Spingomyelinase in atherosclerosis and foam cell biology

动脉粥样硬化和泡沫细胞生物学中的鞘磷脂酶

• 批准号: 6877756
• 负责人: Ira A Tabas
• 金额: $ 22.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877756
• 关键词: apoptosis; atherosclerotic plaque; blood lipoprotein metabolism; blood lipoprotein transport; cardiovascular disorder risk; cholesterol; clinical research; family genetics; genetically modified animals; human subject; isozymes; laboratory mouse; low density lipoprotein; lysosomes; macrophage; microarray technology; racial /ethnic difference; sphingomyelin phosphodiesterase; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by the applicant): Macrophages (MPhi) and endothelial cells in atherosclerotic lesions express two enzymes arising from the acid sphingomyelinase (SMase) gene: secretory (S) and lysosomal (L-) SMase. S-SMase promotes lipoprotein aggregation, which leads to subendothelial lipoprotein retention and MPhi foam cell formation. New data,however, suggest that lysosomal (L-) SMase facilitates cholesterol efflux. Thus, we hypothesize that while S-SMase promotes foam cell lesions, L-SMase plays a role in foam cell regression. Moreover, acid Smase deficient MPhis are protected from free cholesterol-induced MPhi apoptosis, suggesting a role for S- or L-SMase in lesional MPhi death. Our overall objective is to explore these hypotheses and other roles of S- and L-SMase in atherogenesis using genetically engineered mouse models and cultured MPhis. In Aim 1, acid SMase knockout mice will be used to define further the net effect of S- and L-SMase deficiency on foam cell lesions and on aortic LDL retention, degradation, and aggregation in vivo. In addition, we will create two new mouse models specifically to define the roles of S- vs. L-SMase in atherogenesis. In Aim II, we will address three areas in which S- and L-SMase may influence Mo biology related to atherogenesis: (1) cDNA microarrays will be used to test the hypothesis that MPhi interaction with matrix-retained and S-SMase-aggregated LDL alters gene expression; (2) the mechanisms and consequences of SMase-mediated death will be investigated in cultured MPhis and in vivo; and (3) in collaboration with Project 6, we will explore the mechanisms of defective cholesterol efflux in SMase-deficient MPhis. In Aim 1, through a large multiethnic study, we will explore our finding that high plasma sphingomyelin is a potent and independent risk factor for coronary artery disease in humans. To investigate a possible mechanism of this association, we will test the hypothesis that human remnant lipoproteins are relatively rich in sphingomyelin, rendering them susceptible to S-SMase and converting them into potent inducers of foam cells following S-SMase treatment. This work is intimately related to the overall theme of the SCOR-the investigation of arterial-wall molecules involved in atherogenesis using genetically manipulated mouse and cell-culture models-and will involve collaborations with Projects 6, 7, and 8 and use of the Gene Expression, Clinical, and Pathology Cores.

描述（申请人提供）： 动脉粥样硬化病变中的巨噬细胞（MPHI）和内皮细胞表达 由酸鞘磷脂酶（SMASE）基因引起的两种酶：分泌（S） 和溶酶体（L-）Smase。 S-Smase促进脂蛋白聚集，这 导致内皮下脂蛋白保留和MPHI泡沫细胞的形成。 但是，新数据表明溶酶体（L-）SMASE促进胆固醇 外排。因此，我们假设S-Smase促进了泡沫细胞病变，L-SMase 在泡沫细胞回归中起作用。此外，酸不足 MPHI受到保护免受游离胆固醇诱导的MPHI凋亡的保护，表明A S-或L-SMase在病变MPHI死亡中的作用。我们的总体目标是 探索这些假设以及S-和L-Smase在动脉粥样硬化中的作用 使用基因工程的小鼠模型和培养的MPHI。在AIM 1中，酸 Smase敲除小鼠将用于进一步定义S-和L-SMase的净效应 泡沫细胞病变和主动脉LDL保留缺乏， 体内降解和聚集。此外，我们将创建两个新的 鼠标模型专门定义了S-与L-Smase在中的作用 动脉粥样硬化。在AIM II中，我们将解决S-和L-Smase的三个领域 可能影响与动脉粥样硬化有关的MO生物学：（1）cDNA微阵列将 用于检验以下假设，即MPHI与基质保留的相互作用和 S-摩酶聚集的LDL改变基因表达； （2）机制和 Smase介导的死亡的后果将在培养的MPHI中进行研究 和体内； （3）与项目6合作，我们将探索 缺陷型MPHI中胆固醇外排的有缺陷的机制。在AIM 1中， 通过一项大型多种族研究，我们将探讨我们的发现很高 血浆鞘磷脂是冠状动脉的有效且独立的危险因素 人类动脉疾病。调查可能的机制 协会，我们将检验以下假设：人类残留脂蛋白是 相对较丰富的鞘磷脂，使它们容易受到s-smase和 在S-Smase之后，将它们转换为泡沫细胞的有效诱导剂 治疗。这项工作与SCOR的整体主题密切相关 - 研究使用动脉粥样硬化的动脉壁分子的研究 遗传操纵的小鼠和细胞培养模型，将涉及 与项目6、7和8的合作以及基因表达的使用， 临床和病理核心。