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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

基本信息

批准号：
11308025
负责人：
NAKAMURA Toshikazu
金额：
$ 25.13万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

HGF was found and cloned as a hepatotropic factor in our laboratory : We have accumulated evidence that HGF has pleotropic functions such as mitogenesis, motogenesis, morphogenesis and so on. Based on these backgrounds, we hypothesized that HGF plays an important role for morphogenesis and tissue repair, possibly as a mesenchyme-derived factor.To test our hypothesis, we focused during the recent 3 years, on physiological roles by HGF. Using animal models for acute and chronic diseases, we demonstrated that HGF is an essential intrinsic repair factor : In the injury models, endogenous HGF dramatically increased after onset of tissue destruction. Of importance, an anti-HGF IgG strongly suppressed regenerative responses by parenchymal cells (including liver hepatocytes, renal tubular cells lung; alveolar cells etc...); thereby suggesting that endogenous HGF is a key player for eliciting tissue regeneration in vivo. Conversely, supplement of exogenous HGF led to acceleration of tissue repa … More ir in parenchymal injuries (including liver cirrhosis, renal fibrosis, lung and heart diseases and so on).In tumor malignant formation, HGF is participated in tumor invasion and angiogenesis. Thus we prepared NK4/HGF as an antagonist for HGF and found that NK4 minimized tumor malignancy, accompanied with repressed tumor metastasis, invasion and angiogenesis. Of interest, NK4 shows broad anti-angiogenetic activities toward several types of angiogenesis, independent on HGF-mediated endothelial growth. Through these in vivo and in vitro studies, we obtained evidence that NK4 is useful for minimization, of tumor malignancy, possibly through anti-invasive and anti-angiogenetic profiles.Finally, we analyzed a regulation system for activation of LIM-kinase (LIMK) : We found that LIMK1 is activated under regulations under down-streams of Rac and Pac cascades while LIMK2 activation occurs under Rho and ROCK streams. Furthermore, we found that LIMK2 plays a critical role in spermatogenesis in vivo, using a gene-targeted mice for LIMK2.Throughout these experiments, we conclude that HGF (and possibly, its family molecules) are critically involved in morphogenesis and tissue repair. Less

HGF是本实验室发现并克隆的一种促肝细胞生长因子：我们已经积累了大量的证据证明HGF具有多种功能，如有丝分裂、运动发生、形态发生等，基于这些背景，我们推测HGF可能作为间充质源性因子在形态发生和组织修复中发挥重要作用，为了验证我们的假设，近三年来，我们集中研究了HGF的生理作用。使用急性和慢性疾病的动物模型，我们证明了HGF是一种必不可少的内在修复因子：在损伤模型中，内源性HGF在组织破坏发生后显著增加。重要的是，抗HGF IgG强烈抑制实质细胞（包括肝细胞、肾小管细胞、肺细胞、肺泡细胞等）的再生反应;从而表明内源性HGF是体内引发组织再生的关键因素。相反，补充外源性HGF可加速组织再生， ...更多信息在肝实质损伤（包括肝硬化、肾纤维化、肺和心脏疾病等）中，HGF参与肿瘤的恶性形成，并参与肿瘤的侵袭和血管生成。因此，我们制备了NK 4/HGF作为HGF的拮抗剂，并发现NK 4可以降低肿瘤的恶性程度，同时抑制肿瘤的转移、侵袭和血管生成。有趣的是，NK 4对几种类型的血管生成显示出广泛的抗血管生成活性，不依赖于HGF介导的内皮生长。通过这些体内和体外研究，我们获得的证据表明，NK 4是有用的最小化，肿瘤的恶性程度，可能通过抗侵入性和抗血管生成profiles.Finally，我们分析了一个调节系统的激活LIM激酶（LIMK）：我们发现，LIMK 1激活的调节下下游的Rac和Pac级联，而LIMK 2激活下Rho和ROCK流。此外，我们还发现LIMK 2在体内精子发生中起着关键作用，通过这些实验，我们得出结论，HGF（可能还有其家族分子）在形态发生和组织修复中起着关键作用。少