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：
10219256
负责人：
MICHAEL P. FAUTSCH
金额：
$ 50.99万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219256
关键词：
ATP sensitive potassium channel complex Address Affect Animal Model Antihypertensive Agents Blindness Cell Death Cell Survival Clinical Management Data Development Disease Distal Elements Endothelial Cells Event Eye Family Functional disorder Funding Glaucoma Goals Human Laboratories MAPK3 gene Mediating Modeling Molecular Mus National Eye Institute Neurodegenerative Disorders Neurons Neuroprotective Agents Ocular Hypotension Oryctolagus cuniculus Parents Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiologic Intraocular Pressure Physiological Potassium Prodrugs Property Regulation Resistance Retinal Ganglion Cells Risk Factors Role Scientific Advances and Accomplishments Signal Pathway Signal Transduction Structure of sinus venosus of sclera Testing Therapeutic Therapeutic Agents Trabecular meshwork structure Venous Water aqueous base drug action fluid flow human model in vivo Model modifiable risk neuroprotection nonhuman primate normotensive novel novel therapeutics ocular hypotensive response retinal damage side effect therapeutically effective

项目摘要

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.

抽象的眼内压升高（IOP）是青光眼最常见且唯一可治疗的危险因素。虽然眼压升高的原因通常归因于小梁网/施累姆氏管的阻力增加接口，越来越多的证据强调了由远端部分产生的潜在阻力传统的流出途径（施累姆氏管外壁、收集通道以及相关的深部巩膜和巩膜内血管）。该区域内的扰动已被证明有助于促进病理学青光眼。我们已经确定了 KATP 通道开放剂的一个子集作为新型降眼压剂，可降低 IOP 在血压正常的动物模型（小鼠、兔子、非人灵长类动物）中，通过直接影响大脑的远端部分常规流出路径（本文称为远端流出路径）。这种新颖的作用方式为我们提供了一个独特的机会来研究该区域在青光眼中的作用，同时详细描述该药物类别的作用方式。此外，我们有初步数据表明 KATP 通道开放者为视网膜神经节细胞（RGC）提供神经保护。基于我们之前资助完成的研究在此期间，开发了该类药物的水溶性、治疗友好型（cromakalim 前药 1； CKLP1），以及本提案中提出的新初步数据，我们假设 KATP 通道开放剂降低通过靶向远端流出通路中的脉管系统，促进液体流过 Erk1/2 来实现 IOP 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剂并可以保护 RGC 免受各种青光眼损伤。为了检验这些假设，我们建议描述远端流出途径中 KATP 通道的血管调节作用，定义相关的与 Erk1/2 信号通路相关的分子事件，确定相关的神经保护特性与 RGC 中 KATP 通道开放有关，并检查 RGC 中 KATP 通道开放剂的降眼压活性青光眼模型。拟议研究的新发现将为实现这一目标提供重大进展了解青光眼的病理生理学、增强 RGC 存活的新机制以及 KATP 通道开放剂前药 CKLP1 作为潜在治疗剂的表征青光眼的管理。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

Evaluation of neural innervation in the human conventional outflow pathway distal to Schlemm's canal.

DOI：
10.1016/j.exer.2022.109132
发表时间：
2022-08
期刊：
EXPERIMENTAL EYE RESEARCH
影响因子：
3.4
作者：
Hann, Cheryl R;Bentley, Michael D;Vercnocke, Andrew;Roy Chowdhury, Uttio;Fautsch, Michael P
通讯作者：
Fautsch, Michael P

Anatomical Variation of Human Collector Channel Orifices.