Hitoshi Okamura (born December 2, 1952) 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. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.
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. Since 2007, he has worked as a professor of Systems Biology at the Kyoto University Graduate School of Pharmaceutical Sciences. 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.
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. They found that Per1 is light-inducible and can phase shift the circadian clock by light. 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.
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. This negative complex suppresses the transcription of mRNA activated by CLOCK and BMAL1. 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. This negative feedback loop appears to be found in all clocks.
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, 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. 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.
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. They transplanted Per1 and Per2 genes from mice into arrhythmic per0 mutants of Drosophila and found that transplantation restored circadian rhythms.
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