Mechanisms of Photoreceptor Contribution to Retinal Inflammation in Diabetic Retinopathy

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Project Summary/Abstract Diabetic retinopathy (DR) is the principal cause of blindness among working-age adults in the United States. In individuals with diabetes mellitus, the duration and the severity of hyperglycemia correlate with the risk of developing retinopathy, and have long been considered the main factors leading to DR onset. However the mechanism by which hyperglycemia leads to DR pathology is not known. Photoreceptors are both the most abundant and the most metabolically active cells in the retina, and they have been shown to contribute to the pathogenesis of DR, but the photoreceptor response to hyperglycemia remains poorly understood. Our preliminary data suggests that the c2 isoform of nuclear factor of activated T-cells (NFAT) is significantly induced in photoreceptors exposed to hyperglycemia in vivo, and is activated and translocates to the nucleus of photoreceptors treated with high glucose in vitro. NFATc2 target genes include cytokines that have been shown to regulate inflammation and related processes driving the progression of DR. However the functional implications of NFATc2 induction in photoreceptors exposed to high glucose are not known. The hypothesis of this project is that specific inhibition of NFATc2 in photoreceptors under hyperglycemic conditions can reduce the induction of pro-inflammatory proteins and decrease the downstream effects of photoreceptors on other retinal cell types, including Müller glia and retinal microvascular endothelial cells. Under the mentorship of Dr. John Penn, this hypothesis will be tested using a stepwise approach, complementing primary cell culture- based assays (Aim 1) with in vivo mouse models of DR-relevant pathologic processes (Aim 2). Confirming the ability of NFAT inhibitors and NFATc2 loss of function in photoreceptors to reduce the progression of DR will affirm the potential of NFATc2 as a treatment target for this condition. The principal investigator is an M.D. Ph.D. physician-scientist with scientific training in neuroscience and clinical training as a vitreoretinal surgeon. The K08 award will leverage her prior training under the mentorship of a world-class team with extensive experience in retinal vascular disease, retinal cell biology, and animal models of diabetes, and that includes, in addition to Dr. John Penn, Dr. Sabine Fuhrmann an expert in the neural retina and the retinal pigment epithelium, and Dr. Maureen Gannon, an expert in systemic diabetes. The work will take place within the outstanding scientific and collaborative environment of the Vanderbilt University School of Medicine and Vanderbilt University Medical Center, which have an excellent track record of producing successful clinician- scientists. Dr. De la Huerta will develop the necessary skills to become an independent investigator in the field of diabetic retinopathy, while generating pilot data to successfully compete for independent NIH funding, to advance the understanding of DR pathophysiology and to accelerate the development of new DR therapies.