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

基本信息

批准号：
18390087
负责人：
NAKAMURA Toshikazu
金额：
$ 8.57万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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-18390087/
关键词：
HGF c-Met Growth Regulation Signal Transduction Tissue Regeneration Phosohatase Tissue Iniury Knockout Mouse Met 細胞増殖制御分子機構高密度培養

项目摘要

(1) Regulation of HGF/c-Met activation through tyrosine dephosphrylation by LAR:Inhibition of cell proliferation regulated by cell-cell contact is a fundamental characteristic of normal cells. In hepatocytes cultured at a confluent cell density, HGF stimulation induced transient c-Met tyrosine phosphorylation and failed to induce mitogenic response. We found that LAR plays a definitive role in inactivation, i.e. tyrosine dephosphorylation of c-Met through their physical interaction, which specifically occurs in hepatocytes under confluent condition. We published these results in J-Biol-Chem 281 : 8765 (2006).(2) Physiological significance of HGF/c-Met activation in cholestatic injury:We used a surgical technique of bile duct ligation (BDL) to induce cholestatic conditions in mice. After the BDL surgery, HGF and c-Met mRNA levels transiently increased in livers. Furthmore, we obtained evidence that endogenous HGF is involved in the physiological protection of hepatocyte cell death including necrosis and apoptosis. We published these results in Am-J-Physiol 292 : G639 (2007).(3) Generation of knock-in mice expressing only mutated c-Met (ΔJxt-Met):The phosphorylation status of juxtamembrane Ser-985 of c-Met plays functional regulatory role in activation of c-Met. c-Met has a splice variant that lacks a cytoplasmic juxtamembrane region (ΔJxt-Met). To analyze the function of ΔJxt-Met, we generated knock-in mice expressing only ΔJxt form of c-Met. Homozygous mutant mice died during neonatal period. Pathological analysis is now in progress.

(1) LAR 通过酪氨酸去磷酸化调节 HGF/c-Met 活化：通过细胞-细胞接触调节细胞增殖的抑制是正常细胞密度培养的肝细胞的基本特征，HGF 诱导瞬时 c-Met。我们发现 LAR 在失活（即酪氨酸去磷酸化）中起着决定性的作用。 c-Met 通过它们的物理相互作用，特别发生在汇合条件下的肝细胞中。我们在 J-Biol-Chem 281 : 8765 (2006) 中发表了这些结果。(2) HGF/c-Met 激活在胆汁淤积损伤中的生理意义：我们使用胆管结扎 (BDL) 手术技术来诱导小鼠胆汁淤积状态。BDL 手术后，HGF 和 c-Met mRNA 水平短暂增加。此外，我们获得了内源性 HGF 参与肝细胞死亡（包括坏死和凋亡）的生理保护的证据，我们将这些结果发表在 Am-J-Physiol 292 : G639 (2007) 中。 (3) 敲入的产生。仅表达突变c-Met（ΔJxt-Met）的小鼠：c-Met近膜Ser-985的磷酸化状态在c-Met 的激活具有缺乏细胞质近膜区域的剪接变体 (ΔJxt-Met) 为了分析 ΔJxt-Met 的功能，我们产生了仅表达 ΔJxt 形式的 c-Met 的敲入小鼠。突变小鼠在新生期死亡，目前正在进行病理分析。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hepatocyte growth factor attenuates cerebral ischemia-induced increase in permeability of blood-brain barrier and decreases in expression of tight junctional proteins in cerebral vessels.

肝细胞生长因子可减弱脑缺血引起的血脑屏障通透性增加和脑血管中紧密连接蛋白表达的减少。

DOI：
发表时间：
2006
期刊：
Neurosci Lett. 407
影响因子：
0
作者：
Date;I.;Takagi;N.;Takagi;K.;Tanonaka;K.;Funakoshi;H.;Matsumoto;K.;Nakamura;T.;akeo;S;Machide M. et al.;Sumi T.et al.;Matsumoto K. et al.;Namiki Y. et al.;Hosseinkhani H. et al.;Azuma J. et al.;Ogura Y. et al.;Tada T.et al.;Ono K.et al.;Niimura M. et al.;Date I.et al.
通讯作者：
Date I.et al.

Intrathecal delivery of hepatocyte growth factor from amyotrophic lateral sclerosis onset suppresses disease progression in rat amyotrophic lateral sclerosis model