MOLECULAR TOXICOLOGY GENE EXPRESSION AND CELL DEATH

描述：(改编自《调查员摘要》)：长期 暴露在环境和药物毒物中对健康构成风险 人类人口。然而，调查员识别的能力 潜在风险已经超过了他们量化风险的能力。一些人 环境疾病可能是由于基因的细微变化引起的 表情。因此，估计与人类接触相关的风险 需要测量在基因表达期间的反应 导致了累积损害。这项提议的长期目标是 就是确定毒物改变基因表达的机制 潜藏在这些病理基础上。特别是，调查员将 回答这个问题：“c-myc基因是毒物诱导的靶点吗？ 基因表达和c-myc激活的后果是什么 毒物？“初步研究表明，肾上皮细胞 C-myc被毒物激活，包括S-(1，2-二氯乙烯)-L- 半胱氨酸(DCVC)，环境污染物的代谢物 工业溶剂三氯乙烯，以及下游靶向基因 结果是被打开了。此外，这些影响似乎可能 受MAX和MAD蛋白相互作用的调节，MAX和MAD蛋白是 与myc相同的转录因子蛋白家族。因为c-myc 已知基因表达可调节包括细胞死亡在内的过程 (细胞凋亡)，毒物诱导的c-myc表达变化可能起作用 损害肾脏或其他器官的损害拟议的研究将开始 以确定可能导致长期的早期分子变化 化学物质暴露对健康的影响。有人建议，基本 研究将确定毒物暴露的离散基因靶点。 这些靶点可能提供一种生物测定早期人类暴露的手段。 从而能够监测暴露人群的早期反应。因此， 这项应用的长期目标是使用分子技术 了解人类接触药物和化学品的风险。

DESCRIPTION: (Adapted from the Investigator's Abstract): Long term exposure to environmental and drug toxicants is a health risk to the human population. However, the investigator's ability to identify potential risks has outstripped their ability to quantify the risk. Some environmental diseases may occur due to subtle changes in gene expression. Thus, estimating the risk associated with human exposure requires measurement of responses during the time when gene expression is leading to cumulative damages. The long term goal of this proposal is to identify mechanisms by which toxicants change expression of genes underlying these pathologies. In particular the investigator will address the question, "Is the c-myc gene a target for toxicant induced gene expression and what are the consequences of c-myc activation by the toxicants?" Preliminary studies, in kidney epithelial cells suggest that c-myc is activated by toxicants including S-(1,2-dichlorovinyl)-L- cysteine (DCVC), a metabolite of the environmental contaminant and industrial solvent trichlorethylene, and that downstream targets genes are turned on as a result. Moreover, it appears that these effects may be regulated by interactions with MAX and MAD proteins, members of the same family of transcription factor proteins as myc. Because c-myc expression is known to mediate processes including cell death (apoptosis), toxicant induced changes in c-myc expression may contribute to damage in the kidney or other organs. Proposed studies will begin to identify the early molecular changes which may lead to long term health effects of chemical exposure. It is suggested that basic research will identify discrete gene targets for toxicant exposure. These targets may provide a means to bioassay early human exposure allowing early responses to be monitored in exposed populations. Thus, the long term goal of this application is to use molecular technology to understand the risk of human exposure to drugs and chemicals.