Echium Oil Modulates Macrophage Inflammation by Promoting Alternative Activation

描述(由申请人提供)：这项建议侧重于补充和替代的医学方法，旨在了解巨噬细胞激活的分子机制。它提出了一种可能性，即omega-3脂肪酸，就像鱼油中发现的那些，通过促进替代激活来调节炎症。核激素受体PPAR-γ起着脂质传感器的作用，并可能指导omega-3脂肪酸对巨噬细胞激活表型的调节。此外，PPARγ是一种公认的转录因子，已被证明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还知之甚少。这些研究将有助于从细胞、分子和遗传学的角度进一步研究脂肪酸如何缓解慢性病症状。在特定的目标1中，我们将检验这样的假设：在动脉粥样硬化和慢性炎症的小鼠模型中，富含车前草种子油的饮食具有缓解炎症的能力，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脂肪酸是否会导致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、基于细胞和分子的方法来研究PPAR伽马在巨噬细胞对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录抑制通路在调节omega-3脂肪酸反应中的协调作用。我们还检验了omega-3脂肪酸增加引起的巨噬细胞表型转变取决于12/15-脂氧合酶(一种脂质过氧化酶)的酶活性的假设。众所周知，12/15-脂氧合酶可产生脂肪酸衍生的配体，可用于内源性激活PPARγ。这个项目的意义是双重的。首先，它在于确定植物来源的欧米茄-3脂肪酸是否具有鱼油的抗炎潜力。其次，它将提供新的机制数据，说明n-3多不饱和脂肪酸在减轻炎症中的作用，以及这种作用是否通过启动巨噬细胞向炎症分解、交替激活的表型发生，而这一领域缺乏强有力的支持。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理论基础，这些植物油可以提供n-3多不饱和脂肪酸的来源，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.