NF-KB ACTIVATION AND ORAL INFLAMMATION IN ATHEROGENESIS

动脉粥样硬化中的 NF-KB 激活和口腔炎症

• 批准号: 6644956
• 负责人: Timothy Charles Nichols
• 金额: $ 14.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6644956
• 关键词: atherosclerosis; atherosclerotic plaque; inflammation; nuclear factor kappa beta; pathologic process; periodontitis; swine; tissue /cell culture; vascular endothelium; vascular resistance; vascular smooth muscle

Atherosclerosis, the major cause of death and disability in the United States, is a chronic disease with inflammatory components. Our overall objective is to use molecular, cellular and animal models to study how activation of NF-kappaB contributes to atherosclerosis. This nuclear transcription factor controls the expression of many genes linked to atherogenesis, including those involved with inflammation. We hypothesize that one unifying mechanisms in this complex disease is the activation of NF-kappaB. The mechanism(s) that activates NF-kappaB in atherogenesis is unknown and the effect of inhibiting NF-kappaB atherogenesis is untested in animal models. In Aim 1, we focus on shear stress and oxidized LDL-induced activation of NF-kappaB in cultured porcine endothelium and smooth muscle cells as models for determining the mechanism(s) of activation of NF-kappaB in atherogenesis. The role of phosphorylation and degradation of IkapaB and the operative kinases and signal transduction pathways will be identified. In Aim 2, we will develop and test a series of reagents that inhibit NF-kappaB activation in response to shear stress and oxidized LDL. The most promising inhibitors will be tested in Aim 3 where we will use our pigs with shear and diet-induced atherosclerosis to determine the effect of inhibiting activation of NF-kappaB. Periodontal disease has now been established as a risk factor for atherosclerosis and its thrombotic complications. It is unknown if periodontal disease contributes to the initiation or progression of atherosclerosis. NF-kappaB likely plays an essential role in bone loss due to periodontitis since IL-1beta and TNFalpha are key mediators in humans and animal models of the disease and strong activators of NF-kappaB. We hypothesize that the chronic and intense inflammatory response accompanying periodontal disease produces an excess burden of circulating mediators of inflammation that initiate or exacerbate the inflammatory components of atherosclerosis. To test this hypothesis, we will adapt a model of ligature-induced periodontitis to our pig models of atherogenesis. Our goal in Aim 4 will be to determine if the presence of periodontal inflammation contributes to the initiation and/or progression of atherosclerosis. If so, then we will determine whether or not activated NF-kappaB is present in cells in the atherosclerotic lesion that is modulated by oral inflammation. Our data on the mechanisms involved in the critical role of NF-kappaB in atherosclerosis could lead to important therapeutic applications especially as it relates to the impact of periodontitis.

动脉粥样硬化是美国的主要死亡和残疾原因，是一种慢性疾病，患有炎症成分。我们的总体目标是使用分子，细胞和动物模型来研究NF-kappab的激活如何有助于动脉粥样硬化。该核转录因子控制着与动脉粥样硬化有关的许多基因的表达，包括与炎症有关的基因。我们假设这种复杂疾病中的一种统一机制是NF-kappab的激活。在动脉粥样硬化中激活NF-kappab的机制尚不清楚，并且在动物模型中未经测试。在AIM 1中，我们专注于剪切应力和氧化的LDL诱导的NF-kappab在培养的猪内皮和平滑肌细胞中的激活，作为确定动脉粥样硬化中NF-kappab激活机制的模型。 IKAPAB的磷酸化和降解的作用以及手术激酶和信号转导途径的作用将被鉴定。在AIM 2中，我们将开发和测试一系列试剂，这些试剂响应剪切应力和氧化的LDL抑制NF-kappab激活。最有希望的抑制剂将在AIM 3中进行测试，在AIM 3中，我们将使用剪切和饮食引起的动脉粥样硬化的猪来确定抑制NF-kappab激活的作用。现已确定牙周疾病是动脉粥样硬化及其血栓形成并发症的危险因素。未知牙周疾病是否有助于动脉粥样硬化的起步或进展。 NF-kappab可能在牙周炎引起的骨质流失中起着至关重要的作用，因为IL-1Beta和Tnfalpha是人类和动物模型的关键介体以及NF-Kappab的强激活因子。我们假设伴随牙周疾病的慢性和强烈炎症反应会导致循环炎症介质的多余负担，从而引发或加剧动脉粥样硬化的炎症成分。为了检验这一假设，我们将使结扎诱导的牙周炎模型适应我们的动脉粥样硬化模型。我们的目标4目标是确定牙周炎症的存在是否有助于动脉粥样硬化的启动和/或进展。如果是这样，那么我们将确定在动脉粥样硬化病变中是否存在激活的NF-kappab，该细胞受口腔炎症调节。我们关于NF-kappab在动脉粥样硬化中涉及的重要作用机制的数据可能会导致重要的治疗应用，尤其是与牙周炎的影响有关。