Development of new therapy for liver disease by regulating cellular senescence

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06985
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Kanazawa University
• Principal Investigator: Sasaki Motoko 金沢大学, 医学系, 准教授 (70225895)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 病理学 / 原発性胆汁性胆管炎 / 自己免疫性疾患 / 細胞老化

Outline of Final Research Achievements

The hypothesis: “Removing senescent cells (senolysis) may be a novel effective therapy for primary biliary cholangitis (PBC)” was verified in this study. This study revealed that cellular senescence was frequently observed in biliary epithelial cells in small bile ducts and bile ductules in PBC and that the degree of cellular senescence was associated with the stage and activity of PBC and inadequate response to UDCA. Furthermore, cell culture study disclosed that senescence-associated molecules upregulated in biliary epithelial cells in PBC, such as Bcl-xL and IFIT3, could be novel therapeutic targets by senolytic drugs and siRNA.

Free Research Field

人体病理学

Academic Significance and Societal Importance of the Research Achievements

PBCの国内患者数は5-6万人と推定されており,約30-40%のUDCA無効例に対する新しい治療薬の開発基盤の確立は意義がある。本研究では, PBCにおける胆管細胞老化は, 病期, 活動性, UDCA治療不応性に関連することを明らかにした。また, 細胞老化関連分子Bcl-xLやIFIT3などは,老化細胞除去薬やsiRNAなどを用いた老化細胞除去の有効な標的となった。本研究は, PBCの新しい治療法として老化細胞除去療法が有望である可能性を示した。