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）是全球人类发病率和死亡率的主要原因。最近的兴趣集中在慢性传染病等牙周感染等慢性感染疾病上是CAD的潜在因素，因为传统的危险因素（例如高胆固醇血症，吸烟和高血压）无法完全解释人群中CAD的发生率。流行病学研究表明，牙周感染的个体患有CAD的可能性高30％至100％。但是，缺乏这些观察结果和机械研究的混杂因素可能会解释这种联系。牙周疾病与系统性炎症状态有关，并且可能成为循环细胞因子和口服病原体的靶标是血管内皮，在血管稳态调节中起着核心作用。通过炎症细胞因子激活内皮细胞会促进促动脉粥样硬化的表型，炎症因子的表达增加以及抗脉动抑制，生长抑制性和内皮的血管扩张剂的丧失。这些变化发生在动脉粥样硬化的早期，并有助于疾病的发病机理和临床表达。该应用的目的是检验以下假设：宿主炎症反应在感染受损的动脉粥样硬化中起主要作用，并研究解释了这一过程的特定信号传导机制。该应用的具体目的是：目标1。确定全身性炎症与直接细菌入侵动脉壁的相对重要性。目标2：确定抑制Toll样受体2（TLR2）和IL-1受体途径是否限制了细菌挑战后动脉粥样硬化的发生。目标3：确定TLR2和IL-1受体途径的激活是否加剧了动脉粥样硬化斑块的形成。目标4：确定细菌牙周炎的小鼠模型是否加剧了动脉粥样硬化。拟议的研究将提供机械洞察力，以了解牙龈卟啉单胞菌如何有助于动脉粥样硬化的形成和进展。该应用的长期目标是制定旨在控制炎症反应在动脉粥样硬化中的有害影响的治疗策略。