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  Circadian mechanisms in psoriasis: therapeutic opportunities


   Faculty of Biology, Medicine and Health

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  Dr H Young, Dr Mudassar Iqbal, Prof D Ray  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Hallmark features of psoriasis symptoms vary through time, suggesting an important role for circadian circuits in driving disease expression, and offering the potential of chronotherapy. Psoriasis is a chronic immune-mediated inflammatory disease, classified by WHO as a serious non-infectious disease, which affects 3% of the global population.(1) It is associated with significant comorbidities, notably premature cardiovascular disease, insulin resistance and inflammatory arthritis.(1)

All human physiology is circadian; the external environment is sampled by light input through the retina, and neural transmission to the central clock in the suprachiasmatic nucleus (SCN).(2) The core cellular clock comprises a transcription-translation feedback loop in which heterodimers of BMAL1 and CLOCK drive expression of PER, and CRY proteins in one negative feedback arm, and the two REVERB paralogues in the other feedback arm.(2)

Circadian core genes PER2 and NR1D1 are highly expressed in normal skin and notably, the expression of core clock genes (BMAL1, CRY2, PER1, PER2, DBP, and NR1D1) are suppressed in plaques of psoriasis compared to uninvolved skin from the same patient collected at the same time.(3) Th17 cells also have a key role in psoriasis.1 The Th17 lineage is determined by RORgt, a key transcription factor regulated by nuclear factor interleukin 3 (NFIL3), itself highly circadian, and critically regulated by the clock gene REVERBa.(4)

Although there are numerous lines of evidence supporting a role for the circadian clock regulating multiple immunological axes as yet, the dominant cell type driving rhythmic disease expression in psoriasis remains undetermined. Crucially, this innovative, highly translational, cross disciplinary project will address key research priorities in psoriasis.(5) Specifically, this studentship will pioneer the application of single-cell genomics technologies with state-of-the-art circadian science to understand dermatological disease and is well-placed to facilitate discovery of novel therapeutic targets for precision medicine and chronotherapy in psoriasis.

Eligibility 

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject area. Applicants with strong laboratory experience in immunology and genetics or bioinformatics are encouraged to apply.

Before you Apply 

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.  

How 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 the appropriate subject title - PhD Clinical Sciences.

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 https://www.bmh.manchester.ac.uk/study/research/international-phd/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]  

Equality, Diversity and Inclusion  

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/  

Biological Sciences (4) Computer Science (8) Mathematics (25)

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 https://www.bmh.manchester.ac.uk/study/research/fees/

References

1. Griffiths CEM et al. Lancet. 2007; 370:263-71. 2. Gibbs JE et al. Arthritis Res Ther. 2013;15:205. 3. Greenberg EN et al. Proc Natl Acad Sci USA. 2020;117:5761-71. 4. Keniry M et al. Genes Dev. 2013;27:916-27. 5. Ismail D et al. Clin Exp Dermatol. 2021;46:276-85.
Luengas-Martinez A, Paus R, Iqbal M, Bailey L, Ray DW, Young HS. Circadian rhythms in psoriasis and the potential of chronotherapy in psoriasis management. Exp Dermatol. 2022 Jul 19. doi: 10.1111/exd.14649. Online ahead of print.
Baxter M, Poolman T, Cunningham P, Hunter L, Voronkov M, Kitchen GB, Goosey L, Begley N, Kay D, Hespe A, Maidstone R, Loudon ASI, Ray DW. Circadian clock function does not require the histone methyltransferase MLL3. FASEB J. 2022;36:e22356.
Maidstone R, Anderson S, Ray DW, Rutter MK, Durrington HJ, Blaikley JF. Shiftwork is associated with positive COVID-19 status in hospitalised patients. Thorax. 2021;76:53-60.
Luengas-Martinez A, Hardman-Smart J, Rutkowski D, Purba T, Paus R, Young HS. Vascular endothelial growth factor blockade induces dermal endothelial cell apoptosis in a clinically relevant skin organ culture model. Skin Pharmacol Physiol. 2020;33:110-8.
Hunter AL, Pelekanou CE, Adamson A, Downton P, Barron NJ, Cornfield T, Poolman TM, Humphreys N, Cunningham PS, Hodson L, Loudon ASI, Iqbal M, Bechtold DA, Ray DW. Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism. Proc Natl Acad Sci U S A. 2020;117:25869-25879
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