GENE DIVERGENCE OF ARYL HYDROCARBON RECEPTORS (AHR) IN EARLY VERTEBRATES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 暴露于二恶英类化合物对健康的不良影响部分是通过芳香烃受体（AHR）的激活、编码生物转化酶的基因的表达以及毒性反应途径之外的许多基因的失调来介导的。AHR蛋白在AHR配体存在和不存在的情况下在细胞生理学中具有非转录作用。因此，很难区分AHR依赖性毒性反应机制与AHR内源性功能的扰动。我们研究了早期脊椎动物中多个AHR旁系同源物之间的功能分歧，因此我们可以单独测试单个哺乳动物AHR的多效性功能。我们以前的研究表明，AHR基因的每种产物在亚细胞位置和功能上都有重叠和分歧。在目前的研究中，本科生项目旨在评估鲨鱼AHR在细胞过程中的功能，产卵海洋脊椎动物的胚胎发育，并使用比较基因组学研究这些早期脊椎动物AHR基因与灵长类动物的关系。我们的目标是开发一个有效的范例，分别测试关于哺乳动物AHR基因靶点和非转录AHR蛋白功能的假设。我们的研究结果将提供有关人类对环境AHR激动剂暴露的反应以及环境健康与胚胎发育之间关系的信息。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Adverse health effects from exposure to dioxin-like compounds are in part mediated through activation of aryl hydrocarbon receptors (AHR), expression of genes encoding biotransformation enzymes, and dysregulation of numerous genes outside the toxic response pathway. AHR proteins have non-transcriptional roles in cell physiology in the absence and presence of AHR ligands. Thus, it is difficult to distinguish AHR-dependent toxic response mechanisms from the perturbation of endogenous function of AHR. We study the divergence of function among multiple AHR paralogs in early vertebrates so we may separately test the pleiotropic functions of the single mammalian AHR. Our previous studies demonstrate that each product of the AHR gene both overlap and diverge in subcellular location and function. In the current study, undergraduate student projects aim to assess the function of shark AHRs in cellular processes, embryonic development of egg-laying marine vertebrates, and to investigate the relationships of these early vertebrate AHR genes with those of primates using comparative genomics. We aim to develop an effective paradigm to separately test hypotheses about subsets of mammalian AHR gene targets and non-transcriptional AHR protein function. Results from our research will provide information relevant to human responses to environmental AHR agonist exposure, and the relationship between environmental health and embryonic development.