Interrogating ITGA11 signalling in rodent and human for targeted anti-fibrotic therapy in liver fibrosis.

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Liver fibrosis is a devastating scarring reaction that results from injury to the liver (e.g. by alcohol or infection). The scarring impairs liver function. The ultimate treatment of liver fibrosis is transplantation. Unfortunately this is limited due to the high numbers of people in need of a transplant. For this reason, identifying effective anti-fibrotic treatments for the disease would be hugely beneficial as none currently exist. The characteristic scar promotes progression of fibrosis. Discovering how to block scar production or how it signals to surrounding cells that perpetuates fibrosis represents a very attractive therapeutic avenue. We have identified that the scar signals through a receptor on cells called integrin alpha 11 (ITGA11) to drive and perpetuate pro-fibrotic signals during liver fibrosis. We know that downstream of ITGA11 signalling within the cell involves P21-activated kinase (PAK) protein family that can be broadly inhibited to improve liver fibrosis in mice but lack the precise mechanistic detail; a barrier to further translation. As a result, these findings now require refinement. To develop this project further we will prove the important role of ITGA11 in liver fibrosis. We will do this directly in mice models of fibrosis in which we can delete ITGA11 (e.g. anticipated to improve scarring) and using novel imaging analysis allowing us to track the precise functional location and role of ITGA11 in real time. We will determine the exact signalling of ITGA11 inside fibrotic cells during liver fibrosis, including PAKs, and use this knowledge to unpick the potential for therapeutic strategies which accurately targets individual molecules rather than broad protein families. To facilitate the translational capability of this work, importantly, all pathways will be verified directly in human biopsy tissue from patients with varying severity of fibrosis and molecularly in primary human culture models of fibrosis. Taken together, these experiments are anticipated to prove an important role for ITGA11 in liver fibrosis and assist in identifying new pathways of value in the search for urgently needed anti-fibrotic therapies.