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John has spent a decade at the Jackson Laboratory in Bar Harbor, Maine, improving the power of mouse models for studying glaucoma, a group of diseases characterized by the death of nerve cells that connect the eye to the brain. Here, he talks about recent directions in his work.
Using mouse models and genetics is very important for understanding the neurobiology of glaucoma and the involvement of elevated intraocular pressure (IOP) in the disease. Our research has helped overcome reluctance to using mouse models. We created the first method for measuring IOP in mice, which was a big hurdle, and we developed mouse models of inherited glaucoma to illuminate some of the genes and pathways involved in the disease.
We have identified several genes that induce high IOP, but we now know that IOP is not the only issue. Some people have high IOP and no glaucoma, while patients with glaucoma sometimes have low pressure. We need to identify those individuals whose optic nerves are more sensitive to increases in pressure. We also want to understand what changes are taking place in the optic-nerve head as well as in the retina.
I would like to see more translation of our research into the clinical setting, and in that regard I've been talking with clinicians in various places. We need to be resourceful and energetic to make that happen—for example, our research has shown that Bax is a gene that needs exploration in the human population. Is it a susceptibility gene in humans? Bax codes for the BAX protein and induces apoptosis. To explore retinal ganglion cell death, Richard T. Libby, a postdoc in my lab, crossed our glaucoma-prone mice with mice deficient in BAX to generate mice that were either completely missing BAX or had lower amounts of it. Importantly, even the mice missing just one copy of the Bax gene are profoundly protected from glaucoma because the nerve cells in the retina do not die. These mice don't lack BAX, they just have lower levels of it—a more realistic model for treating humans since it is easier to reduce the levels of a protein in patients than completely turn it off. We want to encourage clinicians to look at BAX inhibitors to see if they might be helpful for glaucoma patients.
Photo: Jose Azel
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