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，如 以及2，3，7，8-四氯二苯并对二恶英的作用机理 (TCDD)-受体相互作用与促癌器官毒性有关 和先天缺陷。我们建议使用小鼠遗传学的力量， 胚胎干细胞技术和基因打靶 这一信号通路的分子细节。我们的实验是由 来自最近对小鼠Ahr和Arnt基因座的基因打靶。令人惊讶的 这些动物的表型给我们留下了许多重要的 问题，如：AHR在正常肝脏生长和 与TCDD的发病机制有关 致癌性/毒性？毒素与哪些受体结构域有关 终端？鉴于纯合子Arnt零等位基因对胚胎是致命的， 我们如何描述ARNT在TCDD毒性和致癌中的作用？ 为了解决这些问题，我们建议生成信息性的 AhR和ArnT基因座的等位基因序列，并定义分子 根据它们的表型。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洞察力 在肝脏发育、毒性和肝癌发生中的作用。我们的具体目标 目标1：确定AhR零等位基因的特征并了解 影响表型表达的变量。目标2：生成一个 AHR基因座上的等位基因序列用于描述AHR及其基因的作用 亚结构域对肝脏发育、TCDD肝毒性和 致癌。目标3：在Arnt基因座生成等位基因序列以 阐明Arnt蛋白在TCDD诱导的毒性中的作用， 致畸和致癌。目标4：确定AHR在 调节肝脏大小及对肝脏毒性和致癌性的影响 像TCDD这样的化合物。

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.