A novel mechanism of bioactive lipids with neuroprotective effects: application for treatment of cerebrovascular disease

• Project/Area Number: 19K07098
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Teikyo University (2022); Ochanomizu University (2019-2021)
• Principal Investigator: GOTOH Mari 帝京大学, 医療技術学部, 准教授 (80467050)
• Co-Investigator(Kenkyū-buntansha): 宮本 泰則 お茶の水女子大学, ヒューマンライフイノベーション研究所, 教授 (50272737) ; 毛内 拡 お茶の水女子大学, 基幹研究院, 助教 (90708413)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 環状ホスファチジン酸 / 脳血管障害 / ミクログリア / アストロサイト / 神経細胞 / 代謝物 / テネイシンC / 生理活性脂質

Outline of Research at the Start

環状ホスファチジン酸(cyclic phosphatidic acid, cPA)は海馬において、神経突起伸長を促進し、虚血による遅発性神経細胞死を抑制する。また、cPAは外傷性脳損傷に対し、損傷の修復を促す作用がある。しかしcPAの合成酵素、受容体を含めたcPAの作用機序は未だ明らかとなっていない。本研究は、脳におけるcPAの作用機序の解明を行うとともに、脳血管障害の新たなメカニズムを提唱することを目的としている。

Outline of Final Research Achievements

Cerebrovascular disease causes sequelae such as cognitive impairment, and significantly reduces the patient's QOL. Cognitive dysfunction caused by ischemia is related to delayed neuronal cell death in the hippocampal CA1 region. To suppress neuronal cell death is essential for the treatment and prevention of vascular dementia.
Cyclic phosphatidic acid is abundant bioactive lipid in the brain and have been shown to play important roles in the nervous system. In this study, we analyzed the effects of cyclic phosphatidic acid derivatives, 2ccPA, on microglia and astrocytes. We found that cyclic phosphatidic acid suppressed microglial inflammation, and suppressed neuronal cell death by increasing astrocyte tenascin-C expression.

Academic Significance and Societal Importance of the Research Achievements

脳血管障害における環状ホスファチジン酸による神経細胞死抑制、炎症抑制の作用機序は解明されていなかった。本研究では、環状ホスファチジン酸の未知受容体同定、ミクログリア、アストロサイトへの作用解明、代謝物の同定を行った。神経細胞死や炎症を抑制する責任分子の同定することができ、脳血管障害の制御機構の理解につながった。

Research Products

• [Journal Article] Astrocytic Neuroimmunological Roles Interacting with Microglial Cells in Neurodegenerative Diseases (2023)
  • Author(s): Gotoh Mari、Miyamoto Yasunori、Ikeshima-Kataoka Hiroko
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 2 Pages: 1-17
  • DOI: 10.3390/ijms24021599
  • Peer Reviewed / Open Access
• [Journal Article] 2-carba-cyclic phosphatidic acid modulates astrocyte-to-microglia communication and influences microglial polarization towards an anti-inflammatory phenotype (2023)
  • Author(s): Takei Rino、Nakashima Mari、Gotoh Mari、Endo Misaki、Hashimoto Kei、Miyamoto Yasunori、Murakami-Murofushi Kimiko
  • Journal Title: Neuroscience Letters Volume: 797 Pages: 137063-137063
  • DOI: 10.1016/j.neulet.2023.137063
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with lysophosphatidic acid prevents microglial activation and depression-like behaviours in a murine model of neuropsychiatric systemic lupus erythematosus (2023)
  • Author(s): Nagata Wataru、Koizumi Akiho、Nakagawa Keiichi、Takahashi Sayaka、Gotoh Mari、Satoh Yasushi、Ishizuka Toshiaki
  • Journal Title: Clinical and Experimental Immunology Volume: 212 Issue: 2 Pages: 81-92
  • DOI: 10.1093/cei/uxad010
  • Peer Reviewed / Open Access
• [Journal Article] Optimization of Ultrafast Proteomics Using an LC-Quadrupole-Orbitrap Mass Spectrometer with Data-Independent Acquisition (2022)
  • Author(s): Ishikawa Masaki、Konno Ryo、Nakajima Daisuke、Gotoh Mari、Fukasawa Keiko、Sato Hironori、Nakamura Ren、Ohara Osamu、Kawashima Yusuke
  • Journal Title: Journal of Proteome Research Volume: 21 Issue: 9 Pages: 2085-2093
  • DOI: 10.1021/acs.jproteome.2c00121
  • Peer Reviewed / Open Access
• [Journal Article] The neuroprotective function of 2-carba-cyclic phosphatidic acid: Implications for tenascin-C via astrocytes in traumatic brain injury (2021)
  • Author(s): Nakashima Mari、Gotoh Mari、Hashimoto Kei、Endo Misaki、Murakami-Murofushi Kimiko、Ikeshima-Kataoka Hiroko、Miyamoto Yasunori
  • Journal Title: Journal of Neuroimmunology Volume: 361 Pages: 577749-577749
  • DOI: 10.1016/j.jneuroim.2021.577749
  • Peer Reviewed / Open Access
• [Journal Article] 2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition (2021)
  • Author(s): Fukasawa Keiko、Gotoh Mari、Uwamizu Akiharu、Hirokawa Takatsugu、Ishikawa Masaki、Shimizu Yoshibumi、Yamamoto Shinji、Iwasa Kensuke、Yoshikawa Keisuke、Aoki Junken、Murakami-Murofushi Kimiko
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 17360-17360
  • DOI: 10.1038/s41598-021-96931-2
  • Peer Reviewed / Open Access
• [Journal Article] Adenine nucleotide translocase 2, a putative target protein for 2-carba cyclic phosphatidic acid in microglial cells (2021)
  • Author(s): Tsukahara Tamotsu、Sahara Yasuka、Ribeiro Nigel、Tsukahara Ryoko、Gotoh Mari、Sakamoto Satoshi、Handa Hiroshi、Murakami-Murofushi Kimiko
  • Journal Title: Cellular Signalling Volume: 82 Pages: 109951-109951
  • DOI: 10.1016/j.cellsig.2021.109951
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The effects of coating culture dishes with collagen on fibroblast cell shape and swirling pattern formation (2020)
  • Author(s): Hashimoto Kei、Yamashita Kimiko、Enoyoshi Kanako、Dahan Xavier、Takeuchi Tatsu、Kori Hiroshi、Gotoh Mari
  • Journal Title: Journal of Biological Physics Volume: 46 Issue: 4 Pages: 351-369
  • DOI: 10.1007/s10867-020-09556-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the pharmacokinetics of 2-carba-cyclic phosphatidic acid by liquid chromatography-triple quadrupole mass spectrometry (2020)
  • Author(s): Shimizu Yoshibumi、Fukasawa Keiko、Yamamoto Shinji、Shibaike Yuki、Tsukahara Ryoko、Ishikawa Masaki、Iwasa Kensuke、Yoshikawa Keisuke、Gotoh Mari、Murakami-Murofushi Kimiko
  • Journal Title: Prostaglandins & Other Lipid Mediators Volume: 150 Pages: 106450-106450
  • DOI: 10.1016/j.prostaglandins.2020.106450
  • Peer Reviewed / Open Access
• [Journal Article] Oleic acid is a potent inducer for lipid droplet accumulation through its esterification to glycerol by diacylglycerol acyltransferase in primary cortical astrocytes (2019)
  • Author(s): Nakajima Shingo、Gotoh Mari、Fukasawa Keiko、Murakami-Murofushi Kimiko、Kunugi Hiroshi
  • Journal Title: Brain Research Volume: 1725 Pages: 146484-146484
  • DOI: 10.1016/j.brainres.2019.146484
  • Peer Reviewed / Open Access
• [Journal Article] 2-Carba cyclic phosphatidic acid inhibits lipopolysaccharide-induced prostaglandin E2 production in a human macrophage cell line (2019)
  • Author(s): Shibaike Yuki、Gotoh Mari、Ogawa Chinatsu、Nakajima Shingo、Yoshikawa Keisuke、Kobayashi Tetsuyuki、Murakami-Murofushi Kimiko
  • Journal Title: Biochemistry and Biophysics Reports Volume: 19 Pages: 100668-100668
  • DOI: 10.1016/j.bbrep.2019.100668
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Saturated fatty acid is a principal cause of anxiety-like behavior in diet-induced obese rats in relation to serum lysophosphatidyl choline level (2019)
  • Author(s): Nakajima Shingo、Fukasawa Keiko、Gotoh Mari、Murakami-Murofushi Kimiko、Kunugi Hiroshi
  • Journal Title: International Journal of Obesity Volume: 44 Issue: 3 Pages: 727-738
  • DOI: 10.1038/s41366-019-0468-z
  • Peer Reviewed / Open Access
• [Presentation] 老化促進モデルマウス SAMP8 における認知機能発生機構 (2022)
  • Author(s): 藤井愛、後藤真里、片桐沙紀、内海優里、宮本泰則、橋本恵
  • Organizer: 第32回神経行動薬理若手研究者の集い
• [Presentation] オートタキシンによるリゾホスファチジルコリンからのβ型リゾホスファチジン酸生合成経路の解明 (2022)
  • Author(s): 深澤桂子, 田中誠也, 三宅亮介, 石川将己, 後藤真里
  • Organizer: 第64回日本脂質生化学学会
• [Presentation] Biosynthesis of β-lysophosphatidic acid from cyclic phosphatidic acid by autotaxin, and bioactivity of a novel β-lysophosphatidic acid analogue, 2-carba-lysophosphatidic acid (2022)
  • Author(s): Keiko FUKASAWA, Mari GOTOH, Akiharu UWAMIZU, Takatsugu HIROKAWA, Masaki ISHIKAWA, Yoshibumi SHIMIZU, Shinji YAMAMOTO, Kensuke IWASA, Keisuke YOSHIKAWA, Junken AOKI, Kimiko MURAKAMI-MUROFUSHI
  • Organizer: The Lysophospholipid and Related Mediators Conference: From Bench to Clinic
  • Int'l Joint Research
• [Presentation] 2-carba-cyclic phosphatidic acid contributes to the neuroprotection via astrocytes in traumatic brain injury (2020)
  • Author(s): Mari NAKASHIMA, Kei HASHIMOTO, Ayana HAMANO, Hiroko IKESHIMA-KATAOKA, Mari GOTOH, Kimiko MURAKAMI-MUROFUSHI, Yasunori MIYAMOTO
  • Organizer: 第63回 日本神経化学会大会
• [Presentation] 穿刺脳損傷の修復における環状ホスファチジン酸誘導体2ccPAの効果/The effect of cyclic phosphatidic acid derivative 2-carba-cPA on repair of brain stab wound (2020)
  • Author(s): Misaki ENDO, Mari NAKASHIMA, Hiroko IKESHIMA-KATAOKA, Mari GOTOH, Kimiko MURAKAMI-MUROFUSHI, Yasunori MIYAMOTO
  • Organizer: 第63回 日本神経化学会大会
• [Presentation] 2-carba cyclic phosphatidic acid contributes to the neuroprotection in stab-wounded cerebral cortex via regulation of astrocytes (2019)
  • Author(s): Mari Nakashima, Kei Hashimoto, Ayana Hamano, Hiroko Ikeshima-Kataoka, Mari Gotoh, Kimiko Murakami-Murofushi, Yasunori Miyamoto
  • Organizer: ASCB
  • Int'l Joint Research
• [Presentation] 2-carba cyclic phosphatidic acid suppresses the activation of astrocytes in the stab-wounded mouse cerebral cortex (2019)
  • Author(s): 中島麻里, 橋本恵, 濱野文菜, 池島(片岡)宏子, 後藤真里, 室伏きみ子, 宮本泰則
  • Organizer: 第62回 日本神経化学会大会
• [Presentation] マウス大脳皮質穿刺損傷時のアストロサイトにおける2ccPA のテネイシンC 発現への効果 (2019)
  • Author(s): 中島麻里, 橋本恵, 濱野文菜, 池島(片岡)宏子, 後藤真里, 室伏きみ子, 宮本泰則
  • Organizer: 第6回Matricell フォーラム
• [Remarks] ヒューマンライフサイエンス研究所
  • URL: http://www-w.cf.ocha.ac.jp/ihli/news_20210902/
• [Patent(Industrial Property Rights)] カルバリゾホスファチジン酸 (2019)
  • Inventor(s): 室伏きみ子, 後藤真里, 深澤桂子, 青木淳賢
  • Industrial Property Rights Holder: 室伏きみ子, 後藤真里, 深澤桂子, 青木淳賢
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-211367
  • Filing Date: 2019