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Silencing of Int6 Promotes Recovery of Blood Perfusion after Limb Ischemia via Stabilizing Hypoxia-Inducible Factor 2α

Research Project

Project/Area Number 20591513
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionThe University of Tokyo

Principal Investigator

KIMURA Hideo  The University of Tokyo, 医学部附属病院, 助教 (60327070)

Co-Investigator(Kenkyū-buntansha) KOYAMA Hiroyuki  東京大学, 医学部附属病院, 特任准教授 (10241994)
MIYATA Tetsuro  東京大学, 医学部附属病院, 准教授 (70190791)
SHIGEMATSU Kunihiro  東京大学, 医学部附属病院, 講師 (20215966)
OKAMOTO Hiroyuki  東京大学, 医学部附属病院, 助教 (60348266)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords血管外外科一般 / 血管新生 / 低酸素応答因子 / 乳癌抑制遺伝子 / 低酸素誘導因子 / 血管再生 / RNA干渉
Research Abstract

Hypoxia-inducible factors (HIFs) are the key regulators of hypoxia-responding genes. In particular, the HIF-2α plays an essential role in vascular remodeling, leading to mature angiogenesis by transcribing several angiogenic factors. The aim of current study is to test the hypothesis that silencing of Int6 and concomitant HIF-2α stabilization may enhance the recovery of blood flow in tissue ischemia. Analysis of the effect of Int6 silencing in cultured muscle cells implied that silencing of Int6 led to up-regulation of several genes corresponding to angiogenic proteins, including basic fibroblast growth factor and platelet-derived growth factor-B through induction and stabilization of HIF-2α. Moreover, tube formation analysis of endothelial cells revealed an increase in paracrine response to INT6-silenced muscle cells. In mouse models of hindlimb ischemia, intramuscular injection of small interfering RNA plasmid designed to inhibit Int6 led to significantly enhanced perfusion and functional recovery of damaged tissues. Int6 silencing in muscle leads to enhanced recovery of blood flow in ischemic limb. Int6 may serve as a valuable therapeutic target to control angiogenesis in ischemic diseases.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (3 results)

All 2008

All Presentation (3 results)

  • [Presentation] マウス下肢虚血モデルにおけるInt6抑制による下肢血流の改善-低酸素応答因子HIF-2αの誘導を介した血管新生の可能性2008

    • Author(s)
      橋本拓弥, ら
    • Organizer
      第49回日本脈管学会総会
    • Place of Presentation
      東京(口演)
    • Year and Date
      2008-10-24
    • Related Report
      2010 Final Research Report
  • [Presentation] マウス下肢虚血モデルにおけるInt6抑制による下肢血流の改善2008

    • Author(s)
      橋本拓弥、木村秀生、他
    • Organizer
      第49回日本脈管学会総会
    • Place of Presentation
      東京
    • Year and Date
      2008-10-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] マウス下肢虚血モデルにおけるInt6抑制による下肢血流の改善2008

    • Author(s)
      橋本拓弥, ら
    • Organizer
      The 7th Cell Bilology Summer Meeting
    • Place of Presentation
      鴨川、京都(ポスター)
    • Year and Date
      2008-07-05
    • Related Report
      2010 Final Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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