Lymphotoxin/LIGHT in Lipoprotein Metabolism and Atherosclerosis

淋巴毒素/光在脂蛋白代谢和动脉粥样硬化中的作用

• 批准号: 7634398
• 负责人: GODFREY Shalom GETZ
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634398
• 关键词: A Mouse; Adipose tissue; Affect; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Attention; B-Lymphocytes; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; CD28 gene; CD80 gene; Catabolism; Cells; Chimeric Proteins; Cholesterol; Chronic; Clinical; Collaborations; Data; Dendritic Cells; Development; Experimental Animal Model; Family; Family member; Foam Cells; Genetic; Goals; Hand; Heart Diseases; Hepatic; Hepatocyte; Heterogeneity; Homeostasis; Human; Immune; Immune system; Immunoglobulins; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-10; Interruption; Investigation; Lesion; Ligands; Ligation; Lipids; Lipoprotein (a); Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Measures; Mediating; Metabolism; Modeling; Modification; Mus; Organ; Pathogenesis; Plant Roots; Plasma; Process; Production; Reaction; Regulation; Research Personnel; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Stimulus; Structure of brachiocephalic artery; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; TNFRSF5 gene; TNFSF5 gene; Testing; Therapeutic Intervention; Transgenic Mice; Tumor Necrosis Factor-Beta; Tumor Necrosis Factors; Vascular Diseases; Very low density lipoprotein; Yang; absorption; atherogenesis; base; family influence; high voltage electron microscopy; hypercholesterolemia; improved; information gathering; interest; low density lipoprotein inhibitor; lymphotoxin beta receptor; macrophage; member; novel; overexpression; programs; receptor; receptor expression; vascular bed; vascular inflammation

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.

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级刺激沿着共刺激配体和受体的连接。LIGHT/光敏素是一组共刺激配体。这些配体的信号传导在这里显示影响脂蛋白代谢和动脉粥样硬化。该配体和受体家族的成员由已经显示或被认为影响动脉粥样硬化的发展的免疫细胞以及非免疫细胞如肝细胞表达。我们已经观察到LIGHT/光毒素的操纵和通过其受体的信号传导对血浆脂蛋白产生深远的影响，然而这些影响可能在血管壁水平上被局部血管炎症的影响所抵消。在LDL受体缺陷小鼠中，使用可溶性光毒素β受体阻断LIGHT/光毒素信号传导可显著降低VLDL水平，但对主动脉根部病变的大小没有影响。LIGHT在LDL受体缺陷小鼠T细胞中的过度表达导致小LDL的积累，以及主动脉根部病变大小的减小。我们提出了三个具体的目标处理VLDL（目标1），LDL（目标2）和动脉粥样硬化（目标3）后，操纵光/光敏素信号。具体目标1将研究干扰LIGHT/α-光敏素影响VLDL代谢的机制，以及这种作用是否由LIGHT或α-光敏素α 1 β 2介导，以及apoE的潜在作用。具体目标2将检查LIGHT过表达影响LDL异质性的机制，包括胰岛素抵抗是否起作用。最终的目标是研究这个配体家族在动脉粥样硬化中的作用，包括LIGHT/光敏素家族是否影响斑块稳定性。 本研究的目的是了解LIGHT/光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，并可能指出治疗干预的潜在位点。

项目成果

Animal models of atherosclerosis.

• DOI: 10.1161/atvbaha.111.237693
• 发表时间: 2012-05
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Getz GS;Reardon CA
• 通讯作者: Reardon CA

The mutual interplay of lipid metabolism and the cells of the immune system in relation to atherosclerosis.

• DOI: 10.2217/clp.14.50
• 发表时间: 2014
• 期刊: Clinical lipidology
• 作者: Getz GS;Reardon CA
• 通讯作者: Reardon CA

Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice.

• DOI: 10.1084/jem.20080752
• 发表时间: 2009-01-16
• 期刊: The Journal of experimental medicine
• 作者: Gräbner R;Lötzer K;Döpping S;Hildner M;Radke D;Beer M;Spanbroek R;Lippert B;Reardon CA;Getz GS;Fu YX;Hehlgans T;Mebius RE;van der Wall M;Kruspe D;Englert C;Lovas A;Hu D;Randolph GJ;Weih F;Habenicht AJ
• 通讯作者: Habenicht AJ

T Cells in Atherosclerosis in Ldlr-/- and Apoe-/- Mice.

• DOI: 10.29245/2578-3009/2018/3.1144
• 发表时间: 2018-01-01
• 期刊: Journal of immunological sciences
• 作者: Getz, Godfrey S;Reardon, Catherine A
• 通讯作者: Reardon, Catherine A