MRC DiMeN Doctoral Training Partnership: Investigating the role of novel motor protein in tendon development and aging.
Newcastle University MRC DiMeN Doctoral Training Partnership
Dr K Pirog, Dr A Twelvetrees, Dr EG Laird Friday, December 13, 2024 Competition Funded PhD Project (Students Worldwide)
About the Project
Musculoskeletal ageing is a multifactorial process resulting in joint stiffness and progressive tissue degeneration. This project investigates tendon ageing using tissue engineering and primary cells obtained from a mouse model of human genetic condition characterised by early-onset tendinopathy and joint degeneration. The disease, SEDMJL2, results from mutations in a novel motor protein. Although motor molecules are essential for intracellular transport of varied cargo, they remain largely unstudied in the musculoskeletal context. This project is a new collaboration between a musculoskeletal scientist (primary supervisor) and a kinesin expert (secondary supervisor), which together with the established tissue engineering collaboration (tertiary supervisor) opens up new areas of research to understand the role of kinesins in connective tissue homeostasis. We will use cells and tissues from our mouse model of SEMDJL2 coupled with in vitro and tissue engineering approaches to uncover novel molecular mechanisms of tendon repair and enhance future stem cell and tissue graft approaches. SEMDJL2 and control mesenchymal stem cells and fibroblasts will be used to study molecular pathways and to generate de novo tissues. Proliferation, apoptosis and collagen synthesis will be assessed. To study the molecular mechanisms involved in tendon ageing and repair, RNA sequencing, transmission electron microscopy (TEM) and mechanical testing will be performed on biobanked young and old mouse tendon samples and on the generated tissue engineered constructs. Tissue constructs will be subject to microdamage and their repair ability will be correlated with RNAseq data. Molecular function of the kinesin molecule in the musculoskeletal context will be studied through refining its intracellular localisation by confocal microscopy and analysis of the extracellular vesicle contents by mass spectrometry. In vitro studies of recombinant wild type and mutant protein will be used to assess its activity and motility, understand its function, and discover its binding partners.
This is an opportunity to work on a highly interdisciplinary project where a successful PhD student will receive extensive hands-on training in cell culture, tissue engineering, transcriptomics, biomechanics and biochemical assays, resulting in an exciting portfolio of highly transferrable interdisciplinary skills, and will benefit from Newcastle laboratories’ engagement in large national and international collaborative projects in which all supervisor participate and from expertise shared between Newcastle, Sheffield and Liverpool Universities.
Supervisors:
1. Katarzyna Pirog https://blogs.ncl.ac.uk/piroglab/
2. Alison Twelvetrees https://www.twelvetreeslab.co.uk/
3. Elisabeth Laird https://www.liverpool.ac.uk/people/elizabeth-laird
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, York 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, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk
Funding Notes
Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£19,237 for 2024/25) and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: View Website
Studentships commence: 1st October 2025
Good luck!
References
The adaptor proteins HAP1a and GRIP1 collaborate to activate kinesin-1 isoform KIF5C. Journal of Cell Science 2019, 132(24);
The Dynamic Localization of Cytoplasmic Dynein in Neurons Is Driven by Kinesin-1. Neuron, 2016, 90(5); 1000-1015.
Mild myopathy is associated with COMP but not MATN3 mutations in mouse models of genetic skeletal diseases. PLoS One 2013, 8(11), e82412.
A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia. Human Molecular Genetics 2010, 19(1), 52-64.
A comparison of the stem cell characteristics of murine tenocytes and tendon-derived stem cells. BMC Musculoskelet Disord . 2018 Apr 12;19(1):116.
An experimental model for studying the biomechanics of embryonic tendon: Evidence that the development of mechanical properties depends on the actinomyosin machinery. Matrix Biol. 2010 Oct;29(8):678-89
