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（IOP）升高是青光眼中最普遍，唯一可治疗的危险因素。而 IOP升高的原因通常归因于小梁网/Schlemm的运河的阻力增加界面，一个不断扩展的证据凸显了由远端部分产生的潜在阻力常规的流出路径（Schlemm的运河外墙，收集器通道以及相关的深层硬化和内血管内）。已显示该区域内的扰动有助于青光眼。我们已经确定了KATP通道开启器的一部分是新型的眼部降压剂，可降低IOP 在正常的动物模型（小鼠，兔子，非人类灵长类动物）中传统的流出路径（此处称为远端流出路径）。这种新颖的行动方式为我们提供了一个独特的机会，可以研究该地区在青光眼中的作用，同时详细表征该药物类的作用方式。此外，我们还有初步数据表明KATP通道开启器向视网膜神经节细胞（RGC）提供神经保护作用。基于我们以前的资金完成的研究时期，该药物类别的水溶性，疗法友好形式的发展（Cromakalim Prodrug 1； CKLP1）和本提案中提供的新初步数据，我们假设KATP频道开启器较低 IOP通过靶向远端流出途径中的脉管系统，促进通过ERK1/2的流体流动介导的信号级联。此外，我们假设KATP通道开启器也是神经保护代理商可以保护RGC免受各种青光眼侮辱。为了检验这些假设，我们建议表征KATP通道在远端流出途径中的血管调节作用，定义相关与ERK1/2信号通路有关的分子事件，确定相关的神经保护特性在RGC中打开KATP通道，并检查Katp通道开启器的眼部降压活性青光眼模型。拟议研究的新发现将为了解青光眼的病理生理学的目标，增强RGC存活的新型机制和 KATP通道揭幕室前药CKLP1的表征为潜在的治疗剂青光眼管理。

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.