UC Berkeley

Myopia (near-sightedness) is one of the most common ocular disorders in humans. Due to the dramatic increases in prevalence of myopia worldwide, especially in children and young adults, myopia has also become a significant public health problem, both socially and economically. While the prevalence and severity of myopia continue to increase, effective therapeutic interventions for myopia remain limited. Currently, management of myopia is largely limited to traditional optical corrections - spectacles, contact lenses, and refractive surgery - which correct distance vision but have no effect on myopia progression. While slowed myopia progression has been reported in clinical studies using the contact lens-based, corneal reshaping therapy and atropine, a pharmaceutical agent, these approaches come with limitations and in the latter case, significant ocular side-effects. Uncontrolled progression may lead to high "degenerative" myopia, for which posterior scleral reinforcement surgery remains the only treatment option and a last resort directed at preserving vision. Thus there is a clear need for new myopia control treatments. Understanding more about the molecular and cellular mechanisms underlying myopic eye growth has the potential to uncover novel treatment options.

This dissertation presents results from three investigations into the role of the retinal pigment epithelium (RPE) in eye growth regulation, focusing on molecular and cellular mechanisms, and using both in vivo animal models and in vitro cell culture models. In the first in vivo study (Chapter 2), we investigated expression of candidate genes in chick RPE of imposing short-term optical defocus. Specifically, gene expression levels of the three bone morphogenetic proteins (BMP-2, 4 & 7) were examined after 2 and 48 h of treatment, with negative and positive lenses used to impose defocus of opposite sign. These growth factors were observed to be differentially and bidirectionally expressed in RPE, expression generally increasing with imposed myopia, which is associated with ocular growth inhibition. Because eyes had little chance to change their dimensions with such short-term lens treatments, these genes are assumed to play important roles in the onset and early phase of defocus-induced ocular growth changes. For this reason, these genes represent potential targets for molecular-based myopia treatments. In the second study (Chapter 3), high-through gene expression profiling was employed to examine changes in gene expression in chick RPE with long-term imposed hyperopic defocus, which resulted in eyes being longer than normal and highly myopic. This DNA microarray screening revealed changes in the expression of many genes, including BMPs, noggin (NOG), dopamine receptor D4 (DRD4), retinoic acid receptor, beta (RARB), and retinal pigment epithelium-derived rhodopsin homolog (RRH). Some of these genes showed increased expression while others showed decreased expression. It is plausible that some may be linked the ocular pathological complications seen in myopia, while others may be linked to ocular growth regulation, the imposed visual conditions resulting in sustained, increased ocular growth. The third and final study (Chapter 4), addressed the possibility of an RPE site for the anti-myopia action of apomorphine (APO), a dopamine receptor agonist, observed in animal studies. We further investigated the possibility that TGF-â secretion from RPE mediates this inhibitory growth effect. APO applied to cultured human fetal RPE cells was found to alter the secretion of both TGFâ1 and TGFâ2, which was biased towards the basal (choroidal) side. These growth factors also exhibited constitutive polarized secretion, albeit biased in the opposite direction to APO-induced paracrine secretion. The results for APO are consistent with its observed inhibitory (anti-myopia) effects in vivo and offer the RPE as a possible site of action.

In summary, the research reported in this dissertation provides evidence that RPE plays an important role in postnatal eye growth regulation, (including myopic growth), as a conduit for relaying growth modulatory retinal signals to choroid/sclera. Genes and molecules identified in these studies offer potential directions for novel anti-myopia treatments, with the RPE being a potential target for the same.