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

研究 Eph 受体和肝配蛋白在伤口修复和炎症过程中的功能和治疗潜力

• 批准号: G0901822/1
• 负责人: Paul Martin
• 金额: $ 74.3万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901822%2F1
• 关键词: Investigating; functions; therapeutic; potential; Eph

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.

伤口愈合是身体修复受损组织的过程，适用于所有伤口，无论是手指割伤还是腹部手术后内脏器官的修复。在许多情况下，组织修复失败，导致慢性不愈合伤口，例如静脉性腿部溃疡，这对老年患者来说是一个巨大的临床负担，在英国约有 50 万人遭受这种痛苦。同样，这个过程可能过于激烈，导致过度收缩、愈合和炎症导致纤维化和疤痕。为了了解组织修复如何出错以及如何改进它，我们需要更好地了解这个过程，本质上这意味着弄清楚未受伤的皮肤（或其他器官）的休眠组织如何在受损时被唤醒，使它们能够迁移并填充伤口产生的间隙，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和与它们结合的蛋白质，即 Ephs 和 ephrins，尽管在胚胎发育和癌症方面得到了很好的研究，并且与调节“启动和停止”有关。之前尚未在伤口修复过程中研究过这两种情况下细胞迁移的情况。我们在小鼠身上获得了初步数据，显示了在伤口闭合过程中，这个受体大家族的几个成员如何在特定细胞类型中表达和激活，这些方式表明它们是关键参与者，我们将看看在人类伤口组织中是否也是如此，以及病理性伤口（特别是长期腿部溃疡）的活检是否具有这些受体模式的改变。然后，我们将测试调节特定的 Eph 家族成员是否能让我们改变和改善治疗的某些方面，同时不影响其他方面，以期设计出既可以“启动”又可以“启动”的疗法。使未愈合伤口的组织自我修复，或关闭发炎过度和/或过度旺盛并可能形成严重疤痕的伤口中的修复机制。