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Deciphering the mechanism of enclysis: new tools for cell biology in live human tissues.


Project Description

Background. We recently discovered that hepatocytes, epithelial cells that make up 80% of the liver, can preferentially engulf and delete T cell subsets that dampen inflammation (regulatory T cells, Tregs). We termed this process enclysis (enclosure + lysis) and it is more similar to macropinocytosis (cell internalisation of large amounts of fluid) than the phagocytosis of dead cells, when we investigate cell membrane alterations. Our team has also established methodology to preserve human livers ex vivo with continuous perfusion, in a manner that enables time lapse multiphoton imaging without harming hepatocytes.

Project Aim. To adapt cell biology techniques designed to study membrane alterations, intracellular vesicle communication and molecular mechanisms of endocytosis, to study live human hepatocytes in situ in human liver wedges.

Our team. To define the mechanism of the newly described biological phenomenon of enclysis, we have composed a team that brings together expertise from Biosciences, Chemistry, Cell biology and Immunology, from Universities of Birmingham and Warwick. Dr. Zania Stamataki is a liver immunologist and senior lecturer at the University of Birmingham (MDS, UoB) that described enclysis (Davies et al., Cell Reports, 2019), and works together with Professor Jon Preece (Chemistry, UoB) who generated novel fluorochromes ideal for use in perfused human liver tissue in multi-photon microscopy. We established a high content assay to measure enclysis in hepatocytes, and validated it for use in small molecule screening for enclysis inhibitors. Professor Jason Mercer, an expert in macropinocytosis and high content imaging, is moving to UoB from MRC-LMCB at UCL and has a long track record for bioinformatic analyses of large datasets. Professor Steve Royle from University of Warwick (UoW), brings cell biology expertise in endocytosis. We also collaborate with Professor David Hodson (MDS, UoB), who is a biophotonics expert with knowledge in cell metabolism. This studentship is a great opportunity to bring together a multi-disciplinary team to understand the mechanism of a new cellular process.

Project milestones:
1. Multiphoton training -imaging live human liver
• Select optimal fluorochrome combinations for T cell and hepatocyte viability
• Evaluate readouts for cell migration, metabolic activity (speed, trajectory, mitochondrial activity, endocytic processes)
 Outcomes: validate new fluorochromes in human tissue, bioinformatics training

2. Enclysis mechanism -cytoskeletal and membrane processes
• Perform high content assays to identify the effects of known endocytosis modulators in enclysis
• Validate targets in authentic human disease livers perfused ex vivo
 Outcomes: Understand biology -biochemistry/high content imaging

3. Enclysis mechanism -surface receptors and signalling
• Establish trafficking of fluorescently tagged enclysis receptors in super-resolution imaging (ICAM-1, beta-catenin, others)
• Inhibit enclysis receptors and signalling molecules in vitro and in ex vivo perfused livers (blocking antibodies, small molecules)
 Outcomes: Understand biology -genetic modification/super-resolution imaging

Training. The student will have access to the world-class imaging facilities and associated analyses tools through Birmingham Advanced Light Microscopy Centre, the Centre of Membrane Proteins and Receptors (COMPARE) (UoB) and Centre for Mechanochemical Cell Biology (UoW). Based in the largest solid organ transplant centre in Europe, the student will have access to ~2 explant livers per week, which is unparalleled access to human tissue. The primary supervisor has supervised three award-winning PhD students to completion as a first supervisor, is a trained “Mental Health for PGR” champion and a co-founder for the MDS mentoring scheme.

We would love to discuss the project with you in more detail. Please contact for more information, deadline for applications is the 6th of January 2020.

Funding Notes

The Midlands Integrative Biosciences Training Partnership (MIBTP) is a BBSRC-funded doctoral training partnership between the universities of Warwick, Birmingham and Leicester. It delivers innovative, world-class research training across the Life Sciences to boost the growing Bioeconomy across the UK. View Website

Please check your eligibility for funding here: View Website

References

Hepatocytes Delete Regulatory T Cells by Enclysis, a CD4+ T Cell Engulfment Process. Davies SP, Reynolds GM, Wilkinson AL, Li X, Rose R, Leekha M, Liu YS, Gandhi R, Buckroyd E, Grove J, Barnes NM, May RC, Hubscher SG, Adams DH, Huang Y, Qureshi O, Stamataki Z. Cell Rep. 2019 Nov 5;29(6):1610-1620.e4. doi: 10.1016/j.celrep.2019.09.068.

Nanoscale polarization of the entry fusion complex of vaccinia virus drives efficient fusion. Gray RDM, Albrecht D, Beerli C, Huttunen M, Cohen GH, White IJ, Burden JJ, Henriques R, Mercer J. Nat Microbiol. 2019 Oct;4(10):1636-1644. doi: 10.1038/s41564-019-0488-4.

High-Content Analyses of Vaccinia Plaque Formation. Yakimovich A, Mercer J. Methods Mol Biol. 2019;2023:237-253. doi: 10.1007/978-1-4939-9593-6_15.

Tumor protein D54 defines a new class of intracellular transport vesicles. Larocque G, La-Borde PJ, Clarke NI, Carter NJ, Royle SJ.
J Cell Biol. 2019 Oct 31. pii: jcb.201812044. doi: 10.1083/jcb.201812044.

Optical tools for understanding the complexity of β-cell signalling and insulin release. Frank JA, Broichhagen J, Yushchenko DA, Trauner D, Schultz C, Hodson DJ. Nat Rev Endocrinol. 2018 Dec;14(12):721-737. doi: 10.1038/s41574-018-0105-2.

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