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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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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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 / 糖タンパク質 |
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| Outline of Research at the Start |
本研究では、小胞体ストレスによりCRTが小胞体から減少した場合を想定し、①タンパク質の細胞内輸送に焦点を絞り、シンシチウム化も含めた末梢絨毛形成におけるCRTの役割の解明を目指す。また、②細胞表面に局在するCRTおよび③細胞外に分泌されたCRTがシンシチウム化に与える影響を明らかにすると共に、④臨床検体を用いた解析を行いCRTの病態への関与を検証する。
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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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| 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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Report
(5 results)
Research Products
(39 results)
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[Journal Article] Cytoplasmic p53 aggregates accumulated in p53-mutated cancer correlate with poor prognosis2022
Author(s)
Iwahashi N, Ikezaki M, Komohara Y, Fujiwara Y, Noguchi T, Nishioka K, Sakai K, Nishio K, Ueda M, Ihara Y, Uchimura K, Ino K, Nishitsuji K
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Journal Title
PNAS Nexus
Volume: 1(3)
Issue: 3
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Sulfated glycosaminoglycans mediate prion-like behavior of p53 aggregates2020
Author(s)
Naoyuki Iwahashi, Midori Ikezaki, Taro Nishikawa, Norihiro Namba, Takashi Ohgita, Hiroyuki Saito, Yoshito Ihara, Toshinori Shimanouchi, Kazuhiko Ino, Kenji Uchimura, Kazuchika Nishitsuji
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Journal Title
Proceedings of the National Academy of Sciences of the United States of America
Volume: 117
Issue: 52
Pages: 33225-33234
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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