Ageing and lifelong health research study

Yes Associated Protein 1 mechano-activation during organ fibrosis

• Vacant until filled

Hypothesis: Blocking mechano-sensitive pro-fibrotic YAP1 signalling will provide a means of slowing or reversing fibrotic disease.

Fibrotic disease causes a huge social and economic burden – fibrotic disorders account for up to 45% of deaths.

The ageing population and the global obesity epidemic are causing the socio-economic burden of fibrosis to increase, and there are still no approved anti-fibrotic therapies. There is an urgent need to better understand fibrotic disease processes to identify novel therapeutic targets.

Fibrosis caused by liver injury is driven by hepatic stellate cells (HSCs) that alter their phenotype (activate) from quiescent lipid-rich, vitamin A storing cells, and become proliferative, migratory, contractile cells that secrete the proteins that make up the fibrotic scar.

Our previous work showed that mechano-sensitive signalling via Yes Associated Protein 1 (YAP1) drives and maintains the fibrotic response of HSCs to liver injury. This project will use a liver fibrosis cell line (immortalised human hepatic stellate cells, LX-2), and primary HSCs (from mouse and human) to identify downstream targets of YAP1, and the mechanisms that regulate YAP1 activation in response to changes in mechanical force.

We use techniques including:

• qPCR

• western blot

• siRNA gene silencing

• immunocytochemistry

• proximity ligation assays

• immunoprecipitation (Co-IPs and ChIP)

For candidates with the relevant experience and skills, there are opportunities to use bioinformatics-based approaches to utilise RNA-seq and ChIP-seq datasets.

Supervisor

• Dr James Pritchett