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Understanding differential responses to retinoid treatments in human health and disease: a precision medicine approach


Project Description

Retinoids, such as all-trans retinoic acid (t-RA), are endogenous signalling molecules derived from vitamin A that influence a variety of cellular processes through mediation of transcription events in the cell nucleus. To carry out this function, retinoids are high-affinity ligands for a family of nuclear receptor proteins known as the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Heterodimerization of these receptors (RAR/RXR) permits interactions with short DNA sequences termed retinoic acid response elements (RAREs) and thus facilitate transcriptional regulation of retinoic acid signalling pathways [1].

Retinoids have emerged as therapeutic candidates of enormous potential due to their wide ranging and powerful biological activities. The ‘gold standard’ topical treatment for the management of acne and skin damaged by long-term sunlight exposure is t-RA [2, 3]; however, the efficacy of this treatment is very person-specific. The underlying mechanism that underpins this differential response in human skin remains unknown due to a lack of understanding of the complex and intricate signalling pathways that retinoids control [4].

The supervisory team, led by Professor R Watson and Dr A Langton, have proven excellence in translational research and through the development of the “Manchester Patch Test” assay, the efficacy of both t-RA can be assayed in vivo [5]. Thus, by utilising this unique assay it will be possible to identify why individuals do not respond to t-RA and to explore the signalling pathways that retinoids control. These key insights will facilitate novel product design and allow a targeted, stratified approach to the development of future treatment of skin disease.

Training/techniques to be provided:
The successful candidate will join a multidisciplinary team of researchers at the School of Biological Sciences, University of Manchester. State-of-the-art training will be provided in histological techniques, cell culture and human clinical research. The student will work at the interface between clinical sciences and biosciences, learning how these disciplines can come together to support the translation of scientific findings to clinically relevant applications. They will also benefit from the supervisors’ research collaborations with academic, clinical and industrial groups, and have the opportunity to attend and contribute to national and international meetings and conferences.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in cell culture, immunohistochemistry and dermatology research are encouraged to apply.

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

[1] Bastien, J., and Rochette-Egly, C. Nuclear Retinoid Receptors and the Transcription of Retinoid-Target Genes. Gene. 2004. 328: 1−16.
[2] Griffiths CEM, Finkel LJ, Tranfaglia MG, Hamilton TA, Voorhees JJ. An in vivo experimental model for effects of topical retinoic acid in human skin. Br J Dermatol. 1993. 129(4): 389-94
[3] Singh M, Griffiths CEM. The use of retinoids in the treatment of photoaging. Dermatol Ther. 2006. 19(5): 297-305.
[4] Watson REB, Arjuna Ratnayaka J, Brooke RC, Yee-Sit-Yu S, Ancian P, Griffiths CEM. Retinoic acid receptor alpha expression and cutaneous ageing. Mech Ageing Dev. 2004. 125(7): 465-73
[5] Watson REB, Ogden S, Cotterell LF, Bowden JJ, Bastrilles JY, Long SP, Griffiths CEM. Effects of a cosmetic 'anti-ageing' product improves photoaged skin. Br J Dermatol. 2009. 161(2): 419-26

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