Pressure Regulation of Human Trabecular Meshwork Genes

人类小梁网基因的压力调节

• 批准号: 7269862
• 负责人: Teresa Borras
• 金额: $ 31.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269862
• 关键词: 5' Flanking Region; Adenovirus Vector; Adenoviruses; Anterior; Antibodies; Apoptosis; BMP2 gene; BMP4; Binding; Biochemical; Blindness; Cells; Characteristics; Disease; Elastin; Elements; Extracellular Matrix; Eye; Gene Transfer; Genes; Genetic Transcription; Glaucoma; Goals; Human; Individual; Mediator of activation protein; Molecular Biology; Molecular Profiling; Optic Nerve; Organ Culture Techniques; Physiologic Intraocular Pressure; Physiological; Physiology; Play; Polymerase Chain Reaction; Protein Overexpression; Proteins; Recombinant Proteins; Recombinants; Recruitment Activity; Regulation; Relative (related person); Reporter Genes; Retinal Ganglion Cells; Risk; Role; Sampling; Small Interfering RNA; Technology; Testing; Time; Tissues; Trabecular meshwork structure; Vascular System; Work; base; bone; calcification; human very old age (85+); pressure; prevent; promoter; resistance mechanism; response; scaffold

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.

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，长期高压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压（lOP）调节中发挥重要作用的TM基因/机制。在该项目的第一个周期中，我们使用宏阵列和基因芯片技术来获得承受高压的眼睛与其配对的常压对照之间的差异表达谱。一些已识别的基因编码新的、以前未描述的 TM 功能，这些功能似乎是从骨骼和血管系统中招募的。我们建议利用获得的信息来研究一些新机制和 lOP 参数，而不是继续识别更多基因。 我们的工作假设是 IOP 的调节部分由 TM 基因的协调表达控制。根据我们的发现，我们现在假设防止 TM 细胞外基质 (ECM) 钙化可能是调节 IOP 的关键机制。我们进一步假设以高倍数变化值差异表达的基因可能作为识别响应压力的启动子元件的理想候选者。最后，我们假设每个个体通过不同程度地诱导压力反应基因，从而改变其相对丰度，从而对压力做出不同的反应。由于压力响应基因编码涉及不同功能的蛋白质，因此这种相对丰度可能会影响个体压力阈值并增加他/她患疾病的风险。我们将通过使用人类 TM 细胞和灌注器官培养物、重组正义和 siRNA 腺病毒、构象抗体、报告基因和定量 PCR 来测试这些假设。