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）：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，补充或治疗化学保护剂的治疗性，或防止暴露于启动或肿瘤促进化学物质暴露的情况下，可以大大降低该疾病的发生率。当前流行的化学保护剂的清单包括天然存在的饮食化合物，例如吲哚-3-碳纤维，克莱辛和姜黄素，以及苏莱达克和奥美拉唑等治疗剂。有趣的是，许多提出的化学预防剂是芳基烃受体（AHR）的已知激动剂。我们假设AHR在环境因素如何影响人群中的CRC方面起着重要而复杂的作用。在建议增加对AHR激动剂的建议之前，必须有许多数据差距需要解决。首先，我们必须了解实验动物的AHR激活和AHR缺失如何导致各个部位的癌症增加和减少。其次，我们必须了解AHR激活是否是已知化学预防剂的作用方式的重要步骤。如果受体激动剂与化学预防有机学上的联系，我们如何调节剂量，以使过多的作用不会模仿二恶英的促癌作用？如果它与化学预防没有机械上的关系，我们可以修改化学预防剂的结构以最大程度地减少该关闭目标AHR效应吗？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的促抗癌活性取决于表达和激活受体的细胞类型，以及该细胞类型中受体激活的程度。此外，我们建议许多化学预防剂的活性部分通过它们在特定的细胞室中激活AHR的能力作用，并且可以使用CRC的重组模型系统证明这一点。为了测试这些想法，我们提供了以下特定目的：目标1。使用细胞特定的缺失来确定AHR信号的组织自治和对CRC的易感性。 AIM 2。使用AHR条件激活的模型来确定AHR信号传导的组织自主性和对CRC的敏感性。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。