TRANSGENIC MODELS OF DIOXIN CARCINOGENICITY AND AH RECEPTOR FUNCTION

我们的目标是了解AHR在肝脏发育中的作用， 以及2，3，7，8-四氯二苯并-对-二恶英 （TCDD）-受体相互作用与肿瘤促进器官毒性有关 出生缺陷。我们打算利用鼠类遗传学的力量， 胚胎干细胞（ES）技术和基因靶向，以了解 这个信号通路的分子细节。我们的实验源自 从最近的小鼠Ahr和Arnt基因座的基因靶向。令人惊讶的 这些动物的表型给我们留下了一些重要的 问题，如：AHR在正常肝脏生长中的作用是什么， 与TCDD的作用机制有关 致癌性/毒性？哪些受体结构域参与毒性 终点？考虑到纯合的Arnt无效等位基因是胚胎致死的， 我们如何描述ARNT在TCDD毒性和致癌作用中作用？ 为了解决这些问题，我们建议生成信息 在Ahr和Arnt基因座上的等位基因系列，并定义了 其表型的基础。此外，我们认为这些突变体 菌株将提供对相应蛋白质作用的深入了解 在肝脏发育、毒性和肝癌发生中的作用。我们的具体目标 目的#1：表征Ahr无效等位基因并了解 影响表型表达的变量。目标#2：生成 等位基因系列在Ahr基因座描绘的作用，AHR及其 亚领域对肝脏发育，TCDD诱导的肝毒性， 致癌作用目标#3：在Arnt基因座处产生等位基因系列， 描述ARNT蛋白在TCDD诱导的毒性中的作用， 致畸作用和致癌作用。目标4：确定AHR在以下方面的作用： 调节肝脏大小和肝毒性和致癌性 比如TCDD

Our objective is to understand the AHR's role in liver development, as well as the mechanism by which 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-receptor interactions are related to tumor promotion organ toxicity and birth defects. We propose to use the power of murine genetics, embryonic stem (ES) cell technology and gene targeting to understand the molecular details of this signaling pathways. Our experiments are derived from recent gene targeting of the murine Ahr and Arnt loci. The surprising phenotypes of these animals have left us with a number of important questions, such as: What is the AHR's role in normal liver growth and development and is the related to the mechanism of TCDD carcinogenicity/toxicity? What receptor domains are involved in toxic endpoints? Given that homozygous Arnt null alleles are embryonic lethal, how can we characterize ARNT's role in TCDD toxicity and carcinogenesis? To address these questions, we have proposed to generate informative allelic series at both the Ahr and Arnt loci and define the molecular basis for their phenotypes. In addition, we propose that these mutant strains will provide insights into the roles of the corresponding proteins in liver development, toxicity and hepatocarcinogenesis. Our specific aims are as follows: AIM #1: Characterize the Ahr null allele and understand the variable that affect expression of phenotype. AIM#2: Generate an allelic series at the Ahr locus to delineate the roles of the AHR and its subdomains on liver development, TCDD-induced hepatotoxicity and carcinogenesis. AIM#3: Generate an allelic series at the Arnt locus to delineate the role of the ARNT protein in TCDD-induced toxicity, teratogenesis and carcinogenesis. AIM#4: Determine the AHR' role in modulating liver size and in hepatotoxicity and carcinogenicity of compounds like TCDD.