Identification and analysis of the susceptibility gene for streptozotocin-induced diabetes in mice using the genome editing technology

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K14975
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory animal science
• Research Institution: Nagoya University
• Principal Investigator: Miyasaka Yuki 名古屋大学, 医学系研究科, 助教 (30778098)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: マウス / ストレプトゾトシン / 糖尿病感受性遺伝子 / 膵島脆弱性 / ゲノム編集技術

Outline of Final Research Achievements

A missense mutation (p.Ala132Ser) in N-methylpurine-DNA glycosylase (Mpg) is a candidate mutation for streptozotocin (STZ) susceptibility in A/J mice. Alternatively, a missense mutation (p.Gly200Val) in DNA repair protein RAD50 (Rad50) is a candidate mutation for STZ susceptibility in NSY/Hos (NSY) mice. To confirm the effects of these mutations on STZ susceptibility, we developed a knock-in mice strain in which each mutation was replaced with a normal allele via CRISPR/Cas9-mediated genome editing technology. We analyzed STZ susceptibility in the knock-in mice and revealed that a p.Ala132Ser mutation in Mpg was not associated with STZ susceptibility in A/J mice. Conversely, a p.Gly200Val mutation in Rad50 was confirmed as a mutation that regulates STZ susceptibility in NSY mice.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

マウス系統間にはSTZ感受性に差異が存在する事が知られているが、その原因遺伝子を同定した例は無い。本研究では、効果の小さい変異ではあるもののSTZ感受性を規定する遺伝子変異を特定することに成功した。STZ感受性遺伝子は膵島の脆弱性に関与していることが推定される為、本研究で特定した変異は膵島脆弱性に起因する糖尿病発症機構の解明に繋がるヒントになると期待される。