| Project/Area Number |
17590746
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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 | KYUSHU UNIVERCITY |
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Principal Investigator |
MAKINO Naoki Kyushu University, Medical Institution of Bioregulation, Professor, 生体防御医学研究所, 教授 (60157170)
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| Co-Investigator(Kenkyū-buntansha) |
OYAMA Junichi Kyushu University, Hospital, Research Associate, 大学病院, 助手 (30359939)
MAEDA Toyoki Kyushu University, Hospital, Assistant Professor, 大学病院, 講師 (30264112)
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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: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | angiogenesis / tyrosine phosphorylation / remodeling / gene therapy / myocardial infarction / 血管内皮増殖因子 / SHP-1 / SiRNA / 血管新生療法 |
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| Research Abstract |
Vascular endothelial growth factor (VEGF) promotes the growth of vascular endothelial cells and the development of new blood vessels through interaction with vascular endothelial growth factor (VEGF) receptor-2 (KDR/flk-1). The binding of VEGF to KDR/flk-1 induces conformational changes in the receptor, followed by dimerization and autophosphorylation of the tyrosine residues. The phosphorylated KDR/flk-1 can be a substrate for intracellular protein tyrosine phosphatases. SHP-1,a cytoplasmic protein tyrosine phosphatase that contain two Src homology 2 domains in its N-terminal half, is primarily expressed in hematopoietic cells and is also detected in epithelial cell lineages. SHP-1 interacts with activated cytokine, growth factor, and antigen receptors and plays a negative regulatory role in signal transduction pathways by dephosphorylation of the receptors or receptor substrates to which it binds. TNF-alpha inhibits endothelial cell proliferative response and modulates angiogenesis t
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hrough the inactivation of KDR/flk-1; these are mediated by SHP-1. Here we report that siRNA targeting SHP-1 reduced infarct size in a rat model of acute myocardial infarction (AMI). Upon injection into the ischemic left ventricular wall, the vector-based siRNA significantly suppressed the increase in the SHP-1 mRNA and the SHP-1 protein levels. The siRNA vector also significantly reduced the SHP-1 that bound to Fas-R. The SHP-1 siRNA vector increased phospho-Akt and reduced DNA fragmentation and caspase activity compared with the scramble siRNA vector. Furthermore, the siRNA vector increased phosphorylation of KDR/flk-1, and markedly increased capillary density. Finally, the area of myocardial infarction was significantly smaller with the SHP-1 siRNA vector than with the scramble siRNA vector at 2 days after LCA ligation. In conclusion, SHP-1 in the heart increased from the early stage of AMI, and this increase was thought to contribute to the increased area of myocardial infarction. Suppression of SHP-1 with the SHP-1 siRNA vector markedly reduced the infarct size in AMI. Less
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