Noninvasive Protection Against Retinopathy of Prematurity

在我们正在进行的对儿童失明的主要眼部原因的研究中， 早产（ROP），我们已经记录了许多高度流行的，临床上显著的后遗症， 在ROP活跃的早产年龄后持续很长时间。 这些包括短轴向长度，高 近视、屈光参差以及可能最严重的持续性视网膜功能障碍。 虽然这些 结果是常见的，即使在ROP是轻微的眼睛（绝大多数），机制 这些问题的原因和联系仍然不甚清楚。 我们将研究这些机制。 我们 在人ROP受试者和大鼠模型中的观察强烈表明， 神经视网膜、血管系统和屈光发育在生物学上是相关的 视网膜神经元，尤其是视杆细胞，会引发一系列的 导致所有这些后遗症的事件。 因此，我们将使用氧诱导视网膜病变 “ROP大鼠”模型来检验我们的新假设，即持续的神经血管功能障碍是基础 活动性疾病消退后数年ROP结果较差。 为了便于翻译， 我们的临床研究和病人护理，我们将利用互补的，创新的程序， 研究神经视网膜的功能和结构及其血管供应，以及相关性 在个体的活体眼睛中，屈光发育发生改变。 我们的开创性方法将 允许从血管闭塞到主动ROP到成熟的纵向研究。 这将使 个体化的发育生长曲线，以及每个曲线的定量测量 评价其预测结局的能力， 其他特征，表明因果关系。 在同一时间的横截面测试中， 时间点，在大鼠亚群中的生化信号传导途径的研究将研究 共享的神经、血管和折射模式机制的分子基础。 然后， 注意（1）ROP在早产年龄时发病， 需要能量的杆首先出现，（2）年轻时杆功能障碍的严重程度预示着血管 结果，但反之亦然，（3）给予视觉周期调节剂， 视杆细胞的需求保护未成熟的视网膜神经元并改善血管结局，（4）神经 血管的发育是在分子的协同控制下进行的;（5）视网膜是一个主要的 眼睛生长和屈光发育的控制器，以及 (6)光感受器在光中使用较少的能量因为光抑制循环电流， 我们将尝试有益地调节环境光， 后遗症-血管，神经，和折射-使用一系列的黑暗和光明的曝光设计， 参考光感受器的发育过程。调光安全、经济， 适合作为单一疗法或与其他治疗的联合疗法，甚至适用于轻度 ROP目前没有资格进行任何干预，因此易于翻译。新 我们希望，这里产生的知识将导致改变游戏规则的理解方法， 治疗，不，预防! ROP最常见的后遗症。

In our ongoing research into the leading ocular cause of childhood blindness, retinopathy of prematurity (ROP), we have documented many highly prevalent, clinically significant sequelae that persist long after the preterm ages at which ROP is active. These include short axial length, high myopia, anisometropia and, perhaps most critically, persistent retinal dysfunction. Although these outcomes are common, even in eyes in which the ROP was mild (the vast majority), the mechanisms that cause and link them remain poorly understood. We will examine these mechanisms. Our observations in both human ROP subjects and rat models strongly suggest that abnormalities of the neural retina, of the vasculature, and of refractive development, are biologically related comorbidities, and that retinal neurons, especially rod photoreceptors, instigate the chain of events that results in all these sequelae. Therefore, we will use the oxygen-induced retinopathy 'ROP rat" model to test our novel hypothesis that persistent neurovascular dysfunction is the basis of poor ROP outcomes years after active disease has resolved. To facilitate ready translation to our clinical research and patient care, we will make use of complementary, innovative procedures to study the function and structure of the neural retina and its vascular supply, and associations with altered refractive development, in individual, living eyes. Our pioneering approach will permit longitudinal study from vaso-obliteration through active ROP to maturity. This will enable individualized developmental growth curves to be derived and quantitative measures of each feature (vascular, neural, refractive) to be evaluated for their ability to predict outcomes in other features, suggesting cause-and-effect relationships. In cross-sectional tests at the same timepoints, studies of biochemical signaling pathways in subsets of rats will investigate the molecular bases of the shared neural, vascular, and refractive patterning mechanisms. Then, mindful that (1) ROP has its onset at preterm ages when the outer segments of the energy-demanding rods first appear, (2) the severity of rod dysfunction at a young age predicts vascular outcomes but not vice versa, (3) administration of a visual cycle modulator that lowers metabolic demands of rods protects the immature retinal neurons and improves vascular outcomes, (4) neural and vascular development is under cooperative molecular control, (5) the retina is a major controller of eye growth and refractive development, and (6) photoreceptors use less energy in the light because light suppresses the circulating current, we will attempt to beneficially regulate ambient light to the benefit of all these sequelae-vascular, neural, and refractive-using a series of dark and light exposures designed with reference to the developmental course of the photoreceptors. Light regulation is safe, economical, suitable as monotherapy or combination-therapy with other treatments, and applicable even to mild ROP that does not currently qualify for any intervention, and thus readily translatable. The new knowledge generated herein will, we hope, lead to game-changing approaches to understanding and treating-nay, preventing!-the most common sequelae of ROP.