耐药是肿瘤治疗难及预后差的关键因素之一，目前仍无良策，亟待致病机理及药物研究的理论突破与原始创新。本团队前期发现，AKR1C3及其家族成员与多类肿瘤的耐药形成密切相关，并可导致伊马替尼、甲氨蝶呤等多种一线化疗药物耐药，其机制尚未明了。深入阐明AKR1C3及其家族成员介导耐药形成的分子机制，探索全新的药物治疗靶标，有望成为逆转肿瘤耐药的全新策略，具有重大科研价值。本团队在天然药物机制探究方面基础深厚，我们发现，千层纸素和汉黄芩素具有逆转耐药作用，机制可能与抑制AKR1C3活性有关。本项目基于上述发现，综合运用分子生物学、药理学、药物化学等先进的理念及技术，全面研究AKR1C3及其家族成员与CXCL12/CXCR7生物轴、膜转运蛋白、P450酶和Spry2泛素化等环节的关联，开展靶标发现与确证研究，构建活性分子筛选体系及分子机制研究平台，为后续临床药物的研究提供理论基础和物质基础。

Drug resistance is one of the key factors for refractory treatment and poor prognosis of tumors. Because of few potent therapeutic regimens, it is urgent to make theoretical breakthroughs and innovations for understanding the pathogenesis and drug research. The previous researches of our team find that AKR1C3 and its other family members are tightly associated with chemoresistance for many tumors, which causes tumors resistant to many first-line medications including Imatinib, methotrexate, etc., but the underlying mechanisms remain unclear. Therefore, it is of great scientific significance to further clarify the molecular mechanisms of chemoresistance induced by AKR1C3 and its other family members, and to explore the brand new targets for drug treatment, which is hopeful to be a new strategy for overcoming chemoresistance. Our team is quite experienced in exploring the mechanisms of natural products and we have confirmed that both Oroxylin A and Wogonin can overcome chemoresistance, which might be related with inhibition of AKR1C3 activity. Based on above findings, this project, employing molecular biology, pharmacology, pharmacochemistry and other advanced ideas and technologies, aims at comprehensively studying the relationships of AKR1C3 and its other family members with CXCL12/CXCR7 axis, cell membrane transporters, P450 enzyme and Spry2 ubiquitylation, and conducting researches on target discovery and confirmation, along with setting up systems for screening active molecules and platforms for studying molecular mechanisms , so as to provide theoretical and material bases for the clinical drug researches in the future.