PhD Studentship: Harnessing Protein Degradation as a Therapeutic Strategy to Reduce Cardiovascular Disease

Interested applicants should direct initial queries about the project to Professor Vicky MacRae via email: . For enquiries regarding the process and eligibility please contact .

Candidates for this PhD Studentship must demonstrate outstanding qualities and be motivated to complete a PhD within 3 years., Applicants should have a minimum of a 2.1 Honours degree in a relevant discipline. An IELTS (Academic) score of 6.5 minimum (or equivalent) is essential for candidates for whom English is not their first language. In addition to satisfying basic entry criteria, the University will look closely at the qualities, skills, and background of each candidate and what they can bring to their chosen research project in order to ensure successful and timely completion.

• £20,780 per year
• Contract
• Full-time
• 1 day ago
Cambridge Campus Fixed term contract for 3 years, commencing September 2025 Bursary of £20,780 per annum and a full fee-waiver for UK tuition fees. Harnessing protein degradation as a therapeutic strategy to reduce cardiovascular disease About Anglia Ruskin University: Anglia Ruskin is a vibrant workplace and our University is recognised both nationally and internationally. We have ambitious plans for the future and we are determined that our students and staff will realise their full potential. Our main campuses in the cities of Cambridge, Chelmsford, London and Peterborough have been transformed with major capital investment. With an annual turnover of over £200m, we are a major force for higher education and one of the largest universities in the East of England. About the position: The calcification of arteries 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 therefore reduce the risk of cardiovascular disease. As described in a review from our laboratory (1), vascular smooth muscle cells (VSMCs) are the predominant cell type involved in arterial calcification, and can change into a bone-like phenotype when subjected to a calcified environment. This is evident in the expression of bone-like factors, including the master transcription factor runt-related transcription factor 2 (Runx2). Metformin has been used in type 2 diabetes treatment for over 60 years and is currently the most common diabetes treatment worldwide. However, there is growing evidence that metformin's positive health actions extend beyond its capacity to modulate glucose metabolism, including cardiovascular benefits. Indeed, our recent paper shows that metformin exerts protective effects against arterial calcification through autophagy (cellular recycling) and the subsequent autophagic degradation of Runx2 (2). We also show that this mechanism involves p62, an important regulator of autophagy. Interestingly, a recent model proposes that autophagic cargo proteins can be concentrated and segregated through the polyubiquitin chain-induced phase separation of p62, forming "p62 bodies". These p62 bodies serve as essential platforms for autophagosome formation (3). This PhD project will test the hypothesis that the mechanism through which p62 mediates metformin's protective effect against arterial calcification is phase separation (Aim 1) and the formation of p62 bodies in order to store Runx2 (Aim 2). Furthermore, this project will seek to develop a novel targeted protein degradation therapeutic, mirroring the targeted degradation of Runx2 by metformin (Aim 3). The student will be trained to tackle fundamental scientific questions in a vibrant atmosphere in three laboratories with complementary and wide-ranging expertise in calcification biology (Professor Vicky MacRae), vascular research (Professor Vicky MacRae, Professor Havovi Chichger) and protein self-assembly (Dr Janet Kumita). The student will be trained in our laboratories based at both Anglia Ruskin University Cambridge (School of Life Sciences) and University of Cambridge (Department of Pharmacology), using a multidisciplinary approach including molecular techniques, advanced imaging and protein engineering. The student 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. References:
• Zhu et al. Mechanisms and clinical consequences of vascular calcification. Front Endocrinol (Lausanne). 2012 6;3:95.
• Phadwal et al. Metformin protects against vascular calcification through the selective degradation of Runx2 by the p62 autophagy receptor. J Cell Physiol. 2022 237(11):4303-4316.
• Sun et al. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Res. 2018 28(4):405-415.
About the Studentship: A 3-year studentship is offered, intended to start in 2025, providing a tax-free stipend of £20, 780 per annum plus tuition fees at the UK rate.