Development of decreasing oxidative stress in the ovary to rescue age-related fertility decline

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09248
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hiraike Osamu 東京大学, 医学部附属病院, 准教授 (20529060)
• Co-Investigator(Kenkyū-buntansha): 植田 茉来 (平野茉来) 東京大学, 医学部附属病院, 助教 (80771253) ; 浦田 陽子 東京大学, 医学部附属病院, 助教 (20572598)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 卵巣 / 酸化ストレス / 老化

Outline of Final Research Achievements

Based on the findings that the transcription factor Nrf2/Keap1 and p53/Mdm2 pathways are involved in the oxidative stress pathway in the ovary, low molecular weight compounds that act directly on these pathways are considered as a possible candidates for quenching ovarian aging in this study. The effects on the phenotypical changes and the decrease in the number of eggs were clarified by experiments using mice in addition to the primary culture system of human ovarian granulosa cells. After administration of dimethylfumarate, which enhances Nrf2 function, pathological changes in the ovaries were observed. DMF-administered mice showed that the number of eggs were preserved, the anti-Mullerian hormone level was higher than that of the control group, and oxidative stress markers were increased compared to the control group.

Free Research Field

産婦人科学

Academic Significance and Societal Importance of the Research Achievements

本研究によりラットを用いた実験系においてNrf2の病態生理を追求することが出来た。Nrf2機能を促進することが実際に生体においても抗酸化メカニズムを持つことが示せたことは、分子細胞生物学的理解を深める上で大きい。今回得られた知見は、ヒトへの臨床応用をする上で大前提となるものであり、DMFが酸化ストレス蓄積を改善するための一つの治療選択肢となりうる。DMFが近年の晩婚化の影響で初婚年齢、初回出産年齢が遅れる傾向にある日本人女性における新たな治療選択肢となり得ることを提案することが本課題に課せられた今後の検討課題であろう。