Development of a novel therapy targeting the hypoxia response system in the immune cells for inflammatory diseases.
| Project/Area Number |
17591035
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Asahikawa Medical College (2006)
The University of Tokyo (2005) |
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Principal Investigator |
MAKINO Yuichi Asahikawa Medical College, School of Medicine, Assistant Professor, 医学部, 特任講師 (90345033)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| 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)
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| Keywords | Hypoxia / T cell / HIF-1 / protein degradation / Si RNA / Adrenomedullin |
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| 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
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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
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Report
(3 results)
Research Products
(5 results)
