ガス分子を介した新しい生体制御機構の学際的アプローチによる解明と医学への応用

2009 年度 研究成果報告書

• 研究課題/領域番号: 17GS0419
• 研究種目: 学術創成研究費
• 配分区分: 補助金
• 研究機関: 慶應義塾大学
• 研究代表者: 末松 誠 慶應義塾大学, 医学部, 教授 (00206385)
• 研究分担者: 斎藤 正男 東北大学, 多元物質研究所, 教授 (70302239) ; 曽我 朋義 慶應義塾大学, 環境情報学部, 教授 (60338217) ; 平尾 敦 金沢大学, がん研究所, 教授 (90343350) ; 田中 廣壽 東京大学, 医科学研究所, 准教授 (00171794)
• 研究期間 (年度): 2005 – 2009
• キーワード: 一酸化炭素 / ガスバイオロジー / 酸素センサー / メタボローム / cytochrome oxidase / 構造生物学 / ミトコンドリア / Hypoxia inducible factor

研究概要

ガス分子の受容体探索は、それ自体の技術的困難と、異なるガス分子と受容体が構成する複雑なフィードバックが交錯する代謝システムの系統的解析が困難であったために未開の領域であった。本プロジェクトではメタボロームと分子質量イメージングなどの最新の質量分析技術と計算機科学による予測生物学的アプローチを駆使してこの問題を解決し、新しい酸素センシング機構やストレス応答で変動するCO, NO, H2Sを介した細胞機能制御機構を発見し、それらが構成する複雑かつ精妙なガス分子感受性代謝システム制御機構の存在が示唆された。

研究成果

• [雑誌論文] Regulation of the HIF-1α level is essential for hematopoietic stem cells. (2010)
  • 著者名/発表者名: Takubo K, Goda N, Yamada W, Ikeda E Kubota Y, Shima H Johnson RS, Hirao A, Suematsu M, Suda T
  • 雑誌名: Cell Stem Cell (in press)
• [雑誌論文] Paradoxical ATP elevation in ischemic penumbra revealed by quantitative imaging mass spectrometry. (2010)
  • 著者名/発表者名: Hattori K, Kajimura M, Nakanishi T, Fujiwake H, Ogawa K, Nagahata Y, Hishiki T, Kubo A, Setou M, Suematsu M
  • 雑誌名: Antioxid Redox Signal (In press)
• [雑誌論文] von Hippel-Lindau protein regulates transition from fetal to adult circulatory system in retina. (2010)
  • 著者名/発表者名: Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, M. Simon C, Johnson RS, Suematsu M, Tsubota K, Ishida S, Goda N, Suda T, Okano H
  • 雑誌名: Development 137(9) ページ: 1563-1571
• [雑誌論文] Interactions of multiple gas-transducing systems: Hallmarks and uncertainties of CO, NO and H2S gas biology. (2010)
  • 著者名/発表者名: Kajimura M, Fukuda R, Bateman RM, Yamamoto T, Suematsu M
  • 雑誌名: Antioxid Redox Signal (In press)
• [雑誌論文] TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. (2010)
  • 著者名/発表者名: Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, Nakao S, Motoyama N, Hirao A
  • 雑誌名: Nature 463 ページ: 676-680
• [雑誌論文] Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. (2009)
  • 著者名/発表者名: Endo J, Sano M, Katayama T, Hishiki T, Shinmura K, Morizane S, Matsuhashi T, Katsumata Y, Zhang Y, Ito H, Nagahata Y, Marchitti S, Nishimaki K, Wolf AM, Nakanishi H, Hattori F, Vasiliou V, Adachi T, Ohsawa I, Taguchi R, Hirabayashi Y, Ohta S, Suematsu M, Endo J, Sano M, K
  • 雑誌名: Circ Res 105(11) ページ: 1118-1127
• [雑誌論文] Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin. (2009)
  • 著者名/発表者名: Tamase A, Muraguchi T, Naka K, Tanaka S, Kinoshita M, Hoshii T, Ohmura M, Shugo H, Ooshio T, Nakada M, Sawamoto K, Onodera M, Matsumoto K, Oshima M, Asano M, Saya H, Okano H, Suda T, Hamada JI, Hirao A
  • 雑誌名: Proc Natl Acad Sci U S A. 106 ページ: 17163-17168
• [雑誌論文] Measurement of Internal Body Time by Blood Metabolomics. (2009)
  • 著者名/発表者名: Minami, Y., Kasukawa, T., Kakazu, Y., Iigo, M., Sugimoto, M., Ikeda, S., Yasui, A., van der Horst, G., Soga, T., Ueda, H.
  • 雑誌名: Proc. Natl. Acad. Sci. USA 106 ページ: 9890-9895
• [雑誌論文] Ligand-based gene expression profiling identifies critical role of glucocorticoid receptor in rat neonatal cardiomyocytes. (2009)
  • 著者名/発表者名: Yoshikawa N, Nagasaki M, Sano M, Tokudome S, Ueno K, Shimizu N, Imoto S, Miyano S, Suematsu M, Fukuda K, Morimoto C, Tanaka H
  • 雑誌名: Am J Physiol Endocrinol Metab 296(6) ページ: E1363-1373
• [雑誌論文] Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-flight Mass Spectrometry. (2009)
  • 著者名/発表者名: Hirayama, A., Kami, K., Sugimoto, M., Sugawara, M., Toki, N., Onozuka, H., Kinoshita, T., Saito, N., Ochiai, A., Tomita, M., Esumi, H., *Soga, T.
  • 雑誌名: Cancer Res 69 ページ: 4918-4925
• [雑誌論文] Metabolomic Profiling of Anionic Metabolites by Capillary Electrophoresis Mass Spectrometry. (2009)
  • 著者名/発表者名: Soga, T., Igarashi, K., Itoh, C., Mizobuchi, K., Zimmermann, H., Tomita, M.
  • 雑誌名: Anal. Chem 81 ページ: 6165-6174
• [雑誌論文] Metabolite profiling reveals YihU as a novel hydroxybutyrate dehydrogenase for alternative succinic semialdehyde metabolism in Escherichia coli. (2009)
  • 著者名/発表者名: Saito, N., Robert, M., Kochi, H., Matsuo, G., Kakazu, Y., Soga, T., Tomita, M.
  • 雑誌名: J. Biol. Chem. 109 ページ: 16442-16451
• [雑誌論文] Rescue of anemia and autoimmune responses in SOD1-deficient mice by transgenic expression of human SOD1 in erythrocytes. (2009)
  • 著者名/発表者名: Iuchi, Y., Okada, F., Takamiya, R., Kibe, N., Tsunoda, S., Nakajima, O., Toyoda, K., Nagae, R., Suematsu, M., Soga, T., Uchida, K., Fujii, J.
  • 雑誌名: Biochem. J 422 ページ: 313-320
• [雑誌論文] HIF-1α is necessary to support gluconeogenesis during liver regeneration Biochem. Biophys. (2009)
  • 著者名/発表者名: Tajima, T., Goda, N., Fujiki, N., Hishiki, T., Nishiyama, Y., Senoo-Matsuda, N., Shimazu, M., Soga, T., Yoshimura, Y., Johnson, R.S., Suematsu, M.
  • 雑誌名: Biochem. Biophys. Res. Commun. 387 ページ: 789-794
• [雑誌論文] Mono-(2-ethylhexyl) phthalate Targets Glycogen Debranching Enzyme and Affects Glycogen Metabolism in Rat Testis. (2009)
  • 著者名/発表者名: Kuramori, C., Hase, Y., Hoshikawa, K., Watanabe, K., Nishi, T., Hishiki, T., Soga, T., Nashimoto, A., Kabe, Y., Yamaguchi, Y., Watanabe, H., Kataoka, K., Suematsu, M., Handa, H.
  • 雑誌名: Toxicol. Sci 109 ページ: 143-151
• [雑誌論文] Cystathionine β-synthase as a Carbon Monoxide-sensitive Regulator of Bile Excretion. (2009)
  • 著者名/発表者名: Shintani, T., Iwabuchi, T., Soga, T., Kato, Y., Yamamoto, T., Takano, N., Hishiki, T., Ueno, Y., Ikeda, S., Sakurakawa, T., Ishikawa, K., Goda, N., Yitagawa, Y., Kajiyama, M., Matsumoto, K., Suematsu, M.
  • 雑誌名: Hepatology 49 ページ: 141-150
• [雑誌論文] Identification of Stem Cells During Prepubertal Spermatogenesis Via Monitoring of Nucleostemin Promoter Activity. (2008)
  • 著者名/発表者名: Ohmura M, Naka K, Hoshii T, Muraguchi T, Shugo H, Tamase A, Uema N, Ooshio T, Arai F, Takubo K, Nagamatsu G, Hamaguchi I, Takagi M, Ishihara M, Sakurada K, Miyaji H, Suda T, *Hirao A
  • 雑誌名: Stem Cells 26 ページ: 3237-3246
• [雑誌論文] Exacerbating Role of γδ T Cells in Chronic Colitis of T Cell Receptor αMutant Mice. (2008)
  • 著者名/発表者名: Nanno, M., Kanari, Y., Naito, T., Inoue, N., Hisamatsu, T., Chinen, H., Sugimoto, K., Shimomura, Y., Yamagishi, H., Shiohara, T., Ueha, S., Matsushima, K., Suematsu, M., Mizoguchi, A., Hibi, T., Bhan, A.K., Ishikawa, H
  • 雑誌名: Gastroenterology 134 ページ: 481-490
• [雑誌論文] Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia. (2008)
  • 著者名/発表者名: Akahoshi N, Kobayashi C, Ishizaki Y, Izumi T, Himi T, Suematsu M, Ishii I
  • 雑誌名: Hum. Mol. Genet 17 ページ: 1994-2005
• [雑誌論文] Multiple Highthroughput Analyses Monitor The Response of E. coli to Perturbations" (2007)
  • 著者名/発表者名: Ishii, N., Nakahigashi, K., Baba, T., Robert, M., Soga, T., Kanai, A., Hirasawa, T., Naba, M., Hirai, K., Hoque, A., Ho, P.Y., Kakazu, Y., Sugawara, K., Igarashi, S., Harada, S., Masuda, T., Sugiyama, N., Togashi, T., Hasegawa, M., Takai, Y., Yugi, K., AraIshii, N., Nakahigashi, K., Baba, T., Robert, M., Soga, T., Kanai, A., Hirasawa, T., Naba
  • 雑誌名: Science 316 ページ: 593-597
• [雑誌論文] A peptide bond provides unidirectional respiratory proton pumping in bovine cytochrome c oxidase. (2007)
  • 著者名/発表者名: Shimokata K, Katayama Y, Murayama H, Suematsu M, Tsukihara T, Muramoto K, Yoshikawa S, Shimada H
  • 雑誌名: Proc Natl Acad Sci USA 104(10) ページ: 4200-4205
• [雑誌論文] Method for determination of association and dissociation rate constants of reversible biomolecular reactions by isothermal titration calorimeters. (2007)
  • 著者名/発表者名: Egawa, T., Tsuneshige, A., Suematsu, M., Yonetani, T
  • 雑誌名: Anal. Biochem 79(7) ページ: 2972-2978
• [雑誌論文] Microvascular and systemic effects following top load administration of saturated carbon monoxide-saline solution. (2007)
  • 著者名/発表者名: Hangai-Hoger, N., Tsai, A.G., Carbales, P., Suematsu, M., Intaglietta, M
  • 雑誌名: Crit Care Med 35(4) ページ: 1123-1132
• [雑誌論文] Roles of hemoglobin allostery in hypoxia-induced metabolic alterations in erythrocytes: simulation and its verification by metabolome analysis. (2007)
  • 著者名/発表者名: Kinoshita, A., Tsukada, K., Soga, T., Hishiki, T., Ueno, Y., Nakayama, Y., Tomita, M., Suematsu, M.
  • 雑誌名: J Biol Chem 282(14) ページ: 10731-10741
• [雑誌論文] Menage-a-Trois 1 is critical for the transcriptional function of PPARgamma coactivator 1. (2007)
  • 著者名/発表者名: Sano M, Izumi Y, Helenius K, Asakura M, Rossi DJ, Xie M, Taffet G, Hu L, Pautler RG, Wilson CR, Boudina S, Abel ED, Taegtmeyer H, Scaglia F, Graham BH, Kralli A, Shimizu N, Tanaka H, Makela TP, Schneider MD
  • 雑誌名: Cell Metab 5(2) ページ: 129-142
• [雑誌論文] Visualization of three-way comparisons of omics data. (2007)
  • 著者名/発表者名: Baran, R., Robert, M., Suematsu, M., Soga, T., Tomita, M.
  • 雑誌名: BMC Bioinformatics 8(1) ページ: 72e
• [雑誌論文] Curriculum vitae of intestinal intraepithelial T cells: their developmental and behavioral characteristics. (2007)
  • 著者名/発表者名: Ishikawa H, Naito T, Iwanaga T, Takahashi-Iwanaga H, Suematsu M, Hibi T, Nanno M
  • 雑誌名: Immunol Rev 215 ページ: 154-165
• [雑誌論文] Regulation of reactive oxygen species by atm is essential for proper response to DNA double-strand breaks in lymphocytes. (2007)
  • 著者名/発表者名: Ito K, Takubo K, Arai F, Satoh H, Matsuoka S, Ohmura M, Naka K, Azuma M, Miyamoto K, Hosokawa K, Ikeda Y, Mak TW, Suda T, Hirao A
  • 雑誌名: J Immunol 178 ページ: 103-110
• [雑誌論文] MathDAMP: a package for differential analysis of metabolite profiles. (2006)
  • 著者名/発表者名: Baran, R., Kochi, H., Saito, N., Suematsu, M., Soga, T., Nishioka, T., Robert, M., Tomita, M.
  • 雑誌名: BMC Bioinformatics 7 ページ: 530e
• [雑誌論文] Design of metal cofactors activated by a protein-protein electron transfer system. (2006)
  • 著者名/発表者名: Ueno T, Yokoi N, Unno M, Matsui T, Tokita M, Yamada M, Ikeda-Saito M, Nakajima H, Watanabe Y
  • 雑誌名: Proc Natl Acad Sci USA 103, 14 ページ: 9416-9421
• [雑誌論文] Compound I of heme oxygenase cannot hydroxylate its heme meso-carbon J. Am. (2006)
  • 著者名/発表者名: Matsui T, Kim SH, Jin H, Hoffman BM, Ikeda-Saito M
  • 雑誌名: J. Am. Chem. Soc 128 ページ: 1090-1091
• [雑誌論文] T-state stabilization of hemoglobin allostery by nitric oxide: a protection against post-ischemic hepatobiliary dysfunction. (2006)
  • 著者名/発表者名: Suganuma K, Tsukada K, Tsuneshige A, Kashiba M, Yonetani T, Suematsu M
  • 雑誌名: Antioxid Redox Signal 8 ページ: 1847-1855
• [雑誌論文] Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. (2006)
  • 著者名/発表者名: Soga T, Baran R, Suematsu M, Ueno Y, Ikeda S, Sakuragawa T, Kakazu Y, Ishikawa T, Robert M, Nishioka, T., Tomita, M.
  • 雑誌名: J Biol Chem 281(24) ページ: 16768-16776
• [雑誌論文] Maintaining the redox balance intact: gosha-jinki-gan but not insulin activates guanylate cyclase in diabetic rats. (2006)
  • 著者名/発表者名: Cameron-Scaefer S, Kondo K, Ishige A, Tsuyama S, Uchida K, Hanawa T, Suematsu M, Watanabe K.
  • 雑誌名: Ophthalmic Res 38(2) ページ: 95-104
• [雑誌論文] Various adhesion molecules impair microvascular leukocyte kinetics in ventilator-induced lung injury. (2006)
  • 著者名/発表者名: Miyao N, Suzuki Y, Takeshita K, Kudo H, Ishii M, Hiraoka R, Nishio K, Tamatani T, Sakamoto S, Suematsu M, Tsumura H, Ishizaka A, Yamaguchi K
  • 雑誌名: Am J Physiol Lung Cell Mol Physiol 290 ページ: L1059-L1068
• [雑誌論文] O2-and H2O2-dependent verdoheme degradation by heme oxygenase: Reaction mechanisms and potential physiological roles of the dual pathway degradation J (2005)
  • 著者名/発表者名: Matsui T, Nakajima A, Fujii H, Mansfield K, Matera C. Migita T, Yoshida T, Ikeda-Saito M.
  • 雑誌名: Biol Chem 280 ページ: 36833-40
• [雑誌論文] Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: Identification of??-ketoglutarate decarboxylase. (2005)
  • 著者名/発表者名: Tian J, Bryk R, Itoh M, Suematsu, M, Nathan C
  • 雑誌名: Proc Natl Acad Sci USA 102 ページ: 10670-10675
• [雑誌論文] Carbon monoxide from heme oxygenase-2 is a tonic regulator against nitric oxide-dependent vasodilatation in the adult rat cerebral microcirculation. (2005)
  • 著者名/発表者名: Ishikawa M, Kajimura M, Adachi T, Maruyama K, Makino N, Goda N, Yamaguchi T, Sekizuka E, Suematsu M
  • 雑誌名: Circ Res 97(12) ページ: e104-e114
• [雑誌論文] Hydrogen sulfide as an endogenous modulator of biliary bicarbonate excretion in the rat liver. (2005)
  • 著者名/発表者名: Fujii K, Sakuragawa T, Kashiba M, Sugiura Y, Maruyama K, Goda N, Nimura Y, Suematsu M
  • 雑誌名: Antioxid Redox Signal 7(5-6) ページ: 788-794
• [雑誌論文] Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes. (2005)
  • 著者名/発表者名: Sugiura, Y., Kashiba, M., Hoshikawa, K., Sasaki, R., Saito, K., Kimura, H., Maruyama, K., Goda, N., Suematsu M.
  • 雑誌名: Antioxid. Redox Signal 7(5-6) ページ: 781-787
• [学会発表] Biomedical application of metabolome analysis to mine gaseous signal transducers in the liver (2007)
  • 著者名/発表者名: Suematsu M
  • 学会等名: APS Symposium: Frontiers in the Cellular and Molecular Physiology of the Hepatic Microcirculation. for EB2007
  • 発表場所: Invited Lecture. Washington DC
  • 年月日: 2007-04-29
• [学会発表] Metabolome analyses reveal roles of cystathionine beta synthase as a CO-responsive metabolic regulator in mammals (2006)
  • 著者名/発表者名: Suematsu M
  • 学会等名: In NO and CO: distinct biological properties. The 20th IUBMB Symposium
  • 発表場所: Organizer, Kyoto
  • 年月日: 20060619-20060622
• [学会発表] Biomedical application of metabolome analysis (2006)
  • 著者名/発表者名: Suematsu M
  • 学会等名: Harvard-Kitasato Symposium for Critical Path for Translational Research
  • 発表場所: Tokyo(Invited Lecture)
  • 年月日: 2006-10-24
• [学会発表] Erythrocytes as an oxygen-sensing metabomic sink determining microvascular tone (2005)
  • 学会等名: IUPS Plenary Symposium
  • 発表場所: San Diego CA
  • 年月日: 20050405-20050408
• [学会発表] Carbon monoxide as a guardian against the liver injury (2005)
  • 著者名/発表者名: Suematsu M
  • 学会等名: Plenary Lecture
  • 発表場所: ISBRA Satellite Symposium
  • 年月日: 2005-09-02