Aqueous humor outflow control and intraocular pressure

房水流出控制和眼压

基本信息

批准号：
7271873
负责人：
MORTIMER MORDECAI CIVAN
金额：
$ 44.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7271873
关键词：
Address Adenosine A3 Receptor Agonist Animal Organ Animals Anterior Aqueous Humor Blindness Cell Volumes Cell physiology Cells Cholinergic Agents Collaborations Complex Consensus Data Development Electrons Genetic Glaucoma Goals Human In Situ In Vitro Life Mammals Measures Mediating Methods Modems Molecular Monitor Mus Organ Pathogenesis Pharmaceutical Preparations Pharmacology Physiologic Intraocular Pressure Physiological Physiology Primates Prostaglandins Publishing Purinergic P1 Receptors Purines Range Rate Regulation Research Resistance Role Signal Transduction Site Structure of sinus venosus of sclera Swelling Techniques Testing Tight Junctions Tissues Trabecular meshwork structure Transmembrane Transport Work adenosine transporter aqueous humor flow base cell growth regulation cell type cholinergic design in vivo new technology novel novel strategies purine receptor response species difference

项目摘要

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上的膜运输生理学与完整组织中细胞的电子微探针分析以及测量小鼠眼内压（IOP）和房水流量的新方法相结合，以解决房水的机制体液流出和眼压。小梁网 (TM) 和施累姆氏管 (SC) 内的细胞肿胀会降低房水流出能力，而该小区域内的细胞收缩会增加流出能力。亚型特异性腺苷受体激动剂也会改变流出和 IOP。根据已发表的证据和我们自己的数据，我们提出：(1) SC、近管和 TM 细胞对嘌呤能药物和体积变化反应的机制和调节信号级联是不同的； (2) 部分采用新技术，探讨细胞、组织、器官和整个动物水平上对嘌呤和体积变化的反应，将为房水流出的动态控制提供新的认识； (3) 安我们将测试的统一假设是施累姆氏管内壁细胞之间的紧密连接是房水流出的限速屏障； (4) 直接研究流出调节的细胞动力学可以产生降低 IOP 的新方法。主要具体目标是： (1) 制定差异化的药理学策略肿胀/收缩内壁 SC 和 TM 细胞，并区分这些细胞对亚型特异性腺苷受体激动剂和拮抗剂； (2) 确定完整组织中内壁 SC、近管细胞和 TM 细胞对体积变化以及腺苷受体激动剂和拮抗剂的反应； (3)通过测量小鼠的IOP和房水更新来分析房水动力学来测试细胞和组织研究的预测。