Saturday, March 15, 2025
3/15/2025
Project Summary/Abstract The prevalence of myopia in the U.S. population and globally is constantly growing, increasing the risk for associated blinding diseases such as glaucoma and retinal detachment. Evidence from animal studies indicates that locally modulated biomechanical weakening of the sclera underlies accelerated scleral remodeling and axial elongation in myopia. Our goal is to elucidate the mechanisms that control scleral remodeling and evaluate their potential to control all forms of myopia. Our central hypothesis is that scleral remodeling in myopia is controlled by two interacting mechanisms: (i) vision-guided, aggrecan-mediated scleral weakening that promotes collagen sliding, and (ii) natural collagen crosslinking that accumulates with age and limits the biomechanical effects of the first mechanism. We will use our close-to-primate animal model, the tree shrew, and innovative tools to decipher the interacting mechanism between aggrecan and crosslinking in myopia, hyperopia, and aging. In the previous project period, we have shown that artificial crosslinking using genipin can effectively strengthen the biomechanical weakened sclera and slow myopia progression but may cause adverse effects. We will evaluate a new, safer mechanism to induce crosslinking using copper salt, which increases lysyl oxidase activity and accelerates natural crosslinking. Recent findings suggest that peripheral retinal signals play a key role in myopia, but how these signals lead to local scleral changes remains unknown due to missing biomarkers. We will establish two locally sensitive biomarkers of scleral weakening: direct measurements of micro-scale collagen fiber crimp using polarized light microscopy and point-by-point tissue-scale stiffness measurements using nanoindentation. These biomarkers will allow us to (i) gain fundamental understanding of the spatial distribution of biomechanical weakening in myopia and (ii) verify effective biomechanical treatment with our new crosslinking approach across the entire sclera. This mechanism discovery grant will provide fundamental insight into the multi-scale mechanisms that control scleral biomechanics and remodeling; the role of aggrecan in myopia; the interactions between collagen crosslinking, aging, and aggrecan; establish local biomarkers of biomechanical weakening; and evaluate lysyl oxidase activity and aggrecan as potential new treatment targets.
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