Healthy cartilage in our joints is essential for us to maintain an active life into old age, with cartilage breakdown causing chronic pain, joint stiffness and reduced mobility. Chondrocytes, the only cell type present in cartilage, have a specialised phenotype that is initiated during development and then maintained throughout life. Successful maintenance of this chondrocyte phenotype is important for healthy joint ageing, whilst improved understanding of cartilage differentiation from stem cells is important for improving cartilage tissue regeneration approaches.
Alternative RNA splicing (AS) and alternative polyadenylation (AP) are two essential mechanisms for the post-transcriptional control of gene expression in eukaryotes. Over 95% of multi-exonic genes are alternatively spliced in humans, allowing a single gene to encode multiple protein isoforms with different (sometimes antagonistic) functions, distinct subcellular localisations and diverse protein-protein interactions. Alternative polyadenylation results in transcripts pools that share similar protein coding regions but have different length 3’UTRs with different transcript stabilities. These two regulatory mechanisms are crucial for normal physiological processes including tissue development, differentiation and homeostasis. Post-transcriptional gene regulation is dysregulated during ageing, with abnormal AS and AP linked to several age-related pathologies including cancer and cardiovascular disease.
The role of AS and AP in cartilage development, health, age-related dysfunction and disease has not yet been explored at the genome wide level. This studentship offers an exciting opportunity to investigate the role of alternative mRNA isoforms in human cartilage function across the lifespan, from embryonic development to old age. The project will combine bioinformatics analysis with molecular biology techniques including qRT-PCR, western blot, human cell culture and biochemical assays. Cutting-edge CRISPR-Cas9 genetic editing approaches and antisense oligonucleotides will also be used to examine the function of specific age-related mRNAs in cartilage homeostasis.
The student will be primarily supervised by Dr Louise Reynard at Newcastle University, a world-leader in genetic and epigenetic regulation of cartilage gene expression. They will be co-supervised by Dr Simon Tew at the University of Liverpool, a pioneer in understanding post-transcriptional gene regulation in cartilage, and Prof David Elliott at Newcastle University, an expert in alternative splicing. In addition, the project involves placement periods with Dr Tew in Liverpool. The data generated by this studentship will reveal insight into the biological processes underlying cartilage ageing, provide new avenues for improving cartilage regenerative medicine approaches and identify potential targets for therapeutic intervention to treat cartilage age-related dysregulation.
Informal enquiries may be made to [Email Address Removed]
HOW TO APPLY
Applications should be made by emailing [Email Address Removed] with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.
In addition to the CV and covering letter, please email a completed copy of the Newcastle-Liverpool-Durham (NLD) BBSRC DTP Studentship Application Details Form (Word document) to [Email Address Removed], noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
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