eNOS-Dependent Mechanoregulation of Intraocular Pressure

描述(申请人提供)：临床试验的结果表明，青光眼患者显著、持续的眼压(IOP)降低会减缓或阻止视力丧失，即使是在低眼压性青光眼患者中也是如此。虽然青光眼高眼压的病因已知涉及传统的引流途径，但导致这种额外阻力产生的细胞机制尚不清楚。高眼压患者体内调节眼压的动态平衡机制似乎存在缺陷，可能类似于调节全身血压的机制，包括调节血管张力的机制。局部调节血管张力的关键信号分子是一氧化氮(NO)，这是一种由内皮型一氧化氮合酶(ENOS)在血管内皮细胞中产生的自由基。我们的中心假设得到了强有力的初步数据的支持，即Schlemm管(SC)内依赖眼压的剪应力是动态内源性信号系统(“反馈环”)中的关键角色，该系统通过产生NO来调节常规的流出阻力。在一些青光眼患者中，这种切应力-NO系统可能会受到损害，最终导致流出阻力增加和眼压升高。本提案的目的是通过仔细检查SC中高眼压和切应力的影响来检验这一假说，并确定SC细胞产生NO的决定因素和时间过程(目标1)。在目标2和目标3中，分别独立地研究了剪切和NO产生对SC单层渗透性和小梁细胞收缩能力(以及通过小梁网络的流动模式)的影响。这些研究结果将使人们对NO在房水流出阻力调节中的作用有一个基本的了解，发现青光眼治疗的新靶点，并为未来的研究奠定基础。 与公共卫生相关：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压，无论眼压是否升高，都会减缓或阻止视力丧失。不幸的是，目前的药物治疗在大多数情况下都不能充分降低眼压，并且不针对主要的流出途径。本提案研究了一种新的压力敏感机制，该机制涉及一氧化氮的产生，似乎通过主要的流出途径调节房水的运动，主要流出路径是眼压的主要决定因素。对这一途径的更好理解有望确定一组新的可用于眼压控制的药物靶点。

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.