Transcriptional regulation of polycyclic aromatic hydrocarbon metabolism

描述（由申请人提供）：多环芳烃（PAH）是一类已知会导致人类毒性和癌症的环境化学物质。多环芳烃暴露引起的分子变化是由芳烃受体（AHR）介导的。特别是，AHR介导I期和II期外源代谢酶的上调，可以引起多环芳烃的生物活化和解毒。事实上，受ahr依赖信号直接影响的化学致癌物的生物激活和解毒之间存在着微妙的平衡。新出现的证据表明PPAR?/？可能会调节皮肤/角化细胞中的AHR活性，并且这种相互作用将显著改变生物活化和解毒之间的平衡，从而导致对化学诱导毒性的易感性差异。对于具体目标1，我们将确定PPAR?/？可以调节AHR活性，重点是受体异二聚体易位和增加外源代谢表达所必需的关键转录事件，这是多环芳烃生物激活和解毒所必需的。对于具体目标2，我们将确定PPAR?/？可以在功能上改变AHR介导的多环芳烃诱导的皮肤癌。这些研究的结果将阐明ahr依赖性信号的新调控机制，这些信号在介导环境多环芳烃暴露引起的毒性和致癌性作用中起核心作用。重要的是，这些研究的结果可能有助于解释人类Ahr依赖功能的显著差异，因为尚未发现Ahr的功能多态性。

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAH) are a class of environmental chemicals that are known to cause toxicity and cancers in humans. The molecular changes induced by exposure to PAH are mediated by the aryl hydrocarbon receptor (AHR). In particular, the AHR mediates up-regulation of phase I and phase II xenobiotic metabolizing enzymes that can cause both bioactivation and detoxification of PAH. Indeed, there is a fine balance between bioactivation and detoxification of chemical carcinogens that are directly influenced by AHR-dependent signaling. Emerging evidence indicates that PPAR?/? may modulate AHR activity in skin/keratinocytes, and that this interaction will significantly alter the balance between bioactivation and detoxification leading to differences in the susceptibility to chemically-induced toxicity. For Specific Aim 1, we will determine the mechanisms by which PPAR?/? can modulate AHR activity with an emphasis on receptor heterodimer translocation and critical transcriptional events necessary for increasing expression of xenobiotic metabolism that are necessary for bioactivation and detoxification of PAH. For Specific Aim 2, we will determine if PPAR?/? can functionally alter PAH-induced skin carcinogenesis mediated by AHR. Results from these studies will elucidate novel regulatory mechanisms of AHR-dependent signaling that are central in mediating the toxic and carcinogenic effects caused by exposure to environmental PAH. Importantly, results from these studies might help explain the significant variation in AHR-dependent function in humans, since no functional polymorphisms in the Ahr have been identified.