The role of the hepatocyte in progressive liver injury.
Background: Liver injury has many diverse causes which result in a common progression of injury characterised by hepatocyte damage, hepatocyte regeneration, loss of hepatic architecture and bridging fibrosis in what is known pathologically as cirrhosis1. The sequelae of cirrhosis include liver failure and hepatocellular carcinoma (HCC). The global health burden from liver disease is immense with in excess of 450 million individuals infected with viral hepatitis and HCC being the fifth most common human malignancy2,3. Therefore, a better understanding of the pathophysiology of fibrogenesis is essential. The hepatocyte has classically been regarded as a “bystander” in the evolution of intrahepatic fibrogenesis. However, it is now clear that hepatocytes produce matrix metalloproteinases (MMPs) involved in extracellular matrix (ECM) remodelling4 (see preliminary results). Following gene array analysis of human liver disease we have identified increased hepatocyte expression of number of molecules including EMMPRIN, a known regulator of MMPs. Further, we have demonstrated that hepatocyte EMMPRIN regulates MMP production. Our results are the only description of molecules expressed on hepatocytes that are capable of ECM remodelling in fibrotic liver disease.
Project Aims: This project proposal will study the role of hepatocytes in ECM remodelling. Further, we plan to focus on the role of the hedgehog pathway in progressive liver injury as well as using functional genomics approaches, including gene arrays and microRNA arrays, to better understand the molecular pathways pivotal to the progression of liver fibrosis. Achieving the aims of this project will lead to a new understanding of hepatic fibrogenesis and ultimately lead to better therapeutic interventions targeting the progression of liver fibrosis.
The opportunity ID for this research opportunity is 134