1997 年度実績報告書

海馬及び運動ニューロン生存を担う新規神経栄養因子の探索と機能解析

研究課題

研究課題/領域番号	09280220
研究機関	大阪大学
研究代表者	船越洋大阪大学, 医学部, 助手 (40273685)
研究分担者	中村敏一大阪大学, 医学部, 教授 (00049397)
キーワード	Molecular cloning / neurotrophic / Sky / Axl / Gas6 / HGF / synthetic neurotrophic factor / tyrosine kinase
研究概要	(1)新規神経栄養システム(Gas6/Skyレセプター型チロシンキナーゼシステム)の同定ラットGas6が、培養海馬ニューロンに対する神経生存促進因子、すなわち新規神経栄養因子であることを見い出した。このことは、Gas6/Skyレセプター型チロシンキナーゼファミリーシステムの新規神経栄養システムとしての発見である。また、Skyファミリー分子ラットAxlを分子クローニングし、同定された配列をもとにラットSkyおよびAxlに対する抗体を作製し組織・細胞分布を解析すると共に、Skyのファミリーレセプター、リガンドmRNAの発現分布、発達過程における発現制御、更には神経損傷時における生理的発現制御(カイニン酸モデルと座骨神経損傷モデル)を解析した。発生過程および神経損傷モデルにおける協調したGas6/Skyファミリー分子の神経系における発現制御は、新規神経栄養システムとしてのGas6/Skyファミリーシステムの機能が生理的に重要であることを裏づけている。 (2)HGF/c-Metの運動神経系における発現制御 HGF/c-Metが運動神経系の発生過程、神経損傷時ともに発現制御を受けていた。現在HGFの神経系特異的発現マウスを作製、さらに解析をすすめている。 (3)人工神経栄養因子(汎ニューロトロフィン) ニューロトロフィン遺伝子を組み替え全てのニューロトロフィンレセプターに結合、活性化する人工神経栄養因子(汎ニューロトロフィン)遺伝子を損傷神経に特異的に発現させ、神経再生に与える効果を評価した。電気生理学的、電子顕微鏡学的、筋肉湿重量で解析したところ、1つのニューロトロフィンでは難しい感覚・運動両神経の再生を促進していた。人工神経栄養因子のアプローチは、新しいアプローチとして期待される。

研究成果

(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] H.Funakoshi, et al.: "Targeted expression of a multifunctional chimeric neurotrophin to the lesioned nerve accerelate both sensory and motor axons." Proc.Natl.Acad.Sci USA. (in press.).
[文献書誌] T.Miyazawa, et al.,: "Protection of hippocampal meurons from ischemia-induced delayed neuronal death by hepatocyte growth factor:A novel neurotrophic factor." J.Celebral Blood Flow Metabolism. (in press.).
[文献書誌] R.Gal-Levi, et al.: "Hepatocyte growth factor as a potent regulator of skeletal muscle satellite cell proliferation and differentiation." Biochem.Biophys.Acta.(in press.).
[文献書誌] H.Ohmichi, et al.: "Hepatocyte growth factor (HGF) acts as a mesenchymal-derived morphogenic factor during fetal ling develpment." Development. (in press.).
[文献書誌] S.Mizuno, et al.: "Hepatocyte growth factor prevents renal fibrosis and dysfunction in mouse model of chronio renal disease." J.Clin.Invest.(in press.).
[文献書誌] K.Kosai, et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis in mice." Biochem.Biophys.Res.Commun.(in press.).
[文献書誌] M.Lyon, et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)
[文献書誌] M.Trupp, et al.: "Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF),c-ret proto-oncogene,and GDNF receptor alpha indicates multiple mechanisms of trophic actions in the adult rat CNS." J.Neurosci.10. 3554-3567 (1997)
[文献書誌] K.Takai, et al.: "Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and promotes erythropoiesis." Blood. 89. 1560-1565 (1997)
[文献書誌] I.S.Weimar, et al.: "Hepatocyte growth factor/scatter factor (HGF/SF) promotes adhesion of lymphoma cells to extra-cellular matrix molecules via α4β,and α5β,integrins." Blood. 89. 990-1000 (1997)
[文献書誌] T.Takahashi, et al.: "Xenopus LIM motif-containing protein kinase,XLIMK,is expressed in the developing head structure of the embryo." Dev.Dyn.209. 196-205 (1997)
[文献書誌] S.Aoki, et al.: "Activation of Met tyrosine kinase by hepatocyte growth factor is essential for internal organogenesis in Xenopus embryo." Biochem.Biophys.Res.Commun.234. 8-14 (1997)
[文献書誌] Y.Matsuda, et al.: "Prevential and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis." Hepatology. 26. 81-89
[文献書誌] T.Nakamura, et al.: "Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells:In vitro analysis of tumor-stromal interaction." Cancer Res.57. 3305-3313 (1997)
[文献書誌] T.Kaido, et al.: "Continous hepatocyte growth factor supply prevents lipopolysacharide-induced liver injury in rats." FEBS Lett.411. 378-382 (1997)
[文献書誌] S.Wakitani, et al.: "Hepatocyte growth factor faulitates Cartilage repair:full thickness articular cartilage defect studied in rabbit knee." Acta Orthop.Stand.68. 474-480 (1997)
[文献書誌] T.Adachi, et al.: "Possible involvement of pertussis toxin-sensitive G protein in hepatocyte growth factor (HGF)-induced signal transduction in cultured rat hepatocytes." Hepatology. 26. 295-300 (1997)
[文献書誌] K.Date, et al.: "HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor." FEBS Lett.420. 1-6 (1997)
[文献書誌] 船越洋: "シナプス-形成と再形成:Sprouting." Clin.Neurosci.15. 65-68 (1997)
[文献書誌] 船越洋、中村敏一: "運動ニューロン変性と神経栄養因子" 神経研究の進歩. 885-898 (1997)

1997 年度 実績報告書

海馬及び運動ニューロン生存を担う新規神経栄養因子の探索と機能解析

研究代表者

船越 洋 大阪大学, 医学部, 助手 (40273685)

研究成果

[文献書誌] H.Funakoshi, et al.: "Targeted expression of a multifunctional chimeric neurotrophin to the lesioned nerve accerelate both sensory and motor axons." Proc.Natl.Acad.Sci USA. (in press.).

[文献書誌] T.Miyazawa, et al.,: "Protection of hippocampal meurons from ischemia-induced delayed neuronal death by hepatocyte growth factor:A novel neurotrophic factor." J.Celebral Blood Flow Metabolism. (in press.).

[文献書誌] R.Gal-Levi, et al.: "Hepatocyte growth factor as a potent regulator of skeletal muscle satellite cell proliferation and differentiation." Biochem.Biophys.Acta.(in press.).

[文献書誌] H.Ohmichi, et al.: "Hepatocyte growth factor (HGF) acts as a mesenchymal-derived morphogenic factor during fetal ling develpment." Development. (in press.).

[文献書誌] S.Mizuno, et al.: "Hepatocyte growth factor prevents renal fibrosis and dysfunction in mouse model of chronio renal disease." J.Clin.Invest.(in press.).

[文献書誌] K.Kosai, et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis in mice." Biochem.Biophys.Res.Commun.(in press.).

[文献書誌] M.Lyon, et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)

[文献書誌] M.Trupp, et al.: "Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF),c-ret proto-oncogene,and GDNF receptor alpha indicates multiple mechanisms of trophic actions in the adult rat CNS." J.Neurosci.10. 3554-3567 (1997)

[文献書誌] K.Takai, et al.: "Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and promotes erythropoiesis." Blood. 89. 1560-1565 (1997)

[文献書誌] I.S.Weimar, et al.: "Hepatocyte growth factor/scatter factor (HGF/SF) promotes adhesion of lymphoma cells to extra-cellular matrix molecules via α4β,and α5β,integrins." Blood. 89. 990-1000 (1997)

[文献書誌] T.Takahashi, et al.: "Xenopus LIM motif-containing protein kinase,XLIMK,is expressed in the developing head structure of the embryo." Dev.Dyn.209. 196-205 (1997)

[文献書誌] S.Aoki, et al.: "Activation of Met tyrosine kinase by hepatocyte growth factor is essential for internal organogenesis in Xenopus embryo." Biochem.Biophys.Res.Commun.234. 8-14 (1997)

[文献書誌] Y.Matsuda, et al.: "Prevential and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis." Hepatology. 26. 81-89

[文献書誌] T.Nakamura, et al.: "Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells:In vitro analysis of tumor-stromal interaction." Cancer Res.57. 3305-3313 (1997)

[文献書誌] T.Kaido, et al.: "Continous hepatocyte growth factor supply prevents lipopolysacharide-induced liver injury in rats." FEBS Lett.411. 378-382 (1997)

[文献書誌] S.Wakitani, et al.: "Hepatocyte growth factor faulitates Cartilage repair:full thickness articular cartilage defect studied in rabbit knee." Acta Orthop.Stand.68. 474-480 (1997)

[文献書誌] T.Adachi, et al.: "Possible involvement of pertussis toxin-sensitive G protein in hepatocyte growth factor (HGF)-induced signal transduction in cultured rat hepatocytes." Hepatology. 26. 295-300 (1997)

[文献書誌] K.Date, et al.: "HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor." FEBS Lett.420. 1-6 (1997)

[文献書誌] 船越洋: "シナプス-形成と再形成:Sprouting." Clin.Neurosci.15. 65-68 (1997)

[文献書誌] 船越洋、中村敏一: "運動ニューロン変性と神経栄養因子" 神経研究の進歩. 885-898 (1997)

1997 年度実績報告書

船越洋大阪大学, 医学部, 助手 (40273685)