The proliferation of new preretinal blood vessels into the vitreous is a major cause of visual loss in a number of common eye diseases. Although certain endogenous growth factors play a role in this neovascularization (NV), recent evidence indicates these growth factors are constantly available in the retina. In addition, NV is often associated with focal retinal areas of ischemia and it is presumed that a metabolic trigger (for example hypoxia, elevated glucose utilization and lactate concentration, or increased blood flow) activates the ambient growth factors and stimulates the initiation of NV. It has not been possible however, to establish the actual role of a specific metabolic factor in the trigger and regulation of NV since these factors are interdependent processes. We hypothesize that the stimulus of NV is an ischemia-related trigger, such as a significant perturbation (either singly or in combination) of retinal oxygen level, glucose utilization, lactate concentration, and retinal blood flow, which causes the ambient growth factors to become efficacious. To date, direct evaluation of the quantitative contributions of these interdependent factors has been lacking because it has not been possible to perform experiments in which various metabolic signals can be noninvasively assessed over long periods of time following controlled induction of NV. We have developed multinuclear nuclear magnetic resonance (NMR) techniques that circumvent these technical problems and can simultaneously record from intact tissue the quantitative contributions of oxygen level, glucose utilization, and lactate concentration prior to and during the development of NV in the same animal. We propose to employ these newly-developed NMR methods in a rat pup model of NV to answer the following question during the onset and progression of NV: What are the quantitative contributions of metabolic factors (preretinal oxygen level, lactate concentration, glucose utilization, and retinal blood flow) to the development and progression of NV? We will manipulate the occurrence of NV in our model and measure changes in the metabolic factors in relationship to: a) the spatial location of NV on retina; b) the occurrence and severity of the NV; c) changes in the occurrence of NV over time. These experiments will demonstrate the quantitative contributions of these metabolic factors and whether or not that are predictive of the occurrence of NV in this model.
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