A clinically applicable model of retinal oxygen metabolism

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Project Summary This proposal seeks to establish a correlation between the metabolism of the inner retina and the oxygen supply from the inner retinal vascular network measured by optical coherence tomography. This work will be done in rats, but will have immediate clinical application. Several important diseases cause damage to the inner retina, including diabetes, glaucoma, and vascular occlusion. Considerable effort has gone into measuring parameters that provide some information about the metabolism of the inner retina, particularly oxygen saturation (sO2) in the retinal vessels and retinal blood flow (RBF), but each alone is insufficient to allow strong conclusions. It has now become possible in animals and humans to measure saturation and blood flow together and combine them to yield the Inner Retinal Metabolic Rate of Oxygen (IR-MRO2), which is the total amount of oxygen extracted from the retinal circulation per unit time. These non-invasive measurements of IR-MRO2 could potentially be predictive of functional damage in disease before other measures, and could be useful in evaluating treatments for those diseases. The most promising way to measure IR-MRO2 is a novel method using visible-light optical coherence tomography (vis-OCT). However, the retina is a unique tissue with a dual blood supply, so further validation is required to understand how IR-MRO2 corresponds to the actual oxygen utilization of the inner retina (IR-QO2). It is often assumed that these two quantities are equal, but this is not true. There are conditions under which the retinal circulation provides an important component of the oxygen needed by the photoreceptors in the outer retina, so IR-MRO2 overestimates IR-QO2, and other conditions under which oxygen derived from the choroid provides oxygen to the inner retina, so that IR-MRO2 underestimates IR-QO2. If the actual correspondence between IR-MRO2 and IR-QO2 is not understood, the great promise of the new methods of measuring IR-MRO2 will be lost due to confusion and false conclusions. It is really IR-QO2 that is needed for understanding the progression of inner retinal changes in diabetes, glaucoma, and vein occlusion. We propose to perform experiments on the same rats with both well-established oxygen-sensitive microelectrode methods and vis-OCT to identify the conditions under which IR-MRO2 can be used to infer IR-QO2 directly, and to provide a clinically useful model to allow a prediction of the deviations between IR-MRO2 and IR-QO2. No study has previously used both imaging and microelectrodes in the same animals, or attempted to provide validation of oximetry methods with other methods. The proposed work is important for any method of characterizing IR- MRO2, not just vis-OCT. The specific aims are 1) to develop an analytical model to relate the inner retinal sO2 and IR-MRO2, measured by vis-OCT, to the metabolic demands of the inner and outer retina in both rats and humans and 2) to validate and refine this model in rats by nearly simultaneous measurement of IR-MRO2 and oxygen consumption derived from microelectrode measurements during air breathing in light and darkness, hypoxia and hyperoxia.