Our long-term goal is to understand the mechanisms of neurodegeneration in glaucoma and find new ways to abate it. Vision loss in glaucoma involves selective loss of retinal ganglion cell (RGC) neurons through two broad degenerative programs: in the optic projection, affecting RGC axons, and in the retina, affecting RGC dendrites, synapses and cell bodies. Degeneration arises from sensitivity to intraocular pressure (IOP), but IOP-lowering regimens do not always slow progression. Thus, to intervene at the neuronal level requires a better understanding of how the RGC pathway responds to IOP-related stressors and whether this response includes mechanisms to counter loss of function. Our objective in this project is focused on characterizing one such mechanism involving the TRPV1 (transient receptor potential vanilloid-1) receptor. Our central hypothesis is that TRPV1 counters RGC degeneration by enhancing excitatory activity in response to IOP- related stress. In other systems, increased TRPV1 at the neuronal membrane maintains cytoskeletal integrity and augments synaptic excitation by enhancing Ca2+ activity in response to stress. We propose a similar role for TRPV1 in RGCs, having established TRPV1 as a robust Ca2+ channel in RGCs that, when activated, increases excitation and influences their survival. We will test our hypothesis using both acute (microbead occlusion) and chronic (DBA2J) mouse models for which we have mapped key RGC degenerative outcome measures.
For Aim 1, we will apply the acute model to a TRPV1 knock-out mouse to identify TRPV1- dependent axonal and retinal outcomes and their progression in RGC degeneration.
For Aim 2, we will compare in the acute and chronic models IOP-dependent changes in TRPV1 expression and localization and link these changes to RGC subcellular compartments to identify structural correlates of TRPV1's action.
For Aim 3 we will measure in both models how changes in IOP influence TRPV1's contribution to RGC excitation and determine if modulating TRPV1 sensitivity promotes survival. These new studies will capitalize on our completed studies of TRPV1 and a unique toolbox already in place to illuminate a novel cascade that could counter and slow stress-induced loss of function associated with glaucoma.

Public Health Relevance

Glaucoma is the leading cause of irreversible blindness worldwide and will afflict an estimated 80 million people by 2020. The disease causes optic nerve degeneration through sensitivity to ocular pressure, but lowering pressure does not always stop progression. The work proposed here will test how a novel mechanism involved in pressure sensitivity might counter degeneration by enhancing nerve activity and whether this response represents a potential therapeutic opportunity.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY017427-06
Application #
8500292
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2006-04-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$407,550
Indirect Cost
$146,300
Name
Vanderbilt University Medical Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
Ward, Nicholas J; Ho, Karen W; Lambert, Wendi S et al. (2014) Absence of transient receptor potential vanilloid-1 accelerates stress-induced axonopathy in the optic projection. J Neurosci 34:3161-70
Weitlauf, Carl; Ward, Nicholas J; Lambert, Wendi S et al. (2014) Short-term increases in transient receptor potential vanilloid-1 mediate stress-induced enhancement of neuronal excitation. J Neurosci 34:15369-81
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
Crish, S D; Dapper, J D; MacNamee, S E et al. (2013) Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target. Neuroscience 229:55-70
Crish, S D; Calkins, D J (2011) Neurodegeneration in glaucoma: progression and calcium-dependent intracellular mechanisms. Neuroscience 176:1-11
Crish, Samuel D; Sappington, Rebecca M; Inman, Denise M et al. (2010) Distal axonopathy with structural persistence in glaucomatous neurodegeneration. Proc Natl Acad Sci U S A 107:5196-201
Sappington, Rebecca M; Carlson, Brian J; Crish, Samuel D et al. (2010) The microbead occlusion model: a paradigm for induced ocular hypertension in rats and mice. Invest Ophthalmol Vis Sci 51:207-16
Sappington, Rebecca M; Sidorova, Tatiana; Long, Daniel J et al. (2009) TRPV1: contribution to retinal ganglion cell apoptosis and increased intracellular Ca2+ with exposure to hydrostatic pressure. Invest Ophthalmol Vis Sci 50:717-28