| Project/Area Number |
19K17609
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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 |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 肺高血圧症 / JAK2V617F / 骨髄増殖性疾患 / クローン性造血 / JAK2 V617F / Pulmonary hypertension / 骨髄増殖性腫瘍 |
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| Outline of Research at the Start |
骨髄増殖性腫瘍(myeloproliferative neoplasm: MPN) の本態は、JAK2、calreticulin等の変異により、JAK-STAT 系が恒常的に活性化するために生じる骨髄系細胞の増殖である。MPNに合併した肺高血圧症は、ニース分類第5群に含まれ、その発症機序は明らかではない。一方で、血液学的に正常でも、MPNで認められる遺伝子変異が血液細胞に出現する「クローン性造血」の存在が健常な集団で高頻度に認められることが明らかとなった。本研究は、MPN のドライバー変異であるJAK2 V617F変異の肺高血圧症の発症および進展における役割を解明することを目的とする。
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| Outline of Final Research Achievements |
Pulmonary hypertension (PH) is one of major complications of hematological diseases such as myeloproliferative neoplasms (MPNs). An acquired mutation of JAK2V617F is causally related with MPNs including polycythemia vera, essential thrombocythemia and myelofibrosis. However, the role of JAK2V617F on PH remains unclear. We used the transgenic mice expressing JAK2V617F. JAK2V617F mice and WT mice were exposed continuous hypoxia (10% O2) for 2 weeks to induce PH. Controls were bred under normoxia. Although hypoxia significantly increased RVSP in both JAK2V617F mice and WT mice compared to the normoxic groups, RVSP in JAK2V617F mice was significantly higher than those in WT mice after hypoxia. Elastica-Masson staining demonstrated that the medial wall thickening of pulmonary arteries was significantly increased in hypoxia-exposed JAK2V617F mice compared to hypoxia-exposed WT mice. MPNs caused by JAK2V617F is associated with development of PH by remodeling of pulmonary arteries in mice.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、JAK2V617変異を有する肺高血圧症患者において、JAK/STAT経路の活性を制御できれば新たな肺高血圧症治療のターゲットになり得るものと期待される。
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