Intraocular pressure regulation via ATP-sensitive potassium channels

摘要 眼内压升高（IOP）是青光眼中最普遍和唯一可治疗的风险因素。而 IOP升高的原因通常归因于小梁网/Schlemm管阻力增加 接口，越来越多的证据强调了由远端部分产生的潜在阻力。 常规的流出路径（Schlemm管外壁、收集器通道和相关的深层巩膜和 巩膜内脉管系统）。该区域内的扰动已被证明有助于导致 青光眼我们已经确定了一个KATP通道开放剂的子集，作为新的降眼压剂， 在血压正常的动物模型（小鼠、兔、非人灵长类动物）中，通过直接影响 在一个实施例中，远端流出路径包括常规流出路径（本文中称为远端流出路径）。这种新颖的行动方式 为我们提供了一个独特的机会，研究该区域在青光眼中的作用，同时详细描述了 这类药物的作用方式。此外，我们有初步的数据表明，KATP通道开放剂 对视网膜神经节细胞（RGC）提供神经保护。根据我们以前资助的研究 期间，开发了这类药物的水溶性、治疗友好形式（cromakalim前药1; CKLP1），以及本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道中的血管系统，促进液体流过Erk 1/2 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， 能保护RGCs免受各种肿瘤的损伤。为了验证这些假设，我们建议 描述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信号通路相关的分子事件决定了与神经保护相关的神经保护特性。 与RGC中KATP通道开放的关系，并检查KATP通道开放剂在RGC中的眼水肿活性。 青光眼模型。拟议研究的新发现将为实现 目的是了解青光眼的病理生理学，提高RGC生存的新机制， KATP通道开放剂前体药物CKLP 1作为潜在的治疗剂的表征 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.