癌性疼痛的分子机制和治疗靶点研究：Hippo信号通路和YAP/TAZ转录因子核门控

癌痛对于中晚期癌症患者的生活乃至生命构成严重威胁。癌痛的发生发展机制仍然不清楚，临床缺乏有效治疗措施。阐明癌痛机制，探索有效的防治措施是重要而紧迫的科研和医疗任务。本研究首次探索在骨癌痛的发生发展中转录因子YAP/TAZ的细胞核门控机制和Hippo通路对YAP/TAZ在细胞浆和细胞核转运中的精准控制。综合运用分子生物学、免疫组织化学、电生理学、细胞内钙成像以及动物行为学等技术方法，对YAP/TAZ的胞浆-胞核转运及其调控机制Hippo通路、YAP/TAZ上游WNT信号通路和下游基因表达、膜离子通道、突触可塑性以及疼痛行为等进行系统深入研究，并筛选特异小分子化合物，为后续理论研究和癌痛临床治疗药物研发提供依据。申请者近年在包括JCI, Cancer Res, J Neurosci, Pain等核心期刊发表20余篇与本研究密切相关的高水平研究论文。本项目预期将取得国际水平的研究成果。

Treatment of cancer pain continues to be a major medical challenge. Mechanisms underlying cancer pain remain elusive and clinical approaches for the treatment of cancer pain are very limited. It is of theoretical significant and clinical urgent to better understand the mechanisms underlying cancer pain and exploring new potent methods for treating cancer pain. This research proposal is, for the first time, to investigate the nuclear gate-control of YAP/TAZ transcription and its precision regulation by Hippo pathway activation in cancer pain using bone cancer pain models in rats and mice. We will investigate the nuclear transportation of YAP/TAZ and the precision regulation of Hippo pathway on YAP/TAZ, as well as their upstream WNT signaling and the downstream pathways including new gene expression, membrane ion channels (Na+, K+, and Ca2+), nociceptive C-afferents-induced enhanced synaptic plasticity (the long-term-potentiation, LTP), as well as the behaviorally expressed painful syndromes due to the bone cancer, by means of combination of the advanced approaches of molecular biology, immunohistochemistry, electrophysiology, calcium imaging, and pain behavioral measurements. Then, based on the new findings, we will screen novel, potent small molecules, targeting on YAP/TAZ and/or Hippo pathway, for new drug research and development for treating cancer pain. Based on our solid research records in the fields of neuroscience and pain medicine, we believe that we will produce high quality research outcomes with global impact in the field with the strong support from NSFC.