Study of medianism for the cell growth inhibition by HB-EGF in cardiac valve development

HB-EGF抑制心脏瓣膜发育中细胞生长的中位作用研究

基本信息

批准号：
18570176
负责人：
IWAMOTO Ryo
金额：
$ 2.57万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18570176/
关键词：
HB-EGF EGFR ErbB HSPG Snail Valvulogenesis Intercellular signaling Extracellular matrix 細胞・組織発生・分化増殖因子

项目摘要

HB-EGF is a member of the EGF family of growth factors that has a high affinity for heparin and heparan sulfate (HS), and is known to be involved in cardiac valve development. HB-EGF suppresses proliferation of mesenchymal cells in this process. In this research, we investigated the regulatory mechanisms involved in the HB-EGF-induced cell growth inhibition in cardiac valve development (valvulogenesis).1) Significance of the interaction of HB-EGF with HS-proteoglycans (HSPGs) in valvulogenesis. We generated the knock-in mice expressing a heparin-binding domain-truncated form (HB^<Δbb>) of the molecule, which lacks HS-binding activity. HB^<Δbb/Δbb> mice developed enlarged cardiac valves with abnormal hyperproliferation of the mesenchymal cells during valvulogenesis, phenotypes similar to that in HB-EGF null (HB^<dcl/del>) mice. In vitro study using endocardial cushion explants culture demonstrated requirement of HB-EGF-HSPGs interaction for HB-EGF-EGFR signal-mediated growth-inhibition … More of mesenchymal cells. These results indicate that interaction of HB-EGF with HSPGs promotes growth-inhibition of differentiated mesenchymal cells in developing cardiac valve. (Manuscript in preparation)2) HB-EGF and Snail signaling negatively regulates proliferation of mesenchymal cells during valvulogenesis. We found that the expression of Snail was dramatically decreased in HB^<del/del> mutant valves during remodeling process in valvulogenesis. Exogenously introduced Snail and HB-EGF into the HB^<del/del> mutant valves were able to rescue the overproliferation of mesenchymal cells. These results demonstrate that HB-EGF inhibits proliferation of mesenchymal cells via Snail during valve remodeling. (Manuscript in preparation)3) Perinatal distal lung development: another physiological process in which HB-EGF induces cell growth inhibition. HB^<del/del> newborns displayed abnormally thick alveolar walls, occurring from E18.5, that reduced the terminal saccular space area, with a increase in cell proliferation, indicating that HB-EGF suppresses distal lung cell proliferation. Furthermore, an analysis of alveolar morphology and proliferation in HB-EGF and TGFα double mutant newborns revealed that HB-EGF and TGFa function synergistically in this suppression. Crosses between HB^<del/del> mice and waved 2 mice, a hypomorphic EGFR mutant strain, suggest that HB-EGF and EGFR cooperate in this process. Thus, HB-EGF has a suppressive function that contributes to decelerating distal lung cell proliferation synergistically with TGFa through EGFR in perinatal distal lung development. (Dev. Dyn. 2008, 237, 247-258) Less

HB-EGF 是 EGF 生长因子家族的成员，对肝素和硫酸乙酰肝素 (HS) 具有高亲和力，已知 HB-EGF 参与心脏瓣膜发育，在此过程中抑制间充质细胞的增殖。在本研究中，我们研究了心脏瓣膜发育（瓣膜形成）中 HB-EGF 诱导的细胞生长抑制所涉及的调节机制。1) HB-EGF 与瓣膜形成中的 HS 蛋白聚糖 (HSPG) 我们生成了表达该分子的肝素结合结构域截短形式 (HB^<Δbb>) 的敲入小鼠，该分子缺乏 HB^<Δbb/Δbb> 结合活性。小鼠心脏瓣膜增大，瓣膜形成过程中间充质细胞异常过度增殖，表型与 HB-EGF null 相似(HB^<dcl/del>) 小鼠。使用心内膜垫外植体培养的体外研究表明，HB-EGF-HSPG 相互作用对于 HB-EGF-EGFR 信号介导的间充质细胞的生长抑制是必需的。 HB-EGF 与 HSPG 促进心脏瓣膜发育中分化间充质细胞的生长抑制（手稿正在准备中）2) HB-EGF 和 Snail 信号负向。在瓣膜形成过程中调节间充质细胞的增殖我们发现，在瓣膜形成的重塑过程中，HB^<del/del>突变瓣膜中Snail的表达显着降低。突变瓣膜能够挽救间充质细胞的过度增殖。这些结果表明，HB-EGF 在瓣膜重塑过程中通过 Snail 抑制间充质细胞的增殖。（手稿准备中）3）围产期远端肺发育：HB-EGF 诱导细胞生长抑制的另一个生理过程，HB^<del/del> 新生儿表现出异常厚的肺泡壁，发生于 E18.5，从而减少了终末囊泡。空间区域，细胞增殖增加，表明 HB-EGF 抑制远端肺细胞增殖。此外，对 HB-EGF 和 TGFα 双突变新生儿的肺泡形态和增殖进行分析。揭示HB-EGF和TGFα在该抑制中协同作用。HB^<del/del>小鼠和waved 2小鼠（一种低效型EGFR突变株）之间的杂交表明HB-EGF和EGFR在该过程中协同作用。 EGF 具有抑制功能，在围产期远端肺发育中通过 EGFR 与 TGFa 协同减缓远端肺细胞增殖 (Dev.动态 2008, 237, 247-258) 少