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EASTBIO Dissecting the role of the immune system in tumour initiation using experimental & computational analysis


Project Description

The mechanisms that modulate the pre-neoplastic stage of tumourigenesis in vivo are largely unknown due to the lack of suitable animal models. Our previous work with a zebrafish tumour initiation model has revealed a supportive role of the host innate immune system during pre-neoplastic development. Our in vivo live imaging studies allowed us to directly visualize leukocyte (neutrophils and macrophages) migration toward the pre-neoplastic cell (PNC) at its inception, however the precise identity of attractants that modulate leukocyte migration toward the PNC remain unclear. So far, we have identified H2O2 as one of the earliest signals required for leukocyte recruitment to the PNC, analogous to that of leukocyte recruitment following tissue damage. More recently, we found that leukocytes take advantage of pre-existing gaps in the basement membrane to gain access to PNCs, and PNCs residing in the vicinity of the basement membrane gap gain growth advantage due to increased interaction with leukocytes. Our data suggest that in vivo both mechanical and chemical factors impact on leukocyte recruitment and interaction with PNCs. Previously, an inference-based computational approach was used to extract information concerning the spatio -temporal properties of the putative attractants from in vivo inflammatory cell migration during wound inflammation [3]. Here we propose to develop a similar computational framework based on existing approaches to analyse leukocyte dynamics in the PNC niche. We aim to determine spatio-temporal properties of the attractants within the PNC niche, and to characterise the dynamics of leukocyte retention therein so as to generate a testable hypotheses concerning the underlying molecular mechanism. Based on the analysis of our findings, we will attempt to modulate the PNC niche so as to test the hypotheses. More importantly, we will examine PNC progression under conditions where leukocyte recruitment toward the PNC is altered. Ultimately, a better understanding of how leukocytes sense the environment, integrate incoming signals and navigate in vivo in the PNC niche will provide us with an opportunity to target leukocyte/ PNC interaction, and subsequently block PNC development for therapeutic intervention.

The student will receive training in relevant ‘wet lab’ techniques and microscopy/image analysis, while working with existing preliminary data and computational tools for modelling and analysis of immune cell migration.

This project is a great opportunity for students with previous experience in mathematics or statistics and interest in computer programming. The student will benefit from integration in an active biomedical research environment at the Centre for Inflammation Research and Centre for Regenerative Medicine.

Training in professional and research skills will be tailored to the individual student’s background and training needs. The student’s critical understanding of primary data and research literature will be advanced through regular group meetings and journal clubs. The student will also have the opportunity to engage with the mathematical and systems biology research community at other departments in Edinburgh.

Application Process:

For instructions on how to apply for an EASTBIO PhD studentship please refer to http://www.eastscotbiodtp.ac.uk/how-apply-0

Contact Dr Yi Feng and Dr Linus Schumacher before you apply.

Please submit all required documents directly to

We anticipate that our first set of interviews will be in the week commencing 10th February 2020 with awards made the following week.

The research group is located in the University of Edinburgh Centre for Inflammation Research; a world-class research environment at the interface between biological and medical science, with multidisciplinary groupings focused on inflammation, infection, disease and repair. The Centre is based within the Edinburgh Medical School in the outstanding facilities of the Queen’s Medical Research Institute at the site of the Royal Infirmary of Edinburgh hospital, maximising future translational opportunities.

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body.

References

1. Ramezani T., et al. Live Imaging of Innate Immune and Pre-neoplastic Cell Interactions using an Inducible Gal4/UAS Expression System in Larval Zebrafish Skin. JoVE (2015) Feb. PMCID: PMC4354608

2. van den Berg et al. Proteolytic and Opportunistic Breaching of the Basement Membrane Zone by Immune Cells during Tumor Initiation. Cell Rep. (2019) 27(10):2837-2846. PMID: 31167131

3. Weavers, et al. Systems Analysis of the Dynamic Inflammatory Response to Tissue Damage Reveals Spatiotemporal Properties of the Wound Attractant Gradient. Curr. Biol. 2016;26(15):1975–1989. http://dx.doi.org/10.1016/j.cub.2016.06.012.


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