| Project/Area Number |
19K17532
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Fukushima Medical University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 肺高血圧症 / CALR変異 / 骨髄増殖性疾患 / Calreticulin変異 |
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| Outline of Research at the Start |
骨髄増殖性疾患は肺高血圧症を高頻度で合併し、かつ肺高血圧症合併例は予後不良であることが知られている。しかしながら骨髄増殖性疾患における肺高血圧症の病態はいまだに不明であり、詳細な機序の解明が待たれている。近年、骨髄増殖性疾患の新たな原因遺伝子変異としてcalreticulin（CALR）変異が同定された。我々は、CALR変異に着目し、CALR変異陽性患者における肺高血圧症を検討するとともに、骨髄増殖性疾患に合併した肺高血圧症の分子メカニズムを解明するため、CALR変異ノックインマウスを用いてCALR変異における肺高血圧症の病態について明らかにする。
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| Outline of Final Research Achievements |
To investigate whether the hematopoietic CALR mutation contributes to pulmonary hypertension, we applied a bone marrow transplantation (BMT) with the donor cells from Calr with a 10-bp deletion knock-in mice or control wild-type (WT) mice. The recipient mice transplanted with bone marrow cells from Calr with a 10-bp deletion knock-in mice (Del-R mice) and WT mice (WT-R mice) were exposed to chronic hypoxia to induce pulmonary hypertension. After chronic hypoxia exposure, the right ventricular pressure in the Del-R mice was significantly increased compared to that in the WT-R mice. Hematopoietic Calr mutation accelerated pulmonary artery muscularization as well as elevation of endothelin-1 expression. Macrophage infiltration was observed under chronic hypoxia. Bone-marrow derived macrophages carrying Calr mutation showed increases in endothelin-1 expression. These results indicated a novel mechanism through endothelin-1 expression in pulmonary hypertension associated with CALR mutation.
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| Academic Significance and Societal Importance of the Research Achievements |
これまで明らかではなかった、CALR変異を有する骨髄増殖性疾患における肺高血圧症発症のメカニズムを、エンドセリン1に着目して解明した。
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