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Project

Evaluation of the role of the proprotein convertase furin in liver: involvement in non-alcoholic steatohepatitis and hepatocellular carcinoma.

Furin is a proprotein convertase involved in the activation of many proteins like growth factors, receptors, enzymes, and cell adhesion molecules, by endoproteolytic cleavage at basic amino acid motifs. Liver-specific inactivation of furin in mice has unexpectedly resulted in a phenotype that closely resembles non-alcoholic steatohepatitis (NASH). This mouse model will further be characterized biochemically and morphologically. The molecular mechanisms leading to NASH will be unraveled by identifying substrates of furin in both a candidate substrate approach and by differential proteomics. In addition, the potential of this mouse model for drug testing will be evaluated, using established and experimental drugs for the treatment of NASH. Furin also plays a role in the regulation of carcinogenesis, angiogenesis and metastasis. It has been shown that inhibition, knockdown and genetic ablation of furin reduces tumorigenesis in various human cancer cells. Furthermore, we previously demonstrated that furin inhibition can be of therapeutic benefit in cancer in a salivary gland tumor model. Here, we will extend these findings in a study of the role of furin in hepatocellular carcinoma (HCC) progression in a transgenic mouse model. Carcinogenesis, angiogenesis and metastasis will be studied in a mouse model for HCC in the presence and absence of furin.
Date:1 Jan 2011 →  31 Dec 2014
Keywords:Furin, Non-alcoholic steatohepatitis, Hepatocellular carcinoma, Liver, Proprotein convertase, Mouse model
Disciplines:Morphological sciences, Oncology, Endocrinology and metabolic diseases, Biochemistry and metabolism, Medical biochemistry and metabolism