| Project/Area Number |
15390255
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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)
ASADA Yujiro University of Miyazasaki, School of Medicine, Professor, 医学部, 教授 (70202588)
NISHIDA Takahiro Kyushu University, Graduate School of Medical Sciencs, Research Associate, 大学院・医学系研究科, 助手 (50284500)
武谷 浩之 産業医科大学, 医学部, 講師 (60222105)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2004: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2003: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | thrombosis / inflammation / injured arteries / PAF-AH / oxidized lipoproteins / angiopoietin-1 / gene transfer / bone marrow-derived progenitor cell / 血小板活性化因子水解酵素(PAF-AH) / Angiopoietin-1 / 血栓 / 腫瘍血管新生 / 可溶型受容体 / 酸化LDL / 傷害 / 血管 / アデノウイルス |
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| Research Abstract |
We tried to analyze the molecular pathophysiology of injured arteries using in vivo gene transfer technique focusing on the development of local anti-inflammatory and anti-thrombotic therapy, and investigated the use of bone marrow-derived progenitor cells as a carrier of therapeutic molecules.
1. PAF-AH (Platelet activating factor acetylhydrolase) inactivates PAF and PAF-like phospholipids, a wide range of inflammatory lipid mediators. Gene transfer of PAF-AH into injured arteries inactivated specifically oxidized lipoproteins and showed potent anti-inflammatory, anti-thrombotic and anti-proliferative effects. PAF-AH could resolve once- accumulated oxidized lipoproteins, thus it can be a useful anti-atherosclerosis molecule. Importance of oxidative stress and oxidized lipoproteins was well recognized.
2. Local expression of angiopoietin-1 also showed potent anti-thrombotic and anti-inflammatory effects. These therapeutic effects were canceled by a soluble Tie2, a specific receptor for a
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ngiopoietin-1. However, no Tie2 was detectable in the media. Thus, angiopoietin-1. may exert its effects via some unidentified surface molecules. This issue is now under Investigation.
3. We demonstrated that statin can inhibit injury-induced activation of NFkB, and suppresses inflammation and thrombosis. Further detailed molecular mechanisms will be investigated.
4. We established multipotent adult progenitor cells (MAPC) from mouse bone marrow. With VEGF (vascular endothelial growth factor), MAPC were differentiated to endothelial progenitor cells (EPC). Using the same method, we developed MAPC and EPC from a LacZ-expressing mouse, and transplanted the LacZ-expressing EPC into peripheral region of tumor made of human cancer cells in a nude mouse. The lacZ-positive cells were found within the tumor. When a soluble VEGF receptor was gene transduced into the EPC, then transplanted near tumor, tumor growth was suppressed and even regressed because of the suppression of tumor angiogenesis. Bone marrow-derived MAPC may have a potential as a carrier of therapeutic molecules into injured arterial walls and tumor angiogenesis. Less
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