The Role of 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其他NSAID。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。在有信心地提出增加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。如果受体激动作用与化学预防机制有关，我们如何调节剂量，使我们不模仿二恶英的致癌作用？如果它不是机械相关的， 在化学预防中，我们能否修改化学预防剂的结构以最小化这种脱靶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，在结肠粘膜上皮细胞中的AHR的激活导致结肠内的淋巴细胞反应的改变，并且通过这种AHR依赖的淋巴细胞生物学产生抗癌活性。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定义AHR信号传导的细胞自主性和对CRC的易感性。目标二。使用AHR的条件激活模型来确定组织自主性，并测试AHR信号传导的变阻器模型和对CRC的易感性。目标3。阐明CRC模型中AHR介导的肿瘤抑制的潜在机制。通过这些目标，我们建议开发新的动物模型，这几乎肯定会为我们理解环境和膳食化学物质如何影响屏障器官的疾病（如CRC）提供重要的一步。在这项工作之前，AHR在抗癌作用中的作用的彻底表征从未被仔细地进行过，使得这些实验是必要的、及时的和新颖的。

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 other NSAIDs. 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 made 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 we do not mimic the pro-carcinogenic 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 activation of the AHR in colonic mucosal epithelial cells leads to an altered lymphocyte response within the colon and that it us through this AHR-dependent lymphocyte biology that anti-carcinogenic activity is produced. To test these ideas, we offer the following specific aims: Aim 1. Use cell specific deletion to define cell autonomy of AHR signaling and susceptibility to CRC. Aim 2. Use models of conditional activation of AHR to determine tissue autonomy and test the rheostat model of AHR signaling and susceptibility to CRC. Aim 3. Clarify the underlying mechanism of AHR-mediated tumor suppression in the CRC model. Through these aims, we propose the development of novel animal models that will almost certainly provide a significant step forward in our understanding of how environmental and dietary chemicals influence diseases such as CRC at barrier organs. Prior to this work, a thorough characterization of AHR's role in anti- carcinogenesis has never been carefully performed, making these experiments essential, timely and novel.