| Project/Area Number |
09044329
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
General surgery
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| Research Institution | Jichi Medical School, School of Medicine |
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Principal Investigator |
MATSUDA Michio Jichi Medical School, School of Medicine, Division of Hemostasis and Thrombosis Research, Professor, 医学部, 教授 (50048980)
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| Co-Investigator(Kenkyū-buntansha) |
WEISEL John W. University of Pennsylvania, School of Medicine, Professor, 医学部, 教授
ASAKURA Shinji Jichi Medical School, School of Medicine, Division of Hemostasis and Thrombosis, 医学部, 講師 (70245033)
MIMURO Jun Jichi Medical School, School of Medicine, Division of Hemostasis and Thrombosis, 医学部, 講師 (10221607)
SUGO Teruko Jichi Medical School, School of Medicine, Division of Hemostasis and Thrombosis, 医学部, 講師 (60183844)
SAKATA Yoichi Jichi Medical School, School of Medicine, Division of Hemostasis and Thrombosis, 医学部, 助教授 (40129028)
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| Project Period (FY) |
1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1997: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | dysfibrinogen / ultrastructure of fibrin / extra glycosylation / cross-linking / thrombosis |
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| Research Abstract |
1. Studies on the structure-function relationship of hereditary dysfibrinogens : More than 10 samples have been referred to us from the institutions in Japan and from abroad, and the analyzes so far completed have been reported (See the publication list). Among them, we would like to introduce two unique molecules, one from abroad and the other from Niigata. (1) Fibrinogen Marburg : This dysfibrinogen was found in a 20 year-old German lady who manifested severe post-operative bleeding, recurrent thrombo-embolic diseases and would healing disturbance, all apparently related to functional abnormalities of fibrinogen. This molecule has a pair of 150 residues-truncated Aalpha-chains due to premature appearance of a stop codon TAA for AAA coding Aalpha Lys-461. Because of this truncation of the C-terminal (461-610) residues of the Aalpha-chain, Aalpha Cys-442 has lost its disulfide-bridge partner, and is partly disulfide-bridged with serum albumin. On clotting with thrombin, factor XIII and
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Ca^<2+>, part of the Aalpha-linked albumin was cross-linked to the gamma-chain of another fibrin molecules. The cross-linked fibrin was found to be extremely resistant against plasmic digestion, accounting for at least partly the thrombo-embolic complications in the patient. (2) Fibrinogen Niigata : Because of an Asn to Ser mutation at Bbeta-160, a new Asn-X-Ser type sequence is created at Bbeta 158-159-160, and indeed, a biantennary olibosaccharide was found to be N-linked to Bbeta Asn-158. As this mutant segment is spatially apart from the primary polymerization site in the D domain, we have been searching for the mechanism underlying functional abnormalities.
2. Analyzes of the ultrastructure of the abnormal fibrin clots : In collaboration with two experts in U.S.A., Michael W.Mosesson and John W.Weisel, we have obtained several important pieces of information on representative molecules selected for our international collaboration studis. The Marburg fibrin clots were found to consist of very thin and highly branched fibers, which give rise to compactly interwoven textures. Liquid permeability studies showed that the Marburg fibrin would allow liquids to flow far less smoothly in their textures than in th normal contrl. The thrombo-embolic diseases and would healing disturbances seem to be partly accounted for by this abnormality. The Niigata fibrin clots were composed of highly branched fibrin fibers and the Kurashiki fibrin clots appeared to be irregular as compared with the normal clots. After removal of the oligosaccharides, the Niigata fibrin fibers were found to be extraordinarily thick and far less branched than the control fibers. The relevance of the structural alteration to these abnormal features are currently under investigation. Less
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