Receptors Mediating Lymphotoxin Effects on Athersclerosis

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。共刺激分子的LIGHT/淋巴毒素家族成员由免疫细胞表达，这些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。已经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。提出的研究基于我们实验室的两个主要观察结果(a) t细胞上的LIGHT过表达增加血浆脂质水平，导致hdl1样颗粒的积累，并通过淋巴素β受体（LTbetaR）依赖途径降低肝脏中肝脂酶的表达；(b)将LIGHT转基因小鼠（LIGHT-tg）的骨髓转移到以西式饮食喂养的LDLR-/-小鼠中，导致主动脉根部动脉粥样硬化的减少。本提案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脂质/脂蛋白和动脉粥样硬化反应。我们的假设是，通过LTbetaR的信号在很大程度上负责脂蛋白效应，而通过HVEM的信号在很大程度上负责动脉粥样硬化效应。为了验证这一假设，我们将研究敲除小鼠中整体受体缺乏的影响（目的1），骨髓来源细胞中受体缺乏的影响（目的2），肝细胞中LTbetaR特异性缺乏（目的3）对脂质/脂蛋白代谢和动脉粥样硬化的影响。这将在LDLR-/-小鼠背景下进行，并将涉及配体LIGHT和淋巴毒素β在生理水平上的表达以及T细胞中LIGHT的过表达。

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.