Antithrombin deficiency in mice results in embryonic lethality and thrombotic tendency.
| Project/Area Number |
13470203
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
TAKAMATU Junki Nagoya University Hospital, Prefessor, 医学部附属病院, 教授 (80221365)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Koji Nagoya University Hospital, Medical Staff, 医学部附属病院, 医員
MATSUSHITA Tadashi Nagoya University Hospital, Research Associate, 医学部附属病院, 助手 (30314008)
KOJIMA Tetsuhito Nagoya University, School of Medicine, Professor, 医学部, 教授 (40161913)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 2002: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2001: ¥11,500,000 (Direct Cost: ¥11,500,000)
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| Keywords | Antithrombin / Sindecan / Thrombosis / recombination / Knock owt / LPS / antithrombin / Svndecan / Polymerase chain reaction / platelet / thrombosis / Knock out mouse |
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| Research Abstract |
Antithrombin is a plasma protease inhibitor that inhibits thrombin and contributes to the maintenance of blood fluidity. Using targeted gene disruption, we investigated the role of antithrombin in embryogenesis. Mating mice heterozygous for antithrombin gene (ATIII) disruption, ATIII (+/-), yielded the expected Mendelian distribution of genotypes until 14.5 gestational days (gd). However, approximately 70% of the ATIII (-/-) embryos at 15.5 gd and 100% at 16.5 gd had died and showed extensive subcutaneous hemorrhage. Histological examination of those embryos revealed extensive fibrin (ogen) deposition in the myocardium and liver, but not in the brain or lung. Furthermore, no apparent fibrin (ogen) deposition was detected in the extensive hemorrhagic region, suggesting that fibrinogen might be decreased due to consumptive coagulopathy and/or liver dysfunction. These finding suggest that antithrombin is essential for embryonic survival and that it plays an important role in regulation of
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blood coagulaation in the myocardium and liver. In contrast, heterozygous AT-deficient mice with 50% AT activities have not shown spontaneous thromboembolic episodes To demonstrate a thrombotic tendency in heterzygous AT deficiency, we challenged heterozygous AT- deficient mice (AT+/-mice) with the administration of lipopolysaccharide (LPS) or with restraint stress by immobilization. LPS injection markedly induced fibrin deposition in the kidney glomeruli, myocardium, and liver sinusoids in AT+/-mice compared with wild-type mice (AT+/+mice). Restraint stress tests were performed by placing mice in 50-mL conical centrifuge tubes for 20 hours. Fibrin deposition was observed in the kidney of AT+/+and AT+/-mice, but AT+/- mice exhibited more extensive fibrin deposition than AT+/+ mice. After prophylactic administration of human AT concentrates to increase plasma AT activities of AT+/-mice, LPS-induced fibrin deposition was effectively prevented. These results suggest that heterozygous AT deficiency is significantly associated with a tendency toward thrombosis formatin in the kidney. The AT+/-mouse thus is a useful model for studying the effect of environmental or genetic risk factors on thrombogenesis. Less
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(3 results)
Research Products
(10 results)
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[Publications] Ishiguro K, Kadomatsu K, Kojima T, Muramatsu H, Iwase M, Yoshikai Y, Yanada M, Yamamoto K, Matsushita T, Nishimura M, Kusugami K, Saito H, Muramatsu T: "Syndecan-4 deficiency leads to high mortality of lipopol ysaccharide-injected mice"J Biol Chem. 3. 3 (2001)
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