Neurobiology of Pressure-Induced Damage in Glaucoma
The neurobiology of pressure-induced cell death in glaucoma is poorly understood. DBA/2J mice provide a tractable model for dissecting pathways of cell death in inherited glaucoma and for investigating neuroprotective strategies. The inherited nature of the DBA/2J disease, marked by a progressive, relatively mild onset of pressure insult, is an important feature of this model.
We use the DBA/2J model to address how and why retinal ganglion cells (RGCs) die in glaucoma. It is now known that the pathways that destroy the soma and axon of the same neuron can differ. Using mutants in which somal and axonal degeneration are separately impeded, we have started experiments to determine whether high IOP insults the RGC soma, axon, or both in glaucoma. We recently demonstrated that the pro-apoptotic molecule BAX is required for RGC death in DBA/2J glaucoma. However, BAX is not required for RGC axon degeneration. This indicates that distinct somal and axonal degeneration pathways are active in this glaucoma.
Future efforts will focus on understanding the different somal and axonal degeneration pathways. To understand these processes, we are using a variety of approaches including genetics and genomics. We are completing a comprehensive genomic study of gene expression changes at different stages of glaucoma and are identifying very early changes. These studies will provide new insights into RGC death in glaucoma and will identify potential therapeutic targets.
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