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Opioid-Induced Epigenetic Mechanisms in Glaucoma

Award Number: R01EY034514
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Opioid-Induced Epigenetic Mechanisms in Glaucoma - 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 δ-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 δ-opioids treatment. We also have shown that transcription start sites (TSS) of numerous genes in “CpG” Island were differentially affected by δ-opioids. Based on our Preliminary Data, we hypothesize that “Activation of δ-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 δ-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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $421,439 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Vision Research	000	4	2/3/2026	NON-COMPETING CONTINUATION	$421,439
														Subtotal = $421,439

Issue Date FY: 2025 ( Subtotal = $421,439 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Vision Research	000	3	1/23/2025	NON-COMPETING CONTINUATION	$421,439
														Subtotal = $421,439

Issue Date FY: 2024 ( Subtotal = $421,439 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Vision Research	000	2	2/8/2024	NON-COMPETING CONTINUATION	$421,439
														Subtotal = $421,439

Issue Date FY: 2023 ( Subtotal = $443,072 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Vision Research	000	1	2/27/2023	NEW	$443,072
														Subtotal = $443,072

Grand Total All Awards = $1,707,389

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Opioid-Induced Epigenetic Mechanisms in Glaucoma

Award Number: R01EY034514

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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