Role of the Nuclear Receptor Nor-1 in Atherosclerosis

描述(申请人提供)：对血管损伤后动脉粥样硬化和新生内膜形成的机制的不断发展的理解已经确定，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。尽管过氧化体增殖物激活受体(PPAR)和肝X受体(LXR)亚家族的作用已引起人们的广泛关注，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，还有待于进一步研究。 神经元来源的孤儿受体-1(NOR-1)是核激素受体超家族的一种结构性活性转录因子。我们的初步数据证实了NOR-1在人类动脉粥样硬化病变和血管损伤后形成的新生内膜中的表达。作为对生长因子刺激的反应，血管平滑肌细胞(SMC)迅速表达NOR-1，这表明该核受体是一种早期反应基因。使用从NOR-1缺陷小鼠分离的SMC的实验进一步表明，NOR-1的表达是SMC增殖、细胞周期进展和端粒酶活性所必需的。 基于这些发现，这一建议的中心假设是NOR-1作为SMC增殖的转录调节因子，从而促进血管损伤后动脉粥样硬化和新生内膜的形成。 为了验证这一假说，我们提出了以下目标：特定目标1：确定SMC中NOR-1表达的转录调控。具体目的2：确定NOR-1调控SMC增殖的分子机制。具体目的3：通过将NOR-1缺陷小鼠与动脉粥样硬化易感的载脂蛋白E缺陷小鼠杂交，确定NOR-1在动脉粥样硬化发生发展中的作用。具体目的4：建立NOR-1缺陷小鼠股动脉损伤模型，研究NOR-1在新生内膜形成中的作用。 最终，这些实验可能表征一种新的转录途径，调节血管疾病中的SMC增殖，并确定抑制核受体NOR-1是以前未被认识到的心血管疾病治疗的靶点。

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.