Saturday, December 21, 2024
12/21/2024
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.
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