Advisors:

Machelle Pardue, Ph.D.

C. Ross Ethier, Ph.D.

Committee Members:

Rafael Grytz, Ph.D.

J. Brandon Dixon, Ph.D.

Wilbur Lam, MD, Ph.D.

An Investigation of Scleral Biomechanics and Myopia in the Mouse

The prevalence of myopia, or ”nearsightedness” is on the rise globally, set to affect about half of the global population by 2050. A myopic eye is characterized by a mismatch between the focal point of incoming light and the position of the photosensitive retina, most commonly due to excessive axial elongation of the eye (axial myopia). Axial myopia is thought to be driven by remodeling of the scleral microstructure and altered biomechanics. Certain types of visual cues drive or protect against myopigenic axial elongation, coupling retinal signaling to scleral remodeling via a complex ”retinoscleral” signaling cascade. However, the key signaling molecules that may propagate retinal signal(s) through the choroid to the sclera are largely unknown. All-trans retinoic acid (atRA) has been suggested to be both capable of trans-choroidal signaling and influencing scleral remodeling of glycosaminoglycans, biomechanically relevant extracellular matrix components known to change rapidly upon presentation of visual cues.

The mouse can be an excellent model organism for causal studies of myopigenesis, yet its small eye makes confirming axial elongation and scleral changes technically challenging. The central hypothesis of this work was that visual cues will lead to scleral remodeling and altered biomechanics comparable to other species. Additionally, we hypothesized that artificially increasing atRA concentration in the eye leads to a myopic phenotype.

To address these hypotheses, we developed a method to quantify the material properties of the mouse sclera using compression testing and a poroelastic material model, permitting the first characterizations of mouse scleral compressive/tensile stiffness and hydraulic permeability. In the mouse model of form-deprivation myopia, we then showed that the extensibility and permeability of the mouse sclera are greatly increased during myopigenesis, even without measurable axial elongation. We then characterized the ocular phenotype of mice treated with atRA, showing that atRA is myopigenic in the mouse and that scleral biomechanics are altered in a manner similar to that seen in visually mediated myopigenesis. These results implicate retinoic acid in the myopigenic retinoscleral signaling cascade and lay the groundwork for future studies of myopigenesis in the mouse.