Accelerated NO/02 Reactions in Low Density Lipoprotein

低密度脂蛋白中加速 NO/02 反应

基本信息

批准号：
7281747
负责人：
Jack R Lancaster
金额：
$ 3.79万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7281747
关键词：
Acceleration Address Anti-Inflammatory Agents Anti-inflammatory Arginine Arterial Fatty Streak Atherosclerosis Biochemical Biochemistry Biological Blood Vessels Cell Respiration Cells Characteristics Chemistry Clinical Collaborations Condition Consumption Country Environment Event Foundations Free Radicals Generations Goals Grant Immune response Investigation Kinetics Knowledge Laboratories Lipids Lipoproteins Low Density Lipoprotein oxidation Low-Density Lipoproteins Measures Mediating Membrane Modification Morbidity - disease rate Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Nitrogen Nitrogen Oxides Nitrosamines Nitrosation Numbers Phase Physiological Plasma Process Rate Reaction Regulation Relative (related person)Research Schools Science Signal Transduction Site Solutions Source Testing Time Translating United States National Institutes of Health Universities Uruguay Vasodilation Work aqueous atherogenesis base cellular targeting clinically relevant concept design in vivo medical schools mortality nitrate nitration nitrogen trioxide novel oxidation parent grant particle vascular inflammation

项目摘要

This research will be done primarily in Uruguay at the Physical Biochemistry Laboratory, School of Science as well as the Biochemistry Department, School of Medicine at the University of the Republic, Montevideo, in collaboration with Dr. Denicola as an extension of NIH grant 1 R01 HL074391-02; 7/10/03 - 6/30/07. The experimental goals described in this FIRCA application address fundamental mechanisms underlying the principal source of morbidity and mortality in westernized countries, atherosclerosis. Specifically, the questions arose in the parent grant, how hydrophobic phases influence the kinetics and mechanism of NO reaction with O2, will be extended considering a clinically relevant hydrophobic environment:: the low density lipoprotein (LDL). It is hypothesized that the hydrophobic compartment of circulating LDL serves to catalyze and focus the reaction of NO with O2, yielding secondary nitroso (RNO) and nitrated (RNO2) products that translate the cell signaling actions of NO. Specifically, a mechanistic rationale is proposed for examining a relative shift in nitrosation vs. nitration under biological conditions. To address this concept, two key experimental aims will be pursued: 1) delineate the kinetics, mechanisms and novel product formation (nitrosation and nitration) from NO/O2 reaction within the LDL particle, and 2) identify the vascular signaling actions.(vasodilation and vascular anti-inflammatory action) of the NO/O2-modified LDL. The proposed investigations will provide a strong foundation for understanding the mechanistic basis of the effects of NO and O2 reaction on LDL oxidation and consequent atherogenic events in particular, and on vascular inflammation in general.

这项研究将主要在乌拉圭蒙得维的亚共和国大学理学院物理生物化学实验室以及医学院生物化学系与 Denicola 博士合作进行，作为 NIH 拨款 1 R01 的延伸HL074391-02； 2003 年 7 月 10 日 - 2007 年 6 月 30 日。本 FIRCA 申请中描述的实验目标解决了西方国家发病率和死亡率主要来源动脉粥样硬化的基本机制。具体来说，母基金中出现的问题，即疏水相如何影响 NO 与 O2 反应的动力学和机制，将在考虑临床相关疏水环境：低密度脂蛋白 (LDL) 的情况下进行扩展。据推测，循环 LDL 的疏水区室用于催化和集中 NO 与 O2 的反应，产生仲亚硝基 (RNO) 和硝化 (RNO2) 产物，从而翻译 NO 的细胞信号传导作用。具体来说，提出了用于检查生物条件下亚硝化与硝化的相对变化的机械原理。为了解决这个概念，我们将追求两个关键的实验目标：1) 描述 LDL 颗粒内 NO/O2 反应的动力学、机制和新产物形成（亚硝化和硝化），2) 确定血管信号传导作用。（血管舒张） NO/O2 修饰的 LDL 的作用（和血管抗炎作用）。拟议的研究将为了解 NO 和 O2 反应对 LDL 氧化和随后的动脉粥样硬化事件以及一般血管炎症影响的机制基础提供坚实的基础。