外周组织和癌症中NMDA型谷氨酸受体对核内体转运的调控

谷氨酸受体的NMDA受体亚型（NMDAR）通过钙信号在中枢神经系统（CNS）中发挥关键作用。NMDAR也在外周组织中表达。然而，NMDAR在外周组织中的具体功能仍不清楚。我们最近的研究首次发现，NMDAR在人成纤维细胞中具有重要功能。NMDAR信号在成纤维细胞和其它几种细胞中调节核内体的结构，且此作用与其在乳腺癌细胞中的作用相反。据此我们假设：外周组织中NMDAR信号能够调节膜运输功能，并且这种调节功能的异常与癌症相关。本项目拟通过以下研究揭示外周组织中NMDAR介导的核内体膜转运功能及其细胞生物学机制：1) 采用成像技术检测成纤维细胞中NMDAR的组成和分布；2) 确定NMDAR信号对核内体转运的调控机制；3) 检测NMDAR信号介导的膜转运在癌细胞系中的作用。研究结果将揭示谷氨酸受体在外周组织中的生物学功能及其在癌症中的作用及机制。

Calcium signalling through NMDA-type glutamate receptors (NMDARs) plays a key role in the functioning of the central nervous system (CNS). NMDAR expression has also been detected in many other tissues of the body, where it has been linked to cancer; however, the exact function of NMDARs outside of the CNS remains unknown. Our recent data shows that NMDAR are functionally active in human primary fibroblasts. NMDAR signalling regulates the structure of endosomes in fibroblasts and several unrelated cell types; importantly, this regulation is inverted in a breast cancer cell line. These preliminary findings reveal regulation of membrane trafficking as a previously unknown general function of NMDAR signalling and suggest that aberrations in NMDAR-regulated membrane trafficking may be associated with cancer. This project intends to reveal the function of NMDAR-mediated endosomal membrane trafficking and its underlying mechanism in the peripheral tissues through the following studies: 1) detect the composition and distribution of NMDARs in fibroblasts by imaging technique; 2) determine the regulatory mechanism of NMDAR signal on endosomal membrane trafficking; 3) detect the role of NMDAR signaling-mediated membrane trafficking in cancer cell lines. The results of this investigation will establish a fundamentally new role for glutamate receptor signalling across the body in health and disease, and will generate new insight into mechanisms of cell signalling in cancer.