申请者围绕两个重要临床问题：发现取代吗啡的镇痛药和逆转肿瘤靶向药耐药的增敏剂，开展了中药药效物质基础与作用机理研究，主要成果：1. 结合生化分离和多肽组学手段，构建了镇痛动物药东亚钳蝎多肽毒素资源库，发现了35条新型蝎毒素；建立了适合不同结构特点的多肽毒素制备方法；阐述了新型蝎毒素在镇痛与抗癌方面的用途；2.提出JAK/STAT3活化是肺癌分子靶向药获得性耐药的主要机制，发现了3种具有抑制JAK/STAT3途径的中药成分，并揭示了直接靶点。主持4项国家自然基金，发表SCI论文70篇；拥有授权专利13项；曾获江苏省杰青等项目资助。本项目拟测定新发现的蝎毒素与钠离子通道亚型的选择性作用，研究其与靶标相互作用，建立多肽毒素作用膜受体功能数据库；结合计算生物学与化学生物学方法研究蝎毒素活性中心,在原子水平阐明蝎毒素多肽结构和功能的关系。本项目为理解镇痛动物药毒素调制膜通道功能的共性与个性奠定基础。

The applicant’s study focuses on two important clinical problems: finding new drug to replace morphine and to overcome the resistance to EGFR-targeted therapies in cancer. The applicant carried out the study of mechanism of active components from herbs eight years ago. The main research results include: 1. Combining transcriptome and proteomics means, the applicant constructed East Asia scorpion polypeptide toxin peptide library, discovered 35 new scorpion toxins, established several high efficient expression system for toxins with different structural features, and illustrated the new potential uses in analgesia and anticancer. 2. The applicant found the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in EGFR mutant NSCLC where it plays important roles in drug resistance. The applicant also discovered three nature compounds from Chinese Medicine herbs could inhibit JAK-STAT3 pathway and demonstrated the direct protein target. The applicant has hosted four NSFC projects since 2006. As the corresponding author, the applicant has published 70 peer-review articles in international journals, has been authorized 13 international/national patents and selected as editorial board members of eight international journals. Additionally, the applicant was also supported by the Science Fund of Jiangsu Province for Distinguished Young Scholars. In this study, this project will illustrate the selective effects between scorpion toxin and sodium channel isoforms, and establish the function database of scorpion polypeptide toxin. With a multidisciplinary research approach, including polypeptide conformation analysis, total energy calculations, effective fragments exploration, point mutations and peptide synthesis, here the applicant will intend to explore the activity center of toxin and attempt to find out the structure-function relationship of toxin at atomic level by using electrophysiological and behavioral approaches, which would help us know more about the specific target. This project lays the foundation for the generality and individuality of understanding.