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

项目1：基因毒性

• 批准号: 7089753
• 负责人: Tom K. Hei
• 金额: $ 20.93万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089753
• 关键词: DNA damage; PC12 cells; animal genetic material tag; apoptosis; arsenic; biological signal transduction; carcinogenesis; cell line; environmental contamination; environmental toxicology; free radical oxygen; free radicals; gene mutation; human genetic material tag; hybrid cells; laboratory rabbit; methylation; mitochondrial DNA; neoplastic cell; neuroprotectants; nitrogen; nuclear factor kappa beta; oxidative phosphorylation; restriction fragment length polymorphism

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，通过以下方式影响全世界数百万人 受污染的水源。尽管砷会诱发多种人类癌症，包括皮肤癌、肺癌、膀胱癌、 肾和肝，致癌机制尚不清楚。在本次补助金的资助下， 申请人首次证明砷是一种有效的基因和染色体诱变剂 哺乳动物细胞并诱导大部分多位点缺失。这些发现首次提供了两者之间的直接联系 体外经常证实的染色体异常和体内致癌性。 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 突变和细胞信号通路介导砷对哺乳动物的遗传毒性和细胞凋亡 细胞。为了实现这一目标，提出了一系列八个相互关联的具体目标来解决四个问题 可检验的假设。人仓鼠杂交 (A-L) 细胞测定将用于确定 线粒体 DNA 突变和线粒体在调节砷（亚砷酸钠和 甲基化砷）诱导 CD59 位点突变。由于线粒体损伤常常 与诱导细胞死亡相关，人类黑色素细胞和黑色素瘤细胞将被用来定义 细胞信号通路参与介导砷诱导的细胞凋亡。存在着深刻的必要性 为这种通常致命的癌症制定有效的治疗策略。此外，还有相当多的互动， 该项目与项目 2、3 和 4 的项目在概念上和共享材料上都存在差异。 了解砷的基因毒性和细胞凋亡机制将提供更好的干预措施 治疗和预防砷引起的人类疾病的方法。