Echium Oil Modulates Macrophage Inflammation by Promoting Alternative Activation

蓝蓟油通过促进替代激活来调节巨噬细胞炎症

基本信息

批准号：
7544672
负责人：
Amanda Wibley
金额：
$ 3.56万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544672
关键词：
A Mouse Acute Address Anti-Inflammatory Agents Anti-inflammatory Apoptotic Arachidonate 15-Lipoxygenase Arginine Atherosclerosis Bacteriophages Binding Biological Assay Biological Models Bone Marrow Botanicals CD36 gene Cells Chronic Chronic Disease Conditioned Culture Media Consumption Data Diabetes Mellitus Diet Dinoprostone Docosahexaenoic Acid n-3 Echium Eicosapentaenoic Acid Enzymes Fatty Acids Fish Oils Fishes Flow Cytometry Food Gene Expression Genes Genetic Genomics Goals Greater sac of peritoneum Incidence Incubated Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Interleukin-10 Interleukin-4 Interleukin-6 Knockout Mice Leukotrienes Ligand Binding Ligands Ligation Linolenic Acids Linseed Oil Lipids Low Density Lipoprotein Receptor Macrophage Activation Mammals Measures Mediating Medicine Metabolism Modeling Modification Molecular Mus Nuclear Hormone Receptors Oils Omega-3 Fatty Acids Oxis PPAR gamma PTGS2 gene Pathogenesis Pathway interactions Peritoneal Peritoneal Macrophages Peroxisome Proliferator-Activated Receptors Personal Satisfaction Persons Phagocytosis Phenotype Physiological Play Population Population Decreases Rate Research Resolution Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Risk Role Seeds Severity of illness Small Interfering RNA Source Spleen Supplementation Surveys Symptoms Testing Thioglycolates Transactivation Transcriptional Activation Ubiquitin United States United States Environmental Protection Agency Week acquired immunity arginase base cell motility chromatin immunoprecipitation cytokine dietary supplements enzyme activity feeding in vivo lymph nodes macrophage mannose receptor mouse model novel palm oil protein inhibitor of activated STAT 1 response sensor stearidonic acid toll-like receptor 4 transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): This proposal is focused on complementary and alternative approaches to medicine geared toward understanding the molecular mechanisms of macrophage activation. It addresses the possibility that omega-3 fatty acids, like those found in fish oil, modulate inflammation by promoting alternative activation. The nuclear hormone receptor PPAR gamma acts as a lipid-sensor and likely directs this modulation of macrophage activation phenotypes by omega-3 fatty acids. Furthermore, PPAR gamma is a well recognized transcription factor that has been shown to regulate several aspects of macrophage cellular metabolism. However, the regulatory roles of fatty acids in macrophage inflammation are poorly understood. The studies herein will help to further investigate cellularly, molecularly, and genetically, how fatty acids may alleviate chronic diseases symptoms. In specific aim 1 we will test the hypothesis that dietary enrichment with seed oil from Echium plantagineum has the ability to ameliorate inflammation similar to fish oil in a mouse model of atherosclerosis and chronic inflammation. This will serve as an in vivo approach to ask the question if supplementation with a botanical source of omega-3 fatty acids causes alternative activation in macrophages, as a means to reduce pro-inflammatory phenotypes and responses. In specific aim 2 we will use genomic, cell based and molecular approaches to address the role of PPAR gamma in the macrophage response to omega-3 fatty acids. We will systematically look at the coordinate roles of PPAR gamma transcriptional activation and inflammatory gene transrepression pathways in modulating omega-3 fatty acid responses. We also test the hypothesis that the shifting of macrophage phenotypes caused by omega-3 fatty acid enrichment is dependent on the enzymatic activity of 12/15-lipoxygenase, a lipid-peroxidizing enzyme. It is well established that 12/15-lipoxygenase produces fatty acid-derived ligands that may serve to activate PPAR gamma endogenously. The significance of this project is two-fold. First, it lies in the determination of whether echium oil, a botanical source of omega-3 fatty acids, possesses the anti-inflammatory potential offish oil. Secondly, it will provide novel mechanistic data on the role of n-3 PUFAs in ameliorating inflammaiton and whether this occurs through priming macrophages toward inflammationresolving, alternatively activated phenotypes, a field in which strong support is lacking. If our hypothesis is correct, the results will support the rationale for inclusion of stearidonic acid-enriched botanical oils, as from Echium plantagineum, in food products providing a source of n-3 PUFAs that could reduce inflammation in the population, and decrease the risk of atherosclerosis and other chronic diseases.

描述（由申请人提供）：该提案的重点是旨在了解巨噬细胞激活的分子机制的补充和替代医学方法。它解决了 omega-3 脂肪酸（如鱼油中的脂肪酸）通过促进替代激活来调节炎症的可能性。核激素受体 PPAR γ 作为脂质传感器，可能通过 omega-3 脂肪酸指导巨噬细胞激活表型的调节。此外，PPAR γ 是一种公认的转录因子，已被证明可以调节巨噬细胞代谢的多个方面。然而，脂肪酸在巨噬细胞炎症中的调节作用尚不清楚。本文的研究将有助于进一步从细胞、分子和遗传学角度研究脂肪酸如何缓解慢性疾病症状。在具体目标 1 中，我们将测试以下假设：在动脉粥样硬化和慢性炎症的小鼠模型中，添加蓝蓟种子油的饮食能够像鱼油一样改善炎症。这将作为一种体内方法来询问补充植物来源的 omega-3 脂肪酸是否会引起巨噬细胞的替代激活，作为减少促炎表型和反应的一种手段。在具体目标 2 中，我们将使用基因组、细胞和分子方法来解决 PPAR γ 在巨噬细胞对 omega-3 脂肪酸反应中的作用。我们将系统地研究 PPAR γ 转录激活和炎症基因反式抑制途径在调节 omega-3 脂肪酸反应中的协调作用。我们还测试了这样的假设：omega-3 脂肪酸富集引起的巨噬细胞表型的转变取决于 12/15-脂氧合酶（一种脂质过氧化酶）的酶活性。众所周知，12/15-脂氧合酶产生脂肪酸衍生的配体，可用于内源性激活 PPAR γ。该项目的意义有两个。首先，要确定蓝蓟油（omega-3 脂肪酸的植物来源）是否具有鱼油的抗炎潜力。其次，它将提供有关 n-3 PUFA 在改善炎症中的作用的新机制数据，以及这种作用是否通过启动巨噬细胞向炎症消解、替代激活表型而发生，而这一领域缺乏强有力的支持。如果我们的假设正确，结果将支持在食品中添加富含十八碳四烯酸的植物油（如车前蓝蓟）的基本原理，提供 n-3 PUFA 来源，从而减少人群炎症并降低风险动脉粥样硬化和其他慢性疾病。