Mechanisms of axial elongation in myopia

在过去的30年里，近视的流行率迅速上升，在许多国家成为流行病。 由于眼轴过长，眼睛的焦面落在视网膜前面，就会发生近视。高 近视增加了多种威胁视力的眼部疾病的风险。开发阻止近视的干预措施 是一个重要的未得到满足的公共卫生需求，因为我们对关键分子信号的了解不足 近视发生中的S通路。 众所周知，屈光性眼睛的生长是由刺激局部视网膜信号的视觉输入来调节的 并导致巩膜细胞外基质(ECM)重塑，这是眼轴伸长的必经步骤。尽管有几个 已知的分子参与近视信号，这里的重点是全反式维甲酸(AtRA)。 由于：1)它在巩膜重塑中的双向作用，2)初步数据显示，当atRA水平 在小鼠的眼组织中，近视的形成和巩膜ECM的重塑，以及3)我们的能力 测量相关眼组织中的atRA，以获得atRA在哺乳动物近视发生中的作用的新见解。 总体目标是开发创新的方法来确定atRA在近视中的作用，重点是 对基底层的时间和区域影响。该提案将使用直接的实验和工程方法。 建模工具，以评估近视信号分子，特别是atRA，如何横切脉络膜，从而 验证atRA作为近视眼巩膜ECM重塑的“主调制器”的假设。 为了检验这一假说，我们提出了三个目标。首先，小鼠体内的atRA水平将通过实验方式进行调节 单独提供或联合提供：(I)单眼形觉剥夺(FD，一种近视刺激)；(Ii)口服型RA；或 (Iii)口服全反式维甲酸合成抑制剂。关键的近视相关结果将在一段时间内进行测量。我们 预测外源性atRA会导致近视、脉络膜变薄和巩膜重塑，类似于FD，而 抑制atRA的产生将减弱FD的近视效应。第二，视网膜中atRA的水平， RPE/脉络膜和巩膜将随着时间的推移使用质谱仪进行测量，以及数量和分布 全反式维甲酸受体的β将被测定。我们预测随着时间的推移，atRA在关键眼部的浓度 组织将与其他近视相关的结果相关。第三，巩膜的运输特性 近视重塑信号将通过工程传质模型来建立，以确定 信号分子通过眼层的运输，从而识别分子特征 (大小、费用等)影响近视信号分子在RPE、脉络膜和巩膜的运输。 由于在近视生物学/生理学、动物模型、 生物力学和建模，以及维甲酸生化，这个项目有可能阐明atRA的作用 近视发生中的信号传递。此外，这项研究将确定通过干预治疗近视的可行性。 全反式维甲酸介导的巩膜ECM重塑，翻译上可行的方法。

The prevalence of myopia has rapidly increased over the last 30 years, becoming epidemic in many countries. Myopia occurs when the eye’s focal plane falls in front of the retina due to excessive ocular axial length. High myopia increases the risk for multiple sight-threatening ocular conditions. Developing interventions to halt myopia is an important unmet public health need hampered by our poor understanding of the key molecular signaling pathway(s) in myopigenesis. It is well-established that refractive eye growth is modulated by visual input which stimulates local retinal signaling and leads to scleral extracellular matrix (ECM) remodeling, an obligate step in axial elongation. Although several molecules are known to participate in myopigenic signaling, here the focus is on all-trans retinoic acid (atRA) due to: 1) its bidirectional role in scleral remodeling, 2) preliminary data showing that when atRA levels are modulated in ocular tissues in the mouse, myopia develops and the scleral ECM remodels, and 3) our ability to measure atRA in relevant ocular tissues to gain novel insights into the role of atRA in myopigenesis in mammals. The overall objective is to develop innovative approaches to determine the role of atRA in myopia, focusing on temporal and regional effects on the fundal layers. The proposal will use direct experiments and engineering modeling tools to assess how myopigenic signaling molecules, specifically atRA, transverse the choroid, thereby testing the hypothesis that atRA acts as a “master modulator” of scleral ECM remodeling in myopia. To test this hypothesis 3 aims are proposed. First, atRA levels in mice will be experimentally modulated by delivering, singly or in combination: (i) monocular form deprivation (FD, a myopigenic stimulus); (ii) oral atRA; or (iii) an oral inhibitor of atRA synthesis. Key myopia-associated outcomes will then be measured across time. We predict that exogenous atRA will induce myopia, choroidal thinning and scleral remodeling, similar to FD, while inhibition of atRA production will attenuate the myopigenic effects of FD. Second, atRA levels in retina, RPE/choroid, and sclera will be measured over time using mass spectrometry, and the amount and distribution of the atRA receptor RARβ will be determined. We predict that atRA concentrations over time in key ocular tissues will correlate with other myopia-associated outcomes. Third, transport characteristics for scleral remodeling signals in myopia will be established by using engineering mass transfer modeling to determine transport of signaling molecules through the ocular layers, thereby identifying how molecular characteristics (size, charge, etc.) affect transport of myopigenic signaling molecules across the RPE, choroid and sclera. Thanks to the combined expertise of a team with unique expertise in myopia biology/physiology, animal models, biomechanics and modeling, and retinoid biochemistry, this project has the potential to elucidate the role of atRA signaling in myopigenesis. Further, this study will determine the feasibility of treating myopia by intervening in atRA-mediated scleral ECM remodeling, a translationally feasible approach.