Intraocular pressure regulation via ATP-sensitive potassium channels

通过 ATP 敏感钾通道调节眼压

基本信息

批准号：
8731240
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
项目类别：
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/8731240
关键词：
ATP sensitive potassium channel complex Acute Adenosine Triphosphate Affect Age American Anterior Aqueous Humor Axoplasmic Streaming Basement membrane Blindness Blood Pressure 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 fluid flow improved in vivo modifiable risk novel relating to nervous system therapeutic target

项目摘要

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，用于研究眼压相关的分子事件（IOP）通过三磷酸腺苷敏感钾（KATP）通道进行调节。眼压升高是青光眼唯一可治疗的危险因素。不幸的是，参与流出阻力的关键分子和 IOP 控制未知。缺乏这方面的知识限制了药物的开发这将针对这些流程。我们最近发现了 IOP 的一个关键细胞效应器，它可能会导致新的高眼压症和青光眼的药物治疗。我们发现KATP的激活 KATP 通道开放剂二氮嗪、尼可地尔和 P-1075 降低人眼前节的 IOP 灌注模型。 KATP 可以阻断药理开放剂对 KATP 通道的激活通道闭合剂、格列本脲和甲苯磺丁脲。此外，用 KATP 通道开放剂二氮嗪治疗前列腺素类似物拉坦前列素比任何一种药物都更能增加流出能力单独来看，表明这些药物使用不同的机制来降低眼压。迄今为止，还没有研究涉及 KATP 通道的研究已在小梁流出通路中进行。的开启和关闭 KATP 通道已被证明可以改变细胞收缩性和渗透性，提供代谢保护对抗缺血和缺氧，增强细胞对非眼组织应激的适应。所有这些细胞事件与青光眼的病因直接或间接相关。我们相信，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参与降低眼压的分子和生理机制。我们的中心假设是细胞 KATP 通道激活导致的事件会导致 IOP 降低。我们的前提是KATP 通道激活导致小梁网松弛，从而增加渗透性、改善流体流动、增强流出设施和降低眼压。我们建议表征 KATP 通道亚基结构，识别 KATP 通道开放剂激活的细胞通路，并确定将 KATP 通道开放与增加的流出设施耦合的生理功能，通过小梁流出途径降低眼压。此外，我们将确定 KATP 的效果正常和原发性开角型青光眼 (POAG) 眼中 IOP 的通道开放剂。在vivo中，我们将分析 C57BL/6 野生型和特异性 KATP 通道亚基敲除中 KATP 通道开放剂及其对 IOP 的影响老鼠。该提案的完成将为我们提供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，并将有助于评估可行性使用 KATP 通道开放剂作为增加 POAG 流出设施的治疗方式。