Aqueous Humor Outflow Control and Intraocular Pressure

房水流出控制和眼压

基本信息

批准号：
7730234
负责人：
MORTIMER MORDECAI CIVAN
金额：
$ 47.72万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7730234
关键词：
Actins Address Adenosine Adenosine A1 Receptor Adenosine A3 Receptor Agonist Animals Anterior Aqueous Humor Biochemical Biological Blindness Cell Volumes Cells Ciliary epithelium Cytoskeleton Data Dexamethasone E-Selectin Employee Strikes Epithelial Epithelial Cells Eye Fluorescence Gelatinase A Glaucoma Goals Grant Human Interleukin-1 Intervention Knock-out Knowledge Lead Life Measurement Mediating Methods Modification Molecular Monkeys Mus Normal Cell Organ Oryctolagus cuniculus Ouabain Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiologic Intraocular Pressure Physiological Physiology Preparation Publishing Purinergic P1 Receptors Purines Purinoceptor Regulation Resistance Signaling Molecule Site Stimulus Stretching Structure of sinus venosus of sclera Techniques Testing Trabecular meshwork structure Transmembrane Transport base cell type depolymerization design fluorexon innovation novel novel strategies public health relevance purine receptor

项目摘要

DESCRIPTION (provided by applicant): Purine receptors are important regulators of intraocular pressure (IOP) since knockout of A3 adenosine receptors lowers mouse IOP, and activation of A1 adenosine receptors lowers IOP in rabbits, mice and monkeys. IOP depends directly on inflow rate and resistance to outflow of aqueous humor, and available data suggest that A3 and A1 receptors likely modulate inflow and outflow, respectively. This proposal integrates membrane transport physiology on a cellular level with measurements at both organ and whole-animal levels to address the fundamental, initiating step in purinergic IOP regulation, release of cellular ATP that also delivers adenosine by ectoenzymatic conversion. Recently, multiple large-bore channels have been found to mediate this release in other preparations. The proposal's major focus is on purinergic regulation of outflow, the site of pathology in glaucoma. Studies of isolated cells will use biochemical, fluorometric, electrophysiologic, pharmacologic and molecular biological measurements. The hypothesis is that: (1) conduits and regulation of ATP release may differ among Schlemm's canal (SC) and trabecular meshwork (TM) cells of the outflow pathway and ciliary epithelial cells of the inflow pathway; (2) identifying the ATP-exit mechanisms by isolated cells, activated by both physiologic and pathophysiologic stimuli, will lead to a strategy for differentially modifying ATP release in the inflow and in different sites of the trabecular outflow pathway; (3) the results will lead to a broader perspective of outflow regulation; and (4) the results may generate new approaches to lower IOP. The major specific aims are: (1) to identify and compare the conduits and regulation of ATP release following physiologic stimulation of SC and TM cells, and to compare these ATP exit pathways with those of ciliary epithelial inflow cells; (2) to exploit relevant pathophysiologic stimuli to activate/inhibit ATP-release channels in normal TM cells and to compare the ATP-release conduits and regulation in TM cells of normal and glaucomatous eyes; and (3) to test whether inhibiting or activating different ATP-release conduits change outflow resistance of isolated, perfused human anterior segments and mouse IOP as predicted from analyses of isolated cells. PUBLIC HEALTH RELEVANCE: Lowering IOP is the only intervention as yet documented to delay the onset and reduce the rate of progression of irreversible blindness from glaucoma. The current proposal seeks to identify the fundamental step in the regulation of IOP by the purine class of signaling molecules. Successful results may lead to an innovative strategy for lowering IOP in glaucoma.

描述（由申请人提供）：嘌呤受体是眼内压（IOP）的重要调节剂，因为A3腺苷受体的敲除会降低小鼠的IOP，而A1腺苷受体的激活会降低兔子、小鼠和猴子的IOP。 IOP 直接取决于房水的流入速率和流出阻力，现有数据表明 A3 和 A1 受体可能分别调节流入和流出。该提案将细胞水平的膜运输生理学与器官和整个动物水平的测量相结合，以解决嘌呤能 IOP 调节的基本起始步骤，即细胞 ATP 的释放，同时通过外酶转化传递腺苷。最近，在其他制剂中发现多个大口径通道可以介导这种释放。该提案的主要重点是嘌呤能对流出物的调节，即青光眼的病理部位。对分离细胞的研究将使用生化、荧光、电生理、药理学和分子生物学测量。假设是：（1）流出途径的施莱姆氏管（SC）和小梁网（TM）细胞与流入途径的睫状上皮细胞之间ATP释放的管道和调节可能不同； (2) 识别被生理和病理生理刺激激活的分离细胞的 ATP 退出机制，将导致差异性地改变小梁流出途径流入和不同部位的 ATP 释放的策略；（3）研究结果将为资本流出监管带来更广阔的视角； (4) 研究结果可能会产生降低眼压的新方法。主要具体目标是：（1）识别和比较SC和TM细胞生理刺激后ATP释放的通道和调节，并将这些ATP退出途径与睫状上皮流入细胞的ATP退出途径进行比较； (2)利用相关的病理生理刺激来激活/抑制正常TM细胞中的ATP释放通道，并比较正常眼和青光眼眼TM细胞中ATP释放通道和调节； (3) 测试抑制或激活不同的 ATP 释放导管是否会改变分离的、灌注的人眼前节和小鼠 IOP 的流出阻力，如分离细胞分析预测的那样。公共卫生相关性：降低眼压是迄今为止唯一有记录的可延迟青光眼不可逆性失明的发病并降低其进展速度的干预措施。目前的提案旨在确定嘌呤类信号分子调节眼压的基本步骤。成功的结果可能会带来降低青光眼眼压的创新策略。