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）： 青光眼是不可逆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产生重大影响，其中包括约285，000名退伍军人。由于自20世纪90年代以来没有新的用于治疗青光眼的药物类别引入临床实践，因此仍然持续需要更有效地治疗青光眼的改进方案。我们的长期目标是促进这些改进的疗法的发展，使疾病不那么虚弱。在这里，我们专注于一种新的治疗策略，旨在防止夜间眼内压（IOP）上升。眼压升高是导致青光眼的主要危险因素。每天晚上，患有和不患有青光眼的人的IOP都会升高。在青光眼患者中，这些夜间IOP升高被怀疑在促进疾病进展方面具有特别重要的意义。该提案的目的是确定导致夜间IOP升高的可重复靶向分子。我们的中心假设是酪蛋白激酶2（CK2）是生理性IOP调节的关键参与者，其抑制将防止IOP夜间升高并抑制青光眼。我们已经产生了这个假设，我们的实验来测试它，基于我们的初步数据，确定了小鼠中的一种突变，这种突变能够防止夜间IOP升高并挽救青光眼。随后的实验使我们怀疑CK2是这些现象的核心，包括CK2的药理学抑制剂防止夜间IOP升高的初步数据。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的房水动力学的生理测定来描绘CK2影响IOP的机制，并确定相同的途径是否也在人眼中活跃。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，CK2的靶向破坏，以及基于人肌球蛋白基因中引起青光眼突变的转基因表达的青光眼新模型。作为对小鼠实验的补充，该设计还结合了对人体组织房水动力学的研究。为了验证我们的假设并实现我们的目标，我们提出：（具体目标1）确定CK2抑制对小鼠眼组织的影响，（具体目标2）确定CK2抑制对人眼组织的影响。在完成这些研究后，我们希望确定CK2的调节是否是一种有效的方法，可用于治疗青光眼患者。