| Project/Area Number |
18K09239
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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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| Review Section |
Basic Section 56040:Obstetrics and gynecology-related
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| Research Institution | Nippon Medical School |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
片山 映 日本医科大学, 医学部, 助教 (10333113)
竹下 俊行 日本医科大学, 大学院医学研究科, 大学院教授 (60188175)
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
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| Keywords | 頸管熟化 / 早産予防 / 無菌性炎症応答 / プロゲステロン消退 / プロゲステロン / 頸管リモデリング |
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| Outline of Final Research Achievements |
A culture system for human uterine cervical fibroblasts (UCFs) was established using a small amount of cervical tissue collected on cesarean section. RNA sequencing analysis identified novel molecules induced by the addition of progesterone (P4). In UCFs derived from patients with refracting cervical incompetence who experienced recurrent late miscarriages, the expression of P4 receptors was significantly reduced, and an increased sterile inflammatory response was observed. In addition, Specific molecules showing expressive change in response to P4 withdrawal were identified using the P4 receptor antagonist. Next, a P4 receptor antagonist was administered to pregnant mice, and an eosinophilic inflammatory response mediated by the CCL11-CCR3 axis was identified in cervical tissue. Furthermore, the establishment of Single-cell RNA sequencing of cervical tissue visualized molecular expression dynamics during cervical ripening in response to P4 withdrawal.
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| Academic Significance and Societal Importance of the Research Achievements |
早産は周産期死亡の主要な原因であり、新生児期の集中治療管理を乗り越えても神経発達予後に関わる長期的な問題をもたらす。その克服は周産期医療における中心命題であり、自然早産の多くに先行する子宮頸管熟化の制御は、早産予防戦略の鍵と考えられてきた。本研究成果により、難治性頸管無力症にみられる早期頸管熟化が、プロゲステロン（P4）受容体の発現低下によって誘導されている可能性が強く示唆された。マウス早産モデルとヒト線維芽細胞培養系を用いた網羅的解析により、P4消退で無菌的に誘導される頸管熟化機構における主要な分子シグナルを絞り込み、新たな早産マーカーや治療開発へ展開する基盤を確立した。
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