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

人的胃被组织成数百万个深度内陷，被称为胃腺，这些腺体具有明确的结构，并被单层上皮细胞覆盖。每个腺体包含两个不同的干细胞池：慢周期干细胞维持较低区域的上皮；积极循环干细胞维持细胞周转较快的较高区域。壁细胞分泌胃酸，对胃的正常功能至关重要。它们也被证明是邻近细胞增殖的屏障，因此调节腺体再生。胃腺在正常条件下维持的机制，以及损伤后驱动再生的过程，仍有待完全了解。为了提高我们对正常和病理腺体生理学的理解，我建立了胃腺细胞动力学的多细胞随机模型，重点研究干细胞的增殖、再生和细胞命运的指定。在我的博士学位期间，我的目标是将这个模型扩展到更大规模的、空间分辨率更高的二维或三维模型，以捕捉更复杂的胃腺动力学。这些模型将包括形态梯度(如BMP、EGF和Noggin)、突变以及细胞沿腺的轴向增殖和移动。作为平行工作，我计划分析和模拟二维粘液样体的细胞模式形成。当喂食不同的信号蛋白组合时，这些粘液体可以模拟腺体的不同部分，因此可以帮助在整个过程中以适当的频率设计具有不同细胞类型的完整腺体的准确模型。通过这个模型，我希望了解人类胃腺如何维持内环境平衡，以及细菌感染如何破坏这种内环境平衡。我的目标是探索幽门螺杆菌感染是如何导致胃癌的，以及在癌变过程中腺体所经历的形态变化。胃是这类研究的模型器官，这项工作将有助于理解其他癌症的原因。该项目属于EPSRC数学、生物学和物理科学研究领域。我将在数学研究所的海伦·伯恩教授和露丝·贝克教授的监督下，与路德维希癌症研究所的弗朗西斯科·博切拉托博士合作进行这项研究。Boccellato团队将在我们的建模工作的同时进行实验，这将允许精确的模型参数设置，并为与模拟结果进行比较提供生物学基础。

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.