Mechanism of Stress-Induced Developmental Abnormalities

接触过渡金属与多种人类疾病和发育有关 异常现象。超级基金化学物质铜(第141号)和无机汞(第3号)可能通过调节各种细胞内信号转导途径的活性来影响转录。我们认为，接触过渡金属会“不适当地”激活信号转导通路，从而扰乱正常发育。在这些金属“适当地”激活一条途径的情况下，防御和修复基因就会表达出来，金属就会解毒。然而，这些通路的“不适当”或不受控制的激活可能会导致金属诱导的发育异常。我们将研究汞和铜调节细胞内信号转导通路活性的假设 影响转录，最终扰乱正常发育。本申请中概述的研究将使用DNA微阵列和基因敲除技术，使用模式生物秀丽线虫(C.elegans)和培养的哺乳动物细胞来验证这一假说。在本申请概述的研究中，将评估铜和无机汞影响基因表达和同源转录因子活性的能力。本申请概述的研究目标是：(A)表征线虫和肝细胞与铜和无机汞暴露相关的转录本的变化，并确定防御金属毒性所必需的基因；(B)确定金属反应的信号转导途径；(C)通过基因组分析确定的途径与金属诱导的转录因子功能的变化相联系；以及(D)应用信息和技术 在汞和铜对其他环境毒物的研究期间开发的，包括， 有机磷杀虫剂、多氯联苯和多环芳烃。在拟议的研究中获得的信息将有助于阐明金属诱导其毒性反应的分子途径。这一信息可直接应用于临床干预和可能的金属诱导病理的预防。

Exposure to transition metals is associated with a variety of human diseases and developmental abnormalities. The Superfund chemicals copper (No. 141) and inorganic mercury (No. 3) have the potential to affect transcription by modulating the activity of a variety of intracellular signal transduction pathways. We propose that exposure to transition metals disrupts normal development by "inappropriately" activating signal transduction pathways. In situations where these metals "appropriately" activate a pathway, defense and repair genes are expressed and the metals are detoxified. However, "inappropriate" or uncontrolled activation of these pathways may lead to metal-induced developmental abnormalities. We will investigate the hypothesis that mercury and copper modulate the activity of intracellular signal transduction pathways to affect transcription, which ultimately disrupts normal development. The research outlined in this application will test this hypothesis using DNA microarrays and gene knockout technologies using the model organism, Caenorhabditis elegans (C. elegans) and cultured mammalian cells. In the studies outlined in this application, the ability of copper and inorganic mercury to affect gene expression and the activity of cognate transcription factors will be assessed. The goals of the research outlined in this application are to (a) characterize the changes in C. elegans and liver cell transcriptomes associated with copper and inorganic mercury exposure, and identify the genes that are essential for defense against metal toxicity; (b) identify metal-responsive signal transduction pathways; (c) link pathways identified through genomic analyses to metal-induced alterations in transcription factor function; and (d) apply the information and technologies developed during the studies of mercury and copper to other environmental toxicants, including, organophosphate insecticides, polychlorinated biphenyls, and polyaromatic hydrocarbons. The information gained in the proposed studies will help to elucidate the molecular pathways by which metals induce their toxic response. This information may be directly applied to the clinical intervention and possible prevention of metal-induced pathologies.