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应用程序，用于研究与眼压有关的分子事件 通过三磷酸腺苷敏感钾(KATP)通道调节眼压。高眼压 是青光眼的唯一可治疗的危险因素。不幸的是，参与外流阻力的关键分子 和眼压控制是未知的。这些知识的缺乏限制了药理制剂的发展。 这将针对这些过程。我们最近发现了眼压的一个关键细胞效应因子，它可能导致新的 高眼压和青光眼的药物治疗。我们发现KATP的激活 KATP通道开放剂二氮卓、尼可地尔和P-1075可降低人眼前节的眼压 灌流模型。这种由药物开放剂激活的KATP通道可以被KATP阻断 通道封闭剂、格列本脲和甲苯丁胺。此外，使用KATP通道开放剂二氮嗪治疗 前列腺素类似物拉坦前列素增加流出功能的作用强于任何一种药物 单独来看，这表明这些药物使用不同的机制来降低眼压。到目前为止，还没有研究 在小梁流出通路中已经进行了KATP通道的参与。开业和闭幕 KATP通道已被证明可以改变细胞的收缩和通透性，提供代谢保护 抗缺血缺氧，增强细胞对非眼组织应激的适应。所有这些都是 细胞事件与青光眼的病因有直接或间接的联系。我们认为，为了 开发治疗高眼压的药物，我们必须首先确定关键的内在因素 与降低眼压有关的分子和生理机制。我们的中心假设是细胞 KATP通道激活引起的事件导致眼压降低。我们的前提是KATP 通道激活导致小梁网松弛，导致 渗透性、改善的液体流动、增强的流出设施和降低眼压。我们建议 表征KATP通道亚单位结构，识别由KATP通道开放剂激活的细胞通路， 并确定KATP通道开放与增加的流出设施的生理功能 通过小梁流出途径降低眼压。此外，我们将确定KATP的效果 开角型青光眼与开角型青光眼眼压的关系。在体内，我们将分析 KATP通道开放剂及其对C57BL/6野生型和特异性KATP通道亚基敲除后眼压的影响 老鼠。这项提案的完成将提供一个完整的描述性和机械性的理解 KATP通道在小梁流出途径中的作用，将有助于评估 在POAG中使用KATP通道开放剂作为增加流出设施的治疗方式。