The effect of macrophage sphingomyelin synthase (SMS) on atherosclerosis

描述（由申请人提供）：巨噬细胞是动脉粥样硬化病变中最突出的细胞类型，与疾病的三个标志相关：脂质沉积、炎症和巨噬细胞源性泡沫细胞无序凋亡。调节SMS活性的能力可能成为调节这些巨噬细胞功能的有前途的途径，从而影响动脉粥样硬化。SMS利用神经酰胺和磷脂酰胆碱（PC）作为底物产生鞘磷脂（SM）和甘油二酯。SM是细胞膜（包括巨噬细胞）的主要脂质成分之一。这些质膜中富含SM的脂筏为许多重要的细胞过程提供了平台，如胆固醇流出和信号转导。上面列出的SMS活动相关事件很可能对动脉粥样硬化的发展有影响。SMS有两种亚型：SMS 1和SMS 2。我们有证据表明SMS活性与巨噬细胞质膜结构和功能密切相关。这些发现强调了在我们探索巨噬细胞SMS（SMS 1和SMS 2）与动脉粥样硬化之间的关系时，需要更好地理解这些SMS功能。我们现在假设，SMS1和SMS2的缺陷降低巨噬细胞SM水平，促进胆固醇流出，减少炎症细胞因子和趋化因子的产生，并减少细胞凋亡。因此，它们可以防止动脉粥样硬化的发展，而SMS1和SMS2的过度产生则具有相反的作用。该项目的主要重点将是操纵SMS活动，使用SMS 1和2基因敲除或过表达的方法来操纵SM水平。值得一提的是，我们实验室已经有了基因敲除小鼠和腺病毒介导的表达系统。我们的具体目标是：1）确定SMS1和SMS2缺陷在巨噬细胞胆固醇流出中的作用，2）探索SMS1和SMS2缺陷和过度表达对巨噬细胞中的炎症反应和凋亡的影响，以及3）研究巨噬细胞SMS1和SMS2缺陷在动脉粥样硬化中的作用。这一提议的成功将有助于我们阐明巨噬细胞SMS与动脉粥样硬化相关的独特功能，确定巨噬细胞SMS 1和巨噬细胞SMS 2在动脉粥样硬化过程中的差异和相似性，并评估SMS作为治疗动脉粥样硬化的治疗靶点。揭示了巨噬细胞SMS1和SMS2在动脉粥样硬化过程中的差异和相似性，并评估了SMS作为动脉粥样硬化治疗的治疗靶点。

DESCRIPTION (provided by applicant): Macrophages are the most prominent cell type in atherosclerotic lesions, and are associated with three hallmarks of the disease:lipid deposition, inflammation, and macrophage-derived foam cell disordered apoptosis. The ability to regulate SMS activity could become a promising approach for regulating these macrophage functions, thus influencing the atherosclerosis. SMS utilizes ceramide and phosphatidylcholine (PC) as substrates to produce sphingomyelin (SM) and diacylglycerol. SM is one of the major lipid components of cell membranes, including macrophages. SM-enriched lipid rafts in these plasma membranes provide a platform for many important cellular processes, such as cholesterol efflux and signal transduction. The SMS activity-related events listed above may well have an impact on the development of atherosclerosis. SMS has two isoforms: SMS1 and SMS2. We have evidence demonstrating that SMS activity is closely related to macrophage plasma membrane structure and function. Such findings emphasize the need for better understanding of these SMS functions in our exploration of the relationship between macrophage SMS (SMS1 and SMS2) and atherosclerosis. We now hypothesize that both SMS1 and -2 deficiencies decrease macrophage SM levels, promote cholesterol efflux, diminish the production of inflammatory cytokines and chemokines, and reduce apoptosis. They thus prevent the development of atherosclerosis, while SMS1 and -2 overproduction have the opposite effect. The major focus of this project will be to manipulate SMS activity using SMS1 and -2 gene knockout or over expression approaches to manipulate SM levels. It should be mentioned that the gene knockout mice and adenovirus-mediated expression system necessary for this work are already available in our laboratory. Our Specific Aims are to: 1) determine the role of SMS1 and SMS2 deficiencies in macrophage cholesterol efflux, 2) explore the impact of SMS1 and -2 deficiencies and over expression on inflammatory response and apoptosis in macrophages, and 3) investigate the role of macrophage SMS1 and -2 deficiencies in atherosclerosis. Success with this proposal will help us elucidate the distinctive functions of macrophage SMS relative to atherosclerosis, determine the differences and similarities between macrophage SMS1 and macrophage SMS2 in the process of atherosclerosis, and evaluate SMS as a therapeutic target for treatment of it. PUBLIC HEALTH RELEVANCE: The success of this proposal will help us to elucidate the distinctive function of macrophage SMS relative to atherosclerosis; disclose the difference and similarity between macrophage SMS1 and SMS2, in the process of atherosclerosis; and evaluate SMS as a therapeutic target for atherosclerosis treatment.