The Biophysics of Mucus Hydration and Adhesion/Cohesion

粘液水合和粘附/内聚力的生物物理学

• 批准号: 9087321
• 负责人: MICHAEL C RUBINSTEIN
• 金额: $ 38.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087321
• 关键词: Acute; Adhesions; Adhesives; Animals; Back; Biophysics; Cell Adhesion; Cell Separation; Cell surface; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Coughing; Culture Media; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Dehydration; Development; Disease; Elasticity; Epithelial Cells; Exhibits; Functional disorder; Gel; Genetic; Goals; Goblet Cells; Human; Hydration status; Hyperplasia; In Vitro; Inflammatory Response; Injury; Instruction; Ion Transport; Lead; MUC4 mucin; MUC5AC gene; MUC5B gene; Measures; Modeling; Mucins; Mucolytics; Mucous body substance; Obstruction; Obstructive Lung Diseases; Osmotic Pressure; Patients; Phenotype; Reducing Agents; Rehydrations; Role; Severity of illness; Sodium Chloride; Solid; Solvents; Surface; Swelling; Techniques; Testing; Therapeutic; Therapeutic Agents; Validation; Viscosity; Water; base; cohesion; cystic fibrosis patients; environmental tobacco smoke exposure; microorganism; mouse model; mucin hypersecretion; novel; novel strategies; novel therapeutics; patient population; physical model; physical process; physical property; response

Patients with cystic fibrosis (CF) and chronic bronchitis, i.e. COPD, exhibit a significantly reduced mucus clearance. The overarching goal of this project is to test the hypothesis that reduced rates of mucociliary and cough clearance in these patients are related to mucus dehydration and the resulting increased adhesion of mucus to cells as well as increased mucus cohesion strength. Both CF and COPD subjects exhibit an increase in ainvay mucus concentration, reflecting: 1) reduced ainway surface solvent (salt/water), e.g., as observed with CFTR dysfunction; 2) mucin hypersecretion, as observed with goblet cell hyperplasia; or 3) a combination of the two. Based on our recent theoretical and experimental data, we have developed a novel model, referred to as the "two-gel" model, that suggests that in addition to a mucus gel, ain/vays exhibit a "periciliary" layer (PCL), which is also a gel formed by tethered mucins (MUC1, MUC4, and MUC16). Efficient clearance requires hydration of the PCL that is sustained as long as its osmotic pressure is higher than that of the mucus gel layer. Importantly, the osmotic pressure of the mucus layer is largely determined by the concentration of the secreted mucins MUC5AC and MUC5B. To test our two-gel hypothesis, we have developed novel techniques to measure mucus osmotic pressure, adhesion/cohesion strength, viscosity, and elastic modulus and to determine the effect of these physical properties on mucus transport rate for both normal and CF cultures. We propose that reducing mucus concentration, cohesion strength, and mucus adhesion to epithelial cells will restore effective mucus clearance and thus benefit both CF and COPD patients. The novel approach to physical processes in airway surface layer will allow us to identify the optimal combination of rehydration and pharmacological agents to restore/accelerate the rate of mucus clearance. The identified agents that reduce the adhesion/cohesion strength and restore normal mucus clearance will be tested in mouse models of obstructive lung disease (Project II) and in COPD patients (Projects III). RELEVANCE (See instructions): This project focus on the developments and validation of new physical models of airway surface layer and the role of mucus hydration, adhesion and cohesion in controlling mucus clearance. These new ideas lead to systematic developments of new drugs aimed at restoring and maintaining mucus clearance in patients with obstructive lung diseases.

囊性纤维化(CF)和慢性支气管炎(即COPD)患者的粘液显著减少 通行证。该项目的首要目标是检验粘液纤毛率降低的假设 这些患者的咳嗽消除与粘液脱水和由此导致的增加有关 粘液与细胞的粘附性以及增加粘液的凝聚力。慢性阻塞性肺疾病和慢性阻塞性肺疾病患者 表现出粘液浓度的增加，反映：1)航道表面溶剂减少 (盐/水)，如观察到的CFTR功能障碍；2)粘蛋白高分泌，如高脚杯观察到的 细胞增生症；或3)两者的结合。根据我们最近的理论和实验数据， 我们已经开发了一种新的模型，称为“双凝胶”模型，它表明除了 粘液凝胶，AIN/vays显示出一层“睫状层”(PCL)，这也是一种由粘蛋白形成的凝胶 (MUC1、MUC4和MUC16)。有效的清除需要PCL的水化作用 因为它的渗透压高于粘液凝胶层。重要的是，水的渗透压 粘液层主要由分泌的粘蛋白MUC5AC和MUC5B的浓度决定。 为了验证我们的双凝胶假说，我们开发了测量粘液渗透的新技术。 压力、粘附力/内聚力、粘度和弹性模数，并确定这些因素的影响 正常和CF培养的粘液传输速率的物理特性。我们建议减少 粘液浓度、粘附力和粘液对上皮细胞的黏附将恢复有效 粘液清除，因此对慢性阻塞性肺疾病和慢性阻塞性肺疾病患者都有好处。一种新的物理方法 呼吸道表层的过程将使我们能够确定再水化和 恢复/加速粘液清除速度的药物。已确定的特工 降低粘附力/粘附力和恢复正常粘液清除将在小鼠身上进行测试 阻塞性肺病模型(项目II)和慢性阻塞性肺病患者(项目III)。 相关性(请参阅说明)： 该项目的重点是开发和验证新的呼吸道表层物理模型和 粘液的水化、黏附和凝聚在控制粘液清除中的作用。这些新想法导致了 旨在恢复和维持慢性阻塞性肺疾病患者粘液清除的新药的系统开发 阻塞性肺病。