Therapy of Nocturnal Intraocular Pressure Elevation Causing Glaucoma Progression

夜间眼压升高导致青光眼进展的治疗

• 批准号: 9182823
• 负责人: Michael G Anderson
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182823
• 关键词: Affect; American; Aqueous Humor; Binding Proteins; Biological Assay; Blindness; CHS1 gene; Clinical Trials; Complement; Data; Development; Disease; Disease Management; Disease Progression; Epithelial Cells; Ethnic Origin; Eye; Eye diseases; Future; Genes; Genetic; Glaucoma; Goals; Hour; Human; Investigational New Drug Application; Light; Modeling; Molecular; Mus; Mutation; Organ Culture Techniques; Outcome; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiologic Intraocular Pressure; Physiological; Production; Productivity; Quality of life; Regulation; Risk Factors; Role; Services; Testing; Tissues; Toxic effect; Transgenic Organisms; Translating; United States; Veterans; Visual; Wild Type Mouse; Work; animal data; animal resource; base; casein kinase II; clinical practice; design; disability; experimental study; genetic manipulation; human tissue; improved; inhibitor/antagonist; myocilin; novel; pre-clinical; prevent; public health relevance; treatment strategy

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.

描述（由申请人提供）： 青光眼是导致不可逆失明和视力障碍的主要原因，对美国人（包括大约 285,000 名退伍军人）的生活质量和生产力产生重大影响。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，因此仍然持续需要改进的治疗方案以更有效地治疗青光眼。我们的长期目标是促进这些改进疗法的开发，从而减轻这种疾病的衰弱程度。在这里，我们重点关注一种旨在预防夜间眼压（IOP）升高的新治疗策略。眼压升高是导致青光眼的主要危险因素。每天晚上，无论是否患有青光眼，眼压都会升高。在青光眼患者中，眼压的夜间升高被怀疑对于促进疾病进展特别重要。该提案的目的是确定导致夜间眼压升高的药理学靶向分子。我们的中心假设是酪蛋白激酶 2 (CK2) 是生理 IOP 调节的关键参与者，其抑制作用将防止 IOP 夜间升高并抑制青光眼。我们根据初步数据确定了小鼠体内的一种突变，该突变能够防止夜间眼压升高并挽救青光眼，从而提出了这一假设，并通过实验对其进行了测试。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 的药理学抑制剂可防止夜间眼压升高。为了证实这一发现，我们目前的实验利用小鼠和人体组织中房水动力学的生理测定来描述 CK2 影响 IOP 的机制，并确定相同的通路在人眼中是否也活跃。实验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 的靶向破坏，以及基于人类肌纤蛋白基因中引起青光眼的突变的转基因表达的新青光眼模型。作为对小鼠实验的补充，该设计还结合了人体组织房水动力学的研究。为了检验我们的假设并实现我们的目标，我们建议：（具体目标 1）确定 CK2 抑制对小鼠眼组织的影响，以及（具体目标 2）确定 CK2 抑制对人眼组织的影响。完成这些研究后，我们希望确定 CK2 的调节是否是可用于治疗青光眼患者的有效方法。