Diurnal Rhythms Gene Expression in the Anterior Eye

描述：高眼压是青光眼的主要危险因素，而药物降低眼压是治疗青光眼和防止进展为失明的最重要的治疗策略。虽然最近在了解眼前段组织如何调节房水的产生和流出(决定眼压的过程)方面取得了进展，但目前在分子水平上对这些过程的了解很少。对前眼房水调节分子机制的详细了解很可能最终将为青光眼的诊断和治疗提供新的更好的方法。像眼生理的许多其他重要方面一样，眼压是由昼夜节律系统调节的，昼夜节律的特点是24小时周期性。这种周期性是由内源性昼夜节律振荡器产生的，在每日明暗循环的情况下，它被称为“昼夜节律”。昼夜节律系统对生理通路的主要调节形式似乎是在转录水平上，在各种哺乳动物组织中，成百上千的基因显示出每日的表达节奏。眼压的昼夜节律似乎反映了眼前段组织参与房水调节的基因的昼夜转录调节。在这项探索性/发展性研究拨款申请中，我们建议识别在小鼠眼前段结构中表现出昼夜节律表达的基因，特别是那些与眼压调节相关的位置。在之前尚未发表的工作中，我们使用全基因组微阵列分析来识别1000多个在小鼠眼睛中表现出显著的昼夜节律的基因。以这个数据集为起点，我们建议在这里研究眼前节节律性表达的一个重要基因子集，特别是睫状体上皮，房水产生的部位。这一努力可能被证明是发现调控房水产生和眼压的基因和分子途径的一条有价值的途径。

DESCRIPTION: 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.