Molecular basis of NADPH oxidase activation

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Neutrophils and macrophages are types of white blood cell and are key components of the innate immune system. These cells are professional phagocytes and rapidly engulf and destroy microbes. One of the early events in this process is production of superoxide (02) by activated NADPH oxidase. Hereditary mutations in the NADPH oxidase complex in individuals with chronic granulomatous disease result in recurring life-threatening infections, underlining the importance of this enzyme. However, because of the potential tissue damage that can also be caused by the reactive oxygen species produced by NADPH oxidase, it is tightly regulated. Too much NADPH oxidase activity can be harmful. When neutrophil recruitment and activation by the immune system is abnormally high, life-threatening acute inflammatory tissue injury can result. This is especially prevalent in certain acute viral and bacterial lung infections.

The core catalytic machinery of the enzyme requires the association of four regulatory protein subunits to become fully active. The molecular organisation of the active NADPH oxidase has been the subject of many investigations, however, much remains unexplained about how signalling pathways activate NADPH oxidase. The goal of this research is to understand the structural basis of NADPH oxidase activation and to develop specific chemical inhibitors of this process.
 
Description We discovered several new elements in the biochemical pathways that allow a type of white blood cell (neutrophil) to find and kill pathogens.
Exploitation Route They will aid the pharmaceutical sector in the development of novel anti-inflammatory molecules (PI3K inhibitors).
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Condliffe - neutrophil biology 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
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 Mocsai - neutrophil biology 
Organisation Semmelweiss University
Country Hungary 
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 Rab27 in neutrophil oxidase activation 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
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 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 Van haesebroeck - PI3K 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
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 Lubeck
Country Germany 
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-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019