Search for a new prevention strategy of proliferative vitreoretinopathy by targeting Smad-dependent epithelial-mesenchymal transition

• Project/Area Number: 15591871
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Wakayama Medical University
• Principal Investigator: SAIKA Shizuya Wakayama Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (40254544)
• Project Period (FY): 2003 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
• Keywords: Transforming growth factor beta / Proliferative vitreoretinopathy / retinal pigment epithelium / Epithelial-mesenchymal transition / Smad / Signal transduction / Gene therapy / Adenoviral vector / トランスフォーミング成長因子ベータ / 増殖硝子体網膜症 / 上皮-間葉系移行 / ノックアウトマウス / 細胞培養

Research Abstract

Objective: Retinal pigment epithelium is known to undergo epithelial-mesenchymal transition (EMT), which is mediated mainly by transforming growth factor b (TGFb)/Smad2(3)4 signaling. Smad7 suppresses such signaling by blocking this Smad complex from entering the nucleus. Accordingly, we determined the effects of Smad7 gene transfer in prevention of fibrogenic responses by retinal pigment epithelium, one of the major causes of post-retinal detachment proliferative vitreoretinopathy (PVR) in mice.
Methods: Retinal detachment induced PVR in a mouse model. An eye received either an adenoviral gene transfer of Smad7 or Cre recombinase gene only. The eyes were histologically analyzed. A retinal pigment epithelial cell line, ARPE-19, was used to determine if Smad7 gene transfection suppresses the fibrogenic response to TGFb2exposure.
Results: Smad7 gene transfer inhibited TGFb2/Smad signaling in ARPE 19 cells and expression of collagen type I and TGFb1, but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to EMT by retinal pigment epithelium.
Conclusion: Smad7 gene transfer suppresses fibrogenic responses to TGFb2 by retinal pigment epithelial cells in vitro and in vivo.
Clinical relevance: Smad7 gene transfer might be a new strategy to prevent and treat PVR.

Research Products

• [Journal Article] Adenoviral gene transfer of BMP-7, ld2 or ld3 suppresses injury-induced epithelial-mesenchymal transition of lens epithelium in mice. (2006)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Ohnishi Y, Nakajima Y, Muragaki Y, Ooshima A
  • Journal Title: Am J Physiol- Cell Physiol- 290
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of tumor necrosis factor α potentiates transforming growth factor β-mediated pathogenic tissue response during wound healing. (2006)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Okada Y, Miyamoto T, Kitano A, Ooshima A, Nakajima Y, Ohnishi Y, Kao WW
  • Journal Title: Am J Pathol 168 Pages: 1848-1860
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TGFβ pathobiology in the eye. (2006)
  • Author(s): Saika S
  • Journal Title: Lab Invest 86 Pages: 106-115
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenoviral gene transfer of BMP-7, Id2 or Id3 suppresses injury-induced epithelial-mesenchymal transition of lens epithelium in mice. (2006)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Ohnishi Y, Nakajima Y, Muragaki Y, Ooshima A.
  • Journal Title: Am J Physiol-Cell Physiol- 290
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] of tumor necrosis factor a potentiates transforming growth factor β-mediated pathogenic tissue response during wound healing. (2006)
  • Author(s): Saika S, Ikeda K, Yamanaka 0, Flanders KC, Okada Y, Miyamoto T, Kitano A, Ooshima A, Nakajima Y, Ohnishi Y, Kao WW.Loss
  • Journal Title: Am J Pathol 168 Pages: 1848-1860
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TGFβ pathobiology in the eye (2006)
  • Author(s): Saika S
  • Journal Title: Lab Invest 86 Pages: 106-115
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenoviral gene transfer of BMP-7, Id2 or Id3 suppresses injury-induced epithelial-mesenchymal transition of lens epithelium in mice. (2006)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Ohnishi Y, Nakajima Y, Muragaki Y, Ooshima A
  • Journal Title: Am J Physiol -Cell Physiol- 290
• [Journal Article] Therapeutic effects of adenoviral gene transfer of bone morphogenic protein-7 on a corneal alkali burn model in mice. (2005)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Flanders KC, Nakajima Y, Miyamoto T, Ohnishi Y, Kao WW-Y, Muragaki Y, Ooshima A.
  • Journal Title: Lab Invest 85 Pages: 474-486
• [Journal Article] Therapeutic effect of topical administration of SN50, an inhibitor of NF-κB, in treatment of corneal alkali burns in mice. (2005)
  • Author(s): Saika S, Miyamoto T, Yamanaka O, Kato T, Ohnishi Y, Flanders KC, Ikeda K, Nakajima Y, Kao WW-Y, Sato M, Muragaki Y, Ooshima A.
  • Journal Title: Am J Pathol 166 Pages: 1393-1403
• [Journal Article] Expression of Smad7 in mouse eyes accelerates healing of corneal tissue following exposure to alkali. (2005)
  • Author(s): Saika S, Ikeda K, Yamanaka O, Miyamoto T, Ohnishi Y, Sato M, Muragaki Y, Ooshim A, Nakajima Y, Kao WW-Y, Flanders KC, Roberts AB.
  • Journal Title: Am J Pathol 166 Pages: 1405-1418
• [Journal Article] Growth factor deposition in anterior subcapsular cataract. (2005)
  • Author(s): Ishida I, Saika S, Okada Y, Ohnishi Y.
  • Journal Title: J Cataract Refract Surg 31 Pages: 1219-1225
• [Journal Article] Transcriptional activation in lens epithelial cells following an ocular blunt trauma. (2005)
  • Author(s): Shirai K, Saika S, Okada Y, Miyamoto T, Ueyama T, Ohnishi Y.
  • Journal Title: J Cataract Refract Surg 31 Pages: 1226-1230
• [Journal Article] Biological compatibility of polymethyl methacrylate, hydrophilic acrylic and hydrophobic acrylic intraocular lenses. (2005)
  • Author(s): Barbour W, Saika S, Miyamoto T, Ohnishi Y.
  • Journal Title: Ophthalmic Res 37 Pages: 255-261
• [Journal Article] TGF-beta signal transduction in corneal wound healing as a therapeutic target. (2004)
  • Author(s): Saika S
  • Journal Title: Cornea 8 Suppl
• [Journal Article] Accumulation of thrombospondin-1 in post-operative capsular fibrosis and its down-regulation in lens cells during lens fiber formation (2004)
  • Author(s): Saika S, Miyamoto T, Ishida I, Barbour WK, Ohnishi Y, Ooshima A
  • Journal Title: Exp Eye Res. 79(2) Pages: 147-156
• [Journal Article] Sonic hedgehog expression and role in healing corneal epithelium (2004)
  • Author(s): Saika S, Muragaki Y, Okada Y, Miyamoto T, Ohnishi Y, Ooshima A, Kao WW
  • Journal Title: Invest Ophthalmol Vis Sci 45(8) Pages: 2577-2785
• [Journal Article] Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice (2004)
  • Author(s): Saika S, Kono-Saika S, Tanaka T, 他
  • Journal Title: Lab Invest 84(10) Pages: 1245-1258
• [Journal Article] Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice (2004)
  • Author(s): Saika S, Ikeda K, Yamanaka O, 他
  • Journal Title: Lab Invest 84(10) Pages: 1259-1270
• [Journal Article] Relationship between posterior capsule opacification and intraocular lens biocompatibility (2004)
  • Author(s): Saika S
  • Journal Title: Prog Retin Eye Res 23(3) Pages: 283-305
• [Book] 眼科プラクテイス1/術後眼内炎 (2005)
  • Author(s): 雑賀 司珠也
  • Total Pages: 3
  • Publisher: 文光堂
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