Effect of heavy metals on aryl hydrocarbon receptor-regulated genes

重金属对芳烃受体调节基因的影响

• 批准号: 250139-2012
• 负责人: ElKadi, Ayman
• 金额: $ 2.48万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=547519
• 关键词: Effect; heavy; metals; aryl; hydrocarbon

Humans are exposed to numerous stressors, including heavy metals, products of combustion, pesticides, herbicides, and other environmental pollutants. To ensure survival in the face of such challenges, mammalian cells have evolved a variety of inducible genetic programs that enable them to adapt to the presence of harmful foreign compounds. These programs entail upregulation of discrete batteries of genes for foreign compounds metabolizing enzymes, foreign compounds transporters, and various protective proteins that allow an increased rate of foreign compounds elimination from the body, restoration of normal homeostasis, and removal of damaged macromolecules. Rarely is the response regulated by one transcription factor; rather, it is generally a coordinated effort between two or more transcription factors. Among the factors that mediate adaptation to foreign compounds, the aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) have been widely studied. Historically, the AhR has been associated with toxicity and carcinogenesis, whereas Nrf2 is associated with cell protection. Understanding the cross-talk between these two transcription factors can be exploited to therapeutic advantage or to improve chemopreventive strategies. My long-term objectives is to understand the potential outcome upon exposure to heavy metals and environmental pollutants, which commonly co-exist in the environment, on the expression of genes that is involved in the cellular response to toxicants and oxidative stress. This research uses a collaborative and multidisciplinary approach to elucidate the cellular and molecular mechanisms responsible for the modulation of genes that is involved in the cellular response to toxicants. This research may reveal novel points of intervention to be exploited in the development of new therapies for the treatment and prevention of heavy metals toxicity.

人类暴露于许多压力源，包括重金属，燃烧产物，杀虫剂，除草剂和其他环境污染物。为了确保在面对这些挑战时的生存，哺乳动物细胞已经进化出各种可诱导的遗传程序，使它们能够适应有害外来化合物的存在。这些程序需要上调外源化合物代谢酶、外源化合物转运蛋白和各种保护性蛋白质的离散基因组，这些基因组允许增加外源化合物从体内消除的速率，恢复正常的稳态，并去除受损的大分子。这种反应很少受一个转录因子的调控;相反，它通常是两个或多个转录因子之间的协调作用。在介导对外来化合物的适应的因素中，芳烃受体（AhR）和核因子红细胞2相关因子2（Nrf 2）已被广泛研究。历史上，AhR与毒性和致癌作用有关，而Nrf 2与细胞保护有关。了解这两个转录因子之间的相互作用可以利用治疗优势或改善化学预防策略。我的长期目标是了解暴露于重金属和环境污染物（通常在环境中共存）对参与细胞对毒物和氧化应激反应的基因表达的潜在影响。本研究采用协作和多学科的方法来阐明负责调节参与细胞对毒物反应的基因的细胞和分子机制。这项研究可能会揭示新的干预点，以开发新的治疗和预防重金属中毒的疗法。