Biochemistry and function of mucins and related molecules in diseases of the respiratory tract

The intestinal and respiratory tracts are protected by mucus.

Our discoveries that the colon bacteria were physically separated from the host epithelial cell surface by an inner mucus layer impenetrable to bacteria revolutionized our understanding of how we can tolerate our intestinal bacteria.

We have now and will use this knowledge to address the respiratory mucus system.Normal lungs are cleared by rolling mucus bundles from the submucosal glands, but our focus is now the colon-like attached mucus layer in chronic lung diseases.

In healthy individuals, this is temporarily protecting the lung epithelium, but when stagnant as in COPD or cystic fibrosis, bacteria will remain and destroy the lungs.

This application focuses on the detailed structures of the molecules building and attaching the lung mucus layer at disease. This includes understanding of the role of different goblet cells and their products.

The major mucin increased at disease is called MUC5AC where we have identified structural role of SNP variants that is increased in COPD. Mucus is anchored by FCGBP of which we have obtained a high-resolution structure by cryo-EM.

We will determine how this is assembled into long filaments and develop potential drugs that interfere with its assembly. A small domain, CysD, inserted in the highly glycosylated central domains is suggested to organize the mucus.

The transient interaction by the CysD domains is locked by transglutamination, bonds  suggested to stabilize the mucus.