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Hitoshi Okamura (born December 2, 1952 [1]), MD/PhD, is a Japanese scientist who specializes in chronobiology. He is currently a Professor of Biological Systems at Kyoto University Graduate School of Pharmaceutical Sciences. He is regarded for his research on mammalian PER1, PER2, PER3 and the mechanisms of mammalian clocks. He has received a Medal of Honor with Purple Ribbon for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. [2] His lab is currently researching sleep disorders and life-style diseases. [3]
Hitoshi Okamura | |
|---|---|
| Born | December 2, 1952 |
| Nationality | Japanese |
| Website | Okamura Lab |
Academic Career
[edit]Dr. Okamura recieved his undergraduate, medical, and doctorate in science degrees from the Kyoto Prefectural School of Medicine. He was a Professor of Brain Sciences at the Kobe University School of Medicine from 1995-2008. [3] He is currently a Professor of Biological Systems in the Department of Anatomy II at the Kyoto University Graduate School of Pharmaceutical Sciences.[4] His work has focused on understanding mammalian circadian rhythms.
Scientific Career
[edit]Discovery of mPer Genes
[edit]Okamura's lab discovered the mammalian period gene PER1 in 1997 using intra-module scanning–polymerase chain reaction (IMS-PCR) to isolate the gene in mice. In 1998 they discovered PER2, PER3, and the mammalian homolog of the Drosophila gene timeless. They also discovered that mPer1 is light-inducible and can phase shift the circadian clock by light. [5] Okamura worked with Jay Dunlap, a chronobiologist specializing in circadian rhythms in Neurospora, to discover that mammals are similar to Neurospora than Drosophila in this way. [6]
Restoration of Circadian Rhythms Using Mammalian Per
[edit]Okamura's lab collaborated with Amita Sehgal's lab to determine if the mPer1 and mPer2 genes were able to generate oscillations. [4] They transplanted mPer1 and mPer2 genes from mice into arrhythmic per0 mutants of Drosophila and found that transplantation restored rhythms [7].
Arrhythmic mCry1/mCry2-Double Knockout Mice
[edit]Okamura's lab determined that the mCry gene products play a critical role as negative regulators, showing that mPer1 and mPer2 levels become arrhythmic when mCry is knocked out. [8] His lab also found that behavioral rhythmicity was recovered when wild-type mice SCN were transplanted into mCry deficient mice, suggesting that the suprachiasmatic nucleus (SCN) synchronizes and generates behavioral rhythms. [9]
Protein Level Regulation of mPer
[edit]Okamura's lab discovered that mPER proteins made in the cytoplasm translocate into the nucleus of the cell and form a complex composed of mCRY1, mCRY2, mPER1, mPER2, mPER3, and mTIM. [10] This negative complex suppresses the transcription of mRNA activated by CLOCK and BMAL1.[11] Okamura's lab has also done research on mPER1 and mPER2 degradation. They found that mPER and mCRY forms a dimer that inhibits mPER degradation and the inhibition of mPER degradation suppresses mPer1 and mPer2 transcription. [10] This negative feedback loop appears to be found in all clocks.[12]
Core Clock Loop of Clock Genes is Universal Among Mammalian Cells
[edit]Okamura's lab became interested in the possible differences of autonomously rhythmic clock genes in fibroblast cell lines and those in the SCN. He discovered that in mice, both types of cells showed temporal expression of profiles of all known clock genes,[13] the phases of various mRNA rhythms, the delay between maximum mRNA levels and appearance of nuclear mPER1 and mPER2 protein, the inability to produce oscillations in the absence of functional mCry genes, and the control of period length by mCRY proteins.
SCN as the Central Clock
[edit]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.[14] 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.[15] Okamura demonstrated that hepatic gene expression of clock genes was regulated by sympathetic nerves. He also demonstrated that the SCN regulates the circadian expression of adrenal corticosterone by the activation of various genes by the route of the innervating sympathetic adrenal nerve. [9] So, the sympathetic nerve conveys the time 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. [9]
Other Research
[edit]Okamura and his lab 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, and wee1, the gene for a kinase that inhibits mitosis by inactivating CDC2/cyclin B, was negatively correlated to M-phase. [16] Okamura's research showed that mouse hepatocyte proliferation is under circadian control. [17]
Awards and Honors
[edit]♦Recipient of Medal of Honor with Purple Ribbon
♦Recipient of Aschoff's Ruler in 2009
References
[edit]- ^ "Kyoto University Activity Database on Education and Research".
- ^ "Prize Winners of Aschoff's Ruler". EBRS.
- ^ a b "Prof Hitoshi Okamura". ISH 2012.
- ^ a b "Okamura Laboratory". Kyoto University Graduate School of Pharmaceutical Sciences, Department of Systems Biology.
- ^ Albrecht, Urs; Zheng, Binhai; Larkin, David; Sun, Zhong; Lee, Cheng (April 2001). "mPer1 and mPer2 Are Essential for Normal Resetting of the Circadian Clock". Journal of Biological Rhythms. 16 (2): 100–104. doi:10.1177/074873001129001791.
- ^ Liu, Yi (June 2003). "Molecular Mechanisms of Entrainment in the Neurospora Circadian Clock". Journal of Biological Rhythms. 18 (3): 195–205. doi:10.1177/0748730403018003002.
- ^ Hendricks, Joan C. (2003). "Invited Review: Sleeping flies don't lie: the use ofDrosophila melanogasterto study sleep and circadian rhythms". Journal of Applied Physiology. 94 (4): 1660–1672. doi:10.1152/japplphysiol.00904.2002. ISSN 8750-7587.
- ^ Bae, Kiho; Jin, Xiaowei; Maywood, Elizabeth S.; Hastings, Michael H.; Reppert, Steven M.; Weaver, David R. (2001). "Differential Functions of mPer1, mPer2, and mPer3 in the SCN Circadian Clock". Neuron. 30 (2): 525–536. doi:10.1016/S0896-6273(01)00302-6. ISSN 0896-6273.
- ^ a b c Dibner, Charna; Schibler, Ueli; Albrecht, Urs (2010). "The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks". Annual Review of Physiology. 72 (1): 517–549. doi:10.1146/annurev-physiol-021909-135821. ISSN 0066-4278.
- ^ a b Preitner, Nicolas; Damiola, Francesca; Lopez-Molina, Luis; Zakany, Joszef; Duboule, Denis; Albrecht, Urs; Schibler, Ueli (26 July 2002). "The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator". Science Direct. 110 (2): 251–260. doi:10.1016/S0092-8674(02)00825-5.
- ^ Reppert, Steven; Weaver, David (29 August 2002). "Coordination of circadian timing in mammals". Nature. 418: 935–941.
- ^ Balsalobre, Aurélio (24 January 2014). "Clock genes in mammalian peripheral tissues". Cell and Tissue Research. 309 (1): 193–199.
- ^ Hastings, Michael; Reddy, Akhilesh; Maywood, Elizabeth (August 2003). "A clockwork web: circadian timing in brain and periphery, in health and disease". Nature. 4: 649–661.
- ^ Colwell, Christopher (20 December 2001). "NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus: gating by the circadian system". European Journal of Neuroscience. 13 (7): 1420–1428.
- ^ Bartness, Timothy; Demas, Gregory; Song, C. Kay (2002). "Seasonal Changes in Adiposity: the Roles of the Photoperiod, Melatonin and Other Hormones, and Sympathetic Nervous System". Experimental Biology and Medicine. 227.
- ^ Mitra, Jayashree; Schultz, Richard (1 September 1996). "Regulation of the acquisition of meiotic competence in the mouse: changes in teh subcellular localization of cdc2, cyclin B1, cdc25C and wee1, and in the concentration of these proteins and their transcripts". Journal of Cell Science: 2407–2415.
- ^ Fausto, Nelson; Campbell, Jean S.; Riehle, Kimberly J. (2006). "Liver regeneration". Hepatology. 43 (S1): S45 – S53. doi:10.1002/hep.20969. ISSN 0270-9139.