| Project/Area Number |
22790923
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hematology
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
BANNO Fumiaki 独立行政法人国立循環器病研究センター, 研究所, 研究員 (00373514)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | プロテインS / プラスミノーゲン / ノックインマウス / 遺伝子変異 / 日本人の血栓症 / 血液凝固 / 線溶 |
|---|
| Research Abstract |
The K196E mutation in protein S (PS) is found in one of 55 Japanese and is a genetic risk factor for vein thrombosis in Japanese. The A620T mutation in plasminogen (PLG) is found in one of 25 Japanese and causes decreased fibrinolytic activity. In this study, we generated PS-K196E and PLG-A622T (corresponding to human PLG-A620T) knock-in mice for investigating effects of these mutations in vivo. Following the induction of pulmonary embolism, PS-K196E mice showed increased degree of lung vascular occlusion and decreased survival compared with wild-type mice. These results support a direct causal relationship between the PS-K196E mutation and increased susceptibility to venous thromboembolism. To examine effects of the mutation on arterial ischemic diseases, temporary cerebral ischemia was applied in mice. Mice with the factor V－Leiden mutation, the common thrombotic risk in Caucasian, showed larger infarction and lower survival than wild-type mice. In contrast, cerebral infarction in PS-K196E mice was not aggravated. Consistent with these findings, the FV-Leiden mutation has been reported as a risk factor for early-onset ischemic stroke, whereas there are no epidemiological data to suggest significant association between the PS-K196E mutation and stroke. The PS-196E mice represent a suitable animal model to uncover genetic characteristics of thrombosis in Japanese. The PLG-A622T mutation in mice had little effect on the severity of pulmonary embolism and cerebral infarction, suggesting that the PLG-A620T mutation does not cause thrombosis by itself.
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