Intraocular pressure regulation via ATP-sensitive potassium channels

这是一个新的R 01应用程序，用于研究与眼内压相关的分子事件 (IOP)通过腺苷三磷酸敏感钾（KATP）通道调节。IOP升高 是青光眼唯一可治疗的危险因素。不幸的是，与外流阻力有关的关键分子 和IOP控制未知。缺乏这方面的知识限制了药物的发展 针对这些过程的。我们最近发现了IOP的一个关键细胞效应物，可能导致新的 用于高眼压和青光眼的药物治疗。我们发现KATP的激活 KATP通道开放剂二氮嗪、尼可地尔和P-1075降低人眼前节IOP 灌注模型药物开放剂对KATP通道的激活可被KATP阻断 通道封闭剂格列本脲和甲苯磺丁脲。此外，KATP通道开放剂二氮嗪治疗 并且前列腺素类似物拉坦前列素增加流出便利性大于任何一种药物 这表明这些药物使用不同的机制来降低IOP。迄今为止，没有研究 涉及KATP通道的研究已经在小梁流出途径中进行。的打开和关闭 KATP通道已被证明可以改变细胞的收缩性和渗透性，提供代谢保护， 抗缺血和缺氧，并增强非眼组织中细胞对应激的适应。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IOP升高的药物，我们必须首先确定关键的内在因素， 分子和生理机制参与降低IOP。我们的核心假设是， 由KATP通道激活引起的事件导致IOP降低。我们的前提是KATP 通道激活导致小梁网松弛，导致增加的 渗透性、改善的流体流动、增强的流出便利性和IOP降低。我们建议 表征KATP通道亚基结构，鉴定由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IOP。此外，我们将确定KATP的作用 通道开放剂对正常和原发性开角型青光眼（POAG）眼IOP的影响。在体内，我们将分析 KATP通道开放剂及其对C57 BL/6野生型和特异性KATP通道亚基敲除小鼠眼内压的影响 小鼠本建议书的完成将提供一个完整的描述性和机械的理解， KATP通道在小梁流出通路中的作用，将有助于评估 使用KATP通道开放剂作为增加POAG流出功能的治疗方式。

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.