Position Title

Professor

Office Location

540 E. Canfield - 9314 Scott Hall

Office Phone

313-577-9731

Biography

Work in the lab is focused on cellular pathways involved in retinal damage in response to diabetes. A key focus is regulation of inflammatory pathways that induce damage to the retina. We have a focus on PKA and Epac1, as upstream regulators of retinal inflammation in diabetic retinopathy. We also have interests in the cellular mechanisms of insulin resistance in the diabetic retina. We use protein biology, cell culture and animal models to test our hypotheses.

Research Educator, Full time, PhD, Gross Anatomy

Education

• Post-Doc (Vascular Biology)--Texas A&M University, Temple, TX 2003
• PhD---University of Kansas Medical Center, Kansas City, KS, 2001
• BS--University of Bridgeport, Bridgeport, CT, 1997

Areas of Research

Retinal Vascular Biology

Research Focus: Diabetic Retinopathy, Vascular Biology of Ocular Cancersiology

 

Research

Current Projects:

Inhibition of HMGB1 as a protective mechanism against diabetic retinopathy

Diabetic retinopathy remains the leading cause of vision loss in working age adults. Previous research has led to the development of anti-VEGF therapy, which is an effective treatment for proliferative diabetic retinopathy and macular edema in some patients, while other patients are unresponsive. For treatment of non-proliferative diabetic retinopathy, few options are available save good glycemic control, which is problematic for many patients. Recent discoveries offer new insights into the molecular mechanisms underlying diabetic retinopathy and suggest that in addition to oxidative stress, increased inflammation may be a major causative factor in diabetes-induced retinal damage. We recently reported that high glucose significantly increased high mobility group box 1 (HMGB1) protein levels, suggesting a potential role for the alarmin system in regulating retinal responses to high glucose. HMGB1 is extensively involved in inflammation; it can serve as a chaperone to regulate transcription in the nucleus, is secreted by immune cells, interacts with p53, and activates cytokine release. As such, it provides a promising target to blunt the inflammatory response in the retina. Due to its multiple mechanisms of activation and roles in various cell types, an improved understanding of the cellular regulation of HMGB1 actions in the retina becomes increasingly important. Our preliminary data demonstrate that insulin-like growth factor binding protein 3 (IGFBP-3) can inhibit high glucose-induced increases in HMGB1 levels in retinal endothelial cells (REC). We have previously reported that IGFBP-3 KO mice have retinal damage similar to rodent models of diabetic retinopathy, despite normal glucose levels. Furthermore, inhibition of HMGB1 activity using an inhibitor (glycyrrhizin) restored retinal thickness and reduced retinal degenerate capillaries in an in vivo model of retinal ischemia/reperfusion injury in mice. These data have led to the hypothesis that inhibition of HMGB1 activity in the retina protects against diabetes-induced damage. Our overall goal is to determine the mechanisms by which the PKA and Epac1 pathways inhibit HMGB1/inflammation-induced retinal injury and serve as protective pathways that may block diabetic retinal damage.

 

PKA and Epac1 inhibit TLR4 to protect the diabetic retina

Diabetic retinopathy is the leading cause of blindness in working age adults; however, much of this blindness occurs in the later phases of the disease due to proliferative disease or macular edema. Recently, the role of inflammation has become a focus of potential therapies targeted to treat earlier stages and/or prevent progression of the disease. While it is clear that a large number of cytokines/chemokines are increased in the diabetic retina, the role of innate immunity has only recently been investigated. Recent work has demonstrated that toll-like receptors (TLRs) are altered in diabetes. Work has also shown that TLR4 is increased in the streptozotocin-induced diabetic retina. Additionally, TLR4 may have actions in retinal endothelial cells (REC), as both TLR2/4 pathways are active in these retinal cells. Our preliminary data has expanded on those findings to demonstrate that β-adrenergic receptors can decrease TLR4 signaling in the diabetic mouse retina, as well as in both REC and retinal Müller cells. Supporting our findings in retina, studies in macrophages also demonstrate that β-adrenergic receptors can regulate TLR4. The response to Compound 49b was blocked when Epac1 or PKA were knocked down by siRNA, suggesting these proteins act as damage associated molecular pattern molecules (DAMPs) regulating TLR4 signaling in the diabetic retina. Our primary hypothesis for this proposal is that PKA and Epac1 can regulate TLR4 and may represent a key pathway that controls retina damage in diabetes. Our overall goal is to better understand the role of downstream mediators of β-adrenergic receptors in the regulation of TLR4 signaling in the diabetic retina, with the intent of identifying key pathways in innate immunity that can be targeted for novel therapeutics.

Links of Interest

Kresge Eye Institute

Selected publications

• Ye, EA* and Steinle, JJ. miR-146a suppresses STAT3/VEGF pathways and reduces apoptosis through IL-6 signaling in primary human retinal microvascular endothelial cells in high glucose conditions. 2017. Vision Research. PMID: 2843375
• Jiang, Y, Liu, L, Curtiss, E*, and Steinle, JJ. Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1β in Retinal Endothelial Cells and Mouse Retinal Vasculature. 2017. Mediators of Inflammation. PMID:2834846
• Li, Liu, Jiang, Y, Chahine, A*, Curtiss, E*, and Steinle, JJ. Epac1 agonist decreased inflammatory proteins in retinal endothelial cells, and loss of Epac1 increased inflammatory proteins in the retinal vasculature of mice. 2017. Molecular Vision. 23:1-7. PMID: 28210097
• Jiang, Y, Liu, L, and Steinle, JJ. Compound 49b regulates ZO-1 and occludin levels in human retinal endothelial cells and in mouse retinal vasculature. 2017. Invest. Ophthalmol. Vis. Sci. 2017. 58:185–189. PMID:28114578
• Ye, EA*, Liu, L, Jiang, Y, Jan, J*, Gaddipati*, S, Suvas, S, Steinle, JJ. miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling. 2016. J. Neuroinflammation. 13 (1): 305. PMID: 2793122
• Liu L, Jiang Y, Steinle JJ. Compound 49b Restores Retinal Thickness and Reduces Degenerate Capillaries in the Rat Retina following Ischemia/Reperfusion. 2016. PLoS One. 11(7):e0159532. PMID: 27439004
• Chintalapudi SR, Djenderedjian L, Stiemke AB, Steinle JJ, Jablonski MM, Morales-Tirado VM. Isolation and Molecular Profiling of Primary Mouse Retinal Ganglion Cells: Comparison of Phenotypes from Healthy and Glaucomatous Retinas. Front. Aging. Neurosci. May 2016. Vol 8. PMID: 27242509
• Shi, H*, Carion, TW, Jiang, Y, Steinle, JJ, Berger, EA. VIP protects human retinal microvascular endothelial cells against high glucose-induced increases in TNF-α and enhances RvD1. 2016. Prostaglandins Other Lipid Mediators. 123: 28-32. PMID: 27026343
• Ye, E*, and Steinle, JJ. MiR-146a attenuates inflammatory pathways mediated by TLR4/NFkB and TNF to protect primary human retinal microvascular endothelial cells grown in high glucose. 2016. Mediators of Inflammation. PMID:26997759
• Berger, EA, Carion, TW, Jiang, Y, Liu, L, Chahine, A*, Walker, RJ, Steinle, JJ. -adrenergic receptor agonist, Compound 49b, inhibits TLR4 signaling pathway in diabetic retina. 2016. Immunol Cell Biol. PMID: 26888251

PubMed Link

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