| Project/Area Number |
14570636
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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 |
Circulatory organs internal medicine
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| Research Institution | Gunma university |
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Principal Investigator |
YOKOYAMA Tomoyuki Gunma university, Laboratory science, professor, 医学部, 教授 (70312890)
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| Co-Investigator(Kenkyū-buntansha) |
KURABAYASHI Masahiko Gunma university, Second department of internal medicine, professor, 医学部, 教授 (00215047)
ARAI Masashi Gunma university, Second department of internal medicine, lecturer, 医学部, 講師 (60270857)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | tumor necrosis factor-α / transcriptional factor / angiotensin II / lipopolysaccharide / promoter / endothelin-1 |
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| Research Abstract |
(1)Molecular mechanisms of the tumor necrosis factor-α (TNF-α) production by angiotensin II (ANGII)
We examined the molecular mechanisms by which ANGII and lipopolysaccharide (LPS) up-regulate TNF-α gene expression. Competition analysis by electrophoretic mobility shift assay with and without specific antibodies showed that LPS increased binding of Sp1 and Sp3 to the Sp1 binding site, while Egr-1 was unimportant. With ANGII, binding of ATF-2/c-jun to the CRE site was required for TNF-α gene induction ; neither Ets nor NF-κB was essential.
Mutation analysis confirmed that response to LPS relied upon the Sp1 site in the TNF-α promoter, while the CRE binding site was essential to stimulation by ANGII. We concluded that since TNF-α gene expression is transcriptionaly activated by ANGII or LPS via different cis-acting sequences in the TNF-α promoter and different transcriptional factors, mechanisms inducing TNF production differ between heart failure or cardiac hypertrophy and infectious disease.
(2)Mechanisms of the TNF-α production in the human preripheral mononuclear cells
We examined the production of TNF-α by endothelin-1 in the human peripheral mononuclear cells. Endothelin-1 significantly increased the TNF-α mRNA expression by the concentration-and time-dependent manner. Thus, the activation of mononuclear cells by endothelin-1 and/or ANGII may be important for the development of heart failure and/or cardiac hypertrophy.
We believe that these minute study for the TNF-α production in heart failure or cardiac hypertrophy are necessary for the development of specific drugs.
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