| Project/Area Number |
04454320
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
General surgery
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| Research Institution | Jichi Medical School |
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Principal Investigator |
MATSUDA Michio Division of Hemostasis and Thrombosis Research, Professor, 医学部, 教授 (50048980)
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| Co-Investigator(Kenkyū-buntansha) |
ASAKURA Shinji Division of Hemostasis and Thrombosis Research, Instructor, 医学部, 講師 (70245033)
MIMURO Jun Division of Hemostasis and Thrombosis Research, Instructor, 医学部, 講師 (10221607)
SUGO Teruko Division of Hemostasis and Thrombosis Research, Instructor, 医学部, 講師 (60183844)
SAKATA Yoichi Division of Hemostasis and Thrombosis Research, Associate Professor, 医学部, 助教授 (40129028)
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 1993: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1992: ¥5,200,000 (Direct Cost: ¥5,200,000)
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| Keywords | abnormal fibrinogen / hereditary dysfibrinogenemia / fibrin polymerization / hemophilia B / abnormal factor IX / cell adhesion / high-molecular-weight kininogen / integrin / 異常第IV因子 / グリオーマ細胞 / フィブリン重合障害 / 出血性素因 / 血栓塞栓症 |
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| Research Abstract |
1. Analyzes of hereditary abnormal molecules of blood coagulation and fibrinolysis. 1) Hereditary dysfibrinogenemias : During 1992-1993, we have completed a study on two dysfibrinogens, fibrinogen (Fbg) Bremen (Aalpha Gly-17 to Val) and Fbg Mitaka II(Aalpha Glu-11 to Gly). Fbg Bremen had been found in a 14-year-old German boy with surgical bleeding and delayd wound healing, and the blood sample was sent to our laboratory for structure analysis. The Aalpha Gly-17 to Val substitution provided supporting evidence that the amino terminal three-residue peptide of fibrin alpha-chain, Gly-Pro-Arg, constitutes a polymerization site, "A" exposed onto the central domain of fibrinogen. By utilizing synthetic peptides with a normal or a Bremen type sequence, or their related sequences, we have shown that the free amino group of the amino-terminal residue of fibrin alpha-chain is most critical for the function of the "A" site, since the replacement of Gly to Ala or Val manifested only a minute func
… More
tional disturbance, whereas that to other amino acids failed to manifest polymerization-promoting activity (Publication No. 15). Fbg Mitaka II was characterized by defective binding with thrombin. Thus Aalpha Glu-11 appears to play a crucial role in the binding with thrombin. indeed, the side-chain carboxy group of this amino acid has recently been shown by X-ray crystallography to form a salt bridge with the side-chain guanidino group of Arg-173 of thrombin, and also to stabilize the type II beta-turn which is mandatory for fibrinogen to be fitted into the enzyme pocket of thrombin. Our data support this hypothesis, and provide important implications in the study of thrombus formation (publications No. 13 and 15). 2) An abnormal factor IX Tokyo I found in a mild hemophiliac : By gene analysis, we have identified a T to C mutation at nucleotide 20525 coding for Val-182 of factor IX.Thus the patient's factor IX must have an ala-182 substitute. This site is close to the cleavage site by
2. Study on the cell adhesion : High-molecular-weight kininogen was found to manifest cell attachment promoting activity when converted to a two-chain molecule (HKa). We have been analyzing the molecular basis for this phenomenon by utilyzing a battery of synthetic peptides and monoclonal antibodies produced by the support of this research fund. We have also identified specific integrins on cultured glioma cells upon contact with vitronectin and fibrinonectin, which are normally absent but exposed upon contact with these adhesion molecules. Interestingly these integrins appear to migrate on the cell surface in accordance with the cell shape changes (submitted to Brain Research). Less
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