The Role of Aryl Hydrocarbon Receptor in Colon Tumorigenesis

描述（由申请人提供）：考虑到环境因素在结直肠癌（CRC）中的重要性，人们普遍认为，通过改变饮食、补充或治疗性施用化学保护剂，或者通过预防暴露于引发或促进肿瘤的化学物质，可以显着降低这种疾病的发病率。目前流行的化学保护剂包括天然存在的膳食化合物，例如吲哚-3-甲醇、白杨素和姜黄素，以及治疗剂，例如舒林酸和其他非甾体抗炎药。有趣的是，许多提出的化学预防剂都是已知的芳烃受体（AHR）激动剂。我们假设 AHR 在环境因素如何影响人群中的 CRC 中发挥着重要但复杂的作用。在自信地提出增加 AHR 激动剂暴露的建议之前，必须解决许多数据差距。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药物作用模式中的重要一步。如果受体激动在机制上与化学预防相关，那么我们如何调节剂量，以免模仿二恶英的致癌作用？如果没有机械上的关系 化学预防，我们能否修改化学预防剂的结构以尽量减少这种脱靶 AHR 效应？我们建议可以使用重组小鼠模型来解释 AHR 在 CRC 中的双功能作用。我们假设 AHR 的促癌和抗癌活性取决于受体表达和激活的细胞类型，以及受体在该细胞类型中激活的程度。此外，我们提出，结肠粘膜上皮细胞中 AHR 的激活会导致结肠内淋巴细胞反应的改变，并且通过这种 AHR 依赖性淋巴细胞生物学，产生抗癌活性。为了测试这些想法，我们提出以下具体目标： 目标 1. 使用细胞特异性删除来定义 AHR 信号传导的细胞自主性和对 CRC 的易感性。目标 2. 使用 AHR 条件激活模型来确定组织自主性并测试 AHR 信号传导和 CRC 易感性的变阻器模型。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，我们建议开发新型动物模型，这几乎肯定会在我们理解环境和膳食化学物质如何影响屏障器官的结直肠癌等疾病方面迈出重要一步。在这项工作之前，从未仔细地对 AHR 在抗癌作用中的作用进行过彻底的表征，这使得这些实验变得必要、及时和新颖。

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.