Regulation of the Ras cycle in neutrophils

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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.