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

砷是一种重要的环境致癌物，通过以下途径影响全球数百万人： 受污染的水源。虽然砷可诱发多种人类癌症，包括皮肤癌、肺癌、膀胱癌， 肾脏和肝脏，致癌机制仍然未知。有了这笔拨款的资助， 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，并主要诱导多基因座缺失。这些发现提供了第一个直接联系， 在体外和体内致癌性中经常被证明的染色体异常。 此外，我们最近的数据表明，线粒体是介导砷诱导的细胞凋亡的主要靶点。 遗传毒性本申请的总体目标是阐明线粒体DNA的贡献 砷致哺乳动物遗传毒性和细胞凋亡的基因突变和细胞信号通路 细胞为了实现这一目标，提出了一系列八个相互关联的具体目标，以解决四个问题 可检验的假设人-仓鼠杂交（A-L）细胞试验将用于确定 线粒体DNA突变和线粒体功能在调节砷（亚砷酸钠和 甲基化砷种类）诱导CD 59基因座突变。由于线粒体损伤通常 与诱导细胞死亡相关，人黑素细胞和黑素瘤细胞将用于定义 细胞信号通路参与介导砷诱导的细胞凋亡。有一个深刻的必要性， 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， 在概念上和在共享材料中，本项目与项目2、3和4之间存在差异。更好的 了解砷的遗传毒性和细胞凋亡机制将为砷的治疗提供更好的方法。 在治疗和预防砷引起的人类疾病方面，

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.