Receptors Mediating Lymphotoxin Effects on Athersclerosis

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/淋巴毒素共刺激分子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。已在动脉粥样硬化斑块中检测到配体Light及其受体之一hvem，体外研究表明，它们有可能影响影响动脉粥样硬化发展和斑块稳定性的过程。这项拟议的研究基于我们实验室的两个主要观察结果(A)LIGH在T细胞上的过度表达增加了血脂水平，导致HDL1样颗粒积聚，并通过淋巴毒素β受体(LTbetaR)依赖的途径降低了肝脏中脂肪酶的表达；(B)将LIGH转基因小鼠(LIGH-TG)的骨髓转移到喂养LDLR-/-小鼠的西式饮食中，可以减少主动脉根部动脉粥样硬化的发生。这项建议的目的是了解哪些光/淋巴毒素受体，即LTbetaR或Hvem，以及哪些细胞和组织参与了脂/脂蛋白和动脉粥样硬化的反应。我们的假设是，通过LTbetaR的信号在很大程度上是脂蛋白效应的原因，而通过HVEM的信号在动脉粥样硬化效应中起主要作用。验证这一假说将包括检测基因敲除小鼠的整体受体缺陷(目标1)、骨髓来源细胞的受体缺陷(目标2)和肝细胞LTbetaR的特异性缺陷(目标3)对脂/脂蛋白代谢和动脉粥样硬化的影响。这将在LDLR-/-小鼠背景下完成，并将涉及配体LIGH和淋巴毒素β在生理水平的表达以及在T细胞中的LIGH过度表达。

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. Members of the LIGHT/lymphotoxin family of costimulatory molecules 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. The ligand LIGHT and one of its receptors HVEM have been detected in atherosclerotic plaques and in vitro studies have shown that they have the potential to impact on processes that can influence atherosclerosis development and plaque stability. The proposed study is based upon two major observations in our laboratory (a) overexpression of LIGHT on T-cells increases plasma lipid levels, leads to the accumulation of an HDL1-like particle, and reduces hepatic lipase expression in the liver via a lymphotoxin beta receptor (LTbetaR) dependent pathway and (b) that the transfer of bone marrow from LIGHT transgenic mice (LIGHT-tg) to Western-type diet fed LDLR-/- mice results in the reduction in aortic root atherosclerosis. The goal of this proposal is to understand which LIGHT/lymphotoxin receptors, i.e. LTbetaR or HVEM, and which cells and tissues are involved in the lipid/lipoprotein and atherosclerosis response. Our hypothesis is that signaling via LTbetaR is largely responsible for the lipoprotein effects and that signaling via HVEM is largely responsible for the atherosclerosis effects. Testing this hypothesis will involve examining the effect of global receptor deficiency in knockout mice (aim 1), effect of receptor deficiency in bone marrow derived cells (aim 2), and specific deficiency of LTbetaR in hepatocytes (aim 3) on lipid/lipoprotein metabolism and atherosclerosis. This will be done in the LDLR-/- mouse background and will involve the expression of the ligands LIGHT and lymphotoxin beta at physiological levels and LIGHT overexpression in T cells.