Elucidation of SOX9 function in a liver for the development of novel therapies for liver diseases

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18059
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: Yoshii Daiki 熊本大学, 大学院生命科学研究部(医), 学術研究員 (00792582)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: SOX9 / 細胆管反応 / 肝傷害 / 胆管発生 / Sox9ノックアウトマウス

Outline of Final Research Achievements

The purpose of this study was to elucidate the mechanism of ductular reaction (DR) seen in chronic liver diseases, such as biliary atresia, and to build the basis of a new therapeutic strategy for liver diseases.
In order to elucidate the mechanism of DR, we have analyzed the functional role of SOX9 in the development and morphogenesis of the bile duct. During the embryonic period, no significant changes were found in the development of the bile duct between in the SoX9 conditional knockout (cKO) mice and control mice. The low efficiency of Cre, a DNA recombinase, in the Cre driver mice was suggested to affect the result during the embryonic period. On the other hand, a clear difference in the bile duct morphogenesis was observed between in the adult Sox9 cKO mice and control mice. Next, in order to evaluate the morphogenesis of the bile duct, the whole liver tissue-clearing was performed, and the bile duct was visualized successfully.

Free Research Field

肝臓

Academic Significance and Societal Importance of the Research Achievements

今までの我々の研究成果により、SOX9が肝傷害時のDRの進展に寄与している可能性が明らかとなってきている。本研究ではさらに、今まで報告されてきた研究では重要視されていない、胆管発生や形態形成にも関与している可能性があることが分かった。これは、胆管発生のメカニズムを考える上で新たな知見となる重要な結果である。また、胆管の形態形成を視覚化する新たな方法が確立できた。DRの進展メカニズムを考える上で胆管発生のメカニズムは知っておくべきことであり、これらの結果は、DRを伴う慢性肝疾患において、病態の進行を抑制するため、SOX9やその上流シグナル経路をターゲットとした治療の基盤となる結果である。