Defining RGC-intrinsic Signaling Pathways in Glaucoma
An important challenge is to decipher whether changes that occur in glaucomatous eyes are harmful, protective, or inconsequential. To obtain a clearer understanding of the deleterious signaling pathways involved in glaucomatous neurodegeneration, we aim to define the relationship(s) between critical events in the degenerative process. Using animal models of glaucoma, we have shown that somal and axonal degeneration are distinct compartmentalized molecular processes in ocular hypertension-induced RGC death. The progression from early, focal injury to RGC axons to distinct compartmental degeneration processes in glaucoma suggests that axonal stress signaling pathways operate along the somal-axonal axis. Despite many advances in understanding experimentally-induced axonal injuries (e.g. axotomy, optic nerve crush (ONC)) the fundamental signals that link axonal damage to compartmental degeneration processes remain incompletely defined. They are particularly poorly understood for ocular hypertensive injuries in glaucoma. Important questions to address for ocular hypertension/glaucoma include: (i) Does axonal stress activate different signaling pathways proximally and distally to cause somal and axonal degeneration, respectively? (ii) How does degeneration of one compartment affect (and potentially activate) the degeneration cascade of the other cellular compartments? (iii) Is axonal degeneration driven by an active death signal or set off passively by the depletion of axonal survival/maintenance factors? By carefully characterizing axonal damage signaling events initiated in RGC axons at the lamina, the somal responses to axonal injury, and responses in the axonal segment distal to the insult, we can begin to answer these questions and define the degenerative cascade(s) that control compartmentalized destruction of both the RGC soma and axon. Therefore, we are focusing on defining the fundamental signaling systems that control RGC viability after an ocular hypertensive insult, including how these systems ultimately activate somal and axonal degeneration pathways.
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