Towards an Understanding of Steroid Hormone Mediated Mechanisms of Myopia Progression: A Scleral Perspective

The eye is an incredibly complex organ, composed of a wide spectrum of tissues. This ranges from the vascular (e.g. choroid) to the extracellular matrix (ECM) rich (e.g. cornea) to the neural (e.g. retina). Working together in concert, these tissues coordinate a wide variety of disparate activities, with exquisite temporal, spatial and functional precision, in order to facilitate vision. Given this high degree of complexity and variability across its components, the eye in many ways approximates the body in miniature. And just like the body at large, ocular tissues utilize the full complement of steroid hormones to facilitate these activities; both in the normal and under pathological conditions.The impact of steroid hormones has been particularly well studied in the context of (1) sexually dimorphic processes and structures and (2) tissue growth and remodeling of ECM rich tissues (e.g. solid tumors and skin), as they appear exquisitely sensitive to steroid hormone signaling to drive their growth. Interestingly, myopia, an ocular pathology that is one the leading drivers of blindness worldwide, is characterized by (1) excessive ECM tissue remodeling of the sclera, leading to scleral thinning and ocular elongation (often, with greatest effect, during childhood and/or adolescence), and (2) its sexually dimorphic character; on the average it presents both more commonly and with greater phenotypic severity in females. Despite these characteristics, the affect and regulation of steroid hormones and their receptors on myopia progression, and with particular emphasis on the sclera, has received sparingly little study. In this dissertation we work to remedy this. Here we explore the changes that occur in steroid hormones and their cognate receptors, both systemically and locally (i.e. at the level of the sclera), as myopia progresses, in a well validated form-deprivation, chicken based model of the pathology. Leveraging a host of biometric (i.e. high frequency a-scan ultrasonography and retinoscopy), biochemical (i.e. western blotting), analytical chemistry (tandem mass spectrometry) and molecular biology (i.e. quantitative real-time polymerase chain reaction) tools we discover a strong associations between glucocorticoid metabolism in the sclera and myopia progression. More explicitly we observe lower scleral levels of the major glucocorticoid species in chicken, corticosterone, concomitant with a drop in transcripts of its biosynthetic enzyme (HSD11β1) and myopia progression, irrespective of sex (chapter 3). We also find several sex-specific disparities including: higher degrees of myopia in female subjects (Chapter 2), differences in the transcriptional expression levels of several sex hormone receptors (Chapter 4) and elevated progesterone levels in female form deprived sclera (Chapter 3). In aggregate our findings argue for a possible role of steroid hormones regulating ocular growth and tissue remodeling during myopia progression, both in manners that are independent from and dependent upon subject’s sex