SDF-1/CXCR7信号轴对角膜新生血管的作用及其机制的研究

Corneal neovascularization (CorNV) is a sight-threatening condition. Although the mechanism of CorNV has not been clear yet, angiogenesis occurs in tissue when the balance between angiogenic and anti-angiogenic factors is tilted towards angiogenic molecules. Chemokines, a large family of inflammatory cytokines, have been shown to play a critical role in the regulation of angiogenesis during several pathophysiologic processes.. The stromal-derived factor 1 (SDF-1/CXCL12) is a CXC chemokine which was thought to bind exclusively to CXCR4 for many years. It has been found that SDF-1/CXCR4 is involved in the pathogenesis of CorNV. However, recent studies showed that SDF-1 binds to an additional chemokine receptor, CXCR7. In our pilot study, we found that the expression of CXCR7 was increased in alkali bruned corneal tissue besides CXCR4. Then, we subconjunctivally administered TC14012, a CXCR7 agonist and CXCR4 antagonist. It showed that TC14012 initially enhanced alkali burn-induced CorNV, suggesting that CXCR7 is also involved in the pathogenesis of CorNV.. Thus, in the present study, we will assess the role of SDF-1/CXCR7 in alkali burn-induced CorNV, explore the signaling pathway of CXCR7, and investigate the effect of the inhibition of CXCR7 on CorNV in vitro and in vivo. The results might help us to understand the mechanism of SDF-1/CXCR7 in CorNV, which might provide us a new clue to study CorNV and another potential treatment target molecule for CorNV.

角膜新生血管(CorNV)是一种严重危害视功能的症状体征。以往研究表明趋化因子SDF-1/CXCR4信号轴参与了角膜新生血管的调控。但新近发现SDF-1还存在另一个特异性受体--CXCR7。有关后者在角膜血管新生中的作用及其分子机制目前知之甚少。前期我们发现CXCR7在小鼠碱烧伤角膜组织中表达显著增加, 局部应用CXCR7激动剂TC14012可促进碱烧伤后早期角膜新生血管的生长，故推测CXCR7也参与了角膜新生血管的调控。本项目拟以小鼠角膜碱烧伤及人脐静脉内皮细胞为模型，进一步明确SDF-1/CXCR7轴在角膜新生血管形成中的作用,挖掘其促血管作用的下游靶基因及相关信号通路,探讨干预SDF-1/CXCR7轴抑制角膜新生血管的可能性。上述研究将有助于揭示角膜新生血管形成的新机制,为角膜新生血管的临床治疗提供新的分子靶点。

角膜新生血管（CorNV）是一种严重危害视功能的症状体征。以往研究表明趋化因子SDF -1/CXCR4信号轴参与了角膜新生血管的调控。但新近发现SDF-1还存在另一个特异性受体——CXCR7。有关后者在角膜血管新生中的作用及其分子机制目前知之甚少。前期我们发现CXCR7在小鼠碱烧伤角膜组织中表达显著增加, 局部应用CXCR7激动剂TC14012可促进碱烧伤后早期角膜新生血管的生长，故推测CXCR7也参与了角膜新生血管的调控。.本项目以人脐静脉内皮细胞为模型，研究了SDF-1/CXCR7周对脐静脉内皮细胞增殖、凋亡、迁移、成管、内皮细胞间质化等作用，并探索了SDF-1/CXCR7可能的信号通路。研究发现，抑制CXCR7的表达，可抑制SDF-1诱导的脐静脉内皮细胞的增殖，而CXCR7高表达可加强SDF-1诱导的细胞增殖。SDF-1可以抑制细胞凋亡，抑制CXCR7的表达，可减弱SDF-1的抗细胞凋亡作用，CXCR7高表达则可以进一步抑制细胞凋亡。另外，抑制CXCR7可以抑制SDF-1诱导的细胞迁移及成管，高表达可以促使细胞迁移及成管。在相关信号通路的研究中我们发现，抑制CXCR7表达，磷酸化的ERK和AKT均降低，而高表达CXCR7后，磷酸化的ERK和AKT也随之增加。但相反的，抑制CXCR7的表达后，β-catenin的表达增高，而高表达CXCR7后，β-catenin表达下降，且Wnt/β-catenin的下游分子c-Myc, survivin和CyclinD1也符合这种变化趋势。虽然Wnt/β-catenin对角膜新生血管有一定作用，但文献也表示抑制Wnt/β-catenin通路可抑制内皮细胞间质化。于是我们研究了CXCR7对内皮细胞间质化的作用。我们发现，抑制CXCR7，可使α-SMA的表达增高，细胞形态也从圆形、短梭形趋于向长梭形转变。而过表达的CXCR7可以抑制α-SMA的表达。这提示了CXCR7可能是血管新生过程中的调节因子，在血管新生的过程中启动了抗纤维化，CXCR7在一些血管新生类疾病中的高表达也可能是机体的一种保护性的反馈机制。这为角膜血管新生、伤口愈合等病理生理过程提供了一种新的思路。该结论仍需体内实验进一步验证。