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：
8147464
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/8147464
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

DESCRIPTION (provided by applicant): This is an 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. PUBLIC HEALTH RELEVANCE: The proposed studies on KATP channels will yield novel information regarding the mechanisms used to lower IOP in normal and POAG eyes. Analysis of KATP channel subunit structure and determination of cellular pathways affected by KATP channel openers will identify novel target molecules to which future therapies can be directed. More importantly, the analysis of KATP channel openers may result in a new class of drugs for the treatment of ocular hypertension and glaucoma.

描述（由申请人提供）：这是一个研究通过三磷酸腺苷敏感钾（KATP）通道调节眼内压（IOP）的分子事件的应用程序。眼压升高是青光眼唯一可治疗的危险因素。不幸的是，参与流出阻力和眼压控制的关键分子尚不清楚。缺乏这方面的知识限制了针对这些过程的药物的开发。我们最近发现了 IOP 的一个关键细胞效应器，它可能导致高眼压和青光眼的新药物治疗。我们发现，在人眼前段灌注模型中，KATP 通道开放剂二氮嗪、尼可地尔和 P-1075 激活 KATP 通道可降低 IOP。药理学开放剂对 KATP 通道的激活可以被 KATP 通道封闭剂、格列本脲和甲苯磺丁脲阻断。此外，用 KATP 通道开放剂二氮嗪和前列腺素类似物拉坦前列素治疗比任何一种药物单独治疗都能增加流出能力，表明这些药物使用不同的机制来降低 IOP。迄今为止，尚未在小梁流出通路中进行涉及 KATP 通道的研究。 KATP 通道的打开和关闭已被证明可以改变细胞收缩性和渗透性，提供针对缺血和缺氧的代谢保护，并增强细胞对非眼组织应激的适应。所有这些细胞事件都与青光眼的病因直接或间接相关。我们认为，为了开发治疗眼压升高的药物，我们必须首先确定降低眼压的关键内在分子和生理机制。我们的中心假设是 KATP 通道激活引起的细胞事件导致眼压降低。我们的前提是，KATP 通道激活会导致小梁网松弛，从而导致渗透性增加、液体流动改善、流出设施增加和眼压降低。我们建议表征 KATP 通道亚基结构，识别由 KATP 通道开放剂激活的细胞途径，并确定将 KATP 通道开放与小梁流出途径增加流出设施和降低 IOP 耦合的生理功能。此外，我们将确定 KATP 通道开放剂对正常和原发性开角型青光眼 (POAG) 眼眼压的影响。在体内，我们将分析 KATP 通道开放剂及其对 C57BL/6 野生型和特定 KATP 通道亚基敲除小鼠 IOP 的影响。该提案的完成将为 KATP 通道在小梁流出通路中的作用提供完整的描述性和机制性理解，并将有助于评估使用 KATP 通道开放器作为增加 POAG 流出设施的治疗方式的可行性。公共健康相关性：拟议的 KATP 通道研究将产生有关降低正常眼和 POAG 眼眼压的机制的新信息。对 KATP 通道亚基结构的分析和受 KATP 通道开放剂影响的细胞途径的确定将确定未来治疗可以针对的新靶分子。更重要的是，对KATP通道开放剂的分析可能会产生一类用于治疗高眼压症和青光眼的新药物。