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一种慢性炎症性疾病。这是通过对影响疾病严重程度的高脂血症小鼠特异性炎症基因缺失的研究证实的。先天免疫系统中的toll样受体（TLR）感知病原体并介导细胞活化，在感染、炎症和动脉粥样硬化之间提供了重要的联系。我们发现tlr2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。致动脉粥样硬化性炎症tlr2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的，包括内皮细胞、平滑肌细胞和外层成纤维细胞。相反，对已知的外源性合成TLR2激动剂Pam3的致动脉粥样硬化性炎症反应至少部分是由包括巨噬细胞在内的骨髓源性细胞介导的。我们将证实我们的假设，即内源性或外源性TLR2激动剂介导的TLR2介导的细胞活化主要是促动脉粥样硬化，并分析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的内源性激动剂。我们将描述TLR2在体内非骨髓源性细胞中的区域特异性表达，并记录TLR2对巨噬细胞浸润病变的影响的时间过程。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的外源性激动剂。我们将确定巨噬细胞是否足以介导由外源性激动剂诱导的动脉粥样硬化性炎症。我们将定义TLR2共受体与已知外源性激动剂的作用，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.