| Research Abstract |
Hepatocyte growth factor (HGF) is thought to play an important role in the repair of damaged gastrointestinal mucosa by promoting proliferation and migration of mucosal epithelial cells. HGF is secreted by stromal cells as an inactive precursor form and is specifically activated by HGF activator (HGFA) to the active form. HGFA is also produced as a precursor form and activated by thrombin in injured tissue. Activity of HGFA is regulated by two recently identified specific inhibitors, namely HGF activator inhibitor type 1 (HAI-I) and type 2 (HAI-2), both of which have two Kunitz-type serine proteinase inhibitor domains. Although the activation of HGF is a critical limiting step in HGF-induced signaling pathway mediated by Met receptor tyrosine kinase, little is known concerning the regulation of HGF activation in damaged gastrointestinal mucosa. In this study, we generated the knock-out mice of these HGF regulatory molecules and examine their function in vivo. Immunohistochemically, bot
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h HGF and HGFA were detected in the gastrointestinal tissue and HGF was up-regulated in regenerative region. During the course of acetic acid-induced murine experimental colitis, HGF gene expression was up-regulated in the early phase, while HGFA expression was not drastically altered. HGFA knockout mice were born and developed normally without apparent anomalies, although HGF knockout mice were embryonal lethal due to liver and placental defects. However, the regeneration of epithelial cells in dextran sodium sulfate (DSS) -induced colitis is markedly delayed in HGFA knockout mice relative to normal control mice. HAI-1 knockout mice was embryonal lethal, as same as HGF knockout mice. These results suggested that HGFA activated by thrombin in damaged intestinal tissue is involved in the activation of HGF and the following regenerating processes involving the growth, differentiation, and migration of gastrointestinal epithelial cells, and angiogenesis of endothelial cells. We also reported a novel nuclear peptide namely HAI-2 related small peptide (H2RSP). Less
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