Unravelling the molecular mechanisms controlling respiratory tract mucus gel formation in health and disease

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The lungs produce the jelly-like substance mucus in order to defend the body from environmental challenges (pollution or bacteria and viruses present in the air). This mucus traps these environmental agents and they are moved out of the lung by what is called the 'mucociliary escalator'; this is made up from many cells lining the surface of the upper airways, which have hair-like protrusions (cilia). The cilia beat and move the mucus up to the throat where it is swallowed. One of the major struggles faced by individuals suffering from airway diseases such as asthma, cystic fibrosis and chronic recurrent obstruction of their airway is that they make too much mucus, and the mucus is stickier than normal. The consequence of this is that the mucus cannot be moved by cilia and it blocks the respiratory system, which leads to infection and risk of death. The framework of the mucus is provided extremely large molecules called mucins. Unlike many other molecules in mucus, mucins are made and then stored within special structures inside cells awaiting the appropriate signal to be released and, via interactions with themselves and other molecules, form mucus. During their release the structure of mucins changes from a highly condensed form to an expanded, rope-like form. There are two types of mucin (MUC5AC and MUC5B) found in airways mucus and we know that in disease larger amounts of these molecules are produced; in particular overproduction of one of these (MUC5B) with an abnormal structural form (more condensed and web-like rather than the more normal rope-like form) contributes to obstruction of the airways. Importantly, recent research suggests that MUC5B is crucial for the generation of mucus that is easily moved by cilia. Therefore, the principal question of our research proposal is how abnormal mucus is generated; is it defective condensation, defective expansion, or altered interactive properties (or a combination of these factors) of the main gel-forming molecule, MUC5B. To answer this question we are employing state-of-the-art methods spanning biology and physics. Our goal in this project is to understand the mechanisms that control the production of mucins with properties that cause the failure of mucus to protect the lung. This new knowledge of mucus biology in the lung will help design novel treatments for people suffering with obstruction of their airways.