Pressure Regulation of Human Trabecular Meshwork Genes

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DESCRIPTION (provided by applicant): Physiological pressure inside the eye is maintained by a resistance mechanism provided by the trabecular meshwork (TM) tissue. In most cases, prolonged elevated pressure leads to retinal ganglion cell degeneration, optic nerve damage and blindness (Glaucoma). Our long-term goal is to search for TM genes/mechanisms playing an essential role in regulation of intraocular pressure (lOP). During the first cycle of this project we used macroarray and GeneChip technology to obtain differential expression profiles between eyes subjected to elevated pressure and their paired normotense controls. Some of the identified genes encode new, previously undescribed TM functions, which appear recruited from bone and vascular systems. Rather than continue identifying more genes, with the information obtained we propose to investigate some of the new mechanisms and lOP parameters. Our working hypothesis is that regulation of lOP is governed in part by the coordinated expression of TM genes. Based on our findings, we now hypothesize that preventing calcification of the extracellular matrix (ECM) of the TM might be a key mechanism contributing to the regulation of lOP. We further hypothesize that genes differentially expressed with high fold change values might serve as ideal candidates to identify promoter elements responding to pressure. Finally, we hypothesize that each individual responds differently to pressure by inducing to different extent pressure-responding genes, thus changing their relative abundance. Because pressure-responding genes encode proteins involved in different functions, this relative abundance could influence an individual pressure threshold and contribute to his/her risk of developing of the disease. We will test these hypotheses by using human TM cell and perfused organ cultures, recombinant sense and siRNA adenoviruses, conformational antibodies, reporter genes, and quantitative PCR.