The long-term goal of this research is to elucidate how aging and intraocular pressure (IOP) influence retinal ganglion cell (RGC) degeneration in glaucoma and to leverage this knowledge to identify novel therapies based on neuronal protection, repair, and regeneration. This is an important goal, since all of vision is encoded by action potentials propagated along RGC axons in the optic projection. These axons degenerate steadily from adulthood to death and are susceptible early in glaucoma. Axonal signals are determined primarily by excitatory, glutamatergic synapses summed and integrated in the RGC dendritic arbor. The objective here is focused on understanding how RGC axon degeneration in the optic projection in aging and glaucoma relates to synapse degradation in the retina. To gain this understanding, experiments will test a novel central hypothesis: that early axonal stress due to aging and IOP induces self-repair and adaptive remodeling of the RGC synaptic complex to prolong signaling, similar to homeostatic plasticity of excitatory synapses in other systems. This dynamic relationship stands in stark contrast to the most prevalent current hypothesis in which early and irrevocable synaptic and dendritic pruning drives RGC axon loss. A series of rigorous, quantitative and functional assays will test this remodeling hypothesis by leveraging both chronic (DBA2J) and inducible (microbead occlusion) models of glaucoma. Experiments in Aim 1 will vary IOP and map changes in synaptic and cytoskeletal components to dendritic complexity and axonal function for different RGC types.
Aim 2 will assess how synaptic and dendritic changes for RGC types characterized by axon function depend on age and whether aging influences the response to elevated IOP. Finally, Aim 3 will use established transgenic tools to modulate axonal and somatic degeneration and determine for key ages and IOPs whether dendrites and synapses in individual RGC types are conserved or undergo remodeling independently. These innovative studies combining neurochemical, morphological, and physiological measures will enrich the understanding of how synaptic and axonal activity interrelate at the molecular level and lay the foundation for novel therapeutics based on neuronal self-repair.

Public Health Relevance

Glaucoma is the leading age-related cause of irreversible blindness worldwide and will afflict an estimated 80 million people by 2020. The disease causes optic nerve degeneration with aging and sensitivity to ocular pressure, but lowering pressure does not always stop progression. The work proposed here will test how a novel mechanism for self-repair in the retina might slow optic nerve degeneration in both normal aging and in glaucoma by remodeling lost retinal activity.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024997-04
Application #
9181431
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2014-12-02
Project End
2019-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Bernardo-Colón, Alexandra; Vest, Victoria; Clark, Adrienne et al. (2018) Antioxidants prevent inflammation and preserve the optic projection and visual function in experimental neurotrauma. Cell Death Dis 9:1097
Risner, Michael L; Pasini, Silvia; Cooper, Melissa L et al. (2018) Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma. Proc Natl Acad Sci U S A 115:E2393-E2402
Cooper, Melissa L; Collyer, John W; Calkins, David J (2018) Astrocyte remodeling without gliosis precedes optic nerve Axonopathy. Acta Neuropathol Commun 6:38
Bond, Wesley S; Hines-Beard, Jessica; GoldenMerry, YPaul L et al. (2016) Virus-mediated EpoR76E Therapy Slows Optic Nerve Axonopathy in Experimental Glaucoma. Mol Ther 24:230-239
Cooper, Melissa L; Crish, Samuel D; Inman, Denise M et al. (2016) Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. Exp Eye Res 150:22-33
Sappington, Rebecca M; Sidorova, Tatiana; Ward, Nicholas J et al. (2015) Activation of transient receptor potential vanilloid-1 (TRPV1) influences how retinal ganglion cell neurons respond to pressure-related stress. Channels (Austin) 9:102-13
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