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Genomic landscape of neutrophil states in inflammation: morphology, behaviour, function and interactions


   Kennedy Institute of Rheumatology

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  Prof Irina Udalova, Prof H Byrne, Dr Abhinandan Devaprasad  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Neutrophils represent a major arm of the innate immune defence system, with a long- held view of them being transcriptionally inactive, fast responders, mobilised in response to microbial and tissue insults. Recent developments in the field have changed this perception and firmly positioned neutrophils as transcriptionally active cells with the ability to adapt their transcriptional program. Our recent findings demonstrate that, despite limited residence times in tissues, neutrophils can tailor their properties to support organ homeostasis and mount tissue specific and transcriptionally regulated inflammatory response1,2. Importantly, in inflammation neutrophils are presented as functionally, morphologically and behaviourally heterogeneous cells in circulation and tissue3.

The goal of this project is to reveal transcriptional circuits that control neutrophil differentiation and function in a signal-driven microenvironment. In particular, we aim to discover what transcriptional regulators control stage-specific expression of (1) cytoskeletal genes, that establish structural function and transcriptional regulation in the cell nucleus and distinct morphological features; (2) leukocyte migration and cell-cell interaction genes, responsible for distinct behaviour of neutrophils in the vasculature and tissue and (3) inflammatory response genes. This will be done by using a combination of cutting-edge imaging, genomic and spatial single cell transcriptomic approaches, as well as advanced immunological techniques2. Mathematical modelling of transcriptional circuits will be applied to understand the interaction between neutrophil development and activation. The project will also explore the spatial interactions of neutrophils with other immune cells in tissue using spatial transcriptomic and multimodal imaging data4. It will benefit from the already generated by us multiple genomic datasets and unique tools, such as genetically modified in vitro and in vivo models based on the recently discovered new key regulators2.

The outcomes of this study are expected to progress fundamental biology of neutrophils and increase our understanding of neutrophil subsets in disease. This will ultimately lead to the development of a new class of therapeutic strategies, based on selective modulation of neutrophil biology, for therapeutic interventions in inflammatory disorders5.

Training Opportunities

The Kennedy Institute is a world-renowned research centre and is housed in a state-of-the-art research facility. Training will be provided in a wide range of functional genomics approaches (e.g. RNA-Seq, ATAC-Seq, ChIP-Seq etc), immunological (cell isolation, tissue culture, FACS), and imaging (immunofluorescence on tissue sections) approaches, as well as cutting edge single cell platforms (10x, Nanostring GeoMx, Nanostring CosMx) 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 strong foundation across a broad range of subjects, including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. The student will attend weekly seminars within the department and those relevant in the wider University. They will present their research regularly to the department and the Genomics of Inflammation group, and at the Computational Genomics Forum. They will also attend external conferences at which they will present their research to a global audience.  The student will also have the opportunity to work closely with members of the Wolfson Centre for Mathematical Biology at the Mathematical Institute, University of Oxford, and to further broaden their theoretical knowledge by attending lecture courses in mathematical biology, statistics and related subjects.


References

(1) Ballesteros I, Rubio-Ponce A, Genua M, Lusito E, Kwok I, Fernández-Calvo G, Khoyratty TE, van Grinsven E, González-Hernández S, Nicolás-Ávila JÁ, Vicanolo T, Maccataio A, Benguría A, Li JL, Adrover JM, Aroca-Crevillen A, Quintana JA, Martín-Salamanca S, Mayo F, Ascher S, Barbiera G, Soehnlein O, Gunzer M, Ginhoux F, Sánchez-Cabo F, Nistal-Villán E, Schulz C, Dopazo A, Reinhardt C, Udalova IA, Ng LG, Ostuni R, Hidalgo A. Co-option of Neutrophil Fates by Tissue Environments. Cell. 2020 Nov 25;183(5):1282-1297.e18.
(2) Khoyratty T*, Ai Z*, Ballesteros I, Mathie S, Eames HL, Martín-Salamanca S, Wang L, Hemmings A, Willemsen N, von Werz V, Zehrer A, Walzog B, van Grinsven E, Hidalgo A, Udalova IA. Distinct transcription factor networks control neutrophil-driven inflammation. Nature Immunology, 2021 Sep;22(9):1093-1106.
(3) Wang L, Luqmani R, Udalova IA. The role of neutrophils in rheumatic disease-associated vascular inflammation. Nature Reviews Rheumatology. 2022 Mar;18(3):158-170.
(4) O Vipond, JA Bull, PS Macklin, U Tillman, CW Pugh, HM Byrne, HA Harrington (2021). Multiparameter persistent homology landscapes identify immune cell spatial patterns in tumours. PNAS 118 (41): e2102166118.
(5) Devaprasad A, Radstake TRDJ, Pandit A. Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies. Frontiers in Immunology. 2021 May 24;12:669400.
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