The Aqueous Humor Outflow Resistance

房水流出阻力

• 批准号: 10610934
• 负责人: TED S ACOTT
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610934
• 关键词: Address; Affect; Agreement; Anterior; Aqueous Humor; Area; Basement membrane; Basic Science; Blindness; Cell Wall; Cells; Confocal Microscopy; Development; Dexamethasone; Disease; Endothelial Cells; Endothelium; Extracellular Matrix; Eye; Functional disorder; Future; GAG Gene; Glaucoma; Goals; Homeostasis; Human; Knowledge; Liquid substance; Literature; Location; Modeling; Modification; Molecular; Nature; Obstruction; Optic Nerve; Organ Culture Techniques; Pathway interactions; Perfusion; Persons; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; Probability; Process; Property; Proteoglycan; Regulation; Research; Research Personnel; Resistance; Resolution; Risk Factors; Route; Sampling; Site; Structure of sinus venosus of sclera; Surface; System; Testing; Therapeutic Agents; Thick; Trabecular meshwork structure; aqueous; effective therapy; insight; knock-down; lamina densa; nerve damage; pressure; response; therapeutically effective; therapy resistant

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.

项目概要 青光眼是导致全球超过 6700 万人失明的主要原因。 眼压（IOP）是青光眼的主要危险因素，降低眼压是目前唯一有效的治疗方法 适用于小梁网 (TM) 近小管区域 (JCT) 内的所有形式的青光眼。 可能与施累姆氏管内壁内皮 (SCE) 一起工作，负责 强大的眼压稳态机制，其中房水流出的阻力通常在 对压力失衡的反应是青光眼的一个关键组成部分是眼压稳态能力的丧失。 这种房水流出阻力长期以来被认为是青光眼的主要因素 的发展，并已进行了超过 65 年的主要研究，产生了大量不同的 令人惊讶的是，改变它的监管和调节过程，包括一些最近的治疗药物。 在正常人或青光眼患者中，这种抵抗的确切位置和分子组成尚不清楚 毫不奇怪，开发针对流出阻力的有效治疗方案非常困难。 功能障碍，当我们甚至不知道它是什么或在哪里时。 该应用主要集中于识别和定位正常和正常状态下的流出阻力。 青光眼的眼睛。 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，即这 阻力主要存在于 2 μm SC 基底膜内，SC 的直接贡献很小 内皮细胞本身可能存在青光眼抵抗力的增加。 相同的分子，也可能不同。 我们提出了一系列直接研究，将定位这种阻力和操纵，从而确定 研究将主要在灌注的人类眼前节器官培养物中进行。 在我们最近开发的新型灌注前段楔形培养系统中。 局部化这种流出阻力将促进针对青光眼眼压升高的更有效的新疗法 眼压稳态能力的丧失。