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.

项目总结 随着哮喘的加重，粘液阻塞呼吸道会显著造成气流阻塞。此外, 患有哮喘的人往往容易感染病毒呼吸道感染，这可能导致严重的 疾病症状的恶化。最近的证据表明，从重症患者身上获得的粘液 哮喘的粘蛋白成分发生了改变。但是，这些更改如何改变 粘液凝胶还没有完全被理解。本申请的总体目标是：(I)建立新的模型 粘液成分可以精确控制，以便对其功能进行机械评估；以及(Ii) 了解粘液成分在病毒感染引起的疾病恶化中的作用。中环 假设是两种主要形成凝胶的呼吸道粘蛋白浓度不平衡的呼吸道粘液， MUC5B和MUC5AC具有显著改变的生物物理性质，导致粘液 哮喘患者粘液过度堆积和功能受损，是呼吸道病毒的屏障。中环 假说将通过开发基因工程人肺组织培养模型来验证 能够产生粘液，其组合物代表健康和哮喘的呼吸道。我们的方法 能够从机械上理解粘液凝胶变得不能移动的条件，因此 降低其被有效清除的能力，并增加肺部粘液堵塞形成的可能性 哮喘患者的健康状况。此外，我们还将探讨粘蛋白组成对屏障功能的影响 粘液向流感病毒扩散。在这些机制研究的基础上，我们将开发一种新的靶向粘蛋白 扭转疾病症状和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，因为它使用了以下工具 分子生物学、生物物理学和工程学，以开发一种操作和评估粘液的新方法 通过密切模拟其在健康和哮喘呼吸道中的特性来合成。如果成功，则结果为 这项工作将具有重要意义，因为我们的方法可能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Unique的研究方向的重大转变 解决关于MUC5B和MUC5B的紧急性质的长期问题的方法和新技术 哮喘患者中的MUC5AC。