Echium Oil Modulates Macrophage Inflammation by Promoting Alternative Activation

描述（由申请人提供）：该提案侧重于了解巨噬细胞活化的分子机制的补充和替代医学方法。它提出了一种可能性，即omega-3脂肪酸，就像在鱼油中发现的那样，通过促进替代激活来调节炎症。核激素受体PPAR γ充当脂质传感器，并可能通过omega-3脂肪酸指导巨噬细胞活化表型的调节。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几个方面。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，我们将在小鼠动脉粥样硬化和慢性炎症模型中测试假设，即在饮食中添加车前草籽油具有改善炎症的能力，类似于鱼油。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，作为一种减少促炎表型和反应的手段。在具体目标2中，我们将使用基因组，基于细胞和分子的方法来解决PPAR γ在巨噬细胞对omega-3脂肪酸的反应中的作用。我们将系统地研究PPAR γ转录激活和炎症基因转抑制途径在调节omega-3脂肪酸反应中的协调作用。我们还验证了由omega-3脂肪酸富集引起的巨噬细胞表型转移依赖于12/15-脂氧合酶（一种脂质过氧化物酶）的酶活性的假设。12/15-脂氧合酶产生脂肪酸衍生的配体，可能内源性激活PPAR γ。这个项目的意义是双重的。首先，它在于确定echium油是否具有鱼油的抗炎潜力，echium油是一种omega-3脂肪酸的植物来源。其次，它将提供关于n-3 PUFAs在改善炎症中的作用的新机制数据，以及这是否通过引发巨噬细胞炎症消退，替代激活表型发生，这是一个缺乏强有力支持的领域。如果我们的假设是正确的，结果将支持在食品中加入富含硬脂酸的植物油的基本原理，如从金车前草中提取的富含n-3 PUFAs的食物，可以减少人群中的炎症，降低动脉粥样硬化和其他慢性疾病的风险。

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.