This proposal outlines a set of experiments under broad challenge area (05) Comparative Effectiveness Research which will address the highest-priority challenge 05-EY-102 Treatment of Pediatric Eye Diseases and Disorders. Specifically, it will compare results from two preclinical trials of novel interventions in retinopathy of prematurity (ROP). In one sense, the continuing ROP epidemic is a good problem to have: Advances in neonatology are permitting the most prematurely born infants to survive. Unfortunately, these are the very patients at highest risk for ROP. Thus, the incidence and severity of ROP in middle income countries is near all-time highs. Worldwide, at least 50,000 children are binocularly blind, many times that number monocularly blind, and many fold again suffering from lifelong visual impairment as a consequence of ROP. In the United States, approximately 15,000 cases are newly diagnosed each year and, despite the best available medical management, 400-600 progress to blindness. This ranks ROP as the leading ocular cause of childhood blindness and strongly motivates research into the effectiveness of interventions. Treatment of the vasculopathy has been the focus of much good work, but the insult to the neural retina has received less attention. Recent discoveries indicate that oxidative stress in the rod photoreceptors plays a causal role in ROP. This inspires an alternative way to treat ROP: modulating rod metabolism. We will conduct a preclinical trial in rat models of ROP by downregulating two energy-demanding processes in the rods: the dark current and the visual cycle. We anticipate that this approach will compare favorably with the best currently available medical management. To produce in rats vascular abnormalities similar to those that characterize human ROP, pups are exposed to high and low oxygen during the first days after birth;the induction ends at postnatal day 14. Rats are grouped two ways: by oxygen exposure history and by treatment. """"""""ROP rats"""""""" and controls are assigned to either dark current modulation (DCM) treatment with dorzolamide, visual cycle modulation (VCM) treatment with retinylamine, or vehicle treatment. At around postnatal age 19, when the vascular abnormalities are near their peak (in untreated animals), function of the neural retina (both photoreceptor and postreceptor) is objectively assessed by electroretinography (ERG). Unbiased, numeric measures of abnormality of the superficial vessels are obtained by application of image analysis software (RISA) to digital photographs of the ocular fundus. Both the ERG and retinal imaging are noninvasive techniques that permit subsequent analyses to be conducted in the same eye. A small subset of rats, selected based on the results of their ERG analyses to be near the medians for their group, are assigned to rigorous psychophysical (behavioral) testing of their vision;five threshold measurements (absolute plus four increment) are made in each rat and a transposition of the data, diagonally or vertically relative to controls, will provide clues as to the site of any dysfunction. Detailed anatomic and molecular studies are undertaken in the remaining animals. Assessment of the retinal layers in light micrographs of toluidine blue-stained retinal cross-sections yields information about damage to retinal cells. Markers of oxidative stress are assessed by ELISA and western blotting. qPCR is used to supplement these measures and to evaluate the expression of neurogenic and angiogenic growth factors such as VEGF, PEDF and semaphorins. Improved retinal structure, function and vasculature, as well as reduction in molecular markers of oxidative stress and normalization of growth factor expression, are all hypothesized in both DCM and VCM treated ROP rats.
Retinopathy of prematurity (ROP) is clinically diagnosed by abnormal retinal vasculature, but damage to retinal neurons underpins functional sequelae and may also underpin the vasculopathy. At the same age as the onset of acute vasculopathy, an escalation in the metabolic demands of the rod photoreceptors occurs that simultaneously renders them vulnerable to blood oxygen swings and powerful provocateurs of pathological angiogenesis. Thus, suppression of metabolically demanding processes in the rods promises preservation of visual function and prevention of vascular disease.
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