Towards an integrated understanding of neutrophil biology and their role in resisting infection

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

We will have started to exploit imaging tools (eg Raichu-Rac reporter mouse strain) and have progressed our systematic gene-targetting strategy to understand spatio-temporal regulation of PI3Ks and small GTPases that is known to be essential for neutrophil migration and pathogen-killing. This activity should lead to 2 or 3 papers being either accepted or under review at the mid term review. We will have established the cell lines expressing Fc Rs and GFP-iPX construct to enable us to commence a genome-wide screen for regulators of vps34 in the context of phagosome formation in comparison to our on-going screen for regulators of vps34 upstream of autophagosome formation (see below). We will have begun to define the primary transcriptional networks of mouse neutrophils and how that is determined by different stimuli in preparation for our studies to address how some aspects of the reduced functionality of neutrophils in aged animals maybe related to changes in their transcriptional landscape. We will validate the tools to probe the identity of endogenous protein cysteine residues modified by ROS in work with other cell types and apply them to neutrophils in the later stages of the ISPG

Publications


10 25 50
Boyle KB (2012) Activation of the neutrophil NADPH oxidase by Aspergillus fumigatus. in Annals of the New York Academy of Sciences
 
Description Our work has revealed new aspects of the way the immune system works. Some of these ideas also change the way we understand how inflammatory responses arise and hence potential ways to try and reduce inflammation in disease. This includes possible pharmaceutical targets such as PI3Ks, RhoG, and PRex.
Our work has underpinned recetn advances in ageing research suggesting that in neutrophils from aged people there is excessive class I PI3K activity that drives increased chemokinesis and inteferes with efficient chemotaxis. We are collaborating with the Lord and Sapey labs in Birmingham to take this forward.
Exploitation Route Our work has mapped out core signalling events following activation of pro-inflammatory receptors on neutrophils. Not only does this have great value as a physiological model of GPCR signalling and immune cell activation by G-protein signalling it is also very relevant to companies attempting to reduce inflammation. Many pharmaceutical companies are attempting to generate PI3K and PRex inhibitors to treat inflammatory disease. these could lead to drugs with the potential to impact the quality of life of many patients and in some cases be life-saving therapeutics.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description Our work has led to commercial activity targetting PI3K and PRex in the immune system, including neutrophils, as potential targets for anti-inflammatories. This work led directly to collaborations with GSK including an MRC-MICA award with GSK, to understand the role of PI3Kgamma in neutrophil biology relevant to disease.
Sector Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic
 
Title Gbg-PI3Kbeta knock-in mice 
Description Generation of a genetically engineered mouse strain in which mutations to the p110beta catalytic subunit of Class I PI3Kbeta were mutated to selectively block interaction with Gbg subunits of heterotrimeric G proteins. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact Houslay et al (2016) Sci Signal. 9(441):ra82. doi: 10.1126/scisignal.aae0453. 
 
Description Alison Condliffe 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution In vitro work with human neutrophils, measurements of phosphoinositides.
Collaborator Contribution Human patient samples.
Impact Publications fully reported
 
Description Beatson Institute, Glasgow: Characterisation of our Rac-activity Fret reporter mice 
Organisation Cancer Research UK (CRUK)
Department The Beatson Institute for Cancer Research
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution joint experiments exchange of reagents lab visits joint publications
Collaborator Contribution joint experiments exchange of reagents lab visits joint publications
Impact 2 joint papers
Start Year 2011
 
Description Bretschneider - chemotaxis 
Organisation University of Warwick
Department School of Life Sciences Warwick
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution reagents and expertise
Collaborator Contribution expertise
Impact Norton et al (2016) Adv Biol Regul. 60:36-45. doi: 10.1016/j.jbior.2015.10.005 Du et al (2013) BMC Bioinformatics. 14:296. doi: 10.1186/1471-2105-14-296. Cell biology, mathematical modelling
Start Year 2010
 
Description Chiesi 
Organisation Chiesi Farmaceutici S.p.A.
Country Italy, Italian Republic 
Sector Charity/Non Profit 
PI Contribution Measurements of phosphoinositides
Collaborator Contribution Development of PI3K inhibitors towards clinical trials
Impact Multi-disciplinary. We provide lipidomics expertise , Chiesi provide med chem and models
Start Year 2016
 
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 Downward_RBD of Class I PI3Ks 
Organisation Francis Crick Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution We designed the study and performed all experiments
Collaborator Contribution They provided genetically engineered mouse embryonic fibroblast cell lines with mutations in the Ras Binding Domain (RBD) of Class I PI3K alpha and beta.
Impact Houslay et al (2016) Sci Signal. 16;9(441):ra82. doi: 10.1126/scisignal.aae0453.
Start Year 2014
 
Description GSK/Gus 
Organisation GlaxoSmithKline (GSK)
Department Respiratory Biology GSK
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution Research into the physiological roles of Pi3kgamma in inflammatory signalling in neutrophils
Collaborator Contribution Knowledge of commercially important directions and implications of our experiments
Impact In the first year of the study.
Start Year 2011
 
Description Jonathan Clark (BBT, Cambridge): 
Organisation Babraham Bioscience Technologies
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Private 
PI Contribution Development of a first-generation small-molecule P-Rex inhibitor
Collaborator Contribution Development of a first-generation small-molecule P-Rex inhibitor
Impact production of small molecule compounds to inhibit P-Rex
Start Year 2009
 
Description Lindsay Hall 
Organisation University of East Anglia
Department Institute of Food Research
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Discussion/advice about possible roles of inhibitory receptors on immune cells in gut
Collaborator Contribution Advice about gut immune biology
Impact None yet
Start Year 2011
 
Description Orion Weiner 
Organisation University of California, San Francisco
Department Department of Biochemistry and Biophysics
Country United States of America 
Sector Academic/University 
PI Contribution Analysis of phosphoinositides, advice about neutrophils, reagents.
Collaborator Contribution Samples, reagents, technological advice.
Impact Publications fully reported.
 
Description Sasaki_ mass spec and prostate 
Organisation Akita University
Country Japan 
Sector Academic/University 
PI Contribution Intellectual input, reagents, mass spectrometric methods, personnel
Collaborator Contribution Intellectual input, reagents, mass spectrometric methods, personnel
Impact Norton et al (2016) Adv Biol Regul. 60:36-45. doi: 10.1016/j.jbior.2015.10.005 Ferguson et al (2007) Nat Cell Biol. 9(1):86-91.
 
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 Simon Pitchford 
Organisation King's College London (KCL)
Department Department of Pharmacology & Therapeutics
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Collaboration on the interactions of proinflammatory platelets with leukocytes during the recruitment of neutrophils and other types of leukocytes to sites of inflammation. Our lab has contributed the identification of platelet Rac-GEFs that are crucial for these interactions. I nthe absence of these platelet Rac-GEFs, platelet/leukocyte interactions are blocked and, in consequence, leukcoyte recruitment to sites of inflammation is also blocked.
Collaborator Contribution Our collaborators have contributed their esxpertise in platelet biology, pulmonary inflammation and intravital microscopy.
Impact Joint publication in Blood in 2015. Planned joint grant applications. Continued collaboration on related projects.
Start Year 2012
 
Description Simon Pitchford and Clive Page (KCL, London) 
Organisation King's College London (KCL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Role of P-Rex and Vav GEFs in leukocyte recruitment to inflamed lungs
Collaborator Contribution joint experiments lab visits joint publications
Impact joint paper under revision in Blood
Start Year 2009
 
Description Till Bretschneider 
Organisation University of Warwick
Department School of Life Sciences Warwick
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We collected imaging data describing neutrophil migration using a number of imaging modalities.
Collaborator Contribution Data analysis
Impact Publications and presentations at meetings
Start Year 2010
 
Description Williams - PI3K 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Intellectual input, reagents, personnel
Collaborator Contribution Intellectual input, reagents, personnel
Impact Angulo et al (2013) Science 342(6160):866-71. doi: 10.1126/science.1243292 Zhang et al (2011) Mol Cell. 41(5):567-78. doi: 10.1016/j.molcel.2011.01.026 Houslay et al (2016) Sci Signal. 9(441):ra82. doi: 10.1126/scisignal.aae0453 Krugmann et al (2004) Curr Biol.14(15):1380-4
 
Description Yonathan Lissanu-Deribe and Lynda Chin (Anderson Cancer Center, Texas University, USA): 
Organisation University of Texas
Department M. D. Anderson Cancer Center
Country United States of America 
Sector Academic/University 
PI Contribution Role of P-Rex2 in melanoma growth and metastasis
Collaborator Contribution joint experiments
Impact none yet
Start Year 2012
 
Description Career Advice Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Lecture to Babraham students and Post Docs on career in academia

Improved communication between post docs, more senior researchers and the Institute's executive committee.
Year(s) Of Engagement Activity 2012,2014,2016
 
Description Career Advice Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact lecture to students and postdocs on a career in bioscience

Answered many questions from the audience who never had the chance to experience work in a Research Institute as opposed to University.
Year(s) Of Engagement Activity 2009,2012,2014
 
Description Editorial board member 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Editorial board member of
Cell Reports
Small GTPases (from 2015)
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
 
Description European Phagocyte Workshop - Member of steering committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Steering committee of Annual European Phagocyte Workshop
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
 
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 Organisor/chair of international conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact FASEB meeting Small GTPAses FL June 2016, organizer and chair
Year(s) Of Engagement Activity 2015
 
Description Phagocytes.Net 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I am Editor of this website for fellow phagocyte researchers, postdocs, students and the general public that provides information on phagocyte-related events, research groups, and jobs. www.phagcytes.net

Better communication among research groups in the phagocyte field. Markedly increased numbers of participants at the annual meetings of the European Phagocyte Workshop.
Year(s) Of Engagement Activity 2006,2008,2009,2010,2011
URL http://www.phagcytes.net
 
Description Public feedback exercise 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The Signalling Department, in parallel with other BI departments, presented our research to a professionally selected sample of the UK public with the interntion of gaining public feedback on our institute and research.
Year(s) Of Engagement Activity 2015
 
Description School visits in Cambridgeshire 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact talks at primary schools

Raised image of "the scientist" among scholl chidren in the area over the past years (questionnaires).
Year(s) Of Engagement Activity 2006,2008,2010,2011,2012
 
Description Schools Days at 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 host 10 GCSE or A level students for one day every year to conduct experiments.

Rasied image of "science" as a profession and of "scientists" among young people in the area.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Work experience for year 12 school students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Work shadowing for a yr 12 school student to understand biomedical research

Student applied and got an offer on a biomedical degree course
Year(s) Of Engagement Activity 2014
 
Description speaker/session chair at international conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact invited speaker and/or session chair at international conferences
Year(s) Of Engagement Activity 2016,2017