Diversity Supplement: Understanding mucus composition and function in asthma

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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.