NUCLEAR FACTOR KAPPA BETA AND INITIATION OF THE ATHEROSC

核因子 KAPPA Beta 和动脉粥样硬化的引发

• 批准号: 7056678
• 负责人: Tucker O Collins
• 金额: $ 36.96万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056678
• 关键词: atherosclerotic plaque; cardiovascular disorder risk; disease /disorder etiology; gene expression; gene induction /repression; genetic regulation; genetically modified animals; laboratory mouse; low density lipoprotein receptor; nuclear factor kappa beta; pathologic process; protein kinase; vascular endothelium

DESCRIPTION (provided by the applicant): Atherosclerosis is a major cause of morbidity and mortality among both men and women. Multiple systemic risk factors, including hypertension, diabetes mellitus, smoking, and 1ipoprotein disorders are involved in the pathogenesis of this chronic inflammatory disease of arteries, but to date, it has not been possible to associate the risk factors with common pathogenic mechanism. Recent evidence suggests that a small group of transcription factors may be critical in linking the diverse risk factors to the initiation of the atherosclerotic lesion. This project emphasizes one of these transcription factors, nuclear factor-kappaB (NF-kappaB), whose activation has been linked to the onset of atherosclerosis through a remarkable series of correlations. These include observations that activated endothelial NF-kappaB is found predominately in atherosclerotic lesions where NF-kappaB-dependent endothelial genes are also selectively expressed; atherosclerosis develops in response to diverse stimuli that share the ability to create oxidant stress and activate the NF-kappaB system; several agents inhibiting lesion formation also act as antioxidants and stabilize NF-kappaB and; atherosclerotic lesions form at distinct regions of the arterial tree, especially at or near branch points or major curvatures where the endothelial NF-kappaB system is selectively activated. Although these correlations are provocative, there is no direct evidence demonstrating that NF-kappaB activation is necessary or sufficient for atherosclerosis or for defining lesion-prone regions. The goal of this proposal, therefore, is to determine the role of endothelial NF-kappaB in initiation of the atherosclerotic lesion. Unfortunately, loss of function mutants of several NF-kappaB system components in mice present significant developmental abnormalities precluding their use for studies of atherosclerosis. In this application, strategies using conditional mouse genetics are proposed to avoid this complication and test the hypothesis that the NF-kappaB system plays a key role in the formation of the early atherosclerotic lesion. In the First Specific Aim, the LDLR-/- mouse model of atherosclerosis will be used to determine if NF-kappaB expression is required for early lesion formation in vivo. These studies utilize the Cre-loxP system to achieve endothelial -restricted conditional mutation of NF-kappaB system components. In the Second Specific Aim, we will determine if dysregulated expression in endothelium of a gene that normally inhibits NF-kappaB activation alters early lesion formation in LDLR-/- mice. These studies will use tetracycline-regulated transgene expression to generate mice with inducible and endothelial-restricted expression of an inhibitor of NF-kappaB activation. In the Third Specific Aim, we will determine if NF-kappaB signaling plays a role in specifying lesion prone and lesion resistant regions of aorta in LDLR-/- mice. Taken together these studies should determine if the NF-kappaB system is necessary and/or sufficient for the initiation of the atherosclerotic lesion.

描述（由申请人提供）： 动脉粥样硬化是男性和女性发病率和死亡率的主要原因。 妇女多种全身性风险因素，包括高血压、糖尿病 糖尿病、吸烟和脂蛋白紊乱参与了发病机制 这种慢性动脉炎性疾病，但到目前为止，它还没有 这些危险因素可能与共同的致病机制有关。 最近的证据表明，一小群转录因子可能是 关键是将各种风险因素与启动 动脉粥样硬化病变 该项目强调这些转录因子之一，核因子-κ B （NF-kappaB），其激活与 动脉粥样硬化通过一系列显著的相关性。这些包括 观察到活化的内皮NF-κ B主要在 动脉粥样硬化病变，其中NF-κ B依赖性内皮基因也是 选择性表达;动脉粥样硬化的发展对不同的刺激 共同产生氧化应激并激活NF-κ B的能力 系统;几种抑制病变形成的药物也起抗氧化剂的作用 并稳定NF-κ B，动脉粥样硬化病变在不同区域形成 动脉树的，尤指在或靠近分支点或主要弯曲处 其中内皮NF-κ B系统被选择性激活。 尽管这些相关性具有挑衅性，但没有直接证据表明 证明NF-κ B活化是必要的或足够的， 动脉粥样硬化或用于定义病变倾向区域。这个目标 因此，我们的建议是确定内皮细胞NF-κ B在 动脉粥样硬化病变的开始。不幸的是，功能丧失 小鼠中几种NF-κ B系统组分的突变体呈现显著的 发育异常，使其无法用于研究 动脉粥样硬化在这个应用程序中，策略使用条件鼠标 遗传学被提出来避免这种复杂性，并测试假设， NF-kappaB系统在早期的形成中起着关键作用， 动脉粥样硬化病变在第一个具体目标中，LDLR-/-小鼠模型 动脉粥样硬化将用于确定是否需要NF-κ B表达 用于体内早期损伤形成。这些研究利用Cre-loxP系统 实现NF-κ B系统的内皮限制性条件突变 件.在第二个具体目标中，我们将确定是否失调 正常情况下抑制NF-κ B的基因在内皮中的表达 活化改变LDLR-/-小鼠中的早期损伤形成。这些研究将 使用四环素调节的转基因表达产生小鼠， NF-κ B抑制剂诱导型和内皮限制型表达 activation.在第三个具体目标中，我们将确定NF-κ B是否 信号传导在指定易损伤区域和抗损伤区域中起作用 LDLR-/-小鼠的主动脉。综合这些研究， NF-κ B系统是启动免疫反应所必需的和/或足够的。 动脉粥样硬化病变