Periodontal Pathogens and Cardiovascular Disease

描述(申请人提供)：牙周病是人类最常见的慢性多菌感染之一，大量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在一起。一些研究已经检测到在主动脉组织、冠状动脉和颈动脉的动脉粥样硬化病变中存在牙周细菌基因组DNA(牙龈卟啉单胞菌、齿密螺旋体、连翘坦纳氏菌、伴生放线菌聚集体、直肠弯曲杆菌、中间普雷沃特氏菌、核梭杆菌和腐蚀性艾肯氏杆菌)。许多动脉粥样硬化的冠状动脉样本中含有不止一种类型的牙周细菌基因组DNA。同样，很少有活体研究表明，主要病原体牙龈假单胞菌可以加速小鼠模型的动脉粥样硬化。我们的主要目标是检测其他牙周病病原体，如齿状念珠菌、连翘和核假单胞菌，了解它们加速动脉粥样硬化的能力，并将牙龈假单胞菌作为多菌感染。总的前提是几种不同的口腔细菌导致牙周疾病，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机制中发挥着中心和持续的作用，从发病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区分不同的针对病原体的分子模式，并激活快速的先天性免疫反应。最近的证据表明，TLRs的激活有助于动脉粥样硬化的发生和发展，这一证据来自于遗传和临床研究，这些研究将TLRs、炎症和动脉粥样硬化机械地联系在一起。炎症牙龈组织中TLR的表达升高提示TLRs介导的过度炎症是牙周病的一个驱动因素。然而，没有直接证据表明，在动脉粥样硬化斑块中这些病原体的顺序聚集中存在单个菌种(牙龈假单胞菌除外)或细菌群的感染性病原学。这一建议的具体假设是，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。具体目的1将在ApoE-/-小鼠慢性全身炎症模型中，研究牙周病原体在诱导牙周疾病和动脉粥样硬化中的协同作用。特异目的2将研究TLR2和TLR4在TLR基因缺陷小鼠模型中是否在病原体介导的牙周疾病和相关的动脉粥样硬化中起作用。目的是明确动脉粥样硬化的感染性病因和发病机制，并为动脉粥样硬化的干预提供一种合理的方法。

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.