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）是全世界发病和死亡的主要原因。最近的兴趣集中在牙周感染等慢性传染病上，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 的发病率，因此牙周感染等慢性传染病是 CAD 的潜在诱因。流行病学研究表明，患有牙周感染的人患 CAD 的可能性高出 30% 至 100%。在过去的资助周期中，我们在牙龈卟啉单胞菌（P.g）相关动脉粥样硬化小鼠模型中产生了与感染感应回路的作用和随后的炎症细胞因子表达相关的大量数据。与这一竞争性应用相关，我们评估了 P.g 侵入在动脉粥样硬化形成中的作用。我们发现，当入侵缺陷时，P.g.将菌株 DPG3 替换为野生型 P.g，或者当使用侵入干扰抗生素甲硝唑进行治疗时，随后的动脉粥样硬化形成减少了约 50%，这支持了侵入介导的胞质过程的存在，该过程对 P.g 驱动的动脉粥样硬化有显着贡献。我们还开始描述感染和动脉粥样硬化形成之间的联系机制。核苷酸结合寡聚化结构域样受体（NOD1 和 NOD2）代表一种免疫监视系统，可检测细胞内微生物分子的存在。最近，肽聚糖（PGN；一种 TLR2 配体）被证明可以被细胞表面 TLR2 独立于其胞壁酰二肽 (MDP) 成分（NOD2 配体）识别，并且还可以通过涉及 MyD88 的独特 TLR 信号通路激活 NF-:B。这引入了 TLR2 和 NOD2 信号传导相互关联的可能性，并且 NOD2 的功能之一是 TLR2 的调节。然而，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 刺激的巨噬细胞可增强促炎反应。然而，NOD2 激活 TLR2 介导的细胞因子反应依赖于 MDP 剂量：低配体刺激似乎是协同的，而高配体水平似乎是抑制性的。这种调节导致 NF:B 调节以及 IL-1 和 TNF 转录调节。我们的假设是，NOD2 的激活会负向调节 TLR2 反应，从而减少动脉粥样硬化；缺乏这种调节会导致免疫反应增强和动脉粥样硬化加剧。为了检验我们的假设，我们在目标 1 中建议使用功能丧失研究来确定 NOD2 在 P.g 驱动的动脉粥样硬化中的作用；目标 2 确定参与 NOD2 调节先天炎症反应和侵袭介导的细胞质过程的分子机制；在目标 3 中，通过功能增益研究确定给予胞壁酰二肽 (MDP) 或 NOD2 阻滞剂是否可以保护小鼠免受 P.g 诱导的动脉粥样硬化。这些实验将明确界定 NOD2 在 P.g 动脉粥样硬化形成中的作用，并为旨在减少或预防动脉粥样硬化形成的药物干预铺平道路。公共卫生相关性：冠状动脉疾病 (CAD) 是全世界人类发病和死亡的主要原因。拟议实验的结果将确定免疫传感在感染相关动脉粥样硬化形成中的作用，并为旨在减少或预防动脉粥样硬化形成的药物干预铺平道路。