Controlling the core airway mucin secretion machinery to prevent pathophysiology

University Of Tx Md Anderson Can Ctr, Houston TX

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Abstract

? DESCRIPTION (provided by applicant): Mucus forms an essential barrier that protects the lungs from inhaled particles, pathogens, and chemicals. These toxicants are entrapped in mucus, then swept out of the lungs by ciliary action. Paradoxically however, mucus dysfunction contributes to the pathobiology of all of the common diseases of the airways, including asthma, cystic fibrosis, and COPD, as well as interstitial lung diseases. Mucin glycoproteins are the principal macromolecular component of mucus, responsible for its structure as a semi-solid gel by binding more than 100-fold their mass of water. Mucins are secreted both at a low basal rate and a high stimulated rate. A common feature of airway mucus dysfunction is the rapid secretion of overproduced mucins into the airway lumen, forming mucus that is excessively viscoelastic and cannot be cleared by ciliary action. This impedes airflow and provides a protected environment for microbial growth. While the control of mucin production and hydration have been studied intensively, the mechanism of secretion is incompletely understood. Exocytosis in all eukaryotes is mediated by the cooperative interactions of a SNARE complex and an SM scaffolding protein, which are the core exocytic machinery. Our studies show that for some components of this machinery, different isoforms function in basal versus stimulated mucin secretion. Our central hypothesis is that the differential roles of certain exocytic proteins in basal and stimulated mucin secretion allows their manipulation to augment basal secretion and inhibit stimulated secretion, attenuating the pathophysiology of mucus hypersecretion without impairing toxicant clearance. Aim 1. Determine the identity and function of the SM protein that mediates basal mucin secretion (we have already determined the identity of the SM protein in stimulated mucin secretion). Aim 2. Determine the identity and function of the Syntaxins (key components of SNARE complexes) that mediate basal and stimulated mucin secretion. Aim 3. Augment basal and inhibit stimulated mucin secretion to improve lung pathophysiology in mouse models of asthma-like airway obstruction and microbial infection. Completion of these aims will provide fundamental understanding of the mucin secretory mechanism, and build on that knowledge to test translational strategies to mitigate mucus dysfunction while preserving protective benefits of the mucus barrier.