MICA: The role of arginase in chronic delayed wound healing

随着年龄的增长，我们的皮肤需要更长的时间才能愈合。在每二十个老年人中就有一个人的愈合变得如此延迟，以至于失败，导致慢性伤口（例如。糖尿病足溃疡或静脉性腿溃疡）。这些慢性创伤严重降低生活质量，甚至可能导致死亡。不幸的是，没有有效的治疗慢性伤口和他们的管理构成了一个重大的金融问题，为世界的医疗保健经济，特别是随着全球老年人口正在迅速扩大。这种缺乏治疗的主要原因是对导致愈合不良的不同伤口细胞中的基因变化知之甚少。我们最近的研究已经确定了一个新的基因，可能是特别重要的愈合，精氨酸酶（Arg 1）。精氨酸酶在其他组织的修复中起着关键作用，并与慢性疾病如哮喘或牛皮癣有关。我们的新数据表明，许多对皮肤修复很重要的细胞类型都含有这种酶，并且它在延迟愈合中被强烈下调。我们相信这些细胞中的酶在伤口修复中起着至关重要的作用，但尚未确定。在这项研究中，我们将使用一系列技术在小鼠伤口和人类志愿者的伤口组织中检验这一假设，我们将使用在这些重要的伤口修复细胞类型中缺乏β-内酰胺酶的特殊繁殖的小鼠（细胞特异性敲除）。对整体愈合和一系列愈合参数的影响将揭示酶在每种细胞类型中的作用。我们还将培养细胞，并直接测试酶对细胞功能的影响。同时，我们将测量人体组织中的脱氢酶水平和活性。特别值得注意的是，我们将能够比较在愈合或不愈合的人类慢性伤口中随时间的酶水平。该项目的最后一部分将测试使用药物改变酶激活以促进愈合的可能性。我们将在人类延迟愈合的小鼠模型和直接在人类皮肤中进行这一研究。这项研究完成后，我们将处于有利地位，进入对人类慢性伤口患者的研究。此外，鉴于β-淀粉酶在其他慢性疾病中的重要性，我们的研究结果可能对其他慢性退行性疾病的理解和治疗产生广泛的影响。

As we age our skin takes longer to heal. In one in every twenty older people healing becomes so delayed that it fails, leading to chronic wounds (eg. diabetic foot ulcers or venous leg ulcers). These chronic wounds severely decrease quality of life and can even lead to death. Unfortunately, there are no effective treatments for chronic wounds and their management poses a major financial problem for the world's healthcare economy, particularly as the global elderly population is rapidly expanding. This lack of treatments is mainly because there is little understanding of the gene changes in different wound cells that result in poor healing. Our recent studies have indentified a new gene that may be particularly important for healing, arginase (Arg1). Arginase has critical roles in repair of other tissues and has been linked to chronic diseases, such as asthma or psoriasis. Our new data shows that a number of cell types important for skin repair contain the arginase enzyme, and that it is strongly down-regulated in delayed healing. We believe that arginase in these other cells plays crucial, as yet unidentified, roles in wound repair. In this study we will test this hypothesis using a range of techniques in both mouse wounds and wound tissue from human volunteers.We will use specially bred mice that lack arginase in each of these important wound repair cell types (cell-specific knockout). The effect on overall healing and a range of healing parameters will reveal the role of arginase in each cell type. We will also culture the cells and directly test the effect of arginase on cell function. In parallel we will measure arginase levels and activity in human tissue. Of particular note we will be able to compare arginase level over time in human chronic wounds that either do or do not heal. The final part of the project will test the possibility of using drugs that alter arginase activation to promote healing. We will do this in mouse models of human delayed healing and directly in human skin. Upon completion of this study we will be in a strong position to move into studies on human patients with chronic wounds. In addition, given the importance of arginase in other chronic diseases, our findings will potentially have wide reaching implications for the understanding and treatment of other chronic degenerative diseases.