Study of NASH using human hepatocyte chimeric mouse and biopsy specimen

Research Project

Project/Area Number	21H04817
Research Category	Grant-in-Aid for Scientific Research (A)
Allocation Type	Single-year Grants
Section	一般
Review Section	Medium-sized Section 52:General internal medicine and related fields
Research Institution	Hiroshima University
Principal Investigator	Chayama Kazuaki 広島大学, 医系科学研究科(医), 共同研究講座教授 (00211376)
Co-Investigator(Kenkyū-buntansha)	茶山弘美広島大学, 医系科学研究科(医), 准教授 (70572329) 三木大樹広島大学, 医系科学研究科(医), 講師 (10584592) Hayes C.Nelson 広島大学, 医系科学研究科(医), 准教授 (50572327)
Project Period (FY)	2021-04-05 – 2024-03-31
Project Status	Completed (Fiscal Year 2023)
Budget Amount *help	¥42,510,000 (Direct Cost: ¥32,700,000、Indirect Cost: ¥9,810,000) Fiscal Year 2023: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000) Fiscal Year 2022: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000) Fiscal Year 2021: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Keywords	脂肪化 / ヒト肝細胞 / 成長ホルモン / 線維化 / 治療 / 脂肪肝 / ヒト肝細胞キメラマウス / NASH / モデル動物 / 肥満
Outline of Research at the Start	非アルコール性脂肪性肝炎(Non Alcoholic Steato-Hepatitis; NASH)は肝細胞の脂肪化と炎症により繊維化が進展する。申請者はヒト肝細胞を移植したuPA/scidマウスに肝炎ウイルスを感染させるモデルを構築した (Tsuge, Hepatology 2005, Sainz, Nature Medicine 2012)。これにhigh fat dietを投与するとヒト肝細胞への脂肪沈着が認められ、進展に伴いヒトALTの上昇も認められた。この動物モデルを使用し、同一ドナーに由来する肝細胞の脂肪化した肝細胞としていない肝細胞のmulti-omix解析による解析を行う。
Outline of Final Research Achievements	Non-alcoholic fatty liver disease (NAFLD) is an inflammatory condition that can progress to cirrhosis and hepatocellular carcinoma. The global incidence of NAFLD is rapidly increasing in parallel with rising obesity rates. In this study, a fatty liver mouse model was generated using human hepatocyte chimeric mice. Six mice were fed a high-fat diet, six were fed a normal diet, and three mice from each group received growth hormone (GH), resulting in four distinct groups. After being fed their respective diets for eight weeks, the mice were sacrificed, and human hepatocytes were extracted for RNA-Seq, proteomics, and metabolomics analysis. A multi-omics approach was employed to investigate the metabolic status within each group. This approach offers a powerful model for the future development of therapeutic agents for NAFLD.
Academic Significance and Societal Importance of the Research Achievements	ヒトの肝細胞の代謝が観察できるモデルはなく、これまで薬剤の開発の妨げとなっていた。本研究で開発したモデルはヒト肝細胞の代謝そのものの変化を観察できるうえに、繊維化などのメカニズムの解明、発達防止の治療開発などに有用であり、今後の応用研究が期待される。