Glaucoma is the second leading cause of irreversible blindness worldwide and it is estimated that 79.6 million people throughout the world will have glaucoma by 2020. Currently, increased intraocular pressure is the only known modifiable risk factor in glaucoma pathophysiology, and therefore the only treatment option available to patients and their physicians. Here we propose to investigate rhythmic stimulation of injured adult retinal ganglion cells (RGCs) as a novel therapeutic option in glaucoma. Our central hypothesis is that replication of the rhythmic RGC activity observed during development (retinal waves) will promote survival and axon regeneration of injured adult RGCs. To test this hypothesis we will specifically stimulate RGCs expressing a light-gated proton channel from the green algae Chlamydomonas reinhardtii. The Channelrhodopsin2 protein is expressed exclusively by RGCs of Thy1- COP4/EYFP line 9 (ChR2-YFP) transgenic mice. Using RGC specific Thy-1 expression of ChR2-YFP fusion protein allows us to both stimulate and track RGC survival overtime in vivo and in vitro.
In specific aim 1 we will use a proteomics approach to assess whether in vivo rhythmic stimulation of RGCs modulates the expression of proteins involved in neurotrophic pathways.
In specific aim 2, we will determine whether light induced rhythmic stimulation promotes cAMP independent RGC survival and neurite outgrowth in vitro by culturing RGCs in media containing cAMP inhibitors.
In aim 3 a we will determine whether rhythmic stimulation promotes RGC survival following optic nerve injury. Lastly, in aim 3b we will assess whether rhythmic stimulation promotes axon regeneration following optic nerve crush. The goal of this proposal is to explore a clinically applicable treatment modality to aid adult RGC neuron survival and axon regeneration after injury.
Glaucoma is the leading cause of irreversible blindness worldwide, affecting over 67 million people and up to 4% of individuals over 40 years of age. Disease incidence in the USA is disproportionately elevated in minority populations such as African Americans and Hispanic Americans and is responsible for nearly $3 billion (USD) in healthcare spending every year. Currently, increased intraocular pressure is the only known modifiable risk factor in glaucoma pathophysiology, and therefore the only treatment option available to patients and their physicians. Here we propose to investigate in vivo rhythmic stimulation of injured adult RGCs as a novel therapeutic option to support retinal ganglion survival in glaucoma.
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