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

项目1：基因毒性

• 批准号: 8065864
• 负责人: Tom K. Hei
• 金额: $ 28.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-21 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065864
• 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; effective therapy; genotoxicity; human disease; in vivo; melanocyte; mitochondrial DNA mutation; mitochondrial genome; mitochondrial membrane; response; sodium arsenite; treatment strategy

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，影响着全球数百万人