Anti inflammatory properties of cholesteryl linoleate-d*

胆固醇亚油酸酯-d* 的抗炎特性

基本信息

批准号：
7341726
负责人：
Bruce Alan Freeman
金额：
$ 3.4万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-17 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341726
关键词：
Acute Address Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Biochemistry Biological Biological Models Blood Vessels Cell model Cells Chemicals Cholesterol Clinical Collaborations Condition Cyclic GMP Development Diagnostic Disease Progression Doctor of Philosophy Equilibrium Event Evolution Exposure to Fatty Acids Foundations Free Radicals Gene Expression Generations Goals Grant Human Inflammation Inflammatory Inflammatory Response Injury Intervention Lipids Lipoproteins Low-Density Lipoproteins Mediating Mediator of activation protein Membrane Metabolic Modeling Molecular Nitrates Nitric Oxide Nitrogen Nitrogen Dioxide Nitrogen Oxides Oxidants Oxidation-Reduction Pathologic Pathway interactions Phenotype Plasma Process Production Property Purpose Reaction Reactive Oxygen Species Regulation Relaxation Research Research Personnel Research Training Resolution Side Signal Transduction Signaling Molecule Smooth Muscle Myocytes Specimen Structure System Testing Tissues United States National Institutes of Health Universities Unsaturated Fatty Acids Uruguay adduct base c new chemical reaction cholesteryl linoleate cholesteryl nitrolinoleate concept design insight interest lipid mediator macrophage medical schools monocyte nitrate nitration novel novel strategies oxidized lipid parent grant particle research study response

项目摘要

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.

描述（由申请人提供）：这项研究将主要在蒙特维迪奥大学与Bruce A. Freeman合作，作为NIH Grant＃R01 HL058115的扩展。该新的FIRCA应用中描述的实验目标旨在扩大与UAB医学学院的研究人员共同进行互惠互利的协作研究和培训，与炎症信号传导和组织损伤机制有关，以及乌鲁加伊蒙特维迪奥大学的De la Republica大学的研究人员。博士。弗里曼（Freeman）和鲁博（Rubbo）自1993年鲁博博士在UAB进行了博士学位论文和研究生研究以来就一直在合作。在提出的FIRCA支持的新研究计划中，父母赠款的主题 - 非衍生物种和靶分子之间的反应形成了含氮的生物活性脂质加合物 - 将朝着新的重要方向扩展。外国合作者将解决一个新颖的概念，即硝化脂质（尤其是胆固醇 - 硝化脂蛋白）可以通过反平衡氧化过程来发挥独特的抗炎信号动作。我们选择单核细胞/巨噬细胞模型，该模型代表了炎症反应的启动和演变的关键因素。假设早期的炎症性氧化剂对急性炎症的反应产生了炎症环境，从而促进了二级硝化脂质介质的产生，而二级硝化脂质介质反过来又可以“重编程”组织基因表达和巨噬细胞对抗炎性表型的巨噬细胞的代谢反应，从而促进抗炎症的抗炎性表型。为了解决这些概念，将追求两个关键的实验目标。我们将：1。表征人血浆，LDL和活化的巨噬细胞中胆固醇Linoleate的主要硝化衍生物以及形成机制。 2。评估胆固醇硝酸盐群以调节巨噬细胞分化向抗炎性表型的能力。成功完成所提出的目标将发展并巩固-NO衍生的物种与氧化脂质之间的反应缓解病理事件，通常是通过形成不饱和脂肪酸（Linoleate）含有独特氮的胆固醇的独特的含氮加合物。