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 the effector molecules that mediate scleral remodeling as they may facilitate the design of therapies to slow or prevent the progression of myopia. Evidence is accumulating to suggest that all-trans-retinoic acid (atRA) is an important molecular signal for the control of postnatal ocular growth. Our recent work indicates that atRA is regulated by choroidal expression of retinaldehyde dehydrogenase 2 (RALDH2) and transported to the sclera by the HDL-associated protein, apolipoprotein A-1 (ApoA-1). The identity of the choroidal cell type(s) responsible for RALDH2 and ApoA-1 synthesis is currently unknown. Furthermore the role of ApoA-1 in the regulation of atRA activity and transport in the eye remains to be elucidated. Most importantly, a direct connection between choroidal atRA, scleral remodeling and eye growth in vivo has yet to be established. Therefore, the objective of the current proposal is to define the key events that regulate choroidal atRA synthesis, transport and activity in scleral remodeling during visually guided ocular growth. The central hypothesis of this proposal is that choroidal atRA concentrations, regulated by the activity of RALDH2, effect changes in scleral ECM remodeling and thereby control the rate of ocular elongation. Based on this hypothesis, we predict that modulation of choroidal RALDH2 activity will directly affect ocular elongation. We propose to test our central hypothesis and accomplish the objective of this application by pursuing the following three specific aims: 1) Identify the atRA synthesizing cells in the choroid; 2) Elucidate the role of ApoA-1 in retinoid transport for the regulation of ocular growth; and 3) Assess the effects of pharmacologic inhibition of RALDH activity on eye growth. The work proposed in aims 1 and 2 is anticipated to describe a previously uncharacterized cell population(s) responsible for atRA synthesis, and will elucidate a new mechanism of extracellular atRA transport. These results will be applied to the development of new strategies for in vivo modulation of choroidal atRA synthesis (Aim 3). The approach is innovative, because it takes advantage of the latest technologies available in imaging, transcriptome analyses and proteomics to define the ?final common pathway? in the retinal-to-scleral chemical cascade that regulates postnatal, visually guided ocular growth. The proposed research is significant because it will provide a broader understanding of the regulation of atRA synthesis, transport and activity, that will likely be relevant to other organ systems under normal and disease conditions. Moreover, the identification of atRA and RALDH2 as visually modulated ocular growth regulators has high potential for development of 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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