Project 4: Biophysical and structural characterization of airway submucosal gland mucus in health and disease

项目4：健康和疾病中气道粘膜下腺粘液的生物物理和结构特征

• 批准号: 10684217
• 负责人: Ronit Freeman
• 金额: $ 38.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684217
• 关键词: Affect; Air; Bicarbonates; Binding; Biophysics; Bundling; Calcium; Cell surface; Charge; Chelating Agents; Cilia; Complement; Coughing; Coupled; Defect; Devices; Diameter; Dimensions; Disease; Duct (organ) structure; Encapsulated; Engineering; Epithelium; Exhibits; Failure; Family suidae; Functional disorder; Gel; Gland; Goals; Health; Host Defense; Human; Inhalation; Investigation; Ions; Irritants; Length; Liquid substance; Lung; MUC5AC gene; MUC5B gene; Mediating; Microfluidics; Modeling; Mucins; Mucociliary Clearance; Mucous body substance; Peptides; Peripheral; Prevalence; Process; Property; Proteins; Relaxation; Resolution; Role; Saline; Side; Stretching; Structure; Submucosa; Surface; System; Testing; Width; aspirate; cholinergic; fluid flow; lung health; meter; mimetics; novel; particle; prevent; respiratory; response; sugar; surfactant

Abstract The contribution of submucosal gland (SMG) mucus to the host defense functions of airway surfaces is not well understood. SMG mucus emerges from the SMG onto airway surfaces in the form of micron long bundles. However, it is unknown how SMG mucus bundles are formed, what regulates their structure, and what is their functional role. The minimal understanding of SMG mucus structure has limited our ability to predict how SMG mucus promotes lung health and contributes to disease. The prevalence of SMGs in the proximal airways suggests SMG mucus defense functions include clearing large, aspirated, or inhaled particles by cough. However, understanding how SMG bundles are configured for this role requires a comprehensive characterization of SMG gland mucus as well as engineering of novel models to elucidate the mechanisms of SMG bundle formation. We have identified three key gaps in our understanding of the structure and function/dysfunction of SMG mucus for investigation, encapsulated in our three specific aims. Specific Aim 1: Do SMGs secrete a different mucus in basal versus stimulated conditions? This aim will test the hypothesis that SMG basal secretions constitute a soluble gel that dissolves into the air surface liquid, whereas stimulated SMG secretions consists of both soluble and insoluble fractions, the insoluble component constituting a “permanent” mucus bundle. Specific Aim 2: How do SMG bundles form and what is their functional role? This aim will engineer gland mimetic systems to test the hypothesis that glands are configured to produce strong fluid flows to extrude bundles in a two-level hierarchical process involving primary strand formation by mucin stretching and sticking through open globular domains in peripheral gland ‘nozzle’ junctions, followed by their extrusion as bundles through the ciliated duct nozzle. This aim will also test how bundles are configured to bind and clear large particles by cough. Specific Aim 3: How and why SMGs fail in CF? This aim will test the hypothesis that reduced fluid flows in the CF SMG is the critical failure, generating insufficient mucin extensional forces, producing disorganized mucus bundles that stick to cell surfaces and reduce cilia-dependent transport. Resolution of the hypotheses advanced in this proposal will establish a new paradigm of how glands produce mucus bundles in response to stimulation and complement superficial epithelial responses to clear large irritants by cough.

抽象的 粘膜腺（SMG）粘液对气道表面的宿主防御功能的贡献不是 理解。 SMG粘液以微米长束的形式从SMG出现到气道表面。 但是，尚不清楚SMG粘液束的形成如何，是什么调节其结构，什么是 功能作用。对SMG粘液结构的最低了解限制了我们预测SMG的能力 粘液促进肺部健康并为疾病做出贡献。代理航空公司中SMG的患病率 建议SMG粘液防御功能包括通过咳嗽清除大型，吸气或遗传的颗粒。 但是，了解如何为此角色配置SMG捆绑包 SMG腺体粘液的表征以及新型模型的工程以阐明机制 SMG束组。 我们在理解SMG的结构和功能/功能障碍时已经确定了三个关键差距 投资粘液，封装在我们的三个特定目标中。特定目标1：做SMG秘密不同 基础与刺激条件下的粘液？这个目标将检验SMG基本分泌的假设 构成溶解在空气表面液体中的固体凝胶，而刺激的SMG分泌物组成 在可溶性的和不溶性的部分中，构成“永久性”粘液束的不溶性组件。 特定目标2：SMG束如何形成，它们的功能作用是什么？这个目的将设计腺体 模拟系统测试腺体配置以产生强液流动以挤出的假设 在两级分层过程中，捆绑涉及粘蛋白拉伸和粘附，涉及一链形成 通过外围腺体“喷嘴”连接处的开放全球域，然后延伸为捆 通过纤毛的管道喷嘴。此目标还将测试捆绑包的配置如何绑定和清除大的 咳嗽的颗粒。特定目标3：CF中SMG如何以及为什么失败？这个目标将检验以下假设 CF SMG中的流体流量减少是严重失败，导致粘蛋白伸展力不足， 产生混乱的粘液束，可粘在细胞表面并减少纤毛依赖性转运。 该提案中提出的假设的解决方案将建立一个新的范式 产生的粘液束响应于刺激和补充浅表上皮反应以清除 咳嗽大的刺激性。