干扰素诱导蛋白16通过转录调控CTGF表达影响类风湿性关节炎疾病进程的分子机制研究

申请人前期发现结缔组织生长因子（CTGF）通过促进滑膜细胞过度增殖生成侵蚀性血管翳损伤软骨加速类风湿性关节炎（RA）疾病进程，队列研究证实其对RA具有优良诊断价值，结果发表在ARD，AR和ART等杂志上。CTGF转录调控机制研究发现干扰素诱导蛋白16（IFI16）可以与CTGF启动子结合。IFI16蛋白属于PYHIN家族是一种胞内外源DNA传感器，具有潜在转录因子功能。本项目在明确IFI16在RA血清，滑液和滑膜表达上调的基础上，通过单细胞测序，细胞水平和动物水平实验研究IFI16蛋白通过调节免疫平衡，炎症反应和血管翳生成促进RA疾病进程的分子机制；明确IFI16蛋白识别和结合的CTGF启动子序列及转录调控机制；开展多中心回顾性和前瞻性队列研究明确IFI16对RA的临床诊断意义。该研究为IFI16蛋白作为生物标志物用于RA临床诊断及作为药物干预靶点用于抗风湿病药物研发打下坚实的理论基础。

With the aid of NSFC, we found that connective tissue growth factor (CTGF) could accelerate the progression of rheumatoid arthritis (RA) by promoting the proliferation of synovial cells to produce aggressive pannus, which was of good diagnostic biomarker for RA. The results were published in ARD, AR, ART and other journals. Studies on the transcriptional regulation mechanism of CTGF have found that interferon-induced protein 16 (IFI16) can bind to CTGF promoter. IFI16 protein belongs to PYHIN family and is an DNA sensor with potential transcription factor function. On the basis of previous findings that IFI16 was up-regulated in RA serum, this study will investigate the molecular mechanism of IFI16 protein promoting RA disease progression by regulating pannus formation, inflammatory response and immune balance through in vitro and in vivo experiments. Clarify the CTGF promoter sequence bound by IFI16 protein and its transcriptional regulation mechanism. A multicenter retrospective and prospective cohort study will be conducted to clarify the significance of IFI16 in the clinical diagnosis of RA. This study lays a solid theoretical foundation for the application of IFI16 protein as a biomarker in the clinical diagnosis of RA and the development of anti-rheumatic drugs as a drug intervention target.