RA因其发病机制复杂，阻断TNF或IL-6等单一通路皆有约1/3患者疗效不佳。新近发现VGLL3能直接调控IL-7、ICAM-1、BAFF、MMP-9、Ets-1等靶基因的表达，既往研究表明这些靶基因的产物参与RA的发病机制，提示下调VGLL3将可抑制IL-7、ICAM-1、MMP-9、Ets-1的表达，从而达到一石多鸟地治疗RA。我们拟采用免疫组化和免疫印迹证明RA滑膜表达VGLL3，致炎因子可上调其表达；采用定量PCR、流式细胞术、免疫印迹、ELISA，在培养的滑膜成纤维细胞中，阐明siRNA抑制VGLL3表达可减低IL-7、ICAM-1、MMP-9表达；VGLL3过表达可增高它们的表达。并阐明细胞内转导机制。为抗VGLL3抗体治疗RA提供初步依据。

Because of complicated pathophysiology, blocking a single pathway such as IL-1 and TNF will be ineffective or poorly effective in about one-third of patients with rheumatoid arthritis (RA). Recently, it is found that VGLL3 (Vestigial-like 3) regulates the expression of IL-7, ICAM-1, BAFF, MMP-9 and Ets-1, all of which were demonstrated to play important roles in the pathophysiology of RA. These data suggest that knockdown VGLL3 will inhibit the expression of IL-7, ICAM-1, BAFF, MMP-9 and Ets-1, and then block multiple pathways to treat RA. We will study the expression of VGLL3 in RA synovial tissues and modulatory effects of pro-inflammatory factors on the expression level of VGLL3 with immunohistochemistry staining and Western blotting. In cultured synovial fibroblasts, it will be elucidated whether knockdown VGLL3 inhibits the expression of IL-7, ICAM-1, BAFF, MMP-9 and Ets-1, whereas VGLL3 overexpression enhances the expression of IL-7, ICAM-1, BAFF and MMP-9 with quantitative PCR, flow cytometric analysis, Western blotting and ELISA. The intracellular signal transduction pathways will be studied. The results derived from the present studies will provide the preliminary evidences for neutralizing anti-VGLL3 antibodies to treat rheumatoid arthritis.