Signal transduction systems in response to environmental stress in CNS pericytes.

• Project/Area Number: 19590992
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyushu University
• Principal Investigator: KAMOUCHI Masahiro Kyushu University, 大学病院, 助教 (80346783)
• Co-Investigator(Kenkyū-buntansha): 北園 孝成 九州大学, 大学病院, 講師 (70284487)
• Co-Investigator(Renkei-kenkyūsha): KITAZONO Takanari 九州大学, 大学病院, 講師 (70284487) ; 黒田 淳哉 ; 松尾 龍 ; 中村 晋之
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2008: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 神経病態薬理学 / 周皮細胞 / 微小循環 / 血管新生 / 脳血管

Research Abstract

具体的内容脳血管ペリサイトは血管新生、血液脳関門、微小循環調節に重要な役割を果たしている。本研究は、脳血管ペリサイトにおいて細胞外環境の変化が惹起する細胞応答、細胞機能について検討した。
脳血管ペリサイトにおいて、細胞外のアシドーシスは、Na/H exchanger 1NHE1を逆回転モードとして活性化し、細胞内Ca貯蔵部位よりCaを周期的に放出させるCa oscillation。PDGF-B はPDGFR-βを介して、PLCγをリン酸化しCa oscillationを惹起する。PDGF-Bは、Ca依存性転写因子であるCREBcAMP response element binding proteinをリン酸化し、細胞内シグナルの調節を行っている。また、Ca oscillation はCa 依存性転写因子であるnuclearfactor of activated T cellsNFATの核内移行を促進し、核内に移行したNFAT が種々の遺伝子の転写を制御している。NFAT を介したサイトカインの分泌調節は細胞増殖を制御している。脳血管ペリサイトには、活性酸素生成酵素であるNAD(P)HNox4 が発現し、活性酸素を生成し細胞増殖を制御している。Angiotensin II はNox4 の発現を増加させ、活性酸素の生成を増加させる。過度の酸化ストレスは細胞内Ca 貯蔵部位からのCa 放出を起こす。酸化ストレスはNHE、NCX、ASIC、ENaC 以外のamiloride 感受性蛋白のSH 基の酸化を介して、細胞内Ca 上昇を引き起こす。
意義、重要性脳毛細血管の成熟、血管新生には脳血管ペリサイトの存在が不可欠である。また、神経再生に必須なniche微小環境の重要な構成細胞と考えられる。近年、神経活動に応じた血流の制御も行っていることや、脳血管ペリサイトには間葉系幹細胞に類似した多能性多能性を有していることも示唆されている。本研究は、脳血管ペリサイトにおけるシグナル伝達機構を明らかにした。本研究の成果は、脳血管ペリサイトの制御を介した、新規の中枢神経疾患治療法の開発に寄与すると考えられる。

Research Products

• [Journal Article] Amiloride inhibits hydrogen peroxide-induced Ca^<2+> responses in human CNS pericytes. (2009)
  • Author(s): Nakamura K, et al.
  • Journal Title: Microvasc Res (印刷中)
  • Peer Reviewed
• [Journal Article] Protective effects of angiotensin II type 1 receptor blocker on cerebral circulation independent of blood pressure (2008)
  • Author(s): Kumai Y, Ooboshi H, Ago T, Ishikawa E, Takada J, Kamouchi M, Kitazono T, Ibayashi S, Iida M
  • Journal Title: Exp Neurol 210 Pages: 441-448
• [Journal Article] Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes (2008)
  • Author(s): Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Matsuo R, Hagiwara N, Ishikawa E, Ooboshi H, Ibayashi S, Iida M.
  • Journal Title: Am J Physiol Heart Circ Physiol 294
• [Journal Article] Polymorphisms in the lymphotoxin alpha gene and the risk of ischemic stroke in the Japanese population (2008)
  • Author(s): Hagiwara N, Kitazono T, Kamouchi M, Kuroda J, Ago T, Hata J, Ninomiya T, Ooboshi H, Kumai Y, Yoshimura S, Tamaki K, Fujii K, Nagao T, Okada Y, Toyoda K, Nakane H, Sugimori H, Yamashita Y, Wakugawa Y, Kubo M, Tanizaki Y, Kiyohara Y, Ibayashi S, Iida M.
  • Journal Title: The Fukuoka Stroke Registry and the Hisayama Study 25 Pages: 417-422
• [Journal Article] Fukuoka Stroke Registry ; Hisayama study. Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population : the Fukuoka Stroke Registry and the Hisayama study (2008)
  • Author(s): Hagiwara N, Kitazono T, Kamouchi M, Kuroda J, Ago T, Hata J, Ninomiya T, Ooboshi H, Kumai Y, Yoshimura S, Tamaki K, Fujii K, Nagao T, Okada Y, Toyoda K, Nakane H, Sugimori H, Yamashita Y, Wakugawa Y, Kubo M, Tanizaki Y, Kiyohara Y, Ibayashi S, Iida M.
  • Journal Title: Eur J Neurol 15 Pages: 481-486
• [Journal Article] Protective effects of angiotensin II type 1 receptor blocker on cerebral circulationindependent of blood pressure (2008)
  • Author(s): Kumai Y, et a1.
  • Journal Title: Exp Neurol 210 Pages: 441-448
  • Peer Reviewed
• [Journal Article] Role of NHEI in calcium signaling and cell proliferation in human CNS pericytes. (2008)
  • Author(s): Nakamura K, et al.
  • Journal Title: Am J Phvsiol Heart Circ Phvsiol 294
  • Peer Reviewed
• [Journal Article] Polymorphisms in the lymphotoxin alpha gene and the risk of ischemic stroke inthe Japanese population. The Fukuoka Stroke Registry and the Hisayama Studv. (2008)
  • Author(s): Hagiwara N, et al.
  • Journal Title: Cerebrovasc Dis 25 Pages: 417-422
  • Peer Reviewed
• [Journal Article] Polymorphism in the sorbin and SH3-domain-containing-l (SORBSI)gene and the risk of brain infarction in the Japanese population : the Fukuoka Stroke Registry and the Hisayama study. (2008)
  • Author(s): Hagiwara N, et al.
  • Journal Title: Eur J Neurol 15 Pages: 481-486
  • Peer Reviewed
• [Journal Article] Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes (2008)
  • Author(s): Nakamura K, Kamouchi M, Kitazono T, et. al.
  • Journal Title: Am J Physiol Heart Circ Physiol (in press)
  • Peer Reviewed
• [Journal Article] Polymorphisms in the lymphotoxin-a gene and the risk of ischemic stroke in the Japanese population;The Fukuoka Stroke Registry and the Hisayama Study (2008)
  • Author(s): Hagiwara N, Kitazono T, Kamouchi M, et. al.
  • Journal Title: Cerebrovasc Dis (in press)
  • Peer Reviewed
• [Journal Article] Polymorphism in the sorbin and SH3-domain-containing-1(SORBS1)gene and the risk of brain infarction in the Japanese population;The Fukuoka Stroke Registry and the Hisayama Study (2008)
  • Author(s): Hagiwara N, Kitazono T, Kamouchi M, et. al.
  • Journal Title: Eur J Neurol (in press)
  • Peer Reviewed
• [Journal Article] Protective effects of angiotensin II Type I receptor blocker on cerebral circulation independent of blood pressure (2008)
  • Author(s): Kumai Y, Ooboshi H, Ago T, et. al.
  • Journal Title: Exp Neurol (in press)
  • Peer Reviewed
• [Journal Article] Protective effects of angiotensin II Type 1 receptor blocker on cerebral circulation independent of blood pressure (2007)
  • Author(s): Kumai Y, Ooboshi H, Ago T, Ishikawa E, Takada J, Kamouchi M, Kitazono T, Ibayashi S, Iida M.
  • Journal Title: Exp Neurol (Epub ahead of print)
• [Journal Article] NAD(P)H oxidase p22phox C242T polymorphism and ischemic stroke in Japan : the Fukuoka Stroke Registry and the Hisayama study (2007)
  • Author(s): Kuroda J, Kitazono T, Ago T, Ninomiya T, Ooboshi H, Kamouchi M, Kumai Y, Hagiwara N, Yoshimura S, Tamaki K, Kusuda K, Fujii K, Nagao T, Okada Y, Toyoda K, Nakane H, Sugimori H, Yamashita Y, Wakugawa Y, Asano K, Tanizaki Y, Kiyohara Y, Ibayashi S, Iida M.
  • Journal Title: Eur J Neurol 14(10) Pages: 1091-7
• [Journal Article] Hydrogen peroxide-induced Ca2+ responses in CNS pericytes (2007)
  • Author(s): Kamouchi M, Kitazono T, Ago T, Wakisaka M, Kuroda J, Nakamura K, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.
  • Journal Title: Neurosci Lett 416(1) Pages: 12-16
• [Journal Article] Role of substantia innominata in cerebral blood flow autoregulation (2007)
  • Author(s): Ota K, Kitazono T, Ooboshi H, Kamouchi M, Katafuchi T, Aou S, Yamashita Y, Ibayashi S, Iida M.
  • Journal Title: Brain Res 1135(1) Pages: 146-153
• [Journal Article] Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability (2007)
  • Author(s): Kumai Y, Ooboshi H, Ibayashi S, Ishikawa E, Sugimori H, Kamouchi M, Kitazono T, Egashira K, Iida M.
  • Journal Title: J Cereb Blood Flow Metab 27 Pages: 1152-1160
• [Journal Article] NAD(P)H oxidase p22phox C242T polymorphism and ischemic stroke in Japan:the Fukuoka Stroke Registry and the Hisayama study (2007)
  • Author(s): Kuroda J, Kitazono T, Ago T, et. al.
  • Journal Title: Eur J Neurol Pages: 1091-1097
  • Peer Reviewed
• [Journal Article] Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood-brain barrier permeability (2007)
  • Author(s): Kumai Y, Ooboshi H, Ibayashi S, et. al.
  • Journal Title: J Cereb Blood Flow Metab 27 Pages: 1152-1160
  • Peer Reviewed
• [Journal Article] Role of substantia innominata in cerebral blood flow autoregulation (2007)
  • Author(s): Ota K, Kitazono T, Ooboshi H, et. al.
  • Journal Title: Brain Res 1135 Pages: 146-153
  • Peer Reviewed
• [Journal Article] Hydrogen peroxide-induced Ca^<2+> responses in CNS pericytes (2007)
  • Author(s): Kamouchi M, Kitazono T, Ago T, et. al.
  • Journal Title: Neurosci Lett 416 Pages: 12-16
  • Peer Reviewed
• [Journal Article] Amiloride inhibits hydrogen peroxide-induced Ca2+ responses in human CNS pericytes
  • Author(s): Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Shono Y, Hagiwara N, Ago T, Ooboshi H, Ibayashi S, Iida M.
  • Journal Title: Microvasc Res (in press)
• [Presentation] Expression of NHE1 and cell proliferation in human CNS pericytes (2007)
  • Author(s): Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Matsuo R, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.
  • Organizer: Asian Stroke Forum
  • Place of Presentation: Kyoto
  • Year and Date: 2007-09-27
• [Presentation] Role of NHE1 in Ca2+ oscillation and cell proliferation in human CNS pericytes (2007)
  • Author(s): Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Matsuo R, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.
  • Organizer: Brain 07
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-23
• [Presentation] Mechanisms of oxidative stress-induced calcium signaling in human CNS pericytes (2007)
  • Author(s): Kamouchi M, Kitazono T, Kuroda J, Nakamura K, Shono Y, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.
  • Organizer: Brain 07
  • Place of Presentation: Osaka
  • Year and Date: 2007-05-21