Modeling gastric mucus layer physiology

这项提议汇集了一个由应用数学家、实验物理学家、工程师、 和生物学家，在生物凝胶、粘液物理、微生物学和细菌运动性方面具有专业知识，以及 胃肠病学要解决一个重要的生理学和病理学问题：胃粘液层是如何 以及它如何对感染细菌以及胃的拓扑结构和大小的变化做出反应 有机化合物(GO)。胃上皮细胞分泌粘蛋白，形成粘液层，保护胃粘膜 来自恶劣环境的胃腔上皮，它是酸性的，含有消化成分 胃酶等酶。上皮细胞还分泌酸、中和碳酸氢盐和胃蛋白酶原，即 胃酶的非活性前体。 这些分泌物形成一个复杂的耦合系统，因为粘蛋白的流变性取决于pH和离子 强度上，酸可以被带负电荷的粘蛋白结合，离子和粘蛋白静电相互作用， 胃蛋白酶原的激活依赖于pH，而胃酶催化粘蛋白的降解。本提案的第一个目标 就是了解这个耦合系统如何维持动态平衡。目标2是通过以下方式了解感染 幽门螺杆菌，它必须游过粘液层才能定植上皮。它在本地修改 当它游泳时，凝胶通过分泌中和氨来进行流变性。目标3是了解胃部是否 有机类化合物(GO)是单层分化的上皮细胞的球形3D培养物，可以准确地 模型胃粘液层生理学和病理学。 方法是A：建立一个完全耦合粘蛋白、离子和酶运输的数学模型 和互动。通过体外粘蛋白传输酸的实验来验证它。B：调查 用平面2D层数学模型研究粘液层的动态平衡和酸的传输机制 以及粘液的物理模型，通过探索体积、空间和时间 分泌率的变化。C：用数学模型模拟幽门螺杆菌与粘液和 实验成像和跟踪单个细菌以及局部离子浓度和微流变学。 建立致密细菌感染模型，并通过实验观察其集体感染效应。D：型号 并通过实验测试分泌物的大小和空间位置的变化如何影响粘液层 在GO中形成，以了解它们如何以及何时可以用作准确的生理/病理模型。

This proposal brings together a team of applied mathematicians and experimental physicists, engineers, and biologists, with expertise in biogels, mucus physics, microbiology and bacterial motility, and gastroenterology to tackle an important problem in physiology and pathology: how the gastric mucus layer is maintained and how it responds to infecting bacteria and to changes in topology and size in gastric organoids (GOs). Cells in the stomach epithelium secrete the mucin that forms a mucus layer to protect the epithelium from the harsh environment of the stomach lumen, which is acidic and contains digestive enzymes such as pepsin. Epithelial cells also secrete acid, neutralizing bicarbonate, and pepsinogen, the inactive precursor to pepsin. These secretions form a complex coupled system since the rheology of mucin depends on pH and ionic strength, acid can be bound by negatively charged mucin, ions and mucin electrostatically interact, pepsinogen activation is pH dependent, and pepsin catalyzes mucin degradation. Goal #1 of this proposal is to understand how this coupled system maintains homeostasis. Goal #2 is to understand infection by Helicobacter pylori, which must swim across the mucus layer to colonize the epithelium. It locally modifies the gel rheology as it swims by secreting neutralizing ammonia. Goal #3 is to understand whether gastric organoids (GOs), spherical 3D cultures of a monolayer of differentiated epithelial cells, can accurately model gastric mucus layer physiology and pathology. The approach is to A: Build a mathematical model that fully couples mucin, ion, and enzyme transport and interactions. Validate it through in vitro experiments on acid transport through mucin. B: Investigate mechanisms of mucus layer homeostasis and acid transport using the mathematical model, flat 2D layers of cultured epithelium, and physical models of mucus, by exploring volumetric, spatial, and temporal variations of secretion rates. C: Mathematically model interaction of swimming H. pylori with mucus and experimentally image and track single bacteria together with local ion concentrations and micro-rheology. Model and experimentally observe collective effects of infection by dense populations of bacteria. D: Model and experimentally test how variations in size and spatial localization of secretion affect mucus layer formation in GOs to learn how and when they may be used as accurate models of physiology/pathology.