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.

摘要 青光眼是一种导致不可逆性失明的视神经病变。我们研究青光眼的方法 包括选择与这种疾病相关的成熟的临床情况，并调查 分子水平上的临床参数。眼压升高是导致眼压升高的主要危险因素。 青光眼的发展。在人类中，90%的房水通过小梁离开眼睛。 网络(TM)。因此，TM功能障碍会导致阻力增加和眼压升高。因为 在我们研究的前一个捐赠周期中，组织的生理学是由其基因的表达决定的 TM在高眼压条件下的差异表达。在分析了多个芯片阵列的对比后 正常和高眼压灌注死后的人的眼睛，我们解开了一些涉及 钙化过程。我们进一步发现，这样的过程不仅存在于TM中，而且 他们在青光眼患者的TMS中似乎更活跃。基于这些发现，我们 假设TM钙化与眼压和流出功能的调节有关。基因和 控制骨和血管组织中生理性和病理性钙化的机制是活跃的。 这些过程以及抑制它们的努力，是监管制度的一部分， 控制房水流出。我们进一步假设，未能保持TM矿化受控将 影响沉积的胶原蛋白和弹性蛋白的交联性，从而有害于细胞外基质硬化。 为了检验这些假设，我们建议通过三个新的 林荫道。第一个将通过使用转基因小鼠在体内研究这一现象。第二 将在人体器官培养中研究这一过程。第三个将使用原代人类TM细胞来确定 两条途径(WNT和LOX相关的弹性蛋白/胶原交联)参与TM矿化。 这两条途径分别与血管钙化和成骨细胞有关。 分化和，随着影响TM功能的条件。 随着这些假说的发展而获得的结果将为我们提供对 调节流出阻力的机制，并可能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