以YAP-TLRs通路为核心探讨复方血栓通效应成分群防治糖尿病视网膜病的构效关系与药理机制

糖尿病视网膜病（DR）是糖尿病最重要的微血管并发症之一，患病率高，危害大, 标志性病理特征是血管增生。复方血栓通作为国家保护品种，治疗糖尿病视网膜病效果显著，而且显著抑制血管增生，但是其药效物质与作用规律的科学阐释未取得突破性进展，严重限制其临床应用。Yes相关蛋白（YAP）作为转录辅助因子，是血管增生的核心病理机制。课题组证实复方血栓通发挥药效的关键环节是YAP。本课题计划精准解析复方血栓通积蓄于视网膜内皮细胞中的药源性成分，揭示复方血栓通的效应成分群；运用表面等离子体共振技术，计算效应成分与靶蛋白YAP的亲和力，揭示效应成分的构效关系；最后利用转录组学、基因编辑以及多种多层次的药效模型，以YAP-Toll样受体（TLRs）通路为核心，揭示效应成分群的药理机制。本课题将为揭示复方血栓通的物质基础与药理机制提供科学依据，为开发新颖的治疗DR及其他复杂疾病的药物奠定基础，具有重大的应用价值。

Diabetic retinopathy (DR) is one of the most important microvascular complications of diabetes mellitus, with a high prevalence and great harm. Its characteristic pathological feature is angiogenesis. Fufang xueshuantong (FXST) is one of the Protection of Varieties of Traditional Chinese Medicine, which can arrest the development of DR and inhibit angiogenesis. But there is no breakthrough in material basis and pharmacological mechanism in FXST, which retards its clinical use. Yap, a transcription cofactor, is the core pathological mechanism of angiogenesis. FXST exerted its effect by targeting YAP. This project will develop the mass spectrometry to accurately analyze the pharmaceutical components stored in the endothelial cells of the retina, and reveal the effective components of FXST. Then the surface plasmon resonance (SPR) technique will be used to calculate the affinity of the effective components and the target protein YAP, and the structure-activity relationship of those effective components will be clarified. Finally, the transcriptomics, the knock out technology, the cell culture and animal model will be integrated. The YAP-TLRs pathway will be stressed, and the molecular mechanism of FXST effective components will be clarified thoroughly. This project will provide scientific basis for revealing the material basis and pharmacological mechanism of FXST, and lay the foundation for the development of new drugs for DR and other diseases. This project has great scientific and social application value.