AHR FUNCTION IN MURINE STRATIFIED SQUAMOUS EPITHELIA

小鼠分层鳞状上皮的 AHR 功能

• 批准号: 6094151
• 负责人: LORI A WHITE
• 金额: $ 1.06万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-26 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6094151
• 关键词: aromatic hydrocarbon receptor; cell differentiation; cell growth regulation; epithelium; gene targeting; genetically modified animals; keratinocyte; laboratory mouse; skin

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.

暴露于多环和芳烃导致组织 特异性病理学效应，包括肿瘤促进，免疫毒性， 肝毒性和致畸作用。芳香烃受体（AhR）和 其配偶体芳烃受体核转运蛋白（Arnt） 二聚化形成配体诱导型转录因子， 介导这些化合物的生物效应。 这些蛋白质 基本螺旋-环-螺旋-PAS转录家族的成员 因子，并且它们的表达在时间和空间上受到调节 在胚胎发生和分化过程中。了解生物学 这些蛋白质的功能是理解它们在 病理然而，很少有人知道这些内源性的作用， 受体。本研究的目的是建立一个动物模型来研究 AhR在完整生物系统中的功能 独立地，两个实验室已经构建了缺乏AhR的小鼠， 这些动物具有不同的表型。通过制造具有 AhR外显子2侧接lox位点，组织特异性敲除小鼠可以是 通过与具有Cre重组酶的转基因小鼠交配产生 在组织特异性控制下。AhR基因改变的小鼠可以 也可以与其他Cre转基因小鼠交配，以产生其他条件性的 令人倾倒的动物只在小鼠的大脑中产生缺乏AhR的小鼠。 复制皮肤的隔室，将绕过间接的 基因丢失的影响，并允许研究AhR的作用， 分化的鳞状上皮。这种动物一旦产生， 用于研究创伤和外源性治疗。角质形成细胞从 这些小鼠可以被培养并用于研究AhR基因是如何 在体外影响细胞类型特异性生长和分化，和 为进一步研究提供了AhR缺陷角质形成细胞的来源。