骨肉瘤是原发性骨肿瘤中发病率最高的恶性肿瘤。转移后的骨肉瘤病人生存率显著下降，因此，了解骨肉瘤发生和转移的分子机制并进一步进行靶向药物研究十分迫切。申请人从具有黏附结构域的黏附G蛋白偶联受体（adhesion GPCR）家族入手，通过表达和功能筛选，发现黏附GPCR家族成员CELSR2能在体内和体外调控骨肉瘤迁移和转移。基于这些工作基础，本项目将利用多种骨肉瘤小鼠模型，结合体外细胞模型，研究CELSR2在骨肉瘤发生、发展和转移中的功能和分子机理。特别是针对黏附GPCR的特点，利用CRISPR/CAS基因编辑技术构建CELSR2胞外各个黏附结构域突变小鼠模型和细胞模型，阐释该结构域调控骨肉瘤发生发展和转移过程，以及深刻解析其分子机理。并进一步结合临床肿瘤病例分析，揭示CELSR2在骨肉瘤中的作用，并基于这些基础研究开发靶向CELSR2或其信号通路的先导化合物，以期为骨肉瘤的防治提供靶向药物。

Osteosarcoma is the highest incidence of malignant tumors in primary bone tumors. The survival rate of metastatic osteosarcoma patients is significantly reduced, therefore, to understand the molecular mechanism of osteosarcoma metastasis and further to find the drug target is very urgent. From the adherent GPCR family with adherent domains, the CELSR2, a member of the adherent GPCR family, was able to regulate osteosarcoma in vivo and in vitro by expression and functional screening. Based on these working methods, the project will apply a variety of osteosarcoma mouse models in vivo and cell models in vitro to study the function and molecular mechanism of CELSR2 in osteosarcoma occurrence, development and metastasis. To understand domains’ function and mechanism in CELSR2, CRISPR/CAS gene editing technique was used to construct the mutant mouse model and cell model. Based on these basic studies and clinical tumor tissue analysis, lead compounds targeting CELSR2 or its signaling pathways will be screened and developed for prevention and treatment of osteosarcoma.