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。此外， 患有哮喘的人通常容易受到病毒呼吸道感染的影响，这可能会导致严重 疾病症状恶化。最近的证据表明，从严重的个体中获得的粘液 哮喘具有改变的粘蛋白成分。但是，这些变化如何改变 粘液凝胶尚未完全理解。此应用程序中的总体目标是（i）建立新模型 可以精确控制粘液组成的机理评估其功能和（ii） 了解粘液组成在病毒感染引起的疾病加剧中的作用。中央 假设是气道粘液，具有不平衡的2个主要凝胶气道粘蛋白，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 过度蓄积和粘液作为哮喘中呼吸道病毒的障碍的功能受损。中央 假设将通过开发基因工程的人肺组织培养模型来检验 能够用健康和哮喘性气道的组成产生粘液。我们的方法 将启用对粘液凝胶变得不动的条件的机械理解，从而 降低其有效清除的能力，并增加肺部粘液塞形成的可能性 患有哮喘的人。此外，我们将探讨粘蛋白成分对屏障功能的影响 对流感病毒的粘液。基于这些机械研究，我们将开发一种新的粘蛋白靶向 逆转疾病症状并防止严重感染的治疗方法，该方法将使用 过敏性哮喘的小鼠模型。本应用程序中提出的研究具有创新性，因为它采用了工具 分子生物学，生物物理学和工程学，以开发一种新型手段来操纵和评估粘液 通过紧密模仿其在健康和哮喘气道中的特性来组成。如果成功，结果 这项工作将是重要的，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，也与其他相关的粘膜肺部疾病有关。这项工作与目标的目标保持一致 Stephen I. Katz机制，因为它代表了使用唯一的PI研究方向的显着转移 方法和新技术，以解决有关MUC5B和 哮喘中的MUC5AC。