Rhythms in Disease- Determining Circadian Clock Mechanism in Asthma

Asthma is a common disease affecting the airways by causing narrowing, leading to symptoms of wheeze and breathlessness. Everyday in the UK, 3 people die from asthma, mostly during the night-time. Those with severe asthma are difficult to treat and there is an urgent need for new therapeutic options. Asthma is a very rhythmic disease; symptoms go up and down during the day, often peaking during the night. My research has shown that many aspects of lung function and disease processes (e.g. airway narrowing) fluctuate over the day, and this fluctuation impacts not only symptoms of asthma but also diagnosis (since patients are seen in the day when symptoms are typically reduced). Critically, we do not know why asthma is so rhythmic. Understanding what causes this rhythmicity may lead us to new treatment options and how to use existing drugs at the best time of the day.

My recent work, and that of my collaborators have shown that the daily variation in lung function in asthma is strongly influenced by innate timing mechanisms present in our bodies, known as the circadian clock. The circadian system allows us to track the external environment (e.g. light/dark, mealtimes) to ensure that biological processes in the body happen at the correct time of day. There is a master clock, centrally, within the brain, which dictates major rhythms in the body such as body temperature and sleep/wake cycles; however we now know that virtually every organ in the body (including the lung) has its own internal clock and that these peripheral clocks are essential to tissue function. My research has shown that the circadian clock in asthma may not be working as it should and this leads to more pronounced rhythmicity in asthma compared to healthy individuals. Furthermore, my research has found that night shift workers (who have an imbalance between their circadian clock and their environment) have an increased risk of having asthma and having more severe disease. This fellowship proposal...