The role of the aryl hydrocarbon receptor in colon tumorigenesis

描述（由申请人提供）：鉴于环境因素在结直肠癌（CRC）中的重要性，人们普遍认为，通过饮食改变、补充或治疗性给予化学保护剂，或通过预防暴露于引发或促进肿瘤的化学品，可以显著降低该疾病的发病率。目前流行的化学保护剂的列表包括天然存在的膳食化合物如吲哚-3-甲醇、白杨素和姜黄素，以及治疗剂如舒林酸和奥美拉唑。有趣的是，许多提出的化学预防剂是已知的芳烃受体（AHR）激动剂。我们假设AHR在环境因素如何影响人群中的CRC中起着重要而复杂的作用。在有信心地推荐增加AHR激动剂暴露的建议之前，必须解决一些数据缺口。首先，我们必须了解实验动物中AHR激活和AHR缺失如何导致不同部位癌症的增加和减少。其次，我们必须了解AHR激活是否是已知化学预防剂作用模式中的重要步骤。如果受体激动作用在机制上与化学预防有关，我们如何调节剂量，使过多的作用不会模拟二恶英的致癌作用？如果它与化学预防无关，我们是否可以修改化学预防剂的结构，以最大限度地减少这种脱靶AHR效应？我们建议，在CRC中的AHR的双功能的作用，可以解释使用重组小鼠模型。我们推测，促和抗癌活性的AHR依赖于细胞类型，其中受体的表达和激活，以及在何种程度上受体被激活的细胞类型。此外，我们提出，许多化学预防剂的活性部分是通过它们在特定细胞隔室中激活AHR的能力来实现的，并且这可以使用CRC的重组模型系统来证明。为了验证这些想法，我们提出了以下具体目标：目标1。使用细胞特异性缺失来确定AHR信号传导的组织自主性和对CRC的易感性。目标二。使用AHR的条件性激活模型来确定AHR信号传导的组织自主性和对CRC的易感性。目标3。使用Arnt和Ahrr的重组等位基因阐明AHR介导的肿瘤抑制的潜在机制。

DESCRIPTION (provided by applicant): Given the importance of environmental factors in colorectal cancer (CRC), it is widely held that the incidence of this disease can be significantly reduced through dietary alterations, supplementation or therapeutic administration of chemoprotective agents, or by preventing exposure to initiating or tumor promoting chemical exposures. The list of currently popular chemoprotective agents includes naturally occurring dietary compounds such as indole-3- carbinol, chrysin and curcumin, as well as therapeutic agents like Sulindac and Omeprazole. Interestingly, many proposed chemopreventative agents are known agonists of the aryl hydrocarbon receptor (AHR). We hypothesize that the AHR plays an important, yet complex, role in how environmental factors influence CRC in human populations. There are a number of data gaps that must be addressed before recommendations for increasing exposure to AHR agonists can be recommended with confidence. First, we must understand how AHR activation and AHR deletion in experimental animals lead to both increases and decreases in cancers at various sites. Second, we must understand whether AHR activation is an important step in the mode of action of known chemopreventative agents. If receptor agonism is mechanistically linked to chemoprevention, how do we modulate doses so that too much action does not mimic the procarcinogenic effects of dioxins? If it is not mechanistically related to chemoprevention, can we modify structures of the chemopreventative agents to minimize this off target AHR effect? We propose that the bifunctional role of the AHR in CRC can be explained using recombinant mouse models. We hypothesize that the pro- and anti-carcinogenic activity of the AHR depends upon the cell type in which the receptor is expressed and activated, as well as the degree to which the receptor is activated in that cell type. In addition, we propose that the activity of many chemopreventatives act, in part, by their ability to activate the AHR in specific cellular compartments and that this can be proven using recombinant models systems for CRC. To test these ideas, we offer the following specific aims: Aim 1. Use cell specific deletion to determine tissue autonomy of AHR signaling and susceptibility to CRC. Aim 2. Use models of conditional activation of AHR to determine tissue autonomy of AHR signaling and susceptibility to CRC. Aim 3. Clarify the underlying mechanism of AHR-mediated tumor suppression using recombinant alleles of Arnt and Ahrr.