Modeling gastric mucus layer physiology

模拟胃粘液层生理学

• 批准号: 9974529
• 负责人: AARON L FOGELSON
• 金额: $ 36.57万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9974529
• 关键词: Acids; Address; Affect; Ammonia; Bacteria; Behavior; Bicarbonates; Cells; Charge; Chemistry; Complex; Coupled; Couples; Diffusion; Electrostatics; Engineering; Environment; Enzymes; Epithelial; Epithelial Cells; Epithelium; Gastric ulcer; Gastroenterology; Gel; Goals; Helicobacter Infections; Helicobacter pylori; Homeostasis; Image; In Vitro; Infection; Ion Transport; Ionic Strengths; Ions; Lead; Learning; Measures; Microbiology; Modeling; Mucins; Mucous body substance; Organoids; Pathology; Pepsin A; Pepsinogens; Phase; Physics; Physiology; Population; Rheology; Stomach; Swimming; System; Testing; Validation; Variant; Work; cell motility; chemical reaction; experimental study; improved; in vitro Model; malignant stomach neoplasm; mathematical model; monolayer; physical model; response; spatial temporal variation; three dimensional cell culture

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.

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，在细菌学、粘液物理学、微生物学和细菌运动方面具有专长， 胃肠病学要解决的一个重要问题，在生理和病理：如何胃粘液层 以及它如何对感染细菌以及胃粘膜拓扑结构和大小的变化作出反应。 类器官（organoids，OCs）。胃上皮细胞分泌粘蛋白，形成粘液层以保护胃粘膜。 上皮细胞从胃腔的恶劣环境，这是酸性的，并含有消化 酶如胃蛋白酶。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。 这些分泌物形成复杂的耦合系统，因为粘蛋白的流变学取决于pH和离子浓度。 强度，酸可被带负电荷的粘蛋白结合，离子与粘蛋白静电相互作用， 胃蛋白酶原活化是pH依赖性的，并且胃蛋白酶催化粘蛋白降解。本提案的目标#1 就是了解这个耦合系统是如何维持体内平衡的。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在上皮细胞中定植。局部修改 当它游动时通过分泌中和氨来改变凝胶的流变性。目标#3是了解胃是否 类器官（GO）是单层分化上皮细胞的球形3D培养物，可以准确地 模型胃粘液层生理和病理。 方法是A：建立一个完全耦合粘蛋白，离子和酶转运的数学模型 和互动。通过体外粘蛋白酸转运实验验证。B：调查 使用数学模型的粘液层稳态和酸运输的机制，平坦的2D层 培养的上皮细胞和粘液的物理模型，通过探索体积，空间和时间 分泌速率的变化。C：数学模型的相互作用游泳H。幽门带粘液， 实验成像和跟踪单个细菌连同局部离子浓度和微流变学。 模型和实验观察密集的细菌群体感染的集体效应。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 形成的，以了解如何以及何时可以使用它们作为生理学/病理学的准确模型。