Peroxidation Profiles and Antioxidants
过氧化谱和抗氧化剂
基本信息
- 批准号:8375461
- 负责人:
- 金额:$ 31.14万
- 依托单位:
- 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:2005-09-12 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AerobicAffinityAlkynesAmino Acid SequenceAnimalsAntioxidantsArachidonic AcidsAzidesBiologicalBiological MarkersBiological ModelsCarbon TetrachlorideCellsChemicalsCholesterol EstersCollaborationsComplexComplex MixturesCoupledDietDietary intakeDiseaseDocosahexaenoateDrug toxicityEnvironmentEquilibriumEstersFatty AcidsFish OilsFishesFree RadicalsGlycerolGlycerophosphatesHeadHealth BenefitHigh Pressure Liquid ChromatographyHumanHuman ResourcesIndividualInjuryLifeLinkLinoleic AcidsLipid PeroxidationLipidsLiquid substanceMembraneMembrane LipidsMethodologyMethodsMolecularNatureNucleic AcidsOrganismOxidative StressOxygenOzonePathway interactionsPeroxidesPhospholipidsPolyunsaturated Fatty AcidsPositioning AttributeProcessProtein ChemistryProteinsProteomicsProtocols documentationReactionReagentReducing AgentsResearchResidual stateRodentScreening procedureSignal TransductionStressStress-Induced ProteinTissuesToxic effectUnsaturated FatsVitamin Eadductanalogarachidonatebasecycloadditionenvironmental agentenvironmental chemical exposurefatty acid oxidationfree radical oxygenhuman diseasehydroxypyridinein vivointerestmembrane modelnoveloxidationperoxidationpolyunsaturated fatprogramsresearch studyresponsetool
项目摘要
Peroxidation of polyunsaturated fatty acids (PUFAs) and their biologically relevant phospholipid esters is a
complex reaction giving scores of possible products from a single molecular species. This process is a
hallmark of diverse environmental chemical exposures, drug toxicities and oxidative stresses. In addition to
the many peroxide products that form from polyunsaturated lipids, a set of reactive electrophiles is also
generated. These electrophilic residuals of lipid peroxidation modify nucleic acids and proteins and in this
way, the consequence of lipid oxidative degradation is distributed to other important biomolecules. This
proposal outlines experiments that probe the chemical mechanisms of lipid peroxidation, provides a
framework for understanding the oxidation of highly unsaturated lipids present in fish oils, describes novel
new affinity-tags useful in the isolation of lipid electrophile-protein adducts and examines new phenolic
antioxidants more potent than vitamin E. Highly unsaturated co-3 PUFAs are better reducing agents than
more saturated co-6 lipids and we will look for consequences of this difference by analyzing peroxidation
biomarkers formed in model membrane oxidations and in tissues and fluids of stressed animals on fish oil
diets. Our affinity-tag lipids are analogs of natural lipids having a terminal alkyne substituted at the 00
position (co-yne) of fatty acid chains. This terminal alkyne undergoes "click" cycloaddition with biotinsubstituted
azides, permitting "pull-down" of any proteins covalently attached to lipid-derived electrophiles
bearing an (co-yne). The proposed research is based on the hypothesis that the chemical mechanisms of
lipid peroxidation and the formation of electrophilic byproducts that are a hallmark of this process can be
rationally defined. The affinity tags when coupled to powerful HPLC/MS/MS proteomics methods permit the
structural identification of individual lipid-protein adducts even though such species are only a small part of a
very complex mixture. Profiling of human THP-1 cells exposed to an oxidative stress will include studies in
which affinity tag (co-yne) lipids are incorporated into the cells, permitting isolation of lipid-protein adducts.
The electrophiles identified from phospholipids will form the basis of a screening program in collaboration
with Projects 3 and 4 of the Program Project. New powerful pyridinol antioxidants will be studied in "proof of
concept" in vivo rodent experiments.
多不饱和脂肪酸(PUFAs)及其生物相关磷脂酯的过氧化是一个重要的研究领域。
一个复杂的反应,从单一的分子种类中产生许多可能的产物。这个过程是一
这是多种环境化学品暴露、药物毒性和氧化应激的标志。除了
由多不饱和脂质形成的许多过氧化物产物中,还存在一组反应性亲电体,
生成的.脂质过氧化的这些亲电残余物修饰核酸和蛋白质,并且在这种情况下,
另一方面,脂质氧化降解的后果被分配到其他重要的生物分子。这
提案概述了探索脂质过氧化化学机制的实验,提供了一个
的框架,用于理解鱼油中存在的高度不饱和脂质的氧化,描述了新的
用于分离脂质亲电蛋白加合物和检测新酚类化合物的新亲和标记
比维生素E更有效的抗氧化剂。高度不饱和的co-3 PUFA是比
更多饱和的co-6脂质,我们将通过分析过氧化作用来寻找这种差异的后果。
在模型膜氧化和鱼油应激动物的组织和体液中形成的生物标志物
节食。我们的亲和标签脂质是天然脂质的类似物,其末端炔在00位被取代
脂肪酸链的位置(co-炔)。该末端炔与生物素取代的炔进行“点击”环加成反应,
叠氮化物,允许共价连接到脂质衍生的亲电体的任何蛋白质的“下拉”
有一个(co-yne)。这项研究是基于这样一个假设,即:
脂质过氧化和亲电子副产物的形成是该过程的标志,
理性定义。当与强大的HPLC/MS/MS蛋白质组学方法偶联时,
单个脂质-蛋白质加合物的结构鉴定,即使这些物质只是
非常复杂的混合物。对暴露于氧化应激的人THP-1细胞的分析将包括以下研究:
所述亲和标记(co-yne)脂质被掺入细胞中,从而允许分离脂质-蛋白质加合物。
从磷脂中鉴定出的亲电体将构成合作筛选计划的基础
项目3和项目4的项目。新的强大的吡啶醇抗氧化剂将在“证明
概念”在体内啮齿动物实验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ned Allen Porter其他文献
Ned Allen Porter的其他文献
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{{ truncateString('Ned Allen Porter', 18)}}的其他基金
FREE RADICALS, MEMBRANES AND ENZYME PHOTOACTIVATION
自由基、膜和酶光活化
- 批准号:
7605523 - 财政年份:2006
- 资助金额:
$ 31.14万 - 项目类别:
FREE RADICALS, MEMBRANES AND ENZYME PHOTOACTIVATION
自由基、膜和酶光活化
- 批准号:
7731348 - 财政年份:2006
- 资助金额:
$ 31.14万 - 项目类别:
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