2002 Fiscal Year Annual Research Report

傷害察知と連携したMet/HGF受容体シグナル変換能の調節を介した再生制御の研究

Research Project

Project/Area Number	13470037
Research Institution	Osaka University
Principal Investigator	松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
Co-Investigator(Kenkyū-buntansha)	町出充大阪大学, 医学系研究科, 助手 (90346198) 中村敏一大阪大学, 医学系研究科, 教授 (00049397)
Keywords	HGF / c-Met / トランスジェニックマウス / 細胞内シグナル / 細胞接着 / 肝細胞 / 再生・修復 / 恒常性維持
Research Abstract	c-Met/HGFレセプターは組織傷害時にはHGFに応答して組織修復作用を惹起するが、組織が無傷害の時(健常時)にはHGFに応答しない。この傷害の察知と連携するc-Metの機能変換機構は組織の恒常性を維持する上できわめて重要である。本研究はc-Metの機能変換機構を分子的に解明することを目的とし、以下の研究を実施した。 1.c-Metのjuxtamembraneドメインを介した機能制御:c-Metのjuxtamembrane近傍の985番目のセリン残基のリン酸化を認識する抗体を作成した。この抗体を用いて、マウスの傷害肝では985番目のセリン残基のリン酸化が減衰し、c-Metの活性化が起こること、一方、健常な肝臓では985番目のセリン残基のリン酸化は高いレベルで持続されており、その時c-Metの活性化は認められないことを明らかにした。現在985番目のセリンをリン酸化・脱リン酸化する分子を検索中である。(松本) 2.遺伝子改変動物を用いたc-Metの機能制御の解析:985番目のセリンのリン酸化修飾の生理学的意義を解析する目的で、このセリンを他のアミノ酸に置換した遺伝子改変マウスの作成を開始し、生殖細胞へ組み換え遺伝子が導入されたマウスを樹立した。(中村) 3.c-Metの機能を変換する細胞環境の解析:HGFによる肝細胞の増殖に影響を与える細胞環境を解明するために、ラット初代培養肝細胞を用いて、細胞培養密度のc-Met活性化への影響を調べた。その結果、生体内の健常な肝臓を模倣する高密度培養下ではHGFを投与してもc-Metの活性化は認められなかった。よって細胞接着がc-Metの機能に影響を与えることが明らかとなり、生体内のおいても細胞接着の変化がc-Metの機能変換に関わることが示唆された。(町出)

Research Products

(23 results)

All Other

All Publications (23 results)

[Publications] Morishita R et al.: "Impairment of collateral formation in lipoprotein(a) transgenic mice : therapeutic angiogenesis induced by human hepatocyte growth factor gene"Circulation. 105. 1491-1496 (2002)
[Publications] Taniyama Y et al.: "Development of safe and efficient novel nonviral gene transfer using ultrasound : enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle"Gene Ther. 9. 372-380 (2002)
[Publications] Sakamaki Y et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice"Am J Respir Cell Mol Biol. 26. 525-533 (2002)
[Publications] Yoshimura S et al.: "Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model"Hypertension. 39. 1028-1034 (2002)
[Publications] Kishi Y.A.et al.: "Molecular cloning, expression and partial characterization of Xksy, Xenopus member of the Sky family of receptor tyrosine kinases"Gene. 288. 29-40 (2002)
[Publications] Sumi T et al.: "LIM-kinases in actin cytoskeletal regulation and their physiological role"Seikagaku. 74. 402-407 (2002)
[Publications] Taniyama Y et al.: "Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy. Hypertension"Hypertension. 40. 47-53 (2002)
[Publications] Hirao S et al.: "Tumor suppression effect using NK4, a molecule acting as an antagonist of HGF, on human gastric carcinomas"Cancer Gene Ther.. 9. 700-707 (2002)
[Publications] Nakagami H et al.: "Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane"Diabetes. 51. 2604-2011 (2002)
[Publications] To Y et al.: "A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell line"Am J Respir Cell Mol Biol. 27. 220-226 (2002)
[Publications] Maehara N et al.: "Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer"Clin Exp Metastasis. 19. 417-426 (2002)
[Publications] Saimura M et al.: "Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice"Cancer Gene Ther.. 9. 799-806 (2002)
[Publications] Ono M et al.: "In vivo gene transfection with hepatocyte growth factor via the pulmonary artery induces angiogenesis in the rat lung"Circulation. 106. 1264-1269 (2002)
[Publications] Saimura M et al.: "Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4"Clin Cancer Res.. 8. 3243-3249 (2002)
[Publications] Matsumoto K et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol Dial Transplant. 17. 59-61 (2002)
[Publications] Kikuchi T et al.: "Tumor suppression induced by intratumor administration of adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte growth factor, and naive dendritic cells"Blood. 100. 3950-3959 (2002)
[Publications] Nakanishi K et al.: "Gene transfer of human hepatocyte growth factor into rat skin wounds mediated by liposomes coated with the sendai virus (hemagglutinating virus of Japan)"Am J Pathol.. 161. 1761-1772 (2002)
[Publications] Qian LW et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production"Cancer Lett. 190. 105-112 (2003)
[Publications] Yoshida S et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J Invest Dermatol. 120. 335-343 (2003)
[Publications] Koike H et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene"FASEB J. (印刷中). (2003)
[Publications] Qian L.W.et al.: "Radiation stimulates HGF receptor/c-Met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells"Int J Cancer. 104. 542-549 (2003)
[Publications] Bessho K et al.: "Counteractive Effects of HGF on PDGF-induced Mesangial Cell Proliferation in a Rat Model of Glomerulonephritis"Am J Physiol Renal Physiol. (印刷中). (2003)
[Publications] 町出充, 他: "HGFによる肝再生医療の展開"再生医療. 1-2. 47-55 (2002)

2002 Fiscal Year Annual Research Report

傷害察知と連携したMet/HGF受容体シグナル変換能の調節を介した再生制御の研究

Principal Investigator

松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780)

Research Products

[Publications] Morishita R et al.: "Impairment of collateral formation in lipoprotein(a) transgenic mice : therapeutic angiogenesis induced by human hepatocyte growth factor gene"Circulation. 105. 1491-1496 (2002)

[Publications] Taniyama Y et al.: "Development of safe and efficient novel nonviral gene transfer using ultrasound : enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle"Gene Ther. 9. 372-380 (2002)

[Publications] Sakamaki Y et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice"Am J Respir Cell Mol Biol. 26. 525-533 (2002)

[Publications] Yoshimura S et al.: "Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model"Hypertension. 39. 1028-1034 (2002)

[Publications] Kishi Y.A.et al.: "Molecular cloning, expression and partial characterization of Xksy, Xenopus member of the Sky family of receptor tyrosine kinases"Gene. 288. 29-40 (2002)

[Publications] Sumi T et al.: "LIM-kinases in actin cytoskeletal regulation and their physiological role"Seikagaku. 74. 402-407 (2002)

[Publications] Taniyama Y et al.: "Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy. Hypertension"Hypertension. 40. 47-53 (2002)

[Publications] Hirao S et al.: "Tumor suppression effect using NK4, a molecule acting as an antagonist of HGF, on human gastric carcinomas"Cancer Gene Ther.. 9. 700-707 (2002)

[Publications] Nakagami H et al.: "Hepatocyte growth factor prevents endothelial cell death through inhibition of bax translocation from cytosol to mitochondrial membrane"Diabetes. 51. 2604-2011 (2002)

[Publications] To Y et al.: "A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell line"Am J Respir Cell Mol Biol. 27. 220-226 (2002)

[Publications] Maehara N et al.: "Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer"Clin Exp Metastasis. 19. 417-426 (2002)

[Publications] Saimura M et al.: "Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice"Cancer Gene Ther.. 9. 799-806 (2002)

[Publications] Ono M et al.: "In vivo gene transfection with hepatocyte growth factor via the pulmonary artery induces angiogenesis in the rat lung"Circulation. 106. 1264-1269 (2002)

[Publications] Saimura M et al.: "Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4"Clin Cancer Res.. 8. 3243-3249 (2002)

[Publications] Matsumoto K et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol Dial Transplant. 17. 59-61 (2002)

[Publications] Kikuchi T et al.: "Tumor suppression induced by intratumor administration of adenovirus vector expressing NK4, a 4-kringle antagonist of hepatocyte growth factor, and naive dendritic cells"Blood. 100. 3950-3959 (2002)

[Publications] Nakanishi K et al.: "Gene transfer of human hepatocyte growth factor into rat skin wounds mediated by liposomes coated with the sendai virus (hemagglutinating virus of Japan)"Am J Pathol.. 161. 1761-1772 (2002)

[Publications] Qian LW et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production"Cancer Lett. 190. 105-112 (2003)

[Publications] Yoshida S et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J Invest Dermatol. 120. 335-343 (2003)

[Publications] Koike H et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene"FASEB J. (印刷中). (2003)

[Publications] Qian L.W.et al.: "Radiation stimulates HGF receptor/c-Met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and MAP kinase activity in pancreatic cancer cells"Int J Cancer. 104. 542-549 (2003)

[Publications] Bessho K et al.: "Counteractive Effects of HGF on PDGF-induced Mesangial Cell Proliferation in a Rat Model of Glomerulonephritis"Am J Physiol Renal Physiol. (印刷中). (2003)

[Publications] 町出充, 他: "HGFによる肝再生医療の展開"再生医療. 1-2. 47-55 (2002)

松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)