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.

伤口愈合是人体修复受损组织的过程，并发生在所有伤口上，无论是手指的痕迹还是腹部手术后内部器官的修复。在许多情况下，组织修复发生故障，导致慢性非愈合伤口，例如静脉腿溃疡，这对老年患者来说是巨大的临床负担，在英国大约有50万人遭受了约50万人的痛苦。同样，由于收缩过度，愈合和炎症，该过程可能会导致纤维化和疤痕。为了了解组织修复的问题以及如何改进，我们需要更好地理解该过程，而做到这一点的一种方法是转向非常简单的模型，即果蝇果蝇。使用苍蝇，可以制作活动物中治愈伤口的电影，并准确地观察每个阶段单个细胞的参与。此外，果蝇还具有更简单的遗传学，因此我们可以相对轻松地确定修复过程每个阶段的每个组成部分中的哪些基因是关键的。我们已经表明，对于伤口闭合步骤，对于将白细胞招募到伤口的相关炎症步骤，我们在苍蝇中发现的大部分对于小鼠和人来说都是如此。在这里，我们建议使用果蝇以获得快速的了解：1。皮肤细胞中的分子切换（包括伤口边缘和向后的那些）如何响应伤口信号，以组装肌动蛋白收缩电缆（就像在肌肉中一样），这些电缆将细胞向前移动以治愈伤口。这些信号不仅将是化学的，而且我们也认为机械性，例如拉伸，我们的苍蝇研究也可以使我们对此进行调查。我们还想知道，在伤口边缘细胞中开启的哪些基因最重要，以及使它们能够打开的步骤。在设计潜在的治疗剂以“开始”患有慢性，非治疗伤口的患者时，这种基本知识将为“踢开”治疗时提供线索。2。哪些信号将白细胞吸引到伤口，它们如何感觉到这些信号？由于白细胞在那里处理伤口感染，因此我们想注意他们如何做到这一点，并确定是什么迫使他们在愈合完成时离开伤口部位，因为许多人体病理是炎症无法解决的结果。能够人为地调节患者的炎症反应将使我们能够防止包括纤维化在内的伤口部位炎症的某些负面后果。苍蝇提供了一个实现这一目标的第一步。因为我们正在做所有这些实验，这些实验具有非常短的生命周期和非常有力的遗传学，我们可以在任何其他模型生物体中找到这些问题的答案，而在任何其他模型生物体中都可以比其他任何模型的生物体更快，但是对于我们在苍蝇中发现并将其应用于临床上相关的模型至关重要。对于我们来说，这一重要步骤变得非常容易，因为我们的一个实验室还可以在斑马鱼和老鼠的脊椎动物伤口愈合模型上工作，并且与加的夫的一个小组进行了临床合作，该组织与人类患者样本有关伤口愈合的诊所。

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

Inflammation and metabolism in tissue repair and regeneration

• DOI: 10.1126/science.aam7928
• 发表时间: 2017-06-09
• 期刊: SCIENCE
• 影响因子: 56.9
• 作者: Eming, Sabine A.;Wynn, Thomas A.;Martin, Paul
• 通讯作者: Martin, Paul

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

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

• 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

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