About the Project
There is strong evidence that the circadian clock is a major regulator of immunity, and energy metabolism in man and animals. Our laboratory has discovered important new mechanisms showing how the core circadian clock within cells is coupled to inflammatory outputs, thus opening up new exciting ways to target inflammatory diseases. A key component linking the clock to immunity is REV-ERBα, which acts both as a core clock gene – driving rhythmic oscillations in the cell – and as a critical output, coupling the clock to immunity. Importantly, REVERB proteins are implicated in the control of metabolism and oxidative (redox) state, which is also central to how immune cells become activated in response to external threat. This studentship will now tackle the fundamental scientific question as to whether clock-control of metabolism directly couples timing systems to immunity. This is suggested by the emergence of a conserved PXDLS motif within REVERBα which can couple to redox sensing, through NAD/H sensing, with the core clockwork of the cell. Your project will use genetically modified cells and animals to investigate redox sensing signaling through REVERB to the core clock machinery. You will exploit these in physiological models such as inflammation, which affect redox state, to determine the role of REVERB proteins for integrating metabolic, circadian, and inflammatory responses. Other approaches will include proteomics, computational biology methods to study inflammation/circadian interactions. From this, you may discover fundamental new approaches to tackle chronic inflammatory diseases, which represent one the major current clinical challenges for Medicine.
This prestigious PhD studentship will be based in an outstanding laboratory environment at Manchester (Ray, Loudon) and at our partner institution, the Weizmann Institute of Science in Israel (Asher).
Between us we have a long track record of high quality scientific papers, linked to successful training of post-graduate students, and we provide a large well-funded base for an ambitious applicant, who may now wish to tackle a major scientific question in BioMedical research.
References
1. Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, Farrow SN, Else KJ, Singh D, 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 109:582-7. Joint corresponding author
Trebble PJ, Woolven JM, Saunders KA, Simpson KD, Farrow SN, Matthews LC, Ray DW. (2013) A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function. J Cell Sci 126:3159-69. Epub 2013 May 17.
2. Poolman TM, Farrow S, Matthews L, Loudon AS, Ray DW. (2013) Pin1 promotes GR transactivation by enhancing recruitment to target genes. Nucleic Acids Res 41:8515-25. Epub 2013 Jul 25.
3. Trump RP, Bresciani S, Cooper AW, Tellam JP, Wojno J, Blaikley J, Orband-Miller LA, Kashatus JA, Boudjelal M, Dawson HC, Loudon A, Ray D, Grant D,Farrow SN, Willson TM, Tomkinson NC. (2013) Optimized Chemical Probes for REV-ERBα. J Med Chem 56:4729-37. Epub 2013 May 23.
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 20:919-26. Epub 2014 Jul 27. Joint corresponding author
Matthews LC, Berry AA, Morgan DJ, Poolman TM, Bauer K, Kramer F, Spiller DG, Richardson RV, Chapman KE, Farrow SN, Norman MR, Williamson AJ, Whetton AD, Taylor SS, Tuckermann JP, White MR, Ray DW. (2015) Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy. Proc Natl Acad Sci U S A 112(17):5479-84. doi: 10.1073/pnas.1411356112. Epub 2015 Apr 6.
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. 2016 Nov;30(11):3759-3770.
Shalev M, Aviram R, Adamovich Y, Kraut-Cohen J, Shamia T, Ben-Dor S, Golik M, Asher G. The PXDLS linear motif regulates circadian rhythmicity through protein-protein interactions. Nucleic Acids Res. 2014 Oct 29;42(19):11879-90. doi: 10.1093/nar/gku873.