Resp. Scientifico: Dott.ssa Sara Rezzola
Dipartimento di Medicina Molecolare e Traslazionale
Finanziato da: Fondazione Cariplo nell’ambito del Bando “Giovani Ricercatori 2021”
Durata del Progetto: 36 mesi
Abstract
Unravelling the mechanisms of drug resistance in Diabetic Retinopathy: translational implications
Diabetic retinopathy (DR), a main complication of diabetes mellitus, represents the leading cause of visual impairment in the working-age population in the Western world. Currently, DR affects more than 93 million people in the world with an overall prevalence close to 35% of the diabetic population. DR begins as non-proliferative DR (NPDR) and progresses to moderate and severe proliferative DR (PDR), characterized by the presence of soft and hard exudates, haemorrhages, venous bleeding, and neovascularization. Exudate accumulation in the macula due to the increased vascular permeability, may give rise to diabetic macular edema (DME), the leading cause of vision loss in many countries.
Vascular endothelial growth factor (VEGF) is considered to play a major role in eye pathologies, including DME. Thus, single targeting therapeutic strategies have been developed to inhibit its activity. However, even though anti-VEGF inhibitors are widely used in DR therapy, no-response occurs in 50% of treated DR patients, 20% of them showing disease progression. Moreover, recurrence occurs in 40% of patients treated with the anti-VEGF ranibizumab, 75% of them needing further treatments after drug discontinuation. Thus, the lack of response to anti-VEGF therapy represents a major clinical concern in DR and the development of novel therapeutics is eagerly required.
This project is aimed at investigating the mechanisms of DME resistance to anti-VEGF treatment that lead to neovascularization and blindness in DR patients. To this purpose, we propose an approach in which vitreous fluid collected from anti-VEGF drug non-responder (non-RES) and responder (RES) DR patients will be used as human eye-derived stimuli on endothelial cells exposed to high glucose and in diabetic mice. This strategy will allow the study of the mechanisms involved in anti-VEGF drug resistance by molecular and biological means using in vitro and in vivo experimental approaches that mimic, at least in part, the pathogenic feature of the disease. Moreover, using an affinity-purification approach, we will take advantage of the multi-target inhibitor K5-N,OS(H) in the attempt to identify the mediators responsible for anti-VEGF, drug tolerance and DME recurrence. Finally, as a translational implication of this project, we will assess the efficacy of neutralizing strategies against the identified mediators for their anti-angiogenic/anti-inflammatory effect on the biological responses exerted by non-RES and RES vitreous.
Costo totale del progetto: Euro 250.000,00
Contributo Cariplo ricevuto da UNIBS: Euro 250.000,00