Fellowship for Yue Zhao: The Regulation of Function of NOR1 in Endothelial Cells

The evolving understanding of mechanisms contributing to the development of atherosclerosis has identified members of the nuclear hormone receptor superfamily as key transcriptional regulators of gene expression programs controlling inflammation. Although much attention has focused on the role of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies, the nuclear receptor superfamily comprises a large number of so-called orphan nuclear receptors, whose target genes and physiological functions are unknown and remain to be discovered. The neuron-derived orphan receptor-1 (NOR1) belongs to the NR4A subfamily and functions as a constitutively active transcription factor. Our preliminary data demonstrated NOR1 expression in endothelial cells of human atherosclerotic lesions. In response to inflammatory activation, endothelial cells rapidly express NOR1 through a nuclear factor (NF)-kappaB dependent transcriptional mechanism. Utilizing endothelial cells isolated from NOR100deficient mice, we further demonstrated that NOR1 is required for the expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine implicated in the recruitment of monocytes during atherosclerosis development. Based on these findings, the central hypothesis of this proposal is that the transcriptional induction of NOR1 during endothelial cell activation is required for MCP-1 expression and subsequent monocyte recruitment during atherogenesis. To investigate this hypothesis, we propose: 1) To determine the transcriptional regulation of NOR 1 expression in response to inflammatory activation of endothelial cells; 2) To characterize the mechanisms by which NOR1 regulates MCP-1 expression and determine the significance of NOR1 for monocyte recruitment. Ultimately, these experiments may characterize a novel transcriptional pathway regulating endothelial cell activation and monocyte migration in vascular disease and identify suppression of the nuclear receptor NOR1 as a previously unrecognized target for the treatment of cardiovascular diseases.