Genetic Insight Into AH Receptor-Mediated Promotion Of Hepatocarcinogenesis

AH 受体介导的肝癌发生的遗传学见解

基本信息

批准号：
7642788
负责人：
Gregory Dean Kennedy
金额：
$ 15.54万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7642788
关键词：
ARNT gene Alleles Aryl Hydrocarbon Receptor Biological Biological Models Blood Vessels CYP1A1 gene CYP1A2 gene CYP1B1 gene Candidate Disease Gene Carcinogens Cells Chemicals Development Dioxins Environment Event Gene Expression Regulation Gene Targeting Genetic Goals Hepatocarcinogenesis Hepatocyte Inflammatory Interleukin-1 Knockout Mice Lesion Ligands Light Liver neoplasms Mediating Modeling Molecular Mus Nature Organ Pathway interactions Pattern Play Primary carcinoma of the liver cells Process Research Personnel Role Series Signal Transduction Signaling Protein Small Interfering RNA Staging Technology Testing Tetrachlorodibenzodioxin Tissues Tumor Promotion Xenobiotic Metabolism activating transcription factor carcinogenesis carcinogenicity cell type cytokine design insight neoplastic promoter prototype receptor response

项目摘要

DESCRIPTION (provided by applicant) The objective of this project is to understand the mechanism of Ah receptor-mediated liver tumor promotion using the mouse as a model system. To accomplish this task, the investigators will attempt to unravel the mechanism by which a prototype chemical, 2,3,7,8-tetra-chlorodibenzo-p-dioxin ("dioxin"), acts as promoter of hepatocellular carcinoma in the two-stage model. The choice of dioxin is related to its biological potency and the large volume of genetic and pharmacological evidence that suggests its effects are mediated through a single ligand-activated transcription factor known as the Ah Receptor (AHR). Given the central nature of this signaling protein, efforts will be made to elucidate the molecular details of the dioxin-AHR pathway as it relates to liver tumor promotion. To this end, gene targeting will be used to manipulate various functional domains and expression patterns of the AHR, as well as its heterodimeric partner ARNT. The overall goal is to identify the signaling steps, transcriptional targets and cell types that are essential for dioxin-promoted hapatocarcinogenesis and receptor mediated hepatovascular development. To this end, the following specific aims are proposed. Specific Aim 1: Use conditional and null alleles to determine the cell types that participate in the promotional effects of dioxin. Specific Aim 2: Determine if the signal transduction of dioxin promotion is similar to AHR pathways that regulate xenobiotic metabolism and hepatovascular development. Specific Aim 3: Examine existing candidate genes for roles upstream of AHR-mediated tumor promotion. Specific Aim 4: Identify additional genes that are candidates for roles in AHR-mediated tumor promotion.

描述（由申请人提供）该项目的目的是使用小鼠作为模型系统来了解 Ah 受体介导的肝脏肿瘤促进机制。为了完成这项任务，研究人员将尝试揭示原型化学物质 2,3,7,8-四氯二苯并-对二恶英（“二恶英”）在两种疾病中作为肝细胞癌促进剂的机制。舞台模型。二恶英的选择与其生物效力有关，并且大量遗传和药理学证据表明其作用是通过称为 Ah 受体 (AHR) 的单一配体激活转录因子介导的。鉴于这种信号蛋白的核心性质，我们将努力阐明二恶英-AHR 通路的分子细节，因为它与肝脏肿瘤的促进有关。为此，基因靶向将用于操纵 AHR 及其异二聚体伙伴 ARNT 的各种功能域和表达模式。总体目标是确定二恶英促进的肝细胞癌发生和受体介导的肝血管发育所必需的信号传导步骤、转录靶点和细胞类型。为此，提出以下具体目标。具体目标 1：使用条件等位基因和无效等位基因来确定参与二恶英促进作用的细胞类型。具体目标 2：确定二恶英促进的信号转导是否与调节异生物质代谢和肝血管发育的 AHR 途径相似。具体目标 3：检查现有候选基因在 AHR 介导的肿瘤促进上游的作用。具体目标 4：确定在 AHR 介导的肿瘤促进中发挥作用的其他候选基因。