Transcriptional regulation of polycyclic aromatic hydrocarbon metabolism

多环芳烃代谢的转录调控

基本信息

批准号：
8388807
负责人：
Jeffrey M Peters
金额：
$ 27.48万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8388807
关键词：
Affect Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Carcinogens Cell Line Chemically Induced Toxicity Cytochromes DNA Adducts Data Diabetes Mellitus Disease Drug Metabolic Detoxication Dyslipidemias Enzymes Equilibrium Event Exposure to Genes Genetic Polymorphism Genetic Transcription Human Lead Malignant Neoplasms Mediating Metabolic Control Metabolism Molecular Obesity Pathway interactions Peroxisome Proliferator-Activated Receptors Phase Predisposition Proteins Receptor Signaling Regulation Role Signal Transduction Skin Skin Carcinogenesis Toxic effect Transcriptional Regulation Up-Regulation Variant Xenobiotic Metabolism Xenobiotics carcinogenesis chemical carcinogen chemical carcinogenesis cost environmental chemical in vivo Model keratinocyte novel prevent public health relevance receptor response

项目摘要

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.

描述（由申请人提供）：多环芳烃（PAH）是一类环境化学物质，已知会引起人类毒性和癌症。暴露于PAH引起的分子变化是由芳基烃受体（AHR）介导的。特别是，AHR介导了I期和II期异种生物代谢酶的上调，这些酶可能引起PAH的生物活化和排毒。实际上，直接受AHR依赖性信号传导影响的化学致癌物的生物活化与解毒之间存在良好的平衡。新兴证据表明PPAR？/？可能调节皮肤/角质形成细胞中的AHR活性，并且这种相互作用将显着改变生物活化和排毒之间的平衡，从而导致化学诱导毒性的易感性差异。对于特定目标1，我们将确定哪种PPAR的机制？/？可以调节AHR活性，重点是受体异二聚体易位以及增加生物活化和PAH排毒所必需的异生物代谢表达所必需的关键转录事件。对于特定的目标2，我们将确定PPAR是否？/？在功能上可以改变PAH诱导的皮肤致癌作用，AHR介导。这些研究的结果将阐明AHR依赖性信号传导的新型调节机制，这些机制是介导由环境PAH引起的毒性和致癌作用的中心。重要的是，这些研究的结果可能有助于解释人类AHR依赖性功能的显着差异，因为尚未鉴定出AHR中的功能多态性。