Pressure Regulation of Human Trabecular Meshwork Genes

人类小梁网基因的压力调节

• 批准号: 7887797
• 负责人: Teresa Borras
• 金额: $ 47.87万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887797
• 关键词: Adult; Affect; African American; Anterior; Aqueous Humor; Arthritis; Atherosclerosis; Blindness; Blood Vessels; Cardiovascular Diseases; Cells; Clinical; Collagen; Collagen Fiber; Crystallins; Deposition; Development; Disease; Elasticity; Elastin; Evolution; Extracellular Matrix; Eye; Failure; Family; Gene Family; Genes; Glaucoma; Goals; Grant; Human; Keratoplasty; Kidney Diseases; Knock-out; Knowledge; LOX gene; Lead; Link; Long-Term Effects; Lymphoid; MGP gene; Maintenance; Malignant Neoplasms; Measures; Molecular; Morphology; Mus; Nuclear Translocation; Organ Culture Techniques; Pathway interactions; Patients; Perfusion; Physiologic Intraocular Pressure; Physiological; Physiology; Process; Property; Regulation; Residual state; Resistance; Risk; Risk Factors; Role; Rupture; SFRP4 gene; Signal Transduction; System; TCF Transcription Factor; Testing; Tissues; Trabecular meshwork structure; Transgenic Animals; Transgenic Mice; Vascular calcification; WNT Signaling Pathway; aqueous humor flow; base; bone; calcification; calcification inhibitor; crosslink; enhancing factor; functional outcomes; high intraocular pressure; in vivo; mineralization; optic nerve disorder; osteoblast differentiation; physical property; pressure; programs; promoter; public health relevance; scaffold; soft tissue; transcription factor; transglutaminase 2

DESCRIPTION (provided by applicant): Glaucoma is an optic neuropathy which causes irreversible blindness. Our approach to study glaucoma consists of selecting a well-established clinical condition associated with the disease and investigating the clinical parameter at the molecular level. Elevated intraocular pressure (IOP) is the major risk factor for the development of glaucoma. In humans, 90% of the aqueous humor exits the eye through the trabecular meshwork (TM). Thus, a dysfunctional TM results in increased resistance and elevated IOP. Because the physiology of a tissue is governed by the expression of its genes, during the previous grant cycle we examined TM differential expression under conditions of elevated IOP. After analyzing many chip arrays comparing normal and high IOP perfuse post-mortem human eyes, we unraveled a number of genes involved in calcification processes. We further uncovered that such processes were not only present in the TM, but also that they seemed to be more active in TMs from glaucomatous patients. Based on these findings, we hypothesize that TM calcification is linked to regulation of IOP and outflow facility. That genes and mechanisms that govern physiological and pathological calcification in the bone and vascular tissues are active in the TM, and that these processes, as well as efforts to inhibit them, are part of the regulatory systems that control aqueous humor outflow. We further hypothesize that failure to maintain TM mineralization in check will affect deposited collagen and elastin cross-linking with deleterious consequences to ECM hardening. To test these hypotheses we propose to further characterize the identified mechanism through three new avenues. The first will investigate the phenomenon in vivo, through the use of transgenic mice. The second will investigate the process in human organ cultures. The third will use primary human TM cells to determine the involvement of two pathways (WNT and LOX-related elastin/collagen cross-linking) in TM mineralization. These two pathways have been independently associated with vascular calcification and osteoblastic differentiation and, with conditions affecting TM function. Results to be obtained with the development of these hypotheses will provide new understanding on the mechanisms regulating outflow resistance and would potentially lead to new treatments for glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is the second leading cause of irreversible blindness and the most common cause among African- Americans. Currently, there is no cure for glaucoma. Elevated intraocular pressure (IOP) is the major risk factor for the developing of glaucoma. IOP is maintained by the resistance of the trabecular meshwork to the flow of aqueous humor. The goal of our project is to investigate the relevance of a previously undescribed process of mineralization occurring in the trabecular meshwork for the regulation of IOP. The trabecular meshwork needs to have in place molecular mechanisms that would maintain the physical properties of elasticity, tension and softness. Maintenance of the softness is of highest relevance to the trabecular meshwork's function. Pathological calcification occurs in soft tissues and has important clinical implications. Ectopic calcifications are well known to occur in cardiovascular diseases, atherosclerosis, arthritis, kidney disease and cancers. Vascular calcification decreases elasticity of the blood vessels and increases their brittleness, leading to increase risk of arterial rupture. In this project we aim to characterize this process in the eye of transgenic animals, human eyes from post-mortem donors and primary trabecular meshwork cells obtained from residual tissue after corneal transplants. We will aim to further study the role of inhibitors of calcification in the trabecular meshwork and ultimate open a new door for the development of new treatments for Glaucoma.

描述（由申请人提供）：青光眼是一种导致不可逆失明的视神经病变。我们研究青光眼的方法包括选择与该疾病相关的明确临床状况并在分子水平上研究临床参数。眼内压（IOP）升高是青光眼发生的主要危险因素。在人类中，90% 的房水通过小梁网 (TM) 排出眼睛。因此，功能失调的 TM 会导致阻力增加和 IOP 升高。由于组织的生理学受其基因表达的控制，因此在之前的资助周期中，我们检查了 IOP 升高条件下的 TM 差异表达。在分析了许多芯片阵列，比较正常和高眼压灌注的死后人眼后，我们解开了一些参与钙化过程的基因。我们进一步发现，这样的过程不仅存在于 TM 中，而且在青光眼患者的 TM 中似乎更活跃。基于这些发现，我们假设 TM 钙化与 IOP 和流出设施的调节有关。控制骨和血管组织生理和病理钙化的基因和机制在 TM 中活跃，这些过程以及抑制它们的努力是控制房水流出的调节系统的一部分。我们进一步假设，如果未能控制 TM 矿化，将会影响沉积的胶原蛋白和弹性蛋白交联，从而对 ECM 硬化产生有害后果。 为了检验这些假设，我们建议通过三种新途径进一步表征已确定的机制。第一个将通过使用转基因小鼠来研究体内现象。第二个将研究人体器官培养的过程。第三个项目将使用原代人类 TM 细胞来确定 TM 矿化中两条途径（WNT 和 LOX 相关的弹性蛋白/胶原蛋白交联）的参与情况。这两条途径与血管钙化和成骨细胞分化以及影响 TM 功能的条件独立相关。 随着这些假设的发展而获得的结果将为调节流出阻力的机制提供新的理解，并可能导致青光眼的新治疗方法。 公共卫生相关性：青光眼是导致不可逆性失明的第二大原因，也是非裔美国人中最常见的原因。目前，青光眼无法治愈。眼内压（IOP）升高是青光眼发生的主要危险因素。眼压是通过小梁网对房水流动的阻力来维持的。我们项目的目标是调查小梁网中发生的先前未描述的矿化过程与 IOP 调节的相关性。小梁网需要具有适当的分子机制来保持弹性、张力和柔软的物理特性。保持柔软度与小梁网的功能最为相关。 病理性钙化发生在软组织中，具有重要的临床意义。众所周知，异位钙化发生在心血管疾病、动脉粥样硬化、关节炎、肾病和癌症中。血管钙化会降低血管的弹性并增加其脆性，导致动脉破裂的风险增加。在这个项目中，我们的目标是在转基因动物的眼睛、来自死后捐赠者的人眼以及从角膜移植后残留组织中获得的原代小梁网细胞中描述这一过程。我们的目标是进一步研究钙化抑制剂在小梁网中的作用，并最终为青光眼新疗法的开发打开一扇新的大门。