The role of modified microRNAs in fibrosis during ageing

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate the expression of multiple mRNAs posttranscriptionally (Brown & Goljanek-Whysall, Aging Res Rev 2015). Recently, a set of miRNAs, regulators of fibrosis, has been shown to be regulated via ROS signalling, previously shown to promote fibrosis (Fierro-Fernandez et al., Redox Biology, 2016). Moreover, oxidative modification of miRNAs by ROS resulting in miRNA targeting of non-native rather than native microRNA targets, or simply “off-targeting”, has been demonstrated (Wang et al., Mol Cell, 2015).

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterised by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function (King et al., Lancet 2011). Currently, there is no effective treatment for IPF. Moreover, ageing is associated with accumulation of fibrotic tissues in other organs, such as muscle.

We hypothesize that ROS-induced modifications of microRNAs lead to changes in miRNA targeting of mRNAs and therefore may contributes to loss of tissue homeostasis. Specifically, we propose that key miRNAs regulating the expression of fibrosis-driving transcription factors, such as CCN2, are oxidized and can no longer target these factors, thus leading to development of pulmonary fibrosis. As synthetic miRNA mimics and inhibitors can be efficiently delivered into lungs in vivo, miRNAs provide a potential therapeutic avenue against lung fibrosis.

The student will be trained in a broad context of lung and fibrosis biology, biology of ageing, ROS signalling and epigenetics. This will include:
- research-specific skills related to lung and fibrosis biology (in vitro cell culture and in vivo animal models), bioinformatics and molecular approaches (tools predicting miRNA targets, molecular biology techniques, including gene and protein expression analyses, molecular cloning, gene expression manipulations in vitro/in vivo);
- generic research skills: critical thinking, IT skills, scientific integrity, ethics, animal licensing, project and time management, scientific writing, presentation skills and public engagement;
- transferable skills: personal effectiveness, oral and written communication skills, networking and teamwork, management and leadership, understanding of research context.
This training will be provided on an everyday basis and during specific courses.
The student will also be provided training in personal and professional development skills, by learning the following: planning their PhD, presenting research at seminars/conferences, creative thinking, problem solving and project management.

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.