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.
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.
The aim of this project is to develop zebrafish as an in silico system to study the dynamical processes of the innate immune response. The transparent skin of zebrafish embryos made it an ideal model organism to investigate cell migration processes using fluorescent time-lapse microscopy. The innate immune system of zebrafish embryos closely resembles that of humans and is at early stages clearly separable from the adaptive response.
Many different data types, such as cell migration imaging data or transcriptomics data, have been collected over the past years. However, the full potential of such data has not been explored so far. I will perform a detailed network analysis of immune cell signalling pathways in zebrafish. The constructed network will be used to generate an improved model of macrophage and neutrophil migration during acute injury. In particular, the cell dynamics will be described by an agent-based hybrid model, which will capture the internal cellular signalling process of each individual cell, as well as the migration process inside the extracellular matrix. Most cell migration data have been analysed using simple statistics, e.g. the velocity of a cell or the straightness index of a cell. Such statistics fail to describe the detailed migration process. I will further develop random walk models and analysis tools to identify migration patterns in 2D, but even more important in 3D. The developed algorithms will provide powerful tools to study migration processes. The analysis of leukocyte migration in 3D will be the basis to develop a 3D in silico model of the innate immune response in zebrafish. This model will be extended to the whole organism level.
Liepe J, Sim A, Weavers H, Ward L, Martin P, Stumpf MP (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.
Jones PJ, Sim A, Taylor HB, Bugeon L, Dallman MJ, Pereira B, Stumpf MP, Liepe J (2015). Inference of random walk models to describe leukocyte migration. Phys Biol 12(6): 066001. doi: 10.1088/1478-3975/12/6/066001.