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：眼压升高是青光眼的主要危险因素，青光眼是全世界不可逆性失明的最常见原因。这项研究的长期目标是确定有助于眼内压生理调节的内源性机制，并确定导致青光眼个体病理生理性压力升高的因素。该应用特别关注激肽释放酶/激肽系统的作用，我们发现该系统可以增加前房内的流出设施。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，可能对流出阻力的调节有显着贡献。工作假设是，眼内局部产生的激肽以自分泌/旁分泌方式发挥作用，通过调节小梁网细胞中基质调节蛋白的分泌来调节常规流出。还提出，小梁网细胞响应激肽而产生的 PGE2 可促进激肽作用，从而增强房水流出。为了检验这些想法，将在分离的灌注牛和人前段以及牛和人小梁网细胞的原代培养物中进行研究。建议进行实验：1) 确定缓激肽作用的受体机制，以增加眼前节的流出能力，2) 检查调节小梁网细胞中 MMP/TIMP 分泌和激活的激肽信号传导机制，以及这些作用与对照的关系流出设施，3) 确定小梁细胞中激肽/PGE2 信号相互作用的机制，以及这些相互作用对流出设施调节的贡献。拟议的研究将有助于定义调节眼睛传统流出设施的内源性介质和信号通路，并应深入了解这些系统的功能障碍如何导致眼内压升高。