The long-term goal of our laboratory is to determine the mechanism involved in the crosstalk between innate immunity and the development of metabolic syndrome and its vascular complications. We are particularly interested in understanding the mechanisms of the interactions between vitamin D signaling and endoplasmic reticular stress in critical tissues contributing to metabolic dysregulation. Recent work from our laboratory has identified potential mechanisms by which vitamin D regulates macrophage cholesterol metabolism and monocyte function in patients with diabetes. We have generated multiple mouse models with diet-induced vitamin D deficiency or genetically modified mice of vitamin D signaling in order to identify the role of this vitamin in vivo on endoplasmic reticulum function in different tissues. In addition, we explored the effect of different environmental conditions that program signaling pathways to regulate monocyte/macrophage differentiation and function in models of type 2 diabetes. Our findings in mice and in human innate immune cells have laid the groundwork for our active randomized controlled trials assessing the effects of vitamin D supplementation on blood pressure and on subclinical markers of cardiovascular disease in type 2 diabetics.