Anti inflammatory properties of cholesteryl linoleate-d*

描述（由申请人提供）：本研究将主要在乌拉圭蒙得维的亚大学与Bruce A. Freeman合作完成，作为NIH资助# R01 HL058115的延伸。在这个新的FIRCA申请中描述的实验目标有助于扩大与炎症信号和组织损伤机制相关的互利合作研究和培训努力，这些研究和培训由UAB医学院和乌拉圭蒙得维的亚共和国大学医学院的研究人员共同进行。Drs。Freeman和rubo从1993年开始合作，当时rubo博士在UAB进行博士论文和研究生研究。在为FIRCA提出的新研究计划中，母体资助的主题- no衍生物种与靶分子之间的反应形成生物活性含氮脂类加合物-将在一个新的重要方向上扩展。国外合作者将解决新的概念，即硝化脂质（特别是胆固醇-硝基亚油酸酯）可以通过平衡氧化过程发挥独特的抗炎信号作用。我们选择单核细胞/巨噬细胞模型，这代表了炎症反应开始和进化的关键因素。据推测，急性炎症的早期炎症氧化反应创造了一种炎症环境，促进了次生硝化脂质介质的产生，从而“重编程”了组织基因表达和巨噬细胞的代谢反应，从而促进了炎症的解决。为了解决这些概念，将追求两个关键的实验目标。我们将：1；表征亚油酸胆固醇在人血浆、LDL和活化巨噬细胞中的主要硝化衍生物及其形成机制。2. 评估胆固醇-硝基亚油酸调节巨噬细胞向抗炎表型分化的能力。所提出的目标的成功实现将发展和巩固无衍生物种和氧化脂质之间的反应减轻病理事件的概念，通常通过形成独特的含氮的不饱和脂肪酸（亚油酸）-含胆固醇的加合物。

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.