核糖核酸酶L：类风湿性关节炎发病的凋亡调控因子及雷公藤甲素治疗的新靶点？

慢性滑膜炎症("肿瘤样"增生）是类风湿关节炎(RA)的主要病理特征，细胞凋亡不足是其重要的发病机制。核糖核酸酶L（RNaseL）是近年发现的肿瘤细胞凋亡调控因子，最近我们发现RNaseL在RA滑膜表达显著降低，提示RNaseL在RA发病中的重要作用；研究证实促细胞凋亡是雷公藤甲素(TP)抗RA的重要机制，且TP调节细胞凋亡的作用点与RNaseL的调控点高度吻合，因此我们提出"RNaseL是TP促凋亡治疗RA的新靶点"的假说。本项目拟以RA和正常人滑膜组织、原代滑膜细胞及RNaseL基因敲除小鼠为研究对象，以RNaseL为切入点，分别从整体、细胞和分子水平验证RNaseL与RA细胞凋亡的关系，以及TP靶向RNaseL的促凋亡作用。本项目首次将RNaseL引入RA研究，结果将有助于阐释RA发病机制及TP抗RA机理，也将为基于细胞凋亡的抗RA治疗提供新靶点，并进一步丰富RNaseL的生物学作用。

Chronic synovitis,tumor-like hyperplasia, is the main pathological features of rheumatoid arthritis (RA)，insuffient apoptosis is one of the most important pathogenesises of RA.It is found that RNaseL is an important upstream regulatory factor of tumor cells apoptosis ,as well as RA synovium cells have the same proliferating feature like them.Forthemore, we find that RNaseL in RA synovium is at low level expression.In sum, RNaseL maybe a significant role in the pathogenesis of RA.The post reports and our prophase studies make sure that triptolide(TP) has exact anti-RA function which is induced by it's apoptosis promotion.Meanwhile, they share many targets between TP and RNase L.Therefore,we present the hypothesis that RNaseL is a new target of TP apoptosis promotion.In order to prove this hypothesis, we build a model of RNase L knockout mice with CIA and clinical people hip rheumatoid joint specimens and primary culture synovium cells , to find the correlation between RNaseL expression and RA cells apoptosis, and the regulation mechanism of TP to RNaseL expression in apoptosis promotion, from the whole, cell and molecular level respectively.In a word,the aim of our study is to provide experiment support for pathogenesises of RA and the protection mechanism of TP.Also we aim to find the new targets of anti-RA treatment based on apoptosis, and enrich the biological effects of RNase L.