Understanding of the regulatory mechanisms of the xenoreceptors for chemical risk assessment

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07044
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Okayama University
• Principal Investigator: Kodama Susumu 岡山大学, 医歯薬学域, 准教授 (20621460)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 核内受容体 / 異物センサー / ヘテロ二量体 / 転写調節

Outline of Final Research Achievements

In this study, focusing on the fact that the nuclear receptors CAR and PXR function as heterodimers with their partner nuclear receptor RXR, we investigated the regulation of the transcriptional activity of each heterodimer in response to RXR agonists using in vitro methods. The results showed that both nuclear receptors undergo regulation based on their responsiveness to RXR agonists under certain conditions. A novel system for the evaluation of chemical-PXR interactions was also developed, which detects the reconstitution of split-luminescent enzyme based on receptor-transcriptional cofactor interaction induced by ligand binding.

Free Research Field

衛生薬学

Academic Significance and Societal Importance of the Research Achievements

核内受容体CARとPXRは、体外から侵入した多種多様な化学物質に誘導される多岐にわたる生体応答の起点となる。これまでに、両核内受容体の多くの生理的役割やその分子機序の理解が進展してしてきたが、これらのRXRと協働することに着目した研究の実施例は少ない。本研究では、RXRとの協働という点からCARとPXRによる転写調節のメカニズムの解析を実施し、化学暴露に対する応答機構を理解する上で有用な知見を得ると共に、それらの機能に基づいた新しい化学物質との相互作用評価法を構築した。