Intraocular pressure regulation via ATP-sensitive potassium channels

描述（由申请人提供）：这是一项研究通过三磷酸腺苷敏感钾（KATP）通道参与眼内压（IOP）调节的分子事件的申请。眼压升高是青光眼唯一可治疗的危险因素。不幸的是，参与流出阻力和IOP控制的关键分子是未知的。缺乏这方面的知识限制了针对这些过程的药物的发展。我们最近发现了一种关键的IOP细胞效应，可能会导致高眼压和青光眼的新药物治疗。我们发现，在人前段灌注模型中，KATP通道开放剂二氮氧化合物、尼可地尔和P-1075激活KATP通道可降低IOP。药理学打开剂对KATP通道的激活可被KATP通道关闭剂、格列本脲和甲苯丁胺阻断。此外，使用KATP通道开启剂二氮氧化物和前列腺素类似物latanoprost治疗比单独使用任何一种药物更能增加流出设施，这表明这些药物使用不同的机制来降低IOP。到目前为止，还没有在小梁流出通道中进行涉及KATP通道的研究。在非眼组织中，KATP通道的打开和关闭可改变细胞的收缩性和通透性，提供抗缺血和缺氧的代谢保护，并增强细胞对应激的适应。所有这些细胞事件都直接或间接地与青光眼的病因有关。我们认为，为了开发治疗IOP升高的药物，我们必须首先确定降低IOP的关键内在分子和生理机制。我们的中心假设是由KATP通道激活引起的细胞事件导致IOP降低。我们的假设是，KATP通道激活导致小梁网松弛，从而增加渗透性，改善流体流动，增强流出设施，降低眼压。我们提出表征KATP通道亚基结构，识别由KATP通道打开剂激活的细胞通路，并确定KATP通道打开与通过小梁流出通道增加的流出设施和降低IOP之间的生理功能。此外，我们将确定KATP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C57BL/6野生型和特异性KATP通道亚单位敲除小鼠IOP的影响。该提案的完成将对KATP通道在小梁流出通道中的作用提供完整的描述性和机制理解，并将有助于评估使用KATP通道开放剂作为增加POAG流出设施的治疗方式的可行性。

DESCRIPTION (provided by applicant): This is an 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. PUBLIC HEALTH RELEVANCE: The proposed studies on KATP channels will yield novel information regarding the mechanisms used to lower IOP in normal and POAG eyes. Analysis of KATP channel subunit structure and determination of cellular pathways affected by KATP channel openers will identify novel target molecules to which future therapies can be directed. More importantly, the analysis of KATP channel openers may result in a new class of drugs for the treatment of ocular hypertension and glaucoma.