新型SDF-1α受体CXCR7促进神经干细胞的抗凋亡和生存

Neuroinflammation activates neurogenesis of neural stem cells in neural injury regions and pathological areas of neurodegenerative diseases. SDF-1, a chemokine, also known as CXCL12, is widely expressed in the central nervous system (CNS). It is critical for human neual progenitor cells (hNPCs) migration through its receptor CXCR4 . Recently, CXCR7 has been found binding to CXCL12 with higher affinity than CXCR4. However, CXCR7 is not a common G-protein receptor, but may recruit beta-arrestin2 after CXCL12 treatment. Little is known about the function of CXCR7 in hNPCs. In addition, CXCR4 ad CXCR7 may form a heterodimer. In this project, we will base on the our former study which demonstrates that SDF-1 rescues apoptosis induced by starvation and camptothecin(CAMP) through both CXCR4 and CXCR7. Furthermore, we hypothesize that CXCR7 may play an independent critical role in anti-apoptosis and survival. The interaction of CXCR4 and CXCR7 may have special function via SDF-1 for cell apoptosis and survival. The hypothesis also involves in recruitment of beta-arrestin2 at early endosome, and function of beta-arrestin 2 as a scaffold protein to activate phosphorylation of AKT and ERK.

神经系统炎症反应可激活病变部位和周围区域神经干细胞的神经再生。神经再生过程涉及到神经干细胞的生存，迁移和分化。SDF-1α结合CXCR4激活下游信号通路从而促进神经干细胞的生存和迁移。最近，对趋化因子SDF-1α的另一新型受体CXCR7的研究已成为热点，已有报道CXCR7影响神经干细胞的生存和迁移，并揭示CXCR7的作用与CXCR4密切相关。CXCR4和CXCR7在生理条件下可形成二聚体,提示受体之间的相互作用调节某种生理功能。我们将通过对CXCR7过表达，siCXCR7，CXCR4和CXCR7基因敲除鼠等技术的使用，阐明在SDF-1α介导下CXCR7对神经干细胞抗凋亡的作用；通过对SDF-1α介导的CXCR4/CXCR7相互作用的研究， 阐明CXCR7对SDF-1α/CXCR4通路的影响；并揭示CXCR7，作为一个非G蛋白依赖受体的生物学意义和应用的潜在价值。

自从2012年获得项目资助后，我们对微环境中重要的细胞因子，趋化因子CXCL12及其新型受体CXCR7进行研究。该研究已经衍生了7篇发表论文，2个专利，3篇待发表论文。既往研究涉及CXCL12/CXCR7功能和机制的多个方面，如对神经干细胞的抗凋亡，生存，迁移，血管再生等，这些工作揭示在疾病状态下细胞因子的调节作用，并提示了细胞保护，神经发育，神经修复方面的新作用靶点。在最近的研究过程中，特别关注高表达CXCR7在病理状态下（缺氧或创伤）的特征性及其意义，并利用肿瘤细胞作为工具，探索高表达CXCR7的细胞行为，微环境调节和潜在临床价值。尤其是2016年部分工作涉及高表达CXCR7对肿瘤细胞的影响，并初步开展了CXCL12在2D或3D条件下细胞之间相互关系的机制研究。