Toll Receptors in Atherosclerosis

动脉粥样硬化中的 Toll 受体

基本信息

批准号：
7213932
负责人：
Linda K Curtiss
金额：
$ 46.6万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-09 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213932
关键词：
Agonist Alleles Animals Atherosclerosis Blood Vessels Bone Marrow CD14 gene CD36 gene Cells Chronic Communicable Diseases Dendritic Cells Diet Disease Disease Progression Disease regression Doctor of Philosophy Endothelial Cells Environment Fatty acid glycerol esters Fibroblasts Gene Deletion Genes Genetic Programming HMGB1 Protein Human Hyaluronic Acid Hyperlipidemia Immune Immune system In Vitro Infection Infectious Agent Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Response Lesion Ligands Link Lipids Lipoproteins Low Density Lipoprotein Receptor Lymphocyte Mediating Modeling Mus Natural Killer Cells Play Prevention Process Publishing Receptor Activation Reporting Research Personnel Risk Risk Factors Role Severity of illness Signal Transduction Smooth Muscle Myocytes Sterility TLR1 gene TLR2 gene TLR4 gene TLR6 gene Testing Therapeutic Intervention Thinking Time Toll-Like Receptor 1 Toll-like receptors Wound Healing biglycan disorder risk feeding in vivo lipoteichoic acid macrophage macrophage stimulatory lipopeptide 2 monocyte oxidized lipid pathogen receptor research study response sensor

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is not just a simple lipid storage disease. It is now appreciated that atherosclerosis is also a chronic inflammatory disease of the arterial wall. This has been established by studies of specific inflammatory gene deletions in hyperlipidemic mice that influence disease severity. The Toll-like receptors (TLR) of the innate immune system, which sense pathogens and mediate cell activation, can provide an important link between infection, inflammation and atherosclerosis. We discovered that TLR2-mediated inflammation influences disease progression in low density lipoprotein receptor-deficient (LDLr-/-) mice. Proatherogenic inflammatory TLR2-mediated responses to unknown endogenous agonists are mediated by non bone marrow-derived cells including endothelial cells, smooth muscle cells and adventitial fibroblasts. In contrast the proatherogenic inflammatory responses to the known exogenous, synthetic TLR2 agonist, Pam3, are mediated at least in part by bone marrow-derived cells including macrophages. We will confirm our hypothesis that TLR2-mediated cell activation by either endogenous or exogenous TLR2 agonists is predominately proatherogenic and analyze how TLR2-mediated inflammation influences atherosclerosis. In Aim 1 we will study endogenous agonists of TLR2. We will characterize region-specific expression of TLR2 in vivo in non-bone marrow-derived cells and document the time course of the effect of TLR2 on macrophage infiltration into lesions. We will identify candidate endogenous proatherogenic agonists and define the role of the TLR2 co-receptors, TLR1, TLR6, CD14 and and CD36, in TLR2 signaling. In Aim 2 we will study exogenous agonists of TLR2. We will determine if macrophages are sufficient for mediating proatherogenic inflammation induced by defined exogenous agonists. We will define the role of the TLR2 co-receptors with known exogenous agonists and finally, we will examine if TLR2-mediated signaling participates in disease regression. These studies will enhance our understanding of inflammatory responses in atherosclerosis and potentially identify new TLR targets for therapeutic intervention to reverse or reduce disease risk.

描述（由申请人提供）：动脉粥样硬化不仅是一种简单的脂质储存疾病。现在认为，动脉粥样硬化也是动脉壁的慢性炎症性疾病。这是通过对影响疾病严重程度的高脂小鼠中特定炎症基因缺失的研究来确定的。先天免疫系统的收费受体（TLR）感知病原体和介导细胞激活，可以在感染，炎症和动脉粥样硬化之间提供重要联系。我们发现TLR2介导的炎症会影响低密度脂蛋白受体缺陷型（LDLR - / - ）小鼠的疾病进展。促进性炎症性TLR2介导的对未知内源性激动剂的反应是由包括内皮细胞，平滑肌细胞和外在成纤维细胞在内的非骨髓衍生细胞介导的。相比之下，对已知的外源性TLR2激动剂PAM3的促进性炎症反应至少部分是由包括巨噬细胞在内的骨髓衍生细胞介导的。我们将证实我们的假设，即内源性或外源性TLR2激动剂通过TLR2介导的细胞激活主要是促进的，并分析了TLR2介导的炎症如何影响动脉粥样硬化。在AIM 1中，我们将研究TLR2的内源激动剂。我们将表征非骨髓衍生的细胞中TLR2在体内特异性表达，并记录TLR2对巨噬细胞浸润的影响的时间过程。我们将确定候选的内源性促进性激动剂，并定义TLR2共受体，TLR1，TLR6，CD14和CD36在TLR2信号传导中的作用。在AIM 2中，我们将研究TLR2的外源激动剂。我们将确定巨噬细胞是否足以介导定义的外源激动剂诱导的促孕花源性炎症。我们将定义TLR2共受体与已知的外源激动剂的作用，最后，我们将检查TLR2介导的信号是否参与疾病回归。这些研究将增强我们对动脉粥样硬化中炎症反应的理解，并可能确定新的TLR靶标，以逆转或降低疾病的风险。