Translatomic landscape of Type I diabetes at the Blood-Retinal-Barrier: Effects of Therapeutic Iron Chelation.

This research-oriented project addresses a priority health need in ophthalmology by investigating the molecular mechanisms underlying bloodretinal barrier (BRB) dysfunction in type I diabetes mouse models and exploring innovative therapeutic strategies targeting iron toxicity and ferroptosis. Diabetic retinopathy (DR), a leading cause of blindness, involves early BRB breakdown, oxidative stress, and neurodegeneration before overt vascular pathology. Recent evidence, including our own, shows systemic and retinal iron overload in diabetes, implicating iron-driven oxidative damage and ferroptosis in disease progression. However, the cell-type specificity of these processes within BRB-associated endothelial cells and RPE remains poorly understood. To overcome limitations of bulk transcriptomics and scRNA-seq, we will apply RiboTag technology to STZ-induced diabetic mice, enabling cell-specific profiling of actively translated mRNAs (translatome) in BRB cells without dissociation artifacts, concretelly we will characterize translatomic changes in endothelial and RPE cells during early and late diabetes, correlating these with BRB integrity and iron status. The project will also evaluate the therapeutics of iron chelators and ferroptosis inhibitors on diabetes progression, assessing their translatomic shift as well as their impact on BRB function, iron handling, ferroptosis markers, and oxidative stress. Finally we will validate the key output pathways using human BRB cells to promote the transatability of our findings. The novelty of this proposal lies in its integrative approach: combining cell-specific translatomics with mechanistic studies of iron metabolism and ferroptosis, and testing chelation-based strategies as a translational therapeutic avenue. This dual focus on mechanistic insight and therapeutic innovation aligns with priority health objectives and has the potential to identify new pharmacological targets for DR treatment.