Regulation of the Ras cycle in neutrophils

被称为中性粒细胞的白细胞在对抗感染的免疫系统中起着重要作用。它们能够迁移到感染部位并消灭细菌。我们已经用转基因小鼠证明，在中性粒细胞中发现的一类特殊蛋白质，Ras蛋白，对迁移和破坏过程至关重要。目前还不知道Ras蛋白是如何在中性粒细胞中被控制的。建立这种机制是试图理解迁移和细菌杀灭的更大过程的重要组成部分，从而更清楚地认识到在关节炎和家族性感染无力等许多疾病中这些过程出了什么问题。吸引剂，驱动迁移，细菌通过与细胞表面的特殊分子结合，开始杀死和迁移的过程，这种分子被称为受体。一旦被激活，这些受体就会通过细胞内的分子网络，包括Ras蛋白，刺激进一步的信号传递给细胞前部和后部的迁移机制，以及细胞内的杀菌机制。我们假设Ras蛋白在将信号聚焦到细胞中发现相关细胞机制的正确位置方面发挥了重要作用。目前还不清楚Ras是如何在中性粒细胞中被激活的，无论是从负责的分子的身份还是机制方面都不清楚。我们计划使用一种方法，使我们能够创造出白细胞中特异性缺乏Ras或特异性Ras激活分子的小鼠，然后测试这些小鼠的白细胞是否正常工作。如果我们移除了Ras或者正确的Ras激活剂那么我们就会看到Ras激活的丧失以及某些白细胞的正常反应。然后我们知道我们已经正确地识别了真正的ras激活分子。我们知道所有可能的ras激活分子（大约18种可能性）可以通过查看由小鼠染色体测序创建的dna序列数据库来完成这项工作。一旦我们知道了这些调节Ras的分子的身份，那么未来制药公司或生物技术公司就有可能测试它们作为治疗关节炎等疾病的药物的良好靶点的可能性。

White blood cells called neutrophils play an important role within the immune system fighting infections. They are able to migrate towards sites of infection and destroy germs. We have proven, using genetically modified mice, that a special class of protein, Ras proteins, found inside neutrophils is essential for the processes of migration and destruction. At the moment it is not known how Ras proteins are controlled in neutrophils. Establishing the mechanism is an important part of the bigger process of attempting to understand migration and germ-killing and hence more clearly appreciate what goes wrong with these processes in a number of diseases such as arthritis and familial weakness to infection. The attractants, that drive migration, and the germs initiate the processes of killing and migration by binding to specialised molecules found on the cell surface, called receptors. Once activated the receptors stimulate further signalling through networks of molecules inside cells, including Ras proteins, to the machinary that causes migration, found at the front and back of the cell, and germ-killing, found inside the cell. We hypothesise that Ras proteins play an important role in focusing the signals down to the correct locations in the cell where the relevant cell machinary is found. At the moment it is not clear how Ras is activated in neutrophils, neither in terms of the identity of the molecules responsible or the mechanism. We plan to use an approach that enables us to create mice specifically lacking Ras or specific Ras activating molecules in their white blood cells and then to test whether the white blood cells from those mice work normally. If we have removed Ras or the correct Ras-acivator then we would expect to see a loss of Ras activation and also certain of the white blood cells normal responses. We then know we have correctly identified the real ras activating molecule. We know about all of the possible ras activating molecules (about 18 possibilities) that could do the job by looking in the DNA-sequence data bases created by sequencing of the mouse chromosomes. Once we know the identity of these molcules that regulate Ras then it is possible in the future for drug or Biotech companies to test the possibility that they might represent good targets for drugs designed to treat diseases like arthritis.