School of Medicine

Wayne State University School of Medicine

Profile View

Jena Steinle
Professor

540 E. Canfield
9314 Scott Hall

313-577-9731
 
Biography

Work in Dr. Steinle's lab is focused on cellular pathways involved in retinal damage in response to diabetes. A key focus is beta-adrenergic receptor actions to protect the diabetic retina. Additionally, we focus on the role of beta-adrenergic receptor signaling in the regulation of insulin resistance in type 2 diabetes. We have developed a novel drug to test the role of beta-adrenergic receptors in the diabetic retina. We use protein biology, cell culture and animal models to test our hypotheses.

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
     

Area/Subject of Research: Retinal Vascular Biology

Research Focus: Diabetic Retinopathy, Vascular Biology of Ocular Cancers

Current Projects:

R01 from NEI: Compound 49b Prevents Retinal Endothelial Cell Death Through IGFBP-3 Levels
Diabetic retinopathy remains the fifth leading cause of preventable blindness worldwide. Interventions to prevent progression of diabetic retinopathy are limited to improved glycemic control (a challenging goal for all diabetic patients) and to laser photocoagulation (available only for advanced stages of retinopathy). We and others have reported that adrenergic signaling is lost in the diabetic retina, suggesting that development of novel agents to restore autonomic homeostasis is necessary. Unfortunately, currently available adrenergic agents are associated with adverse systemic or non-specific effects. These problems inspired our group to synthesize compound 49b, a novel and selective -adrenergic receptor agonist, as a potential paradigm shift in the prevention of diabetic retinopathy.

Our preliminary data suggest that compound 49b prevents the formation of degenerate capillaries, which involves degenerate capillary formation, which are the hallmark pathology noted in the diabetic retinal vasculature. In addition to preventing degenerate capillaries in vivo, compound 49b prevents the cleavage of caspase 3, a well-established marker of apoptosis, in retinal endothelial cells (REC) in vitro, suggesting that Compound 49b can decrease apoptosis. In the oxygen-induced model of retinopathy, others have associated increased levels of insulin-like growth factor binding protein-3 (IGFBP-3) with protection from REC apoptosis. Furthermore, using the streptozotocin-induced diabetic rat model, we observed that chronic insulin deficiency reduced IGFBP-3 protein levels in whole retinal lysates, but topical application of compound 49b to the eye restored retinal IGFBP-3 to its control level in these insulin-deficient rats. Thus, we hypothesize that compound 49b prevents the critical vascular damage underlying diabetic retinopathy in part by restoring IGFBP-3 levels in retinal endothelial cells. This project focuses on a deeper understanding of the mechanisms underlying this protective action.

R01 from NEI Mechanisms of TNFalpha-Induced Insulin Resistance in Retinal Cells

The proposed study will test the novel hypothesis that in the diabetic retina, hyperglycemia stimulates production of tumor necrosis factor (TNF), 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 TNF 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.
 

Research Educator, Full time, PhD, Gross Anatomy

Publications
  • Thakran S, Zhang Q, Morales-Tirado VM, Steinle JJ. Pioglitazone restores IGFBP-3 levels through DNA PK in retinal endothelial cells cultured in hyperglycemic conditions. Invest Ophthalmol Vis Sci. 2014 Dec 18. pii: IOVS-14-15550. PMID: 25525174
  • Jiang, Y, Zhang, Q, Steinle, JJ. Etanercept restores normal insulin signal transduction in β2-adrenergic receptor knockout mice. Journal of Neuroinflammation. PMID: 25138272
  • Zhang, Q, Steinle, JJ. 2014. IGFBP-3 inhibits TNF production and TNFR-2 signaling to protect against retinal endothelial cell apoptosis. Microvasc. Res. 95C:76-81. PMID: 25086184
  • Jiang, Y, Thakran, S, Bheemreddy, R, Ye, EA, He, H, Walker, RJ, Steinle, JJ. 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(38):26395-405. PMID: 25086044
  • Jiang, Y, Pagadala, J, Miller, DD, Steinle, JJ. 2014. Insulin-like growth factor-1 binding protein 3 (IGFBP-3) promotes recovery from trauma-induced expression of inflammatory and apoptotic factors in the retina. Cytokine. PMID: 25082650
  • Zhang, Q, Soderland, D, Steinle, JJ. 2014. TNF inhibits IGFBP-3 through Activation of p38 and Casein Kinase 2 in Human Retinal Endothelial Cells. PLoS One. 9(7):e103578. PMID: 25073020
  • Jiang, Y, Zhang, Q, Ye, EA, Steinle, JJ. 2014. 1-adrenergic receptor stimulation by agonist Compound 49b restores insulin signal transduction in vivo. Mol Vis. 20:872-80. PMID: 24966659Jiang, Y, Zhang, Q, and Steinle, JJ. 2014. Intravitreal injection of IGFBP-3 restores normal insulin signaling in diabetic rat retina. PLoS One. 9(4):e93788. PMID: 24695399
  • Zhang, Q*, Jiang, Y, Toutounchian, J, Wilson, MW, Morales-Tirado, V, Miller, DD, Yates, CR, Steinle, JJ. 2013. Novel Quinic Acid Derivative KZ-41 Prevents Retinal Endothelial Cell Apoptosis Without Inhibiting Retinoblastoma Cell Death Through p38 Signaling. Invest. Ophthalmol. Vis. Sci. 54(9):5937-43. PMID: 23942968
  • Zhang, Q*, Soderland, C, Steinle, JJ. Regulation of retinal endothelial cell apoptosis through activation of the IGFBP-3 receptor. 2013. Apoptosis. Mar;18(3):361-8. PMID: 23291901