The regulation of neutrophil chemotaxis

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

We have established a collaboration with researchers in the Warwick University Systems Biology Centre to study the regulation of neutrophil chemotaxis. Neutrophils are 'white cells' that are a key component of our innate immune system, responsible primarily for fighting bacterial and fungal infections. Neutrophils find pathogens by moving with remarkable efficiency towards sources of chemicals that are generated directly by the pathogens themselves, or indirectly via the interaction of pathogens with body cells. These chemicals are called chemoattractants and the process is known as 'chemotaxis'.  The molecular mechanisms which underlie the ability of neutrophils to detect and move up shallow gradients of chemoattractants are still poorly understood. Our group is experienced in studying the signalling pathways which couple the activation of chemottractant receptors on the surface of neutrophils with events inside the cells. One of the main problems we face in trying to understand how these receptors regulate directed cell movement is in describing the movement itself in sufficient quantitative detail that that the process can be de-convoluted into aspects that can be aligned against molecular events.  We are currently using state of the art 3-D microscopy to create live images of neutrophil movement.  Our collaborators in Warwick are looking at these images to see if they can use their mathematical knowledge and experience to define common motifs that define the process of chemotaxis.  This is a short grant to see if enough progress can be made to warrant a full collaborative grant application to be made in the near future.

Publications

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Hawkins PT (2010) PI3K signaling in neutrophils. in Current topics in microbiology and immunology

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Norton L (2016) Localizing the lipid products of PI3K? in neutrophils. in Advances in biological regulation

 
Description PI3K inhibitors reduced neutrophil migration by inhibiting cells starting to migrate, not by changing their speed or directionalty.
Exploitation Route This work suggests use of PI3K inhibitors could reduce inflammation by reducing migration of pro inflmmaotory cells in to sites of inflammation.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description We established that we could express fluorescent reporters in mouse neutrophils using adoptive chimeraism. This allowed us to visualise actin and pi3k activity during migration of living neutrophils. This provided evidence we could provide data for computational analysis of migration and showed how pi3k inhibitors impact the ability of cells to start migrating and not their directionality, a new concept in the field that supported the idea that pi3k inhibitors could reduce inflammation but gave a more precise mechainsitc explanation. This served to encourage more investment in developing pi3k inhibitors as anti-inflammatories.
First Year Of Impact 2010
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Bretschneider - chemotaxis 
Organisation University of Warwick
Department School of Life Sciences
Country United Kingdom 
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 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. Malek M, Kielkowska A, Chessa T, Anderson KE, Barneda D, Pir P..... Stephens LR, (2017). PTEN Regulates PI(3,4)PSignaling Downstream of Class I PI3K.. Molecular cell, 68 (3), pp. 566-580.e10
 
Description Till Bretschneider 
Organisation University of Warwick
Department School of Life Sciences
Country United Kingdom 
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 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
 
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