MRC Transition Support CSF John Blaikley

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Circadian rhythms are thought to control many biological pathways, yet its role in disease is only now beginning to be explored. At the heart of the circadian rhythm are clock proteins which oscillate over 24 hours. In our studies concerning circadian rhythms, we have recently made two exciting findings. Firstly, we have discovered that the incurable human disease, pulmonary fibrosis, results in an augmented circadian rhythm. This allows clock proteins to play a key role in disease pathogenesis. One of these proteins, called REVERBalpha, affects fibroblasts, a key cell type in fibrosis. Removing REVERBalpha promotes fibroblasts turning into myofibroblasts, which then results in scarring of the lung. This explains why getting rid of REVERBalpha promotes the formation of fibrosis. It also explains why factors that disrupt the circadian clock e.g. sleep duration, shift work and chronotype are associated with the development of fibrosis. This protein can be targeted with chemical compounds, and indeed use of these compounds inhibits scar formation in human fibrotic lung tissue, making it a viable drug target. The second finding concerned the role of circadian rhythms in infection. We have now discovered that this is due to altered macrophage engulfment of bacteria regulated by the clock protein BMAL1, potentially explaining why susceptibility to infection is time-of-day dependent.I now plan to investigate the consequences of infection in pulmonary fibrosis, focusing on whether the time-of-day variability is increased. Initially we will use a model of fibrosis to investigate what times of day you are more likely to get an infection. We then plan to stop the circadian clock to investigate what proportion of these effects are due to this molecular mechanism.To find out how the circadian clock might exert its effects we plan to study macrophages cultured with sliced lung tissue. Using special microscopes we are able to identify circadian oscillations in real-time allowing us to investigate how these alter engulfment of bacteria. We can then interfere with known fibrotic mediators to see if these factors are driving the increase in circadian oscillation. We now believe that you can also define circadian mechanisms by studying individual single cells. We will aim to assign each cell a specific clock time and then study these cells to see how they change at different phases of the clock. This will mean for the first time that we can gain circadian information from one blood or biological sample, which will be an invaluable tool for circadian biology.