An investigation of the in vivo expression and function of the D6-chemokine decoy receptor

在进化过程中，系统已经发展，使我们能够非常迅速地对组织损伤或入侵的细菌或其他病原体作出反应。这种反应涉及到我们免疫系统的细胞，我们免疫反应最直接的方面是炎症反应。在炎症期间，白细胞被吸收到炎症部位，它们帮助清除任何细菌或其他外来生物，以及我们受损细胞中的碎片。此外，它们还有助于修复受损组织。因此，炎症在一系列反应中很重要，包括由化学刺激物引起的伤口愈合和组织损伤修复。在许多疾病中，如风湿性关节炎和牛皮癣，炎症已经出错，因此了解炎症反应对我们理解许多非常突出的疾病至关重要。到目前为止，我们对进入炎症部位的白细胞以及它们在炎症过程中所起的作用了解甚多。此外，炎症组织产生的导致白细胞募集的信号也被很好地表征。这些分子被称为趋化因子，它们对白细胞导航到受损或发炎的组织很重要。最近，我们对关闭炎症反应的机制产生了兴趣，因为这是这个过程中的一个关键控制点。我们是如何做到这一点的，我们知之甚少。我们已经确定了一种叫做D6的分子，它可以破坏帮助白细胞到达炎症部位的趋化因子。因此，我们认为D6通过去除趋化因子参与关闭炎症，从而阻断白细胞募集的信号。事实上，在皮肤炎症模型中，没有D6的小鼠无法正确地关闭炎症。这表明D6是炎症反应消退的重要调节因子。现在我们想要更详细地了解D6是如何工作的。具体来说，我们建议生成一个小鼠模型，其中D6被标记为一个标签，这将使我们能够准确地看到，在炎症反应期间，D6在一个完整的动物体内何时何地表达。此外，我们想仔细观察D6工作的发炎情况，试图更广泛地理解D6的重要性及其在发炎环境中的表达。最后，我们想看看D6在表达D6的细胞中的表达和功能的调节。我们相信这些实验将对提高我们对炎症反应的解决和控制的理解具有重要意义。

During evolution, systems have been developed that allow us to respond very rapidly to damage to our tissues or to invading bacteria or other agents. This response involves the cells of our immune system and the most immediate aspect of our immune response is the inflammatory response. During inflammation, white blood cells are recruited into the inflamed sites and they help remove any bacteria or other foreign organisms and also debris from our damaged cells. In addition they help in the processes of repair of the damaged tissues. Thus inflammation is important in a range of responses including wound healing and repair of tissue damage caused by chemical irritants. In many diseases, such as rheumatoid arthritis and psoriasis, inflammation has gone wrong and therefore understanding the inflammatory response is central to our understanding of a number of very prominent diseases. Thus far we know a great deal about the white blood cells that enter inflamed sites and about the roles they play in the inflammatory process. In addition, the signals produced by inflamed tissues that lead to recruitment of the white blood cell are also well characterised. These molecules are called chemokines and they are important for white blood cell navigation to damaged or inflamed tissues. Recently we have become interested in the mechanisms whereby we switch off inflammatory responses as this is a crucial control point in the process. Little is known about the ways in which we do this. We have identified a molecule called D6 which can destroy the chemokines which help the white blood cells get to inflamed sites. We believe therefore that D6 is involved in switching off inflammation by removing the chemokines and therefore blocking the signals for white blood cell recruitment. Indeed mice that do not have D6 are unable to properly switch off inflammation in models of skin inflammation. This suggests that D6 is a fundamentally important regulator of the resolution of the inflammatory response. We now want to try to understand how D6 functions in much more detail. Specifically we propose to generate a mouse model in which D6 is tagged with a label that will allow us to look at exactly where, and when, it is expressed in an intact animal during an inflammatory response. In addition we want to look carefully at the inflamed situations in which D6 works to try to get a broader understanding of the importance of D6 and of its expression in the inflamed context. Finally we want to look at the regulation of D6 expression and function in cells that express D6. We believe that these experiments will be of great importance in improving our understanding of the resolution and control of an inflammatory response.