Genetic Control of Microglia and Neural Macrophages

摘要 该项目将利用斑马鱼遗传学的力量来发现对人类生存至关重要的新基因。 小胶质细胞和神经巨噬细胞的发育、迁移和活化。小胶质细胞是高度能动的， 中枢神经系统（CNS）内的吞噬性神经胶质细胞，其破坏病原体并清除碎片， 凋亡细胞和受损的轴突。巨噬细胞在周围神经中执行类似的功能。在疾病或 损伤后，小胶质细胞和巨噬细胞的不适当激活可导致神经系统损伤。 例如，在多发性硬化症（MS）和CNS中的其他疾病中，活化的小胶质细胞释放细胞毒性物质， 损害有髓轴突的因素。同样，活化的巨噬细胞损伤糖尿病患者的有髓轴突， 周围神经病变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，在理解发育，迁移和 激活这些细胞。因此，研究调节小胶质细胞功能的机制， 神经巨噬细胞将为神经系统疾病的病理生理学提供重要的见解。 系统，包括MS，周围神经病和许多其他疾病。此外，这些研究将提出新的 预防和修复神经系统损伤的治疗方法。 发现对小胶质细胞和神经胶质细胞的发育和功能至关重要的新基因， 我们将对这些细胞被破坏的突变进行遗传筛查。使用 我们发现，小胶质细胞和巨噬细胞 在我们以前筛选髓鞘形成突变体时发现的突变体中， nsf。有趣的是，一种阻断小胶质细胞和巨噬细胞活化的药物改善了nsf的表型 突变体，表明激活的吞噬细胞有助于这些突变体的病理。这些结果 证明了发现影响小胶质细胞和神经巨噬细胞的突变的可行性， 强调了有髓鞘轴突和相关吞噬细胞之间关系的重要性。 对具有异常小胶质细胞和巨噬细胞的其他突变体的分析将检验激活 这些细胞中的大多数导致神经系统的多种病理，使得它们起到加剧和 在不同情况下改善症状。该项目将分离出更多的基因突变， 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， 斑马鱼模型的重要人类疾病，增加了对过程的理解，被打乱， 患病和受伤的轴突，并提供了基础，以寻求治疗性修复损伤的神经 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.