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

• 批准号: 8068016
• 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
• 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/8068016
• 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

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） 该项目的目的是了解使用小鼠作为模型系统促进AH受体介导的肝肿瘤的机理。为了完成这项任务，研究人员将试图揭示原型化学物质，即2,3,7,8-氯二苯二甲苯 - 二恶英（“二恶英”）在两阶段模型中充当肝细胞癌的启动子。二恶英的选择与其生物学效能以及大量遗传和药理学证据有关，这些证据表明其作用是通过称为AH受体（AHR）的单个配体激活转录因子介导的。 鉴于该信号蛋白的核心性质，将努力阐明与肝肿瘤促进有关的二恶英-AHR途径的分子细节。 为此，基因靶向将用于操纵AHR的各种功能域和表达模式，以及其异二聚体伴侣ARNT。总体目标是确定对二恶英促进的Hapatocinogenogeny和受体介导的肝血管发育至关重要的信号传导步骤，转录靶标和细胞类型。 为此，提出了以下特定目标。具体目标1：使用条件和无效等位基因确定参与二恶英促销作用的细胞类型。 具体目标2：确定二恶英促进的信号转导是否类似于调节异种生物代谢和肝血管发育的AHR途径。 特定目标3：检查现有的候选基因是否在AHR介导的肿瘤促进的上游角色。 特定目的4：确定其他基因，这些基因是候选AHR介导的肿瘤促进作用的基因。