The Aqueous Humor Outflow Resistance

房水流出阻力

• 批准号: 9919563
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919563
• 关键词: Address; Affect; 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; Masks; Modeling; Modification; Molecular; Nature; Obstruction; Optic Nerve; Organ Culture Techniques; Pathway interactions; Persons; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; 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; Treatment Efficacy; aqueous; effective therapy; insight; knock-down; lamina densa; pressure; response; 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.

项目摘要 青光眼是失明的主要原因，影响了全球超过6700万人。眼内升高 压力（IOP）是青光眼和减少IOP的主要危险因素是当前唯一的有效治疗 对于所有形式的青光眼。小梁网（TM）的近粒区域（JCT）内的细胞 可能与Schlemm的运河内壁内皮（SCE）一起工作是为了 强大的IOP稳态机制通常调整对水幽默出口的抵抗力 对压力破坏的反应。青光眼的关键组成部分是失去IOP稳态能力。 长期以来，这种水性幽默出口阻力已被认为是青光眼的主要因素 开发，已经专门研究了65年以上，导致了大量潜水员 改变它的监管和调节过程，包括一些最近的治疗剂。出奇， 该电阻的确切位置和分子组成均不知道正常或青光眼中 眼睛。毫不奇怪，开发有效的治疗分辨率来输出抗性非常困难 功能障碍，当我们甚至不知道它在哪里或位置时。 该应用程序狭义地着重于识别和定位在正常和中的出口电阻 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 电阻主要驻留在2英里SC的基底膜内，SC的直接贡献很小 内皮细胞本身。青光眼耐药性的增加可能存在于同一区域，涉及 相同的分子，或者可能不是。 我们提出了一系列直接研究，这些研究将定位这种抵抗和操纵，以确定 涉及的分子。研究将主要用于灌注的人体前部器官培养和 在新的灌注前部楔形培养系统中，我们最近开发了。识别和 定位这种出口耐药性将有助于新的有效疗法，用于青光眼IOP升高和 IOP稳态能力的丧失。