Molecular Mechanisms of Emmetropization and Experimental Myopia at Single Cell Resolution

项目摘要 预计到2050年，世界上一半以上的人口将是近视眼，这将大大提高世界人口的增长率。 相关视力威胁疾病的风险，包括视网膜脱离、黄斑病变和青光眼。 尽管开发了几种循证治疗方法来控制近视进展， 并发症发生率持续上升，治疗效果也只是部分的。实验与临床研究 表明复杂的基因-环境相互作用参与了眼睛出生后生长的控制 及其光学发展，包括近视的发生和发展。使用动物模型的研究 证实了视觉经验和视网膜离焦控制眼睛的生长和屈光状态的发展 通过正视化的过程。虽然已经取得了进展，揭示了一些生物化学 与实验性近视相关的因素，对潜在的细胞和分子机制知之甚少。 控制正视化和近视发展的机制。 这个多PI财团赠款汇集了经验丰富的研究人员和他们建立的实验非- 具有国际公认眼基因组学的正视化和近视的人灵长类动物模型 研究中心进行的视网膜，RPE，脉络膜和巩膜生物学的主要调查出生后 眼睛生长和近视发展。本项目研究功能基因组学和基因环境 在灵长类动物眼睛的屈光发展的相互作用，并将确定分子机制参与 使用单细胞和批量转录组学、表观基因组学和蛋白质组学研究近视的发展。的 研究人员将使用已建立的生物信息学方法，确定和确认 正视化和近视发展的调节途径。这些研究将提供直接 证据和更完整的理解的机制，视觉调节眼睛的生长和近视 并将提供迄今为止最大和最全面的细胞和分子靶点共享资源 帮助开发新的治疗方法来控制眼睛生长和管理屈光不正。 这项研究符合NEI近视研究的四个目标中的三个：研究近视眼的生物化学特征， 调节眼睛生长的途径;识别导致屈光不正发展的基因;以及 将有助于开发评估或治疗屈光不正的新技术。

PROJECT SUMMARY More than half of the world’s population is projected to be myopic (nearsighted) by 2050, significantly raising the risk of associated vision-threatening conditions including retinal detachment, maculopathy, and glaucoma. Despite the development of several evidence-based treatments to manage myopia progression, the prevalence and complication rates continue to rise, and treatment efficacy is only partial. Experimental and clinical research shows that complex gene-environment interactions are involved in the control of the post-natal growth of the eye and its optical development, including myopia onset and progression. Research using animal models has confirmed that visual experience and retinal defocus control eye growth and the development of refractive state through the process of emmetropization. While progress has been made uncovering some of the biochemical factors associated with experimental myopia, very little is known about the underlying cellular and molecular mechanisms controlling emmetropization and myopia development. This multi-PI consortium grant brings together experienced researchers and their established experimental non- human primate model of emmetropization and myopia with an internationally recognized ocular genomics research center to perform a major investigation of the retinal, RPE, choroidal, and scleral biology of post-natal eye growth and myopia development. This project examines the functional genomics and gene-environment interactions in the refractive development of the primate eye and will identify molecular mechanisms involved in the development of myopia using single cell and bulk transcriptomics, epigenomics, and proteomics. The investigators will identify and confirm, using established bioinformatic approaches, the main components of key regulatory pathways underlying emmetropization and myopia development. These studies will provide direct evidence and a more complete understanding of the mechanisms of visually regulated eye growth and myopia and will provide the largest and most comprehensive shared resource of cellular and molecular targets to date helping develop new therapies to control eye growth and manage refractive errors. This investigation meets three of the four NEI objectives for myopia research: to investigate the biochemical pathways that regulate eye growth; to identify genes that contribute to the development of refractive errors; and will help develop new technologies for assessing or treating refractive errors.