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Development of a novel therapy targeting the hypoxia response system in the immune cells for inflammatory diseases.

Research Project

Project/Area Number 17591035
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionAsahikawa Medical College (2006)
The University of Tokyo (2005)

Principal Investigator

MAKINO Yuichi  Asahikawa Medical College, School of Medicine, Assistant Professor, 医学部, 特任講師 (90345033)

Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsHypoxia / T cell / HIF-1 / protein degradation / Si RNA / Adrenomedullin
Research Abstract

Peripheral T lymphocytes circulate through different tissues with various concentrations of environmental oxygen. Upon activation by antigenic stimulation, T lymphocytes migrate and function in areas of inflammation that are likely to be hypoxic. We have demonstrated in T cells accumulating in inflammatory tissues enhanced expression of the hypoxia-inducible factor-la (HIF-1α), indicating a role of hypoxia-mediated signals in regulation of T cell function. Unlike other tissues, stabilization of HIF-la protein in peripheral T cells required not only hypoxia but also additional signals following T cell receptor/CD3-mediated activation. Peripheral T cells under hypoxic conditions showed increased survival defying activation-induced cell death (AICD). Microarray analysis suggested the involvement of HIF-1-target gene product adrenomedullin (AM) in this process. In support of this model, activated T cells expressed the AM receptor complex, and AM receptor antagonist abrogated hypoxia-mediat … More ed resistance to AICD. Moreover, synthetic AM peptides protected T cells from AICD even under normoxic condition. Taken together, we propose that tissue hypoxia critically regulates survival of the activated T cells through HIF-la-dependent expression of AM by an autocrine regulatory loop mechanism, thus providing HIF system as a potential target of regulation of peripheral immunity.
In this term, we have developed a system to modify HIF-1 function in lymphocytes.
1)Modification of HIF-1 expression in the animal model for inflammatory diseases; in an animal over expressing IPAS, a dominant negative regulator of HIF-1 function, we demonstrated that suppression of HIF system resulted in a delay of wound healing, indicating that negative modification of HIF-1 is a potential strategy for controlling angiogenesis-related diseases.
2)Generation of an inflammatory disease model in the animal with SiRNA HIF-1 over expression: we established an efficient system for knocking down of HIF-1 expression level in the animal cells. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (5 results)

All 2007 2005

All Journal Article (5 results)

  • [Journal Article] Transcriptional upregulation of IPAS gene expression by HIF-1 : A negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells.2007

    • Author(s)
      Yuichi Makino
    • Journal Title

      J. Biol. Chem 282

      Pages: 14073-14082

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transcriptional upregulation of IPAS gene expression by HIF-1 : a negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells2007

    • Author(s)
      Yuichi Makino, Rie Uenishi, Kensaku Okamoto, Tsubasa Isoe, Osamu Hosono, Hirotoshi Tanaka, Arvydas Kanopka, Lorenz Poellinger, Masakazu Haneda, Chikao Morimoto
    • Journal Title

      J.Biol.Chem. 282

      Pages: 14073-14082

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transcriptional upregulation of IPAS gene expression by HIF-1 : A negative feedback regulatory circuit in HIF-1-mediated signaling in hypoxic cells.2007

    • Author(s)
      Yuichi Makino
    • Journal Title

      J. Biol. Chem

    • Related Report
      2006 Annual Research Report
  • [Journal Article] TCR-engagement increases HIF-1α protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells2005

    • Author(s)
      Hiroshi Nakamura
    • Journal Title

      J.Immunol 174(12)

      Pages: 7592-7592

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Physiological activation of hypoxia-inducible factor-1 in human skeletal muscle2005

    • Author(s)
      Helene Ameln
    • Journal Title

      FASEB J 19(8)

      Pages: 1009-1009

    • Related Report
      2005 Annual Research Report

URL: 

Published: 2005-04-01   Modified: 2016-04-21  

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