| Project/Area Number |
21H03004
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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 55020:Digestive surgery-related
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
三森 功士 九州大学, 大学病院, 教授 (50322748)
吉住 朋晴 九州大学, 医学研究院, 教授 (80363373)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Fiscal Year 2021: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | iPS細胞 / 脂肪性肝炎 / 肝硬変 / 脂肪肝 / NASH / 非アルコール性脂肪性肝炎 / 星細胞 / PNPLA3 / 人工肝臓 / iPS / 肝がん |
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| Outline of Research at the Start |
脂肪肝が増加しており、肝硬変や肝細胞癌の原因となっているが、脂肪肝の有効な治療法はないPNPLA3 遺伝子異常が脂肪肝や肝細胞癌発癌との関連が報告された。今回、iPS細胞を用いて、PNPLA3遺伝子異常が脂肪肝を発症するメカニズムを追求し、脂肪肝の新しい治療法を確立することで、肝臓病や肝臓癌の発症を抑えることを目標とする。
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| Outline of Final Research Achievements |
PNPLA3 variant was reported to be related with metabolic associated fatty liver disease. However, the mechanism has not been unveiled yet. The aim of this study is to generate iPSC-derived hepatic stellate cells (iHSC) from human-induced pluripotent stem cells (iPSC) with PNPLA3 single nucleotide polymorphism (SNP) and to clarify the mechanism of liver fibrosis caused by PNPLA3 SNP. Two types of iPSC (Wild, Variant) were differentiated into iHSC. TGF-β stimulation resulted in significantly higher secretion of the liver fibrosis markers, αSMA and Col1A1 in Variant-iHSCs than in Wild-iHSC. Variant-iHSC secreted significantly more PDGF and TGF-β, and had significantly higher cell proliferative and migration ability. AMIGO2 knockdown using siRNA in variant-iHSC significantly reduced migration and proliferation ability. The staining for AMIGO2 in cirrhotic liver and normal liver samples showed that AMIGO2 protein expression was observed in PNPLA3-variant samples.
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| Academic Significance and Societal Importance of the Research Achievements |
非アルコール性脂肪性肝疾患(NAFLD)の一部は非アルコール性脂肪肝炎(nonalcoholic steatohepatitis; NASH)を発症し、肝硬変や肝細胞癌へと進展する。本邦におけるNAFLD の有病率は年々増え続けており、NAFLD/NASH への対策が急務であることは明らかであるが、現在まで有効な治療法は確立されていない。
今回の研究にて、PNPLA３ SNPを認める症例では、肝星細胞の活性化が惹起しやすく、AMIGO２遺伝子発現を介して起こっていることがわかった。このAMIGO2をターゲットとして、今後、治療法の確立につながる可能性が非常に高い。
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