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 ?-adrenergic receptors can decrease TLR4 signaling in the diabetic mouse retina, as well as in both REC and retinal Mller cells. Supporting our findings in retina, studies in macrophages also demonstrate that ?-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 ?-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. !
Wehavepreviouslyreportedthat?-?adrenergicreceptorscanreduceTLR4inthediabetic retina.ThegoalofthisproposalisthepotentialmechanismsbywhichPKAorEpac1are responsibleforthe?-?adrenergicregulationofTLR4.InhibitionofTLR4byeitherPKAor Epac1willlikelylaythegroundworkfornewtherapeuticdevelopmentfordiabetic retinopathy.