Intraocular pressure regulation via ATP-sensitive potassium channels

摘要 眼压升高是青光眼最常见也是唯一可治疗的危险因素。而当 高眼压的原因通常归因于小梁网/Schlemm管阻力增加 界面，越来越多的证据突显了由远端部分造成的潜在阻力 常规流出途径(Schlemm管外壁、集流通道和相关的深巩膜和 巩膜内血管构筑)。该区域内的扰动已被证明是导致 青光眼。我们已经确定KATP通道开放剂的一部分是新型的降低眼压的降压药 在血压正常的动物模型(小鼠、兔子、非人灵长类动物)中，通过直接影响 常规流出路径(这里称为远端流出路径)。这一新颖的行动模式 为我们提供了一个独特的机会来研究这个区域在青光眼中的作用，同时详细描述 这类药物的作用模式。此外，我们有初步数据表明，KATP通道开放剂 为视网膜神经节细胞(RGC)提供神经保护。根据我们之前的资助完成的研究 期间，开发了一种水溶性的、治疗友好的这种药物类别(克罗卡林前体药物1； CKLP1)，以及该提案中提出的新的初步数据，我们假设KATP通道开放剂降低 通过靶向远端流出通路中的血管系统，促进体液通过ERK1/2的流动 介导的信号级联。此外，我们假设KATP通道开放剂也具有神经保护作用。 能够保护视网膜节细胞免受各种青光眼伤害。为了检验这些假设，我们建议 表征KATP通道在远端流出通路中的血管调节作用，定义相关的 与ERK1/2信号通路有关的分子事件决定了相关的神经保护特性 观察KATP通道开放剂对视网膜神经节细胞的降压作用。 青光眼模型。拟议研究的新发现将在以下方面取得重大进展 目的是了解青光眼的病理生理学，提高RGC存活率的新机制，以及 KATP通道开放剂前药CKLP1作为一种潜在的治疗药物的鉴定 青光眼的治疗。

ABSTRACT Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor in glaucoma. While the cause of elevated IOP is commonly attributed to increased resistance at the trabecular meshwork/Schlemm's canal interface, an expanding body of evidence highlights the potential resistance created by distal portions of the conventional outflow pathway (Schlemm's canal outer wall, collector channels, and associated deep scleral and intrascleral vasculature). Perturbations within this region have been shown to contribute towards the pathology of glaucoma. We have identified a subset of KATP channel openers as novel ocular hypotensive agents that lower IOP in normotensive animal models (mice, rabbits, non-human primates) by directly affecting the distal portion of the conventional outflow pathway (herein referred to as the distal outflow pathway). This novel mode of action provides us with a unique opportunity to study the role of this region in glaucoma while characterizing in detail the mode of action of this drug class. In addition, we have preliminary data suggesting that KATP channel openers provide neuroprotection to retinal ganglion cells (RGCs). Based on studies completed in our previous funding period, the development of an aqueous soluble, therapy friendly form of this drug class (cromakalim prodrug 1; CKLP1), and new preliminary data presented in this proposal, we hypothesize that KATP channel openers lower IOP by targeting the vasculature in the distal outflow pathway, facilitating fluid flow through an Erk1/2 mediated signaling cascade. Additionally, we hypothesize that KATP channel openers are also neuroprotective agents and can protect RGCs from various glaucomatous insults. To test these hypotheses, we propose to characterize the vasoregulatory role of KATP channels within the distal outflow pathway, define the relevant molecular events pertaining to the Erk1/2 signaling pathway, determine the neuroprotective properties associated with KATP channel opening in RGCs, and examine the ocular hypotensive activity of KATP channel openers in models of glaucoma. New findings from the proposed studies would provide major advancements towards the goal of understanding the pathophysiology of glaucoma, novel mechanisms that enhance RGC survival, and characterization of the KATP channel opener prodrug CKLP1 as a potential therapeutic agent for the management of glaucoma.