Sarah Walmsley (Affiliate)
Hypoxic regulation of neutrophilic inflammation
Research in a Nutshell
Hypoxia and limited nutrient availability frequently characterize the inflammatory site. My work has focused on understanding the importance of hypoxia, metabolic adaptations and the oxygen sensing HIF/hydroxylase pathway in defining outcomes of neutrophilic inflammation in the context of host pathogen responses, and more recently in the cancer niche. This work has resulted in three inter-related observations and future programs of work.
1. Interaction between hypoxia and the host response
Our group is exploring the interaction between hypoxia and the host response. This is important because hypoxia and bacterial infection frequently co-exist and are associated with adverse outcomes. In the context of acute hypoxia, both local bacterial infection and systemic infection results in rapidly progressive neutrophil-mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. This response is ameliorated by prior exposure of animals. How hypoxia preconditions the neutrophil response remains an area of considerable research interest.
2. Regulation of neutrophil survival and function by the HIF/hydroxylase pathway
Unique to the neutrophil hypoxia is a profound survival stimulus. Neutrophils both sense oxygen and respond to changes in oxygenation via the HIF pathway, which involves regulation of the transcription factor hypoxia inducible factor (HIF) by von Hippel Lindau protein and a group of oxygen sensitive hydroxylases – prolyl hydroxylase domain (PHD) containing enzymes and factor inhibiting HIF (FIH). A greater understanding of the mechanisms by which the members of his oxygen sensitive pathway regulate neutrophil responses in health and disease states will be critical in developing strategies to limit neutrophilic inflammation.
3. Metabolic specialisation of neutrophils
Neutrophils demonstrate metabolic adaptations that enable them to function at sites of limited oxygen availability for example in the cancer niche. How interplay between oxygen sensing responses and metabolite utilization define neutrophil activation, function and survival both during acute inflammatory responses and in both local and metastatic cancer niches remains to be explored.
|Patricia Coelho||MRC Clinical Training Fellow|
|Rebecca Dickinson||MRC Clinical Training Fellow|
|Cathy Doherty||Research Assistant|
|Robert Grecian||CRUK ECAT Fellow|
|Alison Harris||Post doctoral Research Fellow|
|Jessie May-Morgan||EPSRC and MRC CDT in Optical Medical Imaging PhD student|
|Ananda Mirchandani||Wellcome Postdoctoral Clinical Fellow|
|Fiona Murphy||Research Fellow|
|Tracie Plant||ECAT Fellow|
|Eilise Ryan||Clinical Research Fellow|
|Pranvera Sadiku||Post Doctoral Research Fellow|
|Emily Watts||Clinical Research Fellow|
|Joseph Wilson||EPSRC and MRC CDT in Optical Medical Imaging PhD student|
- Professor Ratcliffe and Professor Pugh, University of Oxford
- Professor Schofield, University of Oxford
- Professor Cantrell, University of Dundee
- Professor Dockrell, University of Edinburgh
- Professor Carmeliet, VIB and KU Leuven
- Professor Mazzone, VIB and KU Leuven
Partners and Funders
- Wellcome Trust
- Medical Research Council