Understanding alterations to mucus composition and function in asthma

项目摘要 当哮喘发作时，气道被粘液阻塞显著地导致气流阻塞。此外，本发明还提供了一种方法， 患有哮喘的个体通常易受病毒性呼吸道感染的影响， 疾病症状恶化。最近的证据表明，从患有严重 哮喘具有改变的粘蛋白组成。然而，这些变化如何改变 粘液凝胶还没有被完全理解。本申请的总体目标是（i）建立新模型 其中粘液组成可以被精确控制以用于其功能的机械评估，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。中央 假设是气道粘液具有不平衡浓度的2种主要的形成凝胶的气道粘蛋白， MUC5B和MUC5AC具有显著改变的生物物理特性，导致粘液分泌。 在哮喘中，粘液作为呼吸道病毒屏障的过度积聚和功能受损。中央 将通过开发基因工程人肺组织培养模型来检验这一假设 能够产生具有代表健康和哮喘气道的组成的粘液。我们的方法 将使得能够机械地理解粘液凝胶变得不动的条件，因此 降低其被有效清除的能力并增加肺中粘液栓形成的可能性 哮喘患者的情况。此外，我们将探讨粘蛋白组成对屏障功能的影响 对流感病毒的反应基于这些机制的研究，我们将开发一种新的粘蛋白靶向 逆转疾病症状和预防严重感染的治疗方法，将使用 小鼠过敏性哮喘模型。本申请中提出的研究是创新的，因为它采用了来自 分子生物学、生物物理学和工程学，以开发一种新的方法来操纵和评估粘液 通过密切模仿其在健康和哮喘气道中的性质，来制备组合物。如果成功， 这项工作将是重要的，因为我们的方法可能会提供新的见解粘液的生物功能， 哮喘，也与其他相关的粘膜阻塞性肺疾病有关。这项工作符合 斯蒂芬岛Katz机制，因为它代表了PI研究方向的重大转变， 方法和新技术，以解决长期存在的问题上的紧急性质MUC5B和 哮喘中的MUC5AC。

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.