miRNA-GDRisk: unraveling the miRNAs involved in Gestational Diabetes-associated Diabetic Retinopathy risk

Diabetic retinopathy (DR) is a leading cause of visual impairment worldwide, with the number of affected individuals expected to rise from 103.12 million in 2020 to 160.5 million by 2045. This condition poses significant public health and economic challenges. It is commonly associated with type 1 and type 2 diabetes (T1DM and T2DM) and can also result from gestational diabetes mellitus (GDM), which affects 7-10% of pregnant women due to increased obesity rates. At present, besides the control of blood glucose, various therapeutic approaches are employed for managing DR. However, the frequent asymptomatic nature of DR in its initial stages often leads to delayed diagnosis and treatment resulting in vision loss. Hence, the identification of sensible biomarkers able to predict DR and to determine the therapeutic targets could improve detection of DR at earlier stages, thus improving prognosis. In this context microRNAs (miRNAs), small non-coding RNA molecules that regulate gene expression, have emerged as potential biomarkers and therapeutic targets due to their role in DR pathogenesis. Although the levels of several miRNAs linked to cell proliferation, angiogenesis, apoptosis, fibrosis, and inflammation processes are reported to be dysregulated in GDM, their association with the development of DR remains unknown. Therefore, the employment of a cellular model of GDM to study the correlation of these miRNAs with DR could enhance our understanding of the genetic and epigenetic modifications potential linked to this debilitating eye disease. Based on these assumptions, the proposal aims to use the model of primary human umbilical vein endothelial cells (HUVECs) from women with GDM (GDM-HUVECs) to better explore the pathophysiology of DR and to identify and predict the biological relevance of possible miRNAs involved in the risk of GDM-associated DR. Additionally, their role in the pathophysiology of DR will be assessed setting up a novel experimental model based on GDM-HUVECs co-cultured with porcine neuroretinal explants. Finally, this proposal aims to confirm the potential as biomarkers and therapeutic targets of the identified miRNAs in GDM-HUVECs by using of specific anti-miRNA oligonucleotides .