Understanding alterations to mucus composition and function in asthma

了解哮喘中粘液成分和功能的改变

• 批准号: 10641012
• 负责人: Gregg Duncan
• 金额: $ 30.55万
• 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/10641012
• 关键词: Address; Affect; Affinity; Allergens; Aspergillus oryzae; Asthma; Binding; Biochemical; Biological Models; Biological Process; Biophysics; CRISPR/Cas technology; Cell Culture Techniques; Chronic lung disease; Coughing; Data; Development; Disease; Elasticity; Engineering; Extrinsic asthma; Functional disorder; Gel; Gene Delivery; Genes; Genetic Engineering; Goals; Health; Human; Human Engineering; Immobilization; Impairment; Individual; Infection; Influenza A virus; Interleukin-13; Knowledge; Left; Life; Lung; MUC5AC gene; MUC5B gene; Measurement; Measures; Mediating; Modeling; Molecular Biology; Mucins; Mucociliary Clearance; Mucous body substance; Mus; Penetration; Predisposition; Property; Publishing; Research; Rheology; Role; Severities; Severity of illness; Small Interfering RNA; Specific qualifier value; Structure; Structure of parenchyma of lung; Surface; Symptoms; System; Techniques; Testing; Tetracyclines; Therapeutic; Thick; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Viscosity; Work; airway epithelium; airway hyperresponsiveness; airway obstruction; asthma exacerbation; asthmatic airway; biophysical properties; clinically relevant; defined contribution; delivery vehicle; improved; in vivo evaluation; influenzavirus; innovation; insight; mouse model; mucus clearance; mucus-associated lung diseases; new therapeutic target; novel; overexpression; particle; pathogen; prevent; pulmonary function; respiratory virus; siRNA delivery; targeted treatment; tissue culture; tool; translational impact; translational potential; viscoelasticity

PROJECT SUMMARY As asthma worsens, occlusion of airways with mucus significantly contributes to airflow obstruction. In addition, individuals suffering with asthma are often susceptible to viral respiratory infections which may lead to severe worsening of disease symptoms. 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 mucus overaccumulation and impaired function of mucus as a barrier to respiratory viruses in asthma. The central hypothesis will be tested through development of genetically engineered human lung tissue culture models capable of producing mucus with a composition representative of healthy and asthmatic airways. Our approach will enable for a mechanistic understanding of conditions under which the mucus gel becomes immobile, thus reducing its ability to be effectively cleared and increasing the likelihood for mucus plug formation in the lungs of individuals with asthma. In addition, we will explore the impact of mucin composition on the barrier function of mucus towards influenza virus. Based on these mechanistic studies, we will develop a new mucin-targeted therapeutic approach to reverse disease symptoms and prevent severe infection which will be tested using a mouse model of allergic 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 manipulate 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. This work aligns with the goals of the Stephen I. Katz mechanism as it represents a significant shift in research direction for the PI using unique approaches and new techniques to address long-standing questions on the emergent properties of MUC5B and MUC5AC in asthma.

项目概要 随着哮喘恶化，粘液阻塞气道会显着导致气流阻塞。此外， 患有哮喘的人通常容易受到病毒性呼吸道感染，这可能会导致严重的症状 疾病症状恶化。最近的证据表明，从患有严重疾病的人身上获得的粘液 哮喘具有改变的粘蛋白成分。然而，这些变化如何改变了功能特性 粘液凝胶尚未完全了解。该应用程序的总体目标是（i）建立新模型 可以精确控制粘液成分以对其功能进行机械评估，并且（ii） 了解粘液成分在病毒感染引起的疾病恶化中的作用。中央 假设气道粘液中两种主要形成凝胶的气道粘蛋白浓度不平衡， MUC5B 和 MUC5AC 具有显着改变的生物物理特性，导致粘液 哮喘中粘液作为呼吸道病毒屏障的过度积累和功能受损。中央 该假设将通过开发基因工程人类肺组织培养模型来检验 能够产生具有代表健康和哮喘气道成分的粘液。我们的方法 将使人们能够从机制上理解粘液凝胶变得不可移动的条件，从而 降低其有效清除的能力并增加肺部形成粘液栓的可能性 患有哮喘的人。此外，我们还将探讨粘蛋白成分对屏障功能的影响 粘液对抗流感病毒。基于这些机制研究，我们将开发一种新的粘蛋白靶向药物 扭转疾病症状并预防严重感染的治疗方法将使用 过敏性哮喘小鼠模型。本申请中提出的研究具有创新性，因为它采用了来自 分子生物学、生物物理学和工程学，开发操纵和评估粘液的新方法 通过密切模仿其在健康和哮喘气道中的特性来合成成分。如果成功，结果为 这项工作将具有重要意义，因为我们的方法可能会为粘液的生物学功能提供新的见解。 哮喘，也与其他相关的粘液阻塞性肺部疾病有关。这项工作符合以下目标： Stephen I. Katz 机制，因为它代表了 PI 使用独特的研究方向的重大转变 解决有关 MUC5B 的新兴特性的长期存在的问题的方法和新技术 MUC5AC 治疗哮喘。