Research

Mouse models, simple epithelia, fibrosis, IBD, carcinogenesis

In recent years, our main research interest has been cytoskeleton organization and dynamics, cell adhesion, and cell signaling. Specifically, we focus on plectin-dependent regulation of actin microfilaments, intermediate filament cytoarchitecture, adhesion mediated signaling, and cell motility using molecular cell biology in various cell types derived from transgenic mice models. The current aim of our lab has the following core project objectives: 1) identification of genes with unique and essential functions in simple epithelia; 2) generation of mouse models with targeted selected genes; and 3) phenotypic characterization of generated mouse models addressing gene functions in healthy and diseased simple epithelia. Our research has practical applications to the understanding of liver fibrosis, inflammatory bowel diseases and carcinogenesis.

Current Research

  • The impact of liver-specific plectin deficiency on pathogenesis of liver diseases. Using liver-specific plectin knock-out mice, we have recently shown (Jirouskova et al., J. Hepatol., 2018) that plectin deficiency has a detrimental effect in fibrosis and also leads also to stress-induced overactivation of hepatic progenitor cells. The major objective of this project is a detailed analysis of the underlying molecular mechanism, consisting of the governing role of plectin for keratin networks and integrin clusters. Using hepatocellular carcinoma cells, we will also dissect the isoform-specific role of plectin in motility and invasion, i.e. key processes in primary liver cancer. This project should expand the knowledge of pathogenesis of liver diseases.
  • Experimental colitis and colorectal cancer in mouse model of plectinopathy. The inflammatory bowel disease (IBD) is characterized by a compromised intestinal barrier function in association with excessive activation of the mucosal immune system. Using the mouse model of plectinopathy, we show that the absence of plectin in intestinal epithelium aggravates experimentally induced colitis and potentiates associated carcinogenesis. The major goal of this project is a detailed analysis of the molecular mechanism underlying the governing role of plectin in intestinal barrier maintenance. In addition, we will study the impact of plectin deficiency on initiation and progression of colorectal cancer.
  • Analysis of extracellular niche in mouse models of liver fibrosis. Liver fibrosis is an excessive scarring process resulting from chronic insults of heterogeneous etiology. Together with primary liver cancer, it represents the end-stage liver pathology with high mortality. The hallmark of liver fibrosis is the deposition of fibrous extracellular matrix (ECM) synthetized mainly by hepatic stellate cells (HSCs). Using mouse models, we propose to analyze changes in the composition of ECM during the development and resolution of liver fibrosis by differential mass spectroscopy analysis. Further, we will study the interplay between HSCs and altering ECM niche, using a newly developed mouse model harboring HSCs with compromised ECM-receptor signaling. This phenomenon will be studied also in vitro, using a human HSC line and mouse primary HSCs to better understand the processes regulating the deposition and the composition of ECM in liver fibrosis.
  • Inflammatory bowel disease in primary sclerosing cholangitis: Prognostic markers and models. Primary sclerosing cholangitis (PSC) frequently associates with inflammatory bowel diseases (IBD), in particular ulcerative colitis (UC) and colorectal cancer. Although a different clinical course and features (a higher carcinogenic potential) suggest that IBD in PSC represents a disease entity distinct from IBD without a hepatobiliary component, underlying molecular mechanisms remain unknown. In this project, we will analyze the transcriptome of colon biopsy samples collected in a prospective study of patients diagnosed with PSC without UC, UC without PSC, PSC with concurrent UC, and a control group. Using whole-genome transcriptome profiling, we will identify the expression signatures of the different diagnoses. In parallel, we will characterize available experimental PSC/IBD mouse models with respect to alterations in colonic tissues and genes identified in the transcriptome analysis. The understanding of the mechanism involved in pathogenesis of UC in PSC will help to define new targets for disease screening and new strategies for its prevention and treatment.

 

 

Last change: October 2, 2019