Investigating the functions and therapeutic potential for Eph receptors and ephrins during wound repair and inflammation

伤口愈合是身体-S修复受损组织的过程，发生于所有的伤口，无论是手指的划痕还是腹部手术后内脏的修复。在许多情况下，组织修复失败会导致慢性无法愈合的伤口，如静脉性腿部溃疡，这是老年患者的巨大临床负担，在英国约有50万人遭受痛苦。同样，由于过度收缩、愈合和炎症，这一过程可能过于活跃，导致纤维化和疤痕形成。为了了解组织修复是如何出错以及如何改善的，我们需要更好地了解这一过程，本质上这意味着弄清楚未受损伤的皮肤(或其他器官)的休眠组织是如何在受损时被唤醒的，允许它们迁移并填补伤口造成的缺口，以及它们如何知道在伤口愈合时何时停止。这里概述的研究是调查一系列受体及其结合蛋白，Ephs和Ephins，尽管在胚胎发育和癌症中进行了很好的研究，并与调节启动和停止有关？在这两种情况下的细胞迁移，以前还没有在伤口修复过程中进行研究。我们在小鼠身上的初步数据显示，在伤口闭合过程中，这个受体大家族的几个成员如何在特定的细胞类型中表达和激活，这表明它们是关键参与者，我们将研究在人类伤口组织中是否如此，以及来自病理性伤口的活检组织，特别是长期的腿部溃疡，是否改变了这些受体的模式。然后我们将测试调节特定的Eph家庭成员是否允许我们在不影响其他方面的情况下改变和改善康复的某些方面，以期设计出既可以启动？未愈合伤口的组织，用于自我修复或关闭过于发炎和/或过于旺盛并可能形成严重疤痕的伤口的修复机械。

Wound healing is the body?s process of repairing damaged tissue and takes place for all wounds, be they a nick to the finger or the repair of internal organs after abdominal surgery. There are many occasions when tissue repair fails, leading to chronic non-healing wounds such as venous leg ulcers which are a huge clinical burden for elderly patients and suffered by about 500,000 people in the UK. Equally, the process can be too exuberant leading to fibrosis and scarring as a consequence of excessive contraction, healing and inflammation. In order to understand how tissue repair goes awry and how it might be improved, we need to better understand the process, and essentially that means figuring out how the dormant tissues of unwounded skin (or other organs), are awakened upon damage, allowing them to migrate and fill the gap created by the wound, and how they know when to stop when the wound is healed.The studies outlined here are to investigate a family of receptors and the proteins that bind to them, the Ephs and ephrins, that, despite being very well studied in embryonic development and in cancer and implicated in regulating the ?starting and stopping? of cell migrations in both these scenarios, have not previously been studied in the wound repair process. We have preliminary data in mouse that shows how several members of this large family of receptors become expressed and activated in particular cell types during the wound closure process, in ways that are suggestive of their being key players, and we will look to see whether the same is true in human wound tissues and whether biopsies from pathological wounds, in particular longstanding leg ulcers, have an altered pattern of these receptors. We will then test whether modulating particular Eph family members will allow us to alter and improve some aspects of healing while not affecting others, with a view to designing therapies that can either ?kickstart? the tissues of a non-healing wound to repair itself or shut down the repair machinery in a wound that is too inflamed and/or too exuberant and likely to form a bad scar.