- 22 November 2018
1:00 pm - 2:00 pm
Thursday 22 november 2018, 1.00 PM
Auditorium, Level 3, central Building
Biomarker development aids in identification of liver disease mechanism in children with Cystic Fibrosis
Professor Grant Ramm,
QIMR Berghofer Medical Research Institute
Cystic Fibrosis (CF)-associated liver disease is an important paediatric cholestatic liver disease leading to biliary fibrosis and cirrhosis, where aetiopathogenesis is poorly characterized, diagnosis is difficult and often delayed, treatment lacks efficacy, and outcomes without liver transplantation are suboptimal including premature mortality. Progression from fibrosis to cirrhosis is the major determinant of outcome. Further improvements in outcome are unlikely without elucidation of the aetiology, pathogenesis or mechanism of fibrosis, which importantly, may be reversible if specific intervention points can be identified. CF is the most common lethal inherited disease affecting Caucasians (1/2,500 live births), with CF liver disease causing significant morbidity and mortality in up to 15% of children by the second decade of life, due to the combined effects of hepatic and respiratory failure. Thus, CF liver disease is a high impact disease in paediatric practice, with the average age of diagnosis between 8–10 years of age. The pathogenic mechanism of this disease is unclear, but the non-functional/mutant CFTR (cystic fibrosis transmembrane conductance regulator) protein on bile duct cells suggests abnormal ion transport leads to bile stasis resulting in multilobular biliary cirrhosis and portal hypertension.
Research conducted within the Hepatic Fibrosis Group has demonstrated that elevated biliary levels of the hydrophobic bile acid taurocholate induces a histological liver event termed the Ductular Reaction as an initiating nexus in CF liver disease pathogenesis. We have evidence for specific regulatory mechanisms via microRNAs, identified in biomarker development studies, associated with (potentially reversible) hepatic stellate cell (liver myofibroblast) activation + liver stem (progenitor) cell differentiation into reactive biliary cells forming the Ductular Reaction in driving hepatic fibrogenesis. This research aims to improve diagnostic capability and uncover novel therapeutic intervention points associated with hepatic fibrosis progression, leading to new anti-fibrotic therapies, relating this to clinically relevant outcomes.
Professor Grant A. Ramm is Department Coordinator – Cell and Molecular Biology, Group Leader – Hepatic Fibrosis, NHMRC Senior Research Fellow and Principal Research Fellow at QIMR Berghofer. His PhD was conducted in The University of Queensland Department of Medicine at RBWH as well as QIMR Berghofer, before a post-doc in St Louis University Medical School. He returned to QIMR Berghofer in 1994 and was appointed Laboratory Head in 1995. His research is focussed on the mechanisms associated with hepatic stellate cell transdifferentiation into fibrosis-causing myofibroblasts and their interaction with liver progenitor cells driving wound healing, inflammation, fibrogenesis and liver regeneration. In addition, translation of mechanistic observations into clinical application for the differential diagnosis, monitoring progression, and predicting clinical outcome in chronic liver disease.