Identifying the Role of RALDH2 Mediated Retinoic Acid Synthesis in Visually Guided Eye Growth

 描述(申请人提供)：正视化是一个视觉依赖的过程，它协调眼睛的生长，使眼轴长度将视网膜与焦平面对齐，从而提供清晰的、未矫正的视力。对于人类来说，这一过程远非完美，可能会导致眼睛轴向异常延长，导致近视或近视的发展。视觉引导的眼睛生长所涉及的化学信号和机制在很大程度上仍不清楚。基于对鸡和灵长类动物模型的研究，脉络膜全反式维甲酸(AtRA)和视黄醛脱氢酶(RALDH)被认为在调节视觉引导的眼睛生长的脉络膜到巩膜的化学级联中发挥重要作用。因此，本项目的目的是确定脉络膜的作用 ATRA和RALDH2在调节视觉引导的眼睛生长中的作用，以及开始揭示这些分子促进这一过程的机制。该项目的总体假设是，在视觉引导的眼睛生长期间，RA在脉络膜中产生的RALDH2调节巩膜ECM重塑。这一假设将通过追求以下具体目标来验证：1)确定脉络膜生成的RA的眼靶。在这个目标中，创新的体外成像和生化方法将被用来确定脉络膜atRA在视觉引导的眼睛生长过程中是否移动到其他眼组织。2)确定脉络膜中调节atRA合成的RALDH亚型(S)。在这一目标中，脉络膜RALDH 1、2和3的水平将被特别耗尽，并测量由此产生的对脉络膜atRA合成的影响。3)体内检测RALDH抑制对眼生长和屈光状态的影响。在这个目标中，基于结构的药物设计将被用来开发一种针对RALDH酶的特异性抑制剂。该抑制剂将用于体内模型，以测试RALDH抑制对眼生长的生化和物理影响。国际和平协会和她的赞助人乔迪·萨默斯博士组建了一支共同赞助者团队和一名合作者，他们拥有成功实现这些目标所需的工具和经验。该项目的完成将阐明脉络膜atRA和RALDH在视觉引导的眼睛生长中的作用，并可能导致这些分子作为治疗近视的潜在靶点的开发。

 DESCRIPTION (provided by applicant): Emmetropization is a vision-dependent process that coordinates the growth of the eye such that the ocular axial length will align the retina with the focal plane to give clear, uncorrected vision. In humans, this process is far from perfect and can result in abnormal axial elongation of the eye, resulting in the development of myopia or nearsightedness. The chemical signals and mechanisms involved in visually guided eye growth remain largely unknown. Based on research in animal models, such as the chick and primate, choroidal all-trans-retinoic acid (atRA) and retinaldehyde dehydrogenase (RALDH) have been implicated as playing a major role in the choroidal to scleral chemical cascade that modulates visually guided eye growth. Thus, the purpose of this project is to determine the role of choroidal atRA and RALDH2 in mediating visually guided eye growth, as well as to begin to uncover the mechanism by which these molecules facilitate this process. The overall hypothesis for this project is that RALDH2 generated at RA in the choroid regulates scleral ECM remodeling during periods of visually guided eye growth. This hypothesis will be tested by pursuing the following specific aims: 1) determine the ocular target for choroidally generated atRA. In this aim, innovative ex-vivo imaging and biochemical approaches will be used to determine if choroidal atRA moves to other ocular tissues during visually guided eye growth. 2) Identify the RALDH isoform(s) that regulates atRA synthesis in the choroid. In this aim, choroidal levels of RALDH 1, 2, and 3 will be specifically depleted and the resulting effect on choroidal atRA synthesis measured. 3) Determine the effect of RALDH inhibition on ocular growth and refraction in vivo. In this aim, structure based drug design will be used to develop an inhibitor specific to the RALDH enzymes. This inhibitor will be used in an in vivo model to test the biochemical and physical effects of RALDH inhibition on ocular growth. The PI and her sponsor, Dr. Jody Summers, have assembled a team of co-sponsors and a collaborator that have the necessary tools and experience for the successful achievement of these aims. Completion of this project will shed light on the role of choroidal atRA and RALDH in visually guided eye growth and could lead to the development of these molecules as potential targets for the treatment of myopia.