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

描述（由申请方提供）：早产儿视网膜病变（ROP）和支气管肺发育不良相关肺动脉高压（BPD-PH）是两种在许多新生儿中共存的疾病，共同导致高发病率。目前的治疗方法分别解决每种情况，而不考虑潜在的共享血管机制。在这个建议中，我们试图剖析环GMP途径在ROP发病机制中的作用。我们将测试的假设，有一个窗口的机会来治疗ROP使用磷酸二酯酶-5（PDE 5）抑制剂，这是同时与建议的治疗窗口BPD-PH。通过研究操纵cGMP对新生小鼠视网膜的神经血管发育的影响，我们将检查可逆的不良反应的可能性在这个微妙的过程。然后，我们将使用氧诱导的视网膜病变（OIR）小鼠和大鼠模型作为人类ROP的试验床，以剖析cGMP在OIR不同阶段的作用。我们假设全身使用PDE 5抑制剂将在OIR的初始血管闭塞阶段稳定HIF 1 α并促进正常视网膜血管发育具有有益作用，同时促进正常肺血管发育和预防BPD-PH。我们进一步假设，在OIR的血管生成第二阶段启动PDE 5抑制可能与通过HIF 1 α有害地增强视网膜血管生成有关，而在BPD中无效。本文提出的研究将使我们能够确定在新生小鼠和大鼠OIR模型中使用PDE 5抑制剂的安全有效的治疗窗口，并为增强对cGMP在视网膜感光细胞和血管发育中所起作用的理解铺平道路。本文提出的机制实验将利用两位临床医生-科学家共同PI的跨学科专业知识。Fawzi博士是一位临床科学家视网膜专家，在视网膜变性，电生理学和视网膜血管疾病方面具有特殊专长，她是NIH资助的缺血性视网膜病研究新的功能性视网膜成像模式。Farrow博士是一名临床科学家，拥有一个由NIH资助的肺血管实验室，在cGMP信号传导和肺动脉高压动物模型方面具有特殊专长。这项研究利用了成功的合作努力，使用已经建立在各自的实验室，证明了这里提出的初步数据。当前提案的成功将允许在更大的动物模型中进一步证明原理研究，作为人体临床试验的先决条件。PDE 5抑制剂很容易获得，并且已经用于患有肺动脉高压的足月婴儿，其中药代动力学已经得到验证，并且药物显示是安全的。将PDE抑制剂的使用扩展到早产儿以预防BPD-PH和ROP将是这些研究人员的长期目标，他们正在Lurie儿童医院和西北大学密切合作。

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.