Intraocular pressure regulation via ATP-sensitive potassium channels

通过 ATP 敏感钾通道调节眼压

• 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
• 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

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）：这是研究通过腺苷 - 三磷酸盐敏感钾（KATP）通道参与眼内压（IOP）调节的分子事件的应用。 IOP升高是青光眼唯一可治疗的风险因素。不幸的是，涉及流出阻力和IOP控制的关键分子是未知的。缺乏这些知识限制了针对这些过程的药理剂的发展。我们最近确定了IOP的关键细胞效应因子，该效应可能会导致新的药物治疗眼睛高血压和青光眼。我们发现，在人体前部灌注模型中，KATP通道开瓶器二氮氧化物，尼古兰和P-1075的KATP通道降低IOP。药理学开瓶器对KATP通道的激活可以被KATP通道关闭器，格列本比和Tolbutamide阻止。此外，用KATP通道揭示剂二氮氧化物和前列腺素类似物拉甘油螺旋体的治疗增加了流出设施比任何一种药物的单独处理都大，这表明这些试剂使用不同的机制来降低IOP。迄今为止，在小梁流出途径中尚未进行涉及KATP通道的研究。已经证明，KATP通道的开放和结束可以改变细胞的收缩力和渗透率，为缺血和缺氧提供代谢保护，并增强细胞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。我们认为，为了开发用于治疗IOP升高的药理学剂，我们必须首先确定降低IOP涉及的关键内在分子和生理机制。我们的中心假设是由KATP通道激活引起的细胞事件导致IOP降低。我们的前提是，KATP通道激活会导致小梁网的放松，从而增加了渗透率，增强的流体流动，增强流出设施以及IOP的减少。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，并通过小梁流出途径降低IOP。此外，我们将确定KATP通道开启器对正常和原发性开角青光眼（POAG）眼中IOP的影响。在体内，我们将分析KATP通道开启器及其对C57BL/6野生型和特定KATP通道亚基敲除小鼠的影响。该提案的完成将对KATP渠道在小梁流出途径中的作用提供完整的描述性和机械理解，并将有助于评估使用KATP通道开启器作为增加POAG中流出设施的治疗方式的可行性。 公共卫生相关性：关于KATP渠道的拟议研究将产生有关在正常和POAG眼中降低IOP的机制的新信息。 KATP通道亚基结构的分析和受KATP通道开启影响的细胞途径的测定将确定可以将未来疗法定向的新型靶标分子。更重要的是，对KATP通道开启器的分析可能会导致一类新的药物治疗眼部高血压和青光眼。