Lymphotoxin/LIGHT in Lipoprotein Metabolism and Atherosclerosis

描述(申请人提供)：动脉粥样硬化是一种慢性炎症反应，涉及先天免疫系统和获得性免疫系统。适应性免疫系统的激活需要初级刺激以及共刺激配体和受体的连接。光/淋巴毒素是一组共刺激配体。这些配体发出的信号可以影响脂蛋白代谢和动脉粥样硬化。这个配体和受体家族的成员由免疫细胞表达，免疫细胞已经被证明或被认为影响动脉粥样硬化的发展，以及非免疫细胞，如肝细胞。我们观察到，光/淋巴毒素的操纵和通过其受体的信号对血浆脂蛋白产生深远的影响，但这些影响可能在血管壁水平上被抵消，可能是通过对局部血管炎症的影响来实现的。使用可溶性淋巴毒素β受体阻断低密度脂蛋白受体缺陷小鼠的光/淋巴毒素信号显著降低极低密度脂蛋白水平，但对主动脉根部病变的大小没有影响。在低密度脂蛋白受体缺陷小鼠的T细胞中，光过表达导致了小的低密度脂蛋白的积累，并缩小了主动脉根部病变的大小。在光/淋巴毒素信号的调控下，我们提出了三个处理极低密度脂蛋白(目标1)、低密度脂蛋白(目标2)和动脉粥样硬化(目标3)的特定靶点。具体目标1将研究干扰光/淋巴毒素影响极低密度脂蛋白代谢的机制，这种作用是由光还是淋巴毒素α1β2介导的，以及载脂蛋白E的潜在作用。具体目标2将研究光的过度表达影响低密度脂蛋白异质性的机制，包括胰岛素抵抗是否起作用。最终目的将检验该配体家族在动脉粥样硬化中的作用，包括光/淋巴毒素家族是否影响斑块稳定性。 这项建议的目标是了解光/淋巴毒素配体家族如何影响脂蛋白稳态和动脉粥样硬化。这些研究将进一步加深我们对免疫系统如何影响这些过程的理解，并可能指出潜在的治疗干预地点。

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.