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Development of novel therapeutics targeting the function of intestinal cells of Cajal in gastrointestinal motility disorder

Research Project

Project/Area Number 11557042
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Gastroenterology
Research InstitutionOsaka University

Principal Investigator

SHINOMURA Yasuhisa  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90162619)

Co-Investigator(Kenkyū-buntansha) MURAYAMA Yoko  Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
KIYOHARA Tatsuya  Osaka Unversity Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (50322178)
MIYAZAKI Yoshiji  Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (30303960)
上山 晴美  大阪大学, 医学部・付属病院, 医員
金山 周次  大阪大学, 医学系研究科, 助手 (40185913)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2000: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1999: ¥6,600,000 (Direct Cost: ¥6,600,000)
Keywordsgastrointestinal motility / interstitial cells of Cajal / pacemaker / c-kit / 消化管運動異常症 / カハール
Research Abstract

Interstitial cells of Cajal (ICCs) are found as networks of cells associated with neuronal plexuses in gastrointestinal tract. Recent studies have provided evidence that ICCs function in the gut as pacemaker cells responsible for the generation of spontaneous electrical activity. We have shown the deficiency of ICCs and the decrease in the contractile activity of the intestine in spontaneous mutant rats with a small deletion at the tyrosine kinase domain of c-kit. We have also shown the deficiency of ICCs in patients with a myopathic form of chronic intestinal pseudo-obstruction. Most types of chronic intestinal pseudo-obstruction do not respond to conventional prokinetic drugs. Therefore, methods of novel therapeutics need to be developed by targeting the molecules associated with the regulation of proliferation, differentiation and function of ICCs. We are investigating the mechanism of the regulation of proliferation, differentiation and function of ICCs. We have established in vitro culture system for ICCs isolated from mouse intestine and intestinal stromal cell line. Stem cell factor (SCF), which is a ligand of c-kit, stimulated the proliferation of ICCs from day-8 postcoitus embryos. SCF did not stimulate the proliferation of ICCs from day-6 postpartum neonates but SCF was needed for their survival. We have developed stromal cell lines originating from the small intestine of the mouse. The stromal cells transfected with c-kit complementary DNA showed the tendency to differentiate to ICCs. We are going to identify the molecules that can be targeted to induce differentiation.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] S.Kondo,Y.Shinomura,Y.Miyazaki,T.Kiyohara, et al.: "Mutations of the bak gene in human gastric and colorectal cancers."Cancer Research. 60(16). 4828-4830 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kitamura,S.Kondo,Y.Shinomura,S.Kanayama,Y.Miyazaki, et al.: "Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers."British Journal of Cancer. 83(5). 668-673 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kitamura,S.Kondo,Y.Shinomura,K.Isozaki,S.Kanayama, et al.: "Expression of hepatocyte growth factor and c-met in ulcerative colitis."Inflammation Research. 49(7). 320-324 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Shinomura: "Expression of c-kit in gastrointestinal stromal tumors."Internal Medicine. 39(11). 869-870 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Sugimachi,T.Kiyohara,Y.Shinomura,Y.Matsuzawa, et al.: "Endogenous endothelin in a rat model of acute colonic mucosal injury."Journal of Gastroenterology and Hepatology. 15. 1125-1131 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Miyazaki,S.Hiraoka,S.Tsutsui,S.Kitamura,Y.Shinomura, et al.: "Epidermal growth factor receptor mediates the stress-induced expression of its ligands in rat gastric epithelial cells."Gastroenterology. 120(1). 108-116 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kitamura, Y.Miyazaki, S.Hiraoka, M.Toyota, Y.Nagasawa, S.Kondo, T.Kiyohara, Y.Shinomura, Y.Matsuzawa: "PPARγ inhibits the expression of c-MET in human gastric cancer cells through the supression of Ets."Biochem.Biophys.Res.Commun.. 265(2). 453-456 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Nagasawa, Y.Miyoshi, K.Iwao, Y.Shinomura, Y.Matsuzawa, Y.Nakamura: "Transformation and morphological changes of murine L cells by transfection with a mutated form of β-catenin."Cancer Res.. 59. 3539-3542 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Murayama, J.Miyagawa, Y.Shinomura, S.Kanayama, Y.Yasunaga, H.Nishibayashi, K.Yamamori, Y.Higashimoto, Y.Matsuzawa: "Morphological and functional restoration of parietal cells in helicobacter pylori associated enlarged fold gastritis after eradication."Gut. 45(5). 653-661 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kitamura, S.Kondo, Y.Shinomura, S.Kanayama, Y.Miyazaki, T.Kiyohara, S.Hiraoka, Y.Matsuzawa: "Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers."Br.J.Cancer. 83(5). 668-673 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] N.Sawada-Hase, T.Kiyohara, J.Miyagawa, H.Ueyama, K.Isozaki, Y.Murayama, T.Kashihara, M.Nakahara, R.Nezu, Y.Shinomura, Y.Matsuzawa: "Enhanced CD40 expression and high IL-12 production by intestinal macrophages and peripheral blood monocytes in patients with Crohn's disease."Am.J.Gastroenterol. 95(6). 1516-1523 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kitamura, S.Kondo, Y.Shinomura, K.Isozaki, S.Kanayama, Y.Higashimoto, T.Minami, T.Kiyohara, Y.Yasunaga, H.Ishikawa, T.Ohtani, S.Ishiguro, Y.Matsuzawa: "Expression of hepatocyte growth factor and c-met in ulcerative colitis."Inflamm.Res.. 49(7). 320-324 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kondo, Y.Shinomura, Y.Miyazaki, T.Kiyohara, S.Tsutsui, S.Kitamura, Y.Nagasawa, M.Nakahara, S.Kanayama, Y.Matsuzawa: "Mutations of the bak gene in human gastric and colorectal cancers."Cancer Res.. 60(16). 4828-4830 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Sugimachi, T.Kiyohara, Y.Murayama, T.Minami, Y.Miyazaki, J.Miyagawa, Y.Shinomura, Y.Matsuzawa: "Endogenous endothelin in a rat model of acute colonic mucosal injury."J.Gastroenterol.Hepatol.. 15. 1125-1131 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Shinomura: "Expression of c-kit in gastrointestinal stromal tumors."Intern Med. 39(11). 869-870 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Miyazaki, S.Hirota, S.Tsutsui, S.Kitamura, Y.Shinomura, Y.Matsuzawa: "Epidermal growth factor receptor mediates the stress-induced expression of its ligands in rat gastric epithelial cells."Gastroenterology. 120(1). 108-116 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Kondo,Y.Shinomura,Y. Miyazaki,T. Kiyohara, et al.: "Mutations of the bak gene in human gastric and colorectal cancers."Cancer Research. 60(16). 4828-4830 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Kitamura,S.Kondo,Y.Shinomura,S.Kanayama,Y.Miyazaki, et al.: "Met/HGF receptor modulates bcl-w expression and inhibits apoptosis in human colorectal cancers."British Journal of Cancer. 83(5). 668-673 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Kitamura,S.Kondo,Y.Shinomura,K.Isozaki,S.Kanayama, et al.: "Expression of hepatocyte growth factor and c-met in ulcerative colitis."Inflammation Research. 49(7). 320-324 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Shinomura: "Expression of c-kit in gastrointestinal stromal tumors."Internal Medicine. 39(11). 869-870 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Sugimachi,T.Kiyohara,Y.Shinomura,Y.Matsuzawa, et al.: "Endogenous endothelin in a rat model of acute colonic mucosal injury."Journal of Gastroenterology and Hepatology. 15. 1125-1131 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Miyazaki,S.Hiraoka,S.Tsutsui,S.Kitamura,Y.Shinomura, et al.: "Epidermal growth factor receptor mediates the stress-induced expression of its ligands in rat gastric epithelial cells."Gastroenterology. 120(1). 108-116 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyazaki Y, et al.: "Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor"Gastroenterology. 116(1). 78-89 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Murayama Y, et al.: "Morphological and functional restoration of parietal cells in helicobacter pylori associated enlarged fold gastritis after eradication"Gut. 45(5). 653-661 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitamura S, et al.: "Peroxisome proliferator-activated receptor g induces growth arrest and differentiation markers of human colon cancer cells"Jpn.J.Cancer Res.. 90(1). 75-80 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitamura S, et al.: "PPARgamma inhibits the expression of c-MET in human gastric cancer cells through the suppression of Ets"Biochem. Biophys. Res. Commun.. 265(2). 453-456 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nagasawa Y, et al.: "Transformation and morphological changes of murine L cells by transfection with a mutated from of β-catenin"Cancer Res.. 59. 3539-3542 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sawada-Hase N, et al.: "Enhanced CD40 expression and high IL-12 production by intestinal macrophages and peripheral blood monocytes in patients with Crohn's disease"Am.J. Gastroenterol.. (in press). (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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