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

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.

Fibrosis of the liver is characterised by progressive accumulation of ECM proteins and is a major cause of morbidity and mortality. End-stage liver fibrosis can be treated by liver transplantation, but this is limited by donor numbers. Anti-fibrotic therapies are an urgent priority, but no drugs have been approved to date. Pathological ECM and scarring drive progression of fibrosis. Discovering how to block scar production and the signalling in surrounding cells that perpetuates fibrosis represents a very attractive therapeutic avenue.

Cells contact the scar via cell surface integrin (ITG) receptors and signal intracellularly to mediate a broad range of cellular responses. We have identified ITGA11, and its partner subunit ITGB1, drives and perpetuates major pro-fibrotic signals in liver fibrosis. Moreover, intracellularly, downstream pathways involving P21-activated kinase (PAK) can be targeted pharmacologically to improve fibrosis in rodent models of liver fibrosis. The pressing challenges are now to test these data in vivo to determine the function and response of ITGA11 during liver fibrosis and if loss of ITGA11 prevents or ameliorates liver fibrosis. Moreover, we need determine the genome-wide effects of ITGA11 signalling to help identify new downstream pathways that may facilitate novel therapeutic intervention and interrogate the role of PAK to determine whether drugs already in development can be used as antifibrotic therapy in liver fibrosis. 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 organ fibrosis and assist in identifying new pathways of value in the search for new therapies.

Liver fibrosis is increasing in incidence and is a major cost to the NHS. It is associated with major morbidity and mortality. Largely, this problem comes from the lack of effective therapies at stages of the disease where the damage is reversible. This makes transplantation the last option and only then for lucky individuals where a donor organ is available. This research project will discover whether loss of the collagen binding integrin (integrin alpha-11; ITGA11) can ameliorate or reverse fibrosis and provide in depth insight into whether drug re-positioning for inhibition of and P21-activated kinase (PAK) is a realistic opportunity. It will discover new genes involved in liver fibrosis through identifying intracellular signalling pathways downstream of ITGA11 and it will place these in the context of known fibrosis pathways. Importantly, all data will be verified directly in human biopsy tissue from patients with varying severity of fibrosis and molecularly in primary human culture models of fibrosis. All of these steps will increase the likelihood of identifying new candidates for targeted drug development to treat liver fibrosis prior to end-stage disease. Therefore, this work carries substantial health and wealth implications.