Role of Toll-Like Receptors in Atherogenesis

动脉粥样硬化是一种动脉壁的慢性炎症性疾病。这是通过研究确定的 高脂血症小鼠中影响疾病严重程度的特定炎症基因缺失，Toll样 先天性免疫系统的TLR能感知病原体并介导细胞活化， 提供了感染、炎症和动脉粥样硬化之间的重要联系。我们发现TLR 2- 介导的炎症影响低密度脂蛋白受体缺陷（LDLr-/-）患者的疾病进展 小鼠致动脉粥样硬化炎性TLR 2介导的对未知内源性激动剂的反应是 由非骨髓来源的细胞介导，包括内皮细胞、平滑肌细胞和外膜细胞， 成纤维细胞相反，对已知的外源性合成TLR 2的促动脉粥样硬化炎症反应 激动剂Pam 3由骨髓来源的细胞（包括巨噬细胞）介导。在项目4中， 我们将证实内源性或外源性TLR 2介导的细胞激活 TLR 2激动剂主要是致动脉粥样硬化的，并分析TLR 2介导的炎症如何影响 动脉粥样硬化在目标1中，我们将研究TLR 2的内源性激动剂。我们将描述特定区域的 TLR 2在非骨髓来源的细胞中的体内表达，并记录TLR 2的作用的时间过程。 TLR 2对巨噬细胞浸润到病变中的影响。我们将确定候选的内源性致动脉粥样硬化 本发明涉及TLR 2共受体激动剂，并定义了TLR 2共受体、TLR 1、TLR 6和CD 36在TLR 2信号传导中的作用。在目标2中 我们将研究TLR 2的外源性激动剂。我们将确定巨噬细胞是否足以介导 由确定的外源性激动剂诱导的致动脉粥样硬化性炎症。我们将定义TLR 2的作用 与已知的外源激动剂共受体。这些研究将增进我们对 动脉粥样硬化炎症反应，并可能确定新的TLR治疗靶点 采取干预措施，降低患病风险。

Atherosclerosis is 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 advential fibroblasts. In contrast the proatherogenic inflammatory responses to the known exogenous, synthetic TLR2 agonist, Pam3, are mediated by bone marrow-derived cells including macrophages. In Project 4 of this program project grant we will confirm 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 endogenoous proatherogenic agonists and define the role of the TLR2 co-receptors, TLR1, TLR6 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. These studies will enhance our understanding of inflammatory responses in atherosclerosis and potentially identify new TLR targets for therapeutic intervention to reduce disease risk.