Hippo信号转导通路同癌症的发生发展密切相关。作为主要研究人员，申请人发现了首个调节Hippo通路的生理信号，并表明Hippo通路是GPCR信号的重要下游分支（Cell，2012年最佳Cell论文，Science Signaling年度突破）。申请人的研究也揭示了Hippo通路在葡萄膜黑色素瘤等癌症发病过程中的重要性（Cancer Cell，2014）。同时，申请人还发现多个小分子药物可以调节Hippo通路的活性并影响其生物学功能（Genes Dev，2013；Cell Res，2015）。这些成果显著地推动了Hippo研究领域的发展。在本项目中，申请人将立足于前期工作基础，深入研究GPCR信号调节Hippo通路的分子机制，并以斯特奇-韦伯综合征和髓母细胞瘤为例，系统研究Hippo通路在GPCR信号紊乱致癌过程中的作用，为探索癌症的病理机制及研发分子靶向疗法提供理论和实验基础。

The Hippo signaling pathway is critical in regulating tissue homeostasis and organ size in multicellular organisms，and its dysregulation often results in tumorigenesis. Previously, the applicant has discovered, for the first time, physiological hormones regulating the Hippo pathway, and positioned the Hippo pathway as a downstream branch of the GPCR signaling (Cell 2012; Best of Cell 2012, Science Signaling breakthrough of the year). The applicant has also demonstrated a crucial function of the Hippo pathway in the development of uveal melanoma and kaposi's sarcoma (Cancer Cell, 2014；Oncogene 2015). In addition, the applicant has identified multiple small molecules which can effectively modulate the Hippo pathway activity (Genes Dev, 2013；Cell Res 2015). These discoveries have greatly improved our understanding about the Hippo pathway regulation and its pathological functions. In this project, the applicant will further study molecular mechanisms underlying Hippo pathway regulation by GPCR signaling, and by using Sturge-Weber Syndrome and Medulloblastoma as examples, investigate the importance of the Hippo pathway in cancers driven by aberrant GPCR signaling. These studies will provide not only insights about cancer pathogenesis, but also basis of molecular targeted therapyies for relevant cancers.