Receptors Mediating Lymphotoxin Effects on Athersclerosis

受体介导淋巴毒素对动脉粥样硬化的影响

基本信息

批准号：
7370782
负责人：
GODFREY Shalom GETZ
金额：
$ 37.1万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-14 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7370782
关键词：
Antibody Formation Antigen-Presenting Cells Antigens Arterial Fatty Streak Atherosclerosis B7-2 protein Bone Marrow CD28 gene CD80 gene Cell Surface Receptors Cell membrane Cells Cholesterol Chronic Dendritic Cells Development Diet Family Goals Hand Hepatocyte Herpesviridae Homeostasis Human Immune Immune system In Vitro Inflammatory Knockout Mice Laboratories Ligands Ligation Lipids Lipoproteins Liver Mediating Mediator of activation protein Metabolism Mus Myocardial Infarction Numbers Pathway interactions Peptides Phenotype Physiological Plant Roots Plasma Play Process Production Protein Overexpression Reaction Risk Role Signal Transduction Stimulus System T-Lymphocyte TNF gene TNFRSF5 gene TNFSF4 gene TNFSF5 gene Testing Thinking Tissues Transgenic Mice Tumor Necrosis Factor-Beta Work anergy atherogenesis base feeding hepatic lipase lipid metabolism lymphotoxin beta lymphotoxin beta receptor macrophage member monocyte particle receptor response tumor necrosis factor ligand superfamily member 4

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化是一种涉及先天和适应性免疫系统的慢性炎症反应。自适应免疫系统的激活需要主要刺激以及共刺激配体和受体的连接。亚免疫细胞表达的光/淋巴毒素家族的成员被证明或被认为会影响动脉粥样硬化的发展以及肝细胞等非免疫细胞的发育。在动脉粥样硬化斑块中发现了配体光及其受体HVEM之一，体外研究表明，它们有可能影响可能影响动脉粥样硬化发育和斑块稳定性的过程。拟议的研究是基于我们实验室中的两个主要观察结果（a）对T细胞的光的过表达增加了血浆脂质水平，导致HDL1样颗粒的积累，并通过lymphotoxin beta受体（LTBETAR）依赖（ltbetar）依赖（b）的（b）的光线（b）在肝脏中的肝脂肪酶表达降低（B）。西方型饮食喂养LDLR - / - 小鼠导致主动脉根动脉粥样硬化的减少。该建议的目的是了解哪种光/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的信号传导很大程度上是脂蛋白效应的原因，并且通过HVEM信号传导在很大程度上负责动脉粥样硬化的作用。检验该假设将涉及检查敲除小鼠全球受体缺乏症的影响（AIM 1），骨髓衍生细胞中受体缺乏症的影响（AIM 2）以及肝细胞中LTBETAR的特异性缺乏（AIM 3）对脂质/脂蛋白代谢蛋白代谢症和动脉粥样硬化的影响。这将在LDLR - / - 小鼠背景中进行，并将涉及在T细胞中生理水平和光过度表达的配体光和淋巴毒素β的表达。