Myopia (near-sightedness) refers to the ocular condition in which there is a mismatch between the eye's optical power and its length, typically the product of increased scleral remodeling and eye elongation during childhood and/or adolescence, and leading to blurred distance vision. Myopia is associated with increased risk of potentially blinding pathologies, including glaucoma, maculopathies and retinal detachments, with risks increasing with the level of myopia. Myopia is now one of the leading causes of acquired blindness worldwide. Interestingly, a number of epidemiological studies have reported myopia to be more common among females who also show faster progression of the disease, while realizing poorer clinical outcomes. Traditionally, these apparent sex-specific differences have been attributed to behavioral differences, with little supportive scientific evidence. However, associations between myopia and growth spurts and early menarche as well as accelerated progression around puberty have also been reported. The project described here is based on the hypothesis that the observed sex-related bias in myopia reflects, at least in part, sex-specific, endocrine-related influences on the sclera, as has been observed in other connective tissues in the body. The over-riding goal of proposed research is understand the role and related mechanisms for endocrine regulation of scleral and thus eye growth. Unpublished pilot data has confirmed the expression of key class III sex hormone receptors in the sclera of young chicks, which will be used as our myopia model.
Under Aim 1, we will profile scleral sex hormone receptors and related enzymes during development in young normal chicks, age-matched chicks induced to undergo precocious puberty and chicks reaching puberty naturally (validation step). Age-related changes in circulating levels of key sex hormones will also be measured. Experiments will investigate how expression of scleral sex hormone receptors and related enzymes vary, at both the gene and protein levels, with age and the onset of puberty, with sex being an over- riding variable. Local scleral and systemic levels of key ligands and enzymes will also be assessed. Precocious puberty will be induced using systemic tamoxifen. This approach takes into account practical and time constraints of an R21 grant.
Under Aim 2, we will determine how transcriptional and translational levels of sex hormone receptors and enzymes, as well as local scleral sex hormone levels, change during myopia development in tamoxifen-treated compared to normal chicks. In experiments under both Aims, RT-PCR, western blotting and immunohistochemical analyses will be undertaken to examine gene and protein expression and LC-MS/MS used to assess local scleral and systemic levels of key ligands. An improved understanding of the link between sex and myopia prevalence and severity has potentially broad implications related to environmental endocrine disruptors and the timing of school vision screening programs, as well as for the individual patient, customization of clinical intervention strategies for myopia control.
Women are more likely to develop myopia (near-sightedness), exhibit higher levels of myopia and generally realize poorer clinical outcomes compared to men. We will investigate using the chick as an animal model for myopia, the role of sex hormones in ocular growth regulation and myopia, as a potential contributor to these differences. New insights into underlying mechanisms may lead to new therapeutic strategies for myopia, which is projected to affect about 50% of the world's population by 2050.
