Intraocular pressure regulation via ATP-sensitive potassium channels

通过 ATP 敏感钾通道调节眼压

• 批准号: 8916736
• 负责人: MICHAEL P. FAUTSCH
• 金额: $ 38.64万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916736
• 关键词: ATP sensitive potassium channel complex; Acute; Adenosine Triphosphate; Affect; Age; American; Anterior; Aqueous Humor; Axoplasmic Streaming; Basement membrane; Blindness; Brain Hypoxia-Ischemia; Cell Death; Cells; Couples; Coupling; Data; Development; Diabetes Mellitus; Diazoxide; Disease Progression; Drainage procedure; Endothelium; Event; Eye; Family; Future; Glaucoma; Glyburide; Human; Individual; Knockout Mice; Knowledge; Laboratories; Latanoprost; Lead; Link; Metabolic; Modality; Modeling; Modification; Molecular; Mus; National Eye Institute; Nicorandil; Ocular Hypertension; Ocular Physiology; Operative Surgical Procedures; Organ Culture Techniques; Pathway interactions; Patients; Perfusion; Permeability; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Physiological; Potassium; Primary Open Angle Glaucoma; Process; Prostaglandins; Race; Recording of previous events; Regulation; Relaxation; Research; Resistance; Retinal Ganglion Cells; Risk Factors; Role; Signal Transduction; Site; Stress; Structure; Structure of sinus venosus of sclera; Synthetic Prostaglandins; Testing; Tissues; Tolbutamide; Trabecular meshwork structure; Work; aqueous; base; blind; blood pressure reduction; fluid flow; improved; in vivo; modifiable risk; novel; relating to nervous system; targeted treatment; therapeutic target

This is a new R01 application to study the molecular events involved in intraocular pressure (IOP) regulation through adenosine-triphosphate-sensitive potassium (KATP) channels. Elevated IOP is the only treatable risk-factor for glaucoma. Unfortunately, the key molecules involved in outflow resistance and IOP control are unknown. Lack of this knowledge has limited the development of pharmacologic agents that would target these processes. We recently identified a key cellular effector of IOP that may lead to new pharmacologic treatment for ocular hypertension and glaucoma. We have found that activation of KATP channels by KATP channel openers diazoxide, nicorandil, and P-1075 lower IOP in a human anterior segment perfusion model. This activation of KATP channels by the pharmacologic openers can be blocked by KATP channel closers, glyburide, and tolbutamide. In addition, treatment with the KATP channel opener diazoxide and the prostaglandin analogue latanoprost increases outflow facility greater than either agent does individually, suggesting that these agents use distinct mechanisms to lower IOP. To date, no studies involving KATP channels have been performed in the trabecular outflow pathway. The opening and closing of KATP channels have been shown to alter cellular contractility and permeability, provide metabolic protection against ischemia and hypoxia, and enhance cellular adaptation to stress in non-ocular tissues. All of these cellular events have been directly or indirectly linked to the cause of glaucoma. We believe that in order to develop pharmacologic agents for the treatment of elevated IOP, we must first identify key intrinsic molecules and physiological mechanisms involved in lowering IOP. Our central hypothesis is that cellular events resulting from KATP channel activation leads to IOP reduction. It is our premise that KATP channel activation leads to a relaxation of the trabecular meshwork resulting in increased permeability, improved fluid flow, augmented outflow facility, and a decrease in IOP. We propose to characterize KATP channel subunit structure, identify cellular pathways activated by KATP channel openers, and determine the physiological function that couples KATP channel opening to increased outflow facility and a lowering of IOP through the trabecular outflow pathway. In addition, we will determine the effect of KATP channel openers on IOP in normal and primary open-angle glaucoma (POAG) eyes. In vivo, we will analyze KATP channel openers and its effect on IOP in C57BL/6 wild-type and specific KATP channel subunit knockout mice. The completion of this proposal will provide a complete descriptive and mechanistic understanding of the role KATP channels have in the trabecular outflow pathway, and will help in evaluating the feasibility of using KATP channel openers as a treatment modality for increasing outflow facility in POAG.

这是一个新的R01应用，用于研究与眼内压的分子事件 （IOP）通过腺苷 - 三磷酸敏感钾（KATP）通道调节。升高的IOP 是青光眼唯一可治疗的风险因素。不幸的是，涉及流出阻力的关键分子 IOP控制是未知的。缺乏这种知识限制了药理学剂的发展 这将针对这些过程。我们最近确定了IOP的关键细胞效应子，可能导致新的 眼部高血压和青光眼的药理学治疗。我们发现Katp的激活 KATP通道开瓶器二氮氧化物，尼古兰和P-1075的通道下部段 灌注模型。药理学开瓶器对KATP通道的激活可以被KATP阻止 关闭渠道，格列本和托丁酰胺。此外，用KATP通道开宗二氮氧化物处理 前列腺素类似物拉丁螺旋螺杆菌增加的流出设施比任何一种代理都要大 单独地表明这些试剂使用不同的机制来降低IOP。迄今为止，没有研究 涉及KATP通道已在小梁流出途径中进行。开放和关闭 已显示KATP通道可以改变细胞收缩性和渗透性，提供代谢保护 针对缺血和缺氧，并增强了对非眼组织应激的适应性。所有这些 细胞事件已直接或间接地与青光眼原因联系在一起。我们相信为了 开发用于治疗升高IOP的药理学剂，我们必须首先确定关键的内在固有 降低IOP的分子和生理机制。我们的中心假设是细胞 KATP通道激活引起的事件导致IOP减少。 katp是我们的前提 通道激活导致小梁网的放松，导致增加 渗透性，提高流体流动，增加流出设施以及IOP的降低。我们建议 表征KATP通道亚基结构，识别由KATP通道开启器激活的细胞路径， 并确定伴侣KATP通道开放以增加流出设施的生理功能和 通过小梁流出路径降低IOP。此外，我们将确定KATP的效果 IOP上的通道开启器在正常和原发性开态青光眼（POAG）眼中。在体内，我们将分析 KATP频道开启器及其对C57BL/6野生型和特定KATP频道亚基敲除中IOP的影响 老鼠。该提案的完成将提供对 KATP通道在小梁流出途径中的作用，并将有助于评估可行性 使用KATP通道开启器作为治疗方式，以增加POAG中的流出设施。