权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

损伤胃肠黏膜再生与修复的分子机制研究

基本信息

批准号：
14370079
负责人：
KATAOKA Hiroaki
金额：
$ 7.17万
依托单位：
University of Miyazaki (2004)宮崎医科大学 (2002-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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

细胞表面蛋白水解是产生介导多种细胞功能的生物活性蛋白的重要机制。本课题研究了蛋白酶和膜蛋白酶抑制剂在胃肠道粘膜损伤修复中的作用，重点探讨了在胃肠道再生中起重要作用的多功能生长因子肝细胞生长因子（HGF）的活化机制。为此，我们已经产生了HGF激活剂（一种负责损伤组织中HGF激活的蛋白酶）及其同源整合膜抑制剂HAI-1（HGF激活剂抑制剂1型）的敲除小鼠。总体结果表明，HGF激活剂在肠粘膜的早期再生阶段（称为恢复）中具有重要作用。 ...更多信息事实上，肝细胞生长因子激活物缺陷小鼠的肠粘膜损伤的初始再生明显受损。另一方面，HAI-1基因敲除小鼠在胚胎早期（E10.5左右）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基因敲除小鼠表现出严重受损的迷路层的形成。因此，HAI-1可能在体内具有尚未明确但非常重要的生物学作用。H2 RSP在胃肠道上皮细胞中表达。该分子含有核转位信号结构域。H2 RSP定位于增殖期上皮细胞胞浆内。但在分化的上皮细胞中，它被转位到细胞核中。因此，假设H2 RSP易位到细胞核中可能涉及上皮细胞从细胞增殖到终末分化的转变的信号。少