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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）是一种病因不明的自身免疫性疾病，主要累及育龄期妇女，影响多个器官，包括皮肤和关节，重要器官如肾脏和大脑。T细胞功能障碍由于改变细胞内信号，基因表达和功能被认为是该疾病发病机制的中心。申请人使用了发现的方法，并确定了一种蛋白质，即丝氨酸丝氨酸丰富的剪接因子1（SRSF 1）作为一个调节人T细胞中的关键信号基因-CD 3 zeta链。此外，申请人表示， SRSF 1是一种新的白细胞介素（IL）-2调节剂，IL-2是T细胞功能所必需的细胞因子。有趣的是，T 来自几个SLE患者的细胞具有降低的SRSF 1水平，其过表达提高IL-2 生产这表明SRSF 1表达异常可能导致T细胞功能缺陷，因此也是疾病的病理生理学。为了推进这些概念，并确定SRSF 1在在整个生物体内的免疫系统中，申请人已经产生了缺乏Srsf 1基因的小鼠在T细胞中。有趣的是，这只小鼠在T细胞表型和功能方面存在缺陷，包括减少了 CD 3 ζ链的表达，减少IL-2和增加促炎性IL-17细胞因子的产生。的小鼠产生自身抗体和肾脏疾病的迹象。有趣的是，雌激素下调SRSF 1，在健康女性T细胞中的表达水平，而不是男性。根据初步证据，在人类T细胞和T细胞Srsf 1缺陷小鼠中，假设SRSF 1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。为了验证这一 1）确定SRSF 1如何控制T细胞稳态和功能，并使自身免疫和相关病理学的发展2）确定T细胞特异性缺失SRSF 1 影响自发性和诱导性自身免疫性疾病; 3）确定SRSF 1的作用和调节 SLE患者和正常人的T细胞。申请人提出了一部小说的特征这将有助于确定SRSF 1在T细胞功能和自身免疫表达中的作用，使用细胞和分子免疫学方法的相关病理学。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。