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Employing a range of approaches to address the physiological importance of the circadian:nuclear receptor system, ranging from population genetics, experimental medicine studies, CRISPR engineered mice, and cell biology.

Ray

About the research

Circadian mechanisms regulate most mammalian physiology, with particular importance in the regulation of innate immunity, through the macrophage in particular, and energy metabolism, regulating liver, adipose and muscle.  These circuits are also regulated by a number of nuclear receptors, which show a striking interdependency on the circadian machinery; some having ligand availability regulated by the clock, others varying in expression level through the day.  We have employed a range of approaches to address the physiological importance of the circadian:nuclear receptor system, ranging from population genetics, experimental medicine studies, CRISPR engineered mice, and cell biology.  In particular the group are making great progress using systems microscopy to resolve cell signalling events in fine temporal resolution, coupled to computational approaches to model single molecule behaviour.  These approaches have discovered how the important dimension of time regulates metabolism and coordinates diverse tissues to deliver optimal organismal performance.  Importantly, we are identifying how external stressors can de-couple these systems, with deleterious effects. This work has attracted Wellcome Investigator and MRC programme grant support, allowing the group to perform ambitious studies at scale, speed, and with agility.  David is a passionate advocate of research training, serving on the MRC clinical fellowship panel for seven years, three as deputy chair.

We propose to define the impact of inflammation on the function of the core clock components cryptochrome and REVERB; and their interactions with the glucocorticoid receptor. The glucocorticoid receptor binds to both cryptochrome and REVERB, and regulates core circadian clock phase, as well as being the major endogenous regulator of inflammatory signaling, and carbohydrate metabolism.  We will use vital stage microscopy, with analysis of trafficking and molecular interaction using number and brightness assay, fluorescence correlation spectroscopy, and FRAP.  The molecular interactions between GR and both REVERB and cryptochrome will be further pursued using fluorescence cross correlation spectroscopy, and FRET.  We will define where in the cell the interactions take place, how circadian phase regulates the molecular function of the GR, and how inflammatory signaling impacts on the GR:clock interface. 

We will then move to define how inflammation impacts on the rhythmic repertoire of metabolites and gene expression.  We will use computational approaches to build predictive models, which we will directly test using genetic and pharmacological intervention.  As an example of the approach, we have recently discovered that ceramides, potent regulators of insulin action, acquire a strong circadian oscillation in patients with active rheumatoid arthritis. 

Finally, we will interrogate the liver responses to chronic inflammation.  We will investigate humoral signals responsible for triggering hepatic circadian change and use combined metabolomics and transcriptomics to build functional networks capable of explaining the emergence of newly rhythmic processes under the inflamed state.

Taken together we will identify how inflammation re-wires the clock, and what the implications are for inflammatory persistence, metabolic consequences and drug response.

Training Opportunities

The student will gain training in cell and molecular biology, in-vivo physiology, genomics, and computational biology.  The techniques we use are covered in the recent publication, as attached.  In addition, we will provide high-level training in systems microscopy, coupled to image analysis, which we will use to build in-silico models, and inform the design of hypothesis testing experiments.  We have full-time computational biology researchers within the group, and encourage all graduate students to learn to code.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Publications

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
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. Epub 2015 Apr 6. 
Lane JM, Liang J, Vlasac I, Anderson SG, Bechtold DA, Bowden J, Emsley R, Gill S, Little MA, Luik AI, Loudon A, Scheer FA, Purcell SM, Kyle SD, Lawlor DA, Zhu X, Redline S, Ray DW, Rutter MK, Saxena R. (2017) Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits. Nat Genet. 2017 Feb;49(2):274-281.
Marie Pariollaud1, Julie Gibbs1, Thomas Hopwood1, Nicola Begley1, Ryan Vonslow1, Toryn Poolman1, Baoqiang Guo1, Ben Saer1, D Heulyn Jones2, James P Tellam2, Stefano Bresciani2, Nicholas CO Tomkinson2, Justyna Wojno-Picon2,3, Anthony WJ Cooper2,3, Dion A Daniels3, Ryan P Trump4, Daniel Grant4,5, William Zuercher4,6, Timothy M. Willson4,6, Brian Bolognese7, Patricia L. Podolin7, Yolanda Sanchez7, Andrew S.I. Loudon1 and David W. Ray1.  Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation. J Clin Invest 2018 128:2281-2296.  
Caratti G, Iqbal M, Hunter L, Kim D, Wang P, Vonslow RM, Begley N, Tetley AJ, Woodburn JL, Pariollaud M, Maidstone R, Donaldson IJ, Zhang Z, Ince LM, Kitchen G, Baxter M, Poolman TM, Daniels DA, Stirling DR, Brocker C, Gonzalez F, Loudon AS, Bechtold DA, Rattray M, Matthews LC, Ray DW. REVERBa couples the circadian clock to hepatic glucocorticoid action. J Clin Invest. 2018 Sep 4. pii: 96138. [Epub ahead of print]

 

Supervisors