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

细胞表面蛋白分解是产生生物活性蛋白的重要机制，这些蛋白介导多种细胞功能。多年来，我们一直在研究蛋白水解酶和整膜蛋白水解酶抑制剂在这一过程中的作用。在这项研究中，我们研究了细胞表面蛋白水解酶和整膜蛋白水解酶抑制剂在受损胃肠黏膜再生中的可能作用，重点研究了肝细胞生长因子(HGF)的激活机制，肝细胞生长因子是一种多功能生长因子，在胃肠道再生中具有重要作用。为此，我们产生了HGF激活物(一种负责损伤组织中HGF激活的蛋白酶)及其同源整膜抑制物HAI-1(HGF激活物抑制物1)的基因敲除小鼠。提示HGF激活剂在肠粘膜早期再生修复过程中具有重要作用。…更确切地说，在HGF激活剂缺乏的小鼠中，受损肠粘膜的初始再生显著受损。另一方面，HAI-1基因敲除小鼠在胚胎早期(约E10.5)死亡。这一致死点明显早于HGF缺陷小鼠。详细的组织学分析表明，HAI-1基因敲除小鼠迷路层的形成严重受损。因此，HAI-1在活体中可能具有尚未确定但非常重要的生物学作用。在本项目中，我们还发现了一种新的小肽，即H_2RSP。H2 RSP在胃肠上皮细胞中表达。该分子含有核转位信号域。在增殖的上皮细胞中，H_2RSP定位于胞浆内。然而，在分化的上皮细胞中，它被移位到细胞核中。因此，推测H_2RSP移位到细胞核中可能参与了细胞从增殖到终末分化的信号转导。较少

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