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.

Public Health Relevance

Glaucoma is a potentially blinding eye disease affecting approximately 2.2 million Americans, including 285,000 Veterans. The goal of all existing therapies for glaucoma center on reducing intraocular pressure. We have discovered a molecular pathway influencing how intraocular pressure levels naturally cycle throughout a 24-hour cycle, typically becoming elevated at night. Our proposed experiments manipulate this molecular pathway to test whether preventing the rise of intraocular pressure at night is capable of slowing, or preventing, glaucoma. In completing these experiments, our goal is to improve glaucoma treatments that make the disease less debilitating for Veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Sensory Systems & Communication Disorders (RRD3)
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Iowa City VA Medical Center
Iowa City
United States
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Anderson, Michael G; Meyer, Kacie J; Hedberg-Buenz, Adam et al. (2018) Update on Animal Models of Exfoliation Syndrome. J Glaucoma 27 Suppl 1:S78-S82
Batawi, Hatim; Lollett, Ivonne Valentina; Maliakal, Cima et al. (2018) A Comparative Study of Central Corneal Epithelial, Stromal, and Total Thickness in Males With and Without Primary Open-Angle Glaucoma. Cornea 37:712-719
Dutca, Laura M; Rudd, Danielle; Robles, Victor et al. (2018) Effects of sustained daily latanoprost application on anterior chamber anatomy and physiology in mice. Sci Rep 8:13088
Wang, Chen; Brancusi, Flavia; Valivullah, Zaheer M et al. (2018) A novel iris transillumination grading scale allowing flexible assessment with quantitative image analysis and visual matching. Ophthalmic Genet 39:41-45
Fingert, John H; Miller, Kathy; Hedberg-Buenz, Adam et al. (2017) Transgenic TBK1 mice have features of normal tension glaucoma. Hum Mol Genet 26:124-132
Meyer, Kacie J; Anderson, Michael G (2017) Genetic modifiers as relevant biological variables of eye disorders. Hum Mol Genet 26:R58-R67
Zarei, Kasra; Scheetz, Todd E; Christopher, Mark et al. (2016) Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ. Sci Rep 6:26559
Hedberg-Buenz, Adam; Christopher, Mark A; Lewis, Carly J et al. (2016) Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification. Exp Eye Res 146:370-85
Hedberg-Buenz, Adam; Christopher, Mark A; Lewis, Carly J et al. (2016) RetFM-J, an ImageJ-based module for automated counting and quantifying features of nuclei in retinal whole-mounts. Exp Eye Res 146:386-92