Metabolismo Celular e Mecanismos Regenerativos na Retina

Our research aims to address the pressing need for effective therapies to counteract the devastating impact of retinal diseases on individuals' quality of life, which pose significant challenges to patients and healthcare systems worldwide. By elucidating the mechanisms of retina regeneration and developing innovative therapeutic strategies, we aspire to unlock the regenerative potential of Muller glia (MG) in the mammalian retina and counteract retinal diseases. In mammals, particularly in humans, the regenerative capacity of retina cells is very limited. However, in some vertebrate species, such as zebrafish, the MG cells display impressive regenerative properties. Thus, re-activating MG regenerative properties in mammals represents an exciting new area to explore. Growing evidence has revealed that metabolic reprogramming goes beyond simple energy production and has rapidly become an important player influencing cell reprogramming during the regeneration of multiple tissues. Thus, the need to consider the effects of metabolism in the design of novel therapeutic strategies for vision disorders is clear. Importantly, pathways branching from glycolysis provide intermediate metabolites necessary for post-translational modification of proteins, such as histones and DNA. These metabolites establish the connection between metabolism and the epigenetic profile, ultimately regulating gene expression and changing cell function and fate. Considering this, an in-depth understanding of the metabolic regulation of epigenetic mechanisms in the context of retina regeneration is crucial to generate novel ideas for the treatment of human retina diseases. A possible role of metabolic reprogramming in inducing MG fate specifications in the early stages of the retina regenerative response remains unexplored. To bridge this knowledge gap, the objectives outlined in the proposal are: 1) investigate the requirement of glycolysis metabolites, namely lactate and GlcNAc, in regulating protein Lactylation and O-GlcNAcylation, respectively, and how these modifications shape the chromatin landscape and influence gene expression programs activated in the early stages of retina regeneration; 2) transfer the knowledge learnt in the zebrafish model system to a stem cell-derived human retinal organoid model, by inducing regeneration in human retinal tissue. To accomplish these objectives, we propose an innovative approach using leading-edge technologies, such as single-cell sequencing, proteomics, and advanced imaging, and two powerful and complementary models, the genetically amenable zebrafish and a 3D retinal organoid model derived from human induced pluripotent stem cells (iPSCs). The multidisciplinary nature of this project, combining expertise from various fields, will be central to its success. Combining the strengths of these two powerful systems, zebrafish and human organoids, will help to uncover the conservation of metabolic adaptation in different regenerative processes and across species.