Elevated intraocular pressure is a major risk factor for glaucoma, and pharmacological reduction of intraocular pressure is the most important therapeutic strategy available for treating glaucoma and preventing progression to blindness. Although there has been recent progress in understanding how tissues of the anterior segment regulate production and outflow of aqueous humor, the processes that determine intraocular pressure, there is at present a poor understanding of these processes at the molecular level. It is likely that detailed knowledge of the molecular mechanisms of aqueous humor regulation in the anterior eye will ultimately offer new and better ways to diagnose and treat glaucoma. Intraocular pressure, like many other important aspects of ocular physiology, is regulated by the circadian system, the hallmark of which is a 24-hour periodicity. This periodicity is generated by an endogenous circadian oscillator, and under conditions of a daily light-dark cycle it is referred to as a """"""""diurnal rhythm."""""""" The predominant form of regulation of physiological pathways by the circadian system appears to be at the transcriptional level, with hundreds-to-thousands of genes showing a daily rhythm of expression in various mammalian tissues. It seems likely that the diurnal rhythm of intraocular pressure reflects diurnal transcriptional regulation of genes involved in aqueous humor regulation by tissues of the anterior segment. In this exploratory/developmental research grant application, we propose to identify genes showing a diurnal rhythm of expression in structures of the anterior segment of the mouse eye, particularly those sites relevant to the regulation of intraocular pressure. In previous work, not yet published, we used whole-genome microarray analysis to identify over a thousand genes showing a significant diurnal rhythm of expression in the mouse eye. Using this dataset as a starting point, we propose here to examine a significant subset of the genes for rhythmic expression in the anterior segment, particularly the ciliary epithelium, the site of aqueous humor production. This effort could prove a valuable route to discovering genes and molecular pathways regulating aqueous humor production and intraocular pressure. ? ? ? ?
