Novel approach to liver disease from aspect of cellular senescence

• Project/Area Number: 21590366
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• 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): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 病理学 / 生体分子 / 再生医学 / 細胞老化

Research Abstract

This study revealed that cellular senescence is involved in the pathogenesis of liver diseases such as primary biliary cirrhosis(PBC). Senescent biliary epithelial cells in inflamed and damaged small bile ducts in PBC show increased expression of chemokines such as CCR2 and CX3CL1. Cultured senescent biliary epithelial cells showed increased expression of various chemokines and induced migration of monocytes and hepatic stellate cells in co-culture. These findings suggests that senescent biliary epithelial cells may play a role in augmentation of inflammation around bile ducts by regulating microenvironment in PBC.

Research Products

• [Journal Article] A possible involvement of p62/sequestosome-1 in the process of biliary epithelialautophagy and senescence in primary biliarycirrhosis (2012)
  • Author(s): Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y
  • Journal Title: Liver Int Volume: 32 Pages: 487-99
  • Peer Reviewed
• [Journal Article] Novel approach tobile duct damage in primary biliary cirrhosis : participation of cellular senescence andautophagy (2012)
  • Author(s): Sasaki M, Nakanuma Y
  • Journal Title: Int J Hepatol Volume: 2012 Pages: 452143-452143
  • Peer Reviewed
• [Journal Article] Autophagy may precede cellular senescenceof bile ductular cells in ductular reaction inprimary biliary cirrhosis (2012)
  • Author(s): Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y
  • Journal Title: Dig Dis Sci Volume: 57 Pages: 660-666
  • Peer Reviewed
• [Journal Article] A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis (2012)
  • Author(s): Sasaki M, et al
  • Journal Title: Liver Int Volume: 32 Issue: 3 Pages: 487-499
  • DOI: 10.1111/j.1478-3231.2011.02656.x
  • Peer Reviewed
• [Journal Article] Novel approach to bile duct damage in primary biliary cirrhosis : participation of cellular senescence and autophagy (2012)
  • Author(s): Sasaki M, et al
  • Journal Title: Int J Hepatol
  • NAID: 120004186277
  • Peer Reviewed
• [Journal Article] Autophagy may precede cellular senescence of bile ductular cells in ductular reaction in primary biliary cirrhosis (2012)
  • Author(s): Sasaki M, et al
  • Journal Title: Dig Dis Sci Volume: 57 Pages: 660-666
  • NAID: 120003497596
  • Peer Reviewed
• [Journal Article] Participation ofbile ductular cells in the pathological progressionof non-alcoholic fatty liver disease (2011)
  • Author(s): Chiba M, Sasaki M
  • Journal Title: J Clin Pathol Volume: 64 Pages: 564-70
  • Peer Reviewed
• [Journal Article] Participation of bile ductular cells in the pathological progression of non-alcoholic fatty liver disease (2011)
  • Author(s): Chiba M, Sasaki M, et al
  • Journal Title: J Clin Pathol Volume: 64 Pages: 564-570
  • Peer Reviewed
• [Journal Article] Biliary epithelialapoptosis, autophagy, and senescence in primarybiliary cirrhosis (2010)
  • Author(s): Sasaki M, Nakanuma Y
  • Journal Title: Hepat Res Treat Pages: 205128-205128
  • Peer Reviewed
• [Journal Article] Modulation of the microenvironment by senescentbiliary epithelial cells may be involved in thepathogenesis of primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y
  • Journal Title: J Hepatol Volume: 53 Pages: 318-25
  • Peer Reviewed
• [Journal Article] Application of a new histological stagingand grading system for primary biliary cirrhosis toliver biopsy specimens : Interobserver agreement (2010)
  • Author(s): Nakanuma Y, Zen Y, Harada K, Sasaki M, (他26名)
  • Journal Title: Pathol Int Volume: 60 Pages: 167-74
  • Peer Reviewed
• [Journal Article] Autophagy mediates the process of cellularsenescence characterizing bile duct damages inprimary biliary cirrhosis (2010)
  • Author(s): Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y
  • Journal Title: Lab Invest Volume: 90 Pages: 835-43
  • Peer Reviewed
• [Journal Article] Bileductular cells undergoing cellular senescenceincrease in chronic liver diseases along withfibrous progrerssion (2010)
  • Author(s): Sasaki M, Ikeda H, Sato Y, Nakanuma Y
  • Journal Title: Am J Clin Pathol Volume: 133 Pages: 212-223
  • Peer Reviewed
• [Journal Article] Biliary epithelial apoptosis, autophagy, and senescence in primarybiliary cirrhosis (2010)
  • Author(s): Sasaki M, et al.
  • Journal Title: Hepat Res Treat
  • Peer Reviewed
• [Journal Article] Modulation of microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, et al.
  • Journal Title: J Hepatol Volume: 53 Pages: 319-325
  • Peer Reviewed
• [Journal Article] Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens : Interobser veragreement. (2010)
  • Author(s): Nakanuma Y, Sasaki M, et al.
  • Journal Title: Pathol Int Volume: 60 Pages: 167-174
  • Peer Reviewed
• [Journal Article] Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, et al.
  • Journal Title: Lab Invest Volume: 90 Pages: 835-843
  • Peer Reviewed
• [Journal Article] Bile ductular cells undergoing cellular senescence increase in chronic liver diseases along with fibrous progrerssion (2010)
  • Author(s): Sasaki M, et al.
  • Journal Title: Am J Clin Pathol 133 Pages: 212-223
  • Peer Reviewed
• [Journal Article] Large cellchange of hepatocytes in chronic viral hepatitisrepresents a senescent-related lesion (2009)
  • Author(s): Ikeda H, Sasaki M, (他5名)
  • Journal Title: Hum Pathol Volume: 40 Pages: 1774-1782
  • Peer Reviewed
• [Journal Article] Polycomb group proteinBmi1 is overexpressed and essential inanchorage-independent colony formation, proliferation and repression of cellularsenescence in cholangiocarinoma : tissue andculture studies (2009)
  • Author(s): Sasaki M, (他5名)
  • Journal Title: Hum Pathol Volume: 40 Pages: 1723-1730
  • Peer Reviewed
• [Journal Article] Bile ductularcell reaction with senescent hepatovcytes inchronic viral hepatitis is lost duringhepatocarcinogenesis (2009)
  • Author(s): Ikeda H, Sasaki M, (他5名)
  • Journal Title: Pathol Int Volume: 59 Pages: 471-478
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitor (SAHA) and repression ofEZH2 synergistically inhibit proliferation of gallbladder carcinoma (2009)
  • Author(s): Yamaguchi J, Sasaki M, et al.
  • Journal Title: Cancer Sci (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Large cell change of hepatocytes in chronic viral hepatitis represents a senescent-related lesion (2009)
  • Author(s): Ikeda H, Sasaki M, et al.
  • Journal Title: Hum Pathol 40 Pages: 1774-1782
  • Peer Reviewed
• [Journal Article] Polycomb group protein Bmil is overexpressed and essential in anchorage-independent colony formation, proliferation and repression of cell ular senescence in cholangiocarinoma : tissue and culture studies (2009)
  • Author(s): Sasaki M, et al
  • Journal Title: Hum Pathol 40 Pages: 1723-1730
  • Peer Reviewed
• [Journal Article] Papillary hyperplasia of the gallbladder in pancreatobiliary maljunction represents a senescence-related lesion induced by lysolecithin (2009)
  • Author(s): Yamaguchi J, Sasaki M, et al.
  • Journal Title: Lab Invest 89 Pages: 1018-1031
  • Peer Reviewed
• [Journal Article] Bile ductular cell reaction with senescent hepatovcytes in chronic viral hepatitis is lost during hepatocarcinogenesis (2009)
  • Author(s): Ikeda H, Sasaki M, et al
  • Journal Title: Pathol Int 59 Pages: 471-478
  • Peer Reviewed
• [Journal Article] Cyclooxygenase-2 is involved in the up-regulation of matrix metalloproteinase-9 in cholangiocarcinoma induced by tumor necrosis factor-alpha (2009)
  • Author(s): Itatsu K, Sasaki M, et al
  • Journal Title: Am J Pathol 174 Pages: 829-841
  • Peer Reviewed
• [Presentation] The deregulated autophag y of mitochondria may be involved in the pa thogenesis in primary biliary cirrhosis (2012)
  • Author(s): Sasaki M, et al
  • Organizer: 101st Annual Meeting of the United States and Canadian Academy of Pathology
  • Place of Presentation: Vancouver convention center, Canada
  • Year and Date: 2012-03-19
• [Presentation] The deregulated autophagy of mitochondria may be involved in the pathogenesis in primary biliary cirrhosis (2012)
  • Author(s): Sasaki M, et al
  • Organizer: 101st Annual Meeting of the United States and Canadian Academy of Pathology
  • Place of Presentation: Vancouver convention center (Vancouver, Canada)
  • Year and Date: 2012-03-19
• [Presentation] パネルデスカッション2 :自己免疫性肝疾患の病態と治療:原発性胆汁性肝硬変の胆管病変におけるsenescence-associated secretory phenotypes(SASP)の関与 (2011)
  • Author(s): 佐々木素子
  • Organizer: 第39回肝臓学会西部会
  • Place of Presentation: 岡山コンベンションセンター,岡山
  • Year and Date: 2011-12-10
• [Presentation] パネルデスカッション2:自己免疫性肝疾患の病態と治療:原発性胆汁性肝硬変の胆管病変におけるsenescence-associated secretory phenotypes (SASP)の関与 (2011)
  • Author(s): 佐々木素子
  • Organizer: 第39回肝臓学会西部会
  • Place of Presentation: 岡山コンベンションセンター(岡山)
  • Year and Date: 2011-12-10
• [Presentation] Increased expression of mitochondrial proteins associated with autophagy in the biliary epithelial lesions in primary biliary cirrhosis (2011)
  • Author(s): Sasaki M, et al
  • Organizer: 62th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West convention center, USA
  • Year and Date: 2011-11-06
• [Presentation] Increased expression of mitochondrial proteins associated with autophagy in the biliary epithelial lesions in primary biliary cirrhosis (2011)
  • Author(s): Sasaki M, et al
  • Organizer: 62th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West convention cencer (San Francisco, USA)
  • Year and Date: 2011-11-06
• [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の発現 (2011)
  • Author(s): 佐々木素子
  • Organizer: 第48回消化器免疫学会総会
  • Place of Presentation: エクセルホテル金沢,石川
  • Year and Date: 2011-07-22
• [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の発現 (2011)
  • Author(s): 佐々木素子
  • Organizer: 第48回消化器免疫学会総会
  • Place of Presentation: エクセルホテル金沢(石川)
  • Year and Date: 2011-07-22
• [Presentation] 非アルコール性脂肪性肝炎における線維性隔壁及び門脈域の線維化の進展と細胆管反応:細胞老化との関連性 (2011)
  • Author(s): 千葉真由美, 佐々木素子
  • Organizer: 第48回消化器免疫学会総会
  • Place of Presentation: エクセルホテル金沢(石川)
  • Year and Date: 2011-07-22
• [Presentation] ワークショップ11「自己免疫性肝疾患upgrade」原発性胆汁性肝硬変の胆管病変におけるオートファジー (2011)
  • Author(s): 佐々木素子
  • Organizer: 異常第47回日本肝臓学会総会
  • Place of Presentation: ホテルグランパシフィック・LE DAIBA,東京
  • Year and Date: 2011-06-02
• [Presentation] ワークショップ11「自己免疫性肝疾患upgrade」原発性胆汁性肝硬変の胆管病変におけるオートファジー異常 (2011)
  • Author(s): 佐々木素子
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: ホテルグランパシフィック・LE DAIBA(東京)
  • Year and Date: 2011-06-02
• [Presentation] 原発性胆汁性肝硬変の細胆管反応におけるオートファジーの関与 (2011)
  • Author(s): 佐々木素子
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2011-04-28
• [Presentation] A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, et al
  • Organizer: 61th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center, USA
  • Year and Date: 2010-11-02
• [Presentation] Autophagy may precede cellular senescence of bile ductular cells in ductuar reaction in primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, et al
  • Organizer: 61th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center, USA
  • Year and Date: 2010-11-02
• [Presentation] A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, et al.
  • Organizer: 61th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center(Boston, USA)
  • Year and Date: 2010-10-31
• [Presentation] Autophagy may precede cellular senescence of bile ductular cells in ductuar reaction in primary biliary cirrhosis (2010)
  • Author(s): Sasaki M, et al.
  • Organizer: 61th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center(Boston, USA)
  • Year and Date: 2010-10-31
• [Presentation] 肝臓学会特別企画「肝臓病理1日コース4-1」細胆管反応と肝疾患 (2010)
  • Author(s): 佐々木素子
  • Organizer: 第14回日本肝臓学会大会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2010-10-14
• [Presentation] シンポジウム2「肝胆膵疾患の免疫病態の新たな展開」原発性胆汁性肝硬変での老化胆管細胞による免疫調節 (2010)
  • Author(s): 佐々木素子, ら
  • Organizer: 第47回消化器免疫学会総会
  • Place of Presentation: 大津プリンスホテル(滋賀)
  • Year and Date: 2010-07-08
• [Presentation] WS2「自己免疫性肝疾患研究の進歩」原発性胆汁性肝硬変の胆管細胞老化におけるオートファジーの関与 (2010)
  • Author(s): 佐々木素子, ら
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: ホテルメトロポリタン山形(山形)(招待講演)
  • Year and Date: 2010-05-27
• [Presentation] 細胞老化に着日した肝胆道系疾患の解明 (2010)
  • Author(s): 佐々木素子
  • Organizer: 第46回肝形態科学研究会
  • Place of Presentation: ホテルメトロポリタン山形(山形)
  • Year and Date: 2010-05-26
• [Presentation] 原発性胆汁性肝硬変の老化胆管細胞によるケモカイン発現とその意義 (2010)
  • Author(s): 佐々木素子, ら
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京)
  • Year and Date: 2010-04-28
• [Presentation] 酸化ストレス、胆汁酸による障害胆管細胞における細胞老化、オートファジー、アポトーシスの関連の検討 (2009)
  • Author(s): 宮腰茉沙美, 佐々木素子, ら
  • Organizer: 第38回肝臓学会西部会
  • Place of Presentation: 米子コンベンションセンター鳥取
  • Year and Date: 2009-12-04
• [Presentation] 細胞老化に着目した肝胆道系疾患の発生・進展機構の解明 (2009)
  • Author(s): 佐々木素子
  • Organizer: 第55回日本病理学会秋期特別総会
  • Place of Presentation: 京王プラザホテル,東京
  • Year and Date: 2009-11-20
• [Presentation] 細胞老化に着目した肝胆道系疾患の発生・進展機構の解明 (2009)
  • Author(s): 佐々木素子
  • Organizer: 第55回日本病理学会秋期特別総会
  • Place of Presentation: 九段会館, 東京
  • Year and Date: 2009-11-20
• [Presentation] A possible involvement of autophagy in the process of biliary epithelial senescence in primary biliary cirrhosis (2009)
  • Author(s): Sasaki M, et al
  • Organizer: 60th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center, USA
  • Year and Date: 2009-11-02
• [Presentation] A modulation of microenvironment by senescent biliary epithelial cells in the pathogenesis of bile duct lesions in primary biliary cirrhosis (2009)
  • Author(s): Sasaki M, et al
  • Organizer: 60th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes convention center, USA
  • Year and Date: 2009-11-02
• [Presentation] A possible involvement of autophagy in the process of biliary epithelial senescence in primary biliary cirrhosis (2009)
  • Author(s): 佐々木素子, et al.
  • Organizer: 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: John B. Hynes Convention Center, Boston, USA
  • Year and Date: 2009-11-02
• [Presentation] A modulation of microenvironment by senescent biliary epithelial cells in the pathogenesis of bile duct lesions in primary biliary cirrhosis (2009)
  • Author(s): 佐々木素子, et al.
  • Organizer: 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: John B. Hynes Convention Center, Boston, USA
  • Year and Date: 2009-11-02
• [Presentation] ヒストン脱アセチル化酵素阻害剤 (SAHA) およびEZH2抑制による胆嚢癌増殖抑制効果 (2009)
  • Author(s): 山口淳平, 佐々木素子, ら
  • Organizer: 第45回胆道学会
  • Place of Presentation: アパホテル&リゾート, 東京ベイ幕張, 千葉
  • Year and Date: 2009-09-18
• [Presentation] 肝疾患の細胆管反応 Ductular reaction における細胞老化の関与 (2009)
  • Author(s): 佐々木素子, ら
  • Organizer: 第45回日本肝臓学会総会
  • Place of Presentation: 神戸ポートピアホテル, 兵庫
  • Year and Date: 2009-06-04
• [Presentation] 肝内胆管癌におけるポリコーム群蛋白 Bmil の発現とその意義 (2009)
  • Author(s): 佐々木素子, ら
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都国際会議場, 京都
  • Year and Date: 2009-05-01