Biological Response to Environmental Stress: Epigenome/Proteome Analysis

2022 Fiscal Year Final Research Report

• Project Area: Preventive medicine through inflammation cellular sociology
• Project/Area Number: 17H06396
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo
• Principal Investigator: OHSAKO Seiichiroh 東京大学, 大学院医学系研究科(医学部), 准教授 (00274837)
• Co-Investigator(Kenkyū-buntansha): 藤渕 航 京都大学, iPS細胞研究所, 教授 (60273512) ; 市原 学 東京理科大学, 薬学部薬学科, 教授 (90252238)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Keywords: AHR / エピゲノム / Th17 / 潰瘍性大腸炎 / NRF2 / 中枢神経系 / アクリルアミド / 新電子性物質

Outline of Final Research Achievements

To analyze the mechanisms by which environmental stress induces chronic inflammation, various omics methods were used.　1) By using mice deficient in Nrf2, an environmental chemical sensor molecule, we investigated the effects of some soft electrophile substances on the central nervous system. We found that acrylamide induces antioxidant proteins in the cerebral cortex and that Nrf2 activation has anti-inflammatory effects.　2) Several new phenotypes were discovered during the breeding of mice deficient in another environmental chemical sensor molecule Ahr. We clarified the mechanism by which intestinal microflora developed in a specific breeding environment promotes Th17 differentiation in Ahr-deficient mice and induces ulcerative colitis-like diseases. Additionally, the mechanism by which Ahr-deficiency results in silencing of the pheromone protein Mup family genes was revealed.

Free Research Field

社会医学

Academic Significance and Societal Importance of the Research Achievements

慢性炎症によって発生する中枢神経系異常や難治性自己免疫疾患は、有害な環境因子や近年の食生活の変化による従来ではなかった微量な化学物質曝露や、それに伴う腸内菌叢の変動によって引き起こされている可能性が示唆されている。この研究班で行った、アクリルアミド曝露やダイオキシン受容体であるAHRの機能不全による自己免疫疾患様病態発生に関する所見は、環境毒性学的、予防医学的に極めて重要であり、社会的にも今後重要な所見となると予想される。