As a pediatric ophthalmologist concerned by the growing incidence of obesity, metabolic syndrome, and diabetes in the pediatric population, especially in Hispanic patients, I have chosen to focus my research on diabetic retinopathy. Inflammation and angiogenesis herald the development of vision-threatening complications of diabetic retinopathy (DR), including retinal edema, hemorrhages, glaucoma and detachments. Vascular endothelial growth factor (VEGF) inhibitors are the standard of care drugs used to treat vision threatening DR complications; however, their effectiveness is limited to certain patient populations and no alternative therapies have emerged into clinical practice. The chemokine CXCL8, which is known to affect pathologic mechanisms associated with DR, accumulates in the eyes of diabetics and its levels correlate with DR progression. However, we do not fully understand the functional implications of its induction and subsequent accumulation. We have found that multiple pro-inflammatory and pro-angiogenic molecules associated with DR induce CXCL8 in human retinal cells, and that CXCL8 can affect human retinal endothelial cell responses associated with DR onset and progression. I believe that CXCL8 is a key intermediary at the juncture of multiple signaling pathways that regulate and promote both early and late events in DR pathology, including VEGF signaling. Therefore, CXCL8 receptors may be ideal targets for novel DR therapies. Several inhibitors of CXCL8 receptors are in clinical trials for non-ocular conditions, yet their potential to interfere with mechanisms of DR in the retina has not been explored. I believe that there is value in testing these inhibitors in clinical trials and repurposing them to treat patients with DR. However, before pursuing that goal, the significance of CXCL8 induction in the eye in relation to mechanisms of DR pathology (Aim 1) and the value of these inhibitors to interfere with those mechanisms (Aim 2) must be rigorously evaluated. I intend to do this using a stepwise approach complimenting human primary cell culture-based in vitro assays (Mller glia and vascular endothelial cells, Aim1), with in vivo mouse models of DR-associated pathologic events (Streptozotocin-induced diabetes and oxygen-induced retinopathy models, Aim 2). Confirming the ability of commercially-available CXCL8 receptor inhibitors to block DR-relevant pathogenic processes would affirm their therapeutic potential to treat DR, and inform the design of future pre-clinical and clinical trials. This mentored experience will allow me to generate pilot data to successfully compete for R-level funding, to advance the understanding of DR pathophysiology, and to accelerate the development of new DR therapies, therefore promoting my independence as a clinician investigator. The skills, collaborative relationships, and data acquired by the execution of this proposal and its training plan, along with my ophthalmology training, should optimally position my career for successful long term funding and significant impact on patient care.
Diabetic retinopathy is the leading cause of blindness among working-age adults and its incidence is expected to increase due to the surge of diabetes and metabolic dysregulation in children. While there are currently no therapeutic strategies directed at its early stages, there is accumulating evidence from other organ systems that inhibitors of the CXCL8 chemokine receptors can block several cellular responses known to be involved in both early and late diabetic retinopathy. Repurposing CXCL8 receptor inhibitors, which are in clinical trials for other diseases, may prove to be efficacious not only in stopping progression, but also in potentially preventing the onset of vision threatening pathology in diabetic retinopathy.
