The role of the aryl hydrocarbon receptor in colon tumorigenesis

芳烃受体在结肠肿瘤发生中的作用

• 批准号: 8447129
• 负责人: Gregory Dean Kennedy
• 金额: $ 15.05万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447129
• 关键词: AHR gene; ARNT protein; Address; Adverse effects; Agonist; Alleles; Animals; Aryl Hydrocarbon Receptor; Azoxymethane; Biological Models; Bypass; CYP1A1 gene; Cancer Etiology; Cancer Model; Cecum; Cells; Chemical Exposure; Chemicals; Chemoprevention; Chemopreventive Agent; Chemoprotective Agent; Chronic; Colon; Colorectal Cancer; Complex; Curcumin; Data; Dependence; Diet; Dioxins; Disease; Dose; Endothelial Cells; Environmental Risk Factor; Epithelial Cells; Epithelium; Event; Exposure to; Goals; Hepatocyte; Human; Immune; Incidence; Indole-3-Carbinol; Inflammatory disease of the intestine; Intestines; Lead; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Mutagens; New Agents; Omeprazole; Outcome; Play; Population; Predisposition; Process; Receptor Activation; Receptor Signaling; Recombinants; Recommendation; Regulation; Reporting; Risk; Role; Sebaceous Glands; Signal Transduction; Site; Sodium Dextran Sulfate; Structure; Sulindac; Sum; Supplementation; Testing; Tetrachlorodibenzodioxin; Therapeutic; Therapeutic Agents; Tissues; Toxic Environmental Substances; Tumor Suppression; United States; base; cancer risk; cell type; chrysin; foodborne; malignant stomach neoplasm; mortality; mouse model; prevent; receptor; research study; tumor; tumorigenesis

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.

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、补充或治疗性给予化疗保护剂，或通过预防暴露，可以显着降低这种疾病的发病率引发或促进肿瘤的化学暴露。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，例如舒林酸和奥美拉唑。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 方面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，以免过多的作用模仿二恶英的致癌作用？如果它在机制上与化学预防无关，我们是否可以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，我们认为许多化学预防剂的活性部分是通过它们在特定细胞区室中激活 AHR 的能力起作用的，并且这可以使用 CRC 重组模型系统来证明。为了检验这些想法，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 2. 使用 AHR 条件激活模型来确定 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。