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

描述(申请人提供)：早产儿视网膜病变(ROP)和支气管肺发育不良相关性肺动脉高压(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针对每种情况，没有考虑潜在的共同血管机制。在这项建议中，我们试图剖析环状GMP通路在ROP发病机制中的作用。我们将检验这一假设，即存在使用磷酸二酯酶-5(PDE5)抑制剂治疗ROP的机会之窗，这与建议的BPD-PH治疗窗口是一致的。通过研究cGMP对新生小鼠视网膜发育中的神经血管成分的影响，我们将检查这一微妙过程中可逆的不利影响的可能性。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ROP的试验床，以剖析cGMP在OIR不同阶段的作用。我们假设，全身应用PDE5抑制剂将在OIR的早期血管闭塞阶段起到稳定HIF1�和促进正常视网膜血管发育的有益作用，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PDE5抑制可能与通过HIF1�促进视网膜血管生成有关，而对BPD-PH无效。这项研究将为PDE5抑制剂在新生小鼠和大鼠OIR模型中的应用提供一个安全有效的治疗窗口，并为进一步了解cGMP在视网膜光感受器和血管发育中的作用铺平道路。这里提出的机制实验将利用两位临床医生和科学家共同的跨学科专业知识。Fawzi博士是一名临床医生兼科学视网膜专家，在视网膜退行性变、电生理学和视网膜血管疾病方面具有专门知识，她由美国国立卫生研究院资助，研究缺血性视网膜疾病的新型功能性视网膜成像方式。法罗博士是一名临床科学家兼新生儿科医生，拥有一家由美国国立卫生研究院资助的肺血管实验室，在cGMP信号和肺动脉高压动物模型方面拥有专门的专业知识。这项研究利用了利用各自实验室已经建立的技术的成功的合作努力，这里提供的初步数据证明了这一点。目前的提议的成功，将允许在更大的动物模型中进一步证明原理研究，作为人类临床试验的先决条件。PDE5抑制剂很容易获得，并且已经用于患有肺动脉高压的足月儿，那里的药代动力学已经得到验证，药物被证明是安全的。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.