ROLE PARTITIONING BY ARYL HYDROCARBON RECEPTORS IN CELL REGULATION AND TOXICITY

芳基烃受体在细胞调节和毒性中的作用分配

• 批准号: 7960140
• 负责人: REBEKA RAND MERSON
• 金额: $ 13万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960140
• 关键词: AHR gene; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Behavioral Research; 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; Modeling; Normal Cell; Physiological; Play; Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Structure; Testing; Tissues; Toxic effect; United States National Institutes of Health; Vertebrates; activating transcription factor; aryl hydrocarbon receptor ligand; insight; novel; paralogous gene; receptor; 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. 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, other vertebrates express two or more divergent AHR genes. These proteins differ in their structure, function, and developmental and tissue specific expression, but their roles in cell regulation are not known. We will test the following hypotheses using cartilaginous fish models: 1) AHR proteins differ in their ability to bind ligands and activate transcription, 2) multiple AHR paralogs have distinct transcriptional targets germane to cell regulation, and 3) exposure to HAHs disrupts cell cycle regulation by an AHR-dependent mechanism. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 总体目标是阐明环境污染物的基因失调和细胞毒性的基础机制。卤化芳基烃（HAH）和多环芳烃（PAH）在环境中普遍存在，在低浓度下剧毒，并且与人类和野生动植物的众多健康影响有关。芳基碳氢化合物受体（AHR）是配体激活的转录因子，这些转录因子响应HAH和PAH暴露，调节编码生物转化酶的基因。在存在和不存在外源配体的情况下，AHR调节了许多与代谢无关的基因，包括正常细胞生理的基因。因此，AHR从其生理功能中劫持的劫持可能在细胞毒性中起主要作用。与拥有单个AHR的哺乳动物不同，其他脊椎动物表达两个或多个发散的AHR基因。这些蛋白质的结构，功能，发育和组织特异性表达有所不同，但是它们在细胞调节中的作用尚不清楚。我们将使用软骨鱼模型测试以下假设：1）AHR蛋白在结合配体和激活转录的能力上有所不同，2）多个AHR旁系同源物具有明显的转录靶标与细胞调节的不同，3）暴露于HAHS HAHS通过依赖AHR依赖性机制破坏细胞周期。研究这些AHR可能会揭示新的调节功能，并洞悉AHR配体细胞毒性的机制。了解多个AHR旁系同源物中功能的分区可以揭示单个哺乳动物AHR的生理作用，并提供有效的范式来分别检验有关哺乳动物AHR基因靶标子集的假设。