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。Freeman作为NIH资助#R 01 HL 058115的扩展。在这个新的FIRCA应用程序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利合作研究和培训工作，这些工作由UAB医学院和乌拉圭蒙得维的亚大学医学院的研究人员联合进行。Freeman博士和Rubbo博士自1993年以来一直合作，当时Rubbo博士在UAB进行博士论文和研究生研究。在为FIRCA支持提出的新研究计划中，母基金的主题-NO衍生物种和靶分子之间的反应形成生物活性含氮脂质加合物-将在一个新的重要方向上扩展。国外合作者将解决硝化脂质（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的新概念。我们选择单核细胞/巨噬细胞模型，代表炎症反应的启动和演变的关键因素。假设对急性炎症的早期炎性氧化剂反应产生促进次级硝化脂质介质产生的炎性环境，所述次级硝化脂质介质继而用于“重编程”组织基因表达和巨噬细胞的代谢反应，朝向促进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.描述人血浆、低密度脂蛋白和活化巨噬细胞中胆固醇亚油酸酯的主要硝化衍生物及其形成机制。2.评价胆固醇-硝基亚油酸酯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的概念，即-NO -衍生的物种和氧化脂质之间的反应减轻病理事件，往往是通过形成独特的含不饱和脂肪酸（亚油酸酯）-含胆固醇的含氮加合物。

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.