AHR FUNCTION IN MURINE STRATIFIED SQUAMOUS EPITHELIA

暴露于多环和芳香烃会导致组织 特殊的病理效应，包括促进肿瘤，免疫毒性， 肝脏毒性和致畸作用。芳香烃受体(AhR)和 它的伙伴，芳香烃受体核转运体(ARNT) 二聚形成配体可诱导的转录因子，负责 调节这些化合物的生物效应。这些蛋白质是 基本螺旋-环-螺旋-PAS转录家族成员 因子，并且它们的表达在时间和空间上是受调节的 在胚胎发生和分化过程中。理解生物学 这些蛋白质的功能是理解它们在 病理学。然而，人们对这些基因的内源性作用知之甚少。 感受器。本研究的目的是制作一种动物模型以供研究 在一个完整的生物系统中，AhR的功能。 独立地，两个实验室已经构建了缺乏AhR的小鼠，以及 这些动物有不同的表型。通过培育出具有 AHR外显子2两侧有lox位点，组织特异性基因敲除小鼠可以 通过与带有Cre重组酶的转基因小鼠交配而产生 在组织特异性控制下。携带改变的AhR基因的小鼠可能 也可以与其他Cre转基因小鼠交配，创造出其他条件 被淘汰的动物。缺乏AhR的小鼠的生产仅在 复制皮肤的隔间，将绕过间接 基因丢失的影响，并允许研究AhR在 分化的鳞状上皮。这种动物，一旦产生，就可以 用于研究创伤和异种生物治疗。角质形成细胞来自 这些小鼠可以被培养并用于研究AhR基因如何 在体外影响特定细胞类型的生长和分化，以及 为进一步研究AhR缺陷型角质形成细胞提供来源。

Exposure to polycyclic and aromatic hydrocarbons results in tissue specific pathological effects including tumor promotion, immunotoxicity, hepatoxicity, and teratogenesis. The Aryl hydrocarbon receptor (AhR) and its partner, the aryl hydrocarbon receptor nuclear translocator (Arnt) dimerize to form a ligand inducible transcription factor responsible for mediating the biological effects of these compounds. These proteins are members of the basic Helix-Loop-Helix-PAS family of transcription factors, and their expression is temporally and spatially regulated during embryogenesis and differentiation. Understanding the biological function of these proteins is key to understanding their role in pathology. However, little is known about the endogenous role of these receptors. The goal of this study is to produce an animal model to study the functioning of the AhR in an intact biological system. Independently, two laboratories have constructed mice lacking AhR, and these animals have differing phenotypes. By producing mice that have the AhR Exon 2 flanked by lox sites, tissue specific knockout mice can be generated through the mating to transgenic mice with the Cre recombinase under tissue specific control. The mouse with the altered AhR gene could also be mated with other Cre transgenic mice to create other conditional knockout animals. Production of mice lacking the AhR only in the replicating compartment of the skin, would circumvent the indirect effects of the gene loss, and allow the study of the role of AhR in differentiating squamous epithelia. This animal, once generated, can be used to study wounding and xenobiotic treatment. The keratinocytes from these mice can be cultured and utilized to study how the AhR gene effects cell type-specific growth and differentiation in vitro, and provide a source for AhR deficient keratinocytes for further studies.