Manipulating cGMP Pathway to Impact Vascular Development in Neonatal BPD and ROP

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DESCRIPTION (provided by applicant): Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) are two conditions that co-exist in many neonates and together contribute to a high rate of morbidity. Current therapeutic approaches address each condition separately, without considering the potentially shared vascular mechanism. In this proposal, we seek to dissect the role of cyclic GMP pathway in the pathogenesis of ROP. We will test the hypothesis that there is a window of opportunity to treat ROP using phosphodiesterase-5 (PDE5) inhibitors that is concurrent with the suggested treatment window for BPD-PH. By studying the effects of manipulating cGMP on the developing neurovascular elements of the retina in neonatal mice, we will examine the potential for reversible adverse effects on this delicate process. We will then use the oxygen-induced retinopathy (OIR) mouse and rat models as test beds for human ROP, in order to dissect the role of cGMP on the different phases of OIR. We hypothesize that systemic use of PDE5 inhibitors will have a beneficial role stabilizing HIF1¿ and promoting normal retinal vascular development in the initial vaso- obliterative phase of OIR, while simultaneously promoting normal lung vascular development and preventing BPD-PH. We further hypothesize that initiating PDE5 inhibition during the angiogenic second phase of OIR may be associated with detrimental enhancement of retinal angiogenesis through HIF1¿ while being ineffective in BPD-PH. The study proposed herein will allow us to identify a safe and effective therapeutic window for the use of PDE5 inhibitors in neonatal mouse and rat OIR model, and pave the way towards an enhanced understanding of the role played by cGMP in retinal photoreceptor and vascular development. The mechanistic experiments proposed herein will capitalize on the interdisciplinary expertise of the two clinician-scientist co-PI's. Dr. Fawzi is a clinician-scientst retinal specialist with special expertise in retinal degenerations, electrophysiology and retinal vascular diseases, and she is NIH funded to study novel functional retinal imaging modalities in ischemic retinopathies. Dr. Farrow is a clinician-scientist neonatologist with an established NIH-funded pulmonary vascular laboratory with a special expertise in cGMP signaling and animal models of pulmonary hypertension. This study capitalizes on a successful collaborative effort using techniques already established in the respective laboratories, as evidenced by the preliminary data presented here. Success of the current proposal, will allow further proof of principle studies in larger animal models, as a pre-requisite for human clinical trials. PDE5 inhibitors are readily available and are already being used in term infants with pulmonary hypertension, where the pharmacokinetics have been validated and the drug shown to be safe. The extension of the use of PDE inhibitors to preterm neonates to prevent BPD-PH and ROP will be the long-term goal of these investigators, who are closely collaborating at the Lurie Children's Hospital and Northwestern University.