Physiological significance of proHB-EGF ectodomain shedding in epideimal development

proHB-EGF胞外域脱落在表皮发育中的生理意义

基本信息

  • 批准号:
    14580696
  • 负责人:
  • 金额:
    $ 2.62万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
  • 财政年份:
    2002
  • 资助国家:
    日本
  • 起止时间:
    2002 至 2003
  • 项目状态:
    已结题

项目摘要

1)HB-EGF is a member of the EGF family of giowth factors. To examine the role of HB-EGF in viva, we generated HE-EGF-knockout mice HB^<del/del>). HB^<del/del> mice developed severe heart failure with dilated ventricular chambers, similarly to conditional ErbB2 knockout mice. HB^<del/del> mice developed also enlarged cardiac valves, similarly to EGFR knockout mice. Constitulive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB^<del/del> hearts. These indicated that HB-EGFactivalion of ErbB is essential for normal heartfunclion.2)HB-EGF is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding fiom proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, xpressing either an uncleavable form (HB^<uc>) or a transmembrane domain-truncated form (HB^<Δtm>) of the molecule. HB^<uc/uc> mice developed severe heart failure and e … More nlarged heart valves, phenotypes similar to those in proHB-EGF-null mice. On the other hand, mice canying HB^<Δtm> exhibited severe hyperplasia in both skin and heart These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in viva, and that this piocess requires strict control.3)HB^<del/del> mice did not show any abnormalities in developmental piocess of epidermis. Thus, we investigated the role of HE-EGF in re-epithelization. HB-EGF expression in adult epidermis was hardly detected at the steady state, but it was strongly induced after full-thickness wounding and topical treatment with retinoic acid (tRA). The level of hyperprolifemtion of keratinocytes induced by tRA-ireatinent and that of wound healing were estimated among the mutant mice selectively ablated HB-EGF expression in basal keratinocytes (HB^<del/del>-K5-Cre),HB^<uc/uc> mice and normal HB-EGF cDNA knock-in mice (HB^<lox/iox>) as an experimenrtal control. In HB^<del/del>-K5-Cre mice and in HBuc/uc mice, both tRA-induced epidermal hyperproliferation and wound healing activity was reduced compared with HBlox/lox mice. These indicated that the induction of HB-EGF and its ectodomain shedding is an important event in the re-epithelization in vivo. Less
HB-EGF是EGF家族的一员。为了检查HB-EGF在体内的作用,我们产生了HE-EGF敲除小鼠HB(<del/del>)。与条件性ErbB 2敲除小鼠类似,HB^<del/del>小鼠发展出严重的心力衰竭,伴有扩张的心室腔。HB^<del/del>小鼠也发展出增大的心脏瓣膜,类似于EGFR敲除小鼠。在HB^<del/del>心脏中,ErbB 2和ErbB 4的组成型酪氨酸磷酸化显著降低。(2)HB-EGF首先以膜锚定形式(proHB-EGF)合成,其可溶性形式(sHB-EGF)由proHB-EGF的胞外域脱落释放。为了研究proHB-EGF在体内加工的意义,我们通过靶向基因置换产生突变小鼠,表达分子的不可切割形式(HB^<uc>)或跨膜结构域截短形式(HB^&lt;Δtm&gt;)。HB^&lt;uc/uc&gt;小鼠出现严重心力衰竭, ...更多信息 心脏瓣膜增大,表型与proHB-EGF-null小鼠相似。HB^&lt;Δtm&gt;小鼠的皮肤和心脏均出现严重的增生,提示proHB-EGF的胞外区脱落是HB-EGF在体内发挥功能所必需的,这一过程需要严格控制。3)HB^&lt;del/del&gt;小鼠表皮发育过程未见异常。因此,我们研究了HE-EGF在再上皮化中的作用。HB-EGF在成人表皮中的表达在稳态时几乎没有检测到,但在全层创伤和局部用维甲酸(tRA)处理后强烈诱导。以选择性阻断基底层角质形成细胞HB-EGF表达的突变小鼠(HB^&lt;del/del&gt;-K5-Cre)、HB^&lt;uc/uc&gt;小鼠和正常HB-EGF cDNA基因敲入小鼠(HB^&lt;lox/lox&gt;)为实验对照,观察tRA诱导角质形成细胞增殖和伤口愈合的情况。在HB^&lt;del/del&gt;-K5-Cre小鼠和HBuc/uc小鼠中,与HBlox/lox小鼠相比,tRA诱导的表皮过度增殖和伤口愈合活性均降低。提示HB-EGF的诱导及其胞外区的脱落是体内再上皮化过程中的一个重要环节。少

项目成果

期刊论文数量(26)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ryo Iwamoto et al.: "Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function"Proc. Natl. Acad. Sci. USA.. 100. 3221-3226 (2003)
Ryo Iwamoto 等人:“肝素结合 EGF 样生长因子和 ErbB 信号传导对于心脏功能至关重要”Proc。
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  • 影响因子:
    0
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Xiaochun Yu et al.: "Ligand-independent dimmer formation of epidermal growth factor receptor (EGFR) is a step separable from ligand-induced EGFR signaling"Molecular Biology of the Cell. 13. 2547-2557 (2002)
Xiaochun Yu 等人:“表皮生长因子受体 (EGFR) 的配体独立二聚体形成是与配体诱导的 EGFR 信号传导分开的一个步骤”《细胞分子生物学》。
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    0
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Shimizu, T., et al.: "Elevated levels of anti-CD9 antibodies in the celebrospinal fluid of patients with subacute sclerosing panencephalitis."J.Infect.Dis.. 185. 1346-1350 (2002)
Shimizu, T., et al.:“亚急性硬化性全脑炎患者的脑脊液中抗 CD9 抗体水平升高。”J.Infect.Dis.. 185. 1346-1350 (2002)
  • DOI:
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    0
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Yamazaki, S., et al.: "Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities."J.Cell Biol.. 163. 469-475 (2003)
Yamazaki, S., et al.:“HB-EGF 胞外域脱落缺陷的小鼠表现出严重的发育异常。”J.Cell Biol.. 163. 469-475 (2003)
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  • 影响因子:
    0
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Yu, X., et al.: "Ligand-independent dimmer formation of epidermal growth factor receptor (EGFR) is a step separable fnm ligand-induced EGFR signaling."Mol.Biol.Cell.. 13. 2547-2557 (2002)
Yu, X., 等人:“表皮生长因子受体 (EGFR) 的配体独立二聚体形成是配体诱导的 EGFR 信号传导的一个可分离的步骤。”Mol.Biol.Cell.. 13. 2547-2557 (2002)
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IWAMOTO Ryo其他文献

IWAMOTO Ryo的其他文献

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{{ truncateString('IWAMOTO Ryo', 18)}}的其他基金

Inhibition of cell proliferation by induction of HB-EGF-HSPG-ErbB4 signaling system
通过诱导 HB-EGF-HSPG-ErbB4 信号系统抑制细胞增殖
  • 批准号:
    18K06218
  • 财政年份:
    2018
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Regulation of cell proliferation by HB-EGF in mouse cardiac valve development
HB-EGF 对小鼠心脏瓣膜发育中细胞增殖的调节
  • 批准号:
    20570183
  • 财政年份:
    2008
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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
  • 批准号:
    18570176
  • 财政年份:
    2006
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Physiological function of HB-EGF : Study of the knock-in mice of the mutant form of HB-EGF
HB-EGF的生理功能:HB-EGF突变体敲入小鼠的研究
  • 批准号:
    12680705
  • 财政年份:
    2000
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Study of the activity of proHB-EGF complex.
proHB-EGF复合物活性的研究。
  • 批准号:
    09680706
  • 财政年份:
    1997
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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选择性剪接调控胞外域脱落的分子机制及功能意义
  • 批准号:
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胞外域脱落的分子解剖:BACE1 和其他脱落酶的生物学。
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