The roles of arachidonic acid- and docosahexaenoic acid-derived epoxides and their endocannabinoid derivatives in diabetes-induced retinal vascular inflammation

Abstract

The studies described in this dissertation sought to better understand the role of vascular inflammation in the pathogenesis of blinding retinal disease, and explored routes to mitigate this inflammation in the pursuit of therapeutic intervention. Our lab is particularly interested in understanding the mechanisms underlying the early stages of diabetic retinopathy (DR), which is a visually destructive secondary complication of diabetes mellitus. DR is the leading cause of vision loss among working age Americans, and effects roughly 10 million people in the US alone. Current therapeutic interventions target late-stage DR after the appearance of irreparable damage; thus, we aim to fuel the development of novel therapeutic targets that would intervene in earlier stages of the condition, before irreversible vision loss occurs. Herein, our studies focused on the anti-inflammatory potential of arachidonic acid- and docosahexaenoic acid-derived epoxides and their endocannabinoid derivatives to mitigate diabetes-induced retinal vascular inflammation. This work constitutes the first comprehensive evaluation of the role of these lipids in, and their potential benefits to, DR. We employed a balance of in vitro and in vivo models, first to identify relevant and druggable targets in monocultures of specific retinal cells, and then to validate the targets and employ the therapeutic objectives in reliable animal models of DR. Ultimately, this dissertation’s primary focus is to contribute to the development of effective treatments for DR by evaluating the efficacy of pharmacotherapeutic strategies in relevant pre-clinical models.