1998 Fiscal Year Final Research Report Summary
Development of gene therapy for retinal neovascular disorders by controlling expression of VEGF
| Project/Area Number |
09470378
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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 |
Ophthalmology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
TAKAGI Hitoshi Kyoto Univ.Graduate Sch.of Med, Assistant professor, 医学研究科, 助手 (70283596)
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| Co-Investigator(Kenkyū-buntansha) |
KIRYU Junichi Kyoto univ.Graduate Sch.of Med, Assistant professor, 医学研究科, 助手 (80281096)
TANIHARA Hidenobu Kyoto Univ.Graduate Sch.of Med, Lecturer, 医学研究科, 講師 (60217148)
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| Project Period (FY) |
1997 – 1998
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| Keywords | VEGF / Gene therapy / Angiogenesis / Angiotensin II / Integrins / CNVM / Tranilast / Ischemia |
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| Research Abstract |
To establish the gene therapy for retinal neovascular disorders, we have examined the regulatory mechanism of VEGF-dependent neovascularization.
Integlin alphaVbeta3, alphaVbeta5, and these ligans, thrombospondin-1 (TSP-1) and osteopontin (OPN) are considered to be key factors in angiogenesis. We found in retinal endothelial cells that hypoxic stimulation induces these integlins Through VEGF stimulation and, TSP-1 and OPN are upregulated in hypoxic retina. This shows that antibodies for TSP-1 or OPN are effective in blocking neovascularization. We found Angiotensin II (AII) upregulates VEGF receptor, KDR expression through AT-1 receptor and PKC-dependently in retinal endothelial cells. These effect of AII induces VEGF-dependent neovascularization. AII also induces VEGF expression in retinal pericytes and we detected transcriptional factor AP-1 mediates that. These data suggest a possibility that medication of ACE inhibitor or AT-1 receptor inhibitor, and regulation of AP-1 might be effective therapies for ischemic retinal angiogenic deseases such as diabetic retinopathy.
We also found the importance of VEGF in surgically excised choroidal neovascular membranes and diabetic hard exudates. Cytokines, including TNF-alpha or IL-1beta induced the expression of VEGF in retinal pigment epithelial cells, and that shows the importance of cytokines in the. formation of neovascularization in macular degeneration.
Tranilast, first developed as an anti-allergic drug, inhibited VEGF-induced angiogenesis and vasopermeability through suppression of PKC-dependent signal transduction in retinal endothelial cells. Tranilast might prove an effective inhibitor to prevent retinal neovascularization in ischemic retinal diseases.
We concluded that controling these factors is useful as a therapy for ischemic retinal neovascular disorders.
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