Research of the fimction of SOCS3 in the pathogenesis ofpscriasis using keratinocyte specific SOCS3 knozkout mice

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 18390314
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Ehime University
• Principal Investigator: HASHIMOTO Koji Ehime University, Graduate School of Medicine, Professor (00110784)
• Co-Investigator(Kenkyū-buntansha): SHIRAKATA Yuji Ehime University, Graduate School of Medicine, Senior Assistant Professor (50226320) ; HANAKAWA Yasushi Ehime University, Graduate School of Medicine, Assistant Professor (90284398) ; HIRAKAWA Satoshi Ehime University, University Hospital, Senior Assistant Professor (50419511)
• Project Period (FY): 2006 – 2007
• Keywords: psoriasis / keratinocytes / SOCS3 / STAT3 / keratinocyte-specific knockout mouse / regeneration / RT-PCR / epidermal thickenin

Research Abstract

STAT3 is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with IL-6, EGF and many other growth factors. STAT3 plays critical roles in biological function such as cell proliferation, migration and so on. Suppressors of cytokine signaling (SOCS) regulate the strength of cytokine signals. SOCS3 is strongly induced by a variety of cytokines and other stimulators. The suppressive effect of SOCS3 has been shown to be relatively specific to STAT3. Therefore we investigated the role of SOCS3 in epidermal keratinocytes. Since germline targeting of the SOCS3 gene resulted in embryonic lethality, we generated keratinocyte-specific SOCS3-deficient mice (KS-SOCS3-/-mice) using Cre/loxP technology in combination with the keratin 5 promoter. KS-SOCS3-/-mice were viable and their skin appeared normal at birth. No histological alterations were found in skin of KS-SOCS3-/-mice, however, after 20 weeks, their skin was red and scaly, hyperkeratotic lesions developed in the ear, tail and the back skin in some mice. Histological analysis of skin lesions showed a marked hyperplasia, elongation of rete ridge, loss of granular layer and parakeratosis. These phenotype and histology show a strong resemblance to human psoriasis lesions. Next we utilized tape stripping which is a mild form of epidermal injury. KS-SOCS3-/-mice developed scaly lesions as early as 4days after stripping, whereas wild type mice showed a mild phenotype. The phenotype found in KS-SOCS3-/-mice prolonged until 14 days after stripping when wild type mice showed no obvious clinical phenotype. Tape stripping-induced lesions of KS-SOCS3-/-mice also showed histological feature of human psoriasis. Keratinocytes in the epidermis of KS-SOCS3-/-mice were highly positive for Ki67. Phosphorylated STAT3 staining was strong in KS-SOCS3-/-mice compared to wild type mice. In conclusion, loss of SOCS3, an endogenous inhibitor of STAT3, in epidermal keratinocytes leads to clinical phenotype of human psoriasis.

Research Products

• [Journal Article] An intermediary role of proHB-EGF shedding in growth factor-induced c-Myc gene expression (2008)
  • Author(s): Nanba D, Inoue H, Shigemi Y, Shirakata Y, Hashimoto K, Higashiyama S
  • Journal Title: J Cell Physiol 214 Pages: 465-73
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] PPARgamma is an important transcription factor in lalpha,25-dihydroxyvitamin D3-induced involucrin expression (2008)
  • Author(s): Dai X, Sayama K, Shirakata Y, Tokumaru S, Yang L, Tohyama M, Hirakawa S, Hanakawa Y, Hashimoto K
  • Journal Title: J Dermatol Sci 50 Pages: 53-60
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] An intermediary role of proBB-EGF shedding in growth factor-induced c-Myc gene expression (2008)
  • Author(s): Nanba, D, Inoue, H, Shigemi, Y, Shirakata, Y, Hashimoto, K, Higashiyama, S
  • Journal Title: J Cell Physiol 214 Pages: 465-73
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PPARgamma is an important transcription factor in lalpha,25-dihyclroxyvitamin 03-induced involucrin expression (2008)
  • Author(s): Dai, X, Sayama, IC, Shirakata, Y, Tokunaru, S, Yang, L, Tohyama, M, Hirakawa, S, Hanakawa, Y, Hashimoto, K
  • Journal Title: I Dermatol Sci 50 Pages: 53-60
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pre-B-cell leukemia transcription factor 1 is a major target of promyelocytic leukemiazinc-finger-mediated melanoma cell growth suppression (2007)
  • Author(s): Shiraishi K, Yamasaki K, Nanba D, Inoue H, Hanakawa Y, Shirakata Y, Hashimoto K, Higashiyama S
  • Journal Title: Oncogene 26 Pages: 339-48
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Human corneal epithelial cell proliferation by epiregulin and its cross-induction by other EGF family members (2007)
  • Author(s): Morita S, Shirakata Y, Shiraishi A, 1 Kadota Y, Hashimoto K, Higashiyama S, Ohashi Y
  • Journal Title: Molecular Vision 13 Pages: 2119-2128
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Epiregulin,a member of the EGF family,is over-expressed in psoriatic epidermis (2007)
  • Author(s): Shirakata Y, Kishimoto J, Tokumaru S, Yamasaki K, Hanakawa Y, Tohyama M, Sayama K, Hashimoto K
  • Journal Title: J Dermatol Sci 45 Pages: 69-72
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Hair follicle regeneration using grafted rodent and human cells (2007)
  • Author(s): Ehama R, Ishimatsu-Tsuji Y, Iriyama S, Ideta R, Soma T, Yano K, Kawasaki C, Suzuki S, Shirakata Y, Hashimoto K, Kishimoto J
  • Journal Title: J Invest Dermatol 127 Pages: 2106-15
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] STATSa/PPARgamma Pathway Regulates Involucrin Expression in Keratinocyte Differentiation (2007)
  • Author(s): Dai X, Sayama K, Shirakata Y, Hanakawa Y, Yamasaki K, Tokumaru S, Yang L, Wang X, Hirakawa S, Tohyama M, Yamauchi T, Takashi K, Kagechika H, Hashimoto K
  • Journal Title: J Invest Dermatol 127 Pages: 1728-35
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Suppressor of cytokine signaling 3 negative regulation of signal transducer and activator of transcription 3 in platelet-derived growth factor-induced fibroblast migration (2007)
  • Author(s): Nagai H, Tokumaru S, Sayama K, Shirakata Y, Hanakawa Y, Hirakawa S, Dai X, Tohyama M, Yang L, Hashimoto K
  • Journal Title: J Dermatol 34 Pages: 523-530
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] CXCL16 is a novel mediator of the innate immunity of epidermal keratinocytes (2007)
  • Author(s): Tohyma M, Sayama K, Komatsuzawa H, Hanakawa Y, Shirakata Y, Dai X, Yang L, Tokumaru S, Nagai H, Hirakawa S, Sugai M, Hashimoto K
  • Journal Title: Int Immunol 19 Pages: 1095-1102
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome (2007)
  • Author(s): Tohyama M, Hashimoto K, Yasukawa M, Kimura H, Horikawa T, Nakajima K, Urano Y, Matsumoto K, Iijima M, Shear NH
  • Journal Title: Br J Dermatol 157 Pages: 934-40
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pre-B-cell leukemia transcription factor is a major target of promyelocytic leukemia zinc-finger-mediated melanoma cell growth suppression (2007)
  • Author(s): Shiraishi, K, Yamasaki, K, Nanba, D, Inoue, H, Hanakawa, Y, Shirakata, Y, Hashimoto, K, Higashiyama, S
  • Journal Title: Oncogene 26 Pages: 339-48
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human corneal epithelial cell proliferation by epiregulin and its cross-induction by other EGF family members (2007)
  • Author(s): Morita, S, Shirakata, Y, Shiraishi, A,1 Kadota, Y, Hashimoto, K, Higashiyama, S, Ohashi, Y
  • Journal Title: Molecular Vision 13 Pages: 2119-2128
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Epiregulin, a member of the EGF family, is over-expressed in psoriatic epidennis. (2007)
  • Author(s): Shirakata, Y, Kishimoto, J, Tokumaru, S, Yamasaki, K, Hanakawa, Y, Tohyama, M, Sayama, K, Hashimoto, K
  • Journal Title: J Dermatol Sci 45 Pages: 69-72
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hair follicle regeneration using grafted rodent and human cells (2007)
  • Author(s): Ehama, R, Ishimatsu-Tsuji, Y, Iriyama, S, Ideta, R, Soma, T, Yano, K, Kawasaki, C, Suzuki, S, Shirakata, Y, Hashimoto, K, Kishimoto, J
  • Journal Title: J Invest Dennatol 127(9) Pages: 2106-15
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] STATSa/PPARgamma Pathway Regulates Involucrin Expression in Keratinocyte Differentiation (2007)
  • Author(s): Dai, X, Sayama, K, Shirakata, Y, Hanakawa, Y, Yamasaki, K, Tokumaru, S, Yang, L, Wang, X, Hirakawa, S, Tohyama, M, Yamauchi, T, Takashi, K, Kagechika, H, Hashimoto, K
  • Journal Title: I Invest Dermatol 127(7) Pages: 1728-35
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppressor of cytokine signaling 3 negative regulation of signal transducer and activator of transcription 3 in platelet-derived growth factor-induced fibroblast migration (2007)
  • Author(s): Nagai, H, Tokumaru, S, Sayama, K, Shirakata, Y, Hanakawa, Y, Hirakawa, S, Dai, X, Tohyaraa, M, Yang, L, Hashimoto, K
  • Journal Title: Dermatol 34 Pages: 523-530
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CXCL16 is a novel mediator of the innate immunity of epidermal keratinocytes (2007)
  • Author(s): Tohyma, M, Sayama, K, Komatsuzawa, H, Hanakawa, Y, Shirakata, Y, Dai, X, Yang, L, Tokumara, S, Nagai, H, Hirakawa, S, Sugai, M, Hashimoto, K
  • Journal Title: Int Inununol 19 Pages: 1095-1102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome (2007)
  • Author(s): Tohyama, M, Hashimoto, K, Yasukawa, M, Kimura, H, Horikawa, T, Nakajima, K, Urano, Y, Matsumoto, K, lijima, M, Shear, NH
  • Journal Title: Br J Dermatol 157 Pages: 934-40
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TAK1 is essential for differentiation and the prevention of apoptosis in epidermis (2006)
  • Author(s): Sayama K, Hanakawa Y, Nagai H, Shirakata Y, Dai X, Hirakawa S, Tokumaru S, Tohyama M, Yang L, Sato S, Shizuo A, Hashimoto K
  • Journal Title: The Journal of Biological Chemistry 281 Pages: 22013-20
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] New skin-equivalent model from de-epithelialized amnion membrane (2006)
  • Author(s): Yang L, Shirakata Y, Shudou M, DailX, Tokumaru S, Hirakawa S, Sayama K, Hamuro J, Hashimoto K
  • Journal Title: Cell and Tissue Research 326 Pages: 69-77
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A novel function of angiotensin II in skin wound healing (2006)
  • Author(s): Yahata Y, Shirakata Y, Tokumaru S, Yang L, Dai X, Tohyama M, Tsuda T, Sayama K, Iwai M, Horiuchi M, Hashimoto K
  • Journal Title: The Journal of Biological Chemistry 281 Pages: 13209-16
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] SOCS1 negative feedback of STAT1 activation is a key pathway in the dsRNA-inducedinnate immune response of human keratinocytes (2006)
  • Author(s): Dai X, Sayama K, Yamasaki K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yahata Y, Yang L, Yoshimura A, Koji Hashimoto K
  • Journal Title: J Invest Dermatol 126 Pages: 1574-81
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] TAK I is essential for differentiation and the prevention of apoptosis in epidermis (2006)
  • Author(s): Sayama, K, Hanakawa, Y, Nagai, H, Shiralcata, Y, Dai, X, Hirakawa, S, Tokumaru, S, Tohyama, M, Yang, L, Sato, S, Shizuo, A, Hashimoto, K
  • Journal Title: J Biol Chem 281 Pages: 22013-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] New skin-equivalent model from de-epithelialized amnion membrane (2006)
  • Author(s): Yang, L, Shirakata, Y, Shudou, M, Dai, IX, Tokumaru, S, Hirakawa, S, Sayama, K, Hamuro, J, Hashimoto, K
  • Journal Title: Cell Tissue Res 326 Pages: 69-77
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A novel function of angiotensin II in skin wound healing (2006)
  • Author(s): Yahata, Y, Shirakata, Y, Tokumaru, S, Yang, L, Dai, X, Tohyama, M, Tsuda, T, Sayama, K, Iwai, M, Horiuchi, M, Hashimoto, K
  • Journal Title: J Biol Chem 281 Pages: 13209-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] SOCSI negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes (2006)
  • Author(s): Dai, X, Sayama, K, Yamasaki, K, Tohyama, M, Shirakata, Y, Hanakawa, Y, Tokumaru, S, Yahata, Y, Yang, L, Yoshimura, A, Koji, Hashimoto, K
  • Journal Title: J Invest Dermatol 126 Pages: 1574-81
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A new skin equivalent using de-epithelialized amnion membrane (2007)
  • Author(s): Shirakata Y, Yang L, Hashimoto K
  • Organizer: 8th Congress of the German-Japanese Society of Dermatology
  • Place of Presentation: Yokohama
  • Year and Date: 20071115-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Milroy's disease: a case report of the congenital lymphedema pedigree (2007)
  • Author(s): Hirakawa S, Murakaami S, Hashimoto K
  • Organizer: The 15th Korea-Japan Joint Meeting of Dermatology
  • Place of Presentation: Jeju
  • Year and Date: 20070602-03
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Milroy's dicense : a case report of the congenital lymphedema pedigree (2007)
  • Author(s): Hirakawa, S, Murakaami, S, Hashimoto, K
  • Organizer: The 15th Korea-Japan Joint Meeting of Dermatology
  • Place of Presentation: Jeju
  • Year and Date: 20070602-03
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] PPAR-gamma is involved in 1.25-dihydroxyvitamin D3-induced beta-defensin-3 and cathelicidin expression in normal keratinocyte. (2007)
  • Author(s): Dai X, Shirakata Y, Sayama K, Tokumaru S, Hirakawa S, Tohyama M, Yang L, Hashimoto K
  • Organizer: 68th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Los Angeles
  • Year and Date: 20070509-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Development of a new skin equivalent model using de-epithelialized amnion membrane (2007)
  • Author(s): Yang L, Shirakata Y, Dai X, Tokumaru S, Hirakawa S, Sayama K, Hashimoto K
  • Organizer: 68th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Los Angeles
  • Year and Date: 20070509-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Ablation of TAK1 in mouse keratinocytes disturbed hair follicle development (2007)
  • Author(s): Sayama K, Kajiya K, Shirakata Y, Hanakawa Y, Hirakawa S, Dai X, Nagai H, A kira S, Kishimoto J, Hashimoto K
  • Organizer: 68th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Los Angeles
  • Year and Date: 20070509-12
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] PPAR-gamma is involved in 1.25-dihydroxyvitamin D3-induced beta-defensin-3 and cathelicidin expression in normal keratinocyte (2007)
  • Author(s): Dai, X, Shirakata, Y, Sayama, K, Tokumaru, S, Hirakawa, S, Tohyama, M, Yang, L, Hashimoto, K
  • Organizer: 68th Annual Meeting of the Society for investigative Dermatology
  • Place of Presentation: Los Angeles
  • Year and Date: 20070509-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Ablation of TAKI in mouse keratinocytes disturbed hair follicle development (2007)
  • Author(s): Sayama, K, Kajiya, K, Shirakata, Y, Hanakawa, Y, Hirakawa, S, Dai, X, Nagai, H, Akira, S, Kishimoto, J, Hashimoto, K
  • Organizer: 68th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Los Angeles
  • Year and Date: 20070509-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Targeted overexpression of VEGF-A or-C in the skin promotes lymph node lymphangiogenesis and metastasis (2007)
  • Author(s): Hirakawa S, Kodama S, Brown LF, Paavonen K, Hashimoto K, Alitalo K, Detmar M
  • Organizer: 2nd International symposium on cancer metastasis and the lymphovascular system
  • Place of Presentation: Sanfrancisco
  • Year and Date: 20070502-05
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Targeted overexpression of VEGF-A or -C in the skin promotes lymph node lymphangiogenesis and metastasis (2007)
  • Author(s): Hirakawa, S, Kodama, S, Brown, LF, Paavonen, K, Hashimoto, K, Alitalo, K, Detmar, M
  • Organizer: 2nd International symposium on cancer metastasis and the lymphovascular system
  • Place of Presentation: Sanfrancisco
  • Year and Date: 20070502-05
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] PPARγ/C/EBPalpha signaling pathway plays a key role in 1,25-dihydroxyvitamin D3-induced keratinocyte differentiation. (2006)
  • Author(s): Y Shirakata, X Dai, S Tokumaru, Y Hanakawa, M Tohyama, L Yang, K Sayama, and K Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] hBD1-induced keratinocyte migration is mediated through HB-EGF/EGFR transactivation mechanism. ays a key role in 1,25-dihydroxyvitamin D3-induced keratinocyte differentiation. (2006)
  • Author(s): S Tokumaru, Y Shirakata, Y Hanakawa, X Dai, K Kameda, M Tohyama, K Sayama, K Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Bone morphogenetic protein-2 modulates Wnt and frizzled expression and enhances the canonical pathway of Wnt signaling in normal human keratinocytes. (2006)
  • Author(s): L Yang, K Yamasaki, Y Shirakata, X Dai, S Tokumaru, M Tohyama, Y Hanakawa, K Kameda, K Sayama, K Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Pbx1 is a major target of PLZF-mediated melanoma cell growth suppression. (2006)
  • Author(s): K Shiraishi, Y Shirakata, K Yamasaki, Y Hanakawa, S Higashiyama, K Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] PPARy/C/EBPalpha signaling pathway plays a key role in 1,25-dihydroxyvitamin D3-induced keratinocyte differentiation (2006)
  • Author(s): Y, Shirakata, X, Dai, S, Tokumaru, Y, Hanakawa, M, Tohyama, L, Yang, K, Sayama, K, Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] hBD1-induced keratinocyte migration is mediated through HB-EGF/EGFR transactivation mechanism.ays a key role in 1,25-dihydroxyvitamin D3-induced keratinocyte differentiation (2006)
  • Author(s): S, Tokumaru, Y, Shirakata, Y, Hanakawa, X, Dai, K, Kameda, M, Tohyama, K, Sayama, K, Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Bone morphogenetic protein-2 modulates Wnt and frizzled expression and enhances the canonical pathway of Wnt signaling in normal human keratinocytes (2006)
  • Author(s): L, Yang, K, Yamasaki, Y, Shirakata, X, Dai, S, Tokummu, M, Tohyama, Y, Hanakawa, K, Kameda, K, Sayama, K, Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Pbxl is a major target of PLZF-mediated melanoma cell growth suppression (2006)
  • Author(s): K, Shiraishi, Y, Shirakata, K, Yamasaki, Y, Hanakawa, S, Higashiyama, K, Hashimoto
  • Organizer: The 67th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Philadelphia
  • Year and Date: 20060504-06
  • Description: 「研究成果報告書概要(欧文)」より