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.
The proposed research is relevant to public health because the identification of intraocular growth regulators of scleral remodeling will provide new therapeutic targets in the choroid and/or sclera for the treatment and prevention of ocular growth disorders. Thus the proposed research is relevant to the part of NEI's mission to obtain fundamental understanding on the development and prevention or treatment of myopia.
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