eNOS-Dependent Mechanoregulation of Intraocular Pressure

eNOS 依赖性眼压机械调节

• 批准号: 8272122
• 负责人: DARRYL R OVERBY
• 金额: $ 35.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272122
• 关键词: Affect; Aqueous Humor; Biological Models; Biomedical Engineering; Blindness; Blood Pressure; Blood Vessels; Cells; Clinical Trials; Data; Drainage procedure; Endothelium; Etiology; Feedback; Foundations; Free Radicals; Future; Generations; Glaucoma; Goals; Human; Individual; Intercellular Junctions; Investigation; Medical; Molecular; Molecular and Cellular Biology; Movement; Mutation; NOS3 gene; Nitric Oxide; Nitric Oxide Synthase; Ocular Hypertension; Outcome; Pathway interactions; Patients; Pattern; Permeability; Pharmacologic Substance; Pharmacology; Physiologic Intraocular Pressure; Physiology; Primary Open Angle Glaucoma; Production; Publishing; Regulation; Research; Resistance; Role; Signal Transduction; Signaling Molecule; Structure of sinus venosus of sclera; System; Testing; Time; Tissues; Trabecular meshwork structure; Up-Regulation; Vascular Endothelium; Vision; Work; aqueous; base; design; effective therapy; human NOS3 protein; improved; in vivo; monolayer; new therapeutic target; novel; overexpression; pressure; response; shear stress

DESCRIPTION (provided by applicant): Results from clinical trials demonstrate that significant, sustained intraocular pressure (IOP) reduction in people with glaucoma slows or halts vision loss, even in patients with low-tension glaucoma. While the etiology of ocular hypertension in glaucoma is known to involve the conventional drainage pathway, the cellular mechanisms responsible for generation of this extra resistance are unknown. It seems likely that the homeostatic mechanisms that regulate IOP in people with ocular hypertension are defective and may be similar to those involved in the regulation of systemic blood pressure, including those that regulate vascular tone. A key signaling molecule for local regulation of vascular tone is nitric oxide (NO), a free radical produced in vascular endothelia by endothelial NO synthase (eNOS). Our central hypothesis, supported by strong preliminary data, is that IOP-dependent shear stress within Schlemm's canal (SC) is a key player within a dynamic endogenous signaling system ("feedback loop") that regulates conventional outflow resistance through NO production. In some glaucomatous individuals, this shear stress-NO system may be compromised, leading ultimately to increased outflow resistance and elevated IOP. The goal of the present proposal is to test this hypothesis by careful examination of the effect of elevated IOP and shear stress in SC and establish the determinants of, and the time course for, NO production by SC cells (aim 1). Consequences of shear and NO production on SC monolayer permeability and trabecular meshwork cell contractility (and flow patterns through the trabecular meshwork) are looked at independently in aim 2 and aim 3, respectively. Results obtained from these investigations will provide a basic understanding of the role of NO in aqueous outflow resistance regulation, uncover novel therapeutic targets for glaucoma therapy and generate a foundation for future investigations. PUBLIC HEALTH RELEVANCE: Glaucoma is treatable. Data from large clinical trials demonstrate that lowering intraocular pressure in people with glaucoma, whether intraocular pressure is elevated or not, slows or stops vision loss. Unfortunately, current medical therapies do not lower intraocular pressure sufficiently in most, and do not target the primary outflow pathway. The present proposal examines a novel pressure-sensitive mechanism involving nitric oxide production that appears to regulate the movement of aqueous humor out through the primary outflow pathway, the chief determinant of intraocular pressure. Improved understanding of this pathway is expected to identify a new group of druggable targets for intraocular pressure control.

描述（由申请人提供）：临床试验的结果表明，青光眼患者显著、持续的眼内压（IOP）降低可减缓或阻止视力丧失，即使是低眼压性青光眼患者也是如此。虽然青光眼高眼压的病因学已知涉及传统的引流途径，但负责产生这种额外阻力的细胞机制尚不清楚。在高眼压患者中，调节IOP的稳态机制似乎存在缺陷，可能与调节全身血压的机制相似，包括调节血管张力的机制。一氧化氮（NO）是一种由内皮NO合酶（eNOS）在血管内皮中产生的自由基，是局部调节血管张力的关键信号分子。我们的中心假设，支持强有力的初步数据，是IOP依赖性的剪切应力在Schlemm的运河（SC）是一个关键的球员在一个动态的内源性信号系统（“反馈回路”），调节传统的外流阻力通过NO的生产。在某些青光眼患者中，这种剪切应力-NO系统可能受损，最终导致外流阻力增加和IOP升高。本提案的目的是通过仔细检查升高的IOP和SC中的剪切应力的影响来检验这一假设，并建立SC细胞产生NO的决定因素和时间过程（目的1）。剪切和NO产生对SC单层渗透性和小梁网细胞收缩性（以及通过小梁网的流动模式）的影响分别在目标2和目标3中独立观察。从这些调查中获得的结果将提供一个基本的了解的作用，一氧化氮在水流出阻力调节，发现新的治疗目标青光眼治疗，并为未来的调查产生的基础。 公共卫生相关性：青光眼是可以治疗的。来自大型临床试验的数据表明，降低青光眼患者的眼内压，无论眼内压是否升高，都会减缓或阻止视力丧失。不幸的是，目前的医学治疗在大多数情况下不能充分降低眼内压，并且不靶向主要流出途径。目前的建议探讨了一种新的压力敏感机制，涉及一氧化氮的生产，似乎调节通过主要流出途径，眼内压的主要决定因素的房水的运动。对这一途径的进一步理解有望确定一组新的可用于眼内压控制的药物靶点。