Our long-term objective is to understand the early molecular events leading to the death of retinal ganglion cells (RGCs) and their axons in glaucoma. The defining feature of glaucoma is sensitivity to intraocular pressure (IOP), and elevated IOP represents a significant risk factor for the disease. Lowering IOP pharmacologically is the standard treatment to slow the disease, but there is no cure because the neurobiological mechanisms linking RGC degeneration to pressure remain unresolved. The death of RGCs in glaucoma demonstrates key aspects of neuronal death in other degenerative diseases, most prominently somatic (cell body) loss via apoptosis and axonal degeneration. In other diseases, somatic and axonal degenerative are often linked to elevated intracellular Ca2+, and Ca2+-dependent cascades are also likely to contribute to RGC degeneration in glaucoma. Our studies demonstrate that for RGCs exposed to elevated pressure in culture, rapidly increased intracellular Ca2+ predicates both somatic and axonal loss. These observations raise the questions of whether pressure-induced RGC death is dependent on increased intracellular Ca2+ and, if so, what is the mechanism of this dependence. We have hypothesized that pressure-induced RGC degeneration involves the activation of a mechanosensitive channel that directly gates an increase in intracellular Ca2+. In support of this hypothesis, we recently identified in RGCs the capsaicin-sensitive, vanilloid-1 transient receptor potential (TRPV1) channel. TRPV1 is characterized by a robust Ca2+ conductance that contributes to pressure sensitivity and Ca2+-dependent cell death in other systems. Here we will probe the relationships between pressure-induced changes in intracellular Ca2+, RGC death and TRPV1 activation using an in vitro preparation of purified RGCs optimized for studying somatic degeneration and a retinal explant preparation optimized for studying axonal degeneration ex vivo. By applying pharmacological tools to these systems we will (1) test the Ca2+-dependence of pressure-induced RGC degeneration and the contribution of TRPV1 to pressure-induced increases in RGC intracellular Ca2+ and (2) determine the dependence of pressure-induced RGC degeneration on TRPV1 activation. Finally, by applying genetic tools for gene inhibition and over-expression developed in our laboratory and a TRPV1 knock-out mouse we will (3) test the relationship between TRPV1 expression and RGC susceptibility to pressure-induced degeneration.
. With the aging of the population, glaucoma will afflict nearly 80 million people worldwide by 2020, making the disease the leading cause of irreversible blindness. Glaucoma remains incurable, largely because our understanding of how pressure sensitivity translates to RGC degeneration is incomplete. The work proposed here will explore a viable molecular mechanism for contributing to RGC susceptibility to pressure-related injury and test its relevance as a novel therapeutic target.
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|Ho, Karen W; Lambert, Wendi S; Calkins, David J (2014) Activation of the TRPV1 cation channel contributes to stress-induced astrocyte migration. Glia 62:1435-51|
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|Dapper, Jason D; Crish, Samuel D; Pang, Iok-Hou et al. (2013) Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy. Neurobiol Dis 59:26-37|
|Calkins, David J (2013) Age-related changes in the visual pathways: blame it on the axon. Invest Ophthalmol Vis Sci 54:ORSF37-41|
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