Cellular Determinants of Ah Receptor Signaling

Ah 受体信号转导的细胞决定因素

• 批准号: 8625298
• 负责人: THOMAS R SUTTER
• 金额: $ 30.68万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625298
• 关键词: Address; Affect; Alleles; Amino Acids; Aryl Hydrocarbon Receptor; Binding; Biochemical; Biopsy; Calcium; Cell Culture Techniques; Cell Differentiation process; Cells; Ceramide glucosyltransferase; Chemicals; Complex; Cytochromes; Dermatology; Dioxins; Down-Regulation; EP300 gene; Environment; Environmental Pollutants; Enzymes; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epidermis; Exposure to; Future; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Hair follicle structure; Health Policy; Homeostasis; Homologous Gene; Human; Hyperplasia; In Vitro; Integrins; Keratin; Kinetics; Knowledge; Lead; Ligands; Manuscripts; Maps; Measures; Mediating; Metabolism; Metaplastic; Methods; Modeling; Modification; Mus; Names; Pathway interactions; Pharmaceutical Preparations; Physiological Processes; Process; Protein Biosynthesis; Proteins; Public Health; Publishing; Receptor Activation; Receptor Signaling; Repression; Risk; Role; Sebaceous Glands; Sebum; Signal Pathway; Signal Transduction; Skin; Spermatocytes; Squamous Epithelium; Stratified Epithelium; Stratum corneum; Tertiary Protein Structure; Testing; Tetrachlorodibenzodioxin; Time; Toxic effect; Xenobiotics; activating transcription factor; aryl hydrocarbon receptor ligand; body system; body water loss; carcinogenicity; cytokine; design; exposed human population; extracellular; filaggrin; improved; in vivo; keratinization; keratinocyte; keratinocyte differentiation; minimally invasive; pregnant; prenatal; prevent; public health relevance; pup; response; skin hyperkeratosis; translational study

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects, including carcinogenicity and teratogenicity, of a large class of environmental pollutants known as 'dioxinlike' compounds, named after the most potent congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Studies in Ahr null allele mice show that the AHR is necessary for most of the toxic effects of TCDD. However, the mechanism(s) of toxicity downstream of AHR activation remain(s) elusive. As dioxin toxicity does not require concordant exposure to xenobiotics, and dioxin is not metabolized to a reactive intermediate, additional physiologic processes must be disrupted by exposure to TCDD. In humans exposed to dioxin, the most often observed and best studied toxic response is chloracne. Chloracne is manifested in the skin as hyperkeratinization of the interfollicular squamous epithelium, hyperproliferation and hyperkeratinization of cells of the hair follicle, as well as a metaplastic response of the ductular sebaceous glands. How AHR-mediated changes in gene expression lead to toxicity is not well understood for any organ system including skin. Recently, dioxin via the AHR, was shown to enhance human keratinocyte differentiation and to elevate the expression of three genes involved in cornification, a late part of the differentiation process. Formation of the outermost layer of the skin, the stratum corneum, is essential to epidermal barrier function and provides protection against the outside environment and loss of water from the body. Of importance, epidermal growth factor (EGF) receptor (EGFR) signaling was shown to block both TCDD-AHR-mediated gene expression and cell differentiation. These results may in part explain how dioxin affects epidermal homeostasis and identify one mechanism by which EGFR signaling can repress AHR-mediated transcription in keratinocytes. We propose to test the hypothesis that in the epidermis, TCDD-activated AHR disrupts the epidermal barrier by increasing the transcription of genes involved in the formation and function of the stratum corneum, and that EGFR signaling acts to repress this effect. In this proposal, Aim 1 determines whether the TCDD-activated AHR transcriptionally regulates a prioritized set of epidermal target genes and whether these genes are regulated by the AHR and EGFR pathways by mechanisms similar to what has been described for CYP1A1, the prototypic AHR-regulated gene. Aim 2 elucidates the mechanism(s) by which EGFR signaling represses AHR ligand-dependent activation. Aim 3 extends our results in vivo, to determine whether TCDD affects the timing of formation and the function of the epidermal barrier. Collectively, these proposed studies will greatly enhance our understanding of the effects of TCDD on the skin, and will generate the knowledge that is necessary to design minimally invasive studies using small skin biopsies and tape stripping methods in translational studies of human populations exposed to dioxin.

描述（由申请人提供）：芳香烃受体（AHR）是一种配体激活的转录因子，可介导一类称为“二恶英样”化合物的环境污染物的毒性效应，包括致癌性和致畸性，该化合物以最有效的同系物2，3，7，8-四氯二苯并-对-二恶英（TCDD）命名。对Ahr基因缺失小鼠的研究表明，AHR是TCDD大部分毒性作用所必需的。然而，AHR激活下游的毒性机制仍然难以捉摸。由于二恶英的毒性不需要一致暴露于异生物质，二恶英不会代谢为反应性中间体，其他生理过程必须通过暴露于TCDD而被破坏。在暴露于二恶英的人类中，最常观察到和研究最多的毒性反应是氯痤疮。氯痤疮在皮肤中表现为毛囊间鳞状上皮的过度角化、毛囊细胞的过度增殖和过度角化以及导管皮脂腺的化生反应。AHR介导的基因表达变化如何导致毒性对于包括皮肤在内的任何器官系统都没有很好的理解。最近，二恶英通过AHR，被证明可以增强人角质形成细胞的分化，并提高参与角化的三个基因的表达，角化是分化过程的后期部分。皮肤最外层角质层的形成对于表皮屏障功能是必不可少的，并且提供针对外部环境和身体水分流失的保护。重要的是，表皮生长因子（EGF）受体（EGFR）信号传导被证明可以阻止TCDD-AHR介导的基因表达和细胞分化。这些结果可能部分解释了二恶英如何影响表皮的稳态，并确定一种机制，EGFR信号可以抑制AHR介导的角质形成细胞的转录。我们建议测试的假设，在表皮，TCDD激活AHR破坏表皮屏障，通过增加参与角质层的形成和功能的基因的转录，EGFR信号传导的行为，以抑制这种效果。在这个提议中，目标1确定TCDD激活的AHR是否转录调节一组优先的表皮靶基因，以及这些基因是否通过与原型AHR调节基因CYP 1A 1相似的机制由AHR和EGFR途径调节。目的2阐明EGFR信号转导抑制AHR配体依赖性激活的机制。目的3扩展我们的结果在体内，以确定是否TCDD影响的形成时间和功能的表皮屏障。总的来说，这些拟议中的研究将大大提高我们对TCDD对皮肤的影响的理解，并将产生的知识，是必要的设计微创研究，使用小皮肤活检和胶带剥离方法在人类接触二恶英的转化研究。