Development and progression mechanism of NASH from the viewpoint of cell-cell interaction and medical application
Project/Area Number |
19H01054
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
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Research Institution | Kyushu University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
国府島 庸之 九州大学, 医学研究院, 准教授 (00650748)
宮澤 崇 九州大学, 大学病院, 講師 (30443500)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥45,890,000 (Direct Cost: ¥35,300,000、Indirect Cost: ¥10,590,000)
Fiscal Year 2021: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2020: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2019: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
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Keywords | NASH / ミトコンドリア / 細胞間相互作用 / マクロファージ / シングルセルトランスクリプトーム解析 / hCLS / C型レクチン受容体 / 一細胞遺伝子発現解析 / 肝実質細胞 |
Outline of Research at the Start |
糖尿病・肥満を背景としてNASHあるいはNASH肝癌の罹患率が急増しており、脂肪肝からNASHを経てNASH肝癌を発症する一連の経時変化を踏まえたNASHの病態解明と予防・治療戦略の開発は喫緊の課題である。研究代表者らは既に、ヒトの病態に酷似した新しいNASHマウスの開発に成功し、過剰な脂肪蓄積により細胞死に陥った肝実質細胞をマクロファージが取り囲んで貪食・処理する特徴的な組織像であるhCLSが起点となって炎症の慢性化と線維化を誘導することを報告した。本研究では、hCLSに着目し、NASHマウスを用いた基礎研究と臨床検体を用いた臨床研究によりNASHとNASH肝癌の発症・進展機構を検討する。
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Outline of Final Research Achievements |
This study focused upon hepatic crown-like structures (hCLS) as an origin of hepatic inflammation and fibrosis in the NASH liver, so that we may understand the pathogenesis of NASH, from the viewpoint of the crosstalk between parenchymal cells and non-parenchymal cells.
We demonstrated that mitochondrial fission factor (Mff) plays an important role in the development of NASH. Using the single cell RNA sequencing (scRNA-seq) analysis, we identified a SPP1-positive macrophage cell population which increases during the progression from simple steatosis to NASH. The SPP-1 positive macrophages were located around hCLS and in close proximity to activated Ito cells. Recently, using a microdissection-based technique, we established a highly efficient method to obtain non-parenchymal cells from hCLS, which are to be subjected to scRNA-seq analysis.
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Academic Significance and Societal Importance of the Research Achievements |
近年、糖尿病・肥満患者の増加や超高齢社会を背景として、NASHあるいはNASH肝癌の罹患率が急増している。NASHは肝不全や虚血性心疾患の発症に関連するため、脂肪肝からNASHを経て胞癌を発症する一連の病態変化の解明と予防・治療戦略の開発は喫緊の課題である。本研究により、我々が独自に開発したヒトNASH病態に酷似した新しいNASHマウスを用いて、肝実質細胞とマクロファージあるいは線維芽細胞などの間質細胞の相互作用に着目して、脂肪肝からNASHを経て肝癌を発症する一連の経時変化と分子機構を明らかにすることができ、現在有効な治療法がないNASHに対する医学応用の手掛かりが得られた。
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Report
(5 results)
Research Products
(41 results)
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[Journal Article] Differential effect of canagliflozin, a sodium-glucose cotransporter (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice.2022
Author(s)
Otsuka H, Yokomizo H*, Nakamura S, Izumi Y, Takahashi M, Obara S, Nakao M, Ikeda Y, Sato N, Sakamoto R, Miyachi Y, Miyazawa T, Bamba T, Ogawa Y*.
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Journal Title
Biochem. J.
Volume: 479(3)
Issue: 3
Pages: 425-444
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Efficacy of Tofogliflozin onMetabolic Dysfunction-Associated Fatty Liver Disease2022
Author(s)
Takeshi Goya, Koji Imoto, Shigeki Tashiro, Tomomi Aoyagi, Motoi Takahashi, Miho Kurokawa, Hideo Suzuki, Masatake Tanaka, Masaki Kato, Motoyuki Kohjima, Yoshihiro Ogawa
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Journal Title
Gastroenterology Insights
Volume: 13
Issue: 1
Pages: 20-26
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model.2021
Author(s)
Yoshioka N, Tanaka M, Ochi K, Watanabe A, Ono K, Sawada M, Ogi T, Itoh M, Ito A, Shiraki Y, Enomoto A, Ishigami M, Fujishiro M, Ogawa Y, Suganami T.
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Journal Title
Biomed Pharmacother
Volume: 140
Pages: 111738-111738
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Importance of Intestinal Environment and Cellular Plasticity of Islets in the Development of Postpancreatectomy Diabetes.2021
Author(s)
Fukuda T, Bouchi R, Takeuchi T, Amo-Shiinoki K, Kudo A, Tanaka S, Tanabe M, Akashi T, Hirayama K, Odamaki T, Igarashi M, Kimura I, Tanabe K, Tanizawa Y, Yamada T, Ogawa Y
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Journal Title
Diabetes Care
Volume: 44(4)
Issue: 4
Pages: 1002-1011
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Direct reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor.2020
Author(s)
Hiroki Inada, Miyako Udono , Kanae Matsuda-Ito, Kenichi Horisawa, Yasuyuki Ohkawa, Shizuka Miura, Takeshi Goya, Junpei Yamamoto, Masao Nagasaki, Kazuko Ueno, Daisuke Saitou, Mikita Suyama, Yoshihiko Maehara, Wataru Kumamaru, Yoshihiro Ogawa, Sayaka Sekiya, Atsushi Suzuki.
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Journal Title
cellsNat Commun.
Volume: 11
Issue: 1
Pages: 5292-5292
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis?associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects2020
Author(s)
Kawakubo M, Tanaka M, Ochi K, Watanabe A, Saka-Tanaka M, Kanamori Y, Yoshioka N, Yamashita S, Goto M, Itoh M, Shirakawa I, Kanai S, Suzuki H, Sawada M, Ito A, Ishigami M, Fujishiro M, Arima H, Ogawa Y, Suganami T
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Journal Title
Scientific Reports
Volume: 10
Issue: 1
Pages: 983-983
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis2019
Author(s)
Asakawa M, Itoh M, Suganami T, Sakai T, Kanai S, Shirakawa I, Yuan X, Hatayama T, Shimada S, Akiyama Y, Fujiu K, Inagaki Y, Manabe I, Yamaoka S, Yamada T, Tanaka S, Ogawa Y.
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Journal Title
Sci Rep.
Volume: 9
Issue: 1
Pages: 19601-19601
DOI
Related Report
Peer Reviewed / Open Access
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