The study of antifibrotic effect of combined treatment by hyaluronan synthase inhibitor and nuclear orphan receptors agonists.

Annotation

The project is dedicated to hepatic fibrosis combination therapy development and testing. Liver fibrosis is socially significant disease that reduces the quality and duration of life. Fibrosis is a pathological process of hepatic parenchyma substitution with connective tissue, which leads to organ’s insufficient functionality and failure. A characteristic marker of the fibrotic process is the accumulation of the extracellular matrix (ECM) components, primarily collagen and hyaluronic acid (HA). The fibrotic process develops in response to hepatocytes injury and is characterized by the activation of liver stellate cells - the main producers of ECM, and resident liver macrophages (Kupffer cells), initiating inflammatory reactions. Up to date, there are no specific approaches for liver fibrosis therapy. In recently published paper, we have shown that the development of hepatic fibrosis is suppressed by the administration of 4-methylumbelliferone (4MU) in mice. 4MU is a coumarin derivative which inhibit the hyaluronic acid synthesis. Moreover, 4MU has a significant effect on gene expression in various tissues. The undelaying mechanisms of this effect are unknown. In our work, we showed that 4MU treatment suppresses the synthesis of ECM components by activated stellate cells and also significantly affects the expression of a specific gene set in hepatocytes. All these genes are involved in the regulation of lipid, glucose and xenobiotic metabolism, which are under control of nuclear orphan receptors FXR and PXR - promising targets for liver diseases therapy, fibrosis in particular. Both of these receptors are master regulators of lipid metabolism, are widely expressed in various cells in the body. Moreover, the natural ligands of these receptors show structural similarity to 4MU. This project is devoted to the study of the activation of these receptors under the 4MU treatment alone or in combination with specific ligands of these receptors. In the course of the project, the 4MU-induced activation of FXR and PXR receptors will be analyzed both in vitro and in vivo. Also, additional 4MU target proteins will be discovered through database analysis and search. Next, we will exam the expression of these target genes in various human cell types. This will expand the list of potential 4MU target organs and related diseases.

Expected results

• In this work, the mechanisms underlying 4MU influence on gene expression, will be investigated and described for the first time. • The effects of combination therapy with 4MU and specific agonists of the PXR and FXR receptors on hepatic fibrosis development will be estimated. • The results of this study will form the basis for the development of specific therapy, based on modulation of the activity of the PXR and FXR receptors by 4MU, for inflammatory and fibrotic processes in human liver • The obtained data about additional targets of 4MU in different human cell types can be used to develop the new approaches for treatment the wide range of condition, including autoimmune decease and cancer.