Modeling of wound repair and inflammation in the Drosophila embryo

伤口愈合是人体修复受损组织的过程，所有伤口都会愈合，无论是手指上的划痕，还是腹部手术后内脏的修复。在许多情况下，组织修复失败，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50万人患有这种疾病。同样，这个过程可能过于活跃，导致过度收缩、愈合和炎症导致纤维化和疤痕。为了理解组织修复是如何出错的以及如何改进，我们需要更好地理解这个过程，其中一种方法就是求助于一个非常简单的模型，果蝇。利用这种苍蝇，有可能拍摄活体动物伤口愈合的影像，并精确观察每个阶段单个细胞的作用。此外，果蝇的基因也非常简单，因此我们可以相对容易地确定哪些基因在修复过程的每个阶段的每个组成部分中起关键作用。我们已经证明，在伤口愈合的步骤和相关的炎症步骤中，白细胞被招募到伤口上，我们在苍蝇身上发现的大部分情况对老鼠和人都适用。在这里，我们建议使用果蝇来快速理解：皮肤细胞中的分子开关（包括伤口边缘和后面的细胞）如何对伤口信号做出反应，组装肌动球蛋白收缩电缆（就像肌肉一样），使细胞向前移动以愈合伤口。这些信号不仅是化学的，我们认为也是机械的，比如拉伸，我们对苍蝇的研究也会让我们研究这个。我们还想知道哪些基因在伤口边缘细胞中被激活是最重要的，以及哪些步骤使它们被激活。这一基本知识将为设计潜在的治疗方法提供线索，以“启动”患有慢性、不愈合伤口的患者的愈合。什么信号将白细胞吸引到伤口上？白细胞是如何感知这些信号的？由于白细胞是用来处理伤口感染的我们想观察它们是如何做到这一点的，同时也想确定是什么迫使它们在愈合完成后离开伤口部位，因为许多人类疾病都是炎症无法消退的结果。能够人为地调节患者的炎症反应将使我们能够防止伤口部位炎症的一些负面后果，包括纤维化。苍蝇为实现这一目标提供了迈出第一步的机会。因为我们是在生命周期很短的苍蝇身上做这些实验，它们的基因非常强大，我们可以比在任何其他模式生物身上更快地找到这些问题的答案，但重要的是把我们在苍蝇身上发现的东西应用到更多的临床相关模型上。这一重要步骤对我们来说相当容易，因为我们的一个实验室也在研究斑马鱼和老鼠的脊椎动物伤口愈合模型，并与卡迪夫的一个小组进行临床合作，该小组有一个处理人类患者样本的伤口愈合诊所。

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 one way to do this is by turning to a very simple model, the fruitfly, Drosophila. Using the fly it is possible to make movies of healing wounds in living animals and observe precisely how individual cells are involved at every stage. Moreover, Drosophila also have hugely simpler genetics so we can relatively easily determine which genes are pivotal in each component of each stage of the repair process. We have already shown that for the wound closure step and for the associated inflammatory step where white blood cells are recruited to the wound, much of what we find in flies holds true for mice and man. Here we propose using Drosophila to gain a fast track understanding of:1. How molecular switches in skin cells (both those at the wound edge and the ones further back), respond to the wound signals to assemble the actomyosin contractile cables (just like in muscle) that move the cells forward to heal the wound. These signals will not only be chemical but we think also mechanical, like stretch, and our studies in fly will let us investigate this too. We also want to know which of the genes that are switched on in the wound edge cells are most important, and what the steps are that enable them to be switched on. This fundamental knowledge will lend clues when designing potential therapeutics to "kick start" healing in patients suffering from chronic, non-healing wounds.2. What signals draw white blood cells to the wound and how do they sense these signals? Since the white blood cells are there to deal with wound infection we want to watch how they do this and also to determine what it is that forces them to leave the wound site when healing is complete because many human pathologies are a consequence of inflammation failing to resolve. Being able to artificially modulate the inflammatory response in patients would enable us to prevent some of the negative consequences of inflammation at wound sites including fibrosis. The fly offers a chance to take the first steps in achieving this goal.Because we are doing all these experiments in flies which have a very short lifecycle and very powerful genetics, we can find answers to these questions much faster than would be possible in any other model organism, but it will be important to take what we discover in flies and apply it to more clinically relevant models. This important step is made considerably easier for us since one of our labs also works on vertebrate wound healing models in zebrafish and mouse and has clinical collaborations too with a group in Cardiff that have a wound healing clinic dealing with human patient samples.