About the Project
Many aspects of mammalian physiology are driven through coordinated actions of internal circadian clocks. In man, lifestyles that disturb these clocks, such as shift-work, increase the incidence of diseases including cancer and diabetes. Circadian disruption is also recognized as an important feature of many neurological disorders including dementia and bipolar depression. Thus, understanding how circadian clocks respond to alterations in our environment is critical. This PhD will examine the impact of clock disruption on mammalian physiology, and test how pharmacological targeting of the clockwork may be used to counteract clock dysfunction. We have demonstrated previously that casein kinase 1δ/ε (CK1δ/ε) are important in setting the inherent properties of the mammalian clock (clock speed and phase).
These studies also highlight pharmacological targeting of CK1δ/ε as a novel strategy to ‘fix’ broken clocks, and to strengthen adaption of the clock to changes in the environment. We will now examine more fully how the molecular clockwork responds to environmental challenge, to manipulations of CK1δ/ε activity, and to novel clock acting drugs. This project will depend critically on understanding the physiological impact of clock-disruption on mammalian physiology, and will take advantage of our state-of-the-art facilities for long-term recording of behavioural and physiological rhythms (e.g. metabolic rate, thermogenesis, feeding behaviour, locomotor activity, heart rate). During this PhD, you will gain valuable experience in many in vivo and laboratory-based techniques, including profiling gene/protein expression, cell and tissue culture, as well as use of clock-gene reporters and novel in vivo recording techniques which allow longitudinal real-time recordings circadian clock gene activity in free moving mice. This work will also benefit from the involvement of an industrial co-supervisor and a 3-month overseas placement at Pfizer.
Applicants are expected to hold, or about to obtain, a minimum upper second class undergraduate degree (or equivalent) in neuroscience, physiology, biomedical sciences, or related subject. A Masters degree and/or other laboratory research experience in a relevant subject is desirable.
If you wish to apply for this project please visit the following website:
https://www.bmh.manchester.ac.uk/study/research/apply/
Funding Notes
This is a 3.5-year full-time PhD funded by an BBSRC Industrial CASE studentship with Pfizer. It covers UK/EU tuition fees and an annual tax-free stipend. Applicants must be from the UK/EU. Candidates from outside of the UK should meet the eligibility criteria as stated by the BBSRC and have resided in the UK for three years prior to the start date in order to be eligible the full award. Start date is September 2017. On the online application form select PhD Neuroscience.
References
Pilorz V, Cunningham P, Jackson A, West A, Wager T, Loudon AS, Bechtold DA (2014) A novel mechanism controlling clock resetting to environmental stimuli. Current Biology. 24(7):766-73
Gibbs JE, Blaikley J, et al Ray DW, Loudon AS. (2012) The nuclear receptor REV-ERBα mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc Natl Acad Sci U S A. 109(2):582-7
Meng QJ Maywood ES, Bechtold DA, et al Loudon AS. (2010) Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 enzymes. Proc Natl Acad Sci USA 107(34):15240-5.
Bechtold DA, Gibbs JE, Loudon AS. (2010) Circadian dysfunction in disease. Trends Pharmacol Sci 31(5):191-8.
Bechtold DA, Loudon AS (2013) Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci.36(2):74-82.