HGFによる脳神経系の生存維持とHGFからみた神経変性疾患の病態解析

1996 Fiscal Year Annual Research Report

• Project/Area Number: 08256220
• Research Institution: Osaka University
• Principal Investigator: 松本 邦夫 大阪大学, 医学部, 助教授 (90201780)
• Co-Investigator(Kenkyū-buntansha): 船越 洋 大阪大学, 医学部, 助手 (40273685)
• Keywords: HGF / c-Met / 神経栄養因子 / 脳梗塞 / ニューロン / 脳虚血

Research Abstract

HGF(hepatocyte growth factor)はin vivoにおいて肝臓、腎臓、肺など臓器の再生を促すとともに臓器傷害にともなう細胞死を防止する。私達はHGFならびにそのレセプターc-Metチロシンキナーゼが脳内に広く発現され、HGFは海馬初代培養ニューロンの生存を促し、さらに脳虚血傷害にともないHGFならびにc-Metの発現が高まることを報告した(1)。HGFは新しい神経栄養因子の一つであると考えられる。HGFが脳虚血傷害によって引き起こされる海馬領域における遅発性神経細胞死を防止するかどうか検討した結果、HGFは海馬遅発性神経細胞死を強力に抑制することを見い出した。
スナネズミに5分間の脳虚血傷害を与えると7日後には海馬CAI領域におけるニューロン数はsham手術群の4%に減少し、著しい遅発性神経細胞死が引き起こされた。一方、リコンビナンHGFを脳室内に投与した場合、HGFの投与量に依存して遅発性神経細胞死が抑制され、HGFを30μg/week投与した場合、sham手術群のコントロールに比べ約66%のニューロンが生存した。また、HGFの遅発性神経細胞死に対する防止作用は脳虚血傷害を引き起こしてから6時間後より投与を開始しても有効であった。
以上の結果はHGFが脳梗塞など脳虚血傷害に対し遅発性神経細胞死を防止する有効な薬剤となりうることを示唆している。また、HGFはドーパミンニューロンなど生存/成熟を促進することが知られており(2)、各種脳神経の傷害、疾患に対し有効な治療薬となる可能性がある。
(1)Honda,S.,Kagoshima,M.Wanaka,A.,Tohyama,M.Matsumoto,K.,and Nakamura T.(1995) Mol.Brain Res.,32,197-210.
(2)Hamanoue,M.,Takemoto,N.,Matsumoto,K.,Nakamura,T.,Nakajima,K.,and Kohsaka,S.(1996) J.Neurosci.Res.,43,554-564.

Research Products

• [Publications] N.Nishi: "Changes in gene expression of growth factors and their receptors during castration-induced involusion and androgen-induced regrowth of rat prostate." Prostate. 28. 139-152 (1996)
• [Publications] M.Hamanoue: "Neurotrophic effect of hepatocyte growth factor on CNS neurons in vivo." J.Neurosci.Res. 43. 554-564 (1996)
• [Publications] M.Inui: "Enhanced gene expression of transforming growth factor-α and c-met in rat urinary bladder cancer." Urol.Res. 24. 55-60 (1996)
• [Publications] H.Ymazaki: "Biphasic changes in serum hepatocyte growth factor after transcatheter arterial chemoembolization theraphy for hepatocellular carcinoma." Cytokine. 8. 178-182 (1996)
• [Publications] S.Takada: "Serum HGF levels in acute renal rejection after living related renal transplantation." Transplant.Intern. 9. 151-154 (1996)
• [Publications] M.J.Tabata: "Hepatocyte growth factor is involved in the morphogenesis of tooth gern in murine molars." Development. 122. 1243-1251 (1996)
• [Publications] Y.Kobayashi: "Induction of hepatocyte growth by intraportal infusion of hepatocyte growth factor into beagle dogs." Biochem.Biophys.Res.Commun. 220. 7-12 (1996)
• [Publications] K.Sugimoto: "Molecular cloning and characterization of a newly identified member of the cadherin family,PB-cadherin." J.Biol.Chem. 271. 11548-11556 (1996)
• [Publications] S.Takada: "HGF prevent tacrolimus (FK506)-induced nephrotoxicity in SHR rats." Transplant.Proc. 28. 1089-1090 (1996)
• [Publications] H.Amaike: "Human recombinant HGF prevents lethal side effects of cyclosporin A in mice." Cytokine. 8. 387-394 (1996)
• [Publications] N.Nakayama: "Hepatocyte growth factor and c-met expression in Long-Evans Cinnamon rats with spontaneous hepatitis and hepatoma." Hepatology. 24. 596-602 (1996)
• [Publications] H.Ohmichi: "In vivo mitogenic action of hepatocyte growth factor on branchial epithelial cells:Pulmotrophic role of HGF in lung regeneration." Am.J.Physiol. 270. L1031-L1039 (1996)
• [Publications] K.Matsumoto: "Acquisition of invasive phenotype in gallblader cancer cells via looped interaction of stromal fibroblasts and cancer cells mediated by HGF." Jap.J.Cancer Res. 87. 702-710 (1996)
• [Publications] T.Nakamura: "Cloning and expression of xenopus HGF-like protein(HLP)and Ron/HLP receptor implicate their involvement in early neural development." Biochem.Biophys.Res.Commun. 224. 564-573 (1996)
• [Publications] Y.Nakamura: "A vaschlar modulator,hepatocyte growth factor(HGF),is associated with systolic blood pressure." Hypertension. 28. 409-413 (1996)
• [Publications] K.Matsumoto: "Heparin functions as a hepatotrophic factor by inducing production of hepatocyte growth factor" Biochem.Biophys.Res.Commun.227. 455-461 (1996)
• [Publications] Y.Nakamura: "Hepatocyte growth factor(HGF) is a novel member of endothelium-specific growth factors:additive stimulatory effect of HGF with basic fibroblast growth factor,but not vascular endothelial growth factor" J.Hypertens.14. 1067-1072 (1996)
• [Publications] S.Aoki: "Molecular cloning of Xenopus c-met/hepatocyte growth factor receptor and its regional expression during early development" J.Biochem.120. 961-968 (1996)
• [Publications] T.Iwazawa: "Primary human fibroblasts induce diverse tumor invasiveness -Involvement of HGF as an important paracrine factor" Jap.J.Cancer Res.87. 1134-1142 (1996)
• [Publications] S.Kasai: "Hepatocyte growth factor is a paracrine regulator of rat prostate epithelial growth" Biochem.Biophys.Res.Commun.228. 646-652 (1996)
• [Publications] K.Takai: "Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and promotes erythropoiesis" Blood. (in press). (1997)
• [Publications] R.Morishita: "Potential role of endothelium-specific growth factor hepatocyte growth factor,on endothelial damage in diabetes militus" Diabetes. (in press). (1997)
• [Publications] I.S.Weimar: "Hepatocyte growth factor/scatter factor(HGF/SF)promotes adhesion of lymphoma cells to extra-cellular matrix molecules via α_4β,and α_5β,integrens" Blood. (in press). (1997)
• [Publications] Y.Matsuda: "Prevential and therapeutic effects in rats of hepatocyte growth factor on liver fibrosis/cirrhosis" Hepatology. (in press). (1997)
• [Publications] T.Takahashi: "Xenopus LIM motif-containing protein kinase 1 XLIMK 1 is expressed mainly in embryonic neural tissues that develop sensoryorgans" Develop.Dyn.(in press). (1997)
• [Publications] K.Matsumoto: "Emerging multipotent aspects of hepatocyte growth factor" J.Biochem.119. 591-600 (1996)
• [Publications] K.Matsumoto: "HGF in lung morphogenesis and tumor invasion:roles as a mediator in epithelial-mesenchymal and tumor-stromal interactions" Cancer Chemother.and Pharmacol.38. S42-S47 (1996)
• [Publications] U.Koshimizu: "Liver and Environmental Xenobiotics" Narosa-Elsevier Verlag, 10 (1997)