Role of the Nuclear Receptor Nor-1 in Atherosclerosis

描述（由申请人提供）：对血管损伤后动脉粥样硬化和新内膜形成机制的不断发展的理解已经确定了核激素受体超家族的成员是控制炎症和增殖的基因表达程序的关键转录调节因子。尽管人们对过氧化物酶体增殖体激活受体（PPAR）和肝脏X受体（LXR）亚家族的作用关注甚多，但核受体超家族包括大量所谓的孤儿核受体，其靶基因和生理功能尚不清楚，有待发现。

DESCRIPTION (provided by applicant): The 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 proliferation. 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 (Nor-1) is a constitutively-active transcription factor belonging to the nuclear hormone receptor superfamily. Our Preliminary Data identified Nor-1 expression 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 isolated 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 a transcriptional regulator of SMC proliferation and thereby contributes 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 by which Nor-1 regulates SMC proliferation. Specific Aim 3: To determine the contribution of Nor-1 to the development of atherosclerosis by cross- breeding 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 a novel transcriptional pathway regulating SMC proliferation in vascular disease and identify suppression of the nuclear receptor Nor-1 as a previously unrecognized target for the treatment of cardiovascular diseases.