Cell biological analysis for studying the target-specific mechanism involved in immune-mediated cholangitis.

• Project/Area Number: 19590744
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tohoku University
• Principal Investigator: UENO Yoshiyuki Tohoku University, 病院, 講師 (70282126)
• Co-Investigator(Kenkyū-buntansha): FUKUSHIMA Koji 東北大学, 病院, 助教 (20400476)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 原発性胆汁性肝硬変 / プロテオミクス / 胆管細胞 / MALDI-TOFMS / 動物モデル / 等電点電気泳動

Research Abstract

ヒト胆管細胞を用いて、等電点蛋白電気泳動法にて小葉間胆管および細胆管由来の蛋白を展開し、スポットの同定を行った。さらに、インターフェロンγにて誘導されるスポットを検討することにより、表出される蛋白をスクリーニングし臨床的な意義付けを行った。その結果、約15の分子が、発現上昇していることがわかり、そのうち同定が可能であったAnnexin A2について検討を進めたところ、細胞内のカルシウム濃度やATPによりその作用が調整されていた。

Research Products

• [Journal Article] Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms (2008)
  • Author(s): Glaser S, Demorrow S, Francis H, Ueno Y, Gaudio E, Vaculin S, Venter J, Franchitto A, Onori P, Vaculin B, Marzioni M, Wise C, Pilanthananond M, Savage J, Pierce L, Mancinelli R, Alpini G
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 295
  • Peer Reviewed
• [Journal Article] Gershwin ME. Animal models of primary biliary cirrhosis (2008)
  • Author(s): Chuang YH, Ridgway WM, Ueno Y
  • Journal Title: Clin Liver Dis 12 Pages: 333-347
  • Peer Reviewed
• [Journal Article] Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation (2008)
  • Author(s): Demorrow S, Francis H, Gaudio E, Ueno Y, Venter J, Onori P, Franchitto A, Vaculin B, Vaculin S, Alpini G
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294
  • Peer Reviewed
• [Journal Article] Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway (2008)
  • Author(s): Francis H, Glaser S, Demorrow S, Gaudio E, Ueno Y, Venter J, Dostal D, Onori P, Franchitto A, Marzioni M, Vaculin S, Vaculin B, Katki K, Stutes M, Savage J, Alpini G
  • Journal Title: pathway. Am J Physiol Cell Physiol 295
  • Peer Reviewed
• [Journal Article] Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway (2008)
  • Author(s): Francis H, Glaser S, Demorrow S, Gaudio E, Ueno Y, Venter J, Dostal D, Onori P, Franchitto A, Marzioni M, Vaculin S, Vaculin B, Katki K, Stutes M, Savage J, Alpini G.
  • Journal Title: Am J Physiol Cell Physiol 295
  • Peer Reviewed
• [Journal Article] 1. Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox facto r 1 and AP-1 activation. 2008 ;: (2008)
  • Author(s): Demorrow S, Francis H, G audio E, Ueno Y, Venter J, Onori P, Franchitto A Vaculin B, Vaculin S, Alpini G.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294
  • Peer Reviewed
• [Journal Article] Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation. (2008)
  • Author(s): 1Demorrow S, Francis H, Gaudio E, Ueno Y, Venter J, Onori P, et. al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294
  • Peer Reviewed
• [Journal Article] Benedetti A, Alpini G. Novel interaction of bile acid and neural signaling in the regulation of cholangiocyte function (2007)
  • Author(s): Fava G, Marzioni M, Francis H, Glaser S, Demorrrow S, Ueno Y
  • Journal Title: Hepatol Res 37
  • Peer Reviewed
• [Journal Article] Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP3/Ca^<2+->dependent downregulation of SRC/ERK1/2 (2007)
  • Author(s): Fava G, Ueno Y, Glaser S, Francis H, Demorrow S, Marucci L, Marzioni M, Benedetti A, Venter J, Vaculin B, Vaculin S, Alpini G
  • Journal Title: Am J Physiol Cell Physiol 292
  • Peer Reviewed
• [Journal Article] H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway (2007)
  • Author(s): Francis H, Franchitto A, Ueno Y, Glaser S, Demorrow S, Venter J, Gaudio E, Alvaro D, Fava G, Marzioni M, Vaculin B, Alpini G
  • Journal Title: Lab Invest 87 Pages: 473-487
  • Peer Reviewed
• [Journal Article] The alpha2-adrenergic receptor agonist UK 14, 304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats (2007)
  • Author(s): Francis H, LeSage G, DeMorrow S, Alvaro D, Ueno Y, Venter J, Glaser S, Mancino MG, Marucci L, Benedetti A, Alpini G
  • Journal Title: Am J Physiol Cell Physiol 293
  • Peer Reviewed
• [Journal Article] Knockout of alpha-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice (2007)
  • Author(s): Glaser SS, Ueno Y, Demorrow S, Chiasson VL, Katki KA, Venter J, Francis HL, Dickerson IM, Dipette DJ, Supowit SC, Alpini GD
  • Journal Title: Lab Invest 87 Pages: 914-926
  • Peer Reviewed
• [Journal Article] Extracellular branched-chain amino acids, especially valine, regulate maturation and function of monocyte-derived dendritic cells (2007)
  • Author(s): Kakazu E, Kanno N, Ueno Y, Shimosegawa T
  • Journal Title: J Immunol 179 Pages: 7137-7146
• [Journal Article] Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver (2007)
  • Author(s): Marzioni M, Ueno Y, Glaser S, Francis H, Benedetti A, Alvaro D, Venter J, Fava G, Alpini G
  • Journal Title: Liver Int 27 Pages: 558-568
  • Peer Reviewed
• [Journal Article] The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes (2007)
  • Author(s): Meng F, Henson R, Wehbe-Janek H, Smith H, Ueno Y, Patel T
  • Journal Title: J Biol Chem 282 Pages: 8256-8264
  • Peer Reviewed
• [Journal Article] AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers (2007)
  • Author(s): Moritoki Y, Lian ZX, Wulff H, Yang GX, Chuang YH, Lan RY, Ueno Y, Ansari AA, Coppel RL, Mackay IR, Gershwin ME
  • Journal Title: Hepatology 45 Pages: 314-322
  • Peer Reviewed
• [Journal Article] Amniotic epithelial cell-derived cholangiocytes in experimental cholestatic ductal hyperplasia (2007)
  • Author(s): Moritoki Y, Ueno Y, Kanno N, Yamagiwa Y, Fukushima K, Gershwin ME, Shimosegawa T
  • Journal Title: Hepatol Res 37 Pages: 286-294
  • NAID: 10020164395
  • Peer Reviewed
• [Journal Article] Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency (2007)
  • Author(s): Nakagome Y, Ueno Y, Kogure T, Fukushima K, Moritoki Y, Ridgway WM, Eric Gershwin M, Shimosegawa T
  • Journal Title: J Autoimmun 29 Pages: 20-29
  • Peer Reviewed
• [Journal Article] Prolactin stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2^<+->dependent PKC isoforms (2007)
  • Author(s): Taffetani S, Glaser S, Francis H, Demorrow S, Ueno Y, Alvaro D, Marucci L, Marzioni M, Fava G, Venter J, Vaculin S, Vaculin B, Lam IP, Lee VH, Gaudio E, Carpino G, Benedetti A, Alpini G
  • Journal Title: BMC Physiol 7 Pages: 6-6
  • Peer Reviewed
• [Journal Article] Taurocholic acid feeding prevents tumor necrosis factor-alpha-induced damage of cholangiocytes by a PI3K-mediated pathway (2007)
  • Author(s): Ueno Y, Francis H, Glaser S, Demorrow S, Venter J, Benedetti A, Fava G, Marzioni M, Alpini G
  • Journal Title: Exp Biol Med (Maywood) 232 Pages: 942-949
  • Peer Reviewed
• [Journal Article] Bioinformatic approach for cholangiocyte pathophysiology (2007)
  • Author(s): Ueno Y, Fukushima K, Nakagome Y, Kido O, Shimosegawa T
  • Journal Title: Hepatol Res 37 Suppl
  • NAID: 10019797315
  • Peer Reviewed
• [Journal Article] Primary biliary cirrhosis : what we know and what we want to know about human PBC and spontaneous PBC mouse models (2007)
  • Author(s): Ueno Y, Moritoki Y, Shimosegawa T, Gershwin ME
  • Journal Title: J Gastroenterol 42 Pages: 189-195
  • Peer Reviewed
• [Journal Article] Mapping of a disease susceptibility locus in the HLA region for Primary Biliary Cirrhosis in Japan (2007)
  • Author(s): Yahagi K, Ueno Y, Nomura E, Fukushima K, Moritoki Y, Kogure T, Kojima Y, Negoro K, Kinouchi Y, Shimosegawa T
  • Journal Title: Hepatol Res 37 Pages: 270-275
  • NAID: 10020164315
  • Peer Reviewed
• [Journal Article] Autoimmune cholangitis in NOD.c3c4 mice is associated with cholangiocyte-specific Fas antigen deficiency. (2007)
  • Author(s): Nakagome Y, Ueno Y, Kogure T, Fukushima K, Moritoki Y, Ridgway WM, et. al.
  • Journal Title: J Autoimmun 29 Pages: 20-9
  • Peer Reviewed
• [Journal Article] Bioinformatic approach for cholangiocyte pathophysiology. (2007)
  • Author(s): Ueno Y, Fukushima K, Nakagome Y, Kido O and Shimosegawa T
  • Journal Title: Hepatol Res 37Suppl3
  • NAID: 10019797315
  • Peer Reviewed
• [Presentation] DIFFERENTIAL EFFECTS OF RETINOIC ACID (RA) ON RAR AND PPAR delta SIGNALING INCREASES APOPTOSIS IN LARGE CHOLANGIOCYTES AND PROMOTES SURVIVAL IN SMALL CHOLANGIOCYTES (2008)
  • Author(s): Xia XF, Xiao YH, Gao DB, Ueno Y, LeSage GD
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] Functional Differences in Atp Release and P2 Receptor-Mediated Secretion between Small and Large Mouse Cholangiocytes : Potential Existence of a Purinergic Signaling Axis Along the Intrahepatic Biliary Tract (2008)
  • Author(s): Woo K, Sathe MN, Kresge C, Parameswara V, Esser V, Ueno Y, Venter J, Alpini G, Feranchak AP
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] B Cell Deficiency Exacerbates Liver and Intestinal Inflammation in a Murine Model of Autoimmune Cholangitis (2008)
  • Author(s): Moritoki Y, Lian ZX, Tsuneyama K, Wakabayashi K, Yang GX, Yoshida K, Ueno Y, Gershwin ME
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] Taurocholate Feeding to Bile Duct Ligated (Bdl) Rats Prevents Caffeic Acid-Induced Bile Duct Damage by Increased Cholangiocyte Vegf Expression (2008)
  • Author(s): Mancinelli R, Gaudio E, Onori P, Franchitto A, Carpino G, DeMorrow S, Ueno Y, Alvaro D, Francis H
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] Knockout of Secretin Receptor Decreases the Proliferation of Large Cholangiocytes in Bile Duct Ligated (Bdl) Mice (2008)
  • Author(s): Lam IP, Glaser SS, Gaudio E, Ueno Y, Chow BK, Antonello V, Sferra R, Onori P, Alvaro D, Vaculin B, Venter J, Francis H, Mancinelli R, Carpino G, Chiasson V, Alpini G
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] An Imbalance in Plasma Amino Acids of Advanced Cirrhotic Patients Influences the Intracellular Amino Acids of Peripheral Blood Mononuclear Cells, and the Imbalance Suppresses the Maturation of Dendritic Cells Via Mtor/S6k Signaling Pathway (2008)
  • Author(s): Kokazu E, Ueno Y, Kondo Y, Fukushima K, Shiina M, Yamagiwa Y, Kogure T, Inoue J, Tamai K, Shimosegawa T
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] LACK OF alpha-CALCITONIN GENE-RELATED PEPTIDE (alpha-CGRP) REDUCES BILE ACID-INDUCED INCREASE IN BILIARY PROLIFERATION (2008)
  • Author(s): Alpini G, Gaudio E, Supowit S, Ueno Y, Franchitto A, Onori P, Venter J, Francis H, Vaculin B, Kopriva S, Wise C, Mancinelli R, Savage JM, Chiasson V, DiPette DJ, Glaser S
  • Organizer: AASLD SanFrancisco
  • Place of Presentation: U.S.A
  • Year and Date: 2008-11-02
• [Presentation] Bile acid feeding prevents hepatic artery ligation-induced bile duct injury in bile duct ligated rats (BDL) by PI3K/AKT-dependent activation of cholangiocyte VEGF-a expression (2008)
  • Author(s): Glaser S, Gaudio E, Francis H, Ueno Y, Onori P, Franchitto A, Venter J, Alvaro D, Vaculin BT, Kopriva S, Savage J, Alpini G
  • Organizer: DDW San Diego
  • Place of Presentation: U.S.A
  • Year and Date: 2008-05-14
• [Presentation] Compensatory role of inducible annexin A2 for impaired biliary epithelial anion exchange activity of inflammatory cholangiopathy (2008)
  • Author(s): Kido O, Fukushima K, Ueno Y, Inoue J, Jefferson DM, Shimosegawa T
  • Organizer: DDW San Diego
  • Year and Date: 2008-05-14
• [Presentation] Compensatory role of inducible annexin A2 for impaired biliary epithelial anion exchange activity of inflammatory cholangiopathy (2008)
  • Author(s): Kido O, Fukushima K, Ueno Y, Inoue J, Jefferson DM
  • Organizer: Journal of Hepatology2008
  • Place of Presentation: EASL, Milan, Italy(48 : S173-S173)
  • Year and Date: 2008-04-17
• [Presentation] NOD.c3c4マウス胆管上皮におけるFas抗原発現減弱と病態との関連 (2007)
  • Author(s): 中込 悠, 上野義之他
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-01
• [Presentation] プロテオミクスによる新たな胆汁うっ滞性肝疾患特異的マーカーの探索 (2007)
  • Author(s): 城戸治、上野義之他
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-01
• [Presentation] α-Calcitonin gene-related peptide(CGRP)は胆汁うっ滞時の胆管細胞増殖を抑制する (2007)
  • Author(s): 上野義之他
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-01
• [Book] Pathophysiology of the intrahepatic biliary epithelium (2008)
  • Author(s): Fukushima K, and Ueno, Y
  • Publisher: Transworld Research Network