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Catalyst for a Cure Research Consortium of the Glaucoma Research Foundation
The long term goal of these studies is to uncover cellular and molecular mechanisms that underlie why retinal ganglion cells (RGCs) die in glaucoma. Glaucoma is a blinding disease that affects over 60 million people worldwide. Though most blindness due to glaucoma occurs in aged individuals, there are various congenital forms of the disease that affect children. And while increased intraocular pressure (IOP) is an important risk-factor for the disease, it neither always precedes the disease nor is it the only therapeutic target, as reducing IOP produces effective though incomplete protection. Recent effort from the Catalyst for a Cure Consortium and many other laboratories has focused on the possibility of developing therapeutic strategies for glaucoma based on neuroprotection.
One goal of the proposed research is to characterize disease progression in a mouse model that mimics the chronic aspects of glaucoma, and in a rat model that is more acute. Analyses of molecular markers in both the retina and the optic nerve have helped to define the timeline of glaucomatous degeneration. The primary insult has been anatomically localized to axons, probably at the optic nerve head. The RGCs survive after their axons are severely damaged or lost, and generally downregulate gene expression but increase somatic expression of phosphorylated neurofilaments, a feature observed in other neurodegenerative disorders. Within the nerve, astrocytes become reactive early, followed later by the loss of oligodendrocytes. Another goal of the studies is to explore the possible role of a gene expressed at high levels in RGC, gamma-synuclein. Based on the similarity of this gene to alpha-synuclein, which is central to neurodegeneration in Parkinson’s Disease, the possibility that glaucoma is a synucleinopathy is being explored. These studies will contribute to the understanding of disease mechanisms in glaucoma, and hopefully will lead to the development of novel therapeutic approaches for this and other neurodegenerative diseases.
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