Inflammation and Infection in Atherosclerosis

动脉粥样硬化的炎症和感染

• 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
• 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

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）是世界范围内发病率和死亡率的主要原因。由于传统的危险因素，包括高胆固醇血症、吸烟和高血压不能完全解释冠心病的发病率，因此最近的兴趣集中在慢性感染性疾病，如牙周感染，作为CAD的潜在因素。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）相关动脉粥样硬化的小鼠模型中获得了大量与感染感应回路和随后的炎症细胞因子表达相关的数据。针对这一竞争性应用，我们评估了pg侵袭在动脉粥样硬化发生中的作用。我们发现，当侵袭不足的P.g.菌株DPG3取代野生型P.g.时，或者当使用入侵干扰抗生素甲硝唑治疗时，随后的动脉粥样硬化减少了约50%，这支持了侵袭介导的细胞质过程的存在，该过程对P.g.驱动的动脉粥样硬化有重要贡献。我们也开始描述连接感染和动脉粥样硬化的机制。核苷酸结合寡聚化结构域样受体（NOD1和NOD2）是一种检测细胞内微生物分子存在的免疫监视系统。最近的研究表明，肽聚糖（PGN，一种TLR2配体）可以独立于其muramyl二肽（MDP）成分（NOD2配体）被细胞表面TLR2识别，并通过与MyD88相关的TLR信号通路激活NF-:B。这就提出了TLR2和NOD2信号关联的可能性，而NOD2的一个功能就是调控TLR2。然而，NOD2在tlr介导的细胞因子反应中的作用仍然存在争议。我们的初步数据显示，将NOD2 siRNA引入pg刺激的巨噬细胞可增强促炎反应。然而，发现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，而高配体水平则表现为抑制。这种调节导致NF:B的调节以及IL-1和TNF的转录调节。我们的假设是，NOD2的激活负调控TLR2反应，从而减少动脉硬化；缺乏这种调节导致免疫反应增强和动脉粥样硬化加重。为了验证我们的假设，我们在目标1中提出使用功能丧失研究来确定NOD2在pg驱动的动脉粥样硬化中的作用；在Aim 2中，确定NOD2调节先天炎症反应和侵袭介导的胞质过程的分子机制；在目的3中，通过功能研究的增加来确定给予muramyl二肽（MDP）或NOD2阻滞剂是否能保护小鼠免受P. g诱导的动脉粥样硬化。这些实验将明确NOD2在pg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物干预铺平道路。