LXR as a Novel Therapeutic Target in DR

Diabetic retinopathy (DR) is a disabling microvascular complication. Despite recent advances using pharmacotherapy, a cure for DR has yet to be realized. Thus, a conceptual and technical breakthrough to identify novel targets, and a strategy to cure this complication is paramount. We believe that the recent clinical evidence from large clinical trials demonstrating a strong association between lipid abnormalities and DR progression and the discovery that activation of the nuclear hormone receptors liver X receptors (LXRα/LXRβ) prevents DR in rodent models offers such a breakthrough. The detrimental effect of dyslipidemia is not limited to the vasculature but also leads to dysfunction of circulating angiogenic cells (CAC) and of macrophages. The endogenous ligands for LXRs are oxidative metabolites of cholesterol that serve as intracellular cholesterol "sensors". LXR agonists operate, in part, by transcriptional upregulation of genes involved in promoting cholesterol efflux and inhibition of cholesterol uptake; and by inhibiting inflammation. Our published studies and new preliminary data show that pharmacological LXR activation prevents DR development in both T1D and T2D rodent models. In this application, we seek to understand the mechanisms involved in this beneficial effect. We put forth the hypothesis that LXR activation will restore cholesterol homeostasis in the diabetic retina and correct diabetes-induced bone marrow dysfunction to sustain CAC levels and function and to reduce of myeloid cell production.