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

描述（由申请人提供）：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）是许多新生儿中共存的两种疾病，它们共同导致了高发病率。目前的治疗方法分别针对每种疾病，而没有考虑潜在的共同血管机制。在本提案中，我们试图剖析循环GMP途径在ROP发病机制中的作用。我们将验证这样一个假设，即使用磷酸二酯酶-5 （PDE5）抑制剂治疗ROP的机会窗口与BPD-PH的建议治疗窗口同时存在。通过研究操纵cGMP对新生小鼠视网膜神经血管元素发育的影响，我们将研究对这一微妙过程的可逆不利影响的可能性。然后，我们将使用氧诱导视网膜病变（OIR）小鼠和大鼠模型作为人类ROP的试验平台，以解剖cGMP在OIR不同阶段的作用。我们假设系统使用PDE5抑制剂将具有稳定HIF1 -和促进OIR初始血管闭塞期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HIF1对视网膜血管生成的有害增强有关，而对BPD-PH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PDE5抑制剂的安全有效的治疗窗口，并为加强对cGMP在视网膜感光器和血管发育中的作用的理解铺平道路。本文提出的机械实验将利用两位临床科学家联合pi的跨学科专业知识。她是一名临床科学家视网膜专家，在视网膜变性，电生理和视网膜血管疾病方面具有特殊的专业知识，她是NIH资助的研究缺血性视网膜病变的新型功能性视网膜成像方式。Farrow博士是美国国立卫生研究院资助的肺血管实验室的临床科学家和新生儿学家，在cGMP信号和肺动脉高压动物模型方面具有特殊的专业知识。本研究利用各自实验室已经建立的技术，成功地进行了合作，本文提供的初步数据证明了这一点。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。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婴儿，其中药代动力学已得到验证，药物显示是安全的。将PDE抑制剂应用于早产儿以预防BPD-PH和ROP将是这些研究人员的长期目标，他们与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.