Periodontal Pathogens and Cardiovascular Disease

描述（由申请人提供）：牙周病是人类最常见的慢性多微生物感染之一，大量的流行病学数据正在积累，将牙周病与人类心血管事件风险增加联系起来。一些研究已经在主动脉组织、冠状血管和颈动脉的动脉粥样硬化病变中检测到牙周细菌基因组DNA的存在（牙龈卟啉单胞菌、牙齿密螺旋体、连翘Tannerella、聚合放线菌、直弯杆菌、中间普雷沃氏菌、核梭菌和腐蚀艾肯氏菌）。许多冠状动脉粥样硬化样本含有不止一种牙周细菌基因组DNA。同样，很少有体内研究表明，优势病原体牙龈卟啉单胞菌可以加速小鼠模型的动脉粥样硬化。我们的主要目的是检查其他牙周病病原体，如牙齿假单胞菌、连翘假单胞菌和有核假单胞菌，它们加速牙龈假单胞菌多微生物感染动脉粥样硬化的能力。一般的前提是几种不同的口腔细菌引起牙周病，也许是这些病原体的组合协同诱导动脉粥样硬化。尽管动脉粥样硬化性心血管疾病几乎肯定是一种多因素疾病，但现在有越来越多的有力证据表明，感染和炎症是重要的危险因素。炎症在动脉粥样硬化的发病过程中起着核心和持续的作用，从它的开始到临床并发症的发展，特别是心脏病发作、中风和周围血管闭塞。此外，toll样受体（TLRs） 1、2、4和5区分病原体特异性的不同分子模式，并激活快速的先天免疫反应。最近的证据表明，TLRs的激活有助于动脉粥样硬化的发生和进展，来自遗传和临床研究，将TLRs、炎症和动脉粥样硬化机制联系起来。炎症牙龈组织中TLR表达升高提示TLR介导的过度炎症是牙周病的驱动因素。然而，没有直接证据表明单个物种（牙龈假单胞菌除外）的感染性细菌病原学或这些病原体在动脉粥样斑块中的顺序积累的细菌联合体。该建议的具体假设是，感染牙周组织的牙周病原体可以感染血管组织并诱导动脉粥样硬化斑块的形成。特异性目的1将在ApoE-/-慢性全身性炎症小鼠模型中研究牙周病原体在诱导牙周病和动脉粥样硬化中的协同作用。SPECIFIC AIM 2将研究TLR2和TLR4在TLR基因缺失的小鼠模型中是否在病原体介导的牙周病和相关动脉粥样硬化中起作用。目的是明确动脉粥样硬化的感染病因和发病机制，并为动脉粥样硬化的干预提供合理的方法。

DESCRIPTION (provided by applicant): Periodontal diseases are among the most common chronic polymicrobial infections of mankind and a substantial amount of epidemiological data is accumulating linking periodontal disease with increased risk for cardiovascular events in humans. Several studies have detected the presence of periodontal bacterial genomic DNA (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Aggregator actinomycetemcomitans, Campylobacter rectus, Prevotella intermedia, Fusobacterium nucleatum, and Eikenella corrodens) in atherosclerotic lesions of aortic tissue, coronary vessels, and carotid artery. Many of the atherosclerotic coronary artery samples contained more than one type of periodontal bacterial genomic DNA. Similarly, few in vivo studies have shown that the predominant pathogen P. gingivalis can accelerate atherosclerosis in mouse model. Our major objective is to examine additional periodontal disease pathogens such as T. denticola, T. forsythia, and F. nucleatum for their ability to accelerate atherosclerosis with P. gingivalis as polymicrobial infection. The general premise is that several different oral bacteria cause periodontal disease and that perhaps it is a combination of these pathogens that synergistically induce atherosclerosis. Although atherosclerotic cardiovascular disease is almost certainly a multifactorial disease, there is now strong and increasing evidence that infection and inflammation represent important risk factors. Inflammation plays a central and continuous role in the pathogenesis of atherosclerosis from its initiation to the development of clinical complications, specifically heart attacks, strokes, and peripheral vascular occlusion. Furthermore, Toll-like receptors (TLRs) 1, 2, 4, and 5 distinguish between different molecular patterns specific to pathogens and activate a rapid innate immune response. Recent evidence that TLRs activation contributes to the development and progression of atherosclerosis, has come from genetic and clinical studies mechanistically linking TLRs, inflammation, and atherosclerosis. Elevated TLR expression in inflamed gingival tissues suggests that excess inflammation mediated by TLRs is a driving factor in periodontal disease. However, there is no direct evidence for an infectious bacterial etiology of individual species (except P. gingivalis) or bacterial consortia in the sequential accumulation of these pathogens in atheromatous plaque. The specific hypothesis of this proposal is that periodontal pathogens that infect the periodontal tissue can infect vascular tissue and induce atherosclerotic plaque formation. Specific Aim 1 will investigate the synergistic role of periodontal pathogens in the induction of periodontal disease and atherosclerosis in the ApoE-/- mouse model of chronic systemic inflammation. SPECIFIC AIM 2 will investigate whether TLR2 and TLR4 have a role in pathogen-mediated periodontal disease and associated atherosclerosis in the mouse models with defined TLR genetic deficiency. The Goals are to define the infectious etiology and pathogenesis of atherosclerosis and will enable a rational approach for intervention in atherosclerosis.