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

伤口愈合是身体吗？它是修复受损组织的过程，适用于所有伤口，无论是手指上的划痕还是腹部手术后的内脏修复。在许多情况下，组织修复失败，导致慢性不愈合伤口，如静脉性腿部溃疡，这对老年患者来说是一个巨大的临床负担，在英国约有50万人患有这种疾病。同样，该过程可能过于旺盛，导致纤维化和疤痕，作为过度收缩、愈合和炎症的结果。为了了解组织修复是如何出错的，以及如何改进，我们需要更好地了解这个过程，本质上这意味着要弄清楚未受伤皮肤的休眠组织是如何（或其他器官）在损伤时被唤醒，允许它们迁移并填充由伤口产生的差距，以及当伤口愈合时，它们如何知道何时停止。这里概述的研究是为了调查一个受体家族和与它们结合的蛋白质，Ephs和ephrin，尽管在胚胎发育和癌症中已经有了很好的研究，并且涉及到调节？开始和停止？在这两种情况下的细胞迁移，以前没有在伤口修复过程中进行过研究。我们在小鼠中获得的初步数据显示，在伤口闭合过程中，这个受体大家族的几个成员是如何在特定细胞类型中表达和激活的，其表达方式表明它们是关键参与者，我们将研究人类伤口组织是否也是如此，以及病理伤口的活检，特别是长期的腿部溃疡，是否改变了这些受体的模式。然后，我们将测试是否调节特定的Eph家族成员将允许我们改变和改善愈合的某些方面，而不影响其他方面，以期设计治疗，可以？kickstart？不愈合伤口的组织进行自我修复，或者关闭伤口中的修复机制，该修复机制过于发炎和/或过于旺盛，并且可能形成严重的疤痕。

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.