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Molecular regulation of neutrophil responses in inflammation. (#202011)

About This PhD Project

Project Description

Neutrophils exert anti-microbial activity through several mechanisms including release of cytotoxic products, reactive oxygen species (ROS), neutrophil extracellular traps (NETs) and pore-forming molecules (1). These activities cause tissue damage if poorly controlled. Our work 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 leads to significant improvement in the pathogenesis of inflammatory arthritis and other forms of acute inflammation (2,3).

The molecular control of pathogenic neutrophil responses is largely unknown. We have recently developed a state-of-the-art genomic platform (4) to reveal transcriptional circuits that control neutrophil function and identified novel putative regulators. The identified transcriptional regulators were functionally validated using genetic CRISPR-Cas9 mediated ablation ex vivo. We assessed the ability of genetically modified neutrophils to control the production of inflammatory mediators and ROS, form NETs etc and highlighted the regulators that were essential for neutrophil maturation and/or activation. We are currently developing new mouse models for neutrophil-specific deletion of the identified key regulators.

The goal of this project is to generate the regulatory blueprint of neutrophil states en route to the tissue and in a signal-driven microenvironment based on the already identified and functionally validated novel neutrophil regulators. This will be done by using a combination of advanced genomic, epigenomic, immunological techniques, including cutting edge single cell technologies. The mechanistic multi-scale computational models will be used to provide a knowledge constrained framework for quantitative analysis and interpretation of resulting experimental data (5). The new mouse models will be generated and used during the DPhil project to validate the role of the identified key regulators in various neutrophil-driven inflammatory conditions in vivo.

The outcome of this study is expected to progress fundamental biology of neutrophils, increase our understanding of neutrophil activated subsets in disease and aid the development of new targets for therapeutic interventions in inflammatory disorders.

Training Opportunities

The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Training will be provided in techniques in a wide range of functional genomics approaches (RNA-Seq, ATAC-Seq, ChIP-Seq), immunological (cell isolation, tissue culture, FACS), and imaging (immunofluorescence on tissue sections) approaches, as well as cutting edge single cell platforms (10x, CyTOF) and computational pipelines. Recently developed novel in vivo models of inflammatory diseases will be extensively used and new models will be generated. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. Students will attend weekly seminars within the department and those relevant in the wider University. Students will be expected to present data regularly to the department, the Genomics of Inflammation group and to attend external conferences to present their research globally. Students will also have the opportunity to work closely with members of the Rheumatoid Arthritis Pathogenesis Centre of Excellence (Glasgow/Birmingham/Newcastle/Oxford) as well as Novonordisk Immunometabolism consortium (Oxford/Karolinska Institute/University of Copenhagen).

Key Publications

(1) Ng LG, Ostuni R, Hidalgo A. Heterogeneity of neutrophils. Nature Reviews Immunology. 2019, 19(4):255-265.

(2) Weiss M, Byrne AJ, Blazek K, Saliba DG, Pease JD, Perocheau D, Feldmann M, Udalova IA. IRF5 controls both acute and chronic inflammation. Proceedings of the National Academy of Sciences. 2015, 112(35):11001-6.

(3) 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-1-production. Journal of Experimental Medicine. 2015, 212(6):845-53.

(4) 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 Reports. 2014 Sep 11;8(5):1308-17.

(5) Jansen JE, Gaffney EA, Wagg J, Coles MC. Combining Mathematical Models With Experimentation to Drive Novel Mechanistic Insights Into Macrophage Function. Frontiers in Immunology. 2019,10:1283

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