The candidate is a retina trained clinician scientist who's clinical and research focus is improving treatments for patients suffering from retinal edema. To achieve his goal he will elucidate the mechanisms of retinal edema with a specific focus on the role of Mller glia (MG) and will generate and utilize animal models to identify and validate novel targets for therapy. He has completed an M.D./Ph.D., clinical training as a medical retina specialist and is currently one year into a two year commitment to the Duke Eye Center NEI K12 Career Development Program. During his first year as a K12 scholar, he has developed and begun to characterize a mouse laser-induced retinal vein occlusion (RVO) model for the study of retinal edema pathobiology. The candidate has chosen to study the causes of MG pump dysfunction, the failure of MG to transport fluid out of the retinal tissue. His immediate focus outlined in this proposal will be 1) understanding mechanisms driving MG pump dysfunction and swelling in retinal edema and 2) determining the role of RVO- induced MG mitochondrial dysfunction in this process. The candidate plans to submit an R01 early in his final year of K08 support that will utilize in vivo and ex vivo model systems and data generated during this proposal as a spring board to investigate the specific signaling events causing MG pump dysfunction. Additional didactic training in neurobiology and vascular biology, departmental research seminars, and advanced responsible conduct of research will be obtained during the award period, and the candidate will present his findings at national meetings and submit his work for publication. Environment: The candidate will have access to the world class clinical and research faculty of Duke's Department of Ophthalmology and will benefit more broadly from the intellectual environment present at Duke University. The mentoring team is comprised of experienced faculty who possess the necessary expertise to assist the candidate in accomplishing the proposed research. The significant institutional commitment on the part of the Departments of Ophthalmology and Neurobiology and ongoing mentoring from scientists and clinicians who are dedicated to his long term success will ensure a successful transition to an independent R01-funded research program. Research: Retinal edema (RE) causes vision loss in numerous retinal disorders including diabetes, vein occlusion, and uveitis. While anti-vascular endothelial growth factor agents and corticosteroids often improve RE, they are not universally effective, often resulting in incomplete vision recovery. Retinal edema results from a combination of leaking retinal blood vessels and loss of MG pump function which removes fluid from the retina. The central hypothesis is that cysts seen in RE represent swollen MG and that this swelling is caused by inability of MG to export fluid, termed MG pump dysfunction. To explore our conceptual hypothesis, we have developed a mouse model of cystic RE in experimental laser-induced retinal vein occlusion (RVO). Preliminary data demonstrate that RVO produces retinal thickening and development of cystic spaces in the retina. MG in the RVO-affected area show redistribution of water (AQP4) and potassium (Kir4.1) channels and increased cellular cross sectional area, suggesting intracellular fluid accumulation. These features occur in association with mitochondrial dysfunction, and we find that prevention of mitochondrial dysfunction reduces AQP4/Kir4.1 redistribution. Based on these observations, the model of RVO-induced retinal edema will be used to test two specific hypotheses (1) AQP4/ Kir4.1 redistribution following RVO causes MG swelling, which is driven by the inability of MG to export imbibed fluid; and (2) RVO causes MG mitochondrial dysfunction resulting in AQP4/Kir4.1 redistribution and MG pump dysfunction.
This project will elucidate the role of Mller glial cells, a specialized type of retinal support cell, in retinal edema (swelling) using a mouse model of retinal vein occlusion. Retinal edema affecting the macula, termed 'macular edema', affects central vision and can result from a variety of diseases including diabetic retinopathy, retinal vein occlusion and uveitis (inflammation of the eye). Diabetic macular edema is the leading cause of vision loss in working aged adults in the United States and retinal vein occlusion and uveitis also represent major causes of vision loss. Thus better understanding of the causes and possible treatments for macular edema represents an important public health goal. Current treatments for macular edema include monthly intraocular injections of anti-vascular endothelial growth factor drugs, corticosteroid treatments or thermal laser directed at the retina. No therapy is universally effective and all have disadvantages including cost and risk of side effects. Importantly, despite current therapies a significant proportion of patients experience persistent macular edema and vision loss in spite of treatment. The studies proposed here will help understand the role of Mller glial cells in retinal edema and may identify new targets for therap for patients who continue to lose vision despite current treatments.