ARRA: Role of the Nuclear Receptor Nor-1 in Atherosclerosis and Vascular Injury

In an era marked by the increasing prevalence of obesity, diabetes, and associated cardiovascular disease, members of the nuclear hormone receptor superfamily have emerged as attractive pharmacological treatment possibilities for atherosclerotic vascular disease. The neuron-derived orphan receptor-1 (Nor-1) belongs to the evolutionary highly conserved and most ancient NR4A subfamily, which integrates metabolic and vascular gene expression networks. The parent grant for this request for an administrative supplement through the American Recovery and Reinvestment Act of 2009 investigates the expression and function of Nor-1 in vascular diseases. Using different animal models, we have demonstrated that Nor-1 deficiency reduces neointima formation and atherosclerosis development. Our cellular studies provide evidence for a fundamental role of Nor-1 to regulate essential mechanisms involved in the pathogenesis of atherosclerotic lesion formation. However, the molecular mechanisms underlying this atherogenic function of Nor-1 remain undefined. Funds provided through the Recovery Act will allow us to investigate the cell-specific contribution of Nor-1 to atherosclerosis development within the scope of the approved aims of the parent grant. Using a series of cellular and molecular studies, we will further define the transcriptional mechanisms underlying the important role of Nor-1 in mediating macrophage recruitment during lesion formation. Funds are explicitly requested to support Dr. Florence Gizard, an exceptionally talented and productive postdoctoral scholar. Her addition to the research team and addressing the molecular mechanisms underlying the important function of Nor-1 in the control of vascular gene expression will considerably accelerate our research program. Ultimately, these studies will identify previously unappreciated inflammatory gene expression networks involved in atherosclerosis formation and aid the development of novel therapeutical approaches for this most prevalent disease.