Mechanisms of axial elongation in myopia

近视眼轴伸长的机制

• 批准号: 10344059
• 负责人: C ROSS ETHIER
• 金额: $ 59.88万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10344059
• 关键词: Abbreviations; Affect; Angiography; Animal Model; Attenuated; Biochemistry; Biology; Biomechanics; Blood; Blood flow; Characteristics; Charge; Choroid; 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; 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; biomechanical model; biophysical properties; deprivation; experimental study; falls; inhibitor; innovation; insight; monocular; mouse model; novel; outcome prediction; 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.

近视的患病率在过去30年中迅速增加，在许多国家成为流行病。 当眼睛的焦平面福尔斯由于眼轴长度过长而落在视网膜前面时发生近视。高 近视增加了多种威胁视力的眼部病症的风险。开发干预措施以阻止近视 是一个重要的未满足的公共卫生需求，由于我们对关键分子信号的理解不足， 在近视形成中的通路。 众所周知，屈光性眼睛生长是由刺激局部视网膜信号的视觉输入调节的 并导致巩膜细胞外基质（ECM）重塑，这是眼轴伸长中的一个必要步骤。尽管几 已知分子参与近视信号传导，此处重点关注全反式维甲酸（atRA） 由于：1）其在巩膜重塑中的双向作用，2）初步数据显示当atRA水平为 在小鼠的眼组织中调节，近视发展和巩膜ECM重塑，和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，如何横贯脉络膜，从而 检验atRA作为近视中巩膜ECM重塑的“主调节剂”的假设。 为了验证这一假设，提出了3个目标。首先，小鼠中的atRA水平将通过以下方法进行实验性调节： 单独或组合地递送：（i）单眼形觉剥夺（FD，近视刺激）;（ii）口服atRA;或 (iii)一种atRA合成的口服抑制剂。然后将随时间测量与近视相关的关键结局。我们 预测外源性atRA将导致近视、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的近视形成作用。第二，视网膜中的atRA水平， 将使用质谱法随时间测量RPE/脉络膜和巩膜，并且测量RPE/脉络膜和巩膜的量和分布。 将测定atRA受体RARβ的含量。我们预测，随着时间的推移，atRA浓度在关键眼 组织将与其他近视相关的结果相关。第三，巩膜的输送特性 近视眼的重塑信号将通过使用工程传质模型来建立，以确定 信号分子通过眼层的运输，从而确定分子特征如何 (size、收费等）影响致近视信号分子穿过RPE、脉络膜和巩膜的运输。 感谢一个在近视生物学/生理学，动物模型， 生物力学和建模，以及维甲酸生物化学，该项目有可能阐明atRA的作用 在近视形成中的信号传导。此外，这项研究将确定通过干预近视的可行性。 atRA介导的巩膜ECM重塑，预防上可行的方法。