2004 Fiscal Year Final Research Report Summary
Gene transfer-mediated molecular analysis of pathophysiology in injured arteries and development of local anti-inflammatory and anti-thrombotic therapy
| 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)
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| Project Period (FY) |
2003 – 2004
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| Keywords | thrombosis / inflammation / injured arteries / PAF-AH / oxidized lipoproteins / angiopoietin-1 / gene transfer / bone marrow-derived progenitor cell |
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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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Research Products
(22 results)
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[Journal Article] Local expression of platelet-activating factor-acetylhydrolase reduces accumulation of oxideized lipoproteins, and inhibits inflammation, shear stress-induced thrombosis,and neointima formation in balloon-injured carotid arteries in non-hyperlipidemic rabbits.2005
Author(s)
Arakawa H, Qian J-Y, Baatar D, Karasawa K, Asada Y, Sasaguri Y, Miller ER, Witztum JL, Ueno H
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Journal Title
Description
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[Journal Article] CaMK II activates ASK1 and NF-kB to induce cardiomyocyte hypertrophy.2005
Author(s)
Kashiwase K, Higuchi Y, Hirotani S, Yamaguchi O, Hikoso S, Takeda T, Watanabe T, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Ueno H, Nishida K, Hori M, Otsu K
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Journal Title
Biochemical and Biophysical Research Communications 327
Pages: 136-142
Description
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[Journal Article] TGF-beta is not involved in early phase growth inhibition of keratinocytes by 1alpha, 25(OH)(2)vitamin D(3).2004
Author(s)
Shirakata, Ueno H, Hanakawa Y, Kameda K, Yamasaki K, Tokumaru S, Yahata Y, Tohyama M, Sayama K, Hashimoto K
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Journal Title
J Dermatol Sci. 36
Pages: 41-50
Description
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[Journal Article] The small GTP-binding protein Rac1 induces cardiac myocyte hypertrophy through the activation of apoptosis signal-regulation kinase 1 and nuclear factor-κB.2003
Author(s)
Higuchi Y, Otsu K, Nishida K, Hirotani S, Nakayama H, Yamaguchi O, Hikoso S, Kashiwase K, Takeda T, Watanabe T, Mano T, Matsumura Y, Ueno H, Tada M, Hori M
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Journal Title
J Biol Chem. 278
Pages: 20770-20777
Description
「研究成果報告書概要(欧文)」より
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