Cellular Responses to Oxidative Stress in Models of Colon Cancer Development

结肠癌发展模型中细胞对氧化应激的反应

基本信息

项目摘要

The central theme of this interdisciplinary translational research program revolves around the molecular toxicology of a nephrotoxic human carcinogen, aristolochic acid (AA). We will bring an interdisciplinary approach (chemistry, cell physiology and genetics) to bear on the pathogenesis of aristolochic acid nephropathy, combining molecular epidemiology and toxicogenomics to provide insights into genetic factors that contribute to susceptibility or resistance to this widespread disease,. Additionally, AAN serves as a model for currently idiopathic kidney diseases and disorders characterized by fibrogenesis, and this research provides a mechanistic strategic approach to environmental diseases in general. Our long-term goals are to: (a) establish the molecular mechanisms by which aristolochic acids exert their profound nephrotoxic and genotoxic effects in humans and animals; (b) relate the 3-D structures of AA-DNA adducts to the mutagenic potential of these lesions and to establish structure-function relationships involved in their removal by nucleotide excision repair; (c) utilize a mouse model of AAN to study biotransformation of AA and to validate AA-DNA adducts as potential biomarkers of exposure and risk of disease; (d) identify mouse and human genes involved in the cytotoxic response of renal proximal tubules to AA, differentiating this singular effect from the genotoxic effects of AA on urothelial cells; (e) dissect the genetic and cellular events involved in AA-induced renal interstitial fibrosis; (f) use molecular epidemiologic and toxicogenomic approaches to explore the pathogenesis of a similar disease, endemic nephropathy, and its associated urothelial cancer, and to identify genes that control development of this devastating disease. Findings emanating from this research are expected to impact directly on public health. Most obviously, establishing the relationship between dietary exposure to aristolochic acid and an increased risk of nephropathy and urothelial cancer suggests preventive strategies that will mitigate and potentially eliminate this nephropathy from the endemic region. In addition, as fibrogenesis is an irreversible process associated with end-stage renal disease, interstitial lung diseases, hepatic cirrhosis and heart disease, our research has the potential to impact disorders responsible for morbidity and mortality in the US and throughout the world.
这个跨学科转化研究项目的中心主题围绕肾毒性人类致癌物马兜铃酸(AA)的分子毒理学。我们将采用跨学科方法(化学、细胞生理学和遗传学)来研究马兜铃酸肾病的发病机制,结合分子流行病学和毒物基因组学,深入了解导致这种广泛疾病的易感性或抵抗力的遗传因素。此外,AAN 可作为当前特发性肾脏疾病和以纤维形成为特征的疾病的模型,这项研究 总体上为环境疾病提供了一种机械的战略方法。 我们的长期目标是: (a) 建立马兜铃酸在人类和动物中发挥其深远的肾毒性和基因毒性作用的分子机制; (b) 将 AA-DNA 加合物的 3-D 结构与这些病变的诱变潜力联系起来,并建立涉及通过核苷酸切除修复去除它们的结构-功能关系; (c)利用AAN小鼠模型来研究AAN的生物转化 AA 并验证 AA-DNA 加合物作为暴露和疾病风险的潜在生物标志物; (d) 鉴定参与肾近曲小管对 AA 的细胞毒性反应的小鼠和人类基因,将这种单一效应与 AA 对尿路上皮细胞的基因毒性效应区分开来; (e) 剖析与 AA 诱导的肾间质纤维化有关的遗传和细胞事件; (f) 使用分子流行病学和毒物基因组学方法探索类似疾病、地方性肾病及其相关疾病的发病机制 尿路上皮癌,并确定控制这种破坏性疾病发展的基因。 这项研究的结果预计将直接影响公众健康。最明显的是,确定饮食中马兜铃酸暴露与肾病和尿路上皮癌风险增加之间的关系表明,可以采取预防策略,减轻并有可能消除流行地区的这种肾病。此外,由于纤维形成是与终末期肾病、间质性肺疾病、肝硬化和心脏病相关的不可逆过程,我们的研究发现 可能影响导致美国和全世界发病率和死亡率的疾病。

项目成果

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Arthur Patrick Grollman其他文献

Arthur Patrick Grollman的其他文献

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{{ truncateString('Arthur Patrick Grollman', 18)}}的其他基金

PROJECT 3- TOXICOGENOMICS ARISTOLOCHIC ACID NEPHROPATHY
项目 3 - 毒理学马兜铃酸肾病
  • 批准号:
    8069937
  • 财政年份:
    2010
  • 资助金额:
    $ 177.83万
  • 项目类别:
ADMINISTRATIVE CORE
行政核心
  • 批准号:
    7305794
  • 财政年份:
    2007
  • 资助金额:
    $ 177.83万
  • 项目类别:
PROJECT 3- TOXICOGENOMICS ARISTOLOCHIC ACID NEPHROPATHY
项目 3 - 毒理学马兜铃酸肾病
  • 批准号:
    7305793
  • 财政年份:
    2007
  • 资助金额:
    $ 177.83万
  • 项目类别:
Etiology of Balkan endemic nephropathy
巴尔干地方性肾病的病因学
  • 批准号:
    7418616
  • 财政年份:
    2006
  • 资助金额:
    $ 177.83万
  • 项目类别:
Etiology of Balkan endemic nephropathy
巴尔干地方性肾病的病因学
  • 批准号:
    7214766
  • 财政年份:
    2006
  • 资助金额:
    $ 177.83万
  • 项目类别:
Etiology of Balkan endemic nephropathy
巴尔干地方性肾病的病因学
  • 批准号:
    7050797
  • 财政年份:
    2006
  • 资助金额:
    $ 177.83万
  • 项目类别:
Molecular Pharmacology of Tumor and Virus Inhibitors
肿瘤和病毒抑制剂的分子药理学
  • 批准号:
    6894590
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    6990372
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
  • 项目类别:
Mutagenic and Repair Mechanisms of Endogenous DNA Damage
内源性DNA损伤的诱变与修复机制
  • 批准号:
    6990324
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
  • 项目类别:
EXOCYCLIC ADDUCTS--SITE-SPECIFIC MUTAGENESIS
外环加合物——位点特异性诱变
  • 批准号:
    6563823
  • 财政年份:
    2002
  • 资助金额:
    $ 177.83万
  • 项目类别:

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DYRK protein kinases regulate p62/SQSTM1 to orchestrate cellular responses to oxidative stress, protein misfolding and nutrient starvation
DYRK 蛋白激酶调节 p62/SQSTM1 协调细胞对氧化应激、蛋白质错误折叠和营养饥饿的反应
  • 批准号:
    BB/P007015/1
  • 财政年份:
    2017
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    Research Grant
Specialised ribosomes facilitating cellular responses to oxidative stress
特殊核糖体促进细胞对氧化应激的反应
  • 批准号:
    BB/N014049/1
  • 财政年份:
    2016
  • 资助金额:
    $ 177.83万
  • 项目类别:
    Research Grant
Cellular Responses to Adversity: Oxidative Stress and Protection Against Oxidative Damage
细胞对逆境的反应:氧化应激和针对氧化损伤的保护
  • 批准号:
    DP0988470
  • 财政年份:
    2009
  • 资助金额:
    $ 177.83万
  • 项目类别:
    Discovery Projects
Cellular Responses to Localized Oxidative Stress
细胞对局部氧化应激的反应
  • 批准号:
    6815592
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
  • 项目类别:
Cellular Responses to Localized Oxidative Stress
细胞对局部氧化应激的反应
  • 批准号:
    6943081
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
  • 项目类别:
Cellular Responses to Localized Oxidative Stress
细胞对局部氧化应激的反应
  • 批准号:
    7268863
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
  • 项目类别:
Free radical analyzer and refrigerated microfuge to study the evolution of cellular responses to oxidative
自由基分析仪和冷冻微量离心机研究细胞氧化反应的演变
  • 批准号:
    315082-2005
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
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    Research Tools and Instruments - Category 1 (<$150,000)
Cellular Responses to Localized Oxidative Stress
细胞对局部氧化应激的反应
  • 批准号:
    7095224
  • 财政年份:
    2004
  • 资助金额:
    $ 177.83万
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Cellular Responses to Oxidative Damage: Cell Aging
细胞对氧化损伤的反应:细胞衰老
  • 批准号:
    DP0344964
  • 财政年份:
    2003
  • 资助金额:
    $ 177.83万
  • 项目类别:
    Discovery Projects
Cellular Responses to Oxidative Stress in Models of Colon Cancer Development
结肠癌发展模型中细胞对氧化应激的反应
  • 批准号:
    7885521
  • 财政年份:
    2002
  • 资助金额:
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