Characterization of Mutagenesis, Mutational Spectra and Mechanisms of Toxicity

诱变特征、突变谱和毒性机制

基本信息

  • 批准号:
    7514462
  • 负责人:
  • 金额:
    $ 35.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-01-01 至 2013-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT 3. A continuing programmatic goal is elucidation of mechanisms through which reactive nitrogen species (RNS) and reactive oxygen species (ROS) contribute to increased cancer risks. Project 3 addresses this goal by testing the hypothesis that damage to DMAand other cellular macromolecules by RNS from NO- producing macrophages and/or ROSfrom neutrophils either drives cells into apoptosis or inhibits apoptosis and enhances mutation. We employ models enabling mechanistic studies of DNA damage, genotoxicity, mutagenicity and cell death. Project 3 also defines DNA lesions with biological properties that explain mutagenic and lethal endpoints in cellular- and organism-level systems. Association of inflammatory bowel disease with risk of colon cancer is well-documented, and evidence also clearly associates high frequency of iNOS-containing tumor cells with poor survival of stage III melanoma patients. Thus, our first specific aim is to elucidate mechanisms underlying relationships among dose and dose-rate, DNA damage, mutagenesis and apoptosis induced in human colon carcinoma cells and human melanoma cells by exposure to RNS and ROS. The pivotal role of p53 in modulating responses will be evaluated by parallel studies in closely related p53-mutant and p53-null cells. Second, we shall characterize effects of dose and dose-rate on mutagenic potency and mutation spectra induced by RNS and ROS in the gpt reporter gene in three settings: (a) in pSV2gpt-transformed CHO AS52 cells exposed in vitro to NO* under controlled conditions; (b) in AS52 cells co-cultivated with activated RAW264.7 mouse macrophages and/or HL60 cells; and (c) integrated into the genome of Rag 2-1- IL10-/- mice developing inflammation-related colon adenocarcinoma. Our third aim concerns genetic prioritization of DNA adducts as biomarkers of lethal and mutagenic endpoints. Adducts already nominated for potential as inflammation-derived pre-mutagenic lesions will first be evaluated by insertion into oligodeoxynucleotides, ligation into a viral genome and replication in E. coli cells of differing repair proficiency. Secondly we shall use the novel tool of chemical-biological fingerprinting to accelerate functional linkage of DNA damage and mutational spectra to lesions responsible for specific biological endpoints. Mutagenicity corresponding to features of mutational spectra in the gpt gene damaged with RNS or ROS (aim #2), will be characterized structurally (in collaboration with Project 2).
项目3.一个持续的计划目标是阐明反应性氮 RNS和活性氧(ROS)的增加会增加癌症风险。项目3地址 这一目标是通过检验一种假设,即来自NO的RNS对DMA和其他细胞大分子的损伤, 从中性粒细胞产生巨噬细胞和/或ROS,驱动细胞凋亡或抑制细胞凋亡 并增强突变。我们采用模型,使DNA损伤,遗传毒性, 致突变性和细胞死亡。项目3还定义了具有生物学特性的DNA损伤, 细胞和生物体水平系统中的致突变和致死终点。炎症性肠病 结肠癌风险的疾病是有据可查的,证据也清楚地表明, III期黑色素瘤患者的存活率差的含iNOS的肿瘤细胞。因此,我们的第一个具体目标是 阐明剂量和剂量率、DNA损伤、诱变之间的潜在关系机制 和通过暴露于RNS诱导的人结肠癌细胞和人黑素瘤细胞的凋亡, 罗斯p53在调节反应中的关键作用将通过密切相关的平行研究进行评估。 p53突变和p53缺失细胞。其次,我们将描述剂量和剂量率对致突变性的影响, 在三种情况下,由RNS和ROS在gpt报告基因中诱导的效力和突变谱:(a)在 在受控条件下体外暴露于NO* 的pSV 2gpt转化的CHO AS 52细胞;(B)在AS 52细胞中 与活化的RAW264.7小鼠巨噬细胞和/或HL 60细胞共培养;和(c)整合到 Rag 2-1-IL 10-/-小鼠的基因组发生炎症相关的结肠腺癌。我们的第三个目标 涉及DNA加合物作为致死和致突变终点的生物标志物的遗传优先级。加合 已被提名为潜在炎症源性致突变前病变的患者将首先通过以下方式进行评价: 插入到寡脱氧核苷酸中,连接到病毒基因组中并在E.大肠杆菌细胞 维修熟练度。其次,我们将使用化学生物指纹的新工具来加速 DNA损伤和突变谱与特定生物学损伤的功能联系 端点。RNS损伤gpt基因突变谱特征与致突变性的关系 或ROS(目标#2),将在结构上进行表征(与项目2合作)。

项目成果

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GERALD N WOGAN其他文献

GERALD N WOGAN的其他文献

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{{ truncateString('GERALD N WOGAN', 18)}}的其他基金

SENSITIVE DETECTION OF DNA ADDUCT FOR HPLC/LIF W/ FLUORESCENCE DERIVATIZATION
使用荧光衍生化的 HPLC/LIF 灵敏检测 DNA 加合物
  • 批准号:
    7181144
  • 财政年份:
    2005
  • 资助金额:
    $ 35.99万
  • 项目类别:
Characterization of Mutational Spectra, Mechanisms of Toxicity and Homologous Rec
突变谱的表征、毒性机制和同源重组
  • 批准号:
    6990331
  • 财政年份:
    2004
  • 资助金额:
    $ 35.99万
  • 项目类别:
MUTATIONAL SPECTRA INDUCED BY NITRIC OXIDE, PEROXYNITRITE AND REACTIVE OXIDANTS
一氧化氮、过氧亚硝酸盐和活性氧化剂诱导的突变谱
  • 批准号:
    6563792
  • 财政年份:
    2002
  • 资助金额:
    $ 35.99万
  • 项目类别:
MOLECULAR BIOMARKERS OF EXPOSURE AND EFFECTS OF ENVIRONMENTAL CARCINOGENS
环境致癌物暴露和影响的分子生物标志物
  • 批准号:
    6501073
  • 财政年份:
    2000
  • 资助金额:
    $ 35.99万
  • 项目类别:
MOLECULAR BIOMARKERS OF EXPOSURE AND EFFECTS OF ENVIRONMENTAL CARCINOGENS
环境致癌物暴露和影响的分子生物标志物
  • 批准号:
    6312757
  • 财政年份:
    2000
  • 资助金额:
    $ 35.99万
  • 项目类别:
MUTATIONAL SPECTRA INDUCED BY NITRIC OXIDE, PEROXYNITRITE AND REACTIVE OXIDANTS
一氧化氮、过氧亚硝酸盐和活性氧化剂诱导的突变谱
  • 批准号:
    6300203
  • 财政年份:
    2000
  • 资助金额:
    $ 35.99万
  • 项目类别:
MUTATIONAL SPECTRA INDUCED BY NITRIC OXIDE, PEROXYNITRITE AND REACTIVE OXIDANTS
一氧化氮、过氧亚硝酸盐和活性氧化剂诱导的突变谱
  • 批准号:
    6102036
  • 财政年份:
    1999
  • 资助金额:
    $ 35.99万
  • 项目类别:
MOLECULAR BIOMARKERS OF EXPOSURE AND EFFECTS OF ENVIRONMENTAL CARCINOGENS
环境致癌物暴露和影响的分子生物标志物
  • 批准号:
    6106282
  • 财政年份:
    1999
  • 资助金额:
    $ 35.99万
  • 项目类别:
FIC SCHOLARS IN RESIDENCE PROGRAM
FIC 学者居住项目
  • 批准号:
    2651027
  • 财政年份:
    1998
  • 资助金额:
    $ 35.99万
  • 项目类别:
MOLECULAR BIOMARKERS OF EXPOSURE AND EFFECTS OF ENVIRONMENTAL CARCINOGENS
环境致癌物暴露和影响的分子生物标志物
  • 批准号:
    6271161
  • 财政年份:
    1998
  • 资助金额:
    $ 35.99万
  • 项目类别:

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