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Thrombotic Diathesis: Molecular Biology and Clinical Investigation.

Research Project

Project/Area Number 03304049
Research Category

Grant-in-Aid for Co-operative Research (A)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

AOKI Nobuo  Tokyo Medical & Dental University, Department of Medicine, Professor, 医学部, 教授 (20048937)

Co-Investigator(Kenkyū-buntansha) SAITO Hidehiko  Nagoya University, Department of Medicine, Professor, 医学部, 教授 (20153819)
OHKUMA Minoru  Kyoto University, Department of Medicine, Professor, 医学部, 教授 (50026986)
IWANAGA Sadaaki  Kyushu University, Department of Science, Professor, 理学部, 教授 (90029942)
KURAMOTO Atsushi  Hiroshima University, Research Institute for Nuclear Medicine and Biology, Profe, 原爆放射能医学研究所・臨床部門, 教授 (50034070)
TITANI Koichi  Fujita Health University, Institute for Medical Sciences, Professor, 総合医科学研究所, 教授 (60179942)
Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥23,900,000 (Direct Cost: ¥23,900,000)
Fiscal Year 1992: ¥11,000,000 (Direct Cost: ¥11,000,000)
Fiscal Year 1991: ¥12,900,000 (Direct Cost: ¥12,900,000)
Keywordsthrombosis / blood coagulation / platelet / fibrinolysis / blood group / blood vessels / プロテインC / 組織因子 / プラスミノゲンアクチベ-タ-インヒビタ- / 血小板膜糖蛋白 / フオンウイルブランド因子
Research Abstract

The study was focused mainly on the four subjects : Regulatory components of thrombus formation, initiation steps of extrinsic coagulation system, sugar chains of coagulation-related components, and platelet membrane. 1. Reguratory components of thrombus formation : Thrombomodulin, anticoagulant protein on surface membrane of endothelial cells, is increased by many stimulants. Its increase was found to be caused mainly by the increase of a high molecular weight type (a sugar-rich type). Four genetic abnormalities causing protein-C deficiency in 3 independent families were elucidated.The deficiency was found to be caused by failure of intracellular transport and secretion of the abnormal proteins produced. Structurally and functionally abnormal protein S, a cofactor of activated protein C, was newly discovered and characterized. 2. Initiation steps of extrinsic coagulation system : Cloning of cDNA for tissue factor in coagulation and its expression were successfully carried out. Monoclonal antibodies to recombinant tissue factor were produced, and the antibodies were used for the study on tissue factor antigen levels in circulation under various disease states. 3. Sugar chains of coagulation-related proteins : Sugar chains of coagulation factors VII, IX, XII and von Willebrand factor were characterized. ABO(H) blood type sugar chains were found to be present in von Willebrand factor and alpha 2 macroglobulin. 4. Cloning and structural characterization of cDNA for platelet membrane GPV were carried out. GPV was found to contain leucin-rich repeated structure and be released into plasma as a soluble form by thrombin. Interaction reaction of platelet and collagen was analyzed, and platelet membrane glycoprotein p62 (GP VI) was suggested to be involved in the reaction leading to the platelet activation. Platelet membrane receptor for thromboxane A2, a powerful agonist for platelet aggregation, was cloned and purified.

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (46 results)

All Other

All Publications (46 results)

  • [Publications] Sugahara,Yuichi: "Protein C deficiency Hong Kong 1 and 2:Hereditary protein C deficiency coused by two mutant alles,a 5.nucleotide deletion and a missence mutation" Blood. 80. 126-133 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Matsui,Taei: "Structures of the asparagine-linked oligusaccharide chains of human von Willebrand factor:Occurrence of blood group A,B,and H(O) structures." Journal of Biological Chemistrmy. 267. 8723-8731 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Shigematsu,Yoshitake: "Expression of Human soluble tissue factor in Yeast and enzymatic properties of its complex with factor VIIa" Journal of Biological Chemistry. 267. 21329-21337 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamamoto,Koji: "Impaired secretion of the elongated mufant of protein C(protein C Nagoya):molecular and cellular basis for hereditory protein C deficiency" Journal of Clinical Inverstigation. 90. 2439-2446 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishika,Junji: "The role of the COOH-terminal region of antithrombin-III.Eridence that the COOH-terminal region of the inhibitor enhances the reachirty of shrombin and factor Xa with the inhibitor." Journal of Biological Chemistry. 267. 22224-22229 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Moroi,Masaaki: "Platelet adhesion to collagen-coated wells:Analysis of this complex process and a compariscn with the adhesion to matrigel-coated wells." Biochimica Biophysica Acto. 1137. 1-9 (1192)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishimura,Hitoshi: "Human factor X has a tetrasaccharide O-glycosidically linked to serine-61 through the fucose residue" Journal of Biological Chemistry. 267. 17520-17529 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ueyama,Masashi: "Marked increase in plasma interleukin-6 in burn patients." Journal of Laboratoy and Clinical Medicine. 120. 693-698 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Fujimura,Yoshihiro: "The interaction of botrocetin with normal or valiant von Willebrand factor (types IIA and IIB)and its inhibition by monoclonal antibodies that block receptor binding." Thrombosis and Haemostasis. 68. 464-469 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyata,Toshiaki: "Substitution of glutamic acid-466 by alanine reduces the fibrinogen clotting activity and the esterase activity" Biochemistry. 31. 7457-7462 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ushibuki,Fumitaka: "Analysis of the defective signal transduction mechanism through the platelet thromboxane receptor in a patient with polycythemia vera." Thrombosis and Haemostasis. 67. 144-146 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamamoto,Koji: "Homozyyous protein C deficiency:ldentification of a novel missense mutation that causes impaired secretion of the mutant protien C." Journal of Laboratory and Clinical Medicine. 119. 682-689 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ryo,Ryukichi: "Oeficiency of p62,a putative collagen receptor,in platelets from a patient with defactive collagen-induced platelet aggregation." American Journal of Hematology. 39. 25-31 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hayashi,Tatsuya: "An atherogenic stimulus homocysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells." Blood. 79. 2930-2936 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Komoriya,Keiji: "Inhibitory effect if actibated protein C on platelet aggregation inguced by the prothrombin-conberting reaction" Thrombosis Research. 67. 705-710 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Wada,Hideo: "Plasma thrombomodulin as a marker of vascular disorders in thrombotic thrombocytopenic purbura and disseminated intravascular coagulation." American Journal of Hematology. 39. 20-24 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Akashi,Mitsuru: "Immobilization of human thrombomodulin of glass beads and its anticoagulant activity" Bioconjugate Chemicals. 3. 363-365 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Kato,Atsushi: "Molecular basis for Glanzmann's thrombasthenia (GT) in a compound heterozygote with glycoprotein IIb gene:A proposal for the classification of GT based on the biosynthetic pathway of glycoprotein IIb-IIIa Complex." Blood. 79. 3212-3218 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sugahara Y et al: "Protein C deficiency Hong Kong 1 and 2: Hereditary Protein C deficiency caused by two mutant alles. a 5-nucleotide deletion and a missence mutation." Blood. 80. 126-133 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Matsui T et al: "Structures of the asparagine-linked oligosaccharide chains of human von Willebrand factor: Occurrence of blood group A,B, and H(O) structures." J. Biol, Chem.267. 8723-8731 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Shigematsu Y et al: "Expression of human soluble tissue factor in Yeast and enzymatic properties of its complex with factor Vlla." J. Biol. Chem.267. 21329-21339 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamamoto K et al: "Impaired secretion of the elongated mutant of protein C (protein C Nagoya) : molecular and cellular basis for hereditary protein C deficiency." J. Clin. Invest.90. 2439-2446 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishioka J et al: "The role of the COOH-terminal region of antithrombin-III. Evidence that the COOH-terminal region of the inhibitor enhances the reactivity of thrombin and factor Xa with the inhibitor." J. Biol. Chem.267. 22224-22229 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Moroi M et al: "Platelet adhesion to collagen-coated wells : Analysis of this complex process and a comparison with the adhesion to matrigel-coated wells." Biochim. Biophys. Acta. 1137. 1-9 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Nishimura H et al: "Human factor X has a tetrasaccharide O-glycosidically linked to serine-61 through the fucose residue." J. biol. Chem.267. 17520-17529 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ueyama M et al: "Marked increase in plasma interleukin-6 in burn patients." J. Lab. Clin. Med.120. 693-698 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Fujimura Y et al: "The interaction of botrocetin with normal or variant von Willebrand factor (types IIA and IIB) and its inhibition by monoclonal antibodies that block receptor binding." Thromb. Haemostasis. 68. 464-469 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Higashi S et al: "Tissue Factor Potentiates the Factor Vlla-catalyzed Hydrolysis of an Ester Substrate." J. Biol. Chem.267(25). 17990-17996 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Takeya H et al: "Coagulation Factor X activating Enzyme from Russell's Viper Venom (RVV-X) : A Nobel Metalloproteinase with Disintegrin (platelet aggregation inhibitor)-like and C-type Lectin-like Domains." J. Biol. Chem.267. 141109-14117 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Miyata T et al: "Substitution of Glutamic Acid-466 by Alanine Reduces the Fibrinogen Clotting Activity and the Estarase Activity." Biochemistry. 31. 7457-7462 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Ushikubi F et al: "Analysis of the defective signal transduction mechanism through the platelet thromboxane recptor in a patient with polycythemia vera." Thromb Haemost. 67. 144-146 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yamamoto K et al: "Homozygous protein C deficiency: identification of a novel missense mutation that causes impaired secretion of the mutant protein C." J Lab Clin Med. 119. 682-689 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Hayashi T et al: "An atherogenic stimulus homo-cysteine inhibits cofactor activity of thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial cells." Blood. 79. 2930-2936 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] M Kaneko et al: "Interaction between finger and kringle-2 domains of tissue-type plasminogen activator and plasminogen activator inhibitor-1." J Biochem. 111. 244-248 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Sugahara,Yuichi: "Protein C deficiency Hong Kong 1 and 2:Hereditary Protin C deficiency caused by two mutant alles,a5-mucleatide deletion and a missence mutation." Blood. 80. 126-133 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Matsui,Taei: "Structures of the asfaragine-linked oligosaccharide chains of human von Willebrand factor:Occurrence of blood group A,B,and H(O)structures." Journal of Biological Chemistry. 267. 8723-8731 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Shigematsu,Yoshitake: "Exprtssion of human soluble tissue factor in Yeast and engymatic properties of its complex with factor Vlla" Journal of Biological Chemistry. 267. 14109-14117 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yamamoto,Koji: "Imhaired secretion of the elangoted mutant of protein C(protein C Nagaya):molecular and cellular basis for hereditory protein C deficiency" Journal of Clinical Investigation. 90. 2439-2446 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nishioka,Junji: "The role of the COOH-terminal regian of antithrombim-III.Evidence that the COOH-terminal regian of the inlilrtor enhances the reactivity of thrambin and factar Xa with the inlibitor." Journal of Biological Chemistry. 267. 22224-22229 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Moroi,Masaaki: "Platelet adhesicn to collagen-coated wells:Analysis of this complex process and a comparison with the adkesion to matrigel-coated wells." Biohimica Biophysica Acta. 1137. 1-9 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Mie Kainoh: "Enhancement by Beraprost Sodium,a stable analogue of prostacyclin,in thrbomadulin expression on membrane surface of cultured vascular endathelial cells via increase in cyclic AMP level" Biochemical Pharmacology. 41. 1135-1140 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tatsushi Muta: "Limulus clatting facton(Factor C):A novel protease that has a mosaic structure with complememt‐like and lectin‐like dmains." Journal of Biological Chemistry. 266. 6554-6561 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Yoshihiro Fujimura: "Studies on anti‐von Willebrand factor(VWF)monoclonal antibody(Moab)NMC‐4 which inhibito both the ristocetin‐and botrocetim‐imduced VWF brindingo to platelet glycopratein(GP↓Ib" Blood. 77. 113-120 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Masaaki Moroi: "Analysis of a variant form of platelet glycoprotein(GP)IIb:A second patient with abnormal malecular weight GP II b" Thrombosis Research. 62. 217-225 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Munenori Kaneko: "The plasminogen activator inhilitorー1 binding site in the kringle‐2 domain of tissue‐type plasinagen actiuaton." Biochemical Biophysical Research Communication. 178. 1160-1166 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kazunori Hirokawa: "Up‐regulatin of thronbumodulin by actiuation of histamine H1‐receptar in human umbilical‐uein endathelial cells in vitro" Biochemical Journal. 276. 739-743 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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