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）是致盲的主要原因，其异常流出阻力的来源尚未确定。我们发现，正常牛和人的眼内压（IOP）的急性升高会导致水流出可用面积减少，施勒姆管（SC）塌陷和可逆疝进入集流通道（CC）口。相比之下，即使在0 mmHg下，人类POAG眼也经常观察到疝，这表明正常可逆的疝形成过程在病变状态下变得不可逆。与正常眼急性IOP升高后的突出区相比，POAG眼的许多突出区显得更密集，并伴有局部细胞外基质的积累。我们认为，随着越来越多的不可逆的疝在CC口发展，流出设施将逐渐减少，IOP将上升。支持这一假设的关键数据来自临床研究，这些研究表明，注射到POAG眼睛SC的荧光素或台锥蓝在某些区域无法进入锁膜外静脉。POAG眼非穿透性青光眼手术后较差的预后似乎与这些阻塞的数量增加有关。我们的目的是确定我们发现的POAG眼的不可逆疝是否可以解释POAG患者临床观察到的从SC到锁膜外静脉的荧光素或台锥蓝出口阻塞，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学意义。我们假设，POAG眼流出设施的减少与骶管旁结缔组织和SC内壁有效滤过面积的减少有关，并与进入CC口的不可逆疝数量的增加成比例相关。在临床研究中，我们假设这些突出是阻断荧光素或台锥蓝从SC进入锁膜外静脉的原因。为了研究这一假设，提出了三个具体目标：1。区分正常人急性IOP升高的可逆性CC孔疝与POAG眼不可逆性疝的水动力和结构差异。2. 确定临床上观察到的从SC进入锁膜外静脉的台泮蓝或荧光素阻塞是否由青光眼与正常眼相比的不可逆疝引起。在自然发生的和激光诱导的青光眼猴眼体内注射后，通过这些突出区域追踪纳米颗粒进行组织学检查。3. 建立正常眼睛中从SC到外膜静脉的染料出口模式，称为“通道图”，并研究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。如果我们能够确认进入CC口的不可逆疝确实是阻断水流出的部位，那么POAG中一个新的增加阻力的部位将被确定。公共卫生相关性：原发性开角型青光眼是导致永久性失明的主要原因，约占40岁以上人群的2%，影响着全球7000多万人。我们研究的目的是确定导致原发性开角型青光眼流出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.