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.

该建议将一组应用数学家和实验物理学家，工程师， 和生物学家，具有沼气，粘液物理学，微生物学和细菌运动的专业知识，以及 胃肠病学以解决生理学和病理学的重要问题：胃粘液层如何 维护以及它如何应对感染细菌以及胃的拓扑变化和大小的反应 器官（GOS）。胃上皮的细胞分泌形成粘液层的粘蛋白 胃腔的刺激性环境中的上皮，该环境是酸性的，含有消化 酶等酶。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。 这些分泌形成一个复杂的耦合系统，因为粘蛋白的流变学取决于pH和离子 强度，酸可以通过带负电荷的粘蛋白，离子和粘蛋白静电相互作用的酸结合， 胃蛋白原激活取决于pH，胃蛋白酶催化粘蛋白降解。该提议的目标1 是要了解该耦合系统如何维持稳态。目标＃2是通过 幽门螺杆菌必须在粘液层上游泳才能定居上皮。它在局部修改 凝胶流变学通过分泌中和氨的游泳。目标3是了解胃是否 器官（GOS），分化上皮细胞的单层的球形3D培养物可以准确地 模型胃粘液层生理和病理学。 方法是：建立一个完全伴随粘蛋白，离子和酶传输的数学模型 和互动。通过在通过粘蛋白酸转运的体外实验来验证它。 B：调查 使用数学模型，扁平2D层的粘液层稳态和酸转运的机理 培养的上皮和粘液的物理模型，通过探索体积，空间和时间 分泌率的变化。 C：幽门螺杆菌与粘液和粘液的数学相互作用 通过实验图像和局部离子浓度和微侵蚀学跟踪单个细菌。 模型和实验观察到细菌密集种群感染的集体影响。 D：模型 并通过实验测试分泌大小和空间定位的变化如何影响粘液层 在GO中形成，以了解如何以及何时将它们用作精确的生理/病理模型。