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MRC DiMeN Doctoral Training Partnership: How does a common SNP predispose to age-related cardiovascular and musculoskeletal disease? A tissue engineering and lncRNA approach using MSCs


Project Description

IMPORTANCE: A single nucleotide polymorphism (SNP) present in one quarter of the population (rs1800012) is associated with osteoporotic fracture, intervertebral disc degeneration and cardiovascular disease1-3. The SNP is present at an intronic Sp1 binding site of COL1A1 and is postulated to increase transcription to skew the proportion of abnormal homotrimeric (α1)3 versus normal heterotrimeric (α1)2(α2)1 type I collagen in tissues. Type I collagen plays a structural role in tissues whilst aberrant type I collagen homotrimer is degradation-resistant and alters tissue biomechanics. The abnormal homotrimeric form is present in osteoarthritis, carcinomas and fibrotic disease. Obesity could further exacerbate the effects of the SNP on the musculoskeletal and cardiovascular systems via the adipokine resistin, which increases COL1A1 transcription and translation to skew the proportion of aberrant collagen (I) homotrimer in osteoarthritic bone. The disease-associated SNP also overlaps with a COL1A1 antisense long non-coding RNA (lncRNA) that may direct disease pathogenesis by novel epigenetic/epitranscriptomic mechanisms as lncRNAs are a largely unexplored family of RNAs involved in gene regulation.

AIM: The aim of the project is to determine whether the SNP acts directly to affect tissue biomechanics via altered synthesis of structural type collagen, or whether it acts epigenetically on the epitranscriptome via an overlapping long non-coding RNA (lncRNA).

OBJECTIVES: 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 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.

IMPLICATIONS/IMPACT: The project will facilitate personalised medicine approaches to age-related musculoskeletal and cardiovascular disease due to the prevalence and broad medical impact of the SNP.

TRAINING: This PhD program will include training in laboratory techniques such as SNP genotyping, MSC isolation and characterisation, 2D and 3D cell culture, use 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 be expected to develop parallel skills in critical analysis, problem-solving and self-directed learning throughout the training program.

DOCTORAL SUPERVISION: Together the supervisory team provides world-class expertise in stem / progenitor cell isolation and culture, use of bioreactors for tissue engineering, 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 (, +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/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs.
Includes:
- Stipend at national UKRI standard rate
- Tuition fees
- Research training and support grant (RTSG)
- Travel allowance

Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

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.

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