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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 总体目标是阐明环境污染物引起的基因失调和细胞毒性的潜在机制。卤代芳香烃(HAH)和多环芳烃(PAH)广泛存在于环境中，在低浓度下具有高度毒性，与人类和野生动物的许多健康影响有关。芳香烃受体(AHR)是配体激活的转录因子，调节编码生物转化酶的基因，以响应HAH和PAH的暴露。此外，许多与新陈代谢无关的基因，包括那些正常细胞生理所必需的基因，在有或没有外源配体的情况下也受到AHR的调控。因此，AHR从生理功能上的劫持可能在细胞毒性中起主要作用。与哺乳动物不同，哺乳动物只有一个AHR，而骨鱼和软骨鱼有两个或更多不同的AHR并列动物。这些蛋白质在结构、功能、发育和组织特异性表达上有所不同，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，并为AHR配体潜在的细胞毒性机制提供洞察力。了解多个AHR同源基因之间的功能划分可以揭示单个哺乳动物AHR的生理作用，并提供一个有效的范例来分别检验关于哺乳动物AHR基因靶点亚群的假设。我们将检验以下假设：1)新的AHR结构在结合配体和激活转录方面的能力不同，2)同一生物体中的多个AHR类似物具有与细胞调控相关的不同转录靶点，以及3)暴露于HAHS通过AHR依赖的机制扰乱细胞周期调节。