Development of new diagnostic markers and reversible fertility inhibitors for mammalian spermatozoa

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19198
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 42:Veterinary medical science, animal science, and related fields
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Fujihara Yoshitaka 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (70578848)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 診断マーカー / 雄性不妊 / 哺乳類精子 / 小分子化合物

Outline of Final Research Achievements

In this study, we focused on the newly discovered "morphologically normal spermatozoa with fertilization defects". We developed antibodies to detect abnormal spermatozoa in humans and domestic animals and identified new candidates through the development of genome-edited mice. While we could not obtain high-quality antibodies, we did find that sperm membrane protein SPACA4 and epididymal proteins LCNs and LY6G5B/C are necessary for the sperm fertilizing ability and can be candidates for diagnostic infertility markers. Furthermore, we discovered that the PDCL2 protein is essential for spermatogenesis via mutant mouse analysis and succeeded in identifying two types of small-molecule compounds that specifically bind to the human PDCL2 protein. Currently, we are investigating the reversible fertility inhibitory effects using these compounds.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、研究代表者が一貫して進めてきた男性不妊の新たな表現型「見かけ正常な受精不全精子」を示す原因遺伝子の探索と検出方法の開発に貢献する。原因遺伝子の発見は、哺乳類精子の受精能力制御メカニズムの解明に繋がり、検出法はヒトや家畜等の精子性状検査の主項目である精子量、形態、運動性に続く第四の検査項目としての可能性を再検証できた。また、精子タンパク質を対象に小分子化合物による受精機能阻害はホルモン療法に頼らない可逆的な男性避妊薬の開発に向けて研究を推進できた。