Pressure Regulation of Human Trabecular Meshwork Genes

人类小梁网基因的压力调节

• 批准号: 8249088
• 负责人: Teresa Borras
• 金额: $ 46.06万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249088
• 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; Elastin Fiber; 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; Measures; Molecular; Morphology; Mus; Nuclear Translocation; Organ Culture Techniques; Pathway interactions; Patients; Perfusion; Physiologic Intraocular Pressure; Physiological; Physiology; Process; Property; Regulation; Renal carcinoma; Residual state; Resistance; Risk; Risk Factors; Role; Rupture; SFRP4 gene; Signal Transduction; Small Interfering RNA; 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; scaffold; soft tissue; transcription factor; transglutaminase 2

ABSTRACT 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 perfused 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.

抽象的 青光眼是一种视神经病变，会引起不可逆的失明。我们研究青光眼的方法 包括选择与该疾病相关的良好临床状况并研究 分子水平的临床参数。升高的人眼压（IOP）是该的主要危险因素 青光眼的发展。在人类中，有90％的水性幽默从小梁中脱离眼睛 网格工作（TM）。因此，功能失调的TM导致抗药性增加和IOP升高。因为 组织的生理学受其基因表达的控制，在上一个赠款周期中，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之后 正常和高IOP灌注后人类眼睛，我们揭示了许多涉及的基因 钙化过程。我们进一步发现，此类过程不仅存在于TM中，而且还存在 他们似乎在青光眼患者的TMS中更为活跃。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。该基因和 控制骨和血管组织生理和病理钙化的机制是活跃的 在TM中，这些过程以及抑制它们的努力是监管系统的一部分 控制水性幽默流出。我们进一步假设无法在检查中维持TM矿化化 影响沉积的胶原蛋白和弹性蛋白交联，对ECM硬化产生有害后果。 为了检验这些假设，我们建议通过三个新的新机制进一步表征已确定的机制 途径。第一个将通过使用转基因小鼠来研究体内现象。第二个 将研究人体器官文化的过程。第三个将使用原代人TM细胞确定 两种途径（Wnt和LOX相关的弹性蛋白/胶原蛋白交联）参与TM矿化。 这两个途径与血管钙化和成骨细胞独立相关 分化以及影响TM功能的条件。 这些假设的发展将获得的结果将为您提供新的了解 调节流出抗性的机制，可能会导致青光眼的新治疗方法。

项目成果

Tissue bioengineering: potential applications to glaucoma.

组织生物工程：青光眼的潜在应用。

• DOI: 10.1001/archopht.123.12.1725
• 发表时间: 2005
• 期刊: Archives of ophthalmology (Chicago, Ill. : 1960)
• 作者: Young,MichaelJ;Borrás,Teresa;Walter,Michael;Ritch,Robert
• 通讯作者: Ritch,Robert

Matrix Gla protein deficiency impairs nasal septum growth, causing midface hypoplasia.

基质 Gla 蛋白缺乏会损害鼻中隔生长，导致中面部发育不全。

• DOI: 10.1074/jbc.m116.769802
• 发表时间: 2017
• 期刊: The Journal of biological chemistry
• 作者: Marulanda,Juliana;Eimar,Hazem;McKee,MarcD;Berkvens,Michelle;Nelea,Valentin;Roman,Hassem;Borrás,Teresa;Tamimi,Faleh;Ferron,Mathieu;Murshed,Monzur
• 通讯作者: Murshed,Monzur