中枢性低酸素換気応答機構の全容解明

• Project Area: Oxygen biology: a new criterion for integrated understanding of life
• Project/Area Number: 17H05540
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Hospital Organization Murayama Medical Center
• Principal Investigator: 岡田 泰昌 独立行政法人国立病院機構村山医療センター(臨床研究部), 電気生理学研究室, 室長 (80160688)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000); Fiscal Year 2018: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 低酸素換気応答 / 呼吸調節 / グリア細胞 / アストロサイト / 脳幹 / 延髄 / 低酸素 / 換気応答 / 生理学 / 薬理学 / 神経科学 / 解剖学 / トランスレーショナルリサーチ

Outline of Annual Research Achievements

体内酸素レベルの恒常性を維持することは、ヒトを含めた哺乳類の生命維持に不可欠である。この体内の酸素レベルの恒常性維持には、呼吸による調節、特に生体が低酸素状態になった時の呼吸増強応答（低酸素換気応答）が、最も重要な役割を果たしている。ここで、低酸素換気応答の機序について、従来は、末梢化学受容体が体内で唯一の低酸素受容体であると考えられていた。しかし、研究代表者は、脳内低酸素受容体の存在を想定し、以下の仮説を提唱した。(1)末梢化学受容体とは別に、脳内（視床下部や延髄）にも低酸素に応答して換気増強応答を惹起する低酸素受容体が存在している。(2)その低酸素センサー細胞は、ニューロンand/or アストロサイトである。(3)低酸素センサー細胞における低酸素感受は、TRPA1をはじめとするTRPチャネルの開口や、カリウムチャネルの閉鎖による。本研究では、この仮説を検証し、中枢性低酸素換気応答機構の全容を解明することを目的とし、以下の実験を実施した。(1) in vitro摘出脳幹脊髄標本を用いた解析：末梢化学受容体を有さない 摘出脳幹脊髄標本を用い、灌流液の酸素レベルを下げた際の呼吸出力応答を記録することにより、低酸素呼吸応答を解析した。そのうえで延髄断面における低酸素に対する細胞応答をカルシウムイメージングにより解析した。それにより低酸素呼吸応答は、ニューロンおよびアストロサイトによることを明らかにした。次いで、TRPチャネル、特にTRPA1に注目し、その阻害剤による低酸素呼吸応答の抑制を認め、低酸素センサーチャネルとしてTRPA1が重要であることを示した。(2) in vivo覚醒マウスを用いた解析:アストロサイトの活性化阻害剤であるarundic acidを成熟マウスに投与し、低酸素換気応答の抑制効果を検証して、低酸素換気応答におけるアストロサイトの関与を証明した。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] The Florey Institute(オーストラリア)
• [Int'l Joint Research] カルガリー大学(カナダ)
• [Int'l Joint Research] The Florey Institute(オーストラリア)
• [Int'l Joint Research] カルガリー大学(カナダ)
• [Journal Article] Mechanism of dyspnea sensation: A comprehensive review for better practice of pulmonary rehabilitation. (2019)
  • Author(s): Fukushi Isato, Okada Yasumasa
  • Journal Title: Journal of Rehabilitation Neurosciences Volume: in press
  • NAID: 130007733992
  • Peer Reviewed / Open Access
• [Journal Article] Possible involvement of monoamine neurons in the emotional abnormality in Kir6.2-deficient mice (2018)
  • Author(s): Saito Atsumi、Miyagawa Kazuya、Miyagishi Hiroko、Kurokawa Kazuhiro、Umeda Akira、Okada Yasumasa、Tsuji Minoru、Takeda Hiroshi
  • Journal Title: Physiology & Behavior Volume: 188 Pages: 251-261
  • DOI: 10.1016/j.physbeh.2018.02.014
  • Peer Reviewed
• [Journal Article] Structural and functional identification of two distinct inspiratory neuronal populations at the level of the phrenic nucleus in the rat cervical spinal cord (2018)
  • Author(s): Shinozaki Yoshio、Yokota Shigefumi、Miwakeichi Fumikazu、Pokorski Mieczyslaw、Aoyama Ryoma、Fukuda Kentaro、Yoshida Hideaki、Toyama Yoshiaki、Nakamura Masaya、Okada Yasumasa
  • Journal Title: Brain Structure and Function Volume: 224 Issue: 1 Pages: 57-72
  • DOI: 10.1007/s00429-018-1757-3
  • Peer Reviewed / Open Access
• [Journal Article] The role of the hypothalamus in modulation of respiration (2018)
  • Author(s): Fukushi Isato、Yokota Shigefumi、Okada Yasumasa
  • Journal Title: Respiratory Physiology & Neurobiology Volume: in press Pages: 172-179
  • DOI: 10.1016/j.resp.2018.07.003
  • Peer Reviewed
• [Journal Article] ATP 感受性カリウムチャネル Kir6.2 のストレス応答における役割. (2018)
  • Author(s): 齋藤淳美、宮川和也、宮岸寛子、黒川和宏、梅田 啓、岡田泰昌、辻 稔、武田弘志.
  • Journal Title: 国際医療福祉大学学会誌 Volume: 23 Pages: 44-51
  • NAID: 120006461255
• [Journal Article] 呼吸調節研究における最新のトピックス (2018)
  • Author(s): 岡田泰昌.
  • Journal Title: 日本呼吸器学会誌 Volume: 7 Pages: 363-363
• [Journal Article] 低酸素換気応答におけるアストロサイトの役割. (2017)
  • Author(s): 福士勇人, 堀内城司, 岡田泰昌
  • Journal Title: 自律神経 Volume: 54 Pages: 109-117
  • Peer Reviewed
• [Journal Article] 呼吸の制御機構. (2017)
  • Author(s): 岡田泰昌, 横田茂文, 福士勇人.
  • Journal Title: Clinical Neuroscience Volume: 35 Pages: 685-688
• [Presentation] Astrocytes mediate persistent respiratory augmentation in the recovery phase after hypoxic exposure. (2019)
  • Author(s): Fukushi I, Kono Y, Takeda K, Okazaki S, Yokota S, Yazawa I, Onimaru H, Okada Y
  • Organizer: The 9th Federation of Asian and Oceanian Physiological Societies Congress (FAOPS2019) in conjunction with the 96th Annual Meeting of the Physiological Society of Japan
  • Int'l Joint Research
• [Presentation] Function of inhibitory neurons in the solitarynucleus in the control of respiration. (2019)
  • Author(s): Hama N, Yokota S, Fujitani M, Okada Y, Koshiya N, Koizumi H
  • Organizer: The 9th Federation of Asian and Oceanian Physiological Societies Congress (FAOPS2019) in conjunction with the 96th Annual Meeting of the Physiological Society of Japan
  • Int'l Joint Research
• [Presentation] Hypoxic responses of the respiratory system. In symposium “Adaptation mechanisms to external or internal environmental changes of respiratory system” (2019)
  • Author(s): Okada Y, Yazawa I, Takeda K, Okazaki S, Uchiyama M, Kurita Y, Fukushi I, Yokota S, Mori Y, Onimaru H
  • Organizer: The 9th Federation of Asian and Oceanian Physiological Societies Congress (FAOPS2019) in conjunction with the 96th Annual Meeting of the Physiological Society of Japan
  • Int'l Joint Research
• [Presentation] The roles of KATP channels including Kir6.2 in regulation of emotional behaviors and stress responses. (2018)
  • Author(s): Saito A, Miyagawa K, Miyagishi H, Kurokawa K, Umeda A, Okada Y, Tsuji M, Takeda H
  • Organizer: WCP2018 KYOTO / 18th WORLD CONGRESS OF BASIC AND CLINICAL PHARMACOLOGY
  • Int'l Joint Research
• [Presentation] Functional and anatomical connectivity from the dorsomedial hypothalamus to the ventral medullary cardiovascular regions: possible neural substrate mediatingstress-induced sympathoexcitation. (2018)
  • Author(s): Kono Y, Arima Y, Yokota S, Onimaru H, Fukushi I, Koizumi K, Hasebe Y, Yoshizawa M, Kise H, Hoshiai M, Sugita K, Toda T, Okada Y
  • Organizer: European Society of Cardiology Congress 2018
  • Int'l Joint Research
• [Presentation] Activation of astrocytes is requred for the persistence of poststress blood pressure elevation (2018)
  • Author(s): Hasebe Y, Yokota S, Takeda K, Sugama S, Kono Y, Koizumi K, Fukushi I, Hoshiai M, Kakinuma Y, Pokorski M, Horiuchi J, Sugita K, Okada Y
  • Organizer: European Society of Cardiology Congress 2018
  • Int'l Joint Research
• [Presentation] Cardiorespiratory regulation by glutamatergic neurons in the caudal solitary nucleus. (2018)
  • Author(s): Yokota S, Takeda K, Lazarus M, Arima Y, Fujitani M, Okada Y
  • Organizer: Society for Neuoscience Meeting (Neuoscience2018)
  • Int'l Joint Research
• [Presentation] Significance of medulla-spinal cord preparation of the newborn rat. (2018)
  • Author(s): Fukushi I, Uchiyama M, Kurita Y, Yazawa I, Okazaki S, Hasebe Y, Kono Y, Yokota S, Takeda K, Mori Y, Onimaru H, Okada Y
  • Organizer: Society for Neuoscience Meeting (Neuoscience2018)
  • Int'l Joint Research
• [Presentation] Neural pathway supposedly mediating the descending autonomic information from the dorsomedial hypothalamus to the ventral medullary cardiorespiratory regions. (2018)
  • Author(s): Okada Y, Kono Y, Arima Y, Yokota S, Onimaru H, Fukushi I, Koizumi K, Hasebe Y, Yoshizawa M, Kise H, Toda T
  • Organizer: Neuoscience Meeting (Neuoscience2018)
  • Int'l Joint Research
• [Presentation] Astrocytic activation is necessary for hypoxic respiratory facilitation (2018)
  • Author(s): Fukushi I, Uchiyama M, Kurita Y, Yazawa I, Okazaki S, Kono Y, Takeda K, Onimaru H, Mori Y, Okada Y
  • Organizer: The 23rd Congress of the Asian Pacific Society of Respirology (APSR 2018)
  • Int'l Joint Research
• [Presentation] Does chronic intermittent hypoxia always increase blood glucose levels in mice? (2018)
  • Author(s): Umeda A, Okada Y, Tsushima K, Takeda K, Saito A, Miyagawa K, Takeda H, Kubota N, Kadowaki T, Gozal D
  • Organizer: The 23rd Congress of the Asian Pacific Society of Respirology (APSR 2018)
  • Int'l Joint Research
• [Presentation] 呼吸調節研究における最新のトピックス (2018)
  • Author(s): 岡田泰昌
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] Discovery of Respiration-synchronized Rhythmic Activity in the Hypothalamus: Implication for Hypothalamic Involvement in Respiratory Rhythm Generation. (2018)
  • Author(s): Fukushi I, Kono Y, Yokota S, Okazaki S, Takeda K, Onimaru H, Okada Y
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] The responses of the cardiovascular ventral medullary regions evoked by electrical stimulation of the hypothalamus (2018)
  • Author(s): 河野洋介、岡田泰昌、有馬陽介、福士勇人、小泉敬一、長谷部洋平、吉沢雅史、喜瀬広亮、星合美奈子、杉田完爾、戸田孝子
  • Organizer: 第54回日本小児循環器学会総会・学術集会
• [Presentation] Sustainment of post-stress blood pressure elevation requires activation of astrocytes: implication in the pathophysiological mechanism of hypertension. (2018)
  • Author(s): 長谷部洋平、岡田泰昌、横田茂文、小泉敬一、福士勇人、吉沢雅史、河野洋介、喜瀬広亮、星合美奈子、杉田完爾.、戸田孝子
  • Organizer: 第54回日本小児循環器学会総会・学術集会
• [Presentation] Diencephalon plays an active role in respiratory drive (2018)
  • Author(s): Fukushi I, Kono Y, Yokota S, Arima Y, Takeda K, Okazaki S, Yazawa I, Onimaru H, Okada Y
  • Organizer: The 5th Japanese Society of Respiratory Physical Therapy
• [Presentation] A computational approach for understanding the role of astrocytes in neuronal firing pattern modulation in the preBötzinger Complex during hypoxia. (2018)
  • Author(s): Vivar C, Yazawa I, Fukushi I, Okazaki S, Okada Y
  • Organizer: 第41回 日本神経科学大会
• [Presentation] The role of the diencephalon in the central control of respiration investigated with the isolated diencephalon-lower brainstem-spinal cord preparation (2018)
  • Author(s): Fukushi I, Kono Y, Yokota S, Takeda K, Okazaki S, Yazawa I, Onimaru H, Okada Y
  • Organizer: 第41回 日本神経科学大会
• [Presentation] Anatomical connectivity from the dorsomedial hypothalamus to the ventral medullary cardiovascular regions: neural pathway mediating the descending sympathetic information (2018)
  • Author(s): Kono Y, Arima Y, Yokota S, Onimaru H, Fukushi I, Koizumi K, Hasebe Y, Yoshizawa M, Kise H, Hoshiai M, Sugita K, Toda T, Okada Y
  • Organizer: 第41回 日本神経科学大会
• [Presentation] Role of glutamatergic neurons in the caudal solitary nucleus in cardiorespiratory regulation (2018)
  • Author(s): Yokota S, Arima Y, Takeda K, Okada Y
  • Organizer: 第41回 日本神経科学大会
• [Presentation] Modification of respiratory rhythm by optogenetical stimulation of inhibitory neurons in the nucleus of the solitary tract (2018)
  • Author(s): Hama N,Yokota S, Fujitani M, Okada Y, KoshiyaN, Koizumi H
  • Organizer: 第41回 日本神経科学大会
• [Presentation] Neural pathway supposedly mediating the descending autonomic information from the dorsomedial hypothalamus to the ventral medullary cardiorespiratory regions. (2018)
  • Author(s): Okada Y, Kono Y, Arima Y, Yokota S, Onimaru H, Fukushi I, Koizumi K, Hasebe Y, Yoshizawa M, Kise H, Toda T
  • Organizer: Society for Neuoscience Meeting (Neuoscience2018)
  • Int'l Joint Research
• [Presentation] Astrocytic activation is necessary for hypoxic respiratory facilitation. (2018)
  • Author(s): Fukushi I, Uchiyama M, Kurita Y, Yazawa I, Okazaki S, Kono Y, Takeda K, Onimaru H, Mori Y, Okada Y
  • Organizer: The 23rd Congress of the Asian Pacific Society of Respirology (APSR 2018)
  • Int'l Joint Research
• [Presentation] The role of the diencephalon in the central control of respiration investigated with the isolated diencephalon-lower brainstem-spinal cord preparation. (2018)
  • Author(s): Fukushi I, Kono Y, Yokota S, Takeda K, Okazaki S, Yazawa I, Onimaru H, Okada Y
  • Organizer: 第41回 日本神経科学大会
• [Presentation] Anatomical connectivity from the dorsomedial hypothalamus to the ventral medullary cardiovascular regions: neural pathway mediating the descending sympathetic information. (2018)
  • Author(s): Kono Y, Arima Y, Yokota S, Onimaru H, Fukushi I, Koizumi K, Hasebe Y, Yoshizawa M, Kise H, Hoshiai M, Sugita K, Toda T, Okada Y
  • Organizer: 第41回 日本神経科学大会