Mathematical modelling to understand homeostasis and bacterial infection in human gastric glands

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The human stomach is organized into millions of deep invaginations, called gastric glands, which have a well-defined architecture and are covered by a monolayer of epithelial cells. Each gland contains two distinct pools of stem cells: slow-cycling stem cells maintain the epithelium in the lower regions; actively cycling stem cells maintain the upper regions where cell turnover is rapid. Parietal cells secrete gastric acid and are crucial to the normal function of the stomach. They have also been shown to act as a barrier to adjacent cell proliferation, and so regulate gland regeneration. The mechanisms by which gastric glands are maintained under normal conditions, and the processes driving regeneration following injury, remain to be fully understood. To improve our understanding of normal and pathological gland physiology, I have developed a multicellular stochastic model of gastric gland cellular dynamics, focusing on stem cell proliferation, regeneration, and cell fate specification. During my PhD, I aim to extend this model to a larger scale, spatially resolved two- or three-dimensional model that captures more complex dynamics of gastric glands. These models will incorporate morphogen gradients (such as BMP, EGF and Noggin), mutation, and axial proliferation and movement of cells along the glands. As parallel work, I plan to analyse and model cellular pattern formation of two-dimensional mucosoids. These mucosoids can simulate different sections of the gland when fed different combinations of signalling proteins, and so can aid in designing accurate models of the full gland with different cell types at appropriate frequencies throughout. Through this modelling, I hope to understand how homeostasis is maintained in human gastric glands and how this homeostasis can be disrupted by bacterial infection. I aim to explore how infection by helicobacter pylori can lead to gastric cancer and the morphological changes the glands undergo in the progression towards carcinogenesis. The stomach is a model organ for such investigations, and this work will aid understanding in the study of the causes of other cancers. This project falls within the EPSRC mathematical biology and physical sciences research areas. I will undertake this research under supervision of Prof. Helen Byrne and Prof. Ruth Baker at the mathematical institute in collaboration with Dr Francesco Boccellato at the Ludwig Institute for Cancer Research. The Boccellato group will undertake experiments in parallel with our modelling work, which will allow accurate parameterisation of models and provide a biological basis for comparison with the simulated results.