Extraordinary teamwork model generates breakthroughs in glaucoma research

Glaucoma researchers at OHSU Casey Eye Institute work cooperatively to improve glaucoma care. Many institutions study
either anterior mechanisms that affect aqueous humor outflow dynamics or posterior mechanisms of glaucomatous optic nerve damage. In contrast, our glaucoma research encompasses both, forming a team that currently holds 14 grants, representing over $24 million in total funding from the National Institutes of Health.

“The longitudinal dedication and the sheer breadth of the work on the glaucoma problem by our group is remarkable,” said clinician-scientist John Morrison, M.D., whose glaucoma research career began in the early 1980s.

Anterior research

Much of this impressive work builds on the research of Ted Acott, Ph.D., who has made crucial contributions over the last 40 years to understanding how aqueous humor outflow is regulated by the trabecular meshwork (TM) and how this affects glaucoma. Acott has mentored several members of the team who have stayed at OHSU to continue their basic science research. Areas of interest include:

• TM: Kate Keller, Ph.D., studies proteins and gene expression in TM cells and how cells communicate. She also studies the effect of netarsudil (Rhopressa) on the actin cytoskeleton and how it stimulates phagocytosis to clear outflow channels in TM tissue.
• Stem cells: Mary Kelley, Ph.D., winner of the 2017 Lewis Rudin Glaucoma Prize from the New York Academy of Medicine, is studying how autologous stem cells transplanted to the TM might restore intraocular pressure (IOP) homeostasis.
• Gene variants: Geneticist Mary Wirtz, Ph.D., has identified genes linked to glaucoma, including one variant that may affect TM tissue and eye pressure regulation. Studies are underway to elucidate the effects of this gene variant on TM cell function.
• TM outflow: The late Janice Vranka, Ph.D., investigated outflow regulation through the TM, showing how regional molecular and biomechanical differences in the extracellular matrix produce a pattern of high and low aqueous humor outflow regions.

Knowledge gained from these studies will lead to better understanding of the causes of glaucoma as well as improved treatments for increasing aqueous humor outflow and IOP, a major risk factor for glaucoma.

Posterior research

In the early 1990s, Morrison and his associate, Elaine Johnson, Sc.D., pioneered the development of preclinical models of glaucoma. They initially described gene and cellular responses to chronically elevated IOP within the optic nerve 16 head (ONH), the site of axonal injury in glaucoma. Later, they developed a short-term, acute pressure elevation model. This has led to work by several other investigators, including:

• Diana Lozano, Ph.D., has demonstrated which cells are responsible for ONH gene and protein response in chronic glaucoma, and that similar responses can appear sequentially following a discrete, short period of elevated IOP. She is now using this knowledge to determine which gene and protein responses might protect from pressureinduced axonal injury.
• Vision neuroscientist Benjamin Sivyer, Ph.D., is using this short-term model to study the impact of pressure-induced optic nerve damage on retinal ganglion cells and their projections to the brain, providing information that may lead to new approaches to help these injured cells survive. In collaboration with a national team of glaucoma researchers, Sivyer recently received a National Eye Institute Audacious Goals Initiative U24 grant to understand barriers to using stem cell therapy to replace retinal ganglion cells.
• Clinician-scientist Shandiz Tehrani, M.D., Ph.D., has used both chronic and acute animal models to determine how ONH astrocytes respond to elevated IOP, and is now using the short-term model to determine how these cells influence glaucomatous nerve injury. He has also developed a unique method of small molecule delivery to uncover mechanisms of astrocyte response and explore new treatments for preventing axonal degeneration.

Collaboration leads to innovative new research targets

These investigators have formed active collaborations among their team and with other OHSU Casey Eye Institute investigators. These synergies create opportunities, according to Keller. “The collegial environment in all of our labs allows for a lot of mentoring and excitement in discovery,” she said. “Our shared purpose is to take our collective research and design new and novel therapeutics for glaucoma.”

Collaborative research examples include:

• Keller, Lozano and Morrison have combined their expertise in anterior and posterior glaucoma research to generate a newly funded grant to understand the gene profile of IOP homeostasis. “Because we are working in two different aspects of the eye, our team can ask and answer questions that lead us in new directions with translational potential,” Morrison said. “For example, our preclinical model allows Dr. Keller to use the living trabecular meshwork to confirm observations she previously could only make using cell and organ culture techniques.”
• Morrison and Yali Jia, Ph.D., associate director of OHSU Casey Eye Institute’s Center for Ophthalmic Optics and Lasers (COOL lab), have an NIH grant to develop visible-light OCT angiography (OCT-A) to image blood flow and determine oxygenation of retinal capillaries. This technology may provide new insights into the pathogenesis of glaucoma and lead to new, early indicators of glaucoma progression.
• David Huang M.D., Ph.D., director of the COOL lab and co-inventor of OCT, is collaborating with glaucoma specialists Beth Edmunds, M.D., Ph.D., Aiyin Chen, M.D., and Eliesa Ing, M.D., Tehrani and Morrison, to develop novel objective functional and structural OCT and OCT-A technologies for glaucoma. These translational studies, funded by the NIH, offer exciting new opportunities to  detect early glaucoma, and improve the sensitivity and accuracy of detecting significant disease progression.
• Hiroshi Ishikawa, M.D., who is also funded by the NIH and makes use of glaucoma clinical and image data, is collaborating with the IBM Watson Research Team for developing various deep-learning applications in clinical glaucoma. These include glaucoma diagnosis and estimation and prediction of visual function based on 3D retinal imaging data.

Casey Glaucoma Research Team

Ted Acott, Ph.D.
Aiyin Chen, M.D.
Beth Edmunds, M.D., Ph.D.
David Huang, M.D., Ph.D.
Eliesa Ing, M.D.
Hiroshi Ishikawa, M.D.
Yali Jia, Ph.D.
Kate Keller, Ph.D.
Mary Kelley, Ph.D.
Diana Lozano, Ph.D.
John Morrison, M.D.
Benjamin Sivyer, Ph.D.
Shandiz Tehrani, M.D., Ph.D.