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

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.

Phosphoinositide 3-kinases (PI3Ks) are a conserved family of lipid kinases which generate lipid second messengers inside cells. 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 area for drug development. Mammals have 8 isoforms of PI3K, subdivided into three classes. While the class I PI3Ks have been extensively studied (by ourselves included), the roles and mechanism of signalling of the class II and III PI3Ks remain largely unknown. Indeed, despite thousands of publications on PI3K in the public domain, the physiological roles of the majority of PI3K isoforms remains unknown. This research proposal aims to characterise the roles of the class II and III PI3Ks in normal physiology, their integration in signalling by extracellular stimuli and their downstream signalling and cell biology, at the organismal and cellular level. We will hereby exploit new, gene-targeted mice that we have generated (unpublished). A first round of characterisation of these mice has yielded interesting biological observations that we now seek to understand at the molecular level. This is a multi-disciplinary project that covers animal physiology, embryology, cell biology, signal transduction and proteomic approaches, at the cellular and whole organism level.

This proposal seeks to investigate the roles of a group of lipid kinases, PI3Ks, which we believe play important roles in cell signalling. We have created a panel of mice in which the genes for these kinases have been inactivated, and we wish to investigate these to delineate the roles of these PI3Ks in cell biology and signalling. In particular, we aim to decipher the molecular mechanism why some mice respond better to metabolic stimuli. This could elucidate the mechanisms underlying metabolic diseases and ultimately lead to the use of inhibitors of class II/III PI3Ks as insulin-sensitizers for the treatment of these diseases. Beneficiaries of the proposed research include the academic research community, the commercial private sector and the wider public, who will benefit as follows: - this is a cross-UK University collaboration which is expected to strengthen interactions within the sector. For the academic researchers, we expect that our research will open new interdisciplinary avenues for exploration, shedding light on a broad range of key cell biological phenomena. In the past, the biology of PI3Ks has impacted on science far beyond our own field, mainly because they control fundamentals of biology. Immediate academic beneficiaries will be the named senior RAs who are likely to exploit this to set up their own independent research teams, or become involved in drug development, through our extensive interactions with industry. - this proposal has the potential to benefit the commercial sector by identifying kinases as new targets for therapeutic intervention. The enzymes under study are potential targets for small molecule inhibitors, although the disease indication of such inhibitors is preliminary. - in the longer term, the wider public might also benefit from our research, in that it leads to a better understanding of disease processes, especially in the context of diabetes and obesity. More than 2.5 million people in the UK have been diagnosed with diabetes. Thus, the proposed project may lead in the longer term to the development of new medicines to cure these diseases, enhancing quality of life in the UK and worldwide. We believe that the timescales for the benefits to be realised are not too distant. In the academic context, impact will be within the time frame of the grant proposal. Indeed, we have already carried out substantial preliminary work in this area, and all research staff are in place, allowing us to progress at a fast pace. The research and professional skills that the staff on this project will develop are very broad. Other than being involved in high profile and cross-discipline research in multiple UK Universities, staff will also be trained in project management and communicating their science in the broadest sense, providing them with transferable skills beyond pure academic research. Plans to ensure that the beneficiaries will benefit are in place and can be summarised as follows: - the research outputs will be communicated to the academic community through traditional scientific communication routes including high-profile peer-reviewed publications and international scientific conferences. All applicants will also actively engage in efforts to promote the public understanding of the science underlying the proposed project. - the proposed partnerships are a formal extension of successful ongoing collaborations with track records in generating impact and increasing UK competitiveness. The majority of the work will be managed from the PI's laboratory, with clearly identified roles and responsibilities of all partners. - BV and co-applicants have ample experience in commercialising the output of their research. BV and PC hold several patents and have recently co-founded a new spin out company (Activiomics; Feb 2010). Through their broad network of contacts and interactions with industry, they are aiming to protect and exploit the IP generated from the proposed research.