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The translational effects of circadian disruption in patients


Faculty of Biology, Medicine and Health

About the Project

The cellular clock oscillates over a 24 hour period enabling temporal control of the transcriptome, proteome and biological pathways. We and others have described that this clock consists of key clock proteins including PERIOD, CRYPTOCHROME, CLOCK, BMAL1 and REV-ERB1. All these proteins are regulated by a transcriptional/translational feedback loop creating a robust 24-hour period. The robustness of these oscillations also means that “clock” time can be measured through analysis of these genes permitting calculation of internal time for both individual cells and organs. This analysis also permits categorisation of circadian disruption by quantifying changes in phase, amplitude and periodicity.

Circadian disruption is likely to result in adverse effects and disease. Initially this was shown by inoculating mice with bacteria at different phases of the circadian clock resulting in different inflammatory or fibrotic responses. Other studies have focused on circadian disruption showing that disruption drives altered inflammatory or fibrotic pathogenic responses. The relevance of these mechanisms to humans has also been explored, especially in the context of pulmonary disease. Studies in asthma or pulmonary fibrosis have shown that pathogenic pathways are under circadian control in disease models but the relevance to patients is still poorly understood. Therefore we welcome application form students wishing to explore these issues specifically around three key questions: 1) Is it possible to measure circadian disruption in patients; 2) Does changing a patient’s circadian rhythm have beneficial or adverse effects; 3) Can we understand the mechanism behind this by mimicking circadian disruption in the laboratory.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a biomedical relevant degree. Candidates with some experience in applied mathematics are also encouraged to apply.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Bioinformatics.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk




Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit

References

2020 Night Shift Work is associated with an increased Risk of Asthma Maidstone, R., Turner, J., Vetter, C., Dashti, H. S., Saxena, R., Scheer, F. A. J. L., Shea, S. A., Kyle, S. D., Lawlor, D. A., Loudon, A., Blaikley, J., Rutter, M. K., Ray, D. & Durrington, H. Aug 2020 Thorax (online first)

2020 Circadian asthma airway responses are gated by REV-ERBα Durrington HJ, Krakowiak K, Meijer P, Begley N, Maidstone R, Goosey L, Gibbs JE, Blaikley JF, Gregory LG, Lloyd CM, Loudon A, Ray DW Eur Respir J 2020 Jun 25;1902407

2020 The circadian clock protein REVERBα inhibits pulmonary fibrosis development Cunningham P, Meijer P, Nazgiewicz A, Borthwick L, Bagnall J, Anderson S, Kitchen G, Lodyga M, Begley N, Venkatesawaran R, Shah, R, Mercer P, Durrington H, Henderson N, Piper-Hanley K, Fisher A, Chambers R, Bechtold D, Gibbs, J, Loudon A, Rutter M, Hinz B, Ray D, Blaikley J Proc Natl Acad Sci U S A. 14 Jan 20 117, 2, p. 1139-1147 biorxiv doi:10.1101/781666v1

2020 The clock gene BMAL1 inhibits macrophage motility, phagocytosis, and impairs defence against pneumonia Kitchen G, Cunningham P, Poolman T, Iqbal M, Maidstone R, Baxter M, Bagnall J, Begley N, Saer B, Hussell T, Matthews L, Dockrell D, Durrington H, Gibbs J, Blaikley J, Loudon A, Ray D 21 Jan 2020, In : Proceedings of the National Academy of Sciences. 117, 3, p. 201915932.

2019 Incidence of Primary graft dysfunction after lung transplantation is altered by timing of allograft implantation Cunningham, P., Maidstone, R., Durrington, H., Venkateswaran, R., Cypel, M., Keshavjee, S., Gibbs, J., Loudon, A., Chow, C. W., Ray, D., Blaikley, J. Thorax Apr;74(4):413-416.

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