Scleral Remodeling in Myopia

项目总结/摘要 近视在美国人口和全球范围内的患病率不断增长，增加了近视的风险。 相关的致盲性疾病，如青光眼和视网膜脱离。来自动物研究的证据 表明巩膜的局部调节的生物力学弱化是加速的巩膜收缩的基础。 近视眼的眼轴延长和眼轴重塑。我们的目标是阐明控制巩膜的机制， 重塑和评估他们的潜力，以控制各种形式的近视。我们的中心假设是巩膜 近视中的重塑由两种相互作用的机制控制：（i）视觉引导的、聚集蛋白聚糖介导的巩膜 促进胶原滑动的弱化，和（ii）随着年龄积累的天然胶原交联， 限制了第一种机制的生物力学效应。我们将使用我们的接近灵长类动物的模型，树 和创新的工具，以破译聚集蛋白聚糖和交联之间的相互作用机制， 近视、远视和衰老。在前一个项目期间，我们已经表明，人工交联使用 京尼平可以有效地加强生物力学减弱的巩膜，减缓近视进展，但可能 造成不良影响。我们将评估一种新的、更安全的机制来使用铜盐诱导交联， 其增加赖氨酰氧化酶活性并加速自然交联。最近的研究结果表明， 周边视网膜信号在近视中起着关键作用，但这些信号如何导致局部巩膜变化仍然存在 由于缺少生物标志物而未知。我们将建立两种巩膜弱化的局部敏感生物标志物： 使用偏振光显微镜和逐点直接测量微尺度胶原纤维卷曲 使用纳米压痕的组织尺度刚度测量。这些生物标志物将使我们能够（i）获得 基本了解近视生物力学减弱的空间分布，以及（ii）验证 我们的新的交联方法在整个巩膜有效的生物力学治疗。这 机制发现赠款将提供基本的洞察多尺度机制，控制 巩膜生物力学和重塑;聚集蛋白聚糖在近视中的作用;胶原蛋白之间的相互作用 交联、老化和聚集蛋白聚糖;建立生物力学弱化的局部生物标志物;并评估赖氨酰 氧化酶活性和聚集蛋白聚糖作为潜在的新治疗靶点。

Project Summary/Abstract The prevalence of myopia in the U.S. population and globally is constantly growing, increasing the risk for associated blinding diseases such as glaucoma and retinal detachment. Evidence from animal studies indicates that locally modulated biomechanical weakening of the sclera underlies accelerated scleral remodeling and axial elongation in myopia. Our goal is to elucidate the mechanisms that control scleral remodeling and evaluate their potential to control all forms of myopia. Our central hypothesis is that scleral remodeling in myopia is controlled by two interacting mechanisms: (i) vision-guided, aggrecan-mediated scleral weakening that promotes collagen sliding, and (ii) natural collagen crosslinking that accumulates with age and limits the biomechanical effects of the first mechanism. We will use our close-to-primate animal model, the tree shrew, and innovative tools to decipher the interacting mechanism between aggrecan and crosslinking in myopia, hyperopia, and aging. In the previous project period, we have shown that artificial crosslinking using genipin can effectively strengthen the biomechanical weakened sclera and slow myopia progression but may cause adverse effects. We will evaluate a new, safer mechanism to induce crosslinking using copper salt, which increases lysyl oxidase activity and accelerates natural crosslinking. Recent findings suggest that peripheral retinal signals play a key role in myopia, but how these signals lead to local scleral changes remains unknown due to missing biomarkers. We will establish two locally sensitive biomarkers of scleral weakening: direct measurements of micro-scale collagen fiber crimp using polarized light microscopy and point-by-point tissue-scale stiffness measurements using nanoindentation. These biomarkers will allow us to (i) gain fundamental understanding of the spatial distribution of biomechanical weakening in myopia and (ii) verify effective biomechanical treatment with our new crosslinking approach across the entire sclera. This mechanism discovery grant will provide fundamental insight into the multi-scale mechanisms that control scleral biomechanics and remodeling; the role of aggrecan in myopia; the interactions between collagen crosslinking, aging, and aggrecan; establish local biomarkers of biomechanical weakening; and evaluate lysyl oxidase activity and aggrecan as potential new treatment targets.