Modeling of wound repair and inflammation in the Drosophila embryo

果蝇胚胎伤口修复和炎症的建模

• 批准号: MR/J002577/1
• 负责人: Paul Martin
• 金额: $ 140.07万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ002577%2F1
• 关键词: Modeling; wound; repair; inflammation; Drosophila

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.

伤口愈合是身体修复受损组织的过程，发生在所有伤口上，无论是手指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善它，我们需要更好地理解这个过程，其中一种方法是转向一个非常简单的模型，果蝇。利用苍蝇，可以制作活体动物伤口愈合的电影，并精确观察单个细胞在每个阶段的参与情况。此外，果蝇的遗传学也非常简单，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。我们已经表明，对于伤口闭合步骤和相关的炎症步骤，其中白色血细胞被招募到伤口，我们在苍蝇中发现的大部分内容适用于小鼠和人。皮肤细胞中的分子开关（包括伤口边缘和更后面的细胞）如何响应伤口信号，组装肌动球蛋白收缩电缆（就像肌肉中的一样），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对此进行研究。我们还想知道在伤口边缘细胞中哪些基因被开启是最重要的，以及使它们被开启的步骤是什么。这些基础知识将为设计潜在的治疗方法提供线索，以“启动”慢性不愈合伤口患者的愈合。2.什么信号吸引白色血细胞到伤口，它们如何感知这些信号？由于白色血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，也想确定是什么迫使它们在愈合完成时离开伤口部位，因为许多人类病理是炎症未能解决的结果。能够人工调节患者的炎症反应将使我们能够预防伤口部位炎症的一些负面后果，包括纤维化。果蝇为实现这一目标提供了第一步的机会，因为我们在果蝇中进行的所有这些实验都具有非常短的生命周期和非常强大的遗传学，我们可以比任何其他模式生物更快地找到这些问题的答案，但重要的是将我们在果蝇中发现的应用于更临床相关的模型。这一重要步骤对我们来说变得相当容易，因为我们的一个实验室也在斑马鱼和小鼠的脊椎动物伤口愈合模型上工作，并且与卡迪夫的一个小组也有临床合作，该小组有一个处理人类患者样本的伤口愈合诊所。

项目成果

Cell migration by swimming: Drosophila adipocytes as a new in vivo model of adhesion-independent motility.

• DOI: 10.1016/j.semcdb.2019.11.009
• 发表时间: 2019-12
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Paul Martin;Will Wood;Anna Franz

Recapitulation of morphogenetic cell shape changes enables wound re-epithelialisation.

• DOI: 10.1242/dev.107045
• 发表时间: 2014-05
• 期刊: Development (Cambridge, England)
• 作者: Razzell W;Wood W;Martin P
• 通讯作者: Martin P

Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release.

• DOI: 10.1016/j.cub.2013.01.058
• 发表时间: 2013-03-04
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Razzell, William;Evans, Iwan Robert;Martin, Paul;Wood, Will
• 通讯作者: Wood, Will

Fat Body Cells Are Motile and Actively Migrate to Wounds to Drive Repair and Prevent Infection.

脂肪体细胞是运动的，并积极迁移到伤口以驱动修复并防止感染。

• DOI: 10.1016/j.devcel.2018.01.026
• 发表时间: 2018-02-26
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Franz A;Wood W;Martin P
• 通讯作者: Martin P

Wound repair and regeneration: mechanisms, signaling, and translation.

• DOI: 10.1126/scitranslmed.3009337
• 发表时间: 2014-12-03
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Eming SA;Martin P;Tomic-Canic M
• 通讯作者: Tomic-Canic M