Animal Models for Lipid Metabolism and Atherosclerosis

脂质代谢和动脉粥样硬化的动物模型

• 批准号: 6661835
• 负责人: LAWRENCE CHAN
• 金额: $ 7.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661835
• 关键词: alleles; apolipoprotein E; atherosclerosis; diet; disease /disorder etiology; disease /disorder model; enzyme mechanism; gene expression; gene targeting; genetic manipulation; genetic models; genetic promoter element; genetic techniques; genetically modified animals; immunocytochemistry; laboratory mouse; lipoxygenase; liquid chromatography; low density lipoprotein receptor; macrophage; microinjections; mifepristone; model design /development; nutrition related tag; polymerase chain reaction; transfection

DESCRIPTION (provided by applicant): The primary objective is to advance our knowledge of lipid metabolism and atherosclerosis using animal models. A major area is the role of 12/15-lipoxygenase (LO) in atherosclerosis. 12/l5LOs are lipid-peroxidizing enzymes that oxygenate polyenoic fatty acids to their corresponding hydroperoxy derivatives. 12/15LOs have proatherogenic properties via their capacity to oxidize LDL, as well as antiatherogenic activities via their predominantly anti-inflammatory action. We previously showed that macrophage-specific 15LO overexpression in rabbits protects against atherosclerosis. In pilot experiments we found that, compared to 12/15LO+/+ apoE-/- mice, 12/15LO-/- apoE-/- mice are protected against atherosclerosis, a finding that is at variance with that of. A major goal of this application is to examine the biochemical milieu associated with 12/15LO expression that may underlie the divergent effects of the enzyme on atherosclerosis. Another major area is the role of intracellular lipolysis in lipid homeostasis. We produced perilipin (plin) knockout mice that displayed constitutional activated lipolysis. Perilipin is a major adipose lipid droplet protein that regulates the activity of hormone-sensitive lipase. Plin-/- mice were lean and resistant to diet-induced obesity. Breeding the plin-/- alleles into ob/ob and db/db mice reversed their obesity phenotype. Interestingly, ruptured atherosclerotic plaques in humans and advanced plaques of apoE-/- mice expressed perilipin. We will investigate the role of 12/15LO and perilipin with 5 specific aims. In the first 2 aims, we will study atherosclerosis development in 12/15LO-/- apoE-/- and 12/15LO+/+ apoE-/- mice, and, identify and quantify the eicosanoids and other metabolites in the atherosclerotic aortas from the 2 genotypes. In aims 3 and 4, to obtain mechanistic insight into the obesity-resistant phenotype of plin-/- mice, we will perform biochemical and molecular characterization as well as in vivo stable isotope and energy expenditure experiments on plin+/+ and plin-/- mice with and without ob/ob or db/db background. The creation of non-obese ob/ob and db/db mice (i.e., those that also inherited the plin-/- alleles) provides a unique opportunity to study the role of leptin in lipid and carbohydrate homeostasis in the presence and absence of obesity. Since perilipin, a lipid droplet-associated protein, is expressed in atherosclerotic lesions, in the last aim and in collaboration with we will compare the atherosclerosis susceptibility and plaque morphology of plin-/- and plin+/+ mice bred into apoE-/- and LDLR-/- background. We believe that the mechanistic experiments proposed will advance our understanding of lipid and carbohydrate metabolism, energy homeostasis, and atherosclerosis.

描述（由申请人提供）：主要目的是 提高我们对使用动物的脂质代谢和动脉粥样硬化的了解 型号。一个主要区域是12/15-脂氧酶（LO）在动脉粥样硬化中的作用。 12/l5los是脂质过氧化的酶 它们相应的水过氧衍生物。 12/15los具有促进质基 通过其氧化LDL的能力以及抗动脉粥样硬化的性能 通过其主要抗炎作用的活动。我们以前 表明兔子中的巨噬细胞特异性15lo过表达可防止 动脉粥样硬化。在飞行员实验中，我们发现，相比12/15lo+/+ apoe - / - 小鼠，12/15lo - / - apoE-/ - 小鼠受到保护，以防止动脉粥样硬化，A 发现与之不同。一个主要目标 该应用是要检查与12/15 Lo相关的生化环境 可能是酶对酶对不同作用的表达 动脉粥样硬化。另一个主要领域是细胞内脂解的作用 脂质稳态。我们生产了显示的紫脂蛋白（PLIN）敲除小鼠 宪法活化的脂解。 Perilipin是主要的脂肪脂质液滴 调节激素敏感脂肪酶活性的蛋白质。 plin - / - 小鼠 苗条，对饮食引起的肥胖症具有抗性。繁殖plin - / - 等位基因 进入ob/ob和db/db小鼠扭转了肥胖表型。有趣的是， 破裂的动脉粥样硬化斑块 在人类和APOE - / - 小鼠的先进斑块中表达围peripin。我们将 以5个特定目的研究12/15lo和Peripin的作用。在 第一个目标，我们将研究12/15lo的动脉粥样硬化发展 - / - / - 和12/15lo+/+ apoe - / - 小鼠，并识别并量化类固醇和其他 来自两种基因型的动脉粥样硬化主动脉中的代谢产物。在目标3和 4，以获取对肥胖表型的机械洞察力 plin - / - 小鼠，我们将执行生化和分子表征为 以及plin+/+的体内稳定同位素和能量消耗实验 带有和不带OB/OB或DB/DB背景的Plin - / - 小鼠。创建 非肥胖的OB/OB和DB/DB小鼠（即，那些也继承了Plin - / - 等位基因）提供了一个独特的机会来研究瘦素在脂质中的作用 在存在和不存在肥胖症的情况下，碳水化合物稳态。自从 Perilipin是一种脂质液滴相关蛋白，在动脉粥样硬化中表达 病变，在最后一个目标中，并与我们合作 比较plin的动脉粥样硬化易感性和斑块形态 - / - PLIN+/+小鼠繁殖到ApoE - / - 和LDLR - / - 背景。我们相信 提出的机械实验将使我们对脂质和 碳水化合物代谢，能量稳态和动脉粥样硬化。