Modeling gastric mucus layer physiology

模拟胃粘液层生理学

基本信息

批准号：
9752617
负责人：
AARON L FOGELSON
金额：
$ 35.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-05-31
项目状态：
已结题

项目摘要

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.

该提案汇集了应用数学家和实验物理学家、工程师、和生物学家，拥有生物凝胶、粘液物理学、微生物学和细菌运动方面的专业知识，以及胃肠病学要解决一个重要的生理学和病理学问题：胃粘液层如何的维持以及它如何对感染细菌以及胃中拓扑和大小的变化做出反应类器官（GO）。胃上皮细胞分泌粘蛋白，形成粘液层以保护胃来自胃腔恶劣环境的上皮，呈酸性，含有消化液酶，例如胃蛋白酶。上皮细胞还分泌酸、中和碳酸氢盐和胃蛋白酶原，胃蛋白酶的无活性前体。这些分泌物形成了一个复杂的耦合系统，因为粘蛋白的流变学取决于 pH 值和离子强度，酸可以与带负电的粘蛋白结合，离子和粘蛋白静电相互作用，胃蛋白酶原的激活依赖于 pH 值，胃蛋白酶催化粘蛋白降解。本提案的目标#1 的目的是了解这个耦合系统如何维持体内平衡。目标#2 是通过以下方式了解感染幽门螺杆菌必须游过粘液层才能在上皮细胞中定殖。它在本地修改通过分泌中和氨来改变凝胶游动时的流变性。目标#3是了解胃是否类器官（GO），单层分化上皮细胞的球形 3D 培养物，可以准确地胃粘液层生理学和病理学模型。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。通过粘蛋白酸转运的体外实验对其进行验证。乙：调查使用数学模型、平面 2D 层实现粘液层稳态和酸运输的机制通过探索体积、空间和时间来研究培养的上皮细胞和粘液的物理模型分泌率的变化。 C：游动的幽门螺杆菌与粘液和粘液相互作用的数学模型对单个细菌以及局部离子浓度和微流变学进行实验成像和跟踪。建立模型并通过实验观察密集细菌群感染的集体效应。 D：型号并通过实验测试分泌物的大小和空间定位的变化如何影响粘液层 GO 中的形成，以了解如何以及何时将它们用作准确的生理学/病理学模型。