Epac1 as a novel therapeutic target for diabetic retinopathy

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Each year, millions of Americans face vision loss related to diabetes. According to the U.S. Centers for Disease Control and Prevention, more than 30 million Americans have diabetes, and a third of diabetics aged 40 or over in the U.S. have diabetic retinopathy (DR) and related diabetic eye diseases. While the pathogenic mechanisms underpinning the development of DR appear multifactorial and remain incompletely understood, abnormal neovascularization is a key contributing factor, supported by the fact that therapy with anti-VEGF (vascular endothelial growth factor) drugs has become the gold standard treatment for DR and its complications among other interventions. Whilst anti-VEGFs demonstrate modest clinical benefits, these drugs fail to fully attenuate clinical progression or reverse damage to the retina and have to be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. A better understanding of the etiology and the molecular mechanism of DR, as well as the development of novel mechanism-based therapeutics, will address a major unmet medical need. This study combines genetic and pharmacological approaches to determine the functions and mechanisms of Epac1-mediated pathogenic neovascularization and vascular dysfunction during DR development. Successful completion of our proposed studies will not only provide new mechanistic insights into understanding cAMP/Epac1-mediated vascular remodeling but also will lead to the discovery of a new class of in vivo pharmacological agents that can be used as lead compounds for developing medications targeting DR and other vascular proliferative diseases.