Synergistic Pharmacologicjntervention for Prevention of ROP (SPIPROP STUDY)

早产儿视网膜病变（ROP）是一种血管增殖性视网膜疾病，约60%的极低胎龄新生儿（elgan, <1250g/<28周）患有此病，约5%的新生儿终生失明。咖啡因和非甾体抗炎药已经被证明可以降低elgan中严重ROP的风险。我们提出了一种新的方法，将局部酮罗拉酸或全身布洛芬与全身咖啡因联合使用，以优化其预防ROP的功效。本提案的总体目标是研究非甾体抗炎药与全身咖啡因增强对ROP发生率和严重程度的协同作用。我们的具体目标有三个方面：1)建立局部眼科nsiad和全身咖啡因的协同作用，作为减轻和/或预防严重ROP的最佳疗法。我们假设眼酮酸或全身布洛芬与全身咖啡因增强可以预防或减轻ROP的严重程度；2)确定动脉氧饱和度的“临界”值作为严重ROP的关键危险因素。我们假设，elgan在生命的前两周内经历的每日动脉氧饱和度是一个“临界”数，这是严重ROP的关键危险因素；3)确定有严重ROP风险的婴儿是否存在δ样配体4单倍体不足（D114）。我们假设具有严重ROP风险的elgan具有与Notch信号通路特异性相关的不同基因表达模式，正如之前在动物模型中所显示的那样。我们将使用基因谱来确定DII4的单倍不足是否与严重的ROP有关。我们将使用最先进的技术来提供与ROP相关的生物分子机制的见解。我们拥有所有必要的技术和系统，以成功完成这些拟议的工作。

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease that afflicts as much as 60% of all extremely low gestational age neonates (ELGANs, <1250g/<28 weeks) with approximately 5% condemned to a lifetime of blindness. Caffeine and NSAIDs have already been shown to decrease the risk of severe ROP in ELGANs. We propose a novel approach of combining topical ketorolac or systemic ibuprofen with systemic caffeine to optimize their efficacy for prevention of ROP. The overarching goal of this proposal is to investigate the synergistic effects of NSAIDs potentiated with systemic caffeine on the incidence and severity of ROP. Our specific aims are three-fold: 1) To establish the synergistic effect of local ophthalmic NSIADs and systemic caffeine as optimal therapies for the attenuation and/or prevention of severe ROP. We hypothesize that ocular ketotolac or systemic ibuprofen potentiated with systemic caffeine will prevent or diminish the severity of ROP; 2) To identify a "critical" number of arterial oxygen desaturations as a key risk factor for severe ROP. We hypothesize that there is a "critical" number of daily arterial oxygen desaturations experienced by ELGANs during the first two weeks of life that is a key risk factor for severe ROP; and 3) To determine whether infants at risk for severe ROP are haploinsufficient for the delta-like ligand 4 (D114). We hypothesize that ELGANs at risk for severe ROP will have different pattern of gene expression specifically related to the Notch signaling pathway, as has been previously shown in animal models. We will use gene profiling to determine whether haploinsufficiency of DII4 is associated with severe ROP. We will use state-of-the-art technologies to provide insights on the biomolecular mechanisms associated with ROP. We have all the necessary technologies and systems in order to successful accomplish these proposed works.