Aqueous humor outflow control and intraocular pressure

房水流出控制和眼压

• 批准号: 6826885
• 负责人: MORTIMER MORDECAI CIVAN
• 金额: $ 44.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826885
• 关键词: adenosine; cell morphology; flow cytometry; glaucoma; human tissue; inflammation; intraocular aqueous flow; intraocular pressure; ion transport; laboratory mouse; molecular cloning; particle counter; polymerase chain reaction; purinergic receptor; sclera; trabecular meshwork; video microscopy; voltage /patch clamp

DESCRIPTION (provided by applicant): The proposed research integrates membrane transport physiology on a cellular level with electron microprobe analyses of cells in intact tissue and novel methods of measuring intraocular pressure (lOP) and aqueous humor flow in the mouse to address the mechanisms of aqueous humor outflow and intraocular pressure. Cell swelling within the trabecular meshwork (TM) and Schlemm's canal (SC) decreases the aqueous humor outflow facility, and cell shrinkage within this small region increases outflow facility. Subtype-specific adenosine receptor agonists also alter outflow and lOP. On the basis of published evidence and our own data, we propose that: (1) The mechanisms and regulatory signaling cascades underlying responses to purinergic drugs and to volume changes are different in SC, juxtacanalicular and TM cells; (2) Probing the responses to purines and to volume changes at cellular, tissue, organ and whole-animal levels, in part with new technology, will provide new understanding of the dynamic control of aqueous humor outflow; (3) An unifying hypothesis, which we shall test, is that the tight junctions between inner-wall Schlemm's canal cells are the rate-limiting barrier to aqueous humor outflow; and (4) Direct study of the cellular dynamics of outflow regulation can generate new approaches for lowering lOP. The major specific aims are to: (1) Develop pharmacologic strategies for differentially swelling/shrinking inner-wall SC and TM cells and to differentiate responses of these cells to subtype-specific adenosine-receptor agonists and antagonists; (2) Identify responses of inner-wall SC, juxtacanalicular and TM cells to volume changes and to adenosine receptor agonists and antagonists in intact tissue; and (3) Test predictions from cellular and tissue studies by analysis of aqueous humor dynamics by measuring lOP and aqueous humor turnover in the mouse.

描述（由申请人提供）：拟议的研究将细胞水平的膜转运生理与完整组织中细胞的电子微探针分析以及测量眼内压（LOP）和水中的新方法相结合，以解决小鼠中的水中流动，以解决水上幽默流出和内部压力的机制。小梁网（TM）和Schlemm的运河（SC）内的细胞肿胀减少了幽默流出设施，并且在这个小区域内的细胞收缩增加了流出设施。亚型特异性腺苷受体激动剂也会改变流出和LOP。在公开的证据和我们自己的数据的基础上，我们建议：（1）SC，近去核和TM细胞的机理和调节信号级联反应以及对嘌呤能药物的响应的响应不同； （2）探测对嘌呤的反应以及对细胞，组织，器官和全动物水平的质量变化的部分，部分将借助新技术，提供对水幽默流出的动态控制的新理解； （3） 我们将测试的统一假设是，内壁schlemm的运河细胞之间的紧密连接是幽默流出的限速障碍。 （4）直接研究流出调节的细胞动力学可以生成降低LOP的新方法。 主要的具体目的是：（1）为差异化制定药理学策略 肿胀/收缩内壁SC和TM细胞，以区分这些细胞的反应 亚型特异性腺苷受体激动剂和拮抗剂； （2）确定内壁SC，近去核和TM细胞对体积变化以及对完整组织中腺苷受体激动剂和拮抗剂的反应； （3）通过测量小鼠中的LOP和水性幽默的分析，通过分析水性幽默动力学来测试细胞和组织研究的预测。