Mechanisms of axial elongation in myopia

近视眼轴伸长的机制

• 批准号: 10844969
• 负责人: C ROSS ETHIER
• 金额: $ 59.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10844969
• 关键词: Abbreviations; Affect; Angiography; Animal Model; Attenuated; Biochemistry; Biology; Biomechanics; Blood; Blood flow; Characteristics; Charge; Choroid; Communication; Complex; Country; Coupled; Data; Development; Dimensions; Engineering; Enzymes; Epidemic; Extracellular Matrix; Eye; Foundations; Future; Glaucoma; Glossary; Growth; Incidence; Intervention; Knowledge; Length; Mammals; Mass Spectrum Analysis; Measurement; Measures; Mediating; Modeling; Molecular; Movement; Mus; Myopia; Nature; Optics; Oral; Outcome; Pathway interactions; Perfusion; Physiology; Prevalence; Production; Property; Public Health; Refractive Errors; Refractometry; Reporter; Retina; Retinal Detachment; Retinal Diseases; Retinoic Acid Receptor; Retinoids; Risk; Risk Factors; Role; Sclera; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Techniques; Testing; Thick; Thinness; Time; Tissue Harvesting; Tissues; Tretinoin; Vision; Visual; biophysical properties; deprivation; experimental study; falls; inhibitor; innovation; insight; monocular; mouse model; novel; outcome prediction; temporal measurement; theories; time use; tool

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.

过去30年来，近视患病率迅速上升，在许多国家成为流行病。 当眼睛的焦平面由于眼轴过长而落在视网膜前面时，就会发生近视。高的 近视会增加多种威胁视力的眼部疾病的风险。制定干预措施来阻止近视 由于我们对关键分子信号传导知之甚少，这一重要的未满足的公共卫生需求受到阻碍 近视发生的途径。 众所周知，眼睛的屈光生长是通过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，这是轴向伸长的必然步骤。虽然有几个 已知分子参与近视信号传导，这里重点关注全反式视黄酸 (atRA) 由于：1) 它在巩膜重塑中的双向作用，2) 初步数据表明，当 atRA 水平为 在小鼠眼组织中受到调节，近视发生，巩膜 ECM 重塑，3）我们的能力 测量相关眼组织中的 atRA，以获得对 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。该提案将使用直接实验和工程 建模工具来评估近视信号分子（特别是 atRA）如何横穿脉络膜，从而 检验 atRA 作为近视巩膜 ECM 重塑“主调节器”的假设。 为了检验这一假设，提出了 3 个目标。首先，小鼠中的 atRA 水平将通过实验调节 单独或组合地提供：（i）单眼形式剥夺（FD，近视刺激）； (ii) 口服 atRA；或者 (iii) atRA合成的口服抑制剂。然后将随着时间的推移测量与近视相关的关键结果。我们 预测外源性 atRA 会诱发近视、脉络膜变薄和巩膜重塑，与 FD 类似，而 抑制 atRA 的产生将减弱 FD 的近视作用。其次，视网膜中的 atRA 水平， 随着时间的推移，将使用质谱法测量 RPE/脉络膜和巩膜，以及其数量和分布 atRA 受体 RARβ 的活性将被确定。我们预测 atRA 浓度随着时间的推移在关键眼部 组织将与其他近视相关的结果相关。三、巩膜运输特点 近视重塑信号将通过使用工程传质模型来确定 信号分子通过眼层的运输，从而识别分子特征如何 （大小、电荷等）影响近视信号分子穿过 RPE、脉络膜和巩膜的运输。 得益于在近视生物学/生理学、动物模型方面拥有独特专业知识的团队的综合专业知识， 生物力学和建模以及类维生素A生物化学，该项目有可能阐明 atRA 的作用 近视发生中的信号传导。此外，这项研究将确定通过干预来治疗近视的可行性 atRA 介导的巩膜 ECM 重塑，一种转化可行的方法。