基于活性小分子探针的原发性肝癌组织内蛋白酶表达谱的研究

项目名称： 基于活性小分子探针的原发性肝癌组织内蛋白酶表达谱的研究

项目编号： No.21472172

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 沈蔚

作者单位： 浙江大学

项目金额： 80万元

中文摘要： 肝癌是全球发病率最高的恶性肿瘤之一，蛋白酶在其发生、发展展过程中具有极为重要的作用。利用活性探针技术从蛋白酶中寻找肝癌新的标志物和治疗靶点，是目前化学生物学及肿瘤学的一个研究热点。项目组成员在前期工作基础上，为拓宽活性探针的应用范围及提高探针的灵敏度，设计、构建一类由氨基苦杏仁酸、炔基及叠氮生物组成的活性小分子探针，通过酶催化反应、生物正交反应，揭示其标记蛋白酶的规律，获得人体肝癌组织完整的蛋白酶表达谱，阐明低表达及差异表达蛋白酶与肝癌的相关性，进而建立一种具有普适性的肿瘤组织蛋白酶表达谱研究的新方法。通过本项目的实施，有望发现肝癌特异性蛋白酶，从中找到新的肿瘤标志物和治疗靶点。研究成果不仅有助于深入探讨肝癌发生、发展和转移的机制，具有重要的理论意义；而且可为肝癌的早诊断、早发现、早治疗提供潜在的新靶点，有着显著地临床医学价值。

中文关键词： 化学生物学；小分子探针；原发性肝癌；蛋白酶；标志物

英文摘要： Primary liver carcinoma is one of the cancers with the highest incidence rate worldwide. The study on the new tumor marker, pathogenesis and target for anticancer therapy from low abundance proteins is one of the hottest topics in proteomics. Proteases play important roles in the generation, development, recurrence and progression of primary liver carcinoma. Unfortunately, the current proteomic technologies have the low sensitivity to low abundance proteins and differential proteins, and thus their roles in vicious transformation and dedifferentiation remain unclear. In this study, to improve the sensitivity and widen range of application of probes, a novel series of activity-based probes targeting four classes of proteases were designed based on the catalytic mechanism of proteases. The covalent bond between protease and probe enables the enrichment of the low abundance proteases. Therefore, this technology makes it possible to identify new differential expression proteins in tissues of primary liver carcinoma, and their functions in the generation, development, recurrence and progression of the cancer will be further discussed. These results may help discover new tumor makers and drug targets. In addition, these probes could be used to screen, isolate and identify biomarker for the other cancers, including breast cancer, lung cancer, prostate cancer and so on.

英文关键词： chemical biology;small molecular probe;liver cancer;protease;biomarker