Development of new therapy and investigation into the pathology of ocular microcirculatory disorders by controlling the blood cell-endothelial cell interactions
| Project/Area Number |
16591749
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 |
MIYAMOTO Kazuaki Kyoto University, Graduate School to Medicine, Instructor, 医学研究科, 助手 (90359810)
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| Co-Investigator(Kenkyū-buntansha) |
KIRYU Junichi Kawasaki Medical School, Professor, 教授 (80281096)
TAKAHASHI Masayo Kyoto University, Graduate School to Medicine, Associate Professor, 医学研究科, 助教授 (80252443)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | leukocyte-endothelial cell interactions / diabetic retinopathy / statin / hypertension / retinal ischemia-reperfusion injury / three dimensional observation in retina / macular edema / steroid / 糖尿病 / 網膜光凝固 / アルガトロバン / P-selectin / ICAM-1 / ぶどう膜炎 / 白血球 |
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| Research Abstract |
We investigated the effects of simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on leukocyte-induced diabetic changes in retinas. Simvastatin suppressed significantly the number of leukocytes adhering to retinal vessel endothelium and the number of leukocytes accumulated in the retinal tissue by 72.9% and 41.0%, respectively (P<0.01). The expression of intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) in the retina were both suppressed with simvastatin. Treatment with simvastatin markedly reduced retinal permeability (P=0.014). This suggests that simvastatin attenuates leukocyte-endothelial cell interactions and subsequent blood-retinal barrier breakdown via suppression of vascular endothelial growth factor-induced ICAM-1 expression in the diabetic retina. Simvastatin may thus be useful in the prevention of diabetic retinopathy.
We evaluated the effects of hypertension on leukocyte-endothelial interactions after retinal isc
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hemia-reperfusion. In spontaneously hypertensive rats (SHR), the number of accumulated leukocytes peaked at 48 hours after reperfusion, and it was upregulated to 5.2- fold, as compared with that of control rats (P<0.001). ICAM-1 mRNA expression and ICAM-1 protein levels were increased significantly in the ischemia-reperfused retina in SHR (P<0.05). Histological examination demonstrated marked increase in the retinal ischemia-reperfusion damage in SHR (P<0.01) and a significant amelioration of the damage by treatment with superoxide dismutase in SHR (P<0.05). Oxidative stress may thus be an important mechanism for the deterioration seen in ischemia-reperfusion injury in hypertension.
We developed a new method to observe leukocyte behavior three-dimensionally in mouse retina. In endotoxin-induced uveitis (EIU), leukocytes were seen to extravasate from the deeper capillary layers and to migrate toward the outer layer of the retina. The traveling velocity of extravasated leukocytes in retinal tissue was 2.0±0.1 μm/h.
We investigated the mechanism to improve diabetic macular edema by intravitreal injection of corticosteroids. The number of leukocytes accumulated in the retina, once increased in the diabetic group, was decreased by 31.6% (P=0.0001) after dexamethasone injection. The level of blood-retinal barrier breakdown, also elevated in the diabetic group, was suppressed by 61.1% (P=0.0046) after dexamethasone injection. The level of ICAM-1 mRNA expression and its protein, upregu-lated in the diabetic group, were downregulated by dexameth-asone treatment by 70.0% (P<0.0001) and 56.4% (P=0.0003). Intravitreal injection of corticosteroids improves diabetic retinal edema through inhibiting leukocyte recruitment in the diabetic retina. Less
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Report
(3 results)
Research Products
(11 results)
