Elucidation of molecular mechanisms of unusual circadian locomotor behavior and non-obese early onset diabetes mellitus in mutant (Cys414-Ala) cryptochrome1 transgenic mice

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590473
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Yamagata University
• Principal Investigator: OKANO Satoshi 山形大学, 医学部, 助教 (60300860)
• Co-Investigator(Kenkyū-buntansha): NAKAJIMA Osamu 山形大学, 医学部, 教授 (80312841)
• Co-Investigator(Renkei-kenkyūsha): YASUI Akira 東北大学, 加齢医学研究所, 教授 (60191110) ; HAYASAKA Kiyoshi 山形大学, 医学部, 名誉教授 (20142961)
• Research Collaborator: IGARASHI Masahiko 山形市立病院済生館, 糖尿病内分泌内科, 科長
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 膵β細胞 / mCRY1亜鉛結合部位 (Cys414残基) / 脱分化 / 細胞老化 / ヘッジホッグシグナル伝達経路 / 分化転換 / 視交叉上核（SCN) / 給餌同調振動体（FEO)

Outline of Final Research Achievements

We previously showed that Cys414(zinc-binding site)-Ala mutant mCRY1 Tg mice display diabetes characterized by β-cell dysfunction resembling human MODY. To uncover the molecular pathogenesis, we conducted DNA microarray analysis of the islet of the Tg mice at 4 weeks. mRNA levels of various secretory factors including cytokines and chemokines as well as CDK inhibitors were promoted in Tg mice. This expression pattern is similar to that of SASP. The cells, which are Sox9-positive and insulin-negative, were observed prominently in the islet of mature Tg mice, indicating that the dedifferentiation of β-cells occurs in Tg mice. The factors in the hedgehog signalling pathway were up-regulated from the young stage, suggesting that the factors are involved in the induction the dedifferentiation. Thus the dedifferentiation of β-cells, along with the lowered proliferation of β-cells due to the senescence-like changes, are accountable for the age-dependent β-cell failure in the Tg mice.

Free Research Field

時間生物学, 分子糖尿病学, 加齢医学