溶酶体的生成及稳态对细胞的正常生理功能十分重要，其功能紊乱可导致溶酶体贮积症（LSDs）和神经退行性疾病。溶酶体的生成机制复杂，促溶酶体生成的天然产物可为解析该复杂机制提供工具箱，亦可为LSDs的治疗发展药物先导。前期研究我们筛选aspidosperma-eburnea类吲哚生物碱库，发现了生物碱mekongenine B能特异诱导TFE3入核进而促进溶酶体生成；还发现了该类生物碱的新资源—夹竹桃科山橙族植物。本申请项目将深入开展mekongenine B特异诱导TFE3入核促进溶酶体生成的作用机制研究；运用植物化学-化学合成手段定向获取该类生物碱，探讨其促进溶酶体生成的构效关系。本申请项目可望不仅揭示溶酶体生成的新机制，而且为抗LSDs的潜在新药靶标TFE3的发展及其先导药物的发现奠定基础。

Lysosome biogenesis and homeostasis are vital for cellular processes. Lysosome dysfunction causes Lysosome Storage Diseases (LSDs) and neurodegenerative disorders. The mechanisms of lysosome biogenesis are sophisticated. The natural products having lysosome biogenesis-inducing activity could provide toolbox for deciphering these complicated mechanisms as well as provide lead compounds for the drug development for the therapy of LSDs. Our previous studies revealed that mekongenine B, an aspidosperma-eburnea-type indole alkaloid, could regulate lysosome biogenesis through specifically inducing the nuclear translocation of TFE3. Moreover, the plants of Melodineae (Apocynaceae family) were identified as a new resource for this type of alkaloids. This project is focused on identification of the mechanism of lysosome biogenesis-inducing action of mekongenine B through nuclear translocation and activation of TFE3. Besides, the lysosome biogenesis-inducing SARs of these alkaloids will be investigated on the basis of diversified structures by direct isolation and structural modifications. The results of this project will not only has the potential to identify the underlying mechanism of lysosome biogenesis but also will pave the way to the development of TFE3 as the promising drug target for LSDs, and the discovery of novel anti-LSDs drug leads of targeting TFE3.