Using animal models to develop a drug screening platform targeting the changes in mitochondrial function associated with arterial calcification University of Edinburgh in United Kingdom

Arterial calcification is a significant risk factor in the development of heart attacks and stroke. Identifying new pathways and novel pharmacological targets that prevent this process could reduce the risk of cardiovascular disease. There is huge potential for the use of large animal models to investigate the pathways that contribute to cardiovascular disease.

Our recent review discusses evidence suggesting that mitochondrial dysfunction plays a role in arterial calcification ⁽¹⁾ . Mitochondria are crucial organelles for energy generation, cell signalling regulation and apoptosis amplification. During a cell’s lifetime, the mitochondrial network is continuously shaped by fission and fusion events, which underpin mitochondrial elongation and shortening. We have demonstrated that calcifying vascular smooth muscle cells (VSMCs) show elongated mitochondria ⁽²⁾ , and have now established a high content imaging and analysis platform for the assessment of mitochondrial dysfunction during murine VSMC calcification. The assay uses high throughput imaging on a spinning disk microscope to generate images of ~160,000,000 cells, the mitochondria in which are analysed using AI ⁽³⁾ .

This PhD project will test the hypothesis that high throughput imaging of mitochondria coupled with AI can be upscaled to screen compound libraries targeting mitochondrial dysfunction, using calcification as a model system. Specifically, this project will (i) develop and optimise the calcification assay for use with vascular smooth muscle cells VSMCs in key animal models, including mouse, sheep and pig (ii) undertake screening with an FDA-approved library and (iii) develop drug library hits into lead compounds.

The student will be trained to tackle fundamental scientific questions in a vibrant atmosphere in three laboratories with complementary and wide-ranging expertise using state-of-the-art methods.

They will be encouraged to present work at UK and International scientific conferences. Past students of the supervisors’ have typically published at least 2 scientific papers during their studentships, and have secured high profile post-doctoral or industry positions.

Funding information and application procedures:

This 3.5 year studentship opportunity is open to UK and international students and provides funding to cover stipend, tuition fees and consumable/travel costs.

Application form can be downloaded via https://vet.ed.ac.uk/sites/default/files/2024-12/R%28D%29SVS%20and%20Roslin%20Foundation%20PhD%20studentship%20application%20form_0.docx

Please send your completed Application Form to [email protected]

If you are applying for more than one studentship please submit a separate application with a closing date of noon on 13 ^th February 2025 at Studentships | The Royal (Dick) School of Veterinary Studies