Pressure Regulation of Human Trabecular Meshwork Genes

人类小梁网基因的压力调节

• 批准号: 7473824
• 负责人: Teresa Borras
• 金额: $ 31.26万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473824
• 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）：眼睛内部的生理压力由小梁网（TM）组织提供的电阻机制维持。在大多数情况下，延长的压力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）。我们的长期目标是搜索TM基因/机制在调节眼内压（LOP）中起着至关重要的作用。在该项目的第一个周期中，我们使用了宏观阵列和Genechip技术来获得受压力升高的眼睛及其成对的正常义对照的差异表达曲线。一些已鉴定的基因编码了新的未描述的TM功能，这些函数似乎是从骨和血管系统中募集的。我们没有继续识别更多基因，而是通过获得的信息来研究一些新的机制和LOP参数。 我们的工作假设是，LOP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的细胞外基质（ECM）钙化可能是有助于调节LOP的关键机制。我们进一步假设，用高倍数变化值差异表达的基因可能是识别响应压力响应的启动子元素的理想候选者。最后，我们假设每个人通过在不同程度的压力响应基因上诱导压力，从而改变其相对丰度，对压力的反应不同。由于压力反应基因编码参与不同功能的蛋白质，因此这种相对丰度可能会影响个体的压力阈值，并有助于他/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，重组感和siRNA腺病毒，构象抗体，报告基因和定量PCR来检验这些假设。