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 #
5R01EY022330-04
Application #
8856250
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Curtiss, Elizabeth; Jiang, Youde; Liu, Li et al. (2018) Epac1 Restores Normal Insulin Signaling through a Reduction in Inflammatory Cytokines. Mediators Inflamm 2018:3809092
Jiang, Youde; Liu, Li; Steinle, Jena J (2018) miRNA15a regulates insulin signal transduction in the retinal vasculature. Cell Signal 44:28-32
Curtiss, Elizabeth; Liu, Li; Steinle, Jena J (2018) miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature. Exp Eye Res 176:98-102
Liu, Li; Steinle, Jena J (2017) Toll-like receptor 4 regulates insulin signal transduction in retinal Müller cells. Growth Factors 35:234-238
Liu, Li; Jiang, Youde; Steinle, Jena J (2017) Inhibition of HMGB1 protects the retina from ischemia-reperfusion, as well as reduces insulin resistance proteins. PLoS One 12:e0178236
Liu, Li; Steinle, Jena J (2017) Loss of TLR4 in mouse Müller cells inhibits both MyD88-dependent and -independent signaling. PLoS One 12:e0190253
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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