eNOS-Dependent Mechanoregulation of Intraocular Pressure

项目摘要 临床试验的结果表明，显著、持续的眼压(IOP)降低 青光眼患者会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。而当 青光眼高眼压的病因已知涉及传统的引流途径，即 产生这种额外抗性的细胞机制尚不清楚。看起来很可能是 调节高眼压患者眼压的稳态机制是有缺陷的，可能是 类似于参与调节全身血压的那些，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)，这是一种自由基 血管内皮细胞产生内皮型一氧化氮合酶(ENOS)。我们的中心假设，得到了 强有力的初步数据表明，Schlemm管(SC)内取决于眼压的剪应力是一个关键因素 在调节常规流出的动态内生信号系统(“反馈环”)内 通过不生产来抵抗。在一些青光眼患者中，这种剪切力-没有系统可能是 妥协，最终导致流出阻力增加和眼压升高。当前的目标是 建议通过仔细检查高眼压和剪应力对SC的影响来检验这一假说 并确定干细胞产生NO的决定因素和时间进程(目标1)。 剪切力和NO产生对SC单层通透性和小梁细胞的影响 在Aim 2和Aim 2中单独研究了收缩性(和流经小梁网状结构) 目标3。从这些调查中获得的结果将提供对这一角色的基本了解 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 为未来的调查奠定基础。

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.