| Project/Area Number |
14370078
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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 |
Experimental pathology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
NAKAGAWA Kazunori KYUSHU UNIVERSITY, Graduate School of Medical Science, assistant professor, 大学院・医学研究院, 講師 (50217668)
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| Co-Investigator(Kenkyū-buntansha) |
SUEISHI Katsuo GKYUSHU UNIVERSITY, Graduate School of Medical Science, Professor, 大学院・医学研究院, 教授 (70108710)
YONEMITSU Yoshikazu KYUSHU UNIVERSITY, Graduate School of Medical Science, Associate Professor, 大学院・医学研究院, 助教授 (40315065)
中島 豊 九州大学, 大学院・医学研究院, 助教授 (50135349)
橋本 修一 九州大学, 大学院・医学研究院, 助手 (00243931)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2004: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2002: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | Endothelial Cell / cross-talk sianal / Gene Transfer / Angiogenesis / Vascular Remodeling / Gene Therapy |
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| Research Abstract |
The mechanism of intracellular crosstalk of angiogenic factors and its patho-physiological role in physiological and pathological angiogenesis remain unclear. To elucidate this time-dependent and spatial angiogenic crosstalk and to establish the novel and effective therapy on the basis of our evidences obtained for positive and negative angiogenic diseases, we studied the molecular mechanisms of angiogenesis/vasculogenesis, and we have got the following results.
(1)Time-dependent and spatial hierarchy of angiogenic factors durhg molecular and cellular crosstalks :
FGF 2-induced angiogenesis is mediated by MEK in early phase and p70^<s6k>, and Ras/PDGF in late phase of VEGF and HGF expressions. In murine tumor transplantation models, p70^<s6k> and Ras/PDGF pathways were important enhancers of VEGF-A and other angiogenic factors expressed by not only stromal mesenchymal cells but also tumor cells. In addition, FGF-2 gene transferred to ischemic limbs could induce a well harmonizing and fun
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ctional angiogeness partly as a hierarchical enhancer of other angiogenic factors such as VEGF,VEGF-C,VEGF-D,HGF and PDGF.
(2)Atherosderosis and infra-neohtimal angiogenesis :
The number of VEGF-C-positive cells correlate with the degree of atherosclerosis and the number of newly formed vessels in atherosclerotic intima. Increased expression and activity of VEGF are essential in the development of experimental restenosis after intraluminal catheterization by recruiting monocytes/macrophages. There were two disribution patterns of pigment epithelium derived factor (PEDF) in atherosclerotic intima of human coronary arteries. The difference of distribution pattern is closey related to intimal angiogenesis pattern. Moreover, significant inverse correlation between the number of IL-10-positive cells expressed mainly by macrophages and the number of lymphocytes infiltrated in the same areas. These findings suggest that VEGF,VEGF-C,PEDF and IL-10 play important roles in progression of atherosclerosis.
(3)Biological characteristics of our novel gene transfer vectors and their therapeutic implications :
Simian immunodeficiency virus(SIV) vector is efficiently and safely applicable to retinal gene transfer by assessing the transgene expression activity, retinal function and histologies over about 1-year period following subretinal injection of target genes into adult rat retinas. We also demonstrated that neuroprotective gene therapy using SIV-PEDF could be protective from retinal degeneration and functional loss in mice with retintis pigmentosa. These data indicate that SIV-mediated stable gene expression might be a high potential tool for gene therapy. Therapeutic angiogeness using SeV hFGF-2 may be applicable for ischemic organs such as limbs and coronary insuficiency. In porcine model of myocardial infarction, we demonstrated that SeV-FGF-2 could suppress the cardiac ischemia, rupture and heart failure, by using a novel catheter for gene transfer to myocardium from ventricular lumen.
These findings suggest that well harmonized cellular and spatial closstalks/feedback loops of angiogenic factors play important roles in angiogenesis. Rhexis of the harmonized balance leads to several angiogenic diseases. Our novel gene transfer vectors could be expected to be powerful therapeutic tools. Less
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