Diversity Supplement: Understanding mucus composition and function 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。近期 有证据表明，从严重哮喘患者身上获得的粘液含有改变的粘蛋白 组成。然而，这些变化如何改变粘液凝胶的功能特性还不完全 明白了。本申请的总体目标是：(I)建立粘液成分的新模型 可以精确控制以机械地评估其功能和(Ii)了解粘液的作用 病毒感染引起的疾病恶化的成分。中心假说是呼吸道粘液与 两种主要形成凝胶的呼吸道粘蛋白MUC5B和MUC5AC的浓度不平衡 显著改变生物物理特性，导致哮喘患者功能受损。中心假说 将通过开发两个新的模型系统进行测试：一种模仿天然生物工程水凝胶 粘液和能够产生粘液的基因工程人肺组织培养模型 代表健康和哮喘呼吸道的成分。与使用的标准型号相比， 我们的模型系统的主要优势是能够系统地改变粘液的成分以 捕捉这些变化可能如何影响其生理功能。我们的方法将使机械式的 对粘液凝胶变得不能移动的条件的理解，从而降低其被 有效清除并增加慢性阻塞性肺疾病患者肺内粘液堵塞形成的可能性 哮喘。此外，成分对粘液对流感病毒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。这个 本申请中提出的研究具有创新性，因为它使用了分子生物学、生物物理学和 工程学开发一种新的方法来控制和评估粘液成分，通过密切模拟其 健康和哮喘呼吸道的特性。如果成功，这项工作的结果将是重要的，因为我们的 该方法可能为哮喘中粘液的生物学功能提供新的见解，也与其他 相关的粘液阻塞性肺疾病。

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.