Endothelin Signaling in Glaucomatous Neurodegeneration
The endothelin (EDN) system has been implicated in human and animal models of glaucoma. Activation of the EDN system has been shown to be an early, pathogenic response in animal models of glaucoma. The EDN system consists of three ligands, EDN1, EDN2, EDN3, and two receptors, endothelin receptor subtype A and B (EDNRA and EDNRB respectively). Many organ systems, including the central nervous system, use the EDN system to maintain normal physiology.
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Role of Proinflammatory Signaling in Glaucoma
The molecular signaling pathway leading from initial glaucomatous injury to retinal ganglion cell (RGC) death remains incompletely defined. Recent studies have supported a novel role for inflammatory extrinsic signaling as an early driver of glaucomatous neurodegeneration. Genomic analysis after ocular hypertension (OHT) revealed that astrocytes become reactive prior to RGC loss. However, when astrocyte reactivity was impaired, RGC death was exacerbated after both OHT and optic nerve crush (ONC) glaucoma-relevant injuries, suggesting activated astrocytes have a beneficial role in mitigating RGC degeneration.
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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.
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