Lipid Peroxidation and Antioxidant Mechanisms

描述(由申请人提供)： 脂质过氧化和抗氧化机制是NIEHS计划的竞争性更新建议，该计划于2005年9月获得资助。在美国，环境压力和生活方式在导致死亡率的疾病中起着重要作用。吸烟、饮酒和不良饮食与其他环境因素结合在一起，影响了几种疾病的发病率。氧化剂的形成是许多此类疾病的标志，而脂质过氧化是各种环境侮辱的共同结果。事实上，氧化应激与癌症和心血管疾病等各种病理疾病的发生密切相关。将环境压力与疾病发病机制联系起来的潜在机制仍然不清楚。这里提出的研究将检验这一假设，即不同脂质底物的竞争氧化途径的平衡管理着对氧化应激和氧化损伤的适应。该计划项目还直接解决了这样的假设，即脂质过氧化产物导致的蛋白质加成改变了细胞信号，并调节了与氧化应激相关的疾病。该计划项目包括四个研究项目和一个紧密联系在一起的科学核心设施，将为氧化和抗氧化剂在人类病理生理学中扮演的角色提供重要的见解。项目1为理解过氧化情况提供了一个机械框架，并引领了为研究蛋白质亲和加合物提供新的脂类亲和标记的化学。项目2探索了二十碳五烯酸(EPA)的化学和生物学，这是一种在鱼油中突出的脂肪酸，并探索了EPA氧化产物可能对这种脂肪酸的生物学特性有重要贡献的假设。项目3评估了在细胞信号传递中发挥关键作用的亲电体，并为研究整个细胞中的脂类亲和力标签提供了生物学平台。项目4认为，脂质过氧化的次级亲电产物在氧化剂相关的分子病理学中起着关键作用，并探索了鉴定和分析这些亲电体的蛋白质加合物的方法。所有这些项目都是高度协作的，并且高度依赖于脂质组学分析的科学核心。 背景 这是一个由波特博士领导的高度整合的调查团队对项目项目拨款的续签申请，该团队最初于2005年获得资助。PPG寻求继续研究脂质氧化的机制和脂质衍生的亲电体在生物对氧化应激反应中的作用，使用创新的战略和先进的分析工具来确定脂质衍生的亲电体的生物靶标。尽管最初的提议被要求为期5年，上一次审查小组一致建议减少到3年，以便集中精力开发工具和分析战略，并随后用于生物学研究。目前的申请包括4个项目，由与最初申请相同的研究人员领导，包括2个核心、一个管理核心和一个新增加的脂组分析核心，它取代了原来的质谱学和蛋白质组学核心。 将计划作为一项综合努力

DESCRIPTION (provided by applicant): Lipid Peroxidation and Antioxidant Mechanisms is a competitive renewal proposal for an NIEHS Program- Project that was funded in September of 2005. Environmental stress and lifestyle play an important role in diseases that contribute significantly to mortality in the U.S. Cigarette smoking, alcohol consumption and poor diet combine with other environmental factors to affect the incidence of several diseases. The formation of oxidants is a hallmark of many of these diseases and lipid peroxidation is a common result of diverse environmental insults. Indeed, oxidative stress has been closely associated with the onset of pathologies as diverse as cancer and cardiovascular disease. The underlying mechanisms linking environmental stresses with disease pathogenesis remain obscure. The studies proposed here will test the hypothesis that the balance of competing oxidation pathways for different lipid substrates governs adaptation to oxidative stress and oxidative injury. The Program Project also directly addresses the hypothesis that protein adduction by lipid peroxidation products alters cellular signaling and modulates diseases linked to oxidative stress. This Program Project includes four research projects and one scientific core facility in a tightly-knit group that will provide important insights into the role that oxidation and antioxidants play in human pathophysiology. Project 1 provides a mechanistic framework for understanding peroxidation profiles and leads the chemistry that provides novel lipid affinity-tags for studying protein-electrophile adducts. Project 2 explores the chemistry and biology of eicosapentaenoic acid (EPA), a fatty acid prominent in fish oil, and explores the hypothesis that EPA oxidation products may contribute significantly to the biological properties of this fatty acid. Project 3 evaluates electrophiles that play critical roles in cell signaling and provides the biological platform for studying lipid affinity tags in whole cells. Project 4 suggests that secondary electrophilic products of lipid peroxidation play critical roles in oxidant-associated molecular pathologies and explores methodologies for identification and analysis of protein adducts of these electrophiles. All of the projects are highly collaborative and are highly dependent on the Lipidomics Analysis scientific core. BACKGROUND This is a renewal application of a Program Project Grant by a highly integrated team of investigators, led by Dr. Porter, which was initially funded in 2005. The PPG seeks to continue studies towards the mechanisms of lipid oxidation and the role of lipid-derived electrophiles in biological responses to oxidative stress, using innovative strategies and advanced analytical tools to identify biological targets for lipid-derived electrophiles. Although the original proposal was requested for a 5-year period, and the previous review team unanimously recommended reduction to 3 years, in order to focus on development of tools and analytical strategies and for subsequent use in biological studies. The current application consists of 4 Projects, led by the same investigators as in the original application, and includes 2 Cores, an Administrative Core and a newly added Lipidomics Analytical Core, which replaces the original Mass Spectrometry and Proteomics Core. PROGRAM AS AN INTEGRATED EFFORT