ROLE PARTITIONING BY ARYL HYDROCARBON RECEPTORS (AHR) IN CELL REGULATION AND TOX

芳基烃受体 (AHR) 在细胞调节和毒性中的作用分配

• 批准号: 7609977
• 负责人: REBEKA RAND MERSON
• 金额: $ 16.1万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609977
• 关键词: AHR gene; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Cell Cycle Regulation; Cell physiology; Cells; Chondrichthyes; Computer Retrieval of Information on Scientific Projects Database; Development; Environment; Environmental Pollution; Enzymes; Exposure to; Funding; Gene Targeting; Genes; Genetic Transcription; Grant; Health; Human; Institution; Ligand Binding; Ligands; Link; Mammals; Metabolic Biotransformation; Metabolism; Normal Cell; Organism; Osteichthyes; Physiological; Play; Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Structure; Testing; Tissues; Toxic effect; United States National Institutes of Health; activating transcription factor; aryl hydrocarbon receptor ligand; insight; novel; paralogous gene; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective is to elucidate mechanisms underlying gene dysregulation and cell toxicity by environmental contaminants. Halogenated aromatic hydrocarbons (HAH) and polycyclic aromatic hydrocarbons (PAH) are widespread in the environment, highly toxic at low concentrations, and are linked to numerous health effects in humans and wildlife. Aryl hydrocarbon receptors (AHR) are ligand-activated transcription factors that regulate genes encoding biotransformation enzymes in response to HAH and PAH exposure. Moreover, numerous genes not associated with metabolism, including those necessary for normal cell physiology, are also regulated by AHR in the presence and absence of exogenous ligands. Thus, the hijacking of AHR from its physiological functions may play a major role in cell toxicity. Unlike mammals, which possess a single AHR, bony and cartilaginous fishes possess two or more divergent paralogs of the AHR. These proteins differ in their structure, function, and developmental and tissue specific expression, however their roles in cell regulation are not known. Investigating these AHRs may reveal novel regulatory functions and provide insight to the mechanisms underlying cell toxicity by AHR ligands. Understanding partitioning of functions among multiple AHR paralogs can reveal physiological roles of the single mammalian AHR, and provide an effective paradigm to separately test hypotheses about subsets of mammalian AHR gene targets. We will test the following hypotheses centered on role partitioning by AHR paralogs in cartilaginous and bony fishes: 1) Novel AHR structures differ in their ability to bind ligands and activate transcription, 2) multiple AHR paralogs in the same organism have distinct transcriptional targets germane to cell regulation, and 3) exposure to HAHs disrupts cell cycle regulation by an AHR-dependent mechanism.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 总体目标是阐明环境污染物导致的基因失调和细胞毒性的潜在机制。卤代芳烃 (HAH) 和多环芳烃 (PAH) 在环境中广泛存在，低浓度时具有剧毒，并对人类和野生动物产生多种健康影响。芳烃受体 (AHR) 是配体激活的转录因子，可调节编码生物转化酶的基因以响应 HAH 和 PAH 暴露。此外，许多与代谢无关的基因，包括正常细胞生理学必需的基因，在存在或不存在外源配体的情况下也受到 AHR 的调节。因此，AHR 生理功能的劫持可能在细胞毒性中发挥重要作用。 与拥有单一 AHR 的哺乳动物不同，骨鱼和软骨鱼拥有两个或多个不同的 AHR 旁系同源物。这些蛋白质在结构、功能以及发育和组织特异性表达方面有所不同，但它们在细胞调节中的作用尚不清楚。研究这些 AHR 可能会揭示新的调节功能，并深入了解 AHR 配体细胞毒性的机制。了解多个 AHR 旁系同源物之间的功能划分可以揭示单个哺乳动物 AHR 的生理作用，并提供有效的范例来单独检验有关哺乳动物 AHR 基因靶标子集的假设。 我们将测试以 AHR 旁系同源物在软骨鱼和硬骨鱼中的角色分配为中心的以下假设：1）新的 AHR 结构在结合配体和激活转录的能力方面有所不同，2）同一生物体中的多个 AHR 旁系同源物具有与细胞调节，3) 暴露于 HAH 会破坏 AHR 依赖性机制的细胞周期调节。