Combinatorial Control of Toxin Induced Gene Expression in C. elegans

描述(申请人提供)：该项目的长期目标是确定环境中的化学物质如何影响人类健康。这些化学物质，通常被称为异生物质，有多种形式，包括环境污染物、药物、膳食补充剂以及通常在食物和饮料中发现的化合物。当异生物质存在于体内时，被称为核受体的蛋白质感受到。外源生物与核受体的结合导致这些调节器诱导细胞机械的产生，该细胞机械可以解毒并将这些化合物从体内排出。最近关于异种感应核受体的许多发现表明，它们对基因表达的影响往往与基本细胞代谢的调节有关，包括碳水化合物和脂类的动态平衡。这项研究旨在发现转录调控因子的组合如何控制解毒酶和出口商的生产，以应对摄入的外源生物。这种对解毒的组合控制，以及对基本细胞代谢的重叠控制，表明外源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生物如何通过诱导外源传感核受体来影响与解毒无关的酶的产生。对线虫--秀丽线虫的研究为实现这些目标提供了一个强大的系统。通过使用一种名为RNA介导的干扰技术的高通量筛选，将分析线虫的一整套转录调控因子，以确定它们在异种防御中的需求。一种这样的转录调控因子就是已知的：NHR-8，它在结构和功能上与人类中的异种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为它们在基因调控方面与NHR-8的合作。NHR-8被假设为控制正常细胞代谢所涉及的酶的产生，如脂肪和碳水化合物代谢，以及外源解毒。因此，NHR-8为研究正常代谢和异源代谢之间的交叉点提供了一个独特的入口。我们将分析NHR-8‘S转录调控靶点在异种生物攻击过程中的表达。此外，NHR-8在异种生物传感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新陈代谢状态，以及清除有害和有益的外来生物。 与公共健康相关：该项目旨在发现食品、药物和环境中的化学物质如何影响人类新陈代谢。最近的发现表明，这些化学物质与能量代谢和荷尔蒙信号等基本细胞功能之间存在联系。该项目中提出的研究将有助于揭示允许这些外来化学物质对人类健康产生意想不到的有害后果的机制。

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.