DiMeN Doctoral Training Partnership: Defining the role and mechanisms of miRs in cartilage ageing and disease

The musculoskeletal system is severely affected by the ageing process, with many tissues undergoing changes that lead to loss of function and frailty. Articular cartilage is particularly susceptible to the age-related disease, osteoarthritis (OA). OA is the most common degenerative joint disorder worldwide, affecting 8.75 million people in the UK and presents with degradation of articular cartilage, leading to loss of joint mobility, function, and chronic pain. However the molecular mechanisms associated with age-specific and OA-specific changes in cartilage are poorly understood.

MicroRNAs (miRs) are novel gene expression regulators, which control tissue homeostasis in response to environment and intracellular changes. Their expression has been shown to be dysregulated during human and animal ageing in a number of different systems/tissues.
miRNAs are differentially expressed in cartilage during ageing and in OA, and are thought to play a role in the regulation of important transcription factors involved in the development, maintenance, and repair of cartilage. Moreover, our small RNA-sequencing data from the femorotibial joint of C56BL6/J male mice, confirmed the differential expression of specific miRNAs with age and an in vivo model of OA (destabilisation of the medial meniscus). In addition we have preliminary data which has identified biologically relevant mRNAs and their targets in human knee OA and ageing cartilage.


We postulate that alterations in miRNA expression in the ageing cartilage result in a dysregulation of gene expression and hence altered chondrocyte phenotype contributing to the age-related disease OA. This will be tested by investigating the following overarching objectives:

1. Establish differentially expressed miRs in normal and OA chondrocytes during ageing using small RNAsequencing. This data will be produced as a by-product of a study being undertaken by the primary applicant to generate findings for small nucleolar RNAs and is funded by a Wellcome Trust Clinical Intermediate Fellowship.

2. Characterise selected target genes based on known or predicted function microRNAs validated from objective 1 through qPCR analysis and 3’UTR reporter assays, as well as microRNA gain- and loss-of-function approaches.

3. Investigating the role of physiologically relevant microRNA:target interactions predicted to regulate extracellular maintenance and cartilage homeostasis in chondrocytes. These studies will be undertaken in vitro and in vivo by analysing the phenotypes resulting from microRNA gain- and loss-of-function approaches.

The project supervision team will bring two junior Fellows (Dr Mandy Peffers and Dr Kasia Whysall) into a cross institution experienced supervisory panel (Professor Peter Clegg and Professor David Young) which will enhance the research environment and nurture further interdisciplinarity.

Funding notes:
DiMeN (Discovery Medicine North) DTP studentships are funded for 3.5 years and include the following annual package of financial support over the duration of the studentship:
•A tax-free maintenance grant set at the UK Research Council’s national postgraduate rate
•Full payment of tuition fees at the Home/EU rate
•A research training support grant (RTSG) to support your research studies (managed through the host institution)
•Opportunity to apply to our Flexible Fund to enable you to attend training workshops and visit research groups to advance your skills training.

Successful Home students will receive a full studentship. EU students will be considered for a full studentship or just fee support depending on the excellence of their qualifications and their employment/residency status (http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/). Overseas students are not eligible to apply.

Entry requirements:
You should be someone with an outstanding academic track record and can demonstrate your potential for the research project of your choice.
You must hold (or be expected to hold by October 2016) a First or a good 2:1 UK undergraduate degree, a suitable qualification at Masters level or an equivalent degree from a recognised EU institution, in the biosciences or a related area. The multidisciplinary training experience and interdisciplinary nature of some of our projects means that we welcome applications from students with physical science and/or mathematical backgrounds who are interested in using their skills to address the challenges of 21st century bioscience research.

How to apply:
Please carefully read the instructions on how to apply at our website and use the link on the page to apply: http://www.dimen.org.uk/how-to-apply/application-overview