Noninvasive Protection Against Retinopathy of Prematurity

无创性预防早产儿视网膜病变

• 批准号: 10019555
• 负责人: James Daniel Akula
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019555
• 关键词: Acute; Adopted; Adult; Age; Air; Angiography; Anisometropia; Astigmatism; Attenuated; Biochemical; Biological; Biometry; Blindness; Blood Vessels; Blood capillaries; Cardiopulmonary; Caring; Child; Childhood; Clinical Research; Clinical Trials; Combined Modality Therapy; Contrast Sensitivity; Darkness; Data; Development; Developmental Course; Disease; Event; Eye; Flowmetry; Functional disorder; Genus Hippocampus; Goals; Growth; Growth Factor; Histology; Human; Hypoxia; Image; Individual; Infant; Interruption; Intervention; Knowledge; Lasers; Lead; Length; Light; Light Adaptations; Link; Longitudinal Studies; Maintenance; Maps; Measures; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Monitor; Morphology; Myopia; Neural Retina; Neuronal Dysfunction; Neurons; Ophthalmoscopy; Optical Coherence Tomography; Outcome; Oxygen; Pathogenesis; Pathologic Neovascularization; Patient Care; Pattern; Peripheral; Pharmacology; Photoreceptors; Phototransduction; Plant Roots; Premature Birth; Premature Infant; Procedures; Rattus; Refractive Errors; Regimen; Regulation; Research; Retina; Retinal Detachment; Retinal Diseases; Retinopathy of Prematurity; Risk; Rod; Scanning; Series; Severities; Signal Pathway; Structure; Supplementation; System; Testing; Translations; Vascular Endothelial Growth Factors; Vascular blood supply; Vascularization; Visual impairment; adaptive optics; angiogenesis; base; blind; choroidal circulation; clinically significant; comorbidity; design; effective intervention; high risk; improved; infancy; innovation; mindfulness; monocular; neovascularization; neurogenesis; neurovascular; novel; outcome prediction; prevent; relating to nervous system; response; retina blood vessel structure; retinal neuron; retinal rods; sensor; treatment trial; vascular abnormality; visual cycle; visual threshold

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.

在我们正在进行的关于儿童失明的主要眼病原因的研究中，视网膜病变 早产儿(ROP)，我们已经记录了许多高度流行的、临床上有意义的后遗症 在ROP活跃的早产年龄后持续很长时间。包括短轴向长度、高轴向长度 近视、屈光参差，也许最关键的是持续性视网膜功能障碍。尽管这些 结果是常见的，即使在ROP很轻微的眼睛(绝大多数)，机制 人们对它们的起因和联系仍知之甚少。我们将研究这些机制。我们的 在人类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。 以及视网膜神经元，尤其是视杆细胞感受器，煽动了 导致所有这些后遗症的事件。因此，我们将使用氧诱导的视网膜病变 “ROP大鼠”模型来验证我们的新假设，即持续性神经血管功能障碍是基础 活动性疾病解决后数年的不良ROP结局。以便于随时翻译到 我们的临床研究和患者护理，我们将利用互补的创新程序来 研究神经视网膜的功能和结构及其血管供应，以及它们之间的联系 在个体活生生的眼睛里，屈光发育发生了变化。我们的开拓性方法将 允许从血管闭塞到活动性ROP到成熟的纵向研究。这将使 拟导出的个性化发育生长曲线及其量化度量 功能(血管、神经、屈光)要评估其预测预后的能力 其他特征，暗示因果关系。在同一横断面试验中 时间点，对大鼠亚群中生化信号通路的研究将调查 共同的神经、血管和屈光模式形成机制的分子基础。然后, 注意：(1)ROP在早产儿发病时，当 能量需求棒首次出现，(2)年轻时棒功能障碍的严重程度预示着血管 结果，但不是相反，(3)使用视觉周期调节剂，降低新陈代谢 视杆的需求保护未成熟的视网膜神经元并改善血管预后，(4)神经 血管的发育处于协同的分子控制之下。(5)视网膜是主要的 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，因为光抑制了循环电流， 我们将尝试对环境光进行有益的调节，以造福于所有这些 后遗症-血管、神经和屈光-使用一系列由 参考光感受器的发育过程。光调节是安全、经济、 适用于单一疗法或与其他疗法联合治疗，甚至适用于轻度 目前没有资格进行任何干预的ROP，因此很容易翻译。新的 我们希望，这里产生的知识将导致改变游戏规则的方法来理解和 治疗--不，预防！--ROP最常见的后遗症。