Periodontal Pathogens and Cardiovascular Disease

牙周病原体与心血管疾病

基本信息

批准号：
8431682
负责人：
Kesavalu Naidu Lakshmyya
金额：
$ 35.16万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431682
关键词：
Actinobacillus actinomycetemcomitans Adaptor Signaling Protein Affect Alveolar Bone Loss Aorta Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Automobile Driving Bacteria Belief Blood Vessels Campylobacter rectus Cardiovascular Diseases Carotid Arteries Cell Adhesion Molecules Cells Chlamydophila pneumoniae Chronic Clinical Clinical Research Complex Coronary Coronary Vessels Coronary artery Cytomegalovirus DNA Data Development Disease Eikenella corrodens Endothelial Cells Environmental Exposure Epidemiology Etiology Event Exhibits Exposure to Forsythia Fusobacterium nucleatum Genetic Genomics Gingiva Goals Gram-Negative Bacterial Infections Helicobacter pylori Homeostasis Human Immune Immune response Individual Infection Infectious Agent Inflammation Inflammation Mediators Inflammatory Intervention Leukocytes Link Mediating Modeling Molecular Mono-S Mus Myocardial Infarction Oral Pathogenesis Patients Pattern Periodontal Diseases Periodontium Peripheral Play Porphyromonas gingivalis Prevotella intermedia Process Receptor Activation Receptor Signaling Risk Risk Factors Role Sampling Seminal Simplexvirus Stroke Surface Systemic infection T-Lymphocyte TLR2 gene TLR4 gene Tissues Toll-Like Receptor 1 Toll-like receptors Treponema denticola animal model development cardiovascular disorder risk cardiovascular risk factor cell motility chemokine cytokine in vivo monocyte mouse model neutrophil oral bacteria oral infection pathogen public health relevance receptor expression response sensor

项目摘要

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.

描述（由申请人提供）：牙周病是人类最常见的慢性多种微生物感染之一，并且正在积累大量流行病学数据，表明牙周病与人类心血管事件风险增加有关。多项研究已检测到主动脉组织、冠状血管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、齿垢密螺旋体、连翘坦纳氏菌、Aggregator actinomycetemcomitans、直肠弯曲杆菌、中间普氏菌、具核梭杆菌和腐蚀艾肯氏菌）。许多动脉粥样硬化冠状动脉样本含有不止一种类型的牙周细菌基因组 DNA。同样，很少有体内研究表明主要病原体牙龈卟啉单胞菌可以加速小鼠模型中的动脉粥样硬化。我们的主要目标是检查其他牙周病病原体，例如齿垢毛菌、连翘毛霉和具核镰刀菌，以了解它们以牙龈卟啉单胞菌作为多种微生物感染加速动脉粥样硬化的能力。总的前提是，几种不同的口腔细菌会引起牙周病，并且可能是这些病原体的组合协同诱发动脉粥样硬化。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核心和持续的作用，从动脉粥样硬化的发生到临床并发症的发展，特别是心脏病发作、中风和外周血管闭塞。此外，Toll 样受体 (TLR) 1、2、4 和 5 可以区分病原体特有的不同分子模式，并激活快速的先天免疫反应。最近的证据表明，TLRs 激活有助于动脉粥样硬化的发生和进展，这些证据来自将 TLRs、炎症和动脉粥样硬化机制联系起来的遗传和临床研究。发炎牙龈组织中 TLR 表达升高表明 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（牙龈卟啉单胞菌除外）的感染性细菌病因或这些病原体在动脉粥样斑块中连续积累的细菌菌群。该提案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形成。具体目标 1 将研究牙周病原体在慢性全身炎症 ApoE-/- 小鼠模型中诱导牙周病和动脉粥样硬化的协同作用。 SPECIFIC AIM 2 将在具有明确 TLR 遗传缺陷的小鼠模型中研究 TLR2 和 TLR4 是否在病原体介导的牙周病和相关动脉粥样硬化中发挥作用。目标是确定动脉粥样硬化的感染性病因和发病机制，并为干预动脉粥样硬化提供合理的方法。