Role of the Nuclear Receptor Nor-1 in Atherosclerosis

核受体 Nor-1 在动脉粥样硬化中的作用

• 批准号: 7085725
• 负责人: Dennis Christopher Bruemmer
• 金额: $ 36.61万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085725
• 关键词: animal breeding; aorta; apolipoprotein E; atherosclerosis; cardiovascular injury; cell proliferation; gene expression; genetic promoter element; genetically modified animals; inflammation; laboratory mouse; laboratory rat; molecular pathology; nuclear receptors; protein structure function; transcription factor; vascular endothelium; vascular smooth muscle

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.

描述（由申请人提供）：对血管损伤后动脉粥样硬化发展和新生内膜形成机制的不断理解已经确定核激素受体超家族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。尽管过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）和肝X受体（liver X receptor，LXR）亚家族的作用已引起广泛关注，但核受体超家族中存在大量孤儿核受体，其靶基因和生理功能尚不清楚，有待进一步研究。 神经元源性孤儿受体-1（Nor-1）是一种组成型激活的转录因子，属于核激素受体超家族。我们的初步数据确定了在人类动脉粥样硬化病变和血管损伤后新生内膜中的Nor-1表达。在响应生长因子刺激，血管平滑肌细胞（SMC）迅速表达Nor-1，其特征是这种核受体作为早期反应基因。使用从Nor-1缺陷小鼠分离的SMC的实验进一步揭示了Nor-1表达对于SMC增殖、细胞周期进展和端粒酶活性是必需的。 基于这些发现，该建议的中心假设是，Nor-1作为SMC增殖的转录调节因子发挥作用，从而有助于血管损伤后动脉粥样硬化和新生内膜形成的发展。 为了验证这一假设，我们提出了以下目标：具体目标1：确定SMC中Nor-1表达的转录调控。具体目标2：确定Nor-1调节SMC增殖的分子机制。具体目标3：通过将Nor-1缺陷小鼠与动脉粥样硬化易感的apoE缺陷小鼠杂交，确定Nor-1对动脉粥样硬化发展的作用。具体目标4：在Nor-1缺陷小鼠中使用导丝诱导的股动脉损伤模型来确定Nor-1对新生内膜形成的贡献。 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SMC增殖，并确定抑制核受体Nor-1作为以前未被认识到的治疗心血管疾病的靶点。