Toll Receptors in Atherosclerosis

描述（由申请人提供）：动脉粥样硬化不仅仅是一种简单的脂质储存疾病。现在认识到动脉粥样硬化也是动脉壁的慢性炎症性疾病。这一点已经通过对高脂血症小鼠中影响疾病严重程度的特异性炎症基因缺失的研究得到了证实。先天免疫系统的Toll样受体（TLR）可以感知病原体并介导细胞活化，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TLR 2介导的炎症影响低密度脂蛋白受体缺陷（LDLr-/-）小鼠的疾病进展。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、平滑肌细胞和外膜成纤维细胞。相反，对已知的外源性合成TLR 2激动剂Pam 3的致动脉粥样硬化性炎症反应至少部分地由骨髓来源的细胞（包括巨噬细胞）介导。我们将证实我们的假设，即内源性或外源性TLR 2激动剂介导的TLR 2细胞活化主要是促动脉粥样硬化的，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。我们将在非骨髓来源的细胞中表征TLR 2在体内的区域特异性表达，并记录TLR 2对巨噬细胞浸润到病变中的作用的时间过程。我们将确定候选的内源性促动脉粥样硬化激动剂，并确定TLR 2共受体，TLR 1，TLR 6，CD 14和CD 36，在TLR 2信号转导中的作用。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。我们将确定TLR 2共受体与已知外源性激动剂的作用，最后，我们将检查TLR 2介导的信号传导是否参与疾病消退。这些研究将增强我们对动脉粥样硬化炎症反应的理解，并有可能确定新的TLR靶点，用于治疗干预以逆转或降低疾病风险。

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.