Glaucoma, a leading cause of blindness worldwide, is characterized by progressive loss of retinal ganglion cells
(RGCs), an excavated appearance of the optic nerve, and vision loss. The etiology of glaucoma is complex,
involving biomechanical stress, pro-inflammatory cytokines, deprivation of neurotrophic factors, and epigenetic
changes. Currently, there is no clinical treatment to rescue RGCs in glaucoma patients. Therefore, effective
neuroprotective strategies and agents are needed to rescue RGCs. Epigenetic modification is an emerging and
promising novel approach to modulate cellular function in neurodegenerative diseases, however, its role in
glaucoma remains poorly defined. Our laboratory has demonstrated that sustained activation of d-opioid receptor
by SNC-121 for 7-days offered significant long-term (42-days) RGC neuroprotection in a chronic rat glaucoma
model. This long-term neuroprotective response supports the idea that opioids induce epigenetic changes in the
retina allowing RGCs to maintain their functional integrity under conditions that normally lead to progressive
RGCs loss. Pain management studies have shown that epigenetic changes are associated with opioid-induced
tolerance and dependence that develops following chronic opioid-administration. We provided preliminary data
showing that epigenetic regulators such as class I and IIb histone deacetylases, DNA methyltransferases
(DNMTs) activities and expression, and genome wide DNA methylation were significantly increased in response
to ocular hypertension-induced injury. Additionally, RNA Seq, PCR array, immunohistochemistry, and ATAC Seq
data provide significant leads that cytokines, pro-apoptotic pathways, transcriptional factors, neurotrophins, and
chromatin structure are significantly affected by ocular hypertension injury and d-opioids treatment. We also
have shown that transcription start sites (TSS) of numerous genes in “CpG” Island were differentially affected by
d-opioids. Based on our Preliminary Data, we hypothesize that “Activation of d-opioid receptors induces
hyperacetylation and hypomethylation that attenuates RGCs death in glaucoma”. To test this hypothesis,
we propose the following two Specific Aims. Specific Aim 1. Determine the crucial roles of class I and IIb histone
deacetylases (HDACs) in RGC death in ocular hypertensive animals. Specific Aim 2. Determine the role of DNA
methylation in d-opioid-mediated RGC neuroprotection in ocular hypertensive animals. The outcome of the
proposed studies will not only have a positive impact on the understanding of mechanisms underlying the
opioid-mediated RGC neuroprotection, but will also identify novel and innovative targets for glaucoma therapy.