治疗方法。 发现小胶质细胞和神经发育和功能所必需的新基因 巨噬细胞，我们将进行基因筛查，寻找这些细胞被破坏的突变。使用 小胶质细胞和巨噬细胞的快速、可靠的标记分析，我们发现小胶质细胞和巨噬细胞 在我们之前对髓鞘形成突变体的筛选中发现的突变体中， 国家科学基金会。有趣的是，一种阻断小胶质细胞和巨噬细胞激活的药物可以改善NSF的表型。 突变型，提示吞噬细胞激活在这些突变型的病理中起作用。这些结果 论证了发现影响小胶质细胞和神经巨噬细胞的突变的可行性，还 强调有髓轴突和相关吞噬细胞之间关系的重要性。 对其他具有异常小胶质细胞和巨噬细胞的突变体的分析将检验激活 这些细胞中的一部分有助于神经系统的不同病理，从而使它们加剧和 在不同的情况下改善症状。该项目将分离出更多的必需基因突变。 在小胶质细胞和巨噬细胞中的功能，并表征这些基因在细胞和 生化水平。这些实验将阐明脊椎动物神经生物学的基本方面，建立 斑马鱼模型的重要人类疾病，增加了对过程的理解 病变和损伤的轴突，并为寻求神经损伤的治疗性修复提供基础 系统。

Abstract This project will exploit the power of zebrafish genetics to discover new genes that are essential for the development, migration, and activation of microglia and neural macrophages. Microglia are highly motile, phagocytic glial cells within the central nervous system (CNS) that destroy pathogens and clear debris such as apoptotic cells and damaged axons. Macrophages perform similar functions in peripheral nerves. In disease or after injury, inappropriate activation of microglia and macrophages can cause damage to the nervous system. For example, in multiple sclerosis (MS) and other diseases in the CNS, activated microglia release cytotoxic factors that harm myelinated axons. Similarly, activated macrophages damage myelinated axons in diabetic peripheral neuropathy. Despite the importance of microglia and macrophages in the healthy and diseased nervous system, there are fundamental gaps in the understanding of the development, migration, and activation of these cells. Thus investigation of the mechanisms that regulate the function of microglia and neural macrophages will provide important insights into the pathophysiology of diseases of the nervous system, including MS, peripheral neuropathies, and many others. In addition, these studies will suggest new avenues toward therapies to prevent and repair damage to the nervous system. To discover new genes essential for the development and function of microglia and neural macrophages, we will conduct a genetic screen for mutations in which these cells are disrupted. Using a rapid, robust marker assay for microglia and macrophages, we have found that microglia and macrophages are increased and strongly activated in a mutant recovered in our previous screens for myelination mutants, nsf. Interestingly, a drug that blocks activation of microglia and macrophages ameliorates the phenotype of nsf mutants, suggesting that activated phagocytes contribute to pathology in these mutants. These results demonstrate the feasibility of finding mutations that affect microglia and neural macrophages, and also underscore the importance of the relationship between myelinated axons and the associated phagocytes. Analysis of additional mutants with abnormal microglia and macrophages will test the hypothesis that activation of these cells contributes to diverse pathologies of the nervous system, such that they act to exacerbate and ameliorate symptoms in different contexts. This project will isolate more mutations in genes with essential functions in microglia and macrophages and characterize the functions of these genes at the cellular and biochemical level. These experiments will elucidate fundamental aspects of vertebrate neurobiology, establish zebrafish models of important human diseases, add to the understanding of the processes that are disrupted in diseased and injured axons, and provide a basis to pursue the therapeutic repair of damage to the nervous system.