KININ/PGE INTERACTION IN CONTROL OF INTRAOCULAR PRESSURE

激肽/PGE 相互作用控制眼内压

• 批准号: 7388799
• 负责人: JERRY G WEBB
• 金额: $ 27.79万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388799
• 关键词: Agonist; Anterior; Blindness; Bos taurus; Bradykinin; Cattle; Cells; Dinoprostone; Dose; Elevation; Event; Eye; Functional disorder; Glaucoma; Human; Individual; Interstitial Collagenase; Kallikrein-Kinin System; Kinins; Lead; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Physiologic Intraocular Pressure; Physiological; Prostaglandins E; Proteins; Receptor Activation; Regulation; Research; Resistance; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; System; Testing; Time; Trabecular meshwork structure; Work; anterior chamber; aqueous; autocrine; insight; optic nerve disorder; paracrine; pressure; receptor; research study; response

DESCRIPTION: Elevated intraocular pressure is a major risk factor in glaucoma, the most common cause of irreversible blindness worldwide. The long-term objectives of this research are to determine endogenous mechanisms that contribute to the physiological regulation of intraocular pressure, and to define factors that contribute to the pathophysiological pressure rise in glaucomatous individuals. This application focuses specifically on actions of the kallikrein/kinin system that we have found to increase outflow facility within the anterior chamber. We have also observed a synergistic interaction between bradykinin and PGE2 signaling in trabecular meshwork cells that may contribute significantly to the regulation of outflow resistance. The working hypothesis is that kinins, produced locally within the eye, act in an autocrine/paracrine fashion to regulate conventional outflow by modulating secretion of matrix regulating proteins in cells of the trabecular meshwork. It is also proposed that PGE2, produced by trabecular meshwork cells in response to kinins, facilitate kinin actions to enhance aqueous outflow. To test these ideas, studies will be performed in isolated perfused bovine and human anterior segments and in primary cultures of bovine and human trabecular meshwork cells. Experiments are proposed 1) to determine receptor mechanisms of bradykinin actions to increase outflow facility in the anterior segment, 2) to examine kinin signaling mechanisms that regulate MMP/TIMP secretion and activation in trabecular meshwork cells, and the relationship of these actions to the control of outflow facility, and 3) to determine the mechanism of kinin/PGE2 signal interactions in trabecular cells, and the contribution of these interactions to the regulation of outflow facility. The studies proposed will serve to define endogenous mediators and signaling pathways that regulate conventional outflow facility in the eye, and should provide insight into how dysfunction in these systems may lead to elevation of intraocular pressure.

描述：升高的眼内压是青光眼的主要危险因素，这是全球不可逆失明的最常见原因。这项研究的长期目标是确定有助于眼内压力的生理调节的内源性机制，并定义有助于绿糖实个体病理生理压力升高的因素。该应用专门针对Kallikrein/Kinin系统的动作，我们发现该系统增加了前室内的流出设施。我们还观察到小梁网细胞中缓激肽和PGE2信号传导之间的协同相互作用，这可能会对流出阻力的调节产生重大贡献。工作假设是，在眼睛内局部生产的基因素以自分泌/旁分泌方式起作用，通过调节小梁网细胞中调节蛋白质的矩阵分泌来调节常规流出。还提出，小梁网细胞对动力素产生的PGE2促进了Kinin的作用以增强水性流出。为了测试这些思想，将在孤立的灌注牛和人类前部以及牛和人类小梁网细胞的原发性培养物中进行研究。提出了实验1）确定头决定动作的受体机制，以增加前段中的流出设施，2）检查基因蛋白信号传导机制，这些信号传导机制是小梁网状工作中MMP/TIMP的分泌和激活的激活，以及这些动作与这些动作的关系，以及确定流出设施的控制和3）机构/PRETION的关系。这些与流出设施调节的相互作用。提出的研究将用于定义内源性介体和信号传导途径，以调节眼睛中常规流出设施，并应深入了解这些系统中的功能障碍如何导致眼内压的升高。