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Molecular basis for hypoxic sensing and regulation of ventilatory responses

Research Project

Project/Area Number 16390071
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionTohoku University

Principal Investigator

SHIBAHARA Shigeki  Tohoku University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (70206142)

Co-Investigator(Kenkyū-buntansha) HIDA Wataru  Tohoku University, Graduate School of Information Sciences, Professor, 大学院情報科学研究科, 教授 (10142944)
FURUYAMA Kazumichi  Tohoku University, Graduate School of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (80280874)
TAKEDA Kazuhisa  Tohoku University, Graduate School of Medicine, Research Associate, 大学院医学系研究科, 助手 (30311559)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2005: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2004: ¥6,000,000 (Direct Cost: ¥6,000,000)
Keywordsheme oxygenase / MITF / oxygen sensor / ventilatory response / erythrocyte
Research Abstract

We have shown that homozygous mice lacking heme oxygenase-2 (HO-2) show blunted hypoxic ventilatory response and homozygous black-eyed white (bw) mice, a mutant in microphthalmia-associated transcription factor (Mitf), show augmented hypoxic ventilatory response. These results suggest the involvement of HO-2 and Mitf in hypoxic ventilatory response. Moreover, we have obtained the following results.
1 HO-2 deficient mice exhibit mild hypxoemia and thickening of the pulmonary venous myocardium, in which HO-1,an inducible isozyme of heme oxygenase, is over-expressed.
2 The expression levels of HO-1 and HO-2 proteins were transiently decreased in the mouse liver at 7 days of normobaric hypoxia, whereas HO-1 and HO-2 proteins were increased in the heart at 28 days of hypoxia.
3 Using nine inbred mouse strains, we measured ventilatory responses to hypoxia (10% O_2) and hypercapnia (10% CO_2) of unanesthetized mice by whole body plethysmography. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the lowest in SWR/J mice. Thus, genetic factors may have influenced the hypoxic ventilatory response.
4 Using cDNA microarrays, we have identified lipocalin-type prostaglandin D synthase (L-PGDS), whose mRNA is undetectable in the homozygous bw mouse skin. L-PGDS represents a newly identified melanocyte marker. MITF may modulate the production of prostaglandin D_2 by activating the L-PGDS gene in melanocytes.
5 Hypoxia (1% O_2) reduces the expression levels of HO-1 and HO-2 protein in several human cell lines, such as YN-1 human erythroleukemia and HepG2 human hepatoma, after 48 h of incubation. Moreover, heme contents were increased in YN-1 and HepG2 cells after 48-h incubation under hypoxia.

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (39 results)

All 2007 2006 2005 2004

All Journal Article (34 results) Book (5 results)

  • [Journal Article] Augmented chemosensitivity in black-eyed white Mitf^<mi-bw> mice, lacking melanocytes.2007

    • Author(s)
      Takeda K.
    • Journal Title

      J. Biochem. (Tokyo) 141・3

      Pages: 327-333

    • NAID

      10020100508

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Augmented chemosensitivity in black-eyed white Mitf^<mi-bw> mice, lacking melanocytes.2007

    • Author(s)
      Takeda K, Adachi T, Han F, Yokoyama S, Yamamoto H, Hida W, Shibahara S
    • Journal Title

      J.Biochem.(Tokyo) 141 (3)

      Pages: 327-333

    • NAID

      10020100508

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Augmented chemosensitivity in black-eyed white Mitf^<mi-bw> mice, lacking melanocytes.2007

    • Author(s)
      Takeda K.
    • Journal Title

      J. Biochem. (Tokyo) 141

      Pages: 327-333

    • NAID

      10020100508

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Down-regulation of heme oxygenase-2 is associated with the increased expression of heme oxygenase-1 in human cell lines.2006

    • Author(s)
      Ding Y.
    • Journal Title

      FEBS J. 273・23

      Pages: 5333-5346

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Functional difference of the SOX10 mutant proteins responsible for the phenotypic variability in auditory-pigmentary disorders.2006

    • Author(s)
      Yokoyama, S
    • Journal Title

      J. Biochem. (Tokyo) 140・4

      Pages: 491-499

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines : A possible strategy for the maintenance of intracellular heme level.2006

    • Author(s)
      Zhang Y.
    • Journal Title

      FEBS J. 273・14

      Pages: 3136-3147

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mice with blunted hypoxic ventilatory response are susceptible to respiratory disturbance during hypoxia2006

    • Author(s)
      Adachi T.
    • Journal Title

      Tohoku J. Exp. Med. 209・2

      Pages: 125-134

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] SOX10, in combination with Sp1, regulates the endothelin receptor type B gene in human melanocyte lineage cells.2006

    • Author(s)
      Yokoyama S.
    • Journal Title

      FEBS J. 273・8

      Pages: 1805-1820

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Arg452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity2006

    • Author(s)
      Furuyama K.
    • Journal Title

      Eur. J. Haematol. 76・1

      Pages: 33-41

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Lipocalin-type prostaglandin D synthase as a melanocyte marker regulated by MITF.2006

    • Author(s)
      Takeda K.
    • Journal Title

      Biochem. Biophys. Res. Commun. 339・4

      Pages: 1098-1106

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Down-regulation of heme oxygenase-2 is associated with the increased expression of heme oxygenase-1 in human cell lines.2006

    • Author(s)
      Ding Y, Zhang Y-Z, Furuyama K, Ogawa K, Igarashi K, Shibahara S
    • Journal Title

      FEBS J. 273 (23)

      Pages: 5333-5346

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Functional difference of the SOX10 mutant proteins responsible for the phenotypic variability in auditory-pigmentary disorders.2006

    • Author(s)
      Yokoyama S, Takeda K, Shibahara S
    • Journal Title

      J.Biochem.(Tokyo) 140 (4)

      Pages: 491-499

    • NAID

      10018841466

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines : A possible strategy for the maintenance of intracellular heme level.2006

    • Author(s)
      Zhang Y, Furuyama K, Kaneko K, Ding Y, Ogawa K, Yoshizawa M, Kawamura M, Takeda K, Yoshida T, Shibahara S
    • Journal Title

      FEBS J. 273 (14)

      Pages: 3136-3147

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mice with blunted hypoxic ventilatory response are susceptible to respiratory disturbance during hypoxia.2006

    • Author(s)
      Adachi T, Ogawa H, Okabe S, Kitamuro T, Kikuchi Y, Shibahara S, Shirato K, Hida W
    • Journal Title

      Tohoku J.Exp.Med. 209 (2)

      Pages: 125-134

    • NAID

      10017493065

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] SOX10, in combination with Sp 1, regulates the endothelin receptor type B gene in human melanocyte lineage cells.2006

    • Author(s)
      Yokoyama S, Takeda K, Shibahara S
    • Journal Title

      FEBS J. 273 (8)

      Pages: 1805-1820

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Arg452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity.2006

    • Author(s)
      Furuyama K, Harigae H, Heller T, Hamel BC, Minder EI, Shimizu T, Kuribara T, Blijlevens N, Shibahara S, Sassa S
    • Journal Title

      Eur.J.Haematol. 76 (1)

      Pages: 33-41

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Lipocalin-type prostaglandin D synthase as a melanocyte marker regulated by MITF.2006

    • Author(s)
      Takeda K, Yokoyama S, Aburatani H, Masuda T; Han F, Yoshizawa M, Yamaki N, Yamamoto H, Eguchi N, Urade Y, Shibahara S
    • Journal Title

      Biochem.Biophys.Res.Commun. 339 (4)

      Pages: 1098-1106

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Down-regulation of heme oxygenase-2 is associated with the increased expression of heme oxygenase-1 in human cell lines.2006

    • Author(s)
      Ding Y.
    • Journal Title

      FEBS J. 273

      Pages: 5333-5346

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Functional difference of the SOX10 mutant proteins responsible for the phenotypic variability in auditory-pigmentary disorders.2006

    • Author(s)
      Yokoyama, S
    • Journal Title

      J. Biochem. (Tokyo) 140

      Pages: 491-499

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Hypoxia reduces the expression of heme oxygenase-2 in various types of human cell lines : A possible strategy for the maintenance of intracellular heme level.2006

    • Author(s)
      Zhang Y.
    • Journal Title

      FEBS J. 273

      Pages: 3136-3147

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Mice with blunted hypoxic ventilatory response are susceptible to respiratory disturbance during hypoxia2006

    • Author(s)
      Adachi T.
    • Journal Title

      Tohoku J. Exp. Med. 209

      Pages: 125-134

    • Related Report
      2006 Annual Research Report
  • [Journal Article] SOX10, in combination with Sp1, regulates the endothelin receptor type B gene in human melanocyte lineage cells.2006

    • Author(s)
      Yokoyama S.
    • Journal Title

      FEBS J. 273

      Pages: 1805-1820

    • Related Report
      2006 Annual Research Report
  • [Journal Article] SOX10, in combination with Sp1, regulates the endothelin receptor type B gene in human melanocyte lineage cells.2006

    • Author(s)
      Yokoyama S.
    • Journal Title

      FEBS J. (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Arg452 substitution of the erythroid-specific 5-aminolaevulinate synthase, a hot spot mutation in X-linked sideroblastic anaemia, does not itself affect enzyme activity2006

    • Author(s)
      Furuyama K.
    • Journal Title

      Eur.J.Haematol. 76

      Pages: 33-41

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Lipocalin-type prostaglandin D synthase as a melanocyte marker regulated by MITF.2006

    • Author(s)
      Takeda K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 339

      Pages: 1098-1106

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Dynamic changes in expression of heme oxygenases in mouse heart and liver during hypoxia2005

    • Author(s)
      Han F.
    • Journal Title

      Biochem. Biophys. Res. Commun. 338・1

      Pages: 653-659

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Dynamic changes in expression of heme oxygenases in mouse heart and liver during hypoxia.2005

    • Author(s)
      Han F, Takeda K, Yokoyama S, Ueda H, Shinozawa Y, Furuyama K, Shibahara S
    • Journal Title

      Biochem.Biophys.Res.Commun. 338 (1)

      Pages: 653-659

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Association of susceptibility to the development of lung adenocarcinoma with the heme oxygenase-1 gene promoter polymorphism.2005

    • Author(s)
      Kikuchi A.
    • Journal Title

      Hum.Genet. 116

      Pages: 354-360

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Expression of heme oxygenase-1 is repressed by interferon-γ and induced by hypoxia in human retinal pigment epithelial cells.2004

    • Author(s)
      Udono-Fujimori R.
    • Journal Title

      Eur. J. Biochem. 271・14

      Pages: 3076-3084

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-22004

    • Author(s)
      Adachi T.
    • Journal Title

      Biochem. Biophys. Res. Commun. 320・2

      Pages: 514-522

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of heme oxygenase-1 is repressed by interferon-y and induced by hypoxia in human retinal pigment epithelial cells.2004

    • Author(s)
      Udono-Fujimori R, Takahashi K, Takeda K, Furuyama K, Kaneko K, Takahashi S, Tamai M, Shibahara S
    • Journal Title

      Eur.J.Biochem. 271 (14)

      Pages: 3076-3084

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2.2004

    • Author(s)
      Adachi T, Ishikawa K, Hida W, Matsumoto H, Masuda T, Date F, Ogawa K, Takeda K, Furuyama K, Zhang Y, Kitamuro T, Ogawa H, Maruyama Y, Shibahara S
    • Journal Title

      Biochem.Biophys.Res.Commun. 320 (2)

      Pages: 514-522

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expression of heme oxygenase-1 is repressed by interferon-γ and induced by hypoxia in human retinal pigment epithelial cells2004

    • Author(s)
      Udono-Fujimori R.
    • Journal Title

      Eur.J.Biochem. 271

      Pages: 3076-3084

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-22004

    • Author(s)
      Adachi T.
    • Journal Title

      Biochem.Biophys.Res.Commun. 320

      Pages: 514-522

    • Related Report
      2004 Annual Research Report
  • [Book] Genetic Regulation of the Pigment Cell. In The Pigmentary System. Physiology and Pathophysiology, 2e (Edited by J. J. Nordlund et al.)2006

    • Author(s)
      Takeda K., Shibahara S.
    • Total Pages
      1248
    • Publisher
      Blackwell Publishing, New York, NY
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Genetic Regulation of the Pigment Cell. The Pigmentary System.Physiology and Pathophysiology,2e(Edited by J.J.Nordlund et al.)2006

    • Author(s)
      Takeda K., Shibahara S.
    • Total Pages
      1248
    • Publisher
      Blackwell Publishing, New York, NY
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Heme oxygenase and human disease. In Heme Oxygenase (Edited by Otterbein L.E. et al.)2005

    • Author(s)
      Yamaya M., Shibahara S.
    • Total Pages
      417
    • Publisher
      Nova Science Publishers, Inc., Carbondale, IL
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Heme oxygenase and human disease. Heme Oxygenase(Edited by Otterbein L.E.et al.)2005

    • Author(s)
      Yamaya M., Shibahara S.
    • Total Pages
      417
    • Publisher
      Nova Science Publishers, Inc., Carbondale, IL
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Book] Heme Oxygenase (Edited by Otterbein L.E. et al.)2005

    • Author(s)
      Yamaya M., Shibahara S.
    • Total Pages
      417
    • Publisher
      Nova Science Publishers, Inc., Carbondale, IL
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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