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Fellowship

Signalling pathways of leukocyte migration in silico

Dr Juliane Liepe

At a glance

Completed
Award date
August 2013 - October 2016
Grant amount
£195,000
Principal investigator
Dr Juliane Liepe
Institute
Imperial College London

R

  • Replacement
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View the grant profile on GtR

Contents

Overview

Aims

This project aims to develop mathematical and computational models of immune cell migration following acute injury in the zebrafish embryo, providing new tools for replacing and reducing some animal studies on inflammation and the immune response. 

Background

After an injury, immune cells migrate through the tissue to the site of the injury. Understanding the molecular and cellular mechanisms underlying this response are key research questions. The zebrafish embryo is increasingly used for studies on inflammation, partly because it is transparent and therefore amenable to studying cell migration using fluorescent time lapse microscopy. The innate immune system of zebrafish embryos closely resembles that of mammals and therefore new models and tools developed in the fish have the potential to be extrapolated to minimise the use of mice in some inflammation studies.

Research details and methods

Historical data on cell migration from imaging and transcriptomic studies will be used to develop in silico models of macrophage and neutrophil migration following acute injury, focusing on intracellular signalling processes and migration through the extracellular matrix. The new model will provide a system to test hypotheses in order to better inform in vivo studies and avoid uninformative animal experiments.

Impacts

Publications

  1. MacLean AL et al. (2017). Single Cell Phenotyping Reveals Heterogeneity Among Hematopoietic Stem Cells Following Infection. Stem Cells 35(11):2292-2304. doi: 10.1002/stem.2692
  2. Liepe J et al. (2016). Accurate reconstruction of cell and particle tracks from 3D live imaging data. Cell Syst 3(1):102-7. doi: 10.1016/j.cels.2016.06.002
  3. Liepe J et al. (2016). A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science (New York, N.Y.) 354(6310):354-358. doi: 10.1126/science.aaf4384
  4. Platteel AC et al. (2016). CD8(+) T cells of Listeria monocytogenes-infected mice recognize both linear and spliced proteasome products. European Journal of Immunology 46(5):1109-18. doi: 10.1002/eji.201545989
  5. Weavers H et al. (2016). Systems Analysis of the Dynamic Inflammatory Response to Tissue Damage Reveals Spatiotemporal Properties of the Wound Attractant Gradient. Current Biology 26(15):1975-89. doi: 10.1016/j.cub.2016.06.012
  6. Jones PJ et al. (2015). Inference of random walk models to describe leukocyte migration. Phys Biol 12(6):066001. doi: 10.1088/1478-3975/12/6/066001
  7. Liepe J et al. (2015). Quantitative time-resolved analysis reveals intricate, differential regulation of standard- and immuno-proteasomes. eLife 4:e07545. doi: 10.7554/eLife.07545
  8. Sim A et al. (2015). Goldstein-Kac telegraph processes with random speeds: Path probabilities, likelihoods, and reported Lévy flights. Physical Review E 91(4):042115 doi: 10.1103/PhysRevE.91.042115
  9. Textoris-Taube K et al. (2015). The T210M Substitution in the HLA-a*02:01 gp100 Epitope Strongly Affects Overall Proteasomal Cleavage Site Usage and Antigen Processing. The Journal of Biological Chemistry 290(51):30417-28. doi: 10.1074/jbc.M115.695189
  10. Liepe J et al. (2014). A framework for parameter estimation and model selection from experimental data in systems biology using approximate Bayesian computation. Nature Protocols 9(2):439-56. doi: 10.1038/nprot.2014.025
  11. Liepe J et al. (2014). Modelling proteasome and proteasome regulator activities. Biomolecules 4(2):585-99. doi: 10.3390/biom4020585
  12. Mc Mahon SS et al. (2014). Information theory and signal transduction systems: from molecular information processing to network inference. Seminars in Cell & Developmental Biology 35:98-108. doi: 10.1016/j.semcdb.2014.06.011
  13. Mishto M et al. (2014). Proteasome isoforms exhibit only quantitative differences in cleavage and epitope generation. European Journal of Immunology 44(12):3508-21. doi: 10.1002/eji.201444902