The Role of Epithelial Pten in Epithelial Cell Fate and Programmed Cellular Senescence during Lung Development

• Project/Area Number: 17K16051
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Miyazaki
• Principal Investigator: Miura ayako 宮崎大学, 医学部, 助教 (70710903)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肺発生 / Pten / 老化 / 肺上皮 / Notchシグナル / 発生 / 発生・分化

Outline of Final Research Achievements

Proper cell fate determination and programmed cellular senescence are important for normal mammalian embryonic development.Functional analysis of Pten in the differentiation of epithelial stem cells and progenitor cells during lung development has not been investigated in detail.Based on the results of previous studies and the results of preliminary experiments, this study comprehensively analyzed the function of lung epithelial Pten using lung epithelial-specific Pten-deficient mice.We found that epithelial Pten expression has a decisive role in lung development by two mechanisms: regulation of cell fate determination and regulation of "programmed cellular senescence" by regulating mitotic spindle formation.Analyzing cell fate control and morphogenetic molecular mechanisms during development contributes to the elucidation of organ formation programs in embryology in general.

Academic Significance and Societal Importance of the Research Achievements

正常肺発生における上皮Ptenの役割を、「上皮細胞運命制御」と「プログラムされた細胞老化」という本質的な視点から網羅的に解析し、普遍的な臓器形成の分子機構解明に資することを目的とした。本研究では、肺上皮特異的Pten欠損マウスを用い、上皮Ptenが与える肺構成細胞の細胞運命制御と、肺形態形成に重要な「プログラムされた細胞老化」への影響を解析した。本研究の推進は、肺上皮細胞での分化方向決定と細胞老化のメカニズムを解析するだけでなく、COPDやIPFをはじめとする多様な呼吸器リモデリング疾患の病態解明と治療薬開発に繋がる臨床応用への研究展開も期待できる。

Research Products

• [Journal Article] Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome (2021)
  • Author(s): Matsuo Ayako、Tanida Ryota、Yanagi Shigehisa、Tsubouchi Hironobu、Miura Ayako、Shigekusa Takafumi、Matsumoto Nobuhiro、Nakazato Masamitsu
  • Journal Title: European Journal of Pharmacology Volume: 892 Pages: 173754-173754
  • DOI: 10.1016/j.ejphar.2020.173754
  • Peer Reviewed / Open Access
• [Journal Article] Conformational Change in the Ligand-Binding Pocket via a KISS1R Mutation (P147L) Leads to Isolated Gonadotropin-Releasing Hormone Deficiency (2017)
  • Author(s): Shimizu Koichiro、Yonekawa Tadato、Yoshida Morikatsu、Miyazato Mikiya、Miura Ayako、Sakoda Hideyuki、Yamaguchi Hideki、Nakazato Masamitsu
  • Journal Title: Journal of the Endocrine Society Volume: 1 Issue: 10 Pages: 1259-1271
  • DOI: 10.1210/js.2017-00277
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice. (2017)
  • Author(s): Ishii N, Tsubouchi H, Miura A, Yanagi S, Ueno H, Shiomi K, Nakazato M.
  • Journal Title: Eur J Pharmacol. Volume: 819 Pages: 35-42
  • DOI: 10.1016/j.ejphar.2017.11.024
  • Peer Reviewed / Open Access
• [Journal Article] Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic β cells. (2017)
  • Author(s): Zhang W, Sakoda H, Miura A, Shimizu K, Mori K, Miyazato M, Takayama K, Hayashi Y, Nakazato M.: Neuromedin U
  • Journal Title: Biochem Biophys Res Commun, Volume: 493 Issue: 1 Pages: 677-683
  • DOI: 10.1016/j.bbrc.2017.08.132
  • Peer Reviewed / Open Access
• [Journal Article] Ghrelin does not influence cancer progression in a lung adenocarcinoma cell line (2017)
  • Author(s): Tsubouchi H, Onomura H, Saito Y, Yanagi S, Miura A, Matsuo A, Matsumoto N, Nakazato M.
  • Journal Title: Endocrine Journal Volume: 64 Issue: Suppl. Pages: S41-S46
  • DOI: 10.1507/endocrj.64.S41
  • NAID: 130007307940
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections (2017)
  • Author(s): Shigehisa Yanagi, Hironobu Tsubouchi, Ayako Miura, Ayako Matsuo, Nobuhiro Matsumoto and Masamitsu Nakazato
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 3 Pages: 503-503
  • DOI: 10.3390/ijms18030503
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of epithelial Pten in programmed cellular senescence during lung development (2018)
  • Author(s): Ayako Miura, Shigehisa Yanagi, Hironobu Tsubouchi, Ayako Matsuo, Nobuhiro Matsumoto, Masamitsu Nakazato
  • Organizer: European Respiratory Society International Congress 2018
  • Int'l Joint Research
• [Presentation] グレリンの癌進行への影響と抗悪液質作用の検討 (2018)
  • Author(s): 三浦綾子、坪内拡伸、柳重久、中里雅光
  • Organizer: 第91回日本内分泌学会学術総会
• [Presentation] 肥満状態に合併した喘息にグレリンが果たす役割 (2018)
  • Author(s): 三浦綾子、坪内拡伸、柳重久、中里雅光
  • Organizer: 平成3０年 日本糖尿病・肥満動物学会
• [Presentation] 肺発生時の上皮細胞分化と肺形態形成におけるPTENの役割 (2017)
  • Author(s): 三浦綾子、坪内拡伸、柳重久、中里雅光
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] 肥満状態に合併した喘息にグレリンが果たす役割 (2017)
  • Author(s): 三浦綾子、坪内拡伸、柳重久、中里雅光
  • Organizer: 平成３０年 日本糖尿病・肥満動物学会
• [Presentation] グレリンの癌進行への影響と抗悪液質作用の検討 (2017)
  • Author(s): 三浦綾子、坪内拡伸、柳重久、中里雅光
  • Organizer: 第91回日本内分泌学会学術総会