Cellular Determinants of Ah Receptor Signaling

Ah 受体信号转导的细胞决定因素

• 批准号: 8060536
• 负责人: THOMAS R SUTTER
• 金额: $ 31.09万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060536
• 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. PUBLIC HEALTH RELEVANCE: Our proposed studies address a major challenge to understand the causal relationships between activation of the AHR by TCDD, changes in gene expression, and the effects of TCDD on the epidermis. By elaborating the mechanisms of dioxin toxicity and the repression of the AHR by EGFR signaling these proposed studies will greatly improve our knowledge of the effects of dioxin on the skin as well as the risk characterization and public health policy decisions on dioxin exposure. The results of these studies will generate the knowledge that is necessary to design minimally invasive studies using small skin biopsies and tape stripping methods in future translational studies of human populations exposed to dioxin.

描述（由申请人提供）：芳烃受体（AHR）是一种配体激活的转录因子，介导一大类被称为“二恶英类”化合物的环境污染物的毒性作用，包括致癌性和致畸性，这些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 无效等位基因小鼠的研究表明，AHR 对于 TCDD 的大部分毒性作用是必需的。然而，AHR 激活下游的毒性机制仍然难以捉摸。由于二恶英毒性不需要同时接触异生素，并且二恶英不会代谢为反应性中间体，因此接触 TCDD 必须扰乱额外的生理过程。在接触二恶英的人类中，最常观察到和研究得最好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。对于包括皮肤在内的任何器官系统，AHR 介导的基因表达变化如何导致毒性尚不清楚。最近，二恶英通过 AHR 被证明可以增强人类角质形成细胞的分化，并提高与角质化有关的三个基因的表达，角质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至关重要，并提供针对外部环境和体内水分流失的保护。重要的是，表皮生长因子 (EGF) 受体 (EGFR) 信号传导可阻断 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稳态，并确定了 EGFR 信号传导抑制角质形成细胞中 AHR 介导的转录的一种机制。我们建议测试以下假设：在表皮中，TCDD 激活的 AHR 通过增加参与角质层形成和功能的基因转录来破坏表皮屏障，并且 EGFR 信号传导可抑制这种效应。在该提案中，目标 1 确定 TCDD 激活的 AHR 是否在转录上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 CYP1A1 所描述的机制类似的机制受到 AHR 和 EGFR 途径的调节。目标 2 阐明 EGFR 信号转导抑制 AHR 配体依赖性激活的机制。目标 3 将我们的结果扩展到体内，以确定 TCDD 是否影响表皮屏障的形成时间和功能。总的来说，这些拟议的研究将极大地增强我们对 TCDD 对皮肤影响的理解，并将产生在接触二恶英人群的转化研究中使用小型皮肤活检和胶带剥离方法设计微创研究所需的知识。 公共健康相关性：我们提出的研究解决了理解 TCDD 激活 AHR、基因表达变化以及 TCDD 对表皮影响之间因果关系的重大挑战。通过阐述二恶英毒性的机制和 EGFR 信号传导抑制 AHR 的机制，这些拟议的研究将极大地提高我们对二恶英对皮肤的影响以及二恶英暴露的风险特征和公共卫生政策决策的了解。这些研究的结果将产生必要的知识，以便在未来接触二恶英人群的转化研究中使用小型皮肤活检和胶带剥离方法设计微创研究。