Molecular Basis of Anti-fibrosis via Destruction of an Organ Self-repair System
通过破坏器官自我修复系统抗纤维化的分子基础
基本信息
- 批准号:14207005
- 负责人:
- 金额:$ 28.87万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (A)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2005
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Myofibroblast formation and overproduction of extra-cellular matrix (ECM) are common events in the pathogenesis of tissue fibrosis under chronic injuries, such as liver cirrhosis, pulmonary fibrosis and cardiomyopathy. In the present study, we found that HGF directly targeted the interstitial myofibroblasts and reduced ECM accumulation using the animal model of pulmonary fibrosis, liver cirrhosis and dilated cardiomyopathy.1) Regression of pulmonary fibrosis by HGE :We used bleomycin-injected mice as a model of lung fibrosis and found that HGF elicited apoptotic changes in the myofibroblast cell population in vivo. Furthermore, we obtained in vitro evidence that : (i) HGF degraded ECM proteins (i.e., cell anchorage) around the myofibroblasts, via induction of proteinases such as MMP-9/-1/-2 ; (ii) under such ECM-deficient conditions, the myofibroblasts lose the anchorage then anoikis-like apoptotic cell death occurred. Importantly, an MMP-inhibitor diminished HGF-mediated apoptotic cell death of myofibroblasts, in vitro as well as in vivo, thus indicating that HGF-induced anti-fibrotic effects largely depended on inductions of MMPs by HGF. We published these results in FASEB-Journal 19 : 580 (2005)2) Reduction of interstitial fibrosis in liver cirrhosis and cardiomyopathy by HGF :In the rat model of liver cirrhosis, HGF enhanced myofibroblast apoptosis and inhibited proliferation of interstitial myofibroblasts. These effects were associated with the reduction of ECM-accumulated areas. In vitro, HGF counteracted the PDGF-mediated proliferation of the lipocyte-derived myofibroblasts. In the hamster model of cardiomyopathy, HGF reduced TGF-beta production in the interstitial myofibroblasts, followed by the reduction of ECM as well as improvement in the cardiac functions. These outcomes were published in Am-J-Pathol 166 : 1017 (2005) and in Am-J-Physiol 288 : H2131 (2005), respectively.
肌成纤维细胞的形成和细胞外基质(ECM)的过量产生是慢性损伤(如肝硬化、肺纤维化和心肌病)下组织纤维化发病机制中的常见事件。在本研究中,我们通过肺纤维化、肝硬化和扩张型心肌病动物模型发现HGF直接靶向间质肌成纤维细胞,减少ECM积累。1) HGF对肺纤维化的回归:我们以博莱霉素注射小鼠作为肺纤维化模型,发现HGF在体内引起了肌成纤维细胞群的凋亡改变。此外,我们在体外获得的证据表明:(i) HGF通过诱导蛋白酶(如MMP-9/-1/-2)降解肌成纤维细胞周围的ECM蛋白(即细胞锚定);(ii)在这种缺乏ecm的条件下,肌成纤维细胞失去锚定,然后发生anoilike凋亡细胞死亡。重要的是,一种mmp抑制剂在体外和体内均可减少HGF介导的肌成纤维细胞凋亡,从而表明HGF诱导的抗纤维化作用在很大程度上依赖于HGF对MMPs的诱导。2) HGF减少肝硬化和心肌病间质纤维化:在肝硬化大鼠模型中,HGF增强肌成纤维细胞凋亡,抑制间质肌成纤维细胞增殖。这些影响与ecm累积面积的减少有关。在体外,HGF抵消了pdgf介导的脂肪细胞来源的肌成纤维细胞的增殖。在心肌病仓鼠模型中,HGF减少了间质肌成纤维细胞中tgf - β的产生,随后减少了ECM并改善了心功能。这些结果分别发表在Am-J-Pathol 166: 1017(2005)和Am-J-Physiol 288: H2131(2005)上。
项目成果
期刊论文数量(395)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Angiogenesis inhibitors : From laboratory to clinical application.
血管生成抑制剂:从实验室到临床应用。
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:Nakamura T;Matsumoto K
- 通讯作者:Matsumoto K
K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 59-61 (2003)
K.Matsumoto 等人:“HGF 在肾脏中的促肾作用和治疗潜力”Nephrol.Dial.Transplant.. 17. 59-61 (2003)
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
L.W.Quin, et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells"Intern.J.Cancer. 104.
L.W.Quin 等人:“辐射刺激 HGF 受体/c-met 表达,通过上调胰腺癌细胞中的受体酪氨酸磷酸化和图谱激酶活性,导致细胞对 HGF 刺激的反应放大”Intern.J.Cancer。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
橋ガ迫敦子, 他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)
Atsuko Hashigasako 等人:“血液/免疫学/肿瘤”医学评论出版 8 (2003)。
- DOI:
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- 影响因子:0
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NAKAMURA Toshikazu其他文献
NAKAMURA Toshikazu的其他文献
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{{ truncateString('NAKAMURA Toshikazu', 18)}}的其他基金
DISTANCE MEASUREMENTS OF FIBROUS PRION PROTEINS BY PULSE ESR SPECTROSCOPY
通过脉冲 ESR 光谱法测量纤维状朊病毒蛋白的距离
- 批准号:
24654112 - 财政年份:2012
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Analysis of molecular mechanisms that reciprocally regulate growth and differentiation of mature hepatocytes
成熟肝细胞生长和分化相互调节的分子机制分析
- 批准号:
21390079 - 财政年份:2009
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Investigation of Spin Dynamics and Development of Devices for Low-Dimensional Electronic Phases
自旋动力学研究和低维电子相器件的开发
- 批准号:
20340095 - 财政年份:2008
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Molecular Mechanisms of Tissue Regeneration through the Conversion of HGF Receptor Signaling in Response of Injury
通过损伤反应中 HGF 受体信号转导实现组织再生的分子机制
- 批准号:
18390087 - 财政年份:2006
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Investigation of the electronic states in the successive SDW transitions of one-dimensional organic conductors
一维有机导体连续 SDW 跃迁中电子态的研究
- 批准号:
13640375 - 财政年份:2001
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Studies on Tissue Morphogenesis, Organogenesis and Repair by HGF
HGF 的组织形态发生、器官发生和修复研究
- 批准号:
11308025 - 财政年份:1999
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Molecular and cellular biological analyzes of morphogenesis modulated by HGF
HGF 调节形态发生的分子和细胞生物学分析
- 批准号:
08408027 - 财政年份:1996
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Inhibitory effects of HGF antagonist on invasion/metastasis of tumor cells.
HGF拮抗剂对肿瘤细胞侵袭/转移的抑制作用。
- 批准号:
07557199 - 财政年份:1995
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Molecular mechanisms of organ regeneration and homeoslasis by injurin/HGF system.
Injurin/HGF 系统器官再生和稳态的分子机制。
- 批准号:
05404080 - 财政年份:1993
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for General Scientific Research (A)
Development of Large Scale Expression, Preparation, and Highly Sensitive Immunoassay Methods for Hepatocyte Growth Factor
肝细胞生长因子大规模表达、制备和高灵敏免疫分析方法的开发
- 批准号:
03558020 - 财政年份:1991
- 资助金额:
$ 28.87万 - 项目类别:
Grant-in-Aid for Developmental Scientific Research (B)