Regulation of the Ras cycle in neutrophils

中性粒细胞 Ras 循环的调节

• 批准号: BB/D013593/1
• 负责人: Len Stephens
• 金额: $ 33.92万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD013593%2F1
• 关键词: Regulation; Ras; cycle; neutrophils

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.

称为中性粒细胞的白色血细胞在免疫系统对抗感染中发挥着重要作用。它们能够迁移到感染部位并消灭细菌。我们已经证明，使用转基因小鼠，一类特殊的蛋白质，Ras蛋白，发现在中性粒细胞是必不可少的迁移和破坏的过程。目前还不清楚Ras蛋白在中性粒细胞中是如何控制的。建立这种机制是试图理解迁移和杀菌的更大过程的重要组成部分，因此更清楚地了解这些过程在许多疾病中出现了什么问题，如关节炎和家族性感染。引诱剂，驱动迁移，和细菌通过结合细胞表面上发现的专门分子，称为受体，启动杀死和迁移的过程。一旦被激活，受体通过细胞内的分子网络（包括Ras蛋白）刺激进一步的信号传导，导致细胞前部和后部的迁移和细胞内的杀菌。我们假设Ras蛋白在将信号集中到细胞中发现相关细胞机器的正确位置中起重要作用。目前还不清楚Ras在中性粒细胞中是如何被激活的，无论是在负责分子的身份还是机制方面。我们计划使用一种方法，使我们能够创造出在白色血细胞中特异性缺乏Ras或特定Ras激活分子的小鼠，然后测试这些小鼠的白色血细胞是否正常工作。如果我们已经去除Ras或正确的Ras活化剂，那么我们将期望看到Ras活化的丧失以及某些白色血细胞的正常反应。然后我们知道我们已经正确地鉴定了真实的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），通过查看小鼠染色体测序创建的DNA序列数据库，可以完成这项工作。一旦我们知道了这些调节Ras的分子的身份，那么未来药物或生物技术公司就有可能测试它们可能成为治疗关节炎等疾病的药物的良好靶点。