2005 Fiscal Year Final Research Report Summary
Reserch on clock-gene polymorphisms, which are relevant to circadian rhythm sleep disorders
| Project/Area Number |
15390352
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | The University of Tokyo (2004-2005)
Saitama Medical University (2003) |
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Principal Investigator |
EBISAWA Takashi The University of Tokyo, Graduate School of Medicine, Visiting Associate Professor, 大学院・医学系研究科, 寄付講座教員(客員助教授) (00201369)
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| Project Period (FY) |
2003 – 2005
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| Keywords | circadian rhythm sleep disorders / clock genes / gene polymorphisms / transcription factor / knock-in mouse / melatonin receptor / casein kinase |
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| Research Abstract |
1. We have found that S408N variation in Casein kinase1 epsilon (CK1ε) gene plays a protective role in the development of circadian rhythm sleep disorders (delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24)). In vitro kinase assay revealed that CK1ε with S408N variation was more active on α-casein and PER proteins, endogenous substrates of CK1ε, than wild-type CK1ε.
2. In order to establish a mouse strain with S408N variation in their endogenous CK1ε gene, which will show the phenotypal outcome of the variation, a knock-in vector to insert the variation by homologous recombination, was successfully constructed.
3. Gene variations were searched for in all of the exons for Per2 gene. One of the missense mutations was observed only in one of the N-24 patients and none of the 106 DSPS patients or 500 control subjects carried the mutation. Functional assay for the Per2 gene with the mutation is now in progress.
4. To observe the circadian clock function in Rat-1 cultured cells, a reporter gene, in which the promoter region of the Bmal1 gene was inserted upstream of the firefly luciferase gene, was transiently transfected into Rat-1 cells. 48 hours after transfection, 2-hour-stimulation with dexamethasone was administered and circadian rhythm was observed through alteration of the amount of the luminescence.
5. In collaboration with the researchers in another institute, Chinese hamster ovary cells, which permanently express melatonin receptor with or without missense variations which were first reported by us, were established to study the functional alteration of the melatonin receptors by the variations.
6. Gene variations were searched for in other clock genes, melanopsin, Bmal2,CK1δ,however, no variation was detected which was relevant to circadian rhythm sleep disorders.
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Research Products
(30 results)
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[Book] 時計遺伝子の分子生物学2004
Author(s)
海老澤尚(岡村均, 深田吉孝編集)
Total Pages
204
Publisher
シュプリンガー・フェアラーク東京
Description
「研究成果報告書概要(和文)」より
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