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Development of Gene Therapy for Progrssive Glomerular Diseases

Research Project

Project/Area Number 08457288
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionOsaka University

Principal Investigator

IMAI Enyu  Osaka University Medical School, Assistant Professor, 医学部, 助手 (00223305)

Co-Investigator(Kenkyū-buntansha) MORIYAMA Toshiki  Osaka University Faculty of Sport Science, Lecturer, 健康体育部, 講師 (30283815)
YAMAUCHI Atsushi  Osaka University Medical School, Assistant Professor, 医学部, 助手 (10271024)
KANEDA Yasufumi  Osaka University Institute for Molecular and Cellular Biology, Associate Profess (10177537)
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1997: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥5,100,000 (Direct Cost: ¥5,100,000)
KeywordsTGF-beta / PDGF / extracellular matrix / glomerulonephritis / Glomerulosclerosis / HVJ-liposome / gene therapy / receptor-IgGFc chimera / PDGF-B / 遺伝子治療
Research Abstract

Action of various growth factors in pathophysiological condition in the process of progressive renal diseases has been demonstrated by several lines of evidences. The up-regulation of transforming growth factor-beta (TGF-beta) and Platelet-derived growth factor (PDGF) as well as their receptors are observed in glomerular and tubulointerstitial lesions in experimental and human glomerulonephritis. In experimental animals, overproduction of TGF-beta by gene transfection to kidney or transgenic mouse carrying TGF-beta gene causes glomerulosclerosis. These evidences which support the pivotal role of growth factor prompt us to intervene the development of glomerulosclerosis by gene technology. To inhibit the action of TGF-beta or PDGF we created the expression plasmids for extracellular domain of receptor-immunoglobulin Fc chimera. The purified TGF-betaR-Fc, which was obtained from cultured COS cells, inhibited the suppression of cell growth and extracellular matrix synthesis by TGF-beta. We transfected the expression vector for TGFbeta-R-Fc to the gluteal muscle of the anti-Thy 1 glomerulonephritis by HVJ-liposome method. The synthesized TGF-betaR-Fc accumulated to the kidney through the systemic circulation. Consequently, the glomerular TGF-betamRNA were suppressed and the extracellular matrix accumulation was concomitantly reduced. Similarly, The purified betaPDGFR-Fc inhibited cell proliferation induced by PDGF-B.Transfected betaPDGF-Fc into skeletal muscle suppressed PCNA expression and the cell number of glomerulus in comparable with reduction of ECM accumulation. These results suggest that the molecular intervention by growth factor receptor-Fc chimera may be feasible for the therapy of glomerulosclerosis.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report

Research Products

(28 results)

All Other

All Publications (28 results)

  • [Publications] Imai, E: "Gene therapy for the treatment of renal disease:prospects for the future" Curr Opin Hypert Nephrol. 6・5. 496-503 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Isaka Y, et al.: "Application of gene therapy to diabetic nephropathy." Kidney Int. 52. S100-S103 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E, et al: "New therapeutic strategies of molecular intervention in glomerulonephritis" Nephrology. 3. S755-S757 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E, Akagi Y, Isaka Y: "Molecular intervention with antisense oligonucleotides(ODNs)in nephrology" Nephrol Dial Transplant. 12・1. 2213-2215 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E and Isaka: "Strategies of gene transfer to the kidney" Kidney Int. 53・2. 264-272 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Enyu Imai, et al: "Gene transfer and Kidney diseases" J Nephrol. (in press). (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Akagi Y,Isaka Y,Arai M,Kaneko T,Takenaka M,Moriyama T,Kaneda Y,Ando A,Orita Y,Kamada T,Ueda N,Imai E.: "Inhibition of TGF-beta1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis." Kidney Int. 50. 148-155 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Isaka Y,Brees DK,Ikegaya K,Kaneda Y,Imai E,Noble NA,Border W.: "Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney." Nature Med. 2. 418-423 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E,Isaka Y,Akagi Y,Arai M,Moriyama T,Takenaka M,Kaneko T,Horio M,Ando A,Orita Y,Kaneda Y,Ueda N,Kamada T.: "Application of antisense oligonucleotides (ODNs) for the intervention of kidney disease." Cont Nephrol. 118. 86-93 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Isaka Y,Imai E.: "Molecular biological Intervention." Semi Nephrol. 16. 591-598 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E,Isaka Y,Akagi Y,Kaneda Y: "Gene transfer into the glomerulus by hemagglutinating virus of Japan (HVJ) liposome methods." Exp Neprol.5. 112-117 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Akagi Y,Isaka Y,Akagi A,Ikawa M,Takenaka M,Moriyama T,Yamauchi A,Horio M,Ueda N,Okabe M,Imai E.: "Transcriptional activation of a hybrid promoter composed of cytomegalovirus enhancer and beta-actin/beta-globin gene in glomerular epithelial cells in vivo." Kidney Int.51. 1265-1269 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai, E.: "Gene therapy for the treatment of renal disease : prospects for the future" Curr Opin Hypert Nephrol. 6. 496-503 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Isaka Y.Akagi Y,Ando Y,Imai E: "Application of gene therapy to diabetic nephropathy" Kidney Int. 52. S100-S103 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E,Isaka Y,Akagi Y,Ando Y,Arai M,Kaneko T,Takenaka M,Moriyama T,yamauchi A,Horio M,Ando A,Orita Y,Ueda N: "New therapeutic strategies of molecular intervention in glomerulonephritis." Nephrology. 3. S755-S757 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E,Akagi Y,Isaka Y: "Molecular intervention with antisense oligonucleotides (ODNs) in nephrology" Nephrol Dial Transplant. 12. 2213-2215 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai E and Isaka: "Strategies of gene transfer to the kidney" Kidney Int. 53. 264-272 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Enyu Imai, Yoshitaka Isaka, Yoshitaka Akagi, Yoshifumi Kaneda and Masatsugu Hori: "Gene transfer and Kidney diseases" J Nephrol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Akagi Y, et al: "Inhibition of TGF-b1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis." Kidney Int. 50・1. 148-155 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Isaka Y, et al: "Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney." Nature Med. 2・4. 418-423 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Imai E,Iet al: "Application of antisense oligonucleotides (ODNs) for the intervention of kidney disease." Contribution to Nephrology. 118. 86-93 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Isaka Y, Imai E: "Molecular biological Intervention" Semi.Nephrol. 16・6. 591-598 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Imai E, et al: "Gene transfer into the glomerulus by hemagglutinating virus of Japan (HVJ) liposome methods." Exp.Neprol. 5・2. 112-117 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Akagi Y, et al: "Transcriptional activation of a hybrid promoter composed of cytomegalovirus enhancer and β-actin/β-globin gene in glomerular epithelial cells in vivo." Kidney Int. 51・4. 1265-1269 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Isaka Y,et.al.: "Gene therapy by skeletal muscle expression of decorin prevents fibrotic diseases in the rat kidney" nature medicine. 2(4). 418-423 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Imai E et al.: "Application of Autisense Oligonucleotides (ODNs) for the intervesstion of kidney disease" Contribution to nephrology. 118. 86-93 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Akagi Y et.al.: "Inhibition of TGF-β 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glorerulacphvitis" Kidney Int. 50. 148-155 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Isaka Y,Imai E: "Molecular Bioioglcal Intervention" Seminars in Nephrology. 16(5). 591-598 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-03-31   Modified: 2016-04-21  

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