Central Nervous System Autoimmunity and Immunoregulation in the Zebrafish

描述(申请人提供)：这是一份修改后的申请表。多发性硬化症S(MS)是由中枢神经系统对自身抗原的免疫反应失控引起的：免疫系统中的自身反应成分通常由调节性T细胞(Treg)控制。不足为奇的是，Treg区的缺陷与MS和小鼠患实验性自身免疫性脑脊髓炎(EAE)的易感性有关，EAE是MS的实验模型。因此，需要研究控制Treg功能的分子机制来了解MS的病理并确定新的治疗靶点；然而，这些研究不容易在哺乳动物中进行。蠕虫和苍蝇在识别控制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点，包括驱动Treg分化的基因。在这项应用中，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.高通量筛选以识别调节Treg分化的化学物质。3.转录因子和化合物在EAE过程中对Treg激活作用的表征。该项目有可能确定多发性硬化症的治疗靶点，并建立斑马鱼作为高通量鉴定免疫调节药物的平台。总而言之，这是一个创新的项目，将结合老鼠和斑马鱼提供的实验优势来确定控制Treg生成的途径，并与新的独立途径奖励计划的目标一致。相关性：多发性硬化症(MS)是由于免疫系统对中枢神经系统(CNS)的攻击所致。在正常情况下，免疫系统的自身反应成分由一种名为调节性T细胞(Treg)的特殊T细胞控制，但Treg在MS患者及其实验性小鼠模型实验性自身免疫性脑脊髓炎(EAE)中功能障碍。在这个项目中，我们将描述控制Treg生物学的代谢途径和化合物的特征，这可能会导致对MS进行新的药物干预。

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.