Anti inflammatory properties of cholesteryl linoleate-d*

描述(由申请人提供)：这项研究将主要在乌拉圭蒙得维的亚大学与布鲁斯·A·弗里曼合作完成，作为NIH#R01 HL058115号拨款的延伸。这一新的FIRCA申请中描述的实验目标旨在扩大与炎症信号和组织损伤机制相关的互惠合作研究和培训努力，这些研究和培训是由乌拉圭蒙得维的亚共和国大学的UAB医学院和Facultad de Medicina的研究人员联合开展的。弗里曼博士和鲁博博士自1993年以来一直合作，当时鲁博博士在UAB进行博士论文和研究生研究。在为FIRCA支持而提出的新的研究计划中，父母赠款的主题--NO衍生物种与目标分子之间的反应形成生物活性的含氮脂质加合物--将朝着一个新的重要方向扩展。外国合作者将解决硝化脂(特别是胆固醇-亚油酸盐)可以通过平衡氧化过程发挥独特的抗炎信号作用这一新概念。我们选择了单核/巨噬细胞模型，它代表了炎症反应的启动和演变中的一个关键因素。据推测，急性炎症的早期炎性氧化反应创造了一个炎性环境，促进了次级硝酸脂介质的产生，而次级硝酸脂介体反过来又有助于将组织基因表达和巨噬细胞的代谢反应重新编程为有利于炎症消退的抗炎表型。为了解决这些概念，将追求两个关键的实验目标。我们将：1.鉴定人血浆、低密度脂蛋白和活化巨噬细胞中主要的亚油酸胆固醇硝化衍生物及其形成机制。2.评估胆固醇-亚油酸盐调节巨噬细胞向抗炎表型分化的能力。拟议目标的成功实现将发展和巩固这样一个概念，即非衍生物种与氧化脂质之间的反应通常通过形成含不饱和脂肪酸(亚油酸盐)的胆固醇的独特含氮加合物来减轻病理事件。

DESCRIPTION (provided by applicant): This research will be done primarily in Uruguay at Montevideo University in collaboration with Bruce A. Freeman as an extension of NIH grant # R01 HL058115. The experimental goals described in this new FIRCA application serve to expand the mutually beneficial collaborative research and training endeavors related to inflammatory signaling and tissue injury mechanisms being jointly conducted by investigators at the UAB School of Medicine and the Facultad de Medicina of the Universidad de la Republica in Montevideo, Uruguay. Drs. Freeman and Rubbo have collaborated since 1993, when Dr. Rubbo conducted PhD dissertation and postgraduate research studies at UAB. In the new research plan proposed for FIRCA support, the theme of the parent grant -that reactions between -NO-derived species and target molecules form bioactive nitrogen-containing lipid adducts - will be expanded in a new and important direction. The foreign collaborators will address the novel concept that nitrated lipids (in particular cholesteryl-nitrolinoleate) can exert unique anti-inflammatory signaling actions by counter-balancing oxidative processes. We select the monocyte/macrophage model that represent a critical factor in the initiation and evolution of the inflammatory response. It is hypothesized that early inflammatory oxidant response to acute inflammation create an inflammatory milieu that promotes the generation of secondary nitrated lipid mediators that in turn serve to "reprogram" tissue gene expression and metabolic responses of macrophages towards an anti- inflammatory phenotype that facilitates resolution of inflammation. To address these concepts, two key experimental aims will be pursued. We will: 1. Characterize the major nitrated derivatives of cholesteryl linoleate in human plasma, LDL and activated macrophages as well as the mechanisms of formation. 2. Evaluate the capacity of cholesteryl-nitrolinoleate to modulate macrophage differentiation towards an anti- inflammatory phenotype. Successful accomplishment of the proposed aims will develop and solidify the concept that reactions between -NO -derived species and oxidized lipids mitigate pathologic events, often by forming unique nitrogen-containing adducts of unsaturated fatty acid (linoleate)-containing cholesterol.