Regulation of superoxide formation

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

White blood cells are responsible for the destruction of many potentially infectious pathogens. A key event in the destruction process is the localised production of highly reactive molecular species by white blood cells as they engulf the pathogens. This work aims to identify the role of a molecule that is known to be physically associated with the structures formed during the engulfment process and we predict is important for production of reactive molecular species; called p40Phox.

Publications


10 25 50
 
Description We have defined the relative importance of different individual members of an enzyme family (PI3Ks) in the regulation of a type of white blood cell (neutrophil) that is important for combating fungal and bacterial infections but also contributes to inflammatory pathology.
Exploitation Route They will inform further academic research in this area and will directly influence the pharmaceutical sector in the development of potentially new anti-inflammatory drugs (PI3K inhibitors).
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description They have been used by the pharmaceutical sector to develop their strategy for which PI3K isoforms to target in different pathologies. They have also been used directly by a small UK biotechnology company (Karus Therapeutics) to evaluate the specificity and efficacy of their pre-clinical compounds.
First Year Of Impact 2008
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic
 
Description Condliffe - neutrophil biology 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Intellectual input, reagents, measurement of phopshoinositides
Collaborator Contribution Intellectual input, personnel, reagents, clinical samples
Impact Angulo et al (2013) Science. 342(6160):866-71. doi: 10.1126/science.1243292 Juss et al (2012) PLoS One. 7(9):e45933. doi: 10.1371/journal.pone.0045933
 
Description Curi - neutrophils and lipids 
Organisation University of Sao Paulo
Country Brazil, Federative Republic of 
Sector Academic/University 
PI Contribution expertise, reagents, hosted exchange visits
Collaborator Contribution expertise, exchange of personnel
Impact Vinolo et al (2011) PLoS One. 6(6):e21205. doi: 10.1371/journal.pone.0021205. Epub 2011 Jun 15
Start Year 2008
 
Description Mocsai - neutrophil biology 
Organisation Semmelweiss University
Country Hungary, Republic of 
Sector Academic/University 
PI Contribution expertise and reagents
Collaborator Contribution expertise, reagents and exchange of personnel
Impact Gyori et al (2014) Arthritis Rheumatol. 66(8):2210-21. doi: 10.1002/art.38660 Boyle et al (2011) J Immunol. 186(5):2978-89. doi: 10.4049/jimmunol.1002268. Research Grant from Karus Therapeutics, UK
Start Year 2010
 
Description Role of CD18 in neutrophil oxidase activation by bacteria and fungi 
Organisation University of Ulm
Department Department of Dermatology and Allergic Diseases
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution We provided the majority of the intellectual input and technical resources for this collaboration
Collaborator Contribution Access to CD18 knock-out mice
Impact PMID: 18755982 listed under 'publications'. This collaboration also provided reagents for a current 'manuscript under review', which is listed under 'other outputs and knowledge'
Start Year 2007
 
Description Role of Dectin-1 in neutrophil activation by Aspergillus 
Organisation Cardiff University
Department Cardiff University School of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We took the intellectual lead in this project and contributed the majority of the work and reagents, including strains of mice deficient in PI3K and NADPH oxidase subunits
Collaborator Contribution access to Dectin-1 knock-out mice plus intellectual contribution to project
Impact Boyle et al (2011) J Immunol. 186(5):2978-89. doi: 10.4049/jimmunol.1002268.
Start Year 2009
 
Description Role of Rab27 in neutrophil oxidase activation 
Organisation Faculty of Medicine
Department Department of Medicine
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided the majority of the intellectual input and technical resources for this collaboration
Collaborator Contribution Provided access to Rab27 knock-out mice
Impact PMID: 20813901 listed under 'publications'
Start Year 2009
 
Description Role of Rac proteins in neutrophil oxidase activation by bacteria 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We provided the majority of the intellectual input and technical resources for this collaboration
Collaborator Contribution Provided access to Rac1 knock-down and Rac2 knock-out mouse strains
Impact PMID: 20813901 listed under 'publications'
Start Year 2007
 
Description Role of Rac proteins in neutrophil oxidase activation by bacteria 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution We provided the majority of the intellectual input and technical resources for this collaboration
Collaborator Contribution Provided access to Rac1 knock-down and Rac2 knock-out mouse strains
Impact PMID: 20813901 listed under 'publications'
Start Year 2007
 
Description Role of Syk in neutrophil activation by Aspergillus 
Organisation Faculty of Medicine
Department Department of Physiology
Country Hungary, Republic of 
Sector Academic/University 
PI Contribution We took the intellectual lead in this project and contributed the majority of the work and reagents, including strains of mice deficient in PI3K and NADPH oxidase subunits
Collaborator Contribution Our collaborators provided access to two strains of knock-out mice (syk KO; Fcgamma/DAP12 double KO) and hosted a visit from Keith Boyle (post-doctoral scientist employed on grant) to their laboratory in Budapest to conduct experiments.
Impact Boyle KB et al (2011) J Immunol. 186(5):2978-89. doi: 10.4049/jimmunol.1002268.
Start Year 2009
 
Description Role of Syk in neutrophil activation by Aspergillus 
Organisation Semmelweiss University
Country Hungary, Republic of 
Sector Academic/University 
PI Contribution We took the intellectual lead in this project and contributed the majority of the work and reagents, including strains of mice deficient in PI3K and NADPH oxidase subunits
Collaborator Contribution Our collaborators provided access to two strains of knock-out mice (syk KO; Fcgamma/DAP12 double KO) and hosted a visit from Keith Boyle (post-doctoral scientist employed on grant) to their laboratory in Budapest to conduct experiments.
Impact Boyle KB et al (2011) J Immunol. 186(5):2978-89. doi: 10.4049/jimmunol.1002268.
Start Year 2009
 
Description Role of the Fc gamma chain in neutrophil oxidase activation by bacteria 
Organisation School of Biological Sciences Cambridge
Department Department of Biochemistry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We provided the majority of the intellectual input and technical resources for this collaboration
Collaborator Contribution provided access to Fc gamma chain knock-out mice
Impact PMID: 18755982 listed under 'publications'
Start Year 2007
 
Description Sebo_cAMP Signaling of Adenylate Cyclase toxin in neutrophils 
Organisation Academy of Sciences of the Czech Republic
Department Laboratory of Molecular Biology of Bacterial Pathogens
Country Czech Republic 
Sector Learned Society 
PI Contribution We hosted a visiting student to perform some assays of neutrophil function, including the production of reactive oxygen species and the activation of some signalling pathways
Collaborator Contribution They instigated the study, provided biological material and reagents and conducted experiments.
Impact Cerny et al (2017) J Immunol. 198(3):1285-1296. doi: 10.4049/jimmunol.1601309. Epub 2016 Dec 30.
Start Year 2013
 
Description UCB pharma studentship 
Organisation UCB Pharma
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution We provided the majority of the intellectual input and technical resources for this collaboration
Collaborator Contribution funded a PhD studentship that contributed to the project, also provided reagents and intellectual input
Impact PMID: 20813901 and PMID: 18755982 listed under 'publications'
 
Description Van haesebroeck - PI3K 
Organisation University College London (UCL)
Department UCL Cancer Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Intellectual input, reagents and mass spectrometric analysis of phosphoinositides
Collaborator Contribution Intellectual input, biological samples. Wide ranging collaboration covering several projects.
Impact Alliouachene et al (2015) Cell Rep. 13(9):1881-94. doi: 10.1016/j.celrep.2015.10.052 Gyori et al (2014) Arthritis Rheumatol. 66(8):2210-21. doi: 10.1002/art.38660. Kulkarni et al (2011) Sci Signal. 4(168):ra23. doi: 10.1126/scisignal.2001617.
Start Year 2009
 
Description Zillikens - EBA 
Organisation University of Luebeck
Country Germany, Federal Republic of 
Sector Academic/University 
PI Contribution We provided the intellectual frame work for the study and performed most of the experiments
Collaborator Contribution reagents, mouse model of EBA skin blistering disease
Impact Kulkarni et al (2011) Sci Signal. 4(168):ra23. doi: 10.1126/scisignal.2001617. Research Grant from Karus Therapeutics, UK
Start Year 2009
 
Description Invited lecturer to international meetings (average 2-3 per year) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact promoted discussions, collaborations

scientific collaborations, joint grants and publications
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
 
Description lecture - Cambridge science festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact increased public understanding of our work - many stimulating discussions

live interview on local radio
Year(s) Of Engagement Activity 2014
URL http://www.cam.ac.uk/science-festival/events-and-booking/cambridge-stars-big-ideas-2
 
Description radio cambridgeshire interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact stimulated further discussions with the public

further interest in public lecture at the Cambridge Science Festival
Year(s) Of Engagement Activity 2014
 
Description schools day - Babraham 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact We provided laboratory experiments based on our research for secondary school children (GCSE and A-level). Two groups of 5-7 children attended for one day each year. Three members of my team spent a total of about 10 hrs preparing for this event and were each fully occupied on the day.

Students report that they gained a real sense of what working in scientific research is like. Schools have always reported a favourable impact on pupls decisions to pursue science at both 'A-level' and degree level and return each year.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010