Combinatorial Control of Toxin Induced Gene Expression in C. elegans

秀丽隐杆线虫毒素诱导基因表达的组合控制

• 批准号: 8076437
• 负责人: TIM H LINDBLOM
• 金额: $ 1.41万
• 依托单位: LYON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076437
• 关键词: Affect; Animal Model; Animals; Basal metabolic rate; Binding; Biochemical; Biochemistry; Biology; Caenorhabditis elegans; Carbohydrates; Cell physiology; Cells; Chemicals; Chemistry; DNA Binding Domain; Drug Metabolic Detoxication; Drug Prescriptions; Energy Metabolism; Environment; Environmental Pollution; Enzymes; Event; Excision; Food; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genomics; Goals; Health; Homeostasis; Hormonal; Human; Intestines; Ligands; Link; Lipids; Mediating; Metabolic; Metabolism; Molecular; NR1 gene; Nematoda; Nuclear Receptors; Pathway interactions; Pharmaceutical Preparations; Phase; Physiology; Production; Proteins; RNA; Regulation; Reporter Genes; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Structure; System; Techniques; Toxin; Transcriptional Activation; Transcriptional Regulation; Xenobiotic Metabolism; Xenobiotics; carbohydrate metabolism; cell type; chemotherapeutic agent; combinatorial; design; dietary supplements; drinking; high throughput screening; member; mutant; pollutant; public health relevance; receptor; receptor binding; response; sensor; systems research; tool; transcription factor

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.

描述（由申请人提供）：本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，有多种形式，包括环境污染物、药物、膳食补充剂和通常在食物和饮料中发现的化合物。当存在于体内时，异生物质被称为核受体的蛋白质感知。外源性物质与核受体的结合导致这些调节剂诱导细胞机制的产生，该细胞机制将这些化合物解毒并从体内输出。近年来发现的许多异生素敏感核受体表明，它们对基因表达的影响往往与细胞基本代谢（包括碳水化合物和脂质稳态）的调节因子密切相关。本研究的目的是发现如何组合的转录调控控制解毒酶和出口商的生产，以应对摄入的外源性物质。这种解毒的组合控制，沿着基本细胞代谢的重叠控制，表明异生物质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性物质如何通过诱导外源性物质传感核受体来影响不参与解毒的酶的产生。线虫的研究，秀丽隐杆线虫，提供了一个强大的系统，在其中实现这些目标。通过RNA介导干扰技术的高通量筛选，获得了C.将分析秀丽线虫在异生物防御中的需求。已知一种这样的转录调节因子：NHR-8，其在结构和功能上与人类中的异生物质感应核受体非常相似。因此，在筛选中发现的转录调节因子也将被分析其与NHR-8在基因调控中的合作。NHR-8被假设控制参与正常细胞代谢（例如脂质和碳水化合物代谢）以及异生物质解毒的酶的产生。因此，NHR-8为研究正常代谢和异生物质代谢之间的交叉提供了一个独特的入口。将分析NHR-8的转录调节的靶标在异生物质挑战期间的表达。此外，NHR-8在异生物质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代谢状态，以及如何去除有害和有益的外源性物质。 公共卫生相关性：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，这些化学物质与基本的细胞功能，如能量代谢和激素信号之间的联系。该项目中提出的研究将有助于揭示这些外来化学品对人类健康产生意想不到的有害后果的机制。