Targeted prostanoid inhibition as an anti-inflammatory therapy for diabetic retinopathy

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PROJECT SUMMARY Diabetic retinopathy (DR), a microvascular complication of diabetes, is the leading cause of irreversible vision loss in working-age Americans. As the number of Americans with diabetes continues to climb, the prevalence of DR is expected to rise in coordination. Current therapies for DR treat only late stages of disease after irreparable damage to the retina has occurred, highlighting the need for therapeutic interventions to prevent early-stage progression. Since the 1960s, it has been hypothesized that retinal inflammation may drive early DR progression in a cyclooxygenase (COX)-dependent manner. However, trials of various nonsteroidal anti- inflammatory drugs (NSAIDs) to inhibit COX as a DR treatment have failed in large part due to severe cardiovascular or gastrointestinal side effects associated with chronic, broad-spectrum COX inhibition by these drugs. Alternatively, targeting specific prostanoids—the lipid signaling molecules downstream of COX—and/or their receptors could offer a therapeutic approach that isolates anti-inflammatory benefits while avoiding the severe side effects of NSAIDs. Five prostanoids are generated in the COX pathway, signaling through nine prostanoid receptors. The goal of the research proposed here is to determine the therapeutic potential of inhibiting individual prostanoid signaling to slow DR onset and progression. My preliminary studies have identified that two of the five prostanoids—PGE2 and PGF2α—are elevated in primary human retinal cells cultured in conditions of dyslipidemia or inflammation relevant to diabetes. PGE2 is elevated in Müller glia, cells responsible for maintaining homeostasis in the retina, and PGF2α is elevated in retinal microvascular endothelial cells, which form retinal blood vessels. I hypothesize that these two prostanoids are critical drivers of proinflammatory cytokine production and leukostasis, hallmark pathologies associated with DR. This proposal expands upon these findings to define the landscape of retinal prostanoid elevation under conditions relevant to systemic diabetes and to determine the preclinical efficacy of small molecule prostanoid receptor antagonists as targeted therapeutic strategies against DR progression. I propose utilizing primary human cultures of Müller glia and retinal microvascular endothelial cells as well as a diabetic mouse model to interrogate antagonism of prostanoid signaling in both cell- and animal-based disease-relevant experimental models. In completing these studies, I aim to characterize a novel therapeutic strategy to precisely target molecular signaling pathways that may drive retinal vascular inflammation in early-stage DR before irreversible damage occurs. I will carry out my work in the supportive mentoring environment of Dr. John Penn’s laboratory at Vanderbilt University, an institute with rich support of both prostanoid and vision research and with a long history of exemplary graduate training. The training plan outlined in this proposal, paired with my research goals, will aid invaluably in my training to become an independent academic research scientist.