UPR regulation and novel therapeutic strategy by targeting IRE1a in obesity-induced diabetes

Research Project

Project/Area Number	21K08562
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 54040:Metabolism and endocrinology-related
Research Institution	Wakayama Medical University
Principal Investigator	Morita Shuhei 和歌山県立医科大学, 医学部, 准教授 (50372868)
Project Period (FY)	2021-04-01 – 2024-03-31
Project Status	Completed (Fiscal Year 2023)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords	恒常性維持機構 / UPR / 膵β細胞 / 糖尿病 / 小胞体ストレス応答
Outline of Research at the Start	肥満・糖尿病の病態を明らかにし、新規治療薬の開発を進める上で、小胞体と呼ばれる細胞内小器官の働きをコントロールすることは重要であると考えられる。本研究では小胞体の働きを左右する鍵分子であるIRE1αに着目し、肥満・糖尿病の病態解明、新規治療法開発を目指す。
Outline of Final Research Achievements	Unfolded Protein Response (UPR), which could be regulated by IRE1α, was increased just before and after the onset of diabetes in db/db mouse islets, a mouse model of obese diabetes mellitus. We identified factors associated with pancreatic β-cell injury induced by excessive endoplasmic reticulum stress. We confirmed that these candidate factors are expressed in islets of db/db mice at approximately the same time as the expression of UPR markers. We confirmed that KIRA suppressed the deterioration of glucose tolerance in obese diabetic mouse models.
Academic Significance and Societal Importance of the Research Achievements	本研究は肥満・糖尿病の病態における生体の恒常性維持機構の一つUnfolded Protein Response (UPR)機構とその主要制御因子IRE1αの役割の一旦を明らかにした。新規開発したIRE1α特異的阻害薬の肥満・糖尿病に対する治療法の開発基盤構築のため、肥満・糖尿病モデルマウスにおいてその耐糖能に対する効果を確認した。肥満糖尿病において、糖尿病初期状態もしくは発症直前の膵β細胞のUPRシグナルへの介入が、新たな治療法の一つとなり得る可能性が示唆された。