| Project/Area Number |
21H03010
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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 | Tokyo Women's Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
徳重 克年 東京女子医科大学, 医学部, 教授 (60188729)
岡田 浩介 筑波大学, 医学医療系, 准教授 (80757526)
正田 純一 筑波大学, 医学医療系, 客員教授 (90241827)
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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 |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2021: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
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| Keywords | p62/Sqstm1 / NASH / 肝癌 / autophagy / p62 / lipophagy / 臨床標本 / 遺伝子改変マウス / 非アルコール性脂肪性肝疾患 / 脂質代謝 |
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| Outline of Research at the Start |
p62は細胞組織中の中性脂肪を遊離脂肪酸に分解する新たな代謝経路であるlipophagyへの関与も明らかとなった. p62がlipophagyを介して全身の脂肪酸代謝の制御に関わる因子であることが示唆されている.本研究では,「p62欠損が惹起するlipophagy障害が, 中性脂肪-脂肪酸-Acyl-CoAから脂肪酸beta-酸化へ至る一連の代謝をどう変化させ, どのようにNASHの発症・進展に関与するか」, また,「NASH発症・進展に対してp62の抑止的役割について脂肪酸代謝と臓器連関の視点から解明する.」について解明していく.
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| Outline of Final Research Achievements |
The aim of this research is to elucidate the mechanisms of development of NASH and hepatocellular carcinoma from both basic and clinical medicine. The hepatocytes, adipocytes, or macrophages specific conditional p62 knock-in (rescued) mice were product and analyzed in NASH development. The hepatocyte specific p62 knock-in mice were suppressed the development of NASH with severe hepatic inflammation and fibrosis compared with other p62 gene modified-mice despite their similar obese. Moreover, p62 immunohistochemical analyses using clinical liver specimens from 50 hepatocellular carcinoma developed from NASH, 49 HCCs developed from chronic viral hepatitis C, and 48 liver metastases of colorectal cancer from both tumorous and non-tumorous areas which were collected by hepatic resection surgery showed that p62 immunohistochemical expression and pattern was correlated with liver inflammation and fibrosis.
p62 of hepatocytes could be a new target for NASH treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
非アルコール性脂肪性肝炎（NASH）の進行および肝癌発生を阻止するための薬物治療は確立していない．本研究は，肝細胞のp62がNASHの防御に重要であること，ヒトでもNASH進展に関連することを示した．これらの結果は，特に肝細胞のp62の発現が肝脂肪化のみならず肝炎症線維化をもコントロールし得る可能性と，p62が新しいNASHの治療標的と成り得る可能性を示した．NASHの今後の薬物治療開発のうえで，本研究の意義は大きいと考えられる．
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