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Dr Steve Renshaw

MRC Senior Clinical Fellow

I studied medical sciences at Cambridge before moving to Oxford, where I qualified as a doctor in 1994. I then moved through various junior doctor posts until I ended up in Nottingham. After passing my MRCP I moved to Sheffield to take up a Wellcome Trust Clinical Training Fellowship, to work on the role of death receptor signalling in the regulation of neutrophil lifespan in inflammation with Professor Moira Whyte. I was awarded my PhD in 2001, and became Clinical Lecturer in Respiratory Medicine. I somehow managed to complete my specialist training in respiratory and general medicine at the same time as taking my research forward in new directions. In 2004 I was awarded an MRC Clinician Scientist Fellowship, to work with Professor Ingham in Biomedical Sciences to take my work forward in a zebrafish model of inflammation. In 2008 I was awarded an MRC Senior Clinical Fellowship to continue these studies. I am also an honorary consultant physician at Sheffield Hospitals NHSFT, working in respiratory medicine.

Research

Summary for nonspecialist

Inflammatory diseases such as emphysema, asthma, heart disease and arthritis cause much illness in the developed world. We have little understanding of how the severe inflammation associated with something like pneumonia can completely resolve, while other sorts of inflammation persist with associated tissue damage.

In fact, we know little of the processes that cause resolution of inflammation in any setting. There is considerable evidence that the main inflammatory cell, the neutrophil, turns itself off by a process called apoptosis (=programmed cell death), and is then recognised by macrophages and then removed. What triggers this process in neutrophils is not known.

If we could find this out, we would be a step closer to understanding inflammatory disease, and might have new ideas about the sorts of treatments that might be successful. In order to fully explore the molecular events determining neutrophil lifespan, I have set up a model system in which the genes controlling resolution of inflammation can be identified.

 The model I have chosen is the Zebrafish, which is both genetically manipulable and transparent, leading to easy visualisation of neutrophils during development. I am currently studying inflammation in this system, and characterising how it resolves. This model allows me to test the ability of a range of candidate genes to influence the resolution of inflammation, and additionally to screen for novel genes involved in this process. These studies aim to identify the genes important in the resolution of inflammation, and so understand how this is dysregulated in chronic inflammatory disease.

Timelapse images showing a neutrophil involved in the inflammatory response in a zebrafish tail. The images show a transgenic zebrafish expressing a nuclear targeted Green Fluorescent protein specifically in the neutrophil lineage. The dynamic nature of both the neutrophil and its polymorphic nucleus can be clearly seen.

Technical Summary

Inflammatory diseases are widespread, life-threatening and poorly responsive to current treatments. I am working to understand how the resolution of inflammation is regulated at a molecular level with a view to developing new therapies for inflammatory disease.

The Zebrafish is an ideal model which is both genetically manipulable and transparent, leading to easy visualisation of neutrophils during development. We are characterising inflammation in this model, and using transgenic approaches to visualise inflammation in vivo in real-time, and characterising how it resolves.

This model allows me to test the ability of a range of candidate genes to influence the resolution of inflammation, by morpholino antisense knockdown and overexpression.

3 dimernsional representation of spinning disc confocal data showing movement of inflammatory neutrophils through the tailfin of a zebrafish following an inflammatory stimulus.

In addition, we are screening for novel genes involved in this process. These studies aim to identify the genes important in the resolution of inflammation, and so understand how this is dysregulated in chronic inflammatory disease.

A confocal image showing neutrophils (green) and apoptotic cells (red) during resolution of inflammation. Dual stained cells are seen, demonstrating the presence of apoptotic neutrophils during the resolution of inflammation in vivo.

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