In adult mammals, wounds inflicted to most major organs result in scarring or lack of growth; however, the adult liver retains an exceptional capacity to undergo compensatory regeneration following surgical resection or toxic injury. Previous work has demonstrated that surgically perturbed liver mass in mice and other animals returns to an established liver to body mass ratio, suggesting the role of organ size sensing as a molecular mediator which can identify liver insufficiency and correspondingly adjust signals of liver regeneration. Currently, the molecular signals which sense organ size and integrate this information in response to liver insufficiency to confer regenerative capacity to the liver are unknown. In effort to reconstruct the signals which sense organ size, we are interested in identifying key mediators by examining the nature of these signaling pathways to respond to changes or outliers in whole liver mass to body mass ratio.
Thus, for this three-year project, our main research question is: Could the UK Biobank Cohort study help to identify factors in humans which alter liver mass to body mass ratio? For this purpose, we will first examine the associations of genotypes and outlying cases of phenotypes reconstructed from existing UK Biobank datafields which represent liver mass to body mass ratio using statistical methods (e.g., GWAS). We will then use the results of this study to strengthen our concurrent analysis of candidate factors being collected from natural and surgical perturbations of the Mus musculus set point liver:body mass ratio.
Understanding the molecular mechanisms behind organ size sensing and more broadly liver regeneration could help inform the development of novel therapeutic strategies for liver diseases and injuries. The ability to reconstruct and harness the capability of the regenerative pathways of the liver could help us to enhance natural liver regeneration in patients with liver failure, improve outcomes for transplant recipients, and possibly circumvent the need for transplants in cases where the liver could be redirected to a regenerative state. Further, understanding this unique regenerative capacity of the liver could identify strategies for researchers to confer this ability to other organs.