Study for the molecular mechanisms involved in regeneration and repair of injured gastrointestinal mucosa

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Cell surface proteolysis is an important mechanism for the generation of biologically active proteins that mediate a diverse range of cellular functions. We have studied the roles of proteinases and integral-membrane proteinase inhibitors in this process for many years.In this project, we studied possible roles of cellular surface interactions of proteinases and integral-membrane proteinase inhibitors in regeneration of injured gastrointestinal mucosae, focusing on the activation mechanism of hepatocyte growth factor(HGF), a multifunctional growth factor having important roles in the regeneration of gastrointestinal tracts. For this purpose, we have generated knockout mice of HGF activator (a proteinase that is responsible for the activation of HGF in injured tissue) and its cognate integral-membrane inhibitor, HAI-1(HGF activator inhibitor type 1). The overall results indicated that HGF activator has important role in early regeneration phase of intestinal mucosa, called restitution. … More Indeed, initial regeneration of injured intestinal mucosa was significantly impaired in HGF activator-deficient mice. On the other hand, HAI-1 knockout mice died in early embryonic stage (around E10.5). This lethal point was obviously earlier than that of HGF-deficient mice. Detailed histological analyses indicated that HAI-1 knockout mice show severely impaired formation of the labyrinth layer. Therefore, HAI-1 might have yet undefined, but very important biological roles in vivo.In this project, we also have identified a novel small peptide, namely H2RSP. H2RSP is expressed in the gastrointestinal epithelial cells. This molecule contains nuclear translocation signal domain. The localization of H2RSP was intracytoplasmic in proliferating epithelial cells. However, it was translocated into the nuclei in differentiated epithelial cells. Thus, it was assumed that the translocation of H2RSP into the nuclei might be involved in a signal for the transition from cellular proliferation to terminal differentiation of the epithelium. Less