How do airways mucins form a functional protective barrier?

In normal physiology, the polymeric mucins MUC5AC and MUC5B provide the organizing framework of the airways mucus gel and are major contributors to its properties. In conjunction with the ciliated cells in the airways epithelium, mucus maintains unobstructed lungs that are free from infection.

MUC5AC and MUC5B are stored, pre-formed within secretory granules awaiting a stimulus for secretion. The current thinking is that mucins change their macromolecular form (or mature) from a cross-linked form in the secretory granule to a linear, expanded form upon release into mucus; this transition being essential for the formation of ‘normal’ mucus. However, the mechanism controlling this transition is not known.

This studentship will address the hypothesis that aberrant mucin maturation results in mucus with sub-optimal properties that leads to obstruction of the airways and infection. The studentship will focus on this fundamentally important issue and will provide the student with a training in a range of state-of-the-art methodologies; these include primary epithelial cell culture, advanced polymer imaging using electron microscopy and AFM, mass spectrometry, and glycoprotein purification and characterization.

This work is a vital first step in understanding the packing and unpacking of mucins within secretory granules. It is anticipated that greater understanding of these processes will lead to better understanding of mucus gel formation and may ultimately lead to the development of novel agents to treat obstructive lung disease.