The proposed study will test the novel hypothesis that in the diabetic retina, hyperglycemia stimulates production of tumor necrosis factor a (TNFa), which in turn decreases insulin receptor binding leading to decreased signal transduction. The overall effect of this signaling cascade would be to create insulin resistance, exacerbate problems caused by limited insulin production in diabetes, and thus contribute to development of diabetic retinopathy seen in both type 1 and type 2 diabetes. While our preliminary data and previous reports by others support a major role for inflammatory mediators such as TNFa in diabetic retinopathy, the pathways involved are largely unknown. Our proposed studies will focus on one likely candidate, the suppressor of cytokine signaling 3 (SOCS3) pathway (Fig.1), which is poorly understood in retina and yet represents a promising therapeutic target in future treatments for diabetic retinopathy. Our overall goal is to 1) establish the role of the SOCS3 pathway in regulating insulin signaling (through insulin receptor substrate-1;IRS-1) and apoptosis in normal and diabetic rats and 2) evaluate effects of upstream drug targets on the SOCS3 pathway and their downstream effects on insulin signaling and retinal cell apoptosis.
Increased TNFa levels are a key component of insulin resistance. We have shown that hyperglycemia-induced increases in TNFa in the retina promote apoptosis of retinal endothelial cells. This study will dissect the cellular mechanisms by which TNFa interferes with insulin signal transduction to promote apoptosis.
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|Curtiss, Elizabeth; Liu, Li; Steinle, Jena J (2018) miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature. Exp Eye Res 176:98-102|
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|Liu, Li; Jiang, Youde; Steinle, Jena J (2017) Toll-Like Receptor 4 Reduces Occludin and Zonula Occludens 1 to Increase Retinal Permeability Both in vitro and in vivo. J Vasc Res 54:367-375|
|Liu, Li; Jiang, Youde; Curtiss, Elizabeth et al. (2017) TLR4 regulates insulin-resistant proteins to increase apoptosis in the mouse retina. Inflamm Res 66:993-997|
|Ye, Eun-Ah; Steinle, Jena J (2017) miR-146a suppresses STAT3/VEGF pathways and reduces apoptosis through IL-6 signaling in primary human retinal microvascular endothelial cells in high glucose conditions. Vision Res 139:15-22|
|Shi, Haoshen; Carion, Thomas W; Jiang, Youde et al. (2017) A regulatory role for ?-adrenergic receptors regarding the resolvin D1 (RvD1) pathway in the diabetic retina. PLoS One 12:e0185383|
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