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

操纵 cGMP 途径影响新生儿 BPD 和 ROP 的血管发育

基本信息

批准号：
8771174
负责人：
KATHRYN N FARROW
金额：
$ 20.13万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771174
关键词：
Address Adverse effects Affect Age Animal Model Beds Blindness Blood Circulation Blood Vessels Bronchopulmonary Dysplasia Cessation of life Characteristics Childhood Clinical Trials Cyclic GMP Data Defect Development Disease Dose Drug Kinetics Electrophysiology (science)Electroretinography Elements Europe Eye Funding Goals Health Care Costs Human Hyperoxia Infant Laboratories Lead Lung Measures Mediating Modality Modeling Morbidity - disease rate Morphology Mus Neonatal Neurons North America Oral Outcome Oxygen Pathogenesis Pathologic Pathway interactions Pediatric Hospitals Pharmaceutical Preparations Phase Photoreceptors Phototransduction Physiological Play Population Premature Infant Process Pulmonary Hypertension Rattus Reactive Oxygen Species Research Personnel Retina Retinal Retinal Degeneration Retinal Diseases Retinal Neovascularization Retinal Photoreceptors Retinopathy of Prematurity Right Ventricular Hypertrophy Risk Role Scientist Signal Transduction Source Specialist Staging Structure Techniques Testing Therapeutic United States National Institutes of Health Universities Vascular Diseases Vascular Endothelial Growth Factors Vascularization Vasodilation Visual Visual impairment angiogenesis animal data behavior test cost critical developmental period hypertension prevention hypoxia inducible factor 1 imaging modality improved inhibitor/antagonist morphometry mortality mouse development mouse model neonate neovascularization novel phosphodiesterase V phosphoric diester hydrolase postnatal premature prevent public health relevance research study retinal angiogenesis retinal ischemia safety study sildenafil success therapeutic target vision development

项目摘要

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.

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的肺动脉高压（BPD-PH）是许多新生儿中共存的两种疾病，并且共同导致高发病率。目前的治疗方法针对这两种疾病。在本提案中，我们试图剖析环 GMP 通路在 ROP 发病机制中的作用，我们将检验这一假设。通过研究操纵 cGMP 对新生小鼠视网膜神经血管元件发育的影响，有一个使用磷酸二酯酶 5 (PDE5) 抑制剂治疗 ROP 的机会窗口，该窗口与 BPD-PH 的建议治疗窗口同时进行。我们将研究对这一微妙过程产生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 的试验台，以剖析其作用。 cGMP 对 OIR 不同阶段的影响我们认为，全身使用 PDE5 抑制剂将对稳定 HIF1 产生有益作用。并在 OIR 初始血管闭塞期促进正常视网膜血管发育，同时促进正常肺血管发育并预防 BPD-PH。我们进一步发现，在 OIR 血管生成第二期启动 PDE5 抑制可能与应激增强相关。通过 HIF1 促进视网膜血管生成¿虽然对 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，并为加深对 PDE5 所发挥的作用的理解铺平道路。本文提出的 cGMP 在视网膜感光器和血管发育中的机制实验将利用两位临床医生兼科学家的跨学科专业知识。 Fawzi 博士是一位临床医生兼科学家。 Farrow 博士是一位视网膜专家，在视网膜变性、电生理学和视网膜血管疾病方面具有特殊的专业知识，她获得 NIH 的资助，研究缺血性视网膜病的新型功能性视网膜成像模式。这项研究利用了各自实验室已经建立的技术的成功合作努力，正如这里提供的初步数据所证明的那样，当前提案的成功将允许在更大的动物模型中进行进一步的原理研究，作为人体临床试验的先决条件，并且已经在足月婴儿中使用。肺动脉高压，其药代动力学已得到验证，并且该药物被证明是安全的。将 PDE 抑制剂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，他们密切关注。卢里儿童医院和西北大学合作。