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Redox-sensitive activation of REDD1 in diabetic retinopathy

Award Number: R01EY032879
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Redox-sensitive activation of REDD1 in diabetic retinopathy - Project Summary Diabetes promotes cellular concentrations of the stress response protein Regulated in Development and DNA damage 1 (REDD1) in the retina, which contributes to the development of retinal disease and impaired visual function. Indeed, intravitreal administration of a siRNA targeting the REDD1 mRNA has demonstrated some limited therapeutic benefit in improving visual function of patients with diabetic macular edema. However, the approach was abandoned over a decade ago due to its failure to outperform vascular endothelial growth factor (VEGF) blockade, despite the partially effective results of this current standard of care. During the prior funding period, we discovered that the REDD1 protein acts as a critical intracellular redox sensor. Specifically, formation of a redox-sensitive disulfide bond acts allosterically to prevent the normally rapid degradation of REDD1 protein in the context of diabetes. This discovery suggests that REDD1 mRNA knockdown may be a poor strategy for reducing REDD1 protein abundance and activity in the context of diabetes. This renewal application is designed to identify new evidence-based therapeutic strategies for preventing the retinal pathology that is caused by REDD1. The rationale is that inhibiting the specific molecular events that lead to increased REDD1 protein abundance or those that are responsible for its deleterious effects on vision may provide new interventions early in the preclinical and non-proliferative stages of diabetic retinopathy (DR). The central hypothesis is that diabetes activates the REDD1 redox sensor to promote glycogen synthase kinase 3 (GSK3E)-dependent gliosis, neurodegeneration, vascular permeability, and impaired visual function. Aim 1 will explore inhibition of REDD1 allostery as a therapeutic target for DR. The studies will evaluate diabetes-induced retinal defects in a new point mutation knockin mouse that expresses a REDD1 variant that continues to be degraded even after redox- modification. To complement this genetic approach, we will also use cutting-edge artificial intelligence (AI) and molecular binding assays to explore small molecule inhibition of REDD1 allostery as a clinically translatable therapeutic for retinal disease. Aim 2 will examine a role for REDD1-dependent GSK3E signaling in the failed adaptive response of retinal Müller glia to diabetes. The proposed studies will determine if Müller glial GSK3E signaling enhances cytosolic calcium influx by promoting the expression of a stress-induced cation channel, leading to downregulation of synaptic glutamate uptake and consequently retinal neurodegeneration. A new Müller glia-specific MITO-Tag mouse will also be used to explore a role for GSK3E signaling in mitochondrial permeability, mitochondrial DNA leak, and activation of STING (stimulator of interferon genes). Finally, the proposed studies will use ribosome profiling of translationally active mRNAs isolated from the retina of diabetic mice to characterize the reprogramming of Müller glia toward reactive gliosis. This project is expected to have a powerful impact on the field, because it addresses a clinical need for therapeutics that provide interventions in the early stages of retinal disease by targeting specific molecular events that cause loss of retinal homeostasis.


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 = $542,767 )
2026	2026	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	6	8/4/2026	NON-COMPETING CONTINUATION	$542,767
														Subtotal = $542,767

Issue Date FY: 2025 ( Subtotal = $461,273 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	001	5	9/19/2025	NON-COMPETING CONTINUATION	$461,273
2025	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	3	4/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $461,273

Issue Date FY: 2024 ( Subtotal = $543,314 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	001	4	8/14/2024	COMPETING CONTINUATION	$543,314
2024	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	3	8/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $543,314

Issue Date FY: 2023 ( Subtotal = $472,818 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	3	6/30/2023	NON-COMPETING CONTINUATION	$472,818
														Subtotal = $472,818

Issue Date FY: 2022 ( Subtotal = $458,632 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	2	6/29/2022	NON-COMPETING CONTINUATION	$458,632
														Subtotal = $458,632

Issue Date FY: 2021 ( Subtotal = $472,818 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Vision Research	000	1	9/17/2021	NEW	$472,818
														Subtotal = $472,818

Grand Total All Awards = $2,951,622

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Redox-sensitive activation of REDD1 in diabetic retinopathy

Award Number: R01EY032879

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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