膜结合蛋白LRRC4入核发挥转录因子功能的调控机制并参与神经元-胶质瘤细胞突触形成的作用研究

LRRC4是本课题组自主克隆的脑组织相对特异性表达基因，参与正常脑组织发育和胶质瘤的形成。课题组前期研究发现，LRRC4除了定位在细胞膜浆发挥胶质瘤抑瘤基因的功能外，还存在细胞核定位现象，但核内LRRC4发挥怎样的功能尚不清楚。结合前期工作基础，并辅以大量文献，我们提出科学假说：“核内LRRC4可能发挥转录因子的作用。LRRC4可能是一个内质网膜结合转录因子，通过未发生糖基化修饰的状态经逆转高尔基体以全长蛋白进入细胞核后，以单位点结合靶基因的远端调控元件或作为染色质环调控因子调控双位点结合靶基因发挥转录因子的作用。LRRC4可能通过多种形式转录调控胶质瘤细胞膜上的兴奋性突触受体复合物参与神经元和胶质瘤细胞之间的突触形成和传递，影响胶质瘤细胞的生长”。通过该科学假说的验证，不仅能扩展LRRC4基因的功能作用机制，而且还能为阐明胶质瘤的发生发展机制和治疗靶点的筛选提供实验依据和理论基础。

Our previous research indicated that LRRC4（Leucine-rich repeat containing-4，Genbank：AF196976） is a relative specific expressed gene in brain tissues, and also is a tumor suppressive gene for glioma. LRRC4 is involved in normal brain tissue development, and glioma initiation and development. Except for the membrane and cytoplasm location, LRRC4 is located in nucleus in multiple cells. LRRC4 has been widely studied as a signal molecule on cell membrane and cytopalsm, however, the function of LRRC4 in cell nucleus is not clear. Based on the previous work and a large number of references, we proposed the following scientific hypothesis, "LRRC4 may play a role as a transcription factor. LRRC4 may be an endoplasmic reticulum binding transcription factor. By deglycosylation modification status and reversing to Golgi apparatus, LRRC4 finally enter the nucleus. LRRC4 plays the role of transcription factor by binding the distal regulatory element of single site binding target gene or regulating the double site binding target gene as a chromatin loop regulator. Furthermore, LRRC4 may be involved in the synaptic formation and transmission between neurons and glioma cells and affect the initiation and progression of glioma cells by transcriptional regulating the excitatory synaptic receptor AMPAR complex on the cell membrane of glioma cells". This project will not only broaden the functional mechanism of LRRC4, but also provide experimental and theoretical foundation for elucidating the mechanism of glioma dprogression, and use for screening of therapy targets.