Peroxisomes are multifunctional cellular organelles that are highly enriched in the liver. Our preliminary data show that defects in a peroxisomal protein affect the ability of the liver to respond to toxic insults. In this research proposal, we build on these important and exciting findings to examine the relationship between peroxisome dysfunction and liver disease.
The overall aims of this project are to examine the expression and function of peroxisomal proteins in the liver, to specifically deplete peroxisomal proteins in the hepatocytes of mice and examine its effect on liver function and disease progression, to analyse markers of peroxisomal disorders and peroxisome gene variants in a well-defined cohort of patients with fatty liver disease.
In the proposed research, we will identify the cellular roles of peroxisomal proteins in the hepatocytes and their importance in the progression of liver disease. The project aims to examine the expression of these proteins in the specific cell-types of the liver and examine the consequences of depletion of these genes in vitro on markers of liver disease and iron metabolism. We will use high throughput next-generation technologies to identify transcriptomic and proteomic changes in these models to further delineate the molecular mechanisms underlying the role of these proteins in liver disease progression. We will then develop a genetic panel to be used to identify variants in genes known to affect the progression of liver disease to be used clinically. All resources, equipment, and facilities required for the successful completion of the proposed research project are available including animal and cell culture facilities, microscopes, real-time PCR instruments, FACS, and histochemical facilities. Knockout mice and conditionally deleted mice are already breeding and the murine models of liver disease are routinely used in the laboratory. This project has the potential of developing into a PhD project.
Expected outcomes will be understanding the relationship between peroxisome dysfunction and liver disease with the aims of developing diagnostics and therapeutics.