2021 Fiscal Year Final Research Report

A new approach to the pathogenesis of pancreatic cancer and the disorders of circadian rhythm based on the analysis of CRY1-binding proteins

Research Project

PDF

Project/Area Number	19K07498
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 49030:Experimental pathology-related
Research Institution	Yamagata University
Principal Investigator	Okano Satoshi 山形大学, 医学部, 助教 (60300860)
Co-Investigator(Kenkyū-buntansha)	佐藤賢一東北医科薬科大学, 医学部, 教授 (10282055) 中島修山形大学, 医学部, 教授 (80312841) 安井明東北大学, 加齢医学研究所, 加齢研フェロー (60191110)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	概日リズム / 膵β細胞 / 分化転換 / 脱分化 / 膵癌前駆病変 / 生物時計 / 糖尿病 / 上皮間葉転換
Outline of Final Research Achievements	Cysteine414 (zinc-binding site of mCRY1)-alanine mutant CRY1 transgenic mice (established by the CRY-Clock Gene Research Group in Tohoku area; hereafter simply referred to as TG) show diabetes characterized by the reduction of β-cell proliferation due to the characters of senescence-associated secretory phenotype (SASP) in β-cells (reviewed in Okano S. 2016).To explore the mechanisms of keeping of the number of β-cells under hyperglycemia for prolonged period in TG, and also of the generation of mucin-producing atypical intra-islet ducts, we further conducted detailed analysis of TG. The results showed that trefoil factor family 2 (TFF2) is up-regulated in the β-cell of TG life-stage dependently. Our results suggest the possible δ- cell to β-cell transdifferentiation in aged TG:δ-cells may predominantly play roles as the source for β-cells to supply new β-cells for islets in TG. The function of newly found CRY-binding proteins were also analyzed in MIN6 and Panc-1 cells.
Free Research Field	実験病理学
Academic Significance and Societal Importance of the Research Achievements	膵癌の前駆病変が如何に生成されるかを明らかにする研究は広く行われ,一定の知見が得られている。しかしながら,膵β細胞の異常に起因した膵癌前駆病変の発生機序に関しては,未だほとんど明らかになっていない。本研究に於いては,膵β細胞が障害され,膵ラ氏島に前癌病変が多発するユニークなマウスと,すでに広く活用されている各種細胞株の両方を研究対象として用いた。プロテオミクス解析と網羅的発現解析から新たに特定した病態関連候補タンパク質の解析のアプローチから,膵島内微小環境,膵癌前駆病変,及び膵ラ氏島リモデリングの関係を具体的に明らかにした。