{{short description|Japanese scientist (born 1952)}} {{Infobox scientist | name = Hitoshi Okamura | image = | caption = | birth_date = {{birth date and age|1952|12|02}} | fields = Chronobiology, Physiology | website = [http://www.pharm.kyoto-u.ac.jp/system-biology/e/history.html Okamura Lab] }} '''Hitoshi Okamura''' (born December 2, 1952)<ref name="activity database">{{cite web|title=Kyoto University Activity Database on Education and Research|url=https://kyouindb.iimc.kyoto-u.ac.jp/e/zE9xN}}</ref> is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents.<ref>{{cite web|title=Prize Winners of Aschoff's Ruler|url=http://www.ebrs-online.org/history/prize-winners-of-aschoff-s-ruler|website=EBRS|access-date=2015-04-09|archive-url=https://web.archive.org/web/20161021154907/http://ebrs-online.org/history/prize-winners-of-aschoff-s-ruler|archive-date=2016-10-21}}</ref> His lab recently revealed the effects of m<sup>6</sup>A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.<ref name="RNA-Methylation-Dependent RNA Proce">{{cite journal|last1=Fustin|first1=Jean-Michael|last2=Doi|first2=Masao|last3=Yamaguchi|first3=Yoshiaka|last4=Nishimura|first4=Shinichi|last5=Yoshia|first5=Minoru|last6=Isagawa|first6=Takayuki|last7=Morioka|first7=Masaki|last8=Kayeka|first8=Hideaki|last9=Manabe|first9=Ichiro|last10=Okamura|first10=Hitoshi|title=RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock|journal=Cell|date=November 7, 2013|volume=155|issue=4|doi=10.1016/j.cell.2013.10.026|pages=793–806|pmid=24209618|doi-access=free}}</ref>
==Education== Hitoshi Okamura received his undergraduate, medical, and doctorate in science degrees from the Kyoto Prefectural University of Medicine. After training as a pediatrician at the Children's Medical Center of the Okayama National Hospital (1979-1981), he worked on neuroanatomy at the Kyoto Prefectural University of Medicine (1981-1995). He was then a professor of Brain Sciences at the Kobe University School of Medicine from 1995 to 2008.<ref name ="ISH">{{cite web|title=Prof Hitoshi Okamura|url=http://emobilise.com.au/ish2012.speakers.6356.app|website=ISH 2012}}</ref> Since 2007, he has worked as a professor of Systems Biology at the Kyoto University Graduate School of Pharmaceutical Sciences.<ref name="Okamura lab">{{cite web|title=Okamura Laboratory|url=http://www.pharm.kyoto-u.ac.jp//system-biology/e/history.html|website=Kyoto University Graduate School of Pharmaceutical Sciences, Department of Systems Biology}}</ref> Since 2014, he has worked as the Research Director of the Japan Science Technology Institute, CREST. His work has focused on understanding mammalian circadian rhythms.
==Awards and honors== * Recipient of Medal of Honor with Purple Ribbon in 2007 * Recipient of Aschoff's Ruler in 2009
==Scientific contributions==
===Suprachiasmatic Nucleus research=== Okamura began his study of circadian rhythms in 1982 with the peptide work in the suprachiasmatic nucleus (SCN) using the technique of histochemistry in Yasuhiko Ibata's laboratory in the Kyoto Prefectural University of Medicine. He established quantitative histochemistry of the suprachiasmatic nucleus (SCN) in the 1980s, and together with Shin-Ichi Inouye, established in vitro slice cultures of the SCN in the early 1990s.<ref>{{cite journal|last1=Tanaka|first1=Masani|last2=Ichitani|first2=Yukio|last3=Hitoshi|first3=Okamura|last4=Tanaka|first4=Yoshifumi|last5=Ibata|first5=Yasuhiko|title=The direct retinal projection to VIP neuronal elements in the rat SCN|journal=Brain Research Bulletin|date=14 December 1992|doi=10.1016/0361-9230(93)90134-w|volume=31|issue=6|pages=637–640|pmid=8518955|s2cid=4762448}}</ref>
===Discovery of Mammalian Period Genes=== In 1997, Hajime Tei, Yoshiyuki Sakaki, and Hitoshi Okamura discovered the mammalian period gene PER1 in mice and humans. They also discovered PER2, PER3, and the mammalian homolog of the Drosophila gene ''timeless''.<ref name="ReppertWeaver2001">{{cite journal|last1=Reppert|first1=Steven M|last2=Weaver|first2=David R|title=Molecular Analysis of Mammalian Circadian Rhythms|journal=Annual Review of Physiology|volume=63|issue=1|year=2001|pages=647–676|issn=0066-4278|doi=10.1146/annurev.physiol.63.1.647|pmid=11181971}}</ref> They found that Per1 is light-inducible and can phase shift the circadian clock by light.<ref name=mper1and2essential>{{cite journal|last1=Albrecht|first1=Urs|last2=Zheng|first2=Binhai|last3=Larkin|first3=David|last4=Sun|first4=Zhong|last5=Lee|first5=Cheng|title=mPer1 and mPer2 Are Essential for Normal Resetting of the Circadian Clock|journal=Journal of Biological Rhythms|date=April 2001|volume=16|issue=2|pages=100–104|doi=10.1177/074873001129001791|pmid=11302552|s2cid=9067400|doi-access=free}}</ref> Okamura worked with Jay Dunlap, a chronobiologist specializing in circadian rhythms in Neurospora, to show that mammalian clocks are similar to neurospora clocks in their use of induction to phase shift. This is in contrast to the drosophila clock, which phase shift via protein degradation rather than induction.<ref>{{cite journal|last1=Liu|first1=Yi|title=Molecular Mechanisms of Entrainment in the Neurospora Circadian Clock|journal=Journal of Biological Rhythms|date=June 2003|volume=18|issue=3|pages=195–205|doi=10.1177/0748730403018003002|pmid=12828277|s2cid=29200514}}</ref>
===Protein Level Regulation of Mammalian Per=== Okamura's team discovered that mammalian PER proteins made in the cytoplasm translocate into the nucleus of the cell and form a complex composed of CRY1, CRY2, PER1, PER2, PER3, and TIM.<ref name=reverbalpha>{{cite journal|last1=Preitner|first1=Nicolas|last2=Damiola|first2=Francesca|last3=Lopez-Molina|first3=Luis|last4=Zakany|first4=Joszef|last5=Duboule|first5=Denis|last6=Albrecht|first6=Urs|last7=Schibler|first7=Ueli|title=The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator|journal=Cell|date=26 July 2002|volume=110|issue=2|pages=251–260|doi=10.1016/S0092-8674(02)00825-5|pmid=12150932|s2cid=15224136|doi-access=free}}</ref> This negative complex suppresses the transcription of mRNA activated by CLOCK and BMAL1.<ref name="ReppertWeaver2002">{{cite journal|last1=Reppert|first1=Steven M.|last2=Weaver|first2=David R.|title=Coordination of circadian timing in mammals|journal=Nature|volume=418|issue=6901|year=2002|pages=935–941|issn=0028-0836|doi=10.1038/nature00965|pmid=12198538|bibcode=2002Natur.418..935R|s2cid=4430366}}</ref> Okamura has also done research on mPER1 and mPER2 degradation. They found that PER and CRY form a dimer that inhibits PER degradation and that the inhibition of PER degradation suppresses Per1 and Per2 transcription.<ref name=reverbalpha /> This negative feedback loop appears to be found in all clocks.<ref>{{cite journal|last1=Balsalobre|first1=Aurélio|title=Clock genes in mammalian peripheral tissues|journal=Cell and Tissue Research|date=24 January 2014|volume=309|issue=1|pages=193–199|doi=10.1007/s00441-002-0585-0|pmid=12111549|s2cid=27600488}}</ref>
===Core clock loop of clock genes is universal among mammalian cells=== Okamura became interested in the possible differences of autonomously rhythmic clock genes in fibroblast cell lines and those in the SCN. His team discovered that in mice, both types of cells showed temporal expression of profiles of all known clock genes,<ref>{{cite journal|last1=Hastings|first1=Michael|last2=Reddy|first2=Akhilesh|last3=Maywood|first3=Elizabeth|title=A clockwork web: circadian timing in brain and periphery, in health and disease|journal=Nature Reviews Neuroscience|date=August 2003|volume=4|issue=8|pages=649–661|doi=10.1038/nrn1177|pmid=12894240|s2cid=205499642}}</ref> the phases of various mRNA rhythms, the delay between maximum mRNA levels and appearance of nuclear PER1 and PER2 protein, the inability to produce circadian oscillations in the absence of functional Cry genes, and the control of period length by CRY proteins.
===Total Loss of Oscillation in mCry1/mCry2-double knockout mice=== Okamura collaborated with Gijsbertus T.J. van der Horst and found that both peripheral and central clocks are stopped in Cry deficient mice.<ref name=ReppertWeaver2002 /> Okamura also collaborated with Shin-Ichi Inouye to find that behavioral circadian rhythmicity was recovered when the SCN from wild-type mice was transplanted into Cry deficient mice. This suggests that the suprachiasmatic nucleus (SCN) synchronizes and generates behavioral rhythms.<ref name="DibnerSchibler2010">{{cite journal|last1=Dibner|first1=Charna|last2=Schibler|first2=Ueli|last3=Albrecht|first3=Urs|title=The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks|journal=Annual Review of Physiology|volume=72|issue=1|year=2010|pages=517–549|issn=0066-4278|doi=10.1146/annurev-physiol-021909-135821|pmid=20148687|url=http://doc.rero.ch/record/17505/files/alb_mct.pdf}}</ref>
===Restoration of Circadian Rhythms Using Mammalian Per=== Okamura collaborated with Amita Sehgal to determine if the mPer1 and mPer2 genes were able to generate circadian oscillations.<ref name="Okamura lab"/> They transplanted Per1 and Per2 genes from mice into arrhythmic per<sup>0</sup> mutants of Drosophila and found that transplantation restored circadian rhythms.<ref name="Hendricks2003">{{cite journal|last1=Hendricks|first1=Joan C.|title=Invited Review: Sleeping flies don't lie: the use of Drosophila melanogaster to study sleep and circadian rhythms|journal=Journal of Applied Physiology|volume=94|issue=4|year=2003|pages=1660–1672|issn=8750-7587|doi=10.1152/japplphysiol.00904.2002|pmid=12626480}}</ref>
===SCN as the Central Clock=== Okamura's team also analyzed the SCN at the cellular level. They succeeded in monitoring the rhythmic transcription of genes at the single cell level in real-time. This work was achieved by combining the SCN slice-culture technique, transgenic mice carrying the luciferase gene driven by the Per1 promoter (Per1-luc), and the cryogenic high resolution CCD camera. They have demonstrated that a stable ensemble SCN rhythm is orchestrated within an assembly of cellular clocks that are differentially phased and that sit in a distinct topographic order in the SCN. Tetrodotoxin, which blocks action potentials, not only desynchronizes the cell population, but also suppresses the level of clock gene expression, demonstrating that neuronal networks play a dominant role in oscillation of rhythms in the SCN. Using the same Per-luc mice with the optical fiber inserted to the brain, Okamura's team succeeded in monitoring the rhythmic gene expression of the clock gene in real-time in freely moving mice, demonstrating that the Per gene is activated in the daytime and rests in the nighttime in the SCN. Okamura discovered that flashing NMDA, which is analogous to light stimuli, instantly altered the phase of the core clock oscillation of a slice of SCN.<ref>{{cite journal|last1=Colwell|first1=Christopher|title=NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus: gating by the circadian system|journal=European Journal of Neuroscience|date=20 December 2001|volume=13|issue=7|pages=1420–1428|doi=10.1046/j.0953-816x.2001.01517.x|pmid=11298803|pmc=2577309}}</ref> This proved that there is rhythmic transcription of genes at the single cell level. It has been shown that the SCN regulates peripheral clocks by regulating melatonin in the sympathetic nervous system.<ref>{{cite journal|last1=Bartness|first1=Timothy|last2=Demas|first2=Gregory|last3=Song|first3=C. Kay|title=Seasonal Changes in Adiposity: the Roles of the Photoperiod, Melatonin and Other Hormones, and Sympathetic Nervous System|journal=Experimental Biology and Medicine|date=2002|volume=227|issue=6|pages=363–376|doi=10.1177/153537020222700601|pmid=12037125|s2cid=26813489}}</ref> Okamura's team also demonstrated that the light can activate genes and corticosterone secretion in the adrenal gland through the SCN-sympathetic nerve routes. So, the sympathetic nerve conveys the time signal of the core central clock (SCN) to peripheral organs, and the adrenal gland is the key organ in transforming circadian signals from nerve signals to the endocrine signals.<ref name=DibnerSchibler2010 />
===Cell Clock and Cell Cycle=== Okamura's team has also looked into the relationship between the circadian clock and the cell cycle. They performed DNA arrays and Northern blots to characterize the molecular differences in M-phase entry and found that cyclin B1 and cdc2 were positively correlated. They also found that wee1, the gene for a kinase that inhibits mitosis by inactivating CDC2/cyclin B, was negatively correlated to M-phase.<ref name=mitraandschultz>{{cite journal|last1=Mitra|first1=Jayashree|last2=Schultz|first2=Richard|title=Regulation of the acquisition of meiotic competence in the mouse: changes in the subcellular localization of cdc2, cyclin B1, cdc25C and wee1, and in the concentration of these proteins and their transcripts|journal=Journal of Cell Science|volume=109|issue=9|date=1 September 1996|pages=2407–2415|doi=10.1242/jcs.109.9.2407 |pmid=8886990 |url=http://jcs.biologists.org/content/109/9/2407.short|url-access=subscription}}</ref> Their research showed that mouse hepatocyte proliferation is under circadian control.<ref name="FaustoCampbell2006">{{cite journal|last1=Fausto|first1=Nelson|last2=Campbell|first2=Jean S.|last3=Riehle|first3=Kimberly J.|title=Liver regeneration|journal=Hepatology|volume=43|issue=S1|year=2006|pages=S45–S53|issn=0270-9139|doi=10.1002/hep.20969|pmid=16447274|s2cid=39302882}}</ref>
===Current research pursuits=== In more recent years, Okamura and his team extended their molecular clock work to posttranscriptional, intercellular, and systemic levels.<ref>{{cite journal |title=Raku-Yu |journal=Kyoto University Newsletter |year=2014 |issue=Autumn 2014 |url=http://www.kyoto-u.ac.jp/ja/about/public/issue/rakuyu/documents/26.pdf |access-date=2015-04-23 }}</ref> They found the mRNA methylation alters the speed of circadian rhythms <ref name="RNA-Methylation-Dependent RNA Proce"/> and heterogeneity of G protein signaling is necessary for time-keeping in the SCN.<ref name="DoiIshida2011">{{cite journal|last1=Doi|first1=Masao|last2=Ishida|first2=Atsushi|last3=Miyake|first3=Akiko|last4=Sato|first4=Miho|last5=Komatsu|first5=Rie|last6=Yamazaki|first6=Fumiyoshi|last7=Kimura|first7=Ikuo|last8=Tsuchiya|first8=Soken|last9=Kori|first9=Hiroshi|last10=Seo|first10=Kazuyuki|last11=Yamaguchi|first11=Yoshiaki|last12=Matsuo|first12=Masahiro|last13=Fustin|first13=Jean-Michel|last14=Tanaka|first14=Rina|last15=Santo|first15=Yasuko|last16=Yamada|first16=Hiroyuki|last17=Takahashi|first17=Yukari|last18=Araki|first18=Michihiro|last19=Nakao|first19=Kazuki|last20=Aizawa|first20=Shinichi|last21=Kobayashi|first21=Masaki|last22=Obrietan|first22=Karl|last23=Tsujimoto|first23=Gozoh|last24=Okamura|first24=Hitoshi|title=Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus|journal=Nature Communications|volume=2|year=2011|page=327|issn=2041-1723|doi=10.1038/ncomms1316|pmid=21610730|pmc=3112533|bibcode=2011NatCo...2..327D}}</ref> Moreover, they found the dysregulated clock induces salt-sensitive hypertension through the inappropriate secretion of aldosterone.<ref name="NikolaevaPradervand2012">{{cite journal|last1=Nikolaeva|first1=S.|last2=Pradervand|first2=S.|last3=Centeno|first3=G.|last4=Zavadova|first4=V.|last5=Tokonami|first5=N.|last6=Maillard|first6=M.|last7=Bonny|first7=O.|last8=Firsov|first8=D.|title=The Circadian Clock Modulates Renal Sodium Handling|journal=Journal of the American Society of Nephrology|volume=23|issue=6|year=2012|pages=1019–1026|issn=1046-6673|doi=10.1681/ASN.2011080842|pmid=22440902|pmc=3358761}}</ref> Another discovery was that clock regulation of gap junction protein in the urinary bladder was a cause of abnormal urination.<ref name="TimóteoCarneiro2014">{{cite journal|last1=Timóteo|first1=M. Alexandrina|last2=Carneiro|first2=Inês|last3=Silva|first3=Isabel|last4=Noronha-Matos|first4=José Bernardo|last5=Ferreirinha|first5=Fátima|last6=Silva-Ramos|first6=Miguel|last7=Correia-de-Sá|first7=Paulo|title=ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors|journal=Biochemical Pharmacology|volume=87|issue=2|year=2014|pages=371–379|issn=0006-2952|doi=10.1016/j.bcp.2013.11.007|pmid=24269631}}</ref> Very recently, they found that vasopressin signaling in the SCN is crucial for jet lag.<ref name="SpornsAnanthasubramaniam2014">{{cite journal|last1=Sporns|first1=Olaf|last2=Ananthasubramaniam|first2=Bharath|last3=Herzog|first3=Erik D.|last4=Herzel|first4=Hanspeter|title=Timing of Neuropeptide Coupling Determines Synchrony and Entrainment in the Mammalian Circadian Clock|journal=PLOS Computational Biology|volume=10|issue=4|year=2014|article-number=e1003565|issn=1553-7358|doi=10.1371/journal.pcbi.1003565|pmid=24743470|pmc=3990482|bibcode=2014PLSCB..10E3565A |doi-access=free }}</ref><ref>{{cite journal|last1=Yamaguchi|first1=Yoshiaki|last2=Suzuki|first2=Toru|last3=Mizoro|first3=Yasutaka|last4=Kori|first4=Hiroshi|title=Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag|journal=Science|date=October 2013|volume=342|issue=6154|pages=85–90|doi=10.1126/science.1238599|pmid=24092737|bibcode=2013Sci...342...85Y|s2cid=2681988}}</ref>
Now, Okamura continues investigations of biological clocks, fascinated with the integrational characteristics of "time" in a vertical arrangement, providing a bridge between single genes and the living organism as a whole.
==Comprehensive timeline == {| class="wikitable sortable" |- ! class = "unsortable"|Name<ref name="activity database"/><ref name="Okamura lab"/> ! Year |- |Born |1952 |- |Becomes a professor in the Department of Anatomy II/Lab at Kobe University |1995 |- |Discovery of mammalian Per1, Per2, Per3, Timeless |1997, 1998 |- |Found that mPer is light-inducible |1998 |- |Discovery that clock proteins form complexes and prevent degradation |2000, 2002, 2005 |- |Work on fibroblasts and the universality of the core clock loop among mammalian cells |2001 |- |Loss of oscillations in Cry deficient mice |2001 |- |SCN transplantation restored circadian rhythms |2003 |- |Core clock regulates cell cycle |2003 |- |Light activates the adrenal gland via SCN-sympathetic nerves |2005 |- |Received Medal of Honor with Purple Ribbon |2007 |- |Became Professor of Systems Biology at Kyoto University/Pharmaceutical Sciences |2007 |- |Received Aschoff's Ruler |2009 |- |The role of dysregulated clocks in salt-sensitive hypertension |2010 |- |Circadian G protein signaling RGS16 in the SCN |2011 |- |mRNA methylation in regulation of circadian period length |2013 |- |Vasopressin is critical for jet lag |2013 |- |Became Research Director of the Japan Science Technology Institute, CREST |2014 |}
==References== <references />
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{{DEFAULTSORT:Okamura, Hitoshi}} Category:21st-century Japanese biologists Category:Living people Category:1952 births Category:Chronobiologists Category:Academic staff of Kyoto University Category:Kyoto Prefectural University of Medicine alumni Category:Scientists from Shiga Prefecture