Innate Immunity, Lipid Signaling, and Chronic Infection

先天免疫、脂质信号传导和慢性感染

基本信息

批准号：
7790038
负责人：
FRANK C GIBSON
金额：
$ 25.76万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7790038
关键词：
Acute Agonist Animal Model Atherosclerosis Bacteria Binding Blood Platelets Blood Vessels Bone remodeling Cardiovascular Diseases Carotid Artery Ulcerating Plaque Cell Adhesion Molecules Cells Chemicals Chlamydophila pneumoniae Cholesterol Chronic Clinical Collaborations Communicable Diseases Complex Data Depressed mood Disease Disorder by Site Endothelial Cells Foam Cells Future Gene Expression Genes Genetic Transcription Goals Heterogeneity Immune Immune response In Vitro Infection Infection Control Inflammation Inflammatory Inflammatory Response Integration Host Factors Interleukin-1 Investigation Laboratories Lesion Life Lipid A Lipids Liver Mediating Modeling Mononuclear Mus Natural Immunity Nuclear Hormone Receptors Oral Oral cavity Organism Osteoclasts Pathway interactions Pattern recognition receptor Pentas Periodontal Attachment Loss Periodontal Diseases Periodontitis Plague Play Porphyromonas gingivalis Production Protein Isoforms Receptor Signaling Regulation Regulator Genes Role Signal Pathway Signal Transduction Structure Systemic infection TLR2 gene TLR4 gene Testing Toll-like receptors Virulence Factors base bone loss cytokine defined contribution in vivo inflammatory marker insight lipid transport liver function macrophage novel strategies osteoclastogenesis pathogen prevent programs receptor receptor expression receptor function response scavenger receptor

项目摘要

Inflammation is essential for effective control of infection; however, in chronic infectious diseases such as periodontal disease (PD), the resulting inflammation fails to adequately protect the host. The bacterium most associated with chronic generalized PD is Porphyromonas gingivalis. PD lesions are identified by loss of periodontal attachment, oral bone loss, significant influx of mononuclear cells, and expression of inflammatory markers at sites of disease. Expression of these pro-inflammatory molecules is controlled in part via innate immune pattern recognition receptors including the toll-like receptors (TLR). In vitro studies support roles for TLR signaling pathways regulate inflammation in response to P. gingivalis; however, these pathways are poorly defined. Therefore, a more detailed understanding of the host factors that regulate inflammation in response to P. gingivalis in the context of bone remodeling is needed. In addition to the local inflammatory lesions of the oral cavity associated with P. gingivalis infection, recent clinical and animal model data support a role for infection by organisms such as P. gingivalis and others including Chlamydophila pneumoniae with accelerated vascular plaque accumulation. Atherosclerosis is a complex inflammatory disease. Regulation of inflammation is thought to be key to preventing this disease. The nuclear hormone receptor liver X receptor (LXR) plays a key role in regulating expression of genes involved in cellular cholesterol efflux. Recently, a second function for LXR, namely regulation of TLRdependent inflammatory pathways has been identified. As innate immune signaling via TLRs is implicated in atherosclerosis, PD, and host response to P. gingivalis, and LXR is a regulator of TLR mediated inflammation, we speculated that LXR could influences both oral bone loss and atherosclerosis elicited by P. gingivalis. Here we propose an interrelated set of aims to test the hypothesis that LXR regulates inflammatory gene expression and bone loss elicited by P. gingivalis; moreover, LXR plays a central role in infection-accelerated chronic inflammatory vascular plaque accumulation. These studies will provide a detailed understanding of the role played by LXR in regulating inflammation that accompanies P. gingivalis infection.

炎症对于有效控制感染至关重要。然而，在诸如牙周疾病（PD）等慢性传染病中，由此产生的炎症无法充分保护宿主。与慢性通用PD最相关的细菌是卟啉单胞菌。 PD病变是通过牙周附着，口腔损失，单核细胞的大量流入以及疾病部位炎症标记的表达来鉴定的。这些促炎分子的表达部分通过包括Toll样受体（TLR）在内的先天免疫模式识别受体来部分控制。体外研究支持TLR信号通路的作用，可响应牙龈疟原虫调节炎症。但是，这些途径的定义很差。因此，需要在骨骼重塑的背景下对响应牙龈疟原虫响应炎症的宿主因素进行更详细的了解。除了与牙龈疟原虫感染相关的口腔的局部炎症病变外，最近的临床和动物模型数据还支持诸如牙龈疟原虫和其他生物（包括肺炎肺炎肺炎肺炎肺炎，加速血管斑块积累）感染的作用。动脉粥样硬化是一种复杂的炎症性疾病。炎症的调节被认为是预防这种疾病的关键。核激素受体肝X受体（LXR）在调节涉及细胞胆固醇外排的基因表达方面起关键作用。最近，已经确定了LXR的第二个功能，即对TLRDDEP的调节。由于通过TLR的先天免疫信号传导与动脉粥样硬化，PD和宿主对牙龈疟原虫的反应有关，而LXR是TLR介导的炎症的调节剂，我们推测LXR可以影响口腔骨损失和gingivalis P. gingivalis引起的口腔骨损失和动脉粥样硬化。在这里，我们提出了一组相互关联的目的，以测试LXR调节牙龈疟原虫引起的炎症基因表达和骨质流失的假设。此外，LXR在感染加速慢性炎症血管斑块积累中起着核心作用。这些研究将详细了解LXR在调节牙龈疟原虫感染伴随的炎症中所起的作用。