Martin Gregor Mouse Models for Studying of Physiology and Pathophysilogy of Digestive Epithelia

Intermediate filament cytoskeletal proteins make up a large family of tissue and cell specific cytoplasmic and nuclear proteins. In epithelial cells, keratins are cytoplasmic intermediate filament (IF) proteins derived from more than 30 functional genes that are expressed in an epithelial cell-specific manner. In digestive simple-type epithelia, the major keratins are keratin polypeptide 8 and 18 (K8/K18) with variable levels of K7, K19 and K20 depending on the cell type. A major role of the keratin intermediate filaments in simple epithelia is to protect cells from mechanical and non-mechanical stresses. There is increasing evidence for the involvement of keratin-associated proteins with the modulation of these functions. One of these proteins is plectin, a multimodular cytolinker protein, belonging to the plakin protein family.

Plectins enormous versatility is based on several different plectin isoforms, which are generated by tissue and cell type–dependent alternative splicing of transcripts from a single gene with more than 40 exons.

The major goal of the project is the elucidating of mechanistic links mediating interplay between keratin IFs and integrins and its role in regulation of physiologic and pathologic processes in liver. Liver-specific plectin KO mice will be characterized and impact of plectin deficiency on keratin cytoarchitecture will be studied in primary hepatocytes. Further experiments will focus on characterization of integrin and plectin isoforms responsible for recruitment of keratin filaments to junctional complexes. We will further elucidate the role of plectin/keratin/integrin axis in regulation of TGF-b1 pro-fibrotic pathway with the regard to the contribution of particular integrin and plectin isoforms.