| Project/Area Number |
16310044
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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 |
Risk sciences of radiation/Chemicals
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| Research Institution | KYUSHU UNIVERCITY |
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Principal Investigator |
SHIMOHIGASHI Yasuyuki Kyushu University, Faculty of Sciences, Professor, 大学院理学研究院, 教授 (00211293)
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| Co-Investigator(Kenkyū-buntansha) |
NOSE Takeru Kyushu University, Faculty of Sciences, Associate Professor, 大学院理学研究院, 助教授 (10301334)
SHIMOHIGASHI Miki Fukuoka University, Faculty of Science, Research Associate, 理学部, 助手 (60078590)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2006: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2004: ¥7,500,000 (Direct Cost: ¥7,500,000)
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| Keywords | endocrine disruptor / endocrine disrupting chemicals / nuclear receptor / conformation / antibody / receptor binding / hormone activity / 内分泌撹乱化学物質 / ビスフェノールA / リスク評価 / 低用量問題 |
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| Research Abstract |
The chemicals acknowledged as endocrine-disruptors are believed to perturb an endocrine hormone system mainly by binding to the estrogen receptor (ER) and/or androgen receptor (AR). The human genome project revealed that there are 48 different kinds of nuclear receptors (NRs) in human. Endocrine disruptors are feasible to bind to all of these NRs, and thus these NRs should be examined for the influence of such chemicals. Preparing 'conformation change-sensing antibodies' that distinguish the active and inactive conformations of NRs, we have developed an assay methodology to estimate the receptor binding ability and activation capability of chemicals. This mehod is based on the amount of conformation change induced by ligand binding that causes a change of the NR from inactive apo conformation to active holo conformation. In the present study, we attempted to develop this methodology to all of 48 NRs.
Mainly focusing on group III steroid hormone receptors, we first analyzed 48 human NRs by means of the method established as the 'quantitative evolutionary trace analysis' especially to explore the structure-function relationships. The analyses clearly revealed that there are two distinct types of NRs. One type is in a usual ligand-induced activation mechanism, while the other is in a spontaneous 'self-activation' mechanism. Estrogen-related receptor γ (ERR_γ) of the latter mechanism has shown that it binds specifically bisphenol A (BPA), a putative member of endocrine disruptors. Although BPA has been believed to bind to ER and AR, ERR_γ was found to be a BPA's true receptor. We succeeded in development of a novel conformation-change sensing assay method, which is applicable to even a self-activation type of NRs. The present study has led to significant fruitful results such as the discovery of self-activation type of NRs and ERR_γ as the receptor of an endocrine disruptor BPA.
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