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Clonic granulomaous disease (CGD) and its deficients in bactricidal activity-Basic research for gene therapy for CGD-

Research Project

Project/Area Number 09660311
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Basic veterinary science/Basic zootechnical science
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

INANAMI Osamu  Grad.School of Vet.Med.Hokkaido Univ.Asso.Pro., 大学院・獣医学研究科, 助教授 (10193559)

Co-Investigator(Kenkyū-buntansha) NAGAHATA Hajime  Fac.of Vet.Med.Rakuno Gakuen Univ.Pro., 獣医学部, 教授 (10133571)
KUWABARA Mikinori  Grad.School of Vet.Med.Hokkaido Univ.Pro., 大学院・獣医学研究科, 教授 (10002081)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥2,500,000 (Direct Cost: ¥2,500,000)
Keywordsclonic granulomaous disease (CGD) / neutrophil / superoxide / NADPH oxidase / gene therapy / phagocytosis / signal transduction / kinases / CGD / シグナル伝達 / NADPHオキシターゼ / リン酸化酵素 / 生体防御 / NADPHオキシダーゼ / 電子スピン共鳴法 / ケミルミネッセンス / p47phox / p67phox
Research Abstract

This project was performed to clarify the signal transduction mechanisms for NADPH oxidase activation and phagocytotis by using normal neutrophil, human clonic granulomaous disease (CGD) and bovine leukocyte adhesion deficiency (BLAD) which were genetic deficient in p47phox and beta2-integrin CR3 corresponding to the receptor of complement iC3b, respectively The various reagents to inhibit NADPH oxidase-related signal transduction were used for this purpose. We found that inhibitors for protein kinase C (PKC), phosphatidyl inositol 3 kinase (P1 3-kinase) and p38 mitogen-activated protein kinase (p38 MAPK) were dose-dependently inhibited superoxide generation from serum-opsonized zymosan (s-OZ)-stimulated neutrophils from BLAD and normal calves, although the stimulation of BLAD neutrophils with s-OZ brought about lower generation of superoxide than that of normal neutrophil. These results indicated that the lack of beta2-integrin CR3 did not influence signal transduction pathways of NAD … More PH oxidase but reduced superoxide production from NADPH oxidase. This reduced NADPH oxidase activity in BLAD was partially recovered by transfusion of CD 18-positive granulocytes to disease animal. Furthermore, P1 3-kinase and p38 MAPK but not PKC are shown to be required for phagocytotic activity in normal neutrophil. Concerning the intracellular mechanisms of NADPH oxidase activation, the p47phox, one component of NADPH oxidase. is known to be phosphorylated extensively on serines that are located among its C-terminal amino acids and this phosphorylation is a trigger for the activation of NADPH oxidase. By using site-directed mutagenesis of p47phox and p47phox-deficien B cells from human clonic granulomaous disease (COD), it was showed that the phosphorylation of serines 3031304, 359(370 and possibly serine 379 must take place in order to activate the oxidase. These results seem to be important in not only understanding the signal transduction mechanism of NADPH oxidase activity but also development of therapy for BLAD and p47phox-deficien COD such as granulocyte transfusion and gene therapy. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] Mikinori Kuwabara: "The increased formation of alkali-labile sites by a spin-trapping agent α-phenyl-N-tert-butylnitrone in γ-irradiated frozen aqueous solution of DNA" Journal of Radiation Research. 38・3. 153-155 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hajime Nagahata: "Prevalence and allele frequency estimation of bovine leukocyte adhesion deficiency(BLAD)in Holstein-Friesian cattle in Japan" Jounal of Veterinary Medical Science. 59・4. 233-238 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hajime Nagahata: "Prevalence an PreFc receptor-mediated phagocytosis, superoxide production and calcium signaling of β2 integrin-deficient bovine neutrophils" Microbiology and Immunology. 41・9. 747-750 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hajime Nagahata: "Leukocyte emigration in normal calves and calves with leukocyte adhesion deficiency" Journal of Veterinary Medical Science. 59・12. 1143-1147 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] J.L.Johnson: "Activation of p47(PHOX), a cytosolic subunit of the leukocyte NADPH oxidase. Phosphorylation of ser-359 or ser-370 precedes phosphorylation at other sites is required for activity" Journal of Biological Chemistry. 273・52. 35147-35152 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Futoshi Okada: "Inflammatory-cell-mediated tumour progression and minisatellite mutation correlate with the decrease of antioxidative enzymes in murine fibrosarcoma cells" British Journal of Cancer. 79・3/4. 377-385 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osamu Inanami: "Oral administration of(-)catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radical Research" Free Radical Research. 29・4. 359-365 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osamu Inanami: "The leukocyte NADPH oxidase subunit p47PHOX : the role of the cystein resudiues" Archives of Biochemistry and Biophysics. 350・1. 36-40 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osamu Inanami: "Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphotrylation of p47PHOX on serine 303 or 304" Journal of Biological Chemistry. 273・16. 9539-9543 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hajime Nagahata: "Bone marrow transplantation in a Holstein heifer with bovine leukocyte adhesion deficiency" Veterinary Journal. 156・1. 15-21 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hajime Nagahata: "Survival of transfused CD18-positive granulocytes and their chemiluminescent response in a heifer with leukocyte adhesion deficiency" Journal of Veterinary Medical Science. 60・2. 261-262 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osamu Inanami: "Attenuation of caspase 3-dependent apoptosis by Trolox post-treatment of X-irradiated MOLT-4 cells. International Journal of Radiation Biology, 75(2), 155-163" International Journal of Radiation Biology. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osamu Inanami: "Lipid peroxides and antioxidants in sera of neonatal calves" American Journal of Veterinary Medicine. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osamu Inanami: "H_2O_2-induced activation of SAPK/JNK regulated by phosphatidylinositol 3-kinase in Chinese hamster V79 cells" Antioxidant and Redox Signaling. in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mikinori Kuwabara: "Modern Applications of EPR/ESR : From Biophysics to Material Science" An ESR study of superoxide generation in stimulated neutrophils from a calf with bovine leukocyte adhesion deficiency(BLAD), 8 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuwabara, M., Ohshima, H., Iida, Y.and Inanami, O.: "The increased formation of alkali-labile sites by a spin-trapping agent alpha-phenyl-N-tert-butylnitrone in gamma-irradiated frozen aqueous solution of DNA." Journal of Radiation Research. 38 (3). 153-155 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nagahata, H., Miura, T., Takagi, T., Ohtake, M., Noda, H., Yasuda, T.and Nioka, K.: "Prevalence and allele frequency estimation of bovine leukocyte adhesion deficiency (BLAD) in Holstein-Friesian cattle in Japan" Journal of Veterinary Medical Science. 59 (4). 233-238 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nagahata, H., Sawada, C., Higuchi, H., Teraoka, H.and Yamaguchi, M.: "Prevalence anPreFc receptor-mediated phagocytosis, superoxide production and calcium signaling of beta2 integrin-deficient bovine neutrophils." Microbiology and Immunology. 41 (9). 747-750 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nagahata, H., Matsuyama, A., Masue, M., Yuki, M., Higuchi, H., Ohtsuka, H., Kurasawa, T., Sato, H.and Noda, H.: "Leukocyte emigration in normal calves and calves with leukocyte adhesion deficiency" Journal of Veterinary Medical Science. 59 (12). 1143-1147 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Johnson, J.L., Park, J.W., Benna, J.E., Faust, L.P., Inanami, O.and Babior, B.M.: "Activation of p47 (PHOX), a cytosolic subunit of the leukocyte NADPH oxidase. Phosphorylation of ser-359 or ser-370 precedes phosphorylation at other sites is required for activity" Journal of Biological Chemistry. 273 (52). 35147-35152 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okada, F., Nakai, K., Kobayashi, T., Shibata, T., Tagami, S., Kawakami, Y., Kitazawa, T., Komimami, R., Yoshimura, S., Suzuki, K., Taniguchi, N., Inanami, O., Kuwabara, M., Kishida, H., Nakae, D., Konishi, Y., Moriuchi, T.and Kosokawa, M.: "Inflammatory-cell-mediated tumour progression and minisatellite mutation correlate with the decrease of antioxidative enzymes in murine fibrosarcoma cells." British Journal of Cancer. 79 (3/4). 377-385 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inanami, O., Watanabe, Y., Syuto, B., Nakano, M., Tsuji, M.and Kuwabara, M.: "Oral administration of (-) catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil" Free Radical Research. 29 (4). 359-365 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inanami, O., Jahnson, J.L.and Babior, B.M.: "The leukocyte NADPH oxidase subunit p47PHOX : the role of the cystein resudiues" Archives of Biochemistry and Biophysics. 350 (1). 36-40 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inanami, O., Johnson, J.L., McAdara, J.K., Benna, J.E., Faust, L.R., Newburger, P.E.and Babior, B.M.: "Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphotrylation of p47PHOX on serine 303 or 304" Journal of Biological Chemistry. 273 (16). 9539-9543 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nagahata, H., Matsuki, S., Higuchi, H., Inanami, O., Kuwabara, M.and Kobayashi, K.: "Bone marrow transplantation in a Holstein heifer with bovine leukocyte adhesion deficiency." Veterinary Journal. 156 (1). 15-21 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nagahata, H., Sakurai, N., Matsuki, S., Miura, T., Nioka, K.and Kociba, G.J.: "Survival of transfused CD18-positive granulocytes and their chemilumin-escent response in a heifer with leukocyte adhesion deficiency" Journal of Veterinary Medical Science. 60 (2). 261-262 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inanami, O., Takahashi, K.and Kuwabara, M.: "Attenuation of caspase 3-dependent apoptosis by Trolox post-treatment of X-irradiated MOLT-4 cells" International Journal of Radiation Biology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inanami, O., Shiga, A., Okada, K., Sato, R., Miyake, Y.and Kuwabara, M.: "Lipid peroxides and antioxidants in sera of neonatal calves" American Journal of Veterinary Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Inanami, O., Takahashi, K., Yoshito, A.and Kuwabara, M.: "H_2O_2-induced activation of SAPK/JNK regulated by phosphatidylinositol 3-kinase in Chinese hamster V79 cells" Antioxidant & Redox Signaling. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuwabara, M., Gouji, N.Inanami, O.Higuchi, H.and Nagahata, H.: Modern Applications of EPR/ESR : From Biophysics to Material Science, Rudowitcz, C.Z., Yu, K.N.and Hiraoka, H.eds., Springer, Singapore. An ESR study of superoxide generation in stimulated neutrophils from a calf with bovine leukocyte adhesion deficiency (BLAD), 46-53 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuwabara,M.et al: "The increased formation of alkali-labile sites by a spin-trapping agent alpha-phenyl-N-tert-butylnitrone in gamma-irradiated frozen aqueous solution of DNA" J Radiat Res. 38. 153-155 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagahata,H.et al.: "Prevalence and allele frequency estimation of bovine leukocyte adhesion deficiency (BLAD) in Holstein-Friesian cattle in Japan." J Vet Med Sci. 59(4). 233-238 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagahata,H.et al.: "Prevalence anPreFc receptor-mediated phagocytosis,superoxide production and calcium signaling of deta 2 integrin-deficient bovine neutrophils." Microbiol lmmunol. 41(9). 747-750 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagahata,H.et al.: "Leukocyte emigration in normal calves and calves with leukocyte adhesion deficiency." J Vet Med Sci. 59(12). 1143-1147 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Johnson,J.L.et al.: "Activation of p47 (PHOX) ,a cytosolic subonit of the leukocyte NADPH oxidase.Phosphorylation of ser-359 or ser-370 precedes phosphorylation at other sites and is required for activity." J Biol Chem. 273. 35147-35152 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okada,F.et al.: "Inflammatory cell-mediated tumour progression and minisatellite mutation correlate with the decrease of antioxidative enzymes in murine fibrosarcoma cells" Br J Cancer. 79. 377-385 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inanami,O.et al.: "Oral administration of (-) catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil" Free Radic Res. 29. 359-365 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inanami,O.et al.: "The leukocyte NADPH oxidase subunit p47PHOX : the role of the cysteine residues." Arch Biochem Biophys. 350. 36-40 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inanami,O.et al.: "Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphoryvlation of p47PHOX on serine 303 or 304." J Biol Chem. 273. 9539-9543 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagahata,H.et al.: "Bone Marrow transplantation in a Holstein heifer with bovine leucocyte adhesion deficiency" Vet J. 156. 15-21 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagahata,H.et al.: "Survival of transfused CD18-positive granulocytes and their chemiluminescent response in a heifer with leukocyte adhesion deficiency." J Vet Med Sci. 60(2). 261-262 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inanami,O.et al.: "Attenuation of caspase-3-dependent apoptosis by trolox post-treatment of X-irradiated MOLT-4 cells" Int J Radiat Biol. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inanami,O.et al.: "Lipid peroxides and antioxidants in serum of neonatal calves." Am J Vet Res.(in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Inanami,O.et al.: "H2O2-induced activation of SAPK/JNK regulated by phosphatidylinositol 3-kinase in Chinese hamster V79 cells" Antiox Redox Signal. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kuwabara,M.et al: "Modem Application of EPR/ESR : From Biophysics to Materials Science" An ESR study of superoxide generation in stimulated neutrophils from a calf with bovine leukocyte adkesion deficiency (BLAD), 46-53 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Kuwabara: "The increased formation of alkaline-labile sites by a spin-trapping agent,α-phenyl butylnitrone,in γ-irradiated frozen aqueous solution of DNA" J.Radiat.Res.38. 153-155 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] O.Inanami: "The leukocyte NADPH oxidase subunit p47phox The role of the cysteine residues" Arch.Biochem.Biophys.350(1). 36-40 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Asanuma: "Magnetic Resonance imaging of hepatocellular carcinoma in Long-Evance Cinnamon rat under a magnetic field of 7.05T" Jpn.J.Vet.Res.45(3). 147-151 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 浅沼武敏: "小動物の7.05TMRI" 放射線科学. 40(7). 221-223 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] T.Yamashita: "Progressive effect of α-phenyl butylnitrone(PBN)on rat embryo developement in vitro" Free Radical Biol.Med.23(7). 1073-1077 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] O.Inanami: "Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphorylation of p47phox on serine S303 or S304" J.Biol.Chem.(in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Kuwabara: "Modern Applications of ESR/EPR" An ESR study of superoxide generation stimulated neutrophil from a calf with bovine leukocyte adhesion deficiency, 46-53 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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