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

核受体 Nor-1 在动脉粥样硬化和血管损伤中的作用

• 批准号: 7387407
• 负责人: Dennis Christopher Bruemmer
• 金额: $ 35.56万
• 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/7387407
• 关键词: Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Attention; Blood Vessels; Breeding; Cardiovascular Diseases; Cell Cycle Progression; Cell Proliferation; Data; Development; ERG gene; Failure; Figs - dietary; Functional disorder; Gene Expression; Gene Targeting; Growth Factor; Human; Inflammation; Injury; Ligands; Liver; Modeling; Molecular; Mus; Muscle Cells; Neurons; Nuclear; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Nuclear Receptors; Numbers; Orphan; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Physiological; Play; Process; Role; Smooth Muscle Myocytes; Telomerase; Testing; Transcriptional Regulation; Treatment Failure; Vascular Diseases; base; femoral artery; member; neointima formation; novel; prevent; programs; receptor; research study; response; restenosis; transcription factor

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和新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。尽管人们的注意力集中在过氧化物酶体增殖物激活受体（PPAR）和肝X受体（LXR）亚家族的作用上，但核受体超家族包含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。 神经元衍生的孤儿受体-1 (Nor-1) 是一种组成型活性转录因子，属于核激素受体超家族。我们的初步数据确定了 Nor-1 在人类动脉粥样硬化病变和血管损伤后形成的新内膜中的表达。为了响应生长因子刺激，血管平滑肌细胞 (SMC) 快速表达 Nor-1，将这种核受体表征为早期反应基因。使用从 Nor-1 缺陷小鼠中分离的 SMC 进行的实验进一步表明，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，该提议的中心假设是 Nor-1 作为 SMC 增殖的转录调节因子发挥作用，从而有助于动脉粥样硬化的发展和血管损伤后新内膜的形成。 为了检验这一假设，我们提出以下目标： 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缺陷型小鼠与动脉粥样硬化易感性apoE缺陷型小鼠杂交，确定Nor-1对动脉粥样硬化发展的贡献。具体目标 4：使用 Nor-1 缺陷小鼠的导丝诱导股动脉损伤模型来确定 Nor-1 对新内膜形成的贡献。 最终，这些实验可能表征血管疾病中调节 SMC 增殖的新转录途径，并将核受体 Nor-1 的抑制确定为以前未被识别的心血管疾病治疗靶点。