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）：牙周疾病是人类最常见的慢性多数菌种感染，大量流行病学数据正在累积将牙周疾病与人类心血管事件的风险增加联系在一起。 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血管和颈动脉。许多动脉粥样硬化冠状动脉样品包含多种类型的牙周细菌基因组DNA。同样，很少有体内研究表明，主要的病原体牙龈疟原虫可以在小鼠模型中加速动脉粥样硬化。我们的主要目的是检查其他牙周病原体，例如牙霉菌，T。Forsythia和F. nutleatum，以用牙龈粘膜粘粘剂作为多数菌感染加速动脉粥样硬化的能力。一般的前提是几种不同的口腔细菌会引起牙周疾病，也许是这些病原体协同诱导动脉粥样硬化的结合。尽管动脉粥样硬化心血管疾病几乎可以肯定是一种多因素疾病，但现在有强有力的证据表明感染和炎症代表了重要的危险因素。炎症在动脉粥样硬化的发病机理中起着临床并发症的发育，特别是心脏病发作，中风和周围血管闭塞的核心作用。此外，Toll样受体（TLRS）1、2、4和5区分了特定于病原体的不同分子模式，并激活了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展和进展，来自遗传和临床研究，将TLR，炎症和动脉粥样硬化联系起来。发炎组织中TLR表达升高表明，TLR介导的过量炎症是牙周疾病的驱动因素。然而，没有直接证据表明，在这些病原体在动脉瘤斑块中的顺序积累中，各种物种（牙龈疟原虫）或细菌结合的传染性细菌病因。该提议的具体假设是感染牙周组织的牙周病原体会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的APOE - / - 小鼠模型中牙周疾病和动脉粥样硬化的诱导中的协同作用。具体目标2将研究TLR2和TLR4是否在病原体介导的牙周疾病和与定义的TLR遗传缺乏的小鼠模型中相关的动脉粥样硬化。目标是定义动脉粥样硬化的感染性病因和发病机理，并能够采用理性的干预动脉粥样硬化方法。