我们前期工作发现黄芪酸性多糖能有效抑制多聚谷氨酰胺在人细胞和模式生物秀丽线虫内的聚集及神经毒性，同时还能延长多种亨廷顿疾病秀丽线虫模型的寿命。进一步研究显示，黄芪酸性多糖的这种作用与胰岛素信号通路下游的DAF-16/FOXO转录因直接相关但并不依赖上游的DAF-2/IGF-1R和AGE-1/PI3K。由于DAF-16是多个寿命和应激信号通路的重要整合因子，本项目拟在此基础上利用各种秀丽线虫转基因和突变模型，采用定量PCR、免疫印迹、RNA干扰等手段，探讨黄芪酸性多糖通过AMPK、MAPK和SIR-2等上游交叉信号通路以及端粒长短和端粒酶活性调控DAF-16从而延缓衰老和抑制蛋白聚集毒性的分子机理，为开发多糖类神经保护和神经退行性疾病药物提供药效物质理论基础，并进一步推动秀丽线虫模型在中药研发领域的应用。

We have recently demonstrated that the acidic polysaccharide from Astragalus membranaceus (astragalan) is able to modulate aging and proteotoxic stress pathways in both human cells and C. elegans models. Astragalan not only reduces polyglutamine (polyQ) aggregation but also alleviates the associated neurotoxicity. It can also extend the adult lifespan of wild-type and polyQ C. elegans. Interestingly, although the effect of astragalan is independent of DAF-2/IGF-1R and AGE-1/IP3K but dependent on the DAF-16/FOXO transcription factor, a pivotal integrator of divergent signaling pathways related to both lifespan regulation and stress resistance. In this study we aim to examine the effect of other signaling cascades, such as AMPK, MAPK and SIR-2, as well as telomere and telomerase, upstream to DAF-16 on the neurotoxicity-suppressing and lifespan-extending activities of astragalan. Theses pathways will be explored in a range of transgenic and mutant C. elegans models using real-time PCR, Western and Southern blotting, RNAi and other molecular techniques. Revelation of the mechanism of action of astragalan will provide an important insight into the potential of polysaccharides and other glycotherapeutics in the prevention of proteotoxic disorders and promote more applications of the model animal C. elegans in the studies of traditional Chinese medicine.