BIOLOGY OF 12-LIPOXYGENASE ISOZYMES

12-脂加氧酶同工酶的生物学

• 批准号: 6052052
• 负责人: COLIN D. FUNK
• 金额: $ 30.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6052052
• 关键词: atherosclerosis; cholesterol; disease /disorder model; eicosanoid metabolism; enzyme inhibitors; enzyme mechanism; gene expression; genetically modified animals; isozymes; laboratory mouse; lipoxygenase; low density lipoprotein; macrophage; oxidation; oxidative stress; protein structure function; tocopherols; triglycerides; wound healing

Atherosclerosis, chronic inflammatory process progressing from fatty lesions to fibrous and unstable plaques, is the major underlying factor in most cases of coronary heart disease. Clinical disease as a result of atherosclerotic disease remains as the leading determinant for the extensive mortality and morbidity. and exorbitant health care costs in our society. The "LDL oxidation" hypothesis has gained general acceptance as a leading player in atherogenesis and it is recognized that oxidized LDL exhibits many pro-atherogenic properties. properties. The factors that initiate LDL, oxidating in vivo are poorly understood. However, circumstantial evidence has placed the 12/15-lipoxygenase in the context of atherosclerosis. Thus, in the first specific aim, the role of 12/15- lipoxygenase in mouse models of atherosclerosis (apoB editing catalytic polypeptide-1 (apobec-1)/LDL-receptor deficient and apoE deficient) will be assessed by quantitating lesion development throughout the aorta by the "en face" method using appropriately crossbred 12/15-lipoxygenase deficient mice. The combined effects of the anti-oxidant vitamin E with 12/15-lipooxygenase deficiency will also be examined. Total cholesterol, triglycerides, lipoprotein profiles and oxidative stress markers known as isoprostanes will be measured and correlated with lesion development. If specific 12/15-lipoxygenase inhibitors are ultimately to be used in atherosclerotic disease management they will need to be effective in limiting, or causing regression of, pre-existing lesion. By using an inducible 12/15-lipoxygenase gene disruption strategy in mice with atherosclerosis at various stages this important matter will be addressed. In specific aim 2, the subset of macrophages expressing 12/15- lipoxygenase will be characterized and purified. The effects of lipid loading and factors regulating 12/15-lipoxygenase gene expression will be determined. In specific aim 3, the novel 12(R)-lipoxygenase will be characterized and its relevance to atherosclerosis and LDL oxidation discerned.

在大多数冠状动脉疾病的情况下，动脉粥样硬化，从脂肪病变到纤维损伤和不稳定斑块的慢性炎症过程是主要的潜在因素。由于动脉粥样硬化疾病，临床疾病仍然是广泛死亡率和发病率的主要决定因素。和我们社会中高昂的医疗保健费用。 “ LDL氧化”假设已成为动脉粥样硬化中的主要参与者的普遍接受，并且人们认识到氧化的LDL具有许多亲动氏源性特性。特性。启动LDL，体内氧化的因素知之甚少。然而，间接证据已在动脉粥样硬化的背景下将12/15脂氧合酶放置。因此，在第一个具体目的中，12/15-脂氧酶在动脉粥样硬化的小鼠模型中的作用（APOB编辑催化性多肽-1（APOBEC-1）/LDL受体不足和APOE缺陷将通过“ EN Face”使用“ EN Face”使用“ EN Face”方法来评估病变的发展，以使用“ EN Face”方法来评估。还将检查抗氧化剂维生素E与12/15-氟氧酶缺乏症的综合作用。总胆固醇，甘油三酸酯，脂蛋白谱和氧化应激标志物将被测量并与病变发育相关。如果最终将特定的12/15-氧化加氧酶抑制剂用于动脉粥样硬化疾病管理中，则需要有效地限制或导致预先存在的病变。通过在各个阶段使用动脉粥样硬化的小鼠中使用可诱导的12/15-氧化酶基因破坏策略，这将解决这个重要问题。在特定的目标2中，将表征和纯化表达12/15-脂氧酶的巨噬细胞的子集。将确定脂质负荷和调节12/15-脂氧合酶基因表达的因子的影响。在特定的目标3中，新颖的12（r） - 脂氧合酶将被表征，并且与动脉粥样硬化和LDL氧化相关。