The Effect of SPT Deficiency on Atherosclerosis

SPT 缺乏对动脉粥样硬化的影响

• 批准号: 8141628
• 负责人: XIAN-CHENG JIANG
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141628
• 关键词: Adenoviruses; Aging; Albumins; Anabolism; Animals; Antiatherogenic; Apolipoprotein E; Atherosclerosis; Attenuated; Binding; Blood Circulation; Cardiac; Cell Line; Cell membrane; Cell physiology; Cells; Cholesterol; Chylomicrons; Coronary Arteriosclerosis; Development; Disease; Embryo; Enzymes; Event; Foam Cells; Gene Expression; Glycosphingolipids; Goals; Health; Hepatic; Human; Inflammatory; Inflammatory Response; Knockout Mice; Knowledge; Kupffer Cells; Lipids; Lipoproteins; Liver; Low-Density Lipoproteins; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Metabolism; Mitogen-Activated Protein Kinases; Morbidity - disease rate; Mus; Phenotype; Phospholipids; Plasma; Play; Prevention; Process; Production; Reaction; Relative (related person); Research; Risk Factors; Role; Satellite Viruses; Site; Sphingolipids; Sphingomyelins; Testing; Tissues; Transgenic Mice; Very low density lipoprotein; Veterans; aging population; base; cytokine; hepatoma cell; inhibitor/antagonist; insight; knockout gene; macrophage; mortality; mouse model; novel; overexpression; particle; promoter; receptor; receptor-mediated signaling; recombinase; reverse cholesterol transport; serine palmitoyltransferase; therapeutic target; thermozymocidin

DESCRIPTION (provided by applicant): Summary: Sphingomyelin (SM) is one of the major lipid components in plasma and in the cell membranes. Plasma SM level is an independent risk factor for coronary artery disease, and is a marker for the clearance of atherogenic postprandial remnant-like particles. Thus, SM levels have a clinically important impact on lipoprotein metabolism. Moreover, the interaction of SM, cholesterol, and glycosphingolipids drives the formation of plasma membrane lipid rafts. It is well-known that many receptors and transporters are located in these SM-enriched regions, and mediate important cell functions such as cholesterol efflux, lipoprotein secretion and degradation, and inflammatory responses. All these functions may well have an impact on the development of atherosclerosis. Furthermore, we have found that in mouse models, reduction of plasma and tissue SM, with concomitant reduction of atherosclerosis, can be achieved by pharmacological inhibition of SM biosynthesis. This was done by inhibiting serine palmitoyltransferase (SPT), which is the key enzyme for SM biosynthesis. However, the mechanisms involved in this reaction must still be elucidated. All the discoveries made so far emphasize the need for a better understanding of SM metabolism if we are to explore the relationship between SPT deficiency and SM metabolism, as well as SPT deficiency and atherosclerosis. SPT is composed of two subunits, Sptlc1 and Sptlc2 (with Sptlc3 a probable alternative to Sptlc2). Expression levels of Sptlc2 parallel SPT activity, but those of Sptlc1 do not. Overall hypothesis: Sptlc2 deficiency-mediated SM reduction in the circulation and the plasma membranes creates an anti-atherogenic status. Major focus: Manipulating SPT activity using liver- and macrophage-specific Sptlc2-deficient approaches to manipulate SM levels in the plasma and in the cell plasma membranes. This is important because the liver and the macrophages make significant contributions to the development of atherosclerosis. There are two Specific Aims: Aim 1. To evaluate the effect of liver Sptlc2 deficiency on plasma SM metabolism and atherosclerosis, and Aim 2. To investigate the effect of macrophage Sptlc2 deficiency on membrane SM metabolism and atherosclerosis. This proposal will allow us to determine the contributions of hepatic and macrophage SPT activity to SM metabolism and atherosclerosis, and to evaluate SPT as a therapeutic target for atherosclerosis treatment.

描述（由申请人提供）： 摘要： 鞘磷脂 (SM) 是血浆和细胞膜中的主要脂质成分之一。血浆SM水平是冠状动脉疾病的独立危险因素，并且是导致动脉粥样硬化的餐后残留样颗粒清除的标志物。因此，SM水平对脂蛋白代谢具有临床上重要的影响。此外，SM、胆固醇和鞘糖脂的相互作用驱动质膜脂筏的形成。众所周知，许多受体和转运蛋白位于这些 SM 富集区域，并介导重要的细胞功能，如胆固醇流出、脂蛋白分泌和降解以及炎症反应。所有这些功能很可能对动脉粥样硬化的发展产生影响。此外，我们发现在小鼠模型中，通过药物抑制 SM 生物合成可以减少血浆和组织 SM，同时减少动脉粥样硬化。这是通过抑制丝氨酸棕榈酰转移酶 (SPT) 来实现的，丝氨酸棕榈酰转移酶是 SM 生物合成的关键酶。然而，该反应涉及的机制仍需阐明。迄今为止的所有发现都强调，如果我们要探索 SPT 缺乏与 SM 代谢以及 SPT 缺乏与动脉粥样硬化之间的关系，就需要更好地了解 SM 代谢。 SPT 由两个亚基组成：Sptlc1 和 Sptlc2（Sptlc3 可能是 Sptlc2 的替代品）。 Sptlc2 的表达水平与 SPT 活性平行，但 Sptlc1 的表达水平则不然。总体假设：Sptlc2 缺陷介导的循环和质膜 SM 减少产生抗动脉粥样硬化状态。主要焦点：使用肝脏和巨噬细胞特异性 Sptlc2 缺陷的方法来操纵 SPT 活性，以操纵血浆和细胞质膜中的 SM 水平。这很重要，因为肝脏和巨噬细胞对动脉粥样硬化的发展做出了重大贡献。具体目标有两个：目标1.评估肝脏Sptlc2缺陷对血浆SM代谢和动脉粥样硬化的影响，目标2.研究巨噬细胞Sptlc2缺陷对膜SM代谢和动脉粥样硬化的影响。该提案将使我们能够确定肝脏和巨噬细胞SPT活性对SM代谢和动脉粥样硬化的贡献，并评估SPT作为动脉粥样硬化治疗的治疗靶点。