A Previously Unrecognized Site of Resistance in POAG

描述（由申请人提供）：原发性开角型青光眼（POAG）的异常外流阻力来源尚未确定，POAG是导致失明的主要原因。我们已经发现，在正常的牛和人类眼睛的眼内压（IOP）的急性升高导致减少的可用面积的水流出，Schlemm管（SC）崩溃和可逆的疝入收集通道（CC）口。相比之下，即使在0 mmHg下，在人POAG眼中也经常观察到疝，这表明正常可逆的疝形成过程在患病状态下变得不可逆。与正常眼急性眼压升高后的疝出区域相比，POAG眼的许多疝出区域出现更致密的细胞外基质局部积聚。我们认为，随着CC口出现更多不可逆疝，流出道功能将逐渐降低，IOP将升高。支持这一假设的关键数据来自临床研究，表明注射到POAG眼睛SC中的荧光素或台盼蓝的流动在某些区域被阻止进入巩膜外静脉。POAG患者非穿透性青光眼手术后预后较差似乎与这些阻塞的数量增加有关。我们的目标是确定我们已经确定的POAG眼中的不可逆疝是否可以解释临床上观察到的POAG患者中荧光素或台盼蓝从SC进入巩膜外静脉的阻塞，以及这些发现在POAG发病机制和非穿透性青光眼手术预后中的生理意义。我们假设POAG眼的流出道功能降低与前小管结缔组织和SC内壁的有效滤过面积减少相关，并与CC口不可逆疝入数量增加成比例相关。我们假设这些疝是临床研究中阻止荧光素或台盼蓝从SC进入巩膜外静脉的原因。为了研究这一假设，提出了三个具体的目标：1。区分急性IOP升高的正常人眼中观察到的可逆性疝入CC口与POAG眼中观察到的不可逆性疝入CC口之间的流体动力学和结构差异。2.确定临床观察到的从SC进入巩膜外静脉的台盼蓝或荧光素的阻塞是否是由与正常眼相比的青光眼眼的不可逆疝引起的。这将通过在自然发生的和激光诱导的青光眼猴眼中体内注射后追踪纳米颗粒穿过这些突出区域进行组织学检查。3.建立染料从SC到巩膜外静脉的流出模式，就像正常眼睛中出现的那样，称为“通道造影术”，并研究接受非穿透性青光眼手术的POAG患者的常见变化及其与术后IOP降低的关系。如果我们能证实不可逆的疝入CC口确实是阻塞房水流出的部位，那么将确定POAG中增加阻力的新部位。公共卫生相关性：原发性开角型青光眼是永久性失明的主要原因，在40岁以上的个体中发现约2%，并且影响世界上超过7000万人。我们的研究目的是确定导致原发性开角型青光眼流出道阻力升高的病理因素。

DESCRIPTION (provided by applicant): The source of abnormal outflow resistance in primary open angle glaucoma (POAG), a leading cause of blindness, has yet to be identified. We have found that acute elevation of intraocular pressure (IOP) in normal bovine and human eyes causes a decrease in the available area for aqueous outflow, Schlemm's canal (SC) to collapse and reversible herniations into collector channel (CC) ostia. In contrast, herniations were commonly observed in human POAG eyes even at 0 mmHg, suggesting that a normally reversible process of hernia formation becomes irreversible in the diseased state. A number of herniated regions in POAG eyes appear denser and with local accumulation of extracellular matrix compared with the herniated regions following acute IOP elevation in normal eyes. We propose that as more irreversible herniations develop in the CC ostia, the outflow facility would progressively decrease and IOP would rise. Critical data supporting this hypothesis comes from clinical studies demonstrating that flow of fluorescein or trypan blue injected into SC of POAG eyes is blocked from entering the episcleral veins in certain regions. A poorer prognosis following a non- penetrating glaucoma surgery in POAG eyes seems to be associated with increased numbers of these blockages. Our goal is to determine whether the irreversible herniations in POAG eyes we have identified account for the blockage of the fluorescein or trypan blue egress from SC into episcleral veins observed clinically in POAG patients and the physiological significance of these findings in the pathogenesis of POAG and in the prognosis of non-penetrating glaucoma surgery. We hypothesize that the decreased outflow facility in POAG eyes is associated with a decrease in effective filtration area in the juxtacanalicular connective tissue and inner wall of SC, and is proportionally associated with an increased number of irreversible herniations into CC ostia. We hypothesize that these herniations are responsible for blocking the fluorescein or trypan blue from entering the episcleral veins from SC in clinical studies. To investigate this hypothesis three specific aims are proposed: 1. Distinguish the hydrodynamic and structural differences between the reversible herniations into CC ostia observed in normal human eyes with acute IOP elevation and irreversible herniations in POAG eyes. 2. Determine whether the blockage of trypan blue or fluorescein entering the episcleral veins from SC observed clinically is caused by irreversible herniations in glaucomatous eyes compared to normal eyes. This will be examined histologically by tracing nanoparticles through these herniated regions after in vivo injection in the naturally occurring and laser-induced glaucomatous monkey eyes. 3. Establish an egress pattern of dye from SC to episcleral veins as it appears in normal eyes, termed "channelography" and investigate its common changes in POAG patients undergoing a non-penetrating glaucoma surgery and its relationship to post- operative IOP reduction. If we can confirm that irreversible herniations into CC ostia are indeed the site blocking the aqueous outflow, a new site of added resistance in POAG will be identified. PUBLIC HEALTH RELEVANCE: Primary Open-angle Glaucoma is a major cause of permanent blindness, found in approximately 2% of individuals over the age of 40, and affects over 70 million people in the world. The goal of our research is to identify the pathologic factors contributing to elevated outflow resistance in primary open angle glaucoma.