New mechanism of autophagy inhibition from the study of preeclampsia

• Project/Area Number: 19K09750
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: University of Toyama
• Principal Investigator: NAKASHIMA Akitoshi 富山大学, 学術研究部医学系, 教授 (00436792)
• Co-Investigator(Kenkyū-buntansha): 島 友子 富山大学, 学術研究部医学系, 助教 (00377285)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 妊娠高血圧症候群 / オートファジー / TFEB / Atg4B / 合胞体化 / autophagy / preeclampsia / ER stress / hypoxia / 妊娠高血圧腎症

Outline of Research at the Start

妊婦および胎児死亡に関わる妊娠高血圧症候群の病因として、胎盤オートファジー抑制が関与することを明らかにしてきた。一方で、現在その予防薬の開発が進んでいるが、発症患者の治療薬はない。そこで、妊婦に投与可能なオートファジー活性化剤の開発は、妊婦健康だけでなく、次世代の子供たちの健康につながる。高齢女性は妊娠高血圧症候群の発症率が高く、晩婚化の進む日本には重要な研究である。さらに妊娠高血圧症候群の母から出生した女児は、妊娠高血圧症候群の発症率が高くなる。長期的観点からも重要な開発である。

Outline of Final Research Achievements

The number of women with hypertensive disorders of pregnancy, HDP, will be increased in Japan, in which aging society proceeds rapidly. Therefore, we must tackle this problem to find out a treatment for this disease. This study has been clarified that placental autophagy deficiency is caused of TFEB inactivation and failure of ATG4B functions. In addition, the decrease of serum beta-galactosidase and the increase of aggregated protein were observed in women with HDP, suggesting that they are available for predicting placentas with autophagy failure. International collaborative study also showed that autophagy deficiency in trophoblasts enhanced the occurrence of pyroptosis triggered by endoplasmic reticulum stress. In other words, autophagy might be caused of pathogen-free inflammation in HDP. Taken together with these results, we are going to develop a medicine to activate placental autophagy by modulating TFEB or ATG4B pathway.

Academic Significance and Societal Importance of the Research Achievements

これまで妊娠高血圧症候群におけるオートファジー研究には体系的な検討がなされておらず、本研究によりその病態の原因の一つが明らかになったことは、今後の治療法へと繋がる可能性がある。
一方で、妊婦への薬剤投与は母体のみならず胎児への影響から開発が難しい領域であるが、胎盤を介して病態を紐解くことで将来的な妊娠中治療へと繋がると考える。更に超高齢化社会日本ではHDPによって未熟児出生率の増加も懸念されることから（成人後の糖尿病や高血圧の増加とも関連）、HDP治療法の開発により早産を減らすことができれば、ひいては新生児の健やかな発育の基本となるものであり、日本社会にポジティブに作用する研究である。

Research Products

• [Journal Article] オートファジー抑制と妊娠高血圧症候群発症の病態論 (2022)
  • Author(s): 中島彰俊, 古田惇, 川口美保子
  • Journal Title: 産科と婦人科 Volume: 89 Pages: 162-168
• [Journal Article] Pregnancy depends on a delicate balance of immune activation and regulation (2021)
  • Author(s): Saito Shigeru、Nakashima Akitoshi、Shima Tomoko、Tsuda Sayaka
  • Journal Title: Exploration of Immunology Volume: 1 Pages: 461-478
  • DOI: 10.37349/ei.2021.00031
  • Peer Reviewed
• [Journal Article] Etiological Value of Sterile Inflammation in Preeclampsia: Is It a Non-Infectious Pregnancy Complication? (2021)
  • Author(s): Banerjee Sayani、Huang Zheping、Wang Zhengke、Nakashima Akitoshi、Saito Shigeru、Sharma Surendra、Cheng Shibin
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 11 Pages: 694298-694298
  • DOI: 10.3389/fcimb.2021.694298
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel blood test for early biomarkers of preeclampsia and Alzheimer’s disease (2021)
  • Author(s): Cheng Shibin、Banerjee Sayani、Daiello Lori A.、Nakashima Akitoshi、Jash Sukanta、Huang Zheping、Drake Jonathan D.、Ernerudh Jan、Berg Goran、Padbury James、Saito Shigeru、Ott Brian R.、Sharma Surendra
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 15934-15934
  • DOI: 10.1038/s41598-021-95611-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Preeclampsia complicated with maternal renal dysfunction is associated with poor neurological development at 3 years old in children born before 34 weeks of gestation. (2021)
  • Author(s): Yoneda N, Yoneda S, Tsuda S, Ito M, Shiozaki A, Niimi H, Yoshida T, Saito S
  • Journal Title: Front. Pediatr. Volume: 1 Pages: 1-10
  • DOI: 10.3389/fped.2021.624323
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia. (2021)
  • Author(s): Nakashima A, Shima T, Tsuda S, Aoki A, Kawaguchi M, Furuta A, Yasuda I, Yoneda S, Yamaki-Ushijima A, Cheng SB, Sharma S, Saito S.
  • Journal Title: Int J Mol Sci. Volume: 22 Issue: 5 Pages: 2432-2432
  • DOI: 10.3390/ijms22052432
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular and immunological developments in placentas. (2021)
  • Author(s): Nakashima A, Shima T, Aoki A, Kawaguchi M, Yasuda I, Tsuda S, Yoneda S, Yamaki-Ushijima A, Cheng SB, Sharma S, Saito S.
  • Journal Title: Hum Immunol. Volume: S0198-8859 Issue: 5 Pages: 00033-1
  • DOI: 10.1016/j.humimm.2021.01.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The role of decidual regulatory T cells in the induction and maintenance of fetal antigen-specific tolerance: Imbalance between regulatory and cytotoxic T cells in pregnancy complications. (2021)
  • Author(s): Tsuda S, Nakashima A, Morita K, Shima T, Yoneda S, Kishi H, Saito S.
  • Journal Title: Hum Immunol. Volume: S0198-8859 Issue: 5 Pages: 00040-9
  • DOI: 10.1016/j.humimm.2021.01.019
  • Peer Reviewed
• [Journal Article] Oestrogen receptor α in T cells controls the T cell immune profile and glucose metabolism in mouse models of gestational diabetes mellitus (2021)
  • Author(s): Tanaka T, Wada T, Uno K, Ogihara S, Ie H, Okekawa A, Ishikawa A, Ito T, Miyazawa Y, Sameshima A, Onogi Y, Tsuneki H, Sasahara M, Nakashima A, Saito S, Sasaoka T.
  • Journal Title: Diabetologia Volume: in press Issue: 7 Pages: 1660-1673
  • DOI: 10.1007/s00125-021-05447-x
  • Peer Reviewed
• [Journal Article] オートファジーと妊娠高血圧症候群 (2021)
  • Author(s): 中島彰俊
  • Journal Title: 日本産科婦人科学会雑誌 Volume: 73 Pages: 1081-1088
• [Journal Article] ヒト胎盤形成と異常 (2021)
  • Author(s): 中島彰俊, 古田惇
  • Journal Title: HORM FRONT GYNECOL Volume: 28 Pages: 187-192
• [Journal Article] Bone morphogenetic protein‐2 enhances gonadotropin‐independent follicular development via sphingosine kinase 1 (2020)
  • Author(s): Ito Masami、Yoshino Osamu、Ono Yosuke、Yamaki‐Ushijima Akemi、Tanaka Tomoko、Shima Tomoko、Orisaka Makoto、Iwase Akira、Nakashima Akitoshi、Saito Shigeru
  • Journal Title: American Journal of Reproductive Immunology Volume: 85 Issue: 5
  • DOI: 10.1111/aji.13374
  • Peer Reviewed / Open Access
• [Journal Article] CD206+ M2-like Macrophages are Essential for Successful Implantation. (2020)
  • Author(s): Ono Y, Yoshino O, Ushijima A, Hiraoka T, Fukui Y, Nawaz A, Hirota Y, Wada S, Tobe K, Nakashima A, Osuga Y and Saito S.
  • Journal Title: Front Immunol. Volume: 11 Pages: 557184-557184
  • DOI: 10.3389/fimmu.2020.557184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Placental autophagy failure: A risk factor for preeclampsia. (2020)
  • Author(s): Nakashima A, Shima T, Aoki A, Kawaguchi M, Yasuda I, Tsuda S, Yoneda S, Yamaki-Ushijima A, Cheng SB, Sharma S, and Saito S.
  • Journal Title: J Obstet Gynaecol Res. Volume: 46 Issue: 12 Pages: 2497-2504
  • DOI: 10.1111/jog.14489
  • Peer Reviewed
• [Journal Article] Uterine CD11c+ cells induce the development of paternal antigen-specific Tregs via seminal plasma priming (2020)
  • Author(s): Shima Tomoko、Nakashima Akitoshi、Yasuda Ippei、Ushijima Akemi、Inada Kumiko、Tsuda Sayaka、Yoshino Osamu、Tomura Michio、Saito Shigeru
  • Journal Title: Journal of Reproductive Immunology Volume: - Pages: 103165-103165
  • DOI: 10.1016/j.jri.2020.103165
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic Changes in the Phenotype of Dendritic Cells in the Uterus and Uterine Draining Lymph Nodes After Coitus. (2020)
  • Author(s): Yasuda I, Shima T, Moriya T, Ikebuchi R, Kusumoto Y, Ushijima A, Nakashima A, Tomura M, Saito S.
  • Journal Title: Front Immunol. Volume: 11 Pages: 557720-557720
  • DOI: 10.3389/fimmu.2020.557720
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of TCR repertoire and PD-1 expression in decidual and peripheral CD8+ T cells reveals distinct immune mechanisms in miscarriage and preeclampsia. (2020)
  • Author(s): Morita K, Tsuda S, Kobayashi E, Hamana H, Tsuda K, Shima T, Nakashima A, Ushijima A, Kishi H, Saito S.
  • Journal Title: Front Immunol. Volume: 11 Pages: 1082-1082
  • DOI: 10.3389/fimmu.2020.01082
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of placental homeostasis leads to preeclampsia. (2020)
  • Author(s): Nakashima A, Shima T, Tsuda S, Aoki A, Kawaguchi M, Yoneda S, Yamaki-Ushijima A,Cheng SB, Sharma S, Saito S.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 9 Pages: 3298-3298
  • DOI: 10.3390/ijms21093298
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of autophagy in theca cells induces CYP17A1 and PAI-1 expression via ROS/p38 and JNK signalling during the development of polycystic ovary syndrome (2020)
  • Author(s): Kobayashi Mutsumi、Yoshino Osamu、Nakashima Akitoshi、Ito Masami、Nishio Kazuyuki、Ono Yosuke、Kusabiraki Tae、Kunitomi Chisato、Takahashi Nozomi、Harada Miyuki、Hattori Katsushige、Orisaka Makoto、Osuga Yutaka、Saito Shigeru
  • Journal Title: Molecular and Cellular Endocrinology Volume: 15 Pages: 110792-110792
  • DOI: 10.1016/j.mce.2020.110792
  • Peer Reviewed
• [Journal Article] Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia (2019)
  • Author(s): Nakashima Akitoshi、Cheng Shi-Bin、Ikawa Masahito、Yoshimori Tamotsu、Huber Warren J.、Menon Ramkumar、Huang Zheping、Fierce Jamie、Padbury James F.、Sadovsky Yoel、Saito Shigeru、Sharma Surendra
  • Journal Title: Autophagy Volume: 26 Issue: 10 Pages: 1-15
  • DOI: 10.1080/15548627.2019.1707494
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts (2019)
  • Author(s): Nakashima Akitoshi、Cheng Shi-Bin、Kusabiraki Tae、Motomura Kenichiro、Aoki Aiko、Ushijima Akemi、Ono Yosuke、Tsuda Sayaka、Shima Tomoko、Yoshino Osamu、Sago Haruhiko、Matsumoto Kenji、Sharma Surendra、Saito Shigeru
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 11466-11466
  • DOI: 10.1038/s41598-019-47607-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Autophagy is a new protective mechanism against the cytotoxicity of platinum nanoparticles in human trophoblasts (2019)
  • Author(s): Nakashima Akitoshi、Higashisaka Kazuma、Kusabiraki Tae、Aoki Aiko、Ushijima Akemi、Ono Yosuke、Tsuda Sayaka、Shima Tomoko、Yoshino Osamu、Nagano Kazuya、Yoshioka Yasuo、Tsutsumi Yasuo、Saito Shigeru
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5478-5478
  • DOI: 10.1038/s41598-019-41927-2
  • Peer Reviewed / Open Access
• [Journal Article] Current Understanding of Autophagy in Pregnancy (2019)
  • Author(s): Nakashima Akitoshi、Tsuda Sayaka、Kusabiraki Tae、Aoki Aiko、Ushijima Akemi、Shima Tomoko、Cheng Shi-Bin、Sharma Surendra、Saito Shigeru
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 9 Pages: 2342-2342
  • DOI: 10.3390/ijms20092342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pyroptosis is a critical inflammatory pathway in the placenta from early onset preeclampsia and in human trophoblasts exposed to hypoxia and endoplasmic reticulum stressors (2019)
  • Author(s): Cheng Shi-Bin、Nakashima Akitoshi、Huber Warren J.、Davis Sarah、Banerjee Sayani、Huang Zheping、Saito Shigeru、Sadovsky Yoel、Sharma Surendra
  • Journal Title: Cell Death & Disease Volume: 10 Issue: 12 Pages: 2342-2342
  • DOI: 10.1038/s41419-019-2162-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Symposium “Pathophysiology of PE (II)” The role of autophagy in pathophysiology of PE (2021)
  • Author(s): Nakashima A
  • Organizer: The 22nd World Congress of International Society for the Study of Hypertension in Pregnancy.
  • Int'l Joint Research / Invited
• [Presentation] Can beta-galactosidase predict the autophagy failure in HDP placentas? (2021)
  • Author(s): Nakashima A
  • Organizer: American society of reproductive immunology 2021 Virtual meeting
  • Int'l Joint Research
• [Presentation] 妊娠高血圧症候群における胎盤形成不全~最新トピックスからオートファジーの関与まで. (2021)
  • Author(s): 中島彰俊
  • Organizer: 第144回信州産婦人科連合会 学術講演会
  • Invited
• [Presentation] オートファジーと妊娠高血圧症候群 (Hypertensive disorders of pregnancy, HDP) (2021)
  • Author(s): 中島彰俊
  • Organizer: 第73回日本産科婦人科学会学術講演会
  • Invited
• [Presentation] 胎盤形成におけるオートファジーの役割ー妊娠高血圧症候群との関与ー. (2020)
  • Author(s): 中島彰俊
  • Organizer: 北陸産科婦人科学会
• [Presentation] 抗リン脂質抗体症候群合併により発症リスクが高まる妊娠高血圧腎症ー新規診断法および治療法開発に向けてー. (2020)
  • Author(s): 中島彰俊
  • Organizer: 福井県産婦人科医師連合第90回夏期臨床研修会プログラム
  • Invited
• [Presentation] 胎盤の恒常性維持をするオートファジーー妊娠高血圧腎症の解明へー． (2020)
  • Author(s): 中島彰俊
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Presentation] Disruption of collaboration between autophagy and lysosomes induces preeclampsia: comparative study between trophoblasts-specific Atg7 knockout-mediated poor placentation and human preeclamptic placentas (2019)
  • Author(s): Akitoshi Nakashima
  • Organizer: International society for immunology of reproduction
  • Int'l Joint Research / Invited
• [Presentation] Endoplasmic reticulum stress disrupts lysosomal homeostasis in human trophoblasts (2019)
  • Author(s): Akitoshi Nakashima
  • Organizer: American society of reproductive immunology
  • Int'l Joint Research
• [Presentation] 血清中リソソーム測定による胎盤オートファジー機能低下検出法の確立 (2019)
  • Author(s): 中島彰俊
  • Organizer: 日本妊娠高血圧学会
• [Presentation] リソソーム内酵素測定による胎盤オートファジー機能低下検出法の新規開発 (2019)
  • Author(s): 中島彰俊
  • Organizer: 日本胎盤学会