Regulation of Scleral Growth and Remodeling in Myopia

近视眼巩膜生长和重塑的调节

基本信息

批准号：
8514614
负责人：
Jody A Summers
金额：
$ 31.64万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-01-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8514614
关键词：
Age of Onset Animal Model Binding Proteins Biological Models Chemicals Childhood Choroid Communities Data Development Enzymes Event Extracellular Matrix Eye Gene Delivery Goals Growth Growth Disorders Knowledge Lead Mediating Metabolism Mission Molecular Molecular Genetics Myopia Pharmacologic Substance Prevalence Prevention Proteins Proteoglycan Public Health Publishing Regulation Research Retina Retinal Retinoic Acid Receptor Retinoids Sclera Signal Transduction Stromal Cells Systems Development Testing Tretinoin Work base biological systems cellular targeting effective therapy emmetropization genetic regulatory protein in vivo in vivo Model innovation new therapeutic target novel therapeutics postnatal receptor receptor expression receptor function response retinaldehyde dehydrogenase retinoic acid 4-hydroxylase therapeutic target tool treatment strategy visual stimulus

项目摘要

DESCRIPTION (provided by applicant): Myopia is a significant global public health concern. Despite continued research on the regulation of eye size and refraction, no therapeutic targets have been identified and no pharmaceutical or optometric approaches have proven effective in the majority of cases. The increasing prevalence of myopia and earlier age of onset emphasize the need for the identification of pharmaceutical targets for the development of an effective therapy. Therefore, the long-term goal is to identify intraocular regulators of scleral growth for the treatment and prevention of ocular growth disorders. Studies using several animal models demonstrate changes in choroidal synthesis of all-trans-retinoic acid (atRA) in response to visual stimuli. However, virtually nothing is known about the cellular and molecular events responsible for the regulation of atRA activity in the choroid and sclera. Therefore, the objective of this application is to identify the proteins in the choroid and sclera that regulate the synthess and activity of atRA during visually-guided ocular growth. Preliminary results indicate that a unique subpopulation of choroid stromal cells mediate changes in atRA synthesis in response to visual stimuli via the atRA synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2). Moreover, atRA concentrations generated by the choroid are sufficient to modulate scleral proteoglycan synthesis to levels known to cause in changes in the rate of ocular growth and refraction. Therefore, the central hypothesis of this proposal is that local concentrations of atRA are generated in the choroid to regulate local changes in scleral matrix remodeling and thereby control the rate of ocular elongation. Based on this hypothesis, we predict that manipulation of endogenous concentrations of atRA within the choroid will alter postnatal ocular growth. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims:1) Identify choroidal proteins that regulate the synthesis of atRA during visually-guided ocular growth; 2) Identify the cellular target of choriodal atRA during visually guided ocular growth; and 3) Assess the effects of local retinoid signaling on the modulation of eye growth in vivo. Results from aims 1 and 2 will identify the proteins that regulate the synthesis and action of atRA in the choroid and sclera. These results will be applied to the development of our in vivo model proposed in Aim 3 and are anticipated to demonstrate that in vivo modulation of choroidal atRA synthesis directly effects ocular growth and refraction. The approach is innovative, because it takes advantage of recently developed tools for gene delivery to manipulate expression of atRA-regulatory proteins in a genetically tractable chick model system. The development of this system will enable functional studies to identify the molecular mechanisms that underpin emmetropization and visually guided ocular growth. The proposed research is significant because it will provide a broader understanding of atRA metabolism in a completely uncharacterized biological system. Ultimately, such knowledge will provide multiple avenues for the development of new, specifically targeted pharmacologic strategies for the treatment of myopia.

描述（由申请人提供）：近视是一个重大的全球公共卫生问题。尽管对眼睛大小和屈光调节的研究仍在继续，但尚未确定治疗靶点，也没有药物或验光方法被证明在大多数情况下有效。近视患病率的增加和发病年龄的提早强调需要确定药物靶点以开发有效的治疗方法。因此，长期目标是确定巩膜生长的眼内调节剂，以治疗和预防眼部生长障碍。使用多种动物模型的研究表明，脉络膜合成全反式视黄酸 (atRA) 会因视觉刺激而发生变化。然而，对于脉络膜和巩膜中 atRA 活性调节的细胞和分子事件几乎一无所知。因此，目标该应用的目的是鉴定脉络膜和巩膜中在视觉引导眼睛生长过程中调节 atRA 合成和活性的蛋白质。初步结果表明，脉络膜基质细胞的独特亚群通过 atRA 合成酶视黄醛脱氢酶 2 (RALDH2) 介导 atRA 合成的变化，以响应视觉刺激。此外，脉络膜产生的atRA浓度足以将巩膜蛋白多糖合成调节至已知导致眼睛生长和屈光率变化的水平。因此，该提案的中心假设是 atRA 的局部浓度脉络膜中产生调节巩膜基质重塑的局部变化，从而控制眼伸长率。基于这一假设，我们预测控制脉络膜内 atRA 的内源浓度将改变出生后眼睛的生长。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标进行检验：1）识别在视觉引导的眼睛生长过程中调节 atRA 合成的脉络膜蛋白； 2）在视觉引导眼睛生长过程中识别脉络膜atRA的细胞靶点；和 3) 评估局部类视黄醇信号传导对体内眼睛生长调节的影响。目标 1 和 2 的结果将鉴定调节脉络膜和巩膜中 atRA 的合成和作用的蛋白质。这些结果将应用于我们在目标 3 中提出的体内模型的开发，并有望证明脉络膜 atRA 合成的体内调节直接影响眼睛的生长和屈光。该方法具有创新性，因为它利用最近开发的基因传递工具来操纵遗传易处理的雏鸡模型系统中 atRA 调节蛋白的表达。该系统的开发将使功能研究能够确定支持正视化和视觉引导眼睛生长的分子机制。拟议的研究意义重大，因为它将提供对完全未知的生物系统中 atRA 代谢的更广泛的了解。最终，这些知识将为开发新的、有针对性的治疗近视的药理学策略提供多种途径。