NDORMS DPhil & MSc by Research
Neutrophil heterogeneity in inflammation: scope for selective targeting?
Our recent studies confirmed that neutrophils play a central role in the initiation and perpetuation of aberrant immune responses and organ damage and that modulation of their numbers and functions by two independent approaches (IRF5 inhibition (1) or treatment with IFN-lambda (2)) leads to significant improvement in the pathogenesis of inflammatory arthritis and other forms of acute inflammation. Others have highlighted a remarkable phenotypic diversity of neutrophils at homeostasis and demonstrated the suitability of genomic analyses to neutrophil characterisation.
This project is set to extend the phenotypic characterisation of neutrophils to specific neutrophil subsets present at sites of inflammation in vivo using the state-of-the-art genomic approaches (3) and identify common and microenvironment specific signatures. This is important for understanding the regulation of distinct neutrophil subsets during an immune response and for designing strategies for their selective targeting. As an example of selective targeting, the project will ascertain which specific aspects of neutrophil function are affected by treatment with IFN-lambda.
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Full training will be provided in a range of functional genomics approaches (RNA-Seq, ATAC-Seq, ChIP-Seq, CyTOF), cellular techniques (cell isolation, tissue culture, FACS, CyTOF) techniques and animal models of inflammation under supervision of Prof Udalova and with support of other members of the group. Dr Sansom will provide an expertise with the genome datasets analyses. Subject-specific training will be received through the groups' weekly meetings. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in immunology, inflammation and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Students will also attend external scientific conferences where they will be expected to present the research findings.
(1) Weiss M, Byrne AJ, Blazek K, Saliba DG, Pease JD, Perocheau D, Feldmann M, Udalova IA. IRF5 controls both acute and chronic inflammation. PNAS. 2015 doi:10.1073/pnas.1506254112. (2) Blazek K, Eames HL, Weiss M, Byrne AJ, Perocheau D, Pease JD, Doyle S, McCann F, Williams RO, Udalova IA. IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1β production. J Exp Med. 2015, Jun 1;212(6):845-53. (3) Saliba DG, Heger A, Eames HL, Oikonomopoulos S, Teixeira A, Blazek K, Androulidaki A, Wong D, Goh FG, Weiss M, Byrne A, Pasparakis M, Ragoussis J, Udalova IA. IRF5:RelA interaction targets inflammatory genes in macrophages. Cell Rep. 2014 Sep 11;8(5):1308-17.