Role of splicing factor SRSF1 in T cell function and autoimmunity

剪接因子 SRSF1 在 T 细胞功能和自身免疫中的作用

基本信息

批准号：
10093179
负责人：
Iannis Elias Adamopoulos
金额：
$ 17.5万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2022-08-31
项目状态：
已结题

项目摘要

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause, which mainly afflicts women in their childbearing years and affects multiple organs including the skin and joints with complications in vital organs such as kidneys and brain. T cell dysfunction due to altered intracellular signaling, gene expression, and function, is thought to be central in the pathogenesis of this disease. The applicant used a discovery approach and identified a protein namely serine arginine-rich splicing factor 1 (SRSF1) as a regulator of a critical signaling gene - CD3 zeta chain, in human T cells. Furthermore, the applicant showed that SRSF1 is a novel regulator of interleukin (IL)-2, a cytokine necessary for T cell function. Interestingly, T cells from several patients with SLE have reduced levels of SRSF1 and its overexpression improves IL-2 production. This suggests that aberrant SRSF1 expression may contribute to defective T cell function and therefore to disease pathophysiology. To advance these concepts, and to determine the role of SRSF1 in the immune system within a whole organism, the applicant has generated mice lacking the Srsf1 gene conditionally in T cells. Intriguingly, this mouse has defects in T cell phenotype and function, including reduced expression of CD3 zeta chain, reduced IL-2, and increased proinflammatory IL-17 cytokine production. The mouse develops autoantibodies and signs of kidney disease. Interestingly, estrogen downregulates SRSF1 expression levels in T cells from healthy women but not men. Based on the preliminary evidence generated in human T cells and in the T cell Srsf1-deficient mouse, the hypothesis is that SRSF1 is a critical regulator of T cell function and its deficiency promotes the expression of autoimmunity and related pathology. To test this hypothesis the applicant will - 1) Determine how SRSF1 controls T cell homeostasis and function and enables development of autoimmunity and related pathology 2) Determine how T cell-specific deletion of SRSF1 influences spontaneous and induced autoimmune disease and 3) Determine the role and regulation of SRSF1 in T cells from SLE patients and normal subjects. The applicant proposes the characterization of a novel mouse, which will help define the role of SRSF1 in T cell function and the expression of autoimmunity and related pathology using cellular and molecular immunology approaches. In parallel, studies proposed in human T cells will provide a molecular link to hormonal aspects of SLE pathogenesis.

系统性红斑狼疮（SLE）是一种原因不明的自身免疫性疾病，主要影响育龄妇女会影响多个器官，包括皮肤和关节，并出现并发症肾脏和大脑等重要器官。由于细胞内信号传导、基因改变而导致 T 细胞功能障碍表达和功能被认为是这种疾病发病机制的核心。申请人使用了发现方法并鉴定出一种蛋白质，即富含丝氨酸精氨酸的剪接因子 1 (SRSF1) 作为人类 T 细胞中关键信号基因 - CD3 zeta 链的调节因子。此外，申请人还表明 SRSF1 是白细胞介素 (IL)-2 的新型调节剂，白介素 -2 是 T 细胞功能必需的细胞因子。有趣的是，T 几名 SLE 患者的细胞中 SRSF1 水平降低，其过度表达可改善 IL-2 生产。这表明异常的 SRSF1 表达可能导致 T 细胞功能缺陷和因此对于疾病的病理生理学而言。为了推进这些概念，并确定 SRSF1 在整个生物体内的免疫系统，申请人已经培育出缺乏Srsf1基因的小鼠有条件地存在于 T 细胞中。有趣的是，这只小鼠的 T 细胞表型和功能存在缺陷，包括减少 CD3 zeta 链的表达，减少 IL-2，并增加促炎性 IL-17 细胞因子的产生。这小鼠产生自身抗体并出现肾脏疾病的迹象。有趣的是，雌激素下调 SRSF1 健康女性而非男性的 T 细胞中的表达水平。根据产生的初步证据人类 T 细胞和 T 细胞 Srsf1 缺陷小鼠中，假设 SRSF1 是 T 细胞的关键调节因子细胞功能及其缺陷促进自身免疫和相关病理的表达。为了测试这个假设申请人将 - 1) 确定 SRSF1 如何控制 T 细胞稳态和功能并启用自身免疫和相关病理学的发展 2) 确定 T 细胞特异性删除 SRSF1 影响自发性和诱发性自身免疫性疾病，3) 确定 SRSF1 的作用和调节来自 SLE 患者和正常受试者的 T 细胞。申请人提出小说的特征小鼠，这将有助于确定 SRSF1 在 T 细胞功能以及自身免疫和免疫细胞表达中的作用使用细胞和分子免疫学方法进行相关病理学。与此同时，在人类中提出的研究 T 细胞将为 SLE 发病机制的激素方面提供分子联系。