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

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 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.