HGFによる形態形成および器官形成・再生の分子生物学的解析

2001 Fiscal Year Annual Research Report

• Project/Area Number: 11308025
• Research Institution: Osaka University
• Principal Investigator: 中村 敏一 大阪大学, 医学系研究科, 教授 (00049397)
• Co-Investigator(Kenkyū-buntansha): 船越 洋 大阪大学, 医学系研究科, 助手 (40273685) ; 松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780)
• Keywords: HGF / 再生・修復 / 臓器保護 / 抗線維化 / 病理発生 / 心筋症 / 再生医学 / 再生医療

Research Abstract

本年度は肝再生および肺再生のマウスモデルにおいてHGFブロック実験を行い、傷害認知の元に誘導されて来るHGFが肝臓や肺の再生に必須の生理的因子であることを明らかにした。即ち、70%部分肝切除または左肺切除したマウスにHGF中和抗体を投与したところ、肺細胞や肺胞細胞の増殖は抑制され、逆にリコンビナントHGFの補充が肝臓や肺の傷害モデルにおいて再生を駆動すること、さらに損なわれた生理的機能を改善させることが分かった。さらに胆道閉鎖症および肺線維症のマウスモデルにおいてもHGFの中和処理によって組織再生不良に基づく組織線維化が進行した。このことから、代償期に誘導される内因性HGFは肝臓や肺の実質細胞に再生を促すとともに組織線維化を抑制する生理的機能を有することが判明した。
さらに難治性疾患の代表とされる心筋症のハムスターモデルでも組織繊維化の初期では内因性HGFの産生が冗進しており、線維化の進行、心機能不全の悪化に伴いHGF産生能が阻害されることが分かった。そこでこの因果関係を明らかにすべく、HGF産生が低下し始める27週齢の心筋症ハムスターにリコンビナントHGFを投与したところ、組織繊維化の改善とともに損なわれた心筋収縮能が改善されることも分かった。
以上の結果から、傷害認知の元に誘導されるHGFは急性および慢性の様々な臓器傷害に際して、実質再生を駆動するとともに間質繊維化を抑制する必須の役割を担っていることが明かとなった。このような生理活性を有するHGFの体外的補充は様々な急性・慢性疾患の病態に基づいた合理的な治療戦略となると考えられる。

Research Products

• [Publications] Sumi, T., et al.: "Specific activation of LIM-Kinase 2 via phosphorylation of the threonine-505 by ROCK, a Rho-dependent protein kinase"J. Biol. Chem.. 276. 670-676 (2001)
• [Publications] Sumi, T., et al.: "Activation of LIM kinase by myotonic dystrophy kinase-related Cdc42-binding kinase alpha"J. Biol. Chem.. 276. 23092-23096 (2001)
• [Publications] Tomioka, D., et al.: "Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)
• [Publications] Matsumoto, K., et al.: "Hepatocyte growth factor, renotropic role and potential therapeutics for renal diseases"Kidney Intern.. 59. 2023-2038 (2001)
• [Publications] Ueda H., et al.: "A role of HGF in myocaradial infarction induced in rats"Cardiovas. Res.. 51. 41-50 (2001)
• [Publications] Kuroiwa, T., et al.: "Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function"J Clin Invest.. 107. 1365-1373 (2001)
• [Publications] Maehara, N., et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br. J. Cancer. 84. 864-873 (2001)
• [Publications] Mizuno, S., et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intern.. 59. 1304-1314 (2001)
• [Publications] Nakamura, T., et al.: "Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein"Biochim. Biophys. Acta. 1518. 63-72 (2001)
• [Publications] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindimb ischemia models : preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)
• [Publications] Azuma, H., et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an expenimental rat transplant model"J. Am. Soc. Nephrol.. 12. 12180-1292 (2001)
• [Publications] Matsumoto, K., et al.: "Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model"Hypertension. 37. 270-264 (2001)
• [Publications] Nakagami, H., et al.: "Mitogenic and antiapoptotic actions of hepatocyte growth factor through ERK, STAT3, and AKT in endothelial cells"Hypertension. 37. 581-586 (2001)
• [Publications] Yamamoto, K., et al.: "Contribution of bc1-2, but not bc1-x1 and bax, to antiapoptotic actions of hepatocyte growth factor in hypoxia-conditioned human endothelial cells"Hypertension. 37. 1341-1348 (2001)
• [Publications] Ueda, H., et al.: "A potenital cardioprotective role of hepatocyte growth factor in myocardial infarction in rats"Cardiovascular Res.. 51. 41-50 (2001)
• [Publications] Tsuzuki, N., et al.: "HGF reduces the infarct volume after transient focal cerebral ischemia in rats"Neurol Res.. 23. 417-424 (2001)
• [Publications] Parr, C., et al.: "The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant"Biochem Biophys Res Commun.. 285. 1330-1337 (2001)
• [Publications] Beppu, K., et al.: "Hepatocyte growth factor production by peripheral blood mononuclear cells of recurent cancer patients"Anticancer Res.. 21. 2195-2200 (2001)
• [Publications] Aoki, M., et al.: "Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model"Diabetologia. 44. 1034-1042 (2001)
• [Publications] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2001)
• [Publications] Hayashi, K., et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor. in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CAl neurons"Gene Therapy. 8. 1167-1173 (2001)
• [Publications] Shibuki, H., et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia-reperfusion injury"Invest. Ophthalmol. Vis. Sci.. 43. 528-536 (2002)
• [Publications] Maemondo, M., et al.: "Targeting angiogenesis and HGF function using an adenovirul vector expressing the HGF-antagonist NK4 for cancer therapy"Mol. Therapy. 5. 177-185 (2002)
• [Publications] Sumi, T., et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase-1"Biochem. Biophys. Res. Commun.. (印刷中). (2002)
• [Publications] Sakamaki, Y., et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postneumonectomy compensatory lung growth in mice"Am. J. Respir. Cell Mol. Biol.. (印刷中). (2002)
• [Publications] Funakoshi, H., et al.: "Identification of Gas6, a putative ligand Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J. Neurosci. Res.. (印刷中). (2002)
• [Publications] Kishi, A.Y., et al.: "Molecular cloning expression and partial characterization of Kksy, a novel Xenopus member of Sky receptor tyrosine kinase"Gene. (印刷中). (2002)
• [Publications] 松本邦夫, 中村敏一: "増殖因子による再生医学の展開-HGFを中心にして-"Biotherapy. 15. 95-104 (2001)
• [Publications] 松本邦夫 他: "HGFによる肺の再生と線維化の阻止"呼吸. 20. 935-939 (2001)
• [Publications] 富岡大策 他: "NK4/malignostainによる腫瘍血管新生阻止作用とその制がん効果"最新医学. 56. 1799-1807 (2001)
• [Publications] 松本邦夫: "肝臓の初期発生を支える血管内皮細胞"実験医学. 20. 468-471 (2002)
• [Publications] Matsumoto, K., et al.: "分担:HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer teatrnent with NK4 書名:Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher (分担). 35 (2001)