Graves’病甲亢中miR-4443参与致病的机制研究

Graves' Disease (GD) is a common organ specific autoimmune disorder with varied manifestations，long course and high recurrence rate. The rise of thyroid-stimulating hormone receptor antibody (TRAb) is the cause of symptoms and difficult treatment. CD4+T cells are critical for autoantibody production in GD. As important regulators of gene expression, some miRNAs can modulate T cells differentiation and function. Our preliminary study has found that miR-4443 levels are enhanced in CD4+T cells isolated from initial GD patients and correlated with TRAb levels, however little is known about the pathogenesis of miR-4443 in GD. According to the results of previous trials, we will demonstrate the CD4+T-cell-intrinsic function and the molecular regulatory network of miR-4443, and explore the expression regulation of miR-4443. The expected results of this project will reveal for the first time that the impact of miR-4443 on GD, and provide a basis for understanding the pathogenesis network of GD and developing novel therapeutic strategy.

Graves’病甲亢（GD）是一种常见的器官特异性自身免疫性疾病，临床表现变化多端，疗程长，复发率高。促甲状腺激素受体抗体（TRAb）升高是导致GD临床症状和治疗棘手的关键原因。既往研究发现CD4+T细胞功能异常在GD自身抗体产生过程中起着桥梁作用。而miRNA作为基因转录后调控的重要调节分子，参与多种自身免疫炎症反应过程，可调节T细胞分化及功能发挥。本课题组前期研究发现GD患者外周血CD4+T细胞中miR-4443表达增加，且与TRAb水平显著正相关，但miR-4443在GD中的具体作用机制尚不清楚。本课题组拟深入研究miR-4443在CD4+T细胞中的功能, 结合系统生物学手段阐明miR-4443调节的分子网络，同时探索miR-4443表达调控机制。本项目预期研究结果将首次揭示miR-4443参与GD的细胞和分子机制，为明确GD免疫致病网络和寻找新的治疗靶点打下基础。

Graves’病甲亢（GD）是一种常见的器官特异性自身免疫性疾病，临床表现变化多端，疗程长，复发率高。促甲状腺激素受体抗体（TRAb）升高是导致GD临床症状和治疗棘手的关键原因。既往研究发现CD4+T细胞功能异常在GD自身抗体产生过程中起着桥梁作用。而miRNA作为基因转录后调控的重要调节分子，参与多种自身免疫炎症反应过程，可调节T细胞分化及功能发挥。项目组研究发现1）Graves’病(GD)甲亢患者CD4+T细胞中miR-4443表达增加，且与TRAb成显著正相关；2）miR-4443通过NF-κB途径直接抑制TRAF4的表达，从而促进CD4+T细胞细胞因子的分泌和增殖，因而影响CD4+T细胞的功能，从而参与GD的发生、发展从而参与GD的发生、发展。本项目为明确GD免疫致病网络和寻找新的治疗靶点打下基础。