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Optogenetic programming of inflammation - in vivo Opto-GPCR approaches in neutrophils.


Project Description

White blood cells called 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, we have shown that neutrophils can transit from a harmless quiescent phenotype through a primed state, to a toxic, activated phenotype and back again. There is emerging evidence that the ability to modify neutrophil phenotype (plasticity) 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 functional plasticity is regulated, how it governs the fate of individual neutrophils, and how it contributes to inflammatory diseases. This project aims to help understand neutrophil plasticity and 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 neutrophils 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 student attendance at international conferences, and we operate a publication-focussed lab culture that allows students to publish manuscripts at an early stage.

Funding Notes

Funding:
These studentships will be 42 months in duration, and include home fee and stipend at UKRI rate.

Eligibility:
Candidates must have a first or upper second class honors degree or significant research experience.

References

Enquiries:
Interested candidates should in the first instance contact Prof Steve Renshaw ([email protected])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Infection, Immunity & Cardiovascular Disease' as the department.

Deadline for applications is 5pm on Wednesday 29th January 2020. Late applications will not be accepted. Interviews are scheduled to be held on Tuesday 25th February 2020.

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