Central Nervous System Autoimmunity and Immunoregulation in the Zebrafish

多发性硬化症(MS)是由中枢神经系统对自身抗原的免疫反应失控引起的。 神经系统。免疫系统中的自身反应成分通常由调节性T细胞控制。 细胞(T{reg})。毫不奇怪，T区的缺陷与多发性硬化症和多发性硬化症的易感性有关。 小鼠发展实验性自身免疫性脑脊髓炎(EAE)，这是MS的实验模型，因此， 为了理解MS的病理，需要研究控制T{reg}分化的分子机制 并确定新的治疗靶点；然而，这些研究不容易在哺乳动物身上进行。 蠕虫和苍蝇在识别先天免疫机制方面很有用，但 无脊椎动物没有T{reg}。我们发现斑马鱼有一种免疫系统，它共享几个 与哺乳动物的特征相同，包括驱动T{reg}分化的基因。在此应用程序中 我们将使用小鼠和斑马鱼来确定控制T{reg}生成的分子途径。这一目标将 通过三种独立的方法实现：1.转录因子的生物信息学鉴定 控制T{reg}分化。2.高通量筛选以识别调节T{reg}的化学物质 差异化。3.转录因子和化合物对T{reg}的作用 在EAE过程中的活动。这个项目有可能确定治疗的靶点 管理MS，并建立斑马鱼作为高通量鉴定MS的平台 免疫调节药物。总而言之，这是一个创新的项目，将把试验性的 小鼠和斑马鱼提供的优势来识别控制T{reg}生成的途径，并且是一致的 新的独立之路奖励计划的目标。

Multiple sclerosis (MS) is caused by an uncontrolled immune response against self-antigens in the central nervous system. The autoreactive components in the immune system are usually controlled by regulatory T cells (T{reg}). Not surprisingly, deficits in the T{reg} compartment are associated to MS and the susceptibility of mice to develop experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Thus, the study of the molecular mechanisms controlling T{reg} differentiation is needed to understand MS pathology and identify new therapeutic targets; these studies, however, cannot be easily performed in mammals. Worms and flies have been useful in the identification of the mechanisms governing innate immunity, but invertebrates do not have T{reg}. We found that the zebrafish has an immune system that shares several features with its mammalian counterpart, including the genes driving T{reg} differentiation. In this application we will use mice and zebrafish to identify the molecular pathways that control T{reg} generation. This goal will be achieved by three independent approaches: 1. Bioinformatic identification of transcription factors controlling T{reg} differentiation. 2. High throughput screen to identify chemicals that regulate T{reg} differentiation. 3. Characterization of the role of the transcription factors and chemical compounds on T{reg} activity during the course of EAE. This project has the potential to identify therapeutic targets for the management of MS, and to establish the zebrafish as a platform for the high throughput identification of immunomodulatory drugs. In summary, this is an innovative project that will combine the experimental advantages offered by mice and zebrafish to identify pathways controlling T{reg} generation and is consistent with the aims of the New Pathway to Independence Award Program.