Mechanisms underlying glia-mediated ischemic tolerance

• Project/Area Number: 15K15524
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: University of Yamanashi
• Principal Investigator: KOIZUMI Schuichi 山梨大学, 総合研究部, 教授 (10280752)
• Co-Investigator(Renkei-kenkyūsha): HIRAYAMA Yuri 山梨大学, 総合研究部, 助教 (30732804) ; KINOUCHI Hiroyuki 山梨大学, 総合研究部, 教授 (30241623)
• Research Collaborator: SHINOZAKI Youichi ; SHIGETOMI Eiji
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: アストロサイト / 脳卒中 / 虚血耐性 / P2X7受容体 / HIF1a / グリア細胞

Outline of Final Research Achievements

A mild ischemic episode (preconditioning; PC) induces resistance to a subsequent severe ischemic injury in the brain. This phenomenon, known as ischemic tolerance, is an endogenous process that provides robust neuroprotection. So far there have already been a lot of research on ischemic tolerance, but almost all studies were performed from the point of view of neurons. We found that astrocytes are essential for the induction of ischemic tolerance, for which upregulation of P2X7 receptors is requireide. Here, as a downstream signal, we found that induction of HIF1a is essential HIF1a is well-know molecule that controls oxygen homeostasis, and increases in response to hypoxia/PHD2 in neurons. Here, we found that unlike neurons, astrocytes increased HIF1a in a hypoxia-independent manner but upregulated it in a P2X7 receptor-dependent fashion. Such astrocytic HIF1a is long-lasting, and allows astrocytes to produce ischemic tolerance.

Research Products

• [Int'l Joint Research] University of Saarland(ドイツ)
• [Journal Article] Hypoxia-independent mechanisms of HIF-1α expression in astrocytes after ischemic preconditioning. (2017)
  • Author(s): Hirayama, Y., Koizumi, S.
  • Journal Title: Glia. Volume: 65 Issue: 3 Pages: 523-530
  • DOI: 10.1002/glia.23109
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Clock Genes Regulate the Circadian Expression of Piezo1, TRPV4, Connexin26, and VNUT in an Ex Vivo Mouse Bladder Mucosa. (2017)
  • Author(s): 5.Ihara T, Mitsui T, Nakamura Y, Kira S, Nakagomi H, Sawada N, Hirayama Y, Shibata K, Shigetomi E, Shinozaki Y, Yoshiyama M, Andersson KE, Nakao A, Takeda M, Koizumi S
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0168234-e0168234
  • DOI: 10.1371/journal.pone.0168234
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. (2016)
  • Author(s): Kim SK, Hayashi H, Ishikawa T, Shibata K, Shigetomi E, Shinozaki Y, Inada H, Roh SE, Kim SJ, Lee G, Bae H, Moorhouse AJ, Mikoshiba K, Fukazawa Y, Koizumi S, Nabekura J.
  • Journal Title: J Clin Invest Volume: 126(5) Issue: 5 Pages: 1983-1997
  • DOI: 10.1172/jci82859
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Microglia contact induces synapse formation in developing somatosensory cortex. (2016)
  • Author(s): Miyamoto A， Wake H， Ishikawa AW， Eto K， Shibata K， Murakoshi H， Koizumi S， Moorhouse AJ， Yoshimura Y， Nabekura J
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/ncomms12540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Astrocyte-Mediated Ischemic Tolerance (2015)
  • Author(s): Yuri Hirayama, Yuri Ikeda-Matsuo, Shoji Notomi, Hiroshi Enaida, Hiroyuki Kinouchi, Schuichi Koizumi
  • Journal Title: Journal of Neuroscience Volume: 35(9) Issue: 9 Pages: 3794-3805
  • DOI: 10.1523/jneurosci.4218-14.2015
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 低酸素に依存しないアストロサイトHIF-1α発現上昇メカニズムと虚血耐性 (2017)
  • Author(s): 平山友里、Le Pham Ngoc Ha、小泉修一
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール(長崎県・長崎市）
  • Year and Date: 2017-03-15
• [Presentation] 脳虚血耐性現象におけるグリア細胞の役割 (2017)
  • Author(s): 平山友里
  • Organizer: 北陸大学グリアセミナー
  • Place of Presentation: 北陸大学（石川県・金沢市）
  • Year and Date: 2017-02-15
• [Presentation] アストロサイトP2X7受容体を介する持続的な脳虚血耐性 (2016)
  • Author(s): 平山友里、小泉修一
  • Organizer: 第20回Japan Purine Club Meeting
  • Place of Presentation: 東京慈恵会医科大学（東京都・港区）
  • Year and Date: 2016-10-26
• [Presentation] 持続的なアストロサイト性脳虚血耐性の分子メカニズム解析 (2016)
  • Author(s): 平山友里、小泉修一
  • Organizer: 第135回日本薬理学会関東部会
  • Place of Presentation: アクトシティ浜松（静岡県・浜松市）
  • Year and Date: 2016-10-08
• [Presentation] Ischemic tolerance mediated by microglia-astrocytes communications. 14th meeting of Asian-Pacific Society for Neurochemistry (2016)
  • Author(s): Koizumi, S.
  • Organizer: 14th meeting of Asian-Pacific Society for Neurochemistry
  • Place of Presentation: クアラルンプール（マレーシア）
  • Year and Date: 2016-08-30
  • Int'l Joint Research
• [Presentation] Mechanisms of the long-lasting astrocyte-mediated ischemic tolerance. (2016)
  • Author(s): Hirayama, Y., Ikeda-Matsuo, Y., Koizumi, S.
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] Mechanisms underlying astrocyte-mediated ischemic tolerance. (2015)
  • Author(s): Hirayama, Y., Koizumi, S.
  • Organizer: 第20回グリア研究会
  • Place of Presentation: 名古屋市立大学（愛知県名古屋市）
  • Year and Date: 2015-12-05
  • Invited
• [Presentation] Role of P2X7 receptor/HIF-1 α signal pathway in astrocyte-mediated ischemic tolerance. (2015)
  • Author(s): Hirayama, Y., Ikeda-Matsuo, Y., Koizumi, S.
  • Organizer: Society for Neuroscience Annual Meeting 2015
  • Place of Presentation: McCormic Place(Chicago, U.S.A)
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Activation of P2X7 receptor/HIF-1α signal pathway in astrocytes induces ischemic tolerances. (2015)
  • Author(s): Hirayama, Y., Ikeda-Matsuo, Y., Koizumi, S.
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
  • Year and Date: 2015-09-11
• [Presentation] New insights into glia-mediated ischemic tolerance. (2015)
  • Author(s): Hirayama, Y., Ikeda-Matsuo, Y., Koizumi, S.
  • Organizer: 第38回日本神経科学大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-07-28
• [Presentation] Phagocytes astrocytes after brain ischemia. (2015)
  • Author(s): Morizawa, Y., Hirayama, Y., Shibata, S., Koizumi, S.
  • Organizer: European Meeting on Glial Cells in Health and Disease
  • Place of Presentation: Euskalduna Conference Centre(Bilbao, Spain)
  • Year and Date: 2015-07-15
  • Int'l Joint Research
• [Presentation] Glial cells-triggered ischemic tolerance (2015)
  • Author(s): Koizumi, S., Hirayama, Y.
  • Organizer: The 2015 Cold Spring Harbor Conferences Asia
  • Place of Presentation: Suzhou Dushu Lake Conference Center(Suzhou, China)
  • Year and Date: 2015-06-22
  • Int'l Joint Research / Invited
• [Presentation] Glial-mediated ischemic tolerance (2015)
  • Author(s): Koizumi, S.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県新潟市）
  • Year and Date: 2015-05-20
  • Invited
• [Remarks] 薬理学講座HP
  • URL: http://www.med.yamanashi.ac.jp/clinical_basic/pharmaco/