Kyoto University Graduate school of Pharmaceutical Science Department of System Biology, 
 Graduate School of Pharmaceutical Sciences
What to do
Systems Biology
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Bioluminescence of ticking clock cells in the SCN slice culture of Per1-luc mouse. Image was taken by the Cryogenic CCD camera in 2000.
Note large bleared spots (=clock cells) formed two clusters (=right and left SCN) among dot-like spot cosmic rays.
What to do

How TIME is generated and tuned? We will clarify the secret of generation and tuning of TIME in mammalian circadian system by multi-layered view at intracellular, intercellular and individual levels. Through clarifying the integration network mechanism of TIME, we will develop new drugs for tuning TIME. 

The subject of our study is circadian timing system in mammals. In this system, the circadian TIME generated at molecular clock in the suprachiasmatic nucleus (SCN) evokes the synchronized oscillation of molecular clocks in the whole body. Between them, TIME is transmitted in multilayer systems: 1) intracellular system of generation of cyclic TIME, 2) Intercellular system for synchronizing TIME, and 3) Symphony of TIME in individuals.
Clarification of clock machinery to generate TIME
1.1 Identification of ALL components of CLOCK
We try to isolate all parts of transcription-translation machinery. We focus SCN since all components of the SCN is specialized to generate TIME. From the point of the functional specialization of BRAIN, and from the general rule that CELL expresses a limited number of genes to play specific physiological role, SCN must be rich in expressing TIME-related genes. In this project we will isolate ALL genes expressed in SCN by in situ hybridization. Then, we will perform gene targeting to these SCN-expressing genes.
1.2 Identification of PER associating proteins (PAS) and transcription-translation feedback loop of clock genes
To explain the generation of cyclic TIME, transcription & translation feedback loop of clock genes is hypothesized. This theory is supported by the number of molecular and genetic studies of clock genes. However, the precise mechanism of transcription initiation and suppression is far from understanding. We will clarify this by the whole description of molecular clock components. Per1 & Per2 genes will have the key role for robustness of oscillation. It is known that PER1 & PER2 proteins form huge molecular complex. Thus, we will isolate the all components of PER associating proteins (PAS), and clarify the transcription and translation feedback loop of clock genes.
1.3 Clock genes and cell metabolism, birth, and death
Why virtually all cells in the body have the clock oscillating system inside the cell? We will identify how clock genes work on the energy metabolism, cell cycles, and cell death.
Intercellular system for synchronizing TIME
2.1 Region-specific knockdown of SCN
SCN biological clock is composed of thousands of clock cells which are subdivided into several groups. We will perform region-specific knockdown of these subdivisions to address the functional subdivision of SCN.
2.3 Geography of SCN
SCN clock cells are highly organized in time and space. For example, in our real-time luciferase-imaging system at cell level, time is generated and synchronized in a very highly organized system. We will complete and theorize the time-space geography of the SCN.
Symphony of TIME in individuals
3.1 SCN-adrenal pathway: conversion of time signals from nerve impulse to hormones
Standard time produced in the SCN is released strongly via central and peripheral autonomic nervous system. Sympathetic nerve impulses are conducted to the adrenal gland and converted to the endocrine signals by unknown mechanism. We will clarify what is happening in the adrenal gland.
3.2 Glucocorticoid is the mediators of central time
Glucocorticoid is a mediator of TIME. We will clarify the molecular mechanism how glucocorticoid regulates the peripheral clocks.
3.3 Timing system outside the SCN
In some environmental conditions such as restriction feeding, extra-SCN region sometimes generates SCN-independent rhythm. We will clarify the system from its molecular level.
  VIP cells in the SCN (1983).
VIP cells formed the paired clusters
just above the SCN.
Through above studies at 1), 2), and 3), we will draw the SYSTEMS of TIME at molecular levels, which will help the drug discovery for tuning the rhythm.
Department of System Biology, Graduate School of Pharmaceutical Sciences  ContactLinkSitemapJapaneseKyoto University
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