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

The recent evolving understanding of mechanisms contributing to the development of atherosclerosis and neointima formation following vascular injury has identified members of the nuclear hormone receptor superfamily as key transcriptional regulators of gene expression programs controlling inflammation and cell proliferation. Although much attention has focused on the role of the peroxisome proliferator activated receptor (PPAR) and liver X receptor (LXA) 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. Our Preliminary Data identified the expression of the Neuron-Derived Orphan Aeceptor-1 (Nor-1) in human atherosclerotic lesions and in the developing neointima following vascular injury. In response to growth factor stimulation, vascular smooth muscle cells (SMC) rapidly express Nor-1 characterizing this nuclear receptor as an early response gene. Experiments using SMC from Nor-1 deficient mice further reveal that Nor-1 expression is required for SMC proliferation, cell cycle progression, and telomerase activity. Based on these findings, the central hypothesis of this proposal is that Nor-1 functions as transcriptional regulator of SMC proliferation contributing to the development of atherosclerosis and neointima formation following vascular injury. To test this hypothesis, we propose the following aims: Specific Aim 1: To determine the transcriptional regulation of Nor-1 expression in SMC. Specific Aim 2: To determine the molecular mechanisms governing the regulation of SMC proliferation by Nor-1. Specific Aim 3: To determine the contribution of Nor-1 to the development of atherosclerosis by crossbreeding Nor-1 deficient mice to atherosclerosis-susceptible apoE-deficient mice. Specific Aim 4: To determine the contribution of Nor-1 to neointima formation using a model of guide-wire induced femoral artery injury in Nor-1 deficient mice. Ultimately, these experiments may characterize novel transcriptional pathways regulating SMC proliferation in vascular disease and identify the orphan nuclear receptor Nor-1 as a novel target for the treatment of cardiovascular disease.