Inflammation and Infection in Atherosclerosis

动脉粥样硬化的炎症和感染

基本信息

批准号：
8308411
负责人：
Salomon Amar
金额：
$ 40.22万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308411
关键词：
Accounting Acetylmuramyl-Alanyl-Isoglutamine Address Agonist Animals Antibiotics Apolipoprotein E Arterial Fatty Streak Atherosclerosis Attenuated Bacteria Binding Bone Marrow Cell surface Cells Cellular Membrane Chronic Communicable Diseases Coronary Arteriosclerosis Cytosol Data Diet Disease Dose Endosomes Ensure Epidemiologic Studies Exhibits Extracellular Space Face Funding Gene Deletion Histologic Human Hypertension IRAK3 gene IRF3 gene IRF4 gene Immune Immune response Immune system Immunoblot Analysis Immunocompetent Immunologic Surveillance Immunoprecipitation In Vitro Incidence Individual Infection Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Interleukin-1 Interleukin-10 Intervention Invaded Laboratories Lesion Leukocytes Ligands Link Lipids Lung MAP3K7 gene Measures Mediating Metronidazole Microbe Modeling Molecular Monitor Morbidity - disease rate Mus Myocardial Infarction Nucleotides Oral Pathogenesis Pattern Pattern recognition receptor Peptidoglycan Periodontal Infection Peritoneal Porphyromonas gingivalis Process Proteins RNA Interference Receptor Signaling Regulation Research Risk Factors Role STAT1 gene STAT3 gene Scarlet Red Serum Markers Signal Pathway Signal Transduction Signaling Molecule Site Small Interfering RNA Smoking Staining method Stains Stereoisomer Stimulus System TLR2 gene TNF gene TRAF6 gene Testing Time Toll-Like Receptor 2 Toll-like receptors Transcription Factor AP-1 Transcriptional Regulation Trees atherogenesis bone loss cytokine feeding gain of function hypercholesterolemia in vivo interest loss of function macrophage microbial microorganism microorganism antigen monocyte mortality mouse model pathogen prevent promoter public health relevance receptor research study response stem transcription factor vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent interest has focused on chronic infectious diseases such as periodontal infection as potential contributors to CAD since traditional risk factors, including hypercholesterolemia, smoking, and hypertension fail to fully explain the incidence of CAD. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD. During the past funding cycle, we generated substantial data related to the role of infection-sensing circuits and ensuing inflammatory cytokine expression in a mouse model of Porphyromonas gingivalis (P.g)-associated atherogenesis. Pertinent to this competing application, we evaluated the role of P.g invasion in atherogenesis. We found that when invasion-deficient P.g. strain DPG3 was substituted for wild-type P.g, or when treatment with the invasion interfering antibiotic metronidazole was included, subsequent atherogenesis was reduced by about 50%, supporting the existence of an invasion-mediated cytosolic process that contributes significantly to P.g-driven atherogenesis. We have also begun to characterize the mechanisms linking infection and atherogenesis. Nucleotide binding oligomerization domain- like receptors (NOD1 and NOD2) represent an immune surveillance system that detects the presence of microbial molecules inside the cell. Recently peptidoglycan (PGN; a TLR2 ligand) was shown to be recognized independently of its muramyl dipeptide (MDP) components (NOD2 ligands) by cell-surface TLR2, and also to activate NF-:B through a distinct TLR signaling pathway involving MyD88. This introduced the possibility that TLR2 and NOD2 signaling are linked, and that one function of NOD2 is the regulation of TLR2. However, the role of NOD2 in TLR-mediated cytokine responses remains controversial. Our preliminary data show that introducing NOD2 siRNA into P.g-stimulated macrophages heightens the pro-inflammatory response. However, NOD2 activation of TLR2-mediated cytokine response was found dependent on MDP dose: low ligand stimulation appears to be synergistic while high ligand levels appear inhibitory. This regulation leads to NF:B modulation and IL-1 and TNF transcriptional regulation. Our hypothesis is that activation of NOD2 negatively regulates TLR2 responses, which in turn reduce artherosclerosis; the absence of such regulation leads to heightened immune responses and aggravated atherosclerosis. To test our hypothesis we are proposing in Aim 1 to use loss of function studies to determine the role of NOD2 in P.g- driven atherosclerosis; in Aim 2 to determine the molecular mechanisms involved in NOD2 regulation of the innate inflammatory response and invasion-mediated cytosolic process; and in Aim 3 to determine whether administration of muramyl dipeptide (MDP) or NOD2 blockers protect mice from P. g induced atherosclerosis using gain of function studies. These experiments will clearly define the role of NOD2 in P.g atherogenesis and pave the way for pharmacological interventions aimed at reducing or preventing atherogenesis. PUBLIC HEALTH RELEVANCE: Coronary artery disease (CAD) is a major cause of morbidity and mortality in humans worldwide. The results of the proposed experiments will define the role of immune sensing in infection-associated atherogenesis and pave the way for pharmacological interventions aimed reducing or preventing atherogenesis.

描述（由申请人提供）：冠状动脉疾病（CAD）是全球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上，例如牙周感染作为CAD的潜在因素，因为传统的危险因素（包括高胆固醇血症，吸烟和高血压）无法完全解释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％。在过去的融资周期中，我们生成了与感染感应电路的作用以及随之而来的炎症细胞因子在卟啉单胞菌（P.G）相关的动脉粥样硬化中的作用相关的大量数据。与这种竞争应用有关，我们评估了P.G侵袭在动脉粥样硬化中的作用。我们发现，当入侵缺陷P.G. DPG3菌株被取代为野生型P.G，或者包括入侵干扰抗生素甲硝唑的治疗时，随后的动脉粥样硬化减少了约50％，支持存在浸润介导的胞质过程，从而对P.G-droven驱动的动脉粥样硬化作用显着贡献。我们还开始表征关联感染和动脉粥样硬化的机制。核苷酸结合寡聚结构域（NOD1和NOD2）代表一种免疫监视系统，该系统检测细胞内部微生物分子的存在。最近，肽聚糖（PGN; A TLR2配体）被细胞表面TLR2独立于其穆拉米基二肽（MDP）组件（NOD2配体）独立识别，也可以通过带有MYD88的不同TLR信号通路来激活NF-：B。这引入了TLR2和NOD2信号链接的可能性，并且NOD2的一个函数是TLR2的调节。但是，NOD2在TLR介导的细胞因子反应中的作用仍然存在争议。我们的初步数据表明，将NOD2 siRNA引入P.G刺激的巨噬细胞中会增强促炎反应。然而，发现TLR2介导的细胞因子反应的NOD2激活取决于MDP剂量：低配体刺激似乎是协同作用的，而高配体水平显得抑制。该调节导致NF：B调制以及IL-1和TNF转录调控。我们的假设是，NOD2的激活对TLR2反应进行负调节，从而减少了耳骨硬病。缺乏这种调节会导致免疫反应增强并加剧动脉粥样硬化。为了检验我们的假设，我们在AIM 1中提议使用功能研究丧失来确定NOD2在P.G驱动的动脉粥样硬化中的作用；在AIM 2中，以确定与先天炎症反应和侵袭介导的胞质过程的NOD2调节有关的分子机制；在AIM 3中，确定穆拉米尔二肽（MDP）或NOD2阻滞剂是否使用功能研究获得的动脉粥样硬化诱导了动脉粥样硬化。这些实验将清楚地定义NOD2在P.G动脉粥样硬化中的作用，并为旨在减少或预防动脉粥样硬化的药理干预措施铺平了道路。公共卫生相关性：冠状动脉疾病（CAD）是全球人类发病率和死亡率的主要原因。提出的实验的结果将定义免疫感应在感染相关的动脉粥样硬化中的作用，并为旨在减少或预防动脉粥样硬化的药理干预措施铺平了道路。