神经激肽受体是一种 G 蛋白偶联受体，参与哺乳动物多种生理活性调节。研究表明，神经激肽受体高表达与一些肿瘤发展密切相关，但分子机制尚不明确。申请者前期研究结果显示，白血病患者白细胞中神经激肽受体的表达明显上调，靶向阻断神经激肽受体能显著抑制多种白血病细胞增殖，诱导细胞凋亡。本项目拟在前期结果基础上，通过RNAi等方法确立神经激肽受体在白血病细胞生长过程中的功能；阐明靶向阻断神经激肽受体抑制白血病细胞生长的分子机制，筛选并鉴定相关靶点蛋白；利用白血病荷瘤裸鼠模型和Eμ-Myc白血病小鼠模型，研究靶向阻断神经激肽受体抗白血病的效应；分析白血病患者白细胞中神经激肽受体及靶点蛋白的表达与患者预后之间的关系。本项目的完成将为开发基于神经激肽受体的单克隆抗体或高选择性、低毒副作用的靶向治疗白血病的小分子药物提供基础实验数据支持。同时，本项目研究鉴定出的相关靶点蛋白有可能成为白血病诊治过程的新靶点。

Neurokinin receptors (NK1R and NK2R) are the members of G protein-coupled receptors family involved in the regulation of multiple physiological activities in mammals. In certain types of maligancies, the high expression levels of NK1R and NK2R have been shown to be closely related to tumor formation and progression, but the molecular mechanisms of their actions are unclear. Our previous studies have demonstrated that the expression levels of NK1R and NK2R in the circulated leukocytes of leukemia patients were markedly up-regulated, and targeting NK1R and NK2R significantly inhibited proliferation and induce apoptosis in a panel of leukemia cell lines. In this project, we will extend these data to characterize the functionsal roles of NK1R and NK2R in the growth of leukemia cells; to elucidate the molecular mechanisms of targeting NK1R and NK2R to suppress leukemia cell growth; to identify downstream molecules mediating NK1R and NK2R functions; to determine the inhibitory effects of targeting NK1R and NK2R on leukemia cell growth in vivo; as well as to investigate the relationship among the expression levels of NK1R and NK2R in the circulation and the survival rates and metastasis of leukemia patients. The studies proposed here will support to design NK1R and NK2R based targeting therapeutics including monoclonal antibodies and small molecular inhibitors with high selectivity and low toxic and side effects. Meanwhile, NK1R and NK2R downstream target proteins identified in our present project may become the novel targets for the diagnosis and treatment of leukemia.