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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。

基本信息

批准号：
05404080
负责人：
NAKAMURA Toshikazu
金额：
$ 20.29万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05404080/
关键词：
HGF c-Met organogenesis organ regeneration injurin growth factor c-met IL-1 カルシノーマ PDGF FGF hepatocyte growth factor 肝再生腎再生 MET

项目摘要

(1) Roles of HGF as an organotrophic factor : Recombinant HGF suppressed the onset of liver fibrosis/cirrhosis and fatty liver caused by chronic hepatic injury. We found that HGF functions as renotrophic and pulmotrophic factor for regeneration of the kidney and lung. HGF may well become a new therapeutic drug for the treatment of various organ diseases, including liver fibrosis/cirrhosis, acute renal failure, and lung fibrosis.(2) HGF as a neurotrophic factor : HGF stimulated survival of hippocampal neurons in vitro. Importantly, the infused recombinant HGF markedly prevented neuronal death caused by ischemic injury in rats.(3) HGF as a mediator in epithelial-mesenchymal interactions : Epithelial-mesenchymal interaction is a critical tissue interaction for organogenesis. HGF is expressed in mesenchymal tissue, while c-Met/HGF receptor in epithelial tissue during development of the liver, kidney, lung tooth, limb, etc. HGF supports organogenesis of various organs, such as the liver, kidney, lung, tooth, mammary gland, as a mesenchymal-derived factor.(4) HGF is tumor-stromal interactions : Malignant phenotypes of tumor cells are regulated through their interactions with host stromal cells. We found that various tumor cells produce HGF-inducer (injurin) and stromal-derived HGF enhanced the invation of tumor cells. Matual interaction between tumor cells and host stromal cells mediate tumor-stromal interactions.(5) Identification of injurin (HGF-inducer) : We purified injurin (s) from lung tissue extract and found that these are IL-1, PDGF,and bFGF.Likewise, we identified tumor-derived injurins as IL-1, PDGF,and bFGF.But mouse mammary tumor cells produced novel HGF-inducer. In contrast, we found that TGF-beta and glucocorticoids are negative regulator of HGF expression.

(1)HGF作为器官营养因子的作用：重组HGF抑制慢性肝损伤引起的肝纤维化/肝硬化和脂肪肝的发生。我们发现，肝细胞生长因子作为肾和肺的再生的肾营养因子和肺营养因子。肝细胞生长因子有望成为治疗肝纤维化/肝硬化、急性肾功能衰竭和肺纤维化等多种器官疾病的新的治疗药物。(2)HGF作为神经营养因子：HGF刺激体外海马神经元的存活。重要的是，输注重组HGF显著预防大鼠缺血性损伤引起的神经元死亡。(3)HGF作为上皮-间充质相互作用的介质：上皮-间充质相互作用是器官发生的关键组织相互作用。在肝、肾、肺、牙齿、肢体等的发育过程中，HGF在间充质组织中表达，而c-Met/HGF受体在上皮组织中表达。HGF作为间充质衍生因子支持各种器官的器官发生，如肝、肾、肺、牙齿、乳腺。(4)HGF是肿瘤-基质相互作用：肿瘤细胞的恶性表型通过与宿主基质细胞的相互作用来调节。我们发现多种肿瘤细胞产生HGF诱导物（injuriin），基质来源的HGF促进肿瘤细胞的侵袭。肿瘤细胞和宿主间质细胞之间的相互作用介导肿瘤-间质相互作用。(5)损伤素（HGF诱导剂）的鉴定：我们从肺组织提取物中纯化了损伤素，发现它们是IL-1、PDGF和bFGF。同样，我们鉴定了肿瘤源性损伤素，它们是IL-1、PDGF和bFGF。相反，我们发现TGF-β和糖皮质激素是HGF表达的负调节剂。