Central Nervous System Autoimmunity and Immunoregulation in the Zebrafish

描述（由申请人提供）：这是一份修改后的申请。多发性硬化症（MS）是由中枢神经系统对自身抗原的不受控制的免疫反应引起的：免疫系统中的自身反应成分通常由调节性T细胞（Treg）控制。毫不奇怪，Treg细胞室的缺陷与MS和小鼠发生实验性自身免疫性脑脊髓炎（EAE） （MS的实验模型）的易感性有关，因此，需要研究控制Treg功能的分子机制，以了解MS病理和寻找新的治疗靶点；然而，这些研究不容易在哺乳动物身上进行。蠕虫和苍蝇在确定先天免疫的机制方面很有用，但无脊椎动物没有Treg。我们发现斑马鱼的免疫系统与哺乳动物的免疫系统有几个共同的特征，包括驱动Treg分化的基因。在这个应用程序中，我们将使用小鼠和斑马鱼来识别控制Treg生成的分子途径。这一目标将通过三个独立的方法来实现：1。控制Treg分化的转录因子的生物信息学鉴定。2. 高通量筛选识别调节Treg分化的化学物质。3. 在EAE过程中转录因子和化合物对Treg激活的作用。该项目有潜力确定MS管理的治疗靶点，并将斑马鱼建立为高通量鉴定免疫调节药物的平台。总之，这是一个创新的项目，将结合小鼠和斑马鱼提供的实验优势来确定控制Treg生成的途径，这与独立新途径奖励计划的目标是一致的。相关性：多发性硬化症（MS）是免疫系统攻击中枢神经系统（CNS）的结果。在正常情况下，免疫系统的自身反应成分由一类称为调节性T细胞（Treg）的特殊T细胞控制，但Treg在MS患者及其实验小鼠模型实验性自身免疫性脑脊髓炎（EAE）中功能失调。在这个项目中，我们将描述代谢途径和控制Treg生物学的化合物，这可能会导致新的MS药物干预。

DESCRIPTION (provided by applicant): This is a revised application. Multiple sclerosis s (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 (Treg). Not surprisingly, deficits in the Treg 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 Treg function 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 Treg. We found that the zebrafish has an immune system that shares several features with its mammalian counterpart, including the genes driving Treg differentiation. In this application we will use mice and zebrafish to identify the molecular pathways that control Treg generation. This goal will be achieved by three independent approaches: 1. Bioinformatic identification of transcription factors controlling Treg differentiation. 2. High throughput screen to identify chemicals that regulate Treg differentiation. 3. Characterization of the role of the transcription factors and chemical compounds on Treg activate 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 Treg generation and is consistent with the aims o f the New Pathway to Independence Award Program. RELEVANCE: Multiple sclerosis (MS) results from an attack of the immune system to the central nervous system (CNS). Under normal circumstances, the autoreactive components of the immune system are controlled by a specialized class of T cells termed regulatory T cells (Treg), but Treg are dysfunctional in MS patients and also in its experimental mouse model experimental autoimmune encephalomyelitis (EAE). In this project we will characterize metabolic pathways and compounds that control Treg biology, which might lead to novel pharmacologic interventions for MS.