| Project/Area Number |
12470157
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | University of Occupational and Environmental Health |
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Principal Investigator |
UENO Hikaru University of Occupational and Environmental Health, School of Medicine, Professor, 医学部, 教授 (50260378)
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| Co-Investigator(Kenkyū-buntansha) |
SASAGURI Yasuyuki University of Occupational and Environmental Health, School of Medicine, Professor, 医学部, 教授 (60140646)
MATSUDA Takehisa Kyushu University, Faculty of Medical Sciences, School of Medicine, Professor, 大学院・医学系研究科, 教授 (60142189)
HAMADA Hirofumi Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (00189614)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2002: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2001: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2000: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | thrombosis / inflammation / injured arteries / gene transfer / extracelluar matrix protein / TFPI / C-type natriuretic peptide / PAF-AH / 血栓症 / 再狭窄 / 傷害血管 / 糖尿病 / 不全心筋 / 抗血栓分子 / 遺伝子治療 / 人工血管 / TGF-β |
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| Research Abstract |
We tried to analyze the molecular pathophysiology of injured arteries using in vivo gene transfer technique. We focused on inflammation, thrombosis and fibroproliferative changes (remodeling or fibrosis).
1. Gene transfer of TFP1 (Tissue factor pathway inhibitor) into injured arteries showed an anti-thrombotic effect. A combination of irrigation with TFP1 protein and gene transfer exhibited additional benefits.
2. Over expression of CNP (C-type natriuretic peptide) enhances expression of inducible nitric oxide synthase leading to increased production of NO, thus eliminates thrombosis and suppresses inflammation.
3. PAF-AH (Platelet activating factor acetylhydrolase) inactivates PAF and PAF-like phospholipids. Overexpression of PAF-AH potent anti-inflammatory, anti-thrombotic and anti-proliferative effects. We found that oxidized LDL is accumulated in the walls in a short period of time following injury even in non-hyperlipidemic animals.
4. Local expression of angiopoietin-1 also showed anti-thrombotic and anti-inflammatory effects. Molecular basis underlying these effects are now investigated.
5. In the injured arteries of diabetic animals, extracellular matrix proteins are readily accumulated. When we introduced a soluble form of TGF-β receptor (which adsorbs TGF-β and may function as a dominant-negative receptor to inhibit function of the receptor), the activity of matrix metalloproteinase was reduced, and fibroproliferative changes were almost eliminated. The soluble TGF-β receptor may have a potent therapeutic effect.
6. We analyzed intracellular signaling in failed cardiomyocytes.
7. We investigated a thrombosis-resistant artificial artery which is a hybrid between biomaterials and fibroblasts in which TFPI, CNP and or VEGF gene was transfected.
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