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.
|Jiang, Youde; Zhang, Qiuhua; Ye, Eun-Ah et al. (2014) ?1-adrenergic receptor stimulation by agonist Compound 49b restores insulin receptor signal transduction in vivo. Mol Vis 20:872-80|
|He, Hui; Williams-Guy, Kimberly; Pagadala, Jayaprakash et al. (2014) A sensitive and fast LC-MS/MS method for determination of ?-receptor agonist JP-49b: application to a pharmacokinetic study in rats. J Chromatogr B Analyt Technol Biomed Life Sci 953-954:86-91|
|Jiang, Youde; Thakran, Shalini; Bheemreddy, Rajini et al. (2014) Pioglitazone normalizes insulin signaling in the diabetic rat retina through reduction in tumor necrosis factor ? and suppressor of cytokine signaling 3. J Biol Chem 289:26395-405|
|Jiang, Youde; Biswas, Subrata K; Steinle, Jena J (2014) Serine 307 on insulin receptor substrate 1 is required for SOCS3 and TNF-? signaling in the rMC-1 cell line. Mol Vis 20:1463-70|
|Jiang, Youde; Zhang, Qiuhua; Ye, Eun-Ah et al. (2014) Etanercept restores normal insulin signal transduction in ?2-adrenergic receptor knockout mice. J Neuroinflammation 11:137|