Understanding and solving mucus dysregulation in severe asthma for better clinical outcomes

Asthma is a common lung condition with symptoms such as shortness of breath, wheeze, cough and chest tightness. Approximately 10% of individuals with asthma suffer from a severe form of the disease. They struggle to control their symptoms despite high levels of medications, resulting in lower quality of life, risk of hospitalisation and even death. New therapies are needed for this group of patients. The lungs produce the jelly-like substance mucus that acts as a gatekeeper controlling access of harmful agents (particulates, microbes, and toxins) into the body by trapping and removing them via the mucociliary escalator. However, in asthma, accumulation of mucus with abnormal properties can plug the airways worsening symptoms (known as exacerbations). The framework of mucus is provided by large molecules called mucins; in the lung there are two types of mucin (MUC5AC and MUC5B). We and others have shown that MUC5AC is increased in airway mucus in asthma. Importantly, we identified genetic changes near the genes encoding MUC5AC and MUC5B that alter the levels of these proteins and affect the risk of severe asthma. We propose a highly integrated, multidisciplinary research programme that will provide new understanding of the mechanisms that lead to the increase in mucins and how this changes the properties of the mucus in severe asthma which could lead to the development of new treatments. Main objectives: 1. Determining the genetic changes that affect MUC5AC or MUC5B expression or structure and increase risk of severe asthma. We will assess prioritised genetic changes to pinpoint which may alter the type of MUC5AC or MUC5B produced and at what level including how this is related to the risk of severe asthma. This will provide vital clues about the mechanisms involved in MUC5AC and MUC5B production. 2. Testing the effects of these genetic changes in lung cells. To understand how these genetic changes cause differences in the amount or properties of mucus proteins, we will study these genetic changes in lung cells from asthma patients. Lung epithelial cells can be grown in the laboratory to mimic the airway lining in the lung, enabling study of the different cell types present, their development and function, as well as the composition and properties of the mucins and mucus produced. We will also investigate the effects of exposing cell models to viruses known to trigger asthma exacerbations. Having identified genetic changes, we will try reversing or removing some of these changes in cell models and in human lung slices to confirm their effects on mucus production and properties. This will provide new novel targets for drug development. 3. Testing the effects of genetic changes on mucus production and composition in severe asthma patients before and during exacerbations. We will use lung biopsies and sputum samples from patients with severe asthma to identify the effects of genetic variants on the regulation and mucus composition in patients when stable or when having an exacerbation. Access to other translational studies, including intervention studies, will provide further understanding. We are bringing together international leaders in respiratory research and are employing state-of-the-art techniques spanning biology and physics to understand the mechanisms that control how mucus is regulated in our airways, how it contributes to severe asthma and how we might target it for therapeutic benefit.