Effect of sphingomyelin biosynthesis on atherosclerosis

鞘磷脂生物合成对动脉粥样硬化的影响

基本信息

批准号：
10543518
负责人：
XIAN-CHENG JIANG
金额：
$ 48.67万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543518
关键词：
Ablation Anabolism Aorta Apolipoproteins B Arterial Fatty Streak Atherosclerosis Attenuated Biological Availability Birds Catabolism Cell membrane Cells Ceramides Cholesterol Chylomicrons Circulation Coronary heart disease Defect Endoplasmic Reticulum Enterocytes Enzymes Event Fatty Liver Foam Cells Genes Hepatic Hepatocyte High Fat Diet Human Inflammation Inflammatory Response Intestines Knock-out Knockout Mice LDL-Receptor Related Proteins Lipids Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Macrophage Measures Mediating Membrane Membrane Lipids Membrane Microdomains Metabolism Mus Phospholipids Plasma Plasma Cells Play Process Production Protein Isoforms Reaction Research Risk Factors Role Secretory Vesicles Small Intestines Sphingolipids Sphingomyelins Testing Tissues Triglycerides Very low density lipoprotein absorption atherogenesis chylomicron remnant inhibitor insight knockout gene lipid biosynthesis mouse model novel strategies particle prevent receptor recruit serine palmitoyltransferase sphingomyelin synthase success therapeutic target vesicle transport

项目摘要

Summary Significant evidence indicates that sphingomyelin (SM) content in the aortic wall and in the plasma is closely related to atherogenesis. High SM is an independent risk factor for human coronary heart disease and is associated with human atherosclerotic plaque inflammation. We found that inhibiting serine palmitoyl- transferase, the first enzyme for SM biosynthesis reduced plasma SM and atherogenesis in mouse models. However, mechanisms are unknown, prompting further studies exploring relationships between blocking SM synthase (SMS) and atherogenesis. Two isoforms of SMS (SMS1 and SMS2) reside downstream of serine palmitoyl-transferase and catalyze the conversion of ceramide to SM. SMS1 and SMS2 activities are co- expressed in all tested tissues, including the liver, intestine, and macrophage. Thus, neither SMS1 gene knockout (KO) nor SMS2 KO approach is sufficient to evaluate the effect of SM reduction on atherosclerosis. We will use SMS1/SMS2 double KO approach in this study. Our objective is to test our hypotheses that inhibition of total SMS activity can: a) block SM bioavailability during the process of apoB-containing atherogenic lipoprotein (BLp, i.e. VLDL and chylomicron) production; b) reduce lipid absorption and attenuate inflammation by reducing SM in cell (enterocyte and macrophage) plasma membrane lipid rafts; and c) reduce atherosclerosis progression and regression without causing steatosis (SMS inhibition-mediated ceramide accumulation could suppress lipogenesis). In this study, we will use inducible global, liver-specific, and intestine-specific total SMS KO mouse models, as well as our specific SMS inhibitors. Specific aims: 1. Evaluate effects of blocking SMS on VLDL production and catabolism. 2. Investigate the effects of blocking SMS on lipid absorption and chylomicron secretion. 3. Examine the roles of absence or inhibition of SMS in atherosclerosis progression and regression. Insights gained from the proposed studies will allow us to evaluate SMS as a target for preventing and treating atherosclerosis.

概括大量证据表明，主动脉壁和血浆中的鞘氨质蛋白（SM）含量紧密与动脉粥样硬化有关。高SM是人类冠心病的独立危险因素，是与人动脉粥样硬化斑块炎症有关。我们发现抑制丝氨酸棕榈酰 - 转移酶，第一种用于SM生物合成的酶减少了小鼠模型中的血浆SM和动脉粥样硬化。但是，机制尚不清楚，促使进一步的研究探讨了阻止SM的关系合酶（SMS）和动脉粥样硬化。 SMS的两个同工型（SMS1和SMS2）位于丝氨酸的下游棕榈酰 - 转移酶和催化神经酰胺转化为SM。 SMS1和SMS2活动是共同的在所有测试的组织中表达，包括肝脏，肠和巨噬细胞。因此，两者都不是SMS1基因敲除（KO）或SMS2 KO方法足以评估SM降低对动脉粥样硬化的影响。在这项研究中，我们将使用SMS1/SMS2双KO方法。我们的目标是检验我们的假设抑制总SMS活动可以：a）在含APOB的过程中阻止SM生物利用度动脉粥样硬化脂蛋白（BLP，即VLDL和乳糜微粒）的产生； b）减少脂质吸收并减轻通过减少细胞（肠球菌和巨噬细胞）质膜脂质筏中的SM来炎症； c）减少动脉粥样硬化的进展和回归而不会引起脂肪变性（SMS抑制介导的神经酰胺积累可以抑制脂肪形成）。在这项研究中，我们将使用诱导型全球，肝特异性和肠道特异性的总SMS KO小鼠模型以及我们的特定SMS抑制剂。具体目的：1。评估阻断SMS对VLDL生产和分解代谢的影响。 2。调查阻塞的影响 SMS脂质吸收和乳糜微粒分泌。 3。检查SMS缺失或抑制的作用动脉粥样硬化的进展和回归。从拟议的研究中获得的见解将使我们能够评估 SMS是预防和治疗动脉粥样硬化的目标。