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 该项目的长期目标是确定视觉障碍的神经元和血管机制 以及为了制定预防性和治疗策略而产生的近视。产前和 早期产后脊椎动物视网膜产生相关的赞助神经元活性，称为“视网膜波”， 对于正常的神经元发展和视力至关重要。过早的视网膜波终止可能有助于 早产与出生相关的视力问题和折射错误。早产，结合产后氧气 - Gen Therapy还可能引起常规的血管并发症，称为预期性病变（ROP）。 Rop是 与早产婴儿中无法治愈的视觉障碍和近视密切相关。 与ROP和 早期的视网膜波活性终止尚未很好地定义。我们在这个项目中的目标是定义如何 在视觉体验之前的赞助视网膜波培养基生长以及氧诱导的视网膜病如何 （OIR）引起视力障碍和近视。我们的初步数据表明胆碱能残留波 由Starburst Amaccrene细胞（SAC）产生 眼多巴胺 - 眼部发育调节剂。我们假设胆碱能波驱动正常的眼睛 通过多巴胺信号传导和该途径的抑制会破坏正常的眼部生长。在 AIM 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部生长。 此外，我们发现，在OIR动物模型中，AII amacrine细胞（AII-ACS）和DACS - 两个类别 分别有助于Scotopic和Phopopic Vision的内部残留神经元，我们大大丢失了。我们 假设OIR中AII-AC和DAC的损失会导致近视。在AIM 2中，我们将通过 确定AII-AC和DAC对OIR引起的近视的相对贡献，并评估 OIR引起的视觉障碍对近视发育。 预期结果包括确定视网膜波如何影响多巴胺信号传导介导眼 生长以及氧处理如何通过残留的丢失来使杆和锥信号系统渗透 中间神经元会导致视力丧失和近视的发展。这项工作对 了解早产视力障碍和儿童近视的原因和机制将使 合理发现新的治疗干预措施。