Biological validation of human liver somatic mutations

It is well known that the liver is an organ with extraordinary capacity for regeneration and repair. However we do not understand many of the basic mechanisms by which this occurs and what regulates the growth following injury. Our previous work has shown that certain genes seem to play an important role in enabling liver cells (hepatocytes) to divide and form large groups of cells. My approach is to study what happens in healthy and end stage liver disease in order to identify key genes which are involved in liver regeneration. I will then use a variety of novel scientific techniques, such as stem cell derived hepatocytes to unravel the complex relationship between these different genetic pathways. By understanding what goes on at the molecular and cellular level, we will ultimately be able to design new treatments for liver disease such as growing liver cells in the laboratory for cell therapies or by developing new drugs to combat cirrhosis.

Despite being an organ with substantial regenerative potential, the underlying mechanisms in the human liver are important unknowns. Our previous work has revealed that clonal expansions of hepatocytes occurs in chronic liver disease, some of which have acquired somatic driver mutations. Interestingly these are not typical cancer related driver genes and finding out what role these genes play in hepatocyte clonal biology will be key to understanding liver regeneration. This project takes novel approaches to model and biologically validate the mutated driver genes, starting with ACVR2A, and identify the downstream pathways which promote hepatocyte proliferation. Using a combination of scientific models, the consequences of mutations in ACVR2A on hepatocyte biology and the Activin/TGF-b/BMP pathways will be studied. Finally, clinical samples will be collected from acutely regenerating livers to ascertain if the same gene sets are activated or suppressed as compared to chronic liver disease. It is hoped that the outcome of the project will identify pathways which will act to promote hepatocyte survival and proliferation, enabling development of novel treatments in vivo and strategies to produce hepatocytes in vitro.