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(BBSRC DTP CASE) Applying – omics methods to map the circadian matrisome


Project Description

Circadian rhythm regulates and synchronises biological processes through a daily cycle. Molecular clocks in cells throughout the human body are entrained to a ‘master clock’ located in the hypothalamus, and cells in almost all tissues have been found to contain rhythmic genes. Circadian rhythm ensures the correct sequence and regulation of a broad range of cellular and organ functions. Consequently, disruption to the cycle – for example, in shift-workers – has been linked to risk in many diseases, including hypertension, inflammatory, metabolic and neurological disorders.

Recent work, for example in mouse liver, has shown circadian rhythm in transcriptional regulation to be propagated through to protein levels and post-translational modifications of proteins. Remarkably, a study by the project management team has demonstrated that the secretory system for extracellular matrix proteins – the proteins that provide persistent, life-long structure to the body – also falls under circadian regulation in tendon tissue. The purpose of this project is to discover the extent to which circadian oscillations occur in extracellular matrix proteins throughout the body (the ‘matrisome’), and how these and other rhythmic processes can contribute to the healthy maintenance of tissues subjected to daily activity.

This is a highly multidisciplinary project encompassing aspects of chronobiology, cell biology, matrix biology, bioinformatics and biophysics. An initial task will be to mine existing transcriptional datasets to identify characteristic circadian regulation of secretory-pathway and matrix proteins, informed by our earlier work on tendon, cartilage and intervertebral disc. Candidate tissues, such as skin, will be isolated from mice at defined time-points and subjected to proteomic analysis. There will be opportunity here to learn and develop methods for sample preparation, data processing and interpretation. Unbiased -omics approaches will inform on multiple pathways, including secretion, autophagy, stress response and regulation of cell structure. This will enable us to build an integrated, holistic picture of the fundamental intracellular signalling and secretion pathways that maintain extracellular matrix homeostasis. The importance of key pathways will be tested through manipulation of cell and mouse model systems. Finally, we would like the project to establish an internet-based database of the “circadian matrisome”, thus providing benefit to the broader matrix and chronobiology communities.

The work will be performed in partnership with SCIEX (Cheshire, UK) – a leading developer of instruments for mass spectrometry. This collaboration will give access to training, technical expertise and the latest proteomics technology.

https://www.wellcome-matrix.org
https://www.sciex.com

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP websitewww.manchester.ac.uk/bbsrcdtpstudentships

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. Yeung, C.-Y. C., Garva, R., Pickard, A., Chang, J., Holmes, D. F., Lu, Y., Mallikarjun, V., Swift, J., Adamson, A., Calverley, B., Meng, Q. J., and Kadler, K. E. (2018) Circadian clock regulation of the secretory pathway. BioRxiv https://doi.org/10.1101/304014

2. Pickard, A., Chang, J., Alachkar, N., Calverley, C., Garva, R., Arvan, P., Meng, Q. J., and Kadler, K. E. (2018) Protection of circadian rhythms by the protein folding chaperone, BiP. BioRxiv https://doi.org/10.1101/348078

3. Wang, J., Mauvoisin, D., Martin, E., Atger, F., Galindo, A. N., Dayon, L., Sizzano, F., Palini, A., Kussmann, M., Waridel, P., Quadroni, M., Dulic, V., Naef, F., and Gachon, F. (2017) Nuclear proteomics uncovers diurnal regulatory landscapes in mouse liver. Cell Metab. 25(1): 102-117.

4. Swift, J., Ivanovska, I. L., Buxboim, A., Harada, T., Dingal, P. C., Pinter, J., Pajerowski, J. D., Spinler, K. R., Shin, J. W., Tewari, M., Rehfeldt, F., Speicher, D. W., and Discher, D. E. (2013) Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341: 1240104.

5. Naba, A., Clauser, K. R., Hoersch, S., Liu, H., Carr, S. A., and Hynes, R. O. (2012) The matrisome: In silico definition and in vivo characterisation by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteomics 11(4): M111.014647.

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