Ricerc@Sapienza

Strong evidence indicates that chronic inflammation triggers fibrosis, which, once established, may progress independently. Furthermore, recent studies suggest that the epithelial to mesenchymal transition (EMT) process is involved in fibrosis onset as a result of chronic inflammation. Thus, a strict relationship seems to be established between fibrosis, chronic inflammation and EMT.
ZNF281 has been characterized as an EMT-inducing transcription factor (EMT-TF), suggesting its involvement in regulating pluripotency, stemness, and cancer. Several authors report that ZNF281 is a direct SNAIL target required for SNAIL-induced EMT and that it is phosphorylates by glycogen synthase kinase 3ß (GSK-3ß) to be then selectively ubiquitinated and degraded.
In a preliminary study, we demonstrated for the first time a role of ZNF281 in intestinal chronic inflammation. The aim of present study is to investigate the role of ZNF281 in the onset and progression of intestinal and liver fibrosis through in vitro, in vivo and ex vivo analyses. More specifically, we will assess the expression levels of ZNF281 pathway in gut and liver cell lines (human colorectal fibroblast adherent cell line (CCD-18Co), hepatic stellate cells (HSC) LX2 and murine embryonic fibroblast (MEF)) as well as the effect of ZNF silencing on fibrotic genes. Moreover, we will use two animal models of Cronh¿s disease (CD) and non-alcoholic steatohepatitis (NASH) to induce fibrosis and analyze the expression levels of ZNF281 pathway and fibrotic genes. Finally, the same analyses will be performed in intestinal and hepatic biopsy specimens of pediatric patients affected by structuring CD and NASH.
The identification of transcription factor ZNF281 as a novel player of fibrogenesis in the intestinal and hepatic tissue affected by chronic inflammation will allow a deeper comprehension of the pathogenetic mechanisms involved in fibrogenesis and will provide a new tool for the treatment of fibrosis in NASH and CD.