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EASTBIO: Investigating mitochondria recycling in the calcification process


College of Medicine and Veterinary Medicine

About the Project

Autophagy (which literally translates from the Greek meaning to eat oneself) is the natural, regulated mechanism of the cell that removes unnecessary or dysfunctional components. This is a very new and exciting area of biology, with 2016’s Nobel Prize in Physiology or Medicine recognising the discovery and mechanisms underlying autophagy. Autophagy functions to clear the cell of potentially damaging agents, such as protein aggregates or faulty mitochondria, as well as acting as a recycling station to supply essential building blocks during periods of starvation.

Autophagy is an essential mechanism in the regulation of bone formation and calcification where it protects bone cells to survive various stresses (White and Lowe, 2009). Recently a specialised form of autophagy that specifically degrades dysfunctional or redundant mitochondria, termed mitophagy, has been found to contribute to the calcification of matrix produced by osteoblasts (bone forming cells). However, the precise role of autophagy and mitophagy in osteoblastic function has not been thoroughly explored.

The process of vascular calcification shares many similarities with bone calcification, and involves the transition of vascular smooth muscle cells (VSMCs) into an osteoblast-like cell. Autophagy has been shown to directly influence vascular calcification (see review from our lab by Phadwal et al., 2019). Using a new mouse model in which mitophagy can be visualised by a red fluorescent dye, our laboratory has shown progression of mitochondrial dysfunction and reduced mitochondrial turnover during the vascular calcification process.

Dr MacRae’s laboratory has a long term research programme focused on the actions of ENPP1; a calcification controlling enzyme within the ectonucleotide pyrophosphatase /phosphodiesterase family, (Mackenzie et al., 2012). Specifically, the student will investigate links between the ENPP1 enzyme and the mitophagy process in both bone and vascular calcification.

This project will utilise a range of bone and cardiovascular cells, including osteoblasts, valve interstitial cells, vascular smooth muscle cells and cardiac fibroblasts. Studies will involve the assessment of bone and vascular calcification in vitro and in vivo using transgenic and surgically-induced mouse models, biochemical assays and fluorescent probes. In collaboration with The University of Dundee, we will also use the Mito-QC mouse model to investigate the mitophagy pathways that are regulated by ENPP1 during the calcification process. Additional techniques used will include histology, qPCR, western blotting and immunofluorescent staining. RNAseq with subsequent informatics analysis will be undertaken to identify novel underpinning mechanisms.

The student will be encouraged to present their work at international and European scientific conferences (potentially through online platforms). Past students of the supervisors’ have typically published at least 3 scientific papers during their studentships, and have subsequently secured high profile post-doctoral research positions in the UK, Europe and USA.

Funding information and application procedures:
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0 .

EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to

You should also ensure that two references have been send to by the deadline using the EASTBIO Reference Form.

Funding Notes

This opportunity is open to UK and international students and provides funding covering stipend and UK level tuition fees. The University of Edinburgh covers the difference between home and international fees meaning that the EASTBIO DTP offers fully-funded studentships to all appointees. There is a cap on the number of international students the DTP recruits. It is important that we know from the outset which fees status category applicants fall under when applying to our university.

Please refer to UKRI (View Website ing-people-and-skills/find-studentships-and-doctoral-training/get-a-studentship-to-fund-your-doctorate/) and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria (View Website).


References

1. Mackenzie NC, Huesa C, Rutsch F, MacRae VE 2012 New insights into NPP1 function: lessons from clinical and animal studies. Bone. 51:961-8.
2. Phadwal K, Feng D, Zhu D, MacRae VE 2020 Autophagy as a novel therapeutic target in vascular calcification. Pharmacol Ther 206:107430
3. White, E., Lowe, S. W. (2009). Eating to exit: autophagy-enabled senescence revealed. Genes Dev. 23 (7), 784–787.

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