Molecular Clocks to Biological Rhythms

2010 Fiscal Year Final Research Report

• Project/Area Number: 18002016
• Research Category: Grant-in-Aid for Specially Promoted Research
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University (2007-2010); Kobe University (2006)
• Principal Investigator: OKAMURA Hitoshi 京都大学, 大学院・薬学研究科, 教授 (60158813)
• Co-Investigator(Kenkyū-buntansha): EMOTO Noriaki 神戸薬科大学, 薬学部, 教授 (30294218) ; MASUBUCHI Satoru 北海道, 医学研究科, 特任准教授 (80362771) ; DOI Masao 京都大学, 大学院・薬学研究科, 准教授 (20432578) ; IIGO Masayuki 宇都宮大学, 農学部, 准教授 (10232109) ; NAKAHARA Daiichiro 浜松医科大学, 医学部, 教授 (80128389) ; NAKAO Kazuki 独立行政法人理化学研究所, 動物資源開発室動物実験支援ユニット, 研究員 (20217657) ; YAMAGUCHI Yoshiaki 京都大学, 大学院・薬学研究科, 助教 (30467427) ; MATSUO Masahiro 京都大学, 大学院・薬学研究科, 助教 (70456838)
• Project Period (FY): 2006 – 2010
• Keywords: 時計遺伝子 / 視交叉上核 / G蛋白質 / 臓器の時計 / 高血圧

Research Abstract

The discovery of clock genes at 1997 and the following study of the molecular machinery of clock genes, have enabled “biological time” as a research object. We begin the present study as a project of post-cloning age. We clarified the G-protein mediated novel cellular communications in the suprachiasmatic nucleus. We synthesized an artificial transcriptional factor regulating the clock gene transcriptions. We also clarified a timing mechanism of nucleic acid metabolism in the liver, miturition rhythm in the urinary bladder, and further, we identified a novel steroid synthetic enzyme, which links between circadian clock and hypertension, in the adrenal gland.

Research Products

• [Journal Article] Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm (2012)
  • Author(s): Negoro H, Kanmatsu A, Doi M, Suadicani SO, Matsuo M, Imanura M, Okinami T, Nishikawa N, Oura T, Matsuji S, Seo K, Tainaka M, Urabe S, Kiyokage E, Todo T, Okamura H, Tabata H, Ogawa O
  • Journal Title: Nature Communs. Volume: 3 Pages: 809
  • Peer Reviewed
• [Journal Article] Rhythmic nucleotide synthesis in the liver : Temporal segregation of metabolites (2012)
  • Author(s): Fustin J-M, Doi M, Yamada H, Komatsu R, Shimba S, Okamura H
  • Journal Title: Cell Reports Volume: 1 Pages: 341-349
  • Peer Reviewed
• [Journal Article] Circadian clock signals in the adrenal cortex (2012)
  • Author(s): Ota T, Fustin JM, Yamada H, Doi M, Okamura H
  • Journal Title: Mol. Cell. Endocrinol. Volume: 349 Pages: 30-37
  • Peer Reviewed
• [Journal Article] Temporal regulation of intracellular G protein signaling mediates intercellular synchrony and circadian rhythmicity in mammalian pacemaker neurons (2011)
  • Author(s): Doi M, Ishida A, Miyake A, Sato M, Komatsu R, Yamazaki F, Kimura I, Tsuchiya S, Kori H, Seo K, Yamaguchi Y, Matsuo M, Fustin JM, Tanaka R, Santo Y, Yamada H, Takahashi Y, Araki M, Nakao K, Aizawa S, Kobayashi M, Obrietan K, Tsujimoto G, Okamura H
  • Journal Title: Nature Communs Volume: 2 Pages: 327
  • Peer Reviewed
• [Journal Article] Hypertension due to loss of clock: novel insight from the molecular analysis of Cry1/Cry2-deleted mice (2011)
  • Author(s): Okamura H, Doi M, Yamaguchi Y, Fustin JM
  • Journal Title: Curr Hypertens Rep. Volume: 13 Pages: 103-108
  • Peer Reviewed
• [Journal Article] Control of circadian phase by an artificial zinc finger transcription regulator (2011)
  • Author(s): Imanishi M, Nakamura A, Doi M, Futaki S, Okamura H.
  • Journal Title: Angew Chem Int. Volume: 50(40) Pages: 9396-9399
  • Peer Reviewed
• [Journal Article] Salt-sensitive hypertension in circadian clock-deficient mice involves dysregulated adrenal Hsd3b6 (2010)
  • Author(s): Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, Emoto N, Okuno Y, Tsujimoto G, Kanematsu A, Ogawa O, Todo T, Tsutsui K, van der Horst GTJ, Okamura H
  • Journal Title: Nature Medicine Volume: 16 Pages: 67-74
  • Peer Reviewed
• [Journal Article] Mammalian clock gene Cryptochrome regulates arthritis via proinflammatory cytokine TNF-α (2010)
  • Author(s): Hashiramoto A, Yamane T, Tsumiyama K, Yoshidam K, Komai K., Yamada H, Yamazaki F, Doi M, Okamura H, Shiozawa S
  • Journal Title: J Immunol. Volume: 184 Pages: 1560-1560
  • Peer Reviewed
• [Journal Article] Activation of AMPA receptors in the suprachiasmatic nucleus: Phase-shifts the mouse circadian clock in vivo and in vitro (2010)
  • Author(s): Mizoro Y, Yamaguchi Y, Kitazawa R, Yamada H, Matsuo M, Fustin JM, Doi M, Okamura H
  • Journal Title: Plos ONE Volume: 5(6) Pages: e10951
  • Peer Reviewed
• [Journal Article] Mammalian circadian clock system: Molecular mechanisms for pharmaceutical and medical sciences (2010)
  • Author(s): Okamura H, Doi M, Fustin JM, Yamaguchi Y, Matsuo M
  • Journal Title: Adv Drug Deliv Rev. Volume: 62 Pages: 876-884
  • Peer Reviewed
• [Journal Article] Hypertension due to loss of clock (2010)
  • Author(s): Okamura H, Doi M, Fustin JM, Yamaguchi Y
  • Journal Title: Current hypertension Reports Volume: 13 Pages: 103-108
  • Peer Reviewed
• [Journal Article] Imaging of ultraweak spontaneous photon emission from human body displaying diurnal rhythm (2009)
  • Author(s): Kobayashi M, Kikuchi D, Okamura H
  • Journal Title: Plos ONE Volume: 4(7) Pages: e6256
  • Peer Reviewed
• [Journal Article] Quantification of circadian rhythms in single cells (2009)
  • Author(s): Westermark PO, Welsh DK, Okamura H, Herzel H
  • Journal Title: PLoS Computational Biol. Volume: 5(11) Pages: e1000580
  • Peer Reviewed
• [Journal Article] Molecular clocks in mouse skin (2009)
  • Author(s): Tanioka M, Yamada H, Doi M, Bando H, Yamaguchi Y, Nishigori C, Okamura H
  • Journal Title: J. Invest. Dermatol. Volume: 129 Pages: 1225-1231
  • Peer Reviewed
• [Journal Article] Brain comes to light (2008)
  • Author(s): Okamura H
  • Journal Title: Nature Volume: 452 Pages: 294-295
  • Peer Reviewed
• [Journal Article] MicroRNA modulation of circadian clock period and entrainment (2007)
  • Author(s): Cheng H-YM, Papp JW, Verlamova O, Dziema H, Russell B, Curfman JP, Nakazawa T, Shimizu K, Okamura H, Impey S, Obrietan K
  • Journal Title: Neuron Volume: 54 Pages: 813-829
  • Peer Reviewed
• [Journal Article] Vagal regulation of airway clocks in mice (2007)
  • Author(s): Bando H, Nishio T, van der Horst GTJ, Masubuchi S, Hisa Y, Okamura H
  • Journal Title: J. Neurosci. Volume: 27 Pages: 4359-4365
  • Peer Reviewed
• [Journal Article] Suprachiasmatic nucleus clock time in mammalian circadian system (2007)
  • Author(s): Okamura H
  • Journal Title: Cold Spring Harb Symp Quant Biol. Volume: 72 Pages: 551-556
  • Peer Reviewed
• [Journal Article] Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling (2006)
  • Author(s): Maywood ES, Reddy AB, Wong GKY, O'Nelill JS, O'Brien JA, McMahon DG, Harmar AJ, Okamura H, Hastings MH
  • Journal Title: Current Biol. Volume: 16 Pages: 599-605
  • Peer Reviewed
• [Journal Article] Functional evolution of the photolyase/chryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance (2006)
  • Author(s): Chaves I, Yagita K, Barnhoon S, Okamura H, van der Horst TJ, Tamanini F
  • Journal Title: Mol. Cell. Biol. Volume: 26 Pages: 1743-1753
  • Peer Reviewed
• [Journal Article] Chronic treatment with prednisolone represses the circadian oscillation of clock gene expression in mouse peripheral tissues (2006)
  • Author(s): Koyanagi S, Okazawa S, Kuramoto Y, Ushijima K, Shimeno H, Soeda S, Okamura H, Ohdo S
  • Journal Title: Mol. Endocrinol. Volume: 20 Pages: 573-583
  • Peer Reviewed
• [Journal Article] Role of hepatic STAT3 in brain insulin action on hepatic glucose production (2006)
  • Author(s): Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R, Notohara K, Katayose K, Okamura H, Kahn CR, Noda T, Takeda K, Akira S, Inui A, Kasuga M
  • Journal Title: Cell Metabolism Volume: 3 Pages: 267-275
  • Peer Reviewed
• [Journal Article] Does mPER2 protein oscillate without its coding mRNA cycling? Post- transcriptional regulation by cell clock (2006)
  • Author(s): Fujimoto Y, Yagita K, Okamura H
  • Journal Title: Genes Cells Volume: 11 Pages: 525-530
  • Peer Reviewed
• [Journal Article] Ablation of PDK1 in pancreatic βcells induces diabetes as a result of loss of βcell mass (2006)
  • Author(s): Hashimoto N, Kido Y, Uchida T, Asahara S, Shigeyama Y, Matsuda T, Takeda A, Tsuchihashi D, Nishizawa A, Ogawa W, Fujimoto Y, Okamura H, Karen C. Arden KC, Herrera P, Noda T, and Kasuga M
  • Journal Title: Nature Genetics Volume: 38 Pages: 589-593
  • Peer Reviewed
• [Journal Article] Real-time imaging of the somite segmentation clock: reveration of unstable oscillators in the individual presomitic mesoderm cells (2006)
  • Author(s): Masamizu Y, Ohtsuka T, Takashima Y, Nagahara H, Takenaka Y, Yoshikawa K, Okamura H, Kageyama R
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 103 Pages: 1313-1318
  • Peer Reviewed
• [Journal Article] V1a vasopressin receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity (2006)
  • Author(s): Koshimizu T, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mori T, Takeo S, Okamura H, and Tsujimoto G
  • Journal Title: Proc Natl Acad Sci USA. Volume: 103 Pages: 7807-7812
  • Peer Reviewed
• [Presentation] Clock and hypertension (2012)
  • Author(s): Okamura H
  • Organizer: 15th International Congress of Endocrinology 14th TH European Congress of Endocrinology
  • Place of Presentation: Florence (Italy)
  • Year and Date: 20120505-09
• [Presentation] Circadian clock and diseases (2012)
  • Author(s): Okamura H
  • Organizer: UCLA symposium on Circadian Clocks and Metabolic Disease
  • Place of Presentation: Los Angeles (California)
  • Year and Date: 20120420-22
• [Presentation] Dysregulated circadian clock and diseases (2012)
  • Author(s): Okamura H
  • Organizer: Leopoldina Symposium Circadian System
  • Place of Presentation: Frankfurt (Germany)
  • Year and Date: 20120323-24
• [Presentation] Dysregulated, cell-specific ccg's lead to disease (2011)
  • Author(s): Okamura H
  • Organizer: Gordon Research Conference Chronobiology 2011
  • Place of Presentation: Il Ciocco (Italy)
  • Year and Date: 20110612-17
• [Presentation] Novel molecular link between hyopertension and clock (2010)
  • Author(s): Okamura H.
  • Organizer: Annual Meeting of American Society of Nephrology : Renal Week 2010
  • Place of Presentation: Denver (Colorado)
  • Year and Date: 20101116-21
• [Presentation] Aldosterone and clock (2010)
  • Author(s): Okamura H.
  • Organizer: The 36th International Aldosterone Conference
  • Place of Presentation: San Diego (California)
  • Year and Date: 20100617-18
• [Presentation] Clock genes and diseases (2009)
  • Author(s): Okamura H
  • Organizer: XI Congress of the European Biological Rhythms Society (EBRS2009)
  • Place of Presentation: Strasbourg (France)
  • Year and Date: 20090822-28
• [Presentation] Circadian clock system in the skin (2009)
  • Author(s): Okamura H
  • Organizer: 15th International Congress of Photobiology (ICP 2009)
  • Place of Presentation: Dusseldorf (Germany)
  • Year and Date: 20090618-23
• [Presentation] Chronobiology of the skin (2008)
  • Author(s): Okamura H
  • Organizer: 1st International Conference on Dermatotoxicology
  • Place of Presentation: Bilderberg Kasteel, Vaalsbroek (Netherlands)
  • Year and Date: 20081022-25
• [Presentation] Light, glucocorticoid signaling, and circadian clock genes (2007)
  • Author(s): Okamura H
  • Organizer: World Sleep 07-5th Congress of the World Fed. of Sleep Research and Sleep Medicine Societies
  • Place of Presentation: Cairns (Australia)
  • Year and Date: 20070902-06
• [Presentation] Mammalian circadian time transmission (2007)
  • Author(s): Okamura H
  • Organizer: IBRO World Congress of Neuroscience
  • Place of Presentation: Melbourne (Australia)
  • Year and Date: 20070712-17
• [Presentation] Cell clocks and the system clock (2007)
  • Author(s): Okamura H
  • Organizer: Symposium on "From Molecular Clocks to Human Health"
  • Place of Presentation: Adelaide (Australia)
  • Year and Date: 20070707-10
• [Presentation] Molecular clocks in mammalian circadian system (2007)
  • Author(s): Okamura H
  • Organizer: 72^<nd> Cold Spring Harbor Symposium on Quantitative Biology
  • Place of Presentation: Cold Spring Harbor (New York)
  • Year and Date: 20070530-0604
• [Presentation] Oscillators generate cell functions in mammals (2006)
  • Author(s): Okamura H
  • Organizer: 5th Forum of European Neuroscience Society
  • Place of Presentation: Vienna
  • Year and Date: 20060708-12
• [Remarks] 2008年5月Aschoff-Ruler Prize受賞
• [Remarks] 2007年4月29日紫綬褒章授与
• [Remarks] 第16回日本時間生物学会学術大会会長(会期:2009年10月25-27日:大阪国際会議場)(合同国際学会:"The Joint Congress of the 6th ASRS, the 34th JSSR and the 16th JSC")
• [Remarks] Times of India, 2010年1月30日Body clock disturbance linked to heart disease
• [Remarks] BBC News, 2009年12月13日, Body clock link to heart disease
• [Remarks] 産経新聞2012年5月2日(朝刊18面):体内時計が尿量調整-夜間頻尿治療も、他同記事、朝日新聞(5月2日朝刊26面)、京都新聞(5月2日朝刊21面)、日本経済新聞(5月2日朝刊34面)、毎日新聞(5月2日朝刊2面)、読売新聞(5月2日朝刊26面)、日刊工業新聞(5月10日朝刊21面)、および時事通信(5月2日)
• [Remarks] 京都新聞2012年4月14日(朝刊25面):肝臓の働き24時間周期-抗がん剤応用も、他の同記事:読売新聞(4月15日33面)、および日刊工業新聞(4月17日20面)
• [Remarks] 読売新聞2011年5月25日(朝刊33面):体内時計調節たんぱく質、他の同記事:京都新聞(5月25日朝刊23面)、産経新聞(5月25日朝刊24面)、中日新聞 (5月25日夕刊12面)、日本経済新聞(5月25日夕刊14面)、および朝日新聞(5月26日朝刊33面)
• [Remarks] 産経新聞2009年12月14日(夕刊1面):不規則生活+塩分=高血圧塩分調整に京大チーム解明、他同様の記事が、日本経済新聞(12月14日夕刊14面)、朝日新聞(12月14日夕刊12面)、京都新聞(12月14日夕刊10面)、毎日新聞(12月14日夕刊12面): 読売新聞(12月15日朝刊38面)、日刊工業新聞(12月15日朝刊23面)、および共同通信(12月14日)
• [Remarks] 日本経済新聞2008年6月8日(朝刊11面):生体時計の働く仕組みは 光で調律、「分子機械」説も
• [Remarks] 京都新聞2007年9月20日(朝刊9面):体内時計の異常で疾患に
• [Remarks]
  • URL: http://www.pharm.kyoto-u.ac.jp/system-biology/index.html
• [Patent(Industrial Property Rights)] 体内リズム障害用医薬およびそのクリーニング法 (2009)
  • Inventor(s): 岡村均, 土居雅夫
  • Industrial Property Rights Holder: 岡村均, ファルマフロンティア(株)
  • Industrial Property Number: 特許特許第2009-183821号
  • Filing Date: 2009-08-06
  • Overseas
• [Patent(Industrial Property Rights)] 高血圧治療薬,高血圧治療方法,高血圧診断方法および高血圧治療薬のスクリーニング方法 (2008)
  • Inventor(s): 岡村均, 土居雅夫
  • Industrial Property Rights Holder: 岡村均, ファルマフロンティア(株)
  • Industrial Property Number: 特許特許第2008-317333号
  • Filing Date: 2008-12-12
  • Overseas
• [Patent(Industrial Property Rights)] 化粧品素材のスクリーニング方法 (2008)
  • Inventor(s): 岡村均
  • Industrial Property Rights Holder: 岡村均
  • Industrial Property Number: 特許特許第2008-271455号
  • Filing Date: 2008-10-21