A single nucleotide polymorphism (SNP) present in one quarter of the population (rs1800012) is associated with osteoporotic fracture, intervertebral disc degeneration and cardiovascular disease. The SNP is present at an intronic Sp1 binding site of COL1A1 and is predicted to skew the proportion of collagen homotrimer (α1)3 versus ‘normal’ heterotrimer (α1)2(α2)1 hence alterting tissue biomechanics. The abnormal homotrimeric protein is present in osteoarthritis, carcinomas and fibrotic disease, and obesity could exacerbate the effects of the SNP in osteoarthritis via adipokines acting on collagen transcription and translation.
The aim of the project is to determine whether the SNP acts directly to affect tissue biomechanics via altered synthesis of structural collagen networks, or whether it acts epigenetically on the epitranscriptome via an overlapping long non-coding RNA (lncRNA).
The first objective is to determine whether the SNP directly affects type I collagen synthesis and biomechanics of bioengineered blood vessels, tendon and bone. In the second objective the effects of the adipokine resistin on tissues bioengineered from MSCs of each genotype will be evaluated. The third objective will focus on characterising the expression and function of the long non-coding RNA with bioinformatics, antisense and functional assays.
The project will pave the way towards personalised medicine approaches to age-related musculoskeletal and cardiovascular disease. Due to the prevalence and broad medical impact of the SNP the project has excellent potential for large-scale medical impact and future therapeutics.
This PhD program will include training in laboratory techniques such as Taqman genotyping, MSC isolation and characterisation, 2D and 3D cell culture, development of bioreactors for tissue engineering, qPCR, SDS Page, RNA inhibition and microscopy. Mathematical quantitative skills required for biomechanical testing will be developed with the Sysmic maths/computing training module, and bioinformatics skills training will be provided locally and complemented with recommended online modules. Additional project-specific training in statistical data analysis will be included. The candidate will develop parallel skills in critical analysis, problem-solving and self-directed learning throughout the training program.
Together the supervisory team provides world-class expertise in stem / progenitor cell isolation and culture, designing bioreactors for tissue engineering, extracellular matrix biology, epigenetics and epitranscriptomics each applied to age-related musculoskeletal and cardiovascular disease. We are very happy to speak to potential applications for this exciting opportunity or answer any queries – please contact Dr Laird in the first instance ([email protected]
, +441517946026 )
Dr Liz Laird (University of Liverpool) https://www.liverpool.ac.uk/ageing-and-chronic-disease/staff/elizabeth-laird/ https://www.researchgate.net/profile/Elizabeth_Canty-Laird
Dr James Henstock (University of Liverpool) https://www.liverpool.ac.uk/ageing-and-chronic-disease/staff/james-henstock/ https://uk.linkedin.com/in/jrhenstock
Prof David Young (Newcastle University) https://www.ncl.ac.uk/medicalsciences/research/groups/profile/davidyoung.html#background https://blogs.ncl.ac.uk/davidyoung/
Prof Konstantinos Stellos (Newcastle University) https://www.ncl.ac.uk/igm/staff/profile/konstantinosstellos.html#background https://www.stelloslab.com/
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
1. Ralston, S.H., et al., Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med, 2006. 3(4): p. e90.
2. Zhong, B., et al., Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis. Oncotarget, 2017. 8(43): p. 75488-75499.
3. Brull, D.J., et al., Effect of a COL1A1 Sp1 binding site polymorphism on arterial pulse wave velocity: an index of compliance. Hypertension, 2001. 38(3): p. 444-8.