Wednesday, December 31, 2025 12/31/2025

Unifying Mechanism of Oxidative Stress and Inflammation in AMD

Award Number: R21EY035844
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Unifying Mechanism of Oxidative Stress and Inflammation in AMD - PROJECT SUMMARY Age-related macular degeneration (AMD) is a leading cause of vision loss, yet the molecular events that initiate the early retinal defects that lead to visual dysfunction remain poorly understood. The objective here is to examine a role for the stress response protein regulated in development and DNA damage 1 (REDD1) in the impaired adaptive response of retinal pigment epithelium (RPE) with aging and consequently development of AMD. Proof-of-concept studies support a potential role for REDD1 in AMD pathophysiology. In fact, intravitreal administration of a siRNA targeting the REDD1 mRNA has demonstrated promise for improving visual function in patients with AMD. However, we recently discovered that the REDD1 protein acts as a molecular redox sensor. Specifically, a reversible redox-sensitive disulfide bond prevents degradation of REDD1 by lysosomal proteolysis. Consequently, retinal REDD1 inhibition by siRNA-mediated knockdown may only be partially effective for reducing REDD1 protein expression in retinal disease. The central hypothesis is that activation of the REDD1 redox-sensor in RPE promotes oxidative stress, inflammation, and retinal pathology in AMD. To test the hypothesis, we will employ a preclinical murine model of non-neovascular AMD, transgenic REDD1 mouse lines, and human iPSC-derived RPE in three specific aims. Aim 1 will examine a role for REDD1 as a dominant governor of the nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant response in RPE. We predict that REDD1 prevents a proper antioxidant response in AMD by promoting Nrf2 nuclear exclusion. Aim 2 will investigate a role for REDD1 in RPE inflammation and trans-differentiation via activation of the transcription factor nuclear factor kappa B (NF-κB). The proposed studies will explore NF-κB signaling in AMD models and evaluate the expression of NF-κB target genes, including pro-inflammatory cytokines and epithelial-to- mesenchymal (EMT) transcription factors. Aim 3 will utilize REDD1 knockout mice and a newly developed REDD1 point mutation knockin mouse that expresses a REDD1 variant that is continuously degraded by lysosomal proteolysis to evaluate the formation of hyper-reflective foci, RPE damage, photoreceptor thinning, and impaired visual function in non-neovascular AMD. It is well established that oxidative stress and inflammation are crucial factors in the development and progression of the complications that cause visual impairment. The studies herein are significant because they are designed to identify and characterize specific molecular events that contribute to oxidative stress and inflammation in AMD by addressing key knowledge gaps related to a cutting-edge therapeutic target. To do so, we will explore the concept that activation of the REDD1 redox sensor is a unifying molecular mechanism for improper activation of Nrf2 and NF-κB in AMD.


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 = $0 )
2026	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	2	11/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $209,250 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	001	2	2/21/2025	NON-COMPETING CONTINUATION	$0
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	2	12/20/2024	NON-COMPETING CONTINUATION	$209,250
														Subtotal = $209,250

Issue Date FY: 2024 ( Subtotal = $251,100 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	1	12/22/2023	NEW	$251,100
														Subtotal = $251,100

Grand Total All Awards = $460,350

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Unifying Mechanism of Oxidative Stress and Inflammation in AMD

Award Number: R21EY035844

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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