A nitric oxide(NO)-based metabonomic approach to investigate tobacco addiction

基于一氧化氮 (NO) 的代谢组学方法研究烟草成瘾

• 批准号: 7229882
• 负责人: MARTIN FEELISCH
• 金额: $ 3.12万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229882
• 关键词: nitric; oxide; NO; based; metabonomic

DESCRIPTION (provided by applicant): The interaction of nicotine with specific receptors in the brain is known to trigger the release of a number of neurotransmitters, including nitric oxide (NO). While the latter has been established to play an important role in the development of addiction to tobacco products, the underlying molecular pathways remain unclear. Current pharmacological methods for countering the release of NO include inhibition of NO formation and NO scavenging. However, neither one is a viable option for the treatment of nicotine addiction due to the central role endogenous NO plays in cell homeostasis and signaling, and to the deleterious consequences of a systemic reduction in NO availability. Moreover, NO is a constituent of tobacco smoke, and little is known about its actions on downstream effector mechanisms of nicotine. Nicotine metabolism is associated with the formation of redox-active byproducts that can cause oxidative stress through formation of reactive oxygen species (ROS). Because the latter are known to interact strongly with NO, it is likely that nicotine-induced ROS production globally affects the fate and biological actions of NO in the brain and other organs, leading to local nitrosation, nitration and oxidation of biomolecules with profound alterations in protein function and activity. The central hypothesis of this proposal is that local tissue redox poise and nicotine-induced ROS formation are key determinants of the metabolic fate of NO that triggers or facilitates the development of addiction (Stage I). If true, modulation of these determinants may provide a novel targeted approach for suppressing this nicotine-related NO pathway without the adverse effects associated with a global reduction in NO bioavailability (Stage II). To examine this hypothesis, the effects of NO, nicotine and cigarette smoke will be investigated in rodent models of oxidative stress with and w/o antioxidant supplementation or NO pretreatment using a novel metabonomic approach for simultaneous in vivo quantification of free and protein-bound nitroso, nitro and nitrosyl species as well as nitrite and nitrate. In addition, regional changes in cGMP levels, nicotine metabolites and oxidant biomarkers will be measured. Results from these studies are expected to offer an unprecedented insight into the interplay of ROS with NO and important NO-delivery forms in vivo, providing the "building blocks" and conceptual framework for a Stage II application that focuses on novel, targeted intervention strategies in tobacco-related addiction. Tobacco use is a major, worldwide health problem which claims >3 million lives each year. Although the research efforts and public health education in recent years have helped reducing the smoking prevalence in developed countries tobacco use remains the largest single cause of preventable death in the United States and elsewhere. The tragic consequences of nicotine addiction stress the importance of unraveling the molecular mechanisms involved.

描述（由申请人提供）：已知尼古丁与大脑中特定受体的相互作用可触发多种神经递质的释放，包括一氧化氮（NO）。虽然后者已被确定在烟草制品成瘾的发展中发挥重要作用，但其潜在的分子途径仍不清楚。目前对抗NO释放的药理学方法包括抑制NO形成和清除NO。然而，由于内源性NO在细胞内稳态和信号传导中的中心作用，以及NO可用性全身性降低的有害后果，这两种方法都不是治疗尼古丁成瘾的可行选择。此外，NO是烟草烟雾的一种成分，其对尼古丁下游效应机制的作用知之甚少。尼古丁代谢与氧化还原活性副产物的形成有关，该副产物可通过形成活性氧（ROS）引起氧化应激。由于后者已知与NO强烈相互作用，因此尼古丁诱导的ROS产生可能会全面影响NO在大脑和其他器官中的命运和生物作用，导致生物分子的局部亚硝化、硝化和氧化，并使蛋白质功能和活性发生深刻变化。该建议的中心假设是，局部组织氧化还原平衡和尼古丁诱导的ROS形成是触发或促进成瘾发展（阶段I）的NO代谢命运的关键决定因素。如果是真的，这些决定因素的调节可能提供一种新的靶向方法，用于抑制这种尼古丁相关的NO途径，而不会产生与NO生物利用度整体降低相关的不良反应（II期）。为了检验这一假设，将在氧化应激的啮齿动物模型中研究NO、尼古丁和香烟烟雾的影响，其中使用一种新的代谢组学方法同时体内定量游离和蛋白结合的亚硝基、硝基和亚硝酰基物质以及亚硝酸盐和硝酸盐，并使用W/O抗氧化剂补充或NO预处理。此外，还将测量环鸟苷酸水平、尼古丁代谢物和氧化剂生物标志物的区域变化。这些研究的结果有望为ROS与NO的相互作用以及体内重要的NO传递形式提供前所未有的见解，为第二阶段应用提供“构建模块”和概念框架，该阶段应用专注于烟草相关成瘾的新型靶向干预策略。烟草使用是一个主要的全球性健康问题，每年夺去超过300万人的生命。虽然近年来的研究工作和公共卫生教育有助于减少发达国家的吸烟率，但烟草使用仍然是美国和其他地方可预防死亡的最大单一原因。尼古丁成瘾的悲剧性后果强调了解开相关分子机制的重要性。