The Underlying Mechanisms of Visual Impairment and Myopia in Prematurity

早产儿视力障碍和近视的潜在机制

• 批准号: 10584723
• 负责人: Dao-Qi Zhang
• 金额: $ 43.63万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584723
• 关键词: Ablation; Amacrine Cells; Animal Model; Animals; Anterior; Anterior eyeball segment structure; Autopsy; Biometry; Blindness; Blood Vessels; Brain; Child; Contrast Sensitivity; Cornea; Data; Development; Dimensions; Dopamine; Enzymes; Event; Eye; Eye Development; Eye diseases; Genetic Techniques; Goals; Growth; Human; Impairment; Infant; Interneurons; Knock-out; Lead; Length; Light; Mediating; Molecular; Mus; Myopia; Neurons; Outcome; Oxygen; Oxygen Therapy Care; Pathogenesis; Pathway interactions; Pregnancy; Premature Birth; Premature Infant; Preventive; Primates; Production; Public Health; Recovery; Refractive Errors; Retina; Retinal Diseases; Retinal Ganglion Cells; Retinopathy of Prematurity; Signal Pathway; Signal Transduction; Source; System; Testing; Therapeutic; Tyrosine 3-Monooxygenase; United States; Vascular System; Vertebrate Photoreceptors; Vision; Visual; Visual Acuity; Visual impairment; Work; cholinergic; combat; experience; insight; lens; neonatal mice; neuron development; novel; novel therapeutic intervention; patch clamp; pharmacologic; postnatal; premature; prenatal; preservation; rational design; response; retina blood vessel structure; retinal neuron; starburst amacrine cell

PROJECT SUMMARY The long-term goal of this project is to determine the neuronal and vascular mechanisms of visual impairment and myopia resulting from prematurity in order to develop preventive and therapeutic strategies. Prenatal and early postnatal vertebrate retinas generate correlated spontaneous neuronal activity, termed “retinal waves,” that are essential for normal neuronal development and vision. Premature retinal wave termination may contribute to preterm birth-associated vision problems and refractive errors. Preterm birth, in combination with postnatal oxy- gen therapy, can also cause retinal vascular complications known as retinopathy of prematurity (ROP). ROP is closely associated with incurable visual impairment and myopia in premature infants. The cellular and molecular mechanisms underlying the pathogeneses of eye disorders related to ROP and the early retinal wave activity termination are not yet well defined. Our objectives in this project are to define how spontaneous retinal waves mediate ocular growth before visual experience and how oxygen-induced retinopathy (OIR) causes vision impairment and myopia. Our preliminary data demonstrated that cholinergic retinal waves generated by starburst amacrine cells (SACs) can excite dopaminergic amacrine cells (DACs), the sole source of ocular dopamine—an ocular development regulator. We hypothesize that cholinergic waves drive normal eye development via dopamine signaling and that suppression of this pathway will disrupt normal ocular growth. In Aim 1, we will test this hypothesis by identifying the cholinergic wave–dopamine signaling pathway and assessing how this pathway impacts ocular growth. In addition, we have found that, in an OIR animal model, AII amacrine cells (AII-ACs) and DACs—two classes of inner retinal neurons that contribute to scotopic and photopic vision, respectively—were substantially lost. We hypothesize that the loss of AII-ACs and DACs in OIR causes myopia. In Aim 2, we will test this hypothesis by determining the relative contributions of AII-ACs and DACs to OIR-induced myopia and assessing the impact of OIR-induced visual impairments on myopia development. Expected outcomes include determining how retinal waves influence dopamine signaling to mediate ocular growth and how oxygen treatment perturbs the rod and cone signaling systems through the loss of retinal interneurons to cause vision loss and the development of myopia. The broader impact of this work on understanding the causes and mechanisms of preterm vision impairment and myopia in children will enable the rational discovery of new therapeutic interventions.

项目概要 该项目的长期目标是确定视力障碍的神经和血管机制 和早产引起的近视，以制定产前和治疗策略。 产后早期的脊椎动物视网膜产生相关的自发神经活动，称为“视网膜波”， 对于正常的神经元发育和视力至关重要。视网膜波过早终止可能会导致。 早产相关的视力问题和屈光不正。 gen 治疗还会引起视网膜血管并发症，称为早产儿视网膜病变 (ROP)。 与早产儿无法治愈的视力障碍和近视密切相关。 与 ROP 相关的眼部疾病发病机制的细胞和分子机制以及 早期视网膜波活动终止尚未明确定义，我们在该项目中的目标是定义如何终止。 自发性视网膜波在视觉体验之前介导眼睛生长以及氧诱导的视网膜病变 (OIR) 会导致视力障碍和近视。我们的初步数据表明，胆碱能视网膜波。 由星爆无长突细胞（SAC）产生的可以激发多巴胺能无长突细胞（DAC），这是唯一的来源 我们发现胆碱能波驱动正常的眼睛。 通过多巴胺信号传导进行发育，抑制该途径将破坏正常的眼睛生长。 目标 1，我们将通过识别胆碱能波-多巴胺信号通路和 评估该途径如何影响眼睛生长。 此外，我们发现，在 OIR 动物模型中，AII 无长突细胞 (AII-AC) 和 DAC——两类 分别有助于暗视和明视觉的内部视网膜神经元的数量显着丧失。 接下来，OIR 中 AII-AC 和 DAC 的丢失会导致近视。在目标 2 中，我们将通过以下方式检验这一假设。 确定 AII-AC 和 DAC 对 OIR 引起的近视的相对贡献并评估 OIR 引起的视力障碍对近视发展的影响。 预期结果包括确定视网膜电波如何影响多巴胺信号传导以调节眼部 生长以及氧气治疗如何通过视网膜损失扰乱视杆细胞和视锥细胞信号系统 中间神经元导致视力丧失和近视的发展这项工作的更广泛的影响。 了解儿童早产视力障碍和近视的原因和机制将有助于 合理发现新的治疗干预措施。