eNOS-Dependent Mechanoregulation of Intraocular Pressure

项目摘要 临床试验的结果表明， 青光眼患者减缓或停止视力丧失，即使是低眼压性青光眼患者。而 已知青光眼中高眼压的病因涉及常规的引流途径， 负责产生这种额外抗性的细胞机制是未知的。看来， 调节高眼压患者IOP的稳态机制存在缺陷， 类似于参与全身血压调节的那些，包括调节血管的那些， 语气局部调节血管张力的关键信号分子是一氧化氮（NO），一种自由基 在血管内皮中由内皮NO合酶（eNOS）产生。我们的中心假设， 强有力的初步数据表明，施莱姆氏管（SC）内IOP相关的剪切应力是一个关键因素 在调节常规流出的动态内源性信号系统（“反馈回路”）内， 通过NO的生产。在某些昏迷的个体中，这种切应力-NO系统可能是 受损，最终导致流出阻力增加和IOP升高。目前的目标是 建议通过仔细检查升高的IOP和SC中剪切应力的影响来验证这一假设 并建立SC细胞产生NO的决定因素和时间过程（目的1）。 剪切力和NO产生对SC单层通透性和小梁细胞的影响 在目标2中独立地观察收缩性（和通过小梁网的流动模式）， 目标3，分别。从这些调查中获得的结果将提供对作用的基本了解 NO在房水流出阻力调节中的作用，发现青光眼治疗的新治疗靶点， 为今后的调查奠定基础。

Project Summary 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.