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来愈合。每20个老年人中就有1人的伤口愈合时间过长而无法治愈，从而导致慢性伤口(例如：糖尿病足溃疡或下肢静脉溃疡)。这些慢性伤口严重降低了生活质量，甚至可能导致死亡。不幸的是，慢性伤口没有有效的治疗方法，其管理给世界卫生保健经济带来了重大的财政问题，特别是在全球老年人口迅速扩大的情况下。这种治疗方法的缺乏主要是因为人们对导致愈合不良的不同伤口细胞的基因变化知之甚少。我们最近的研究发现了一种可能对愈合特别重要的新基因，精氨酸酶（Arg1）。精氨酸酶在其他组织的修复中起着至关重要的作用，并与哮喘或牛皮癣等慢性疾病有关。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精氨酸酶，并且它在延迟愈合中被强烈下调。我们相信这些细胞中的精氨酸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验证这一假设。我们将使用在这些重要的伤口修复细胞类型（细胞特异性敲除）中缺乏精氨酸酶的特殊培育小鼠。对整体愈合的影响和一系列愈合参数将揭示精氨酸酶在每种细胞类型中的作用。我们还将培养细胞，直接测试精氨酸酶对细胞功能的影响。同时，我们将测量人体组织中的精氨酸酶水平和活性。特别值得注意的是，我们将能够比较精氨酸酶水平随时间在人类慢性伤口，要么愈合或不愈合。该项目的最后一部分将测试使用改变精氨酸酶激活的药物来促进愈合的可能性。我们将在人类延迟愈合的小鼠模型和直接在人类皮肤上做这个实验。在这项研究完成后，我们将处于有利地位，进入慢性伤口患者的研究。此外，鉴于精氨酸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具有广泛的意义。

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.