Translamina Cribrosa Pressure Gradient Model of Normal Tension Glaucoma

神经退行性疾病，包括青光眼，极大地改变了受影响退伍军人的生活质量。 青光眼仍然是不可逆转失明的主要原因。目前影响着6000多万人 在世界范围内，这种隐匿性的年龄依赖性视神经病变的特征是视网膜神经节逐渐丧失。 预计在20年内将影响到近1.12亿人。全球流行率 40-80岁人群中青光眼的发病率达到了惊人的3.5%。我们老龄化的患病率上升 退伍军人也不例外。对美国医疗保健系统的影响同样令人望而生畏， 据估计，730万美国人预计将因原发性开角型青光眼(POAG)而虚弱，其中 常见的青光眼，在30年内。尽管这是一个非常严重的社会经济负担， 美国退伍军人青光眼的治疗仍然是有限的和姑息的。 几项多中心研究已确定高眼压(IOP)是导致眼压升高的主要危险因素 开角型青光眼的发病和进展。虽然导致受影响患者眼压升高的病理生理机制仍然存在 由于了解不多，解决这一问题的几种新的治疗策略似乎很有希望。的 然而，重要的是，多达三分之一的POAG患者的眼压水平在正常范围内。 虽然许多实验室，包括我们自己的实验室，都专注于开发和推进新颖的 眼压管理的治疗策略，对文献的批判性回顾显示缺乏 关于正常眼压性青光眼发病机制的实验研究。的发展。 针对正常眼压性青光眼病因的有针对性的治疗策略对晚期青光眼至关重要 对这些受影响的退伍军人的管理。 在这个BLR&D功绩审查验证试点项目中，我们建议推进我们目前正在进行的BLR&D资助 筛板压力梯度差对视神经影响的研究 豚鼠头部和视网膜形态计量学及RGC神经元功能的研究 人类视神经病变相关动物模型的建立。这项验证性研究的设计将严格遵循 这一点在Ostrin and Wildsoet(2016)和Yang等人中有详细说明。(2014)使用腰-腹膜脑脊液分流术 调节脑脊液压力。 假设：慢性降低豚鼠脑脊液压力将引发可量化的变化 视神经头形态测量和改变视网膜节神经元功能。这项研究的假设将通过以下方式进行检验 以下两个具体目标。特异靶1将在体内确定脑脊液的时间依赖效应 液体压力降低对豚鼠RGC神经元功能的影响。 特定目标2将确定脑脊液降压对视神经的时间依赖性效应 豚鼠头部和视网膜形态计量学的组织学、免疫组织化学和电子计量 显微照相分析。 本研究的目标是(I)根据RFA BX-20-042进行验证和(Ii)扩展以下发现 Ostrin和Wildsoet(2016)和Yang等人。(2014)关于豚鼠作为相关临床有用指标的适用性 人类视神经病变模型。这项研究产生的新发现将决定这一角色 筛板上的压力梯度差异在人类视神经疾病的发展中起着作用。

Neurodegenerative diseases, including glaucoma, substantially alter quality of life of our affected Veterans. Glaucoma remains a leading cause of irreversible blindness. Currently affecting over 60 million individuals worldwide, this insidious age-dependent optic neuropathy is characterized by a gradual loss of retinal ganglion cell (RGC) neurons and is projected to impact nearly 112 million people within 20 years. The global prevalence of glaucoma for population aged 40-80 years is an alarming 3.5%. An elevated prevalence among our aging Veteran population is no exception. Implications for the US health care system are equally daunting, with an estimated 7.3 million Americans expected to be debilitated by primary open angle glaucoma (POAG), the most common form of glaucoma, within 30 years. Despite being an extraordinarily significant socioeconomic burden, the treatment of US Veterans with glaucoma remains limited and palliative. Several multicenter studies have identified elevated intraocular pressure (IOP) as a primary risk factor for the onset and progression of POAG. While the pathophysiology leading to elevated IOP in affected patients remains poorly understood, several new therapeutic strategies that address this concern appear promising. Of significance, however, is the fact that up to one-third of POAG patients exhibit IOP levels within the normal range. While many laboratories, including our own, have focused on the development and advancement of novel therapeutic strategies for the management of IOP, a critical review of the literature reveals a paucity of experimental studies addressing the mechanistic cause of normal-tension glaucoma. The development of targeted therapeutic strategies directed at the cause of normal tension glaucoma is critical for the advanced management of these affected Veterans. In this BLR&D Merit Review validation pilot project, we propose to advance our current on-going BLR&D-funded studies by determining the effect of pressure gradient differentials across the lamina cribrosa on optic nerve head and retinal morphometrics and on RGC neuronal function using guinea pigs as a novel anatomically- relevant animal model of human optic neuropathic disorders. The design of this validation study will closely follow that detailed in Ostrin and Wildsoet (2016) and Yang et al. (2014) using a lumbar-peritoneal CSF shunt to modulate CSF pressure. Hypothesis: Chronic reduction of cerebrospinal fluid pressure in guinea pigs will elicit quantifiable changes in optic nerve head morphometry and alter RGC neuronal function. The hypothesis of this study will be tested with the following two Specific Aims. Specific Aim 1 will determine, in vivo, time-dependent effects of cerebrospinal fluid pressure reduction on RGC neuronal function in guinea pigs as quantified by pattern electroretinography. Specific Aim 2 will determine the time-dependent effects of cerebrospinal fluid pressure reduction on optic nerve head and retinal morphometrics in guinea pigs as quantified by histological, immunohistochemical, and electron micrographic analyses. The goal of this study is to (i) validate in accordance with the RFA BX-20-042 and (ii) extend the findings of Ostrin and Wildsoet (2016) and Yang et al. (2014) on the applicability of guinea pigs as a relevant clinically useful model of human optic neuropathic disorders. Novel findings produced by this study will determine the role pressure gradient differential across the lamina cribrosa play in the development of human optic neuropathies.