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

 描述（由申请人提供）：正视化是一种视觉依赖性过程，其协调眼睛的生长，使得眼轴长度将使视网膜与焦平面对齐，以提供清晰的未矫正视力。在人类中，这一过程远非完美，并且可能导致眼睛的异常轴向伸长，从而导致近视或近视的发展。参与视觉引导眼睛生长的化学信号和机制在很大程度上仍然未知。基于动物模型的研究，例如小鸡和灵长类动物，脉络膜全反式视黄酸（atRA）和视黄醇脱氢酶（RALDH）被认为在调节视觉引导的眼睛生长的脉络膜至巩膜化学级联中起主要作用。因此，本项目的目的是确定脉络膜的作用， atRA和RALDH 2在介导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该过程的机制。该项目的总体假设是在视引导的眼睛生长期间，在脉络膜中在RA处产生的RALDH 2调节巩膜ECM重塑。该假设将通过追求以下具体目标来检验：1）确定脉络膜产生的atRA的眼部靶标。在这个目标中，创新的离体成像和生物化学方法将用于确定脉络膜atRA是否在视觉引导的眼睛生长期间移动到其他眼部组织。2)鉴定调节脉络膜中atRA合成的RALDH亚型。为此，将特异性地耗尽RALDH 1、2和3的脉络膜水平，并测量对脉络膜atRA合成的影响。3)测定RALDH抑制对体内眼生长和屈光的影响。在这个目标中，基于结构的药物设计将用于开发对RALDH酶特异性的抑制剂。该抑制剂将用于体内模型中，以测试RALDH抑制对眼生长的生物化学和物理效应。PI和她的赞助商Jody Summers博士组建了一个由共同赞助商和合作者组成的团队，他们拥有成功实现这些目标所需的工具和经验。该项目的完成将揭示脉络膜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发展。

 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.