基于Integrinβ1/FAK/MAPK通路研究Sema7A对角膜上皮损伤修复的调控作用

角膜上皮细胞的粘附、移行、增殖及屏障功能恢复在角膜损伤修复中起着至关重要的作用。任何环节功能异常，均可致上皮损伤迁延不愈，引起角膜溃疡甚至穿孔。而目前临床药物作用单一，导致治疗效果不佳。预实验发现，角膜损伤修复时，信号素（Sema）7A在上皮细胞中表达增加，并促进其移行及屏障功能形成，提示Sema7A很可能是角膜损伤治疗的有效靶点。进一步发现Sema7A可激活FAK/MAPK通路，而Integrinβ1为其主要受体。故推测，Sema7A可通过激活Integrinβ1/FAK/MAPK通路多靶点促进角膜上皮损伤修复。为此，本项目利用难治性角膜上皮损伤动物模型、Sema7A基因敲除小鼠探讨Sema7A治疗角膜上皮延迟愈合的有效性；并通过沉默角膜上皮细胞中Integrinβ1、FAK基因、阻断MAPK通路，明晰Sema7A调控角膜上皮损伤修复的分子机制，为角膜损伤相关疾病的临床治疗提供新视角。

The adhesion, migration, proliferation of corneal epithelial cells and the maintenance of barrier function make important roles during the process of corneal wound healing. The dysfunction of any step can lead to delayed wound healing of corneal epithelia, which result in stromal ulceration and corneal perforation. Current agents tend to be unsatisfactory due to the limited effect. In our previous studies, we demonstrated that the expression of semaphorin 7A (Sema7A) was increased markedly in basal cells of the newly healed corneal epithelia. In addition, Sema7A was able to accelerate the migration of human corneal epithelial cells (HCECs) and promote barrier function formation of these cells. These results indicate that Sema7A can be a potential molecule for corneal injury treatment. We further found that Sema7A was able to activate the phosphorylation of FAK and MAPK. It is reported that integrinβ1 is one of major receptors of Sema7A. Based on these findings, we hypothesize that Sema7A can promote corneal epithelial wound healing in a multi-target way by activating integrinβ1/FAK/MAPK pathway. To test our hypothesis, we will investigate the effectiveness of Sema7A as a potential drug to treat delayed epithelial wound healing using animal models with refractory corneal epithelium injury and Sema7A knockout mice. We will further clarify the molecular mechanism of epithelial wound healing regulated by Sema7A by silencing integrinβ1 and FAK gene or blocking MAPK pathway in HCECs. This project will provide a new perspective for the development of new treatment for various corneal wound in clinics.