Project 1: Genotoxic & Cell Signaling Pathways of As in Mammalian Cells

项目1：基因毒性

• 批准号: 7609036
• 负责人: Tom K. Hei
• 金额: $ 21.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-04 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609036
• 关键词: ATP Synthesis Pathway; Address; Affect; Apoptosis; Apoptotic; Arsenic; Arsenicals; Arsenites; Base Pairing; Biological Assay; Bladder; Cell Death Induction; Cells; Chromosome abnormality; DNA Probes; Data; Doctor of Philosophy; Dose; Environmental Carcinogens; Exposure to; Fluorescent Probes; Funding; Genes; Goals; Grant; Hamsters; Human; Hybrids; In Vitro; Incidence; Induced Mutation; Kidney; L Cells; Label; Link; Liver; Lung; Malignant Neoplasms; Mammalian Cell; Mediating; Melanoma Cell; Membrane Potentials; Mitochondria; Mitochondrial DNA; Mutagenesis; Mutagens; Mutation; Nuclear; Nucleotides; Oxygen; Play; Polymerase Chain Reaction; Prevention; Radio; Reactive Nitrogen Species; Respiratory Chain; Restriction Fragment Length Polymorphism Analysis; Role; Sampling; Series; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Southern Blotting; Time; Water Supply; carcinogenicity; cytochrome c oxidase; day; genotoxicity; human disease; in vivo; melanocyte; mitochondrial DNA mutation; mitochondrial genome; mitochondrial membrane; response; sodium arsenite

Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. Although arsenic induces various human cancers including skin, lung, bladder, kidney and liver, the carcinogenic mechanism remains unknown. With the funding support of this grant, the applicant has shown, for the first time, that arsenic is a potent gene and chromosomal mutagen in mammalian cells and induces mostly multilocus deletions. These findings provide the first direct link between chromosomal abnormalities that have frequently been demonstrated in vitro and carcinogenicity in vivo. Furthermore, our recent data have shown that mitochondria are a primary target in mediating arsenicinduced genotoxicity. The overall goal of this application is to elucidate the contribution of mitochondrial DNA mutations and cell signaling pathways in mediating the genotoxicity and apoptosis of arsenic in mammalian cells. To achieve this goal, a series of eight inter-related specific aims are proposed to address the four testable hypotheses. The human-hamster hybrid (A-L) cell assay will be used to ascertain the role of mitochondrial DNA mutations and mitochondrial functions in modulating arsenic (sodium arsenite and methylated arsenic species) induced mutations at the CD59 locus. Since mitochondrial damage is often associated with induction of cell death, human melanocytes and melanoma cells will be used to define the cell signaling pathways involved in mediating arsenic-induced apoptosis. There is a profound necessity to develop effective treatment strategy for this often fatal cancer. Furthermore, there is considerable interaction, both conceptually and in shared materials, between this project and that of Projects 2, 3 and 4. A better understanding of the genotoxic and apoptotic mechanisms of arsenic will provide better interventional approach both in the treatment and prevention of arsenic-induced human diseases.

砷是一种重要的环境致癌物，通过 污染的供水。尽管砷会诱导各种人类癌症，包括皮肤，肺，膀胱， 肾脏和肝脏，致癌机制仍然未知。在这笔赠款的资金支持下， 申请人首次表明砷是一种有效的基因和染色体诱变剂 哺乳动物细胞并主要诱导多焦点缺失。这些发现提供了第一个直接联系 体内经常在体外和致癌性中表现出的染色体异常。 此外，我们最近的数据表明，线粒体是介导砷诱导的主要目标 遗传毒性。该应用的总体目标是阐明线粒体DNA的贡献 培养哺乳动物中砷的遗传毒性和凋亡的突变和细胞信号通路 细胞。为了实现这一目标，提出了一系列相互关联的特定目标来解决这四个目标 可检验的假设。人类汉堡杂种（A-L）细胞测定法将用于确定 线粒体DNA突变和线粒体功能在调节砷（砷钠和 甲基化的砷种类）在CD59基因座诱导突变。由于线粒体损伤通常是 与诱导细胞死亡，人类黑色素细胞和黑色素瘤细胞有关 细胞信号通路参与介导砷诱导的凋亡。有深刻的必要 为这种致命的癌症制定有效的治疗策略。此外，存在相当大的相互作用， 从概念和共享材料，该项目和项目2、3和4之间的材料。更好 了解砷的遗传毒性和凋亡机制将提供更好的介入 在治疗和预防砷引起的人类疾病方面的方法。