Jena Steinle

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.