PERFUSED TRABECULAR MESHWORK AS A MODEL FOR OUTFLOW

拟议研究的总体目标是获得进一步的知识 的生理学和药理学的水流出， 人眼 加强对基本机制的了解 潜在的正常流出生理学可能会导致更大的洞察力 原发性开角型青光眼（POAG）的发病机制。 虽然，猴眼在体内一直是一个有价值的模型， 了解流出生理学的基本概念，最近 对在生物医学研究中使用灵长类动物的担忧 需要可接受的动物实验替代品。 此外，猴眼不是最佳模型，因为猴子 很少发生POAG。 所用的实验系统 在这些研究中是灌注的人流出组织模型。 这 新开发的模型涉及将被取出内脏的动物（例如， 去除透镜和葡萄膜组织）前角巩膜壳 将小梁网（TM）连接到专门的 灌流装置 TM和相关流出组织是 以生理相关的浓度灌注培养基， 在37 ° C下在5%C02环境中的灌注压力。 下 在这些条件下，灌注的TM类似于人体流出 系统在体内几天的形态学，以及 作为功能参数。 相当有趣的是， 肾上腺素增加了灌注TM的流出功能 模型 这一发现说明了这一点的潜在重要性。 模型在水流出动力学的研究，因为这是 仅在体外系统中，肾上腺素诱导的流出 设施的增加得到了证实。 具体目标是 建议如下： 1)进一步表征灌注TM模型; 2)确定肾上腺素诱导的 设施增加并调查其他因素的影响 “小梁作用”药物;和 3)来定义生理发现的形态学相关性。 研究肾上腺素反应的人体流出的能力 组织沿着几天，有机会 建立一个替代动物实验的模型 明确指出了他的模型在 研究流出道系统的生物学。

The overall goal of proposed research is to gain further knowledge of the of the physiology and pharmacology of aqueous outflow in the human eye. Enhanced understanding of the basic mechanism(s) underlying normal outflow physiology may lead to greater insight into the pathogenesis of primary open angle glaucoma (POAG). Although, the monkey eye in vivo has been a valuable model in understanding basic concepts of outflow physiology, the recent concern over the use of primates in biomedical research dictates the need for acceptable alternatives to animal experimentation. Furthermore, the monkey eye is not an optimal model, since monkeys rarely if ever develop POAG. The experimental system to be used in these studies is the perfused human outflow tissue model. This newly developed model involves placement of the eviscerated (e.g. lens and uveal tissue are removed) anterior corneoscleral shell with attached trabecular meshwork (TM) onto a specialized perfusion apparatus. The TM and associated outflow tissues are perfused with culture medium at a physiologically-relevant perfusion pressure in a 5% C02 environment at 37 degree C. Under these conditions, the perfused TM is similar to the human outflow system in vivo for several days with regard to morphology as well as functional parameters. Of considerable interest is the finding that epinephrine increases outflow facility in the perfused TM model. This finding illustrates the potential importance of this model in the study of aqueous outflow dynamics, since this is the only in vitro system in which an epinephrine-induced outflow facility increase has been demonstrated. The specific aims of this proposal are: 1) to further characterize the perfused TM model; 2) to define the mechanism of action of the epinephrine-induced facility increase as well as investigate the effects of other "trabecular acting" drugs; and 3) to define morphological correlates of physiological findings. The ability to study the epinephrine responsive human outflow tissues for a period of several days along with the opportunity to establish a model which serves as an alternative to animal testing clearly points to the potential importance of his model in investigating the biology of the outflow pathway system.