脉络膜视黄酸信号通路在周边离焦调控豚鼠巩膜重塑中的机制研究

Myopia control in juveniles is an urgent task, while the mechanism underlying the effect of orthokeratology on retardation of myopia progression is not clear. This project is aimed at investigating the choroidal retinoic acid signaling pathway underlying the effect of peripheral defocus on scleral remodeling. Established on our previous work that retinal retinoic acid plays an important role in refractive development in young animal models, that orthokeratology changes peripheral defocus, and that retinoic signaling pathway may serve as a mediator between peripheral defocus and refractive development, we achieve our goal by: 1. inducing peripheral retinal defocus with bifocal lenses, and to analyze the dose-effect relationship between peripheral defocus and refractive development in guinea pigs; 2. testing the posterior and mid-peripheral choroidal thickness and regional choroidal retinoic acid concentration, binding protein, and receptors in bifocal lens guinea pig models at different time points, and analyzing their relationships with scleral morphology and refractive development; receptor antagonist is used to consolidate the role of retinoic acid; 3. investigating the influence of different retinoic acid concentration on the morphology and quantity of scleral fibroblast cells and the synthesize rate of scleral glycosaminoglycan in order to find the critical threshold of retinoic acid. This project is anticipated to find the dose-effect relationship between retinal peripheral defocus, scleral remodeling and refractive development, and the underlying molecular mechanism, which will provide theoretical evidence for developing new type of defocus-integrated optical intervention for myopia control.

青少年近视防治刻不容缓，角膜塑形镜有助于减缓近视进展但机理尚未阐明。本课题旨在探讨脉络膜视黄酸信号通路在周边离焦调控巩膜重塑中的作用机制，在前期研究发现视网膜视黄酸在幼年动物屈光发育中扮演重要角色、角膜塑形镜改变视网膜周边离焦、及视黄酸信号通路潜在介导周边离焦对屈光发育调控作用的基础上，拟通过：1.用双焦镜片诱导豚鼠视网膜周边离焦，精确调控离焦程度及比例以建立豚鼠周边离焦模型并分析量-效关系；2.在造模的不同时间点检测双焦镜片豚鼠模型后极部与中周部脉络膜厚度和脉络膜视黄酸、结合蛋白及受体的区域化浓度，分析其与巩膜形态、屈光发育的相关性，并用视黄酸受体抗体反证；3.离体培养豚鼠巩膜成纤维细胞，观察不同浓度视黄酸对巩膜成纤维细胞形态、数量及氨基葡聚糖合成速率的影响，找到关键阈值。本研究预期将获得视网膜周边离焦调控巩膜重塑及屈光发育的量-效及分子信号机制，有望为新型离焦镜片防控近视提供理论依据。

青少年近视防治刻不容缓，角膜塑形镜有效减缓近视进展，但机理尚未阐明。本课题旨在探讨脉络膜视黄酸信号通路在周边离焦调控巩膜重塑中的作用机制，预期获得视网膜周边离焦调控巩膜重塑及屈光发育的量-效关系，有望为新型离焦镜片防控近视提供理论依据。第一部分，我们采用谱域OCT设备中的增强深度成像(PAAA)模式，开发基于深度学习的自动分割算法，准确定位OCT眼底截面图像中的Bruch膜及脉络膜-巩膜交界，进而可以自动计算出各种类型的脉络膜厚度数据。软件通过自动精确测量以感知脉络膜厚度的细微变化，可以为近视风险预测、病理研究、治疗效果评估等提供重要量化指标。第二部分，我们通过以上脉络膜测量方法学，发现屈光参差儿童近视度数较高眼眼轴长度更长、脉络膜厚度更薄、血流密度更低。对近视度数较高眼进行单眼OK镜治疗后屈光参差量减小，双眼眼轴长度差异缩小，配戴OK镜眼脉络膜厚度增加、血流密度增加。在对侧眼变为近视眼之后，亦对其进行OK镜治疗，发现其眼轴增长速度显著减缓，脉络膜厚度增加、血流密度增加。此研究提示OK镜有显著延缓眼轴增长作用，并且这种作用与脉络膜厚度与血流显著相关。第三部分，我们纳入60位眼轴长度快速进展（>0.30mm/年）的受试者。将受试者分为两组，实验组在第一年仅配戴OK镜，第二年加入0.01%阿托品滴眼液每日睡前一次；对照组连续配戴OK镜两年，不使用阿托品。结果发现阿托品的加入使受试者的眼轴增长速率显著减缓，同时脉络膜厚度和血流密度显著增加。此研究提示，对于采用多焦镜片控制近视效果欠佳的受试者，可以用低浓度非选择性M受体阻滞剂阿托品增强控制效果，该作用可能与脉络膜机制相关。