Current treatments for diabetic retinopathy are not entirely successful. We reason that therapies could be more rapidly developed and evaluated than is currently possible if a patient's risk of developing retinopathy could be predicted early in the course of the disease. We have developed a unique functional magnetic resonance imaging (fMRI) technique that measures the change in partial pressure of oxygen (deltaPO2) in the vitreous humor while the subject breathes carbogen (95% O2: 5% CO2). Using this acute retinal """"""""stress"""""""" test, we have shown that carbogen breathing in rats and mice at 3-4 months of diabetes (before the appearance of retinal lesions) produces a significantly reduced retinal deltaPO2 compared to normals. A subnormal deltaPO2 is consistent with the presence of hypoxia but it cannot yet be unambiguously interpreted as a measure of hypoxia. In addition, in 3 month diabetic rats, aminoguanidine (AMG) treatment prevented the decrease in retinal deltaPO2. AMG is known to prevent retinal lesion formation in diabetic rats and inhibit the activity of both the inducible form of nitric oxide synthase (iNOS) and protein kinase C (PKC) (among other actions). Hypothesis: Subnormal retinal deltaPO2 in experimental diabetes is correlated with retinal hypoxia (Aim 1), and increased iNOS and PKC activity (Aims 2 and 3) but precedes the appearance of histopathology.
Specific Aim 1) To compare retinal PO2 and deltaPO2 before, and at 2 wks, and 3 and 9 months of diabetes in rats. fMRI and a carbogen challenge will be used to measure the retinal deltaPO2. To measure PO2, a perfluorocarbon droplet will be injected into the preretinal vitreous over superior or inferior retina and 19F magnetic resonance spectroscopy performed.
Specific Aim 2) To compare the retinal deltaPO2 (at 3 months) and histology (at 3 and 15 months) in normal and diabetic rats with and without treatment with a selective iNOS inhibitor (L-NIL (L-N(6)-(1-iminoethyl)lysine)), and in normal, diabetic, and diabetic iNOS knockout mice.
Specific Aim 3) To compare the retinal deltaPO2 (at 3 months) and histology (at 3 and 15 months) in normal and diabetic rats with and without treatment with a selective PKC inhibitor (LY333531). In addition, we will compare retinal deltaPO2 in normal mice, transgenic mice that overexpress PKC beta II, diabetic mice, and diabetic PKC beta II-knockout mice. The results of the proposed studies will prove whether or not changes in retinal deltaPO2 correlate with the development of retinal hypoxia or multiple biochemical abnormalities that are associated with diabetic retinopathy but cannot be measured in vivo by existing techniques. The results of these studies could lead to the development of a non-invasive real time method for the early evaluation of diabetic retinopathy and its treatment.
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|Berkowitz, Bruce A; Roberts, Robin; Luan, Hongmei et al. (2007) Manganese-enhanced MRI studies of alterations of intraretinal ion demand in models of ocular injury. Invest Ophthalmol Vis Sci 48:3796-804|
|Zheng, L; Du, Y; Miller, C et al. (2007) Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes. Diabetologia 50:1987-96|
|Berkowitz, Bruce A; Roberts, Robin; Penn, John S et al. (2007) High-resolution manganese-enhanced MRI of experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci 48:4733-40|
|Braun, Rod D; Gradianu, Marius; Vistisen, Kerry S et al. (2007) Manganese-enhanced MRI of human choroidal melanoma xenografts. Invest Ophthalmol Vis Sci 48:963-7|
|Roberts, Robin; Luan, Hongmei; Berkowitz, Bruce A (2006) alpha-lipoic acid corrects late-phase supernormal retinal oxygenation response in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci 47:4077-82|
|Luan, Hongmei; Roberts, Robin; Sniegowski, Matthew et al. (2006) Retinal thickness and subnormal retinal oxygenation response in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci 47:320-8|
|Roberts, Robin; Luan, Hongmei; Berkowitz, Bruce A (2006) Blocking ET-1 receptors does not correct subnormal retinal oxygenation response in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci 47:3550-5|
|Berkowitz, Bruce A; Roberts, Robin; Goebel, Dennis J et al. (2006) Noninvasive and simultaneous imaging of layer-specific retinal functional adaptation by manganese-enhanced MRI. Invest Ophthalmol Vis Sci 47:2668-74|
|Trick, Gary L; Edwards, Paul; Desai, Uday et al. (2006) Early supernormal retinal oxygenation response in patients with diabetes. Invest Ophthalmol Vis Sci 47:1612-9|
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