系统性硬皮病中miRNA-4769-3p异常增高机制及其在纤维化中的作用

系统性硬皮病（SSc）是成纤维细胞（FB）功能亢进导致组织器官纤维化为主要病理特征疾病，确切发病机理不清。我们系列研究证实，SSc患者CD4+T细胞相关基因低甲基化并导致其异常活化，在FB功能调控及组织纤维化中起着重要作用，但机制尚不明。近年来，循环MicroRNAs作为细胞间调控分子受到重视。我们初步研究发现，1.活化的CD4+T高表达miRNA-4769-3p、患者血浆中其水平也增高；2.miRNA-4769-3p处理正常人FB后，致其胶原产生增多； 3.miRNA-4769-3p可通过调控PHLPP2表达影响FB的凋亡。提示miRNA-4769-3p可能在疾病的纤维化中发挥重要作用。本课题拟在上述基础上，在体内外进一步研究miRNA-4769-3p在CD4+T中高表达的原因及其对SSc纤维化的作用，为找寻CD4+T细胞对FB调控的途径提供新思路、为该病的治疗研究提供新靶点。

Systemic scleroderma (SSc) is a disease characterized by fibrosis of tissues and organs due to hyperfunction of fibroblasts, and the exact pathogenesis is unclear.Our series of studies have confirmed that hypomethylation of CD4+ T cell-related genes in SSc patients leads to their abnormal activation, which plays a very important role in the regulation of fibroblasts function and tissue fibrosis, but the mechanism is still unknown.In recent years, circulating microRNAs have attracted much attention as intercellular regulatory molecules.Our preliminary study found that 1. Activated CD4+T highly expressed miRNA-4769-3p, and its level was also increased in the plasma of patients; 2. After the treatment of normal human fibroblasts with miRNA-4769-3p, its collagen production was increased; 3. miRNA-4769-3p could affect the apoptosis of fibroblasts by regulating the expression of PHLPP2.It suggests that miRNA-4769-3p may play an important role in the fibrosis of the disease.On the basis of the above, this study intends to investigate the causes of high expression of miRNA-4769-3p in CD4+T and its effect on SSc fibrosis in vitro and in vivo, in order to provide new ideas for finding the pathway of fibroblasts regulation by CD4+T cells and new targets for the treatment of this disease.