MRC DiMeN Doctoral Training Partnership: Investigating the role of novel motor protein in tendon development and aging.

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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)

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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.

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

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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!

Regenerative Medicine, Stem Cells, Transplantation (RMSCT) are offering one PhD studentship in Stem Cell Biology for entry in September 2024. They will be supported by the Newcastle Fund. This is possible due to the generosity of an anonymous benefactor.

The studentship will be awarded in open competition. The studentship is available for projects in diverse areas of Stem Cell Biology. Established research leaders from across the University will supervise the studentship.

Each studentship provides:

• a stipend (£18,622 p.a. for 2023/24)
• standard home fees. Applications are welcome from students in all countries. Students from outside the UK will pay full international fees. International students may be eligible to apply for a Newcastle University Scholarship to cover the additional cost
• a research allowance of £10,000 p.a.

To apply, visit: https://www.ncl.ac.uk/medical-sciences/research/research-themes/regenerative-medicine/studentship/

Applications should be submitted by 29 February 2024

One of the 3 projects that are offered is:

3 – Using human pluripotent stem cells to understand how genetic variation and epigenetic changes increase osteoarthritis risk

Project outline

Osteoarthritis is a common debilitating musculoskeletal disease that affects over 9 million people in the UK, yet there are no drugs that slow disease progression. The disease is typified by loss of cartilage, the tissue which allows joints friction-free movement. Genetic risk loci, along with epigenetic changes, for Osteoarthritis occur predominately in non-coding regulatory regions of the genome, which control target gene transcription. Many of these risk loci are also linked to skeletal developmental and are associated with adult height and joint shape. However, we still need to identify the target genes of these osteoarthritis-associated regulatory regions to know how these contribute to joint formation and to increase our understanding of osteoarthritis susceptibility.

Human pluripotent stem cells (hPSCs) can now be selectively differentiated in a process that recapitulates the developmental system of limb-bud formation to produce accurate articular pre-chondrocytes, cartilage cells. Importantly, hPSCs are amenable to genome-editing (CRISPR) and CRISPR-mediated gene regulation.

In collaboration with colleagues at the University of Manchester, the student will establish hPSC differentiation protocols and use these cells to generate a 3D genomic interaction map to utilise with established CRISPR-editing, CRISPR-gene-activator and CRISPR-gene-inhibitor systems to functionally define important osteoarthritis regulatory regions and effector genes.
This is an opportunity to work on a highly interdisciplinary project where a successful PhD student will learn fundamental molecular, cell biology and bioinformatic skills. Importantly, they will receive training in stem cell biology with a strong focus on aiming to improve clinical outcomes for patients with common and rarer skeletal diseases.

Supervisors

1. David Young (david.young@ncl.ac.uk)
2. Louise Reynard (louise.reynard@ncl.ac.uk)

https://research.ncl.ac.uk/nudmtdtp/

Newcastle University invites applications to a doctoral training programme on multiple long-term conditions and social inequalities funded by The Dunhill Medical Trust.  This PhD programme focuses on multiple long-term conditions (MLTCs) and social inequalities. The projects build on our Newcastle University-led James Lind Alliance Priority Setting Partnership on MLTCs in later life that highlighted unanswered questions in this area.

Theme 1 of the studentships is “Understanding the mechanisms of ageing and age-related disease” and a studentship is offered in the Skeletal Research Group (SRG) in Newcastle with Dr Louise Reynard, to investigate “Epigenetic alterations in cellular ageing”. Epigenetic alterations are a primary hallmark of cellular ageing, with many common age-related diseases such as cancer, diabetes and osteoarthritis characterised by abnormal epigenetic signatures. This project aims to understand the role of DNA methylation, an epigenetic regulator of gene expression, in musculoskeletal ageing and multi-morbidity. CRISPR-Cas9 genomic and epigenomic editing of cartilage and bone cells will be used to determine the effect of DNA methylation on ELOVL2 and FHL2 gene expression and investigate the function of these genes in cellular ageing. This project offers an opportunity for a student to work at the forefront of ageing research. 

To apply please send a CV and covering letter (no more than 500 words) to dmtdtp@newcastle.ac.uk that contains your reasons for applying and how you are qualified. Please also list up to three projects in your letter, and number them in order of preference from 1 (top choice) to 3 (least preferred).

Deadline: Thursday, 7th July 2022 at 17:00

Interviews expected to take place in the week ending 15th July 2022.

To apply, please click: https://www.ncl.ac.uk/postgraduate/funding/sources/ukeustudents/bi034.html

This interdisciplinary project combines the expertise of two supervisors (a cartilage biologist and a tissue engineer) to develop a bioprinted mechanically responsive tissue engineered model of cartilage and generate a transcriptomic and proteomic profile of healthy cartilage ageing.

For more details of the project, please check: https://nc3rs.org.uk/investigating-biomechanical-responses-healthy-and-diseases-ageing-cartilage-tissue-engineering.

Details of the project can be found here: https://nc3rs.org.uk/investigating-biomechanical-responses-healthy-and-diseases-ageing-cartilage-tissue-engineering

The studentship will be advertised shortly, watch this space!