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: 8986673
• 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/8986673
• 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; Health; Hour; Human; Investigational New Drug Application; Lead; Light; Modeling; Molecular; Mus; Mutation; Organ Culture Techniques; Outcome; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacologic Substance; 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; genetic manipulation; human tissue; improved; inhibitor/antagonist; myocilin; novel; pre-clinical; prevent; research study; 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）：