Novel approach to primary biliary cirrhosis putting focus on deregulated autophagy

• Project/Area Number: 24590409
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kanazawa University
• Principal Investigator: SASAKI Motoko 金沢大学, 医学系, 准教授 (70225895)
• Co-Investigator(Renkei-kenkyūsha): SATO Yasunori 金沢大学, 医学系, 講師 (30324073) ; NAKANUMA Yasuni 金沢大学, 医学系, 教授 (10115256)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 病理学 / オートファジー / 細胞老化 / 生体分子

Outline of Final Research Achievements

This study revealed that deregulated autophagy followed by cellular senescence in biliary epithelial cells (BECs) may be closely related to the abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in primary biliary cirrhosis (PBC). Cell culture study using mouse biliary epithelial cells supported the immunohistochemical findings in human PBC livers, suggesting autophagy of the mitochondrial proteins. Furthermore, this study disclosed that endoplasmic reticulum stress may play a role in the pathogenesis of deregulated autophagy and cellular senescence in biliary epithelial lesions in PBC.

Research Products

• [Journal Article] A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. (2015)
  • Author(s): Sasaki M, Yoshimura-Miyakoshi M, Sato Y, Nakanuma Y
  • Journal Title: J Gastroenterol Volume: [Epub ahead of print] Pages: 000-000
  • Peer Reviewed
• [Journal Article] Autophagy and senescence in fibrosing cholangiopathies. (2015)
  • Author(s): Nakanuma Y, Sasaki M, Harada K.
  • Journal Title: J Hepatol. Volume: 62 Issue: 4 Pages: 934-945
  • DOI: 10.1016/j.jhep.2014.11.027
  • Peer Reviewed / Open Access
• [Journal Article] Cellular senescence in biliary pathology. Special emphasis on expression of a polycomb group protein EZH2 and a senescent marker p16INK4a in bile ductular tumors and lesions. (2015)
  • Author(s): Sasaki M, Nakanuma Y.
  • Journal Title: Histol Histopathol Volume: 30 Pages: 267-275
  • Peer Reviewed
• [Journal Article] Clinicopathological study of primary biliary cirrhosis with interface hepatitis compared to autoimmune hepatitis. (2014)
  • Author(s): Kobayashi M, Kakuda Y, Harada K, Sato Y, Sasaki M, Ikeda H, Terada M, Mukai M, Kaneko S, Nakanuma Y.
  • Journal Title: World J Gastroenterol. Volume: 20 Issue: 13 Pages: 3597-608
  • DOI: 10.3748/wjg.v20.i13.3597
  • NAID: 120007139982
  • Peer Reviewed / Open Access
• [Journal Article] Infiltration of inflammatory cells expressing mitochondrial proteins around bile ducts and in biliary epithelial layer may be involved in the pathogenesis in primary biliary cirrhosis. (2014)
  • Author(s): Sasaki M, et al.
  • Journal Title: Journal of Clinical Pathology Volume: in press Issue: 6 Pages: 470-6
  • DOI: 10.1136/jclinpath-2013-201917
  • Peer Reviewed
• [Journal Article] Chemokine-Chemokine Receptor CCL2-CCR2 and CX3CL1-CX3CR1 Axis May Play a Role in the Aggravated Inflammation in Primary Biliary Cirrhosis. (2014)
  • Author(s): Sasaki M, et al.
  • Journal Title: Dig Dis Sci Volume: 59 Issue: 2 Pages: 358-364
  • DOI: 10.1007/s10620-013-2920-6
  • Peer Reviewed
• [Journal Article] Evaluation of a new histologic staging and grading system for primary biliary cirrhosis in comparison with classical systems. (2013)
  • Author(s): Kakuda Y, Harada K, Sawada-Kitamura S, Ikeda H, Sato Y, Sasaki M, Okafuji H, Mizukoshi E, Terasaki S, Ohta H, Kasashima S, Kawashima A, Kaizaki Y, Kaneko S, Nakanuma Y.
  • Journal Title: Hum Pathol Volume: - Issue: 6 Pages: 1107-1117
  • DOI: 10.1016/j.humpath.2012.09.017
  • NAID: 120005253269
  • Peer Reviewed
• [Journal Article] Increased expression of mitochondrial proteins associated with autophagy in biliary epithelial lesions in primary biliary cirrhosis. (2013)
  • Author(s): Sasaki M, et al.
  • Journal Title: Liver International Volume: 33 Issue: 2 Pages: 312-20
  • DOI: 10.1111/liv.12049
  • Peer Reviewed
• [Presentation] A possible involvement of endoplasmic reticulum stress in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis. (2014)
  • Author(s): Sasaki M, Yoshimura-Miyakoshi M, Sato Y, Nakanuma Y.
  • Organizer: The 65th Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Boston, Hynes convention center, USA.
  • Year and Date: 2014-11-08 – 2014-11-12
• [Presentation] WS4: 自己免疫性肝障害の病態と治療をめぐる問題点 原発性胆汁性肝硬変の胆管病変発生機序における小胞体ストレス, オートファジー, 細胞老化の関与 (2014)
  • Author(s): 佐々木素子 中沼安二
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ, 東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 原発性胆汁性肝硬変(PBC)の病期と肝前駆細胞 (2014)
  • Author(s): 角田 優子, 原田 憲一, 池田 博子, 岡藤 啓史, 佐藤 保則, 佐々木 素子, 水腰 英四郎, 金子 周一, 中沼 安二
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ, 東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 原発性胆汁性肝硬変(PBC)の肝生検における新病期分類を用いた薬物治療反応性・予後 予測の可能性 (2014)
  • Author(s): 角田 優子, 原田 憲一, 北村 星子, 池田 博子, 佐藤 保則, 佐々木 素子, 中沼 安二
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島国際会議場, 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Infiltration of macrophages and plasma cells with coarse granular expression of mitochondrial proteins around bile ducts and intraepithelial layer may be involved in the pathogenesis of bile duct lesions in primary biliary cirrhosis (2013)
  • Author(s): Sasaki M, Kakuda Y, Miyakoshi M, Sato Y, Nakanuma Y
  • Organizer: AASLD: The Liver Meeting 2013
  • Place of Presentation: Walter E. Washington convention center. Washington DC, USA
• [Presentation] Correlation of destruction of canals of Hering with the progression of the primary biliary cirrhosis stage (2013)
  • Author(s): Kakuda Y, Harada K, Ikeda H, Sato Y, Sasaki M, Nakanuma Y
  • Organizer: AASLD: The Liver Meeting 2013
  • Place of Presentation: Walter E. Washington convention center. Washington DC, USA
• [Presentation] ミトコンドリア蛋白陽性炎症細胞と原発性胆汁性肝硬変の胆管病変との関連 (2013)
  • Author(s): 佐々木 素子, 角田 優子, 佐藤 保則, 中沼 安二
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル, 東京
• [Presentation] 原発性胆汁性肝硬変(PBC)における肝幹細胞/前駆細胞と病期との関連について (2013)
  • Author(s): 角田 優子, 原田 憲一, 池田 博子, 岡藤 啓史, 佐藤 保則, 佐々木 素子, 水腰 英四郎, 金子 周一, 中沼 安二
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル, 東京
• [Presentation] 原発性胆汁性肝硬変の胆管病変におけるautophagy異常、ミトコンドリア蛋白発現亢進と細 胞老化の関与 (2013)
  • Author(s): 佐々木 素子, 中沼 安二
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京グランドプリンスホテル新高輪, 東京
• [Presentation] 原発性胆汁性肝硬変におけるORM1-like protein 3 (ORMDL3) 発現細胞と胆管病変との関連 (2013)
  • Author(s): 佐々木 素子, 角田優子, 佐藤保則, 中沼安二
  • Organizer: 肝臓学会西部会
  • Place of Presentation: 長良川国際会議場、岐阜市
• [Presentation] 原発性胆汁性肝硬変の胆管病変におけるCCL2/CCR2, CX3CL1/CX3CR1系の関与 (2013)
  • Author(s): 佐々木素子
  • Organizer: 第99回消化器病学会
  • Place of Presentation: かごしま県民交流センター（鹿児島市)
• [Presentation] 原発性胆汁性肝硬変におけるミトコンドリア蛋白陽性炎症細胞の分布とその意義 (2013)
  • Author(s): 佐々木素子
  • Organizer: 第99回消化器病学会
  • Place of Presentation: かごしま県民交流センター（鹿児島市)
• [Presentation] Infiltration of inflammatory cells expressing mitochondrial proteins around bile ducts and intraepithelial layer may be involved to the pathogenesis in primary biliary cirrhosis (2013)
  • Author(s): Sasaki M, et al.
  • Organizer: 102nd Annual Meeting of the United States and Canadian Academy of Pathology
  • Place of Presentation: Baltimore Convention Center. (Baltimore, USA)
• [Presentation] Intraepithelial infiltration of ORM1-like protein 3 (ORMDL3) –expressing cells may be closely related to the pathogenesis of primary biliary cirrhosis (2012)
  • Author(s): Sasaki M, et al.
  • Organizer: 63th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center (Boston, USA)
• [Presentation] Chemokines CCL2 and CX3CL1 as senescence-associated secretory phenotypes may play a role in aggravated inflammation in primary biliary cirrhosis (2012)
  • Author(s): Sasaki M, et al.
  • Organizer: 63th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center (Boston, USA)
• [Presentation] 原発性胆汁性肝硬変の胆管病変に特徴的なミトコンドリアのオートファジーは胆管上皮細胞特異的か？ (2012)
  • Author(s): 佐々木素子
  • Organizer: 第16回肝臓学会大会
  • Place of Presentation: 神戸国際会議場 （神戸市）
• [Presentation] 原発性胆汁性肝硬変の胆管病変におけるミトコンドリア蛋白発現の亢進とオートファジー異常 (2012)
  • Author(s): 佐々木素子
  • Organizer: 第48回肝臓学会総会
  • Place of Presentation: 石川県立音楽堂 (金沢市)