Therapy of Nocturnal Intraocular Pressure Elevation Causing Glaucoma Progression

描述(由申请人提供)： 青光眼是导致不可逆转的失明和视力残疾的主要原因，对美国人的生活质量和生产力有重大影响，其中包括大约285,000名退伍军人。自20世纪90年代以来，没有新的治疗青光眼的药物类别被引入临床实践，因此仍然需要改进方案，以更有效地治疗青光眼。我们的长期目标是为这些改进的治疗方法的开发做出贡献，使疾病不那么虚弱。在这里，我们关注一种新的治疗策略，旨在防止夜间眼压(IOP)升高。高眼压是导致青光眼的主要危险因素。每天晚上，无论有没有青光眼，眼压都会上升。在青光眼患者中，这些夜间眼压的上升被怀疑在促进疾病进展方面具有特别重要的作用。这项建议的目的是确定与夜间眼压升高有关的药理靶向分子。我们的中心假设是酪蛋白激酶2(CK2)是生理眼压调节的关键参与者，抑制CK2将阻止夜间眼压升高，从而抑制青光眼。我们已经产生了这个假设，我们的实验是基于我们的初步数据，在小鼠身上发现了一种突变，这种突变能够防止夜间眼压上升，并拯救青光眼。随后的实验使我们怀疑CK2是这些现象的核心，包括初步数据表明CK2的药理抑制剂可以防止夜间眼压上升。为了证实这一发现，我们目前的实验利用小鼠和人类组织的房水动力学生理学分析来描述CK2影响眼压的机制，并确定相同的通路是否也在人眼中活跃。实验的设计利用了几种独特的动物资源，包括精心控制的遗传背景，对CK2的靶向干扰，以及基于人类肌球蛋白基因中导致青光眼的突变的转基因表达的新的青光眼模型。作为对小鼠实验的补充，该设计还将房水动力学研究与人体组织结合起来。为了验证我们的假设和实现我们的目标，我们提出：(特定目标1)确定CK2抑制对小鼠眼组织的影响，以及(特定目标2)确定CK2抑制对人眼组织的影响。在这些研究完成后，我们希望确定CK2的调节是否是一种可以用于治疗青光眼患者的有效方法。

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of irreversible blindness and visual disability that has a major impact on the quality of life and productivity of Americans, including approximately 285,000 Veterans. With no new pharmaceutical classes for treating glaucoma introduced into clinical practice since the 1990s, there remains a continuing need for improved regimes that treat glaucoma more effectively. Our long-term goal is to contribute to the development of these improved therapies that make the disease less debilitating. Here, we focus on a novel treatment strategy aimed at preventing nocturnal rises in intraocular pressure (IOP). Elevated IOP is a cardinal risk factor leading to glaucoma. Every night, in people with and without glaucoma, IOP rises. In patients with glaucoma, these nocturnal rises in IOP are suspected of having particular importance in promoting disease progression. The objective of this proposal is to identify pharmacologically targetable molecules contributing to nocturnal rises in IOP. Our central hypothesis is that casein kinase 2 (CK2) is a key participant in physiologic IOP regulation whose inhibition will prevent nocturnal rises in IOP and suppress glaucoma. We have generated this hypothesis, and our experiments to test it, based on our Preliminary Data identifying a mutation in mice that is capable of preventing a nocturnal rise in IOP and that rescues glaucoma. Subsequent experiments have led us to suspect that CK2 is central to these phenomena, including Preliminary Data that a pharmacological inhibitor of CK2 prevents nocturnal rises in IOP. To substantiate this finding, our current experiments utilize physiologic assays of aqueous humor dynamics in mice and human tissues to delineate the mechanisms by which CK2 influences IOP and to establish if the same pathways are also active in human eyes. The design of the experiments makes use of several unique animal resources, including carefully controlled genetic backgrounds, targeted disruptions to CK2, and a new model of glaucoma based on transgenic expression of a glaucoma-causing mutation in the human myocilin gene. Complementing these experiments in mice, the design also incorporates studies of aqueous humor dynamics with human tissue. To test our hypothesis and achieve our objective, we propose: (Specific Aim 1) Determine the influence of CK2 inhibition on mouse ocular tissues, and (Specific Aim 2) Determine the influence of CK2 inhibition on human ocular tissues. Upon completion of these studies we expect to have determined if modulation of CK2 is an effective approach that could be used to treat patients with glaucoma.