Inflammation and Infection in Atherosclerosis

动脉粥样硬化的炎症和感染

• 批准号: 7005828
• 负责人: Salomon Amar
• 金额: $ 39.43万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7005828
• 关键词: Bacteroides gingivalis; atherosclerosis; atherosclerotic plaque; coronary disorder; cytokine; enzyme linked immunosorbent assay; genetically modified animals; immunocytochemistry; inflammation; interleukin 1; laboratory mouse; metronidazole; pathologic process; periodontium disorder; receptor binding; toll like receptor; vascular cell adhesion molecule

DESCRIPTION: Coronary artery disease (CAD) is a major cause of morbidity and mortality in human worldwide. Recent interest has focused on chronic infectious diseases like periodontal infection as potential contributors to CAD since traditional risk factors like hypercholesterolemia, smoking and hypertension fail to fully explain the incidence of CAD in populations. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD; however, it remains possible that confounding factors account for these observations and mechanistic studies to explain this connection are lacking. Periodontal disease is associated with a state of systemic inflammation, and a likely target for circulating cytokines and oral pathogens is the vascular endothelium, which plays a central role in the regulation of vascular homeostasis. Activation of endothelial cells by inflammatory cytokines promotes a pro-atherogenic phenotype with increased expression of inflammatory factors and loss of the anti-thrombotic, growth inhibitory, and vasodilator properties of the endothelium. These changes occur early in the development of atherosclerosis and contribute to the pathogenesis and clinical expression of disease. The purpose of this application is to test the hypothesis that the host inflammatory response plays a primary role in infection-aggravated atherosclerosis and investigate the specific signaling mechanisms that account for this process. The Specific Aims of this application are: Aim 1. To determine the relative importance of systemic inflammation versus direct bacterial invasion of the arterial wall for atherosclerotic lesion formation. Aim 2: To determine whether inhibition of Toll-like Receptor 2 (TLR2) and IL-1 receptor pathways limits atherogenesis following bacterial challenge. Aim 3: To determine whether activation of TLR2 and IL-1 receptor pathways aggravate atherosclerotic plaque formation. Aim 4: To determine whether a mouse model of bacterial periodontitis exacerbates atherosclerosis. The proposed studies will provide mechanistic insights into how Porphyromonas gingivalis contributes to atherosclerosis formation and progression. The long-term goal of this application is to develop therapeutic strategies aimed at controlling the deleterious effects of the inflammatory response in atherosclerosis.

描述：冠状动脉疾病（CAD）是全世界人类发病和死亡的主要原因。最近的兴趣集中在牙周感染等慢性传染病上，因为高胆固醇血症、吸烟和高血压等传统危险因素无法完全解释人群中 CAD 的发病率，因此牙周感染等慢性传染病是 CAD 的潜在诱因。流行病学研究表明，患有牙周感染的人患 CAD 的可能性增加 30% 至 100%；然而，这些观察结果仍然可能存在混杂因素，并且缺乏解释这种联系的机制研究。牙周病与全身炎症状态有关，循环细胞因子和口腔病原体的可能目标是血管内皮，它在血管稳态的调节中发挥着核心作用。炎症细胞因子对内皮细胞的激活促进促动脉粥样硬化表型，同时炎症因子表达增加以及内皮抗血栓、生长抑制和血管舒张特性的丧失。这些变化发生在动脉粥样硬化发展的早期，并有助于疾病的发病机制和临床表现。本申请的目的是检验宿主炎症反应在感染加剧的动脉粥样硬化中起主要作用的假设，并研究解释该过程的特定信号传导机制。本申请的具体目的是： 目的 1. 确定全身炎症与动脉壁直接细菌侵入对于动脉粥样硬化病变形成的相对重要性。目标 2：确定 Toll 样受体 2 (TLR2) 和 IL-1 受体途径的抑制是否会限制细菌攻击后的动脉粥样硬化形成。目标 3：确定 TLR2 和 IL-1 受体途径的激活是否会加剧动脉粥样硬化斑块的形成。目标 4：确定细菌性牙周炎小鼠模型是否会加剧动脉粥样硬化。拟议的研究将为牙龈卟啉单胞菌如何促进动脉粥样硬化的形成和进展提供机制见解。该应用的长期目标是开发旨在控制动脉粥样硬化炎症反应的有害影响的治疗策略。