药物效应与其作用机制、药效毒性密切相关，生物组织中药物效应分子的原位检测，尤其是对不同微区间的差异性表征存在挑战。本项目采用空气动力辅助离子化质谱成像原位代谢组学分析技术，以对照药紫杉醇及其药效相当但毒性低的衍生物（经与肿瘤密切相关的内源性代谢物取代获得）为探针，旨在建立针对主要脏器及肿瘤组织不同微区中的药物效应分子的原位检测方法；建立光学特征图与质谱成像图匹配算法，进行微区药物效应相关的代谢特征信息精准提取，结合多变量统计分析与生物信息学，发现药物效应特异性小分子及其在组织不同微区间的差异性；进一步对效应分子进行代谢通路分析，采用分子生物学技术，将其上游代谢相关的酶及mRNA进行原位表征，并将各自的分布特征进行匹配关联与相互验证，从代谢组→靶向蛋白质组→靶向转录组层次实现“自下而上”的药物效应分析，为候选新药的靶标发现、药效、毒性早期预测与评价研究提供线索和新思路。

Drug effect and toxicity are closely related to their mechanism of action. Currently, in situ detection of drug effect in the biological tissues, especially characterization of the differences between micro-regions is still challenging. This project aims to develop a method of analyzing in-vivo drug effect on the different micro-regions of the main organs and tumor tissues using an in situ metabolomics based on air flow-assisted ionization mass spectrometry imaging (AFAI-MSI), and the control drug paclitaxel (Taxol-I) and its derivatives (Taxol-R, synthetized by the substituting an tumors related endogenous metabolite) with comparable efficacy and low toxicity used as probes. An algorithm of matching the optical feature maps and ion images will also be constructed to accurately extract massive metabolic characteristics of drug effect in micro-regions. With the combination of multivariate statistical analysis and bioinformatics, our study will gain more insights into the molecular level of the pharmacodynamic differences. Based on the analyzing metabolic pathway of effector molecules, the upstream metabolism related enzymes and mRNA and their distributuion will be further characterized and verified by tranditional molecular biology techniques. Therefore a "bottom-up" stratigy for drug effect analysis can be realized from the metabonomics to the proteomics and transcriptomics, which will offer the basis to the target discovery, efficacy and toxicity prediction of candidate drugs.