ストレスに対するホメオサーベイランスのダイナミクスと疾患制御

2011 Fiscal Year Annual Research Report

• Project/Area Number: 22249025
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: 田中 良哉 産業医科大学, 医学部, 教授 (30248562)
• Co-Investigator(Kenkyū-buntansha): 上田 陽一 産業医科大学, 医学部, 教授 (10232745) ; 河野 公俊 産業医科大学, 医学部, 教授 (00153479) ; 中村 利孝 産業医科大学, 医学部, 教授 (50082235)
• Keywords: ストレス科学 / ホメオサーベイランス / 酸化ストレス / 生存脳 / 神経伝達物質 / 免疫伝達物質 / 免疫系 / 代謝系

Research Abstract

生体は多様なストレスを受容し、生存に不可欠な種々の反応を視床下部を中心とした「生存脳の指令センター」を介して、生体の危機管理(ホメオサーベイランス)を行う。本研究では、(1)ストレスをセンシングして。生存脳の指令センター」ヘインプットするメカニズム、(2)「生存脳」から免疫系や代謝系ヘシグナルをアウトプットし、骨格、免疫系を含む全身組織を総動員するメカニズムの解明を目的とした。
平成23年度まで、ストレスセンシングからホメオサーベイランスへの制御システムを各々の系で関連付ける結果が得られた。即ち、疼痛・温度ストレスの視床下部諸核への入力系にバゾプレシン系やTRPチャネルが関与することを明らかにし、生存脳指令センターとして機能する事を解明した。また、酸化ストレスによるDNA損傷に関与する新規転写因子NFlBを同定し、入力異常の分子機構を解明した。一方、代表的な神経伝達物質であるドパミンは、D1様受容体を介して樹状細胞によるナイーブT細胞からTh17細胞への分化、及び、単球から破骨細胞への成熟を誘導し、生存脳から免疫、骨代謝系への出力経路に関与する事を解明した。さらに、力学的ストレスは、PPARγの亢進とTie-2などの血管関連分子抑制を介して、骨芽細胞分化を障害し、骨量低下をもたらす事を解明した。
平成24年度以降は、TRPV1およびTRPV4ノックアウトマウスやヌードマウス移植系を用い、多様なストレスの視床下部への入力情報伝達経路、分子解明を解明する。また、ドパミン等を媒介とする生存脳から骨格、免疫系への出力系が、間葉系幹細胞から骨芽細胞、骨髄幹細胞から破骨細胞、ナイーブT細胞からTh17,Tfh細胞への分化に及ぼす機構を解明する。以上、ストレスに対するホメオサーベイランスのダイナミズムを明らかにし、さらに、生存脳からの出力系の調整を介して免疫・代謝疾患等の制御への戦略を新たな観点から構築することをも目指す。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

ストレスをセンシングして「生存脳の指令センター」へインプットするメカニズムとして、疼痛ストレス・温度ストレスの入力系として生存脳の指令センターとして視床下部に着目し、ストレス受容におけるバゾプレシン系やストレスセンシングに重要なTRPチャネルの関与などを明らかにした。また、ストレスを視床下部へ伝達する際に生ずるDNA損傷や細胞増殖に及ぼす影響を解明した。一方、免疫系や代謝系ヘシグナルをアウトプットについては、ドパミンによるTh17細胞優位の免疫系の誘導機構、破骨細胞の成熟誘導など、及び、力学的ストレスによる骨代謝のバランス制御機構など新たなシグナルアウトプット経路を解明した。以上より、おおむね順調に進展していると考える。

Strategy for Future Research Activity

平成24年度以降は、上記の目的達成のために下記を遂行し、生存脳(視床下部)におけるストレスに対するホメオサーベイランスのダイナミズムを解明し、生存脳から免疫・代謝系への出力経路を解明し、出力経路の調整を介して免疫疾患、代謝疾患等の制御への戦略を新たな観点から目指す。
(1)生存脳として機能する視床下部を中心とした情報伝達経路の解明(上田担当)
バゾプレッシやオキシトシンのトランスジェニックラットを用いて、ストレスに対する視床下部-自律神経系・神経内分泌系の神経回路網の役割を解析する。また、TRPV1およびTRPV4ノックアウトマウスを用いて、慢性疼痛モデルを作成し、急性疼痛に対する反応と比較し、ストレスセンシングとしてのTRPチャネルの役割を検討する。
(2)酸化ストレスなどによるDNA損傷と概日リズム、細胞増殖に関する研究(河野担当)
ヌードマウス移植系での細胞増殖と概日リズムを解析する。即ち、飼育環境照明を変えて細胞増殖、時計関連分子や標的分子の発現を検討し、マイクロアレイにてがん細胞の遺伝子発現を解析し、酸化ストレスとの関連を解明する。
(3)生存脳の出力系から骨・免疫系への情報伝達と病態形成機構の解明(田中担当)
ドパミン、D1様受容体刺激・阻害薬を中心にT細胞や破骨細胞,間葉系幹細胞の分化系における「生存脳」からの出力経路を解明する。また、自己免疫モデルでも出力経路の解明,及び、それらの制御を介した免疫・代謝疾患等の制御への戦略を新たな観点から構築することをも目指す。
(4)力学的ストレス-生存脳-骨代謝調節軸に於ける情報伝達機構の解明(中村担当)
レプチン-交感神経系、DC-STAMP、ephrinB2-Ephb4を介するシグナルについて、力学的ストレス下における、間葉系幹細胞から骨芽細胞への分化、破骨細胞、血管内皮細胞への分化をWnt/β-catehinシグナルやPTH/PTHrPシグナルの解析を中心に関連タンパクと遺伝子の変化を調べ、細胞間シグナルクロストークを解明する。

Research Products

• [Journal Article] In vitro and in vivo analysis of a Jak inhibitor in rheumatoid arthritis (2012)
  • Author(s): Tanaka Y, Maeshima Y, Yamaoaka K
  • Journal Title: Ann Rheum Dis Volume: (in press)
  • Peer Reviewed
• [Journal Article] B-cell or T-cell-dominant recurrence after rituximab therapy in patients with SLE (2012)
  • Author(s): Iwata S, Saito K, Tokunaga M, Tanaka Y
  • Journal Title: Ann Rheum Dis Volume: (in press)
  • Peer Reviewed
• [Journal Article] Amplification of toll-like receptor-mediated signaling through Syk in human B cell activation (2012)
  • Author(s): Iwata S, Yamaoka K, Niiro H, Nakano K, Wang S-P, Akashi K, Tanaka Y
  • Journal Title: J Allergy Clin Immunol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cell autonomous role of TGFss and IL-2 receptor in CD4+ and CD8+ inducible regulatory T cell generation during graft-versus-host disease (2012)
  • Author(s): Sawamukai N, Satake A, Schmidt AM, Lamborn IT, Tanaka Y, Kambayashi T
  • Journal Title: Boold Volume: (in press)
  • Peer Reviewed
• [Journal Article] A JAK inhibitor tofacitinib regulates synovitis through inhibition of IFN-〓 and IL-17 production by human CD4+ T cells (2012)
  • Author(s): Maeshima K, Yamaoaka K, Kubo S, Nakano K, Iwata S, Saito K, Ohishi M, Miyahara H, Tanaka S, Ishi K, Yoshimatsu H, Tanaka Y
  • Journal Title: Arthritis Rheum Volume: (in press)
  • Peer Reviewed
• [Journal Article] Clinical, radiographic, and functional effectiveness of tocilizumab for rheumatoid arthritis patients-REACTION 52-week study- (2012)
  • Author(s): Takeuchi T, Tanaka Y, Amano K, Hoshi D, Nawata M, Nagasawa H, et al
  • Journal Title: Rheumatology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Postmarketing Surveillance of Tocilizumab for Rheumatoid Arthritis in Japan-Interim Analysis of 3,881 Patients (2012)
  • Author(s): Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Tanaka Y, Ito K, et al
  • Journal Title: Ann Rheum Dis Volume: (in press)
  • Peer Reviewed
• [Journal Article] Golimumab, a human anti-TNF-α monoclonal antibody, injected subcutaneously every 4 weeks in Japanese patients with active rheumatoid arthritis in combination with methotrexate : results of the Phase 2/3, multicenter, randomized, double-blind, placebo-controUed GO-FORTH study through 24 weeks (2012)
  • Author(s): Tanaka Y, Harigai M, Takeuchi T, Yamanaka H, Ishiguro N, Yamamoto K, et al
  • Journal Title: Ann Rheum Dis Volume: (in press)
  • Peer Reviewed
• [Journal Article] Efficacy and safety of ocrelizumab in patients with active rheuamatoid arthritis with an inadequate response to at least one TNF inhibitor : results from the phase III SCRIPT trial (2012)
  • Author(s): Tak PP, Mease PJ, Genovese MC, Kremer J, Haraoui B, Tanaka Y, Bingham III CO, et al
  • Journal Title: Arthritis Rheum Volume: (in press)
  • Peer Reviewed
• [Journal Article] A JAK inhibitor tofacitinib regulates synovitis through inhibition of IFN-_Y and IL-17 production by human CD4+ T cells (2012)
  • Author(s): Maeshima K, Yamaoaka K, Kubo S, Nakano K, Iwata S, Tanaka Y, et al
  • Journal Title: Arthritis Rheum Volume: (in press)
  • Peer Reviewed
• [Journal Article] GABA is excitatory in adult vasopressinergic neuroendocrine cells (2012)
  • Author(s): Haam, J., Popescu, IR., Morton, LA., Halmos, KC., Teruyama, R., Ueta, Y., Tasker, JG.
  • Journal Title: Journal of Neuroscience Volume: (in press)
  • Peer Reviewed
• [Journal Article] Induction of arginine vasopressin-enhanced green fluorescent protein expression in the locus coeruleus following kainic acid-induced seizures in rats (2012)
  • Author(s): Ohno, M., Fujihara, H., Iwanaga, M., Todoroki, M., Katoh, A., Ohbuchi, T., Ishikura, T., Hamamura, A., Hachisuka, K., Ueta, Y.
  • Journal Title: Stress Volume: (in press)
  • Peer Reviewed
• [Journal Article] New roles of Mitochondrial Transcription Factor A in Cancer (2012)
  • Author(s): Yoshida, Y, Hoshino, S., Izumi, H., Kohno, K., Yamashita, Y.
  • Journal Title: J.phys.chem Volume: (in press)
  • Peer Reviewed
• [Journal Article] mtTFA regulates BCL2L1 gene expression and is a prognostic factor in serous ovarian cancer (2012)
  • Author(s): Kurita, T., Izumi, H., Kagami, S., Kawagoe, T., Toki, N., Matsuura, Y, Hachisuga, T., Kohno, K.
  • Journal Title: Cancer Sci. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Consistency of fracture risk reduction in Japanese and Caucasian osteoporosis patients treated with teriparatide : a meta-analysis (2012)
  • Author(s): Nakamura T, Tsujimoto M, Hamaya E, Sowa H, Chen P
  • Journal Title: J Bone Miner Metab. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Dose-response study of denosumab on bone mineral density and bone turnover markers in Japanese postmenopausal women with osteoporosis (2012)
  • Author(s): Nakamura T, Matsumoto T, Sugimoto T, Shiraki M
  • Journal Title: Osteoporos Int. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Dopamine induces IL-6-dependent IL-17 production via D1-like receptor on CD4 naive T-cells and a D1-like receptor antagonist SCH-23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model (2011)
  • Author(s): Nakano K, Yamaoka K, Hanami K, Saito K, Sasaguri Y, Yanagihara N, Tanaka S, Katsuki I, Matsushita S, Tanaka Y
  • Journal Title: J Immunol Volume: 186 Pages: 3745-3752
• [Journal Article] Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production (2011)
  • Author(s): Oshita K, Yamaoka K, Udagawa N, Fukuyo S, Sonomoto K, Tanaka Y
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 1658-1667
  • Peer Reviewed
• [Journal Article] Upregulation of arginine vasopressin synthesis in the rat hypothalamus after kainic acid-induced seizures (2011)
  • Author(s): Iwanaga, M., Ohno, M., Katoh, A., Ohbuchi, T., Ishikura, T., Fujihara, H., Nomura, M., Hachisuka, K., Ueta, Y.
  • Journal Title: Brain Research Volume: 1424 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Induction of Fos expression in the rat forebrain after intragastric administration of monosodium L-glutamate, glucose and NaCl (2011)
  • Author(s): Otsubo, H., Kondoh, T., Shibata, M., Ueta, Y., Torii, K.
  • Journal Title: Neuroscience Volume: 196 Pages: 97-103
  • Peer Reviewed
• [Journal Article] Temporal profile of arginine vasopressin release from the neurohypophysis in response to hypertonic saline and hypotension measured using a fluorescent fusion protein (2011)
  • Author(s): Yao, ST., Antunes, VR., Bradley, PM., Kasparov, S., Ueta, Y., Paton, JF., Murphy, D.
  • Journal Title: Journal of Neuroscience Methods Volume: 201 Pages: 191-195
  • Peer Reviewed
• [Journal Article] Angiotensin II type 1 receptor signaling regulates feeding behavior through anorexigenic corticotropin-releasing hormone in hypothalamus (2011)
  • Author(s): Yamamoto, R., Akazawa, H., Fujihara, H., Ozasa, Y., Yasuda, N., Ito, K., Kudo, Y., Qin, Y., Ueta, Y., Komuro, I.
  • Journal Title: Journal of Biological Chemistry Volume: 286 Pages: 21458-21465
  • Peer Reviewed
• [Journal Article] Central effects of ghrelin, a unique peptide, on appetite and fluid/water drinking behavior (2011)
  • Author(s): Hashimoto, H., Ueta, Y.
  • Journal Title: Current Protein and Peptide Science Volume: 12 Pages: 280-287
  • Peer Reviewed
• [Journal Article] Highly visible expression of an oxytocin-monomeric red fluorescent protein 1 fusion gene in the hypothalamus and posterior pituitary of transgenic rats (2011)
  • Author(s): Katoh, A., Fujihara, H., Ohbuchi, T., Onaka, T., Hashimoto, T., Kawata, M., Suzuki, H., Ueta, Y.
  • Journal Title: Endocrinology Volume: 152 Pages: 2768-2774
  • Peer Reviewed
• [Journal Article] Possible contribution of pannexin channel to ATP-induced currents in vitro in vasopressin neurons isolated from the rat supraoptic nucleus (2011)
  • Author(s): Ohbuchi, T., Yokoyama, T., Saito, T., Ohkubo, J., Suzuki, H., Ishikura, T., Katoh, A., Fujihara, H., Hashimoto, H., Suzuki, H., Ueta, Y.
  • Journal Title: Brain Research Volume: 1394 Pages: 71-78
  • Peer Reviewed
• [Journal Article] V2 receptor-mediated autocrine role of somato-dendritic release of arginine vasopressin in volume regulation of rat supraoptic vasopressin neurons under hypoosmotic conditions (2011)
  • Author(s): Sato, K., Numata, T., Ueta, Y., Okada, Y.
  • Journal Title: Science Signaling Volume: 157 Pages: 4-5
  • Peer Reviewed
• [Journal Article] Allyl isothiocyanates and cinnamaldehyde potentiate miniature excitatory postsynaptic inputs in the sipraoptic nucleus in rats (2011)
  • Author(s): Yokoyama, T., Ohbuchi, T., Saito, T., Fujihara, H., Minami, K., Nagatomo, T., Uezono, Y., Ueta, Y.
  • Journal Title: European Journal of Pharmacology Volume: 655 Pages: 31-37
  • Peer Reviewed
• [Journal Article] Hypothalamic vasopressin response to stress and various physiological stimuli : Visualization in transgenic animal models (2011)
  • Author(s): Ueta, Y., Dayanithi, G., Fujihara, H.
  • Journal Title: Hormones and Behavior Volume: 59 Pages: 221-226
  • Peer Reviewed
• [Journal Article] Similar changes of hypothalamic feeding-regulating peptides mRNAs and plasma leptin levels in PTHrP-, LIF-secreting tumors-induced cachectic rats and adjuvant arthritic rats (2011)
  • Author(s): Suzuki, H., Hashimoto, H., Kawasaki, M., Watanabe, M., Otsubo, H., Ishikura, T., Fuiihara, H., Ohnishi, H., Onuma, E., Yamada-Okabe, H., Takuwa, Y., Ogata, E., Nakamura, T., Ueta, Y.
  • Journal Title: International Journal of Cancer Volume: 28 Pages: 2215-2223
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of activating transcription factor 4 under oxidative stress in retinal pigment epithelial ARPE-19/HPV-16 cells (2011)
  • Author(s): Miyamoto, N., Izumi, H., Bin, H., Miyamoto, R., Kondo, H., Tawara, A., Sasaguri, Y., Kohno, K.
  • Journal Title: Invest.Ophthalmol.Vis.Sci. Volume: 52 Pages: 1226-1234
  • Peer Reviewed
• [Journal Article] Quercetin induces the expression of Peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway (2011)
  • Author(s): Miyamoto, N., Izumi, H., Miyamoto, R., Kondo, H., Tawara, A., Sasaguri, Y., Kohno, K.
  • Journal Title: Invest.Ophthalmol.Vis.Sci. Volume: 52 Pages: 1055-1063
  • Peer Reviewed
• [Journal Article] Enhanced expression of nuclear factor I/B in oxaliplatin-resistant human cancer cell lines (2011)
  • Author(s): Kashiwagi, E., Izumi, H., Yasuniwa, Y., Baba, R., Doi, Y., Kidani, A., Arao, T., Nishio, K., Naito, S., Kohno, K.
  • Journal Title: Cancer Sci. Volume: 102 Pages: 382-386
  • Peer Reviewed
• [Journal Article] Involvement of riboflavin kinase expression in cellular sensitivity against cisplatin (2011)
  • Author(s): Hirano, G., Izumi, H., Yasuniwa, Y., Shimajiri, S., Wang, K.Y., Sasaguri, Y., Kusaba, H., Matsumoto, K., Hasegawa, T., Akimoto, M., Akashi, K., Kohno, K.
  • Journal Title: Int.J.Oncol. Volume: 38 Pages: 893-902
  • Peer Reviewed
• [Journal Article] Clinical usefulness of mitochondrial transcription factor A expression as a predictive marker in colorectal cancer patients treated with FOLFOX (2011)
  • Author(s): Yoshida, Y., Hasegawa, J., Nezu, R., Kim, Y.K., Hirota, M., Kawano, K., Izumi, H., Kohno, K.
  • Journal Title: Cancer Sci. Volume: 102 Pages: 578-582
  • Peer Reviewed
• [Journal Article] Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells (2011)
  • Author(s): Izumi, H., Takahashi, M., Uramoto, H., Nakayama, Y., Oyama, T., Wang, K.Y., Sasaguri, Y, Nishizawa, S., Kohno, K.
  • Journal Title: Cancer Sci. Volume: 102 Pages: 1007-1013
  • Peer Reviewed
• [Journal Article] Sasaguri, Y. : Histamine Deficiency Decreases Atherosclerosis and Inflammatory Response in Apolipoprotein E Knockout Mice Independently of Serum Cholesterol Level (2011)
  • Author(s): Wang, K.Y., Tanimoto, A., Guo, X., Yamada, S., Shimajiri, S., Murata, Y., Ding, Y., Tsutsui, M., Kato, S., Watanabe, T., Ohtsu, H., Hirano, K., Kohno, K.
  • Journal Title: ATVB Volume: 31 Pages: 800-807
  • Peer Reviewed
• [Journal Article] Human mitochondrial transcription factor A functions in both nuclei and mitochondria and regulates cancer cell growth (2011)
  • Author(s): Han, B., Izumi, H., Yasuniwa, Y, Akiyama, M., Yamaguchi, T., Fujimoto, N., Matsumoto, T., Wu, B., Tanimoto, A., Sasaguri, Y., Kohno, K.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 408 Pages: 45-51
  • Peer Reviewed
• [Journal Article] Hollingsworth, M.A. : Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth (2011)
  • Author(s): Taniuchi, K., Cerny, R.L., Tanouchi, A., Kohno, K., Kotani, N., Honke, K., Saibara, T.
  • Journal Title: Oncogene Volume: 30 Pages: 4843-4854
  • Peer Reviewed
• [Journal Article] Polypeptide N-acetylgalactos aminyltransferase 6 expression in pancreatic cancer is an independent prognostic factor indicating better overall survival (2011)
  • Author(s): i, Z., Yamada.S., Inenaga, S., Imamura, T., Wu, Y, Wang, K.Y., Shimajiri, S., Nakano, R., Izumi, H., Kohno, K., Sasaguri, Y.
  • Journal Title: Br.J.Cancer Volume: 104 Pages: 1882-1889
  • Peer Reviewed
• [Journal Article] Reduced bone formation in alcohol-induced osteopenia is associated with elevated p21 expression in bone marrow cells in aldehyde dehydrogenase 2-disrupted mice (2011)
  • Author(s): Shimizu Y, Sakai A, Menuki K, Mori T, Isse T, Oyama T, Kawamoto T, Nakamura T
  • Journal Title: Bone. Volume: 48 Pages: 1075-1086
  • Peer Reviewed
• [Journal Article] Lower osteocalcin and osteopontin contents of the femoral head in hip fracture patients than osteoarthritis patients (2011)
  • Author(s): Tanaka S, Narusawa K, Onishi H, Miura M, Hijioka A, Kanazawa Y, Nishida S, Ikeda S, Nakamura T
  • Journal Title: Osteoporos Int. Volume: 22 Pages: 587-597
  • Peer Reviewed
• [Journal Article] Similar changes of hypothalamic feeding-regulating peptides mRNAs and plasm leptin levels in PTHrP-, LIF-secreting tumors-induced cachectic rats and adjuvant arthritic rats (2011)
  • Author(s): Suzuki H, Hashimoto H, Kawasaki M, Watanabe M, Otsubo H, Ishikura T, Fujihara H, Ohnishi H, Onuma E, Yamada-Okabe H, Takuwa Y, Ogata E, Nakamura T, Ueta Y
  • Journal Title: Int J Cancer. Volume: 128 Pages: 2215-2223
  • Peer Reviewed
• [Presentation] In vitro and in vitro analysis of a Jak inhibitor in RA (2011)
  • Author(s): Tanaka Y.
  • Organizer: Advances in Targeted Therapies
  • Place of Presentation: クロアチア(ドブロニク)(招待講演)
  • Year and Date: 20110406-20110409
• [Presentation] Is biologic-free remission possible in patients with RA? (2011)
  • Author(s): Tanaka Y
  • Organizer: Advances in Targeted Therapies
  • Place of Presentation: クロアチア(ドブロニク)(招待講演)
  • Year and Date: 20110406-20110409
• [Presentation] Next stage of RA treatment : bio-free remission will become a possible treatment goal-RRR study update (2011)
  • Author(s): Tanaka Y
  • Organizer: The 5th Asian Congress on Autoimmunity
  • Place of Presentation: シンガポール,サンテック国際会議場(招待講演)
  • Year and Date: 2011-11-18
• [Presentation] Signal transduction inhibitors for the treatment of rheumatoid arthritis (2011)
  • Author(s): Tanaka Y
  • Organizer: Bio-Rheumatology International Congress (BRIC) Tokyo, The 8th GARN Meeting
  • Place of Presentation: 東京商工会議所(東京都)(招待講演)
  • Year and Date: 2011-11-04
• [Presentation] Discontinuation of adalimumab after attaining remisison in patients with rheumatoid arthritis (2011)
  • Author(s): Tanaka Y S.Hirata, M.Nawata, S.Kubo, K.Saito
  • Organizer: The Annual European Congress of Rheumatology
  • Place of Presentation: イギリス、ロンドン,ExCeL LONDON(招待講演)
  • Year and Date: 2011-05-27