Roles of bioactive peptides (growth factors) in the regeneration of injured gastrointestinal mucosa

生物活性肽（生长因子）在受损胃肠粘膜再生中的作用

• 批准号: 13670223
• 负责人: ITOH Hiroshi
• 金额: $ 1.98万
• 依托单位: Miyazaki Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670223/
• 关键词: HGF; HGF Activation (HGFA); HGFA inhibitor (HAI); Gastrointestinal; regeneration; knockout mouse; HGF Activator(HGFA); HGFA inhibitor(HAI); HGF activator; HGF activator inhibitor; Knock out mouse; Gastrointestinal mucosa; Trefoil peptides; Wo

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 … More 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

肝细胞生长因子（HGF）被认为通过促进粘膜上皮细胞的增殖和迁移，在受损胃肠道粘膜的修复中发挥重要作用。HGF由基质细胞分泌为非活性前体形式，并被HGF激活剂（HGFA）特异性激活为活性形式。HGFA也作为前体形式产生，并在受损组织中被凝血酶激活。HGFA的活性受两种最近鉴定的特异性抑制剂调节，即HGF激活物抑制剂1型（HAI-I）和2型（HAI-2），这两种抑制剂均具有两个Kunitz型丝氨酸蛋白酶抑制剂结构域。虽然HGF的活化是Met受体酪氨酸激酶介导的HGF诱导的信号通路中的关键限制步骤，但关于损伤的胃肠道粘膜中HGF活化的调节知之甚少。在这项研究中，我们产生了这些HGF调节分子的敲除小鼠，并检查了它们的体内功能。免疫组织化学，bot ...更多信息 在胃肠道组织中检测到HGF和HGFA，HGF在再生区表达上调。在乙酸诱导的小鼠实验性结肠炎的过程中，HGF基因表达在早期阶段上调，而HGFA表达没有显著改变。HGFA基因敲除小鼠出生和发育正常，没有明显的异常，但由于肝脏和胎盘缺陷，HGF基因敲除小鼠是胚胎致死的。然而，相对于正常对照小鼠，HGFA敲除小鼠中葡聚糖硫酸钠（DSS）诱导的结肠炎中上皮细胞的再生明显延迟。HAI-1基因敲除小鼠与HGF基因敲除小鼠一样，具有胚胎致死性。这些结果表明，在受损的肠组织中由凝血酶激活的HGFA参与HGF的激活和随后的再生过程，包括胃肠道上皮细胞的生长、分化和迁移，以及内皮细胞的血管生成。我们还报道了一种新的核肽HAI-2相关小肽（H2 RSP）。少

项目成果

Itoh, H., Kataoka, H., Meng, J. Y., Hamasuna, R., Kitamura, N., and Koono, M.: "Mouse hepatocyte growth factor activator inhibitor type 1 (HAI-1) and type 2 (HAI-2)/placental bikunin genes and their promoters."Biochim. Biophys. Acta.. 1519. 92-95 (2001)

Itoh, H.、Kataoka, H.、Meng, J. Y.、Hamasuna, R.、Kitamura, N. 和 Koono, M.：“小鼠肝细胞生长因子激活剂抑制剂 1 型 (HAI-1) 和 2 型 (HAI-

Itoh, H., Kataoka, H., Yamauchi, M., Naganuma, S., Akiyama, Y., Nuki, Y., Shimomura, T., Miyazawa, K., Kitamura, N., and Koono, M.: "Identification of hepatocyte growth factor activator inhibitor type 2 (HAI-2) related small peptide (H2RSP) : its nuclear

Itoh, H.、Kataoka, H.、Yamauchi, M.、Naganuma, S.、Akiyama, Y.、Nuki, Y.、Shimomura, T.、Miyazawa, K.、Kitamura, N. 和 Koono, M.

Kataoka H, Itoh H, koono M: "Emerging multifunctional aspects of cellular serine proteinase inhibitors in tumor progression and tissue regeneration"Pathol. Int.. 52. 89-102 (2002)

Kataoka H、Itoh H、koono M：“细胞丝氨酸蛋白酶抑制剂在肿瘤进展和组织再生中的新兴多功能方面”Pathol。

Itoh, H., Kataoka H., Yamauchi, M, Naganuma S, Akiyama Y, Nabi Y, Shimamura T, Misawa K, Kimura N, Koono M: "Identification of hapatocyte growth factor activator inhibitor type 2 (HAI-2) related small peptide (H2RSP) : its naclear inculization and generat

Itoh, H., Kataoka H., Yamauchi, M, Naganuma S, Akiyama Y, Nabi Y, Shimamura T, Misawa K, Kimura N, Koono M：“与肝细胞生长因子激活剂抑制剂 2 型 (HAI-2) 相关的鉴定

Kataoka, H., Itoh. H., Shimomura, T., Nuki, Y., Naganuma, S., and Miyazawa, K.: "Regulation of hepatocyte growth factor (HGF) activation on cell surface : Insight into an emerging class of cell surface protease inhibitors."Int. Arch. Biosci.. 1. 1036-1042

片冈，H.，伊藤。