Adduct Formation in the Toxicity of Dithiocarbamates
二硫代氨基甲酸盐毒性中的加合物形成
基本信息
- 批准号:7367974
- 负责人:
- 金额:$ 38.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-01-01 至 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAgricultureBindingBiologicalBiological MarkersChelating AgentsChemicalsComplexCopperCuprizoneDemyelinationsDoseExposure toIndustryInjuryInvestigationKnowledgeLipid PeroxidationLocationMeasuresMediatingMedicineMetabolic PathwayMolecular TargetMyelinNerveOxidative StressPeripheral NervesPopulationPropertyProteinsRangeRecommendationRelative (related person)Schwann CellsSolubilityStructure-Activity RelationshipSystemTestingToxic effectTransgenic ModelWorkadductbaseexposed human populationin vivoprotein expressionresponse
项目摘要
DESCRIPTION (provided by applicant): Human exposure to dithiocarbamates occurs in agriculture, industry and medicine. Although an understanding of degradative and metabolic pathways is evolving, there is currently little knowledge on the molecular targets and mechanisms underlying the biological affects of dithiocarbamates. The long-range objectives of this project are to delineate the interactions of dithiocarbamates and their metabolites within biological systems and to determine the relevance of these interactions as mechanisms of toxicity and biomarkers. Previous studies revealed the ability of certain dithiocarbamates to produce selective Schwann cell toxicity accompanied by increased levels of copper and lipid peroxidation products in nerve. Investigations in this application are guided by the working hypothesis that these dithiocarbamates bind endogenous copper, form lipophilic complexes and accumulate within myelin resulting in increased lipid peroxidation, oxidative injury and demyelination. This hypothesis will be tested through two specific aims: 1) To determine if copper accumulation and oxidative stress are required for dithiocarbamate-mediated segmental demyelination and 2) To determine the molecular targets and cellular responses in dithiocarbamate-mediated peripheral nerve demyelination. Aim 1 will be achieved through: a) synthesis of dithiocarbamates differing in their affinity for copper and their copper complex solubility and evaluating their relative potency for lipid peroxidation and demyelination in vivo, b) determining the ability of the non-dithiocarbamate copper chelating agent, cuprizone, to elevate copper and lipid peroxidation in nerve, c) determining if lipid peroxidation and copper accumulation are direct affects of dithiocarbamates through defining the dose response and temporal relationship of these affects to the onset of myelin injury and d) determining if transgenic models with compromised defense to oxidative injury and copper toxicity are more sensitive to dithiocarbamate-mediated demyelination. Aim 2 will be achieved through a) determining changes in protein expression, b) identifying damaged proteins, c) measuring cuproenzyme activities and d) characterizing the location and chemical species of excess copper produced in nerve by dithiocarbamates. The significance of these studies lies in establishing structure-activity relationships useful for predicting agents that may act through similar mechanisms, identifying susceptible populations, developing mechanistically based exposure recommendations and predicting the affects of long term low level exposures.
描述(由申请方提供):人类在农业、工业和医学中暴露于二硫代氨基甲酸酯。虽然对降解和代谢途径的理解正在不断发展,但目前对二硫代氨基甲酸酯生物效应的分子靶点和机制知之甚少。该项目的长期目标是描述二硫代氨基甲酸盐及其代谢物在生物系统中的相互作用,并确定这些相互作用作为毒性机制和生物标志物的相关性。先前的研究揭示了某些二硫代氨基甲酸酯产生选择性雪旺细胞毒性的能力,伴随着神经中铜和脂质过氧化产物水平的增加。本申请中的研究由以下工作假设指导:这些二硫代氨基甲酸盐结合内源性铜,形成亲脂性复合物并在髓鞘内积累,导致脂质过氧化、氧化损伤和脱髓鞘增加。该假设将通过两个特定目的进行检验:1)确定铜蓄积和氧化应激是否是二硫代氨基甲酸盐介导的节段性脱髓鞘所需; 2)确定二硫代氨基甲酸盐介导的外周神经脱髓鞘中的分子靶点和细胞反应。目标1将通过以下方式实现:a)合成对铜的亲和力和铜络合物溶解度不同的二硫代氨基甲酸酯,并评价它们在体内对脂质过氧化和脱髓鞘的相对效力,B)测定非二硫代氨基甲酸酯铜螯合剂铜腙提高神经中的铜和脂质过氧化的能力,c)通过定义剂量反应和这些影响与髓鞘损伤发作的时间关系来确定脂质过氧化和铜积累是否是二硫代氨基甲酸酯的直接影响,和确定对氧化损伤和铜毒性的防御受损的转基因模型是否对二硫代氨基甲酸盐介导的脱髓鞘更敏感。目标2将通过a)确定蛋白质表达的变化,B)鉴定受损蛋白质,c)测量铜酶活性和d)表征二硫代氨基甲酸盐在神经中产生的过量铜的位置和化学种类来实现。这些研究的意义在于建立结构-活性关系,用于预测可能通过类似机制起作用的药物,识别易感人群,制定基于机制的暴露建议,并预测长期低水平暴露的影响。
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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WILLIAM M VALENTINE其他文献
WILLIAM M VALENTINE的其他文献
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{{ truncateString('WILLIAM M VALENTINE', 18)}}的其他基金
Pesticide-mediated inhibition of UBA1 and cumulative risk for Parkinson's Disease
农药介导的 UBA1 抑制和帕金森病的累积风险
- 批准号:
8462271 - 财政年份:2011
- 资助金额:
$ 38.67万 - 项目类别:
Pesticide-mediated inhibition of UBA1 and cumulative risk for Parkinson's Disease
农药介导的 UBA1 抑制和帕金森病的累积风险
- 批准号:
8318607 - 财政年份:2011
- 资助金额:
$ 38.67万 - 项目类别:
Pesticide-mediated inhibition of UBA1 and cumulative risk for Parkinson's Disease
农药介导的 UBA1 抑制和帕金森病的累积风险
- 批准号:
8188050 - 财政年份:2011
- 资助金额:
$ 38.67万 - 项目类别:
OXIDATIVE STRESS IN THE CYTOTOXICITY OF DITHIOCARBAMATES
二硫代氨基甲酸盐细胞毒性中的氧化应激
- 批准号:
2596123 - 财政年份:1998
- 资助金额:
$ 38.67万 - 项目类别:
ADDUCT FORMATION IN THE TOXICITY OF DITHIOCARBAMATES
二硫代氨基甲酸盐毒性中加合物的形成
- 批准号:
6164607 - 财政年份:1994
- 资助金额:
$ 38.67万 - 项目类别:
ADDUCT FORMATION IN THE TOXICITY OF DITHIOCARBAMATES
二硫代氨基甲酸盐毒性中加合物的形成
- 批准号:
6285032 - 财政年份:1994
- 资助金额:
$ 38.67万 - 项目类别:
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