Diversity Supplement: Understanding mucus composition and function in asthma

多样性补充：了解哮喘中的粘液成分和功能

• 批准号: 10834550
• 负责人: Gregg Duncan
• 金额: $ 6万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10834550
• 关键词: Affect; Asthma; Biological Models; Biological Process; Biomedical Engineering; Biophysics; Chronic lung disease; Development; Disease; Engineering; Functional disorder; Gel; Genetic Engineering; Human Engineering; Hydrogels; Immobilization; Impairment; Individual; Lung; MUC5AC gene; MUC5B gene; Modeling; Molecular Biology; Mucins; Mucous body substance; Physiological; Property; Research; Role; Structure of parenchyma of lung; Testing; Transgenic Mice; Virus Diseases; Work; airway obstruction; asthmatic airway; biophysical properties; influenzavirus; innovation; insight; mouse model; mucus-associated lung diseases; novel; tissue culture; tool

PROJECT SUMMARY As asthma worsens, occlusion of airways with mucus significantly contributes to airflow obstruction. Recent evidence has suggested mucus obtained from individuals with severe asthma possesses altered mucin composition. However, how these changes alter the functional properties of the mucus gel is not yet fully understood. The overall objectives in this application are to (i) establish new models where mucus composition can be precisely controlled for mechanistic assessment of its function and (ii) understand the role of mucus composition in viral infection-induced exacerbation of disease. The central hypothesis is airway mucus with an imbalanced concentration of the 2 primary gel-forming airway mucins, MUC5B and MUC5AC, possesses significantly altered biophysical properties that leads to impaired function in asthma. The central hypothesis will be tested through development of two new model systems: a bioengineered hydrogel that mimics native mucus and a genetically engineered human lung tissue culture model capable of producing mucus with a composition representative of healthy and asthmatic airways. In comparison to the standard models used, the primary advantage of our model systems is the capability to systematically vary the composition of mucus to capture how these changes might impact its physiological function. Our approach will enable for a mechanistic understanding of conditions under which the mucus gel becomes immobile, thus reduces its ability to be effectively cleared and increases the likelihood for mucus plug formation in the lungs of individuals with asthma. In addition, the impact of composition on the barrier function of mucus towards influenza virus will be examined using these state-of-the art model systems and a transgenic mouse model of severe asthma. The research proposed in this application is innovative as it employs tools from molecular biology, biophysics, and engineering to develop a novel means to control and assess mucus composition by closely mimicking its properties in healthy and asthmatic airways. If successful, the results of this work will be significant as our approach may provide new insights into the biological function of mucus in asthma, also with relevance to other related muco-obstructive lung diseases.

项目摘要 随着哮喘的恶化，带有粘液的气道的阻塞显着导致气流阻塞。最近的 证据表明，从严重哮喘的个体中获得的粘液具有改变的粘蛋白 作品。但是，这些变化如何改变粘液凝胶的功能特性 理解。本应用程序中的总体目标是（i）建立粘液组成的新模型 可以精确控制其功能的机械评估，并且（ii）了解粘液的作用 病毒感染引起的疾病加剧的组成。中心假设是气道粘液 2个主要凝胶形成气道粘蛋白MUC5B和MUC5AC的浓度不平衡 显着改变了生物物理特性，从而导致哮喘功能受损。中心假设 将通过开发两个新模型系统进行测试：一个模仿天然的生物工程水凝胶 粘液和基因工程的人肺组织培养模型，能够与A一起产生粘液 健康和哮喘气道的组成代表。与所使用的标准模型相比 我们的模型系统的主要优势是能够系统地改变粘液成分 捕获这些变化如何影响其生理功能。我们的方法将启用机械 了解粘液凝胶变得不动的条件，从而降低了其BE的能力 有效清除并增加了患有粘液塞形成的可能性 哮喘。此外，成分对粘液对流感病毒的屏障功能的影响将是 使用这些最先进的模型系统和严重哮喘的转基因小鼠模型进行了检查。这 该应用中提出的研究具有创新性，因为它采用了分子生物学，生物物理学和 通过紧密模仿其来控制和评估粘液组成的新颖手段来控制和评估粘液的组成 健康和哮喘气道中的特性。如果成功，这项工作的结果将是我们的 方法可能会提供有关哮喘中粘液生物学功能的新见解，也与其他 相关的粘膜肺疾病。