Functional analysis of SOX9-related signaling pathways in bile duct development and pathological condition of cholestatic liver injury

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08622
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: Yoshii Daiki 熊本大学, 病院, 診療助手 (00792582)
• Co-Investigator(Kenkyū-buntansha): 菰原 義弘 熊本大学, 大学院生命科学研究部(医), 教授 (40449921) ; 横内 裕二 熊本大学, 発生医学研究所, 特定事業研究員 (60252227) ; 本田 正樹 熊本大学, 病院, 助教 (80573609)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: SOX9 / 細胆管反応 / 胆管発生 / 透明化 / ノックアウトマウス

Outline of Final Research Achievements

Our preliminary experiments indicated that SOX9 may play a critical role in the normal development of the bile ducts. Therefore, this study was conducted using Sox9 conditional knockout (cKO) mice. Visualization of the bile ducts by clearing the liver revealed that at five weeks of age, the density of the bile ducts was significantly reduced in Sox9 cKO mice, and in particular, the capillary bile ducts were poorly visualized. Focal hepatic necrosis was observed and the liver enzyme ALT was significantly elevated. In the central region, there was poor development of CK19-positive bile ducts, while in the peripheral region there was an increase in the number of irregular small bile ducts. Periportal fibrosis was also observed. These findings suggested that there may be a problem with the formation of a network between the capillary and small bile ducts. We concluded that SOX9 may contribute to bile duct development.

Free Research Field

肝臓

Academic Significance and Societal Importance of the Research Achievements

前研究で行われた細胆管反応の進展メカニズムとSOX9との関連性に関する研究に加えて、本研究では胆管の正常発生にSOX9が関わっている可能性が示された。SOX9はアラジール症候群の原因遺伝子であるNotch2やJagged1が関わるNotchシグナル経路と密接なかかわりのある転写因子である。そのSOX9が持つ役割について新たな知見を見出すことができたことから、胆管発生の複雑なメカニズムの解明に貢献でき、かつ、先天的な胆管発生異常の解明の一助となる研究であると考えられる。