The role of the microRNAs miR-155 and miR-223 in the development of liver cirrhosis: a functional analysis

• Applicant: Professor Dr. Christoph Roderburg
• Subject Area: Gastroenterology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266189956

Liver fibrosis and cirrhosis represent the common end-point of chronic liver diseases and are major risk factors for the development of hepatocellular carcinoma (HCC). Chronic inflammatory processes, occurring chronic liver diseases led to the destruction of liver parenchyma and the deposition of extracellular matrix proteins, which is associated with an impaired liver function. Despite intensive research no pharmacopreventive strategies against the development of liver cirrhosis during chronic liver diseases could be established so far, highlighting the need for strategies in the treatment of these patients. MicroRNAs (miRNAs) are small, noncoding RNAs that negatively regulate gene-expression by base pairing with the 3-untranslated region of their target messenger RNAs (mRNAs). Recently, an involvement of miRNAs was demonstrated in highly regulated processes such as fibrogenesis. In the last years intensive efforts were taken in order to identify miRNAs deregulated in liver cirrhosis by performing numerous array based studies on samples from patients with hepatic cirrhosis. These analyses revealed a consistent deregulation of the microRNAs miR-155 and miR-223 both in fibrotic and cirrhotic livers. However, up to now, only few functional data on the role of these miRNAs in the pathophysiology of hepatofibrogenesis are available. In first experiments we and another group demonstrated that the loss of miR-155 leads to a more severe fibrosis in response to chronic liver injury, suggesting a protective role for miR-155. The overall aim of this project is to characterize the functional role of miR-155 and miR-223 in the development of liver fibrosis and cirrhosis and by applying specific knock out mice for these miRNAs. The phenotype of these miR-155- and miR-223 knock-out mice will be analysed by using different standardized models of murine liver fibrosis- and chronic liver injury. These will be characterized by histology as well as by different molecular-biological and immunological methods. In a next step in vitro experiments will be applied to further characterize the functions of these miRNAs in hepatofibrogenesis. Finally, results will be correlated with data from patients´ samples in order to identify the relevance of these miRNAs for clinical end-points such as disease progression and overall patients´ survival. In summary, in the present project the role of miR-155 and miR-223 in the development of liver cirrhosis will be evaluated and these data will be correlated with results from patients´ samples.

• DFG Programme: Research Grants