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.

项目摘要 这个项目的长期目标是确定视觉障碍的神经和血管机制 以及早产导致的近视，以便制定预防和治疗策略。产前和 出生后早期脊椎动物视网膜产生相关的自发神经元活动，称为"视网膜波"， 对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导致 早产相关的视力问题和屈光不正。早产，加上产后氧- 基因治疗也可能导致视网膜血管并发症，称为早产儿视网膜病变（ROP）。rop是 与早产儿不可治愈的视力障碍和近视密切相关。 ROP相关眼病发病机制的细胞分子机制及视网膜病变的研究进展 早期视网膜波活动终止还没有很好地定义。我们在这个项目中的目标是定义如何 自发性视网膜波在视觉体验前介导眼生长及氧诱导视网膜病变机制 (OIR)导致视力受损和近视。我们的初步数据表明，胆碱能视网膜波 由星爆状无长突细胞（SAC）产生的多巴胺能神经递质可以刺激多巴胺能无长突细胞（DAC）， 一种眼部发育调节剂。我们假设胆碱能波驱动正常眼 通过多巴胺信号传导的发育，并且抑制该途径将破坏正常的眼生长。在 目的1，我们将通过识别胆碱能波-多巴胺信号通路来验证这一假设， 评估这一途径如何影响眼部生长。 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 分别对暗视觉和明视觉起作用的视网膜内神经元的数量基本上丧失了。我们 假设OIR中AII-AC和DAC的丢失导致近视。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诱导的近视的相对贡献，并评估 OIR引起的视力损害对近视发展的影响 预期的结果包括确定视网膜波如何影响多巴胺信号传导，以介导眼 生长以及氧治疗如何通过视网膜神经元的丢失扰乱视杆细胞和视锥细胞信号系统。 中间神经元引起视力丧失和近视的发展。这项工作的更广泛影响， 了解儿童早产视力障碍和近视的原因和机制， 合理发现新的治疗干预措施。