1999 Fiscal Year Annual Research Report

フィブリノゲンの構造と機能の分子機作-遺伝的変異分子の解析とその応用

Research Project

Project/Area Number	11694308
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	Jichi Medical University
Principal Investigator	松田道生自治医科大学, 医学部, 教授 (50048980)
Co-Investigator(Kenkyū-buntansha)	三室淳自治医科大学, 医学部, 講師 (10221607) 諏合輝子自治医科大学, 医学部, 講師 (60183844) 坂田洋一自治医科大学, 医学部, 助教授 (40129028) 窓岩清治自治医科大学, 医学部, 講師 (70296119)
Keywords	遺伝性異常フィブリノゲン / フィブリノゲン異常症 / 血栓性素因 / 糖付加構造 / 余剰糖鎖 / 電顕学的分析 / フィブリンの超微細構造 / 停止コドンの消失
Research Abstract	前回の科研費補助金(国際学術共同研究10044316)により分析を開始した幾つかの異常fibrinogen(Fbg)分子でそれぞれ新しい知見が得られた(業績目録参照)。中でもFbg Marburgでは生化学的手法からAα鎖150残基の欠失と、この短いAα鎖に結成albuminが、平均してFbg3分子に1分子の割でS-S結合していることが判明していたが、これをrotary shadow法による電顕学的分析で証明することが出来、国外の共同研究者Mosessonらと共に報告した(研究業績6)。また走査電顕では、各fibrin(Fbn)線維はきわめて細く、これらが密に網状構造を形成していた。そのため、水の透過性は著しく低く、一旦Fbn血栓が生じて血流を閉塞すると、血流のうっ滞をもたらし、血栓症を招来したものと考えられる。既報の如くこのFbn線維は線溶酵素plasminによる分解を全く受けず(Blood 91:3282,1998)、これも血栓形成の主因の一つとなったものと結論した。 Fbg Niigataでは新たな型の点変異BβAsn 160→Serが同定され、このためAsn-X-Ser型の糖付加構造が形成され、付加された余剰糖鎖がFbg原線維からFbg束形成への道程を障害し、Fbgゲル形成を遅延させていることを生化学的および電顕学的手法で証明し、国外の共同研究者Mosesson教授らと共に国際誌Blood(研究業績7)に報告した。 Fbg OsakaVIではBβ鎖遺伝子の停止コドン(T__-AA)がlysをコードする(A__-AA)に変じており、このため、Bβ鎖C末に12アミノ酸残基が余剰に付加されていた。このC末から第2位はCysで他の分子の同位のCysとS-S結合していることを電顕学的に証明し、第17回国際血栓止血学会(Washington D.C.)でWeisel教授らと共同発表した。

Research Products
(11 results)

All Other

All Publications (11 results)

[Publications] Wei Yang: "Two-step spreading mode of human glioma cells on fibrin monomer : Interaction of α_yβ_3 with the substratum followed by interaction of α_5β_1 with endogenous cellular fibronectin secreted in the extracellular matrix"Thromb Res. 93. 279-290 (1999)
[Publications] Jun Mimuro: "A new type of Ser substitution for γArg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly"Thromb Haemost. 81(6). 940-944 (1999)
[Publications] Seiji Madoiwa: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation"Blood. 94(2). 475-482 (1999)
[Publications] Mitsuru Nakamura: "Simultaneous core 2β_1→6N-acetylglucosaminyltransferase up-regulation and sialy1-Le^x expression during activation of human tonsillar B lymphocytes"FEBS Lett. 463. 125-128 (1999)
[Publications] Michio Matsuda: "Structure and function of fibrinogen : Insights from dysfibrinogens"Thromb Haemost. 82. 283-290 (1999)
[Publications] DiOrio JP: "Fibrinogen Marburg fibrin network structure"Microsc Microanal. 5. 1120-1121 (1999)
[Publications] Teruko Sugo: "Fibrinogen Niigata : An abnormal fibrinogen with a Bβ Asn-160 to Ser substitution associated with extra glycosylation at Bβ Ans-158"Blood. 94. 3806-3813 (1999)
[Publications] Jiro Kikuchi: "Induction of ubiquitin-conjugating ing enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis"Arterioscler Thromb Basc Biol. 20. 128-134 (2000)
[Publications] Isao Kohno: "A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin : Its application to the measurement of granulocyte-derived elastase-digests in plasma"Blood. 95. (2000)
[Publications] Kant M Matsuda: "A novel strategy for the tumor angiogenesis-targeted gene therapy : Generation of angiostatin from endogenous plasminogen by protease gene transfer"Cancer Gene Therapy. (in press).
[Publications] Michio Matsuda: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens"Intern J Haematol. (in press).

1999 Fiscal Year Annual Research Report

フィブリノゲンの構造と機能の分子機作-遺伝的変異分子の解析とその応用

Principal Investigator

松田 道生 自治医科大学, 医学部, 教授 (50048980)

Research Products

[Publications] Wei Yang: "Two-step spreading mode of human glioma cells on fibrin monomer : Interaction of α_yβ_3 with the substratum followed by interaction of α_5β_1 with endogenous cellular fibronectin secreted in the extracellular matrix"Thromb Res. 93. 279-290 (1999)

[Publications] Jun Mimuro: "A new type of Ser substitution for γArg-275 in fibrinogen Kamogawa I characterized by impaired fibrin assembly"Thromb Haemost. 81(6). 940-944 (1999)

[Publications] Seiji Madoiwa: "Developmental expression of plasminogen activator inhibitor-1 associated with thrombopoietin-dependent megakaryocytic differentiation"Blood. 94(2). 475-482 (1999)

[Publications] Mitsuru Nakamura: "Simultaneous core 2β_1→6N-acetylglucosaminyltransferase up-regulation and sialy1-Le^x expression during activation of human tonsillar B lymphocytes"FEBS Lett. 463. 125-128 (1999)

[Publications] Michio Matsuda: "Structure and function of fibrinogen : Insights from dysfibrinogens"Thromb Haemost. 82. 283-290 (1999)

[Publications] DiOrio JP: "Fibrinogen Marburg fibrin network structure"Microsc Microanal. 5. 1120-1121 (1999)

[Publications] Teruko Sugo: "Fibrinogen Niigata : An abnormal fibrinogen with a Bβ Asn-160 to Ser substitution associated with extra glycosylation at Bβ Ans-158"Blood. 94. 3806-3813 (1999)

[Publications] Jiro Kikuchi: "Induction of ubiquitin-conjugating ing enzyme by aggregated low density lipoprotein in human macrophages and its implications for atherosclerosis"Arterioscler Thromb Basc Biol. 20. 128-134 (2000)

[Publications] Isao Kohno: "A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin : Its application to the measurement of granulocyte-derived elastase-digests in plasma"Blood. 95. (2000)

[Publications] Kant M Matsuda: "A novel strategy for the tumor angiogenesis-targeted gene therapy : Generation of angiostatin from endogenous plasminogen by protease gene transfer"Cancer Gene Therapy. (in press).

[Publications] Michio Matsuda: "Structure and function of fibrinogen inferred from hereditary dysfibrinogens"Intern J Haematol. (in press).

松田道生自治医科大学, 医学部, 教授 (50048980)