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MRC DiMeN Doctoral Training Partnership: Optogenetic programming of inflammation - in vivo Opto-GPCR approaches in neutrophils


Project Description

Diseases of inflammation contribute to the biggest health problems of the 21st century. Mutli-morbidity, the coincidence of multiple pathologies, is driven by processes such as inflammation and by inflammatory cells like neutrophils. Neutrophils have a powerful protective role and without them we develop overwhelming infection, yet they are also directly responsible for the tissue damage that characterises many common inflammatory diseases. Partly explaining this apparent contradiction, recent work has shown that neutrophils can transit from a harmless phenotype through a primed state, to a toxic, activated phenotype and back again. There is emerging evidence that the ability to modify neutrophil phenotype is dysregulated in a range of inflammatory diseases and also influences innate immune interactions with a number of cancers. There remain fundamental gaps in our understanding of how neutrophil function is regulated and how it contributes to inflammatory diseases. This project aims to help understand how we can therapeutically modify neutrophil function, either to enhance bactericidal activity in infection or to suppress tissue-damage in inflammation.

We have assembled a broad range of new and innovative tools to manipulate neutrophil functional in vivo. Transgenic zebrafish allow the non-invasive study of neutrophil function during infection and inflammation, and we have a range of well-validated experimental approaches for challenging neutrophil function in vivo. Sterile tissue injury and response to bacterial infection are well established in our groups. By examining neutrophil phenotype and function in these experimental systems we will precisely define how neutrophil phenotype is regulated.

In this context we will transfer well-established optogenetic approaches from other systems into in vivo zebrafish models using techniques routinely used in our laboratories. With these you will stimulate individual neutrophils using a microscope laser to activate custom-built molecular structures called opto-GPCRs. G-Protein Coupled Receptors (GPCRs) are a family of proteins that include the light-sensitive opsin family as well as receptors for key priming (eg platelet activating factor and leukotriene B4) and activating (eg fMLF and C5a) neutrophil agonists. By fusing components from each of these families together it is possible to generate cell surface receptors that are triggered by light but signal as if they had encountered a chemokine. This allows us to activate neutrophils individually at will and to observe the effects of this on a number of well defined neutrophil functions including recruitment, swarming, phagocytosis, degranulation and inflammation resolution. This is state of the art technology, applied to an important clinical question, and will lead information directly applicable to how we treat infectious and inflammatory diseases.

Our lab is a lively and fun environment to work in. There are lots of post-docs around to help. We strongly encourage students attendance at international conferences, and we operate a publication-focussed lab culture that allows students to publish manuscripts at an early stage.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck.

References

PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Loynes CA, Lee JA, Robertson AL, Steel MJG, Ellet Ft, Feng Y, Levy BD, Whyte MK, Renshaw SA. Science Advances 2018 4(9), eaar8320

A Spaeztle-like role for Nerve Growth Factor b in vertebrate immunity to Staphylococcus aureus. Hepburn L, Prajsnar TK, Klapholz C, Moreno P, Loynes CA, Ogryzko NV, Brown K, Schiebler M, Hegyi K, Antrobus R, Hammond KL, Connolly J, Ochoa B, Bryant C, Otto M, Surewaard B, Seneviratne SL, Grogono DM, Cachat J, Ny T, Kaser A, Rorok ME, Peacock SJ, Holden M, Blundell T, Wang L, Ligoxygakis P, Minichiello L, Woods CG, Foster SJ Renshaw SA*& Floto RA* Science 2014 Oct 31;346(6209):641-6. *Joint corresponding authors.

A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism. Robertson AL, Holmes GR, Bojarczuk AN, Burgon J, Loynes CA, Chimen M, Sawtell AK, Hamza B, Willson J, Walmsley SR, Anderson SR, Coles MC, Farrow SN, Solari R, Jones S, Prince LR, Irimia D, Rainger E, Kadirkamanathan V, Whyte MKB and Renshaw SA. Science Translational Medicine 2014 6 (225) p225ra29.

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