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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 暴露于二恶英类化合物对健康的不良影响部分是通过激活芳香烃受体（AHR）、诱导编码生物转化酶的基因以及毒性反应途径之外的许多基因调节异常来介导的。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。我们以前的研究支持鲨鱼AHR旁系同源物在功能上的分歧。在目前的研究中，几个本科生项目旨在评估鲨鱼受体在细胞生理学，发育和对AHR激动剂的毒性反应中的功能，并利用BAC文库研究这些早期脊椎动物AHR基因的基因组背景。 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与人类生理、发育和环境健康相关的信息。

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. Adverse health effects from exposure to dioxin-like compounds are in part mediated through activation of aryl hydrocarbon receptors (AHR), induction of genes encoding biotransformation enzymes, and dyregulation 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 support that shark AHR paralogs diverge in function. In the current study, several undergraduate student projects are designed to assess the function of shark receptors in cell physiology, development, and toxic responses to AHR agonists, and to investigate the genomic context of these early vertebrate AHR genes with a BAC library. 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 physiology, development, and environmental health.