2022 Fiscal Year Final Research Report
Basic study for developing NASH therapeutic drugs by using a small molecule derived from the cellular slime mold serving as a lead compound
| Project/Area Number |
20H04110
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 59040:Nutrition science and health science-related
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| Research Institution | University of Shizuoka |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
河田 則文 大阪公立大学, 大学院医学研究科, 教授 (30271191)
山口 桃生 静岡県立大学, 薬学部, 助教 (30804819)
濱島 義隆 静岡県立大学, 薬学部, 教授 (40333900)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | NASH / 肝星細胞 / 肝線維化 / DIF-1 |
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| Outline of Final Research Achievements |
Activation of hepatic stellate cells (HSCs) has been proposed to be responsible for the development of liver fibrosis. Accordingly, the deactivation of activated HSCs (aHSCs) is expected to be a therapeutic target for liver fibrosis. We previously showed that differentiation-inducing factor-1 (DIF-1), a small molecule derived from the cellular slime mold, induces the deactivation of aHSCs. In the present study, we investigated the mechanism involved in the DIF-1-induced deactivation of aHSCs, thereby trying to identify target molecules for the treatment of liver fibrosis. We also performed the analysis of the structure-activity correlation by using DIF-1 as the lead compound. The results obtained in the present study suggest that DIF-1 induces deactivation of aHSCs through inhibiting the Hedgehog signaling. In addition, the structure-activity correlation analysis of DIF-1 derivatives suggests possible structural characteristics required for their deactivation effect on aHSCs.
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| Free Research Field |
薬理学
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| Academic Significance and Societal Importance of the Research Achievements |
肥満人口の増加に伴い、肝線維化を伴う非アルコール性脂肪肝炎（NASH）の患者数は年々増加している。しかし、その有効な予防・治療法は、未だに見出されていない。肝星細胞（HSC）は活性化されると、コラーゲンを産生する筋線維芽様細胞へと形質転換することから、活性型HSC（aHSC）は肝線維化の責任細胞と考えられている。本研究では、細胞性粘菌由来物質DIF-1がaHSCを脱活性化させるという我々の知見を基にして、aHSCの脱活性化にHedgehog経路の抑制が関与することを初めて示唆した。また、DIF-1の脱活性化作用に必要な構造的特徴を同定し、NASH治療薬創出に向けた基盤的知見を提供した。
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