Crosstalk between mechanism of metabolic abnormalies in congenital disorders and cancer cell metabolism

• Project/Area Number: 18K19504
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: Aoki Yoko 東北大学, 医学系研究科, 教授 (80332500)
• Co-Investigator(Kenkyū-buntansha): 松原 洋一 国立研究開発法人国立成育医療研究センター, 所長室, 研究所長 (00209602) ; 新堀 哲也 東北大学, 医学系研究科, 准教授 (40436134) ; 井上 晋一 東北大学, 医学系研究科, 助教 (70622091)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 先天異常症 / 代謝 / がん原遺伝子 / Costello症候群

Outline of Final Research Achievements

Costello syndrome is involved in RASopathies. We have generated Costello syndrome model mice and found that the mutant mice are resistant to high-fat diet-induced obesity. Histology of liver showed microvesicular hepatic steatosis, suggesting abnormal beta-oxidation.
In this study, we comprehensively analyzed glycolysis, gluconeogenesis, lipid metabolism, nucleic acid, and amino acid metabolism in addition to the revealed mitochondrial β-oxidation pathway in the liver. In mutant mice, the blood glucose level decreased and the expression of β-oxidation-related genes decreased. In addition, glycolysis and cholesterol synthesis are enhanced with increased glucagon levels, which is a hormone that regulates blood glucose level. Gluconeogenesis is decreased despite high glucagon. Surprisingly, however, changes in the expression of these genes involved in energy metabolism were not observed at all after fasting.

Academic Significance and Societal Importance of the Research Achievements

本研究は、HRASの活性化変異を発現するマウス個体における代謝性変化をみることで、がん細胞の代謝のin vivoモデルになるのではないかという発想から生まれた。HRAS活性化変異を有するマウスの網羅的な代謝パスウェイの解析を行うことで、コステロ症候群の患者さんでの成長障害や低血糖などのメカニズム解明に役だつ可能性がある。さらに研究を進めることでがん細胞における代謝や、がんの進展における代謝的変化などを俯瞰することが可能と考えられる。

Research Products

• [Journal Article] Costello syndrome model mice with a HRAS G12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis. (2020)
  • Author(s): Katata Y, Inoue S-I, Asao A, Kobayashi S, Terui H, Inoue-Shibui A, Abe T, Niihori T, Aiba S, Ishii N, Kure S, Aoki Y
  • Journal Title: Cell Death & Disease Volume: 11 Issue: 8 Pages: 617-617
  • DOI: 10.1038/s41419-020-02845-8
  • Peer Reviewed / Open Access
• [Journal Article] Double‐chambered right ventricle complicated by hypertrophic obstructive cardiomyopathy diagnosed as Noonan syndrome (2020)
  • Author(s): Yamamoto Masahiro、Takashio Seiji、Nakashima Naoya、Hanatani Shinsuke、Arima Yuichiro、Sakamoto Kenji、Yamamoto Eiichiro、Kaikita Koichi、Aoki Yoko、Tsujita Kenichi
  • Journal Title: ESC Heart Failure Volume: 2 Issue: 2 Pages: 721-726
  • DOI: 10.1002/ehf2.12650
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis (2019)
  • Author(s): Takahara, S., Inoue, S., Miyagawa-Tomita, S., Matsuura, K., Nakashima, Y., Niihori, T., Matsubara, Y., Saiki, Y., Aoki, Y
  • Journal Title: EBioMedicine Volume: 42 Pages: 43-53
  • DOI: 10.1016/j.ebiom.2019.03.014
  • Peer Reviewed / Open Access
• [Journal Article] Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome (2019)
  • Author(s): Shoji Y, Ida S, Niihori T, Aoki Y, Okamoto N, Etani Y, Kawai M.
  • Journal Title: Endocrine Journal Volume: 66 Issue: 11 Pages: 983-994
  • DOI: 10.1507/endocrj.EJ18-0564
  • NAID: 130007751668
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Leucine-485 deletion variant of BRAF may exhibit the severe end of the clinical spectrum of CFC syndrome. (2019)
  • Author(s): Suzuki-Muromoto S, Miyabayashi T, Nagai K, Yamamura-Suzuki S, Anzai M, Takezawa Y, Sato R, Okubo Y, Endo W, Inui T, Togashi N, Kikuchi A, Niihori T, Aoki Y, Kure S, Haginoya K.
  • Journal Title: J Hum Genet. Volume: in press
  • Peer Reviewed
• [Presentation] RRAS2の活性化変異はヌーナン症候群を引き起こす (2020)
  • Author(s): 新堀哲也、永井康貴、大橋博文、岡本伸彦、岡田賢、木原裕貴、青木洋子
  • Organizer: 第123回日本小児科学会学術集会
• [Presentation] Costello症候群モデルマウスにおけるアレルゲンによる皮膚炎の誘発と病態メカニズムの解明 (2020)
  • Author(s): 堅田有宇, 堅田有宇, 井上晋一, 浅尾敦子, 小林周平, 小林周平, 照井仁, 井上彩, 阿部太紀, 新堀哲也, 相場節也, 石井直人, 呉繁夫, 青木洋子
  • Organizer: 日本人類遺伝学会第65回大会
• [Presentation] RASopathies : genetic syndromes associated with the Ras/MAPK pathway (2019)
  • Author(s): Yoko Aoki, Shin-Ichi Inoue, Taiki Abe, Yu Katata, Aya Shibui-Inoue, Koki Nagai and Tetsuya Niihori
  • Organizer: Tohoku Forum for Creativity Thematic program 2019 International symposium1 Cancer Etiology
  • Int'l Joint Research / Invited
• [Presentation] Metabolic Effects in Mouse Model of Costello Syndrome (2019)
  • Author(s): Shin-ichi Inoue, Daiju Oba, Sachiko Miyagawa-Tomita, Yasumi Nakashima, Tetsuya Niihori, Seiji Yamaguchi, Yoichi Matsubara, Yoko Aoki
  • Organizer: 6th International RASopathies Symposium:Precision Medicine ; From Promise to Practice
  • Int'l Joint Research
• [Presentation] Noonan syndrome model mice with RIT1 A57G mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis (2019)
  • Author(s): Shingo Takahara, Shin-ichi Inoue, Sachiko Miyagawa-Tomita, Katsuhisa Matsuura, Yasumi Nakashima, Tetsuya Niihori, Yoichi Matsubara, Yoshikatsu Saiki and Yoko Aoki
  • Organizer: 6th International RASopathies Symposium:Precision Medicine ; From Promise to Practice
  • Int'l Joint Research
• [Presentation] 新規コステロ症候群モデルマウスを用いたエネルギー代謝変化の病態解明 (2019)
  • Author(s): 大場大樹、中嶌八隅、新堀哲也、山口清次、松原洋一、青木洋子
  • Organizer: 第122回日本小児科学会学術集会
• [Presentation] RIT1 A57G knock-in mice recapitulate features of Noonan syndrome. (2019)
  • Author(s): Inoue SI , Takahara S, Miyagawa-Tomita S, Matsuura K, Nakashima Y, Niihori T, Matsubara Y, Saiki Y, Aoki Y.
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] The basis of nutritional and metabolic problems in RASopathies:Lessons form mouse models (2018)
  • Author(s): Shin-Ichi Inoue and Yoko Aoki
  • Organizer: 7th International Meeting on Rare Disorders of the RAS-MAPK Pathway A workshop precedomg the ESHG conmferemce Milan 2018
  • Int'l Joint Research / Invited
• [Presentation] Pathogenesis and treatment of esophageal dilation and gastric epithelial hyperplasia in a mouse model for cardio-facio-cutaneous syndrome (2018)
  • Author(s): Shin-ichi Inoue, Shingo Takahara, Takeo Yoshikawa, Kazuhiko Yanai, Yoichi Matsubara and Yoko Aoki
  • Organizer: ESHG/EMPAG 2018
  • Int'l Joint Research
• [Presentation] RASopathies：広がりゆく疾患概念とモデルマウス研究 (2018)
  • Author(s): 青木洋子
  • Organizer: 第６３回日本人類遺伝学会学術集会
• [Remarks] 東北大学大学院医学系研究科遺伝医療学分野
  • URL: http://www.medgen.med.tohoku.ac.jp/
• [Remarks] 東北大学大学院医学系研究科遺伝医療学分野研究室
  • URL: http://www.medgen.med.tohoku.ac.jp/
• [Remarks] 東北大学 大学院医学系研究科 遺伝医療学分野
  • URL: http://www.medgen.med.tohoku.ac.jp/