Dr J Gibbs, Prof K Else, Prof A Loudon, Prof D Ray
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
The circadian clock is an internal timer that allows animals and plants to tune their physiology to the daily (24h) changes in the environment. This includes changes in light, temperature, and food availability. In mammals there is a central clock located within a hypothalamic region of the brain. This is entrained by light input from the eyes. This central clock co-ordinates peripheral clocks found in most cells and tissues throughout the rest of the body. Together these clocks regulate multiple aspects of physiology, including sleep-wake cycles, metabolism and immunity.
Immune cells and tissues contain intrinsic clocks (Man et al. 2016 Science 354:999 Review). This includes both resident immune cells, such as the lung bronchiolar epithelial cells (Gibbs et al. 2014 Nat Med 20:919), and circulating immune cells (e.g. macrophages, monocytes and dendritic cells). Research has shown that immune cell clocks are critical for the maintenance of immune homeostasis, regulating the development, turnover and trafficking of various types of immune cells. But, these clocks also act to temporally gate inflammatory responses after insult. Consequently, many inflammatory diseases show time-of-day variation in disease markers and disease symptoms (e.g. asthma and rheumatoid arthritis) (Gibbs & Ray 2013 Arthritis Res. Ther. 15:205 and Carter et al. 2016 J Leukoc Biol 99:549). Furthermore, disruption of the circadian clock in humans (e.g. shift work) and mice (e.g. altered lighting schedules or genetic targeting) is associated with an increased risk of developing inflammatory disease, including gastrointestinal inflammation.
Intestinal epithelial cells (IECs) line the gastrointestinal tract, and act as a barrier between the external environment (gut lumen) and the rest of the body. In addition to this function as a physical barrier, IECs also respond rapidly to inflammatory challenge, releasing cytokines and inducing recruitment of inflammatory cells, in order to resolve the insult. These resident immune cells are strongly circadian rhythmic and from the basis of the “gut clock”(Mukherji et al 2013 Cell 153:812). We now seek to investigate how the clock within IECs orchestrates chronic intestinal inflammation; impacts on immune cell trafficking to sites of inflammation; and contributes to resolution of inflammation.
https://www.bmh.manchester.ac.uk/research/biological-timing/
http://www.mig.manchester.ac.uk/people/kathrynelse/
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
Hand LE, Hopwood TW, Dickson SH, Walker AL, Loudon AS, Ray DW, Bechtold DA, Gibbs JE.
(2016) The circadian clock regulates inflammatory arthritis. FASEB J. 30(11):3759-3770.
Carter SJ, Durrington HJ, Gibbs JE, Blaikley J, Loudon AS, Ray DW, Sabroe I (2016) A matter of time: study of circadian clocks and their role in inflammation. J Leukoc Biol. 99(4):549-60.
Gibbs J, Ince L, Matthews L, Mei J, Bell T, Yang N, Saer B, Begley N, Poolman T, Pariollaud M, Farrow S, DeMayo F, Hussell T, Worthen GS, Ray D, Loudon A. (2014). An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat Med.
Glymenaki M, Singh G, Brass A, Warhurst G, McBain AJ, Else KJ, Cruickshank SM.
(2017) Compositional changes in the gut mucus microbiota precede the onset of colitis-induced inflammation Inflamm Bowel Dis. 23(6):912-922.
Little MC, Hurst RJ, Else KJ. Dynamic Changes in Macrophage Activation and Proliferation during the Development and Resolution of Intestinal Inflammation. J Immunol. 2014 1;193(9):4684-95.
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