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Lipoxygenases in Atherosclerosis

动脉粥样硬化中的脂氧合酶

基本信息

批准号：
7193423
负责人：
GARRET A FITZGERALD
金额：
$ 33.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-12-01 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7193423
关键词：
Animal Model Antisense RNA Apolipoprotein E Arachidonate 15-Lipoxygenase Arachidonate 5-Lipoxygenase Arterial Fatty Streak Atherosclerosis Bone Marrow Candidate Disease Gene Cells Cholesterol Esters Chronic Clinical Cytokine Signaling Data Development Disease Disease regression Disruption Enzymes Event Exhibits Face Failure Foam Cells Gene Expression Gene Silencing Genes Genetic Goals Grant Health Care Costs Human Hydrogen Peroxide Immunohistochemistry In Vitro Inflammation Inflammatory Institutes Interleukin-12 Knock-out Knockout Mice Lasers Lesion Leukotrienes Link Lipids Lipoxygenase Lymphocyte Mediator of activation protein Microarray Analysis Modeling Molecular Profiling Morbidity - disease rate Mouse Strains Mus Myocardial Nonesterified Fatty Acids Pathway interactions Pattern Peritoneal Macrophages Population Predisposition Process Proteins Role Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Societies Staging Stroke Susceptibility Gene Techniques Therapeutic atherogenesis cell type cytokine functional outcomes in vivo in vivo Model insight laser capture microdissection macrophage mortality mouse model reconstitution response

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease of the vasculature that often progresses to debilitating or fatal myocardial and stroke events. Macrophages are key players in progression of this disorder, interacting with lymphocytes and smooth muscle cells. 12/15-Lipoxygenase (12/15-LO) and 5-Lipoxygenase (5-LO) are present in subpopulations of macrophages and can oxygenate accumulating lipids to form hydroperoxides and leukotrienes, which have a variety of potent pro-inflammatory actions. Data generated during the past cycle of this grant established strong evidence for a pro-atherogenic role of 12/15-LO in three distinct mouse models and provided initial insight into the mechanisms involved. Recent data from other labs have shown the presence of 5-LO in atherosclerotic lesions and implicated this gene as a major atherosclerosis susceptibility gene in mice. The overall goal of this proposal is to establish the role and mechanisms for lipoxygenases in atherosclerosis. A central hypothesis is that subpopulations of 12/15-LO and 5-LO expressing macrophages can contribute to atherogenesis via specific pro-inflammatory gene signaling networks. In Specific Aim 1, the expression and roles of 12/15-LO and 5-LO in atherosclerosis will be investigated. Considerable controversy now exists as to the true expression pattern of these enzymes throughout lesion development in humans and mice. We shall investigate expression patterns of 12/15-LO and 5-LO in atherosclerosis prone mice using immunohistochemistry and in specific macrophage populations using laser capture microdissecfion. The role of 5-LO in atherogenesis throughout the lifetime of mice on apoE and LDL-R genetic backgrounds will be examined by en face lesion analysis and potential additive or synergistic actions with 12/15-LO explored. Preliminary data in atherosclerotic models and microarray studies have indicated that lipoxygenase inhibition via gene disruption influences expression of several important cytokine and inflammatory mediators, which may offer an explanation for the roles of lipoxygenases in atherogenesis. In Specific Aim 2, we will employ a microarray approach to examine the alterations in gene expression in both 12/15-LO and 5-LO deficient macrophages compared to C57BL/6 wildtype controls. Candidate gene changes in expression will be verified and functional links to lipoxygenase/cytokine signaling explored. In Specific Aim 3, a small interfering RNA (siRNA) gene silencing approach will be instituted to block macrophage lipoxygenase expression. Overall, these studies will illuminate the importance of lipoxygenase pathways in macrophages in relation to atherosclerotic disease.

描述(申请人提供)：动脉粥样硬化是一种慢性炎症性血管疾病，通常进展为衰弱或致命的心肌和中风事件。巨噬细胞是这种疾病进展中的关键角色，与淋巴细胞和平滑肌细胞相互作用。12/15-脂氧合酶(12/15-LO)和5-脂氧合酶(5-LO)存在于巨噬细胞亚群中，它们可以氧化累积的脂质形成过氧化氢和白三烯，具有多种强大的促炎作用。在这项资助的上一个周期中产生的数据为12/15-LO在三个不同的小鼠模型中的促动脉粥样硬化作用建立了强有力的证据，并为相关机制提供了初步的见解。最近来自其他实验室的数据显示，在动脉粥样硬化病变中存在5-LO，并暗示该基因是小鼠动脉粥样硬化的主要易感基因。这项建议的总体目标是确定脂氧合酶在动脉粥样硬化中的作用和机制。一个中心假说是，表达巨噬细胞的12/15-LO和5-LO亚群可以通过特定的促炎基因信号网络促进动脉粥样硬化的形成。在特定的目标1中，我们将研究12/15-LO和5-LO在动脉粥样硬化中的表达和作用。关于这些酶在人类和小鼠病变发展过程中的真实表达模式，目前存在相当大的争议。我们将用免疫组织化学方法研究12/15-LO和5-LO在易患动脉粥样硬化的小鼠中的表达模式，并用激光捕获显微解剖技术研究其在特定巨噬细胞群中的表达模式。5-LO在载脂蛋白E和低密度脂蛋白受体遗传背景的小鼠一生中在动脉粥样硬化形成中的作用将通过面部病变分析和12/15-LO的潜在相加或协同作用来检验。在动脉粥样硬化模型和微阵列研究中的初步数据表明，脂氧合酶通过基因中断抑制几种重要的细胞因子和炎症介质的表达，这可能为脂氧合酶在动脉粥样硬化形成中的作用提供解释。在特定的目标2中，我们将使用微阵列方法来检测12/15-LO和5-LO缺陷的巨噬细胞与C57BL/6野生型对照细胞基因表达的变化。候选基因的表达变化将得到验证，并探索与脂氧合酶/细胞因子信号转导的功能联系。在具体目标3中，将建立一种小干扰RNA(SiRNA)基因沉默方法来阻断巨噬细胞脂氧合酶的表达。总体而言，这些研究将阐明巨噬细胞中脂氧合酶途径与动脉粥样硬化性疾病的关系。