The Role of Aryl Hydrocarbon Receptor in Colon Tumorigenesis

芳基烃受体在结肠肿瘤发生中的作用

基本信息

批准号：
8640944
负责人：
Gregory Dean Kennedy
金额：
$ 33.16万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-22 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640944
关键词：
ARNT gene Address Adverse effects Agonist Alleles Animal Model Animals Anti-Inflammatory Agents Anticarcinogenic Agents Antioxidants Aryl Hydrocarbon Receptor Biology Breast Cancer Model Bypass Cancer Etiology Cancer Model Carcinogen Metabolism Carcinogens Cecum Cells Chemical Exposure Chemicals Chemoprevention Chemopreventive Agent Chemoprotective Agent Chronic Clinical Trials Colon Colon Carcinoma Colorectal Colorectal Cancer Colorectal Neoplasms Complex Consumption Curcumin Data Dependence Development Diet Dietary Supplementation Dioxins Disease Dose Endothelial Cells Environment Environmental Risk Factor Epithelial Cells Epithelium Event Exposure to Future Gastrointestinal tract structure Goals Human Immune Immune response Incidence Indole-3-Carbinol Inflammatory disease of the intestine Intake Intestines Knowledge Laboratories Lead Link Liver Lung Lymphocyte Lymphocyte Biology Malignant Neoplasms Malignant neoplasm of liver Mediating Modeling Mutagens New Agents Non-Steroidal Anti-Inflammatory Agents Organ Pathway interactions Play Population Predisposition Process Receptor Activation Receptor Signaling Recombinants Recommendation Regimen Research Risk Rodent Role Sebaceous Glands Signal Transduction Signal Transduction Pathway Signaling Molecule Site Skin Structure Sulindac Supplementation Testing Tetrachlorodibenzodioxin Therapeutic Therapeutic Agents Tissues Transcriptional Activation Tumor Suppression Uncertainty United States Work base cancer chemoprevention cancer risk carcinogenesis cell type chrysin colorectal cancer prevention design foodborne malignant stomach neoplasm mortality mouse model novel prevent public health relevance receptor research study response tumor tumorigenesis

项目摘要

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.

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-碳纤维醇，克莱辛和姜黄素，以及诸如Sulindac和其他NSAID的治疗剂。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，必须解决许多数据差距。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，以免模仿二恶英的促癌作用？如果它与机理无关化学预防，我们可以修改化学预防剂的结构以最大程度地减少靶向AHR效果吗？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，我们提出，结肠粘膜上皮细胞中AHR的激活导致结肠内的淋巴细胞反应改变，并且通过这种抗癌活性产生抗癌活性的这种AHR依赖性淋巴细胞生物学。为了测试这些想法，我们提供以下特定目的：目标1。使用细胞特定的删除来定义AHR信号传导和对CRC的易感性的细胞自主权。 AIM 2。使用AHR的条件激活模型来确定组织自主权并测试AHR信号传导和CRC易感性的变阻器模型。 AIM 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，我们提出了新型动物模型的发展，几乎可以肯定会在我们对环境和饮食化学物质如何影响诸如屏障器官的CRC等疾病的理解方面迈出了重要一步。在这项工作之前，从未仔细执行AHR在抗致癌作用中的作用的彻底表征，从而使这些实验变得必不可少，及时和新颖。