Transcriptional Control of Drosophila Detoxification Genes

果蝇解毒基因的转录控制

基本信息

批准号：
7780408
负责人：
CARL S. THUMMEL
金额：
$ 13.41万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-10 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780408
关键词：
5&apos Flanking Region Affect Animals Binding Sites Biochemical Bioinformatics Biological Models Biological Process Chemicals Complex DNA Binding DNA-Binding Proteins Development Drosophila genus Drosophila melanogaster Drug Industry Drug Metabolic Detoxication Drug Transport Elements Environment Enzymes Evolution Excretory function Foundations Gene Expression Gene Expression Regulation Genes Genetic Genetic Models Genetic Screening Genetic Transcription Goals Heat-Shock Response Homeostasis Human Hypoxia Infection Insecta Life Lung diseases Malignant Neoplasms Maps Mediating Molecular Mus Organism Orthologous Gene Oxidative Stress Pesticides Pharmaceutical Preparations Pharmacologic Substance Phenobarbital Plants Poison Regulation Research Resistance Response Elements Risk Factors Role Scanning Specificity Testing Toxin Trans-Activators Transcriptional Regulation Transgenic Animals Xenobiotics combat coping defense response fly insight mutant null mutation pollutant pregnane X receptor promoter research study response sedative transcription factor yeast genetics

项目摘要

DESCRIPTION (provided by applicant): Animals live with constant threats to their survival in the form of heat shock, oxidative stress, hypoxia, infection, and toxic challenges from the environment. To combat these threats and maintain homeostasis, animals have evolved complex and specific regulatory responses that include the coordinated transcriptional control of key defensive genes. Many of these regulatory networks have been identified and characterized in the fruit fly Drosophila melanogaster, and shown to be conserved through evolution, providing a foundation for understanding their control in humans. These responses have also provided key insights into the molecular mechanisms of coordinate transcriptional control in higher organisms. Remarkably, one of the most critical defense responses in animals - the ability to detoxify harmful chemicals - has not yet been characterized using a simple genetic model system. These compounds, which include pharmaceuticals, pesticides, plant toxins, and pollutants, referred to collectively as xenobiotics, comprise a critical risk factor for cancer and respiratory diseases. Xenobiotic responses also remain a major impediment to the development of new drugs by the pharmaceutical industry. We have shown that treatment of Drosophila with a widely used xenobiotic, the sedative phenobarbital, results in a rapid, widespread, and coordinate change in gene expression. Many phenobarbital-regulated genes encode enzymes and have proposed functions consistent with detoxification, protection, drug transport, or excretion. A null mutation in DHR96 - the single ancestral fly ortholog of the vertebrate xenobiotic receptors PXR and CAR - affects the phenobarbital regulation of some of these genes, demonstrating that DHR96 can function like its vertebrate counterparts by contributing to xenobiotic responses in insects. Most genes, however, are properly regulated by drug in the absence of DHR96, an effect also seen in mouse PXR and CAR mutants, raising the question of how this coordinate transcriptional circuit is controlled. The goal of this proposal is to use Drosophila to define the molecular mechanisms of xenobiotic transcriptional responses. We will identify critical promoter sequences that are required for phenobarbitalregulated transcription and characterize the trans-acting factors that confer this control. We will also determine the molecular mechanisms by which DHR96 contributes to xenobiotic transcriptional responses. This research will provide new insights into how higher organisms, including humans, cope with toxic compounds in their environment and establish Drosophila as a new model system for characterizing xenobiotic response regulation.

描述（由申请人提供）：动物的生存不断受到热休克、氧化应激、缺氧、感染和环境有毒挑战等形式的威胁。为了对抗这些威胁并维持体内平衡，动物进化出了复杂且特定的调节反应，其中包括关键防御基因的协调转录控制。许多这些调控网络已在果蝇果蝇中得到鉴定和表征，并被证明在进化过程中是保守的，为了解它们在人类中的控制提供了基础。这些反应还为高等生物协调转录控制的分子机制提供了重要的见解。值得注意的是，动物最关键的防御反应之一 - 解毒有害化学物质的能力 - 尚未使用简单的遗传模型系统进行表征。这些化合物包括药物、杀虫剂、植物毒素和污染物，统称为异生素，是癌症和呼吸道疾病的关键危险因素。异生素反应仍然是制药行业开发新药的主要障碍。我们已经证明，用广泛使用的外源性镇静剂苯巴比妥治疗果蝇，会导致基因表达发生快速、广泛和协调的变化。许多苯巴比妥调节的基因编码酶，并具有与解毒、保护、药物转运或排泄一致的功能。 DHR96（脊椎动物外源性受体 PXR 和 CAR 的单一祖先果蝇直系同源物）的无效突变会影响其中一些基因的苯巴比妥调节，表明 DHR96 可以通过促进昆虫中的外源性反应而像其脊椎动物对应物一样发挥作用。然而，大多数基因在缺乏 DHR96 的情况下会受到药物的适当调节，这种效应在小鼠 PXR 和 CAR 突变体中也可见，这就提出了如何控制这种协调转录回路的问题。该提案的目标是利用果蝇来定义异生素转录反应的分子机制。我们将鉴定苯巴比妥调节所需的关键启动子序列转录并表征赋予这种控制的反式作用因子。我们还将确定 DHR96 促进异生素转录反应的分子机制。这项研究将为包括人类在内的高等生物如何应对有毒物质提供新的见解环境中的化合物，并将果蝇建立为表征的新模型系统外源性反应调节。