Mechanisms of axial elongation in myopia

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The prevalence of myopia has rapidly increased over the last 30 years, becoming epidemic in many countries. Myopia occurs when the eye’s focal plane falls in front of the retina due to excessive ocular axial length. High myopia increases the risk for multiple sight-threatening ocular conditions. Developing interventions to halt myopia is an important unmet public health need hampered by our poor understanding of the key molecular signaling pathway(s) in myopigenesis. It is well-established that refractive eye growth is modulated by visual input which stimulates local retinal signaling and leads to scleral extracellular matrix (ECM) remodeling, an obligate step in axial elongation. Although several molecules are known to participate in myopigenic signaling, here the focus is on all-trans retinoic acid (atRA) due to: 1) its bidirectional role in scleral remodeling, 2) preliminary data showing that when atRA levels are modulated in ocular tissues in the mouse, myopia develops and the scleral ECM remodels, and 3) our ability to measure atRA in relevant ocular tissues to gain novel insights into the role of atRA in myopigenesis in mammals. The overall objective is to develop innovative approaches to determine the role of atRA in myopia, focusing on temporal and regional effects on the fundal layers. The proposal will use direct experiments and engineering modeling tools to assess how myopigenic signaling molecules, specifically atRA, transverse the choroid, thereby testing the hypothesis that atRA acts as a “master modulator” of scleral ECM remodeling in myopia. To test this hypothesis 3 aims are proposed. First, atRA levels in mice will be experimentally modulated by delivering, singly or in combination: (i) monocular form deprivation (FD, a myopigenic stimulus); (ii) oral atRA; or (iii) an oral inhibitor of atRA synthesis. Key myopia-associated outcomes will then be measured across time. We predict that exogenous atRA will induce myopia, choroidal thinning and scleral remodeling, similar to FD, while inhibition of atRA production will attenuate the myopigenic effects of FD. Second, atRA levels in retina, RPE/choroid, and sclera will be measured over time using mass spectrometry, and the amount and distribution of the atRA receptor RARβ will be determined. We predict that atRA concentrations over time in key ocular tissues will correlate with other myopia-associated outcomes. Third, transport characteristics for scleral remodeling signals in myopia will be established by using engineering mass transfer modeling to determine transport of signaling molecules through the ocular layers, thereby identifying how molecular characteristics (size, charge, etc.) affect transport of myopigenic signaling molecules across the RPE, choroid and sclera. Thanks to the combined expertise of a team with unique expertise in myopia biology/physiology, animal models, biomechanics and modeling, and retinoid biochemistry, this project has the potential to elucidate the role of atRA signaling in myopigenesis. Further, this study will determine the feasibility of treating myopia by intervening in atRA-mediated scleral ECM remodeling, a translationally feasible approach.