Signalling and biological roles of the class II and III PI 3-kinase enzymes

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This proposal seeks to investigate the roles and mechanism of action of a group of molecules, known as phosphoinositide 3-kinases (PI3Ks). When cells receive signals from the outside world, PI3Ks generate signals inside cells to make the cells respond. This output can be very diverse, and includes cell proliferation, survival and resistance against stress, but also the production of hormones, cell migration or even cell death. The PI3K pathway has been implicated in diseases such as cancer, inflammation, auto-immunity and diabetes. This pathway is therefore considered as an interesting new target for drug development. There are three subgroups of PI3K and thus far, scientists (including ourselves) have mainly focused on the so-called class I subset of PI3Ks. Drugs against the class I PI3Ks are currently being tested in clinical trials in human cancer. At the moment, very little is known about the class II and III PI3Ks, despite many years of research by others. We have in the past been very successful in finding out what the class I PI3Ks are doing and how they can be targeted in disease. We have now embarked on a scientific research programme to find the biological roles of the class II and III PI3K, and to identify how they transduce signals inside cells. We will do this by studying mice in which the class II or III PI3Ks have been inactivated, in order to uncover what these PI3Ks do in the living organism, and how they work. We have made some interesting initial observations, and now propose to progress to a full characterisation of these mice and the mechanism of action of these poorly-investigated members of the PI3K family. This is a fundamental science project that will enhance our knowledge about basic biological phenomena. In the past, the biology of PI3Ks has impacted on science far beyond our own field, mainly because these enzymes control fundamentals of biology. This proposal also has the potential to benefit industry, as it might identify PI3Ks as new targets to develop medicines against. In the longer term, it is very likely that this research may lead to a better understanding of disease processes and to the development of new medicines. This proposal is part of an ongoing, multidisciplinary research project with collaborators at five UK Universities and CRUK, as well as international collaborators.