Pharmacosignaling in PDR: The goal of this project is to elucidate the molecular basis of anti-VEGF’s benefit in patients with proliferative diabetic retinopathy (PDR). The clinical observation that neutralizing VEGF reduces retinal edema and improves visual acuity in most patients, motivates us to investigate the underlying mechanism of this phenomenon. To this end we are first identifying changes in gene expression and signaling events that are associated with anti-VEGF treatment in patients. The next step is to determine which of these changes are responsible for the therapeutic benefit. These discoveries will guide the design of alternative therapies for patients that do not fully benefit from existing anti-VEGFs. Furthermore, we will develop biomarkers that will improve our ability to diagnose susceptibility, monitor both disease progression, and the efficacy of intervention. Preventing diabetic retinopathy: Of the various complication of diabetes mellitus (DM), retinopathy is the most-feared, and eventually develops in over 80% of patients with DM. Retinopathy results at least in part due to DM-induced oxidative stress, which drives progressive and self-perpetuating damage of the retinal vasculature. The long delay between the onset of DM to the development of retinopathy suggests the existence of processes that prevent retinal pathogenesis. We discovered that hyperglycemia (HG) induces adaptation at the level of the mitochondria within primary human retinal endothelial cells. Our ongoing research tests the hypothesis that soon after the onset of DM, retinal vessels undergo adaption, which protects them from succumbing to retinopathy that occurs only after loss of such adaption. The aims of this project are to: fully characterize adaptation and elucidate the underlying mechanism using primary human retinal vascular cells (aim 1); determine the relevance of adaptation in experimental animals (aim 2); and investigate the role of adaptation in patients (aim 3).