2022 Fiscal Year Final Research Report
Effects of ER stress-induced alterations in subcellular localization of ER chaperones on placentation
| Project/Area Number |
19K09784
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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 | Wakayama Medical University |
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Principal Investigator |
Ikezaki Midori 和歌山県立医科大学, 医学部, 助教 (40549747)
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| Co-Investigator(Kenkyū-buntansha) |
井原 義人 和歌山県立医科大学, 医学部, 教授 (70263241)
岩橋 尚幸 和歌山県立医科大学, 医学部, 助教 (50750907)
山本 円 和歌山県立医科大学, 医学部, 博士研究員 (70596973)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | 小胞体ストレス / 分子シャペロン / カルレティキュリン / 妊娠高血圧腎症 / 胎盤形成不全 / シンシチウム化 |
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| Outline of Final Research Achievements |
Preeclampsia (PE), a pregnancy-specific syndrome, is the major cause of maternal mortality worldwide. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of preeclampsia due to being a risk factor of poor placentation. The ER-resident chaperone calreticulin (CRT) is reportedly essential in placentation. Here, we investigated the effects of ER stress on CRT subcellular localization in placental cells. We found that CRT was upregulated in PE sera compared to those in sera of normal pregnancies. In our cell-based assays with the cytotrophoblast model BeWo cells, ER stress induced extracellular release of CRT and extracellular CRT inhibited syncytialization of BeWo cells by impairing the membrane localization of E-cadherin which is critical for syncytialization. Taken together, it was suggested that ER stress-induced extracellular release of CRT may contribute to placental dysfunction by interfering with the differentiation of cytotrophoblasts to syncytiotrophoblasts.
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| Free Research Field |
生化学
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| Academic Significance and Societal Importance of the Research Achievements |
PEは母児の予後に大きな影響を与える重篤な妊娠合併症であり、確実に治療するには妊娠を終了するしかない。本研究は胎盤形成不全を主病因とする妊娠合併症の新たな治療標的を示唆するものであり、PEの治療戦略の開発に寄与すると考えられる。また、本来小胞体で機能するCRTが細胞外に放出されること、細胞外に放出されたCRTが糖修飾を受けるE-カドヘリンの膜局在化に影響したことから、CRTの小胞体外における新しい機能の解明にも成功した。本研究成果によりタンパク質品質管理の異常と胎盤形成不全という異なる分野の相互理解が深まることが期待される。
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