Combinatorial Control of Toxin Induced Gene Expression in C. elegans

描述（由申请人提供）：该项目的长期目标是确定环境中的化学品如何影响人类健康。这些化学物质通常被称为外源性物质，以多种形式出现，包括环境污染物、药物、膳食补充剂以及通常在食品和饮料中发现的化合物。当存在于体内时，外源物质会被称为核受体的蛋白质感知。外源药物与核受体的结合导致这些调节因子诱导细胞机制的产生，从而将这些化合物解毒并排出体外。最近许多关于外源感应核受体的发现表明，它们对基因表达的影响往往与包括碳水化合物和脂质稳态在内的基本细胞代谢调节因子合作。本研究旨在发现转录调节因子的组合如何控制解毒酶和出口商的生产，以响应摄取的异种生物。这种对解毒的组合控制，以及对基本细胞代谢的重叠控制，表明异种生物的存在可能会影响正常代谢的基本细胞化学。因此，本研究的第二个目的是发现外源如何通过诱导外源感应核受体影响不参与解毒的酶的产生。对秀丽隐杆线虫（Caenorhabditis elegans）的研究为实现这些目标提供了一个强大的系统。通过使用RNA介导干扰技术的高通量筛选，将分析秀丽隐杆线虫全套转录调节因子在外源防御中的需求。一种这样的转录调节因子是已知的：NHR-8，它在结构和功能上与人类的外源感应核受体非常相似。因此，在筛选中发现的转录调控因子也将被分析它们与NHR-8在基因调控方面的合作。据推测，NHR-8可以控制正常细胞代谢（如脂质和碳水化合物代谢）以及外源解毒过程中酶的产生。因此，NHR-8为研究正常代谢和异种代谢之间的交叉提供了一个独特的入口。我们将分析NHR-8的转录调控靶点在外源胁迫下的表达情况。此外，NHR-8在异种生物感知中的作用将进一步表征。通过这两个目标，这项研究将有助于了解污染物、药物和其他化学物质如何影响人体的代谢状态，以及去除有害的和有益的外来生物。

DESCRIPTION (provided by applicant): The long term goals of this project are to determine how chemicals from the environment impact human health. These chemicals, commonly called xenobiotics, come in many forms including environmental contaminants, drugs, dietary supplements, and compounds normally found in food and drink. When present in the body, xenobiotics are sensed by proteins known as nuclear receptors. Binding of xenobiotics to nuclear receptors causes these regulators to induce the production of the cellular machinery that detoxifies and exports these compounds from the body. Many of the recent discoveries about xenobiotic sensing nuclear receptors indicates that their affect on gene expression is often in cooperation with regulators of basic cellular metabolism including carbohydrate and lipid homeostasis. This study aims to discover how combinations of transcriptional regulators control the production of detoxification enzymes and exporters in response to ingested xenobiotics. This combinatorial control of detoxification, along with overlapping control of basic cellular metabolism, suggests that xenobiotic presence might impact the basic cellular chemistry of normal metabolism. Therefore, a second aim of this study is to discovery how xenobiotics impact the production of enzymes not involved in detoxification through their induction of the xenobiotic sensing nuclear receptors. Research with the nematode, Caenorhabditis elegans, offers a powerful system in which to accomplish these aims. Through a high-throughput screen using a technique known as RNA mediated interference, the complete set of transcriptional regulators in C. elegans will be analyzed for their requirement in xenobiotic defense. One such transcriptional regulator is known: NHR-8, which is very similar in structure and function to the xenobiotic sensing nuclear receptors in humans. Transcriptional regulators discovered in the screen will therefore also be analyzed for their cooperation with NHR-8 in gene regulation. NHR-8 is hypothesized to control the production of enzymes involved in normal cellular metabolism, such as lipid and carbohydrate metabolism, as well as those of xenobiotic detoxification. Thus, NHR-8 offers a unique entryway into study of the intersections between normal and xenobiotic metabolism. Targets of NHR-8's transcriptional regulation will be analyzed for their expression during xenobiotic challenge. Additionally, the role of NHR-8 in xenobiotic sensing will be further characterized. Through these two aims, this research will contribute to the understanding of how pollutants, drugs, and other chemicals impact the body's metabolic state and the removal of offending and helpful xenobiotics. PUBLIC HEALTH RELEVANCE: This project is designed to discover how chemicals in food, drugs, and the environment impact human metabolism. Recent discoveries indicate a link between these chemicals and basic cellular functions such as energy metabolism and hormonal signaling. The research proposed in this project will help uncover the mechanisms that allow such foreign chemicals to have unexpected and deleterious consequences on human health.