Lymphotoxin/LIGHT in Lipoprotein Metabolism and Atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种涉及先天免疫系统和适应性免疫系统的慢性炎症反应。适应性免疫系统的激活需要主刺激以及共刺激配体和受体的连接。LIGHT/淋巴蛋白是一组共刺激配体。这些配体的信号传导影响脂蛋白代谢和动脉粥样硬化。该配体和受体家族的成员由免疫细胞表达，这些免疫细胞已被证明或被认为影响动脉粥样硬化的发展，也影响肝细胞等非免疫细胞。我们已经观察到，操纵光/淋巴毒素及其受体的信号传导对血浆脂蛋白产生深远的影响，然而这些影响可能在血管壁水平上被局部血管炎症的影响所抵消。在LDL受体缺陷小鼠中，使用可溶性淋巴素β受体阻断LIGHT/淋巴素信号传导可显著降低VLDL水平，但对主动脉根部病变的大小没有影响。LDL受体缺陷小鼠的t细胞中LIGHT过表达导致小LDL的积累，并减少主动脉根部病变的大小。我们提出了三个特定的目标处理VLDL（目标1），LDL（目标2）和动脉粥样硬化（目标3）在操纵光/淋巴毒素信号。具体目的1将研究干扰光/淋巴蛋白影响VLDL代谢的机制，以及这种影响是否由光或淋巴蛋白α 1 β 2介导，以及apoE的潜在作用。具体目标2将研究LIGHT过度表达影响LDL异质性的机制，包括胰岛素抵抗是否起作用。最终目的是研究该配体家族在动脉粥样硬化中的作用，包括LIGHT/淋巴毒素家族是否影响斑块稳定性。

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory reaction involving both the innate and adaptive immune system. The activation of the adaptive immune system requires the primary stimulus along with the ligation of costimulatory ligands and receptors. LIGHT/lymphotoxin is one set of costimulatory ligands. Signaling by these ligands is shown here to affect lipoprotein metabolism and atherosclerosis. Members of this family of ligands and receptors are expressed by immune cells that either have been shown to or are thought to influence the development of atherosclerosis as well as on non-immune cells such as hepatocytes. We have observed that manipulation of LIGHT/lymphotoxin and signaling through their receptors exert profound effects on plasma lipoproteins, yet these effects may be counterbalanced at the level of the vascular wall perhaps by effects on local vascular inflammation. Blocking LIGHT/lymphotoxin signaling in LDL receptor deficient mice using a soluble lymphotoxin beta receptor significantly decreased VLDL levels, but had no effect on the size of the aortic root lesion. LIGHT over expression in T-cells in LDL receptor deficient mice resulted in the accumulation of a small LDL, and a reduction in the size of the aortic root lesion. We propose three specific aims dealing with VLDL (aim 1), LDL (aim 2) and atherosclerosis (aim 3) following manipulation of LIGHT/lymphotoxin signaling. Specific aim 1 will examine the mechanism by which interfering with LIGHT/lymphotoxin influences VLDL metabolism, and whether this effect is mediated by LIGHT or lymphotoxin alpha1beta2, and the potential role of apoE. Specific aim 2 will examine the mechanism by which over expression of LIGHT influences LDL heterogeneity, including if insulin resistance has a role. The final aim will examine the role of this family of ligands on atherosclerosis, including if the LIGHT/lymphotoxin family influences plaque stability. The goal of this proposal is to understand how the LIGHT/lymphotoxin ligand family influences lipoprotein homeostasis and atherosclerosis. These studies will further our understanding of how the immune system influences these processes and may point to potential sites for therapeutic intervention.