| Project/Area Number |
18K16330
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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 55020:Digestive surgery-related
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| Research Institution | Kitasato University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 肝類洞閉塞症候群 / トロンボキサン / 類洞内皮 / 肝類洞閉塞 / 肝臓 / 類洞 / 内皮細胞 / 内皮 / 脂質メディエーター |
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| Outline of Final Research Achievements |
Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP-/-) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP-/- mice. Viability of isolated LSECs was lower in cells from TP-/- mice, whereas mRNA levels of MMPs and adhesion molecules were higher; U46619, a TxA2 agonist, reduced these levels in WT mice. These data suggest that TP signaling prevents injury by suppressing LSEC damage.
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| Academic Significance and Societal Importance of the Research Achievements |
SOSの病態解明の基盤研究は大腸がん治療を安全に行うために必要である。これまでマウスではSOSモデルが確立されていなかったことから、申請者らのモデルは研究発展のために極めて有用なツールとなる。SOS発症には肝類洞内皮細胞のTP受容体シグナル発現が重要であることが示唆された。肝修復・肝再生の有効な治療方法の開発につながる可能性のほか、化学療法施行期間，肝切除までの休薬期間，肝予備能に応じた肝切除術式の選択などの判断基準を再考慮する契機となりうる。
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