Pressure Regulation of Human Trabecular Meshwork Genes

描述（由申请人提供）：眼内的生理压力由小梁网（TM）组织提供的阻力机制维持。在大多数情况下，长期的血压升高会导致视网膜神经节细胞变性、视神经损伤和失明（青光眼）。我们的长期目标是寻找在眼内压（lOP）调节中起重要作用的TM基因/机制。在这个项目的第一个周期中，我们使用了macroarray和genecchip技术来获得高压眼睛和正常血压对照眼睛之间的差异表达谱。一些已确定的基因编码新的，以前未描述的TM功能，这些功能似乎来自骨骼和血管系统。与其继续鉴定更多的基因，我们建议利用获得的信息研究一些新的机制和lOP参数。

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.