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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：
9761988
负责人：
Vaishali Moulton
金额：
$ 45.56万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761988
关键词：
Affect Alternative Splicing American Antibodies Arginine Arthritis Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Brain CD3 Antigens CD8B1 gene CRISPR/Cas technology Cell physiology Cells Cellular Immunology Data Defect Deposition Development Disease Disease model Distal Enterobacteria phage P1 Cre recombinase Estrogens Exhibits Experimental Autoimmune Encephalomyelitis Female of child bearing age Functional disorder Funding Gene Expression Gene Silencing Generations Genes Goals Histopathology Homeostasis Hormonal Human Immune Immune System Diseases Immune Tolerance Immune system Immunosuppression In Vitro Infection Infiltration Inflammatory Interleukin-17 Interleukin-2 Joints Kidney Kidney Diseases Knockout Mice Length Link LoxP-flanked allele Lupus Lupus Nephritis Lymphopenia Mass Spectrum Analysis Mature T-Lymphocyte Mediating Memory Mentored Research Scientist Development Award Messenger RNA Molecular Molecular Immunology Molecular Target Mus Names National Institute of Arthritis and Musculoskeletal and Skin Diseases Oligonucleotides Organ Pain Pathogenesis Pathology Patients Phenotype Production Protein Analysis Protein Isoforms Proteins Proteinuria Publishing RNA Splicing Receptor Signaling Regulation Research Personnel Role Serine Serum Signal Transduction Signaling Molecule Skin Steroids System Systemic Lupus Erythematosus T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissues Transcript Whole Organism Woman aged base child bearing chronic autoimmune disease cytokine experimental study immune function immunopathology improved lupus prone mice mortality novel overexpression promoter protein expression targeted biomarker therapeutic target

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. This proposal is well within the scope and goals of the applicant's currently funded NIAMS K01 award, which is to develop to an independent investigator.

系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病