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

Lead Research Organisation: Queen Mary, University of London
Department Name: Sch of Medicine & Dentistry

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Related Projects

Project Reference Relationship Related To Start End Award Value
BB/I007806/1 04/04/2011 05/01/2014 £1,161,839
BB/I007806/2 Transfer BB/I007806/1 06/01/2014 28/02/2015 £208,921
 
Description We have found out the function of previously unknown enzymes by making mice which have inactive genes of these enzymes. We have discovered new potential disease indications for drugs against these enzymes, such as in insulin sensitization.

Assisted by BBSRC GCRF IAA funding, we were able to accelerate the impact of UCL research on PI 3-Kinase Modulators in collaboration with our industrial partner.
Exploitation Route We have been awarded BBSRC follow-on funding.

We have been exploring drug development against these enzymes
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description BBSRC Follow-on Fund
Amount £170,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2014 
 
Description BBSRC Programme Grant (BB/I007806/1and BB/I007806/2)
Amount £1,400,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2011 
End 01/2014
 
Description Deciphering PI3K biology in health and disease
Amount € 495,745 (EUR)
Funding ID Phd 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 11/2015 
End 10/2019
 
Description Global Challenges Research Fund - Impact Acceleration Account
Amount £20,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 03/2017
 
Title Mice with inactive alleles of the class II PI 3-kinase enzymes (PI3K-C2a, PI3K-C2b) 
Description These are genetically modified mice in which the kinase activity of the PI 3-kinase enzymes PI3K-C2a, PI3K-C2b are constitutively inactivated. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2018 
Provided To Others? Yes  
Impact These mice have been distributed to several laboratories. We are currently in the process of submitting frozen stock of these mice to the MRC Harwell repository. This will further facilitate distribution of these model organisms. 
 
Title vps34 mutant mice 
Description Mice in which the vps34 PI 3-kinase is inactivated in a constitutive or conditional manner. This mouse line can be used in pre-clinical models of disease, such as cancer and diabetes. We may ultimately licence these mice to pharma, as we have done for our other PI3K mutant mice. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact - Extensive collaborations in UK, US and France. - Allowed other people to apply for grants using these materials - successful bid to BBSRC for programme grant follow-up funding 
 
Description Collaboration with Novartis Research Institution - Boston USA 
Organisation Novartis Institutes for BioMedical Research (NIBR)
Country United States 
Sector Private 
PI Contribution We have received a small molecule inhibitor from Novartis under MTA, and tested this compound to validate our genetic data
Collaborator Contribution Novartis provided a small molecule inhibitor against the vps34 Pi 3-kinase under MTA,
Impact A manuscript describing the results of these studies has now been published (Bilanges et al - Nature Communications 2017)
Start Year 2016
 
Description Electron Microscopy - Lucy Collinson and Sharon Tooze - London 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of biological samples - co-formulation of scientific questions to be addressed.
Collaborator Contribution Expertise in Electron Microscopy
Impact This work is anticipated to at least one high profile publication. Multidisciplinary: biology, embryology, microscopy
Start Year 2011
 
Description Mass Spectrometry Facility at Barts Cancer Institute - Queen Mary University of London 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution The Centre for Cell Signalling has set up a proteomics facility that has provided a service to Barts Cancer Institute.
Collaborator Contribution CRUK has contributed to the salary of a mass spectrometry technician, as part of the core support grant it provides to Barts Cancer Institute.
Impact Successful grant applications and collaborative papers
Start Year 2012
 
Description Study of Early Mouse Development: Guillaume Halet (France) and Shankar Srinivas (Oxford) 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Department UMR 6061 (Institute of Genetics and Development of Rennes (IGDR))
Country France 
Sector Public 
PI Contribution Provision of biological samples - co-formulation of scientific questions to be addressed.
Collaborator Contribution Expertise in early mouse development
Impact This work is expected to give rise to a high profile publication. We will apply for grants together with Drs. Halet and Srinivas.
Start Year 2012
 
Description Study of Early Mouse Development: Guillaume Halet (France) and Shankar Srinivas (Oxford) 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of biological samples - co-formulation of scientific questions to be addressed.
Collaborator Contribution Expertise in early mouse development
Impact This work is expected to give rise to a high profile publication. We will apply for grants together with Drs. Halet and Srinivas.
Start Year 2012
 
Description Study of Early Mouse Development: Guillaume Halet (France) and Shankar Srinivas (Oxford) 
Organisation University College Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of biological samples - co-formulation of scientific questions to be addressed.
Collaborator Contribution Expertise in early mouse development
Impact This work is expected to give rise to a high profile publication. We will apply for grants together with Drs. Halet and Srinivas.
Start Year 2012
 
Title Patent application filed - insulin sensitization 
Description Methods for identifying agents useful in the treatment of diseases associated with insulin resistance and/or glucose intolerance 
IP Reference WO2013076501 
Protection Patent application published
Year Protection Granted
Licensed No
Impact Potential impact on insulin-resistant related disease
 
Description Lab Tours and School Visits 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact - over 200 lay people have attended tours in our laboratory
- PI presented the work to over 500 schoolchildren over the period 2007-2012
- PI has hosted placements of pupils in the lab


- PI is asked for return visits every year + additional invitations to talk
- stimulates children to consider careers in science and research
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2012
 
Description Science Week Events and Talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Discussion on working in Science - animals in research

various interactions with people interested in science
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013