The Aqueous Humor Outflow Resistance

项目摘要 青光眼是失明的主要原因，影响全世界超过6700万人。升高的眼内 眼压（IOP）是青光眼的主要危险因素，降低IOP是目前唯一有效的治疗方法 治疗各种类型的青光眼小梁网（TM）的小管区域（JCT）内的细胞 可能与Schlemm管内壁内皮细胞（SCE）共同作用， 稳健的IOP稳态机制，其中对房水流出的阻力在正常情况下被调节， 对压力不平衡的反应。青光眼的一个关键组成部分是这种IOP稳态能力的丧失。 这种房水流出阻力长期以来被认为是青光眼的主要因素 发展，并已被广泛研究了超过65年，产生了大量的各种各样的 调节和调制过程来改变它，包括一些最近的治疗药物。令人惊讶的是， 在正常人或昏迷患者中，这种耐药的确切位置和分子组成都不清楚 眼睛毫不奇怪，很难开发出有效的治疗方案来解决外流阻力 功能障碍，当我们甚至不知道它是什么或在哪里。 本申请仅集中于识别和定位正常和非正常情况下的流出阻力。 昏迷的眼睛。 我们和许多其他人的实验和概念研究支持我们的工作假设， 耐药性主要存在于2 μ m SC基底膜内，SC的直接贡献很小 内皮细胞本身。昏迷性阻力增加可能位于同一区域，并涉及 相同的分子，也可能不同 我们提出了一套直接的研究，将本地化这种阻力和操纵，将确定 分子参与。研究将主要在灌注的人眼前节器官培养物中进行， 在我们最近开发的新的灌注眼前节楔形培养系统中。识别和 使这种流出阻力局部化将有助于治疗青光眼IOP升高的新的更有效的疗法， 眼压稳态能力的丧失。

Project Summary Glaucoma is a major cause of blindness affecting over 67 million persons worldwide. Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma and reducing IOP is the only current effective treatment for all forms of glaucoma. Cells within the juxtacanalicular region (JCT) of the trabecular meshwork (TM) probably working in conjunction with Schlemm's canal inner wall endothelium (SCE) are responsible for a robust IOP homeostasis mechanism in which the resistance to aqueous humor outflow is normally adjusted in response to pressure disbalances. A key component of glaucoma is the loss of this IOP homeostatic capability. This aqueous humor outflow resistance has long been recognized as a primary factor in glaucoma development and has been studied extensively for over 65 years resulting in a large number of diverse regulatory and modulatory processes to change it, including some recent therapeutic agents. Surprisingly, neither the exact location nor molecular composition of this resistance is known in normal or in glaucomatous eyes. Not surprisingly, it is very difficult to develop effective therapeutic resolutions to outflow resistance dysfunction, when we do not even know what or where it is. This application is narrowly focused on identifying and localizing the outflow resistance in normal and in glaucomatous eyes. Experimental and conceptual studies by us and many others support our working hypothesis that this resistance resides primarily within the 2 m SC basement membrane with a small direct contribution by the SC endothelial cells themselves. The glaucomatous resistance increase may reside in the same area and involve the same molecules, or it may not. We propose a set of direct studies that will localize this resistance and manipulations that will identify the molecules involved. Studies will be conducted primarily in perfused human anterior segment organ culture and in the new perfused anterior segment wedge culture system we have recently developed. Identifying and localizing this outflow resistance will facilitate new more effective therapies for glaucomatous IOP elevation and the loss of IOP homeostatic capability.