权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8333209
负责人：
MICHAEL P. FAUTSCH
金额：
$ 39.43万
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/8333209
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.

这是研究与眼压相关的分子事件的一个新的R01应用