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A mechanistic understanding of circadian clock-dependent regulation of the secretory pathway


Project Description

The protein secretory pathway comprises a series of membranous compartments and transport vesicles that cells use to synthesise, post-translationally modify, and move proteins for delivery to the plasma membrane or for secretion to the extracellular matrix. The conventional secretory pathway describes protein synthesis at the endoplasmic reticulum, transport of proteins in 60 nm-diameter COPII vesicles to the Golgi apparatus, and subsequent transport to the plasma membrane in Golgi-to-plasma membrane carriers (GPCs). Studies of the secretory pathway have been carried out using fibroblasts in which small viral proteins have been used as the cargo. However, the most abundant cargo in fibroblasts is the relatively large procollagen, which would not be expected to fit into 60 nm-diameter transport vesicles.
Using time-series microarray analysis of gene transcription, proteomics, electron microscopy, and immunofluorescence, we have shown that the secretory pathway is under the control of the circadian clock. Our data show that the circadian clock exercises transcriptional and translational control of key proteins that are chaperones of protein folding, interaction partners for COPII-vesicle formation, and regulators of retrograde Golgi-to-ER transport.
This e project will seek to understand how the circadian clock controls the secretory pathway. We will locate clock regulated proteins in the pathway, identify the membrane trafficking and signalling mechanisms of transporting procollagen through the cell, and identify the critical regulatory mechanisms that control the balance between collagen synthesis and degradation.
Collagen is the most abundant protein in vertebrates where it performs an essential role in tissue scaffolding. Having the right amount of collagen is essential for life: too much and specialised tissues become fibrotic; too little and musculoskeletal, vascular, and other fibrous tissues are fragile. Understanding the role of the circadian clock in regulating the secretory pathway will enable the development of new treatments for fibrosis and degenerative diseases.

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

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 biology or with an interest in protein secretion are encouraged to apply.

This project has a Band 2 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).

Informal enquiries may be made directly to the primary supervisor.

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. Yang, N., Williams, J., Pekovic-Vaughan, V., Wang, P., Olabi, S., McConnell, J., Gossan, N., Hughes, A., Cheung, J., Streuli, C. H., and Meng Q. J. (2017) Cellular mechano-environment regulates the mammary circadian clock. Nature Commun. 8: 14287.
4. Shoham, A. B., Rot, C., Stern, T., Krief, S., Akiva, A., Dadosh, T., Sabany, H., Lu, Y., Kadler, K. E. and Zelzer, E. (2016) Deposition of collagen type I onto skeletal endothelium reveals a new role for blood vessels in regulating bone morphology. Development 143: 3933-3943.
5. Dudek, M., Gossan, N, Yang, N., Im, HJ, Ruckshanthi, J. P., Yoshitane, H., Li, X., Jin, D., Wang, P., Boudiffa, M., Bellantuono, I., Fukada Y., Boot-Handford, R. P., and Meng Q. J. (2016) The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity. J. Clin. Investig. 126: 365-376.

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