2014 Shaffer Research Grants

Protection of retinal neurons that die in glaucoma is a fundamental therapeutic strategy, but one that remains elusive. Although basic research documents that these cells die by a multi-factorial process, the vast majority of therapies tested to date, or in development, are likely to fail because they target only a single injury pathway. A novel way of approaching protection-based therapeutics for glaucoma should derive from evidence accumulating over two decades in stroke and cardiac arrest: That simultaneously activating a variety of self-defense responses in cells with stressful “conditioning” stimuli induces the expression of a host of genes that promote cell survival. We plan to test two such “epigenetics”-based therapeutic strategies in a model of glaucoma. If successful, our studies will provide a viable therapeutic strategy for saving vision in patients with glaucoma.

Use of eye injections of drugs aimed at slowing the growth of abnormal blood vessels in the eye is becoming more common for the treatment of individuals with many eye problems including macular degeneration, diabetic retinopathy and retinal artery or vein blockage. Unfortunately, injections of these drugs can cause high eye pressure that may lead to glaucoma in some patients or make the control of high eye pressure more difficult in others. Considering the large number of people over the age of 40 who have glaucoma, many may be at particular risk of permanent vision loss from loss of pressure control when treated with these injections. Eye pressure by itself is determined by a delicate balance of fluid inflow and outflow from inside the eye. The effect of the injected drugs on any of these parameters has never been formally evaluated. The purpose of this study is to determine the effects of these drugs on the inflow and outflow of fluid from the eye and its consequences on eye pressure. Knowledge of the actual physiological effect of these drugs can have many benefits for glaucoma patients. For one it will help the eye doctor choose the optimal therapy to prevent the eye pressure elevation or to treat the high eye pressure if it does occur. Further research also will help determine which if any of these drugs is safer for glaucoma patients who also have abnormal blood vessel growth.

The purpose of this study is to investigate the role of exosomes, small cell-manufactured vesicles secreted into bodily fluids including blood and the fluid in the eye called aqueous humor. Exosomes contain RNA, which is used to regulate cell function. Secreted RNAs have already been shown to be involved in cell-cell communication between different tissues/organs and to serve as biomarkers for human disorders, such as cancer. We will examine the characteristics of the RNA contained in exosomes in the aqueous humor with special emphasis on its function in exfoliation glaucoma, including the most common form of secondary open-angle glaucoma. This study may provide a potential biomarker and therapeutic targets for glaucoma.

Dr. Liu’s research results from this study were published in the January 18, 2015 edition of the peer-reviewed journal Experimental Eye Research, and the February 1, 2018 issue of the journal Human Molecular Genetics.

In glaucoma, permanent vision loss and blindness occur when retinal ganglion cells (RGCs) that make up the optic nerve are lost. Increasing evidence points to a central role of the immune system in the death of RGCs in glaucoma. A recent finding in our laboratory led to the novel hypothesis that immune system events involving lymphocytes are necessary for RGC cell death and optic nerve axon loss in glaucoma. This project will determine whether specific populations of lymphocytes are required for RGC death in glaucoma. Based on findings from this study, therapies might eventually be designed to modulate the immune system in order to prevent vision loss and blindness in glaucoma patients.

For his research project to determine whether therapies can be designed to modulate the immune system to prevent vision loss and blindness in glaucoma patients, Stuart J. McKinnon, MD, PhD was awarded the 2016 Shaffer Prize for Innovative Glaucoma Research. The Shaffer Prize, presented annually by Glaucoma Research Foundation, recognizes a researcher whose project best exemplifies the pursuit of innovative ideas in the quest to better understand glaucoma.

The central nervous system (CNS) is made up of neuronal cells and support cells, called glia. Whenever there is damage to the CNS, such as in the retina during glaucoma, nerve cells die and glial cells change their behavior in a process called activation. Although glial activation may have short-term benefits, there is consensus that in the long-term, these cells may contribute to the pathology of damaged neurons in glaucoma. Currently, we know that glia become activated in glaucoma, but we do not know by what process. More and more evidence from other parts of the brain suggest that a molecule called ATP is part of the signaling mechanism where damaged neurons tell the glia that they are in distress. We have preliminary evidence that this is also true in the retina after damage to the optic nerve. This proposal is aimed at determining if dying neurons in the retina (ganglion cells) signal to the retinal glia by releasing ATP through specialized channels made up of a protein called Pannexin1. An increased understanding of how the neurons and glia communicate in glaucoma should lead to new developments on how to “tame” the glia into a non-pathologic role, thus increasing the potential for greater preservation of sight.

Glaucoma is the second most common cause of vision loss and blindness in the world. Patients with glaucoma present at the clinic with loss of peripheral vision and eye pressure often above normal levels causing compression and damage in a part of the optic nerve called the lamina cribrosa (situated at the back of the eye). We hope to determine if proteins present in lamina cribrosa of glaucoma patients differ to those found in people who do not have the disease; as these proteins may contribute to disease progression. We are interested in three classes of proteins; one which is responsible for the hardening of the cells and their surrounding environment (these are known as fibrotic proteins) in glaucoma and the other which regulates the level of calcium entering and exiting cells. We hypothesise that a third protein group, the caveolin scaffolding proteins, may provide a link between fibrosis and calcium levels and may be responsible for their disregulation in glaucoma. It is our hope that the long-term outcome of this project will be a strategy for relieving the disease burden for sufferers of glaucoma.

Our goal is to develop a powerful new type of glaucoma decision support tool to help eye doctors quickly and effectively identify which glaucoma patients are at high risk of getting worse and prevent them from losing more vision. Key features of this innovative technology are that it (1) learns more and more about the stability of the patient’s glaucoma with every measurement of eye pressure or visual field, (2) can be personalized to identify the optimal frequency of testing for each individual patient, and (3) would suggest an eye pressure level specific for that particular patient that the care provider would use in the process of recommending treatment. Preliminary results from an early version of this technology demonstrate that it is capable of identifying patients whose glaucoma is getting worse 57% sooner than existing approaches and it is able to significantly reduce the number of eye pressure and visual field measurements required to check for glaucoma worsening. This grant will enable us to advance and expand our technology so that it (1) determines for each patient the ideal level of eye pressure, and (2) guides eye doctors about how frequently each patient should undergo various glaucoma tests like checking eye pressure or undergoing visual field testing. With Glaucoma Research Foundation support, we plan to create this new methodology for a glaucoma decision support tool and further test it so that it will soon be ready to help eye doctors prevent their patients with glaucoma from getting worse.