Receptors Mediating Lymphotoxin Effects on Athersclerosis

受体介导淋巴毒素对动脉粥样硬化的影响

• 批准号: 7774401
• 负责人: GODFREY Shalom GETZ
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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/7774401
• 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; Pathway interactions; Peptides; Phenotype; Physiological; Plant Roots; Plasma; Play; Process; Production; Reaction; Risk; Role; Signal Transduction; Stimulus; System; T-Lymphocyte; TNF gene; TNFRSF5 gene; TNFSF4 gene; TNFSF5 gene; Testing; Tissues; Transgenic Mice; Tumor Necrosis Factor-Beta; Work; anergy; atherogenesis; base; feeding; hepatic lipase; lipid metabolism; lymphotoxin beta; lymphotoxin beta receptor; macrophage; member; monocyte; overexpression; particle; receptor; response

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性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初始刺激以及共刺激配体和受体的连接。 LIGHT/淋巴毒素共刺激分子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，以及肝细胞等非免疫细胞。配体 LIGHT 及其受体之一 HVEM 已在动脉粥样硬化斑块中检测到，体外研究表明它们有可能影响动脉粥样硬化发展和斑块稳定性的过程。拟议的研究基于我们实验室的两个主要观察结果（a）T细胞上LIGHT的过度表达增加血浆脂质水平，导致HDL1样颗粒的积累，并通过淋巴毒素β受体（LTbetaR）依赖性途径减少肝脏中肝脂肪酶的表达，以及（b）将骨髓从LIGHT转基因小鼠（LIGHT-tg）转移到 西式饮食喂养的 LDLR-/- 小鼠可减少主动脉根部动脉粥样硬化。该提案的目标是了解哪些 LIGHT/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 的信号传导在很大程度上负责脂蛋白效应，而通过 HVEM 的信号传导在很大程度上负责动脉粥样硬化效应。检验这一假设将涉及检查基因敲除小鼠中整体受体缺陷的影响（目标 1）、骨髓来源细胞中受体缺陷的影响（目标 2）以及肝细胞中 LTbetaR 的特异性缺陷（目标 3）对脂质/脂蛋白代谢和动脉粥样硬化的影响。这将在 LDLR-/- 小鼠背景下完成，并将涉及配体 LIGHT 和淋巴毒素 β 在生理水平的表达以及 LIGHT 在 T 细胞中的过度表达。