| Project/Area Number |
16K10619
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Cardiovascular surgery
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| Research Institution | Hirosaki University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
古川 賢一 弘前大学, 医学研究科, 客員研究員 (20165468)
瀬谷 和彦 弘前大学, 医学研究科, 助教 (40281919)
福田 幾夫 弘前大学, 医学研究科, 教授 (50344594)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 大動脈弁狭窄 / 石灰化大動脈弁 / 分子標的薬 / 大動脈弁狭窄症 / 大動脈弁石灰化 / 薬物送達 / マトリックスGlaタンパク質 / 大動脈弁間質細胞 / BMP2 / ビタミンK依存性蛋白 / CD34細胞 / 臨床 |
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| Outline of Final Research Achievements |
Human aortic valves were obtained from patients with calcific aortic valve stenosis (CAS group) and patients with aortic dissection or aortic regurgitation (Non-CAS group) who underwent aortic valve replacement. All patients gave written informed consent, and the study was approved by the Institutional Review Board of the Hirosaki University Hospital. Human aortic valve interstitial cells (HAVICs) were isolated by collagenase digestion. The cells were cultured in α-MEM containing 10 % FBS, and fourth passages of cells was used in all experiments. We invested and confirmed the role of Matrix Gla protein (MGP) in TNF-α induced calcification of HAVICs. Our results showed that TNF-α substantially downregulated MGP gene expression in HAVICs. At a inorganic phosphate (Pi) concentration of 3.2 mM, warfarin accelerated the calcification of HAVICs of CAS group. We also found critical roles for pregnane X receptor (PXR) and bone morphogenetic protein 2 (BMP2) in aortic valve calcification.
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| Academic Significance and Societal Importance of the Research Achievements |
大動脈弁狭窄症における大動脈弁石灰化はBMP2-Smad4-Runx2-Dlx5の経路が関与していることを示した。同様にワルファリンやメナキノン4（ビタミンV2)はPXR-BMP2-ALPは石灰化を誘発することを示すことができ、分子生物学的機序の解明の一助になったと思われる。これらの機序から分子標的薬を創薬することで大動脈弁石灰化を抑制することが可能となれば、大動脈弁狭窄症に対する薬物治療を確立することができ、患者は侵襲の高い手術を受けることなく治療を受けることが可能となる。
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