Signalling pathways of leukocyte migration in silico

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.

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

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

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

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

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

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

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

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

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

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

Liepe J et al. (2014). Modelling proteasome and proteasome regulator activities. Biomolecules 4(2):585-99. doi: 10.3390/biom4020585

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

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

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Fellowship

Status:

Closed

Principal investigator

Dr Juliane Liepe

Institution

Imperial College London

Grant reference number

NC/K001949/1

Award date:

Aug 2013 - Oct 2016

Grant amount

£195,000