Genetic Insight Into AH Receptor-Mediated Promotion Of Hepatocarcinogenesis

描述(由申请人提供) 本课题的目的是以小鼠为模型系统，了解ah受体介导的促肝肿瘤作用机制。为了完成这项任务，研究人员将试图解开原型化学物质2，3，7，8-四氯二苯并对二恶英(“二恶英”)在两阶段模型中作为肝细胞癌促进剂的机制。选择二恶英与其生物学效力以及大量遗传和药理学证据有关，这些证据表明，二恶英的作用是通过一种称为AH受体(AHR)的单一配体激活的转录因子介导的。鉴于该信号蛋白的中心性质，将努力阐明二恶英-AHR途径的分子细节，因为它与肝脏肿瘤的促进有关。为此，基因打靶将被用来操纵AHR的各种功能结构域和表达模式，以及它的异二聚体伙伴Arnt。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步骤、转录靶点和细胞类型。为此，提出了以下具体目标。具体目标1：使用条件等位基因和零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：确定促进二恶英的信号转导是否类似于调节异物代谢和肝血管发育的AHR途径。具体目标3：检查AHR介导的肿瘤促进作用上游的现有候选基因。具体目标4：确定在AHR介导的肿瘤促进中扮演角色的其他候选基因。

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.