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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY022330-02S1
Application #
8858906
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Shen, Grace L
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$46,109
Indirect Cost
$15,370
Name
University of Tennessee Health Science Center
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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
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
Chintalapudi, Sumana R; Djenderedjian, Levon; Stiemke, Andrew B et al. (2016) Isolation and Molecular Profiling of Primary Mouse Retinal Ganglion Cells: Comparison of Phenotypes from Healthy and Glaucomatous Retinas. Front Aging Neurosci 8:93
Ye, Eun-Ah; Liu, Li; Jiang, Youde et al. (2016) miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling. J Neuroinflammation 13:305
Ye, Eun-Ah; Steinle, Jena J (2016) miR-146a Attenuates Inflammatory Pathways Mediated by TLR4/NF-?B and TNF? to Protect Primary Human Retinal Microvascular Endothelial Cells Grown in High Glucose. Mediators Inflamm 2016:3958453
Shi, Haoshen; Carion, Thomas W; Jiang, Youde et al. (2016) VIP protects human retinal microvascular endothelial cells against high glucose-induced increases in TNF-? and enhances RvD1. Prostaglandins Other Lipid Mediat 123:28-32
Berger, Elizabeth A; Carion, Thomas W; Jiang, Youde et al. (2016) ?-Adrenergic receptor agonist, compound 49b, inhibits TLR4 signaling pathway in diabetic retina. Immunol Cell Biol 94:656-61
Thakran, Shalini; Zhang, Qiuhua; Morales-Tirado, Vanessa et al. (2015) Pioglitazone restores IGFBP-3 levels through DNA PK in retinal endothelial cells cultured in hyperglycemic conditions. Invest Ophthalmol Vis Sci 56:177-84
Gao, Bradley T; Lee, Ryan P; Jiang, Youde et al. (2015) Pioglitazone alters monocyte populations and stimulates recent thymic emigrants in the BBDZR/Wor type 2 diabetes rat model. Diabetol Metab Syndr 7:72
Jiang, Youde; Thakran, Shalini; Bheemreddy, Rajini et al. (2015) Sodium salicylate reduced insulin resistance in the retina of a type 2 diabetic rat model. PLoS One 10:e0125505

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