microRNAs as tools to regulate senescence of musculoskeletal cells during ageing

As the ageing population continues to increase, it is important to address ageing-related health issues. There is currently no effective treatments for many common musculoskeletal (MSK) disorders, such as sarcopenia or osteoarthritis, which increase in prevalence during ageing. Cellular senescence is an established common mechanism associated with dysfunction of tissues during ageing. We, and others, have shown the presence of senescent satellite cells, mesenchymal stem cells and chondrocytes and the associated MSK deterioration during ageing. Moreover, depletion of senescent cells in mice leads to improved function of various tissues during ageing. The mechanisms associated with senescence and functional deterioration of MSK tissues with ageing are not fully understood, however it is accepted these are multifactorial, with genetic and epigenetic mechanisms involved.

microRNAs (miRNAs, miRs) are a class of potent non-coding RNAs regulating gene expression post-transcriptionally. miRNA regulate the homeostasis of the MSK tissues and their expression is altered with ageing, however the relevance of these changes is still unknown. We have shown that by regulating miRNA expression in vivo, we can restore the function of MSK tissues, such as muscle. As miRNA expression, and therefore function, responds to changes within the cells and in their surrounding environment, and miRNAs can regulate the expression of many genes/signalling pathways simultaneously, they are likely to be involved in regulating many physiological processes, including senescence and ageing. Moreover, miRNAs are likely to be a part of common mechanisms associated with regulation of senescence in various cells of the MSK tissues.

The overall aims of this project are to (1) identify and model changes in miRNA:target interactions in senescent cells of the MSK system, conserved in humans and mice, during ageing resulting in MSK deterioration, and (2) establish the potential of miRNA-based interventions in restoring the functionality of MSK cells undergoing senescence and therefore in preserving MSK homeostasis and preventing MSK disorders during ageing.

This will be achieved by completing the following specific objectives:

1. Identify and model the changes in expression of miRNAs and their putative targets in the population of senescent cells in MSK tissues, using senescence, proliferation and cell type-specific markers. Building on preliminary data showing the presence of senescent cells in MSK tissues during ageing, the identity and percentage of senescent cells will be further confirmed using immunostaining.
2. Validate the disrupted miRNA:target interactions in vitro using sensor constructs, miRNA gain- and loss-of-function approaches followed by histological and functional analyses;
3. Validate the anti-senescent potential of miRNA-based interventions in-vivo in age-related loss of homeostasis and function of MSK cells by using miRNA mimics and antagomiRs. Intravenous and intraarticular injections of miRNA mimic/inhibitor will be followed by comprehensive histological and physiological analyses of MSK tissues.

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.