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Molecular mechanisms of ocular angiogenesis and development of therpeutic agents

Research Project

Project/Area Number 09557136
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Ophthalmology
Research InstitutionUniversity of Tokyo

Principal Investigator

YAMASHITA Hidetoshi  Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Lecturer, 医学部・附属病院, 講師 (90158163)

Co-Investigator(Kenkyū-buntansha) TANAKA Yoshikazu  Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Associate, 医学部・附属病院, 助手 (20292922)
NAGAHARA Miyuki  Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Associate, 医学部・附属病院, 助手 (50262134)
AIHARA Makoto  Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Associate, 医学部・附属病院, 助手
小幡 博人  東京大学, 医学部・附属病院, 助手 (80224301)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 1998: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1997: ¥6,500,000 (Direct Cost: ¥6,500,000)
Keywordsproliferative diubetic retinopathy / VEGF / new vessel / endothelium / TGF-beta / IL-6 / activin A / gene therapy / 非増殖糖尿病網膜症 / 血管新生
Research Abstract

In diabetic retinopathy, vascular barrier breakdown, obstruction and new vessel formation are caused by any cytokines and growth factors, including vascular endothelial growth factor(VEGF), transforming growth factor-beta(TGF-beta)superfamily and interleukin-6(IL-6). The purpose of this presentation is to clarify the roles and the interaction among factors in the pathogenesis of proliferative diabetic retinopathy(PDR).
The Expressions of VEGF, PIGF, TGF-beta superfamily(TGF-beta, activin A), interleukin-6(IL-6)in the intraocular humor and the pathological fibrovascular tissues obtained from PDR eyes were investigated. The correlation between the expression of cytokines/growth factors and clinical characteristics was inquired to know the roles in the pathogenesis of diabetic retinopathy. The concentrations of VEGF, PIGE and IL-6 increased in the intraocular humor from diabetic retinopathy eyes. In the pathological preretinal proliferative tissues obtained from PDR eyes, VEGF, TGF-b2, and … More activin A were expressed. The concentration of VEGF, blood-ocular barrier function and pathological changes of iris vessels were correlated. VEGF is speculated to play important roles in the breakdown of vascular barrier functions and new vessel formation in diabetic retinopathy. Concentrations of PIGF and VEGF in PDR eyes were correlated, because both are induced by hypoxia. Activin A counteracted the growth stimulation by VEGF in the cultured endothelial cells.
The angiogenesis process is regulated by many growth factors and cytokines including VEGF and TGF-beta. In the next step, to investigate the molecular mechanisms of regulation of angiogenesis, angiogenic activity in vivo and the effects on cultured endothelial cells in vitro of VEGF and TGF-beta superfamily.
Angiogenesis in vivo (CAM assay) : VEGF and TGF-beta induced angiogenesis. Activin A did not induce the angiogenesis.
Effects on endothelial cells in vitro : VEGF stimulated 4 steps of angiogenesis. However, TGF-beta and activin A inhibited the endothelial cell function in vitro. These results suggest that the angiogenis activity in vivo and that in vitro may be differetnt, so both experimental systems are mandatory to evaluate the angiogenic activity of various cytokines. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Tanaka Y.et al: "Vascular endothelial growth factor in dialoetic retino pathy." Lancet. 349. 1520 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamashita H.et al: "Growth/differentiation factor-5 induos angiogenesis in vivo." Exp Cell Res. 235. 218-226 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山下 英俊: "トランスフォーミング増殖因子ベータ(TGF-β)スーパーファミリーの眼組織における作用." 日本眼科学会雑誌. 101. 927-947 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Usui T.et al.: "Molecular mechanism of extracellular matrix production by transforming growth factor-β in corneal endothelial cells." Invest Ophthalwol Vis Sci. 39. 1981-1989 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mita T.et al.: "Effects of transforming growth factor-β on corneal epithelial and stromal cell function in rat wound healing moclel." Graefe's Arch Clin Exp Ophthalwol. 236. 834-843 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Obata H.et al: "Expression of transforming growth factor-β superfamily receptors in rat eye." Acta Ophthalwol. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ideta R.et al: "Roles of cytokines in diabetic retinopathy." Arch Ophthalmol. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamashita H.et al.: "Inhibin,Activin and Follistatin(分担)" Springer-Verlag,New York, 333 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tanaka Y,Katoh S,Hori S,Miura M,and Yamashita H.: "Vascular endothelial growth factor in diabetic retinopathy" Lancet. 349. 1520 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamashita H,Shimizu A,Kato M,Nishitoh H,Ichijo H,Hanyu A,Morita I,Kimura M,Makishima F,and Miyazono K: "Growth/dirrerentiation factor-5 induces angiogenesis in vivo." Exp Cell Res. 235. 218-226 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamashita H.: "Functions of the transforming growth factor-beta superfamily in eyes." J Jpn Ophthalmol Soc. 101. 927-947 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamashita H,Shimizu A,Kato M,Nishitoh H,Ichijo H,and Miyazono K: "Regulation of angiogenesis by TGF-beta superfamily." In : Inhibin, Activin and Follistatin. Regulatory Functions in System and Cell Biology. (Aono T,Sugino H,Vale WW eds) (A Serono Symposia S.A.Publication) Springer-Verlag, New York. 312-314 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Usui T,Takase M,Kaji Y,Suzuki K,Ishida K,Tsuru T,Miyata K,Kawabata M,Yamashita H: "Molecular mechanism of extracellular matrix production by transforming growth factor-beta in corneal endothelial cells." Invest Ophthalmol Vis Sci. 39. 1981-1989 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mita T,Yamashita H,Kaji Y,Obata H,Yamada H,Kato M,Hanyu A,Suzuki M,Tobari I: "Effects of transforming growth factor-beta on corneal epithelial and stromal cell function in rat wound healing model after excimer laser karatectomy." Graefe's Archive for Clinical and Experimental Ophthalmology. 236. 834-843 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Obata H,Kaji Y,Yamada H,Kato M,Tsuru T,Yamashita H: "Expression of transforming growth factor-beta superfamily receptors in rat eye." Acta Ophthalmol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ideta R,Yamashita H,et al: "Roles of cytokines in diabetic retinopathy" Arch Ophthalmol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tanaka Y.et al: "Vascular endothelial growth factor in diabetic retinopathy." Lancet. 349. 1520 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamashita H.et al: "Growth/differentiation factor-5 induces angiogenesis in vivo." Exp Cell Res. 235. 218-226 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 山下 英俊: "トランスフォーミング増殖因子ベータ(TGF-β)スーパーファミリーの眼組織における作用。" 日本眼科学会雑誌. 101. 927-947 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Usui T.et al: "Molecular mechanism of extracellular matrix production by transforming growth factor-β in corneal endothelial cells." Invest Ophthalmol Vis Sci. 39. 1981-1989 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Mita T.et al.: "Effects of transforming growth factor-β on corneal epithelial and stromal cell-function in rat wound healing model." Graefe's Arch Clin Exp Ophthalmol. 236. 834-843 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Obata H.et al.: "Expression of transforming growth factor-β superfamily receptors in rat eye." Acta Ophthalmol. (印刷中).

    • Related Report
      1998 Annual Research Report
  • [Publications] Ideta R.et al.: "Roles of cytokines in diabetic retinopathy.(印刷中)" Arch Ophthalmol.

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamashita H.et al.: "Inhibin,Activin and Follistatin(分担)" Springer-Verlag,New York, 333 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tanaka Y, Katoh S, Hori S, Miura M, Yamashita H: "Vascular endothelial growth factor in diabetic retincpathy." Lancet. 349(9064). 1520-1520 (1977)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamashita H, Shimizu A, Kato M, Nishito H et al.: "Growth/differention factor-S induces angiogenesis in vivo." Experimental Cell Research. 235. 218-226 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Mita T, Yamashita H, Kaji Y, Obata H et al: "Effects of transforming growth factor-β on corneal epithelial and stromal cell function in rat wound healing model after excimer laser Keratectomg." Graefe's Archive for Clinical and Experimental Ophthalmology. (in press). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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