Molecular Mechanisms of Emmetropization and Experimental Myopia at Single Cell Resolution

单细胞分辨率正视化和实验性近视的分子机制

• 批准号: 10419734
• 负责人: BOTOND ROSKA
• 金额: $ 60.07万
• 依托单位: STATE COLLEGE OF OPTOMETRY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419734
• 关键词: Age; Agonist; Animal Model; Biochemical; Biochemical Pathway; Bioinformatics; Biological; Biology; Blindness; Callithrix; Candidate Disease Gene; Cell model; Cells; Child; Choroid; Clinical Research; Complex; Complication; Contact Lenses; Data Set; Development; Drug Antagonism; Evidence based treatment; Extracellular Matrix; Eye; Eye Development; Fibroblasts; Future; Gene Expression; Gene Proteins; Genes; Genomics; Glaucoma; Grant; Growth; Growth and Development function; Human; Hyperopia; Immunohistochemistry; In Situ Hybridization; International; Investigation; Mass Spectrum Analysis; Methodology; Methods; MicroRNAs; Modeling; Molecular; Molecular Analysis; Molecular Target; Myopia; Optics; Output; Pathway interactions; Perception; Peripheral; Population; Prevalence; Probability; Process; Proteome; Proteomics; Public Health; Refractive Errors; Regulatory Pathway; Research; Research Personnel; Resolution; Resource Sharing; Retina; Retinal Detachment; Risk; Sclera; Signal Pathway; Signal Transduction; Techniques; Testing; Tissue-Specific Gene Expression; Tissues; Translations; Treatment Efficacy; Validation; Vision; Visual; Visual impairment; cell type; cellular targeting; comparison group; disorder of macula of retina; effective therapy; emmetropization; epigenome; epigenomics; experience; experimental study; functional genomics; gene environment interaction; gene regulatory network; genome sequencing; genome wide association study; insight; knockout gene; large datasets; lens; mouse model; new technology; new therapeutic target; nonhuman primate; novel therapeutics; primate development; response; single cell technology; transcriptome; transcriptomics; validation studies

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.

项目总结 预计到2050年，世界上将有超过一半的人口患有近视，这将显著增加 相关的威胁视力的情况的风险，包括视网膜脱离、黄斑病变和青光眼。 尽管已经开发了几种循证治疗来控制近视的进展，但患病率 并发症发生率继续上升，治疗效果只有部分。实验和临床研究 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 以及它的光学发展，包括近视的发生和发展。使用动物模型进行的研究已经 证实视觉体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。虽然在发现一些生化物质方面取得了进展 与实验性近视相关的因素，对其潜在的细胞和分子机制知之甚少 正视化和近视发展的控制机制。 这个多PI联盟的赠款汇集了经验丰富的研究人员和他们建立的实验非 具有国际公认的眼基因组学的正视化和近视的人类灵长类动物模型 研究中心对出生后的视网膜、RPE、脉络膜和巩膜生物学进行重大调查 眼生长与近视发展。本项目研究功能基因组学和基因-环境。 灵长类眼睛屈光发育中的相互作用，并将确定参与 利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。这个 调查人员将使用已建立的生物信息学方法确定和确认关键的 正视化与近视发展的调控途径。这些研究将直接提供 视觉调节眼睛生长和近视机制的证据和更完整的理解 并将提供迄今为止最大和最全面的细胞和分子靶标共享资源 帮助开发控制眼睛生长和管理屈光不正的新疗法。 这项调查符合NEI近视研究的四个目标中的三个：调查生化 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。