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(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，通过改变饮食、补充或治疗性地给予化学保护剂，或通过防止暴露于引发或促进肿瘤的化学暴露，可以显著降低这种疾病的发病率。目前流行的化学保护剂清单包括天然存在的饮食化合物，如吲哚-3-甲醇、白杨素和姜黄素，以及舒林酸和奥美拉唑等治疗剂。有趣的是，许多已提出的化学预防药物是已知的芳香烃受体(AHR)激动剂。我们假设AHR在环境因素如何影响人类人群中的结直肠癌方面扮演着重要而复杂的角色。在信心十足地推荐增加接触AHR激动剂的建议之前，必须解决一些数据差距。首先，我们必须了解实验动物的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一个重要步骤。如果受体激动性与化学预防有机械联系，我们如何调节剂量，使太多的作用不会模仿二恶英的致癌作用？如果它与化学预防没有机制上的关系，我们是否可以改变化学预防药物的结构，以使这种偏离靶点的AHR效应降到最低？我们认为AHR在结直肠癌中的双功能作用可以用重组小鼠模型来解释。我们假设AHR的促癌和抗癌活性取决于受体被表达和激活的细胞类型，以及受体在该细胞类型中被激活的程度。此外，我们认为，许多化学预防药物的活性部分是通过它们激活特定细胞间隔中的AHR的能力来发挥作用的，这一点可以用用于CRC的重组模型系统来证明。为了验证这些想法，我们提供了以下具体目标：目的1.使用细胞特异性缺失来确定AHR信号转导的组织自主性和对CRC的易感性。目的2.使用AHR条件激活模型来确定AHR信号通路的组织自主性和对结直肠癌的易感性。目的3.利用ARNT和AHRR重组等位基因阐明AHR介导的肿瘤抑制机制。